Disorders of the Gastrointestinal System PART 10

expelled from the rectum. The colon possesses a dense bacterial colo-
Section 1 Disorders of the Alimentary nization that ferments undigested carbohydrates and short-chain fatty
Tract acids. The gut microbiome also modulates immune and physiologic
activity. Esophageal transit takes seconds, and times in the stomach and
small intestine range from minutes to a few hours, but colon propaga-
tion requires >1 day in most individuals. Colon contractions exhibit

321 with
Approach to the Patient
Gastrointestinal
a to-and-fro character that promotes fecal desiccation. The proximal
colon mixes and absorbs fluid, while the distal colon exhibits peristaltic
contractions and mass movements to expel the stool. The colon termi-
Disease nates in the anus, which possesses volitional and involuntary controls
to permit fecal retention until it can be released in a convenient setting.
William L. Hasler, Chung Owyang
EXTRINSIC MODULATION OF GUT
FUNCTION
GI function is modified by influences outside the gut. Unlike other
ANATOMIC CONSIDERATIONS organs, the gut is in continuity with the outside environment. Protec-
The gastrointestinal (GI) tract extends from the mouth to the anus tive mechanisms are vigilant against injury from foods, medications,
and is composed of organs with distinct functions. Sphincters that toxins, and microbes. Mucosal immune mechanisms include epithelial
assist in gut compartmentalization separate the organs. The gut wall is and lamina propria lymphocytes and plasma cells supported by lymph
organized into distinct layers that contribute to regional activities. The node chains to prevent noxious agents from entering the circulation.
mucosa is a barrier to luminal contents or a site for fluid and nutrient Antimicrobial peptides secreted by Paneth cells defend against patho-
transfer. Smooth muscle in association with the enteric nervous system gens. Drugs and toxins absorbed into the bloodstream are filtered
mediates propulsion between regions. Many GI organs possess a sero- and detoxified in the liver via the portal venous circulation. Although
sal layer that provides a supportive foundation and permits external intrinsic nerves control most basic gut activities, extrinsic neural input
input. modulates many functions. Many GI reflexes involve extrinsic vagus
Interactions with other systems serve the needs of the gut and the or splanchnic nerve pathways. The brain-gut axis alters function in
body. Pancreaticobiliary conduits deliver bile and enzymes into the regions not under volitional regulation. Stress can disrupt gut motor,
duodenum. The vascular supply is modulated by GI activity. Lymphatic secretory, and sensory function.
channels assist in gut immune activities. Intrinsic nerves provide the
controls for propulsion and fluid regulation. Extrinsic neural input OVERVIEW OF GI DISEASES
provides volitional or involuntary control that is specific for each gut GI diseases develop as a result of abnormalities within or outside of the
region. gut and range in severity from those that produce mild symptoms and
no long-term morbidity to those with intractable symptoms or adverse
FUNCTIONS OF THE GI TRACT outcomes. Diseases may be localized to one organ or exhibit diffuse
The GI tract serves two main functions—assimilating nutrients and involvement at many sites.
eliminating waste. In the mouth, food is processed, mixed with salivary
amylase, and delivered to the gut lumen. The esophagus propels the ■■CLASSIFICATION OF GI DISEASES
bolus into the stomach; the lower esophageal sphincter prevents oral GI diseases are manifestations of alterations in nutrient assimilation or
reflux of gastric contents. The squamous esophageal mucosa protects waste evacuation or in the activities supporting these main functions.
against significant diffusion or absorption. Aboral esophageal contrac- Impaired Digestion and Absorption Diseases of the stomach,
tions coordinate with relaxation of the upper and lower esophageal intestine, biliary tree, and pancreas can disrupt digestion and absorp-
sphincters on swallowing. tion. The most common maldigestion syndrome, lactase deficiency,
The stomach triturates and mixes the food bolus with pepsin and produces gas and diarrhea after ingesting dairy products and has no
acid. Gastric acid also sterilizes the upper gut. The proximal stomach adverse outcomes. Other intestinal enzyme deficiencies produce sim-
serves a storage function by relaxing to accommodate the meal. Phasic ilar symptoms after consuming other simple sugars. Celiac disease,
contractions in the distal stomach propel food residue against the pylo- bacterial overgrowth, infectious enteritis, Crohn’s ileitis, and radiation
rus, where it is ground and thrust proximally for further mixing before damage, which affect digestion and/or absorption more diffusely,
it is emptied into the duodenum. The stomach secretes intrinsic factor produce anemia, dehydration, electrolyte disorders, or malnutrition.
for vitamin B12 absorption. Gastric hypersecretory conditions such as gastrinoma damage the
Most nutrient absorption occurs in the small intestine. The mucosal intestinal mucosa, impair pancreatic enzyme activation, and accel-
villus architecture provides maximal surface area for absorption and is erate transit due to excess gastric acid. Benign or neoplastic biliary
endowed with specialized enzymes and transporters. Triturated food obstruction impairs fat digestion. Impaired pancreatic enzyme release
from the stomach mixes with pancreatic juice and bile in the duode- in chronic pancreatitis or pancreatic cancer decreases intraluminal
num. Pancreatic juice contains enzymes for nutrient digestion and digestion and can lead to malnutrition.
bicarbonate to optimize the pH for enzyme activation. Bile secreted
by the liver and stored in the gallbladder is essential for lipid diges- Altered Secretion Some GI diseases result from dysregulation
tion. The proximal intestine is optimized for rapid absorption of most of gut secretion. Gastric acid hypersecretion occurs in gastrinoma,
nutrients and minerals, whereas the ileum is better suited for absorbing G-cell hyperplasia, retained antrum syndrome, and some patients
vitamin B12 and bile acids. Bile contains by-products of erythrocyte with duodenal ulcers. Gastric acid is reduced in atrophic gastritis and
degradation, toxins, medications, and cholesterol for fecal evacuation. pernicious anemia. Inflammatory and infectious small-intestinal and
Intestinal motor function delivers indigestible residue into the colon colonic diseases produce fluid loss through impaired absorption or
for processing. The ileocecal junction is a sphincter that prevents enhanced secretion. Common hypersecretory conditions that cause
coloileal reflux, reducing microbial density. diarrhea include acute bacterial or viral infection, chronic Giardia or
The colon prepares waste for evacuation. The mucosa dehydrates cryptosporidia infections, small-intestinal bacterial overgrowth, bile
the stool, reducing daily ileal volumes of 1000–1500 mL to 100–200 mL salt diarrhea, microscopic colitis, and diabetic diarrhea. Less common

HPIM21e_Part10_p2381-p2670.indd 2381 20/01/22 10:02 PM

 2382 causes include large colonic villus adenomas and endocrine neoplasias venous thrombosis, or hypoperfusion from dehydration, sepsis, hem-
with tumor overproduction of secretagogue transmitters such as vaso- orrhage, or reduced cardiac output. These may produce mucosal injury,
active intestinal polypeptide. hemorrhage, or even perforation. Chronic ischemia may result in intes-
tinal stricture. Some cases of radiation enterocolitis exhibit reduced
Altered Gut Transit Impaired gut transit may result from mechan- mucosal blood flow.
ical obstruction. Esophageal occlusion most often is due to stricture
(due to acid exposure or eosinophilic esophagitis) or neoplasm. Gas- Neoplastic Degeneration All GI regions are susceptible to malig-
tric obstruction develops from ulcer disease or gastric cancer. Small- nant degeneration. In the United States, colorectal cancer is most com-
intestinal obstruction most commonly results from adhesions but also mon and usually presents after age 45 years. Worldwide, gastric cancer
occurs with Crohn’s disease, radiation- or drug-induced strictures, and is prevalent, especially in certain Asian populations. Esophageal cancer
less likely malignancy. The most common cause of colonic obstruction develops with chronic acid reflux or after extensive alcohol or tobacco
is colon cancer, although inflammatory strictures develop with inflam- use. Small-intestinal neoplasms are rare but occur with underlying
matory bowel disease (IBD), after certain infections such as diverticu- inflammatory diseases. Anal cancers arise after prior anal infection or
litis, or with some drugs. inflammation. Pancreatic and biliary cancers elicit severe pain, weight
Retardation of propulsion can develop from altered motor function. loss, and jaundice and have poor prognoses. Hepatocellular carcinoma
Achalasia is characterized by impaired esophageal body peristalsis and usually arises in the setting of chronic viral hepatitis or cirrhosis
incomplete lower esophageal sphincter relaxation. Gastroparesis is the secondary to other causes. Most GI cancers exhibit carcinomatous
delay in gastric emptying of meals due to impaired gastric motility. histology; however, lymphomas and other cell types also are observed.
Intestinal pseudoobstruction is the disruption of small-bowel contrac-
tility due to enteric nerve or smooth-muscle injury. Slow-transit consti- Disorders without Obvious Organic Abnormalities The
pation results from diffusely impaired colon propulsion. Constipation most prevalent GI disorders show no abnormalities on biochemical or
also is produced by outlet abnormalities such as rectal prolapse, intus- structural testing and include IBS, functional dyspepsia, and functional
susception, or dyssynergia—a failure of anal or puborectalis relaxation heartburn. These disorders exhibit altered gut motor function, but the
upon attempted defecation. pathogenic relevance of these abnormalities is uncertain. Exaggerated
Disorders of rapid propulsion are less common than those with visceral sensory responses to noxious stimulation may cause discom-
delayed transit. Rapid gastric emptying occurs with postvagotomy fort in these disorders. Symptoms in other patients result from altered
dumping syndrome, gastric hypersecretion, and some cases of func- processing of visceral pain sensations in the central nervous system.
tional dyspepsia and cyclic vomiting syndrome. Exaggerated intestinal Functional bowel patients with severe symptoms may exhibit signifi-
or colonic motor patterns may be responsible for diarrhea in irritable cant emotional disturbances on psychometric testing. Subtle immuno-
bowel syndrome (IBS). Accelerated transit with hyperdefecation is logic defects may contribute to functional symptoms as well.
PART 10

noted in hyperthyroidism.
Genetic Influences Although many GI diseases result from envi-
Immune Dysregulation Many inflammatory GI conditions are ronmental factors, others exhibit hereditary components. Family
consequences of altered gut immune function. Mucosal inflammation members of IBD patients show a genetic predisposition to disease
in celiac disease results from dietary ingestion of gluten-containing development themselves. Colonic, esophageal, and pancreatic malig-
Disorders of the Gastrointestinal System

grains. Some patients with food allergy also exhibit altered immune nancies arise in certain inherited disorders. Rare genetic dysmotility
populations. Eosinophilic esophagitis and eosinophilic gastroenteri- syndromes are described. Familial clustering is observed in the func-
tis are inflammatory disorders with prominent mucosal eosinophil tional bowel disorders, although this may be secondary learned familial
infiltration. Ulcerative colitis and Crohn’s disease are disorders that illness behavior rather than a true hereditary factor.
produce mucosal injury primarily in the lower gut. The microscopic
colitides, lymphocytic and collagenous colitis, exhibit colonic sub- ■■SYMPTOMS OF GI DISEASE
epithelial infiltrates without visible mucosal damage. Bacterial, viral, Symptoms of GI disease include abdominal pain, heartburn, nausea
and protozoal organisms produce ileitis or colitis in selected patients. and vomiting, altered bowel habits, GI bleeding, jaundice, and other
Alterations in the gut microbiome (termed dysbiosis) are proposed to manifestations (Table 321-1).
trigger IBD, celiac disease, and IBS flares and may be factors in onco-
genesis in some cases of pancreatic cancer. Abdominal Pain Abdominal pain results from GI disease and
extraintestinal conditions involving the genitourinary tract, abdominal
Impaired Gut Blood Flow Different GI regions are at variable wall, thorax, or spine. Visceral pain generally is midline in location
risk for ischemic damage from impaired blood flow. Rare cases of gas- and vague in character, whereas parietal pain is localized and precisely
troparesis result from blockage of the celiac and superior mesenteric described. Painful inflammatory diseases include peptic ulcer, appen-
arteries. More commonly encountered are intestinal and colonic ische- dicitis, diverticulitis, IBD, pancreatitis, cholecystitis, and infectious
mia that are consequences of arterial embolus, arterial thrombosis, enterocolitis. Noninflammatory visceral sources include biliary colic,

TABLE 321-1 Common Causes of Common Gastrointestinal (GI) Symptoms

ABDOMINAL PAIN NAUSEA AND VOMITING DIARRHEA GI BLEEDING OBSTRUCTIVE JAUNDICE
Appendicitis Medications Infection Ulcer disease Bile duct stones
Gallstone disease GI obstruction Poorly absorbed sugars Esophagitis Cholangiocarcinoma
Pancreatitis Motor disorders Inflammatory bowel disease Varices Cholangitis
Diverticulitis Functional bowel disorder Microscopic colitis Vascular lesions Sclerosing cholangitis
Ulcer disease Cyclic vomiting syndrome Functional bowel disorder Neoplasm Ampullary stenosis
Esophagitis Cannabinoid hyperemesis syndrome Celiac disease Diverticula Ampullary carcinoma
GI obstruction Enteric infection Pancreatic insufficiency Hemorrhoids Pancreatitis
Inflammatory bowel disease Pregnancy Hyperthyroidism Fissures Pancreatic tumor
Functional bowel disorder Endocrine disease Ischemia Inflammatory bowel disease
Vascular disease Motion sickness Endocrine tumor Infectious colitis
Gynecologic causes Central nervous system disease
Renal stone

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 mesenteric ischemia, and neoplasia. The most common causes of ■■HISTORY 2383
abdominal pain are IBS and functional dyspepsia. The history in suspected GI disease has several components.
Heartburn Heartburn, a burning substernal sensation, is reported Symptom timing, patterns, and duration suggest specific etiologies.
intermittently by 40% of the population. Classically, heartburn results Short-duration symptoms commonly result from acute infection or
from excess gastroesophageal acid reflux, but some cases exhibit nor- inflammation, toxin exposure, or ischemia. Long-standing symptoms
mal esophageal acid exposure and are caused by reflux of nonacidic point to chronic inflammation, neoplasia, or functional bowel dis-
material or heightened sensitivity of esophageal nerves. orders. Luminal obstruction can present with dysphagia, nausea and
vomiting, bloating and distention, or constipation depending on the
Nausea and Vomiting Nausea and vomiting are caused by GI site of blockage. Symptoms from mechanical obstruction, ischemia,
diseases, medications, toxins, infection, endocrine disorders, laby- IBD, and functional bowel disorders are worsened by meals, while
rinthine conditions, and central nervous system disease. Mechanical ulcer symptoms may be relieved by eating or antacids. Ulcer pain
obstructions of the upper gut are commonly excluded as causes of occurs intermittently over weeks to months, whereas biliary colic has
chronic nausea and vomiting, but disorders of propulsion including a sudden onset and lasts up to several hours. Acute pancreatitis pain is
gastroparesis and intestinal pseudoobstruction elicit similar symptoms. severe and persists for days to weeks. Meals elicit diarrhea while def-
Nausea and vomiting also are commonly reported by patients with IBS ecation relieves discomfort in some cases of IBD and IBS. Functional
and functional disorders of the upper gut (including chronic nausea bowel disorders are exacerbated by stress. Sudden awakening from
vomiting syndrome, cyclic vomiting syndrome, and cannabinoid sound sleep by pain suggests organic rather than functional disease.
hyperemesis syndrome). Diarrhea from malabsorption usually improves with fasting, whereas
Altered Bowel Habits Altered bowel habits are common com- secretory diarrhea persists without oral intake.
plaints in GI disease. Constipation may be reported as infrequent Symptom relation to other factors narrows the list of diagnostic
defecation, straining with defecation, passage of hard stools, or a sense possibilities. Obstructive symptoms with prior abdominal surgery
of incomplete fecal evacuation and is caused by obstruction, motor raise concern for adhesions. Loose stools after gastrectomy or chole-
disorders, medications, and endocrine diseases such as hypothyroid- cystectomy suggest dumping syndrome or postcholecystectomy diar-
ism and hyperparathyroidism. Diarrhea may be reported as frequent rhea. Symptom onset after travel prompts consideration of infection.
defecation, passage of loose or watery stools, fecal urgency, or a similar Medications produce pain, altered bowel habits, or GI bleeding. Celiac
sense of incomplete evacuation. The differential diagnosis of diarrhea disease is prevalent in people of northern European descent, whereas
includes infections, inflammatory causes, malabsorption, and medi- IBD is more common in Jewish populations. A sexual history may raise
cations. IBS produces constipation, diarrhea, or an alternating bowel concern for infection or immunodeficiency.

CHAPTER 321 Approach to the Patient with Gastrointestinal Disease

pattern. Fecal mucus is common in IBS, whereas pus and blood char- Working groups have devised symptom criteria to improve diagno-
acterize IBD. Steatorrhea develops with malabsorption. sis of functional bowel disorders to minimize the numbers of unnec-
essary diagnostic tests performed. The best accepted symptom-based
GI Bleeding Hemorrhage may develop from any gut organ. Upper criteria are the Rome criteria, which exhibit sensitivities and speci-
GI bleeding presents with melena or hematemesis, whereas lower GI ficities of only 55–75% when tested against structural findings in IBS
bleeding produces passage of bright red or maroon stools. However, and functional dyspepsia, indicating a need for careful test selection in
briskly bleeding upper sites can elicit voluminous red rectal bleeding, patients at high risk of organic disease.
whereas slowly bleeding ascending colon sites may produce melena.
Chronic occult GI bleeding may present with iron deficiency anemia. ■■PHYSICAL EXAMINATION
Causes of upper GI bleeding include ulcer disease, gastroduodenitis, The physical examination complements information from the history.
esophagitis, portal hypertensive etiologies, malignancy, tears across the Abnormal vital signs provide diagnostic clues and determine the need
gastroesophageal junction, and vascular lesions. Lower GI sources of for acute intervention. Fever suggests inflammation or neoplasm.
hemorrhage include hemorrhoids, anal fissures, diverticula, ischemic Orthostasis is produced by significant blood loss, dehydration, sepsis,
colitis, neoplasm, IBD, infectious colitis, drug-induced colitis, arterio- or autonomic neuropathy. Skin, eye, or joint findings may point to
venous malformations, and other vascular lesions. specific diagnoses. Neck examination with swallowing assessment
Jaundice Jaundice results from prehepatic, intrahepatic, or posthe- evaluates dysphagia. Lung and cardiac examinations evaluate for
patic disease. Posthepatic causes of jaundice include biliary diseases, cardiopulmonary disease as causes of abdominal pain or nausea.
such as choledocholithiasis, acute cholangitis, primary sclerosing Pelvic examination tests for a gynecologic source of abdominal pain.
cholangitis, other strictures, and neoplasm, and pancreatic disorders, Rectal examination may detect blood, indicating mucosal injury or
such as acute and chronic pancreatitis, stricture, and malignancy. neoplasm or a palpable inflammatory mass in appendicitis. Meta-
bolic conditions and gut motor disorders have associated peripheral
Other Symptoms Other symptoms are manifestations of GI dis- neuropathy.
ease. Dysphagia, odynophagia, and unexplained chest pain suggest Abdominal inspection may reveal distention from obstruction,
esophageal disease. A globus sensation is reported with esophago- tumor, or ascites or vascular abnormalities with liver disease. Ecchy-
pharyngeal conditions, but also occurs with functional GI disorders. moses develop with severe pancreatitis. Auscultation detects bruits or
Weight loss, anorexia, and fatigue present with neoplastic, inflamma- friction rubs from vascular disease or hepatic tumors. Loss of bowel
tory, motility, pancreatic, and psychiatric conditions. IBD is associated sounds signifies ileus, whereas high-pitched, hyperactive sounds
with hepatobiliary dysfunction, skin and eye lesions, and arthritis. characterize intestinal obstruction. Percussion assesses liver size and
Celiac disease may present with dermatitis herpetiformis. Jaundice can detects shifting dullness from ascites. Palpation assesses for hepatosple-
produce pruritus. Conversely, systemic diseases have GI consequences. nomegaly and neoplastic or inflammatory masses. Intestinal ischemia
Systemic lupus may cause gut ischemia, presenting with pain or bleed- elicits severe pain but little tenderness. Patients with visceral pain may
ing. Severe burns may lead to gastric ulcer formation. exhibit generalized discomfort, whereas those with parietal pain or
peritonitis have localized pain with involuntary guarding, rigidity, or
EVALUATION OF THE PATIENT rebound. Patients with musculoskeletal abdominal wall pain may note
WITH GI DISEASE tenderness exacerbated by Valsalva or leg lift maneuvers.
Evaluation of the patient with suspected GI disease begins with a care-
ful history and examination. Subsequent investigation with tools to ■■TOOLS FOR PATIENT EVALUATION
test gut structure or function and luminal constituents is indicated in Laboratory, radiographic, and functional tests assist in diagnosis of sus-
selected cases. In patients with normal findings on diagnostic testing, pected GI disease. The GI tract also is amenable to internal evaluation
validated symptom profiles are used to confidently diagnose a func- using endoscopy and to examination of luminal contents. Histopatho-
tional bowel disorder. logic examinations of GI tissues complement these tests.

HPIM21e_Part10_p2381-p2670.indd 2383 20/01/22 10:02 PM

 2384 Laboratory Laboratory tests facilitate diagnosis of GI disease. as IBD. Stool electrolytes can be measured in diarrheal conditions.
Iron-deficiency anemia suggests mucosal blood loss, whereas vitamin B12 Laxative screens are performed for suspected laxative abuse. Fecal
deficiency results from intestinal, gastric, or pancreatic disease. Either immunochemical and DNA tests have assumed roles in colon cancer
can result from inadequate oral intake. Leukocytosis and increased screening in low-risk populations. Gastric acid is quantified to exclude
sedimentation rates and C-reactive proteins are found in inflamma- gastrinoma. Esophageal pH/impedance testing is done for refractory
tion, whereas leukopenia is seen in viremic illness. Severe vomiting or symptoms of gastroesophageal reflux.
diarrhea elicits electrolyte disturbances, acid-base abnormalities, and
elevated blood urea nitrogen. Pancreaticobiliary or liver disease pro- Endoscopy The gut is accessible to endoscopy, which can diagnose
duces elevated pancreatic or liver chemistries. Thyroid chemistries and causes of bleeding, pain, nausea and vomiting, weight loss, altered
cortisol and calcium levels evaluate for endocrinologic causes of symp- bowel function, and fever. Table 321-2 lists common indications for
toms. Pregnancy testing is considered for women with unexplained endoscopic procedures. Upper endoscopy evaluates the esophagus,
nausea. Serologic tests screen for celiac disease, IBD, connective tissue stomach, and duodenum, whereas colonoscopy assesses the colon
diseases, and paraneoplastic dysmotility syndromes. Hormone levels and distal ileum. Upper endoscopy is advocated as the initial test for
are obtained for suspected endocrine neoplasia. Intraabdominal malig- suspected ulcer disease, esophagitis, neoplasm, malabsorption, and
nancies produce tumor markers including the carcinoembryonic anti- Barrett’s metaplasia because of its abilities to visualize and biopsy any
gen CA 19-9 and α-fetoprotein. Blood testing also monitors medication abnormality. Colonoscopy is the preferred procedure for colon cancer
therapy, as with thiopurine metabolite levels in IBD. Pharmacogenetic screening and surveillance and to biopsy colitis or ileitis secondary
methods are being adopted to determine optimal patient populations to IBD, infection, ischemia, and radiation. Sigmoidoscopy examines
for GI medication use. In conditions including IBD, research into the colon to the splenic flexure and excludes distal causes of bleed-
novel biomarkers is being conducted to predict longitudinal course ing, inflammation, or obstruction in young patients not at significant
and treatment response. Other body fluids are sampled under certain risk for colon cancer. For elusive GI bleeding from arteriovenous
circumstances. Ascitic fluid is analyzed for infection, malignancy, or malformations or superficial ulcers, small-intestinal examination is
findings of portal hypertension. Urine samples screen for carcinoid, performed with push enteroscopy, capsule endoscopy, or double-
porphyria, and heavy metal intoxication. balloon enteroscopy. Capsule endoscopy also visualizes small-
intestinal Crohn’s disease in individuals with negative radiography.
Luminal Contents Luminal contents can provide diagnostic clues. Endoscopic ultrasound (EUS) diagnoses and stages GI malignancy,
Stool samples are cultured for bacterial pathogens, examined for leu- excludes choledocholithiasis, evaluates pancreatitis, and assesses anal
kocytes and parasites, or tested for Giardia antigen. Duodenal aspirates continuity. Endoscopic retrograde cholangiopancreatography (ERCP)
can be examined for parasites or cultured for bacterial overgrowth. provides diagnoses of pancreatic and biliary disease.
Fecal fat is quantified in possible malabsorption. Fecal elastase can The development of novel imaging protocols permits opti-
PART 10

be decreased with exocrine pancreatic insufficiency. Elevated fecal cal biopsies to define mucosal histology and detect dysplasia in
calprotectin or lactoferrin is found in inflammatory conditions such selected settings. Methods employed include narrow-band imaging,
Disorders of the Gastrointestinal System

TABLE 321-2 Common Indications for Endoscopy

ENDOSCOPIC RETROGRADE ENDOSCOPIC CAPSULE DOUBLE-BALLOON
UPPER ENDOSCOPY COLONOSCOPY CHOLANGIOPANCREATOGRAPHY ULTRASOUND ENDOSCOPY ENDOSCOPY
Dyspepsia despite Cancer screening Jaundice Staging of malignancy Obscure Ablation of small-
treatment Lower gastrointestinal Postbiliary surgery complaints Characterize and biopsy bleeding intestinal bleeding
Dyspepsia with signs of (GI) bleeding submucosal mass Suspected sources
Cholangitis
organic disease Anemia Bile duct stones Crohn’s disease Biopsy of suspicious
Gallstone pancreatitis of the small small-intestinal
Refractory vomiting Diarrhea Chronic pancreatitis
Pancreatic/biliary/ampullary tumor intestine masses/ulcers
Dysphagia Polypectomy Drain pseudocyst
Unexplained pancreatitis
Upper GI bleeding Obstruction Anal continuity
Pancreatitis with unrelenting pain
Anemia Biopsy radiologic Direct stent placement
Fistulas
Weight loss abnormality
Biopsy radiologic abnormality
Malabsorption Cancer surveillance:
family history prior polyp/ Pancreaticobiliary drainage
Biopsy radiologic
abnormality cancer, colitis Sample bile
Polypectomy Palliate neoplasm Sphincter of Oddi manometry
Place gastrostomy Remove foreign body
Barrett’s surveillance Place stent across
stenosis
Palliate neoplasm
Sample duodenal tissue/
fluid
Remove foreign body
Endoscopic mucosal
resection or endoscopic
submucosal dissection
for dysplasia or early
cancer
Place stent across
stenosis
Endoscopic myotomy
for achalasia or
gastroparesis
Endoscopic bariatric
procedures

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 chromoendoscopy, confocal laser endomicroscopy, and optical coher- TREATMENT 2385
ence tomography in colitis, Barrett’s esophagus, and gastric cancer
surveillance. Artificial intelligence using machine learning techniques Gastrointestinal Disease
shows promise in detecting dysplasia and early cancer in still images
from biopsy tissues. Management options for GI diseases depend on the cause of
symptoms. Available treatments include modifications of dietary
Radiography/Nuclear Medicine Radiographic tests evaluate intake, medications, treatment of gut dysbiosis, luminal intubation,
gut diseases and extraluminal structures. Contrast radiography with interventional endoscopy or radiology techniques, surgery, psycho-
barium provides mucosal definition and can assess gut transit and logical approaches, and physical therapy. Given the hereditary pre-
pelvic floor dysfunction. An esophagram is the initial procedure to disposition of many GI diseases, genetic testing may be indicated
exclude subtle rings, strictures, or achalasia as causes of dysphagia, in some patients. Improved smartphone applications are being
whereas small-bowel contrast radiology detects intestinal tumors, adopted for diverse purposes ranging from providing instructions
strictures, and fistulae and can estimate intestinal transit. Contrast for endoscopy preparation to educating and promoting adherence
enemas are performed when colonoscopy is unsuccessful or contrain- to diet restrictions in several disorders.
dicated. Ultrasound and computed tomography (CT) evaluate regions NUTRITIONAL MANIPULATION
not accessible by endoscopy or contrast studies, including the liver, Dietary modifications for GI disease include those that only
pancreas, gallbladder, kidneys, and retroperitoneum, and are useful for reduce symptoms, those that correct pathologic defects, or those
diagnosing mass lesions, fluid collections, organ enlargement, and, in that replace normal food intake with enteral or parenteral for-
the case of ultrasound, gallstones. CT and magnetic resonance (MR) mulations. Changes that improve symptoms but do not reverse
colonography have been considered as alternatives to colonoscopy organic abnormalities include lactose restriction for lactase
for colon cancer screening but have not commonly been adopted. deficiency, liquid meals in gastroparesis, carbohydrate restric-
MR methods image the pancreaticobiliary ducts to exclude neo- tions with dumping syndrome, and low-FODMAP (fermentable
plasm, stones, and sclerosing cholangitis and the liver to characterize oligo-di-monosaccharides and polyols) diets in IBS. The gluten-
benign and malignant tumors. Specialized CT or MR enterography free diet for celiac disease exemplifies a primary therapy to reduce
quantifies IBD intensity. Angiography excludes mesenteric ischemia mucosal inflammation. Likewise, elimination diets may improve
and determines spread of malignancy. Angiographic techniques also histology and symptoms in some cases of eosinophilic esophagi-
access the biliary tree in obstructive jaundice. CT and MR techniques tis. Medium-chain triglycerides replace normal fats in short-gut
screen for mesenteric occlusion, thereby limiting exposure to angio- syndrome or severe ileal disease. Perfusing liquid meals through

CHAPTER 321 Approach to the Patient with Gastrointestinal Disease

graphic dyes. Positron emission tomography (PET) can distinguish a gastrostomy is performed in those who cannot swallow safely.
malignant from benign disease in several organ systems. Imaging with Enteral jejunostomy feedings are considered for gastric dysmotil-
DOTA-octreotate and related agents has improved detection of neu- ity syndromes that preclude feeding into the stomach. Intravenous
roendocrine tumors by combined PET-CT techniques. hyperalimentation is used for generalized gut malfunction, which
Scintigraphy evaluates structural abnormalities and quantifies lumi- does not permit enteral nutrition.
nal transit. Radionuclide scans localize bleeding sites in patients with
brisk hemorrhage to direct therapy with endoscopy, angiography, PHARMACOTHERAPY
or surgery. Radiolabeled leukocyte scans search for intraabdominal Several medications can treat GI diseases. Considerable resources
abscesses not visualized on CT. Biliary scintigraphy complements are expended on over-the-counter remedies. Many prescription
ultrasound in assessing for cholecystitis. Scintigraphy to quantify drug classes are offered as short-term or continuous therapy of GI
esophageal and gastric emptying is well established, whereas tech- illness. Alternative treatments are popular in conditions for which
niques to measure small-intestinal or colonic transit are less widely traditional therapies provide incomplete relief.
used. Over-the-Counter Agents Over-the-counter agents are reserved
for mild GI symptoms. Antacids, histamine H2 antagonists, and
Histopathology Endoscopic mucosal biopsies evaluate for inflam- proton pump inhibitors (PPIs) decrease symptoms in gastroesopha-
matory, infectious, and neoplastic disease. Deep rectal biopsies facil-
geal reflux disease (GERD) and dyspepsia. Fiber supplements, stool
itate diagnosis of Hirschsprung’s disease or amyloid. Liver biopsy is
softeners, enemas, and laxatives are used for constipation. Laxatives
performed for abnormal liver chemistries, unexplained jaundice, and
are categorized as stimulants, osmotic agents (including isotonic
some cases of viral hepatitis, and following liver transplant to exclude
preparations containing polyethylene glycol), and poorly absorbed
rejection. Biopsies obtained during CT or ultrasound evaluate for
sugars. Nonprescription antidiarrheal agents include bismuth sub-
intraabdominal conditions not accessible by endoscopy.
salicylate, kaolin-pectin combinations, and loperamide, whereas
Functional Testing Tests of gut function provide important data lactase enzyme pills are used for lactose intolerance. Gaseous symp-
when structural testing is nondiagnostic. Functional testing of motor toms may be reduced by bacterial α-galactosidase, antiflatulents,
activity is provided by newer high-resolution manometric techniques. and adsorbents. In general, using a nonprescription preparation for
Esophageal manometry is useful for suspected achalasia, whereas more than a short time for chronic persistent symptoms should be
small-intestinal manometry tests for pseudoobstruction and colon supervised by a health care provider.
manometry evaluates for colonic inertia. A wireless motility capsule Prescription Drugs Prescription drugs are approved for a broad
measures transit and contractile activity in the stomach, small intes- range of GI diseases. Higher-dose prescription PPIs are advocated
tine, and colon in a single test. Anorectal manometry with balloon for GERD when over-the-counter preparations are inadequate.
expulsion testing is used for unexplained incontinence or constipation Cytoprotective agents are available for upper gut ulcers but are less
from outlet dysfunction. Biliary manometry tests for sphincter of Oddi frequently prescribed. Prokinetic drugs stimulate GI propulsion in
dysfunction with unexplained biliary pain. The endoluminal func- gastroparesis, pseudoobstruction, and slow-transit constipation.
tional lumen imaging probe can measure reduced distensibility in the Secretagogue drugs are prescribed for constipation refractory to
lower esophageal sphincter in achalasia, the pylorus in gastroparesis, other agents, whereas peripheral opioid antagonists are offered for
and the anus for defecation disorders. Measurement of breath hydro- opioid-induced constipation. Prescription antidiarrheals include
gen while fasting and after oral mono- or oligosaccharide challenge opioid drugs, anticholinergic antispasmodics, tricyclics, bile acid
can screen for carbohydrate intolerance and small-intestinal bacterial binders, and serotonin antagonists. Antispasmodics and anti-
overgrowth. Urea breath testing assesses for persistent Helicobacter depressants also are useful for functional GI disorders, whereas
pylori infection, while gastric emptying breath testing is an alternative narcotics are used for pain control in organic conditions such as
to scintigraphy for gastroparesis diagnosis. disseminated malignancy and chronic pancreatitis. Antiemetics

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 2386 reduce nausea and vomiting. Potent pancreatic enzymes decrease with stone lithotripsy in the common bile duct, ablation of small
malabsorption and pain from pancreatic disease. Antisecretory ductal tumors, and placement of gallbladder stents to facilitate
drugs such as the somatostatin analogue octreotide treat hyperse- drainage in nonoperative candidates. Methods employing interven-
cretory states. Some functional GI disorders require use of neuro- tional EUS have been developed for pancreatic cyst gastrostomy
modulators, including tricyclic agents, for control of pain, diarrhea, using lumen-apposing metal stents, pancreatic necrosectomy, and
or nausea. Antibiotics treat H. pylori–induced ulcers, infectious placement of fiducial markers to direct pancreatic and rectal radio-
diarrhea, diverticulitis, intestinal bacterial overgrowth, and Crohn’s therapy. EUS also has been used to facilitate endoscopic access to
disease. Anti-inflammatory and immunomodulatory drugs are used the excluded distal stomach in patients who have undergone bariat-
in IBD, microscopic colitis, refractory celiac disease, autoimmune ric gastric bypass surgery using similar stents so that ERCP can
pancreatitis, and gut vasculitis. Over the past decade, several newer be done for pancreaticobiliary conditions. Likewise, EUS-directed
biologic agents, including agents that inhibit tumor necrosis activ- stent placement can manage postsurgical stenoses after pancreatic
ity, other proinflammatory cytokines, and Janus kinase signaling resection. Endoscopy is sometimes used to insert gastric feeding
or serve as antiadhesion molecules, have had dramatic impact in tubes. Peroral endoscopic myotomy is therapeutically performed
Crohn’s disease and ulcerative colitis. Biologics that deplete eosin- on the lower esophageal sphincter in achalasia and on the pylorus
ophils or inhibit mast cells show promise in eosinophilic disorders in gastroparesis. Endoscopic treatments for acid reflux includ-
of the gut. Chemotherapy with or without radiotherapy is offered ing radiofrequency therapy, transoral fundoplication, endoscopic
for GI malignancies. Most GI carcinomas respond poorly to such stapling, and antireflux mucosectomy have been developed, but
therapy, whereas lymphomas may be cured with such intervention. many offer unproved utility. Endoscopic bariatric methodologies,
Complementary and Alternative Medicine Treatments Alterna- including intragastric balloons, endoscopic sleeve gastroplasty, and
tive treatments are marketed to treat GI symptoms. Ginger, acupres- duodenal resurfacing and diversion, have been introduced.
sure, and acustimulation have been advocated for nausea, whereas Radiologic measures also are useful in GI disease. Angiographic
pyridoxine has been investigated for nausea of first-trimester preg- embolization or vasoconstriction decreases bleeding from gut sites
nancy. Peppermint oil and carraway seed oil products and herbal not amenable to endoscopic intervention. Dilatation or stenting
preparations such as STW 5 (a mixture of nine herbs) are useful with fluoroscopic guidance relieves luminal strictures. Contrast
in cases of functional dyspepsia and IBS. Low-potency pancreatic enemas can reduce volvulus and evacuate air in acute colonic pseu-
enzyme preparations are sold as general digestive aids but have little doobstruction. CT and ultrasound help drain abdominal fluid col-
evidence to support their efficacy. lections, in many cases obviating the need for surgery. Percutaneous
transhepatic cholangiography relieves biliary obstruction when
THERAPIES TARGETING GUT DYSBIOSIS ERCP is contraindicated. Transjugular intrahepatic portosystemic
PART 10

Some cases of diarrhea-predominant IBS respond to nonabsorb- shunts are commonly performed by interventional radiologists for
able antibiotics. Oral antibiotics also are the mainstay of managing variceal hemorrhage not amenable to endoscopic therapy. Litho-
intestinal bacterial overgrowth. Probiotics containing active bac- tripsy can fragment gallstones in patients who are not candidates
terial cultures and prebiotics that selectively nourish nonnoxious for surgery. Radiologic approaches are often chosen over endoscopy
commensal bacteria are used as adjuncts in some cases of infectious for gastroenterostomy placement. Finally, central venous cath-
Disorders of the Gastrointestinal System

diarrhea and IBS, with limited evidence of efficacy. Transplantation eters for parenteral nutrition may be placed using radiographic
of donor feces into the colon by colonoscopy or enema is effective techniques.
treatment for recurrent, refractory Clostridium difficile colitis, and SURGERY
numerous trials are being conducted to assess utility of this tech-
nique in IBS, IBD, and liver disease Surgery is performed to cure disease, control symptoms, maintain
nutrition, or palliate unresectable neoplasm. Surgery can cure med-
LUMINAL SUCTION AND LAVAGE ication-unresponsive ulcerative colitis, diverticulitis, cholecystitis,
appendicitis, and intraabdominal abscess, but can only reduce
Nasogastric tube suction decompresses the upper gut in ileus or
symptoms and treat disease complications in Crohn’s disease. Sur-
mechanical obstruction. Nasogastric lavage of saline or water in the
gery is mandated for ulcer complications such as bleeding, obstruc-
patient with upper GI hemorrhage determines the rate of bleeding
tion, or perforation and intestinal obstructions that persist after
and helps evacuate blood before therapeutic endoscopy. Enteral
conservative care. Gastroesophageal fundoplication is performed
feedings can be delivered through nasogastric or nasoenteric tubes.
for severe ulcerative esophagitis and drug-refractory symptom-
Enemas relieve fecal impaction or assist in gas evacuation in acute
atic acid reflux. Achalasia responds to operations to reduce lower
colonic pseudoobstruction. A rectal tube can be placed to vent the
esophageal sphincter tone. Operations for motor disorders include
distal colon in colonic pseudoobstruction and other colonic disten-
implanted electrical stimulators for gastroparesis and electrical
tion disorders.
devices and artificial sphincters for fecal incontinence. Surgery may
INTERVENTIONAL ENDOSCOPY AND RADIOLOGY be needed to place a jejunostomy for long-term enteral feedings.
In addition to its diagnostic role, endoscopy has numerous ther-
PSYCHOLOGICAL APPROACHES AND PHYSICAL THERAPY
apeutic capabilities. Cautery techniques and injection of vasocon-
strictor substances can stop hemorrhage from ulcers and vascular Psychological therapies, including psychotherapy, cognitive behav-
malformations. Endoscopic encirclement of varices and hemor- ioral therapy, and hypnosis, have shown efficacy in functional
rhoids with constricting bands stops hemorrhage from these sites, bowel disorders. Patients with significant psychological dysfunction
whereas endoscopically placed clips can occlude arterial bleed- and those with little response to treatments targeting the gut are
ing sites. Endoscopically delivered hemostatic powder sprays are likely to benefit from this form of therapy. Biofeedback methods
approved to stop brisk GI bleeding. Endoscopy can remove polyps administered by physical therapies are accepted for treating refrac-
or debulk lumen-narrowing malignancies. Colonoscopy can with- tory fecal incontinence or constipation secondary to dyssynergia.
draw excess gas in some cases of acute colonic pseudoobstruction.
Endoscopic mucosal resection, submucosal dissection, and radio-
frequency techniques can ablate some cases of Barrett’s esophagus ■■FURTHER READING
with dysplasia or superficial cancer and early gastric malignancies. Aslanian HR et al: AGA Clinical Practice Update on pancreas cancer
Obstructions of the gut lumen and pancreaticobiliary tree are screening in high-risk individuals: An expert review. Gastroenterol-
relieved by endoscopic dilation or placing plastic or expandable ogy 159:358, 2020.
metal stents. Endoscopic sphincterotomy of the ampulla of Vater Bajaj JS et al: Major trends in gastroenterology and hepatology
relieves symptoms of choledocholithiasis. Cholangioscopy can help between 2010 and 2019: An overview of advances from the past

HPIM21e_Part10_p2381-p2670.indd 2386 20/01/22 10:02 PM

 decade selected by the editorial board of the American Journal of 2387
Gastroenterology. Am J Gastroenterol 115:1007, 2020.
Gupta S et al: Recommendations for follow-up after colonoscopy and
polypectomy: A consensus update by the US Multi-Society Task
Force on Colorectal Cancer. Gastroenterology 158:1131, 2020.
Keefer L et al: Best practice update: Incorporating psychogastroenter-
ology into management of digestive disorders. Gastroenterology
154:1249, 2018.
Lamb CA et al: British Society of Gastroenterology consensus guide-
lines on the management of inflammatory bowel disease in adults.
Gut 68:s1, 2019.
Osadchiy V et al: The gut-brain axis and the microbiome: Mecha-
nisms and clinical implications. Clin Gastroenterol Hepatol 17:322,
2019.

322 Gastrointestinal
Endoscopy
A

Louis Michel Wong Kee Song, Mark Topazian

Gastrointestinal endoscopy has been attempted for >200 years, but

CHAPTER 322 Gastrointestinal Endoscopy

the introduction of semirigid and flexible gastroscopes in the
mid-twentieth century marked the dawn of the modern endoscopic
era. Since then, rapid advances in endoscopic technology have led to
dramatic changes in the diagnosis and treatment of many digestive
diseases. Innovative endoscopic devices and new endoscopic treatment
modalities continue to expand the use of endoscopy in patient care.
Flexible endoscopes provide an electronic video image generated
by a charge-coupled device (CCD) or a complementary metal oxide
semiconductor (CMOS) chip in the tip of the endoscope. Operator
controls permit deflection of the endoscope tip; fiberoptic bundles
or light-emitting diodes provide light at the tip of the endoscope;
and working channels allow washing, suctioning, and the passage of
instruments (Fig. 322-1). Progressive changes in the diameter and
stiffness of endoscopes have improved the ease and patient tolerance of B
endoscopy. High-resolution and high-definition endoscopes equipped
FIGURE 322-2 Flat colon polyp. A. White-light imaging. B. Corresponding narrow-
with electronic and optical magnification capabilities enable acqui- band imaging enhances mucosal features and lesion delineation.
sition of images with a high level of detail. Advanced imaging tech-
niques, including narrow-band imaging (Fig. 322-2) and real-time
image-processing enhancement algorithms, aid in tissue characteriza-
tion or differentiation.

ENDOSCOPIC PROCEDURES
■■UPPER ENDOSCOPY
Upper endoscopy, also referred to as esophagogastroduodenoscopy
(EGD), is performed by passing a flexible endoscope through the
mouth into the esophagus, stomach, and duodenum. The procedure is
the best method for examining the upper gastrointestinal mucosa
(Fig. 322-3). While the upper gastrointestinal radiographic series has
similar accuracy for diagnosis of duodenal ulcer (Fig. 322-4), EGD is
superior for detection of gastric ulcers (Fig. 322-5) and flat mucosal
lesions, such as Barrett’s esophagus (Fig. 322-6), and it permits
directed biopsy and endoscopic therapy. Intravenous sedation is given
to most patients in the United States to ease the anxiety and discom-
fort of the procedure, although in many countries, EGD is routinely
performed with topical pharyngeal anesthesia only. Patient tolerance of
unsedated EGD is improved by the use of an ultrathin, 5-mm diameter
endoscope that can be passed transorally or transnasally.
FIGURE 322-1 Gastrointestinal endoscope. Shown here is a conventional ■■COLONOSCOPY
colonoscope with control knobs for tip deflection, push buttons for suction and
air insufflation (single arrows), and a working channel for passage of accessories Colonoscopy is performed by passing a flexible colonoscope through
(double arrows). the anal canal into the rectum and colon. The cecum is reached in

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A B
PART 10
Disorders of the Gastrointestinal System

C D

E F
FIGURE 322-3 Normal upper endoscopic examination. A. Esophagus. B. Gastroesophageal junction. C. Gastric fundus. D. Gastric body. E. Gastric antrum. F. Pylorus.
G. Duodenal bulb. H. Second portion of the duodenum.

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 2389

G H
FIGURE 322-3 (Continued)

CHAPTER 322 Gastrointestinal Endoscopy

A B

FIGURE 322-4 Duodenal ulcers. A. Ulcer with a small, flat, pigmented spot in its base. B. Ulcer with a visible vessel (arrow) in a patient with recent hemorrhage.

A B
FIGURE 322-5 Gastric ulcers. A. Benign gastric ulcer in the antrum. B. Malignant gastric ulcer involving greater curvature of stomach.

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A B

C D
FIGURE 322-6 Barrett’s esophagus. A. Salmon-colored Barrett’s mucosa extending proximally from the gastroesophageal junction. B. Barrett’s esophagus with a suspicious
nodule (arrow) identified during endoscopic surveillance. C. Histologic finding of intramucosal adenocarcinoma in the endoscopically resected nodule. Tumor extends into
PART 10

the esophageal submucosa (arrow). D. Barrett’s esophagus with locally advanced adenocarcinoma.

>95% of cases, and the terminal ileum (Fig. 322-7) can often be exam- from the anal verge. This procedure causes abdominal cramping, but
ined. Colonoscopy is the gold standard for imaging the colonic mucosa it is brief and usually performed without sedation. Flexible sigmoi-
(Fig. 322-8). Colonoscopy has greater sensitivity than barium enema doscopy is primarily used for evaluation of diarrhea and rectal outlet
Disorders of the Gastrointestinal System

for colitis (Fig. 322-9), polyps (Fig. 322-10), and cancer (Fig. 322-11). bleeding.
CT colonography rivals the accuracy of colonoscopy for detection of
some polyps and cancer, although it is not as sensitive for the detection ■■SMALL-BOWEL ENDOSCOPY
of flat lesions, such as serrated polyps (Fig. 322-12). Moderate seda- Three endoscopic techniques are currently used to evaluate the small
tion is usually given before colonoscopy in the United States, although intestine, most often in patients presenting with presumed small-
a willing patient and a skilled examiner can complete the procedure bowel bleeding. For capsule endoscopy, the patient swallows a dispos-
without sedation in many cases. able capsule that contains a CMOS chip camera. Color still images
(Fig. 322-13) are transmitted wirelessly to an external receiver at
■■FLEXIBLE SIGMOIDOSCOPY several frames per second until the capsule’s battery is exhausted
Flexible sigmoidoscopy is akin to colonoscopy, but it visualizes only or it is passed into the toilet. Capsule endoscopy enables visualiza-
the rectum and a variable portion of the left colon, typically to 60 cm tion of the small-bowel mucosa beyond the reach of a conventional

A B

FIGURE 322-7 Colonoscopic view of terminal ileum. A. Normal-appearing terminal ileum (TI). B. View of normal villi of TI enhanced by examination under water immersion.

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A B

CHAPTER 322 Gastrointestinal Endoscopy

C D

FIGURE 322-8 Normal colonoscopic examination. A. Cecum with view of appendiceal orifice. B. Ileocecal valve. C. Normal-appearing colon. D. Rectum (retroflexed view).

endoscope, and at present, it is solely a diagnostic procedure. Patients ■■ENDOSCOPIC RETROGRADE

with a history of prior intestinal surgery or Crohn’s disease are at risk CHOLANGIOPANCREATOGRAPHY
for capsule retention at the site of a clinically unsuspected small- During endoscopic retrograde cholangiopancreatography (ERCP), a
bowel stricture, and ingestion of a “patency capsule” composed of side-viewing endoscope is passed through the mouth to the duode-
radiologically opaque biodegradable material may be indicated prior num, the ampulla of Vater is identified and cannulated with a thin plas-
to capsule endoscopy in such patients. tic catheter, and radiographic contrast material is injected into the bile
Push enteroscopy is generally performed using a variable-stiffness duct and pancreatic duct under fluoroscopic guidance (Fig. 322-16).
pediatric or adult colonoscope or a dedicated enteroscope with or with- When indicated, the major papilla can be incised using the tech-
out the assistance of a stiffening overtube that extends from the mouth nique of endoscopic sphincterotomy (Fig. 322-17). Stones can be
to the small intestine. The proximal to mid-jejunum is usually reached, retrieved from the ducts, biopsies can be performed, strictures can be
and the instrument channel of the endoscope allows for biopsy or dilated and/or stented (Fig. 322-18), and ductal leaks can be treated
endoscopic therapy. (Fig. 322-19). ERCP is usually performed for therapy but is also
Deeper insertion into the small bowel can be accomplished by important diagnostically as it facilitates tissue sampling of biliary or
device-assisted enteroscopy, which may utilize inflatable balloons at pancreatic ductal strictures.
the tip of the enteroscope and/or an overtube (single- or double-
balloon enteroscopy) or a rotating, screw-like overtube (motorized ■■ENDOSCOPIC ULTRASOUND
spiral enteroscopy) to pleat the small intestine onto the endoscope Endoscopic ultrasound (EUS) utilizes ultrasound transducers incor-
(Fig. 322-14, Video V5-1). With device-assisted enteroscopy, the porated into the tip of a flexible endoscope. Ultrasound images are
entire small intestine can be visualized in some patients when both obtained of the gut wall and adjacent organs, vessels, lymph nodes, and
the oral and anal routes of insertion are used. Biopsies and endo- other structures. High-resolution images are obtained by bringing a
scopic therapy can be performed throughout the visualized small high-frequency ultrasound transducer close to the area of interest via
bowel (Fig. 322-15). endoscopy. EUS provides the most accurate preoperative local staging

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A B
PART 10
Disorders of the Gastrointestinal System

C D

FIGURE 322-9 Causes of colitis. A. Chronic ulcerative colitis with diffuse ulcerations and exudates. B. Severe Crohn’s colitis with deep ulcers. C. Pseudomembranous colitis
with yellow, adherent pseudomembranes. D. Ischemic colitis with patchy mucosal edema, subepithelial hemorrhage, superficial ulcerations, and cyanosis.

A B

FIGURE 322-10 Colonic polyps. A. Pedunculated polyp on a stalk. B. Sessile polyp.

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 2393

FIGURE 322-11 Ulcerated colon adenocarcinoma narrowing the colonic lumen.

FIGURE 322-13 Capsule endoscopy. Image of a jejunal vascular ectasia.

of esophageal, pancreatic, and rectal malignancies (Fig. 322-20), but

it does not detect most distant metastases. EUS is also useful for diag-
nosis of bile duct stones, gallbladder disease, subepithelial gastrointes-
tinal lesions, and chronic pancreatitis. Fine-needle aspirates and core

CHAPTER 322 Gastrointestinal Endoscopy

biopsies of organs, masses, and lymph nodes in the posterior medias-
tinum, abdomen, retroperitoneum, and pelvis can be obtained under
EUS guidance (Fig. 322-21). EUS-guided therapeutic procedures are
increasingly performed, including drainage of abscesses, pseudocysts,
and pancreatic necrosis into the gut lumen (Video V5-2); celiac plexus
A neurolysis for treatment of pancreatic pain; ethanol ablation of pancre-
atic neuroendocrine tumors; treatment of gastrointestinal hemorrhage;
and drainage of obstructed biliary and pancreatic ducts.
■■NATURAL ORIFICE TRANSLUMINAL
ENDOSCOPIC SURGERY
Natural orifice transluminal endoscopic surgery (NOTES) is an
evolving collection of endoscopic methods that entail passage of an

FIGURE 322-12 Flat serrated polyp in the cecum. A. Appearance of the lesion under
conventional white-light imaging. B. Mucosal patterns and boundary of the lesion
enhanced with narrow-band imaging. C. Submucosal lifting of the lesion with dye FIGURE 322-14 Double-balloon enteroscopy. Radiograph of the orally inserted
(methylene blue) injection prior to resection. instrument deep in the small intestine.

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A
PART 10
Disorders of the Gastrointestinal System

FIGURE 322-16 Endoscopic retrograde cholangiopancreatography (ERCP) for bile

duct stones with cholangitis. A. Faceted bile duct stones are demonstrated in the
C common bile duct. B. After endoscopic sphincterotomy, the stones are extracted
with a Dormia basket. A small abscess communicates with the left hepatic duct.
FIGURE 322-15 Nonsteroidal anti-inflammatory drug (NSAID)–induced proximal
ileal stricture managed via double-balloon enteroscopy. A. High-grade ileal
stricture causing obstructive symptoms. B. Balloon dilation of the ileal stricture.
C. Appearance of the stricture after dilation.

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CHAPTER 322 Gastrointestinal Endoscopy

FIGURE 322-17 Endoscopic sphincterotomy. A. A normal-appearing ampulla of Vater. B. Sphincterotomy is performed with electrosurgery. C. Bile duct stones are extracted
with a balloon catheter. D. Final appearance of the sphincterotomy.

A B C D

FIGURE 322-18 Endoscopic diagnosis, staging, and palliation of hilar cholangiocarcinoma. A. Endoscopic retrograde cholangiopancreatography (ERCP) in a patient with
obstructive jaundice demonstrates a malignant-appearing stricture of the biliary confluence extending into the left and right intrahepatic ducts. B. Intraductal ultrasound
of the biliary stricture demonstrates marked bile duct wall thickening due to tumor (T) with partial encasement of the hepatic artery (arrow). C. Intraductal biopsy obtained
during ERCP demonstrates malignant cells infiltrating the submucosa of the bile duct wall (arrow). D. Endoscopic placement of bilateral self-expanding metal stents (arrow)
relieves the biliary obstruction. GB, gallbladder. (Image courtesy of Dr. Thomas Smyrk.)

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 2396 the esophagus, stomach, and colon. Several devices are available for
closure of EMR and ESD defects, as well as gastrointestinal fistulas and
perforations. Endoscopic clips deployed through the working chan-
nel of an endoscope have been used for many years to treat bleeding
lesions, and the development of larger over-the-scope clips has facil-
itated endoscopic closure of gastrointestinal fistulas and perforations
not previously amenable to endoscopic therapy (Video V5-6). Endo-
scopic suturing can be used to close some perforations and large
defects (Fig. 322-27), anastomotic leaks, and fistulas. Other potential
indications for endoscopic suturing include stent fixation to prevent
migration (Fig. 322-28, Video V5-7) and endoscopic bariatric proce-
dures. These technologies are playing an expanding role in patient care.
RISKS OF ENDOSCOPY
Medications used during moderate sedation may cause respiratory
depression or allergic reactions. All endoscopic procedures carry some
risk of bleeding and gastrointestinal perforation. The risk is small with
diagnostic upper endoscopy, flexible sigmoidoscopy, and colonoscopy
(<1:1000 procedures), but it ranges from 0.5 to 5% when therapeutic
procedures such as polypectomy, EMR, ESD, control of hemorrhage,
or stricture dilation are performed. The risk of adverse events for diag-
nostic EUS (without needle aspiration) is similar to that for diagnostic
upper endoscopy.
Infectious complications are uncommon with most endoscopic pro-
FIGURE 322-19 Bile leak (arrow) from a duct of Luschka after laparoscopic cedures. Some procedures carry a higher incidence of postprocedure
cholecystectomy. Contrast leaks from a small right intrahepatic duct into the
gallbladder fossa, then flows into the pigtail of a percutaneous drainage catheter. bacteremia, and prophylactic antibiotics may be indicated (Table 322-1).
Management of antithrombotic agents prior to endoscopic procedures
should take into account the procedural risk of hemorrhage, the agent,
endoscope or its accessories into or through the wall of the gastro- and the patient condition, as summarized in Table 322-2.
intestinal tract to perform diagnostic or therapeutic interventions.
PART 10

ERCP carries additional risks. Pancreatitis occurs in ~5% of patients

Some NOTES procedures, such as percutaneous endoscopic gas- undergoing the procedure, and young, anicteric patients with normal
trostomy (PEG) or endoscopic necrosectomy of pancreatic necrosis, ducts are at increased risk (up to 25%). Post-ERCP pancreatitis is
are well-established clinical procedures (Video V5-2); others such as usually mild and self-limited, but it may result in prolonged hospital-
peroral endoscopic myotomy (POEM) for achalasia (Fig. 322-22) and ization, surgery, diabetes, or death when severe. Significant bleeding
Disorders of the Gastrointestinal System

gastroparesis, peroral endoscopic tumorectomy (POET) (Fig. 322-23), occurs after endoscopic sphincterotomy in ~1% of cases. Ascending
and endoscopic full-thickness resection (EFTR) of gastrointestinal cholangitis, pseudocyst infection, duodenal perforation, and abscess
mural lesions (Fig. 322-24, Video V5-3), are emerging as minimally formation may occur as a result of ERCP.
invasive therapeutic options. NOTES is an area of continuing innova- Percutaneous gastrostomy tube placement during EGD is associated
tion and endoscopic research. with a 10–15% incidence of adverse events, most often wound infec-
tions. Fasciitis, pneumonia, bleeding (Fig. 322-29), buried bumper
■■ENDOSCOPIC RESECTION AND CLOSURE syndrome (Fig. 322-30), and colonic injury may result from gas-
TECHNIQUES trostomy tube placement.
Endoscopic mucosal resection (EMR) (Fig. 322-25, Video V5-4) and
endoscopic submucosal dissection (ESD) (Fig. 322-26, Video V5-5) URGENT ENDOSCOPY
are the two commonly used techniques for the resection of benign
and early-stage malignant gastrointestinal neoplasms. In addition to ■■ACUTE GASTROINTESTINAL HEMORRHAGE
providing larger specimens for more accurate histopathologic assess- Endoscopy is the primary diagnostic and therapeutic technique for
ment and diagnosis, these techniques can be potentially curative for patients with acute gastrointestinal hemorrhage. Although gastroin-
some dysplastic lesions and focal intramucosal carcinomas involving testinal bleeding stops spontaneously in most cases, some patients will

A B C
FIGURE 322-20 Local staging of gastrointestinal cancers with endoscopic ultrasound. In each example, the white arrowhead marks the primary tumor and the black arrow
indicates the muscularis propria (mp) of the intestinal wall. A. T1 gastric cancer. The tumor does not invade the mp. B. T2 esophageal cancer. The tumor invades the mp.
C. T3 esophageal cancer. The tumor extends through the mp into the surrounding tissue and focally abuts the aorta (AO).

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A B
FIGURE 322-21 Endoscopic ultrasound (EUS)–guided fine-needle aspiration (FNA). A. Ultrasound image of a 22-gauge needle passed through the duodenal wall and
positioned in a hypoechoic pancreatic head mass. B. Micrograph of aspirated malignant cells. (Image courtesy of Dr. Michael R. Henry.)

CHAPTER 322 Gastrointestinal Endoscopy

A B C

D E F

G H I

FIGURE 322-22 Peroral endoscopic myotomy (POEM) for achalasia. A. Dilated aperistaltic esophagus with retained secretions. B. Hypertonic lower esophageal sphincter
(LES) region. C. Mucosal incision (mucosotomy) 10 cm proximal to the LES. D. Submucosal dissection using an electrosurgical knife following endoscope entry through the
mucosotomy site into the submucosal space. E. Completion of submucosal tunnel to the cardia. F. Initiation of myotomy of the muscularis propria distal to the mucosotomy
site. G. Completion of myotomy to the cardia. H. Closure of mucosotomy site with clips. I. Patulous gastroesophageal junction following myotomy.

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A B
PART 10
Disorders of the Gastrointestinal System

C D

E F

G H
FIGURE 322-23 Peroral endoscopic tumorectomy (POET). A. Mid-esophageal subepithelial lesion (arrow). B. Mucosal incision (mucosotomy) 5 cm proximal to the
lesion. C. Submucosal dissection and tunneling to the site of the lesion. D. Dissection of the lesion from its attachment to the muscularis propria. E. Postresection defect
through the muscularis propria. F. Mucosotomy site. G. Closure of mucosotomy site with clips. H. Resected specimen (leiomyoma).

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A B

CHAPTER 322 Gastrointestinal Endoscopy

C D
FIGURE 322-24 Endoscopic full-thickness resection (EFTR) of a gastrointestinal stromal tumor. A. Subepithelial lesion in the proximal stomach. B. Hypoechoic lesion arising
from the fourth layer (muscularis propria) at endoscopic ultrasound. C. Full-thickness resection defect. D. Closure of defect using an over-the-scope clip.

have persistent or recurrent hemorrhage that may be life-threatening. of the magnitude of acute bleeding. Nasogastric tube aspiration and
Clinical predictors of rebleeding help identify patients most likely lavage can also be used to judge the severity of bleeding, but these are
to benefit from urgent endoscopy and endoscopic, angiographic, or no longer routinely performed for this purpose. The bedside initial
surgical hemostasis. evaluation, completed well before the bleeding source is confidently
identified, guides immediate supportive care of the patient, triage to
Initial Evaluation The initial evaluation of the bleeding patient the ward or intensive care unit, and timing of endoscopy. The severity
focuses on the severity of hemorrhage as reflected by the presence of of the initial hemorrhage is the most important indication for urgent
supine hypotension or tachycardia, postural vital sign changes, and endoscopy, since a large initial bleed increases the likelihood of ongo-
the frequency of hematemesis or melena. Decreases in hematocrit and ing or recurrent bleeding. Patients with resting hypotension or orthos-
hemoglobin lag behind the clinical course and are not reliable gauges tatic change in vital signs, repeated hematemesis, or bloody nasogastric

A B
FIGURE 322-25 Endoscopic mucosal resection (EMR). A. Large sessile polypoid fold in the transverse colon. B. Lifting of lesion following submucosal fluid injection.
C. Piecemeal hot snare resection. D. Initial resection site. E. Resection defect following completion of piecemeal EMR.

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C D
PART 10
Disorders of the Gastrointestinal System

E
FIGURE 322-25 (Continued)

A B
FIGURE 322-26 Endoscopic submucosal dissection (ESD). A. Large, flat, distal rectal adenoma. B. Circumferential incision following submucosal fluid injection at the
periphery of the lesion. C. ESD using an electrosurgical knife. D. Rectal defect following ESD. E. Specimen resected en bloc.

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 2401

C D

CHAPTER 322 Gastrointestinal Endoscopy

E
FIGURE 322-26 (Continued)

A B
FIGURE 322-27 Closure of large defect using an endoscopic suturing device. A. Ulcerated inflammatory fibroid polyp in the antrum. B. Large defect following endoscopic
submucosal dissection of the lesion. C. Closure of the defect using endoscopic sutures (arrows). D. Resected specimen.

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 2402

C D
FIGURE 322-27 (Continued)

aspirate that does not clear with large-volume lavage or those requiring with rapid intestinal transit. Early upper endoscopy should be consid-
blood transfusions should be considered for urgent endoscopy. In ered in such patients.
addition, patients with cirrhosis, coagulopathy, or respiratory or renal Endoscopy should be performed after the patient has been resus-
failure and those >70 years old are more likely to have significant citated with intravenous fluids and transfusions, as necessary. Marked
rebleeding and to benefit from prompt evaluation and treatment. coagulopathy or thrombocytopenia is usually treated before endos-
Bedside evaluation also suggests an upper or lower gastrointestinal copy, since correction of these abnormalities may lead to resolution of
source of bleeding in most patients. Over 90% of patients with melena bleeding, and techniques for endoscopic hemostasis are limited in such
are bleeding proximal to the ligament of Treitz, and ~85% of patients patients. Metabolic derangements should also be addressed. Tracheal
with hematochezia are bleeding from the colon. Melena can result from intubation for airway protection should be considered before upper
bleeding in the small bowel or right colon, especially in older patients endoscopy in patients with repeated recent hematemesis, particularly in
with slow colonic transit. Conversely, some patients with massive those with suspected variceal hemorrhage. A single dose of erythromy-
PART 10

hematochezia may be bleeding from an upper gastrointestinal source, cin (3–4 mg/kg or 250 mg) administered intravenously 30–90 min prior
Disorders of the Gastrointestinal System

B
A

C D

FIGURE 322-28 Prevention of stent migration using endoscopic sutures. A. Esophagogastric anastomotic stricture refractory to balloon dilation. B. Temporary placement of
a covered esophageal stent. C. Endoscopic suturing device to anchor the stent to the esophageal wall. D. Stent fixation with endoscopic sutures (arrows).

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 2403
TABLE 322-1 Antibiotic Prophylaxis for Endoscopic Procedures
PERIPROCEDURAL ANTIBIOTIC
PATIENT CONDITION PROCEDURE CONTEMPLATED GOAL OF PROPHYLAXIS PROPHYLAXIS
All cardiac conditions Any endoscopic procedure Prevention of infective endocarditis Not indicated
Bile duct obstruction in the absence of ERCP with complete drainage Prevention of cholangitis Not recommended
cholangitis
Bile duct obstruction in the absence of ERCP with anticipated incomplete Prevention of cholangitis Recommended; continue antibiotics
cholangitis drainage (e.g., sclerosing cholangitis, after the procedure
hilar strictures)
Sterile pancreatic fluid collection ERCP Prevention of cyst infection Recommended; continue antibiotics
(e.g., pseudocyst, necrosis), which after the procedure
communicates with pancreatic duct
Sterile pancreatic fluid collection Transmural drainage Prevention of cyst infection Recommended
Solid lesion along upper GI tract EUS-FNA Prevention of local infection Not recommendeda
Solid lesion along lower GI tract EUS-FNA Prevention of local infection Not recommendeda
Cystic lesions along GI tract (including EUS-FNA Prevention of cyst infection Recommended
mediastinum and pancreas)
All patients Percutaneous endoscopic feeding tube Prevention of peristomal infection Recommendedb
placement
Cirrhosis with acute GI bleeding Required for all such patients, Prevention of infectious complications Recommended, upon admissionc
regardless of endoscopic procedures and reduction of mortality
Continuous peritoneal dialysis Lower GI tract endoscopy Prevention of bacterial peritonitis Recommended
Synthetic vascular graft and other Any endoscopic procedure Prevention of graft and device infection Not recommendedd
nonvalvular cardiovascular devices
Prosthetic joints Any endoscopic procedure Prevention of septic arthritis Not recommendedd
a
Low rates of bacteremia and local infection. bCefazolin or an antibiotic with equivalent coverage of oral and skin flora. cRisk for bacterial infection associated with cirrhosis
and GI bleeding is well established; ceftriaxone or a quinolone antibiotic recommended. dVery low risk of infection.

CHAPTER 322 Gastrointestinal Endoscopy

Abbreviations: ERCP, endoscopic retrograde cholangiopancreatography; EUS-FNA, endoscopic ultrasound–fine-needle aspiration; GI, gastrointestinal.
Source: Reproduced with permission from MA Kashab et al: Antibiotic prophylaxis for GI endoscopy. Gastrointest Endosc 81:81, 2015.

to upper endoscopy increases gastric emptying and may clear blood and leads to endoscopic therapy to decrease the rebleeding rate. When
clots from the stomach to improve endoscopic visualization. active spurting from an ulcer is seen, there is a 90% risk of ongoing
Most patients with hematochezia who are otherwise stable can bleeding without endoscopic or surgical therapy.
undergo semielective colonoscopy. Controlled trials have not shown a Endoscopic therapy of ulcers with high-risk stigmata typically low-
benefit to urgent colonoscopy in patients hospitalized with hematoc- ers the rebleeding rate to 5–10%. Several hemostatic techniques are
hezia, although selected patients with massive or recurrent large-volume available, including injection of epinephrine or a sclerosant into and
episodes of hematochezia should probably undergo urgent colonoscopy around the vessel (Fig. 322-32), “coaptive coagulation” of the vessel in
after a rapid colonic purge with an oral polyethylene glycol solution. the base of the ulcer using a thermal probe that is pressed against the
Colonoscopy has a higher diagnostic yield than radionuclide bleeding site of bleeding (Fig. 322-33), placement of through-the-scope clips
scans or angiography in lower gastrointestinal bleeding, and endo- (Fig. 322-34) or an over-the-scope clip (Fig. 322-35), or a combination
scopic therapy can be applied in some cases. Urgent colonoscopy can of these modalities (Video V5-8). Epinephrine injection can slow or
be hindered by poor visualization due to persistent vigorous bleeding stop active bleeding, but it is not enough as a stand-alone technique
with recurrent hemodynamic instability, and other techniques (such as for definitive hemostasis. In conjunction with endoscopic therapy,
angiography or even emergent subtotal colectomy) must be employed. the administration of a proton pump inhibitor decreases the risk of
In such patients, massive bleeding originating from an upper gastro- rebleeding and improves patient outcome.
intestinal source should also be considered and excluded promptly by
upper endoscopy. The anal and rectal mucosa should also be visual- Varices Two complementary strategies guide therapy of bleeding
ized endoscopically early in the course of massive rectal bleeding, as varices: local treatment of the bleeding varices and treatment of the
bleeding lesions in or close to the anal canal may be identified that are underlying portal hypertension. Local therapies, including endoscopic
amenable to endoscopic or surgical transanal hemostatic techniques. variceal band ligation, endoscopic variceal sclerotherapy, stent place-
ment, and balloon tamponade with a Sengstaken-Blakemore tube,
Peptic Ulcer The endoscopic appearance of peptic ulcers provides effectively control acute hemorrhage in most patients, although ther-
useful prognostic information and guides the need for endoscopic apies that decrease portal pressure (pharmacologic treatment, surgical
therapy in patients with acute hemorrhage (Fig. 322-31). A clean- shunts, or radiologically placed intrahepatic portosystemic shunts) also
based ulcer is associated with a low risk (3–5%) of rebleeding; patients play an important role.
with melena and a clean-based ulcer may be discharged home from Endoscopic variceal ligation (EVL) is indicated for the prevention
the emergency room or endoscopy suite if they are young, reliable, of a first bleed (primary prophylaxis) from large esophageal varices
otherwise healthy, and able to return as needed. Flat pigmented spots (Fig. 322-36), particularly in patients in whom nonselective beta
and adherent clots covering the ulcer base have a 10% and 20% risk blockers are contraindicated or not tolerated. EVL is also the preferred
of rebleeding, respectively. Flat pigmented spots do not require treat- endoscopic therapy for control of active esophageal variceal bleeding
ment, but endoscopic therapy is generally applied to an ulcer with an and for subsequent eradication of esophageal varices (secondary pro-
adherent clot. When a fibrin plug is seen protruding from a vessel wall phylaxis). During EVL, a varix is suctioned into a cap fitted on the end
in the base of an ulcer (so-called sentinel clot or visible vessel), the risk of the endoscope, and a rubber band is released from the cap, ligating
of rebleeding from the ulcer approximates 40%. This finding typically the varix (Fig. 322-37, Video V5-9). EVL controls acute hemorrhage

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 2404
TABLE 322-2 Management of Antithrombotic Drugs Prior to Endoscopic Procedures
INTERVAL BETWEEN
BLEEDING RISK LAST DOSE AND
DRUG OF PROCEDURE MANAGEMENT PROCEDURE COMMENTS
Warfarin Lowa Continue N/A Ensure that INR is not supratherapeutic
Highb Discontinue 3–7 days (usually 5), Consider bridging therapy with heparinc; usually safe to
INR should be ≤1.5 for resume warfarin on the same or next day
procedure For life-threatening GI hemorrhage, consider reversal with
unactivated prothrombin complex concentrate
Dabigatran, rivaroxaban, Lowa Continue or hold N/A
apixaban, edoxaban morning dose on day of
procedure
Dabigatran Highb Discontinue 2–3 days if GFR is Bridging therapy not recommended; resume drug when
≥50 mL/min, 3–4 days if bleeding risk is low
GFR is 30–49 mL/min For life-threatening GI hemorrhage, consider use of a
reversal agent
Rivaroxaban, apixaban, Higha Discontinue 2 days if GFR is Bridging therapy not recommended; resume drug when
edoxaban ≥60 mL/min, 3 days if GFR bleeding risk is low
is 30–59 mL/min, 4 days if For life-threatening GI hemorrhage, consider use of a
GFR is <30 mL/min reversal agent
Heparin Lowa Continue N/A
Highb Discontinue 4–6 h for unfractionated Skip one dose if using low-molecular-weight heparin
heparin
Aspirin Any Continue N/A Low-dose aspirin does not substantially increase the risk of
endoscopic procedures
Aspirin with dipyridamole Lowa Continue N/A
Highb Discontinue 2–7 days Consider continuing aspirin monotherapy
P2Y12 receptor antagonists Lowa Continue N/A
(clopidogrel, prasugrel,
PART 10

ticlopidine, ticagrelor,
cangrelor)
Highb Coronary stent in place: 5 days (clopidogrel Risk of stent thrombosis for at least 12 months after
discuss with cardiologist or ticagrelor), 7 days insertion of drug-eluting coronary stent or 1 month after
(prasugrel), 10–14 days insertion of bare metal coronary stent
Disorders of the Gastrointestinal System

(ticlopidine)
No coronary stent:
discontinue, consider
substituting aspirin
a
Low-risk endoscopic procedures include esophagogastroduodenoscopy (EGD) or colonoscopy with or without biopsy, endoscopic ultrasound (EUS) without fine-needle
aspiration (FNA), and endoscopic retrograde cholangiopancreatography (ERCP) with stent exchange. bHigh-risk endoscopic procedures include EGD or colonoscopy with
dilation, polypectomy, or thermal ablation; percutaneous endoscopic gastrostomy (PEG); EUS with FNA; and ERCP with sphincterotomy or pseudocyst drainage. cBridging
therapy with low-molecular-weight heparin should be considered for patients discontinuing warfarin who are at high risk for thromboembolism, including those with (1)
atrial fibrillation with a CHA2DS2-VASc score ≥3, mechanical valve(s), or history of stroke or transient ischemic attack; (2) mechanical mitral valve; (3) mechanical aortic
valve with other thromboembolic risk factors or older-generation mechanical aortic valve; or (4) venous thromboembolism within the past 3 months.
Abbreviations: GFR, glomerular filtration rate; INR, international normalized ratio; N/A, not applicable.
Source: Adapted from RD Acosta et al: Gastrointest Endosc 83:3, 2016; and AM Veitch et al: Gut 65:374, 2016.

A B
FIGURE 322-29 Bleeding from percutaneous endoscopic gastrostomy (PEG) tube placement. A. Patient with melena from a recently placed PEG tube. B. Loosening of the
internal disk bumper of the PEG tube revealed active bleeding from within the PEG tract.

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 2405

A B
FIGURE 322-30 Buried bumper syndrome. A. Migration of the internal disk bumper of a percutaneous endoscopic gastrostomy (PEG) tube through the gastric wall.
B. Close-up view of the disk bumper (arrow) buried in the gastric wall.

in up to 90% of patients. Complications of EVL, such as postligation portal pressure have similar efficacy. The preferred strategy, however,

CHAPTER 322 Gastrointestinal Endoscopy

ulcer bleeding and esophageal stenosis, are uncommon. Endoscopic for secondary prophylaxis of variceal bleeding is the combination of
variceal sclerotherapy (EVS) involves the injection of a sclerosing, EVL with a nonselective beta blocker.
thrombogenic solution into or next to esophageal varices. EVS also
controls acute hemorrhage in most patients, but it is generally used as Dieulafoy’s Lesion This lesion, also called persistent caliber
salvage therapy when band ligation fails because of its higher compli- artery, is a large-caliber arteriole that runs immediately beneath the
cation rate. Bleeding from large gastric fundal varices (Fig. 322-38) is gastrointestinal mucosa and bleeds through a focal mucosal erosion
best treated with endoscopic cyanoacrylate (“glue”) injection (Video (Fig. 322-39). Dieulafoy’s lesion commonly involves the lesser curva-
V5-10), since EVL or EVS of these varices is associated with a high ture of the proximal stomach, causes impressive arterial hemorrhage,
rebleeding rate. Complications of cyanoacrylate injection include and may be difficult to diagnose when not actively bleeding; it is often
infection and glue embolization to other organs, such as the lungs, recognized only after repeated endoscopy for recurrent bleeding.
brain, and spleen. Endoscopic therapy, such as thermal coagulation, band ligation, clip
After treatment of the acute hemorrhage, an elective course of placement, or endoscopic suturing, is typically effective for control
endoscopic therapy can be undertaken with the goal of eradicating of bleeding and sealing of the underlying vessel once the lesion has
esophageal varices and preventing rebleeding months to years later. been identified (Video V5-11). Rescue therapies, such as angiographic
However, this chronic therapy is less successful, preventing long-term embolization or surgical oversewing, are considered in situations
rebleeding in ~50% of patients. Pharmacologic therapies that decrease where endoscopic therapy has failed.

A B
FIGURE 322-31 Stigmata of hemorrhage in peptic ulcers. A. Gastric antral ulcer with a clean base. B. Duodenal ulcer with flat pigmented spots (arrows). C. Duodenal ulcer
with a dense adherent clot. D. Duodenal ulcer with a pigmented protuberance/visible vessel. E. Duodenal ulcer with active spurting (arrow).

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 2406

C D
PART 10
Disorders of the Gastrointestinal System

E
FIGURE 322-31 (Continued)

Mallory-Weiss Tear A Mallory-Weiss tear is a linear mucosal rent

near or across the gastroesophageal junction that is often associated
with retching or vomiting (Fig. 322-40). When the tear disrupts a
submucosal arteriole, brisk hemorrhage may result. Endoscopy is the
best method for diagnosis, and an actively bleeding tear can be treated
endoscopically with coaptive coagulation, band ligation, or hemoclips,
with or without epinephrine injection (Video V5-12). Unlike peptic
ulcer, a Mallory-Weiss tear with a nonbleeding sentinel clot in its base
rarely rebleeds and thus does not necessitate endoscopic therapy.
Vascular Ectasias Vascular ectasias are flat mucosal vascular
anomalies that are best diagnosed by endoscopy. They usually cause
slow intestinal blood loss and occur either in a sporadic fashion or in a
well-defined pattern of distribution (e.g., gastric antral vascular ectasia
[GAVE] or “watermelon stomach”) (Fig. 322-41). Cecal vascular ecta-
sias, GAVE, and radiation-induced rectal ectasias are often responsive
to local endoscopic ablative therapy, such as argon plasma coagulation
(Video V5-13). Patients with diffuse small-bowel vascular ectasias
(associated with chronic renal failure and with hereditary hemorrhagic
telangiectasia) may continue to bleed despite endoscopic treatment of
easily accessible lesions by conventional endoscopy. These patients may
benefit from device-assisted enteroscopy with endoscopic hemostasis
or pharmacologic therapy, such as octreotide or low-dose thalidomide,
FIGURE 322-32 Injection therapy for ulcer hemostasis. Epinephrine injection into a in those who continue to bleed despite endoscopic therapy.
duodenal ulcer with visible vessel (arrow) and adherent clot.

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A B

CHAPTER 322 Gastrointestinal Endoscopy

C
FIGURE 322-33 Contact coagulation for ulcer hemostasis. A. Duodenal ulcer with a visible vessel (arrow). B. Coagulation of the vessel with a contact thermal probe.
C. Obliteration of the treated vessel (arrow).

A B
FIGURE 322-34 Through-the-scope clip placement for ulcer hemostasis. A. Superficial duodenal ulcer with visible vessel (arrow). B. Hemostasis secured following
placement of multiple through-the-scope clips.

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 2408

A
PART 10

B
FIGURE 322-35 Over-the-scope clip placement for ulcer hemostasis. A. Pyloric
channel ulcer with visible vessel (arrow). B. Hemostasis secured following
Disorders of the Gastrointestinal System

placement of an over-the-scope clip.

Colonic Diverticula Diverticula form where nutrient arteries

penetrate the muscular wall of the colon en route to the colonic mucosa
(Fig. 322-42). The artery found in the base of a diverticulum may
bleed, causing painless and impressive hematochezia. Colonoscopy
is indicated in patients with hematochezia and suspected diverticular
hemorrhage, since other causes of bleeding (such as vascular ectasias, B
colitis, and colon cancer) must be excluded. In addition, an actively FIGURE 322-37 Endoscopic variceal ligation. A. Esophageal varices with red wale
bleeding diverticulum may be seen and treated during colonoscopy marks. B. Band ligation of varices.
(Fig. 322-43, Video V5-14).
■■GASTROINTESTINAL OBSTRUCTION AND or treated endoscopically. Esophageal, gastroduodenal, and colonic
PSEUDOOBSTRUCTION obstruction or pseudoobstruction can all be diagnosed and often man-
Endoscopy is useful for evaluation and treatment of some forms of aged endoscopically.
gastrointestinal obstruction. An important exception is small-bowel
obstruction due to surgical adhesions, which is generally not diagnosed Acute Esophageal Obstruction Esophageal obstruction by
impacted food (Fig. 322-44) or an ingested foreign body (Fig. 322-45)
is a potentially life-threatening event and represents an endoscopic
emergency. Left untreated, the patient may develop esophageal ulcer-
ation, ischemia, and perforation. Patients with persistent esophageal
obstruction often have hypersalivation and are usually unable to
swallow water. Sips of a carbonated beverage, sublingual nifedipine
or nitrates, or intravenous glucagon may resolve an esophageal food
impaction, but in many patients, an underlying web, ring, or stricture is
present, and endoscopic removal of the obstructing food bolus is nec-
essary. Endoscopy is generally the best initial test in such patients since
endoscopic removal of the obstructing material is usually possible, and
the presence of an underlying esophageal pathology can often be deter-
mined. Radiographs of the chest and neck should be considered before
endoscopy in patients with fever, obstruction for ≥24 h, or ingestion of
a sharp object, such as a fishbone. Radiographic contrast studies inter-
fere with subsequent endoscopy and are not advisable in most patients
FIGURE 322-36 Esophageal varices. with a clinical picture of esophageal obstruction.

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 2409

A B
FIGURE 322-38 Gastric varices. A. Large gastric fundal varices. B. Stigmata of recent bleeding from the same gastric varices (arrow).

CHAPTER 322 Gastrointestinal Endoscopy

A B

C D
FIGURE 322-39 Dieulafoy’s lesion. A. Actively spurting gastric Dieulafoy’s lesion. B. Coagulation of the lesion using a contact thermal probe. C. Hemostasis secured
following contact coagulation (arrow). D. Histology of a gastric Dieulafoy’s lesion. A persistent caliber artery (arrows) is present in the gastric submucosa, immediately
beneath the mucosa.

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 2410 bowel preparation for an elective one-stage operation (Fig. 322-49,
Video V5-17).
■■ACUTE BILIARY OBSTRUCTION
The steady, severe pain that occurs when a gallstone acutely obstructs the
common bile duct often brings patients to a hospital. The diagnosis of a
ductal stone is suspected when the patient is jaundiced or when serum
liver tests or pancreatic enzyme levels are elevated; it is confirmed by
EUS, magnetic resonance cholangiopancreatography (MRCP), or direct
cholangiography (performed endoscopically, percutaneously, or during
surgery). ERCP is the primary means of treating common bile duct
stones (Figs. 322-16 and 322-17), although they can also be removed by
bile duct exploration at the time of cholecystectomy. Radiologic percu-
taneous biliary drainage may be required in some cases.
Bile Duct Imaging While transabdominal ultrasound diagnoses
only a minority of bile duct stones, MRCP and EUS are >90% accurate
and have an important role in diagnosis. Examples of these modalities
are shown in Fig. 322-50.
If the suspicion for a bile duct stone is high and urgent treatment is
required (as in a patient with obstructive jaundice and biliary sepsis),
ERCP is the procedure of choice since it remains the gold standard
for diagnosis and allows for immediate treatment (Video V5-18). If a
FIGURE 322-40 Mallory-Weiss tear at the gastroesophageal junction.
persistent bile duct stone is relatively unlikely (as in a patient with gall-
stone pancreatitis), ERCP may be supplanted by less invasive imaging
Gastric Outlet Obstruction Obstruction of the gastric outlet is techniques, such as EUS, MRCP, or intraoperative cholangiography
commonly caused by gastric, duodenal, or pancreatic malignancy or performed during cholecystectomy, sparing some patients the risk and
chronic peptic ulceration with stenosis of the pylorus (Fig. 322-46). discomfort of ERCP.
Patients vomit partially digested food many hours after eating. Gas- Ascending Cholangitis Charcot’s triad of jaundice, abdominal
tric decompression with a nasogastric tube and subsequent lavage for pain, and fever is present in ~70% of patients with ascending cholan-
PART 10

removal of retained material is the first step in treatment. Endoscopy is gitis and biliary sepsis. These patients are managed initially with fluid
useful for diagnosis and treatment. Patients with benign pyloric steno- resuscitation and intravenous antibiotics. Abdominal ultrasound is
sis may be treated with endoscopic balloon dilation of the pylorus, and often performed to assess for gallbladder stones and bile duct dila-
a course of endoscopic dilation results in long-term relief of symptoms tion. However, the bile duct may not be dilated early in the course of
in ~50% of patients. Removable, fully covered lumen-apposing metal
Disorders of the Gastrointestinal System

acute biliary obstruction. Medical management usually improves the

stents (LAMS) may also be used to treat benign pyloric stenosis (Video patient’s clinical status, providing a window of ~24 h during which
V5-15). Malignant gastric outlet obstruction can be relieved with biliary drainage should be established, typically by ERCP. Undue delay
endoscopically placed expandable stents in patients with inoperable can result in recrudescence of overt sepsis and increased morbidity and
malignancy (Video V5-16). mortality rates. In addition to Charcot’s triad, the additional presence
Colonic Obstruction and Pseudoobstruction These con- of shock and confusion (Reynolds’s pentad) is associated with a high
ditions both present with abdominal distention and discomfort, mortality rate and should prompt urgent intervention to restore biliary
tympany, and a dilated colon on plain abdominal radiography. The drainage.
radiographic appearance may be characteristic of a particular condi- Gallstone Pancreatitis Gallstones may cause acute pancreatitis
tion, such as sigmoid volvulus (Fig. 322-47). Both obstruction and as they pass through the ampulla of Vater. The occurrence of gallstone
pseudoobstruction may lead to colonic perforation if left untreated. pancreatitis usually implies passage of a stone into the duodenum, and
Acute colonic pseudoobstruction is a form of colonic ileus that is only ~20% of patients harbor a persistent stone in the ampulla or the
usually attributable to electrolyte disorders, narcotic and anticholin- common bile duct. Retained stones are more common in patients with
ergic medications, immobility (as after surgery), or retroperitoneal jaundice, rising serum liver tests following hospitalization, severe pan-
hemorrhage or mass. Multiple causative factors are often present. creatitis, or superimposed ascending cholangitis.
Colonoscopy, water-soluble contrast enema, or CT may be used to Urgent ERCP decreases the morbidity rate of gallstone pancreati-
assess for an obstructing lesion and differentiate obstruction from tis in a subset of patients with retained bile duct stones. It is unclear
pseudoobstruction. One of these diagnostic studies should be strongly whether the benefit of ERCP is mainly attributable to treatment and
considered if the patient does not have clear risk factors for pseu- prevention of ascending cholangitis or to relief of pancreatic ductal
doobstruction, if radiographs do not show air in the rectum, or if the obstruction. ERCP is warranted early in the course of gallstone pan-
patient fails to improve when underlying causes of pseudoobstruction creatitis if ascending cholangitis is suspected, especially in a jaundiced
have been addressed. The risk of cecal perforation in pseudoobstruc- patient. Urgent ERCP may also benefit patients predicted to have
tion rises when the cecal diameter exceeds 12 cm, and decompres- severe pancreatitis using a clinical index of severity, such as the Glas-
sion of the colon may be achieved using intravenous neostigmine or gow or Ranson score. Since the benefit of ERCP is limited to patients
via colonoscopic decompression (Fig. 322-48). Most patients should with a retained bile duct stone, a strategy of initial MRCP or EUS for
receive a trial of conservative therapy (with correction of electrolyte diagnosis decreases the utilization of ERCP in gallstone pancreatitis
disorders, removal of offending medications, and increased mobili- and improves clinical outcomes by limiting the occurrence of ERC-
zation) before undergoing an invasive decompressive procedure for P-related adverse events.
colonic pseudoobstruction.
Colonic obstruction is an indication for urgent intervention. In ELECTIVE ENDOSCOPY
the past, emergent diverting colostomy was usually performed with
a subsequent second operation after bowel preparation to treat the ■■DYSPEPSIA
underlying cause of obstruction. Colonoscopic placement of an Dyspepsia is a chronic or recurrent burning discomfort or pain in
expandable stent is an alternative treatment option that can relieve the upper abdomen that may be caused by diverse processes, such as
malignant colonic obstruction without emergency surgery and permit gastroesophageal reflux, peptic ulcer disease, and “nonulcer dyspepsia,”

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 2411

A B

CHAPTER 322 Gastrointestinal Endoscopy

C

FIGURE 322-41 Gastrointestinal vascular ectasias. A. Gastric antral vascular ectasia (“watermelon stomach”) characterized by stripes of prominent flat or raised vascular
ectasias. B. Cecal vascular ectasia. C. Radiation-induced vascular ectasias of the rectum in a patient previously treated for prostate cancer.

a heterogeneous category that includes disorders of motility, sensa- reflux without esophagitis. The most sensitive test for diagnosis of
tion, and somatization. Gastric and esophageal malignancies are less gastroesophageal reflux disease (GERD) is 24-h ambulatory pH moni-
common causes of dyspepsia. Careful history-taking allows accurate toring. Endoscopy is indicated in patients with reflux symptoms refrac-
differential diagnosis of dyspepsia in only about half of patients. In tory to antisecretory therapy; in those with alarm symptoms, such as
the remainder, endoscopy can be a useful diagnostic tool, especially dysphagia, weight loss, or gastrointestinal bleeding; and in those with
in patients whose symptoms are not resolved by Helicobacter pylori recurrent dyspepsia after treatment that is not clearly due to reflux on
treatment or an empirical trial of acid-reducing therapy. Endoscopy clinical grounds alone. Endoscopy should be considered in patients
should be performed at the outset in patients with dyspepsia and alarm with long-standing (≥10 years) GERD, as they have a sixfold increased
features, such as weight loss, obstructive symptoms, or iron-deficiency risk of harboring Barrett’s esophagus compared to patients with <1 year
anemia. of reflux symptoms.
■■GASTROESOPHAGEAL REFLUX DISEASE Barrett’s Esophagus and Esophageal Squamous Dysplasia
When classic symptoms of gastroesophageal reflux are present, such Barrett’s esophagus is specialized columnar metaplasia that replaces
as water brash and substernal heartburn, presumptive diagnosis and the normal squamous mucosa of the distal esophagus in some persons
empirical treatment are often sufficient. Endoscopy is a sensitive test with GERD. Barrett’s epithelium is a major risk factor for adenocarci-
for diagnosis of esophagitis (Fig. 322-51), but it will miss nonero- noma of the esophagus and is readily detected endoscopically, due to
sive reflux disease (NERD) since some patients have symptomatic proximal displacement of the squamocolumnar junction (Fig. 322-6).

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 2412

FIGURE 322-42 Colonic diverticula. A

A screening EGD for Barrett’s esophagus should be considered in

patients with a chronic (≥10 year) history of GERD symptoms. Endo-
scopic biopsy is the gold standard for confirmation of Barrett’s esopha-
gus and for dysplasia or cancer arising in Barrett’s mucosa.
Periodic EGD with biopsies is recommended for surveillance of
patients with Barrett’s esophagus. Endoscopic resection (EMR or ESD)
PART 10

and/or ablation are performed when high-grade dysplasia or intra-

mucosal cancer are found in the Barrett’s mucosa. Both endoscopic
therapy and periodic surveillance are acceptable options in patients
with Barrett’s esophagus and low-grade dysplasia. Radiofrequency
Disorders of the Gastrointestinal System

ablation (RFA) is the most common ablative modality used for endo-
scopic treatment of Barrett’s esophagus, and other modalities, such as
cryotherapy, are also available.
Esophageal squamous dysplasia is the precursor lesion of esopha-
geal squamous cell cancer (ESCC), the most common type of esoph-
ageal malignancy worldwide. Endoscopic detection of esophageal
squamous dysplasia often requires specialized imaging methods,
such as chromoendoscopy with Lugol’s iodine. Once detected, it can B
be treated endoscopically with EMR, ESD, or RFA (Fig. 322-52).
Population-based screening for esophageal squamous dysplasia has
been shown to decrease the occurrence of ESCC in high-incidence
regions.

■■PEPTIC ULCER
Peptic ulcer classically causes epigastric gnawing or burning, often
occurring nocturnally and promptly relieved by food or antacids.
Although endoscopy is the most sensitive diagnostic test for peptic
ulcer, it is not a cost-effective strategy in young patients with ulcer-like
dyspeptic symptoms unless endoscopy is available at low cost. Patients
with suspected peptic ulcer should be evaluated for H. pylori infection.
Serology (past or present infection), urea breath testing (current infec-
tion), and stool tests are noninvasive and less costly than endoscopy
with biopsy. Patients aged >50 and those with alarm symptoms or
persistent symptoms despite treatment should undergo endoscopy to
exclude malignancy.

■■NONULCER DYSPEPSIA
Nonulcer dyspepsia may be associated with bloating and, unlike peptic
ulcer, tends not to remit and recur. Most patients describe persistent C
symptoms despite acid-reducing, prokinetic, or anti-Helicobacter ther-
apy and are referred for endoscopy to exclude a refractory ulcer and FIGURE 322-43 Diverticular hemorrhage. A. Actively bleeding sigmoid diverticulum.
assess for other causes. Although endoscopy is useful for excluding B. Treatment of the bleeding vessel at the dome of the diverticulum with a contact
other diagnoses, its impact on the treatment of patients with nonulcer thermal probe. C. Hemostasis secured following contact coagulation with tattoo
dyspepsia is limited. injection to aid future localization.

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 2413

FIGURE 322-44 Esophageal food impaction. Meat bolus impacted in the distal
esophagus.

■■DYSPHAGIA
About 50% of patients presenting with difficulty swallowing have a
mechanical obstruction; the remainder has a motility disorder, such
as achalasia or diffuse esophageal spasm. Careful history-taking often

CHAPTER 322 Gastrointestinal Endoscopy

points to a presumptive diagnosis and leads to the appropriate use of
diagnostic tests. Esophageal strictures (Fig. 322-53) typically cause
progressive dysphagia, first for solids, then for liquids; motility dis-
orders often cause intermittent dysphagia for both solids and liquids. B
Some underlying disorders have characteristic historic features: Schatzki’s
ring (Fig. 322-54) causes episodic dysphagia for solids, typically at the
beginning of a meal; oropharyngeal motor disorders typically present
with difficulty initiating deglutition (transfer dysphagia) and nasal
reflux or coughing with swallowing; and achalasia may cause nocturnal
regurgitation of undigested food.
When mechanical obstruction is suspected, endoscopy is a useful
initial diagnostic test, since it permits immediate biopsy and/or dila-
tion of strictures, masses, or rings. The presence of linear furrows
and multiple corrugated rings throughout a narrowed esophagus should
raise suspicion for eosinophilic esophagitis, an increasingly recognized
cause of recurrent dysphagia and food impaction (Fig. 322-55). Blind

FIGURE 322-46 Gastric outlet obstruction due to pyloric stenosis. A. Nonsteroidal

anti-inflammatory agent–induced ulcer disease with severe stenosis of the pylorus
(arrow). B. Balloon dilation of the stenosis. C. Appearance of pyloric ring after
dilation.

or forceful passage of an endoscope may lead to perforation in a patient

with stenosis of the cervical esophagus or a Zenker’s diverticulum
(Fig. 322-56), but gentle passage of an endoscope under direct visual
guidance is reasonably safe. Endoscopy can miss a subtle stricture or
ring in some patients.
When transfer dysphagia is evident or an esophageal motility disor-
der is suspected, esophageal radiography and/or a video-swallow study
are the best initial diagnostic tests. The oropharyngeal swallowing
mechanism, esophageal peristalsis, and the lower esophageal sphincter
can all be assessed. In some disorders, subsequent esophageal manom-
etry is required for diagnosis.
FIGURE 322-45 Esophageal foreign body. Intentionally ingested toothbrush Various causes of dysphagia are amenable to endoscopic ther-
impacted in the esophageal lumen. apy. Benign strictures, rings, and webs can be dilated using a

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 2414

FIGURE 322-47 Sigmoid volvulus with the characteristic radiologic appearance of

a “bent inner tube.”

through-the-scope balloon (Fig. 322-57) or a polyvinyl dilator passed

over a guide wire. In some instances, fibrotic strictures may respond to
needle-knife electroincision (Fig. 322-58) when they prove refractory
to dilation. Self-expanding esophageal stents can be used to palliate
dysphagia from malignant obstruction (Fig. 322-59), and flexible
PART 10

endoscopic myotomy is an option for Zenker’s diverticulum (Video

V5-19). Recent advances in submucosal endoscopy have enabled the
development of procedures, such as POEM (Video V5-20) and POET
(Video V5-21), for the management of achalasia and select subepithe-
lial esophageal tumors, respectively.
Disorders of the Gastrointestinal System

B
■■ENDOSCOPIC TREATMENT OF OBESITY
A significant proportion of Americans are overweight or obese,
and obesity-associated diabetes has become a major public health

A C

FIGURE 322-49 Obstructing colonic carcinoma. A. Colonic adenocarcinoma

causing marked luminal narrowing of the distal transverse colon. B. Endoscopic
placement of a self-expandable metal stent. C. Radiograph of expanded stent
across the obstructing tumor with a residual waist (arrow).

problem. Bariatric surgery is the most effective weight-loss inter-

vention, decreasing long-term mortality in obese persons, but many
patients do not undergo surgery. Endoscopic treatments for obesity
have been developed and include insertion of an intragastric balloon
or duodenojejunal bypass liner, placement of a percutaneous gastric
tube for aspiration of gastric contents after meals, or endoscopic sleeve
B gastroplasty, which utilizes endoscopic suturing to narrow the lumen
FIGURE 322-48 Acute colonic pseudoobstruction. A. Acute colonic dilation of the gastric body (Video V5-22). Prospective trials show that these
occurring in a patient soon after knee surgery. B. Colonoscopic placement of treatments induce total-body weight loss of 7–20% and provide vary-
decompression tube with marked improvement in colonic dilation. ing degrees of glycemic control. Additional endoscopic modalities are

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CHAPTER 322 Gastrointestinal Endoscopy

A B C

FIGURE 322-50 Methods of bile duct imaging. Arrows mark bile duct stones. A. Endoscopic ultrasound (EUS). B. Magnetic resonance cholangiopancreatography (MRCP).
C. Helical computed tomography (CT).

A B

C D
FIGURE 322-51 Causes of esophagitis. A. Severe reflux esophagitis with mucosal ulceration and friability. B. Cytomegalovirus esophagitis. C. Herpes simplex virus
esophagitis with target-type shallow ulcerations. D. Candida esophagitis with white plaques adherent to the esophageal mucosa.

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A B
PART 10
Disorders of the Gastrointestinal System

C D

FIGURE 322-52 Early squamous cell cancer. A. Nodularity in the distal esophagus due to T1 esophageal squamous cell cancer. B. Lesion is unstained under Lugol’s iodine
chromoendoscopy without additional unstained areas. C. Circumferential mucosal incision around the lesion. D. Resection defect following en bloc removal of the lesion
via endoscopic submucosal dissection.

undergoing clinical trials. The long-term efficacy of endoscopic bariat- 322-59, and 322-60; Videos V5-16 and V5-17), and malignant gastro-
ric treatment in comparison to surgery is still unclear. intestinal bleeding can often be palliated endoscopically as well. EUS-
guided celiac plexus neurolysis may relieve pancreatic cancer pain.
■■TREATMENT OF MALIGNANCIES
Endoscopy plays an important role in the treatment of gastrointestinal ■■ANEMIA AND OCCULT BLOOD IN THE STOOL
malignancies. Early-stage malignancies limited to the mucosal and Iron-deficiency anemia may be attributed to poor iron absorption
superficial submucosal layers may be resected using the techniques (as in celiac sprue) or, more commonly, chronic blood loss. Intestinal
of EMR (Video V5-4) or ESD (Video V5-5). RFA and cryotherapy are bleeding should be strongly suspected in men and postmenopausal
effective modalities for ablative treatment of high-grade dysplasia and women with iron-deficiency anemia, and colonoscopy is indicated in
intramucosal cancer in Barrett’s esophagus (Video V5-23). Gastroin- such patients, even in the absence of detectable occult blood in the
testinal stromal tumors can be removed en bloc by EFTR (Video V5-3). stool. Approximately 30% will have large colonic polyps or colorectal
In general, endoscopic techniques offer the advantage of a minimally cancer, and a few patients will have colonic vascular lesions. When a
invasive approach to treatment but rely on other imaging techniques convincing source of blood loss is not found in the colon, upper gas-
(such as CT, MRI, positron emission tomography [PET], and EUS) to trointestinal endoscopy should be considered; if no lesion is found,
exclude distant metastases or locally advanced disease better treated by duodenal biopsies should be obtained to exclude sprue (Fig. 322-61).
surgery or other modalities. The decision to treat an early-stage gas- Small-bowel evaluation with capsule endoscopy (Fig. 322-62), CT or
trointestinal malignancy endoscopically is often made in collaboration magnetic resonance (MR) enterography, or device-assisted enteroscopy
with a surgeon and/or oncologist. may be appropriate if both EGD and colonoscopy are unrevealing.
Endoscopic palliation of gastrointestinal malignancies relieves Tests for occult blood in the stool detect hemoglobin or the heme
symptoms and, in many cases, prolongs survival. Malignant obstruc- moiety and are most sensitive for colonic blood loss, although they will
tion can be relieved by endoscopic stent placement (Figs. 322-18, 322-49, also detect larger amounts of upper gastrointestinal bleeding. Patients

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FIGURE 322-53 Peptic esophageal stricture associated with esophagitis.

FIGURE 322-55 Eosinophilic esophagitis. Multiple circular rings of the esophagus
creating a corrugated appearance and an impacted grape at the narrowed
with occult blood in the stool should undergo colonoscopy to diagnose esophagogastric junction. The diagnosis requires biopsy with histologic finding of
or exclude colorectal neoplasia, especially if they are >50 years old or >15–20 eosinophils/high-power field.
have a family history of colonic neoplasia. Whether upper endoscopy
is also indicated depends on the patient’s symptoms.
The small intestine may be the source of chronic intestinal bleeding, and family history. Individuals with inflammatory bowel disease, a his-

CHAPTER 322 Gastrointestinal Endoscopy

especially if colonoscopy and upper endoscopy are not diagnostic. tory of colorectal polyps or cancer, family members with adenomatous
The utility of small-bowel evaluation varies with the clinical setting polyps or cancer, or certain familial cancer syndromes (Fig. 322-64)
and is most important in patients in whom bleeding causes chronic are at increased risk for colorectal cancer. An individual without these
or recurrent anemia. In contrast to the low diagnostic yield of small- factors is generally considered at average risk.
bowel radiography, positive findings on capsule endoscopy are seen in Screening strategies are summarized in Table 322-3. While fecal
50–70% of patients with suspected small-intestinal bleeding. The most immunochemical tests (FIT) for heme or stool tests for occult blood
common finding is mucosal vascular ectasia. CT and MR enterography have been shown to decrease the mortality rate from colorectal cancer,
accurately detect small-bowel masses and Crohn’s disease and are also they do not detect some cancers and many polyps. FIT-DNA multitar-
useful for initial small-bowel evaluation. Deep enteroscopy may follow geted stool DNA tests appear to be more sensitive, but direct visualiza-
capsule endoscopy for biopsy of lesions or to provide specific therapy, tion of the colon is the gold standard method for detection of polyps
such as argon plasma coagulation of vascular ectasias (Fig. 322-63). and cancers and remains a preferred screening strategy. Sigmoidoscopy
is also used for colorectal cancer screening. However, the distribution
■■COLORECTAL CANCER SCREENING of colon cancers has changed in the United States over time, with
The majority of colon cancers develop from preexisting colonic ade- proportionally fewer rectal and left-sided cancers than in the past.
nomas, and colorectal cancer can be largely prevented by the detection Large American studies of colonoscopy for screening of average-risk
and removal of adenomatous polyps (Video V5-24). The choice of individuals show that cancers are roughly equally distributed between
screening strategy for an asymptomatic person depends on personal the left and right colon and half of patients with right-sided lesions
have no polyps in the left colon. Visualization of the entire colon thus
appears to be the optimal strategy for colorectal cancer screening and
prevention.
Computed tomography colonography (CTC) is a radiologic tech-
nique that images the colon with CT following rectal insufflation of
the colonic lumen. Computer rendering of CT images generates an
electronic display of a virtual “flight” along the colonic lumen, simu-
lating colonoscopy (Fig. 322-65). Findings detected during CTC often
require subsequent conventional colonoscopy for confirmation and
treatment.
■■DIARRHEA
Most cases of diarrhea are acute, self-limited, and due to infections or
medication. Chronic diarrhea (lasting >6 weeks) is more often due to a
primary inflammatory, malabsorptive, or motility disorder; is less likely
to resolve spontaneously; and generally requires diagnostic evaluation.
Patients with chronic diarrhea or severe, unexplained acute diarrhea
often undergo endoscopy if stool tests for pathogens are unrevealing.
The choice of endoscopic testing depends on the clinical setting.
Patients with colonic symptoms and findings such as bloody
diarrhea, tenesmus, fever, or leukocytes in stool generally undergo
sigmoidoscopy or colonoscopy to assess for colitis (Fig. 322-9). Sig-
moidoscopy is an appropriate initial test in most patients. Conversely,
FIGURE 322-54 Schatzki’s ring at the gastroesophageal junction. patients with symptoms and findings suggesting small-bowel disease,

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 2418

A B
PART 10
Disorders of the Gastrointestinal System

C D

FIGURE 322-56 Zenker’s diverticulum. A. Contrast esophagography demonstrates a moderate-sized Zenker’s diverticulum. B. Endoscopic view of the Zenker’s diverticulum
(left) relative to the true esophageal lumen (right) separated by the diverticular septum. C. Flexible endoscopic diverticulotomy using an electrosurgical knife. D. Appearance
post diverticulotomy.

A B C

FIGURE 322-57 Endoscopic management of peptic stricture. A. Peptic stricture. B. Through-the-scope balloon dilation of stricture. C. Improvement in luminal diameter after dilation.

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A B C
FIGURE 322-58 Endoscopic management of an esophagogastric anastomotic stricture. A. Recurrent anastomotic stricture despite periodic balloon dilation. B. Needle-knife
electroincision of stricture. C. Improvement in luminal opening after therapy.

such as large-volume watery stools, substantial weight loss, and malab- immunoglobulin G subclass 4 levels; abdominal ultrasonography; and
sorption of iron, calcium, or fat, may undergo upper endoscopy with CT or MRI). Endoscopic assessment leads to a specific diagnosis in the
duodenal aspirates for assessment of bacterial overgrowth and biopsies majority of such patients, often altering clinical management. Endo-
for assessment of mucosal diseases, such as celiac sprue. scopic investigation is particularly appropriate if the patient has had
Many patients with chronic diarrhea do not fit either of these pat- more than one episode of pancreatitis.
terns. In the setting of a long-standing history of alternating constipa- Microlithiasis, or the presence of microscopic crystals in bile, is
tion and diarrhea dating to early adulthood, without findings such as a leading cause of previously unexplained acute pancreatitis and is
blood in the stool or anemia, a diagnosis of irritable bowel syndrome sometimes seen during abdominal ultrasonography as layering sludge
may be made without direct visualization of the bowel. Steatorrhea and or flecks of floating, echogenic material in the gallbladder. EUS may

CHAPTER 322 Gastrointestinal Endoscopy

upper abdominal pain may prompt evaluation of the pancreas rather identify previously undetected microlithiasis.
than the gut. Patients whose chronic diarrhea is not easily categorized Previously undetected chronic pancreatitis, pancreatic malignancy,
often undergo initial colonoscopy to examine the entire colon and or pancreas divisum may be diagnosed by either ERCP or EUS. Auto-
terminal ileum for inflammatory or neoplastic disease (Fig. 322-66). immune pancreatitis is often suspected based on CT, MRI, or serologic
findings, but it may first become apparent during EUS and may require
■■MINOR HEMATOCHEZIA EUS-guided pancreatic biopsy for histologic diagnosis.
Bright red blood passed with or on formed brown stool usually has an Severe pancreatitis often results in pancreatic fluid collections.
anal, rectal, or sigmoid source (Fig. 322-67). Even trivial amounts of Symptomatic pseudocysts and areas of walled-off pancreatic necro-
hematochezia should be investigated with colonoscopy and/or flexible sis can be drained into the stomach or duodenum endoscopically,
sigmoidoscopy together with anoscopy to exclude polyps or cancers, using transpapillary and transmural endoscopic techniques. Pancreatic
especially in patients >40 years old and those with a personal or family necrosis can be debrided by direct endoscopic necrosectomy (Video
history of colorectal polyps or cancer. Patients reporting red blood V5-2) via an endoscopically created transmural drainage site.
on the toilet tissue only, without blood in the toilet or on the stool,
are generally bleeding from a lesion in the anal canal; careful external
inspection, digital examination, and sigmoidoscopy with anoscopy ■■CANCER STAGING
may be sufficient for diagnosis in such cases. Local staging of esophageal, gastric, pancreatic, bile duct, and rectal
cancers can be obtained with EUS (Fig. 322-20). EUS with fine-needle
■■PANCREATITIS aspiration (Fig. 322-21) currently provides the most accurate preopera-
About 20% of patients with pancreatitis have no identified cause tive assessment of local tumor and nodal staging, but it does not detect
after routine clinical investigation (including a review of medication many distant metastases. Details of the local tumor stage can guide
and alcohol use; measurement of serum triglyceride, calcium, and treatment decisions including resectability and need for neoadjuvant

A B
FIGURE 322-59 Palliation of malignant dysphagia. A. Obstructing distal esophageal cancer. B. Palliative stent placement.

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 2420

A B
PART 10
Disorders of the Gastrointestinal System

C D

FIGURE 322-60 Placement of biliary and duodenal self-expanding metal stents (SEMS) for obstruction caused by pancreatic cancer. A. Endoscopic retrograde
cholangiopancreatography (ERCP) demonstrates a distal bile duct stricture (arrow). B. A biliary SEMS is placed. C. Contrast injection demonstrates a duodenal stricture
(arrow). D. Biliary and duodenal SEMS in place.

therapy. EUS with transesophageal needle biopsy may also be used to

assess the presence of non-small-cell lung cancer in mediastinal nodes.

OPEN-ACCESS ENDOSCOPY
Direct scheduling of endoscopic procedures by primary care physi-
cians without preceding gastroenterology consultation, or open-
access endoscopy, is common. When the indications for endoscopy
are clear-cut and appropriate, the procedural risks are low, and the
patient understands what to expect, open-access endoscopy stream-
lines patient care and decreases costs.

FIGURE 322-62 Capsule endoscopy. Images of a mildly scalloped jejunal fold

FIGURE 322-61 Celiac sprue. Scalloped duodenal folds in a patient with celiac (left) and an ileal tumor (right) in a patient with celiac sprue. (Images courtesy of
sprue. Dr. Elizabeth Rajan; with permission.)

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A B

CHAPTER 322 Gastrointestinal Endoscopy

C

FIGURE 322-63 Small-bowel vascular ectasia. A. Actively bleeding mid-jejunal vascular ectasia identified by double-balloon enteroscopy. B. Ablation of vascular ectasia
with argon plasma coagulation (APC). C. Hemostasis secured following APC.

Patients referred for open-access endoscopy should have a recent

history, physical examination, and medication list that are available
for review when the patient comes to the endoscopy suite. Patients
with unstable or symptomatic cardiovascular or respiratory conditions
should not be referred directly for open-access endoscopy. Those with
particular conditions who are undergoing certain procedures should be
prescribed prophylactic antibiotics prior to endoscopy (Table 322-1).
In addition, patients taking anticoagulants and/or antiplatelet drugs
may require adjustment of these agents before endoscopy based on the
procedural risk for bleeding and their underlying risk for a thrombo-
embolic event (Table 322-2).
Common indications for open-access EGD include dyspepsia resis-
tant to a trial of appropriate therapy, dysphagia, gastrointestinal bleed-
ing, and persistent anorexia or early satiety. Open-access colonoscopy
is often requested in men or postmenopausal women with iron-
deficiency anemia, in patients with hematochezia or occult blood
in the stool, in patients with a previous history of colorectal ade-
nomatous polyps or cancer, and for colorectal cancer screening.
Flexible sigmoidoscopy is commonly performed as an open-access
procedure.
FIGURE 322-64 Familial adenomatous polyposis. Numerous colon polyps in a
patient with familial adenomatous polyposis syndrome.

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 2422
TABLE 322-3 Colorectal Cancer Screening Strategies
CHOICES/RECOMMENDATIONS COMMENTS
Average-Risk Patients
Asymptomatic individuals ≥45 years old Colonoscopy every 10 yearsa Preferred cancer prevention strategy
Multitargeted stool DNA test every 3 years Less sensitive than colonoscopy; colonoscopy if
results are positive
Annual FIT or FOBT, multiple take-home specimen cards, with or Does not detect many polyps; colonoscopy if results
without sigmoidoscopy every 5–10 years are positive
CT colonography every 5 years Colonoscopy if results are positive
Flexible sigmoidoscopy every 5 years Does not detect proximal colon polyps and cancers;
colonoscopy if an adenomatous polyp is found
Personal History of Polyps or CRC
1–2 small (<1 cm) adenomas with low-grade Repeat colonoscopy in 5–10 yearsa Assuming complete polyp resection. Interval may
dysplasia vary based on prior personal history and family
history
3–10 adenomas, or any high-risk adenomab Repeat colonoscopy in 3 yearsa; subsequent colonoscopy based Assuming complete polyp resection
on findings
>10 adenomas Repeat colonoscopy in <3 years based on clinical judgmenta Consider evaluation for FAP or HNPCC; see
recommendations below
Piecemeal removal of a sessile polyp Exam in 2–6 months to verify complete removal
Small (<1 cm) hyperplastic polyps of sigmoid Repeat colonoscopy in 10 yearsa Those with hyperplastic polyposis syndrome merit
and rectum more frequent follow-up
Sessile serrated adenoma/polyp <10 mm, Repeat colonoscopy in 5 yearsa
without dysplasia
Sessile serrated adenoma/polyp ≥10 mm or Repeat colonoscopy in 3 yearsa Serrated polyposis syndrome merits more frequent
with dysplasia, or ≥2 serrated polyps follow-up
Incompletely removed serrated polyp ≥1 cm Exam in 2–6 months to verify complete removal
PART 10

Colon cancer Evaluate entire colon around the time of resection, then repeat Subsequent colonoscopy in 3 years if the 1-year
colonoscopy in 1 yeara examination is normal
Inflammatory Bowel Disease
Long-standing (>8 years) ulcerative pancolitis Colonoscopy with biopsies every 1–2 years Consider chromoendoscopy or other advanced
or Crohn’s colitis, or left-sided ulcerative imaging techniques for detection of flat dysplasia
Disorders of the Gastrointestinal System

colitis of >15 years’ duration during colonoscopy

Family History of Polyps or CRC
First-degree relatives with only small tubular Same as average risk
adenomas
One first-degree relative with CRC or Colonoscopy every 10 years starting at age 40
advanced adenoma at age ≥60 years
One first-degree relative with CRC or Colonoscopy every 5 years beginning at age 40 years or 10 years
advanced adenoma at age <60 years, or two younger than age at diagnosis of the youngest affected relative,
first-degree relatives with CRC or advanced whichever is earlier
adenomas at any age
Familial adenomatous polyposis (FAP) Sigmoidoscopy or colonoscopy annually, beginning at age Consider genetic counseling and testing; consider
10–12 years screening family members
Hereditary nonpolyposis colorectal cancer Colonoscopy every 2 years beginning at age 20–25 years (or 10 Consider histologic evaluation for microsatellite
(HNPCC; Lynch syndrome) years younger than the youngest first-degree relative was when instability in tumor specimens of patients who
diagnosed with CRC) until age 40, then annually thereafter meet modified Bethesda criteria; consider genetic
counseling and testing, consider screening family
members
Serrated polyposis syndrome (SPS) Colonoscopy at age 40 (or the same age at which the youngest Consider screening family members, even of patients
first-degree relative was when diagnosed with SPS, or 10 years with multiple serrated polyps who do not meet SPS
younger than the youngest first-degree relative was when criteria.
diagnosed with CRC), then every 1–2 years thereafter
a
Assumes good colonic preparation and complete examination to cecum. bHigh-risk adenoma: any adenoma ≥1 cm in size or containing high-grade dysplasia or villous
features.
Abbreviations: CRC, colorectal cancer; FIT, fecal immunochemical test; FOBT, fecal occult blood test.
Sources: Adapted from U.S. Preventative Services Task Force Draft Guidelines released in 2020 (https://uspreventiveservicestaskforce.org/uspstf/draft-recommendation/
colorectal-cancer-screening) and American Cancer Society Guidelines (https://www.cancer.org/cancer/colon-rectal-cancer/detection-diagnosis-staging/acs-
recommendations.html), both accessed on December 12, 2020. See also G Mankaney et al: Serrated polyposis syndrome. Clin Gastroenterol Hepatol 18:777, 2020.

When patients are referred for open-access colonoscopy, the the quality of colonic preparation. Osmotic purgative preparations
primary care provider may need to choose a colonic preparation. (such as sodium phosphate) are also effective but may cause fluid and
Commonly used oral preparations include polyethylene glycol lavage electrolyte abnormalities and renal toxicity, especially in patients with
solution, with or without citric acid. A “split-dose” regimen improves renal failure or congestive heart failure and those >70 years of age.

HPIM21e_Part10_p2381-p2670.indd 2422 20/01/22 10:03 PM

 ■■FURTHER READING 2423
ASGE Standards of Practice Committee et al: Antibiotic prophy-
laxis for GI endoscopy. Gastrointest Endosc 81:81, 2015.
ASGE Standards of Practice Committee et al: Open-access endos-
copy. Gastrointest Endosc 81:1326, 2015.
Barkun AN et al: Management of nonvariceal upper gastrointestinal
bleeding: Guideline recommendations from the international con-
sensus group. Ann Intern Med 171:805, 2019.
Garcia-Tsao G et al: Portal hypertensive bleeding in cirrhosis: Risk
stratification, diagnosis, and management: 2016 practice guidance by
the American Association for the Study of Liver Diseases. Hepatology
65:310, 2017.
Rex DK et al: Colorectal cancer screening: Recommendations for
physicians and patients from the U.S. Multi-Society Task Force on
Colorectal Cancer. Gastroenterology 153:307, 2017.
Shaheen NJ et al: ACG clinical guideline: Diagnosis and management
of Barrett’s esophagus. Am J Gastroenterol 111:30, 2016.
Strate LL et al: ACG clinical guideline: Management of patients with
acute lower gastrointestinal bleeding. Am J Gastroenterol 111:459,
2016.

FIGURE 322-65 Virtual colonoscopy image of a colon polyp (arrow). (Image

courtesy of Dr. Jeff Fidler; with permission.)

323 Esophagus
Diseases of the

CHAPTER 323 Diseases of the Esophagus

Peter J. Kahrilas, Ikuo Hirano

ESOPHAGEAL STRUCTURE AND FUNCTION

The esophagus is a hollow, muscular tube coursing through the pos-
terior mediastinum joining the hypopharynx to the stomach with a
sphincter at each end. It functions to transport food and fluid between
these ends, otherwise remaining empty. The physiology of swallowing,
esophageal motility, and oral and pharyngeal dysphagia are described
in Chap. 44. Esophageal diseases can be manifested by impaired func-
tion or pain. Key functional impairments are swallowing disorders and
excessive gastroesophageal reflux. Pain, sometimes indistinguishable
from cardiac chest pain, can result from inflammation, infection, dys-
motility, or neoplasm.

FIGURE 322-66 Crohn’s ileitis. Edema, erythema, ulcers, and exudates involving the SYMPTOMS OF ESOPHAGEAL DISEASE
terminal ileum. The clinical history remains central to the evaluation of esophageal
symptoms. A thoughtfully obtained history will often expedite man-
agement. Important details include weight gain or loss, gastrointestinal
bleeding, dietary habits including the timing of meals, smoking, and
alcohol consumption. The major esophageal symptoms are heart-
burn, regurgitation, chest pain, dysphagia, odynophagia, and globus
sensation.
Heartburn (pyrosis), the most common esophageal symptom, is
characterized by a discomfort or burning sensation behind the sternum
that arises from the epigastrium and may radiate toward the neck.
Heartburn is an intermittent symptom, most commonly experienced
after eating, during exercise, and while lying recumbent. The discom-
fort is relieved with drinking water or taking an antacid but can occur
frequently, interfering with normal activities including sleep. The
association between heartburn and gastroesophageal reflux disease
(GERD) is so strong that empirical therapy for GERD has become
accepted management. However, the term heartburn is often misused
and/or referred to using other terms such as indigestion or repeating,
making it important to clarify the intended meaning.
Regurgitation is the effortless return of food or fluid into the phar-
ynx without nausea or retching. Patients report a sour or burning fluid
FIGURE 322-67 Internal hemorrhoids with bleeding stigmata (arrow) as seen on
in the throat or mouth that may also contain undigested food parti-
retroflexed view of the rectum. cles. Bending, belching, or maneuvers that increase intraabdominal

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 2424 pressure can provoke regurgitation. A clinician needs to discriminate sensitivity for detection of diffuse, nonfocal esophageal strictures, cost,
among regurgitation, vomiting, and rumination. Vomiting is preceded and the need for sedatives or anesthetics.
by nausea and accompanied by retching. Rumination is a behavior in
which recently swallowed food is regurgitated and then reswallowed ■■RADIOGRAPHY
repetitively for up to an hour. Although there is some linkage between Contrast radiography of the esophagus, stomach, and duodenum
rumination and cognitive deficiency, the behavior is also exhibited by can demonstrate reflux of the contrast media, hiatal hernia, mucosal
unimpaired individuals. granularity, erosions, ulcerations, and strictures. The sensitivity of
Chest pain is a common esophageal symptom with characteristics radiography compared with endoscopy for detecting reflux esophagitis
similar to cardiac pain, sometimes making this distinction difficult. reportedly ranges from 22 to 95%, with higher grades of esophagitis
Esophageal pain is usually experienced as a pressure-type sensation in (i.e., ulceration or stricture) exhibiting greater detection rates. Con-
the mid chest, radiating to the mid back, arms, or jaws. The similarity versely, the sensitivity of barium radiography for detecting esophageal
to cardiac pain is likely because the two organs share a nerve plexus strictures is greater than that of endoscopy, especially when the study
and the nerve endings in the esophageal wall have poor discriminative is done in conjunction with a 13-mm barium tablet. Barium studies
ability among stimuli. Esophageal distention or even chemostimulation also provide an assessment of esophageal function and morphology
(e.g., with acid) will often be perceived as chest pain. Gastroesophageal that may be undetected on endoscopy. Tracheoesophageal fistula,
reflux is the most common cause of esophageal chest pain. altered postsurgical anatomy, and extrinsic esophageal compression
Esophageal dysphagia (Chap. 44) is often described as a feeling of are conditions where radiographic imaging complements endoscopic
food “sticking” or even lodging in the chest. Important distinctions are assessment. Hypopharyngeal pathology and disorders of the cri-
between uniquely solid food dysphagia as opposed to liquid and solid, copharyngeus muscle are better appreciated on radiographic exami-
episodic versus constant dysphagia, and progressive versus static dys- nation than with endoscopy, particularly with rapid sequence or video
phagia. If the dysphagia is for liquids as well as solid food, it suggests fluoroscopic recording. The major shortcoming of barium radiography
a motility disorder such as achalasia. Conversely, uniquely solid food is that it rarely obviates the need for endoscopy. Either a positive or
dysphagia is suggestive of a stricture, ring, or tumor. Of note, a patient’s a negative study is usually followed by an endoscopic evaluation to
localization of food hang-up in the esophagus is notoriously imprecise. obtain biopsies, provide therapy, or clarify findings in the case of a
Approximately 30% of distal esophageal obstructions are perceived positive examination or to add a level of certainty in the case of a neg-
as cervical dysphagia. In such instances, the absence of concomitant ative examination.
symptoms generally associated with oropharyngeal dysphagia such as ■■ENDOSCOPIC ULTRASOUND
aspiration, nasopharyngeal regurgitation, cough, drooling, or obvious Endoscopic ultrasound (EUS) instruments combine an endoscope with
neuromuscular compromise should suggest an esophageal etiology. an ultrasound transducer to create a transmural image of the tissue sur-
PART 10

Odynophagia is pain either caused by or exacerbated by swallowing. rounding the endoscope tip. The key advantage of EUS over alternative
Although typically considered distinct from dysphagia, odynophagia radiologic imaging techniques is much greater resolution attributable
may manifest concurrently with dysphagia. Odynophagia is more to the proximity of the ultrasound transducer to the area being exam-
common with pill or infectious esophagitis than with reflux esophagitis ined. Available devices can provide either radial imaging (360-degree,
and should prompt a search for these entities. When odynophagia does cross-sectional) or a curved linear image that can guide fine-needle
Disorders of the Gastrointestinal System

occur in GERD, it is likely related to an esophageal ulcer or extensive aspiration of imaged structures such as lymph nodes or tumors. Major
erosions. esophageal applications of EUS are to stage esophageal cancer, to eval-
Globus sensation, also known as globus pharyngeus, is the per- uate dysplasia in Barrett’s esophagus, and to assess submucosal lesions.
ception of a lump or fullness in the throat that is felt irrespective of
swallowing. Although such patients are frequently referred for an ■■ESOPHAGEAL MANOMETRY
evaluation of dysphagia, globus sensation is often relieved by the act Esophageal manometry, or motility testing, entails positioning a
of swallowing. As implied by its alternative name, “globus hystericus,” pressure-sensing catheter within the esophagus and then observing the
globus sensation often occurs in the setting of anxiety or obsessive- contractility following test swallows. The upper esophageal sphincter
compulsive disorders. Clinical experience teaches that it is often attrib- and lower esophageal sphincter (LES) appear as zones of high pres-
utable to GERD. sure that relax on swallowing, whereas the intersphincteric esophagus
Water brash is excessive salivation resulting from a vagal reflex trig- exhibits peristaltic contractions. Manometry is used to diagnose motil-
gered by acidification of the esophageal mucosa. This is not a common ity disorders (achalasia, diffuse esophageal spasm [DES]) and to assess
symptom. Afflicted individuals will describe the unpleasant sensation peristaltic integrity prior to the surgery for reflux disease. Technologic
of the mouth rapidly filling with salty thin fluid, often in the setting of advances have enhanced esophageal manometry as high-resolution
concomitant heartburn. esophageal pressure topography (Fig. 323-1). Manometry can also
be combined with intraluminal impedance monitoring. Impedance
DIAGNOSTIC STUDIES recordings use a series of paired electrodes added to the manometry
catheter. Esophageal luminal contents in contact with the electrodes
■■ENDOSCOPY decrease (liquid) or increase (air) the impedance signal, allowing
Endoscopy, also known as esophagogastroduodenoscopy (EGD), is detection of anterograde or retrograde esophageal bolus transit.
the most useful test for the evaluation of the proximal gastrointesti-
nal tract. Modern instruments produce high-quality, color images of ■■REFLUX TESTING
the esophageal, gastric, and duodenal lumen. Endoscopes also have GERD is often diagnosed in the absence of endoscopic signs of esoph-
an instrumentation channel through which biopsy forceps, injection agitis, which would otherwise define the disease. This occurs in the
catheters for local delivery of therapeutic agents, balloon dilators, or settings of partially treated disease, an abnormally sensitive esophageal
devices for hemostasis or removal of mucosal lesions can be used. The mucosa, or, most commonly, in nonerosive reflux disease. In such
key advantages of endoscopy over barium radiography are as follows: instances, reflux testing can demonstrate excessive esophageal expo-
(1) increased sensitivity for the detection of mucosal lesions; (2) vastly sure to refluxed gastric fluid, the physiologic abnormality of GERD.
increased sensitivity for the detection of abnormalities mainly iden- This can be done by ambulatory 24- to 96-h esophageal pH recording
tifiable by color, such as Barrett’s metaplasia or vascular lesions; (3) using either a wireless pH-sensitive transmitter that is affixed to the
the ability to obtain biopsy specimens for histologic examination of esophageal mucosa or a transnasally positioned wire electrode with
suspected abnormalities; and (4) the ability to dilate strictures during the tip stationed in the distal esophagus. Either way, the outcome is
the examination. Submucosal endoscopy has emerged as a diagnostic expressed as the percentage of the day that the pH was <4 (indicative
modality for assessment of subepithelial lesions and therapy of esoph- of recent acid reflux), with values exceeding 5% indicative of GERD.
ageal motility disorders. The main disadvantages of endoscopy are low Reflux testing is useful in the evaluation of patients presenting with

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 2425

FIGURE 323-1 High-resolution esophageal pressure topography (right) and conventional manometry (left) of a normal swallow. E, esophageal body; LES, lower esophageal
sphincter; UES, upper esophageal sphincter.

atypical symptoms or an inexplicably poor response to therapy. Intralu- Web-like constrictions higher in the esophagus can be of congen-
minal impedance monitoring can be added to pH monitoring to detect ital or inflammatory origin. Asymptomatic cervical esophageal webs
reflux events irrespective of whether or not they are acidic, potentially are demonstrated in ~10% of people and typically originate along
increasing the sensitivity of the study. the anterior aspect of the esophagus. Depending on the degree of
impingement, they can cause intermittent dysphagia to solids similar to
STRUCTURAL DISORDERS Schatzki rings and are similarly treated with dilation. The combination
of symptomatic proximal esophageal webs and iron-deficiency anemia
■■HIATAL HERNIA in middle-aged women constitutes Plummer-Vinson or Paterson-Kelly

CHAPTER 323 Diseases of the Esophagus

Hiatal hernia is a herniation of viscera, most commonly the stomach, syndrome.
into the mediastinum through the esophageal hiatus of the diaphragm.
Four types of hiatal hernia are distinguished, with type I, or sliding hia- ■■DIVERTICULA
tal hernia, composing at least 95% of the overall total. A sliding hiatal Esophageal diverticula are categorized by location, with the most com-
hernia is one in which the gastroesophageal junction and gastric cardia mon being epiphrenic, hypopharyngeal (Zenker’s), and midesopha-
translocate cephalad as a result of weakening of the phrenoesophageal geal. Epiphrenic and Zenker’s diverticula are false diverticula involving
ligament attaching the gastroesophageal junction to the diaphragm at herniation of the mucosa and submucosa through the muscular layer
the hiatus and dilatation of the diaphragmatic hiatus. The incidence of the esophagus. These lesions result from increased intraluminal
of sliding hernia increases with age. True to its name, sliding hernias pressure associated with distal obstruction. In the case of Zenker’s, the
enlarge with increased intraabdominal pressure, swallowing, and res- obstruction is a stenotic cricopharyngeus muscle (upper esophageal
piration. Conceptually, sliding hernias are the result of wear and tear: sphincter), and the hypopharyngeal herniation most commonly occurs
increased intraabdominal pressure from abdominal obesity, pregnancy, in an area of natural weakness proximal to the cricopharyngeus known
etc., along with hereditary factors predisposing to the condition. The
main significance of sliding hernias is the propensity of affected indi-
viduals to have GERD. Tubular
Type II, III, and IV hiatal hernias are all subtypes of paraesophageal esophagus
Eso tibule
ves

hernia in which the herniation into the mediastinum includes a visceral

pha

structure other than the gastric cardia. With type II and III paraesoph-
gea

ageal hernias, the gastric fundus also herniates, with the distinction Phrenic
l Sli ernia

being that in type II, the gastroesophageal junction remains fixed at ampulla
the hiatus, whereas type III is a combined sliding and paraesophageal A ring
ding
h

hernia. With type IV hiatal hernias, viscera other than the stomach
hiat

herniate into the mediastinum, most commonly the colon. With

type II and III paraesophageal hernias, the stomach may twist as it
al

herniates, and large paraesophageal hernias can lead to an “upside

down stomach,” gastric volvulus, and even strangulation of the stom-
ach. Because of this risk, surgical repair is often advocated for large B ring
paraesophageal hernias, particularly when they are symptomatic. squamo-columnar
junction
■■RINGS AND WEBS
A lower esophageal mucosal ring, also called a B ring, is a thin membra-
nous narrowing at the squamocolumnar mucosal junction (Fig. 323-2). Diaphragmatic Rugal folds
Its origin is unknown, but B rings are demonstrable in ~10–15% of the impression traversing hiatus
general population and are usually asymptomatic. When the lumen
diameter is <13 mm, distal rings are usually associated with episodic
solid food dysphagia and are called Schatzki rings. Patients typically
present older than 40 years, consistent with an acquired rather than
congenital origin. Schatzki ring is one of the most common causes of
intermittent food impaction, also known as “steakhouse syndrome”
because meat is a typical instigator. Symptomatic rings are readily
treated by dilation. FIGURE 323-2 Radiographic anatomy of the gastroesophageal junction.

HPIM21e_Part10_p2381-p2670.indd 2425 20/01/22 10:04 PM

 2426

A B C
FIGURE 323-3 Examples of small (A) and large (B, C) Zenker’s diverticula arising from Killian’s triangle in the distal hypopharynx. Smaller diverticula are evident only
during the swallow, whereas larger ones retain food and fluid.

as Killian’s triangle (Fig. 323-3). Small Zenker’s diverticula are usually fibrovascular polyps, squamous papilloma, granular cell tumors, lipo-
asymptomatic, but when they enlarge sufficiently to retain food and mas, mesenchymal neoplasms, and inflammatory fibroid polyps.
saliva, they can be associated with dysphagia, halitosis, and aspiration.
Treatment is by surgical diverticulectomy and cricopharyngeal myot- CONGENITAL ANOMALIES
omy or transoral, endoscopic marsupialization. The most common congenital esophageal anomaly is esophageal
PART 10

Epiphrenic diverticula are often associated with achalasia, esoph- atresia, occurring in ~1 in 5000 live births. Atresia can occur in several
ageal hypercontractile disorders, or a distal esophageal stricture. permutations, the common denominator being developmental failure
Midesophageal diverticula may be caused by traction from adjacent
inflammation (tuberculosis, histoplasmosis), in which case they are
true diverticula involving all layers of the esophageal wall, or by
Disorders of the Gastrointestinal System

pulsion associated with esophageal motor disorders. Midesophageal

and epiphrenic diverticula are often asymptomatic until they enlarge
sufficiently to retain food and cause dysphagia and regurgitation.
Symptoms attributable to the diverticula tend to correlate more with
the underlying esophageal disorder than the size of the diverticula.
Large diverticula can be removed surgically, usually in conjunction
with a myotomy if the underlying motility disorder is identified. Dif-
fuse intramural esophageal pseudodiverticulosis is a rare entity that
results from dilatation of the excretory ducts of submucosal esophageal
glands (Fig. 323-4). Esophageal candidiasis and proximal esophageal
strictures are commonly found in association with this disorder.
■■TUMORS
Esophageal cancer occurs in ~4.5/100,000 people in the United States,
with the associated mortality being 3.9/100,000. It is ~10 times less
common than colorectal cancer but kills about one-quarter as many
patients. These statistics emphasize both the rarity and lethality of
esophageal cancer. One notable trend is the shift of dominant esoph-
ageal cancer type from squamous cell to adenocarcinoma, strongly
linked to reflux disease and Barrett’s metaplasia. Other distinctions
between cell types are the predilection for adenocarcinoma to affect
the distal esophagus in white males and for squamous cell carcinoma to
affect the more proximal esophagus in black males with the added risk
factors of smoking, alcohol consumption, caustic injury, and human
papillomavirus infection (Chap. 80).
The typical presentation of esophageal cancer is of progressive solid
food dysphagia and weight loss. Associated symptoms may include
odynophagia, iron deficiency, cough from tracheoesophageal fistula,
and hoarseness from left recurrent laryngeal nerve injury. Generally,
respiratory symptoms are manifestations of locally invasive or even
metastatic disease. Even when detected as a small lesion, esophageal
cancer has poor survival because of the abundant esophageal lymphat-
ics leading to regional lymph node metastases. FIGURE 323-4 Intramural esophageal pseudodiverticulosis associated with
Benign esophageal tumors are uncommon and usually discovered chronic obstruction. Invaginations of contrast into the esophageal wall outline deep
incidentally. They include gastrointestinal stromal tumors, leiomyoma, esophageal glands.

HPIM21e_Part10_p2381-p2670.indd 2426 20/01/22 10:04 PM

 of fusion between the proximal and distal esophagus associated with 2427
a tracheoesophageal fistula, most commonly with the distal segment
excluded. Alternatively, there can be an H-type configuration in
which esophageal fusion has occurred, but with a tracheoesophageal
fistula. Esophageal atresia is usually recognized and corrected surgi-
cally within the first few days of life. Later life complications include
dysphagia from anastomotic strictures or absent peristalsis and reflux,
which can be severe. Less common developmental anomalies include
congenital esophageal stenosis, webs, and duplications.
Dysphagia can also result from congenital abnormalities that cause
extrinsic compression of the esophagus. In dysphagia lusoria, the
esophagus is compressed by an aberrant right subclavian artery arising
from the descending aorta and passing behind the esophagus. Alterna-
tively, vascular rings may surround and constrict the esophagus.
Heterotopic gastric mucosa, also known as an esophageal inlet patch,
is a focus of gastric-type epithelium in the proximal cervical esophagus;
the estimated prevalence is 4–5%. The inlet patch is thought to result
from incomplete replacement of embryonic columnar epithelium with FIGURE 323-5 Achalasia with esophageal dilatation, tapering at the gastroesophageal
junction, and an air-fluid level within the esophagus. The example on the left shows
squamous epithelium. The majority of inlet patches are asymptomatic, sigmoid deformity with very advanced disease.
but acid production can occur as most contain fundic-type gastric
epithelium with parietal cells.
infiltration, most commonly seen with carcinoma in the gastric fundus
ESOPHAGEAL MOTILITY DISORDERS or distal esophagus, can also mimic primary achalasia. The resultant
Esophageal motility disorders are diseases attributable to esophageal “pseudoachalasia” accounts for up to 5% of suspected cases and is more
neuromuscular dysfunction commonly associated with dysphagia, likely with advanced age, abrupt onset of symptoms (<1 year), and
chest pain, or heartburn. The major entities are achalasia, diffuse weight loss. Hence, endoscopy is a necessary part of the evaluation of
esophageal spasm (DES), jackhammer esophagus, and GERD. Motil- achalasia. When the clinical suspicion for pseudoachalasia is high and
ity disorders can also be secondary to systemic disease processes, as endoscopy nondiagnostic, computed tomography (CT) scanning or

CHAPTER 323 Diseases of the Esophagus

is the case with pseudoachalasia, Chagas’ disease, and scleroderma. EUS may be of value. Rarely, pseudoachalasia can result from a parane-
Not included in this discussion are diseases affecting the pharynx and oplastic syndrome with circulating antineuronal antibodies.
proximal esophagus, the impairment of which is almost always part of Achalasia is diagnosed by barium swallow x-ray and/or esopha-
a more global neuromuscular disease process. geal manometry. Endoscopy excludes tumors or benign mechanical
strictures of the esophagogastric junction. The barium swallow x-ray
■■ACHALASIA appearance is of a dilated esophagus with poor emptying, an air-
Achalasia is a rare disease caused by loss of ganglion cells within the fluid level, and tapering at the LES giving it a beak-like appearance
esophageal myenteric plexus, with a population incidence estimated to (Fig. 323-5). Occasionally, an epiphrenic diverticulum is observed. In
be 1–3 per 100,000 and presentation usually occurring between age 25 long-standing achalasia, the esophagus may assume a sigmoid config-
and 60 years. With long-standing disease, aganglionosis is noted. The uration. The diagnostic criteria for achalasia with esophageal manome-
disease involves both excitatory (cholinergic) and inhibitory (nitric try are impaired LES relaxation and absent peristalsis. High-resolution
oxide) ganglionic neurons. Functionally, inhibitory neurons mediate manometry has somewhat advanced this diagnosis; three subtypes of
deglutitive LES relaxation and the sequential propagation of peristalsis. achalasia are differentiated based on the pattern of pressurization in the
Their absence leads to impaired deglutitive LES relaxation and absent nonperistaltic esophagus (Fig. 323-6). Because manometry identifies
peristalsis. Increasing evidence suggests that the ultimate cause of gan- early disease before esophageal dilatation and food retention, it is the
glion cell degeneration in achalasia is an autoimmune process attribut- most sensitive diagnostic test.
able to a latent infection with human herpes simplex virus 1 combined No method of preventing or “curing” achalasia is known. Therapy is
with genetic susceptibility. thus directed at reducing LES pressure so that gravity and esophageal
Long-standing achalasia is characterized by progressive dilatation pressurization permit esophageal emptying. While peristalsis does not
and sigmoid deformity of the esophagus with hypertrophy of the recover, remnants of peristalsis masked by esophageal pressurization
LES. Clinical manifestations may include dysphagia, regurgitation, and dilatation prior to therapy may be demonstrable following effec-
chest pain, and weight loss. Most patients report solid and liquid food tive treatment. LES pressure can be reduced by pharmacologic therapy,
dysphagia. Regurgitation occurs when food, fluid, and secretions are pneumatic balloon dilation, or LES myotomy by means of submucosal
retained in the dilated esophagus. Patients with advanced achalasia are endoscopy or laparoscopic surgery. Pharmacologic therapies are rela-
at risk for bronchitis, pneumonia, or lung abscess from chronic regur- tively ineffective but can be offered as temporizing therapies. Nitrates
gitation and aspiration. Chest pain may manifest early in the course of or calcium channel blockers are administered before eating but should
achalasia. Patients describe a squeezing, pressure-like retrosternal pain, be used with caution because of their effects on blood pressure. Botu-
sometimes radiating to the neck, arms, jaw, and back. Paradoxically, linum toxin, injected into the LES under endoscopic guidance, inhibits
some patients complain of heartburn that may be a chest pain equiv- acetylcholine release from nerve endings and improves dysphagia in
alent. Treatment of achalasia is less effective at alleviating chest pain about two-thirds of cases for at least 6 months. Sildenafil and alterna-
than it is in relieving dysphagia or regurgitation. tive phosphodiesterase inhibitors effectively decrease LES pressure, but
The differential diagnosis of achalasia includes jackhammer esoph- practicalities limit their clinical use in achalasia.
agus, DES, Chagas’ disease, opioid-induced esophageal dysmotility, The only durable therapies for achalasia are pneumatic dilation and
and pseudoachalasia. Chagas’ disease is endemic in areas of central LES myotomy. Pneumatic dilation, with a reported efficacy ranging
Brazil, Venezuela, and northern Argentina and spread by the bite of from 32 to 98%, is an endoscopic technique using a noncompliant,
the reduviid (kissing) bug that transmits the protozoan Trypanosoma cylindrical balloon dilator positioned across the LES and inflated to
cruzi. The chronic phase of the disease develops years after infection a diameter of 3–4 cm. The major complication is perforation, with a
and results from destruction of autonomic ganglion cells throughout reported incidence of 0.5–5%. The most common surgical procedure
the body, including the heart, gut, urinary tract, and respiratory tract. for achalasia is laparoscopic Heller myotomy, usually performed in
Manometric features of achalasia have been described in patients on conjunction with an antireflux procedure (partial fundoplication);
chronic opioids and may be confused with primary achalasia. Tumor good to excellent results are reported in 62–100% of cases. A European

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 2428 A. Classic achalasia recovery. An international, multicenter, randomized trial of POEM and
0 Pharynx
150 pneumatic dilation demonstrated greater symptom relief with POEM
125 5 compared to dilation at 2 years. A European, multicenter, randomized
trial of POEM and Heller myotomy reported similar efficacy for symp-
100 10 tom relief, with exceeded 80% with either modality.
75 In untreated or inadequately treated achalasia, esophageal dilatation
15
50 cm predisposes to stasis esophagitis. Prolonged stasis esophagitis is the
25 20 likely explanation for the association between achalasia and esophageal
squamous cell cancer. Tumors develop after years of achalasia, usually
0 25 in the setting of extreme esophageal dilatation, with the overall squa-
–10
30 mous cell cancer risk increased 17-fold compared to controls.
mmHg
35 Stomach
■■DIFFUSE ESOPHAGEAL SPASM
0 1 2 3 4 5 6 7 8 9 10 DES is manifested by episodes of dysphagia and chest pain attributable
Seconds to abnormal esophageal contractions with normal deglutitive LES
relaxation. The pathophysiology and natural history of DES are poorly
B. Achalasia with compression
75 0 Pharynx defined. Radiographically, DES has been characterized by tertiary
70 contractions or a “corkscrew esophagus” (Fig. 323-7), but in many
60
5 instances, these abnormalities are indicative of achalasia. Manomet-
rically, a variety of defining features have been proposed including
50 10
uncoordinated (“spastic”) activity in the distal esophagus, spontaneous
40 15 and repetitive contractions, or high-amplitude and prolonged contrac-
cm tions. High-resolution manometry has defined DES by the occurrence
30 20 of contractions in the distal esophagus with short latency relative to
20 the time of the pharyngeal contraction, a dysfunction indicative of
25
15
10
impairment of inhibitory myenteric plexus neurons. When defined
5 30 with this restrictive criterion (Fig. 323-8), DES is substantially less
0 common than achalasia.
–5
–10
35 Stomach Esophageal chest pain closely mimics angina pectoris. Features sug-
mmHg 0 5 10 15 20 25 gesting esophageal pain include pain that is nonexertional, prolonged,
PART 10

Seconds meal-related, relieved with antacids, and accompanied by heartburn,

mmHg C. Spastic achalasia
dysphagia, or regurgitation and interrupts sleep. However, all of these
100 0 Pharynx features exhibit overlap with cardiac pain, which still must be the
90 primary consideration. Furthermore, even within the spectrum of
Disorders of the Gastrointestinal System

80
5 esophageal diseases, both chest pain and dysphagia are also character-
70
istic of peptic or infectious esophagitis. Only after these more common
10
entities have been excluded by evaluation and/or treatment should a
60
15 diagnosis of DES be pursued.
50
cm Although DES is diagnosed by manometry, endoscopy is useful to
40 20 identify alternative structural and inflammatory lesions that may cause
30 chest pain. Radiographically, a “corkscrew esophagus,” “rosary bead
25 esophagus,” pseudodiverticula, or curling can be indicative of DES,
20
15
10 30
but these are also found with spastic achalasia. Given these vagaries of
5
0
defining DES and the resultant heterogeneity of patients identified for
35 Stomach
–10
0 10 20 30 40 50
Seconds
FIGURE 323-6 Three subtypes of achalasia: classic (A), with esophageal
compression (B), and spastic achalasia (C) imaged with pressure topography. All
are characterized by impaired lower esophageal sphincter (LES) relaxation and
absent peristalsis. However, classic achalasia has minimal pressurization of the
esophageal body, whereas substantial fluid pressurization is observed in achalasia
with esophageal compression, and spastic esophageal contractions are observed
with spastic achalasia.

randomized controlled trial demonstrated an equivalent response rate

of ~90% for both pneumatic dilation and laparoscopic Heller myotomy
at 5-year follow-up. Occasionally, patients with advanced disease fail
to respond to pneumatic dilation or Heller myotomy or relapse years
after response to primary therapy. In such refractory cases, esophageal
resection with gastric pull-up or interposition of a segment of trans-
verse colon may be the only option other than gastrostomy feeding.
An endoscopic approach to LES myotomy is increasingly available,
referred to as peroral esophageal myotomy (POEM). This technique
involves the creation of a tunnel in the submucosa of the esophageal
wall through which the circular muscle of the LES and distal esopha-
gus are transected with electrocautery. As expected, GERD is common
FIGURE 323-7 Diffuse esophageal spasm. The characteristic “corkscrew”
after POEM but managed effectively with medications. Potential esophagus results from spastic contraction of the circular muscle in the esophageal
advantages over the conventional laparoscopic approach include avoid- wall; more precisely, this is actually a helical array of muscle. These findings are
ance of surgical disruption of the diaphragmatic hiatus and more rapid also seen with spastic achalasia.

HPIM21e_Part10_p2381-p2670.indd 2428 20/01/22 10:04 PM

 mmHg to that which is physiologically intended 2429
150 depends on the anatomic and physiologic
Jackhammer esophagus Diffuse esophageal spasm integrity of the esophagogastric junction,
a complex sphincter comprised of both
the LES and the surrounding crural dia-
phragm. Three dominant mechanisms of
100 esophagogastric junction incompetence are
recognized: (1) transient LES relaxations (a
vagovagal reflex in which LES relaxation
is elicited by gastric distention), (2) LES
Latency= 3.5 s hypotension, or (3) anatomic distortion
50 of the esophagogastric junction inclusive
of hiatal hernia. Of note, the third factor,
esophagogastric junction anatomic disrup-
0 5 10 15 0 10 20 30 tion, is significant both unto itself and also
Time (s) Time (s) because it interacts with the first two mech-
0 Normal latency with hypercontractility Short latency, premature contraction
anisms. Transient LES relaxations account
for ~90% of reflux in normal subjects or
FIGURE 323-8 Esophageal pressure topography of the two major variants of esophageal spasm: jackhammer GERD patients without hiatal hernia, but
esophagus (left) and diffuse esophageal spasm (right). Jackhammer esophagus is defined by the extraordinarily patients with hiatal hernia have a more
vigorous and repetitive contractions with normal peristaltic onset and normal latency of the contraction. Diffuse
esophageal spasm is similar but primarily defined by a short latency (premature) contraction. heterogeneous mechanistic profile. Factors
tending to exacerbate reflux regardless of
mechanism are abdominal obesity, preg-
inclusion in therapeutic trials, it is not surprising that trial results have nancy, gastric hypersecretory states, delayed gastric emptying, disrup-
been disappointing. Only small, uncontrolled trials exist, reporting tion of esophageal peristalsis, and gluttony.
response to nitrates, calcium channel blockers, hydralazine, botulinum After acid reflux, peristalsis returns the refluxed fluid to the stom-
toxin, and anxiolytics. POEM with distal esophageal myotomy or sur- ach, and acid clearance is completed by titration of the residual acid by
gical myotomy should be considered only with severe weight loss or bicarbonate contained in swallowed saliva. Consequently, two causes

CHAPTER 323 Diseases of the Esophagus

intractable pain. These indications are extremely rare. of prolonged acid clearance are impaired peristalsis and reduced sali-
vation. Impaired peristaltic emptying can be attributable to disrupted
■■NONSPECIFIC MANOMETRIC FINDINGS peristalsis or superimposed reflux associated with a hiatal hernia.
Manometric studies done to evaluate chest pain and/or dysphagia With superimposed reflux, fluid retained within a sliding hiatal hernia
often report minor abnormalities (e.g., hypertensive or hypotensive refluxes back into the esophagus during swallow-related LES relax-
peristalsis, hypertensive LES) that are insufficient to diagnose either ation, a phenomenon that does not normally occur.
achalasia or DES. These findings are of unclear significance. Reflux Inherent in the pathophysiologic model of GERD is that gastric
and psychiatric diagnoses, particularly anxiety and depression, are juice is harmful to the esophageal epithelium. However, gastric acid
common among such individuals. A lower visceral pain threshold and hypersecretion is usually not a dominant factor in the development
symptoms of irritable bowel syndrome are noted in more than half of of esophagitis. An obvious exception is with Zollinger-Ellison syn-
such patients. Consequently, therapy for these individuals should tar- drome, which is associated with severe esophagitis in ~50% of patients.
get either the most common esophageal disorder, GERD, or cognitive Another caveat is with chronic Helicobacter pylori gastritis, which may
disorders that may be present. have a protective effect by inducing atrophic gastritis with concomi-
tant hypoacidity. Pepsin, bile, and pancreatic enzymes within gastric
GASTROESOPHAGEAL REFLUX DISEASE secretions can also injure the esophageal epithelium, but their noxious
The current conception of GERD is that it encompasses a family of properties are either lessened without an acidic environment or depen-
conditions with the commonality that they are caused by gastroesoph- dent on acidity for activation. Bile warrants attention because it persists
ageal reflux resulting in either troublesome symptoms or an array in refluxate despite acid-suppressing medications. Bile can transverse
of potential esophageal and extraesophageal manifestations. It is the cell membrane, imparting severe cellular injury in a weakly acidic
estimated that 10–15% of adults in the United States are affected by environment, and has also been invoked as a cofactor in the pathogen-
GERD, although such estimates are based on population studies of esis of Barrett’s metaplasia and adenocarcinoma. Hence, the causticity
self-reported chronic heartburn. With respect to the esophagus, the of gastric refluxate extends beyond hydrochloric acid.
spectrum of injury includes esophagitis, stricture, Barrett’s esophagus,
and adenocarcinoma (Fig. 323-9). Of particular concern is the rising ■■SYMPTOMS
incidence of esophageal adenocarcinoma, an epidemiologic trend that Heartburn and regurgitation are the typical symptoms of GERD.
parallels the increasing incidence of GERD. About 9200 incident cases Somewhat less common are dysphagia and chest pain. In each case,
of esophageal adenocarcinoma were noted in the United States in 2020 multiple potential mechanisms for symptom genesis operate that
(estimated as half of all esophageal cancers); this disease burden has extend beyond the basic concepts of mucosal erosion and activation of
increased two- to sixfold in the past 20 years. afferent sensory nerves. Specifically, visceral sensitivity is increasingly
recognized as a cofactor. Nonetheless, the dominant clinical strategy is
■■PATHOPHYSIOLOGY empirical treatment with acid inhibitors, reserving further evaluation
The best-defined subset of GERD patients, albeit a minority overall, for those who fail to respond. Important exceptions to this are patients
have esophagitis. Esophagitis occurs when refluxed gastric acid and with chest pain or persistent dysphagia, each of which may be indica-
pepsin induce inflammation of the esophageal mucosa that leads to tive of more morbid consequences of GERD or alternative diagnoses.
microscopic injury and macroscopic erosions and ulcers. Experimen- With chest pain, cardiac disease must be carefully considered. In the
tal evidence supports a cytokine-mediated inflammatory pathway case of dysphagia, chronic reflux can lead to the development of a pep-
rather than direct caustic injury to the esophageal epithelium. Note tic stricture, eosinophilic esophagitis (EoE), or adenocarcinoma, each
that some degree of gastroesophageal reflux is normal, physiologically of which benefits from early detection and/or specific therapy.
intertwined with the mechanism of belching (transient LES relaxation), Extraesophageal syndromes with an established association to
but esophagitis results from excessive reflux, often accompanied by GERD include chronic cough, laryngitis, asthma, and dental ero-
impaired clearance of the refluxed gastric juice. Restricting reflux sions. A multitude of other conditions including pharyngitis, chronic

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 2430 ■■COMPLICATIONS
The complications of GERD are related to chronic
esophagitis (bleeding and stricture) and the rela-
tionship between GERD and esophageal adenocarci-
noma. However, both erosive esophagitis and peptic
strictures have become increasingly rare in the era
of potent antisecretory medications. Conversely, the
most severe histologic consequence of GERD is Bar-
rett’s metaplasia with the associated risk of esophageal
adenocarcinoma, and the incidence of these lesions
has increased, not decreased, in the era of potent
acid suppression. Barrett’s metaplasia, recognized
endoscopically by salmon-colored mucosa extend-
A Erosive esophagitis B Esophageal stricture with chronic
ing proximally from the gastroesophageal junction
erosive esophagitis (Fig. 323-9) or histopathologically by the finding of
specialized columnar metaplasia, is associated with a
significantly increased risk for development of esoph-
ageal adenocarcinoma.
Barrett’s metaplasia can progress to adenocarci-
noma through the intermediate stages of low- and
high-grade dysplasia (Fig. 323-10). Owing to this
risk, areas of Barrett’s metaplasia and especially any
included areas of mucosal irregularity should be
carefully inspected and extensively biopsied. The rate
of cancer development is estimated at 0.1–0.3% per
year, but vagaries in definitional criteria and of the
extent of Barrett’s metaplasia requisite to establish
the diagnosis have contributed to variability and
inconsistency in this risk assessment. The group at
PART 10

Barrett’s esophagus Esophageal adenocarcinoma

greatest risk is obese white males in their sixth decade
C D
with Barrett’s esophagus
of life. Despite common practice, however, the utility
of endoscopic screening and surveillance programs
FIGURE 323-9 Endoscopic appearance of (A) peptic esophagitis, (B) a peptic stricture, (C) Barrett’s intended to control the adenocarcinoma risk remains
metaplasia, and (D) adenocarcinoma developing within an area of Barrett’s esophagus.
an open question. Also of note, although in a large,
Disorders of the Gastrointestinal System

randomized, controlled chemoprevention trial in

Barrett’s patients high-dose proton pump inhibitor therapy along with
bronchitis, pulmonary fibrosis, chronic sinusitis, cardiac arrhythmias,
aspirin did significantly better at achieving the primary composite
sleep apnea, and recurrent aspiration pneumonia have proposed
endpoint of delaying all-cause mortality, development of esophageal
associations with GERD. However, in both cases, it is important to
adenocarcinoma, or progression to high-grade dysplasia, the effect was
emphasize the word association as opposed to causation. In many
driven mainly by improved overall survival rather than reduced Bar-
instances, the disorders likely coexist because of shared pathogenetic
rett’s progression or esophageal adenocarcinoma development.
mechanisms rather than strict causality. Potential mechanisms for
Although the management of Barrett’s esophagus remains contro-
extraesophageal GERD manifestations are either regurgitation with
versial, the finding of dysplasia in Barrett’s, particularly high-grade
direct contact between the refluxate and supraesophageal structures or
dysplasia, mandates further intervention. In addition to the high rate
via a vagovagal reflex wherein reflux activation of esophageal afferent
of progression to adenocarcinoma, there is also a high prevalence of
nerves triggers efferent vagal reflexes such as bronchospasm, cough,
unrecognized coexisting cancer with high-grade dysplasia. Treatment
or arrhythmias.
recommendations for Barrett’s esophagus with high-grade dysplasia
■■DIFFERENTIAL DIAGNOSIS have evolved over the past several years. Historically, esophagectomy
Although generally quite characteristic, symptoms from GERD need to was the gold standard treatment for high-grade dysplasia. However,
be distinguished from symptoms related to infectious or pill esophagi- esophagectomy has a mortality ranging from 3 to 10%, along with
tis, EoE, peptic ulcer disease, dyspepsia, biliary colic, coronary artery substantial morbidity. Prospective studies have demonstrated the
disease, and esophageal motility disorders. It is especially important efficacy of endoscopic mucosal ablation therapy with substantially less
that coronary artery disease be given early consideration because of its morbidity and essentially no mortality. Consequently, current societal
potentially lethal implications. The remaining elements of the differ- guidelines endorse endoscopic mucosal ablation therapies for the man-
ential diagnosis can be addressed by endoscopy, upper gastrointestinal agement of high-grade dysplasia.
series, or esophageal manometry as appropriate. Erosive esophagitis
at the esophagogastric junction is the endoscopic hallmark of GERD
but identified in only about one-third of patients with GERD. The TREATMENT
distinction among etiologies of esophagitis is readily made by endo- Gastroesophageal Reflux Disease
scopic appearance, but mucosal biopsies may be helpful to evaluate
for infectious or eosinophilic inflammation. In terms of endoscopic Lifestyle modifications are routinely advocated as GERD therapy.
appearance, the ulcerations seen in peptic esophagitis are usually few Broadly speaking, these fall into three categories: (1) avoidance of
and distal, whereas infectious ulcerations are numerous, punctate, and foods that reduce LES pressure, making them “refluxogenic” (these
diffuse. EoE characteristically exhibits multiple esophageal rings, linear commonly include fatty foods, alcohol, spearmint, peppermint,
furrows, white punctate exudate, and strictures. Esophageal ulcera- and possibly coffee and tea); (2) avoidance of acidic foods that are
tions from pill esophagitis are usually singular and deep at points of inherently irritating (citrus fruits, tomato-based foods); and (3)
luminal narrowing, especially near the carina, with sparing of the distal adoption of behaviors to minimize reflux and/or heartburn. In
esophagus. general, minimal evidence supports the efficacy of these measures.

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 Barrett’s metaplasia High-grade dysplasia 2431

Alcian blue stain H&E stain

FIGURE 323-10 Histopathology of Barrett’s metaplasia and Barrett’s metaplasia with high-grade dysplasia. H&E, hematoxylin and eosin.

However, clinical experience dictates that subsets of patients benefit dysphagia, failure or breakdown requiring reoperation, an inability
from specific recommendations based on their individual history to belch, and increased bloating, flatulence, and bowel symptoms
and symptom profile. A patient with sleep disturbance from night- after surgery.
time heartburn is more likely to benefit from elevation of the head
of the bed and avoidance of eating before retiring. The most broadly
applicable recommendation is for weight reduction. Even though ■■EOSINOPHILIC ESOPHAGITIS
the benefit with respect to reflux cannot be assured, the strong epi- EoE is increasingly recognized in adults and children around the
demiologic relationship between body mass index and GERD and world. Current prevalence estimates in the United States identified
the secondary health gains of weight reduction is beyond dispute. 4–8 cases per 10,000 with a predilection for white males between 30
The dominant pharmacologic approach to GERD management and 40 years of age. The increasing prevalence of EoE is attributable
is with inhibitors of gastric acid secretion, and abundant data sup- to a combination of an increasing incidence and a growing recogni-

CHAPTER 323 Diseases of the Esophagus

port the effectiveness of this approach. Pharmacologically reducing tion of the condition. There is also an incompletely understood, but
the acidity of gastric juice does not prevent reflux, but it ameliorates important, interaction between EoE and GERD that may confound the
reflux symptoms and allows esophagitis to heal. The hierarchy of diagnosis of the disease. Genome-wide analysis studied demonstrated
effectiveness among pharmaceuticals parallels their antisecretory susceptibility elements at 5q22 (thymic stromal lymphopoietin) and
potency. Proton pump inhibitors (PPIs) are more efficacious than 2p23 (CAPN14) in EoE.
histamine-2 receptor antagonists (H2RAs), and both are superior to EoE is diagnosed based on the combination of esophageal symptoms
placebo. No major differences exist among PPIs, and only modest and esophageal mucosal biopsies demonstrating eosinophil-predomi-
gain is achieved by increased dosage. nant inflammation. Alternative etiologies of esophageal eosinophilia
Paradoxically, the perceived frequency and severity of heartburn include GERD, drug hypersensitivity, connective tissue disorders,
correlate poorly with the presence or severity of esophagitis. When hypereosinophilic syndrome, Crohn’s disease, eosinophilic gastroen-
GERD treatments are assessed in terms of resolving heartburn, both teritis, and infection. EoE is an immunologic disorder induced by
efficacy and differences among pharmaceuticals are less clear-cut antigen sensitization in susceptible individuals. Food allergens are the
than with the objective of healing esophagitis. Although the same dominant triggers, although aeroallergens may also contribute. The
overall hierarchy of effectiveness exists, observed efficacy rates are natural history of EoE is incompletely understood, but an increased
lower and vary widely, likely reflecting patient heterogeneity. risk of esophageal stricture development paralleling the duration of
Reflux symptoms tend to be chronic, irrespective of esophagitis. untreated disease has been noted.
Thus, a common management strategy is indefinite treatment with EoE should be strongly considered in children and adults with
PPIs or H2RAs as necessary for symptom control. The side effects of dysphagia and esophageal food impactions. In preadolescent chil-
PPI therapy are generally minimal. Rare cases of interstitial nephri- dren, symptom presentations of EoE include chest or abdominal
tis and severe, reversible hypomagnesemia have been reported. pain, nausea, vomiting, and food aversion. Other symptoms in adults
Vitamin B12 and iron absorption may be compromised and suscep- may include atypical chest pain and heartburn. An atopic history of
tibility to enteric infections, particularly Clostridium difficile colitis, IgE-mediated food allergy, asthma, eczema, and/or allergic rhinitis is
increased with treatment. Observational data have also noted an present in the majority of patients. Peripheral blood eosinophilia is
association between PPI exposure and renal disease, dementia, demonstrable in 25–50% of patients, but the specificity of this finding
and cardiovascular disease, but the hazard ratios reported in these is problematic in the setting of concomitant atopy. The characteristic
studies were small, and the potential for unrecognized residual endoscopically identified esophageal findings include loss of vascular
confounding bias was substantial. Population studies have also sug- markings (edema), multiple esophageal rings, longitudinally oriented
gested a slight increased risk of bone fracture with chronic PPI use furrows, and whitish exudate (Fig. 323-11). Histologic confirmation
suggesting an impairment of calcium absorption, but prospective is made with the demonstration of esophageal mucosal eosinophilia
studies have failed to corroborate this. Nonetheless, as with any (peak density ≥15 eosinophils per high-power field) (Fig. 323-12).
medication, PPI dosage should be minimized to that necessary for Complications of EoE include food impaction, esophageal stricture,
the clinical indication. narrow-caliber esophagus, and rarely esophageal perforation.
Laparoscopic Nissen fundoplication, wherein the proximal The goals of EoE management are symptom control and the preven-
stomach is wrapped around the distal esophagus to create an tion of complications. Primary therapy often starts with PPI therapy,
antireflux barrier, is a surgical alternative to the management of which is effective at improving eosinophilic inflammation in 30–50%
chronic GERD. Just as with PPI therapy, evidence on the utility of of patients. Additional first-line therapies include elimination diets
fundoplication is strongest for treating esophagitis, and controlled or swallowed topical glucocorticoids. Elemental formula diets devoid
trials suggest similar efficacy to PPI therapy. However, the benefits of allergenic protein are a highly effective therapy but are limited by
of fundoplication must be weighed against potential deleterious palatability. Notably, allergy testing by means of either serum IgE or
effects, including surgical morbidity and mortality, postoperative skin prick testing has demonstrated poor sensitivity and specificity in

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 2432 the identification of foods responsible for EoE in an individual patient.
Empiric elimination of common food allergies (milk, wheat, egg, soy,
nuts, and seafood) followed by systematic reintroduction has been an
effective diet therapy in both children and adults with EoE. The intent
of the elimination diet approach is the identification of specific food
trigger(s). Swallowed, topical glucocorticoids (e.g., fluticasone propio-
nate or budesonide) are effective in 50–80% of patients, but recurrence
of disease is common following the cessation of short-term therapy.
Systemic glucocorticoids are not generally recommended due to side
effects and lack of proven benefit beyond that achieved with topical
glucocorticoids. Biologic therapies targeting allergic cytokine media-
A B tors including interleukin (IL) 4, IL-5, and IL-13 have shown prom-
ise in initial clinical trials. Esophageal dilation is highly effective at
relieving dysphagia in patients with fibrostenosis but does not address
the underlying inflammatory process. Dilation should be approached
conservatively because of the risk of deep, esophageal mural laceration
or perforation in the stiff-walled esophagus that is characteristic of the
disease.

INFECTIOUS ESOPHAGITIS
As a result of the increased use of immunosuppression for organ trans-
plantation and chronic inflammatory diseases and use of chemotherapy
agents, along with the AIDS epidemic, infections with Candida species,
C D
herpesvirus, and cytomegalovirus (CMV) have become relatively
common. Although rare, infectious esophagitis also occurs among the
FIGURE 323-11 Endoscopic features of (A) eosinophilic esophagitis (EoE), non-immunocompromised, with herpes simplex and Candida albicans
(B) Candida esophagitis, (C) giant ulcer associated with HIV, and (D) a Schatzki ring.
being the most common pathogens. Among AIDS patients, infectious
esophagitis becomes more common as the CD4 count declines; cases
a day for 7–10 days) can be used for immunocompetent hosts, although are rare with a CD4 count >200 and common when <100. HIV itself
PART 10

the disease is typically self-limited after a 1- to 2-week period in such may also be associated with a self-limited syndrome of acute esopha-
patients. Immunocompromised patients are treated with acyclovir geal ulceration with oral ulcers and a maculopapular skin rash at the
(400 mg orally five times a day for 14–21 days), famciclovir (500 mg time of seroconversion. Additionally, some patients with advanced
orally three times a day), or valacyclovir (1 g orally three times a day). disease have deep, persistent esophageal ulcers treated with oral gluco-
corticoids or thalidomide. However, with the widespread use of highly
Disorders of the Gastrointestinal System

effective antiviral therapies, a reduction in these HIV complications

has been noted.
Regardless of the infectious agent, odynophagia is a characteristic
symptom of infectious esophagitis; dysphagia, chest pain, and hem-
orrhage are also common. Odynophagia is uncommon with reflux
esophagitis, so its presence should always raise suspicion of an alter-
native etiology.
■■CANDIDA ESOPHAGITIS
Candida is normally found in the throat but can become pathogenic
and produce esophagitis in a compromised host; C. albicans is most
common. Candida esophagitis also occurs with esophageal stasis
secondary to esophageal motor disorders and diverticula. Patients
complain of odynophagia and dysphagia. If oral thrush is present,
empirical therapy is appropriate, but co-infection is common, and per-
sistent symptoms should lead to prompt endoscopy with biopsy, which
is the most useful diagnostic evaluation. Candida esophagitis has a
characteristic appearance of white plaques or exudate with friability.
Oral fluconazole (400 mg on the first day, followed by 200 mg daily) for
14–21 days is the preferred treatment. Patients refractory to fluco-
nazole may respond to voriconazole or posaconazole. Alternatively,
poorly responsive patients or those who cannot swallow medications
can be treated with an intravenous echinocandin.
■■HERPETIC ESOPHAGITIS
Herpes simplex virus type 1 or 2 may cause esophagitis. Vesicles on
the nose and lips may coexist and are suggestive of a herpetic eti-
ology. Varicella-zoster virus can also cause esophagitis in children
with chickenpox or adults with zoster. The characteristic endoscopic
findings are vesicles and small, superficial ulcerations. Because herpes
simplex infections are limited to squamous epithelium, biopsies from
FIGURE 323-12 Histopathology of eosinophilic esophagitis (EoE) showing
the ulcer margins are most likely to reveal the characteristic ground-
infiltration of the esophageal squamous epithelium with eosinophils. Additional glass nuclei, eosinophilic Cowdry’s type A inclusion bodies, and giant
features of basal cell hyperplasia and lamina propria fibrosis are present. cells. Culture or polymerase chain reaction (PCR) assays are helpful to
Eosinophilic inflammation can also be seen with gastroesophageal reflux disease. identify acyclovir-resistant strains. Acyclovir (200 mg orally five times

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 In patients with severe odynophagia, intravenous acyclovir, 5 mg/kg injury does not exclude possible esophageal involvement. Thus, early 2433
every 8 h for 7–14 days, reduces this morbidity. endoscopic evaluation is recommended to assess and grade the injury
to the esophageal mucosa. Severe corrosive injury may lead to esoph-
■■CYTOMEGALOVIRUS ageal perforation, bleeding, stricture, and death. Glucocorticoids have
CMV esophagitis occurs primarily in immunocompromised patients, not been shown to improve the clinical outcome of acute corrosive
particularly those with HIV, patients with malignancy, and recipients esophagitis and are not recommended. Healing of more severe grades
of bone marrow or organ transplants. CMV is usually activated from a of caustic injury is commonly associated with severe stricture forma-
latent stage. Endoscopically, CMV lesions appear as large serpiginous tion and often requires repeated dilation.
ulcers in an otherwise normal mucosa, particularly in the distal esoph-
agus. Biopsies from the ulcer bases have the greatest diagnostic yield ■■PILL ESOPHAGITIS
for finding the pathognomonic large nuclear or cytoplasmic inclusion Pill-induced esophagitis occurs when a swallowed pill fails to traverse
bodies. Immunohistology with monoclonal antibodies to CMV and in the entire esophagus and lodges within the lumen. Generally, this is
situ hybridization tests are useful for early diagnosis. Data on therapy attributed to poor “pill-taking habits”: inadequate liquid with the pill or
for CMV esophagitis are limited. Treatment studies of CMV gastro- lying down immediately after taking a pill. The most common location
intestinal disease have demonstrated effectiveness of both ganciclovir for the pill to lodge is in the mid-esophagus near the crossing of the
(5 mg/kg every 12 h IV) and valganciclovir (900 mg orally every 12 h). aorta or carina. Extrinsic compression from these structures halts the
Therapy is continued until healing, which may take 3–6 weeks. Mainte- movement of the pill or capsule. Since initially reported in 1970, >1000
nance therapy may be needed for patients with relapsing disease. cases of pill esophagitis have been reported, suggesting that this is not
an unusual occurrence. A wide variety of medications are implicated,
MECHANICAL TRAUMA AND with the most common being doxycycline, tetracycline, quinidine,
IATROGENIC INJURY phenytoin, potassium chloride, ferrous sulfate, nonsteroidal anti-in-
flammatory drugs (NSAIDs), and bisphosphonates.
ESOPHAGEAL PERFORATION Typical symptoms of pill esophagitis are the sudden onset of chest
Most cases of esophageal perforation are from instrumentation of pain and odynophagia. Characteristically, the pain will develop over
the esophagus or trauma. Alternatively, forceful vomiting or retching a period of hours or will awaken the individual from sleep. A classic
can lead to spontaneous rupture at the gastroesophageal junction history in the setting of ingestion of recognized pill offenders obviates
(Boerhaave’s syndrome). More rarely, corrosive esophagitis or neo- the need for diagnostic testing in most patients. When endoscopy is
plasms lead to perforation. Instrument perforation from endoscopy or performed, localized ulceration or inflammation is evident. Histologi-

CHAPTER 323 Diseases of the Esophagus

nasogastric tube placement typically occurs in the hypopharynx or at cally, acute inflammation is typical. Chest CT imaging will sometimes
the gastroesophageal junction. Perforation may also occur at the site of reveal esophageal thickening consistent with transmural inflammation.
a stricture in the setting of endoscopic food disimpaction or esopha- Although the condition usually resolves within days to weeks, symp-
geal dilation. Esophageal perforation causes pleuritic retrosternal pain toms may persist for months and stricture can develop in severe cases.
that can be associated with pneumomediastinum and subcutaneous No specific therapy is known to hasten the healing process, but antise-
emphysema. Mediastinitis is a major complication of esophageal per- cretory medications are frequently prescribed to remove concomitant
foration, and prompt recognition is key to optimizing outcome. CT reflux as an aggravating factor. When healing results in stricture forma-
of the chest is most sensitive in detecting mediastinal air. Esophageal tion, dilation is indicated.
perforation is confirmed by a contrast swallow, usually Gastrografin
followed by thin barium. Treatment includes nasogastric suction and ■■FOREIGN BODIES AND FOOD IMPACTION
parenteral broad-spectrum antibiotics with prompt surgical drainage Food or foreign bodies may lodge in the esophagus, causing complete
and repair in noncontained leaks. Conservative therapy with NPO obstruction, which in turn can cause an inability to handle secretions
status and antibiotics without surgery may be appropriate in cases of (foaming at the mouth) and severe chest pain. Food impaction may
contained perforation that are detected early. Endoscopic clipping or occur due to peptic stricture, carcinoma, Schatzki ring, EoE, or simply
stent placement may be indicated in nonoperated iatrogenic perfora- inattentive eating. If it does not spontaneously resolve, impacted food
tions or nonoperable cases such as perforated tumors. should be removed endoscopically. Use of meat tenderizer enzymes
to facilitate passage of a meat bolus is discouraged because of poten-
■■MALLORY-WEISS TEAR tial esophageal injury. Glucagon (1 mg IV) is sometimes tried before
Vomiting, retching, or vigorous coughing can cause a nontransmural endoscopic dislodgement. After emergent treatment, patients should
tear at the gastroesophageal junction that is a common cause of upper be evaluated for potential causes of the impaction with treatment ren-
gastrointestinal bleeding. Most patients present with hematemesis. dered as indicated.
Antecedent vomiting is the norm but not always evident. Bleeding
usually abates spontaneously, but protracted bleeding may respond ESOPHAGEAL MANIFESTATIONS
to local epinephrine or cauterization therapy, endoscopic clipping, or OF SYSTEMIC DISEASE
angiographic embolization. Surgery is rarely needed. ■■SCLERODERMA AND CONNECTIVE
■■RADIATION ESOPHAGITIS TISSUE DISORDERS
Radiation esophagitis can complicate treatment for thoracic cancers, Scleroderma esophagus (hypotensive LES and absent esophageal con-
especially breast and lung cancers, with the risk proportional to radi- tractility) was initially described as a manifestation of scleroderma or
ation dosage. Radiosensitizing drugs such as doxorubicin, bleomycin, other collagen vascular diseases and thought to be specific for these
cyclophosphamide, and cisplatin also increase the risk. Dysphagia and disorders. However, this nomenclature subsequently has been dis-
odynophagia may last weeks to months after therapy. The esophageal carded because an estimated half of qualifying patients do not have
mucosa becomes erythematous, edematous, and friable. Submucosal an identifiable rheumatologic disease, and reflux disease is often the
fibrosis and degenerative tissue changes and stricturing may occur only identifiable association. When scleroderma esophagus occurs as
years after the radiation exposure. Radiation exposure in excess of a manifestation of a connective tissue disorder, the histopathologic
5000 cGy has been associated with increased risk of esophageal stric- findings are of infiltration and destruction of the esophageal muscu-
ture. Treatment for acute radiation esophagitis is supportive. Chronic laris propria with collagen deposition and fibrosis and reduction in
strictures are managed with esophageal dilation. the number of interstitial cells of Cajal. The pathogenesis of absent
peristalsis and LES hypotension in the absence of a connective tissue
■■CORROSIVE ESOPHAGITIS disorder is unknown. Regardless of the underlying cause, the mano-
Caustic esophageal injury from ingestion of alkali or, less commonly, metric abnormalities predispose patients to severe GERD due to inad-
acid can be accidental or from attempted suicide. Absence of oral equate LES barrier function combined with poor esophageal clearance

HPIM21e_Part10_p2381-p2670.indd 2433 20/01/22 10:04 PM

 2434 of refluxed acid. Dysphagia may also be manifest but is generally mild ■■GASTRIC PHYSIOLOGY
and alleviated by eating in an upright position and using liquids to
facilitate solid emptying. Gastric Anatomy The gastric epithelial lining consists of rugae
that contain microscopic gastric pits, each branching into four or
■■DERMATOLOGIC DISEASES five gastric glands made up of highly specialized epithelial cells. The
A host of dermatologic disorders (lichen planus, pemphigus vulgaris, makeup of gastric glands varies with their anatomic location. Glands
bullous pemphigoid, cicatricial pemphigoid, Behçet’s syndrome, and within the gastric cardia comprise <5% of the gastric gland area and
epidermolysis bullosa) can affect the oropharynx and esophagus, contain mucous and endocrine cells. The 75% of gastric glands are
particularly the proximal esophagus, with blisters, bullae, ulceration, found within the oxyntic mucosa and contain mucous neck, parietal,
webs, and strictures. Topical or systemic anti-inflammatory therapy chief, endocrine, enterochromaffin, and enterochromaffin-like (ECL)
is effective for mucosal healing. Stevens-Johnson syndrome and graft- cells (Fig. 324-1). Highly specialized tuft cells are located in the neck
versus-host disease can also involve the esophagus. Esophageal dilation region of the gastric gland. These specialized cells are thought to sam-
may be necessary to treat strictures. ple luminal contents, which in turn may be important in regulating
gastric acid secretion. Pyloric glands contain mucous and endocrine
■■FURTHER READING cells (including gastrin cells) and are found in the antrum.
Furuta GT, Katzka DA: Eosinophilic esophagitis. N Engl J Med The parietal cell, also known as the oxyntic cell, is usually found in the
373:1640, 2015. neck or isthmus or in the oxyntic gland. The resting, or unstimulated,
Hirano I et al: American Gastroenterological Institute and the joint parietal cell has prominent cytoplasmic tubulovesicles and intracellular
task force on allergy-immunology practice parameters clinical guide- canaliculi containing short microvilli along its apical surface (Fig. 324-2).
lines for the management of eosinophilic esophagitis. Gastroenterol- H+,K+-adenosine triphosphatase (ATPase) is expressed in the tubulovesicle
ogy 158:1776, 2020. membrane; upon cell stimulation, this membrane, along with apical mem-
Kahrilas PJ, Boeckxstaens G: The spectrum of achalasia: Lessons branes, transforms into a dense network of apical intracellular canaliculi
from studies of pathophysiology and high-resolution manometry. containing long microvilli. Acid secretion, a process requiring high energy,
Gastroenterology 145:954, 2013. occurs at the apical canalicular surface. Numerous mitochondria (30–40%
Kahrilas PJ et al: American Gastroenterological Association Institute of total cell volume) generate the energy required for secretion.
technical review on the management of gastroesophageal reflux dis- Gastroduodenal Mucosal Defense The gastric epithelium is
ease. Gastroenterology 135:1392, 2008. under constant assault by a series of endogenous noxious factors,
Katzka DA et al: Phenotypes of gastroesophageal reflux disease: including hydrochloric acid (HCl), pepsinogen/pepsin, and bile salts.
where Rome, Lyon, and Montreal meet. Clin Gastroenterol Hepatol In addition, a steady flow of exogenous substances such as medications,
18:767, 2020. alcohol, and bacteria encounter the gastric mucosa. A highly intricate
PART 10

Pandolfino JE, Gawron AJ: Achalasia: A systematic review. JAMA biologic system is in place to provide defense from mucosal injury and
313:1841, 2015. to repair any injury that may occur.
Shaheen NJ et al: Diagnosis and management of Barrett’s esophagus. The mucosal defense system can be envisioned as a three-level barrier,
Am J Gastroenterol 111:30, 2016. composed of preepithelial, epithelial, and subepithelial elements
Disorders of the Gastrointestinal System

Spechler SJ, Souza RF: Barrett’s esophagus. N Engl J Med 371:836,

2014.

324 Peptic Ulcer Disease Gastric pit

(foveolus)
and Related Disorders Surface mucous cells

John Del Valle

Isthmus
PEPTIC ULCER DISEASE
A peptic ulcer is defined as disruption of the mucosal integrity of the Mucous neck cells
stomach and/or duodenum leading to a local defect or excavation due
to active inflammation. Although burning epigastric pain exacerbated Neck
by fasting and improved with meals is a symptom complex associated
with peptic ulcer disease (PUD), it is now clear that >90% patients with
Oxyntic Gland

this symptom complex (dyspepsia) do not have ulcers and that the
Parietal cells
majority of patients with peptic ulcers may be asymptomatic. Ulcers
occur within the stomach and/or duodenum and are often chronic in
nature. Acid peptic disorders are very common in the United States,
with 4 million individuals (new cases and recurrences) affected per Endocrine cell
year. Lifetime overall prevalence of PUD in the United States is ~8.4%
with a slightly higher prevalence in men. PUD significantly affects Base
quality of life by impairing overall patient well-being and contributing (fundus)
substantially to work absenteeism. Moreover, an estimated 15,000
deaths per year occur as a consequence of complicated PUD. The
Chief cells
financial impact of these common disorders has been substantial,
with an estimated burden on direct and indirect health care costs
of ~$6 billion per year in the United States, with $3 billion spent on FIGURE 324-1 Diagrammatic representation of the oxyntic gastric gland.
hospitalizations, $2 billion on physician office visits, and $1 billion in (Reproduced with permission from S Ito, RJ Winchester: The Fine Structure of the
decreased productivity and days lost from work. Gastric Mucosa in the Bat. J Cell Biol 16:541, 1963.)

HPIM21e_Part10_p2381-p2670.indd 2434 20/01/22 10:04 PM

 Resting Stimulated mucosal blood flow and epithelial cell restitution. Prostaglandins are 2435
derived from esterified arachidonic acid, which is formed from phos-
pholipids (cell membrane) by the action of phospholipase A2. A key
enzyme that controls the rate-limiting step in prostaglandin synthesis
is cyclooxygenase (COX), which is present in two isoforms (COX-1,
Canaliculus HCl
COX-2), each having distinct characteristics regarding structure, tissue
H+,K+–ATPase KCl distribution, and expression. COX-1 is expressed in a host of tissues,
including the stomach, platelets, kidneys, and endothelial cells. This
Tubulovesicles isoform is expressed in a constitutive manner and plays an important
KCl
Active H3O+ Active role in maintaining the integrity of renal function, platelet aggregation,
pump pump and gastrointestinal (GI) mucosal integrity. In contrast, the expression
Ca cAMP of COX-2 is inducible by inflammatory stimuli, and it is expressed in
– macrophages, leukocytes, fibroblasts, and synovial cells. The beneficial
Gastrin effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on tissue
ACh Histamine
inflammation are due to inhibition of COX-2; the toxicity of these
FIGURE 324-2 Gastric parietal cell undergoing transformation after secretagogue- drugs (e.g., GI mucosal ulceration and renal dysfunction) is related to
mediated stimulation. cAMP, cyclic adenosine monophosphate. (Reproduced with inhibition of the COX-1 isoform. The highly COX-2–selective NSAIDs
permission from SJ Hersey, G Sachs: Gastric acid secretion. Am Physiol Soc 75:155, 1995.)
have the potential to provide the beneficial effect of decreasing tissue
inflammation while minimizing toxicity in the GI tract. Selective
(Fig. 324-3). The first line of defense is a mucus-bicarbonate-phospholipid COX-2 inhibitors have had adverse effects on the cardiovascular (CV)
layer, which serves as a physicochemical barrier to multiple molecules, system, leading to increased risk of myocardial infarction. Therefore,
including hydrogen ions. Mucus is secreted in a regulated fashion by the U.S. Food and Drug Administration (FDA) has removed two of
gastroduodenal surface epithelial cells. It consists primarily of water these agents (valdecoxib and rofecoxib) from the market (see below).
(95%) and a mixture of phospholipids and glycoproteins (mucin). The NO is important in the maintenance of gastric mucosal integrity.
mucous gel functions as a nonstirred water layer impeding diffusion of The key enzyme NO synthase is constitutively expressed in the mucosa
ions and molecules such as pepsin. Bicarbonate, secreted in a regulated and contributes to cytoprotection by stimulating gastric mucus,
manner by surface epithelial cells of the gastroduodenal mucosa into increasing mucosal blood flow, and maintaining epithelial cell barrier
the mucous gel, forms a pH gradient ranging from 1 to 2 at the gastric function. The central nervous system (CNS) and hormonal factors also

CHAPTER 324 Peptic Ulcer Disease and Related Disorders

luminal surface and reaching 6–7 along the epithelial cell surface. play a role in regulating mucosal defense through multiple pathways
Surface epithelial cells provide the next line of defense through (Fig. 324-3).
several factors, including mucus production, epithelial cell ionic trans- Since the discovery of Helicobacter pylori and its impact on gastric
porters that maintain intracellular pH and bicarbonate production, pathology, it has become clear that the stomach has an elaborate and
and intracellular tight junctions. Surface epithelial cells generate heat complex inherent immunologic system in place. Although a detailed
shock proteins that prevent protein denaturation and protect cells from description of the gastric immune system is beyond the scope of this
certain factors such as increased temperature, cytotoxic agents, or oxi- chapter, several features are worth highlighting. The gastric immune
dative stress. Epithelial cells also generate trefoil factor family peptides response to certain pathogens such as H. pylori (see below) involves
and cathelicidins, which also play a role in surface cell protection and extensive interplay between innate (dendritic cells, epithelial cells,
regeneration. If the preepithelial barrier is breached, gastric epithe- neutrophils, and macrophages) and adaptive (B and T cells) compo-
lial cells bordering a site of injury can migrate to restore a damaged nents. Helper T cells (TH and TH regulatory cells) have been extensively
region (restitution). This process occurs independent of cell division studied and appear to play an important role in a broad array of gastric
and requires uninterrupted blood flow and an alkaline pH in the sur- physiology extending from gastric secretion to epithelial cell turnover
rounding environment. Several growth factors, including epidermal via production of a number of cytokines.
growth factor (EGF), transforming growth factor (TGF) α, and basic The discovery of H. pylori has also led to the understanding that
fibroblast growth factor (FGF), modulate the process of restitution. the stomach, once thought to be devoid of microorganisms due to
Larger defects that are not effectively repaired by restitution require cell its highly adverse environment (acid and pepsin), can serve as host
proliferation. Epithelial cell regeneration is regulated by prostaglandins for bacterial communities consisting of hundreds of phylotypes,
and growth factors such as EGF and TGF-α. In tandem with epithelial otherwise known as its microbiota. The conceptual framework of
cell renewal, formation of new vessels (angiogenesis) within the injured the microbiome has been receiving extensive attention in light of its
microvascular bed occurs. Both FGF and vascular endothelial growth importance in human health and disease. The overall relevance of the
factor (VEGF) are important in regulating angiogenesis in the gastric gastric microbiome and its impact on gastric pathology remain to be
mucosa. In addition, the gastric peptide gastrin (see below) has been established, but it is likely that alteration of microorganism homeo-
recently found to stimulate cell proliferation, migration, invasion, stasis will play a role in aspects of certain disorders such as PUD,
angiogenesis, and autophagy. Finally, gastric parietal cells (see below) gastritis, and gastric cancer.
express sonic hedgehog, a family of proteins important in regulating
cell lineage in multiple organs. This latter finding suggests that parietal Physiology of Gastric Secretion HCl and pepsinogen are the
cells may also have the ability to regulate gastric stem cells. two principal gastric secretory products capable of inducing mucosal
An elaborate microvascular system within the gastric submu- injury. Gastric acid and pepsinogen play a physiologic role in protein
cosal layer is the key component of the subepithelial defense/repair digestion; absorption of iron, calcium, magnesium, and vitamin B12;
system, providing HCO3−, which neutralizes the acid generated by and killing ingested bacteria. Acid secretion should be viewed as occur-
the parietal cell. Moreover, this microcirculatory bed provides an ring under basal and stimulated conditions. Basal acid production
adequate supply of micronutrients and oxygen while removing toxic occurs in a circadian pattern, with the highest levels occurring during
metabolic by-products. Several locally produced factors including the night and lowest levels during the morning hours. Cholinergic
nitric oxide (NO) (see below), hydrogen sulfide, and prostacyclin con- input via the vagus nerve and histaminergic input from local gastric
tribute to the vascular protective pathway through vasodilation of the sources are the principal contributors to basal acid secretion. Stimu-
microcirculation. lated gastric acid secretion occurs primarily in three phases based on
Prostaglandins play a central role in gastric epithelial defense/ the site where the signal originates (cephalic, gastric, and intestinal).
repair (Fig. 324-4). The gastric mucosa contains abundant levels of Sight, smell, and taste of food are the components of the cephalic phase,
prostaglandins that regulate the release of mucosal bicarbonate and which stimulates gastric secretion via the vagus nerve. The gastric
mucus, inhibit parietal cell secretion, and are important in maintaining phase is activated once food enters the stomach. This component of

HPIM21e_Part10_p2381-p2670.indd 2435 20/01/22 10:04 PM

 2436
PART 10
Disorders of the Gastrointestinal System

FIGURE 324-3 Components involved in providing gastroduodenal mucosal defense and repair. CCK, cholecystokinin; CRF, corticotropin-releasing factor; EGF, epidermal
growth factor; HCl, hydrochloride; IGF, insulin-like growth factor; TGFα, transforming growth factor α; TRF, thyrotropin releasing factor. (Republished with permission of
John Wiley and Son’s Inc, from Bioregulation and Its Disorders in the Gastrointestinal Tract, T Yoshikawa, T Arakawa [eds]: 1998; permission conveyed through Copyright
Clearance Center, Inc.)

secretion is driven by nutrients (amino acids and amines) that directly peripheral) and humoral (amylin, atrial natriuretic peptide [ANP],
(via peptone and amino acid receptors) and indirectly (via stimulation cholecystokinin, ghrelin, interleukin 11 [IL-11], obestatin, secretin,
of intramural gastrin-releasing peptide neurons) stimulate the G cell to and serotonin) factors play a role in counterbalancing acid secretion.
release gastrin, which in turn activates the parietal cell via direct and Under physiologic circumstances, these phases occur simultaneously.
indirect mechanisms. Distention of the stomach wall also leads to gas- Ghrelin, the appetite-regulating hormone expressed in Gr cells in the
trin release and acid production. The last phase of gastric acid secretion stomach, and its related peptide motilin (released from the duodenum)
is initiated as food enters the intestine and is mediated by luminal dis- may increase gastric acid secretion through stimulation of histamine
tention and nutrient assimilation. A series of pathways that inhibit gas- release from ECL cells, but this remains to be confirmed.
tric acid production are also set into motion during these phases. The The acid-secreting parietal cell is located in the oxyntic gland,
GI hormone somatostatin is released from endocrine cells found in the adjacent to other cellular elements (ECL cell, D cell) important in the
gastric mucosa (D cells) in response to HCl. Somatostatin can inhibit gastric secretory process (Fig. 324-5). This unique cell also secretes
acid production by both direct (parietal cell) and indirect mechanisms intrinsic factor (IF) and IL-11. The parietal cell expresses receptors for
(decreased histamine release from ECL cells, ghrelin release from Gr several stimulants of acid secretion, including histamine (H2), gastrin
cells and gastrin release from G cells). Additional neural (central and (cholecystokinin 2/gastrin receptor), and acetylcholine (muscarinic,

HPIM21e_Part10_p2381-p2670.indd 2436 20/01/22 10:04 PM

 from parietal cell cytoplasm to the secretory canaliculi in exchange 2437
Membrane phospholipids for K+. The H+,K+-ATPase is located within the secretory canaliculus
Phospholipase A2
and in nonsecretory cytoplasmic tubulovesicles. The tubulovesicles are
impermeable to K+, which leads to an inactive pump in this location.
The distribution of pumps between the nonsecretory vesicles and the
Arachidonic acid
secretory canaliculus varies according to parietal cell activity (Fig. 324-2).
Stomach Macrophages Proton pumps are recycled back to the inactive state in cytoplasmic
Kidney COX-1 COX-2 Leukocytes vesicles once parietal cell activation ceases. Ezrin (an actin binding pro-
Platelets housekeeping inflammation Fibroblasts tein), actin, myosin, soluble N-ethylmaleimide-sensitive factor attach-
Endothelium Endothelium
ment protein receptors (SNAREs), small G proteins of the Rab family,
and secretory carrier membrane proteins (SCAMPS) are postulated
to participate in parietal cell membrane translocation. In addition,
TXA2, PGI2, PGE2 PGI2, PGE2 acid secretion requires a number of apical and basolateral parietal cell
Gastrointestinal mucosal integrity Inflammation membrane chloride and potassium channels. Parietal cells also express
Platelet aggregation Mitogenesis
Renal function Bone formation
members of the sonic hedgehog (Shh) family proteins, which play an
Other functions? important role in regulating cell types in multiple organs. This family
of proteins may also regulate cell differentiation as well as restitution of
FIGURE 324-4 Schematic representation of the steps involved in synthesis of mucosal defense in the gastric epithelium.
prostaglandin E2 (PGE2) and prostacyclin (PGI2). Characteristics and distribution The chief cell, found primarily in the gastric fundus, synthesizes and
of the cyclooxygenase (COX) enzymes 1 and 2 are also shown. TXA2, thromboxane A2. secretes pepsinogen, the inactive precursor of the proteolytic enzyme
pepsin. The acid environment within the stomach leads to cleavage of
M3). Binding of histamine to the H2 receptor leads to activation of the inactive precursor to pepsin and provides the low pH (<2) required
adenylate cyclase and the phosphoinositol pathways, in turn resulting for pepsin activity. Pepsin activity is significantly diminished at a pH of
in an increase in cyclic adenosine monophosphate (AMP) and intra- 4 and irreversibly inactivated and denatured at a pH of ≥7. Many of the
cellular calcium, respectively. Activation of the gastrin and muscarinic secretagogues that stimulate acid secretion also stimulate pepsinogen
receptors results in activation of the protein kinase C/phosphoinositide release. The precise role of pepsin in the pathogenesis of PUD remains
signaling pathway. Each of these signaling pathways in turn regulates to be established.
a series of downstream kinase cascades that control the acid-secreting

CHAPTER 324 Peptic Ulcer Disease and Related Disorders

pump, H+,K+-ATPase. The discovery that different ligands and their ■■PATHOPHYSIOLOGIC BASIS OF PUD
corresponding receptors lead to activation of different signaling path- PUD encompasses both gastric ulcers (GUs) and duodenal ulcers
ways explains the potentiation of acid secretion that occurs when hista- (DUs). Ulcers are defined as breaks in the mucosal surface >5 mm in
mine and gastrin or acetylcholine are combined. More importantly, this size, with depth to the submucosa. DUs and GUs share many common
observation explains why blocking one receptor type (H2) decreases features in terms of pathogenesis, diagnosis, and treatment, but several
acid secretion stimulated by agents that activate a different pathway factors distinguish them from one another. H. pylori and NSAIDs are
(gastrin, acetylcholine). Parietal cells also express receptors for ligands the most common risk factors for PUD, with estimated odds ratios in
that inhibit acid production (glucagon-like peptide-1, prostaglandins, the United States of 3.7 and 3.3, respectively. Additional risk factors
somatostatin, EGF, neurotensin, and urocortin). Histamine also stim- (odds ratio) include chronic obstructive lung disease (2.34), chronic
ulates gastric acid secretion indirectly by activating the histamine H3 renal insufficiency (2.29), current tobacco use (1.99), former tobacco
receptor on D cells, which inhibits somatostatin release. use (1.55), older age (1.67), three or more doctor visits in a year (1.49),
The enzyme H+,K+-ATPase is responsible for generating the large coronary heart disease (1.46), former alcohol use (1.29), African-
concentration of H+. It is a membrane-bound protein that consists of American race (1.20), obesity (1.18), and diabetes (1.13). Selective
two subunits, α and β. The active catalytic site is found within the α serotonin reuptake inhibitors (SSRIs) and gastric bypass surgery are
subunit; the function of the β subunit is unclear. This enzyme uses the also associated with an increased incidence of PUD. A rise in idio-
chemical energy of adenosine triphosphate (ATP) to transfer H+ ions pathic PUD has also been noted. The mechanisms by which some of
these risk factors lead to ulcer disease are
highlighted below.
Vagus
Epidemiology • DUODENAL ULCERS
DUs are estimated to occur in 6–15% of
the Western population. The incidence
of DUs declined steadily from 1960 to
CGRP PACAP ACh VIP ACh ACh GRP ACh ACh
1980 and has remained stable since then.
The death rates, need for surgery, and
physician visits have decreased by >50%
+ – + – + + + – over the past 30 years. The reason for
– + –
EC Cell D Cell G Cell
+ Parietal D Cell the reduction in the frequency of DUs is
Cell (SST)
(ANP)
+
(SST)
–
(Gastrin)
+ likely related to the decreasing frequency
H2 H3 of H. pylori in turn associated with over-
+
+ + – all improved sanitary conditions across
–
HP ECL Cell
– the world. Before the discovery of H.
(Chronic Antrum) (Histamine) pylori, the natural history of DUs was
typified by frequent recurrences after ini-
Acid
HP (Acute) Antrum Fundus tial therapy. Eradication of H. pylori has
reduced these recurrence rates by >80%.
GASTRIC ULCERS GUs tend to occur
FIGURE 324-5 Regulation of gastric acid secretion at the cellular level. ACh, acetylcholine; ANP, atrial natriuretic
peptide; CGRP, calcitonin gene-related peptide; EC, enterochromaffin; ECL, enterochromaffin-like; GRP, gastrin- later in life than duodenal lesions, with
releasing peptide; PACAP, pituitary adenylate-cyclase activating peptide; SST, somatostatin; VIP, vasoactive intestinal a peak incidence reported in the sixth
peptide. decade. More than one-half of GUs occur

HPIM21e_Part10_p2381-p2670.indd 2437 20/01/22 10:04 PM

 2438 in males and are less common than DUs, perhaps due to the higher encodes ~1500 proteins. Among this multitude of proteins there are
likelihood of GUs being silent and presenting only after a complication factors that are essential determinants of H. pylori–mediated patho-
develops. Autopsy studies suggest a similar incidence of DUs and GUs. genesis and colonization such as the outer membrane protein (Hop
proteins), urease, and the vacuolating cytotoxin (Vac A). Moreover,
Pathology • DUODENAL ULCERS DUs occur most often in the the majority of H. pylori strains contain a genomic fragment that
first portion of the duodenum (>95%), with ~90% located within 3 cm
encodes the cag pathogenicity island (cag-PAI). Several of the genes
of the pylorus. They are usually ≤1 cm in diameter but can occasionally
that make up cag-PAI encode components of a type IV secretion island
reach 3–6 cm (giant ulcer). Ulcers are sharply demarcated, with depth
that translocates Cag A into host cells. Once in the cell, Cag A acti-
at times reaching the muscularis propria. The base of the ulcer often
vates a series of cellular events important in cell growth and cytokine
consists of a zone of eosinophilic necrosis with surrounding fibrosis.
production. H. pylori also has extensive genetic diversity that in turn
Malignant DUs are extremely rare.
enhances its ability to promote disease. The first step in infection by
GASTRIC ULCERS In contrast to DUs, GUs can represent a malignancy H. pylori is dependent on the bacteria’s motility and its ability to pro-
and should be biopsied upon discovery. Benign GUs are most often duce urease. Urease produces ammonia from urea, an essential step in
found distal to the junction between the antrum and the acid secretory alkalinizing the surrounding pH. Additional bacterial factors include
mucosa. Benign GUs are quite rare in the gastric fundus and are histo- catalase, lipase, adhesins, platelet-activating factor, and pic B (induces
logically similar to DUs. Benign GUs associated with H. pylori are also cytokines). Multiple strains of H. pylori exist and are characterized by
associated with antral gastritis. In contrast, NSAID-related GUs are not their ability to express several of these factors (Cag A, Vac A, etc.). It is
accompanied by chronic active gastritis but may instead have evidence possible that the different diseases related to H. pylori infection can be
of a chemical gastropathy, typified by foveolar hyperplasia, edema of attributed to different strains of the organism with distinct pathogenic
the lamina propria, and epithelial regeneration in the absence of H. features.
pylori. Extension of smooth-muscle fibers into the upper portions of Epidemiology The prevalence of H. pylori varies throughout the world
the mucosa, where they are not typically found, may also occur. and depends largely on the overall standard of living in the region. In
Pathophysiology • DUODENAL ULCERS H. pylori and NSAID- developing parts of the world, 80% of the population may be infected
induced injuries account for the majority of DUs. Many acid secretory by the age of 20, whereas the prevalence is 20–50% in industrialized
abnormalities have been described in DU patients. Of these, average countries. In contrast, in the United States, this organism is rare in
basal and nocturnal gastric acid secretion appears to be increased in childhood. The overall prevalence of H. pylori in the United States is
DU patients as compared to controls; however, the level of overlap ~30%, with individuals born before 1950 having a higher rate of infec-
between DU patients and control subjects is substantial. The reason for tion than those born later. About 10% of Americans <30 years of age
this altered secretory process is unclear, but H. pylori infection may con- are colonized with the bacteria. The rate of infection with H. pylori in
PART 10

tribute. Bicarbonate secretion is significantly decreased in the duodenal industrialized countries has decreased substantially in recent decades.
bulb of patients with an active DU as compared to control subjects. The steady increase in the prevalence of H. pylori noted with increasing
H. pylori infection may also play a role in this process (see below). age is due primarily to a cohort effect, reflecting higher transmission
during a period in which the earlier cohorts were children. It has been
GASTRIC ULCERS As in DUs, the majority of GUs can be attributed to calculated through mathematical models that improved sanitation
Disorders of the Gastrointestinal System

either H. pylori or NSAID-induced mucosal damage. Prepyloric GUs or during the latter half of the nineteenth century dramatically decreased
those in the body associated with a DU or a duodenal scar are similar transmission of H. pylori. Moreover, with the present rate of interven-
in pathogenesis to DUs. Gastric acid output (basal and stimulated) tion, the organism will be ultimately eliminated from the United States.
tends to be normal or decreased in GU patients. When GUs develop Two factors that predispose to higher colonization rates include poor
in the presence of minimal acid levels, impairment of mucosal defense socioeconomic status and less education. These factors, not race, are
factors may be present. GUs have been classified based on their loca- responsible for the rate of H. pylori infection in blacks and Hispanic
tion: type I occur in the gastric body and tend to be associated with low Americans being double the rate seen in whites of comparable age.
gastric acid production; type II occur in the antrum, and gastric acid Other risk factors for H. pylori infection are (1) birth or residence in a
can vary from low to normal; type III occur within 3 cm of the pylorus developing country, (2) domestic crowding, (3) unsanitary living con-
and are commonly accompanied by DUs and normal or high gastric ditions, (4) unclean food or water, and (5) exposure to gastric contents
acid production; and type IV are found in the cardia and are associated of an infected individual.
with low gastric acid production. Transmission of H. pylori occurs from person to person, following
H. PYLORI AND ACID PEPTIC DISORDERS Gastric infection with the an oral-oral or fecal-oral route. The risk of H. pylori infection is declin-
bacterium H. pylori accounts for the majority of PUD (Chap. 163). This ing in developing countries. The rate of infection in the United States
organism also plays a role in the development of gastric mucosa-associ- has fallen by >50% when compared to 30 years ago.
ated lymphoid tissue (MALT) lymphoma and gastric adenocarcinoma. Pathophysiology H. pylori infection is virtually always associated with
Although the entire genome of H. pylori has been sequenced, it is still a chronic active gastritis, but only 10–15% of infected individu-
not clear how this organism, which resides in the stomach, causes als develop frank peptic ulceration. The basis for this difference is
ulceration in the duodenum. H. pylori eradication efforts may lead unknown but is likely due to a combination of host and bacterial fac-
to a decrease in gastric cancer in high-risk populations, particularly tors, some of which are outlined below. Initial studies suggested that
in individuals who have not developed chronic atrophic gastritis and >90% of all DUs were associated with H. pylori, but H. pylori is present
gastric metaplasia. in only 30–60% of individuals with GUs and 50–70% of patients with
The Bacterium The bacterium, initially named Campylobacter pyloridis, DUs. The pathophysiology of ulcers not associated with H. pylori or
is a gram-negative microaerophilic rod found most commonly in NSAID ingestion (or the rare Zollinger-Ellison syndrome [ZES]) is
the deeper portions of the mucous gel coating the gastric mucosa or becoming more relevant as the incidence of H. pylori is dropping, par-
between the mucous layer and the gastric epithelium. It may attach to ticularly in the Western world (see below).
gastric epithelium but under normal circumstances does not appear The particular end result of H. pylori infection (gastritis, PUD,
to invade cells. It is strategically designed to live within the aggressive gastric MALT lymphoma, gastric cancer) is determined by a complex
environment of the stomach. It is S-shaped (~0.5–3 μm in size) and interplay between bacterial and host factors (Fig. 324-6).
contains multiple sheathed flagella. Initially, H. pylori resides in the Bacterial factors: H. pylori is able to facilitate gastric residence,
antrum but, over time, migrates toward the more proximal segments induce mucosal injury, and avoid host defense. Different strains of
of the stomach. The organism is capable of transforming into a coccoid H. pylori produce different virulence factors including γ-glutamyl
form, which represents a dormant state that may facilitate survival in transpeptidase (GGT), cytotoxin-associated gene A (Cag A) product,
adverse conditions. The genome of H. pylori (1.65 million base pairs) and virulence components vacuolating toxin (Vac A), in addition to

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 of commensal organisms that may affect the likelihood of H. pylori 2439
infection and subsequent mucosal injury. Moreover, colonization of
the stomach with H. pylori likely alters the composition of the gastric
microbiota. The impact of the latter on gastric pathophysiology remains
unknown. H. pylori also appears to regulate NO formation via different
mechanisms that in turn may contribute to the organism’s cytotoxic
effects. Specifically, H. pylori–derived factors, such as urease, or the bac-
Bacterial factors Host factors
terium itself, stimulate NO synthase (NOS2) expression in macrophages
Structure Duration and in gastric epithelial cells leading to NO release and subsequent cyto-
Adhesins Location toxic effect on surrounding cells. H. pylori also leads to the formation of
Porins Inflammatory response 8-nitroguanine (8-NO2-Gua), which in conjunction with oncoprotein
Enzymes Genetics?? Cag A, may contribute to the development of gastric cancer.
(urease, vac A, cag A, etc.)
The reason for H. pylori–mediated duodenal ulceration remains
unclear. Studies suggest that H. pylori associated with duodenal ulcer-
Chronic gastritis ation may be more virulent. In addition, certain specific bacterial
Peptic ulcer disease
Gastric MALT lymphoma factors such as the DU-promoting gene A (dupA) may be associated
Gastric cancer with the development of DUs. Another potential contributing factor
is that gastric metaplasia in the duodenum of DU patients, which may
FIGURE 324-6 Outline of the bacterial and host factors important in determining
H. pylori–induced gastrointestinal disease. MALT, mucosal-associated lymphoid tissue.
be due to high acid exposure (see below), permits H. pylori to bind to
it and produce local injury secondary to the host response. Another
hypothesis is that H. pylori antral infection could lead to increased
pathogen-associated molecular patterns (PAMPs) such as flagella and acid production, increased duodenal acid, and mucosal injury. Basal
lipopolysaccharide (LPS). A specific region of the bacterial genome, and stimulated (meal, gastrin-releasing peptide [GRP]) gastrin release
the pathogenicity island (cag-PAI), encodes the virulence factors Cag is increased in H. pylori–infected individuals, and somatostatin-
A and pic B. Vac A also contributes to pathogenicity, although it is not secreting D cells may be decreased. H. pylori infection might induce
encoded within the pathogenicity island. These virulence factors, in increased acid secretion through both direct and indirect actions of
conjunction with additional bacterial constituents, can cause mucosal H. pylori and proinflammatory cytokines (IL-8, TNF, and IL-1) on G,
damage, in part through their ability to target the host immune cells. D, and parietal cells (Fig. 324-7). GUs, in contrast, are associated with

CHAPTER 324 Peptic Ulcer Disease and Related Disorders

For example, Vac A targets human CD4 T cells, inhibiting their pro- H. pylori–induced pangastritis and normal or low gastric acid secre-
liferation, and in addition can disrupt normal function of B cells, CD8 tion. The H. pylori–mediated decrease in gastric acid secretion after
T cells, macrophages, and mast cells. Multiple studies have demon- long-term infection may be due to the bacterium’s ability to inhibit
strated that H. pylori strains that are cag-PAI positive are associated H+,K+-ATPase expression. H. pylori infection has also been associated
with a higher risk of PUD, premalignant gastric lesions, and gastric with decreased duodenal mucosal bicarbonate production. Data sup-
cancer than are strains that lack the cag-PAI. In addition, H. pylori porting and contradicting each of these interesting theories have been
may directly inhibit parietal cell H+,K+-ATPase activity through a Cag demonstrated. Thus, the mechanism by which H. pylori infection of
A–dependent mechanism, leading in part to the low acid production the stomach leads to duodenal ulceration remains to be established.
observed after acute infection with the organism. Urease, which allows The development of in vitro organoids, a unique tool that replicates
the bacteria to reside in the acidic stomach, generates NH3, which can in part the multicellular structure of the intact organ, provides a more
damage epithelial cells. The bacteria produce surface factors that are physiologic model for experimentation in an invitro system. Moreover,
chemotactic for neutrophils and monocytes, which in turn contribute the development of advanced microscopic optical imaging techniques
to epithelial cell injury (see below). H. pylori makes proteases and
phospholipases that break down the glycoprotein lipid complex of
the mucous gel, thus reducing the efficacy of this first line of mucosal Parietal cell FUNDUS
defense. H. pylori expresses adhesins (outer membrane proteins like Vagus
BabA), which facilitate attachment of the bacteria to gastric epithelial Canaliculus
cells. Although LPS of gram-negative bacteria often plays an important
role in the infection, H. pylori LPS has low immunologic activity com- Acetylcholine
pared to that of other organisms. It may promote a smoldering chronic
inflammation. Histamine
Host factors: Studies in twins suggest that there may be genetic +
+
predisposition to acquire H. pylori. The inflammatory response to H. H, K ATPase ECL cell
pylori includes recruitment of neutrophils, lymphocytes (T and B), + Tubulovesicles
macrophages, and plasma cells. The pathogen leads to local injury by Histamine
binding to class II major histocompatibility complex (MHC) molecules + –
–
expressed on gastric epithelial cells, leading to cell death (apoptosis). ECL cell Somatostatin
Moreover, bacterial strains that encode cag-PAI can introduce Cag Somatostatin
A into the host cells, leading to further cell injury and activation of D cell
cellular pathways involved in cytokine production and repression of + Gastrin
tumor-suppressor genes. Elevated concentrations of multiple cytokines
ANTRUM
are found in the gastric epithelium of H. pylori–infected individuals, Blood vessel
including interleukin (IL) 1α/β, IL-2, IL-6, IL-8, tumor necrosis factor Gastrin
(TNF) α, and interferon (IFN) γ. H. pylori infection also leads to both G cell
a mucosal and a systemic humoral response, which does not lead to D cell
–
eradication of the bacteria but further compounds epithelial cell injury. Somatostatin
Additional mechanisms by which H. pylori may cause epithelial cell
injury include (1) activated neutrophil-mediated production of reac- FIGURE 324-7 Summary of potential mechanisms by which H. pylori may lead to
gastric secretory abnormalities. D, somatostatin cell; ECL, enterochromaffin-like cell;
tive oxygen or nitrogen species and enhanced epithelial cell turnover G, G cell. (Reproduced with permission from J Calam et al: How does Helicobacter pylori
and (2) apoptosis related to interaction with T cells (T helper 1 [TH1] cause mucosal damage? Its effect on acid and gastrin physiology. Gastroenterology
cells) and IFN-γ. Finally, the human stomach is colonized by a host 113:543, 1997.)

HPIM21e_Part10_p2381-p2670.indd 2439 20/01/22 10:04 PM

 2440 Gastrointestinal mucosal injury
High level of acid production Duodenal ulcer
Mitochondrial uncoupling
MALT
lymphoma Reactive prooxidants
Antral- MOS
predominant
gastritis ATP

Chronic Nonatrophic Asymptomatic

Normal gastric H. pylori H. pylori M itochondrial fission
pangastritis
mucosa infection infection Mucosal PGHS-1
Corpus-
predominant PGE 2
Acute
atrophic Gastric ulcer Mucosal defense
gastritis
H. pylori Intestinal mucosal barrier function
infection Intestinal metaplasia Mucosal inflammation
Apoptosis
Dysplasia FIGURE 324-9 Effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on different
target organs. The action of NSAIDs on major organs including stomach, small
Low level of acid production Gastric intestine, heart, liver, kidney, respiratory tract, and brain is mainly mediated through
cancer prostaglandin endoperoxide synthase (PGHS)–dependent prostanoid modulation
and alteration of mitochondrial functional integrity leading to mitochondrial
Childhood Advanced age
oxidative stress (MOS) generation, depolarization of mitochondrial transmembrane
potential (ΔΨm), and consequent cell death. However, in heart, low-dose aspirin
FIGURE 324-8 Natural history of H. pylori infection. MALT, mucosal-associated actually offers cardioprotection through antithrombotic effect. Upward arrows
lymphoid tissue. (From S Suerbaum, P Michetti: Helicobacter pylori infection. N Engl J indicate upregulation/elevation; downward arrows indicate downregulation/
Med 347:1175, 2002. Copyright © 2002 Massachusetts Medical Society. Reprinted with depletion. (From S Bindu et al: Non-steroidal anti-inflammatory drugs (NSAIDs) and
permission from Massachusetts Medical Society.) organ damage: A current perspective. Biochem Pharmacol 180:114147, 2020.)

alcohol consumption. SSRIs have a synergistic effect on the induction of

will lead to increased understanding of parietal cell adaptation to
GI bleeding believed to be due in part to this agent’s ability to decrease
H. pylori infection.
platelet aggregation by decreasing serotonin content in platelets.
In summary, the final effect of H. pylori on the GI tract is variable
and determined by microbial and host factors. The type and distri- Pathophysiology Prostaglandins play a critical role in maintaining
gastroduodenal mucosal integrity and repair. It therefore follows that
PART 10

bution of gastritis correlate with the ultimate gastric and duodenal

pathology observed. Specifically, the presence of antral-predominant interruption of prostaglandin synthesis can impair mucosal defense
gastritis is associated with DU formation; gastritis involving primarily and repair, thus facilitating mucosal injury via a systemic mechanism.
the corpus predisposes to the development of GUs, gastric atrophy, and Animal studies have demonstrated that neutrophil adherence to the
ultimately gastric carcinoma (Fig. 324-8). gastric microcirculation plays an essential role in the initiation of
Disorders of the Gastrointestinal System

NSAID-induced mucosal injury. A summary of the pathogenetic path-

NSAID-INDUCED DISEASE ways by which systemically administered NSAIDs may lead to mucosal
Epidemiology NSAIDs represent a group of the most commonly used injury is shown in Fig. 324-9. Single nucleotide polymorphisms (SNPs)
medications in the world and the United States. It is estimated that have been found in several genes, including those encoding certain
7 billion dollars per year are spent on NSAIDs worldwide, with >30 bil- subtypes of cytochrome P450 (see below), IL-1β (IL-1β), angiotensino-
lion over-the-counter tablets sold. More than 30 million individuals gen (AGT), and an organic ion transporting polypeptide (SLCO1B1),
take NSAIDs, with >100 million prescriptions sold yearly in the but these findings need confirmation in larger-scale studies.
United States alone. In fact, after the introduction of COX-2 inhibitors Injury to the mucosa also occurs as a result of the topical use of
in the year 2000, the number of prescriptions written for NSAIDs was NSAIDs, leading to increased epithelial surface permeability. Aspirin
>111 million at a cost of $4.8 billion. Side effects and complications due and many NSAIDs are weak acids that remain in a nonionized lipoph-
to NSAIDs are considered the most common drug-related toxicities in ilic form when found within the acid environment of the stomach.
the United States. The spectrum of NSAID-induced morbidity ranges Under these conditions, NSAIDs migrate across lipid membranes of
from nausea and dyspepsia (prevalence reported as high as 50–60%) epithelial cells, leading to cell injury once trapped intracellularly in an
to a serious GI complication such as endoscopy-documented peptic ionized form. Topical NSAIDs can also alter the surface mucous layer,
ulceration (15–30% of individuals taking NSAIDs regularly), which permitting back diffusion of H+ and pepsin, leading to further epithe-
is complicated by bleeding or perforation in as many as 1.5% of users lial cell damage. Moreover, enteric-coated or buffered preparations are
per year. It is estimated that NSAID-induced GI bleeding accounts also associated with risk of peptic ulceration. NSAIDs can also lead to
for 60,000–120,000 hospital admissions per year, and deaths related mucosal injury via production of additional proinflammatory media-
to NSAID-induced toxicity may be as high as 16,000 per year in the tors such as TNF and leukotrienes through simultaneous activation of
United States. Approximately 4–5% of patients develop symptomatic the lipoxygenase pathway.
ulcers within 1 year. Unfortunately, dyspeptic symptoms do not cor- The interplay between H. pylori and NSAIDs in the pathogenesis
relate with NSAID-induced pathology. Over 80% of patients with seri- of PUD is complex. Meta-analysis supports the conclusion that each
ous NSAID-related complications did not have preceding dyspepsia. In of these aggressive factors is an independent and synergistic risk fac-
view of the lack of warning signs, it is important to identify patients who tor for PUD and its complications such as GI bleeding. For example,
are at increased risk for morbidity and mortality related to NSAID usage. eradication of H. pylori reduces the likelihood of GI complications in
Even 75 mg/d of aspirin may lead to serious GI ulceration; thus, no dose high-risk individuals to levels observed in individuals with average risk
of NSAID is completely safe. In fact, the incidence of mucosal injury of NSAID-induced complications.
(ulcers and erosions) in patients taking low-dose aspirin (75–325 mg) In summary, NSAID-induced mucosal injury is a multifaceted pro-
has been estimated to range from as low as 8 to as high as 60%. It appears cess involving the interaction of multiple, often synergistic pathophysi-
that H. pylori infection increases the risk of PUD-associated GI bleeding ologic processes at the epithelium and surrounding interfaces.
in chronic users of low-dose aspirin. Established risk factors include PATHOGENETIC FACTORS UNRELATED TO H. PYLORI AND NSAIDS IN
advanced age, history of ulcer, concomitant use of glucocorticoids, high- ACID PEPTIC DISEASE Cigarette smoking has been implicated in
dose NSAIDs, multiple NSAIDs, concomitant use of anticoagulants or the pathogenesis of PUD. Not only have smokers been found to have
clopidogrel, and serious or multisystem disease. Possible risk factors ulcers more frequently than do nonsmokers, but smoking appears
include concomitant infection with H. pylori, cigarette smoking, and to decrease healing rates, impair response to therapy, and increase

HPIM21e_Part10_p2381-p2670.indd 2440 20/01/22 10:04 PM

 ulcer-related complications such as perforation. The mechanism TABLE 324-1 Causes of Ulcers Not Caused by Helicobacter pylori 2441
responsible for increased ulcer diathesis in smokers is unknown. and NSAIDs
Theories have included altered gastric emptying, decreased proxi- Pathogenesis of Non-Hp and Non-NSAID Ulcer Disease
mal duodenal bicarbonate production, increased risk for H. pylori
infection, and cigarette-induced generation of noxious mucosal free Infection
radicals. Genetic predisposition may play a role in ulcer development. Cytomegalovirus
First-degree relatives of DU patients are three times as likely to develop Herpes simplex virus
an ulcer; however, the potential role of H. pylori infection in contacts is Helicobacter heilmannii
a major consideration. Increased frequencies of blood group O and of Drug/Toxin
the nonsecretor status have also been implicated as genetic risk factors
Bisphosphonates
for peptic diathesis. However, H. pylori preferentially binds to group O
antigens. Additional genetic factors have been postulated to predispose Chemotherapy
certain individuals to developing PUD and/or upper GI bleeding. Spe- Clopidogrel
cifically, genes encoding the NSAID-metabolizing enzymes cytochrome Crack cocaine
P450 2C9 and 2C8 (CYP2C9 and CYP2C8) are potential susceptibility Glucocorticoids (when combined with NSAIDs)
genes for NSAID-induced PUD, but unfortunately, the studies have not Mycophenolate mofetil
been consistent in demonstrating this association. In a United Kingdom Potassium chloride
study, the CYP2C19*17 gain-of-function polymorphism was associated
Miscellaneous
with PUD in a Caucasian cohort, irrespective of ulcer etiology. These
findings need to be confirmed in broader studies. Psychological stress Basophilia in myeloproliferative disease
has been thought to contribute to PUD, but studies examining the role Duodenal obstruction (e.g., annular pancreas)
of psychological factors in its pathogenesis have generated conflicting Infiltrating disease
results. Although PUD is associated with certain personality traits (neu- Ischemia
roticism), these same traits are also present in individuals with nonulcer Radiation therapy
dyspepsia (NUD) and other functional and organic disorders.
Eosinophilic infiltration
Diet has also been thought to play a role in peptic diseases. Certain
foods and beverages can cause dyspepsia, but no convincing studies Sarcoidosis
indicate an association between ulcer formation and a specific diet. Crohn’s disease

CHAPTER 324 Peptic Ulcer Disease and Related Disorders

Specific chronic disorders have been shown to have a strong associ- Idiopathic hypersecretory state
ation with PUD: (1) advanced age, (2) chronic pulmonary disease, Abbreviations: Hp, H. pylori; NSAIDs, nonsteroidal anti-inflammatory drugs.
(3) chronic renal failure, (4) cirrhosis, (5) nephrolithiasis, (6) α1-an-
titrypsin deficiency, and (7) systemic mastocytosis. Disorders with a
GU patients. Endoscopy detects ulcers in <30% of patients who have
possible association are (1) hyperparathyroidism, (2) coronary artery
dyspepsia.
disease, (3) polycythemia vera, (4) chronic pancreatitis, (5) former
The mechanism for development of abdominal pain in ulcer patients
alcohol use, (6) obesity, (7) African-American race, and (8) three or
is unknown. Several possible explanations include acid-induced acti-
more doctor visits in a year.
vation of chemical receptors in the duodenum, enhanced duodenal
Multiple factors play a role in the pathogenesis of PUD. The
sensitivity to bile acids and pepsin, and altered gastroduodenal
two predominant causes are H. pylori infection and NSAID ingestion.
motility.
PUD not related to H. pylori or NSAIDs is increasing. Other less com-
Variation in the intensity or distribution of the abdominal pain,
mon causes of PUD are shown in Table 324-1. These etiologic agents
as well as the onset of associated symptoms such as nausea and/or
should be considered as the incidence of H. pylori is decreasing. Inde-
vomiting, may be indicative of an ulcer complication. Dyspepsia that
pendent of the inciting or injurious agent, peptic ulcers develop as a
becomes constant, is no longer relieved by food or antacids, or radi-
result of an imbalance between mucosal protection/repair and aggres-
ates to the back may indicate a penetrating ulcer (pancreas). Sudden
sive factors. Gastric acid plays an important role in mucosal injury.
onset of severe, generalized abdominal pain may indicate perforation.
Pain worsening with meals, nausea, and vomiting of undigested food
■■CLINICAL FEATURES suggest gastric outlet obstruction. Tarry stools or coffee-ground emesis
History Abdominal pain is common to many GI disorders, includ- indicate bleeding.
ing DU and GU, but it has a poor predictive value for the presence Physical Examination Epigastric tenderness is the most frequent
of either DU or GU. Approximately two-thirds of patients with finding in patients with GU or DU. Pain may be found to the right of
PUD do not have abdominal pain, and up to 87% of patients with the midline in 20% of patients. Unfortunately, the predictive value of
NSAID-induced mucosal disease can present with a complication this finding is low. Physical examination is critically important for dis-
(bleeding, perforation, and obstruction) without antecedent symp- covering evidence of ulcer complication. Tachycardia and orthostasis
toms. Despite this poor correlation, a careful history and physical suggest dehydration secondary to vomiting or active GI blood loss. A
examination are essential components of the approach to a patient severely tender, board-like abdomen suggests a perforation. Presence
suspected of having peptic ulcers. of a succussion splash indicates retained fluid in the stomach, suggest-
Epigastric pain described as a burning or gnawing discomfort can ing gastric outlet obstruction.
be present in both DU and GU. The discomfort is also described as an
ill-defined, aching sensation or as hunger pain. The typical pain pattern PUD-Related Complications
in DU occurs 90 min to 3 h after a meal and is frequently relieved by GASTROINTESTINAL BLEEDING GI bleeding is the most common
antacids or food. Pain that awakes the patient from sleep (between complication observed in PUD. Bleeding is estimated to occur in
midnight and 3 a.m.) is the most discriminating symptom, with two- 19.4–57 per 100,000 individuals in a general population or in ~15%
thirds of DU patients describing this complaint. Unfortunately, this of patients. Bleeding and complications of ulcer disease occur more
symptom is also present in one-third of patients with NUD (see below). often in individuals >60 years of age. The 30-day mortality rate is as
Elderly patients are less likely to have abdominal pain as a manifes- high as 2.5–10%. The higher incidence in the elderly is likely due to
tation of PUD and may instead present with a complication such as the increased use of NSAIDs in this group. In addition, up to 80% of
ulcer bleeding or perforation. The pain pattern in GU patients may be the mortality in PUD-related bleeding is due to nonbleeding causes
different from that in DU patients, where discomfort may actually be such as multiorgan failure (24%), pulmonary complications (24%), and
precipitated by food. Nausea and weight loss occur more commonly in malignancy (34%).

HPIM21e_Part10_p2381-p2670.indd 2441 20/01/22 10:04 PM

 2442 Greater than 50% of patients with ulcer-related hemorrhage bleed Several additional disease processes that may present with “ulcer-
without any preceding warning signs or symptoms. like” symptoms include proximal GI tumors, gastroesophageal reflux,
PERFORATION The second most common ulcer-related complication vascular disease, pancreaticobiliary disease (biliary colic, chronic pan-
is perforation, being reported in as many as 6–7% of PUD patients creatitis), and gastroduodenal Crohn’s disease.
with an estimated 30-day mortality of >20%. Acute abdominal pain,
tachycardia, and abdominal rigidity compose the classic triad asso- Diagnostic Evaluation In view of the poor predictive value of
ciated with this complication. It is essential to remember that elderly abdominal pain for the presence of a gastroduodenal ulcer and the
patients or individuals who are immunosuppressed may not have this multiple disease processes that can mimic this disease, the clinician
classic presentation. As in the case of bleeding, the incidence of perfo- is often confronted with having to establish the presence of an ulcer.
ration in the elderly appears to be increasing secondary to increased Documentation of an ulcer requires either a radiographic (barium
use of NSAIDs. Perforation of DUs has become less common in light study, rarely done in today’s environment) or an endoscopic procedure.
of the increased rates of H. pylori eradication, with NSAID-induced However, a large percentage of patients with symptoms suggestive of an
GUs leading to perforation occurring more commonly. Penetration is ulcer have NUD; testing for H. pylori and antibiotic therapy (see below)
a form of perforation in which the ulcer bed tunnels into an adjacent are appropriate for individuals who are otherwise healthy and <45 years
organ. DUs tend to penetrate posteriorly into the pancreas, leading to of age, before embarking on a diagnostic evaluation (Chap. 45).
pancreatitis, whereas GUs tend to penetrate into the left hepatic lobe. Barium studies of the proximal GI tract are rarely used as a first test
Gastrocolic fistulas associated with GUs have also been described. for documenting an ulcer. The sensitivity of older single-contrast bar-
Mortality for this complication can be >20% within 30 days. ium meals for detecting a DU is as high as 80%, with a double-contrast
study providing detection rates as high as 90%. Sensitivity for detection
GASTRIC OUTLET OBSTRUCTION Gastric outlet obstruction is the
is decreased in small ulcers (<0.5 cm), with presence of previous scar-
least common ulcer-related complication, occurring in 1–2% of ring, or in postoperative patients. A DU appears as a well-demarcated
patients. A patient may have relative obstruction secondary to ulcer- crater, most often seen in the bulb (Fig. 324-10A). A GU may represent
related inflammation and edema in the peripyloric and duodenal region. benign or malignant disease. Typically, a benign GU also appears as a
This process often resolves with ulcer healing. A fixed, mechanical discrete crater with radiating mucosal folds originating from the ulcer
obstruction secondary to scar formation in the peripyloric areas is also margin (Fig. 324-10B). Ulcers >3 cm in size or those associated with
possible. The latter requires endoscopic (balloon dilation with or with- a mass are more often malignant. Unfortunately, up to 8% of GUs that
out placement of a biodegradable stent) or surgical intervention with appear to be benign by radiographic appearance are malignant by
a stricturoplasty or gastrojejunostomy. Signs and symptoms relative to endoscopy or surgery. Radiographic studies that show a GU must be
mechanical obstruction may develop insidiously. New onset of early followed by endoscopy and biopsy.
satiety, nausea, vomiting, increase of postprandial abdominal pain, and
PART 10

Endoscopy provides the most sensitive and specific approach for

weight loss should make gastric outlet obstruction a possible diagnosis. examining the upper GI tract (Fig. 324-11). In addition to permitting
Differential Diagnosis The list of GI and non-GI disorders that direct visualization of the mucosa, endoscopy facilitates photographic
can mimic ulceration of the stomach or duodenum is quite extensive. documentation of a mucosal defect and tissue biopsy to rule out
The most commonly encountered diagnosis among patients seen for malignancy (GU) or H. pylori. Endoscopic examination is particu-
Disorders of the Gastrointestinal System

upper abdominal discomfort is functional dyspepsia (FD) or essential larly helpful in identifying lesions too small to detect by radiographic
dyspepsia, which refers to a group of heterogeneous disorders typified examination, for evaluation of atypical radiographic abnormalities, or
by upper abdominal pain without the presence of an ulcer. The symp- to determine if an ulcer is a source of blood loss.
toms can range from postprandial fullness and early satiety to epigas- Although the methods for diagnosing H. pylori are outlined in
tric burning pain. The dichotomy of this symptom complex has led to Chap. 163, a brief summary will be included here (Table 324-2).
the identification of two subcategories of FD including postprandial Several biopsy urease tests have been developed (PyloriTek, CLOtest,
distress syndrome (PDS) and epigastric pain syndrome (EPS). Dyspep- Hpfast, Pronto Dry) that have a sensitivity and specificity of >90–95%.
sia has been reported to occur in up to 30% of the U.S. population. Up Several noninvasive methods for detecting this organism have been
to 80% of patients seeking medical care for dyspepsia have a negative developed. Three types of studies routinely used include serologic test-
diagnostic evaluation. The etiology of FD is not established, but recent ing, the 13C- or 14C-urea breath test, and the fecal H. pylori (Hp) antigen
studies suggest that postinfectious states, certain foods, and H. pylori test (monoclonal antibody test). A urinary Hp antigen test and a home
infection may contribute to the pathogenesis of this common disorder. breath test appear promising.

A B
FIGURE 324-10 Barium study demonstrating (A) a benign duodenal ulcer and (B) a benign gastric ulcer.

HPIM21e_Part10_p2381-p2670.indd 2442 20/01/22 10:04 PM

 2443

A B
FIGURE 324-11 Endoscopy demonstrating (A) a benign duodenal ulcer and (B) a benign gastric ulcer.

Occasionally, specialized testing such as serum gastrin and gastric antacids (e.g., Maalox, Mylanta) have a combination of both alumi-
acid analysis may be needed in individuals with complicated or refrac- num and magnesium hydroxide in order to avoid these side effects.
tory PUD (see “Zollinger-Ellison Syndrome,” below). Screening for The magnesium-containing preparation should not be used in
aspirin or NSAIDs (blood or urine) may also be necessary in refractory chronic renal failure patients because of possible hypermagnesemia,
H. pylori–negative PUD patients. and aluminum may cause chronic neurotoxicity in these patients.
Calcium carbonate and sodium bicarbonate are potent antacids
TREATMENT with varying levels of potential problems. The long-term use of
calcium carbonate (converts to calcium chloride in the stomach)

CHAPTER 324 Peptic Ulcer Disease and Related Disorders

Peptic Ulcer Disease can lead to milk-alkali syndrome (hypercalcemia and hyperphos-
phatemia with possible renal calcinosis and progression to renal
Before the discovery of H. pylori, the therapy of PUD was centered
insufficiency). Sodium bicarbonate may induce systemic alkalosis.
on the old dictum by Schwartz of “no acid, no ulcer.” Although acid
secretion is still important in the pathogenesis of PUD, eradication H2 Receptor Antagonists Four of these agents are presently avail-
of H. pylori and therapy/prevention of NSAID-induced disease is able (cimetidine, ranitidine, famotidine, and nizatidine), and their
the mainstay of treatment. A summary of commonly used drugs for structures share homology with histamine. Although each has
treatment of acid peptic disorders is shown in Table 324-3. different potency, all will significantly inhibit basal and stimulated
ACID-NEUTRALIZING/INHIBITORY DRUGS acid secretion to comparable levels when used at therapeutic doses.
Moreover, similar ulcer-healing rates are achieved with each drug
Antacids Before we understood the important role of histamine when used at the correct dosage. Presently, this class of drug is often
in stimulating parietal cell activity, neutralization of secreted acid used for treatment of active ulcers (4–6 weeks) in combination with
with antacids constituted the main form of therapy for peptic ulcers. antibiotics directed at eradicating H. pylori (see below).
They are now rarely, if ever, used as the primary therapeutic agent Cimetidine was the first H2 receptor antagonist used for the
but instead are often used by patients for symptomatic relief of treatment of acid peptic disorders. Cimetidine may have weak
dyspepsia. The most commonly used agents are mixtures of alumi-
num hydroxide and magnesium hydroxide. Aluminum hydroxide
can produce constipation and phosphate depletion; magnesium TABLE 324-3 Drugs Used in the Treatment of Peptic Ulcer Disease
hydroxide may cause loose stools. Many of the commonly used DRUG TYPE/MECHANISM EXAMPLES DOSE
Acid-Suppressing Drugs
TABLE 324-2 Tests for Detection of Helicobacter pylori
Antacids Mylanta, Maalox, 100–140 meq/L 1 and 3 h
SENSITIVITY/ Tums, Gaviscon after meals and hs
TEST SPECIFICITY, % COMMENTS
H2 receptor antagonists Cimetidine 400 mg bid
Invasive (Endoscopy/Biopsy Required)
Ranitidine 300 mg hs
Rapid urease 80–95/95–100 Simple, false negative with recent use of Famotidine 40 mg hs
PPIs, antibiotics, or bismuth compounds
Nizatidine 300 mg hs
Histology 80–90/>95 Requires pathology processing and
staining; provides histologic information Proton pump inhibitors Omeprazole 20 mg/d
Culture —/— Time-consuming, expensive, dependent Lansoprazole 30 mg/d
on experience; allows determination of Rabeprazole 20 mg/d
antibiotic susceptibility
Pantoprazole 40 mg/d
Noninvasive Esomeprazole 20 mg/d
Serology >80/>90 Inexpensive, convenient; not useful for Dexlansoprazole 30 mg/d
early follow-up
Mucosal Protective Agents
Urea breath test >90/>90 Simple, rapid; useful for early follow-up;
false negatives with recent therapy (see Sucralfate Sucralfate 1 g qid
rapid urease test); exposure to low-dose Prostaglandin analogue Misoprostol 200 μg qid
radiation with 14C test
 Bismuth-containing Bismuth subsalicylate See anti–H. pylori
Stool antigen >90/>90 Inexpensive, convenient compounds (BSS) regimens (Table 324-4)
Abbreviation: PPIs, proton pump inhibitors. Abbreviation: hs, at bedtime (hora somni).

HPIM21e_Part10_p2381-p2670.indd 2443 20/01/22 10:04 PM

 2444 antiandrogenic side effects resulting in reversible gynecomastia and normal levels within 1–2 weeks after drug cessation. Rebound gas-
impotence, primarily in patients receiving high doses for prolonged tric acid hypersecretion has been described in H. pylori–negative
periods of time (months to years). In view of cimetidine’s ability individuals after discontinuation of PPIs. It occurs even after rela-
to inhibit cytochrome P450, careful monitoring of drugs such as tively short-term usage (2 months) and may last for up to 2 months
warfarin, phenytoin, and theophylline is indicated with long-term after the PPI has been discontinued. The mechanism involves
usage. Other rare reversible adverse effects reported with cimeti- gastrin-induced hyperplasia and hypertrophy of histamine-secreting
dine include confusion and elevated levels of serum aminotransfer- ECL cells. The clinical relevance of this observation is that individ-
ases, creatinine, and serum prolactin. Ranitidine, famotidine, and uals may have worsening symptoms of GERD or dyspepsia upon
nizatidine are more potent H2 receptor antagonists than cimetidine. stopping the PPI. Gradual tapering of the PPI and switching to an
Each can be used once a day at bedtime for ulcer prevention, which H2 receptor antagonist may prevent this from occurring. H. pylori–
was commonly done before the discovery of H. pylori and the devel- induced inflammation and concomitant decrease in acid production
opment of proton pump inhibitors (PPIs). Patients may develop may explain why this does not occur in H. pylori–positive patients.
tolerance to H2 blockers, a rare event with PPIs (see below). Compa- IF production is also inhibited, but vitamin B12 deficiency anemia is
rable nighttime dosing regimens are cimetidine 800 mg, ranitidine uncommon, probably because of the large stores of the vitamin. As
300 mg, famotidine 40 mg, and nizatidine 300 mg. with any agent that leads to significant hypochlorhydria, PPIs may
Additional rare, reversible systemic toxicities reported with H2 interfere with absorption of drugs such as ketoconazole, ampicillin,
receptor antagonists include pancytopenia, neutropenia, anemia, and iron, and digoxin. Hepatic cytochrome P450 can be inhibited by the
thrombocytopenia, with a prevalence rate varying from 0.01 to 0.2%. earlier PPIs (omeprazole, lansoprazole). Rabeprazole, pantoprazole,
Cimetidine and ranitidine (to a lesser extent) can bind to hepatic and esomeprazole do not appear to interact significantly with drugs
cytochrome P450; famotidine and nizatidine do not. Ranitidine and metabolized by the cytochrome P450 system. The overall clinical
nizatidine were taken off of the market due to contamination of the significance of this observation is not definitely established. Caution
drug with N-nitrosodimethylamine (NDMA), a known carcinogen. should be taken when using theophylline, warfarin, diazepam, ata-
zanavir, and phenytoin concomitantly with PPIs.
Proton Pump (H+,K+-ATPase) Inhibitors Omeprazole, esomepra- The list of potential side effects with long-term PPI use has
zole, lansoprazole, rabeprazole, and pantoprazole are substituted steadily grown over the years. These agents are commonly used
benzimidazole derivatives that covalently bind and irreversibly since several formulations have become available as over-the-
inhibit H+,K+-ATPase. Esomeprazole is the S-enantiomer of ome- counter medications. Moreover, up to 70% of current prescriptions
prazole, which is a racemic mixture of both S- and R-optical iso- for long-term PPIs may be unwarranted and between 35 and 60% of
mers. The R-isomer of lansoprazole, dexlansoprazole, is the most in-hospital use of PPIs may be inappropriate. Interpretation of the
recent PPI approved for clinical use. Its reported advantage is a
PART 10

multiple studies should take into consideration that the vast major-
dual delayed-release system aimed at improving treatment of gas- ity were retrospective observational studies in which confounding
troesophageal reflux disease (GERD). These are the most potent factors could not be accounted for entirely.
acid inhibitory agents available. Omeprazole and lansoprazole Long-term acid suppression, especially with PPIs, has been asso-
are the PPIs that have been used for the longest time. Both are ciated with a higher incidence of community-acquired pneumonia
Disorders of the Gastrointestinal System

acid-labile and are administered as enteric-coated granules in a as well as community- and hospital-acquired Clostridium difficile–
sustained-release capsule that dissolves within the small intestine at associated disease. A meta-analysis showed a 74% increased risk of
a pH of 6. Lansoprazole is available in an orally disintegrating tablet C. difficile infection and a 2.5-fold higher risk of reinfection as com-
that can be taken with or without water, an advantage for individu- pared to nonusers. In light of these concerns, the FDA published a
als who have significant dysphagia. Absorption kinetics are similar safety alert regarding the association between C. difficile infection
to the capsule. In addition, a lansoprazole-naproxen combination and PPI use. Although the risk of spontaneous bacterial peritonitis
preparation that has been made available is targeted at decreasing in cirrhotics was thought to be increased, the data here are less
NSAID-related GI injury (see below). Omeprazole is available as supportive. The impact of PPI-induced changes in the host micro-
non–enteric-coated granules mixed with sodium bicarbonate in a biome is postulated to play a role in the increased risk of infection,
powder form that can be administered orally or via gastric tube. The but this theory needs to be confirmed. These observations require
sodium bicarbonate has two purposes: to protect the omeprazole confirmation but should alert the practitioner to take caution when
from acid degradation and to promote rapid gastric alkalinization recommending these agents for long-term use, especially in elderly
and subsequent proton pump activation, which facilitates rapid patients at risk for developing pneumonia or C. difficile infection.
action of the PPI. Pantoprazole and rabeprazole are available as Diarrhea is also associated with PPI use, which in some cases has
enteric-coated tablets. Pantoprazole is also available as a parent- been associated with the development of collagenous colitis (haz-
eral formulation for intravenous use. These agents are lipophilic ard ratio of 4.5), particularly with lansoprazole. The mechanism
compounds; upon entering the parietal cell, they are protonated for PPI-induced collagenous colitis is unclear, but in vitro studies
and trapped within the acid environment of the tubulovesicular demonstrate that PPIs may induce collagen gene expression. The
and canalicular system. These agents potently inhibit all phases of colitis usually resolves with cessation of the PPI.
gastric acid secretion. Onset of action is rapid, with a maximum A population-based study revealed that long-term use of PPIs was
acid inhibitory effect between 2 and 6 h after administration and associated with the development of hip fractures in older women.
duration of inhibition lasting up to 72–96 h. With repeated daily The absolute risk of fracture remained low and may be zero despite
dosing, progressive acid inhibitory effects are observed, with basal an observed increase associated with the dose and duration of acid
and secretagogue-stimulated acid production being inhibited by suppression. The mechanism for this observation is not clear, and
>95% after 1 week of therapy. The half-life of PPIs is ~18 h; thus, this finding must be confirmed before making broad recommenda-
it can take between 2 and 5 days for gastric acid secretion to return tions regarding the discontinuation of these agents in patients who
to normal levels once these drugs have been discontinued. Because benefit from them. Long-term use of PPIs has also been implicated
the pumps need to be activated for these agents to be effective, their in the development of iron, vitamin B12, and magnesium deficiency.
efficacy is maximized if they are administered before a meal (except A meta-analysis of nine observational studies found a 40% increase
for the immediate-release formulation of omeprazole) (e.g., in the in hypomagnesemia in PPI users as compared to nonusers. One
morning before breakfast). Mild to moderate hypergastrinemia has approach to consider in patients needing to take PPIs long term is to
been observed in patients taking these drugs. Carcinoid tumors check a complete blood count looking for evidence of anemia due to
developed in some animals given the drugs preclinically; however, iron or vitamin B12 deficiency, vitamin B12 level, and a magnesium
extensive experience has failed to demonstrate gastric carcinoid level after 1–2 years of PPI use, but these recommendations are not
tumor development in humans. Serum gastrin levels return to evidence based or recommended by expert opinion. PPIs may exert

HPIM21e_Part10_p2381-p2670.indd 2444 20/01/22 10:04 PM

 a negative effect on the antiplatelet effect of clopidogrel. Although GERD. For example, modified H2 blockers with greater potency 2445
the evidence is mixed and inconclusive, a small increase in mortal- and duration as well as novel PPIs with longer half-life and potency
ity and readmission rate for coronary events was seen in patients are under study. For example, tenatoprazole is a PPI containing an
receiving a PPI while on clopidogrel in earlier studies. Subsequently, imidazopyridine ring instead of a benzimidazole ring, which pro-
three meta-analyses reported an inverse correlation between clopi- motes irreversible proton pump inhibition. This agent has a longer
dogrel and PPI use; therefore, the influence of this drug interaction half-life than the other PPIs and may be beneficial for inhibiting
on mortality is not clearly established. The mechanism involves the nocturnal acid secretion, which has significant relevance in GERD.
competition of the PPI and clopidogrel with the same cytochrome Additional PPIs with longer half-life and combined with other
P450 (CYP2C19). Whether this is a class effect of PPIs is unclear; agents are being studied, but the details are beyond the scope of this
there appears to be at least a theoretical advantage of pantoprazole chapter. A second new class of agents is the potassium-competitive
over the other PPIs, but this has not been confirmed. This drug acid pump antagonists (P-CAPs). These compounds inhibit gastric
interaction is particularly relevant in light of the common use of acid secretion via potassium competitive binding of the H+,K+-AT-
aspirin and clopidogrel for prevention of coronary events and the Pase. Revaprazan, vonoprazan and tegoprazan are agents approved
efficacy of PPIs in preventing GI bleeding in these patients. The for use in Korea and Japan. Vonoprazan may be superior to PPIs
FDA has made several recommendations while awaiting further when combined with antibiotics for the treatment of H. pylori, and
evidence to clarify the impact of PPI therapy on clopidogrel use. this novel agent has been awarded Fast Track status by the FDA for
Health care providers should continue to prescribe clopidogrel to the treatment of H. pylori in combination with both amoxicillin and
patients who require it and should reevaluate the need for starting clarithromycin and with amoxicillin alone.
or continuing treatment with a PPI. From a practical standpoint,
additional recommendations to consider include the following: CYTOPROTECTIVE AGENTS
Patients taking clopidogrel with aspirin, especially with other GI Sucralfate Sucralfate is a complex sucrose salt in which the
risk factors for bleeding, should receive GI protective therapy. hydroxyl groups have been substituted by aluminum hydroxide and
Although high-dose H2 blockers have been considered an option, sulfate. This compound is insoluble in water and becomes a viscous
these do not appear to be as effective as PPIs. If PPIs are to be given, paste within the stomach and duodenum, binding primarily to sites
some have recommended that there be a 12-h separation between of active ulceration. Sucralfate may act by several mechanisms:
administration of the PPI and clopidogrel to minimize competition serving as a physicochemical barrier, promoting a trophic action
of the two agents with the involved cytochrome P450. One option by binding growth factors such as EGF, enhancing prostaglan-
is to give the PPI 30 min before breakfast and the clopidogrel at din synthesis, stimulating mucus and bicarbonate secretion, and

CHAPTER 324 Peptic Ulcer Disease and Related Disorders

bedtime. Insufficient data are available to firmly recommend one enhancing mucosal defense and repair. Toxicity from this drug
PPI over another. Additional concerning side effects with long-term is rare, with constipation being most common (2–3%). It should
PPI use include increased cardiac risks independent of clopidogrel be avoided in patients with chronic renal insufficiency to prevent
use, dementia, and acute and chronic kidney injury. Again, the data aluminum-induced neurotoxicity. Hypophosphatemia and gastric
are often retrospective and confounding variables were not consis- bezoar formation have also been reported rarely. Standard dosing
tently eliminated, thus making it difficult to establish a definitive of sucralfate is 1 g qid.
association between PPIs and the toxicities outlined. A summary
Bismuth-Containing Preparations Sir William Osler considered
of the side effects with the corresponding relative risks is shown
bismuth-containing compounds the drug of choice for treating
in Fig. 324–12. Ultimately, heightened awareness of inappropriate
PUD. The resurgence in the use of these agents is due to their effect
long-term use of PPIs is paramount. Patients aged ≥65 years of age
against H. pylori. Colloidal bismuth subcitrate (CBS) and bismuth
have a higher risk for some of the long-term side effects of PPIs
subsalicylate (BSS; Pepto-Bismol) are the most widely used prepa-
highlighted above, in part due to the higher prevalence of concom-
rations. The mechanism by which these agents induce ulcer healing
itant chronic diseases. It is therefore essential to carefully select
is unclear. Adverse effects with short-term use include black stools,
individuals, especially among the elderly, who need long-term PPI
constipation, and darkening of the tongue. Long-term use with high
therapy and discontinue it in those individuals who do not need it.
doses, especially with the avidly absorbed CBS, may lead to neuro-
Abrupt withdrawal of a PPI in a long-term user may result in a com-
toxicity. These compounds are commonly used as one of the agents
ponent of rebound hyperacidity; thus, this agent should be tapered
in an anti–H. pylori regimen (see below).
gradually over the course of 1–2 weeks with possible transition to
an H2 blocker for a short period of time. Prostaglandin Analogues In view of their central role in main-
Development of novel acid inhibitory agents continues in an taining mucosal integrity and repair, stable prostaglandin analogues
attempt to primarily address the need for better agents to treat were developed for the treatment of PUD. The mechanism by which
this rapidly absorbed drug provides its therapeutic effect is through
enhancement of mucosal defense and repair. The most common
Bone fracture toxicity noted with this drug is diarrhea (10–30% incidence).
C. difficile infection Other major toxicities include uterine bleeding and contractions;
Community-acquired misoprostol is contraindicated in women who may be pregnant,
pneumonia and women of childbearing age must be made clearly aware of this
Side effect

(2 studies)
potential drug toxicity. The standard therapeutic dose is 200 μg qid.
Hypermagnesemia
Miscellaneous Drugs A number of drugs including anticholiner-
Acute interstitial gic agents and tricyclic antidepressants were used for treating acid
nephritis
peptic disorders, but in light of their toxicity and the development
Acute kidney disease of potent antisecretory agents, these are rarely, if ever, used today.
Chronic Newer agents such as teprenone, an acyclic polyisoprenoid com-
kidney disease pound used as a gastric mucosal protector that is employed to treat
gastritis and GUs outside of the United States; plant-based thera-
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
5.50
6.00
6.50

pies; and CCK2 receptor antagonists are intriguing therapies but

Adjusted odds ratio (95% confidence interval) require further evaluation.
FIGURE 324-12. Evidence supporting the potential adverse effects of
proton pump inhibitor drugs. (Adapted from AJ Schoenfeld, D Grady: THERAPY OF H. PYLORI
Adverse effects associated with proton pump inhibitors. JAMA Intern The physician’s goal in treating PUD is to provide relief of symp-
Med 176:172, 2016.) toms (pain or dyspepsia), promote ulcer healing, and ultimately

HPIM21e_Part10_p2381-p2670.indd 2445 20/01/22 10:04 PM

 2446 prevent ulcer recurrence and complications. The greatest influence (PPI plus amoxicillin, PPI plus clarithromycin, ranitidine bismuth
of understanding the role of H. pylori in peptic disease has been the citrate [Tritec] plus clarithromycin) is not recommended in view of
ability to prevent recurrence. Documented eradication of H. pylori studies demonstrating eradication rates of <80–85%. The combina-
in patients with PUD is associated with a dramatic decrease in ulcer tion of bismuth, metronidazole, and tetracycline was the first triple
recurrence to <10–20% as compared to 59% in GU patients and regimen found effective against H. pylori. The combination of two
67% in DU patients when the organism is not eliminated. Eradica- antibiotics plus either a PPI, H2 blocker, or bismuth compound has
tion of the organism may lead to diminished recurrent ulcer bleed- comparable success rates. Addition of acid suppression assists in
ing. The effect of its eradication on ulcer perforation is unclear. providing early symptom relief and enhances bacterial eradication.
Extensive effort has been made in determining who of the many Triple therapy, although effective, has several drawbacks, includ-
individuals with H. pylori infection should be treated. The common ing the potential for poor patient compliance and drug-induced side
conclusion arrived at by multiple consensus conferences around effects. Compliance is being addressed by simplifying the regimens
the world is that H. pylori should be eradicated in patients with so that patients can take the medications twice a day. Simpler (dual
documented PUD. This holds true independent of time of pre- therapy) and shorter regimens (7 and 10 days) are not as effective as
sentation (first episode or not), severity of symptoms, presence of triple therapy for 14 days. Two anti–H. pylori regimens are available
confounding factors such as ingestion of NSAIDs, or whether the in prepackaged formulation: Prevpac (lansoprazole, clarithromycin,
ulcer is in remission. Some have advocated treating patients with a and amoxicillin) and Helidac (BSS, tetracycline, and metroni-
history of documented PUD who are found to be H. pylori positive dazole). The contents of the Prevpac are to be taken twice per day
by stool antigen or breath testing. Between 60 and 90% of patients for 14 days, whereas Helidac constituents are taken four times per
with gastric MALT lymphoma experience complete remission of day with an antisecretory agent (PPI or H2 blocker), also for at least
the tumor in response to H. pylori eradication. The Maastricht IV/ 14 days. Clarithromycin-based triple therapy should be avoided in
Florence Consensus Report recommends a test-and-treat approach settings where H. pylori resistance to this agent exceeds 15%.
for patients with uninvestigated dyspepsia if the local incidence Side effects have been reported in up to 20–30% of patients on
of H. pylori is >20%. The American College of Gastroenterology triple therapy. Bismuth may cause black stools, constipation, or
(ACG) clinical guidelines (developed for North America) recom- darkening of the tongue. The most feared complication with amox-
mend that individuals aged <60 years with uninvestigated dyspepsia icillin is pseudomembranous colitis, but this occurs in <1–2% of
should be tested and treated for H. pylori. In addition, recommen- patients. Amoxicillin can also lead to antibiotic-associated diarrhea,
dations from this consensus report and the ACG clinical guidelines nausea, vomiting, skin rash, and allergic reaction. Concomitant use
include testing and offering eradication of H. pylori in patients who of probiotics may ameliorate some of the antibiotic side effects (see
will be using NSAIDs (including low-dose aspirin) on a long-term below). Tetracycline has been reported to cause rashes and, very
PART 10

basis, especially if there is a prior history of PUD. These individuals rarely, hepatotoxicity and anaphylaxis.
will require continued PPI treatment as well as eradication treat- One important concern with treating patients who may not
ment, because eradication of the organism alone does not eliminate need therapy is the potential for development of antibiotic-
the risk of gastroduodenal ulcers in patients already receiving resistant strains. The incidence and type of antibiotic-resistant
long-term NSAIDs. Treating patients with NUD to prevent gastric H. pylori strains vary worldwide. Strains resistant to metronidazole,
Disorders of the Gastrointestinal System

cancer or patients with GERD requiring long-term acid suppression clarithromycin, amoxicillin, and tetracycline have been described,
remains controversial. Guidelines from the ACG suggest eradica- with the latter two being uncommon. Antibiotic-resistant strains
tion of H. pylori in patients who have undergone resection of early are the most common cause for treatment failure in compliant
gastric cancer. The Maastricht IV/Florence Consensus Report also patients. Unfortunately, in vitro resistance does not predict outcome
evaluated H. pylori treatment in gastric cancer prevention and rec- in patients. Culture and sensitivity testing of H. pylori is not per-
ommends that eradication should be considered in the following formed routinely. Although resistance to metronidazole has been
situations: first-degree relatives of family members with gastric can- found in as many as 30% of isolates in North America and 80%
cer; patients with previous gastric neoplasm treated by endoscopic in developing countries, triple therapy is effective in eradicating
or subtotal resection; individuals with a risk of gastritis (severe pan- the organism in >50% of patients infected with a resistant strain.
gastritis or body-predominant gastritis) or severe atrophy; patients Clarithromycin resistance is seen in 13–16% of individuals in the
with gastric acid inhibition for >1 year; individuals with strong United States, with resistance to amoxicillin being <1% and resis-
environmental risk factors for gastric cancer (heavy smoking; high tance to both metronidazole and clarithromycin in the 5% range.
exposure to dust, coal, quartz, or cement; and/or work in quarries); Resistance to tetracycline and rifabutin (see below) is reported to
and H. pylori–positive patients with a fear of gastric cancer. Finally, be <2% in the United States. In light of the paucity of H. pylori
the ACG clinical guidelines recommend testing and offering H. antibiotic real-time resistance data, asking the patient about prior
pylori eradication to patients with unexplained iron deficiency ane- antibiotic exposure should be included in the decision-making and
mia and idiopathic thrombocytopenic purpura. Despite this, con- used as a surrogate for potential antibiotic resistance, especially
cerns have been raised about the widespread use of antibiotics for when it comes to prior macrolide use. Clarithromycin use should
the therapy of all cases of H. pylori positivity, including the potential be excluded in patients with prior macrolide usage. An approach to
for increased bacterial resistance rates, reported weight gain, and antibiotic selection for H. pylori therapy has been recommended in
alteration of the microbiome. the ACG clinical guidelines (Fig. 324-13).
Multiple drugs have been evaluated in the therapy of H. pylori. Failure of H. pylori eradication with triple therapy in a compliant
No single agent is effective in eradicating the organism. Combi- patient is usually due to infection with a resistant organism. A series
nation therapy for 14 days provides the greatest efficacy, although of salvage therapies for H. pylori are shown in Table 324-5. Quadru-
regimens based on sequential administration of antibiotics also ple therapy (Table 324-4), where clarithromycin is substituted for
appear promising (see below). A shorter administration course metronidazole (or vice versa), should be the next step. The combi-
(7–10 days), although attractive, has not proved as successful as nation of PPI, amoxicillin, and rifabutin for 10 days has also been
the 14-day regimens. The agents used with the greatest frequency used successfully (86% cure rate) in patients infected with resistant
include amoxicillin, metronidazole, tetracycline, clarithromycin, strains. Additional regimens considered for second-line therapy
and bismuth compounds. include levofloxacin-based triple therapy (levofloxacin, amoxicillin,
Suggested treatment regimens for H. pylori are outlined in PPI) for 10 days and furazolidone-based triple therapy (furazoli-
Table 324-4. Choice of a particular regimen will be influenced by done, amoxicillin, PPI) for 14 days. Unfortunately, there is no uni-
several factors, including efficacy, patient tolerance, existing anti- versally accepted treatment regimen recommended for patients in
biotic resistance, prior antibiotic use, and cost of the drugs. The whom two courses of antibiotics have failed. If eradication is still not
aim for initial eradication rates should be 85–90%. Dual therapy achieved in a compliant patient, then culture and sensitivity of the

HPIM21e_Part10_p2381-p2670.indd 2446 20/01/22 10:04 PM

 2447
TABLE 324-4 Recommended First-Line Therapies for H. pylori Infection
REGIMEN DRUGS (DOSES) DOSING FREQUENCY DURATION (DAYS) FDA APPROVAL
Clarithromycin triple PPI (standard or double dose) bid 14 Yesa
Clarithromycin (500 mg)
Amoxicillin (1 g) or metronidazole (500 mg tid)
Bismuth quadruple PPI (standard dose) bid 10–14 Nob
Bismuth subcitrate (120–300 mg) or subsalicylate (300 mg) qid
Tetracycline (500 mg) qid
Metronidazole (250–500 mg) qid (250 mg)
tid to qid (500 mg)
Concomitant PPI (standard dose) bid 10–14 No
Clarithromycin (500 mg)
Amoxicillin (1 g)
Nitroimidazole (500 mg)c
Sequential PPI (standard dose) bid 5–7 No
PPI, clarithromycin (500 mg) + nitroimidazole (500 mg)c bid 5–7
Hybrid PPI (standard dose) + amoxicillin (1 g) bid 7 No
PPI, amoxicillin, clarithromycin (500 mg), nitroimidazole (500 mg)c bid 7
Levofloxacin triple PPI (standard or double dose) + amoxicillin (1 g) bid 5–7 No
Levofloxacin (500 mg) qd
Amoxicillin (1 g) bid
Levofloxacin sequential PPI (standard or double dose) + amoxicillin (1 g) bid 5–7 No
PPI, amoxicillin, levofloxacin (500 mg qd), nitroimidazole (500 mg)c bid 5–7
LOAD Levofloxacin (250 mg) qd 7–10 No

CHAPTER 324 Peptic Ulcer Disease and Related Disorders

PPI (double dose) qd
Nitazoxanide (500 mg) bid
Doxycycline (100 mg) qd
a
Several PPI, clarithromycin, and amoxicillin combinations have achieved FDA approval. The regimen of a PPI, clarithromycin, and metronidazole is not an FDA-approved
treatment regimen. bThe regimen of a PPI, bismuth, tetracycline, and metronidazole combined with a PPI for 10 days is an FDA-approved treatment regimen. cMetronidazole
or tinidazole.
Abbreviations: bid, twice daily; FDA, Food and Drug Administration; PPI, proton pump inhibitor; tid, three times daily; qd, once daily; qid, four times daily.
Source: Reproduced with permission from WD Chey et al: ACG clinical guideline: Treatment of Helicobacter pylori infection. Am J Gastroenterol 112:212, 2017.

organism should be considered. One challenge with this approach Innovative non-antibiotic-mediated approaches have been
is that culture and sensitivity testing is cumbersome and not widely explored in an effort to improve eradication rates of H. pylori.
available; thus, H. pylori resistance data within specific communi- Pretreatment of patients with N-acetylcysteine as a mucolytic agent
ties are often not available. Non-culture-based approaches using to destroy the H. pylori biofilm and therefore impair antibiotic
molecular markers to determine potential resistance through stool resistance has been examined, but more studies are needed to con-
testing are being developed but are not widely available. Additional firm the applicability of this approach. In vitro studies suggest that
factors that may lower eradication rates include the patient’s coun- certain probiotics like Lactobacillus or its metabolites can inhibit
try of origin (higher in Northeast Asia than other parts of Asia or H. pylori. Administration of probiotics has been attempted in sev-
Europe) and cigarette smoking. In addition, meta-analysis suggests eral clinical studies in an effort to maximize antibiotic-mediated
that even the most effective regimens (quadruple therapy including eradication with varying results. Overall, it appears that the use of
PPI, bismuth, tetracycline, and metronidazole and triple therapy certain probiotics, such as Lactobacillus spp., Saccharomyces spp.,
including PPI, clarithromycin, and amoxicillin) may have subopti- Bifidobacterium spp., and Bacillus clausii, did not alter eradication
mal eradication rates (<80%), thus demonstrating the need for the rates but importantly decreased antibiotic-associated side effects
development of more efficacious treatments. including nausea, dysgeusia, diarrhea, and abdominal discomfort/
In view of the observation that 15–25% of patients treated with pain, resulting in enhanced tolerability of H. pylori therapies.
first-line therapy may still remain infected with the organism, Additional studies are needed to confirm the potential benefits
new approaches to treatment have been explored. One promising of probiotics in this setting. Statins, specifically atorvastatin, have
approach is sequential therapy. Regimens examined consist of been used with some success as an adjunct to quadruple therapy in
5 days of amoxicillin and a PPI, followed by an additional 5 days patients with NUD.
of PPI plus tinidazole and clarithromycin or levofloxacin. One Reinfection after successful eradication of H. pylori is rare in the
promising regimen that has the benefit of being shorter in duration, United States (<1% per year). If recurrent infection occurs within
easier to take, and less expensive is 5 days of concomitant therapy the first 6 months after completing therapy, the most likely explana-
(PPI twice daily, amoxicillin 1 g twice daily, levofloxacin 500 mg tion is recrudescence as opposed to reinfection.
twice daily, and tinidazole 500 mg twice daily). Initial studies
have demonstrated eradication rates of >90% with good patient THERAPY OF NSAID-RELATED GASTRIC
tolerance. Confirmation of these findings and applicability of this OR DUODENAL INJURY
approach in the United States are needed, although some experts Medical intervention for NSAID-related mucosal injury includes
are recommending abandoning clarithromycin-based triple therapy treatment of an active ulcer and primary prevention of future
in the United States for the concomitant therapy or the alternative injury. Recommendations for the treatment and primary preven-
sequential therapies highlighted above. tion of NSAID-related mucosal injury are listed in Table 324-6.

HPIM21e_Part10_p2381-p2670.indd 2447 20/01/22 10:04 PM

 2448
Key Questions:
1. Is there a penicillin (PCN)
allergy?
2. Previous macrolide (MCL)
exposure for any reason?

PCN allergy: No PCN allergy: No PCN allergy: Yes PCN allergy: Yes
MCL exposure: No MCL exposure: Yes* MCL exposure: No MCL exposure: Yes*

Recommended Recommended Recommended Recommended

treatments: treatments: treatments: treatments:
Bismuth quadruple Bismuth quadruple Clarithromycin Bismuth quadruple
triple with
CONCOMITANT Levofloxacin triple
metronidazole
Clarithromycin triple Levofloxacin
Bismuth quadruple
With amoxicillin sequential
Other options: Other options:
Sequential Concomitant therapy?
HYBRID Sequential therapy?
Levofloxacin triple Hybrid therapy?
Levofloxacin LOAD?
PART 10

sequential
LOAD?

*In regions where clarithromycin resistance is known

Disorders of the Gastrointestinal System

to be >15%, utilize recommendations for patients

with a history of macrolide exposure.

FIGURE 324-13 Approach to selecting antibiotics for patients with H. pylori infection. LOAD, levofloxacin, omeprazole, nitazoxanide, and doxycycline. (Reproduced with
permission from WD Chey et al: ACG clinical guideline: Treatment of Helicobacter pylori infection. Am J Gastroenterol 112:212, 2017.)

TABLE 324-5 Salvage Therapies for H. pylori Infection

REGIMEN DRUGS (DOSES) DOSING FREQUENCY DURATION (DAYS) FDA APPROVAL
Bismuth quadruple PPI (standard dose) bid 14 Noa
Bismuth subcitrate (120–300 mg) or qid
subsalicylate (300 mg)
Tetracycline (500 mg) qid
Metronidazole (500 mg) tid or qid
Levofloxacin triple PPI (standard dose) bid 14 No
Levofloxacin (500 mg) qd
Amoxicillin (1 g) bid
Concomitant PPI (standard dose) bid 10–14 No
Clarithromycin (500 mg) bid
Amoxicillin (1 g) bid
Nitroimidazole (500 mg) bid or tid
Rifabutin triple PPI (standard dose) bid 10 No
Rifabutin (300 mg) qd
Amoxicillin (1 g) bid
High-dose dual PPI (standard to double dose) tid or qid 14 No
Amoxicillin (1 g tid or 750 mg qid) tid or qid
a
PPI, bismuth, tetracycline, and metronidazole prescribed separately is not an FDA-approved treatment regimen. However, Pylera, a combination
product containing bismuth subcitrate, tetracycline, and metronidazole, combined with a PPI for 10 days is an FDA-approved treatment regimen.
Abbreviations: bid, twice daily; FDA, Food and Drug Administration; PPI, proton pump inhibitor; tid, three times daily; qd, once daily; qid, four times daily.
Source: Reproduced with permission from WD Chey et al: ACG clinical guideline: Treatment of Helicobacter pylori infection. Am J Gastroenterol
112:212, 2017.

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 2449
TABLE 324-6 Recommendations for Treatment of NSAID-Related TABLE 324-7 Guide to NSAID Therapy
Mucosal Injury NO/LOW NSAID
CLINICAL SETTING RECOMMENDATION GI RISK NSAID GI RISK
Active ulcer No CV risk (no Traditional NSAID Coxib or
NSAID discontinued H2 receptor antagonist or PPI aspirin) Traditional NSAID + PPI or
misoprostol
NSAID continued PPI
Consider non-NSAID therapy
Prophylactic therapy Misoprostol
CV risk (consider Traditional NSAID + A gastroprotective agent must
PPI aspirin) PPI or misoprostol be added if a traditional NSAID is
Selective COX-2 inhibitor if GI risk warrants prescribed
H. pylori infection Eradication if active ulcer present or there is a gastroprotection Consider non-NSAID therapy
past history of peptic ulcer disease Consider non-NSAID
therapy
Abbreviations: COX-2, isoenzyme of cyclooxygenase; NSAID, nonsteroidal anti-
inflammatory drug; PPI, proton pump inhibitor. Abbreviations: CV, cardiovascular; GI, gastrointestinal; NSAID, nonsteroidal
anti-inflammatory drug; PPI, proton pump inhibitor.
Source: Republished with permission of MJH Life Sciences, LLC, from COX-2
Ideally, the injurious agent should be stopped as the first step in the inhibitor use after Vioxx: careful balance orend of the rope?, Fendrick AM,
therapy of an active NSAID-induced ulcer. If that is possible, then 10(11 Pt 1): 2004; permission conveyed through Copyright Clearance Center, Inc.
treatment with one of the acid inhibitory agents (H2 blockers, PPIs)
is indicated. Cessation of NSAIDs is not always possible because of aspirin and have low potential for NSAID-induced toxicity, should
the patient’s severe underlying disease. Only PPIs can heal GUs or be considered for a non-NSAID agent or use of a traditional NSAID
DUs, independent of whether NSAIDs are discontinued. such as naproxen (lower CV side effects) in combination with
The widespread use of NSAIDs has created some concern due to gastric protection, if warranted. Finally, individuals with CV and
the increasing likelihood of GI and CV side effects associated with GI risks who require aspirin must be considered for non-NSAID
these agents. The approach to primary prevention has included therapy, but if that is not an option, then gastric protection with
avoiding the agent, using the lowest possible dose of the agent for any type of NSAID must be considered. Any patient, regardless
the shortest period of time possible, using NSAIDs that are theoret- of risk status, who is being considered for long-term traditional
ically less injurious, using newer topical NSAID preparations, and/ NSAID therapy should also be considered for H. pylori testing

CHAPTER 324 Peptic Ulcer Disease and Related Disorders

or using concomitant medical therapy to prevent NSAID-induced and treatment if positive. Assuring the use of GI protective agents
injury. Several nonselective NSAIDs that are associated with a lower with NSAIDs is difficult, even in high-risk patients. This is in part
likelihood of GI and CV toxicity include naproxen and ibuprofen, due to underprescribing of the appropriate protective agent; other
although the beneficial effect may be eliminated if higher dosages times, the difficulty is related to patient compliance. The latter may
of the agents are used. Primary prevention of NSAID-induced be due to patients forgetting to take multiple pills or preferring not
ulceration can be accomplished by a PPI and, if not tolerated, to take the extra pill, especially if they have no GI symptoms. Sev-
misoprostol (200 μg qid). High-dose H2 blockers (famotidine 40 mg eral NSAID gastroprotective-containing combination pills are now
bid) have also shown some promise in preventing endoscopically commercially available, including double-dose famotidine with ibu-
documented ulcers, although PPIs are superior. The highly selec- profen, diclofenac with misoprostol, and naproxen with esomepra-
tive COX-2 inhibitors, celecoxib and rofecoxib, are 100 times more zole. Although initial studies suggested improved compliance and a
selective inhibitors of COX-2 than standard NSAIDs, leading to cost advantage when taking these combination drugs, their clinical
gastric or duodenal mucosal injury that is comparable to placebo; benefit over the use of separate pills has not been established. One
their utilization led to an increase in CV events and withdrawal additional concern with NSAID-induced GI complications is the
from the market. Additional caution was engendered when the relatively low rate of primary care provider compliance with estab-
CLASS study demonstrated that the advantage of celecoxib in lished guidelines outlining preventative measures. An intervention
preventing GI complications was offset when low-dose aspirin including professional education, informatics to facilitate review,
was used simultaneously. Therefore, gastric protection therapy is and financial incentives for practices to review patients’ charts to
required in individuals taking COX-2 inhibitors and aspirin pro- assess appropriateness showed a reduced rate of high-risk prescrib-
phylaxis. Finally, much of the work demonstrating the benefit of ing of antiplatelet medications and NSAIDs with a tendency toward
COX-2 inhibitors and PPIs on GI injury has been performed in improved clinical outcomes. Efforts continue toward developing
individuals of average risk; it is unclear if the same level of benefit safer NSAIDs, including topical NSAIDs, NSAID formulations that
will be achieved in high-risk patients. For example, concomitant use are rapidly absorbed (diclofenac potassium powder mixed with a
of warfarin and a COX-2 inhibitor was associated with rates of GI buffering agent, Prosorb and SoluMatrix technology), NO-releasing
bleeding similar to those observed in patients taking nonselective NSAIDs, hydrogen sulfide–releasing NSAIDs, dual COX/5-LOX
NSAIDs. A combination of factors, including withdrawal of the inhibitors, NSAID prodrugs, and agents that can effectively seques-
majority of COX-2 inhibitors from the market, the observation ter unbound NSAIDs without interfering with their efficacy.
that low-dose aspirin appears to diminish the beneficial effect of
COX-2–selective inhibitors, and the growing use of aspirin for pro- APPROACH AND THERAPY: SUMMARY
phylaxis of CV events, has significantly altered the approach to gas- Controversy continues regarding the best approach to the patient who
tric protective therapy during the use of NSAIDs. A set of guidelines presents with dyspepsia (Chap. 45). The discovery of H. pylori and its
for the approach to the use of NSAIDs was published by the ACG role in pathogenesis of ulcers has added a new variable to the equation.
and is shown in Table 324-7. Individuals who are not at risk for CV Previously, if a patient <50 years of age presented with dyspepsia and
events, do not use aspirin, and are without risk for GI complications without alarming signs or symptoms suggestive of an ulcer complica-
can receive nonselective NSAIDs without gastric protection. In tion or malignancy, an empirical therapeutic trial with acid suppression
those without CV risk factors but with a high potential risk (prior was commonly recommended. Although this approach is practiced by
GI bleeding or multiple GI risk factors) for NSAID-induced GI some today, an approach presently gaining approval for the treatment
toxicity, cautious use of a selective COX-2 inhibitor and co-therapy of patients with dyspepsia is outlined in Fig. 324-14. The referral to a
with high-dose PPI or misoprostol are recommended. Individuals gastroenterologist is for the potential need of endoscopy and subsequent
at moderate GI risk without cardiac risk factors can be treated with evaluation and treatment if the endoscopy is negative.
a COX-2 inhibitor alone or with a nonselective NSAID with PPI or Once an ulcer (GU or DU) is documented, the main issue at
misoprostol. Individuals with CV risk factors, who require low-dose stake is whether H. pylori or an NSAID is involved. With H. pylori

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 2450 or GUs) heal after 8 weeks of treatment with higher doses of PPI
New-Onset Dyspepsia (omeprazole 40 mg/d; lansoprazole 30–60 mg/d). This higher dose
>40 years old is also effective in maintaining remission. Surgical intervention
Alarm symptoms may be a consideration at this point; however, other rare causes of
Exclude by history GERD, biliary refractory ulcers must be excluded before recommending surgery.
pain, IBS, aerophagia, Rare etiologies of refractory ulcers that may be diagnosed by gastric
medication-related or duodenal biopsies include ischemia, Crohn’s disease, amyloido-
sis, sarcoidosis, lymphoma, eosinophilic gastroenteritis, smoking
– crack cocaine, or infection (cytomegalovirus [CMV], tuberculosis,
or syphilis).
Noninvasive Hp testing SURGICAL THERAPY
Surgical intervention in PUD can be viewed as being either elec-
+ – + tive, for treatment of medically refractory disease, or as urgent/
emergent, for the treatment of an ulcer-related complication. The
development of pharmacologic and endoscopic approaches for
or
Anti-Hp Empiric trial Refer to the treatment of peptic disease and its complications has led to a
therapy H2 blocker gastroenterologist
substantial decrease in the number of operations needed for this
4 weeks disorder with a drop of >90% for elective ulcer surgery over the past
after therapy four decades. Refractory ulcers are an exceedingly rare occurrence.
Surgery is more often required for treatment of an ulcer-related
Confirm eradication UBT
complication.
Hemorrhage is the most common ulcer-related complication,
Symptoms remain or recur occurring in ~15–25% of patients. Bleeding may occur in any age
group but is most often seen in older patients (sixth decade or
FIGURE 324-14 Overview of new-onset dyspepsia. GERD, gastroesophageal reflux beyond). The majority of patients stop bleeding spontaneously, but
disease; Hp, Helicobacter pylori; IBS, irritable bowel syndrome; UBT, urea breath endoscopic therapy (Chap. 322) is necessary in some. Parenterally
test. (Reproduced with permission from BS Anand, DY Graham: State-of-the-Art: and orally administered PPIs also decrease ulcer rebleeding in patients
Ulcer and Gastritis, Endoscopy 31:215, 1999. © Georg Thieme Verlag KG.)
who have undergone endoscopic therapy. Patients unresponsive or
PART 10

refractory to endoscopic intervention will require angiographic inter-

present, independent of the NSAID status, triple therapy is rec-
vention or surgery (~5% of transfusion-requiring patients).
ommended for 14 days, followed by continued acid-suppressing
Free peritoneal perforation occurs in ~2–3% of DU patients,
drugs (H2 receptor antagonist or PPIs) for a total of 4–6 weeks. H.
with NSAID-induced GU perforations occurring more commonly.
pylori eradication should be documented 4 weeks after completing
Sudden onset of severe abdominal pain with peritoneal signs and
Disorders of the Gastrointestinal System

antibiotics. The test of choice for documenting eradication is the

evidence of pneumoperitoneum on abdominal imaging is the clas-
laboratory-based validated monoclonal stool antigen test or a urea
sic presentation of a perforated viscous, but this presentation occurs
breath test (UBT). The patient must be off antisecretory agents for
in only two-thirds of patients. The latter is especially true in elderly
at least 7 days when being tested for eradication of H. pylori with
patients (>70 years old), obese individuals, and immunocompro-
UBT or stool antigen. Serologic testing is not useful for the purpose
mised patients. It is important to keep in mind that, as in the case
of documenting eradication because antibody titers fall slowly and
of bleeding, up to 10% of these patients will not have antecedent
often do not become undetectable. Some recommend that patients
ulcer symptoms. Delay in diagnosis clearly leads to higher mortal-
with complicated ulcer disease or who are frail should be treated
ity; thus, early suspicion and intervention with nasogastric suction,
with long-term acid suppression, thus making documentation of
intravenous PPI, antibiotics and surgical consultation are essential.
H. pylori eradication a moot point. In view of this discrepancy in
Concomitant bleeding may occur in up to 10% of patients with
practice, it would be best to discuss with the patient the different
perforation, with mortality being increased substantially. Peptic
options available.
ulcer can also penetrate into adjacent organs, especially with a
Several issues differentiate the approach to a GU versus a DU.
posterior DU, which can penetrate into the pancreas, colon, liver,
GUs, especially of the body and fundus, have the potential of being
or biliary tree.
malignant. Multiple biopsies of a GU should be taken initially; even
Pyloric channel ulcers or DUs can lead to gastric outlet obstruc-
if these are negative for neoplasm, repeat endoscopy to document
tion in ~2–3% of patients. This can result from chronic scarring
healing at 8–12 weeks should be performed, with biopsy if the ulcer
or from impaired motility due to inflammation and/or edema
is still present. About 70% of GUs eventually found to be malignant
with pylorospasm. Patients may present with early satiety, nausea,
undergo significant (usually incomplete) healing. Repeat endos-
vomiting of undigested food, and weight loss. Conservative man-
copy is warranted in patients with DU if symptoms persist despite
agement with nasogastric suction, intravenous hydration/nutrition,
medical therapy or a complication is suspected.
and antisecretory agents is indicated for 7–10 days with the hope
The majority (>90%) of GUs and DUs heal with the conventional
that a functional obstruction will reverse. If a mechanical obstruc-
therapy outlined above. A GU that fails to heal after 12 weeks and a
tion persists, endoscopic intervention with balloon dilation may be
DU that does not heal after 8 weeks of therapy should be considered
effective. Surgery should be considered if all else fails.
refractory. Once poor compliance and persistent H. pylori infection
have been excluded, NSAID use, either inadvertent or surrepti- Specific Operations for Duodenal Ulcers Surgical treatment was
tious, must be excluded. In addition, cigarette smoking must be originally designed to decrease gastric acid secretion. Operations
eliminated. For a GU, malignancy must be meticulously excluded. most commonly performed include (1) vagotomy and drainage
Next, consideration should be given to a gastric acid hypersecretory (by pyloroplasty, gastroduodenostomy, or gastrojejunostomy), (2)
state such as ZES (see “Zollinger-Ellison Syndrome,” below) or the highly selective vagotomy (which does not require a drainage pro-
idiopathic form, which can be excluded with gastric acid analysis. cedure), and (3) vagotomy with antrectomy. The specific procedure
Although a subset of patients has gastric acid hypersecretion of performed is dictated by the underlying circumstances: elective
unclear etiology as a contributing factor to refractory ulcers, ZES versus emergency, the degree and extent of duodenal ulceration,
should be excluded with a fasting gastrin or secretin stimulation the etiology of the ulcer (H. pylori, NSAIDs, malignancy), and the
test (see below). More than 90% of refractory ulcers (either DUs expertise of the surgeon. Moreover, the trend has been toward a

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 dramatic decrease in the need for surgery for treatment of refrac- Of these procedures, highly selective vagotomy may be the pro- 2451
tory PUD, and when needed, minimally invasive and anatomy- cedure of choice in the elective setting, except in situations where
preserving operations are preferred. ulcer recurrence rates are high (prepyloric ulcers and those refrac-
Vagotomy is a component of each of these procedures and is tory to medical therapy). Selection of vagotomy and antrectomy
aimed at decreasing acid secretion through ablating cholinergic may be more appropriate in these circumstances.
input to the stomach. Unfortunately, both truncal and selective These procedures have been traditionally performed by standard
vagotomy (preserves the celiac and hepatic branches) result in laparotomy. The advent of laparoscopic surgery has led several
gastric atony despite successful reduction of both basal acid out- surgical teams to successfully perform highly selective vagotomy,
put (BAO; decreased by 85%) and maximal acid output (MAO; truncal vagotomy/pyloroplasty, and truncal vagotomy/antrectomy
decreased by 50%). Drainage through pyloroplasty or gastroduode- through this approach. An increase in the number of laparoscopic
nostomy is required in an effort to compensate for the vagotomy- procedures for treatment of PUD has occurred. Laparoscopic repair
induced gastric motility disorder. This procedure has an interme- of perforated peptic ulcers is safe, feasible for the experienced sur-
diate complication rate and a 10% ulcer recurrence rate. To mini- geon, and associated with decreased postoperative pain, although it
mize gastric dysmotility, highly selective vagotomy (also known as does take longer than an open approach. Moreover, no difference
parietal cell, super-selective, or proximal vagotomy) was developed. between the two approaches is noted in postoperative complica-
Only the vagal fibers innervating the portion of the stomach that tions or length of hospital stay.
contains parietal cells are transected, thus leaving fibers important Specific Operations for GUs The location and presence of a
for regulating gastric motility intact. Although this procedure concomitant DU dictate the operative procedure performed for
leads to an immediate decrease in both BAO and stimulated acid a GU. Antrectomy (including the ulcer) with a Billroth I anasto-
output, acid secretion recovers over time. By the end of the first mosis is the treatment of choice for an antral ulcer. Vagotomy is
postoperative year, basal and stimulated acid output are ~30 and performed only if a DU is present. Although ulcer excision with
50%, respectively, of preoperative levels. Ulcer recurrence rates are vagotomy and drainage procedure has been proposed, the higher
higher with highly selective vagotomy (≥10%), although the overall incidence of ulcer recurrence makes this a less desirable approach.
complication rates are the lowest of the three procedures. Ulcers located near the esophagogastric junction may require a
The procedure that provides the lowest rates of ulcer recurrence more radical approach, a subtotal gastrectomy with a Roux-en-Y
(1%) but has the highest complication rate is vagotomy (truncal or esophagogastrojejunostomy (Csendes’ procedure). A less aggres-
selective) in combination with antrectomy. Antrectomy is aimed sive approach, including antrectomy, intraoperative ulcer biopsy,
at eliminating an additional stimulant of gastric acid secretion, and vagotomy (Kelling-Madlener procedure), may be indicated in

CHAPTER 324 Peptic Ulcer Disease and Related Disorders

gastrin. Two principal types of reanastomoses are used after ant- fragile patients with a high GU. Ulcer recurrence approaches 30%
rectomy: gastroduodenostomy (Billroth I) or gastrojejunostomy with this procedure.
(Billroth II) (Fig. 324-15). Although Billroth I is often preferred
over II, severe duodenal inflammation or scarring may preclude its Surgery-Related Complications Complications seen after sur-
performance. Prospective, randomized studies confirm that partial gery for PUD are related primarily to the extent of the anatomic
gastrectomy followed by Roux-en-Y reconstruction leads to a sig- modification performed. Minimal alteration (highly selective vago-
nificantly better clinical, endoscopic, and histologic outcome than tomy) is associated with higher rates of ulcer recurrence and less
Billroth II reconstruction. GI disturbance. More aggressive surgical procedures have a lower
rate of ulcer recurrence but a greater incidence of GI dysfunction.
Overall, morbidity and mortality related to these procedures are
quite low. Morbidity associated with vagotomy and antrectomy or
pyloroplasty is ≤5%, with mortality ~1%. Highly selective vagotomy
has lower morbidity and mortality rates of 1 and 0.3%, respectively.
In addition to the potential early consequences of any intraab-
dominal procedure (bleeding, infection, thromboembolism), gas-
Antrum troparesis, duodenal stump leak, and efferent loop obstruction can
Fundus be observed.
Duodenum Recurrent Ulceration The risk of ulcer recurrence is directly
related to the procedure performed. Ulcers that recur after partial
gastric resection tend to develop at the anastomosis (stomal or
marginal ulcer). Epigastric abdominal pain is the most frequent
presenting complaint (>90%). Severity and duration of pain tend to
be more progressive than observed with DUs before surgery.
Ulcers may recur for several reasons, including incomplete vago-
tomy, inadequate drainage, retained antrum, and, less likely, persis-
tent or recurrent H. pylori infection. ZES should have been excluded
preoperatively. Surreptitious use of NSAIDs is an important reason
for recurrent ulcers after surgery, especially if the initial procedure
was done for an NSAID-induced ulcer. Once H. pylori and NSAIDs
have been excluded as etiologic factors, the question of incomplete
vagotomy or retained gastric antrum should be explored. For the
latter, fasting plasma gastrin levels should be determined. If ele-
vated, retained antrum or ZES (see below) should be considered.
Incomplete vagotomy can be ruled out by gastric acid analysis cou-
pled with sham feeding. In this test, gastric acid output is measured
while the patient sees, smells, and chews a meal (without swallow-
ing). The cephalic phase of gastric secretion, which is mediated by
the vagus, is being assessed with this study. An increase in gastric
acid output in response to sham feeding is evidence that the vagus
Billroth I Billroth II nerve is intact. A rise in serum pancreatic polypeptide >50% within
FIGURE 324-15 Schematic representation of Billroth I and II procedures. 30 min of sham feeding is also suggestive of an intact vagus nerve.

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 2452 Medical therapy with H2 blockers will heal postoperative ulcera- diarrhea that occurs typically 1–2 h after meals. Occasionally, the
tion in 70–90% of patients. The efficacy of PPIs has not been fully symptoms may be severe and relentless. This is due to a motility
assessed in this group, but one may anticipate greater rates of ulcer disorder from interruption of the vagal fibers supplying the luminal
healing compared to those obtained with H2 blockers. Repeat oper- gut. Other contributing factors may include decreased absorption
ation (complete vagotomy, partial gastrectomy) may be required in of nutrients (see below), increased excretion of bile acids, and
a small subgroup of patients who have not responded to aggressive release of luminal factors that promote secretion. Diphenoxylate or
medical management. loperamide is often useful in symptom control. The bile salt–binding
Afferent Loop Syndromes Although rarely seen today as a result agent cholestyramine may be helpful in severe cases. Surgical rever-
of the decrease in the performance of Billroth II anastomosis, two sal of a 10-cm segment of jejunum may yield a substantial improve-
types of afferent loop syndrome can occur in patients who have ment in bowel frequency in a subset of patients.
undergone this type of partial gastric resection. The more common Bile Reflux Gastropathy A subset of post–partial gastrectomy
of the two is bacterial overgrowth in the afferent limb secondary patients who present with abdominal pain, early satiety, nausea,
to stasis. Patients may experience postprandial abdominal pain, and vomiting will have mucosal erythema of the gastric remnant
bloating, and diarrhea with concomitant malabsorption of fats and as the only finding. Histologic examination of the gastric mucosa
vitamin B12. Cases refractory to antibiotics may require surgical reveals minimal inflammation but the presence of epithelial cell
revision of the loop. The less common afferent loop syndrome injury. This clinical picture is categorized as bile or alkaline reflux
can present with severe abdominal pain and bloating that occur gastropathy/gastritis. Although reflux of bile is implicated as the
20–60 min after meals. Pain is often followed by nausea and reason for this disorder, the mechanism is unknown. Prokinetic
vomiting of bile-containing material. The pain and bloating may agents, cholestyramine, and sucralfate have been somewhat effec-
improve after emesis. The cause of this clinical picture is theorized tive treatments. Severe refractory symptoms may require using
to be incomplete drainage of bile and pancreatic secretions from an either nuclear scanning with 99mTc-HIDA to document reflux.
afferent loop that is partially obstructed. Cases refractory to dietary Surgical diversion of pancreaticobiliary secretions away from the
measures may need surgical revision or conversion of the Billroth gastric remnant with a Roux-en-Y gastrojejunostomy consisting of
II anastomosis to a Roux-en-Y gastrojejunostomy. a long (50–60 cm) Roux limb has been used in severe cases. Bilious
Dumping Syndrome Dumping syndrome consists of a series of vaso- vomiting improves, but early satiety and bloating may persist in up
motor and GI signs and symptoms and occurs in patients who have to 50% of patients.
undergone vagotomy and drainage (especially Billroth procedures). Maldigestion and Malabsorption Weight loss can be observed
Two phases of dumping, early and late, can occur. Early dumping in up to 60% of patients after partial gastric resection. Patients
takes place 15–30 min after meals and consists of crampy abdomi- can experience a 10% loss of body weight, which stabilizes
PART 10

nal discomfort, nausea, diarrhea, belching, tachycardia, palpitations, 3 months postoperatively. A significant component of this weight
diaphoresis, light-headedness, and, rarely, syncope. These signs and reduction is due to decreased oral intake. However, mild steator-
symptoms arise from the rapid emptying of hyperosmolar gastric rhea can also develop. Reasons for maldigestion/malabsorption
contents into the small intestine, resulting in a fluid shift into the gut include decreased gastric acid production, rapid gastric emptying,
Disorders of the Gastrointestinal System

lumen with plasma volume contraction and acute intestinal distention. decreased food dispersion in the stomach, reduced luminal bile
Release of vasoactive GI hormones (vasoactive intestinal polypeptide, concentration, reduced pancreatic secretory response to feeding,
neurotensin, motilin) is also theorized to play a role in early dumping. and rapid intestinal transit.
The late phase of dumping typically occurs 90 min to 3 h after Decreased serum vitamin B12 levels can be observed after partial
meals. Vasomotor symptoms (light-headedness, diaphoresis, palpi- gastrectomy. This is usually not due to deficiency of IF, since a
tations, tachycardia, and syncope) predominate during this phase. minimal amount of parietal cells (source of IF) is removed during
This component of dumping is thought to be secondary to hypogly- antrectomy. Reduced vitamin B12 may be due to competition for
cemia from excessive insulin release. the vitamin by bacterial overgrowth or inability to split the vitamin
Dumping syndrome is most noticeable after meals rich in simple from its protein-bound source due to hypochlorhydria.
carbohydrates (especially sucrose) and high osmolarity. Ingestion Iron-deficiency anemia may be a consequence of impaired
of large amounts of fluids may also contribute. After vagotomy and absorption of dietary iron in patients with a Billroth II gastroje-
drainage, up to 50% of patients will experience dumping syndrome junostomy. Absorption of iron salts is normal in these individuals;
to some degree early on. Signs and symptoms often improve with thus, a favorable response to oral iron supplementation can be
time, but a severe protracted picture can occur in up to 1% of anticipated. Folate deficiency with concomitant anemia can also
patients. develop in these patients. This deficiency may be secondary to
Dietary modification is the cornerstone of therapy for patients decreased absorption or diminished oral intake.
with dumping syndrome. Small, multiple (six) meals devoid of Malabsorption of vitamin D and calcium resulting in osteopo-
simple carbohydrates coupled with elimination of liquids during rosis and osteomalacia is common after partial gastrectomy and
meals is important. Antidiarrheals and anticholinergic agents are gastrojejunostomy (Billroth II). Osteomalacia can occur as a late
complementary to diet. Guar and pectin, which increase the viscos- complication in up to 25% of post–partial gastrectomy patients.
ity of intraluminal contents, may be beneficial in more symptomatic Bone fractures occur twice as commonly in men after gastric
individuals. Acarbose, an α-glucosidase inhibitor that delays diges- surgery as in a control population. It may take years before x-ray
tion of ingested carbohydrates, has also been shown to be beneficial findings demonstrate diminished bone density. Elevated alkaline
in the treatment of the late phases of dumping. The somatostatin phosphatase, reduced serum calcium, bone pain, and pathologic
analogue octreotide has been successful in diet-refractory cases. fractures may be seen in patients with osteomalacia. The high inci-
This drug is administered subcutaneously (50 μg tid), titrated dence of these abnormalities in this subgroup of patients justifies
according to clinical response. A long-acting depot formulation of treating them with vitamin D and calcium supplementation indef-
octreotide can be administered once every 28 days and provides initely. Therapy is especially important in females. Copper defi-
symptom relief comparable to the short-acting agent. In addition, ciency has also been reported in patients undergoing surgeries that
patient weight gain and quality of life appear to be superior with the bypass the duodenum, where copper is primarily absorbed. Patients
long-acting form. may present with a rare syndrome that includes ataxia, myelopathy,
Postvagotomy Diarrhea Up to 10% of patients may seek medical and peripheral neuropathy.
attention for the treatment of postvagotomy diarrhea. This compli- Gastric Adenocarcinoma The incidence of adenocarcinoma in
cation is most commonly observed after truncal vagotomy, which the gastric stump is increased 15 years after resection. Some have
is rarely performed today. Patients may complain of intermittent reported a four- to fivefold increase in gastric cancer 20–25 years

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 after resection. The pathogenesis is unclear but may involve alka- most common clinical manifestation, occurring in >90% of gastrinoma 2453
line reflux, bacterial proliferation, or hypochlorhydria. The role patients. Initial presentation and ulcer location (duodenal bulb) may be
of endoscopic screening is not clear, and most guidelines do not indistinguishable from common PUD. Clinical situations that should
support its use. create suspicion of gastrinoma are ulcers in unusual locations (second
Additional Complications Reflux esophagitis and a higher inci- part of the duodenum and beyond), ulcers refractory to standard
dence of gallstones and cholecystitis have been reported in patients medical therapy, ulcer recurrence after acid-reducing surgery, ulcers
undergoing subtotal gastrectomy. The latter is thought to be due to presenting with frank complications (bleeding, obstruction, and per-
decreased gallbladder contractility associated with vagotomy and foration), or ulcers in the absence of H. pylori or NSAID ingestion.
bypass of the duodenum, leading to decreased postprandial release Symptoms of esophageal origin are present in up to two-thirds of
of cholecystokinin. patients with ZES, with a spectrum ranging from mild esophagitis to
frank ulceration with stricture and Barrett’s mucosa.
Diarrhea, the next most common clinical manifestation, is found in
up to 70% of patients. Although diarrhea often occurs concomitantly
RELATED CONDITIONS with acid peptic disease, it may also occur independent of an ulcer and
classically will abate with PPI therapy. Etiology of the diarrhea is mul-
■■ZOLLINGER-ELLISON SYNDROME
tifactorial, resulting from marked volume overload to the small bowel,
Severe peptic ulcer diathesis secondary to gastric acid hypersecre-
pancreatic enzyme inactivation by acid, and damage of the intestinal
tion due to unregulated gastrin release from a non–β-cell, often
epithelial surface by acid. The epithelial damage can lead to a mild
well-differentiated neuroendocrine tumor (NET; gastrinoma) defines
degree of maldigestion and malabsorption of nutrients. The diarrhea
the components of ZES. Initially, ZES was typified by aggressive and
may also have a secretory component due to the direct stimulatory
refractory ulceration in which total gastrectomy provided the only chance
effect of gastrin on enterocytes or the co-secretion of additional hor-
for enhancing survival. Today, it can be cured by surgical resection in up
mones from the tumor such as vasoactive intestinal peptide.
to 40% of patients with the sporadic form of the disease (see below).
Gastrinomas can develop in the presence of MEN 1 syndrome
Epidemiology The true incidence of ZES is unknown, but esti- (Chaps. 84 and 388) in ~25% of patients. This autosomal dominant
mates suggest that it varies from 0.1 to 1% of individuals presenting disorder involves primarily three organ sites: the parathyroid glands
with PUD, with 0.1–3 individuals per year having this rare diagnosis. (80–90%), pancreas (40–80%), and pituitary gland (30–60%). The
Others have estimated an incidence of 0.5–3 per million population. syndrome is caused by inactivating mutations of the MEN1 tumor-
Females are slightly more commonly affected than males, and the suppressor gene found on the long arm of chromosome 11q13. The

CHAPTER 324 Peptic Ulcer Disease and Related Disorders

majority of patients are diagnosed between ages 30 and 50. Gastrino- gene encodes for menin, which has an important role in DNA replica-
mas are classified into sporadic tumors (80%) and those associated tion and transcriptional regulation. A genetic diagnosis is obtained by
with multiple endocrine neoplasia (MEN) type 1 (see below). The sequencing of the MEN1 gene, which can reveal mutations in 70–90%
widespread availability and use of PPIs have led to a decreased patient of typical MEN 1 cases. A family may have an unknown mutation,
referral for gastrinoma evaluation, delay in diagnosis, and an increase making a genetic diagnosis impossible, and therefore, certain individ-
in false-positive diagnoses of ZES. In fact, diagnosis may be delayed for uals will require a clinical diagnosis, which is determined by whether a
≥6 years after symptoms consistent with ZES are displayed. patient has tumors in two of the three endocrine organs (parathyroid,
pancreas/duodenum, or pituitary) or has a family history of MEN 1
Pathophysiology Hypergastrinemia originating from an autono- and one of the endocrine organ tumors. In view of the stimulatory
mous neoplasm is the driving force responsible for the clinical man- effect of calcium on gastric secretion, the hyperparathyroidism and
ifestations in ZES. Gastrin stimulates acid secretion through gastrin hypercalcemia seen in MEN 1 patients may have a direct effect on ulcer
receptors on parietal cells and by inducing histamine release from ECL disease. Resolution of hypercalcemia by parathyroidectomy reduces
cells. Gastrin also has a trophic action on gastric epithelial cells. Long- gastrin and gastric acid output in gastrinoma patients. An additional
standing hypergastrinemia leads to markedly increased gastric acid distinguishing feature in ZES patients with MEN 1 is the higher inci-
secretion through both parietal cell stimulation and increased parietal dence of gastric carcinoid tumor development (as compared to patients
cell mass. The increased gastric acid output leads to peptic ulcer diath- with sporadic gastrinomas). ZES presents and is diagnosed earlier in
esis, erosive esophagitis, and diarrhea. MEN 1 patients, and they have a more indolent course as compared
Tumor Distribution Although early studies suggested that the to patients with sporadic gastrinoma. Gastrinomas tend to be smaller,
vast majority of gastrinomas occurred within the pancreas, a signifi- multiple, and located in the duodenal wall more often than is seen in
cant number of these lesions are extrapancreatic. Between 60 and 90% patients with sporadic ZES. Establishing the diagnosis of MEN 1 is
of these tumors are found within the hypothetical gastrinoma triangle critical in order to provide genetic counseling to the patient and his or
(confluence of the cystic and common bile ducts superiorly, junction her family and also to determine the recommended surgical approach.
of the second and third portions of the duodenum inferiorly, and Therefore, gastrinoma patients should be screened for MEN 1 by per-
junction of the neck and body of the pancreas medially). Duodenal forming a detailed family history and obtaining several serum markers
tumors constitute the most common nonpancreatic lesion; between 60 including calcium, parathyroid, prolactin, and pancreatic polypeptide
and 100% of gastrinomas are found here. Duodenal tumors are smaller, levels.
slower growing, and less likely to metastasize than pancreatic lesions.
Less common extrapancreatic sites include stomach, bones, ovaries, Diagnosis Establishing an early diagnosis is important in order to
heart, liver, and lymph nodes. More than 60% of tumors are considered minimize the long-term sequelae of gastric acid hypersecretion, pre-
malignant, with up to 30–50% of patients having multiple lesions or vent metastatic disease, and counsel family members if a diagnosis of
metastatic disease at presentation. Histologically, gastrin-producing MEN 1 is established. Biochemical measurements of gastrin and acid
cells appear well-differentiated (grade 1 or 2 histologically), expressing secretion in patients suspected of having ZES play an important role
markers typically found in endocrine neoplasms (chromogranin, neu- is establishing this rare diagnosis. Often, patients suspected of having
ron-specific enolase). Although not clearly established in gastrinomas, ZES will be treated with a PPI in an effort to ameliorate symptoms and
histologic grade in pancreatic NETs generally is an important predictor decrease the likelihood of possible acid-related complications. The
of survival in these rare neoplasms (Chap. 84). presence of the PPI, which will lower acid secretion and potentially
elevate fasting gastrin levels in normal individuals, will make the
Clinical Manifestations Gastric acid hypersecretion is respon- diagnostic approach in these individuals somewhat difficult. Signifi-
sible for the signs and symptoms observed in patients with ZES. The cant morbidity related to peptic diathesis has been described when
most common clinical presentation for gastrinoma patients is abdom- stopping PPIs in gastrinoma patients; therefore, a systematic approach
inal pain in the presence of acid peptic disorders. Peptic ulcer is the in stopping these agents is warranted (see below). The first step in the

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 2454
TABLE 324-8 When to Obtain a Fasting Serum Gastrin Level being highly suggestive of ZES. Pentagastrin is no longer available in
Multiple ulcers the United States, making measurement of MAO virtually impossible.
An endoscopic method for measuring gastric acid output has been
Ulcers in unusual locations; associated with severe esophagitis; resistant
to therapy with frequent recurrences; in the absence of nonsteroidal anti- developed but requires further validation.
inflammatory drug ingestion or H. pylori infection Gastrin provocative tests have been developed in an effort to dif-
Ulcer patients awaiting surgery
ferentiate between the causes of hypergastrinemia and are especially
helpful in patients with indeterminate acid secretory studies. The tests
Extensive family history for peptic ulcer disease
are the secretin stimulation test and the calcium infusion study; the
Postoperative ulcer recurrence latter is rarely, if ever, utilized in our current environment due to the
Basal hyperchlorhydria cumbersome nature of the test and its lower sensitivity and specificity
Unexplained diarrhea or steatorrhea than secretin stimulation. The most sensitive and specific gastrin pro-
Hypercalcemia vocative test for the diagnosis of gastrinoma is the secretin study. An
Family history of pancreatic islet, pituitary, or parathyroid tumor increase in gastrin of ≥120 pg within 15 min of secretin injection has a
sensitivity and specificity of >90% for ZES. PPI-induced hypochlorhy-
Prominent gastric or duodenal folds
dria or achlorhydria may lead to a false-positive secretin test; thus, this
agent must be stopped for 1 week before testing.
evaluation of a patient suspected of having ZES is to obtain a fasting In light of the limited availability of the biochemical studies outlined
gastrin level. A list of clinical scenarios that should arouse suspicion above, more studies make a diagnosis of gastrinoma based on the pres-
regarding this diagnosis is shown in Table 324-8. Fasting gastrin levels ence of elevated gastrin and low gastric pH in the right clinical setting
obtained using a dependable assay are usually <150 pg/mL. A normal coupled with tumor localization tests outlined below and positive
fasting gastrin, on two separate occasions, especially if the patient is histology by biopsy (difficult to obtain). Revised guidelines for the best
on a PPI, virtually excludes this diagnosis. Virtually all gastrinoma approach to establishing a diagnosis of gastrinoma taking into consid-
patients will have a gastrin level >150–200 pg/mL. Measurement of eration the above outlined limitations are being considered, but none
fasting gastrin should be repeated to confirm the clinical suspicion. have replaced the established guidelines outlined earlier in this section.
Some of the commercial biochemical assays used for measuring serum
gastrin may be inaccurate. Variable specificity of the antibodies used Tumor Localization Once the biochemical diagnosis of gastri-
have led to both false-positive and false-negative fasting gastrin levels, noma has been confirmed (if possible), the tumor must be located.
placing in jeopardy the ability to make an accurate diagnosis of ZES. Multiple imaging studies have been used in an effort to enhance
Multiple processes can lead to an elevated fasting gastrin level, the tumor localization (Table 324-9). The broad range of sensitivity is
due to the variable success rates achieved by the different investiga-
PART 10

most frequent of which are gastric hypochlorhydria and achlorhydria,

with or without pernicious anemia. Gastric acid induces feedback tive groups. Endoscopic ultrasound (EUS) permits imaging of the
inhibition of gastrin release. A decrease in acid production will subse- pancreas with a high degree of resolution (<5 mm). This modality is
quently lead to failure of the feedback inhibitory pathway, resulting in particularly helpful in excluding small neoplasms within the pancreas
net hypergastrinemia. Gastrin levels will thus be high in patients using and in assessing the presence of surrounding lymph nodes and vascu-
Disorders of the Gastrointestinal System

antisecretory agents for the treatment of acid peptic disorders and lar involvement, but it is not very sensitive (43%) for finding duodenal
dyspepsia. H. pylori infection can also cause hypergastrinemia. Addi- lesions. This latter observation has led some to not include EUS in
tional causes of elevated gastrin include retained gastric antrum; G-cell the routine preoperative evaluation of a patient suspected of having
hyperplasia; gastric outlet obstruction; renal insufficiency; massive a gastrinoma. Several types of endocrine tumors express cell-sur-
small-bowel obstruction; and conditions such as rheumatoid arthritis, face receptors for somatostatin, in particular the subtype 2 (SSTR2).
vitiligo, diabetes mellitus, and pheochromocytoma. Although a fasting This permits the localization, staging, and prediction of therapeutic
gastrin >10 times normal is highly suggestive of ZES, two-thirds of response to somatostatin analogues (see below) by gastrinomas.
patients will have fasting gastrin levels that overlap with levels found The original functional scinitigraphic tool developed measuring the
in the more common disorders outlined above, especially if a PPI is uptake of the stable somatostatin analogue 111In-pentetreotide (Oct-
being taken by the patient. The effect of the PPI on gastrin levels and reoScan) has demonstrated sensitivity and specificity rates of >80%.
acid secretion will linger several days after stopping the PPI; therefore, More recently, positron emission tomography (PET)–computed
it should be stopped for a minimum of 7 days before testing. During tomography (CT) with 68Ga-DOTATATE has been developed and is
this period, the patient should be placed on a histamine H2 antagonist, superior than OctreoScan for assessing tumor presence in patients
such as famotidine, twice to three times per day. Although this type of with well-differentiated NETs such as gastrinomas, with sensitivity
agent has a short-term effect on gastrin and acid secretion, it needs to and specificity of >90%, making it the functional imaging study of
be stopped 24 h before repeating fasting gastrin levels or performing choice when available. 18F-Fluordeoxyglucose (18F-FDG) PET imaging
some of the tests highlighted below. The patient may take antacids for
the final day, stopping them ~12 h before testing is performed. Height-
ened awareness of complications related to gastric acid hypersecretion TABLE 324-9 Sensitivity of Imaging Studies in Zollinger-Ellison
during the period of PPI cessation is critical. Syndrome
The next step at times needed for establishing a biochemical SENSITIVITY, %
diagnosis of gastrinoma is to assess acid secretion. Nothing further PRIMARY METASTATIC
needs to be done if decreased acid output in the absence of a PPI is STUDY GASTRINOMA GASTRINOMA
observed. A pH can be measured on gastric fluid obtained either dur- Ultrasound 21–28 14
ing endoscopy or through nasogastric aspiration; a pH <3 is suggestive CT scan 55–70 >85
of a gastrinoma, but a pH >3 is not helpful in excluding the diagnosis. Selective angiography 35–68 33–86
In those situations where the pH is >3, formal gastric acid analysis
Portal venous sampling 70–90 N/A
should be performed if available. Normal BAO in nongastric surgery
patients is typically <5 meq/h. A BAO >15 meq/h in the presence of SASI 55–78 41
hypergastrinemia is considered pathognomonic of ZES, but up to 12% MRI 55–70 >85
of patients with common PUD may have elevated BAO to a lesser OctreoScan 67–86 80–100
degree that can overlap with levels seen in ZES patients. In an effort EUS 80–100 N/A
to improve the sensitivity and specificity of gastric secretory studies, a
Abbreviations: CT, computed tomography; EUS, endoscopic ultrasonography;
BAO/MAO ratio was established using pentagastrin infusion as a way MRI, magnetic resonance imaging; N/A, not applicable; OctreoScan, imaging with
to maximally stimulate acid production, with a BAO/MAO ratio >0.6 111
In-pentetreotide; SASI, selective arterial secretin injection.

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 has been found to be useful in pancreatic NETs, including gastrinomas, laparoscopic approach. Finally, patients selected for surgery should 2455
particularly as a prognostic marker. be individuals whose health status would lead them to tolerate a
Up to 50% of patients have metastatic disease at diagnosis. Success more aggressive operation and obtain the long-term benefits from
in controlling gastric acid hypersecretion has shifted the emphasis of such aggressive surgery, which are often witnessed after 10 years.
therapy toward providing a surgical cure. Detecting the primary tumor Therapy of metastatic endocrine tumors in general remains sub-
and excluding metastatic disease are critical in view of this paradigm optimal; gastrinomas are no exception. In light of the observation
shift. Once a biochemical diagnosis has been confirmed, the patient that in many instances tumor growth is indolent and that many
should first undergo an abdominal CT scan, magnetic resonance imag- individuals with metastatic disease remain relatively stable for
ing (MRI), or OctreoScan/PET-CT with 68Ga-DOTATATE (depending significant periods of time, many advocate not instituting systemic
on availability) to exclude metastatic disease. Once metastatic disease tumor-targeted therapy until evidence of tumor progression or
has been excluded, an experienced endocrine surgeon may opt for refractory symptoms not controlled with PPIs are noted. Medical
exploratory laparotomy with intraoperative ultrasound or transillumi- approaches, including biologic therapy (IFN-α, long-acting soma-
nation. In other centers, careful examination of the peripancreatic area tostatin analogues, and peptide receptor radionuclides), systemic
with EUS, accompanied by endoscopic exploration of the duodenum chemotherapy (streptozotocin, 5-fluorouracil, and doxorubicin),
for primary tumors, will be performed before surgery. Selective arterial and hepatic artery embolization, may lead to significant toxicity
secretin injection may be a useful adjuvant for localizing tumors in a without a substantial improvement in overall survival. Use of
subset of patients. The extent of the diagnostic and surgical approach temozolomide with capecitabine has demonstrated radiographic
must be carefully balanced with the patient’s overall physiologic condi- regression and progression-free survival in patients with well-
tion and the natural history of a slow-growing gastrinoma. differentiated NETs in the range of 70% and 18 months, respec-
tively. Systemic therapy with radiolabeled somatostatin analogues
(peptide receptor radiotherapy [PRRT]) has been used in the
TREATMENT therapy of metastatic NETs and appears to be very promising in
Zollinger-Ellison Syndrome terms of radiographic regression, symptoms, and progression-free
survival, but additional studies are warranted. Several promising
Treatment of functional endocrine tumors is directed at ameliorat- therapies are being explored, including radiofrequency ablation or
ing the signs and symptoms related to hormone overproduction, cryoablation of liver lesions and use of agents that block the VEGF
curative resection of the neoplasm, and attempts to control tumor receptor pathway (sunitinib), the mammalian target of rapamycin,
growth in metastatic disease. and immune checkpoint inhibitors (Chap. 87).

CHAPTER 324 Peptic Ulcer Disease and Related Disorders

PPIs are the treatment of choice and have decreased the need Surgical approaches, including debulking surgery and liver
for total gastrectomy. Initial PPI doses tend to be higher than those transplantation for hepatic metastasis, have also produced limited
used for treatment of GERD or PUD. The initial dose of omepra- benefit.
zole, lansoprazole, rabeprazole, or esomeprazole should be in the The overall 5- and 10-year survival rates for gastrinoma patients
range of 60 mg in divided doses in a 24-h period. When gastric acid are 62–75% and 47–53%, respectively. Individuals with the entire
analysis was more widely available, dosing was adjusted to achieve tumor resected or those with a negative laparotomy have 5- and
a BAO <10 meq/h (at the drug trough) in surgery-naive patients 10-year survival rates >90%. Patients with incompletely resected
and to <5 meq/h in individuals who have previously undergone an tumors have 5- and 10-year survival rates of 43 and 25%, respec-
acid-reducing operation. Close monitoring of clinical symptoms tively. Patients with hepatic metastasis have <20% survival at
when starting PPIs and increasing the dose accordingly are para- 5 years. Favorable prognostic indicators include primary duodenal
mount. Although the somatostatin analogue has inhibitory effects wall tumors, isolated lymph node tumor, the presence of MEN 1,
on gastrin release from receptor-bearing tumors and inhibits gastric and undetectable tumor upon surgical exploration. Poor outcome is
acid secretion to some extent, PPIs have the advantage of reducing seen in patients with shorter disease duration; female sex; older age
parietal cell activity to a greater degree. Despite this, octreotide or at diagnosis; higher gastrin levels (>10,000 pg/mL); poor histologic
lanreotide may be considered as adjunctive therapy to the PPI in differentiation; high proliferative index; large pancreatic primary
patients with tumors that express somatostatin receptors and have tumors (>3 cm); metastatic disease to lymph nodes, liver, and bone;
peptic symptoms that are difficult to control with high-dose PPI. and Cushing’s syndrome. Rapid growth of hepatic metastases is also
The ultimate goal of surgery would be to provide a definitive predictive of poor outcome.
cure. Improved understanding of tumor distribution has led to
immediate cure rates as high as 33% with 10-year disease-free inter-
vals as high as 95% in sporadic gastrinoma patients undergoing ■■STRESS-RELATED MUCOSAL INJURY
surgery. A positive outcome is highly dependent on the experience Patients suffering from shock, sepsis, massive burns, severe trauma, or
of the surgical team treating these rare tumors. Surgical therapy of head injury can develop acute erosive gastric mucosal changes or frank
gastrinoma patients with MEN 1 remains controversial because of ulceration with bleeding. Classified as stress-induced gastritis or ulcers,
the difficulty in rendering these patients disease-free with surgery. injury is most commonly observed in the acid-producing (fundus and
In contrast to the encouraging postoperative results observed in body) portions of the stomach. The most common presentation is GI
patients with sporadic disease, <5% of MEN 1 patients are disease- bleeding, which is usually minimal but can occasionally be life-threat-
free 5 years after an operation. Moreover, in contrast to patients ening. Respiratory failure requiring mechanical ventilation and under-
with sporadic ZES, the clinical course of MEN 1 patients tends to be lying coagulopathy are risk factors for bleeding, which tends to occur
benign and rarely leads to disease-related mortality, recommending 48–72 h after the acute injury or insult.
that early surgery be deferred. Some groups suggest surgery only if Histologically, stress injury does not contain inflammation or H.
a clearly identifiable, nonmetastatic lesion is documented by struc- pylori; thus, “gastritis” is a misnomer. Although elevated gastric acid
tural studies. Others advocate a more aggressive approach, where secretion may be noted in patients with stress ulceration after head
all patients free of hepatic metastasis are explored and all detected trauma (Cushing’s ulcer) and severe burns (Curling’s ulcer), mucosal
tumors in the duodenum are resected; this is followed by enucle- ischemia, breakdown of the normal protective barriers of the stomach,
ation of lesions in the pancreatic head, with a distal pancreatectomy systemic release of cytokines, poor GI motility, and oxidative stress
to follow. The outcome of the two approaches has not been clearly also play an important role in the pathogenesis. Acid must contribute
defined. Laparoscopic surgical interventions may provide attractive to injury in view of the significant drop in bleeding noted when acid
approaches in the future but currently seem to be of some limited inhibitors are used as prophylaxis for stress gastritis.
benefit in patients with gastrinoma because a significant percentage Improvement in the general management of intensive care unit
of the tumors may be extrapancreatic and difficult to localize with a patients has led to a significant decrease in the incidence of GI bleeding

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 2456 due to stress ulceration. The estimated decrease in bleeding is from H. pylori acute gastritis has not been extensively studied. It is reported as
20–30% to <5%. This improvement has led to some debate regarding presenting with sudden onset of epigastric pain, nausea, and vomiting,
the need for prophylactic therapy. The high mortality associated with and limited mucosal histologic studies demonstrate a marked infiltrate
stress-induced clinically important GI bleeding (>40%) and the limited of neutrophils with edema and hyperemia. If not treated, this picture
benefit of medical (endoscopic, angiographic) and surgical therapy in a will evolve into one of chronic gastritis. Hypochlorhydria lasting for up
patient with hemodynamically compromising bleeding associated with to 1 year may follow acute H. pylori infection.
stress ulcer/gastritis support the use of preventive measures in high-risk Bacterial infection of the stomach or phlegmonous gastritis is a
patients (mechanically ventilated, coagulopathy, multiorgan failure, or rare, potentially life-threatening disorder characterized by marked and
severe burns). Meta-analysis comparing H2 blockers with PPIs for the diffuse acute inflammatory infiltrates of the entire gastric wall, at times
prevention of stress-associated clinically important and overt GI bleed- accompanied by necrosis. Elderly individuals, alcoholics, and AIDS
ing demonstrates superiority of the latter without increasing the risk patients may be affected. Potential iatrogenic causes include polypec-
of nosocomial infections, increasing mortality, or prolonging intensive tomy and mucosal injection with India ink. Organisms associated with
care unit length of stay. Therefore, PPIs are the treatment of choice for this entity include streptococci, staphylococci, Escherichia coli, Proteus,
stress prophylaxis. Oral PPI is the best option if the patient can tolerate and Haemophilus species. Failure of supportive measures and antibiot-
enteral administration. Pantoprazole is available as an intravenous for- ics may result in gastrectomy.
mulation for individuals in whom enteral administration is not possi- Other types of infectious gastritis may occur in immunocompro-
ble. If bleeding occurs despite these measures, endoscopy, intraarterial mised individuals such as AIDS patients. Examples include herpetic
vasopressin, and embolization are options. If all else fails, then surgery (herpes simplex) or CMV gastritis. The histologic finding of intranu-
should be considered. Although vagotomy and antrectomy may be clear inclusions would be observed in the latter.
used, the better approach would be a total gastrectomy, which has an
exceedingly high mortality rate in this setting. Concerns with the effect Chronic Gastritis Chronic gastritis is identified histologically by
of PPIs on the immune system coupled with the high cost of this agent an inflammatory cell infiltrate consisting primarily of lymphocytes
have led to several comparative studies of PPIs and H2 receptor antago- and plasma cells, with very scant neutrophil involvement. Distribution
nists for stress prophylaxis in patients requiring mechanical ventilation. of the inflammation may be patchy, initially involving superficial and
Although the PEPTIC trial demonstrated comparative efficacy between glandular portions of the gastric mucosa. This picture may progress
the two agents regarding mortality, technical aspects of the study led to to more severe glandular destruction, with atrophy and metaplasia.
some limitation in the final interpretation of the results. Chronic gastritis has been classified according to histologic character-
istics. These include superficial atrophic changes and gastric atrophy.
■■GASTRITIS The association of atrophic gastritis with the development of gastric
The term gastritis should be reserved for histologically documented cancer has led to the development of endoscopic and serologic markers
PART 10

inflammation of the gastric mucosa. Gastritis is not the mucosal of severity. Some of these include gross inspection and classification
erythema seen during endoscopy and is not interchangeable with of mucosal abnormalities during standard endoscopy, magnification
“dyspepsia.” The etiologic factors leading to gastritis are broad and het- endoscopy, endoscopy with narrow band imaging and/or autofluores-
erogeneous. Gastritis has been classified based on time course (acute cence imaging, and measurement of several serum biomarkers includ-
Disorders of the Gastrointestinal System

vs chronic), histologic features, and anatomic distribution or proposed ing pepsinogen I and II levels, gastrin-17, and anti–H. pylori serologies.
pathogenic mechanism (Table 324-10). The clinical utility of these tools is currently being explored.
The correlation between the histologic findings of gastritis, the clin- The early phase of chronic gastritis is superficial gastritis. The
ical picture of abdominal pain or dyspepsia, and endoscopic findings inflammatory changes are limited to the lamina propria of the surface
noted on gross inspection of the gastric mucosa is poor. Therefore, mucosa, with edema and cellular infiltrates separating intact gastric
there is no typical clinical manifestation of gastritis. glands. The next stage is atrophic gastritis. The inflammatory infil-
trate extends deeper into the mucosa, with progressive distortion and
Acute Gastritis The most common causes of acute gastritis are destruction of the glands. The final stage of chronic gastritis is gastric
infectious. Acute infection with H. pylori induces gastritis. However, atrophy. Glandular structures are lost, and there is a paucity of inflam-
matory infiltrates. Endoscopically, the mucosa may be substantially
TABLE 324-10 Classification of Gastritis thin, permitting clear visualization of the underlying blood vessels.
I. Acute gastritis Gastric glands may undergo morphologic transformation in chronic
A. Acute Helicobacter pylori infection gastritis. Intestinal metaplasia denotes the conversion of gastric glands
B. Other acute infectious gastritides to a small intestinal phenotype with small-bowel mucosal glands con-
1. Bacterial (other than H. pylori) taining goblet cells. The metaplastic changes may vary in distribution
2. Helicobacter heilmannii from patchy to fairly extensive gastric involvement. Intestinal metapla-
3. Phlegmonous
sia is an important predisposing factor for gastric cancer (Chap. 80).
Chronic gastritis is also classified according to the predominant site
4. Mycobacterial
of involvement. Type A refers to the body-predominant form (autoim-
5. Syphilitic mune), and type B is the antral-predominant form (H. pylori–related).
6. Viral This classification is artificial in view of the difficulty in distinguishing
7. Parasitic between these two entities. The term AB gastritis has been used to refer
8. Fungal to a mixed antral/body picture.
II. Chronic atrophic gastritis
TYPE A GASTRITIS The less common of the two forms involves primar-
A. Type A: Autoimmune, body-predominant ily the fundus and body, with antral sparing. Traditionally, this form of
B. Type B: H. pylori–related, antral-predominant gastritis has been associated with pernicious anemia (Chap. 95) in the
C. Indeterminate presence of circulating antibodies against parietal cells and IF; thus, it is
III. Uncommon forms of gastritis also called autoimmune gastritis. H. pylori infection can lead to a similar
A. Lymphocytic distribution of gastritis. The characteristics of an autoimmune picture
B. Eosinophilic are not always present.
C. Crohn’s disease Antibodies to parietal cells have been detected in >90% of patients
D. Sarcoidosis with pernicious anemia and in up to 50% of patients with type A
E. Isolated granulomatous gastritis gastritis. The parietal cell antibody is directed against H+,K+-ATPase.
F. Russell body gastritis
T cells are also implicated in the injury pattern of this form of gastritis.
A subset of patients infected with H. pylori develop antibodies against

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 H+,K+-ATPase, potentially leading to the atrophic gastritis pattern (Fig. 324-8; Chap. 80). H. pylori infection is now considered an 2457
seen in some patients infected with this organism. The mechanism independent risk factor for gastric cancer. Worldwide epidemiologic
is thought to involve molecular mimicry between H. pylori LPS and studies have documented a higher incidence of H. pylori infection in
H+,K+-ATPase. patients with adenocarcinoma of the stomach as compared to control
Parietal cell antibodies and atrophic gastritis are observed in family subjects. Seropositivity for H. pylori is associated with a three- to
members of patients with pernicious anemia. These antibodies are sixfold increased risk of gastric cancer. This risk may be as high as
observed in up to 20% of individuals aged >60 and in ~20% of patients ninefold after adjusting for the inaccuracy of serologic testing in the
with vitiligo and Addison’s disease. About one-half of patients with elderly. The mechanism by which H. pylori infection leads to cancer
pernicious anemia have antibodies to thyroid antigens, and ~30% is unknown, but it appears to be related to the chronic inflammation
of patients with thyroid disease have circulating anti–parietal cell induced by the organism. Eradication of H. pylori as a general pre-
antibodies. Anti-IF antibodies are more specific than parietal cell ventative measure for gastric cancer is being evaluated but is not yet
antibodies for type A gastritis, being present in ~40% of patients with recommended.
pernicious anemia. Another parameter consistent with this form of Infection with H. pylori is also associated with development of a low-
gastritis being autoimmune in origin is the higher incidence of specific grade B-cell lymphoma, gastric MALT lymphoma (Chap. 108). The
familial histocompatibility haplotypes such as HLA-B8 and HLA-DR3. chronic T-cell stimulation caused by the infection leads to production
Low pepsinogen levels have also been observed; thus, this marker has of cytokines that promote the B-cell tumor. The tumor should be ini-
been used as an additional diagnostic tool in autoimmune gastritis. tially staged with a CT scan of the abdomen and EUS. Tumor growth
The parietal cell–containing gastric gland is preferentially targeted remains dependent on the presence of H. pylori, and its eradication
in this form of gastritis, and achlorhydria results. Parietal cells are the is often associated with complete regression of the tumor. The tumor
source of IF, the lack of which will lead to vitamin B12 deficiency and its may take more than a year to regress after treating the infection. Such
sequelae (megaloblastic anemia, neurologic dysfunction). patients should be followed by EUS every 2–3 months. If the tumor is
Gastric acid plays an important role in feedback inhibition of gastrin stable or decreasing in size, no other therapy is necessary. If the tumor
release from G cells. Achlorhydria, coupled with relative sparing of grows, it may have become a high-grade B-cell lymphoma. When the
the antral mucosa (site of G cells), leads to hypergastrinemia. Gastrin tumor becomes a high-grade aggressive lymphoma histologically, it
levels can be markedly elevated (>500 pg/mL) in patients with perni- loses responsiveness to H. pylori eradication.
cious anemia. ECL cell hyperplasia with frank development of gastric
carcinoid tumors may result from gastrin trophic effects. Hypergas-
trinemia and achlorhydria may also be seen in nonpernicious anemia–
TREATMENT

CHAPTER 324 Peptic Ulcer Disease and Related Disorders

associated type A gastritis. Chronic Gastritis
TYPE B GASTRITIS Type B, or antral-predominant, gastritis is the Treatment in chronic gastritis is aimed at the sequelae and not the
more common form of chronic gastritis. H. pylori infection is the cause underlying inflammation. Patients with pernicious anemia will
of this entity. Although described as “antral-predominant,” this is likely require parenteral vitamin B12 supplementation on a long-term
a misnomer in view of studies documenting the progression of the basis. Eradication of H. pylori is often recommended even if PUD
inflammatory process toward the body and fundus of infected individ- or a low-grade MALT lymphoma is not present. Expert opinion
uals. The conversion to a pangastritis is time dependent and estimated suggests that patients with atrophic gastritis complicated by intes-
to require 15–20 years. This form of gastritis increases with age, being tinal metaplasia without dysplasia should undergo surveillance
present in up to 100% of persons aged >70. Histology improves after endoscopy every 3 years.
H. pylori eradication. The number of H. pylori organisms decreases
dramatically with progression to gastric atrophy, and the degree of Miscellaneous Forms of Gastritis Lymphocytic gastritis is char-
inflammation correlates with the level of these organisms. Early on, acterized histologically by intense infiltration of the surface epithelium
with antral-predominant findings, the quantity of H. pylori is highest with lymphocytes. The infiltrative process is primarily in the body of
and a dense chronic inflammatory infiltrate of the lamina propria is the stomach and consists of mature T cells and plasmacytes. The etiol-
noted, accompanied by epithelial cell infiltration with polymorphonu- ogy of this form of chronic gastritis is unknown. It has been described
clear leukocytes (Fig. 324-16). in patients with celiac sprue, but whether there is a common factor
Multifocal atrophic gastritis, gastric atrophy with subsequent associating these two entities is unknown. No specific symptoms sug-
metaplasia, has been observed in chronic H. pylori–induced gastritis. gest lymphocytic gastritis. A subgroup of patients has thickened folds
This may ultimately lead to development of gastric adenocarcinoma noted on endoscopy. These folds are often capped by small nodules
that contain a central depression or erosion; this form of the disease
is called varioliform gastritis. H. pylori probably plays no significant
role in lymphocytic gastritis. Therapy with glucocorticoids or sodium
cromoglycate has obtained unclear results.
Marked eosinophilic infiltration involving any layer of the stom-
ach (mucosa, muscularis propria, and serosa) is characteristic of
eosinophilic gastritis. Affected individuals will often have circulating
eosinophilia with clinical manifestation of systemic allergy. Involve-
ment may range from isolated gastric disease to diffuse eosinophilic
gastroenteritis. Antral involvement predominates, with prominent
edematous folds being observed on endoscopy. These prominent antral
folds can lead to outlet obstruction. Patients can present with epigastric
discomfort, nausea, and vomiting. Treatment with glucocorticoids has
been successful.
Several systemic disorders may be associated with granulomatous
gastritis. Gastric involvement has been observed in Crohn’s disease.
Involvement may range from granulomatous infiltrates noted only on
gastric biopsies to frank ulceration and stricture formation. Gastric
FIGURE 324-16 Chronic gastritis and H. pylori organisms. Steiner silver stain of Crohn’s disease usually occurs in the presence of small-intestinal dis-
superficial gastric mucosa showing abundant darkly stained microorganisms
layered over the apical portion of the surface epithelium. Note that there is no tissue ease. Several rare infectious processes can lead to granulomatous gas-
invasion. tritis, including histoplasmosis, candidiasis, syphilis, and tuberculosis.

HPIM21e_Part10_p2381-p2670.indd 2457 20/01/22 10:04 PM

 2458 Other unusual causes of this form of gastritis include sarcoidosis, idio- TREATMENT
pathic granulomatous gastritis, and eosinophilic granulomas involving
the stomach. Establishing the specific etiologic agent in this form of Ménétrier’s Disease
gastritis can be difficult, at times requiring repeat endoscopy with Medical therapy with anticholinergic agents, prostaglandins, PPIs,
biopsy and cytology. Occasionally, a surgically obtained full-thickness prednisone, somatostatin analogues (octreotide), and H2 receptor
biopsy of the stomach may be required to exclude malignancy. antagonists yields varying results. Ulcers should be treated with
Russell body gastritis (RBG) is a mucosal lesion of unknown etiol- a standard approach. The discovery that MD is associated with
ogy that has a pseudotumoral endoscopic appearance. Histologically, it overstimulation of the EGFR pathway has led to the successful
is defined by the presence of numerous plasma cells containing Russell use of the EGF inhibitory antibody, cetuximab, in these patients.
bodies (RBs) that express kappa and lambda light chains. Only 10 cases Specifically, four of seven patients who completed a 1-month trial
have been reported, and 7 of these have been associated with H. pylori with this agent demonstrated near complete histologic remission
infection. The lesion can be confused with a neoplastic process, but it and improvement in symptoms. Cetuximab is now considered the
is benign in nature, and the natural history of the lesion is not known. first-line treatment for MD, leaving partial or total gastrectomy for
There have been cases of resolution of the lesion when H. pylori was severe disease with persistent and substantial protein loss despite
eradicated. therapy with this agent.
Immune checkpoint inhibitor–induced enterocolitis and gastritis
are recognized sequelae of these oncologic therapies. The gastritis
typically occurs later in the course of therapy. The diagnosis is made ■■FURTHER READING
by the histologic findings on gastric mucosal biopsies obtained endo- Bindu S et al: Non-steroidal anti-inflammatory drugs (NSAIDs)
scopically. This is an important diagnosis to make since therapy with and organ damage: A current perspective. Biochem Pharmacol
glucocorticoids and potentially IL-6 receptor blockers will be required. 180:114147, 2020.
Moreover, this side effect will have an effect on the oncologic therapy Bjarnason I et al: Mechanisms of damage to the gastrointestinal
prescribed. tract from nonsteroidal anti-inflammatory drugs. Gastroenterology
154:500, 2018.
■■MÉNÉTRIER’S DISEASE Brandi ML et al: Multiple endocrine neoplasia type 1: Latest insights.
Ménétrier’s disease (MD) is a very rare gastropathy characterized by Endocr Rev 42:133, 2021.
large, tortuous mucosal folds. MD has an average age of onset of Chey WD et al: ACG clinical guideline: Treatment of Helicobacter
40–60 years with a male predominance. The differential diagnosis pylori infection. Am J Gastroenterol 112:212, 2017.
of large gastric folds includes ZES, malignancy (lymphoma, infiltrat- Engevik AC et al: The physiology of the gastric parietal cell. Physiol
PART 10

ing carcinoma), infectious etiologies (CMV, histoplasmosis, syphilis, Rev 100:573, 2019.
tuberculosis), gastritis polyposa profunda, and infiltrative disorders Jensen RT, Ito T: Gastrinoma; Endotext [internet]. South Dartmouth,
such as sarcoidosis. MD is most commonly confused with large or MA, 2020. https://europepmc.org/article/NBK/nbk279075.
multiple gastric polyps (prolonged PPI use) or familial polyposis syn- Kavitt RT et al: Diagnosis and treatment of peptic ulcer disease. Am
dromes. The mucosal folds in MD are often most prominent in the J Med 132:447, 2019.
Disorders of the Gastrointestinal System

body and fundus, sparing the antrum. Histologically, massive foveolar Pennelli G et al: Gastritis: Update on etiological features and histolog-
hyperplasia (hyperplasia of surface and glandular mucous cells) and a ical practice approach. Pathologica 112:153, 2020.
marked reduction in oxyntic glands and parietal cells and chief cells are Savarino V et al: Proton pump inhibitors: Use and misuse in the clin-
noted. This hyperplasia produces the prominent folds observed. The ical setting. Expert Rev Clin Pharmacol 11:1123, 2018.
pits of the gastric glands elongate and may become extremely dilated Yao X, Smolka AJ: Gastric parietal cell physiology and Helicobacter
and tortuous. Although the lamina propria may contain a mild chronic pylori-induced disease. Gastroenterology 156:2158, 2019.
inflammatory infiltrate including eosinophils and plasma cells, MD is
not considered a form of gastritis. The etiology of this unusual clinical
picture in children is often CMV, but the etiology in adults is unknown.
Overexpression of the growth factor TGF-α has been demonstrated in
patients with MD. The overexpression of TGF-α in turn results in over-
stimulation of the epidermal growth factor receptor (EGFR) pathway

325 Disorders of Absorption

and increased proliferation of mucus cells, resulting in the observed
foveolar hyperplasia.
The clinical presentation in adults is usually insidious and progres-
Deborah C. Rubin
sive. Epigastric pain, nausea, vomiting, anorexia, peripheral edema,
and weight loss are signs and symptoms in patients with MD. Occult GI
bleeding may occur, but overt bleeding is unusual and, when present,
is due to superficial mucosal erosions. In fact, bleeding is more often A wide range of diseases affect gastrointestinal (GI) absorptive func-
seen in one of the common mimics of MD, gastric polyposis. Twenty tion and may result in malabsorption syndromes. These disorders
to 100% of patients (depending on time of presentation) develop a affect one or more of the three phases of enteral nutrient processing.
protein-losing gastropathy due to hypersecretion of gastric mucus Luminal digestion is initiated by lingual and gastric lipase and gas-
accompanied by hypoalbuminemia and edema. Gastric acid secretion tric pepsin, and continues in the small bowel by the actions of pan-
is usually reduced or absent because of the decreased parietal cells. creatic enzymes and bile salts. Small intestinal mucosal digestion
Large gastric folds are readily detectable by either radiographic (bar- and absorption are mediated by enterocyte brush border enzymes
ium meal) or endoscopic methods. Endoscopy with deep mucosal including disaccharidases, enterokinases, and peptidases, which digest
biopsy, preferably full thickness with a snare technique, is required nutrients upon contact, and by mixed micelles containing lipids and
to establish the diagnosis and exclude other entities that may present bile salts. Protein and carbohydrate digestive products are transported
similarly. A nondiagnostic biopsy may lead to a surgically obtained into the enterocyte by carriers and transporters, and lipids enter by
full-thickness biopsy to exclude malignancy. Although MD is consid- diffusion mediated by micelles. Once in the enterocyte, nutrients may
ered premalignant by some, the risk of neoplastic progression is not be reprocessed for post mucosal absorption and entry into lymphatics
defined. Complete blood count, serum gastrin, serum albumin, CMV (long-chain triglycerides as part of chylomicrons) or are transported
and H. pylori serology, and pH testing of gastric aspirate during endos- into the bloodstream. Malabsorptive diseases or syndromes can be
copy should be included as part of the initial evaluation of patients with classified by their effects on one or more of these three phases of
large gastric folds. absorption (Table 325-1).

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 TABLE 325-1 Classification of Malabsorption Syndromes and present with isolated iron deficiency, or may cause diffuse intesti- 2459

Inadequate digestion nal mucosal disease, affecting the absorption of multiple nutrients and
causing a constellation of symptoms and clinical presentations.
Postgastrectomya
Deficiency or inactivation of pancreatic lipase Definition of Diarrhea Diarrhea is the most common symptom
   Exocrine pancreatic insufficiency associated with disorders of absorption. For most patients, diarrhea as
   Chronic pancreatitis a symptom is defined as an increase in stool number or frequency, or a
   Pancreatic carcinoma
change in consistency. Because normal bowel patterns may vary from
as many as two to four bowel movements per day to one stool per week,
   Cystic fibrosis
it is critical to use an objective measure of diarrhea to help direct eval-
    Pancreatic insufficiency—congenital or acquired uation. In health, stool volume or weight is <200 mL or <200 g respec-
Gastrinoma—acid inactivation of lipase tively in 24 h. Collection of stool for weight/volume determination is
Drugs—orlistat one of the most useful tools for an evaluation of diarrhea. In particular,
Reduced intraduodenal bile-acid concentration/impaired micelle formation a 72-h collection for weight/volume and fecal fat determination is the
Liver disease gold standard for documenting the presence of steatorrhea, or fatty
stool. Steatorrhea, defined as increased stool fat excretion to >7% of
   Parenchymal liver disease
dietary fat, is a common manifestation of malabsorption. Steatorrhea
   Cholestatic liver disease often results in large, bulky, and malodorous stools. Malabsorption
Bacterial overgrowth in small intestine: of single nutrients like lactose may result in an osmotic diarrhea, in
  Anatomic stasis Functional stasis which the osmotically active unabsorbed nutrient causes fluid to be
   Afferent loop Diabetesa drawn into the GI tract lumen. Malabsorptive diarrhea frequently is
   Stasis/blind Sclerodermaa precipitated by eating and resolves or significantly decreases at night,
   Loop/strictures/fistulae Intestinal pseudo-obstruction
with fasting, and thus can frequently be distinguished from secretory
diarrheas, for example from infectious causes such as bacterial entero-
Interrupted enterohepatic circulation of bile salts toxigenic Escherichia coli. In this circumstance, intestinal fluid and
  Ileal resection electrolyte secretion is stimulated by enterotoxin and will continue
  Crohn’s disease even during fasting.
Drugs (binding or precipitating bile salts)—neomycin, cholestyramine, calcium

CHAPTER 325 Disorders of Absorption

carbonate OVERVIEW: NUTRIENT DIGESTION
Impaired mucosal absorption/mucosal loss or defect AND ABSORPTION
   Intestinal resection or bypassa Luminal digestive processes begin in the mouth and proceed through-
   Inflammation, infiltration, or infection: out the GI tract, mediated by salivary amylase, lingual and gastric
   Crohn’s diseasea Celiac disease lipases, gastric acid, pancreatic enzymes, and bile salts. As nutrients are
   Amyloidosis Collagenous sprue digested in the lumen of the proximal GI tract, they are further pro-
   Sclerodermaa Whipple’s diseasea
cessed by enterocyte brush border enzymes including disaccharidases
such as lactase and sucrase-isomaltase, which produce monosaccha-
   Lymphomaa Radiation enteritisa rides, and peptidases, which hydrolyze polypeptides into tripeptides
   Eosinophilic enteritis Folate and vitamin B12 deficiency and dipeptides and amino acids. Lipids in mixed micelles are then
   Mastocytosis Infections—giardiasis absorbed into enterocytes.
   Tropical sprue Graft vs host disease The surface area of the small bowel, which is normally 6–12 ft
Genetic disorders long, is further enhanced by circular folds, villi, and microvilli. Fol-
  Disaccharidase deficiency
lowing uptake into enterocytes, nutrients are further processed and
transported into the lymphatics or into the portal circulation for use
  Agammaglobulinemia
by other cells throughout the body. The intestine is also presented
  Abetalipoproteinemia with 7–9 L of fluid daily, a volume comprising dietary fluid intake
  Hartnup disease (1–2 L/day) and salivary, gastric, pancreatic, biliary, and intestinal
  Cystinuria fluid (6–7 L/day). In health, almost all of this fluid is reabsorbed by the
Impaired nutrient delivery to and/or from intestine: small bowel and colon, resulting in a normal stool volume of <200 mL
Lymphatic obstruction Circulatory disorders or stool weight of <200 g.
  Lymphomaa Congestive heart failure
■■SPECIFIC NUTRIENTS
  Lymphangiectasia Constrictive pericarditis
Mesenteric artery atherosclerosis Lipids Lipid absorption is a complex process that requires hydroly-
Vasculitis sis by pancreatic enzymes and bile salts for physiochemical dispersion
Endocrine and metabolic disorders
of fats, followed by absorption of processed lipid nutrients dispersed
in bile salt–mixed micelles across the intestinal epithelium. Bile acids
Diabetesa
are synthesized in the liver, secreted into the intestinal lumen, and
Hypoparathyroidism constantly recirculated by absorption in the ileum. The ileum expresses
Adrenal insufficiency fibroblast growth factor 19 (FGF19), which is a physiologic bile acid
Hyperthyroidism sensor. FGF19 is secreted from the ileum into the bloodstream in
Carcinoid syndrome response to bile acid flux and negatively regulates hepatic bile acid
synthesis by affecting the transcription of hepatic CYP7A1.
a
Malabsorption caused by more than one mechanism.
Thus assimilation of dietary lipid requires three integrated pro-
cesses: an intraluminal or digestive phase, a mucosal or absorptive
phase, and a delivery or postabsorptive phase (Table 325-2).
Disorders of absorption also have diverse clinical presentations. For Gastric lipases begin the lipolytic process. Following entry into
example, the deficiency of a single brush border membrane protein the small bowel, long-chain triglycerides, with carbon lengths >12
such as lactase causes symptoms of diarrhea by affecting the absorption and that are the major component of dietary lipid, are hydrolyzed by
of one nutrient, lactose. Celiac sprue may be localized to the duodenum pancreatic lipases into fatty acids and monoglyceride during a process

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 2460
TABLE 325-2 Defects in Lipid Digestion and Absorption in Steatorrhea Proteins Dietary protein digestion begins in the stomach by pepsin.
PATHOPHYSIOLOGIC
Pancreatic proteases including endopeptidases, exopeptidases, and
PHASE, PROCESS DEFECT DISEASE EXAMPLE trypsin are activated in the small-bowel lumen. Trypsinogen is acti-
vated by brush border enterokinase to generate active trypsin. Trypsin
Digestive
in turn activates chymotrypsinogen to chymotrypsin, proelastase to
Lipolysis formation Decreased lipase Chronic pancreatitis elastase, and procarboxypeptidases to carboxypeptidases A and B.
secretion These enzymes digest protein into di peptides, tripeptides, larger poly-
Micelle formation Decreased intraduodenal peptides, or free amino acids. At the brush border, peptidases digest
bile acids larger peptides into dipeptides and tripeptides or free amino acids,
Absorptive which enter the enterocyte via specialized carriers. Most dipeptides
Mucosal uptake and Mucosal dysfunction Celiac disease and tripeptides are further metabolized intracellularly by cytoplasmic
re-esterification peptidase into amino acids, which directly enter the bloodstream via
Postabsorptive carriers in the basolateral membrane. Small amounts of dipeptides and
tripeptides may also enter the bloodstream.
Chylomicron formation Absent β-lipoproteins Abetalipoproteinemia
Delivery from intestine Abnormal lymphatics Intestinal
lymphangiectasia ■■LUMINAL PHASE OF DIGESTION
The luminal phase of digestion begins in the mouth, starting with
mastication and lipase secretion by the tongue and salivary glands.
The stomach continues the luminal digestive process, via gastric acid,
called lipolysis (Fig. 325-1). Long-chain free fatty acids are dispersed gastric lipase, and pepsin secretion as well as mechanical trituration
by bile salts into mixed micelles, which contact the brush border and of contents. In the small-bowel lumen, pancreatic enzymes (amylase,
permit fatty acid absorption into enterocytes across this specialized lipases, carboxypeptidase, trypsin, and other endopeptidases) contrib-
apical membrane. The other two types of fatty acids that compose fats, ute to carbohydrate, lipid, and protein digestion, respectively. Bile salts
medium-chain and short-chain fatty acids, are soluble in the unstirred produced by the liver are secreted into the intestinal lumen (and reab-
water layer. Medium-chain triglycerides with carbon chain lengths of sorbed in the ileum via the enterohepatic circulation) and are required
8–12 are found in coconut oil. Long-chain fatty acids are re-esterified for efficient lipid absorption.
to triglycerides in enterocytes, packaged into chylomicrons that con-
tain apolipoproteins on the surface, which are subsequently secreted Disorders That Affect the Luminal Phase of Digestion The
into the extracellular space, and because of their size, are excluded luminal phase may be disrupted by disorders of gastric and intestinal
PART 10

from capillaries and enter the lymphatics. Medium-chain triglycerides motility including the sequelae of gastric surgery, systemic diseases
do not require micelle formation or pancreatic lipolysis as they are such as scleroderma, or endocrine disorders such as diabetes mel-
directly absorbed intact from the small bowel into the bloodstream, litus, pancreatic diseases leading to pancreatic insufficiency with
and short-chain fatty acids (carbon length <8) are produced by and reduced pancreatic enzyme secretion, or luminal bile salt deficiency
absorbed in the colon. caused by hepatobiliary disease, ileal disease, or small-bowel bacterial
Disorders of the Gastrointestinal System

overgrowth.
Carbohydrates Dietary carbohydrate consists of starch, sucrose,
lactose, maltose, and monosaccharides such as glucose and fructose. Gastric Resection Surgical procedures that remove or bypass part
Starch is digested by salivary α-amylase in the mouth, followed by of the stomach and duodenal bulb such as Roux-en-Y gastric bypass for
pancreatic amylase. The main products include maltotriose, maltose, weight loss, or resection of the gastric antrum and duodenal bulb with
and α-dextrins. These are further digested on the brush border mem- creation of a Billroth II anastomosis for treatment of peptic ulcer dis-
brane by disaccharidases such as glucoamylase and sucrase-isomaltase. ease, result in rapid gastric emptying into the jejunum, which leads to
Dietary lactose is digested by brush border lactase, sucrose by sucrase, diarrhea and weight loss due to inadequate mixing of luminal nutrients
and trehalose by trehalase. The final digested products are glucose, with bile and pancreatic secretions.
fructose, and galactose, which are transported into the enterocyte by
transporters such as SLCA5 (formerly SGLT-1), which transports glu- Disordered Intestinal Motility Hyperthyroidism may cause
cose or galactose in a sodium-dependent manner, and GLUT-5, which diarrhea and malabsorption due to increased intestinal motility with
transports fructose by facilitated diffusion. Glucose, galactose, and rapid transit, also resulting in inadequate nutrient mixing with pan-
fructose exit the cell via GLUT-2. creaticobiliary secretions. Long-standing diabetes mellitus may result
in damage to the enteric nervous system resulting
Pancreas Liver Jejunal Mucosa Lymphatics in increased motility and diarrhea, or reduced
motility and constipation. Disorders that affect
Lipolysis Micellar
Solubilization
Absorption Delivery
the intestinal smooth muscle such as connective
with Bile Acid tissue disorders including scleroderma may have
profound effects on GI motility.
(1) Esterification
Fatty acids
Fatty acids Pancreatic Disorders Chronic pancreatitis
Triglycerides

Triglycerides

To tissues (see Chap. 348) may result in a marked reduc-

for utilization
of fat tion in pancreatic enzyme secretion and pancre-
β-Monoglyceride Cholesterol atic insufficiency, with subsequent fat, protein,
Phospholipid
β-Monoglyceride
β–Lipoprotein and carbohydrate malabsorption. Patients with
(2) Chylomicron
chronic pancreatitis present with steatorrhea, or
formation fatty stools, which are often voluminous, bulky,
and malodorous. Patients with steatorrhea also
develop deficiency of fat-soluble vitamins includ-
ing vitamins A, E, and most commonly, vitamins
FIGURE 325-1 Schematic representation of lipid digestion and absorption. Dietary lipid is in the form of D and K, which depend on the same lipid absorp-
long-chain triglycerides. The overall process can be divided into (1) a digestive phase that includes both
lipolysis and micelle formation requiring pancreatic lipase and conjugated bile acids, respectively, in the
tion mechanisms, and thus are malabsorbed
duodenum; (2) an absorptive phase for mucosal uptake and re-esterification; and (3) a postabsorptive phase along with dietary fat. Weight loss is common.
that includes chylomicron formation and exit from the intestinal epithelial cell via lymphatics. (Courtesy of For a discussion of causes of acute and chronic
John M. Dietschy, MD; with permission.) pancreatitis, please see Chap. 348.

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 NORMAL 2461
TABLE 325-4 Comparison of Bile Acid and Fatty Acid Diarrhea
BILE ACID DIARRHEA FATTY ACID DIARRHEA
Cholesterol
Extent of ileal disease Limited Extensive
Ileal bile-acid absorption Reduced Reduced
Fecal bile-acid excretion Increased Increased
Bile acids
0.5 g synthesized Fecal bile-acid loss Yes No
per day [Bile acids] compensated by hepatic
>4 mM synthesis
Bile acid Bile-acid pool size Normal Reduced
pool size Jejunum Intraduodenal (bile acid) Normal Reduced
4.0 g
Ileum Steatorrhea None or mild >20 g
Na Response to cholestyramine Yes No
Response to low-fat diet No Yes

0.5 g COLON
Bile acids Ileal Resection or Ileal Disease Diseases that involve the ileal
excreted per day mucosa or that result in ileal resection may lead to reduced recycling of
FIGURE 325-2 Schematic representation of the enterohepatic circulation of bile bile acids by the enterohepatic circulation and increased entry into and
acids. Bile-acid synthesis is cholesterol catabolism and occurs in the liver. Bile concentration of bile acids in the colon, which produces a secretory
acids are secreted in bile and are stored in the gallbladder between meals and diarrhea, or malabsorption due to inadequate bile acid concentrations
at night. Food in the duodenum induces the release of cholecystokinin, a potent in the small-bowel lumen. In general, resection or disease involving
stimulus for gallbladder contraction resulting in bile-acid entry into the duodenum. <100 cm of ileum results in bile acid spillage into the colon; resec-
Bile acids are primarily absorbed via an Na-dependent transport process that is tions of >100 cm result in loss of bile acids that exceed liver synthetic
located only in the ileum. A relatively small quantity of bile acids (~500 mg) is not
absorbed in a 24-h period and is lost in stool. Fecal bile-acid losses are matched by capacity, and malabsorption becomes the dominant pathophysiologic
bile-acid synthesis. The bile-acid pool (the total amount of bile acids in the body) is mechanism for diarrhea, due to bile acid deficiency (Table 325-4). The
~4 g and is circulated twice during each meal or six to eight times in a 24-h period. most common disorder of the GI tract that targets the ileum is Crohn’s
disease (Chap. 326), which is a chronic inflammatory disorder that

CHAPTER 325 Disorders of Absorption

may involve the entire GI tract, but most commonly the ileum and
Disorders That Result in Luminal Bile Salt Deficiency Bile colon. If severe or refractory to treatment, Crohn’s disease may lead to
acid synthesis and the enterohepatic circulation (Fig. 325-2): Bile
chronic inflammation, marked epithelial dysfunction, and structuring
acids are synthesized from cholesterol in the liver. The two primary
and fibrosis, and surgical resection may be required to treat small-
bile acids are cholic acid and chenodeoxycholic acid. These are con-
bowel obstruction or refractory disease.
jugated in the liver to taurine and glycine and are secreted into bile
ducts, stored in the gallbladder, and then delivered to the intestinal Primary Bile Acid Diarrhea A subset of patients with functional
lumen. Conjugation prevents bile acids from passive diffusion in the diarrhea or irritable bowel syndrome with diarrhea have been recently
small-bowel lumen, retaining bile acid concentrations required for shown to have bile acid malabsorption. Although the mechanisms are
lipid absorption. Bile acids emulsify fats and fat-soluble vitamins to still being elucidated, reduced FGF19 secretion by ileal enterocytes has
facilitate their absorption. Bile acids are efficiently reabsorbed in the been observed. FGF19 regulates serum 7alpha-hydroxy-4-cholesten-
ileum into the portal circulation and are extracted by the liver in a 3-one (C4) levels; reductions in circulating FGF19 lead to increased
process called enterohepatic circulation (Fig. 325-2). Small amounts hepatic bile acid synthesis via increased C4 expression. Chronic diar-
are deconjugated in the ileum by bacteria, or pass into the colon and rhea results from increased bile acid spillage into the colon, which
are deconjugated and metabolized by colonic bacteria to become sec- induces a secretory diarrhea.
ondary bile acids. The two major secondary bile acids are lithocholic
acid and deoxycholic acid. Treatment Bile acid sequestrants are effective in reducing diarrhea
Processes that affect any of the above pathways may result in luminal by binding bile acids to prevent spillage into the colon. Hepatic synthe-
bile salt deficiency and malabsorption. Thus, hepatobiliary diseases, sis of bile acids is sufficient to maintain intraluminal concentrations
intestinal ileal resection, extensive disease such as Crohn’s disease, and that are adequate for fat absorption.
small-bowel bacterial overgrowth may result in luminal bile salt defi- Small-Bowel Bacterial Overgrowth The intestine contains a
ciency and malabsorption (Table 325-3). rich microbiome. Bacterial titers increase along the horizontal axis of
Hepatobiliary Disease Hepatic disorders that result in decreased the gut from duodenum to ileum. However, intestinal disorders affect-
bile acid synthesis due to hepatocyte dysfunction or reduced secretion ing motility or causing stasis of bowel contents may lead to small-bowel
of bile into the gut lumen caused by diseases of the bile ducts such as bacterial overgrowth. These include scleroderma bowel, chronic intes-
primary sclerosing cholangitis or primary biliary cirrhosis may result tinal pseudo-obstruction, the creation of blind surgical loops such as
in luminal bile salt deficiency and fat malabsorption. These are dis- Billroth II anastomosis, small-bowel strictures, or fibrosis from inflam-
cussed in Chap. 346. matory disorders such as Crohn’s disease, and diffuse diverticulosis
(Fig. 325-3). Surgical resection of the ileocecal valve increases ileal
bacterial counts from the colon. Bacterial overgrowth causes deconju-
TABLE 325-3 Defects in Enterohepatic Circulation of Bile Acids gation of bile acids, which facilitates their absorption in the proximal
PATHOPHYSIOLOGIC bowel and results in luminal bile acid deficiency, which in turn causes
PROCESS DEFECT DISEASE EXAMPLE malabsorptive diarrhea with steatorrhea. Bacterial overgrowth may
Synthesis Decreased hepatic Cirrhosis also damage the brush border and result in carbohydrate maldigestion
function and short-chain fatty acid production in the colon, with diarrhea and
Biliary secretion Altered canalicular Primary biliary cirrhosis gas. These patients are also at risk for B12 deficiency due to bacterial
function metabolism of B12 resulting in macrocytic anemia and peripheral neu-
Maintenance of Bacterial overgrowth Jejunal diverticulosis ropathy. In contrast, elevated serum folate levels may also be observed,
conjugated bile acids derived from bacterial synthesis of folate.
Reabsorption Abnormal ileal function Crohn’s disease
Small-bowel bacterial overgrowth has also been observed in patients
with diarrhea-predominant irritable bowel syndrome. The underlying

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 2462
PART 10
Disorders of the Gastrointestinal System

FIGURE 325-3 Barium contrast small-intestinal radiologic examinations. A. Normal individual. B. Celiac disease. C. Jejunal diverticulosis. D. Crohn’s disease. (Courtesy of
Morton Burrell, MD, Yale University; with permission.)

mechanisms are unclear, but treatment of bacterial overgrowth leads activates trypsinogen and other pancreatic protease proenzymes. The
to resolution of symptoms in a subset of irritable bowel syndrome brush border membrane of the small-bowel epithelium expresses
patients. a wide variety of disaccharidases, peptidases, and other hydrolases
that continue the digestive process for carbohydrates and proteins,
Diagnosis Duodenal aspirate for bacterial titers is the gold standard with enzymatic digestion of disaccharides to monosaccharides and
but is not generally available to most practitioners. Breath hydrogen dipeptidases to amino acids, which are then absorbed by specific
testing with administration of lactulose, a nondigestible disaccha- transporters. Long-chain fatty acids are re-esterified to triglycerides in
ride, is widely available but must be interpreted carefully to avoid enterocytes, packaged into chylomicrons with apolipoproteins on the
false-positive results. Many clinicians choose to treat empirically with surface, which are subsequently secreted into the extracellular space,
antibiotics (see Treatment) and observe for resolution of symptoms. and because of their size, are excluded from capillaries and enter the
Treatment When possible, surgical correction of blind loops, lymphatics.
endoscopic or surgical treatment of strictures, and removal of large
diverticula can be pursued for definitive therapy, in addition to treat- INTESTINAL MUCOSAL DISORDERS
ment of underlying disorders such as Crohn’s disease to avoid recurrent
stricture formation or fibrosis. Other disorders such as scleroderma or ■■DISORDERS OF ENTEROCYTE CARBOHYDRATE
other diffuse motility disorders may not be easily treated. In these cir- TRANSPORTERS AND ENZYME DEFICIENCIES
cumstances, treatment with the nonabsorbable antibiotic, rifaximin, or Lactose Intolerance Due to Lactase Deficiency This is the
with other antibiotics such as metronidazole, doxycycline, amoxicillin- most common brush border disaccharidase deficiency and is a frequent
clavulinic acid, or cephalosporins for several weeks is often pursued. cause of diarrhea, abdominal pain, gassiness, and bloating. Lactose is
Patients may require retreatment or even chronic therapy with rotating present in many dairy products but is also a “hidden” component of a
antibiotics depending on the severity of symptoms. vast number of processed foods.
Lactose malabsorption can result from lactase deficiency, which is
■■MUCOSAL PHASE OF DIGESTION regulated by primary genetic mechanisms (adult-type hypolactasia)
AND ABSORPTION or secondary due to damage to the epithelial (mucosal) lining of the
The intestinal epithelium (also known as the mucosa) plays a critical gut, from infections (viral, bacterial, or parasitic) or from intestinal
role in continued digestion of nutrients and absorption from the intes- mucosal diseases. Congenital lactase deficiency is very rare and is an
tinal lumen into the bloodstream and lymphatics. autosomal recessive disorder. Hypolactasia in adulthood is very com-
The small-bowel epithelial or mucosal digestive and absorptive mon throughout the world and is considered to be the genetic wild-
phase is mediated by enterocytic brush border enzymes, including type; lactase persistence results from a C to T mutation (LACTASE
peptidases and hydrolases. Brush border enterokinase is required for LCT-13910CT and LCT-13910TT) and adults with hypolactasia have
the conversion of pancreatic trypsinogen to trypsin, which further absence of this “persistence” allele. Lactose is metabolized by lactase

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 into glucose and galactose, which are both absorbed by transporters at ■■INTESTINAL MUCOSAL DISORDERS THAT RESULT 2463
the enterocyte surface. Patients who are lactase deficient have elevated IN MALABSORPTION OF MULTIPLE NUTRIENTS
luminal lactose levels upon ingestion of lactose. The mechanism for
diarrhea in lactase deficiency is complex. Undigested lactose acts as an Celiac Disease Celiac disease, also known as celiac sprue or
osmotic substance to draw fluid into the small-bowel lumen. In addi- gluten-sensitive enteropathy, is a small intestinal enteropathy that
tion, when unabsorbed lactose enters the colon, luminal bacteria fer- results from an immune response to gluten ingestion and is character-
ment lactose producing intestinal gas (hydrogen, carbon dioxide, and ized by autoantibodies to tissue transglutaminase. Gluten is found in
methane), bloating, and abdominal pain. Luminal lactose is metabo- foods produced from wheat, rye, barley, and some varieties of oats, and
lized by bacteria into short-chain fatty acids that can be absorbed by it is a common additive to prepared foods and pharmaceuticals. Tissue
the colon, but watery diarrhea may occur when a large lactose load transglutaminase is involved in the pathogenesis of this disorder, as it
exceeds the colon’s absorptive capacity. deamidates glutamine residues of gluten-derived peptides, facilitating
their presentation by antigen-presenting cells.
Diagnosis When lactose intolerance is suspected, a common initial
approach is to institute a lactose-exclusion diet and assess for resolution Epidemiology and Genetics The incidence and prevalence of
of symptoms. This is a rapid and generally effective diagnostic and ther- celiac disease have been increasing worldwide. Increased awareness
apeutic method. Patients are provided with a list of lactose-containing among clinicians and patients has led to increases in detection, but
foods and lactose-free alternatives. Patients are also counseled on there is evidence that the true incidence appears to be increasing as
alternative calcium sources, because dairy-containing foods are a well. Global prevalence has been measured at 1.4%. In the United
major source of dietary calcium, which is important for osteoporosis States, data from the National Health and Nutrition Examination sur-
prevention. vey showed seroprevalence of 0.2% in non-Hispanic black populations,
Should the results of dietary exclusion be ambiguous, a lactose- 0.3% in Hispanic individuals, and 1.0% in white populations.
tolerance test or breath hydrogen test may prove useful. For the lac- The prevalence of celiac disease is 10–15% in first-degree relatives.
tose-tolerance test, patients ingest a standardized liquid lactose solu- Host genetic factors include histocompatibility locus antigens HLADQ2
tion (usually 50 g of lactose) followed by timed measurements of serum and DQ8; the presence of one of the two haplotypes is necessary but
glucose for 90 min. If lactose digestion is normal, glucose levels should not sufficient for developing celiac disease. HLADQ2 and DQ8 are
rise by >20 mg/L. Serum glucose rise <20 mg/L plus the presence of found in 25–35% of the general population; because most carriers
symptoms of lactose intolerance (abdominal discomfort, gassiness, never develop celiac disease, detection of these alleles is not useful for
and diarrhea) is considered a positive test. A breath hydrogen test is diagnosis. However, a negative test is very useful for ruling out celiac
performed by measuring breath hydrogen levels following ingestion of disease, with a negative predictive value of >99%. This is particularly

CHAPTER 325 Disorders of Absorption

a standardized lactose load. Breath hydrogen levels should not exceed helpful in patients who self-discontinued gluten ingestion prior to
>20 ppm above the fasting baseline. Generally the peak occurs between serologic or endoscopic testing.
2–4 h. Both methods may be inaccurate if the patient has abnormal Presentation Patients with celiac disease have a wide variety of
gastric emptying or abnormal intestinal transit. Breath hydrogen mea- disease manifestations, ranging from being asymptomatic, to having
surements may be abnormal in the setting of bacterial overgrowth, isolated iron-deficiency anemia due to duodenal disease, to severe
which may cause very similar symptoms. diarrhea, weight loss, and malabsorption of multiple nutrients with
Treatment Patients may elect to completely eliminate lactose from more diffuse disease. Celiac disease primarily affects the proximal
their diets. It is very important to consider calcium and vitamin D small intestine; it may involve the duodenum only or may cause wide-
supplementation because elimination of milk and soft cheeses removes spread jejunal disease resulting in severe symptoms.
important dietary sources. They also may need to consult a dietitian Diarrhea, weight loss, and growth failure in children are common
for guidance about hidden lactose in prepared or other foods. An alter- presenting complaints, but additional signs and symptoms have become
native is to consider using lactase supplementation, which is available increasingly recognized to be associated with celiac disease, including
over the counter, but which may need to be titrated to avoid symptoms. bloating and irregular bowel habits, migraine headaches, and ataxia. In
addition, patients may be identified after presenting with osteoporosis,
Glucose Galactose Malabsorption This rare congenital dis- iron-deficiency anemia, or detection of abnormal liver enzymes.
order is an autosomal recessive disease in which mutations occur in
the SLC5A1 gene (also known as SGLT1). SLC5A1 is a brush border Mechanism of Diarrhea Patients with celiac disease have villus
protein and member of the sodium-dependent glucose transporter atrophy in the proximal small intestine and thus develop steatorrhea
family; mutations in this gene result in malabsorption of glucose and from mucosal malabsorption and may have lactase deficiency. However,
galactose. Gene sequencing has shown that most patients have loss they also develop a secretory component due to crypt hyperplasia and
of function single-nucleotide variations. SLC5A1 actively transports fluid hypersecretion from the crypt epithelium.
glucose or galactose coupled to sodium cotransport; patients who are Associated Diseases Patients with celiac disease have a higher
homozygous for these loss-of-function variants have severe congenital incidence of other autoimmune disorders such as type 1 diabetes
diarrhea and death if unrecognized. Treatment focuses on eliminating mellitus and autoimmune thyroid disease. Dermatitis herpetiformis is
glucose- and galactose-containing foods and substituting fructose- a skin disorder that is highly associated with celiac disease, character-
containing foods. Fructose is absorbed by the brush border transporter ized by a vesicular rash mediated by IgA deposits in the skin. Down
GLUT5 by facilitated diffusion and is not dependent on SLC5A1. syndrome and Turner syndrome patients also have an increased risk
Abetalipoproteinemia Abetalipoproteinemia is a rare disorder of of celiac disease.
lipid metabolism associated with abnormal erythrocytes (acanthocytes), Diagnosis Patients are screened for celiac disease first by testing
neurologic symptoms, and steatorrhea (see Chap. 407). Lipolysis, for serum antibodies, including tissue transglutaminase IgA, anti-
micelle formation, and lipid uptake are all normal in patients with endomysial, and deamidated anti-gliadin antibodies. Serum IgA lev-
abetalipoproteinemia, but the re-esterified triglyceride cannot exit the els are measured to detect false-negative results from IgA deficiency.
epithelial cell because of the failure to produce chylomicrons. This Deamidated anti-gliadin IgG antibodies or tissue transglutaminase
disorder results from mutation of microsomal triglyceride transfer IgG antibodies are detectable and diagnostic in IgA-deficient patients.
protein, which catalyzes the transfer of triglyceride onto nascent apo- The diagnosis in adults with positive antibody levels is confirmed by
lipoprotein B containing particles. Mutations in MTP decrease this endoscopy with small-intestinal biopsy. Biopsies typically show charac-
transfer and decrease formation of chylomicrons. Small-intestinal teristic villus blunting, crypt hyperplasia, and inflammation, including
biopsy samples obtained from these rare patients in the postprandial increased intraepithelial lymphocytes. The Marsh classification cate-
state reveal lipid-laden small-intestinal epithelial cells that become gorizes different types of celiac disease–related lesions and is currently
normal in appearance after a 72- to 96-h fast. used to quantify severity of disease involvement.

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 2464 Family members of patients with celiac disease are screened if symp- diarrhea, abdominal pain, and weight loss from malabsorption. CNS
tomatic; recommendations regarding screening asymptomatic family involvement is common and may include symptoms such as psychi-
members are still controversial. atric manifestations or memory problems. Dementia and encephalitis
may occur in later stages. Cardiac involvement may include endocar-
Complications Complications of celiac disease include refractory ditis, pericarditis, and myocarditis.
celiac disease, enteropathy-associated T-cell lymphoma, hyposplenism,
and small-bowel adenocarcinoma. Diagnosis For patients with GI manifestations, endoscopy with
biopsies is performed and tissue is tested for T. whipplei by polymerase
Refractory Celiac Disease This complication is most common chain reaction. Tissue is also stained for PAS-positive macrophages and
in patients with ongoing active celiac disease, found in about 10% of immunohistochemistry may also be performed to detect T. whipplei.
patients with persistent active disease. Patients have ongoing diarrhea
and weight loss with persistent villus atrophy on biopsy after 1 year of Treatment Prolonged antibiotics are recommended although the
following a strict gluten-free diet. These patients also have negative optimal regimen is still uncertain. Relapses are common, and often
celiac serology, confirming their adherence to the gluten-free diet. associated with the first manifestations of CNS involvement.
Type 1 refractory celiac disease has a normal intraepithelial lympho-
cyte population whereas type 2 disease has clonal expansion of CD3+ ■■TROPICAL SPRUE
intraepithelial lymphocytes that also contain a monoclonal rearrange- Tropical sprue is a poorly understood syndrome that is manifested by
ment of the gamma chain of the T-cell receptor. Type 2 refractory chronic diarrhea, steatorrhea, weight loss, and nutritional deficiencies,
celiac disease has a worse prognosis due to its association with T-cell including both folate and vitamin B12. Malabsorption of two unrelated
lymphoma, which occurs in 33–50% of cases after 5 years. The therapy substances is required for diagnosis. This disease occurs in 8–20% of
for celiac disease–related lymphoma is intense and includes high-dose people who have had an attack of infectious gastroenteritis in India,
chemotherapy and sometimes stem cell transplantation. and is considered by some to be a postinfectious complication. It is
Small-bowel adenocarcinoma is a very rare cancer in the general prevalent in some but not all tropical areas, including southern India,
population but is increased in celiac disease patients. Pakistan, the Philippines, Puerto Rico, Haiti, and Cuba. It occurs in
Therapy and Follow-up The mainstay of celiac disease treatment residents of as well as visitors to these areas.
is institution of a strict gluten-free diet. This is challenging for patients Chronic diarrhea in a tropical environment is most often caused
because of the widespread presence of gluten in both raw and prepared by infectious agents, including Giardia lamblia, Yersinia enterocolitica,
foods, inaccurate food labeling, and cross-contamination during food Entamoeba histolytica, C. difficile, Cryptosporidium parvum, Isospora
preparation. Patients must receive rigorous dietary instruction from a belli, Strongyloides stercoralis, and Cyclospora cayetanensis. Tropical
dietitian and adhere lifelong to a gluten-free diet. sprue should not be entertained as a possible diagnosis until the pres-
PART 10

For those patients whose symptoms resolve, serologic follow-up ence of cysts and trophozoites has been excluded in three stool sam-
is generally recommended to confirm compliance with a gluten-free ples. Chronic infections of the GI tract and diarrhea are discussed in
diet. A follow-up biopsy to document complete healing of villus atro- Chaps. 46, 133, 134, 163–168, and 223.
phy is also generally recommended. However, subsequent biopsies In the past few years, the term environmental enteropathy has been
introduced as the diagnosis of many patients (especially infants and
Disorders of the Gastrointestinal System

are not recommended unless symptoms recur. For patients without

symptom resolution, a biopsy is required to determine the degree of children) who had previously been diagnosed as tropical sprue. How-
disease activity and to rule out other causes of persistent diarrhea and ever, exact delineation of this newly designated entity is lacking.
complications such as refractory celiac disease or T-cell lymphoma. Etiology Because tropical sprue responds to antibiotics, the con-
The most common cause of residual disease activity is dietary nonad- sensus is that it may be caused by one or more infectious agents. None-
herence or inadvertent gluten exposure. These patients pursue repeat theless, the etiology and pathogenesis of tropical sprue are uncertain.
consultation with a dietitian and efforts to reduce restaurant or other First, its occurrence is not evenly distributed in all tropical areas; it is
out-of-the-home exposure or cross-contamination at home. If biopsies rarely observed in Africa, Jamaica, or Southeast Asia. Second, an occa-
are negative but symptoms persist, other causes of abdominal pain sional individual does not develop symptoms of tropical sprue until
and diarrhea that are associated with celiac disease are considered, long after having left an endemic area. For this reason, celiac disease
including irritable bowel syndrome, microscopic colitis, small-bowel (often referred to as celiac sprue) was originally called nontropical sprue
bacterial overgrowth, and lactose or fructose intolerance. to distinguish it from tropical sprue. Third, multiple microorganisms
Nonceliac Gluten Sensitivity Recently a subset of patients has have been identified in jejunal aspirates, with relatively little consis-
been described with symptoms consistent with celiac disease but with tency among studies. Klebsiella pneumoniae, Enterobacter cloacae, and
negative serology and negative biopsies. Upon discontinuation of glu- E. coli have been implicated in some studies of tropical sprue, while
ten, they have relief of abdominal pain, diarrhea, headaches/migraines, other studies have favored a role for a toxin produced by one or more
and other celiac disease–type symptoms. The etiology of this disorder of these bacteria. Fourth, the incidence of tropical sprue appears to
is unknown. have decreased substantially during the past two or three decades,
perhaps in relation to improved sanitation in many tropical countries
during this time. Some have speculated that the reduced occurrence is
■■WHIPPLE’S DISEASE
attributable to the wider use of antibiotics in acute diarrhea, especially
Whipple’s disease is a chronic, multiorgan disease caused by Troph-
in travelers to tropical areas from temperate countries. Fifth, the role
eryma whipplei, a gram-positive non-acid-fast, periodic acid–Schiff
of folic acid deficiency in the pathogenesis of tropical sprue requires
(PAS) positive rod, which is ubiquitous in the environment. Whipple’s
clarification. Folic acid is absorbed exclusively in the duodenum and
disease most commonly occurs in middle-aged men. Classic Whipple’s
proximal jejunum, and most patients with tropical sprue have evidence
disease is defined by the presence of arthralgias, weight loss, diarrhea,
of folate malabsorption and depletion. Although folate deficiency can
and abdominal pain. Other manifestations including central nervous
cause changes in small-intestinal mucosa that are corrected by folate
system (CNS) and cardiac involvement are common and occur later in
replacement, several earlier studies reporting that tropical sprue could
the disease. T. whipplei can be detected by polymerase chain reaction
be cured by folic acid did not provide an explanation for the “insult”
on involved tissue and is difficult to detect in the bloodstream. The
that was initially responsible for folate malabsorption.
intestinal lesion is also characterized by PAS-positive macrophages.
The clinical pattern of tropical sprue varies in different areas of
Clinical Presentation Arthralgias and arthritis are present for an the world (e.g., India vs Puerto Rico). Not infrequently, individuals in
average of 6 years before the GI symptoms begin, consistent with a per- southern India initially report the occurrence of acute enteritis before
sistent and substantial lag in diagnosis, which is still a problem today. the development of steatorrhea and malabsorption. In contrast, in
Joint disease is present in >80% of patients. GI manifestations include Puerto Rico, a more insidious onset of symptoms and a more dramatic

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 2465

CHAPTER 325 Disorders of Absorption

FIGURE 325-4 Small-intestinal mucosal biopsies. A. Normal individual. B. Untreated celiac disease. C. Treated celiac disease. D. Intestinal lymphangiectasia. E. Whipple’s
disease. F. Lymphoma. G. Giardiasis. (Courtesy of Marie Robert, MD, Yale University; with permission.)

response to antibiotics are seen compared with some other locations. gain, and some morphologic changes in small-intestinal biopsy.
Tropical sprue in different areas of the world may not be the same dis- Because of marked folate deficiency, folic acid is most often given
ease, and similar clinical entities may have different etiologies. together with antibiotics.
Diagnosis The diagnosis of tropical sprue is based on an abnormal
small-intestinal mucosal biopsy in an individual with chronic diarrhea SHORT-BOWEL SYNDROME
and evidence of malabsorption who is either residing or has recently
lived in a tropical country. The small-intestinal biopsy in tropical sprue ■■OVERVIEW
does not reveal pathognomonic features but resembles, and can often Short-bowel syndrome results from intestinal resection to treat a mul-
be indistinguishable from, that seen in celiac disease (Fig. 325-4). The titude of disorders including Crohn’s disease, vascular diseases such
biopsy sample in tropical sprue has less villous architectural alteration as mesenteric arterial or venous thrombosis resulting in intestinal
and more mononuclear cell infiltrate in the lamina propria. In contrast ischemia, volvulus, trauma, internal herniation, radiation enteritis,
to those of celiac disease, the histologic features of tropical sprue man- and diffuse carcinoma, among others. In children, the most common
ifest with a similar degree of severity throughout the small intestine, causes of short-bowel syndrome are necrotizing enterocolitis, intestinal
and a gluten-free diet does not result in either clinical or histologic atresias, volvulus, and malrotation. Short-bowel syndrome is defined
improvement in tropical sprue. as extensive removal of small intestine resulting in <200 cm remain-
ing small bowel. Intestinal failure is functionally defined as persistent
parenteral nutrition dependence, generally found in patients who have
TREATMENT <100 cm of remaining small bowel and no residual colon in continuity.
Tropical Sprue Clinical Features Loss of small-bowel surface area in short-bowel
Broad-spectrum antibiotics and folic acid are most often curative, syndrome results in severe diarrhea, weight loss, and malabsorption
especially if the patient leaves the tropical area and does not return. of multiple nutrients, including fat, protein, and carbohydrate. The
Tetracycline should be used for up to 6 months and may be associ- severity of symptoms and ultimate dependence on parenteral nutrition
ated with improvement within 1–2 weeks. Folic acid alone induces are generally related to the extent of resection, presence or absence
hematologic remission as well as improvement in appetite, weight of residual colon in continuity, retention of the ileocecal valve, and

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 2466 severity of the underlying disease. The intestine has a remarkable contributing several hundred additional kilocalories per day. All
capacity to adapt to loss of small-bowel surface area, but this adaptive patients are asked to take a high-potency multivitamin on a daily basis.
process is variable from patient to patient. Following resection, the Patients in whom oral nutrition fails are fed with parenteral nutrition.
adapting residual intestine exhibits an increase in crypt cell prolifera-
tion resulting in epithelial hyperplasia. The adaptive process generally Monitoring SBS patients are at high risk for osteoporosis due to
continues for up to 2 years post resection, but improvements in nutri- dietary calcium and vitamin D malabsorption, so they are periodically
ent, fluid, and electrolyte absorptive capacity have been reported even monitored for vitamin D deficiency and calcium levels and with DEXA
as late as 3–5 years after surgery. Massive diarrhea generally occurs in studies to assess bone density. Malabsorption of vitamins and miner-
the first three postoperative months, associated with increased gastric als is common; therefore, fat-soluble vitamins, vitamin B12, folic acid,
acid secretion and malabsorption. Gradually, patients show enhanced iron, magnesium, and zinc are monitored periodically. More unusual
functional capacity and reduced diarrhea. Specific nutrient deficien- deficiencies include copper, selenium and chromium, but these are
cies are dependent upon which segment of gut has been removed. For usually in PN-dependent patients and can be corrected by adjusting
example, resection of the ileum results in loss of B12 absorptive and bile daily intravenous dosages. Signs and symptoms of vitamin and mineral
salt reabsorptive capacity. Malabsorbed bile salts reach the colon and deficiency are also carefully monitored (hair loss, skin and nail changes,
cause a secretory diarrhea. In addition, resection of >100 cm of ileum neurologic symptoms such as peripheral neuropathy, etc.).
results in such severe bile salt malabsorption that the liver cannot ■■DISORDERS OF POST-MUCOSAL ABSORPTION
compensate by increased synthesis, thus precipitating fat malabsorp- Following uptake into enterocytes, nutrients are further processed and
tion due to bile salt insufficiency/deficiency. Substantial resection of transported into the lymphatics or into the portal circulation for use
the colon also results in fluid and electrolyte loss and imbalance. The by other cells throughout the body. Primary or secondary disorders
colon also plays a role in nutrient absorption because it metabolizes of the lymphatics may result in significant diarrhea and malabsorp-
malabsorbed carbohydrate into short-chain fatty acids that can be tion. Primary disorders of the intestinal lymphatics include intestinal
absorbed by the colon and can contribute several hundred additional lymphangiectasia, which may be congenital or acquired. Secondary
calories per day. causes of intestinal lymphatic damage or blockage include retroperito-
Long-Term Complications Because massive resection often leads neal fibrosis, fibrosing mesenteritis, and lymphoma. Circulatory causes
to severe fat malabsorption, fat-soluble vitamin deficiency is common, of impaired delivery of nutrients from the intestine include Fontan
and vitamin D deficiency can be very difficult to treat even with high- physiology, congestive heart failure, and constrictive pericarditis. The
dose oral vitamin D supplementation, resulting in an increased risk of end result of damage to lymphatic channels is malabsorption and diar-
osteoporosis. Patients with a history of multiple surgeries often have rhea with concomitant protein-losing enteropathy.
extensive adhesive disease, and the residual intestine may have mark-
PART 10

edly abnormal motility or areas of structuring and narrowing, resulting PROTEIN-LOSING ENTEROPATHY
in recurrent bacterial overgrowth. The frequency of renal calcium Protein-losing enteropathy refers to a large group of GI and non-GI
oxalate stones increases in patients with a shortened small bowel with disorders characterized by hypoproteinemia and edema in the absence
an intact colon in continuity; calcium is saponified in the intestinal of liver disease with reduced protein synthesis, or kidney disease with
proteinuria. These diseases are characterized by excess protein loss in
Disorders of the Gastrointestinal System

luminal contents that contain fatty acids, freeing oxalate to be absorbed

in the colon resulting in hyperoxaluria. the GI tract. Diseases that may result in increased protein loss into the
GI tract can be classified into three groups: (1) mucosal ulceration,
Treatment The major focus of treatment for short-bowel syndrome such that the protein loss primarily represents exudation across dam-
is to control diarrhea and normalize nutrient, fluid, and electrolyte aged mucosa (e.g., ulcerative colitis, GI carcinomas); (2) nonulcerated
absorption so that patients can maintain their weight and have a mucosa, but with evidence of mucosal damage so that the protein
healthy nutritional status without the support of parenteral nutrition. loss represents loss across epithelia with altered permeability (e.g.,
Medications include opiates and derivatives including loperamide celiac disease and Ménétrier’s disease [hypertrophic gastropathy] in
and diphenoxylate-atropine, which slow intestinal motility to allow the small intestine and stomach, respectively); and (3) lymphatic dys-
for more contact time between luminal nutrients and the small-bowel function, representing either primary lymphatic disease or lymphatic
mucosal surface. In the first year following resection, acid-blocking disease secondary to partial lymphatic obstruction that may occur
medications are used to treat gastric hypersecretion, including proton as a result of enlarged lymph nodes or cardiac disease. These result in
pump inhibitors or histamine 2 antagonists. Small-bowel bacterial increased lymphatic pressure causing exudation of protein into the GI
overgrowth is common and is treated with antibiotics if suspected. The tract lumen.
only medication that is specific for short-bowel syndrome but limited
for use in parenteral nutrition or intravenous fluid–dependent patients Diagnosis The diagnosis of protein-losing enteropathy is suggested
is teduglutide, a glucagon-like 2 peptide analog that enhances crypt cell by diarrhea, peripheral edema, and low serum albumin and globulin
proliferation and villus hyperplasia, and increases nutrient and fluid levels in the absence of renal and hepatic disease. An individual with
and electrolyte absorption. Patients treated with teduglutide have an protein-losing enteropathy rarely has selective loss of only albumin or
average reduction of 20% of their parenteral nutrition requirements. only globulins. Therefore, marked reduction of serum albumin with
Greater efficacy has been noted for patients without a residual colon, normal serum globulins should suggest renal and/or hepatic disease.
likely due to lower circulating endogenous GLP-2 levels compared to Likewise, reduced serum globulins with normal serum albumin lev-
those with a colon in continuity. els are more likely a result of reduced globulin synthesis rather than
enhanced globulin loss into the intestine. Alpha-1 antitrypsin, a pro-
Dietary Therapy Patients with short-bowel syndrome must con- tein that accounts for ~4% of total serum proteins and is resistant to
sume three to four times their normal caloric intake to maintain their proteolysis, can be used to detect enhanced rates of serum protein loss
weight. The presence of luminal nutrients is required for the adaptive into the intestinal tract but cannot be used to assess gastric protein loss
process to occur, so early feeding is recommended, even if parenteral because of its degradation in an acid milieu. Alpha-1 antitrypsin can
nutrition is also required. These effects are most likely mediated by be measured in a spot or 24-h stool collection and if elevated, is diag-
direct contact with the mucosa as well as stimulation of secretion of gut nostic. A more accurate determination is alpha-1 antitrypsin clearance,
hormones such as glucagon-like 2. measured by determining stool volume as well as both stool and plasma
If the patient has all or part of their colon remaining in continuity, alpha-1 antitrypsin concentrations. In addition to the loss of protein
a low-fat diet is instituted to reduce the concentration of malabsorbed via abnormal and distended lymphatics, peripheral lymphocytes may
fatty acids that induce a secretory diarrhea. High complex carbohy- be lost via lymphatics, with consequent relative lymphopenia and
drates are encouraged because when malabsorbed and present in the specifically loss of CD3+ T cells. Thus, lymphopenia in a patient with
colon, they are converted to short-chain fatty acids and are absorbed, hypoproteinemia indicates increased loss of protein into the GI tract.

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 Patients with increased protein loss into the GI tract from lymphatic symptoms or signs of selective nutrient deficiency including 2467
obstruction often have steatorrhea and diarrhea. The steatorrhea is a iron deficiency anemia, bone fracture, or osteoporosis suggest-
result of altered lymphatic flow as lipid-containing chylomicrons exit ing vitamin D and/or calcium deficiency, peripheral neuropathy
from intestinal epithelial cells via intestinal lymphatics (Table 325-2; resulting from vitamin B12 deficiency, hair loss that may result
Fig. 325-4). In the absence of mechanical or anatomic lymphatic from generalized protein deficiency, predisposing disorders such
obstruction, intrinsic intestinal lymphatic dysfunction—with or with- as chronic pancreatitis or liver disease particularly involving the
out lymphatic dysfunction in the peripheral extremities—has been des- bile ducts such as primary biliary cholangitis or primary scleros-
ignated intestinal lymphangiectasia. Similarly, ~50% of individuals with ing cholangitis, history of small-bowel resection (due to Crohn’s
intrinsic peripheral lymphatic disease (Milroy’s disease) also have intes- disease, trauma, ischemic bowel disease, etc.), and travel history. A
tinal lymphangiectasia and hypoproteinemia. Other than steatorrhea multitude of nonspecific symptoms such as fatigue and weakness
and enhanced protein loss into the GI tract, all other aspects of intes- may also be reported. The protean manifestations of malabsorption
tinal absorptive function are normal in intestinal lymphangiectasia. and the underlying pathophysiology of clinical manifestations are
summarized in Table 325-5.
Endoscopy and Imaging Endoscopy with biopsy and video
capsule endoscopy may be performed to rule out mucosal disease. PHYSICAL EXAMINATION
Magnetic resonance enterography may be helpful in children with A careful physical examination may provide clues to underlying
lymphangiectasia. nutrient deficiencies and help assess severity of the malabsorptive
Other Causes Patients who have idiopathic protein-losing enterop- process. For example, evidence of significant weight loss may be
athy without evidence of GI disease should be examined for car- detected by bitemporal wasting and reduced arm circumference,
diac disease. As more patients with congenital heart disease reach iron deficiency may cause nail spooning, and vitamin B12 deficiency
adulthood, Fontan physiology has become a more common cause of may result in significant peripheral neuropathy resulting in sensory
protein-losing enteropathy. Other cardiac causes include right-sided reduction with tingling or numbness.
valvular disease and chronic pericarditis (Chaps. 268 and 270). LABORATORY EXAMINATION (TABLE 325-6)
Ménétrier’s disease (also called hypertrophic gastropathy) is an uncom- Diseases that exclusively affect the proximal small intestine
mon entity that involves the body and fundus of the stomach and is (e.g., celiac disease limited to the duodenum) may result in
characterized by large gastric folds, reduced gastric acid secretion, and, iron-deficiency anemia. Resection or disease of the terminal ileum
at times, enhanced protein loss into the stomach. frequently results in B12 deficiency since B12 absorption occurs
exclusively in the ileum, causing a macrocytic anemia. Disorders

CHAPTER 325 Disorders of Absorption

TREATMENT that cause steatorrhea are almost invariably associated with fat-
soluble vitamin deficiency, specifically vitamin D (very common),
Protein-Losing Enteropathy vitamin E, vitamin A, and vitamin K. The functional result of
As excess protein loss into the GI tract is most often secondary to vitamin K deficiency is an elevated prothrombin time/international
a specific disease, treatment should be directed primarily to the normalized ratio (INR) so this blood test is frequently measured
underlying disease process and not to the hypoproteinemia. When instead of vitamin K levels. Serum carotene levels can suggest fat
enhanced protein loss is secondary to lymphatic obstruction, it is malabsorption but may decrease simply due to poor dietary con-
critical to establish the nature of this obstruction. Identification of sumption of leafy vegetables.
mesenteric nodes or lymphoma may be possible by imaging studies. To diagnose steatorrhea, a spot stool can be submitted for Sudan
Similarly, it is important to exclude cardiac disease as a cause of III staining, which is specific for fecal fat. This is a useful qualitative
protein-losing enteropathy. Patients with congenital heart disease but not quantitative test. Stool for elastase is helpful for diagnosing
may be examined by intranodal lymphangiography or noncontrast pancreatic insufficiency. A 24-h assessment of stool volume/weight
magnetic resonance lymphangiography, and may undergo surgical may useful to establish the presence of clinically significant absorp-
lymphatic interventions to decompress the lymphatic system or to tive or secretory diarrhea vs diarrhea from other causes such as
target exclusion of abnormal lymphatic channels. proctitis, which causes frequent, small, low-volume stools. The gold
The increased protein loss that occurs in intestinal lymphang- standard for documenting steatorrhea is the 72-h fecal fat collec-
iectasia is a result of distended lymphatics associated with lipid tion, which is performed in concert with the patient’s consumption
malabsorption. The hypoproteinemia is treated with a low-fat, of a 100-g fat diet. This test is highly accurate but difficult to obtain
high-protein diet and the administration of medium-chain trig- due to patient reluctance to collect stool. Also patients with fat mal-
lycerides, which do not exit from the intestinal epithelial cells via absorption may poorly tolerate a 100-g fat diet. A diet with strictly
lymphatics but are delivered to the body via the portal vein. Other quantified albeit reduced fat calories may be substituted. Finally,
medical therapies including octreotide, a somatostatin analog, the calculation of the stool osmotic gap is a very useful and easy
intravenous heparin, and budesonide have been studied but have way to diagnose an osmotic diarrhea. A spot stool sample is sent
generally been ineffective. to the lab for quantitation of fecal sodium and potassium concen-
tration. Although stool osmolality can also be measured in the lab,
measurements are often inaccurate due to bacterial degradation of
nonabsorbed carbohydrate as the stool sits prior to examination.
APPROACH TO THE PATIENT Because normal stool osmolality reflects serum osmolality at 290
Evaluation of the Patient with Suspected mOsm/kg H2O, the osmotic gap may be calculated as follows:
Malabsorption 290 – 2 (stool [Na+] + stool [K+]).
The evaluation of patients with malabsorption is often challenging If >50–100, a stool osmotic gap is present indicating the pres-
due to the large number of underlying disorders and the wide array ence of unmeasured osmoles (e.g., malabsorbed lactose), and
of available tests. Thus an extensive history and careful physical osmotic diarrhea can be diagnosed. If <50, one can presume a
examination are essential to develop a more limited differential secretory component. Of note, malabsorbed fatty acids may also
diagnosis, and thereby avoid extensive and unnecessary testing. cause a secretory diarrhea by inducing secretion in the colon, so
a malabsorptive diarrhea may have both an osmotic and secretory
HISTORY component. Extensive celiac disease may cause both osmotic diar-
A careful history should include questions about symptoms rhea due to malabsorbed carbohydrate and also secretory diarrhea
including abdominal pain, diarrhea, weight loss, bloating, due to crypt hyperplasia.

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 2468
TABLE 325-5 Pathophysiology of Clinical Manifestations of with documented steatorrhea or chronic diarrhea, as well as to
Malabsorption Disorders evaluate abnormalities detected by radiologic imaging or by cap-
SYMPTOM OR SIGN MECHANISM sule endoscopy. In patients with documented steatorrhea and no
Weight loss/malnutrition Anorexia, malabsorption of nutrients evidence of pancreatic or hepatobiliary disease, an upper endoscopy
Diarrhea Impaired absorption or secretion of water and and possible small-bowel enteroscopy are required to examine the
electrolytes; colonic fluid secretion secondary small-bowel mucosa and to take biopsies for analysis. An upper
to unabsorbed dihydroxy bile acids and fatty endoscopy will visualize the stomach and duodenum; the maxi-
acids mum reach of the typical upper endoscopy scope is the ligament
Flatus Bacterial fermentation of unabsorbed of Treitz. Small-bowel enteroscopy using a longer scope such as a
carbohydrate pediatric colonoscope can be used to visualize the jejunum. Single-
Glossitis, cheilosis, stomatitis Deficiency of iron, vitamin B12, folate, and and double-balloon enteroscopy provide a means for examining
vitamin A much more of the jejunum and, if successful, will reach the ileum.
Abdominal pain Bowel distention or inflammation, pancreatitis Capsule endoscopy provides another means for visualizing the
Bone pain Calcium, vitamin D malabsorption, protein entire small bowel. Colonoscopy can be used for a retrograde view
deficiency, osteoporosis and biopsy of the terminal ileum.
Tetany, paresthesia Calcium and magnesium malabsorption Biopsy Analysis Small-bowel pathology may be divided into the
Weakness Anemia, electrolyte depletion (particularly K+) three groups (Table 325-7) described below.
Azotemia, hypotension Fluid and electrolyte depletion
1. Diffuse histopathologic findings involving the entire or major-
Amenorrhea, decreased libido Protein depletion, decreased calories, ity of the mucosa which are specific for a particular disease
secondary hypopituitarism
entity; these include Whipple’s disease, agammaglobulinemia
Anemia Impaired absorption of iron, folate, vitamin B12 (for example, combined variable immunodeficiency), and abe-
Bleeding Vitamin K malabsorption, hypoprothrombinemia talipoproteinemia. Whipple’s disease exhibits PAS-positive mac-
Night blindness/xerophthalmia Vitamin A malabsorption rophages and immunohistochemical analysis can detect the
Peripheral neuropathy Vitamin B12 and thiamine deficiency pathogenic organism. Immune globulin deficiency is associated
Dermatitis Deficiency of vitamin A, zinc, and essential with a variety of histopathologic findings on small-intestinal
fatty acid mucosal biopsy. The characteristic feature is the absence of or
substantial reduction in the number of plasma cells in the lamina
propria; the mucosal architecture may be either perfectly normal
PART 10

Urinary D-xylose Test The urinary D-xylose test for carbohydrate or flat (i.e., villous atrophy). Abetalipoproteinemia is character-
absorption provides a measure of proximal small-bowel absorptive ized by a normal mucosal appearance except for the presence of
function. d-Xylose, a pentose, is absorbed almost exclusively in the mucosal absorptive cells that contain lipid postprandially and
proximal small intestine and is excreted in the urine. The d-xylose disappear after a prolonged period of either fat-free intake or
Disorders of the Gastrointestinal System

test is usually performed by administering 25 g of d-xylose and fasting.

collecting urine for 5 h. An abnormal test (excretion of <4.5 g) 2. Patchy lesions that are specific for a disease entity include, for
primarily reflects duodenal/jejunal mucosal disease. The d-xylose example, intestinal lymphoma or intestinal lymphangiectasia.
test can also be abnormal in patients with delayed gastric empty- Several diseases feature an abnormal small-intestinal mucosa
ing, impaired renal function, and sequestration in patients with with a patchy distribution. As a result, biopsy samples obtained
large collections of fluid in a third space (i.e., ascites, pleural fluid). randomly or in the absence of endoscopically visualized abnor-
The ease of obtaining a mucosal biopsy of the small intestine by malities may not reveal diagnostic features. Intestinal lymphoma
endoscopy and the false-negative rate of the d-xylose test have led can at times be diagnosed on mucosal biopsy by the identifica-
to its diminished use. When small-intestinal mucosal disease is tion of malignant lymphoma cells in the lamina propria and
suspected, a small-intestinal mucosal biopsy should be performed. submucosa (Chap. 108). Dilated lymphatics in the submucosa
and sometimes in the lamina propria indicate lymphangiectasia
Radiologic Examination A small-bowel follow-through barium associated with hypoproteinemia secondary to protein loss into
examination may be very useful for detecting evidence of small- the intestine. Eosinophilic gastroenteritis comprises a heteroge-
bowel diseases such as celiac disease, jejunal diverticulosis that neous group of disorders with a spectrum of presentations and
predisposes to small-bowel bacterial overgrowth, or Crohn’s disease symptoms, with an eosinophilic infiltrate of the lamina propria,
(Fig. 325-3). Magnetic resonance enterography and CT enterogra- and with or without peripheral eosinophilia. The patchy nature
phy are commonly used for diagnosis and management of inflam- of the infiltrate and its presence in the submucosa often lead to
matory, stricturing disorders such as Crohn’s disease and as an initial an absence of histopathologic findings on mucosal biopsy. As the
assessment of malabsorption, providing a means to visualize the involvement of the duodenum in Crohn’s disease is also submu-
entire luminal GI tract as well as the hepatobiliary tree and pancreas. cosal and not necessarily continuous, mucosal biopsies are not
Endoscopic Evaluation and Small-Bowel Biopsies Endoscopy the most direct approach to the diagnosis of duodenal Crohn’s
with small-bowel biopsy is essential in the evaluation of patients disease (Chap. 326). Amyloid deposition can be identified by

TABLE 325-6 Comparison of Different Types of Fatty Acids

LONG-CHAIN MEDIUM-CHAIN SHORT-CHAIN
Carbon chain length >12 8–12 <8
Present in diet In large amounts In small amounts No
Origin In diet as triglycerides Only in small amounts in diet as Bacterial degradation in colon of
triglycerides nonabsorbed carbohydrate to fatty acids
Primary site of absorption Small intestine Small intestine Colon
Requires pancreatic lipolysis Yes No No
Requires micelle formation Yes No No
Present in stool Minimal No Substantial

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 TABLE 325-7 Diseases That Can Be Diagnosed by Small-Intestinal 325-5 should prove useful for guiding the care of these challenging 2469
Mucosal Biopsies patients.
LESIONS PATHOLOGIC FINDINGS
Acknowledgments
Diffuse, Specific Henry Binder wrote this chapter in prior editions and some material from
Whipple’s disease Lamina propria includes macrophages his chapter has been retained.
containing material positive on periodic
acid–Schiff staining ■■FURTHER READING
Agammaglobulinemia No plasma cells; either normal or absent villi Boutte HJ, Rubin DC: Short bowel syndrome, in Gastrointestinal
(“flat mucosa”) Motility Disorders: A Point-of-Care Clinical Guide. E Bardan, R Shaker
Abetalipoproteinemia Normal villi; epithelial cells vacuolated with fat (eds). Cham, Switzerland, Springer International Publishing, 2017.
postprandially Bushyhead D, Quigley EM: Small intestinal bacterial overgrowth.
Patchy, Specific Gastroenterol Clin North Am 50:463, 2021.
Caio G et al: Celiac disease: A comprehensive current review. BMC
Intestinal lymphoma Malignant cells in lamina propria and
submucosa Med 17:142, 2019.
Camilleri M, Vijayvargiya P: The role of bile acids in chronic diar-
Intestinal lymphangiectasia Dilated lymphatics; clubbed villi
rhea. Am J Gastroenterol 115:1596, 2020.
Eosinophilic gastroenteritis Eosinophil infiltration of lamina propria and Elli L et al: Protein-losing enteropathy. Curr Opin Gastroenterol
mucosa
36:238, 2020.
Amyloidosis Amyloid deposits Johnson LR: Digestion and absorption of nutrients, in Gastrointesti-
Crohn’s disease Noncaseating granulomas nal Physiology, 9th ed. LR Johnson. Philadelphia, Elsevier, 2019, pp
Infection by one or more Specific organisms 102-120.
microorganisms (see text) Lagier JC, Raoult D: Whipple’s disease and Tropheryma whipplei
Mastocytosis Mast cell infiltration of lamina propria infections: When to suspect them and how to diagnose and treat
Diffuse, Nonspecific them. Curr Opin Infect Dis 31:463, 2018.
Lebwohl B, Rubio-Tapa A: Epidemiology, presentation and diagnosis
Celiac disease Short or absent villi; mononuclear infiltrate;
epithelial cell damage; hypertrophy of crypts of celiac disease. Gastroenterology 160:63, 2021.
Levitt DG, Levitt MD: Protein losing enteropathy: comprehensive
Tropical sprue Similar to celiac disease

CHAPTER 326 Inflammatory Bowel Disease

review of the mechanistic association with clinical and subclinical
Bacterial overgrowth Patchy damage to villi; lymphocyte infiltration disease states. Clin Exper Gastro 10:247, 2017.
Folate deficiency Short villi; decreased mitosis in crypts; Misselwitz B et al: Update on lactose malabsorption and intolerance:
megalocytosis pathogenesis, diagnosis and clinical management. Gut 68: 2080, 2019.
Vitamin B12 deficiency Similar to folate deficiency
Radiation enteritis Similar to folate deficiency
Zollinger-Ellison syndrome Mucosal ulceration and erosion from acid
Protein-calorie malnutrition Villous atrophy; secondary bacterial overgrowth
Drug-induced enteritis Variable histology

Congo Red staining in some patients with amyloidosis involving

the duodenum (Chap. 112).
326 Inflammatory
Disease
Bowel

3. Diffuse nonspecific lesions may be found in more than one Sonia Friedman, Richard S. Blumberg
disorder. For example, villus atrophy/absence may be found in
celiac disease, tropical sprue, or bacterial overgrowth, among
other disorders. Several microorganisms can be identified in
small-intestinal biopsy samples, establishing a correct diagno- Inflammatory bowel disease (IBD) is a chronic idiopathic inflamma-
sis. At times, the biopsy is performed specifically to diagnose tory disease of the gastrointestinal tract. Ulcerative colitis (UC) and
infection (e.g., Whipple’s disease or giardiasis). In most other Crohn’s disease (CD) are the two major types of IBD.
instances, the infection is detected incidentally during the ■■GLOBAL CONSIDERATIONS: EPIDEMIOLOGY
workup for diarrhea or other abdominal symptoms. Many of UC and CD have emerged as global diseases in the twenty-first cen-
these infections occur in immunocompromised patients with tury. They affect >2 million individuals in North America, 3.2 million
diarrhea; the etiologic agents include Cryptosporidium, Isospora in Europe, and millions more worldwide. Since the late 1990s, the
belli, microsporidia, Cyclospora, Toxoplasma, cytomegalovirus, majority of studies on CD and UC show stable or falling incidence in
adenovirus, Mycobacterium avium-intracellulare, and G. lamblia. the Western world. The disease burden remains high, with a prevalence
In immunocompromised patients, when Candida, Aspergillus, of >0.3% in North America, Oceania, and most countries in Europe.
Cryptococcus, or Histoplasma organisms are seen on duodenal In newly industrialized countries in Africa, Asia, and South America
biopsy, their presence generally reflects systemic infection. Apart where there is increased urbanization and Westernization, the inci-
from Whipple’s disease and infections in the immunocompro- dence of IBD has been rising and mirrors the prior increase of IBD in
mised host, small-bowel biopsy is seldom used as the primary the Western world in the twentieth century. For example, in Brazil, the
mode of diagnosis of infection. Even giardiasis is more easily annual percent change is +11.1% (95% confidence interval [CI], 4.8–
diagnosed by stool antigen studies and/or duodenal aspiration 17.8%) for CD and +14.9% (95% CI, 10.4–19.6%) for UC, whereas in
than by duodenal biopsy. Taiwan, the annual percent change is +4.0% (95% CI, 1.0–7.1%) for CD
and +4.8% (95% CI, 1.8–8.0%) for UC. In a study of newly diagnosed
SUMMARY IBD cases between 2011 and 2013 from 13 countries or regions in the
The evaluation and management of patients with disorders of absorp- Asia Pacific, the mean annual IBD incidence per 100,000 was 1.50 (95%
tion is challenging due to the complexity of the underlying patho- CI, 1.43–1.57). India (9.31; 95% CI, 8.38–10.31) and China (3.64; 95%
physiology and the large number of associated diseases. A diagnostic CI, 2.97–4.42) had the highest IBD incidences in Asia. The highest
approach based on the information summarized in Tables 325-1 and reported prevalence values were in Europe (UC, 505 per 100,000 in

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 2470
TABLE 326-1 Epidemiology of IBD diagnostic bias. Oral contraceptive use is associated with an increased
risk of CD, with a reported hazard ratio as high as 2.82 among current
ULCERATIVE COLITIS CROHN’S DISEASE
users and 1.39 among past users. The association between oral con-
Age of onset Second to fourth Second to fourth traceptive use and UC is limited to women with a history of smoking.
decades and seventh to decades and seventh to
ninth decades ninth decades Infections in the first year of life are associated with development of
IBD, especially before the ages of 10 and 20 years. Breast-feeding may
Ethnicity Jewish > non-Jewish white > black > Latinx > Asian
also protect against the development of IBD. Infectious gastroenteritis
Female-to-male ratio 0.51–1.58 0.34–1.65 with pathogens (e.g., Salmonella, Shigella, Campylobacter spp., Clostrid-
Smoking May prevent disease May cause disease (odds ium difficile) increases IBD risk by two- to threefold. Diets high in
(odds ratio 0.58) ratio 1.76) animal protein, sugars, sweets, oils, fish and shellfish, and dietary fat,
Oral contraceptives No increased risk Hazard ratio 2.82 especially ω-6 fatty acids, and low in ω-3 fatty acids have been impli-
Appendectomy Protective (risk reduction Not protective cated in increasing the risk of IBD. A protective effect of vitamin D on
13–26%) the risk of CD has been reported.
Monozygotic twins 6–18% concordance 38–58% concordance IBD is a familial disease in 5–10% of patients (Fig. 326-2), and the
Dizygotic twins 0–2% concordance 4% concordance strongest risk factor for the development of IBD is a first-degree rela-
Infections in the first year 1.6 and 3 times the risk of developing IBD by age 10 tive with the disease. The children of mothers and fathers with UC have
of life and 20 years an approximately fourfold increased risk of UC, and the children of
mothers and fathers with CD have an almost eightfold increased risk of
Abbreviation: IBD, inflammatory bowel disease.
CD. Some of these patients may exhibit early-onset disease during the
first decade of life and, in CD, a concordance of anatomic site and clin-
Norway; CD, 322 per 100,000 in Germany) and North America (UC, ical type within families. In twin studies, 38–58% of monozygotic twins
286 per 100,000 in the United States; CD, 319 per 100,000 in Canada). are concordant for CD, and 6–18% are concordant for UC, whereas 4%
The most likely factors that explain the geographic variability of IBD of dizygotic twins are concordant for CD, and 0–2% are concordant for
rates, especially the rising incidence in developing countries and urban UC in Swedish and Danish cohorts. In the remainder of patients, IBD
areas, are environmental variables including changes in diet (with is observed in the absence of a family history (i.e., sporadic disease).
downstream effects on the intestinal microbiota), exposure to sunlight
or temperature differences, and socioeconomic status and hygiene GLOBAL CONSIDERATIONS: IBD
(Table 326-1). PHENOTYPES
Increasing immigration to Western societies also has an impact on IBD location and behavior show racial differences that may reflect
PART 10

the incidence and prevalence of IBD. The prevalence of UC among underlying genetic variations and have important implications for
southern Asians who immigrated to the United Kingdom (UK) was diagnosis and management of disease. Blacks and Latinxs tend to
higher in comparison to the European UK population (17 cases per have an ileocolonic CD distribution. Data from East Asia show that
100,000 persons vs 7 per 100,000). Spanish patients who emigrated ileocolonic CD is the most common CD phenotype (50.5–71%) and
within Europe, but not those who immigrated to Latin America, devel- perianal disease is more common in East Asian patients (30.3–58.8%)
Disorders of the Gastrointestinal System

oped IBD more frequently than controls. Individuals who have immi- than whites (25.1–29.6%). Pancolonic disease is more common than
grated to Westernized countries and then returned to their country of left-sided colitis or proctitis among black, Latinx, and Asian patients
birth also continue to demonstrate an increased risk of developing IBD. with UC. Older Asian patients with UC (age >60) tend to have a more
Peak incidence of UC and CD is in the second to fourth decades, aggressive disease course. Among blacks, joint involvement is the
with 78% of CD studies and 51% of UC studies reporting the highest predominant extraintestinal manifestation (EIM) reported and ranges
incidence among those aged 20–29 years old. A second modest rise from 15.7 to 29.6%. Ocular involvement is also common in African
in incidence occurs between the seventh and ninth decades of life. Americans and ranges from 7.1 to 13%. Dermatologic manifestations
The female-to-male ratio ranges from 0.51 to 1.58 for UC studies and are the most common EIMs reported in Latinxs (10–13%). Few data
0.34 to 1.65 for CD studies, suggesting that the diagnosis of IBD is not shed light on all aspects of disease in Hispanics, on the incidence and
gender-specific. Pediatric IBD (patients <17 years old) composes prevalence of IBD in blacks, and in Asians with IBD outside of Asia.
~20–25% of all IBD patients, and ~5% of all IBD patients are <10 years These ethnic variations indicate the importance of different genetic
old. Children with IBD are also grouped as those with early-onset (EO) and/or environmental factors in the pathogenesis of this disorder.
IBD (patients <10 years old), very-early-onset (VEO) IBD (patients
<6 years old), and infantile IBD (patients <2 years old). VEOIBD and ETIOLOGY AND PATHOGENESIS
infantile IBD mainly affect the colon and are resistant to standard med- Under physiologic conditions, homeostasis normally exists between
ications, and patients often have a strong family history of IBD, with the commensal microbiota, epithelial cells that line the interior of the
at least one first-degree relative affected. In infantile IBD or VEOIBD, intestines (intestinal epithelial cells [IECs]), and immune cells within
a number of rare, single genetic mutations have been identified as the the tissues (Fig. 326-1). A consensus hypothesis is that each of these
basis for this susceptibility in up to 10% of patients, suggesting a simple three major host compartments that function together as an integrated
Mendelian origin of the disease in these cases. “supraorganism” (microbiota, IECs, and immune cells) are affected by
The greatest incidence of IBD is among white and Jewish people, but specific environmental (e.g., smoking, antibiotics, enteropathogens)
the incidence of IBD in Latinx and Asian people is increasing, as noted and genetic factors that, in a susceptible host, cumulatively and inter-
above. Urban areas have a higher prevalence of IBD than rural areas, actively disrupt homeostasis during the course of one’s life and, in so
and high socioeconomic classes have a higher prevalence than lower doing, culminate in a chronic state of dysregulated inflammation; i.e.,
socioeconomic classes. IBD. Although chronic activation of the mucosal immune system may
Epidemiologic studies have identified a number of potential envi- represent an appropriate response to an infectious agent, a search for
ronmental factors that are associated with disease risk (Fig. 326-1). such an agent has thus far been unrewarding in IBD. As such, IBD is
In Caucasian populations, smoking is an important risk factor in IBD currently considered an inappropriate immune response to the endoge-
with opposite effects on UC (odds ratio [OR] 0.58) and CD (OR 1.76), nous (autochthonous) commensal microbiota within the intestines,
whereas in other ethnic groups with different genetic susceptibility, with or without some component of autoimmunity. Importantly, the
smoking may play a lesser role. Previous appendectomy with con- normal, uninflamed intestines contain a large number of immune cells
firmed appendicitis (risk reduction of 13–26%), particularly at a young that are in a unique state of activation, in which the gut is restrained
age, has a protective effect on the development of UC across different from full immunologic responses to the commensal microbiota and
geographical regions and populations. Appendectomy is modestly dietary antigens by very powerful regulatory pathways that function
associated with the development of CD, but this may be due to within the immune system (e.g., T regulatory cells that express the

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 2471
Genetic susceptibility

TLR4
XBP1 IL23R, IL12B, JAK2, STAT3, CCR6,
DLG5 NOD2, TLR4, CARD9, IRF5,
XBP1 ATG16L1, IRGM, LRRK2
ECM1
NOD2 TNFSF15, TNFRSF6B
ITLN1
ATG16L1 TNFAIP3, PTPN2/22
SLC22A5
DMBT1 NLRP3, IL18RAP
PTGER4 ICOSL, ARPC2, STAT3, IL10

Microbial flora IEC Immune dysregulation

Enteropathogens
Antibiotics
Diet, hygiene NSAIDs, smoking
Stress

CHAPTER 326 Inflammatory Bowel Disease

Diet, hygiene

Environmental factors

FIGURE 326-1 Pathogenesis of inflammatory bowel disease (IBD). In IBD, the tridirectional relationship between the commensal flora (microbiota), intestinal epithelial
cells (IECs), and mucosal immune system is dysregulated, leading to chronic inflammation. Each of these three factors is affected by genetic and environmental factors
that determine risk for the disease. NSAIDs, nonsteroidal anti-inflammatory drugs. (Republished with permission Annual Review of Immunology from Inflammatory Bowel
Disease, A Kaser et al: 28:573, 2010. Permission conveyed through Copyright Clearance Center, Inc.)

FoxP3 transcription factor and suppress inflammation). Maintenance GENETIC CONSIDERATIONS

of homeostasis also involves oversight from local parenchymal cells The genetic underpinning of IBD is known from its concordance
including nerve, endothelial, and stromal cells, as well as the commen- in identical twins, its occurrence in the context of several genetic
sal microbiota that provide essential remedial factors necessary for syndromes, and the development of severe, refractory IBD in early
health and serve as a target of the immune response. During the course life in association with single-gene defects that affect the immune sys-
of infections or other environmental stimuli in the normal host, full tem (Table 326-2). More than 60 different gene defects have been iden-
activation of the lymphoid tissues in the intestines occurs but is rapidly tified in patients with VEOIBD by whole exome sequencing (WES), in
superseded by dampening of the immune response and tissue repair. In whom the majority of monogenic mutations have been discovered.
IBD, such processes may not be regulated normally. These include mutations in genes encoding, for example, interleukin
(IL) 10, the IL-10 receptor (IL-10R), cytotoxic T-lymphocyte-associated
Monogenic Oligogenic Polygenic
protein-4 (CTLA4), neutrophil cytosolic factor 2 protein (NCF2),
X-linked inhibitor of apoptosis protein (XIAP), lipopolysaccharide
Environment responsive and beige-like anchor protein (LRBA), and tetratricopeptide
Undiagnosed
infections?

repeat domain 7A protein (TTC7), among many other genes that are
Early onset

involved in host-commensal interactions. A monogenic etiology may

also be possible in a small subset of adult patients with IBD. In addi-
tion, IBD has a familial origin in at least 10% of afflicted individuals,
consistent with an inherited basis for this disease (Fig. 326-2). How-
Genetics
ever, the majority of cases of pediatric (non-VEOIBD) and adult IBD
are multigenic (or polygenic) in origin, suggesting a syndromic nature
Familial Sporadic of this disease that gives rise to multiple clinical subgroups beyond the
(10%) simple classification as UC and CD. The polygenic nature of the disease
FIGURE 326-2 A model for the syndromic nature of inflammatory bowel disease has been elucidated through a variety of genetic approaches, including
(IBD). Genetic and environmental factors variably influence the development and candidate gene studies, linkage analysis, and genome-wide association
phenotypic manifestations of IBD. At the one extreme, IBD is exemplified as a simple studies (GWAS) that focus on the identification of disease-associated
Mendelian disorder as observed in early-onset IBD due to single-gene defects such
as IL10, IL10RA, and IL10RB; and at the other extreme, it may be exemplified by as yet
single nucleotide polymorphisms (SNPs) within the human genome
to be described emerging infectious diseases. (Reproduced with permission from A and WES and whole genome sequencing to elucidate the specific muta-
Kaser et al: Genes and environment: how will our concepts on the pathophysiology tions potentially involved. GWAS have identified ~240 genetic loci;
of IBD develop in the future?, Dig Dis 28:395, 2010.) two-thirds of these loci are associated with both disease phenotypes,

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 2472
TABLE 326-2 Primary Genetic Disorders Associated with IBD the specific causal variants for each identified gene or locus are mostly
unknown as most risk loci are contained within regulatory (noncod-
NAME GENETIC ASSOCIATION PHENOTYPE
ing) regions of the associated genes, it is not clear whether the similar-
Turner’s syndrome Loss of part or all of X Associated with UC and ities in the genetic risk factors associated with CD and UC are shared
chromosome colonic CD
at a structural or functional level. The risk conferred by each identified
Hermansky-Pudlak Autosomal recessive Granulomatous colitis, gene or locus is unequal and generally small, such that only ~20% of
syndrome chromosome 10q23 oculocutaneous albinism,
platelet dysfunction, the disease risk is considered to be explained by the current genetic
pulmonary fibrosis information. Further, many of the genetic risk factors identified are
Wiskott-Aldrich X-linked recessive Colitis, also observed to be associated with risk for other immune-mediated
syndrome (WAS) disorder, loss of WAS immunodeficiency, diseases, suggesting that related immunogenetic pathways are involved
protein function severely dysfunctional in the pathogenesis of multiple different disorders, accounting for the
platelets, and common responsiveness to similar types of biologic therapies (e.g.,
thrombocytopenia anti–tumor necrosis factor [TNF] therapies) and possibly the simulta-
Glycogen storage Autosomal recessive Granulomatous colitis, neous occurrence of these disorders. The diseases and the genetic risk
disease type B1 disorder of SLC37A4 presents in infancy with factors that are shared with IBD include, for example, rheumatoid
resulting in deficiency of hypoglycemia, growth arthritis (TNFAIP3), psoriasis (IL23R, IL12B), ankylosing spondylitis
the glucose-6-phosphate failure, hepatomegaly,
translocase and neutropenia (IL23R), type 1 diabetes mellitus (IL10, PTPN2), asthma (ORMDL3),
and systemic lupus erythematosus (TNFAIP3, IL10), among others.
Immune dysregulation Loss of FoxP3 UC-like autoimmune
polyendocrinopathy, transcription factor and T enteropathy, with
The genetic factors that are recognized to mediate risk for IBD
enteropathy X-linked regulatory cell function endocrinopathy (neonatal have highlighted the importance of shared mechanisms of disease that
(IPEX) type 1 diabetes or variably affect CD and/or UC (Table 326-3). These include the fol-
thyroiditis), dermatitis lowing: those genes that are associated with fundamental cell biologic
Early-onset IBD Deficient IL-10 and IL-10 Severe, refractory IBD in processes such as the unfolded protein response due to endoplasmic
receptor function early life reticulum stress, autophagy, and metabolism that regulate the ability
Abbreviations: CD, Crohn’s disease; IBD, inflammatory bowel disease; IL, interleukin;
of cells to manage the physiologic needs of the intestinal environment;
UC, ulcerative colitis. those associated with innate immunity associated with nonlymphoid
cells that function in responses to and control of microbes; those
with the remainder being specific for either CD or UC (Table 326-3). associated with the regulation of adaptive immunity that control the
These genetic similarities account for the overlapping immunopatho- balance between inflammatory and anti-inflammatory cellular path-
PART 10

genesis and consequently epidemiologic observations of both diseases ways associated with lymphocytes; and, finally, those that are involved
in the same families and similarities in response to therapies. Because in the development and resolution of inflammation associated with

TABLE 326-3 Some Genetic Loci Associated with Crohn’s Disease and/or Ulcerative Colitis
Disorders of the Gastrointestinal System

CHROMOSOME PUTATIVE GENE GENE NAME PROTEIN FUNCTION CD UC

Unfolded Protein Response, Autophagy and Metabolism
2q37 ATG16L1 ATG16 autophagy related 16-like 1 Autophagy +
5q31 SLC22A5 Solute carrier family 22, member 5 β-Carnitine transporter +
5q33 IRGM Immunity-related GTPase family, M Autophagy +
7p21 AGR2 Anterior gradient 2 Unfolded protein response + +
12q12 LRRK2 Leucine-rich repeat kinase 2 Autophagy +
13q14 C13orf1 FAMIN/LACC1 Immunometabolic regulator +
17q21 ORMDL3 Orosomucoid related member 1-like 3 Unfolded protein response and lipid synthesis + +
22q12 XBP1 X-box binding protein 1 Unfolded protein response + +
Innate Immunity
1q23 ITLN1 Intelectin 1 Bacterial binding +
16q12 NOD2 Nucleotide-binding oligomerization Bacterial sensing and autophagy activation +
domain containing 2
Adaptive Immunity
1p31 IL23R Interleukin 23 receptor TH17 cell stimulation + +
1q32 IL10 Interleukin 10 Treg-associated cytokine +
5q33 IL12B Interleukin 12B IL-12 p40 chain of IL-12/IL-23 + +
18p11 PTPN2 Protein tyrosine phosphatase, T-cell regulation +
nonreceptor type 2
Inflammation and Healing
3p21 MST1 Macrophage stimulating 1 Macrophage activation + +
5p13 PTGER4 Prostaglandin E receptor 4 PGE2 receptor + +
6q23 TNFAIP3 Tumor necrosis factor, alpha-induced Toll-like receptor regulation +
protein 3 (A20)
6q27 CCR6 Chemokine (C-C motif) receptor 6 Dendritic cell migration +
9p24 JAK2 Janus kinase 2 IL-6R and IL-23R signaling + +
17q21 STAT3 Signal transducer and activator of IL-6R, IL-23R, and IL-10R signaling + +
transcription 3
Abbreviations: CD, Crohn’s disease; GTPase, guanosine triphosphatase; IL, interleukin; PGE2, prostaglandin E2; Treg, T regulatory cell; UC, ulcerative colitis.
Source: Adapted from A Kaser et al: Ann Rev Immunol 28:573, 2010; Graham DB and Xavier RJ: Nature 578:527, 2020.

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 healing that control leukocyte recruitment and inflammatory medi- with T-cell antigen recognition (e.g., T-cell antigen receptors), or 2473
ator production. Each of these genetic susceptibilities contributes in interfering with IEC barrier function and the regulation of responses
an incremental manner to IBD risk, variably affects the activities of to commensal bacteria (e.g., XBP1, mucus glycoproteins, or nuclear
virtually all subtypes of immune and nonimmune cells within the factor-κB [NF-κB]) leads to spontaneous colitis or enteritis. In the
intestines, and encodes mutations (polymorphisms) that promote or majority of circumstances, intestinal inflammation in these animal
protect from IBD. Some of these loci are associated with specific sub- models requires the presence of the commensal microbiota. However,
types of disease such as the association between NOD2 polymorphisms in some cases, activation of certain elements of the intestinal immune
and fibrostenosing CD or ATG16L1 and fistulizing disease, especially system may be exacerbated by the absence of bacteria, resulting in
within the ileum. However, the clinical utility of these genetic risk severe colitis and emphasizing the presence of protective properties
factors for the diagnosis or determination of prognosis and therapeutic of the commensal microbiota. Thus, a variety of specific alterations in
responses remains to be defined. either the microbiota or host can lead to uncontrolled immune acti-
vation and inflammation directed at the intestines in mice. How these
■■COMMENSAL MICROBIOTA AND IBD relate to human IBD remains to be defined, but they are consistent
The endogenous commensal microbiota within the intestines plays a with inappropriate responses of the genetically susceptible host to the
central role in the pathogenesis of IBD. Humans are born with sterile commensal microbiota.
guts and acquire their commensal microbiota initially from the mother ■■THE INFLAMMATORY CASCADE IN IBD
during egress through the birth canal and subsequently from environ- In both UC and CD, inflammation likely emerges from the genetic
mental sources. A stable configuration of up to 1000 species of bacteria predisposition of the host in the context of yet-to-be-defined envi-
that achieves a biomass of ~1012 colony-forming units per gram of feces ronmental factors. Once initiated in IBD by abnormal innate immune
is achieved by 3 years of age, which likely persists into adult life, with sensing of bacteria by parenchymal cells (e.g., IECs) and hematopoi-
each individual human possessing a unique combination of species. etic cells (e.g., dendritic cells), the immune inflammatory response
In addition, the intestines contain other microbial life forms including is perpetuated by T-cell activation when coupled together with inad-
fungi, archaea, viruses, and protists. The microbiota is thus considered equate regulatory pathways. A sequential cascade of inflammatory
as a critical and sustaining component of the human organism. The mediators extends the response, making each step a potential target
establishment and maintenance of the intestinal microbiota compo- for therapy. Inflammatory cytokines from innate immune cells such as
sition and function are under the control of host (e.g., immune and IL-1, IL-6, IL-12, IL-23, and TNF have diverse effects on tissues. They
epithelial responses), environmental (e.g., diet and antibiotics), and promote fibrogenesis, collagen production, activation of tissue metal-
likely genetic (e.g., NOD2) factors (Fig. 326-1). In turn, the microbiota,

CHAPTER 326 Inflammatory Bowel Disease

loproteinases, and the production of other inflammatory mediators;
through its structural components and metabolic activity, has major they also activate the coagulation cascade in local blood vessels (e.g.,
influences on the epithelial and immune function of the host, which, increased production of von Willebrand factor). These cytokines are
through epigenetic effects, may have durable consequences. During normally produced in response to infection but are usually turned off
early life when the commensal microbiota is being established, these or inhibited by cytokines such as IL-10 and TGF-β at the appropriate
microbial effects on the host may be particularly important in deter- time to limit tissue damage. In IBD their activity is not regulated,
mining later life risk for IBD. Specific components of the microbiota resulting in an imbalance between the proinflammatory and anti-
can promote or protect from disease. The commensal microbiota in inflammatory mediators. Some cytokines activate other inflammatory
patients with both UC and CD is demonstrably different from that of cells (macrophages and B cells), and others act indirectly to recruit
nonafflicted individuals, a state of dysbiosis suggesting the presence other lymphocytes, inflammatory leukocytes, and mononuclear cells
of microorganisms that drive disease (e.g., Proteobacteria such as from the bloodstream into the gut through interactions between
enteroinvasive and adherent Escherichia coli) and to which the immune homing receptors on leukocytes (e.g., α4β7 integrin) and addressins
response is directed and/or the loss of microorganisms that hinder on vascular endothelium (e.g., MadCAM1). CD4+ T helper (TH) cells
inflammation (e.g., Firmicutes such as Faecalibacterium prausnitzii). that promote inflammation are of three major types, all of which may
Many of the changes in the commensal microbiota occur as a conse- be associated with colitis in animal models and perhaps humans: TH1
quence of the inflammation and are thus potential secondary drivers cells (secrete interferon [IFN] γ), TH2 cells (secrete IL-4, IL-5, IL-13),
of disease. In addition, agents that alter the intestinal microbiota such and TH17 cells (secrete IL-17, IL-21, IL-22). TH17 cells may also provide
as metronidazole, ciprofloxacin, and elemental diets, may improve CD. protective functions. Innate immune-like cells (ILCs) that lack T-cell
CD may also respond to fecal diversion, demonstrating the ability of receptors are also present in intestines, polarize to the same functional
luminal contents to exacerbate disease. fates, and may similarly participate in IBD. TH1 cells induce transmural
granulomatous inflammation that resembles CD; TH2 cells and related
■■DEFECTIVE IMMUNE REGULATION IN IBD natural killer T cells that secrete IL-4, IL-5, and IL-13 induce super-
The mucosal immune system does not normally elicit an inflammatory ficial mucosal inflammation resembling UC in animal models; and
immune response to luminal contents due to oral (mucosal) tolerance. TH17 cells may be responsible for neutrophilic recruitment. However,
Administration of soluble antigens orally, rather than subcutaneously or neutralization of the cytokines produced by these cells, such as IFN-γ
intramuscularly, leads to antigen-specific control of the response and the or IL-17, has yet to show efficacy in therapeutic trials. Each of these
host’s ability to tolerate the antigen. Multiple mechanisms are involved T-cell subsets cross-regulates each other. The TH1 cytokine pathway is
in the induction of oral tolerance and include deletion or anergy (non- initiated by IL-12, a key cytokine in the pathogenesis of experimental
responsiveness) of antigen-reactive T cells or induction of CD4+ T cells models of mucosal inflammation. IL-4 and IL-23, together with IL-6
that suppress gut inflammation (e.g., T regulatory cells expressing the and TGF-β, induce TH2 and TH17 cells, respectively, and IL-23 inhibits
FoxP3 transcription factor) and that secrete anti-inflammatory cytok- the suppressive function of regulatory T cells. Activated macrophages
ines such as IL-10, IL-35, and transforming growth factor β (TGF-β). secrete TNF and IL-6.
Oral tolerance may be responsible for the lack of immune responsive- These characteristics of the immune response in IBD explain the
ness to dietary antigens and the commensal microbiota in the intestinal beneficial therapeutic effects of antibodies to block proinflammatory
lumen. In IBD, this suppression of inflammation is altered, leading to cytokines or the signaling by their receptors (e.g., anti-TNF, anti-IL-12,
uncontrolled inflammation. The mechanisms of this regulated immune anti-IL-23, anti-IL-6, or Janus kinase [JAK] inhibitors) or molecules
suppression are incompletely known. associated with leukocyte recruitment (e.g., anti-α4β7). They also
Gene knockout (–/–) or transgenic (Tg) mouse models of IBD, highlight the potential usefulness of cytokines that inhibit inflam-
including those that are directed at genes associated with risk for the mation and promote regulatory T cells or promote intestinal barrier
human disease, have revealed that deleting specific cytokines (e.g., function (e.g., IL-10) in the treatment of IBD. Therapies such as the
IL-2, IL-10, TGF-β) or their receptors, deleting molecules associated 5-aminosalicylic acid (5-ASA) compounds and glucocorticoids are also

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 2474 potent inhibitors of these inflammatory mediators through inhibition
of transcription factors such as NF-κB that regulate their expression.
PATHOLOGY
■■ULCERATIVE COLITIS: MACROSCOPIC FEATURES
UC is a mucosal disease that usually involves the rectum and extends
proximally to involve all or part of the colon. About 40–50% of patients
have disease limited to the rectum and rectosigmoid, 30–40% have dis-
ease extending beyond the sigmoid but not involving the whole colon,
and 20% have a pancolitis. Proximal spread occurs in continuity with-
out areas of uninvolved mucosa. When the whole colon is involved,
the inflammation extends 2–3 cm into the terminal ileum in 10–20%
of patients. The endoscopic changes of backwash ileitis are superficial
and mild and are of little clinical significance. Although variations in
macroscopic activity may suggest skip areas, biopsies from normal-
appearing mucosa are usually abnormal. Thus, it is important to obtain
multiple biopsies from apparently uninvolved mucosa, whether prox-
imal or distal, during endoscopy. One caveat is that effective medical
therapy can change the appearance of the mucosa such that either skip FIGURE 326-4 Medium-power view of colonic mucosa in ulcerative colitis
areas or the entire colon can be microscopically normal. showing diffuse mixed inflammation, basal lymphoplasmacytosis, crypt atrophy and
irregularity, and superficial erosion. These features are typical of chronic active
With mild inflammation, the mucosa is erythematous and has a ulcerative colitis. (Courtesy of Dr. R. Odze, Division of Gastrointestinal Pathology,
fine granular surface that resembles sandpaper. In more severe disease, Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts;
the mucosa is hemorrhagic, edematous, and ulcerated (Fig. 326-3). In with permission.)
long-standing disease, inflammatory polyps (pseudopolyps) may be
present as a result of epithelial regeneration. The mucosa may appear giving rise to cryptitis and, ultimately, to crypt abscesses (Fig. 326-4).
normal in remission, but in patients with many years of disease, it Ileal changes in patients with backwash ileitis include villous atrophy
appears atrophic and featureless, and the entire colon becomes nar- and crypt regeneration with increased inflammation, increased neu-
rowed and shortened. Patients with fulminant disease can develop a trophil and mononuclear inflammation in the lamina propria, and
toxic colitis or megacolon where the bowel wall becomes thin and the patchy cryptitis and crypt abscesses.
PART 10

mucosa is severely ulcerated; this may lead to perforation.

■■CROHN’S DISEASE: MACROSCOPIC FEATURES
■■ULCERATIVE COLITIS: MICROSCOPIC FEATURES CD can affect any part of the gastrointestinal (GI) tract from the mouth
Histologic findings correlate well with the endoscopic appearance and to the anus. Some 30–40% of patients have small-bowel disease alone,
clinical course of UC. The process is limited to the mucosa and super- 40–55% have disease involving both the small and large intestines, and
Disorders of the Gastrointestinal System

ficial submucosa, with deeper layers unaffected except in fulminant 15–25% have colitis alone. In the 75% of patients with small-intestinal
disease. In UC, two major histologic features suggest chronicity and disease, the terminal ileum is involved in 90%. Unlike UC, which
help distinguish it from infectious or acute self-limited colitis. First, almost always involves the rectum, the rectum is often spared in CD.
the crypt architecture of the colon is distorted; crypts may be bifid and CD is often segmental with skip areas throughout the diseased intes-
reduced in number, often with a gap between the crypt bases and the tine (Fig. 326-5). Perianal disease, manifesting as perirectal fistulas,
muscularis mucosae. Second, some patients have basal plasma cells fissures, abscesses, and anal stenosis, is present in one-third of patients
and multiple basal lymphoid aggregates. Mucosal vascular congestion, with CD, particularly those with colonic involvement. Rarely, CD may
with edema and focal hemorrhage, and an inflammatory cell infiltrate also involve the liver and the pancreas.
of neutrophils, lymphocytes, plasma cells, and macrophages may be Unlike UC, CD is a transmural process. Endoscopically, aphthous or
present. The neutrophils invade the epithelium, usually in the crypts, small superficial ulcerations characterize mild disease; in more active
disease, stellate ulcerations fuse longitudinally and transversely to

FIGURE 326-3 Ulcerative colitis. Diffuse (nonsegmental) mucosal disease,

with broad areas of ulceration. The bowel wall is not thickened, and there is no FIGURE 326-5 Crohn’s disease of the colon showing thickening of the wall, with
cobblestoning. (Courtesy of Dr. R. Odze, Division of Gastrointestinal Pathology, stenosis, linear serpiginous ulcers, and cobblestoning of the mucosa. (Courtesy of
Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts; Dr. R Odze, Division of Gastrointestinal Pathology, Department of Pathology, Brigham
with permission.) and Women’s Hospital, Boston, Massachusetts; with permission.)

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 2475
TABLE 326-4 Montreal Classification of Extent and Severity of
Ulcerative Colitis (UC)
EXTENT ANATOMY
E1: Ulcerative proctitis Involvement limited to the rectum
E2: Left-sided UC (distal UC) Involvement limited to the colorectum distal to
the splenic flexure
E3: Extensive UC (pancolitis) Involvement extends proximal to the splenic
flexure
SEVERITY DEFINITION
S0: Clinical remission Absence of symptoms
S1: Mild disease activity ≤4 stools/d (with or without blood), absence of
systemic illness, normal inflammatory
markers (ESR)
S2: Moderate disease ≥4 stools/d but minimal signs of systemic toxicity
activity
S3: Severe disease activity ≥6 bloody stools/d, pulse ≥90 beats/min,
temperature ≥37.5°C, hemoglobin <10.5 g/100 mL,
and ESR ≥30 mm/h
FIGURE 326-6 Medium-power view of Crohn’s colitis showing mixed acute and
chronic inflammation, crypt atrophy, and multiple small epithelioid granulomas Abbreviation: ESR, erythrocyte sedimentation rate.
in the mucosa. (Courtesy of Dr. R Odze, Division of Gastrointestinal Pathology, Source: C Gasche et al: A simple classification of Crohn’s disease: Report of
Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts; the Working Party for the World Congresses of Gastroenterology, Vienna 1998.
with permission.) Inflamm Bowel Dis 6:8, 2000; and J Satsangi et al: The Montreal classification of
inflammatory bowel disease: Controversies, consensus, and implications.
Gut 55:749, 2006.
demarcate islands of mucosa that frequently are histologically normal.
This “cobblestone” appearance is characteristic of CD, both endoscop-
ically and by barium radiography. As in UC, pseudopolyps can form cramping and abdominal pain can occur with severe attacks of the dis-
in CD. ease. Other symptoms in moderate to severe disease include anorexia,

CHAPTER 326 Inflammatory Bowel Disease

Active CD is characterized by focal inflammation and formation nausea, vomiting, fever, and weight loss.
of fistula tracts, which resolve by fibrosis and stricturing of the bowel. Physical signs of proctitis include a tender anal canal and blood
The bowel wall thickens and becomes narrowed and fibrotic, leading on rectal examination. With more extensive disease, patients have
to chronic, recurrent bowel obstructions. Projections of thickened tenderness to palpation directly over the colon. Patients with a toxic
mesentery known as “creeping fat” encase the bowel, and serosal and colitis have severe pain and bleeding, and those with megacolon have
mesenteric inflammation promotes adhesions and fistula formation. hepatic tympany. Both may have signs of peritonitis if a perforation has
occurred. The classification of disease activity is shown in Table 326-4.
■■CROHN’S DISEASE: MICROSCOPIC FEATURES
The earliest lesions are aphthoid ulcerations and focal crypt abscesses Laboratory, Endoscopic, and Radiographic Features Active
with loose aggregations of macrophages, which form noncaseating disease can be associated with a rise in acute-phase reactants (C-reactive
granulomas in all layers of the bowel wall (Fig. 326-6). Granulomas are protein [CRP]), platelet count, and erythrocyte sedimentation rate
a characteristic feature of CD and are less commonly found on mucosal (ESR) and a decrease in hemoglobin. Fecal lactoferrin, a glycoprotein
biopsies than on surgical resection specimens. Other histologic fea- present in activated neutrophils, is a highly sensitive and specific
tures of CD include submucosal or subserosal lymphoid aggregates, marker for detecting intestinal inflammation. Fecal calprotectin is
particularly away from areas of ulceration, gross and microscopic skip present in neutrophils and monocytes, and levels correlate well with
areas, and transmural inflammation that is accompanied by fissures histologic inflammation, predict relapses, and detect pouchitis. Both
that penetrate deeply into the bowel wall and sometimes form fistulous fecal lactoferrin and calprotectin are becoming an integral part of IBD
tracts or local abscesses. management and are used frequently to rule out active inflammation
versus symptoms of irritable bowel or bacterial overgrowth. In severely
CLINICAL PRESENTATION ill patients, the serum albumin level will fall rather quickly. Leukocy-
tosis may be present but is not a specific indicator of disease activity.
■■ULCERATIVE COLITIS Proctitis or proctosigmoiditis rarely causes a rise in CRP. Diagnosis
relies on the patient’s history, clinical symptoms, negative stool and/or
Signs and Symptoms The major symptoms of UC are diarrhea, tissue examination for bacteria, C. difficile toxin, ova and parasites, and
rectal bleeding, tenesmus, passage of mucus, and crampy abdominal viruses depending on epidemiologic considerations and clinical pre-
pain. The severity of symptoms correlates with the extent of disease. sentation; sigmoidoscopic appearance (see Fig. 322-4A); and histology
Although UC can present acutely, symptoms usually have been present of rectal or colonic biopsy specimens.
for weeks to months. Sigmoidoscopy is used to assess disease activity and is usually per-
Patients with proctitis usually pass fresh blood or blood-stained formed before treatment. If the patient is not having an acute flare,
mucus, either mixed with stool or streaked onto the surface of a normal colonoscopy is used to assess disease extent and activity (Fig. 326-7).
or hard stool. They also have tenesmus, or urgency with a feeling of Endoscopically mild disease is characterized by erythema, decreased
incomplete evacuation, but rarely have abdominal pain. With proctitis vascular pattern, and mild friability. Moderate disease is characterized
or proctosigmoiditis, proximal transit slows, which may account for by marked erythema, absent vascular pattern, friability, and erosions,
the constipation commonly seen in patients with distal disease. and severe disease is characterized by spontaneous bleeding and ulcer-
When the disease extends beyond the rectum, blood is usually ations. Histologic features change more slowly than clinical features but
mixed with stool or grossly bloody diarrhea may be noted. Colonic can also be used to grade disease activity.
motility is altered by inflammation with rapid transit through the
inflamed intestine. When the disease is severe, patients pass a liquid Complications Only 15% of patients with UC present initially
stool containing blood, pus, and fecal matter. Diarrhea is often noc- with severe disease. Massive hemorrhage occurs in 1% of patients, and
turnal and/or postprandial. Although severe pain is not a prominent treatment for the disease usually stops the bleeding. Toxic megacolon is
symptom, some patients with active disease may experience lower defined as a transverse or right colon with a diameter of >6 cm, with
abdominal discomfort or mild central abdominal cramping. Severe loss of haustration in patients with severe attacks of UC. It occurs rarely

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 2476 ILEOCOLITIS Because the most common site of inflammation is the
terminal ileum, the usual presentation of ileocolitis is a chronic his-
tory of recurrent episodes of right lower quadrant pain and diarrhea.
Sometimes the initial presentation mimics acute appendicitis with
pronounced right lower quadrant pain, a palpable mass, fever, and
leukocytosis. Pain is usually colicky; it precedes and is relieved by defe-
cation. A low-grade fever is usually noted. High-spiking fever suggests
intraabdominal abscess formation. Weight loss is common—typically
10–20% of body weight—and develops as a consequence of diarrhea,
anorexia, and fear of eating.
An inflammatory mass may be palpated in the right lower quadrant
of the abdomen. The mass is composed of inflamed bowel, induration
of the mesentery, and enlarged abdominal lymph nodes. The “string
sign” on radiographic studies results from a severely narrowed loop
of bowel, which makes the lumen resemble a frayed cotton string. It is
caused by incomplete filling of the lumen as the result of edema, irri-
tability, and spasms associated with inflammation and ulcerations. The
sign may be seen in both nonstenotic and stenotic phases of the disease.
Bowel obstruction may take several forms. In the early stages of
disease, bowel wall edema and spasm produce intermittent obstruc-
FIGURE 326-7 Colonoscopy with acute ulcerative colitis: severe colon tive manifestations and increasing symptoms of postprandial pain.
inflammation with erythema, friability, and exudates. (Courtesy of Dr. M. Hamilton,
Gastroenterology Division, Department of Medicine, Brigham and Women’s Over several years, persistent inflammation gradually progresses to
Hospital, Boston, Massachusetts; with permission.) fibrostenotic narrowing and stricture. Diarrhea will decrease and be
replaced by chronic bowel obstruction. Acute episodes of obstruction
and can be triggered by electrolyte abnormalities and narcotics. About occur as well, precipitated by bowel inflammation and spasm or some-
50% of acute dilations will resolve with conservative management times by impaction of undigested food or medication. These episodes
alone, but urgent colectomy is required for those who do not improve. usually resolve with intravenous fluids and gastric decompression.
Perforation is the most dangerous of the local complications, and the Severe inflammation of the ileocecal region may lead to localized
physical signs of peritonitis may not be obvious, especially if the patient wall thinning, with microperforation and fistula formation to the
PART 10

is receiving glucocorticoids. Although perforation is rare, the mortality adjacent bowel, the skin, or the urinary bladder, or to an abscess cavity
rate for perforation complicating a toxic megacolon is ~15%. In addi- in the mesentery. Enterovesical fistulas typically present as dysuria
tion, patients can develop a toxic colitis and such severe ulcerations or recurrent bladder infections or, less commonly, as pneumaturia or
that the bowel may perforate without first dilating. fecaluria. Enterocutaneous fistulas follow tissue planes of least resis-
Strictures occur in 5–10% of patients and are always a concern in tance, usually draining through abdominal surgical scars. Enterovagi-
Disorders of the Gastrointestinal System

UC because of the possibility of underlying neoplasia. Although benign nal fistulas are rare and present as dyspareunia or as a feculent or
strictures can form from the inflammation and fibrosis of UC, stric- foul-smelling, often painful vaginal discharge. They are unlikely to
tures that are impassable with the colonoscope should be presumed develop without a prior hysterectomy.
malignant until proven otherwise. A stricture that prevents passage of JEJUNOILEITIS Extensive inflammatory disease is associated with a
the colonoscope is an indication for surgery. UC patients occasionally loss of digestive and absorptive surface, resulting in malabsorption and
develop anal fissures, perianal abscesses, or hemorrhoids, but the steatorrhea. Nutritional deficiencies can also result from poor intake
occurrence of extensive perianal lesions should suggest CD. and enteric losses of protein and other nutrients. Intestinal malab-
■■CROHN’S DISEASE sorption can cause anemia, hypoalbuminemia, hypocalcemia, hypo-
magnesemia, coagulopathy, and hyperoxaluria with nephrolithiasis in
Signs and Symptoms Although CD usually presents as acute or patients with an intact colon. Many patients need to take intravenous
chronic bowel inflammation, the inflammatory process evolves toward iron since oral iron is poorly tolerated and often ineffective. Verte-
one of two patterns of disease: a fibrostenotic obstructing pattern or bral fractures are caused by a combination of vitamin D deficiency,
a penetrating fistulous pattern, each with different treatments and hypocalcemia, and prolonged glucocorticoid use. Pellagra from niacin
prognoses. The site of disease influences the clinical manifestations deficiency can occur in extensive small-bowel disease, and malabsorp-
(Table 326-5). tion of vitamin B12 can lead to megaloblastic anemia and neurologic
symptoms. Other important nutrients to measure and replete if low are
TABLE 326-5 Vienna and Montreal Classifications of Crohn’s Disease folate and vitamins A, E, and K. Levels of minerals such as zinc, sele-
VIENNA MONTREAL nium, copper, and magnesium are often low in patients with extensive
small-bowel inflammation or resections, and these should be repleted
Age at diagnosis A1: <40 years A1: <16 years
as well. Most patients should take daily multivitamin, calcium, and
A2: >40 years A2: Between 17 and 40 years
vitamin D supplements.
A3: >40 years Diarrhea is characteristic of active disease; its causes include (1) bac-
Location L1: Ileal L1: Ileal terial overgrowth in obstructive stasis or fistulization, (2) bile acid mal-
L2: Colonic L2: Colonic absorption due to a diseased or resected terminal ileum, (3) intestinal
L3: Ileocolonic L3: Ileocolonic inflammation with decreased water absorption and increased secretion
L4: Upper L4: Isolated upper diseasea of electrolytes and (4) enteroenteric fistula(e).
Behavior B1: Nonstricturing, B1: Nonstricturing, COLITIS AND PERIANAL DISEASE Patients with colitis present with
nonpenetrating nonpenetrating low-grade fevers, malaise, diarrhea, crampy abdominal pain, and
B2: Stricturing B2: Stricturing sometimes hematochezia. Gross bleeding is not as common as in UC
B3: Penetrating B3: Penetrating and appears in about one-half of patients with exclusively colonic dis-
p: Perianal disease modifierb ease. Only 1–2% exhibit massive bleeding. Pain is caused by passage of
a
L4 is a modifier and can be added to L1–L3 when there is concomitant foregut fecal material through narrowed and inflamed segments of the large
disease. bowel. Decreased rectal compliance is another cause for diarrhea in
b
p is added to B1–B3 when there is concomitant perianal disease. Crohn’s colitis patients.

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 Stricturing can occur in the colon in 4–16% of patients and produce 2477
symptoms of bowel obstruction. If the endoscopist is unable to traverse
a stricture in Crohn’s colitis, surgical resection should be considered,
especially if the patient has symptoms of chronic obstruction. Colonic
disease may fistulize into the stomach or duodenum, causing feculent
vomiting, or to the proximal or mid-small bowel, causing malab-
sorption by “short circuiting” the absorptive surface and bacterial
overgrowth. Ten percent of women with Crohn’s colitis will develop a
rectovaginal fistula.
Perianal disease affects about one-third of patients with Crohn’s
colitis and is manifested by incontinence, large hemorrhoidal tags,
anal strictures, anorectal fistulas, and perirectal abscesses. Not all
patients with perianal fistula will have endoscopic evidence of colonic
inflammation.
GASTRODUODENAL DISEASE Symptoms and signs of upper GI tract
disease include nausea, vomiting, and epigastric pain. Patients usually
have a Helicobacter pylori–negative gastritis. The second portion of the
duodenum is more commonly involved than the bulb. Fistulas involv-
ing the stomach or duodenum arise from the small or large bowel and
do not necessarily signify the presence of upper GI tract involvement.
Patients with advanced gastroduodenal CD may develop a chronic gas-
tric outlet obstruction. About 30% of children diagnosed with CD have
esophagogastroduodenal involvement. The classification of disease
activity is shown in Table 326-5.
Laboratory, Endoscopic, and Radiographic Features Laboratory FIGURE 326-8 Wireless capsule endoscopy image in a patient with Crohn’s disease
of the ileum shows ulcerations and narrowing of the intestinal lumen. (Courtesy
abnormalities include elevated ESR and CRP. In more severe disease, of Dr. S. Reddy, Gastroenterology Division, Department of Medicine, Brigham and
findings include hypoalbuminemia, anemia, and leukocytosis. Fecal Women’s Hospital, Boston, Massachusetts; with permission.)

CHAPTER 326 Inflammatory Bowel Disease

calprotectin and lactoferrin levels have been used to distinguish IBD
from irritable bowel syndrome (IBS), to assess whether CD is active,
and to detect postoperative recurrence of CD. Fecal calprotectin is a inflammation. MRI is thought to offer superior soft tissue contrast
more sensitive marker of ileocolonic or colonic inflammation rather and has the added advantage of avoiding radiation exposure changes
than isolated ileal inflammation. (Figs. 326-9 and 326-10). The lack of ionizing radiation is particularly
Endoscopic features of CD include rectal sparing, aphthous ulcera- appealing in younger patients and when monitoring response to ther-
tions, fistulas, and skip lesions. Colonoscopy allows examination and apy where serial images will be obtained. Pelvic MRI is superior to pel-
biopsy of mass lesions or strictures and biopsy of the terminal ileum. vic CT for demonstrating pelvic lesions such as ischiorectal abscesses
Upper endoscopy is useful in diagnosing gastroduodenal involvement and perianal fistulas (Fig. 326-11). An underutilized resource for
in patients with upper tract symptoms. Ileal or colonic strictures may assessing small-bowel CD is small-bowel ultrasound (SBUS). SBUS
be dilated with balloons introduced through the colonoscope. Stric- is at least as sensitive as MR enterography and CT enterography for
tures ≤4 cm in length and those at anastomotic sites respond better detecting small-bowel CD, with a sensitivity of 94%, specificity of 97%,
to endoscopic dilation. The perforation rate is as high as 10%. Most positive predictive value of 97%, and negative predictive value of 94%.
endoscopists dilate only fibrotic strictures and not those associated Use of oral contrast medium can increase the sensitivity and specificity
with active inflammation. Wireless capsule endoscopy (WCE) allows to detect small-bowel lesions to 100%. SBUS is best suited for distal
direct visualization of the entire small-bowel mucosa (Fig. 326-8). The small-bowel assessment, as the sensitivity of detecting lesions within
diagnostic yield of detecting lesions suggestive of active CD is higher the duodenum and proximal jejunum may be lower due to anatomic
with WCE than CT or magnetic resonance (MR) enterography. WCE position. The limitations of SBUS include availability and operator
should be used in the setting of a small-bowel stricture. Capsule reten- dependence.
tion occurs in <1% of patients with suspected CD, but retention rates Complications Because CD is a transmural process, serosal adhe-
of 4–6% are seen in patients with established CD. It is helpful to give sions develop that provide direct pathways for fistula formation and
the patient with CD a patency capsule, which is made of barium and reduce the incidence of free perforation. Perforation occurs in 1–2%
starts to dissolve 30 h after ingestion. An abdominal x-ray can be taken of patients, usually in the ileum but occasionally in the jejunum or
at around 30 h after ingestion to see if the capsule is still present in the as a complication of toxic megacolon. The peritonitis of free perfo-
small bowel, which would indicate a stricture. ration, especially colonic, may be fatal. Intraabdominal and pelvic
In CD, early radiographic findings in the small bowel include abscesses occur in 10–30% of patients with CD at some time in the
thickened folds and aphthous ulcerations. “Cobblestoning” from lon- course of their illness. CT-guided percutaneous drainage of the abscess
gitudinal and transverse ulcerations most frequently involves the small is standard therapy. Despite adequate drainage, most patients need
bowel. In more advanced disease, strictures, fistulas, inflammatory resection of the offending bowel segment. Percutaneous drainage has
masses, and abscesses may be detected. The earliest macroscopic find- an especially high failure rate in abdominal wall abscesses. Systemic
ings of colonic CD are aphthous ulcers. These small ulcers are often glucocorticoid therapy increases the risk of intraabdominal and pelvic
multiple and separated by normal intervening mucosa. As the disease abscesses in CD patients who have never had an operation. Other com-
progresses, aphthous ulcers become enlarged, deeper, and occasionally plications include intestinal obstruction in 40%, massive hemorrhage,
connected to one another, forming longitudinal stellate, serpiginous, malabsorption, and severe perianal disease.
and linear ulcers (see Fig. 322-4B).
The transmural inflammation of CD leads to decreased luminal Serologic Markers Patients with UC and CD show a wide vari-
diameter and limited distensibility. As ulcers progress deeper, they can ation in the way they present and progress over time. Some patients
lead to fistula formation. The segmental nature of CD results in wide present with mild disease activity and do well with generally safe and
gaps of normal or dilated bowel between involved segments. mild medications, but many others exhibit more severe disease and
CT enterography and MR enterography have been shown to can develop serious complications that will require surgery. Current
be equally accurate in the identification of active small-bowel and developing biologic therapies can help halt progression of disease

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 2478

FIGURE 326-9 A coronal magnetic resonance image was obtained using a half
Fourier single-shot T2-weighted acquisition with fat saturation in a 27-year-old
FIGURE 326-10 A coronal balanced, steady-state, free precession, T2-weighted
PART 10

pregnant (23 weeks’ gestation) woman. The patient had Crohn’s disease and was
image with fat saturation was obtained in a 32-year-old man with Crohn’s disease
maintained on mercaptopurine and prednisone. She presented with abdominal
and prior episodes of bowel obstruction, fistulas, and abscesses. He was being
pain, distension, vomiting, and small-bowel obstruction. The image reveals a 7-
treated with mercaptopurine and presented with abdominal distention and diarrhea.
to 10-cm long stricture at the terminal ileum (white arrows) causing obstruction
The image demonstrates a new gastrocolic fistula (solid white arrows). Multifocal
and significant dilatation of the proximal small bowel (white asterisk). A fetus
involvement of the small bowel and terminal ileum is also present (dashed white
is seen in the uterus (dashed white arrows). (Courtesy of Drs. J. F. B. Chick and
Disorders of the Gastrointestinal System

arrows). (Courtesy of Drs. J. F. B. Chick and P. B. Shyn, Abdominal Imaging and

P. B. Shyn, Abdominal Imaging and Intervention, Department of Radiology, Brigham
Intervention, Department of Radiology, Brigham and Women’s Hospital, Harvard
and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; with
Medical School, Boston, Massachusetts; with permission.)
permission.)

and give patients with moderate to severe UC and CD a better quality

of life. There are potential risks of biologic therapies such as infection
and malignancy, and it would be optimal to determine by genetic or
serologic markers at the time of diagnosis which patients will require
more aggressive medical therapy.
For success in diagnosing IBD and in differentiating between CD
and UC, the efficacy of these serologic tests depends on the prevalence
of IBD in a specific population. Increased titers of anti–Saccharomyces
cerevisiae antibody (ASCA) have been associated with CD, whereas
increased levels of perinuclear antineutrophil cytoplasmic antibody
(pANCA) are more commonly seen in patients with UC. However,
when evaluated in a meta-analysis of 60 studies, the sensitivity and
specificity of an ASCA-positive/pANCA-negative pattern for identifi-
cation of CD were 55 and 93%, respectively. In addition to ASCA, mul-
tiple other antibodies to bacterial proteins (Omp-C and I2), flagellin
(CBir1), and bacterial carbohydrates have been studied and associated
with CD. These serologic markers tend to have low sensitivity and
specificity and may be elevated due to other autoimmune diseases,
infections, and inflammation including those outside of the GI tract.
The Prometheus IBD SGI Diagnostic blood test measures a panel of
serologic (S), genetic (G), and inflammatory (I) biomarkers, but the
test is costly, and reliable results are based on the pretest probability
of the patient having IBD. PROSPECT is a validated web-based tool
to display individual CD outcomes and considers multiple variables
including disease location (large or small bowel, perianal), serologies FIGURE 326-11 Axial T2-weighted fat-saturated image obtained in a 39-year-old
(ASCA, CBir1, ANCA), and genetics (NOD2 frameshift mutation). male with Crohn’s disease shows a defect in the internal sphincter at the 6 o’clock
Clinical factors described at diagnosis are more helpful than position of the mid anal canal (open white arrow) communicating with a 1.1-cm
serologies at predicting the natural history of IBD. Except in special intersphincteric collection (black arrow). Wide defect in the external sphincter at the
circumstances (such as before consideration of an ileal pouch-anal 7 o’clock position (solid white arrow) leads to a moderate-sized perianal abscess in
anastomosis [IPAA] in a patient with indeterminate colitis), serologic the ischioanal fossa (asterisk). (Courtesy of Drs. J.S. Quon and P.B. Shyn, Abdominal
Imaging and Intervention, Department of Radiology, Brigham and Women’s Hospital,
markers have only minimal clinical utility. Harvard Medical School, Boston, Massachusetts; with permission.)

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 DIFFERENTIAL DIAGNOSIS OF UC AND CD a tender abdominal mass. The diagnosis is made most directly by 2479
Once a diagnosis of IBD is made, distinguishing between UC and CD colonoscopy with biopsy and culture. Although most of the patients
is impossible initially in up to 15% of cases. These are termed indeter- with viral colitis are immunosuppressed, cytomegalovirus (CMV) and
minate colitis. Fortunately, in most cases, the true nature of the under- herpes simplex proctitis may occur in immunocompetent individuals.
lying colitis becomes evident later in the course of the patient’s disease. CMV occurs most commonly in the esophagus, colon, and rectum
Approximately 5% (range 1–20%) of colon resection specimens are but may also involve the small intestine. Symptoms include abdomi-
difficult to classify as either UC or CD because they exhibit overlapping nal pain, bloody diarrhea, fever, and weight loss. With severe disease,
histologic features. necrosis and perforation can occur. Diagnosis is made by identification
of characteristic intranuclear inclusions in mucosal cells on biopsy.
■■INFECTIOUS DISEASES Herpes simplex infection of the GI tract is limited to the oropharynx,
Infections of the small intestines and colon can mimic CD or UC. They anorectum, and perianal areas. Symptoms include anorectal pain,
may be bacterial, fungal, viral, or protozoal in origin (Table 326-6). tenesmus, constipation, inguinal adenopathy, difficulty with urinary
Campylobacter colitis can mimic the endoscopic appearance of severe voiding, and sacral paresthesias. Diagnosis is made by rectal biopsy
UC and can cause a relapse of established UC. Salmonella can cause with identification of characteristic cellular inclusions and viral cul-
watery or bloody diarrhea, nausea, and vomiting. Shigellosis causes ture. HIV itself can cause diarrhea, nausea, vomiting, and anorexia.
watery diarrhea, abdominal pain, and fever followed by rectal tenesmus Small-intestinal biopsies show partial villous atrophy; small-bowel
and by the passage of blood and mucus per rectum. All three are usu- bacterial overgrowth and fat malabsorption may also be noted.
ally self-limited, but 1% of patients infected with Salmonella become Protozoan parasites include Isospora belli, which can cause a
asymptomatic carriers. Yersinia enterocolitica infection occurs mainly self-limited infection in healthy hosts but causes a chronic profuse,
in the terminal ileum and causes mucosal ulceration, neutrophil inva- watery diarrhea and weight loss in AIDS patients. Entamoeba histolyt-
sion, and thickening of the ileal wall. Other bacterial infections that ica or related species infect ~10% of the world’s population; symptoms
may mimic IBD include C. difficile, which presents with watery diar- include abdominal pain, tenesmus, frequent loose stools containing
rhea, tenesmus, nausea, and vomiting; and E. coli, three categories of blood and mucus, and abdominal tenderness. Colonoscopy reveals
which can cause colitis. These are enterohemorrhagic, enteroinvasive, focal punctate ulcers with normal intervening mucosa; diagnosis is
and enteroadherent E. coli, all of which can cause bloody diarrhea and made by biopsy or serum amebic antibodies. Fulminant amebic colitis
abdominal tenderness. Gonorrhea, Chlamydia, and syphilis can also is rare but has a mortality rate of >50%.
cause proctitis. Other parasitic infections that may mimic IBD include hookworm
GI involvement with mycobacterial infection occurs primarily (Necator americanus), whipworm (Trichuris trichiura), and Strongy-

CHAPTER 326 Inflammatory Bowel Disease

in the immunosuppressed patient but may occur in patients with loides stercoralis. In severely immunocompromised patients, Candida
normal immunity. Distal ileal and cecal involvement predominates, or Aspergillus can be identified in the submucosa. Disseminated histo-
and patients present with symptoms of small-bowel obstruction and plasmosis can involve the ileocecal area.

■■NONINFECTIOUS DISEASES
TABLE 326-6 Diseases That Mimic IBD Diverticulitis can be confused with CD clinically and radiographically.
Both diseases cause fever, abdominal pain, tender abdominal mass,
Infectious Etiologies
leukocytosis, elevated ESR, partial obstruction, and fistulas. Perianal
Bacterial Mycobacterial Viral disease or ileitis on small-bowel series favors the diagnosis of CD. Sig-
Salmonella Tuberculosis Cytomegalovirus nificant endoscopic mucosal abnormalities are more likely in CD than
Shigella Mycobacterium avium Herpes simplex in diverticulitis. Endoscopic or clinical recurrence following segmental
Toxigenic Parasitic HIV resection favors CD. Diverticular-associated colitis is similar to CD,
but mucosal abnormalities are limited to the sigmoid and descending
Escherichia coli Amebiasis Fungal
colon.
Campylobacter Isospora Histoplasmosis Ischemic colitis is commonly confused with IBD. The ischemic
Yersinia Trichuris trichiura Candida process can be chronic and diffuse, as in UC, or segmental, as in CD.
Clostridium difficile Hookworm Aspergillus Colonic inflammation due to ischemia may resolve quickly or may per-
Gonorrhea Strongyloides sist and result in transmural scarring and stricture formation. Ischemic
Chlamydia trachomatis bowel disease should be considered in the elderly following abdominal
aortic aneurysm repair or when a patient has a hypercoagulable state
Noninfectious Etiologies
or a severe cardiac or peripheral vascular disorder. Patients usually
Inflammatory Neoplastic Drugs and Chemicals present with sudden onset of left lower quadrant pain, urgency to
Appendicitis Lymphoma NSAIDs defecate, and the passage of bright red blood per rectum. Endoscopic
Diverticulitis Metastatic Phosphosoda examination often demonstrates a normal-appearing rectum and a
Diversion colitis Carcinoma Cathartic colon sharp transition to an area of inflammation in the descending colon
 Collagenous/ Carcinoma of the ileum Gold and splenic flexure.
lymphocytic colitis The effects of radiotherapy on the GI tract can be difficult to distin-
Carcinoid Oral contraceptives
Ischemic colitis
guish from IBD. Acute symptoms can occur within 1–2 weeks of start-
Familial polyposis Cocaine
ing radiotherapy. When the rectum and sigmoid are irradiated, patients
 Radiation colitis/  Immune checkpoint
enteritis
develop bloody, mucoid diarrhea and tenesmus, as in distal UC. With
inhibitor colitis
small-bowel involvement, diarrhea is common. Late symptoms include
 Solitary rectal ulcer Mycophenolate mofetil
syndrome
malabsorption and weight loss. Stricturing with obstruction and bac-
terial overgrowth may occur. Fistulas can penetrate the bladder, vagina,
 Eosinophilic or abdominal wall. Flexible sigmoidoscopy reveals mucosal granularity,
gastroenteritis
friability, numerous telangiectasias, and occasionally discrete ulcera-
Neutropenic colitis tions. Biopsy can be diagnostic.
Behçet’s syndrome Solitary rectal ulcer syndrome is uncommon and can be con-
 Graft-versus-host fused with IBD. It occurs in persons of all ages and may be caused
disease by impaired evacuation and failure of relaxation of the puborectalis
Abbreviations: IBD, inflammatory bowel disease; NSAIDs, nonsteroidal anti- muscle. Single or multiple ulcerations may arise from anal sphincter
inflammatory drugs. overactivity, higher intrarectal pressures during defecation, and digital

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 2480 removal of stool. Patients complain of constipation with straining EXTRAINTESTINAL MANIFESTATIONS
and pass blood and mucus per rectum. Other symptoms include Up to one-third of IBD patients have at least one extraintestinal disease
abdominal pain, diarrhea, tenesmus, and perineal pain. Ulceration, manifestation. Please see Table 326-7 for a summary of IBD EIMs.
which may be as large as 5 cm in diameter, is usually observed ante-
riorly or anterolaterally 3–15 cm from the anal verge. Biopsies can be ■■DERMATOLOGIC
diagnostic. Erythema nodosum (EN) occurs in up to 15% of CD patients and
Several types of colitis are associated with nonsteroidal 10% of UC patients. Attacks usually correlate with bowel activity;
anti-inflammatory drugs (NSAIDs), including de novo colitis, reactiva- skin lesions develop after the onset of bowel symptoms, and patients
tion of IBD, and proctitis caused by use of suppositories. Most patients frequently have concomitant active peripheral arthritis. The lesions of
with NSAID-related colitis present with diarrhea and abdominal pain, EN are hot, red, tender nodules measuring 1–5 cm in diameter and are
and complications include stricture, bleeding, obstruction, perforation, found on the anterior surface of the lower legs, ankles, calves, thighs,
and fistulization. Withdrawal of these agents is crucial, and in cases of and arms. Therapy is directed toward the underlying bowel disease.
reactivated IBD, standard therapies are indicated. Pyoderma gangrenosum (PG) is seen in 1–12% of UC patients and
Colitis secondary to immune checkpoint inhibitors (ICIs), termed less commonly in Crohn’s colitis. Although it usually presents after
ICI-related colitis, has emerged as these agents have found use in a the diagnosis of IBD, PG may occur years before the onset of bowel
wide variety of cancers. Immune checkpoint proteins such as cytotoxic symptoms, run a course independent of the bowel disease, respond
T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell poorly to colectomy, and even develop years after proctocolectomy. It
death protein 1 (PD-1) are receptors expressed on the surface of effec- is usually associated with severe disease. Lesions are commonly found
tor T cells that interact with their ligands CD80/CD86 (CTLA-4) and on the dorsal surface of the feet and legs but may occur on the arms,
programmed death-ligand 1 (PD-1) on antigen-presenting cells and chest, stoma, and even the face. PG usually begins as a pustule and
normally function as inhibitors of immune responses. ICIs block these then spreads concentrically to rapidly undermine healthy skin. Lesions
inhibitory pathways and promote the activation and proliferation of the then ulcerate, with violaceous edges surrounded by a margin of eryth-
native adaptive T-cell response against malignant cells as their mecha- ema. Centrally, they contain necrotic tissue with blood and exudates.
nism of antitumor activity. While very effective at enhancing antitumor Lesions may be single or multiple and grow as large as 30 cm. They are
T-cell activity, ICIs also activate global T-cell responses that induce sometimes very difficult to treat and often require IV antibiotics, IV
several autoimmune-related adverse events. Although immune-related glucocorticoids, dapsone, azathioprine, thalidomide, IV cyclosporine
adverse events of ICIs occur in multiple organ systems, the GI tract is (CSA), infliximab, or adalimumab.
affected in 21–44% of patients. The most common clinical presentation Other dermatologic manifestations include pyoderma vegetans,
is self-limited diarrhea that can be associated with frank colitis and which occurs in intertriginous areas; pyostomatitis vegetans, which
PART 10

can lead to significant morbidity and mortality if not managed appro- involves the mucous membranes; Sweet syndrome, a neutrophilic
priately. Treatment is generally based on symptom severity. Moderate dermatosis; and metastatic CD, a rare disorder defined by cutaneous
to severe symptoms usually require glucocorticoids, whereas biologics granuloma formation. Psoriasis affects 5–10% of patients with IBD
such as anti-TNF agents and integrin inhibitors are used in steroid- and is unrelated to bowel activity, consistent with the potential shared
refractory cases. immunogenetic basis of these diseases. Perianal skin tags are found in
Disorders of the Gastrointestinal System

75–80% of patients with CD, especially those with colon involvement.

■■THE ATYPICAL COLITIDES Oral mucosal lesions, seen often in CD and rarely in UC, include aph-
Two atypical colitides—collagenous colitis and lymphocytic colitis— thous stomatitis and “cobblestone” lesions of the buccal mucosa.
have completely normal endoscopic appearances. Collagenous colitis
has two main histologic components: increased subepithelial col- ■■RHEUMATOLOGIC
lagen deposition and colitis with increased intraepithelial lympho- Peripheral arthritis develops in 15–20% of IBD patients, is more
cytes. The female-to-male ratio is 9:1, and most patients present in common in CD, and worsens with exacerbations of bowel activity. It
the sixth or seventh decade of life. The main symptom is chronic is asymmetric, polyarticular, and migratory and most often affects
watery diarrhea. Risk factors include smoking; use of NSAIDs, pro- large joints of the upper and lower extremities. Treatment is directed
ton pump inhibitors, or beta blockers; and a history of autoimmune at reducing bowel inflammation. In severe UC, colectomy frequently
disease. cures the arthritis.
Lymphocytic colitis has features similar to collagenous colitis, Ankylosing spondylitis (AS) occurs in ~10% of IBD patients and
including age at onset and clinical presentation, but it has almost equal is more common in CD than UC. About two-thirds of IBD patients
incidence in men and women and no subepithelial collagen deposi- with AS express the HLA-B27 antigen. The AS activity is not related to
tion on pathologic section. However, intraepithelial lymphocytes are bowel activity and does not remit with glucocorticoids or colectomy.
increased. Use of sertraline (but not beta blockers) is an additional It most often affects the spine and pelvis, producing symptoms of dif-
risk factor. The frequency of celiac disease is increased in lymphocytic fuse low-back pain, buttock pain, and morning stiffness. The course
colitis and ranges from 9 to 27%. Celiac disease should be excluded is continuous and progressive, leading to permanent skeletal damage
in all patients with lymphocytic colitis, particularly if diarrhea does and deformity. Anti-TNF therapy reduces spinal inflammation and
not respond to conventional therapy. Treatments for both microscopic improves functional status and quality of life.
colitides vary depending on symptom severity and include, antidiar- Sacroiliitis is symmetric, occurs equally in UC and CD, is often
rheals (e.g., loperamide and diphenoxylate), bismuth, aminosalicylates, asymptomatic, does not correlate with bowel activity, and does not
budesonide, systemic glucocorticoids, and biologics for refractory always progress to AS. Other rheumatic manifestations include hyper-
disease. trophic osteoarthropathy, pelvic/femoral osteomyelitis, and relapsing
Diversion colitis is an inflammatory process that arises in segments polychondritis.
of the large intestine that are not continuous with the fecal stream. It
usually occurs in patients with ileostomy or colostomy when a mucus ■■OCULAR
fistula or a Hartmann’s pouch has been created. Clinically, patients The incidence of ocular complications in IBD patients is 1–10%. The
have mucus or bloody discharge from the rectum. Erythema, granu- most common are conjunctivitis, anterior uveitis/iritis, and episcleritis.
larity, friability, and, in more severe cases, ulceration can be seen on Uveitis is associated with both UC and Crohn’s colitis, may be found
endoscopy. Histopathology shows areas of active inflammation with during periods of remission, and may develop in patients following
foci of cryptitis and crypt abscesses. Crypt architecture is normal, bowel resection. Symptoms include ocular pain, photophobia, blurred
which differentiates it from UC but not necessarily CD. Short-chain vision, and headache. Prompt intervention, sometimes with systemic
fatty acid enemas may help in diversion colitis, but the definitive ther- glucocorticoids, is required to prevent scarring and visual impairment.
apy is surgical reanastomosis. Episcleritis is a benign disorder that presents with symptoms of mild

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 TABLE 326-7 Extraintestinal Manifestations 2481

CATEGORY CLINICAL COURSE TREATMENT

Rheumatologic disorders (5–20%)
Peripheral arthritis Asymmetric, migratory Reduce bowel inflammation
Parallels bowel activity
Sacroiliitis Symmetric: spine and hip joints Steroids, injections, methotrexate, anti-TNF
Independent of bowel activity
Ankylosing spondylitis Gradual fusion of spine Physical therapy, steroids, injections, methotrexate,
Independent of bowel activity anti-TNF, IL-17 inhibitors, tofacitinib
Two-thirds have HLA-B27 antigen
Metabolic bone disorders (up to 40% of patients)
Osteoporosis Risk increased by glucocorticoids, cyclosporine, methotrexate, total parenteral Screening with DEXA scan, check vitamin D levels,
nutrition, malabsorption, and inflammation treat if osteoporosis or osteopenia on long-term
Fracture rates highest in the elderly (age >60) corticosteroids
Osteonecrosis Death of osteocytes and adipocytes and eventual bone collapse; affects hips Pain control, injections, joint replacement
more than knees or shoulders; risk factor is steroid use
Dermatologic disorders (10–20%)
Erythema nodosum Hot, red, tender, nodules/extremities Reduce bowel inflammation
Parallels bowel activity
Pyoderma gangrenosum Ulcerating, necrotic lesions on extremities, trunk, face, stoma Antibiotics, steroids, cyclosporine, infliximab, dapsone,
Independent of bowel activity azathioprine, intralesional steroids; not debridement or
colectomy
Psoriasis Unrelated to bowel activity Topical steroids, light therapy, methotrexate, infliximab,
adalimumab, ustekinumab
Pyoderma vegetans Intertriginous areas Evanescent; resolves without progression

CHAPTER 326 Inflammatory Bowel Disease

Parallels bowel activity
Pyostomatitis vegetans Mucous membranes Evanescent; resolves without progression
Parallels bowel activity
Metastatic Crohn’s CD of the skin Reduce bowel inflammation
disease (CD) Parallels bowel activity
Sweet syndrome Neutrophilic dermatosis Reduce bowel inflammation
Parallels bowel activity
Aphthous stomatitis Oral ulcerations Reduce bowel inflammation/topical therapy
Parallels bowel activity
Ocular disorders (1–11%)
Uveitis Ocular pain, photophobia, blurred vision, headache Topical or systemic steroids
Independent of bowel activity
Episcleritis Mild ocular burning Topical corticosteroids
Parallels bowel activity
Hepatobiliary disorders (10–35%)
Fatty liver Secondary to chronic illness, malnutrition, steroid therapy Improve nutrition, reduce steroids
Cholelithiasis Patients with ileitis or ileal resection Reduce bowel inflammation; cholecystectomy in
Malabsorption of bile acids, depletion of bile salt pool, secretion of lithogenic bile symptomatic patients
Primary sclerosing Intrahepatic and extrahepatic ERCP/high-dose ursodiol lowers risk of colonic
cholangitis (PSC) Inflammation and fibrosis leading to biliary cirrhosis and hepatic failure neoplasia; cholecystectomy in patients with gallbladder
polyps due to the high incidence of malignancy
7–10% cholangiocarcinoma
Small-duct PSC involves small-caliber bile ducts and has a better prognosis
Urologic
Nephrolithiasis (10–20%) CD patients following small-bowel resection; calcium oxalate stones most Low-oxalate diet; control of bowel inflammation;
common surgical intervention
Less common extraintestinal manifestations
Thromboembolic Increased risk of venous and arterial thrombosis; factors responsible include Anticoagulation; control of inflammation
disorders abnormalities of the platelet-endothelial interaction, hyperhomocysteinemia,
alterations in the coagulation cascade, impaired fibrinolysis, involvement of
tissue factor–bearing microvesicles, disruption of the normal coagulation system
by autoantibodies, and a genetic predisposition
Cardiopulmonary Endocarditis, myocarditis, pleuropericarditis, interstitial lung disease Treatment is varied; stop 5-ASA agents as they can
rarely cause interstitial lung disease
Systemic amyloidosis Secondary (reactive) in long-standing IBD, especially CD Colchicine
Pancreatitis Duodenal fistulas, ampullary CD, gallstones, PSC, drugs (MP, azathioprine, Treatment is varied; stop offending medication; diagnose
5-ASAs), autoimmune, primary CD of the pancreas and treat with ERCP and/or cholecystectomy
Abbreviations: 5-ASA, 5-aminosalicylic acid; DEXA, dual-energy x-ray absorptiometry; ERCP, endoscopic retrograde cholangiopancreatography; IBD, inflammatory bowel
disease; IL, interleukin; MP, mercaptopurine; TNF, tumor necrosis factor.

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 2482 ocular burning. It occurs in 3–4% of IBD patients, more commonly in an osteoporotic fracture is ~1% per person per year. Fracture rates, par-
Crohn’s colitis, and is treated with topical glucocorticoids. ticularly in the spine and hip, are highest among the elderly (age >60).
One study noted an OR of 1.72 for vertebral fracture and an OR of 1.59
■■HEPATOBILIARY for hip fracture. The disease severity predicted the risk of a fracture.
Hepatic steatosis is detectable in about one-half of the abnormal liver Only 13% of IBD patients who had a fracture were on any kind of anti-
biopsies from patients with CD and UC; patients usually present fracture treatment. Up to 20% of bone mass can be lost per year with
with hepatomegaly. Fatty liver usually results from a combination of chronic glucocorticoid use. The effect is dose-dependent. Budesonide
chronic debilitating illness, malnutrition, and glucocorticoid therapy. may also suppress the pituitary-adrenal axis and thus carries a risk of
Cholelithiasis occurs in 10–35% of CD patients with ileitis or ileal causing osteoporosis.
resection. Gallstone formation is caused by malabsorption of bile Osteonecrosis is characterized by death of osteocytes and adipocytes
acids, resulting in depletion of the bile salt pool and the secretion of and eventual bone collapse. The pain is aggravated by motion and
lithogenic bile. swelling of the joints. It affects the hips more often than knees and
Primary sclerosing cholangitis (PSC) is a disorder characterized by shoulders, and in one series, 4.3% of patients developed osteonecrosis
both intrahepatic and extrahepatic bile duct inflammation and fibro- within 6 months of starting glucocorticoids. Diagnosis is made by bone
sis, frequently leading to biliary cirrhosis and hepatic failure; ~5% of scan or MRI, and treatment consists of pain control, cord decompres-
patients with UC have PSC, but 50–75% of patients with PSC have IBD. sion, osteotomy, and joint replacement.
PSC occurs less often in patients with CD. Although it can be recog-
nized after the diagnosis of IBD, PSC can be detected earlier or even ■■THROMBOEMBOLIC DISORDERS
years after proctocolectomy. Consistent with this, the immunogenetic Patients with IBD have an increased risk of both venous and arte-
basis for PSC appears to be overlapping but distinct from UC based on rial thrombosis even if the disease is not active. Factors responsible
GWAS, although both IBD and PSC are commonly pANCA positive. for the hypercoagulable state have included abnormalities of the
Most patients have no symptoms at the time of diagnosis; when symp- platelet-endothelial interaction, hyperhomocysteinemia, alterations in
toms are present, they consist of fatigue, jaundice, abdominal pain, the coagulation cascade, impaired fibrinolysis, involvement of tissue
fever, anorexia, and malaise. The traditional gold standard diagnostic factor–bearing microvesicles, disruption of the normal coagulation
test is endoscopic retrograde cholangiopancreatography (ERCP), but system by autoantibodies, and a genetic predisposition. A spectrum of
magnetic resonance cholangiopancreatography (MRCP) is sensitive, vasculitides involving small, medium, and large vessels has also been
specific, and safer. MRCP is reasonable as an initial diagnostic test in observed.
children and adults and can visualize irregularities, multifocal stric-
tures, and dilatations of all levels of the biliary tree. In patients with ■■OTHER DISORDERS
PSC, both ERCP and MRCP demonstrate multiple bile duct strictures More common cardiopulmonary manifestations include endocarditis,
PART 10

alternating with relatively normal segments. myocarditis, pleuropericarditis, and interstitial lung disease. A second-
Gallbladder polyps in patients with PSC have a high incidence of ary or reactive amyloidosis can occur in patients with long-standing
malignancy, and cholecystectomy is recommended, even if a mass IBD, especially in patients with CD. Amyloid material is deposited sys-
lesion is <1 cm in diameter. Gallbladder surveillance with ultrasound temically and can cause diarrhea, constipation, and renal failure. The
Disorders of the Gastrointestinal System

should be performed annually. Endoscopic stenting may be palliative renal disease can be successfully treated with colchicine. Pancreatitis is
for cholestasis secondary to bile duct obstruction. Patients with symp- a rare EIM of IBD and results from duodenal fistulas; ampullary CD;
tomatic disease develop cirrhosis and liver failure over 5–10 years and gallstones; PSC; drugs such as mercaptopurine, azathioprine, or, very
eventually require liver transplantation. PSC patients have a 10–15% rarely, 5-ASA agents; autoimmune pancreatitis; and primary CD of the
lifetime risk of developing cholangiocarcinoma and then cannot be pancreas.
transplanted. Patients with IBD and PSC are at increased risk of colon
cancer and should be surveyed yearly by colonoscopy and biopsy. TREATMENT
In addition, cholangiography is normal in a small percentage of
patients who have a variant of PSC known as small duct primary scle- Inflammatory Bowel Disease
rosing cholangitis. This variant (sometimes referred to as “pericholan-
gitis”) is probably a form of PSC involving small-caliber bile ducts. It 5-ASA AGENTS
has similar biochemical and histologic features to classic PSC. It has a These agents are effective at inducing and maintaining remission
significantly better prognosis than classic PSC, although it may evolve in UC. Peroxisome proliferator–activated receptor γ (PPAR-γ) may
into classic PSC. Granulomatous hepatitis and hepatic amyloidosis are mediate 5-ASA therapeutic action by decreasing nuclear local-
much rarer EIMs of IBD. ization of NF-κB. Sulfa-free aminosalicylate formulations include
alternative azo-bonded carriers, 5-ASA dimers, and delayed-release
■■UROLOGIC and controlled-release preparations. Each has the same efficacy as
The most frequent genitourinary complications are calculi, ureteral sulfasalazine when equimolar concentrations are used.
obstruction, and ileal bladder fistulas. The highest frequency of neph- Sulfasalazine is effective treatment for mild to moderate UC, but
rolithiasis (10–20%) occurs in patients with CD following small-bowel its high rate of side effects limits its use. Although sulfasalazine is
resection. Calcium oxalate stones develop secondary to hyperoxaluria, more effective at higher doses, at 6 or 8 g/d, up to 30% of patients
which results from increased absorption of dietary oxalate. Normally, experience allergic reactions or intolerable side effects such as head-
dietary calcium combines with luminal oxalate to form insoluble cal- ache, anorexia, nausea, and vomiting that are attributable to the
cium oxalate, which is eliminated in the stool. In patients with ileal sulfapyridine moiety. Hypersensitivity reactions, independent of
dysfunction, however, nonabsorbed fatty acids bind calcium and leave sulfapyridine levels, include rash, fever, hepatitis, agranulocytosis,
oxalate unbound. The unbound oxalate is then delivered to the colon, hypersensitivity pneumonitis, pancreatitis, worsening of colitis, and
where it is readily absorbed, especially in the presence of inflammation. reversible sperm abnormalities. Sulfasalazine can also impair folate
absorption, and patients should be given folic acid supplements.
■■METABOLIC BONE DISORDERS Balsalazide contains an azo bond binding mesalamine to the car-
Low bone mass occurs in 14–42% of IBD patients. The risk is increased rier molecule 4-aminobenzoyl-β-alanine; it is effective in the colon.
by glucocorticoids, CSA, methotrexate (MTX), and total parenteral Delzicol and Asacol HD (high dose) are enteric-coated forms
nutrition (TPN). Malabsorption and inflammation mediated by IL-1, of mesalamine with the 5-ASA being released at pH >7. They dis-
IL-6, TNF, and other inflammatory mediators also contribute to low integrate with complete breakup of the tablet occurring in many
bone density. An increased incidence of hip, spine, wrist, and rib frac- different parts of the gut ranging from the small intestine to the
tures has been noted: 36% in CD and 45% in UC. The absolute risk of splenic flexure; they have increased gastric residence when taken

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 with a meal. Lialda is a once-a-day formulation of mesalamine the colon and has minimal to no glucocorticoid side effects. The 2483
(Multi-Matrix System [MMX]) designed to release mesalamine dose is 9 mg/d for 8 weeks, and no taper is required. Topically
in the colon. The MMX technology incorporates mesalamine into applied glucocorticoids (hydrocortisone enemas or budesonide
a lipophilic matrix within a hydrophilic matrix encapsulated in a foam) are also beneficial for distal colitis and may serve as an
polymer resistant to degradation at a low pH (<7) to delay release adjunct in those who have rectal involvement plus more proximal
throughout the colon. The safety profile appears to be comparable disease. Hydrocortisone enemas are significantly absorbed from
to other 5-ASA formulations. the rectum and can lead to adrenal suppression with prolonged
Apriso is a formulation containing encapsulated mesalamine administration. Topical 5-ASA therapy is more effective than topi-
granules that delivers mesalamine to the terminal ileum and colon cal steroid therapy in the treatment of distal UC.
via a proprietary extended-release mechanism (Intellicor). The Glucocorticoids are also effective for treatment of moderate to
outer coating of this agent (Eudragit L) dissolves at a pH >6. In addi- severe CD and induce a 60–70% remission rate compared to a 30%
tion, there is a polymer matrix core that aids in sustained release placebo response. The systemic effects of standard glucocorticoid
throughout the colon. Because Lialda and Apriso are given once formulations have led to the development of formulations that
daily, an anticipated benefit is improved compliance compared with are less well absorbed and have increased first-pass metabolism.
two to four daily doses required for other mesalamine preparations. Controlled-ileal-release budesonide has been nearly equal to pred-
Pentasa is another mesalamine formulation that uses an ethylcel- nisone for ileocolonic CD with fewer glucocorticoid side effects.
lulose coating to allow water absorption into small beads containing Budesonide is used for 2–3 months at a dose of 9 mg/d and then
the mesalamine. Water dissolves the 5-ASA, which then diffuses out tapered. Glucocorticoids play no role in maintenance therapy in
of the bead into the lumen. Disintegration of the capsule occurs in either UC or CD. Once clinical remission has been induced, they
the stomach. The microspheres then disperse throughout the entire should be tapered according to the clinical activity, normally at a
GI tract from the small intestine through the distal colon in both rate of no more than 5–10 mg/week. The side effects are numer-
fasted and fed conditions. ous, including fluid retention, abdominal striae, fat redistribution,
Salofalk Granu-Stix, an unencapsulated version of mesalamine, hyperglycemia, subcapsular cataracts, osteonecrosis, osteoporosis,
has been in use in Europe for induction and maintenance of remis- myopathy, emotional disturbances, and withdrawal symptoms.
sion for several years. Most of these side effects, aside from osteonecrosis, are related to
Appropriate doses of the 5-ASA compounds are shown in the dose and duration of therapy.
Table 326-8. Some 50–75% of patients with mild to moderate UC ANTIBIOTICS
improve when treated with 5-ASA doses equivalent to 2 g/d of

CHAPTER 326 Inflammatory Bowel Disease

mesalamine; the dose response continues up to at least 4.8 g/d. Antibiotics have no role in the treatment of active or quiescent UC.
More common side effects of the 5-ASA medications include However, pouchitis, which occurs in ~30–50% of UC patients after
headaches, nausea, hair loss, and abdominal pain. Rare side effects colectomy and IPAA, usually responds to treatment with a variety
of the 5-ASA medications include renal impairment, hematuria, of antibiotics including metronidazole and ciprofloxacin. Some
pancreatitis, and paradoxical worsening of colitis. Renal function patients require long-term treatment with antibiotics for chronic
tests and urinalysis should be checked yearly. pouchitis.
Topical Rowasa enemas are composed of mesalamine and are AZATHIOPRINE AND MERCAPTOPURINE
effective in mild-to-moderate distal UC. Combination therapy with Azathioprine and mercaptopurine (MP) are purine analogues used
mesalamine in both oral and enema form is more effective than concomitantly with biologic therapy or, much less often, as the sole
either treatment alone for both distal and extensive UC. immunosuppressants. Azathioprine is rapidly absorbed and con-
Canasa suppositories composed of mesalamine are effective in verted to MP, which is then metabolized to the active end product,
treating proctitis. thioinosinic acid, an inhibitor of purine ribonucleotide synthesis
and cell proliferation. Efficacy can be seen as early as 3–4 weeks but
GLUCOCORTICOIDS can take up to 4–6 months. Adherence can be monitored by mea-
The majority of patients with moderate to severe UC benefit from suring the levels of 6-thioguanine and 6-methylmercaptopurine,
oral or parenteral glucocorticoids. Prednisone is usually started at end products of MP metabolism. The doses used range from 2 to
doses of 40–60 mg/d for active UC that is unresponsive to 5-ASA 3 mg/kg per day for azathioprine and 1 to 1.5 mg/kg per day for MP.
therapy. Parenteral glucocorticoids may be administered as hydro- Although azathioprine and MP are usually safe, pancreatitis
cortisone, 300 mg/d, or methylprednisolone, 40–60 mg/d. A newer occurs in 3–4% of patients, typically presents within the first few
glucocorticoid for UC, budesonide (Uceris), is released entirely in weeks of therapy, and is completely reversible when the drug is

TABLE 326-8 Oral 5-Aminosalicylic Acid (5-ASA) Preparations

PREPARATION FORMULATION DELIVERY DOSING PER DAY
Azo-Bond
Sulfasalazine (500 mg) (Azulfidine) Sulfapyridine-5-ASA Colon 3–6 g (acute)
2–4 g (maintenance)
Balsalazide (750 mg) (Colazal) Aminobenzoyl-alanine–5-ASA Colon 6.75–9 g
Delayed-Release
Mesalamine (400, 800 mg) (Delzicol, Asacol HD) Eudragit S (pH 7) Distal ileum-colon 2.4–4.8 g (acute)
1.6–4.8 g (maintenance)
Mesalamine (1.2 g) (Lialda) MMX mesalamine (SPD476) Ileum-colon 2.4–4.8 g
Controlled-Release
Mesalamine (250, 500, 1000 mg) (Pentasa) Ethylcellulose microgranules Stomach-colon 2–4 g (acute)
1.5–4 g (maintenance)
Delayed- and Extended-Release
Mesalamine (0.375 g) (Apriso) Intellicor extended-release mechanism Ileum-colon 1.5 g (maintenance)
Abbreviation: MMX, Multi-Matrix System.

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 2484 stopped. Other side effects include nausea, fever, rash, and hepatitis. among patients treated with oral CSA versus infliximab at the
Bone marrow suppression (particularly leukopenia) is dose-related usual induction dose and maintenance dose regimen (40 and 46%,
and often delayed, necessitating regular monitoring of the com- respectively). In light of data showing equal efficacy of CSA and
plete blood cell count (CBC). Additionally, 1 in 300 individuals infliximab in severe UC, more physicians are relying on infliximab
lacks thiopurine methyltransferase, the enzyme responsible for drug rather than CSA in these patients.
metabolism to inactive end products (6-methylmercaptopurine); an
additional 11% of the population are heterozygotes with interme- TACROLIMUS
diate enzyme activity. Both are at increased risk of toxicity because Tacrolimus is a macrolide antibiotic with immunomodulatory prop-
of increased accumulation of active 6-thioguanine metabolites. erties similar to CSA but 100 times as potent and not dependent on
Although 6-thioguanine and 6-methylmercaptopurine levels can bile or mucosal integrity for absorption. Thus, tacrolimus has good
be followed to determine correct drug dosing and reduce toxicity, oral absorption despite proximal small-bowel Crohn’s involvement.
weight-based dosing is an acceptable alternative. CBCs and liver Tacrolimus is effective in children with refractory IBD and in adults
function tests should be monitored frequently regardless of dosing with extensive involvement of the small bowel. It is also effective in
strategy. adults with glucocorticoid-dependent or refractory UC and CD as
One meta-analysis demonstrated a fourfold risk of lymphoma well as refractory fistulizing CD.
in IBD patients on azathioprine and MP. The highest risk for thi-
opurine-associated lymphoma is in patients >65 years old actively BIOLOGIC THERAPIES
using thiopurines (yearly incidence rate per 1000 patient-years Biologic therapy is now commonly given as an initial therapy for
of 5.41), with a moderate risk in those between the ages of 50 and patients with moderate to severe CD and UC to prevent future
65 (incidence rate of 2.58 compared to an incidence rate of 0.37 in complications of IBD. High-risk patients with UC who are more
patients <50 years old). Patients using thiopurines also have a two- likely to require biologics include those with moderate to severe
to threefold increased risk of nonmelanoma skin cancers. disease, steroid-dependent or steroid-refractory disease, and refrac-
tory pouchitis. High-risk patients with CD who are more likely to
METHOTREXATE require biologics include those who are <30 years old, with exten-
MTX inhibits dihydrofolate reductase, resulting in impaired DNA sive disease, perianal or severe rectal disease and/or deep ulcera-
synthesis. Additional anti-inflammatory properties may be related tions in the colon, and stricturing or penetrating disease behavior.
to decreases in the production of IL-1. It is used most often con- The current goal of IBD treatment is to treat early in the disease
comitantly with biologic therapy to decrease antibody formation course, treat aggressively with biologics, check drug and drug
and improve disease response. Intramuscular (IM) or subcuta- metabolite levels, administer dual therapy with immunomodulators
neous (SC) doses range from 15 to 25 mg/week. Potential toxici- and biologics in appropriate patients, and aim for deep remission
PART 10

ties include leukopenia and hepatic fibrosis, necessitating periodic (endoscopic and histologic remission). Patients who respond to
evaluation of CBCs and liver enzymes. The role of liver biopsy in biologic therapies enjoy an improvement in clinical symptoms; a
patients on long-term MTX is uncertain but is probably limited to better quality of life; less disability, fatigue, and depression; and
those with increased liver enzymes. Hypersensitivity pneumonitis is fewer surgeries and hospitalizations.
Disorders of the Gastrointestinal System

a rare but serious complication of therapy.

Anti-TNF Therapies TNF is a proinflammatory cytokine that
CYCLOSPORINE regulates immune cells to coordinate a systemic immune response.
CSA is a lipophilic peptide with inhibitory effects on both the cel- Dysregulation of TNF production has been associated with
lular and humoral immune systems. CSA blocks the production of immune-mediated disorders including IBD, and inhibition of
IL-2 by T helper lymphocytes. CSA binds to cyclophilin, and this TNF signaling is used in the treatment of IBD. Four TNF inhibi-
complex inhibits calcineurin, a cytoplasmic phosphatase enzyme tors are currently approved for the treatment of IBD: infliximab,
involved in the activation of T cells. CSA also indirectly inhibits adalimumab, certolizumab pegol, and golimumab. Infliximab, a
B-cell function by blocking helper T cells. CSA has a more rapid chimeric IgG1 antibody against TNF-α, was the first biologic ther-
onset of action than MP and azathioprine. apy approved for moderately to severely active inflammatory and
CSA is most effective when given at 2–4 mg/kg per day IV in fistulizing CD and UC.
severe UC that is refractory to IV glucocorticoids, with 82% of The SONIC (Study of Biologic and Immunomodulator-Naive
patients responding. CSA can be an alternative to colectomy. The Patients with Crohn’s Disease) trial compared infliximab plus aza-
long-term success of oral CSA is not as dramatic, but if patients thioprine, infliximab alone, and azathioprine alone in immuno-
are started on MP or azathioprine at the time of hospital discharge, modulator- and biologic therapy–naive patients with moderate to
remission can be maintained. Levels as measured by monoclonal severe CD. At 1 year, the infliximab plus azathioprine group had a
radioimmunoassay or by the high-performance liquid chromatog- glucocorticoid-free remission rate of 46% compared with 35% for
raphy assay should be maintained between 150 and 350 ng/mL. infliximab alone and 24% for azathioprine alone. Complete mucosal
CSA may cause significant toxicity; renal function should be healing was noted in more patients at week 26 with the combined
monitored frequently. Hypertension, gingival hyperplasia, hyper- approach compared with either infliximab or azathioprine alone
trichosis, paresthesias, tremors, headaches, and electrolyte abnor- (44 vs 30 vs 17%). The adverse events were equal between groups.
malities are common side effects. Creatinine elevation calls for dose A similar study in patients with moderate to severe UC showed
reduction or discontinuation. Seizures may also complicate therapy, that after 16 weeks of therapy, UC patients receiving azathioprine
especially if the patient is hypomagnesemic or if serum cholesterol plus infliximab exhibited a glucocorticoid-free remission rate of
levels are <3.1 mmol/L (<120 mg/dL). Opportunistic infections, 40%, compared to rates of 24 and 22% in those on azathioprine
most notably Pneumocystis jirovecii pneumonia, may occur with and infliximab alone, respectively. Together, these studies support
combination immunosuppressive treatment; antibiotic prophylaxis a more aggressive therapy for moderate to severe CD and UC.
with trimethoprim-sulfamethoxazole should be given. Trough infliximab levels can be checked, and if low, the dose can be
To compare IV CSA versus infliximab, a large trial was con- increased or the interval decreased.
ducted in Europe by the GETAID (Group d’Etudes Thérapeu- Hospitalized patients with acute severe glucocorticoid-
tiques des Affections Inflammatoires Digestives) group. The results refractory UC have a high inflammatory burden and may develop a
indicated identical 7-day response rates for CSA 2 mg/kg (with protein-losing enteropathy, leading to an accelerated consumption,
doses adjusted for levels of 150–250 ng/mL) and infliximab 5 mg/kg, excessive fecal wasting, and low serum concentrations of inflixi-
with both groups achieving response rates of 85%. Serious infec- mab. Given a clear exposure–response relationship for infliximab in
tions occurred in 5 of 55 CSA patients and 4 of 56 infliximab patients with IBD, intensive infliximab dosing regimens have been
patients. Response rates were similar in the two groups at day 98 used in these patients.

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 Adalimumab (ADA) is a recombinant human monoclonal IgG1 may have a slight, unexplained, intrinsic higher risk of developing 2485
antibody containing only human peptide sequences and is injected melanoma. The risk of melanoma is increased almost twofold with
subcutaneously. ADA binds TNF and neutralizes its function by anti-TNF and not thiopurine use. The risk of nonmelanoma skin
blocking the interaction between TNF and its cell-surface receptor. cancer is increased with thiopurines and biologics, especially with
Therefore, it seems to have a similar mechanism of action to inflix- ≥1 year of follow-up. Patients on these medications should have a
imab but with less immunogenicity. ADA is approved for treatment skin check at least once a year.
of moderate to severe CD and UC. CHARM (Crohn’s Trial of the Infections All of the anti-TNF drugs are associated with an
Fully Human Adalimumab for Remission Maintenance) is an ADA increased risk of infections, particularly reactivation of latent tuber-
maintenance study in patients who responded to ADA induction culosis and opportunistic fungal infections including disseminated
therapy. About 50% of the patients in this trial were previously histoplasmosis and coccidioidomycosis. Patients should have a
treated with infliximab. Remission rates ranged from 42 to 48% in purified protein derivative (PPD) or a QuantiFERON-TB Gold test
infliximab-naïve patients at 1 year compared with remission rates before initiation of anti-TNF therapy. Patients >65 years old have
of 31–34% in patients who had previously received infliximab. UC a higher rate of infections and death on infliximab or ADA than
results are similar, with a sustained remission rate at 1 year of 22% those <65 years old.
(12.4% placebo) among anti–TNF-naïve patients and a sustained
remission rate at 1 year of 10.2% (3% placebo) among patients who Other Acute liver injury due to reactivation of hepatitis B virus
had previously received anti-TNF agents. In clinical practice, the and to autoimmune effects and cholestasis has been reported.
remission rate in both CD and UC patients taking ADA increases Rarely, infliximab and the other anti-TNF drugs have been asso-
with a dose increase to 40 mg weekly instead of every other week. ciated with optic neuritis, seizures, new onset or exacerbation of
Certolizumab pegol is a pegylated form of an anti-TNF Fab clinical symptoms, and radiographic evidence of central nervous
portion of an antibody administered SC once monthly. SC cer- system demyelinating disorders, including multiple sclerosis. They
tolizumab pegol was effective for induction of clinical response in may exacerbate symptoms in patients with New York Heart Associ-
patients with active inflammatory CD. ation functional class III/IV heart failure.
Golimumab is another fully human IgG1 antibody against TNF-α ANTI-INTEGRINS
and is currently approved for the treatment of moderately to
severely active UC. Like ADA and certolizumab, golimumab is Integrins are expressed on the cell surface of leukocytes and serve
injected SC. as mediators of leukocyte adhesion to vascular endothelium.
α4-Integrin along with its β1 or β7 subunit interact with endothe-

CHAPTER 326 Inflammatory Bowel Disease

Side Effects of Anti-TNF Therapies lial ligands termed adhesion molecules. Interaction between α4β7
Development of Antibodies and Drug Levels The develop- and mucosal addressin cellular adhesion molecule (MAdCAM-1)
ment of antibodies to infliximab is associated with an increased is important in lymphocyte trafficking to gut mucosa.
risk of infusion reactions and a decreased response to treatment. Natalizumab is a recombinant humanized IgG4 antibody against
Current practice does not include giving on-demand or episodic α4-integrin and is effective in induction and maintenance of
infusions in contrast to scheduled periodic infusions because patients with CD. The rates of response and remission at 3 months
patients are most likely to develop antibodies. Anti-infliximab are ~60 and 40%, respectively, with a sustained remission rate of
antibodies are generally present when the quality of response or the ~40% at 36 weeks. Natalizumab is no longer widely used for CD due
response duration to infliximab infusion decreases. Commercial to the risk of progressive multifocal leukoencephalopathy (PML).
assays can detect both infliximab and ADA antibodies and measure Vedolizumab (VDZ), another leukocyte trafficking inhibitor, is
trough levels to determine optimal dosing. If a patient has high a monoclonal antibody directed against α4β7-integrin specifically
anti-infliximab antibodies and a low trough level of infliximab, and has the ability to convey gut-selective immunosuppression.
it is best to switch to another anti-TNF therapy. If a patient has Unlike natalizumab, it inhibits adhesion of a discrete gut-homing
a therapeutic anti-TNF level and active inflammatory symptoms, subset of T lymphocytes to MAdCAM-1, but not to vascular adhe-
the drug should be switched to a different class of biologic. Most sion molecule-1. VDZ decreases GI inflammation without inhibit-
acute infusion reactions and serum sickness can be managed with ing systemic immune responses or affecting T-cell trafficking to the
glucocorticoids and antihistamines. Some reactions can be serious central nervous system. It may be prescribed as a first-line biologic
and would necessitate a change in therapy, especially if a patient has or after failure of a TNF antagonist in patients with CD or UC.
anti-infliximab antibodies. It is now common practice to add an The VARSITY trial, a phase 3B, randomized, double-blind, dou-
immunomodulator such as azathioprine, MP, or MTX to anti-TNF ble-dummy, active-controlled superiority trial, evaluated outcomes
therapy to help prevent antibody formation. among patients with UC who received either VDZ or ADA. Results
showed that, at week 52, patients who were treated with VDZ were
Non-Hodgkin’s Lymphoma (NHL) The baseline risk of NHL in significantly more likely to be in clinical remission (31.3% VDZ vs
CD patients is 2 in 10,000, slightly higher than in the general pop- 22.5% ADA) and show endoscopic improvement (39.7% VDZ vs
ulation. Azathioprine and/or MP therapy increases the risk to ~4 27.7% ADA). Glucocorticoid-free clinical remission was observed
in 10,000. It is difficult to assess whether anti-TNF medications are in 12.6% of the VDZ group and 21.8% of patients who received
associated with lymphoma because most patients are also receiving ADA, but the difference was not statistically significant. This trial
thiopurines. After adjustment for co-treatments, no excess risk of suggests that among patients with UC, VDZ should be considered
lymphoma was found in a Danish study of a cohort of IBD patients as first-line therapy and before treatment with ADA.
exposed to anti-TNF medications. Ustekinumab, a fully human IgG1 monoclonal antibody, blocks
Hepatosplenic T-Cell Lymphoma (HSTCL) HSTCL is a nearly the biologic activity of IL-12 and IL-23 through their common p40
universally fatal lymphoma in patients with or without CD. In subunit by inhibiting the interaction of these cytokines with their
patients with CD, a total of 37 unique cases have been reported. receptors on T cells, natural killer cells, and antigen-presenting
Eighty-six percent of the patients were male, and the median age cells. In the UNITI trial, the remission rate for the highest 6 mg/kg
was 26 years. Patients had CD for a mean of 10 years before the IV induction dose followed by a dose of 90 mg every 8 weeks was
diagnosis of HSTCL. Thirty-six patients had used either MP or 41.7%, compared with 27.4% for placebo, at 22 weeks in patients
azathioprine, and 28 patients had used infliximab. with CD no longer responding to anti-TNF therapy.
Similarly, the UNIFI trial evaluated ustekinumab as 8-week
Skin Lesions New-onset psoriasiform skin lesions develop in induction and 44-week maintenance therapy in moderate to severe
nearly 5% of IBD patients treated with anti-TNF therapy. Most UC. Induction rates at 8 weeks were 15.6% in the ustekinumab
often, these can be treated topically, and occasionally, anti-TNF group compared to 5.3% in the placebo group, and 44-week main-
therapy must be decreased, switched, or stopped. Patients with IBD tenance rates were 43.8% in the ustekinumab group compared to

HPIM21e_Part10_p2381-p2670.indd 2485 20/01/22 10:04 PM

 2486 24% in the placebo group. The rates of serious adverse events were as glucocorticoids in inducing remission but not as effective for
similar for ustekinumab and placebo in the UNITI and UNIFI tri- maintenance therapy. In contrast to CD, active UC is not effectively
als. Therefore, ustekinumab is another option for the treatment of treated by elemental diets or TPN.
moderate to severe CD and UC and is particularly appealing for use Dietary approaches to maintenance therapy in CD have largely
in patients with concomitant psoriatic arthritis. been adapted from epidemiologic studies; however, significant het-
SMALL MOLECULES erogeneity is noted among research study outcomes. In general, low
fiber, refined carbohydrates (especially sweetened beverages), animal
Small molecules (drugs with molecular weight <1 kDa) are a new fats, red meat, and processed meat have been associated with onset
class of orally administered medications developed for IBD that lack of IBD. Therefore, the overall dietary approach is to maximize fiber
the immunogenicity associated with monoclonal antibodies. The intake, particularly from fruits and vegetables, and to limit consump-
advantage of small molecules is their ability to diffuse through cell tion of higher-risk foods. Several defined diets adhere to these prin-
membranes into the intracellular space and alter cytokine signaling ciples with some variation, including the Mediterranean diet pattern,
pathways. This mechanism of action may be more efficacious com- specific carbohydrate diet, semi-vegetarian diet, and IBD anti-inflam-
pared to monoclonal antibodies that inhibit specific targets because matory diet (IBD-AID). However, it remains unclear whether diet
several cytokine pathways are involved in IBD pathogenesis and studies will eventually lead to evidence-based nutrition guidelines.
inhibiting numerous cytokines may be synergistic. A key regulatory Standard medical management of UC and CD is shown in
pathway is the JAK/STAT pathway that activates transcription and Fig. 326-12.
translation of proteins that mediate the immune response. Janus
kinase (JAK) is a family of intracellular, nonreceptor tyrosine kinases SURGICAL THERAPY
that regulate cytokine signaling via the JAK/STAT pathway, ultimately Ulcerative Colitis Nearly one-half of patients with extensive
suppressing the immune response and inflammation. The JAK family chronic UC undergo surgery within the first 10 years of their illness.
members include JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). The indications for surgery are listed in Table 326-10. Morbidity is
Tofacitinib is a reversible and competitive JAK inhibitor used for ~20% for elective, 30% for urgent, and 40% for emergency procto-
the treatment of moderate to severe UC refractory to conventional colectomy. The risks are primarily hemorrhage, contamination and
therapy. It competes with ATP to bind to the ATP-docking site of the sepsis, and neural injury. The operation of choice is an IPAA.
kinase domain of JAK. By competing with ATP, tofacitinib inhibits Because UC is a mucosal disease, the rectal mucosa can be
phosphorylation and activation of JAK, leading to downstream dissected and removed down to the dentate line of the anus or
reduction of cytokine production and alteration of the immune ~2 cm proximal to this landmark. The ileum is fashioned into a
response. Although tofacitinib is a pan-JAK inhibitor, it has higher pouch that serves as a neorectum. This ileal pouch is then sutured
specificity for JAK1 and JAK3 than for JAK2 and TYK2. The pan-
PART 10

circumferentially to the anus in an end-to-end fashion. If per-

JAK inhibition is concerning for adverse events and overall safety. formed carefully, this operation preserves the anal sphincter and
The efficacy of tofacitinib as induction and maintenance therapy, maintains continence. The overall operative morbidity is 10%, with
as well as its safety profile, was evaluated in three phase 3, random- the major complication being bowel obstruction. Pouch failure
ized, double-blind, placebo-controlled trials in adults with moderate necessitating conversion to permanent ileostomy occurs in 5–10%
Disorders of the Gastrointestinal System

to severe UC refractory to conventional therapy including anti-T- of patients. Some inflamed rectal mucosa is usually left behind, and
NFs. Patients who responded to induction therapy were eligible for thus, endoscopic surveillance is necessary. Primary dysplasia of the
OCTAVE Sustain, a maintenance trial of tofacitinib 5 mg versus ileal mucosa of the pouch has occurred rarely.
10 mg versus placebo that continued through 52 weeks, with the Patients with IPAA usually have ~6–10 bowel movements a day.
primary end point of clinical remission at 52 weeks. Remission rates On validated quality-of-life indices, they report better performance
at 8 weeks in the OCTAVE Induction 1 and 2 trials were 18.5 and in sports and sexual activities than ileostomy patients. The most
16.6% in the tofacitinib groups, compared to 8.2 and 3.6% in the pla- frequent complication of IPAA is pouchitis in ~30–50% of patients
cebo groups, respectively. In the OCTAVE Sustain trial, remission with UC. This syndrome consists of increased stool frequency,
rates at 52 weeks were 34.3% with 5 mg and 40.6% with 10 mg of watery stools, cramping, urgency, nocturnal leakage of stool, arth-
tofacitinib, compared to 11.1% with placebo. A recent U.S. Food and ralgias, malaise, and fever. Pouch biopsies may distinguish true pou-
Drug Administration review concluded that there is an increased chitis from underlying CD. Although pouchitis usually responds to
risk of serious adverse events including heart attack, stroke, cancer, antibiotics, 3–5% of patients remain refractory and may require glu-
blood clots, and death in patients with ulcerative colitis and rheuma- cocorticoids, immunomodulators, biologics, or even pouch removal.
toid arthritis who are prescribed tofacitinib. Patients who are at risk
for cardiovascular disease, are current or past smokers and/or are Crohn’s Disease The majority of patients with CD will require
over the age of 50 should consider alternative therapies. at least one operation in their lifetime. The need for surgery is
related to duration of disease and the site of involvement. Patients
OZANIMOD with small-bowel disease have an 80% chance of requiring surgery.
Ozanimod is a potent sphingosine-1-phosphate (S1P1) receptor Those with colitis alone have a 50% chance. Surgery is an option
modulator that binds selectively with high affinity to the S1P recep- only when medical treatment has failed or complications dictate its
tor subtypes S1P1 and S1P5, both of which are involved in immune necessity. The indications for surgery are shown in Table 326-10.
regulation. By preventing trafficking of disease-exacerbating lym-
phocytes to the gut, ozanimod may provide immunomodulatory Small-Intestinal Disease Because CD is chronic and recur-
effects and moderate disease processes. rent, with no clear surgical cure, as little intestine as possible is
Ozanimod has very recently been approved for the treatment of resected. Current surgical alternatives for treatment of obstructing
moderate to severe ulcerative colitis. It is administered as a daily capsule. CD include resection of the diseased segment and strictureplasty.
The biologic and small-molecule therapies used in daily practice Surgical resection of the diseased segment is the most frequently
are detailed in Table 326-9. performed operation, and in most cases, primary anastomosis can
be done to restore continuity. An end-to-end anastomosis may
NUTRITIONAL THERAPIES provide the best opportunity for an optimal functional outcome,
Diet has long been thought to contribute to the pathogenesis of IBD compared to an antiperistaltic side-to-side anastomosis, which
and may also be an avenue for managing disease activity. Diet plays creates a functional block to motility leading to distention and pain
a significant role in shaping the gut microbiome, and dietary com- at the anastomotic site in a subgroup of patients. If much of the
ponents may interact with the microbiome and stimulate a mucosal small bowel has already been resected and the strictures are short,
immune response. In fact, active CD responds to exclusive enteral with intervening areas of normal mucosa, strictureplasties should
nutrition (EEN) or bowel rest with TPN, interventions as effective be done to avoid a functionally insufficient length of bowel. The

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 TABLE 326-9 Biologic Agents in the Treatment of Inflammatory Bowel Disease 2487

OTHER COMMON SIDE

MEDICATION DOSAGE INDICATION SERIOUS TOXICITIES EFFECTS TESTING
Infliximab 5 mg/kg at 0, 2, and 6 Moderate to severe Increased risk of Infusion reactions Prior to infusion:
weeks, then every 8 Crohn’s disease and infections (bacterial and TB testing
weeks; may increase ulcerative colitis fungal), tuberculosis
dose to 10 mg/kg every (TB) reactivation, Hepatitis B testing (HBsAb, HBsAb,
Fistulizing Crohn’s disease HBcAb)
4 weeks depending on hepatitis B reactivation,
trough levels lymphoma (controversial), Maintenance:
Intensive dosing psoriasis, melanoma Skin check yearly
for hospitalized and nonmelanoma skin Influenza, Pneumovax 23, and
corticosteroid-refractory cancers, drug-induced Prevnar 13 vaccinations
patients lupus
Hepatitis B vaccine if not immune
Contraindicated in
multiple sclerosis, class
III/IV congestive heart
failure
Adalimumab 160 mg day 0, 80 mg day Moderate to severe As above Injection site reactions As above
14 and then 40 mg every Crohn’s disease and (better with citrate-free
14 days; may increase ulcerative colitis. preparation)
to 40 mg every 7 days Fistulizing Crohn’s disease
depending on trough
levels
Certolizumab 400 mg on days 0 and 14, Moderate to severe As above As above As above
then 400 mg every 28 days Crohn’s disease
Golimumab 200 mg on day 0, 100 mg Moderate to severe As above As above As above
on day 14, then 100 mg ulcerative colitis
every 28 days
Vedolizumab 300 mg at 0, 2, and 6 Moderate to severe No increased risk of Nasopharyngitis, Prior to infusion:
weeks, then every 8 ulcerative colitis serious systemic or headache, arthralgias, TB testing

CHAPTER 326 Inflammatory Bowel Disease

weeks; may increase (more effective than opportunistic infections nausea
dose to 300 mg every 4 adalimumab as first-line hepatitis B testing (HBsAb, HBsAg,
No increased risk of HBcAb)
weeks therapy in one study) malignancy
Maintenance:
Influenza, Pneumovax 23, and
Prevnar 13 vaccinations
Hepatitis B vaccine if not immune
Natalizumab 300 mg IV every 4 weeks Moderate to severe Progressive multifocal Headache, fatigue, Prior to infusion:
Crohn’s disease (not to be leukoencephalopathy infusions reactions, Anti-JCV antibody, TB testing
used in combination with (monitor anti-JCV urinary tract infections,
other immunosuppressive antibodies every 6 months arthralgia, pain in Hepatitis B testing (HBsAb, HBsAg,
medications) and stop if positive) extremity, rash, HBcAb)
gastroenteritis, vaginitis Maintenance:
Influenza, Pneumovax 23, and
Prevnar 13 vaccinations
Hepatitis B vaccine if not immune
Ustekinumab 6 mg/kg IV, then 90 mg Moderate to severe Reversible posterior Nasopharyngitis, upper Prior to infusion:
every 8 weeks; may Crohn’s disease and leukoencephalopathy respiratory tract infection, TB testing
increase dose to 90 mg ulcerative colitis syndrome (presents fatigue, headache
every 4 weeks with headaches, Hepatitis B testing (HBsAb, HBsAg,
seizures, confusion, and HBcAb)
visual disturbances), Maintenance:
anaphylaxis, and Influenza, Pneumovax 23, and
angioedema Prevnar 13 vaccinations
Hepatitis B vaccine if not immune
Tofacitinib 10 mg bid; can decrease Moderate to severe Increased risk of heart Elevated lipids, Prior to infusion:
to 5 mg bid when patient ulcerative colitis attack, stroke, cancer, neutropenia, anemia, First dose of Shingrix recommended,
in remission blood clots, and death in elevated liver enzymes TB testing
patients with ulcerative
colitis and rheumatoid Hepatitis B testing (HBsAb, HBsAg,
arthritis Patients who are HBcAb)
at risk for cardiovascular Maintenance:
disease, are current or Influenza, Pneumovax 23, and
past smokers and/or are Prevnar 13 vaccinations
over the age of 50 should Hepatitis B vaccine if not immune
consider alternative
therapies.
Increased risk of viral
infections, including
herpes zoster, and
bacterial and invasive
fungal infections

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 2488

Tofacitinib
Cyclosporine IV
Biologic +/–
MP/AZA/MTX
Tofacitinib
Prednisone oral (induction
of remission only)
Biologic +/– MP/AZA/MTX
Hydrocortisone rectal
Hydrocortisone or Solumedrol IV
Budesonide rectal and/or oral (induction of remission only)

Biologic +/–
5-ASA oral and/or rectal MP/AZA/MTX Prednisone oral (induction of remission only)

Mild to Moderate Ulcerative Colitis Moderate to Severe Ulcerative Colitis

Prednisone oral (induction of
remission only)

Total Sulfasalazine (colon) Total

parenteral parenteral
nutrition nutrition and
and bowel rest bowel rest
Budesonide (ileal and right colon)

Biologic +/– MP/AZA/MTX

Mild to Moderate Crohn’s Disease
Biologic +/– MP/AZA/MTX

Hydrocortisone or Solumedrol IV
(induction of remission only)

Abscess drainage and antibiotics

Prednisone oral (induction of remission only)
PART 10

Moderate to Severe Crohn’s Disease Fistulizing Crohn’s Disease

FIGURE 326-12 Medical management of inflammatory bowel disease. 5-ASA, 5-aminosalicylic acid; CD, Crohn’s disease; UC, ulcerative colitis.

strictured area of intestine is incised longitudinally and the incision from the use of a temporary loop ileostomy to resection of segments
Disorders of the Gastrointestinal System

sutured transversely, thus widening the narrowed area. Complica- of diseased colon or even the entire colon and rectum. For patients
tions of strictureplasty include prolonged ileus, hemorrhage, fistula, with segmental involvement, segmental colon resection with pri-
abscess, leak, and restricture. mary anastomosis can be performed. In 20–25% of patients with
Risk factors for early recurrence of disease include cigarette extensive colitis, the rectum is spared sufficiently to consider rectal
smoking, penetrating disease (internal fistulas, abscesses, or other preservation. Most surgeons believe that an IPAA is contraindicated
evidence of penetration through the wall of the bowel), early recur- in CD due to the high incidence of pouch failure. A diverting colos-
rence since a previous surgery, multiple surgeries, and a young age tomy may help heal severe perianal disease or rectovaginal fistulas,
at the time of the first surgery. Aggressive postoperative treatment but disease almost always recurs with reanastomosis. These patients
with biologics should be considered for this group of patients. It is often require a total proctocolectomy and ileostomy.
also recommended to evaluate for endoscopic recurrence of CD via
a colonoscopy, if possible, 3–6 months after surgery. ■■IBD AND PREGNANCY
Colorectal Disease A greater percentage of patients with Patients with quiescent UC and CD have normal fertility rates; the
Crohn’s colitis require surgery for intractability, fulminant disease, fallopian tubes can be scarred by the inflammatory process of CD,
and anorectal disease. Several alternatives are available, ranging especially on the right side because of the proximity of the terminal
ileum. In addition, perirectal, perineal, and rectovaginal abscesses and
TABLE 326-10 Indications for Surgery fistulas as well as pelvic surgery can result in dyspareunia. Infertility
in men can be caused by sulfasalazine but reverses when treatment is
ULCERATIVE COLITIS CROHN’S DISEASE
stopped. Women with an IPAA have decreased fertility due to scarring
Intractable disease Small Intestine or occlusion of the fallopian tubes secondary to pelvic inflammation
Fulminant disease Stricture and obstruction and adhesions, although studies have shown that fertility is improved
Toxic megacolon unresponsive to medical therapy with laparoscopic versus open IPAA.
Colonic perforation Massive hemorrhage Mild or quiescent UC or CD has no effect on birth outcomes. The
Massive colonic hemorrhage Refractory fistula courses of CD and UC during pregnancy mostly correlate with disease
activity at the time of conception. Patients should be in remission for
Extracolonic disease Abscess
6 months before conceiving. Most CD patients can deliver vaginally, but
Colonic obstruction Colon and rectum cesarean delivery may be the preferred route of delivery for patients with
Colon cancer prophylaxis Intractable disease anorectal and perirectal abscesses and fistulas to reduce the likelihood
Colon dysplasia or cancer Fulminant disease of fistulas developing or extending into the episiotomy scar. Unless they
 Perianal disease unresponsive to medical desire multiple children, UC patients with an IPAA may consider a
therapy cesarean delivery due to an increased risk of future fecal incontinence.
Refractory fistula Sulfasalazine and all mesalamines are safe for use in pregnancy
Colonic obstruction and nursing with the caveat that additional folate supplementation
Cancer prophylaxis
must be given with sulfasalazine. Topical 5-ASA agents are safe during
pregnancy and nursing. Glucocorticoids are generally safe for use dur-
Colon dysplasia or cancer
ing pregnancy and are indicated for patients with moderate to severe

HPIM21e_Part10_p2381-p2670.indd 2488 20/01/22 10:04 PM

 disease activity. The amount of glucocorticoids received by the nursing about 1.5 to 2 times higher than in the general population, and colono- 2489
infant is minimal. The safest antibiotics to use for CD in pregnancy for scopic surveillance is the standard of care.
short periods of time (weeks, not months) are ampicillin and cephalo- Annual or biennial colonoscopy with multiple biopsies is recom-
sporins. Metronidazole can be used in the second or third trimester. mended for patients with >8–10 years of extensive colitis (greater than
Ciprofloxacin causes cartilage lesions in immature animals and should one-third of the colon involved) or 12–15 years of proctosigmoiditis
be avoided because of the absence of data on its effects on growth and (less than one-third but more than just the rectum) and has been widely
development in humans. used to screen and survey for subsequent dysplasia and carcinoma.
MP and azathioprine pose minimal or no risk during pregnancy. International guideline societies have recommended chromoendos-
Breast milk has been shown to contain negligible levels of MP/ copy for dysplasia surveillance in IBD. Chromoendoscopy enhances
azathioprine when measured in a limited number of patients. the visualization of the surface and pit pattern of the mucosa, as well as
MTX is teratogenic and should be discontinued at least 3 months borders of lesions, in order to better define areas of dysplasia compared
before conception. to standard-definition white light endoscopy. The evidence behind
In a large prospective and multiple retrospective studies, no increased chromoendoscopy is controversial. A systematic review of randomized
risk of stillbirths, miscarriages, or spontaneous abortions was seen with controlled trials found that chromoendoscopy had a higher likelihood
infliximab, ADA, or certolizumab. Infliximab and ADA are IgG1 of detecting dysplasia compared to standard-definition white light
antibodies and are actively transported across the placenta in the late endoscopy with a relative risk of 2.12. In contrast, a retrospective study
second and third trimesters. Infants can have serum levels of infliximab found no significant difference in dysplasia detection rates between
and ADA up to 12 months of age, and live vaccines should be avoided chromoendoscopy and standard-definition white light endoscopy. In
during this time. Certolizumab crosses the placenta by passive diffu- real-life settings, the practice has been to use standard-definition white
sion, and infant serum and cord blood levels are minimal. The anti- light endoscopy with surveillance biopsies in patients with chronic
TNF drugs are relatively safe in nursing. Miniscule levels of infliximab, colitis at average risk and chromoendoscopy in higher-risk patients
ADA, and certolizumab have been reported in breast milk. These levels including those with a history of dysplasia, PSC, or family history of
are of no clinical significance. It is recommended that drugs should not colorectal cancer.
be switched during pregnancy unless necessitated by the medical con- Risk factors for cancer in UC include long-duration disease, exten-
dition of the IBD. VDZ and ustekinumab appear safe during pregnancy, sive disease, family history of colon cancer, PSC, a colon stricture, and
although the data are limited. Tofacitinib should not be used during the presence of postinflammatory pseudopolyps on colonoscopy.
pregnancy. Animal studies show teratogenic effects with tofacitinib,
and data in humans are limited. A washout period of at least 1 week is ■■CROHN’S DISEASE

CHAPTER 326 Inflammatory Bowel Disease

recommended before conception. Surgery in UC should be performed Risk factors for developing cancer in Crohn’s colitis are long-duration
only for emergency indications, including severe hemorrhage, perfo- and extensive disease, bypassed colon segments, colon strictures, PSC,
ration, and megacolon refractory to medical therapy. Total colectomy and family history of colon cancer. The cancer risks in CD and UC are
and ileostomy carry a 50% risk of postoperative spontaneous abortion. probably equivalent for similar extent and duration of disease. In the
The best time to perform surgery is in the second trimester if necessary. CESAME study, a prospective observational cohort of IBD patients
Patients with IPAAs have increased nighttime stool frequency during in France, the standardized incidence ratios of colorectal cancer were
pregnancy that resolves postpartum. Transient small-bowel obstruction 2.2 for all IBD patients (95% CI, 1.5–3.0; p < .001) and 7.0 for patients
or ileus has been noted in up to 8% of patients with ileostomies. with long-standing extensive colitis (both Crohn’s and UC) (95% CI,
4.4–10.5; p < .001). Thus, the same endoscopic surveillance strategy
used for UC is recommended for patients with chronic Crohn’s colitis.
CANCER IN IBD A pediatric colonoscope can be used to pass narrow strictures in CD
■■ULCERATIVE COLITIS patients, but surgery should be considered in symptomatic patients
Patients with long-standing UC are at increased risk for developing with impassable strictures.
colonic epithelial dysplasia and carcinoma (Fig. 326-13). ■■MANAGEMENT OF DYSPLASIA AND CANCER
The risk of neoplasia in chronic UC increases with duration and Dysplasia can be flat or polypoid. If flat high-grade dysplasia is encoun-
extent of disease. In contrast to the relatively high risk in one large tered on colonoscopic surveillance, the usual treatment is colectomy
meta-analysis (2% after 10 years, 8% after 20 years, and 18% after for UC and either colectomy or segmental resection for CD. If flat low-
30 years of disease), a decrease in the risk of colorectal cancer has been grade dysplasia is found (Fig. 326-13), most investigators recommend
noted over time potentially due to better control of inflammation and immediate colectomy. Adenomas may occur coincidently in UC and
better colonoscopic surveillance. The rates of colon cancer are still CD patients with chronic colitis and can be removed endoscopically
provided that biopsies of the surrounding mucosa are free of dysplasia.
IBD patients are also at greater risk for other malignancies. Patients
with CD may have an increased risk of NHL, leukemia, and myelodys-
plastic syndromes. Severe, chronic, complicated perianal disease in CD
patients may be associated with an increased risk of cancer in the lower
rectum and anal canal (squamous cell cancers). Although the absolute
risk of small-bowel adenocarcinoma in CD is low (2.2% at 25 years in
one study), patients with long-standing, extensive, small-bowel disease
should be considered for screening.

COVID-19 AND IBD

COVID-19, caused by SARS-CoV-2, was first reported in December
2019 and has rapidly spread throughout the world, leading to an inter-
national pandemic. Glucocorticoids, immunomodulators (thiopurines,
MTX), biologics, and JAK inhibitors, commonly used to treat IBD, are
associated with higher rates of serious viral and bacterial infections, and
FIGURE 326-13 Medium-power view of low-grade dysplasia in a patient with patients with IBD using these medications are potentially at increased
chronic ulcerative colitis. Low-grade dysplastic crypts are interspersed among risk of a serious COVID-19 infection. Yet, it is also possible that
regenerating crypts. (Courtesy of Dr. R. Odze, Division of Gastrointestinal Pathology, some forms of immune suppression may blunt the excessive immune
Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts; response/cytokine storm characteristic of severe COVID-19 infection
with permission.) and consequently reduce mortality. Using data from the Surveillance

HPIM21e_Part10_p2381-p2670.indd 2489 20/01/22 10:04 PM

 2490 Epidemiology of Coronavirus Under Research Exclusion for Inflam- TABLE 327-1 Rome IV Diagnostic Criteria for Irritable
matory Bowel Disease, it was found that increasing age (adjusted OR Bowel Syndromea
1.04; 95% CI, 1.01–1.02), two or more comorbidities (adjusted OR 2.9; Recurrent abdominal pain, on average, at least 1 day per week in the
95% CI, 1.1–7.8), and systemic glucocorticoids (adjusted OR 6.9; 95% last 3 months, associated with ≥2 of the following criteria:
CI, 2.3–20.5) are associated with severe COVID-19 in IBD patients. 1. Related to defecation
Anti-TNF treatment was not associated with severe COVID-19 2. Associated with a change in frequency of stool
(adjusted OR 0.9; 95% CI, 0.4–2.2). 3. Associated with a change in form (appearance) of stool
■■FURTHER READING a
Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to
Alexandersson B et al: High-definition chromoendoscopy superior diagnosis.
to high-definition white-light endoscopy in surveillance of inflam-
matory bowel diseases in a randomized trial. Clin Gastroenterol and genitourinary symptoms. Severity of symptoms varies and can
Hepatol 18:2101, 2020. significantly impair quality of life, resulting in high health care costs.
Ananthakrishnan A et al: Changing global epidemiology of inflam- Altered gastrointestinal (GI) motility, visceral hyperalgesia, disturbance
matory bowel disease: Sustaining health care delivery into the 21st of brain–gut interaction, abnormal central processing, autonomic and
century. Clin Gastroenterol Hepatol. 2020;18(6):1252-1260.Bella- hormonal events, genetic and environmental factors, and psychosocial
guarda E, Hanauer ST: Checkpoint-inhibitor-induced colitis. Am J disturbances are variably involved, depending on the individual. This
Gastroenterol 115:202, 2020. progress may result in improved methods of treatment.
Bernstein CM et al: Events within the first year of life, but not the
neonatal period, affect risk for later development of inflammatory ■■CLINICAL FEATURES
bowel diseases. Gastroenterology 156:2190, 2019. IBS is a disorder that affects all ages, although most patients have their
Brenner E et al: Corticosteroids, but not TNF antagonists, are first symptoms before age 45. Women are diagnosed with IBS two to
associated with adverse COVID-19 outcomes in patients with three times as often as men and make up 80% of the population with
inflammatory bowel diseases: Results from an international registry. severe IBS. As indicated in Table 327-1, pain is a key symptom for the
Gastroenterology 159:481, 2020. diagnosis of IBS. This symptom should be associated with defecation
Graham DB, Xavier RJ: Pathway paradigms revealed from the genet- and/or have its onset associated with a change in frequency or form of
ics of inflammatory bowel disease. Nature 578:527, 2020. stool. In comparison to Rome III, the Rome IV criteria are more strin-
Levine A et al: Crohn’s disease exclusion diet plus partial enteral nutri- gent, requiring abdominal pain to occur at a minimum of once a week
tion induces sustained remission in a randomized controlled trial. and eliminating “discomfort” as one of the criteria. Painless diarrhea
Gastroenterology 157:440, 2019. or constipation does not fulfill the diagnostic criteria to be classified as
PART 10

Mahadevan U et al: Pregnancy and neonatal outcomes after fetal IBS. Supportive symptoms that are not part of the diagnostic criteria
exposure to biologics and thiopurines among women with inflamma- include defecation straining, urgency or a feeling of incomplete bowel
tory bowel disease. Gastroenterology 160:1131, 2021. movement, passing mucus, and bloating.
Moller FT et al: Familial risk of inflammatory bowel disease: A
Abdominal Pain According to the current IBS diagnostic criteria,
Disorders of the Gastrointestinal System

population-based cohort study 1977-2011. Am J Gastroenterol

110:564, 2015. abdominal pain is a prerequisite clinical feature of IBS. Abdominal
Ng SC et al: Worldwide incidence and prevalence of inflamma- pain in IBS is highly variable in intensity and location. It is frequently
tory bowel disease in the 21st century: A systematic review of episodic and crampy, but it may be superimposed on a background
population-based studies. Lancet 390:2769, 2018. of constant ache. Pain may be mild enough to be ignored, or it may
Sands BE et al: UNIFI Study Group. Ustekinumab as induction and interfere with daily activities. Despite this, malnutrition due to inade-
maintenance therapy for ulcerative colitis. N Engl J Med 381:1201, quate caloric intake is exceedingly rare with IBS. Sleep deprivation is
2019. also unusual because abdominal pain is almost uniformly present only
Sands BE et al: VARSITY Study Group. Vedolizumab versus adali- during waking hours. Pain is often exacerbated by eating or emotional
mumab for moderate-to-severe ulcerative colitis. N Engl J Med stress and improved by passage of flatus or stools. In addition, female
381:1215, 2019. patients with IBS commonly report worsening symptoms during the
Singh S et al: AGA technical review on the management of moderate premenstrual and menstrual phases.
to severe ulcerative colitis. Gastroenterology 158:1465, 2020. Altered Bowel Habits Alteration in bowel habits is the most
consistent clinical feature in IBS. The most common pattern is consti-
pation alternating with diarrhea, usually with one of these symptoms
predominating. At first, constipation may be episodic, but eventually, it
becomes continuous and increasingly intractable to treatment with lax-
atives. Stools are usually hard with narrowed caliber, possibly reflect-

327 Irritable
Syndrome
Bowel ing excessive dehydration caused by prolonged colonic retention and
spasm. Most patients also experience a sense of incomplete evacuation,
thus leading to repeated attempts at defecation in a short time span.
Patients whose predominant symptom is constipation may have weeks
Chung Owyang or months of constipation interrupted with brief periods of diarrhea. In
other patients, diarrhea may be the predominant symptom. Diarrhea
resulting from IBS usually consists of small volumes of loose stools.
Most patients have stool volumes of <200 mL. Nocturnal diarrhea
Irritable bowel syndrome (IBS) is a functional bowel disorder charac- does not occur in IBS. Diarrhea may be aggravated by emotional stress
terized by abdominal pain or discomfort and altered bowel habits in or eating. Stool may be accompanied by passage of large amounts of
the absence of detectable structural abnormalities. No clear diagnostic mucus. Bleeding is not a feature of IBS unless hemorrhoids are present,
markers exist for IBS; thus, the diagnosis of the disorder is based on and malabsorption or weight loss does not occur.
clinical presentation. In 2016, the Rome III criteria for the diagnosis of Bowel pattern subtypes are highly unstable. In a patient population
IBS were updated to Rome IV (Table 327-1). Throughout the world, with ~33% prevalence rates of IBS-diarrhea predominant (IBS-D),
~10–20% of adults and adolescents have symptoms consistent with IBS. IBS-constipation predominant (IBS-C), and IBS-mixed (IBS-M) forms,
IBS symptoms tend to come and go over time and often overlap with 75% of patients change subtypes, and 29% switch between IBS-C and
other functional disorders such as fibromyalgia, headache, backache, IBS-D over 1 year.

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 Gas and Flatulence Patients with IBS frequently complain of associated with rapid colonic transit and accompanied by abdominal 2491
abdominal distention and increased belching or flatulence, all of pain.
which they attribute to increased gas. Although some patients with
these symptoms actually may have a larger amount of gas, quantitative Visceral Hypersensitivity IBS patients frequently exhibit exag-
measurements reveal that most patients who complain of increased gerated sensory responses to visceral stimulation. The frequency of
gas generate no more than a normal amount of intestinal gas. Most perceptions of food intolerance is at least twofold more common than
IBS patients have impaired transit and tolerance of intestinal gas loads. in the general population. Postprandial pain has been temporally
In addition, patients with IBS tend to reflux gas from the distal to related to entry of the food bolus into the cecum in 74% of patients.
the more proximal intestine, which may explain the belching. Some On the other hand, prolonged fasting in IBS patients is often associated
patients with bloating may also experience visible distention with with significant improvement in symptoms. Rectal balloon inflation
increase in abdominal girth. produces nonpainful and painful sensations at lower volumes in IBS
patients than in healthy controls without altering rectal tension, sugges-
Upper GI Symptoms Between 25 and 50% of patients with IBS tive of visceral afferent dysfunction in IBS. Similar studies show gastric
complain of dyspepsia, heartburn, nausea, and vomiting. This suggests and esophageal hypersensitivity in patients with nonulcer dyspepsia
that other areas of the gut apart from the colon may be involved. Pro- and noncardiac chest pain, raising the possibility that these conditions
longed ambulant recordings of small-bowel motility in patients with have a similar pathophysiologic basis. Lipids lower the thresholds for
IBS show a high incidence of abnormalities in the small bowel during the first sensation of gas, discomfort, and pain in IBS patients. Hence,
the diurnal (waking) period; nocturnal motor patterns are not different postprandial symptoms in IBS patients may be explained in part by a
from those of healthy controls. The overlap between dyspepsia and IBS nutrient-dependent exaggerated sensory component of the gastroco-
is great. The prevalence of IBS is higher among patients with dyspepsia lonic response. In contrast to enhanced gut sensitivity, IBS patients
(31.7%) than among those who reported no symptoms of dyspepsia do not exhibit heightened sensitivity elsewhere in the body. Thus, the
(7.9%). Conversely, among patients with IBS, 55.6% reported symptoms afferent pathway disturbances in IBS appear to be selective for vis-
of dyspepsia. In addition, the functional abdominal symptoms can ceral innervation with sparing of somatic pathways. The mechanisms
change over time. Those with predominant dyspepsia or IBS can flux responsible for visceral hypersensitivity are still under investigation.
between the two. Thus, it is conceivable that functional dyspepsia and
IBS are two manifestations of a single, more extensive digestive system Central Neural Dysregulation The role of central nervous sys-
disorder. Furthermore, IBS symptoms are prevalent in noncardiac chest tem (CNS) factors in the pathogenesis of IBS is strongly suggested by
pain patients, suggesting overlap with other functional gut disorders. the clinical association of emotional disorders and stress with symptom
exacerbation and the therapeutic response to therapies that act on cere-

CHAPTER 327 Irritable Bowel Syndrome

■■PATHOPHYSIOLOGY bral cortical sites. Functional brain imaging studies such as magnetic
The pathogenesis of IBS is poorly understood, although roles of resonance imaging (MRI) have shown that in response to distal colonic
abnormal gut motor and sensory activity, central neural dysfunction, stimulation, the mid-cingulate cortex—a brain region concerned with
psychological disturbances, mucosal inflammation, stress, and luminal attention processes and response selection—shows greater activation
factors such as bile acid malabsorption and gut dysbiosis have been in IBS patients. Modulation of this region is associated with changes
proposed (Fig. 327-1). in the subjective unpleasantness of pain. In addition, IBS patients also
show preferential activation of the prefrontal lobe, which contains a
GI Motor Abnormalities Studies of colonic myoelectrical and vigilance network within the brain that increases alertness. These may
motor activity under unstimulated conditions have not shown consis- represent a form of cerebral dysfunction, leading to the increased per-
tent abnormalities in IBS. In contrast, colonic motor abnormalities are ception of visceral pain.
more prominent under stimulated conditions in IBS. IBS patients may
exhibit increased rectosigmoid motor activity for up to 3 h after eating. Abnormal Psychological Features Abnormal psychiatric fea-
Similarly, inflation of rectal balloons both in IBS-D and IBS-C patients tures are recorded in up to 80% of IBS patients, especially in referral
leads to marked and prolonged distention-evoked contractile activ- centers; however, no single psychiatric diagnosis predominates. Most
ity. Recordings from the transverse, descending, and sigmoid colon of these patients demonstrated exaggerated symptoms in response to
showed that the motility index and peak amplitude of high-amplitude visceral distention, and this abnormality persists even after exclusion
propagating contractions (HAPCs) in diarrhea-prone IBS patients of psychological factors.
were greatly increased compared to those in healthy subjects and were Psychological factors influence pain thresholds in IBS patients, as
stress alters sensory thresholds. An association between
prior sexual or physical abuse and development of IBS
has been reported. Clinical studies suggest that IBS has
Motility “Leaky” gut a strong developmental component that involves interac-
abnormalities dysbiosis Visceral tions of genetic and epigenetic factors early in life. These
hypersensitivity may modulate brain networks related to emotional arousal
Brain–gut and/or central autonomic control, salience, and soma-
interactions tosensory integration. Abuse is associated with greater
• HPA axis pain reporting, psychological distress, and poor health
• Autonomic IBS outcome. Brain functional MRI studies show greater acti-
dysfunction Psychological vation of the posterior and middle dorsal cingulate cortex,
• Anxiety/panic which is implicated in affect processing in IBS patients
Bile acid
Genetic factors • Depression with a past history of sexual abuse.
• Twin studies • Somatization
malabsorption • SERT polymorphisms Postinfectious IBS A GI infection may predispose
a patient to IBS. In an investigation of 544 patients with
FIGURE 327-1 Pathophysiology of irritable bowel syndrome (IBS). The cause of IBS is likely to be confirmed bacterial gastroenteritis, one-quarter devel-
multifactorial. Patients often show evidence of visceral hypersensitivity and motility abnormalities. oped IBS subsequently. Conversely, about a third of IBS
Many IBS patients have increased anxiety and/or depression, and their symptoms are often patients experienced an acute “gastroenteritis-like” illness
exacerbated by mental or physical stress, suggesting abnormal brain–gut interaction. Genetic
studies suggest a few IBS patients may have genetic abnormalities affecting the serotonin
at the onset of their chronic IBS symptomatology. This
transport system in the enteric nerves. Up to 30% of IBS patients may have bile acid malabsorption. group of “postinfective” IBS occurs more commonly in
Gut dysbiosis and impaired mucosa permeability also have been reported in many IBS patients. females and affects younger rather than older patients.
This may lead to subclinical mucosa inflammation. Risk factors for developing postinfectious IBS include, in

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 2492 order of importance, prolonged duration of initial illness, toxicity of IBS vs Controls
infecting bacterial strain, smoking, mucosal markers of inflammation, Healthy controls IBS
female sex, depression, hypochondriasis, and adverse life events in the Lactobacillaceae
preceding 3 months. Age older than 60 years might protect against
Bacteroides
postinfectious IBS, whereas treatment with antibiotics has been associ-
ated with increased risk. The microbes involved in the initial infection Enterobacteriaceae
are Campylobacter, Salmonella, and Shigella. Increased rectal mucosal
enteroendocrine cells, T lymphocytes, and gut permeability are acute
changes following Campylobacter enteritis that could persist for more
than a year and may contribute to postinfective IBS. Bifidobacterium
Faecalibacterium
Immune Activation and Mucosal Inflammation Some
patients with IBS display persistent signs of low-grade mucosal inflam-
FIGURE 327-2 Changes in gut microbiota among patients with irritable bowel
mation with activated lymphocytes, mast cells, and enhanced expres- syndrome. (Adapted from R Pittayanon et al: Gastroenterology 157:97, 2019.)
sion of proinflammatory cytokines. Other studies also indicate that
peripheral blood mononuclear cells (PBMCs) from IBS patients show (phylum Proteobacteria), family Lactobacillaceae, and genus Bacte-
abnormal release of proinflammatory cytokines such as interleukin roides (phylum Bacteroidetes) (Fig. 327-2). Many members of the
(IL) 6, IL-1β, and tumor necrosis factor (TNF). These abnormalities genus Faecalibacterium are butyrate-producing and anti-inflammatory
may contribute to abnormal epithelial secretion and visceral hyper- organisms and may reduce IBS symptoms via mediation of IL-17
sensitivity. Located at the host-environment interface, mast cells are in expression. Similarly, members of the genus Bifidobacterium are also
close proximity to sensory nerves. Electromicroscopic evidence of mast anti-inflammatory organisms and may reduce mucosal inflammation
cell activation is commonly observed in the colonic mucosa of IBS in IBS patients in clinical trials. On the other hand, the three groups
patients. Recent studies show that the proximity of activated mast cells of bacteria that were increased were potentially harmful commensal
to submucosal nerve fibers correlates with the frequency and severity microbiota. The gram-negative Enterobacteriaceae family is capable
of abdominal pain in patients with IBS. Other studies report that the of injuring epithelium lining and inducing mucosal inflammation
colonic mucosa of IBS patients releases increased amounts of mast via a lipopolysaccharide-dependent pathway. Members of the genus
cell mediators, including histamine, proteases, and prostaglandin E2. Bacteroides such as Bacteroides fragilis produces toxin to dissolve gly-
These findings, together with the observation that marked excitation of coproteins and induce mucosal inflammation. Lastly, in the family of
visceral sensory nerves innervating the colon occurs after exposure to Lactobacillaceae, Lactobacillus can produce gas and organic acids from
IBS mucosal supernatant, support a prominent role for mast cells in the glucose and fructose fermentation, resulting in bloating and abdominal
PART 10

pathogenesis of visceral hypersensitivity. Increasing evidence suggests pain. It is conceivable that gut dysbiosis acting in concert with genetic
that some members of the superfamily of transient receptor potential susceptibility and environmental insults may alter mucosal permeabil-
(TRP) cation channels such as TRPV1 (vanilloid) channels are central ity and increase antigen presentation to the immune cells in the lamina
to the initiation and persistence of visceral hypersensitivity. Mucosal propria. This may result in mast cell activation and altered enteric neu-
Disorders of the Gastrointestinal System

inflammation can lead to increased expression of TRPV1 in the enteric ronal and smooth-muscle function causing IBS symptoms. In addition,
nervous system. Enhanced expression of TRPV1 channels in the sen- release of cytokines and chemokines from mucosal inflammation may
sory neurons of the gut has been observed in IBS, and such expression generate extra-GI symptoms such as chronic fatigue, muscle pain, and
appears to correlate with visceral hypersensitivity and abdominal pain. anxiety (Fig. 327-3).
Interestingly, clinical studies have also shown increased intestinal per- Abnormal Serotonin Pathways The serotonin-containing
meability in patients with IBS-D. Psychological stress and anxiety can enterochromaffin cells in the colon are increased in a subset of IBS-D
increase the release of proinflammatory cytokine, and this in turn may patients compared to healthy individuals or patients with ulcerative
alter intestinal permeability. A clinical study showed that 39% of IBS-D colitis. Furthermore, postprandial plasma serotonin levels were signifi-
patients had increased intestinal permeability as measured by the cantly higher in this group of patients compared to healthy controls.
lactulose/mannitol ratio. These IBS patients also demonstrated a Tryptophan hydroxylase 1 (TPH1) is the rate-limiting enzyme in
higher Functional Bowel Disorder Severity Index (FBDSI) score and enterochromaffin cell serotonin biosynthesis, and functional TPH1
increased hypersensitivity to visceral nociceptive pain stimuli. This polymorphism has been shown to be associated with IBS habit sub-
provides a functional link among psychological stress, immune activa- types. In addition, gut microbes promote colonic serotonin production
tion, and symptom generation in patients with IBS. through an effect of short-chain fatty acids on enterochromaffin cells.
Altered Gut Flora A high prevalence of small-intestinal bacterial In IBS patients, the expression of mucosal serotonin reuptake trans-
overgrowth in IBS patients has been noted based on positive lactulose porter (SERT) is downregulated due to gram negative gut dysbiosis.
hydrogen breath test. This finding, however, has been challenged by a Thus, gut and reuptake dysbiosis in IBS may contribute to abnormal
number of other studies that found no increased incidence of bacterial serotonin synthesis in this disorder. Because serotonin plays an impor-
overgrowth based on jejunal aspirate culture. Abnormal H2 breath tant role in the regulation of GI motility and visceral perception, the
test can occur because of small-bowel rapid transit and may lead to increased release of serotonin may contribute to the postprandial
erroneous interpretation. Hence, the role of testing for small-intestinal symptoms of these patients and provides a rationale for the use of sero-
bacterial overgrowth in IBS patients remains unclear. tonin antagonists in the treatment of this disorder.
Studies using culture-independent approaches such as 16S rRNA
gene-based analysis found significant differences between the molec- APPROACH TO THE PATIENT
ular profile of the fecal microbiota of IBS patients and that of healthy
subjects. A review of 24 studies involving 827 IBS patients showed Irritable Bowel Syndrome
extensive variability in bacterial flora among IBS patients and healthy
subjects. However, a few general observations were made: (1) an Because IBS is a disorder for which no pathognomonic abnor-
increase in the ratio of fecal Firmicutes to fecal Bacteroidetes was malities have been identified, its diagnosis relies on recognition of
noted in IBS; (2) the diversity of the microbiota was decreased; and positive clinical features and elimination of other organic diseases.
(3) these changes were accompanied by an increase in instability of the Symptom-based criteria have been developed for the purpose of
bacteria flora in IBS. Despite a lack of consensus on the exact microbial differentiating patients with IBS from those with organic diseases.
difference between IBS patients and controls, IBS patients generally These include the Manning, Rome I, Rome II, Rome III, and Rome
had decreased proportions of the genera Bifidobacterium and Faecal- IV criteria. Rome IV criteria for the diagnosis of IBS were published
ibacterium and increased abundance of family Enterobacteriaceae in 2016 (Table 327-1) and defined IBS on the basis of abdominal

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 2493
-Dysbiosis
-Genetic Increased
Altered Mast cell
susceptibility antigen
permeability activation
-Environmental presentation
insults

Altered
enteric
Systemic
Extra-GI neuronal &
symptoms
cytokines IBS smooth
& chemokines
muscle
function

FIGURE 327-3 Gut dysbiosis and irritable bowel syndrome (IBS). Gut dysbiosis acting in concert with genetic and environmental factors may alter intestinal permeability
and increase antigen presentation, resulting in mast cell activation. Products of mast cell degranulation may alter neuronal and smooth-muscle function causing IBS
symptoms. The cytokines and chemokines generated from mucosal inflammation may cause symptoms such as fibromyalgia, chronic fatigue, and mood changes. GI,
gastrointestinal. (Adapted from NJ Talley, AA Fodor: Gastroenterology 141:1555, 2011.)

pain and altered bowel habits that occur with sufficient frequency the aggressiveness of the diagnostic evaluation. These include the
in affected patients. A careful history and physical examination duration of symptoms, the change in symptoms over time, the
are frequently helpful in establishing the diagnosis. Clinical fea- age and sex of the patient, the referral status of the patient, prior
tures suggestive of IBS include recurrence of lower abdominal diagnostic studies, a family history of colorectal malignancy, and
pain with altered bowel habits over a period of time without the degree of psychosocial dysfunction. Thus, a younger individual
progressive deterioration, onset of symptoms during periods of with mild symptoms requires a minimal diagnostic evaluation,

CHAPTER 327 Irritable Bowel Syndrome

stress or emotional upset, absence of other systemic symptoms while an older person or an individual with rapidly progressive
such as fever and weight loss, and small-volume stool without any symptoms should undergo a more thorough exclusion of organic
evidence of blood. disease. Most patients should have a complete blood count and
On the other hand, the appearance of the disorder for the first sigmoidoscopic examination; in addition, stool specimens should
time in old age, progressive course from time of onset, persistent be examined for ova and parasites in those who have diarrhea. In
diarrhea after a 48-h fast, and presence of nocturnal diarrhea or patients with persistent diarrhea not responding to simple anti-
steatorrheal stools argue against the diagnosis of IBS. diarrheal agents, a sigmoid colon biopsy should be performed to
Because the major symptoms of IBS—abdominal pain, abdominal rule out microscopic colitis. In those age >40 years, an air-contrast
bloating, and alteration in bowel habits—are common complaints barium enema or colonoscopy should also be performed. If the
of many GI organic disorders, the list of differential diagnoses is a main symptoms are diarrhea and increased gas, the possibility of
long one. The quality, location, and timing of pain may be helpful lactase deficiency should be ruled out with a hydrogen breath test
to suggest specific disorders. Pain due to IBS that occurs in the or with evaluation after a 3-week lactose-free diet. Excessive gas
epigastric or periumbilical area must be differentiated from bil- with bloating also raises the possibility of small-bowel bacteria
iary tract disease, peptic ulcer disorders, intestinal ischemia, and overgrowth and should be ruled out with a glucose hydrogen breath
carcinoma of the stomach and pancreas. If pain occurs mainly in test. Some patients with IBS-D may have undiagnosed celiac sprue.
the lower abdomen, the possibility of diverticular disease of the Because the symptoms of celiac sprue respond to a gluten-free diet,
colon, inflammatory bowel disease (including ulcerative colitis and testing for celiac sprue in IBS may prevent years of morbidity and
Crohn’s disease), and carcinoma of the colon must be considered. attendant expense. Decision-analysis studies show that serology
Postprandial pain accompanied by bloating, nausea, and vomiting testing for celiac sprue in patients with IBS-D has an acceptable
suggests gastroparesis or partial intestinal obstruction. Patients with cost when the prevalence of celiac sprue is >1% and is the dominant
small intestinal bacteria overgrowth can present with abdominal strategy when the prevalence is >8%. In patients with concurrent
pain, nausea, and bloating, and this possibility should be ruled symptoms of dyspepsia, upper GI radiographs or esophagogastro-
out before making a diagnosis of IBS. Intestinal infestation with duodenoscopy may be advisable. In patients with postprandial right
Giardia lamblia or other parasites may cause similar symptoms. upper quadrant pain, an ultrasonogram of the gallbladder should
When diarrhea is the major complaint, the possibility of lactase be obtained. Laboratory features that argue against IBS include
deficiency, laxative abuse, malabsorption, celiac sprue, hyperthy- evidence of anemia, elevated sedimentation rate, presence of leu-
roidism, inflammatory bowel disease, and infectious diarrhea must kocytes or blood in stool, and stool volume >200–300 mL/d. These
be ruled out. On the other hand, constipation may be a side effect findings would necessitate other diagnostic considerations.
of many different drugs, such as anticholinergic, antihypertensive,
and antidepressant medications. Endocrinopathies such as hypo-
thyroidism and hypoparathyroidism must also be considered in the TREATMENT
differential diagnosis of constipation. In addition, acute intermit- Irritable Bowel Syndrome
tent porphyria and lead poisoning may present in a fashion similar
to IBS, with painful constipation as the major complaint. These PATIENT COUNSELING AND DIETARY ALTERATIONS
possibilities are suspected on the basis of their clinical presentations Reassurance and careful explanation of the functional nature of
and are confirmed by appropriate serum and urine tests. the disorder and of how to avoid obvious food precipitants are
Few tests are required for patients who have typical IBS symp- important first steps in patient counseling and dietary change.
toms and no alarm features. Unnecessary investigations may be Occasionally, a meticulous dietary history may reveal substances
costly and even harmful. The American Gastroenterological Asso- (such as coffee, disaccharides, legumes, and cabbage) that aggravate
ciation has delineated factors to be considered when determining symptoms. Excessive fructose and artificial sweeteners, such as

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 2494
TABLE 327-2 Some Common Food Sources of FODMAPs
GALACTO-
FOOD TYPE FREE FRUCTOSE LACTOSE FRUCTANS OLIGOSACCHARIDES POLYOLS
Fruits Apple, cherry, mango, Peach, persimmon, Apple, apricot, pear,
pear, watermelon watermelon avocado, blackberries,
cherry, nectarine, plum,
prune
Vegetables Asparagus, artichokes, Artichokes, beetroot, Brussels Cauliflower, mushroom,
sugar snap peas sprout, chicory, fennel, garlic, snow peas
leek, onion, peas
Grains and cereals Wheat, rye, barley
Nuts and seeds Pistachios
Milk and milk products Milk, yogurt, ice
cream, custard, soft
cheeses
Legumes Legumes, lentils, chickpeas Legumes, chickpeas,
lentils
Other Honey, high-fructose corn Chicory drinks
syrup
Food additives Inulin, FOS Sorbitol, mannitol,
maltitol, xylitol, isomalt
Abbreviations: FODMAPs, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols; FOS, fructo-oligosaccharides.
Source: Reproduced with permission from PR Gibson et al: Food choice as a key management strategy for functional gastrointestinal symptoms. Am J Gastroenterol 107:657, 2012.

sorbitol or mannitol, may cause diarrhea, bloating, cramping, or of anticholinergic drugs for pain. Physiologic studies demonstrate
flatulence. As a therapeutic trial, patients should be encouraged to that anticholinergic drugs inhibit the gastrocolic reflex; hence,
eliminate any foodstuffs that appear to produce symptoms. How- postprandial pain is best managed by giving antispasmodics
ever, patients should avoid nutritionally depleted diets. A diet low in 30 min before meals so that effective blood levels are achieved
fermentable oligosaccharides, disaccharides, monosaccharides, and shortly before the anticipated onset of pain. Most anticholinergics
PART 10

polyols (FODMAPs) (Table 327-2) has been shown to be helpful in contain natural belladonna alkaloids, which may cause xerostomia,
IBS patients (see “Low FODMAP Diet”). urinary hesitancy and retention, blurred vision, and drowsiness.
STOOL-BULKING AGENTS They should be used in the elderly with caution. Some physicians
prefer to use synthetic anticholinergics such as dicyclomine that
High-fiber diets and bulking agents, such as bran or hydrophilic
Disorders of the Gastrointestinal System

have less effect on mucous membrane secretion and produce fewer

colloid, are frequently used in treating IBS. The water-holding undesirable side effects. Peppermint oil appears to reduce abdom-
action of fibers may contribute to increased stool bulk because of inal cramps by some undefined mechanism. In a meta-analysis of
the ability of fiber to increase fecal output of bacteria. Fiber also nine double-blind randomized controlled trials evaluating 726 IBS
speeds up colonic transit in most people. In diarrhea-prone patients, patients, peppermint oil was found to be significantly superior to
whole-colonic transit is faster than average; however, dietary fiber placebo for global improvement of IBS symptoms and reduction in
can also delay transit. Furthermore, because of their hydrophilic abdominal pain. The most commonly reported adverse event was
properties, stool-bulking agents bind water and thus prevent both heartburn, which was mild and transient.
excessive hydration and dehydration of stool. The latter observation
may explain the clinical experience that a high-fiber diet relieves ANTIDIARRHEAL AGENTS
diarrhea in some IBS patients. Fiber supplementation with psyllium Peripherally acting opiate-based agents are the initial therapy of
has been shown to reduce perception of rectal distention, indicating choice for IBS-D. Physiologic studies demonstrate increases in
that fiber may have a positive effect on visceral afferent function. segmenting colonic contractions, delays in fecal transit, increases
Controlled trials of dietary fiber in IBS patients have produced in anal pressures, and reductions in rectal perception with these
variable results. This is not surprising since IBS is a heterogeneous drugs. When diarrhea is severe, especially in the painless diarrhea
disorder, with some patients being constipated and other having variant of IBS, small doses of loperamide, 2–4 mg every 4–6 h up
predominant diarrhea. Most investigations report increases in stool to a maximum of 12 mg/d, can be prescribed. These agents are less
weight, decreases in colonic transit times, and improvement in addictive than paregoric, codeine, or tincture of opium. In general,
constipation. Others have noted benefits in patients with alter- the intestines do not become tolerant of the antidiarrheal effect of
nating diarrhea and constipation, pain, and bloating. However, opiates, and increasing doses are not required to maintain antidiar-
most studies observe no response in patients with diarrhea- or rheal potency. These agents are most useful if taken before antici-
pain-predominant IBS. Compared to insoluble dietary fiber such pated stressful events that are known to cause diarrhea. However,
as wheat bran, soluble fibers such as psyllium preparations tend not infrequently, a high dose of loperamide may cause cramping
to produce less bloating and distention. Fiber should be started at because of increases in segmenting colonic contractions. Another
a nominal dose and slowly titrated up as tolerated over the course antidiarrheal agent that may be used in IBS patients is the bile acid
of several weeks to a targeted dose of 20–30 g of total dietary and binder cholestyramine resin because up to 30% of IBS-D patients
supplementary fiber per day. Even when used judiciously, fiber can may have bile acid malabsorption.
exacerbate bloating, flatulence, constipation, and diarrhea. Patients ANTIDEPRESSANT DRUGS
with drug-induced or slow colonic transit constipation usually do
not respond to fiber supplementation. In addition to their mood-elevating effects, antidepressant med-
ications have several physiologic effects that suggest they may be
ANTISPASMODICS beneficial in IBS. In IBS-D patients, the tricyclic antidepressant imi-
Clinicians have observed that anticholinergic drugs may provide pramine slows jejunal migrating motor complex transit propagation
temporary relief for symptoms such as painful cramps related to and delays orocecal and whole-gut transit, indicative of a motor
intestinal spasm. Although controlled clinical trials have produced inhibitory effect. Some studies also suggest that tricyclic agents may
mixed results, evidence generally supports the beneficial effects alter visceral afferent neural function.

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 A number of studies indicate that tricyclic antidepressants may and transporters secrete sodium into the intestine to maintain elec- 2495
be effective in some IBS patients. When stratified according to the troneutrality, followed by the secretion of water. Lubiprostone is a
predominant symptoms, improvements were observed in IBS-D bicyclic fatty acid derived from prostaglandin E1 that activates type
patients, with no improvement being noted in IBS-C patients. The 3 chloride channels in the apical membrane of intestinal epithelial
beneficial effects of the tricyclic compounds in the treatment of IBS cells. Oral lubiprostone was effective in the treatment of patients
appear to be independent of their effects on depression. The thera- with IBS-C in large phase 3, randomized, double-blind, placebo-
peutic benefits for the bowel symptoms occur faster and at a lower controlled multicenter trials. The recommended daily dose is
dosage. The efficacy of antidepressant agents from other chemical 24 mg twice daily. In general, the drug is quite well tolerated. The
classes in the management of IBS is less well evaluated. In contrast major side effects are nausea and diarrhea. Linaclotide and ple-
to tricyclic agents, the selective serotonin reuptake inhibitor (SSRI) canatide are minimally absorbed 14-amino-acid peptide guanylate
paroxetine accelerates orocecal transit, raising the possibility that cyclase-C (GC-C) agonists that bind to and activate GC-C on the
this drug class may be useful in IBS-C patients. The SSRI citalopram luminal surface of intestinal epithelium. The subsequent increase in
blunts perception of rectal distention and reduces the magnitude of cyclic guanosine monophosphate activates the cyclic fibrosis trans-
the gastrocolonic response in healthy volunteers. A small placebo- membrane regulator and induces fluid secretion into the GI tract.
controlled study of citalopram in IBS patients reported reductions These drugs are similar to endogenous peptides secreted by the
in pain. However, these findings could not be confirmed in another small intestine (uroguanylin) or colon (guanylin). In two 12-week,
randomized controlled trial. Hence, the efficacy of SSRIs in the double-blind, randomized, controlled trials, linaclotide (290 or 145 μg,
treatment of IBS needs further confirmation. once daily) reduced constipation and pain. A lower dose (72 μg
ANTIFLATULENCE THERAPY once daily) was also more effective than placebo. Linaclotide has
been approved by the FDA for treatment of constipation in IBS-C
The management of excessive gas is seldom satisfactory, except patients. Plecanatide (3- and 6-mg doses) also has been shown to
when there is obvious aerophagia or disaccharidase deficiency. be more effective than placebo in two phase 3 trials. The 3-mg
Patients should be advised to eat slowly and not chew gum or drink once-daily dose has been approved by the FDA. The only significant
carbonated beverages. Bloating may decrease if an associated gut side effect was diarrhea, which occurred in <5% of patients. Lina-
syndrome such as IBS or constipation is improved. If bloating is clotide and plecanatide are of similar efficacy and tolerability for
accompanied by diarrhea and worsens after ingesting dairy prod- the treatment of chronic constipation. Tenapanor, a small-molecule
ucts, fresh fruits, vegetables, or juices, further investigation or a inhibitor of GI sodium-hydrogen exchange-3, has been shown to
dietary exclusion trial may be worthwhile. Avoiding flatogenic be more effective than placebo when given at 50 mg twice daily in

CHAPTER 327 Irritable Bowel Syndrome

foods, exercising, losing excess weight, and taking activated char- patients with IBS-C.
coal are safe but unproven remedies. A low FODMAP diet has been
shown to be quite effective to reduce gas and bloating (see “Low OSMOTIC LAXATIVES
FODMAP Diet”). Data regarding the use of surfactants such as sim- Osmotic agents such as magnesium citrate–based products, sodium
ethicone are conflicting. Antibiotics may help in a subgroup of IBS phosphate–based products, and nonabsorbable carbohydrates are
patients with predominant symptoms of bloating. Beano, an over- hypertonic products that, through osmosis, extract fluid into the
the-counter oral β-glycosidase solution, may reduce rectal passage intestinal lumen to soften stool and enhance colonic transit. In
of gas without decreasing bloating and pain. Pancreatic enzymes contrast, polyethylene glycol (PEG)–based solution is iso-osmotic
reduce bloating, gas, and fullness during and after high-calorie, and induces bowel movement by high-volume lavage. The osmotic
high-fat meal ingestion. laxatives were better than placebo in improving symptoms of
SEROTONIN RECEPTOR MODULATORS chronic constipation in clinical trials. However, chronic use of
magnesium hydroxide may result in severe hypermagnesemia in
Serotonin 5-HT3 and 5-HT4 receptors are found throughout the GI
patients with renal impairment. Frequent sodium phosphate–based
tract. Prucalopride, a dihydrobenzo-furancarboxamide derivative,
is a new selective agonist of 5-HT4. In six of seven multicenter, bowel cleansing should be avoided as this is associated with hyper-
phosphatasemia, hypocalcemia, and hypokalemia. In 19 trials,
double-blind, randomized trials of prucalopride in patients with
PEG consistently induced more bowel movements than placebo.
chronic constipation, the drug was more effective that placebo. The
A Cochrane review of 10 randomized trials showed that PEG was
most frequently encountered side effects were headache, nausea,
superior to lactulose for improving stool frequency and abdomi-
and diarrhea, which were mostly transient. Unlike with the older
nal pain. Among the nonabsorbable carbohydrates, lactulose and
5-HT4 agonist tegaserod, there were no significant cardiovascular
sorbitol had similar laxative effects. However, bacterial metabolism
side effects. Prucalopride was approved by the European Medicines
of unabsorbed carbohydrates often leads to gas production and
Agency and the U.S. Food and Drug Administration (FDA) for
abdominal pain, which can limit long-term use.
treatment of chronic constipation.
Another 5-HT4 receptor agonist, tegaserod, also exhibits prok- MODULATION OF GUT FLORA
inetic activity by stimulating peristalsis. Clinical studies involving Because altered colonic flora (gut dysbiosis) may contribute to the
>4000 IBS-C patients reported reduction in abdominal discomfort pathogenesis of IBS, this has led to great interest in using antibiot-
and improvements in constipation and bloating compared to pla- ics, prebiotics, probiotics, and dietary measures to treat IBS.
cebo. Diarrhea is the only major side effect. In 2007, the drug was
voluntarily withdrawn from the market after a greater number of Antibiotics Antibiotic treatment benefits a subset of IBS patients.
cardiovascular complications were observed in a database of 18,000 In a double-blind, randomized, placebo-controlled study, neomycin
patients receiving tegaserod (0.11 vs 0.01% in placebo). In 2019, the dosed at 500 mg twice daily for 10 days was more effective than
FDA reviewed additional data and approved the use of tegaserod placebo at improving symptom scores among IBS patients. The
in women younger than 65 years old who do not have a history of nonabsorbed oral antibiotic rifaximin is the most thoroughly stud-
ischemic cardiovascular disease and who have no more than one ied antibiotic for the treatment of IBS. In a double-blind, placebo-
risk factor for cardiovascular disease. controlled study, patients receiving rifaximin at a dose of 550 mg
two times daily for 2 weeks experienced substantial improvement
SECRETAGOGUES of global IBS symptoms over placebo. Rifaximin is the only antibi-
Lubiprostone, linaclotide, and plecanatide are secretagogues that otic with demonstrated sustained benefit beyond therapy cessation
stimulate net efflux of ions and water into the intestinal lumen and in IBS patients. The drug has a favorable safety and tolerability
thus enhance transit and facilitate ease of defecation. By activating profile compared with systemic antibiotics. A systemic review and
channels on the apical (luminal) enterocyte surface, these secret- meta-analysis of five studies of IBS patients found that rifaximin
agogues increase intestinal chloride secretion. Other ion channels is more effective than placebo for global symptoms and bloating

HPIM21e_Part10_p2381-p2670.indd 2495 20/01/22 10:04 PM

 2496 (odds ratio 1.57), with a number needed to treat (NNT) of 10.2. TABLE 327-3 Spectrum of Severity in IBS
The modest therapeutic gain was similar to that yielded by other
MILD MODERATE SEVERE
currently available therapies for IBS. However, currently, there are
still insufficient data to recommend routine use of this antibiotic in Clinical Features
the treatment of IBS. Prevalence 70% 25% 5%
Prebiotics These are nondigestible food ingredients that stimu- Correlations with gut physiology +++ ++ +
late growth and/or activity of bacteria in the GI tract. There have Symptoms constant 0 + +++
been four randomized trials to examine the effects of prebiotics. Psychosocial difficulties 0 + +++
Three of the four studies reported that prebiotics worsened or did Health care issues + ++ +++
not improve IBS symptoms. This is not surprising given the adverse Practice type Primary Specialty Referral
effects of a high-carbohydrate diet on IBS symptoms.
Probiotics These are defined as live microorganisms that when diet, the identification of patients who are more likely to respond
administered in adequate amounts confer a health benefit on the to a low FODMAP diet at baseline would be highly beneficial. In a
host. A meta-analysis of 10 probiotic studies in IBS patients found small clinical study comparing responders to a low FODMAP diet
significant relief of pain and bloating with the use of Bifidobacte- to nonresponders, fecal volatile organic acid profiling at baseline
rium breve, Bifidobacterium longum, and Lactobacillus acidophilus accurately predicted response in 97% of cases. This finding needs
species compared to placebo. However, there was no change in stool to be confirmed by large prospective cohort studies.
frequency or consistency. Large-scale studies of well-phenotyped
IBS patients are needed to establish the efficacy of these probiotics. SUMMARY
Low FODMAP Diet A diet rich in FODMAP (fermentable oligo- The treatment strategy of IBS depends on the severity of the
saccharides, disaccharides, monosaccharides, and polyols) often disorder (Table 327-3). Most IBS patients have mild symptoms.
triggers symptoms in IBS patients. FODMAPs are poorly absorbed They are usually cared for in primary care practices, have little
by the small intestine and fermented by bacteria in the colon to or no psychosocial difficulties, and do not seek health care often.
produce gas and osmotically active carbohydrates (Fig. 327-4). Treatment usually involves education, reassurance, and dietary/
At the same time, on entering the colon, FODMAPs may serve lifestyle changes. A smaller portion have moderate symptoms that
as nutrients for the colonic bacteria and promote the growth of are usually intermittent and correlate with altered gut physiology,
gram-negative commensal bacteria, which may induce epithe- e.g., worsened with eating or stress and relieved by defecation.
lial damage and subclinical mucosa inflammation. Fructose and For IBS-D patients, treatments include gut-acting pharmacologic
agents such as antispasmodics, antidiarrheals, bile acid binders,
PART 10

fructans induce IBS symptoms in a dose-dependent manner. In

contrast, a low FODMAP diet reduces IBS symptoms. A systemic and the newer gut serotonin modulators (Table 327-4). In IBS-C
review and meta-analysis of seven studies of IBS patients found patients, increased fiber intake and the use of osmotic agents
that a low FODMAP diet was associated with reduced global symp- such as polyethylene glycol may achieve satisfactory results. For
toms compared with control interventions. These studies showed patients with more severe constipation, a chloride channel opener
Disorders of the Gastrointestinal System

symptomatic benefit of restricting FODMAPs in 50–80% of patients (lubiprostone) or GC-C agonist (linaclotide or plecanatide) may be
with IBS. There is increasing support for recommending a low considered. For IBS patients with predominant gas and bloating, a
FODMAP diet as first-line treatment for IBS patients. Given that low-FODMAP diet may provide significant relief. Some patients
between 20 and 50% of patients do not respond to a low FODMAP
TABLE 327-4 Possible Drugs for a Dominant Symptom in IBS
SYMPTOM DRUG DOSE
Small poorly absorbed carbohydrates Diarrhea Loperamide 2–4 mg when necessary/
maximum 12 g/d
Cholestyramine resin 4 g with meals
Food source for Alosetrona 0.5–1 mg bid (for severe IBS,
Laxative effect
bacteria women)
Constipation Psyllium husk 3–4 g bid with meals, then adjust
Methylcellulose 2 g bid with meals, then adjust
Water in intestines Gas production Calcium polycarbophil 1 g qd to qid
Lactulose syrup 10–20 g bid
70% sorbitol 15 mL bid
Polyethylene glycol 3350 17 g in 250 mL water qd
Lubiprostone (Amitiza) 24 mg bid
Abdominal Magnesium hydroxide 30–60 mL qd
distention Linaclotide (Plecanatide) 290 μg qd/3 mg qd
Prucalopride 2 mg qd
Abdominal pain Smooth-muscle relaxant qd to qid ac
Tricyclic antidepressants Start 25–50 mg hs, then adjust
Selective serotonin Begin small dose, increase as
Bloating, abdominal discomfort, flatulence, diarrhea reuptake inhibitors needed
Gas and bloating Low FODMAP diet
FIGURE 327-4 Pathogenesis of FODMAP-related symptoms. FODMAPs are poorly Probiotics qd
absorbed by the small intestine and fermented by gut bacteria to produce gas and Rifaximin 550 mg bid
osmotically active carbohydrates. These events act in concert to cause bloating,
flatulence, and diarrhea. FODMAPs may also serve as nutrients for colonic bacteria,
a
Available only in the United States.
which may induce mucosa inflammation. FODMAP, fermentable oligosaccharides, Abbreviation: FODMAP, fermentable oligosaccharides, disaccharides,
disaccharides, monosaccharides, and polyols. (Figure created using data from monosaccharides, and polyols; IBS, irritable bowel syndrome.
http://www.nutritiontoyou.com/wp-content/uploads/2014/06/IBS-symptoms.png.) Source: Reproduced with permission from GF Longstreth et al: Functional bowel
disorders. Gastroenterology 130:1480, 2006.

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 may benefit from probiotics and rifaximin treatment. A small 2497
proportion of IBS patients have severe and refractory symptoms,
are usually seen in referral centers, and frequently have constant
pain and psychosocial difficulties. This group of patients is best
managed with antidepressants and other psychological treatments
(Table 327-4). Clinical trials demonstrating success of a low FOD-
MAP diet in improving IBS symptoms and quality of life provide
strong evidence supporting the use of this dietary approach in the
treatment of IBS. These observations, if confirmed, may lead to the
use of the low FODMAP diet as the first line of treatment of IBS
patients with moderate to severe symptoms.

■■FURTHER READING
Bharucha AE, Lacy BE: Mechanisms, evaluation, and management
of chronic constipation. Gastroenterology 158:1232, 2020.
Dionne J et al: A systematic review and meta-anaylsis evaluating the
efficacy of a gluten-free diet and a low FODMAP diet in treating
symptoms of irritable bowel syndrome. Am J Gastroenterol 113:1290,
2018.
Drossman DA: Functional gastrointestinal disorders: History,
pathophysiology, clinical features, and Rome IV. Gastroenterology
150:1262, 2016.
Mayer EA et al: Brain-gut microbiome interactions and functional
bowel disorders. Gastroenterology 146:1500; 2014.
Pittayanon R et al: Gut microbiota in patients with irritable bowel
syndrome: A systematic review. Gastroenterology 157:97, 2019.
Zhou SY et al: FODMAP diet modulates visceral nociception by
lipopolysaccharide-mediated intestinal barrier dysfunction and

CHAPTER 328 Diverticular Disease and Common Anorectal Disorders

intestinal inflammation. J Clin Invest 128:267, 2018.

328 Diverticular Disease

and Common Anorectal
Disorders
Susan L. Gearhart
FIGURE 328-1 Gross and microscopic view of sigmoid diverticular disease. Arrows
mark an inflamed diverticulum with the diverticular wall made up only of mucosa.
■■DIVERTICULAR DISEASE
Incidence and Epidemiology In the United States, diverticu- diverticulum most commonly affecting the colon is the pseudodiver-
losis affects one-third of the population aged >60 years, and in most ticulum. The diverticula occur at the point where the nutrient artery,
instances, there are no associated symptoms. However, 10–25% of or vasa recta, penetrates through the muscularis propria, resulting in a
individuals with diverticulosis will develop acute diverticular disease. break in the integrity of the colonic wall. This anatomic restriction may
In addition, 10–25% of individuals with diverticular disease will expe- be a result of the relative high-pressure zone within the muscular sig-
rience recurrent symptoms, and up to 10% will develop complications moid colon. Thus, higher-amplitude contractions combined with con-
leading to surgery. Diverticular disease has become the fifth most costly stipated, high-fat-content stool within the sigmoid lumen in an area of
gastrointestinal disorder in the United States and is the leading indica- weakness in the colonic wall result in the creation of these diverticula.
tion for elective colon resection. The incidence of diverticular disease is Consequently, the vasa recta is either compressed or eroded, leading to
on the rise, especially among individuals <40 years of age. The major- either perforation or bleeding.
ity of patients with diverticular disease report a lower health-related Diverticula commonly affect the left and sigmoid colon; the rectum
quality of life and more depression as compared to matched controls, is always spared. However, in Asian populations, 70% of diverticula are
thus adding to health care costs. Formerly, diverticular disease was seen in the right colon and cecum as well. Yamanda et al. found right-
confined to developed countries; however, with the adoption of west- sided colonic diverticulosis in 22% of Japanese patients undergoing
ernized diets in underdeveloped countries, diverticulosis is on the rise colonoscopy. Diverticulitis is inflammation of a diverticulum. Previous
across the globe. Immigrants to the United States develop diverticular understanding of the pathogenesis of diverticulosis attributed a low-
disease at the same rate as U.S. natives. Although the prevalence among fiber diet as the sole culprit, and onset of diverticulitis would occur
females and males is similar, males tend to present at a younger age. acutely when these diverticula become obstructed. However, evidence
now suggests that the pathogenesis is more complex and multifactorial.
Anatomy and Pathophysiology Two types of diverticula occur Better understanding of the gut microbiota suggests that dysbiosis is
in the intestine: true and false (or pseudodiverticula). A true diverticu- an important aspect of disease. Chronic low-grade inflammation is
lum is a saclike herniation of the entire bowel wall, whereas a pseudo- thought to play a key role in neuronal degeneration, leading to dys-
diverticulum involves only a protrusion of the mucosa and submucosa motility and high intraluminal pressure. As a consequence, pockets or
through the muscularis propria of the colon (Fig. 328-1). The type of outpouchings develop in the colonic wall where it is weakest.

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 2498 Presentation, Evaluation, and Management of Diverticular
Bleeding Hemorrhage from a colonic diverticulum is the most
common cause of hematochezia in patients >60 years, yet only 20% of
patients with diverticulosis will have gastrointestinal bleeding. Patients
at increased risk for bleeding tend to be hypertensive, have athero- Abscess
sclerosis, and regularly use antithrombotic therapy and nonsteroidal
anti-inflammatory agents. Additional risk factors include obesity and
a history of diabetes mellitus. Most bleeds are self-limited and stop
spontaneously with bowel rest. The lifetime risk of rebleeding is 25%.
Initial localization of diverticular bleeding may include colonoscopy, I II
multiplanar computed tomography (CT) angiogram, or nuclear med-
icine tagged red cell scan. If the patient is stable, ongoing bleeding is
best managed by angiography. If mesenteric angiography can localize
the bleeding site, the vessel can be occluded successfully with a coil in
80% of cases. The patient can then be followed closely with repetitive
colonoscopy, if necessary, looking for evidence of colonic ischemia.
However, with highly selective coil embolization, the rate of colonic Feces
ischemia is <10%, and the risk of acute rebleeding is <25%. Long-term
results (40 months) indicate that >50% of patients with acute diverticu-
lar bleeds treated with highly selective angiography have had definitive
treatment. Alternatively, colonoscopic ligation with banding or place-
ment of a detachable snare has been shown in a recent meta-analysis
to be an effective way to obtain hemostasis if the bleeding site can III IV
be localized. Ligation has been shown to prevent rebleeding or the
requirement of emergent surgery. In the event that these measures FIGURE 328-2 Hinchey classification of diverticulitis. Stage I: Perforated
diverticulitis with a confined paracolic abscess. Stage II: Perforated diverticulitis
fail to achieve hemostasis, a segmental resection of the colon may be that has closed spontaneously with distant abscess formation. Stage III:
undertaken. This may be advantageous in patients on chronic antico- Noncommunicating perforated diverticulitis with fecal peritonitis (the diverticular
agulation and immunosuppression as delayed bleeding and perforation neck is closed off, and therefore, contrast will not freely expel on radiographic
have been reported in this subpopulation. images). Stage IV: Perforation and free communication with the peritoneum,
PART 10

If the patient is unstable or has had a 6-unit bleed within 24 h, resulting in fecal peritonitis.
current recommendations are that surgery should be performed. If the
bleeding has been localized, a segmental resection can be performed. If material or fluid. In up to 20% of patients, an abdominal abscess may
the site of bleeding has not been definitively identified, a subtotal colec- be present. Symptoms of irritable bowel syndrome (Chap. 327) may
tomy may be required. In patients without severe comorbidities, surgi- mimic those of diverticulitis. Therefore, suspected diverticulitis that
Disorders of the Gastrointestinal System

cal resection can be performed with a primary anastomosis. A higher does not meet CT criteria or is not associated with a leukocytosis
anastomotic leak rate has been reported in patients who received or fever is not diverticular disease. Other conditions that can mimic
>10 units of blood. diverticular disease include an ovarian cyst, endometriosis, acute
appendicitis, and pelvic inflammatory disease.
Presentation, Evaluation, and Staging of Diverticulitis Although the benefit of colonoscopy in the evaluation of patients
Acute uncomplicated diverticulitis (also known as symptomatic with diverticular disease has been called into question, its use is still
uncomplicated diverticular disease [SUDD]) characteristically presents considered important in the exclusion of colorectal cancer. The parallel
with fever, anorexia, left lower quadrant abdominal pain, and obstipa- epidemiology of colorectal cancer and diverticular disease provides
tion (Table 328-1). In <25% of cases, patients may present with gener- enough concern for an endoscopic evaluation before operative man-
alized peritonitis indicating the presence of a diverticular perforation. agement. Therefore, a colonoscopy should be performed ~6 weeks after
If a pericolonic abscess has formed, the patient may have abdominal an attack of diverticular disease.
distention and signs of localized peritonitis. Laboratory investigations Complicated diverticular disease is defined as diverticular disease
will demonstrate a leukocytosis. Rarely, a patient may present with associated with an abscess or perforation and less commonly with a
an air-fluid level in the left lower quadrant on plain abdominal film. fistula (Table 328-1). Perforated diverticular disease is staged using the
This is a giant diverticulum of the sigmoid colon and is managed with Hinchey classification system (Fig. 328-2). This staging system was
resection to avoid impending perforation. developed to predict outcomes following the surgical management of
The diagnosis of diverticulitis is best made on a contrast-enhanced complicated diverticular disease. In recent years, the Hinchey staging
abdominal and pelvic CT scan demonstrating the following findings: system has been modified to include the development of a phlegmon
sigmoid diverticula, thickened colonic wall >4 mm, and inflamma- or early abscess (Hinchey stage Ia). A pericolic abscess is then consid-
tion within the pericolic fat with or without the collection of contrast ered Hinchey stage Ib. In complicated diverticular disease with fistula
formation, common locations include cutaneous, vaginal, or vesicle
fistulas. These conditions present with either passage of stool through
TABLE 328-1 Presentation of Diverticular Disease the skin or vagina or the presence of air in the urinary stream (pneu-
Uncomplicated Diverticular Disease—75% maturia). Colovaginal fistulas are more common in women who have
Abdominal pain undergone a hysterectomy.
Fever
Leukocytosis TREATMENT
Anorexia/obstipation Diverticular Disease
Complicated Diverticular Disease—25%
Abscess 16%
MEDICAL MANAGEMENT
Perforation 10% Asymptomatic diverticular disease discovered on imaging studies
or at the time of colonoscopy is best managed by lifestyle changes.
Stricture 5%
Although the data regarding dietary risks and symptomatic diver-
Fistula 2% ticular disease are limited (Table 328-2), patients may benefit from

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 TABLE 328-2 The Use of Fiber in the Management of Diverticular Disease (DD) 2499
JOURNAL, STUDY YEAR PATIENTS (N) INTERVENTION STUDY LENGTH FINDINGS
Lancet, 1977 18 Wheat or bran crisp bread 3 months Significant reduction of symptoms score
BMJ, 1981 58 Bran, ispaghula, placebo 16 weeks No difference
J Gastroenterol, 1977 30 Methylcellulose 3 months Significant reduction in symptoms
BMJ, 2011 47,033 Vegetarian vs nonvegetarian 11.6 years Vegetarians had a 31% lower risk of DD
Gastroenterology, 2012 2104 Fiber consumption 12 years Fiber associated with great risk of DD
JAMA, 2008 47,288 Nut, corn, popcorn 18 years Higher nut, corn, and popcorn had lower risk of
consumption recurrence
Ann R Coll Surg Engl, 1985 56 Fiber consumption 66 months Higher fiber associated with 19% reduction in symptom
recurrence
Source: Modified from A Turis et al: Review article: The pathophysiology and medical management of diverticulosis and diverticular disease of the colon. Aliment Parmacol
Ther 42:664, 2015.

a fiber-enriched diet that includes 30 g of fiber each day. Supple- cessation and weight loss. Diverticular disease is now considered a
mentary fiber products such as Metamucil, Fibercon, or Citrucel functional bowel disorder associated with low-grade inflammation.
are useful. The use of fiber decreases colonic transit time and, The use of anti-inflammatory medications (mesalazine) in ran-
therefore, prevents increased intraluminal pressure leading to the domized clinical trials has shown them to be beneficial at reducing
development of diverticulosis. The incidence of complicated diver- symptoms and disease recurrence in patients with SUDD. However,
ticular disease appears to also be increased in patients who smoke when objective signs of inflammation such as C-reactive protein
and are obese. Therefore, patients should be encouraged to refrain and computerized imaging are taken into consideration, no benefit
from smoking and to join a weight loss program. The historical for the use of mesalazine has been shown.
recommendation to avoid eating nuts is based on no more than Treatment strategies targeting dysbiosis in diverticular disease
anecdotal data. have also been evaluated using polymerase chain reaction (PCR) on
SUDD with confirmation of inflammation and infection within stool specimens. Stool samples from consumers of a high-fiber diet
the colon should be treated initially with bowel rest. The routine use have different bacterial content than stool samples from consumers
of antibiotics in uncomplicated diverticular disease does not reduce of a low-fiber, high-fat diet. Probiotics are increasingly used by

CHAPTER 328 Diverticular Disease and Common Anorectal Disorders

time to symptom resolution or risk of complications or recurrence. gastroenterologists for multiple bowel disorders and may prevent
There is ample evidence establishing the safety of treating SUDD recurrence of diverticulitis. Specifically, probiotics containing Lac-
without antibiotics. The AVOD trial randomly assigned 623 inpa- tobacillus acidophilus and Bifidobacterium strains may be beneficial;
tients with CT-confirmed uncomplicated left-sided diverticulitis to however, a recent systematic review was unable to show any benefit
receive intravenous fluids alone or intravenous fluids and antibiot- to the use of probiotics alone. The addition of fiber or mesalazine
ics and found no differences between the treatment groups in terms with probiotics has been shown to maintain remission. Rifaximin
of time to recovery, the development of complicated diverticular (a poorly absorbed broad-spectrum antibiotic), when compared
disease, and recurrence. The DIABOLO trial from the Dutch Diver- to fiber alone for the treatment of SUDD, is associated with 30%
ticular Disease Collaborative Study Group compared the efficacy less frequent recurrent symptoms from uncomplicated diverticular
of treating patients with their first episode of sigmoid diverticulitis disease.
with antibiotics or outpatient observation. A total of 528 patients
with CT-proven uncomplicated diverticulitis were randomized to SURGICAL MANAGEMENT
either a 10-day course of amoxicillin/clavulanic acid or observation Preoperative risk factors influencing postoperative mortality rates
in an outpatient setting. This study demonstrated that antibiotics include higher American Society of Anesthesiologists (ASA) phys-
made no difference in symptom duration or management, and the ical status class (Table 328-3) and preexisting organ failure. In
results favored observation over antibiotic therapy for uncompli- patients who are low risk (ASA P1 and P2), surgical therapy can be
cated diverticulitis (SUDD). Currently, the practice guidelines of offered to those who do not rapidly improve on medical therapy.
the American Society of Colon and Rectal Surgery state that “selected For uncomplicated diverticular disease, medical therapy can be
patients with uncomplicated diverticulitis can be treated without continued beyond two attacks without an increased risk of perfora-
antibiotics.” Hospitalization for acute diverticulitis is recommended if tion requiring a colostomy. However, patients on immunosuppres-
the patient is unable to take oral therapy, is affected by several comor- sive therapy, in chronic renal failure, or with a collagen-vascular
bidities, fails to improve with outpatient therapy, or has complicated disease have a fivefold greater risk of perforation during recurrent
diverticulitis. Nearly 75% of patients hospitalized for acute divertic- attacks. A multicentered randomized clinical trial (DIRECT trial)
ulitis will respond to nonoperative treatment with a suitable antimi- comparing surgery with conservative management for recurrent
crobial regimen. The current recommended antimicrobial coverage is SUDD demonstrated that elective surgical resection was associated
a third-generation cephalosporin or ciprofloxacin and metronidazole with an improved quality of life and was more cost-effective at
targeting aerobic gram-negative rods and anaerobic bacteria. Unfor- 5 years following resection as compared to conservative manage-
tunately, these agents do not cover enterococci, and the addition of ment. Surgical therapy is indicated in all low-surgical-risk patients
ampicillin to this regimen for nonresponders is recommended. Alter- with complicated diverticular disease.
natively, single-agent therapy with a third-generation penicillin such The goals of surgical management of diverticular disease include
as IV piperacillin or oral penicillin/clavulanic acid may be effective. controlling sepsis, eliminating complications such as fistula or
The usual course of antibiotics is 7–10 days, although this length of obstruction, removing the diseased colonic segment, and restoring
time is being investigated. Patients should remain on a limited diet intestinal continuity. These goals must be obtained while minimiz-
until their pain resolves. ing morbidity rate, length of hospitalization, and cost in addition to
Once the acute attack has resolved, the mainstay medical man- maximizing survival and quality of life. Table 328-4 lists the opera-
agement of diverticular disease to prevent symptoms has evolved. tions most commonly indicated based on the Hinchey classification
The risk of recurrent hospitalization following an episode of acute and the predicted postoperative outcomes. The current options
diverticular disease is 11%. Established risk factors for symptom- for uncomplicated diverticular disease include an open or a lap-
atic recurrence include younger age, the formation of a divertic- aroscopic resection of the diseased area with reanastomosis to the
ular abscess, more frequent attacks (>2 per year), multimorbidity, rectosigmoid. Preservation of portions of the sigmoid colon may
obesity, and smoking. Prevention strategies may include smoking lead to early recurrence of the disease. The benefits of laparoscopic

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 2500
TABLE 328-3 American Society of Anesthesiologists Physical Status
Classification System
P1 A normal healthy patient
P2 A patient with mild systemic disease
P3 A patient with severe systemic disease
P4 A patient with severe systemic disease that is a constant
threat to life
P5 A moribund patient who is not expected to survive without the
operation
P6 A declared brain-dead patient whose organs are being removed for
donor purposes

resection over open surgical techniques include early discharge (by

at least 1 day), less narcotic use, less postoperative complications,
and an earlier return to work.
The options for the surgical management of complicated diver-
ticular disease (Fig. 328-3) include the following open or laparo-
scopic procedures: (1) proximal diversion of the fecal stream with
an ileostomy or colostomy and sutured omental patch with drain-
age, (2) resection with colostomy and mucous fistula or closure of
distal bowel with formation of a Hartmann’s pouch (Hartmann’s
procedure), (3) resection with anastomosis (coloproctostomy), or
(4) resection with anastomosis and diversion (coloproctostomy
with loop ileostomy or colostomy). (5) Laparoscopic technique of
washout and drainage without diversion has been described for
Hinchey III patients; however, a threefold increased risk of recur- FIGURE 328-3 Methods of surgical management of complicated diverticular
rent peritonitis requiring reoperation with washout alone has been disease. 1. Drainage, omental pedicle graft, and proximal diversion. 2. Hartmann’s
procedure. 3. Sigmoid resection with coloproctostomy. 4. Sigmoid resection with
reported.
PART 10

coloproctostomy and proximal diversion.

Patients with Hinchey stage Ia are managed with antibiotic ther-
apy only followed by resection with anastomosis at 6 weeks. Patients
with Hinchey stages Ib and II disease are managed with percu- More than 80% of patients with distant abscesses (Hinchey stage II)
taneous drainage followed by resection with anastomosis about required surgical resection for recurrent symptoms.
Disorders of the Gastrointestinal System

6 weeks later. Current guidelines put forth by the American Society The management of Hinchey stage III disease is under debate.
of Colon and Rectal Surgeons suggest, in addition to antibiotic In this population of patients, no fecal peritonitis is present, and it
therapy, CT-guided percutaneous drainage of diverticular abscesses is presumed that the perforation has sealed. Historically, Hinchey
that are >3 cm and have a well-defined wall. Abscesses that are stage III has been managed with a Hartmann’s procedure or with
<5 cm may resolve with antibiotic therapy alone. Contraindications primary anastomosis and proximal diversion. Several studies have
to percutaneous drainage are no percutaneous access route, pneu- examined short- and long-term outcomes for laparoscopic peri-
moperitoneum, and fecal peritonitis. Drainage of a diverticular toneal lavage to remove the peritoneal contamination and place
abscess is associated with a 20–25% failure rate. Urgent opera- drainage catheters should a communication to the bowel still exist.
tive intervention is undertaken if percutaneous drainage fails and However, this procedure has been associated with an increased risk
patients develop generalized peritonitis, and most will need to be of requiring reoperation for ongoing peritonitis. Overall, ostomy
managed with a Hartmann’s procedure (resection of the sigmoid rates are lower with the use of laparoscopic peritoneal lavage. No
colon with end colostomy and rectal stump). In selected cases, non- anastomosis of any type should be attempted in Hinchey stage IV
operative therapy may be considered. In one nonrandomized study, disease or in the presence of fecal peritonitis. A limited approach to
nonoperative management of isolated paracolic abscesses (Hinchey these patients is associated with a decreased mortality rate.
stage I) was associated with only a 20% recurrence rate at 2 years.

TABLE 328-4 Outcome Following Surgical Therapy for Complicated Diverticular Disease Based on Modified Hinchey Staging
HINCHEY STAGE OPERATIVE PROCEDURE ANASTOMOTIC LEAK RATE, % OVERALL MORBIDITY RATE, %
Ia (pericolic phlegmon) Laparoscopic or open colon resection 43 15
Ib (pericolic abscess) Percutaneous drainage followed by laparoscopic or 3 15
open colon resection
II Percutaneous drainage followed by laparoscopic 3 15
or open colon resection +/− proximal diversion with
an ostomy
III Laparoscopic washout and drainage 3 30% risk of peritonitis requiring reoperation if
or no resection is performed.
Laparoscopic or open resection with proximal diversion Overall morbidity 50%
(ostomy) Overall mortality 15%
or
Hartmann’s procedure
IV Hartmann’s procedure — Overall morbidity 50%
or Overall mortality 15%
Washout with proximal diversion

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 Recurrent Symptoms Recurrent abdominal symptoms following 2501
surgical resection for diverticular disease occur in 10% of patients.
Recurrent diverticular disease develops in patients following inade-
quate surgical resection. A retained segment of diseased rectosigmoid
colon is associated with twice the incidence of recurrence. The pres-
ence of irritable bowel syndrome may also cause recurrence of initial
symptoms. Patients undergoing surgical resection for presumed diver-
ticulitis and symptoms of chronic abdominal cramping and irregular
loose bowel movements consistent with irritable bowel syndrome have
poorer functional outcomes.

COMMON DISEASES OF THE ANORECTUM

■■RECTAL PROLAPSE (PROCIDENTIA) A C
Incidence and Epidemiology Rectal prolapse is six times more
common in women than in men. The incidence of rectal prolapse
peaks in women >60 years. Women with rectal prolapse have a higher
incidence of associated pelvic floor disorders including urinary incon-
tinence, rectocele, cystocele, and enterocele. About 20% of children
with rectal prolapse will have cystic fibrosis. All children presenting
with prolapse should undergo a sweat chloride test. Less common
associations include Ehlers-Danlos syndrome, solitary rectal ulcer syn-
drome, congenital hypothyroidism, Hirschsprung’s disease, dementia,
cognitively impaired, and schizophrenia.
Anatomy and Pathophysiology Rectal prolapse (procidentia) is
a circumferential, full-thickness protrusion of the rectal wall through
the anal orifice. It is often associated with a redundant sigmoid colon, B D

CHAPTER 328 Diverticular Disease and Common Anorectal Disorders

pelvic laxity, and a deep rectovaginal septum (pouch of Douglas). FIGURE 328-4 Degrees of rectal prolapse. Mucosal prolapse only (A, B, sagittal
Initially, rectal prolapse was felt to be the result of early internal rectal view). Full-thickness prolapse associated with redundant rectosigmoid and deep
intussusception, which occurs in the upper to mid rectum. This was pouch of Douglas (C, D, sagittal view).
considered to be the first step in an inevitable progression to full-thick-
markers on abdominal x-ray 5 days after swallowing. For patients with
ness external prolapse. However, only 1 of 38 patients with internal
fecal incontinence, endoanal ultrasound and manometric evaluation,
prolapse followed for >5 years developed full-thickness prolapse. Oth-
including pudendal nerve testing of their anal sphincter muscles, may
ers have suggested that full-thickness prolapse is the result of damage
be performed before surgery for prolapse (see “Fecal Incontinence,”
to the nerve supply to the pelvic floor muscles or pudendal nerves from
below).
repeated stretching with straining to defecate. Damage to the pudendal
nerves would weaken the pelvic floor muscles, including the external
anal sphincter muscles. Bilateral pudendal nerve injury is more signifi- TREATMENT
cantly associated with prolapse and incontinence than unilateral injury.
Rectal Prolapse
Presentation and Evaluation In external prolapse, the majority
of patient complaints include anal mass, bleeding per rectum, and poor The medical approach to the management of rectal prolapse is
perianal hygiene. Prolapse of the rectum usually occurs following def- limited and includes stool-bulking agents or fiber supplementation
ecation and will spontaneously reduce or require the patient to manu- to ease the process of evacuation. Surgical correction of rectal
ally reduce the prolapse. Constipation occurs in ~30–67% of patients prolapse is the mainstay of therapy. Two approaches are commonly
with rectal prolapse. Differing degrees of fecal incontinence occur in considered: transabdominal and transperineal. Transabdominal
50–70% of patients. Patients with internal rectal prolapse will present approaches have been associated with lower recurrence rates, but
with symptoms of both constipation and incontinence. Other asso- some patients with significant comorbidities are better served by a
ciated findings include outlet obstruction (anismus) in 30%, colonic transperineal approach.
inertia in 10%, and solitary rectal ulcer syndrome in 12%. Common transperineal approaches include a transanal proctec-
Office evaluation is best performed after the patient has been given tomy (Altmeier procedure), mucosal proctectomy (Delorme proce-
an enema, which enables the prolapse to protrude. An important dure), or placement of a Tirsch wire encircling the anus. The goal
distinction should be made between full-thickness rectal prolapse of the transperineal approach is to remove the redundant rectosig-
and isolated mucosal prolapse associated with hemorrhoidal disease moid colon. Common transabdominal approaches include presa-
(Fig. 328-4). Mucosal prolapse is known for radial grooves rather than cral suture or mesh rectopexy (Ripstein) with (Frykman-Goldberg)
circumferential folds around the anus and is due to increased laxity or without resection of the redundant sigmoid. Colon resection,
of the connective tissue between the submucosa and underlying mus- in general, is reserved for patients with constipation and outlet
cle of the anal canal. The evaluation of prolapse should also include obstruction. Ventral rectopexy is an effective method of abdomi-
cystoproctography and colonoscopy. These examinations evaluate nal repair of full-thickness prolapse that does not require sigmoid
for associated pelvic floor disorders and rule out a malignancy or a resection (see description below). This repair may have improved
polyp as the lead point for prolapse. If rectal prolapse is associated functional results over other abdominal repairs. Transabdominal
with chronic constipation, the patient should undergo a defecating procedures can be performed effectively with laparoscopic and,
proctogram and a sitzmark study. This will evaluate for the presence more recently, robotic techniques without increased incidence of
of anismus or colonic inertia. Anismus is the result of attempting to recurrence. The goal of the transabdominal approach is to restore
defecate against a closed pelvic floor and is also known as nonrelaxing normal anatomy by removing redundant bowel and reattaching the
puborectalis. This can be seen when straightening of the rectum fails supportive tissue of the rectum to the presacral fascia. The final
to occur on fluoroscopy while the patient is attempting to defecate. In alternative is abdominal proctectomy with end-sigmoid colos-
colonic inertia, a sitzmark study will demonstrate retention of >20% of tomy. If total colonic inertia is present, as defined by a history of

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 2502

FIGURE 328-5 Stapled transanal rectal resection. Schematic of placement of the

circular stapling device.

constipation and a positive sitzmark study, a subtotal colectomy

with an ileosigmoid or rectal anastomosis may be required at the
time of rectopexy.
Previously, the presence of internal rectal prolapse identified
on imaging studies has been considered a nonsurgical disorder, FIGURE 328-6 Laparoscopic ventral rectopexy (LVR). To reduce the internal prolapse
and biofeedback was recommended. However, only one-third of
PART 10

and close any rectovaginal septal defect, the pouch of Douglas is opened and mesh
patients will have successful resolution of symptoms from biofeed- is secured to the anterolateral rectum, vaginal fornix, and sacrum. (Reproduced
back. Two surgical procedures more effective than biofeedback are with permission from A D’Hoore et al: Long-term outcome of laparoscopic ventral
the stapled transanal rectal resection (STARR) and the laparoscopic rectopexy for total rectal prolapse. B J S 91:1500, 2004.)
ventral rectopexy (LVR). The STARR procedure (Fig. 328-5) is is therefore not under voluntary control. The external anal sphincter
Disorders of the Gastrointestinal System

performed through the anus in patients with internal prolapse. A is formed in continuation with the levator ani muscles and is under
circular stapling device is inserted through the anus; the internal voluntary control. The pudendal nerve supplies motor innervation to
prolapse is identified and ligated with the stapling device. LVR the external anal sphincter. Obstetric injury may result in tearing of
(Fig. 328-6) is performed through an abdominal approach. An the muscle fibers anteriorly at the time of the delivery. This results in
opening in the peritoneum is created on the left side of the recto- an obvious anterior defect on endoanal ultrasound. Injury may also be
sigmoid junction, and this opening continues down anterior on the the result of stretching of the pudendal nerves during pregnancy or
rectum into the pouch of Douglas. No rectal mobilization is per- delivery of the fetus through the birth canal.
formed, thus avoiding any autonomic nerve injury. Mesh is secured
to the anterior and lateral portion of the rectum, the vaginal fornix, Presentation and Evaluation Patients may suffer with varying
and the sacral promontory, allowing for closure of the rectovaginal degrees of fecal incontinence. Minor incontinence includes incontinence
septum and correction of the internal prolapse. In both procedures, to flatus and occasional seepage of liquid stool. Major incontinence is
recurrence at 1 year was low (<10%), and symptoms improved in frequent inability to control solid waste. As a result of fecal incontinence,
more than three-fourths of patients. patients suffer from poor perianal hygiene. Beyond the immediate

TABLE 328-5 Medical Conditions That Contribute to Symptoms of

■■FECAL INCONTINENCE Fecal Incontinence
Incidence and Epidemiology Fecal incontinence is the invol- Neurologic Disorders
untary passage of fecal material for at least 1 month in an individual • Dementia
with a developmental age of at least 4 years. The prevalence of fecal
• Brain tumor
incontinence in the United States is 0.5–11%. The majority of patients
are women and aged >65. A higher incidence of incontinence is seen • Stroke
among parous women. One-half of patients with fecal incontinence • Multiple sclerosis
also suffer from urinary incontinence. The majority of incontinence • Tabes dorsalis
is a result of obstetric injury to the pelvic floor, either while carrying a • Cauda equina lesions
fetus or during the delivery. An anatomic sphincter defect may occur in Skeletal Muscle Disorders
up to 32% of women following childbirth regardless of visible damage
• Myasthenia gravis
to the perineum. Risk factors at the time of delivery include prolonged
labor, the use of forceps, and the need for an episiotomy. Symptoms of • Myopathies, muscular dystrophy
incontinence can present two or more decades after obstetric injury. Miscellaneous
Medical conditions known to contribute to the development of fecal • Hypothyroidism
incontinence are listed in Table 328-5. • Irritable bowel syndrome
Anatomy and Pathophysiology The anal sphincter complex • Diabetes
is made up of the internal and external anal sphincter. The internal • Severe diarrhea
sphincter is smooth muscle and a continuation of the circular fibers of • Scleroderma
the rectal wall. It is innervated by the intestinal myenteric plexus and

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 problems associated with fecal incontinence, these patients are often patients with intact but weak anal sphincters. A temporary nerve 2503
withdrawn and suffer from depression. For this reason, quality-of-life stimulator is placed on the third sacral nerve. If there is at least a
measures are an important component in the evaluation of patients 50% improvement in symptoms, a permanent nerve stimulator is
with fecal incontinence. placed under the skin. Long-term results for sacral stimulation have
The evaluation of fecal incontinence should include a thorough been promising, with nearly 80% of patients having a reduction
history and physical examination including digital rectal examination in incontinence episodes by at least 50%. This reduction has been
(DRE). Weak sphincter tone on DRE and loss of the “anal wink” reflex sustainable in studies out to 5 years. Collagen-enhancing injectables
(S1-level control) may indicate a neurogenic dysfunction. Perianal have been around for several years. More than 50% of inconti-
scars may represent surgical injury. Other studies helpful in the diag- nent patients treated with nonanimal stabilized hyaluronic acid
nosis of fecal incontinence include anal manometry, pudendal nerve (NASHA/DX) achieved a 50% reduction in incontinence episodes,
terminal motor latency (PNTML), and endoanal ultrasound. Centers and these results were sustainable up to 2 years. Currently, this
that care for patients with fecal incontinence will have an anorectal injectable is not universally available. The Fenix is a magnetic ring
physiology laboratory that uses standardized methods of evaluating that is implanted around the anal sphincter muscles. Its long-term
anorectal physiology. Anorectal manometry (ARM) measures resting outcomes are still being studied, and it is currently only available
and squeeze pressures within the anal canal using an intraluminal for compassionate use.
water-perfused catheter. Current methods of ARM include use of a Finally, the use of stem cells to increase the bulk of the sphincter
three-dimensional, high-resolution system with a 12-catheter perfu- muscles is currently being tested. Stem cells can be harvested from
sion system, which allows physiologic delineation of anatomic abnor- the patient’s own muscle, grown, and then implanted into their
malities. Pudendal nerve studies evaluate the function of the nerves sphincter complex. Concern for cost and the need for an additional
innervating the anal canal using a finger electrode placed in the anal procedure dampen enthusiasm. Trial results are awaited.
canal. Stretch injuries to these nerves will result in a delayed response
of the sphincter muscle to a stimulus, indicating a prolonged latency. ■■HEMORRHOIDAL DISEASE
Finally, endoanal ultrasound will evaluate the extent of the injury to
the sphincter muscles before surgical repair. Unfortunately, all of these Incidence and Epidemiology Symptomatic hemorrhoids affect
investigations are user-dependent, and very few studies demonstrate >1 million individuals in the Western world per year. The prevalence
that these studies predict outcome following an intervention. Magnetic of hemorrhoidal disease is not selective for age or sex. However, age is
resonance imaging (MRI) has been used, but its routine use for imag- known to be a risk factor. The prevalence of hemorrhoidal disease is
ing in fecal incontinence is not well established. less in underdeveloped countries. The typical low-fiber, high-fat West-

CHAPTER 328 Diverticular Disease and Common Anorectal Disorders

Rarely does a pelvic floor disorder exist alone. The majority of ern diet is associated with constipation and straining and the develop-
patients with fecal incontinence will have some degree of urinary ment of symptomatic hemorrhoids.
incontinence. Similarly, fecal incontinence is a part of the spectrum Anatomy and Pathophysiology Hemorrhoidal cushions are a
of pelvic organ prolapse. For this reason, patients may present with normal part of the anal canal. The vascular structures contained within
symptoms of obstructed defecation as well as fecal incontinence. Care- this tissue aid in continence by preventing damage to the sphincter
ful evaluation including dynamic MRI or cinedefecography should muscle. Three main hemorrhoidal complexes traverse the anal canal—
be performed to search for other associated defects. Surgical repair the left lateral, the right anterior, and the right posterior. Engorgement
of incontinence without attention to other associated defects may and straining lead to prolapse of this tissue into the anal canal. Over
decrease the success of the repair. time, the anatomic support system of the hemorrhoidal complex weak-
ens, exposing this tissue to the outside of the anal canal where it is sus-
TREATMENT ceptible to injury. Hemorrhoids are commonly classified as external or
internal. External hemorrhoids originate below the dentate line and are
Fecal Incontinence covered with squamous epithelium and are associated with an internal
component. External hemorrhoids are painful when thrombosed.
Medical management of fecal incontinence includes strategies to Internal hemorrhoids originate above the dentate line and are cov-
bulk up the stool, which help in increasing fecal sensation. These ered with mucosa and transitional zone epithelium and represent the
include fiber supplementation, loperamide, diphenoxylate, and bile majority of hemorrhoids. The standard classification of hemorrhoidal
acid binders. These agents harden the stool and delay frequency disease is based on the progression of the disease from their normal
of bowel movements and are helpful in patients with minimal to internal location to the prolapsing external position (Table 328-6).
mild symptoms. Furthermore, patients can be offered a form of
physical therapy called biofeedback. This therapy helps strengthen
the external sphincter muscle while training the patient to relax TABLE 328-6 The Staging and Treatment of Hemorrhoids
with defecation to avoid unnecessary straining and further injury DESCRIPTION OF
to the sphincter muscles. Biofeedback has had variable success and STAGE CLASSIFICATION TREATMENT
is dependent on the motivation of the patient. At a minimum, bio- I Enlargement with Fiber supplementation
feedback is risk-free. Most patients will have some improvement. bleeding Short course of cortisone suppository
For this reason, it should be incorporated into the initial recom- Sclerotherapy
mendation to all patients with fecal incontinence. Infrared coagulation
Historically, the “gold standard” for the treatment of fecal incon- II Protrusion with Fiber supplementation
tinence with an isolated sphincter defect has been the overlap- spontaneous reduction Short course of cortisone suppository
ping sphincteroplasty. The external anal sphincter muscle and
Sclerotherapy
scar tissue, as well as any identifiable internal sphincter muscle,
are dissected free from the surrounding adipose and connective Infrared coagulation
tissue, and then an overlapping repair is performed in an attempt to III Protrusion requiring Fiber supplementation
rebuild the muscular ring and restore its function. However, long- manual reduction Short course of cortisone suppository
term results following overlapping sphincteroplasty have been poor, Rubber band ligation
with a 50% failure rate over 5 years. Operative hemorrhoidectomy
Alternative therapies such as sacral nerve stimulation (SNS), IV Irreducible protrusion Fiber supplementation
collagen-enhancing injectables, and magnetic “Fenix” ring are other Cortisone suppository
options. SNS is an adaptation of a procedure developed for the Operative hemorrhoidectomy
management of urinary incontinence. SNS is ideally suited for

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 2504 Presentation and Evaluation Patients commonly present to a Acute complications associated with the treatment of hemor-
physician for two reasons: bleeding and protrusion. Pain is less com- rhoids include pain, infection, recurrent bleeding, and urinary
mon than with fissures and, if present, is described as a dull ache from retention. Care should be taken to place bands properly and to avoid
engorgement of the hemorrhoidal tissue. Severe pain may indicate overhydration in patients undergoing operative hemorrhoidectomy.
a thrombosed hemorrhoid. Hemorrhoidal bleeding is described as Late complications include fecal incontinence as a result of injury to
painless bright red blood seen either in the toilet or upon wiping. Occa- the sphincter during the dissection. Anal stenosis may develop from
sional patients can present with significant bleeding, which may be a overzealous excision, with loss of mucosal skin bridges for reepithe-
cause of anemia; however, the presence of a colonic neoplasm must be lialization. Finally, an ectropion (prolapse of rectal mucosa from the
ruled out in anemic patients. Patients who present with a protruding anal canal) may develop. Patients with an ectropion complain of a
mass complain about inability to maintain perianal hygiene and are “wet” anus as a result of inability to prevent soiling once the rectal
often concerned about the presence of a malignancy. mucosa is exposed below the dentate line.
The diagnosis of hemorrhoidal disease is made on physical exami-
nation. Inspection of the perianal region for evidence of thrombosis ■■ANORECTAL ABSCESS
or excoriation is performed, followed by a careful digital examination.
Anoscopy is performed paying particular attention to the known Incidence and Epidemiology The development of a perianal
position of hemorrhoidal disease. The patient is asked to strain. If abscess is more common in men than women by a ratio of 3:1. The
this is difficult for the patient, the maneuver can be performed while peak incidence is in the third to fifth decade of life. Perianal pain
sitting on a toilet. The physician is notified when the tissue prolapses. associated with the presence of an abscess accounts for 15% of office
It is important to differentiate the circumferential appearance of a visits to a colorectal surgeon. The disease is more prevalent in immu-
full-thickness rectal prolapse from the radial nature of prolapsing hem- nocompromised patients such as those with diabetes, hematologic
orrhoids (see “Rectal Prolapse,” above). The stage and location of the disorders, or inflammatory bowel disease (IBD) and persons who are
hemorrhoidal complexes are defined. HIV positive. These disorders should be considered in patients with
recurrent perianal infections.

TREATMENT Anatomy and Pathophysiology An anorectal abscess is an

abnormal fluid-containing cavity in the anorectal region. Anorectal
Hemorrhoidal Disease abscess results from an infection involving the glands surrounding the
anal canal. Normally, these glands release mucus into the anal canal,
The treatment for bleeding hemorrhoids is based on the stage of which aids in defecation. When stool accidentally enters the anal
the disease (Table 328-6). In all patients with bleeding, the possibil- glands, the glands become infected, and an abscess develops. Anorectal
PART 10

ity of other causes must be considered. In young patients without abscesses are perianal in 40–50% of patients, ischiorectal in 20–25%,
a family history of colorectal cancer, the hemorrhoidal disease intersphincteric in 2–5%, and supralevator in 2.5% (Fig. 328-7).
may be treated first and a colonoscopic examination performed
if the bleeding continues. Older patients who have not had col- Presentation and Evaluation Perianal pain and fever are the
orectal cancer screening should undergo colonoscopy or flexible hallmarks of an abscess. Patients may have difficulty voiding and have
Disorders of the Gastrointestinal System

sigmoidoscopy. blood in the stool. A prostatic abscess may present with similar com-
With rare exceptions, the acutely thrombosed hemorrhoid can be plaints, including dysuria. Patients with a prostatic abscess will often
excised within the first 72 h by performing an elliptical excision. have a history of recurrent sexually transmitted diseases. On physical
Sitz baths, fiber, and stool softeners are prescribed. Additional examination, a large fluctuant area is usually readily visible. Routine
therapy for bleeding hemorrhoids includes the office procedures laboratory evaluation shows an elevated white blood cell count. Diag-
of rubber band ligation, infrared coagulation, and sclerotherapy. nostic procedures are rarely necessary unless evaluating a recurrent
Sensation begins at the dentate line; therefore, all procedures abscess. A CT scan or MRI has an accuracy of 80% in determining
can be performed without discomfort either endoscopically or in incomplete drainage. If there is a concern about the presence of IBD,
the office. Bands are placed around the engorged tissue, causing a rigid or flexible sigmoidoscopic examination may be done at the
ischemia and fibrosis. This aids in fixing the tissue proximally time of drainage to evaluate for inflammation within the rectosigmoid
in the anal canal. Patients may complain of a dull ache for 24 h region. A more complete evaluation for Crohn’s disease would include
following band application. During sclerotherapy, 1–2 mL of a a full colonoscopy and small-bowel series.
sclerosant (usually sodium tetradecyl sulfate) is injected using a
25-gauge needle into the submucosa of the hemorrhoidal complex.
Care must be taken not to inject the anal canal circumferentially,
or stenosis may occur.
For surgical management of hemorrhoidal disease, excisional
hemorrhoidectomy with sharp dissection or using a ligator, tran-
Abscesses Fistula
shemorrhoidal dearterialization (THD), or stapled hemorrhoidec- tracts
tomy (“the procedure for prolapse or hemorrhoids” [PPH]) is Supralevator
4
the procedure of choice. All surgical methods of management
are equally effective in the treatment of symptomatic third- and Intersphincteric
fourth-degree hemorrhoids. However, because the sutured hem- Ischiorectal
orrhoidectomy involves the removal of redundant tissue down 3
to the anal verge, unpleasant anal skin tags are removed as well. Perianal
1 2
The stapled hemorrhoidectomy is associated with less discomfort;
however, this procedure does not remove anal skin tags, and an
increased number of complications are associated with use of the
stapling device. THD uses ultrasound guidance to ligate the blood
supply to the anal tissue, hence reducing hemorrhoidal engorge- 1
Intersphincteric
ment. No procedures on hemorrhoids should be done in patients 2
who are immunocompromised or who have active proctitis. Fur- Trans-sphincteric 3 4 Extrasphincteric
thermore, emergent hemorrhoidectomy for bleeding hemorrhoids Suprasphincteric
is associated with a higher complication rate. FIGURE 328-7 Common locations of anorectal abscess (left) and fistula in ano (right).

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 TREATMENT Early complications from these procedures include urinary reten- 2505
tion and bleeding. Later complications are rare (<10%) and include
Anorectal Abscess temporary and permanent incontinence. Recurrence is 0–18% fol-
lowing fistulotomy and 20–30% following anorectal advancement
As with all abscesses, the “gold standard” is drainage. Office drain- flap and the LIFT procedure.
age of an uncomplicated anorectal abscess may suffice. A small Fistulizing disease of the anus is common in Crohn’s disease, and
incision close to the anal verge is made, and a Mallenkot drain is recent evidence has suggested that the use of mesenchymal stem
advanced into the abscess cavity. For patients who have a compli- cell therapy may improve healing rates of fistula associated with
cated abscess or who are diabetic or immunocompromised, drain- Crohn’s disease. The ADMIRE study examined the use of allogeneic
age should be performed in an operating room under anesthesia. expanded adipose-derived mesenchymal stem cells in the treatment
These patients are at greater risk for developing necrotizing fasciitis. of complex fistula in ano in Crohn’s disease. The study included 212
The role of antibiotics in the management of anorectal abscesses is patients randomized to stem cell therapy or placebo. Fistula remis-
limited. Antibiotics are only warranted in patients who are immu- sion rates at 52 weeks were significantly higher with the use of stem
nocompromised or have prosthetic heart valves, artificial joints, cell therapy over placebo (59 vs 42%, respectively). Currently, there
diabetes, or IBD. is an international multicenter trial underway.

■■FISTULA IN ANO ■■ANAL FISSURE

Incidence and Epidemiology The incidence and prevalence of Incidence and Epidemiology Anal fissures occur at all ages but
fistulating perianal disease parallel the incidence of anorectal abscess, are more common in the third through the fifth decades. A fissure is
estimated to be 1 in 10,000 individuals. Some 30–40% of abscesses the most common cause of rectal bleeding in infancy. The prevalence is
will give rise to fistula in ano. Although the majority of the fistulas are equal in males and females. It is associated with constipation, diarrhea,
cryptoglandular in origin, 10% are associated with IBD, tuberculosis, infectious etiologies, perianal trauma, and Crohn’s disease.
malignancy, and radiation.
Anatomy and Pathophysiology Trauma to the anal canal occurs
Anatomy and Pathophysiology A fistula in ano is defined as a following defecation. This injury occurs in the anterior or, more com-
communication of an abscess cavity with an identifiable internal open- monly, posterior anal canal. Irritation caused by the trauma to the anal
ing within the anal canal. This identifiable opening is most commonly canal results in an increased resting pressure of the internal sphincter.
located at the dentate line where the anal glands enter the anal canal. The blood supply to the sphincter and anal mucosa enters laterally.

CHAPTER 328 Diverticular Disease and Common Anorectal Disorders

Patients experiencing continuous drainage following the treatment of a Therefore, increased anal sphincter tone results in a relative ischemia
perianal abscess likely have a fistula in ano. These fistulas are classified in the region of the fissure and leads to poor healing of the anal injury.
by their relationship to the anal sphincter muscles, with 70% being A fissure that is not in the posterior or anterior position should raise
intersphincteric, 23% transsphincteric, 5% suprasphincteric, and 2% suspicion for other causes, including tuberculosis, syphilis, Crohn’s
extrasphincteric (Fig. 328-7). disease, and malignancy.
Presentation and Evaluation A patient with a fistula in ano will Presentation and Evaluation A fissure can be easily diagnosed
complain of constant drainage from the perianal region associated
on history alone. The classic complaint is pain, which is strongly
with a firm mass. The drainage may increase with defecation. Perianal
associated with defecation and is relentless. The bright red bleeding
hygiene is difficult to maintain. Examination under anesthesia is the
that can be associated with a fissure is less extensive than that associ-
best way to evaluate a fistula. At the time of the examination, anoscopy
ated with hemorrhoids. On examination, most fissures are located in
is performed to look for an internal opening. Diluted hydrogen perox-
either the posterior or anterior position. A lateral fissure is worrisome
ide will aid in identifying such an opening. In lieu of anesthesia, MRI
because it may have a less benign nature, and systemic disorders should
with an endoanal coil will also identify tracts in 80% of the cases. After
be ruled out. A chronic fissure is indicated by the presence of a hyper-
drainage of an abscess with insertion of a Mallenkot catheter, a fistula-
trophied anal papilla at the proximal end of the fissure and a sentinel
gram through the catheter can be obtained in search of an occult fistula
pile or skin tag at the distal end. Often the circular fibers of the hyper-
tract. Goodsall’s rule states that a posterior external fistula will enter the
trophied internal sphincter are visible within the base of the fissure. If
anal canal in the posterior midline, whereas an anterior fistula will enter
anal manometry is performed, elevation in anal resting pressure and
at the nearest crypt. A fistula exiting >3 cm from the anal verge may
a sawtooth deformity with paradoxical contractions of the sphincter
have a complicated upward extension and may not obey Goodsall’s rule.
muscles are pathognomonic.
TREATMENT TREATMENT
Fistula in Ano Anal Fissure
A newly diagnosed draining fistula is best managed with placement The management of the acute fissure is conservative. Stool softeners
of a seton, a vessel loop or silk tie placed through the fistula tract, for those with constipation, increased dietary fiber, topical anes-
which maintains the tract open and quiets down the surrounding thetics, glucocorticoids, and sitz baths are prescribed and will heal
inflammation that occurs from repeated blockage of the tract. Once 60–90% of fissures. Chronic fissures are those present for >6 weeks.
the inflammation is less, the exact relationship of the fistula tract These can be treated with modalities aimed at decreasing the anal
to the anal sphincters can be ascertained. A simple fistulotomy can canal resting pressure including nifedipine ointment applied three
be performed for intersphincteric and low (less than one-third of times a day and botulinum toxin type A, up to 20 units, injected into
the muscle) transsphincteric fistulas without compromising conti- the internal sphincter on each side of the fissure. Both treatments
nence. For a higher transsphincteric fistula, an anorectal advance- are associated with a fissure healing rate of >80%. Surgical manage-
ment flap in combination with a drainage catheter or fibrin glue ment includes anal dilatation and lateral internal sphincterotomy.
may be used. Very long (>2 cm) and narrow tracts respond better to Usually, one-third of the internal sphincter muscle is divided; it is
fibrin glue than shorter tracts. Simple ligation of the internal fistula easily identified because it is hypertrophied. Recurrence rates from
tract (LIFT procedure) has also been used in the management of medical therapy are higher, but this is offset by a risk of inconti-
simple fistula with good success. nence following sphincterotomy. Lateral internal sphincterotomy
Patients should be maintained on stool-bulking agents, nonnar- may lead to incontinence more commonly in women.
cotic pain medication, and sitz baths following surgery for a fistula.

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 2506 Acknowledgment most commonly occurs in areas of severe atherosclerotic narrowing at
The author thanks Cory Sandore for providing some illustrations for this the SMA and celiac artery.
chapter. Gregory Bulkley, MD, contributed to this chapter in an earlier Nonocclusive mesenteric ischemia represents 20% of the cases and
edition, and some of that material has been retained here. is secondary to intestinal ischemia when subjected to acute hemody-
namic instability. Hypovolemia, shock, and the use of vasoconstrictive
■■FURTHER READING agents (digoxin, α-adrenergic agonists, cocaine) can precipitate ische-
Bharucha AE et al: Surgical interventions and the use of device-aided mia in these patients. It is the most prevalent gastrointestinal disease
therapy for the treatment of fecal incontinence and defecatory disor- complicating cardiovascular surgery. The incidence of ischemic colitis
ders. Clin Gastroenterol Hepatol 15:1844, 2017. following elective aortic repair is 5–9%, and the incidence triples in
Daniels L et al: Randomized clinical trial of observation versus antibi- patients following emergent repair.
otic treatment for a first episode of CT-proven uncomplicated acute Mesenteric venous thrombosis accounts for <10% of cases and is
diverticulitis (DIABOLO trial). BJS 104:52, 2017. generally precipitated by a hypercoagulable state due to an underlying
Guttenplan M: The evaluation and office management of hemor- inherited disorder such as factor V Leiden, prothrombin mutation,
rhoids for the gastroenterologist. Curr Gastroenterol Rep 19:30, 2017. protein S deficiency, protein C deficiency, antithrombin deficiency, and
Panes J et al: Long-term efficacy and safety of stem cell therapy antiphospholipid syndrome. It may also occur as a result of acquired
(Cx601) for complex perianal fistulas in patients with Crohn’s disease. thrombophilia in malignancies, hematologic disorders, or use of oral
Gastroenterology 154:1334, 2018. contraceptives.
Prichard D, Bharucha AE: Management of pelvic floor disorders:
Biofeedback and more. Curr Treat Options Gastroenterol 12:456, ■■ANATOMY AND PATHOPHYSIOLOGY
2014. The blood supply to the intestines is supplied by the celiac artery, SMA,
Salfity HV et al: Minimally invasive incision and drainage technique and inferior mesenteric artery (IMA) (Fig. 329-1). Extensive collat-
in the treatment of simple subcutaneous abscess in adults. Am Surg eralization occurs between major mesenteric trunks and branches of
83:699, 2017. the mesenteric arcades. Collateral vessels within the small bowel are
Sugrue J et al: Sphincter-sparing anal fistula repair: Are we getting numerous and meet within the duodenum and the bed of the pancreas.
better? Dis Colon Rectum 60:1071, 2017. Collateral vessels within the colon meet at the splenic flexure and
Tursi A: Dietary pattern and colonic diverticulosis. Curr Opin Clin descending/sigmoid colon. These areas, which are inherently at risk for
Nutr Metab Care 20:409, 2017. decreased blood flow, are known as Griffiths’ point and Sudeck’s point,
respectively, and are the most common locations for colonic ischemia
(Fig. 329-1, shaded areas). The splanchnic circulation can receive up
PART 10

to 30% of the cardiac output. Protective responses to prevent intestinal

ischemia include abundant collateralization, autoregulation of blood
flow, and the ability to increase oxygen extraction from the blood.

329 Mesenteric Vascular

Disorders of the Gastrointestinal System

Insufficiency Left phrenic a. Aorta

Maryam Ali Khan, Jaideep Das Gupta,

Right phrenic a. Splenic a.
Mahmoud Malas
Griffiths’
Celiac trunk point

Pancreatico-
INTESTINAL ISCHEMIA duodenal a.
Arc of
■■INCIDENCE AND EPIDEMIOLOGY Riolan
Intestinal ischemia occurs when splanchnic perfusion fails to meet the
metabolic demands of the intestines, resulting in ischemic tissue injury.
Mesenteric ischemia affects 2–3 people per 100,000, with an increasing
incidence in the aging population. Mortality with acute presentation
SMA
remains high, between 50 and 80%, and early diagnosis with prompt
intervention is crucial in improving clinical outcomes. Intestinal IMA
ischemia is further classified as chronic mesenteric ischemia (CMI) or
acute mesenteric ischemic (AMI). CMI is secondary to multiple major
visceral arterio-occlusive disease, with involvement of the superior
mesenteric artery (SMA) most worrisome. AMI is most commonly
associated with (1) arterio-occlusive mesenteric ischemia, (2) nonoc-
clusive mesenteric ischemia, and (3) mesenteric venous thrombosis.
CMI is the failure to achieve normal postprandial hyperemic intes- Marginal a.
tinal blood flow. This occurs due to an imbalance between the supply
IIA
and demand of oxygen metabolites to the intestinal tract similar to
cardiac angina. CMI occurs due to significant atherosclerotic disease
Sudeck’s
leading to the narrowing of the SMA and/or celiac artery origins. Hemorrhoidal aa. point
AMI is the occurrence of an abrupt cessation of mesenteric blood Superior
flow, usually embolic or thrombotic in nature. Approximately 50% of Middle
AMI is due to embolus to the mid to distal SMA. Embolus etiology Inferior
includes atrial fibrillation, recent myocardial infarction, soft athero-
FIGURE 329-1 Blood supply to the intestines includes the celiac artery, superior
sclerotic plaque, infective endocarditis, valvular heart disease, and mesenteric artery (SMA), inferior mesenteric artery (IMA), and branches of the
recent cardiac or vascular catheterization. Approximately 25–30% of internal iliac artery (IIA). Griffiths’ and Sudeck’s points, indicated by shaded areas,
cases are characterized by an acute-on-chronic thrombosis in patients are watershed areas within the colonic blood supply and common locations for
with preexisting mesenteric atherosclerosis. Thrombotic occlusion ischemia.

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 Occlusive ischemia is a result of disruption of blood flow by an key determinant. Open revascularization involves antegrade bypass 2507
embolus or progressive thrombosis in a major artery supplying the from the supraceliac aortic or retrograde bypass, typically the common
intestine. In >75% of cases, emboli originate from the heart and pref- iliac arteries, with a synthetic graft to the targeted vessels, usually the
erentially lodge in the SMA just distal to the origin of the middle colic SMA and/or celiac artery. In patients requiring revascularization, the
artery. Progressive thrombosis of typically two of the major vessels endovascular approach is recommended as first-line therapy. It is espe-
supplying the intestine is required for the development of chronic cially favorable for short segment stenosis with minimal to moderate
intestinal angina. The involvement of the SMA is most worrisome. calcification or thrombus. Angioplasty with endovascular stenting in
Nonocclusive ischemia is disproportionate mesenteric vasoconstric- the treatment of CMI is associated with an 80% long-term success
tion (arteriolar vasospasm) in response to severe physiologic stress rate. Open revascularization should be considered in patients with
such as shock. If left untreated, early mucosal stress ulceration will lesions not amenable to endovascular treatment such as severe calci-
progress to full-thickness injury. fication, longer lesions, small vessel diameter, or failed endovascular
interventions.
■■PRESENTATION, EVALUATION, Acute intestinal ischemia remains one of the most challenging
AND MANAGEMENT diagnoses. The mortality rate of AMI is >50%. The most significant
Patients with CMI typically present with insidious onset of symptoms indicator of survival is the timeliness of diagnosis and treatment. An
and classically with recurrent episodes of acute, dull, crampy, post- overview of diagnosis and management of each form of intestinal
prandial epigastric pain, which has also been referred to as “intestinal ischemia is given in Table 329-1.
angina.” Weight loss and chronic diarrhea may also be noted. Dura- AMI resulting from an arterial embolus or thrombosis presentation
tion of symptoms is typically 6–12 months. Physical examination is nonspecific and requires a high index of suspicion for diagnosis.
often reveals a malnourished patient with other manifestations of Severe, acute, unremitting abdominal pain strikingly out of propor-
atherosclerosis. tion to the physical findings is the most common complaint (95%).
Duplex ultrasound has gained popularity as a screening tool for This may be associated with nausea (44%), vomiting (35%), diarrhea
the evaluation of the mesenteric vessels due to high sensitivity and (35%), and blood per rectum (16%). Later findings will demonstrate
specificity. Mesenteric duplex scan demonstrating a high peak veloc- peritonitis and cardiovascular collapse. Specific clinical features can
ity of flow in the SMA is associated with an ~80% positive predictive help differentiate the underlying etiology, whether embolic or throm-
value of mesenteric ischemia. More significantly, a negative duplex botic. Patients with embolic ischemia are typically older adults with an
scan virtually precludes the diagnosis of mesenteric ischemia. It is underlying condition that predisposes to embolism such as atrial fibril-
important to perform the test while the patient is fasting because the lation, prior embolic event, or recent infective endocarditis. Throm-

CHAPTER 329 Mesenteric Vascular Insufficiency

presence of increased bowel gas prevents adequate visualization of flow botic ischemia typically presents as an acute occlusion in patients with
disturbances within the vessels or the lack of a vasodilation response to the underlying atherosclerotic disease who may have been previously
feeding during the test. diagnosed with CMI.
The management of CMI includes medical management of the ath- AMI is a surgical emergency, and emergent admission to a moni-
erosclerotic disease by exercise, cessation of smoking, and antiplatelet tored bed or intensive care unit is recommended for resuscitation with
and lipid-lowering medications. A full cardiac and vascular evaluation fluids and administration of broad-spectrum antibiotics in addition
should be performed before intervention on CMI. Before intervention, to further evaluation. If the diagnosis of intestinal ischemia is being
a CT angiogram is recommended to assess the degree of atherosclerotic considered, consultation with a surgical service is necessary. Often
disease of the aortic and visceral vessels. the decision to operate is made on a high index of suspicion from
Treatment involves either endovascular or open surgical revascu- the history and physical exam despite normal laboratory findings. In
larization and should be individualized based on the patient’s comor- patients with suspected AMI, CT angiography with a 1-mm or thinner
bidities and anatomy. Endovascular revascularization involves targeted cut should be used to detect mesenteric arterial occlusive disease most
vessel treatment with visceral stents, with the SMA anatomy being the likely due to embolic or thrombotic etiology and is the gold standard.

TABLE 329-1 Overview of the Management of Acute Intestinal Ischemia

TREATMENT OF UNDERLYING TREATMENT OF SYSTEMIC
CONDITION KEY TO EARLY DIAGNOSIS CAUSE TREATMENT OF SPECIFIC LESION CONSEQUENCE
Arterio-occlusive Computed tomography (CT) Anticoagulation Laparotomy Anticoagulation
mesenteric ischemia angiography Cardioversion Embolectomy Resuscitation
1. Arterial embolus Early laparotomy Thrombectomy Assess viability and resect Broad-spectrum antibiotics
Broad-spectrum antibiotics nonviable bowel Emergent surgical intervention
Assessment of bowel
2. Arterial thrombosis Duplex ultrasound Anticoagulation Endovascular approach: Anticoagulation
CT angiography Broad-spectrum antibiotics thrombolysis, angioplasty, and Resuscitation
stenting
Resuscitation Broad-spectrum antibiotics
Endarterectomy/thrombectomy or
vascular bypass Emergent surgical intervention
Assess viability and resect Assessment of bowel
nonviable bowel
Mesenteric venous CT with venous phase Anticoagulation Anticoagulation Anticoagulation
thrombosis Resuscitation Hypercoagulable workup Resuscitation
Venous thrombosis Broad-spectrum antibiotics
Support cardiac output
Avoid vasoconstrictors
Nonocclusive mesenteric Vasospasm: CT Resuscitation Vasospasm: intraarterial Resuscitation
ischemia Hypoperfusion: CT Support cardiac output vasodilators Broad-spectrum antibiotics
Avoid vasoconstrictors Hypoperfusion: assess viability Support cardiac output
and resect dead bowel
Broad-spectrum antibiotics Avoid vasoconstrictors
Source: Modified from GB Bulkley, in JL Cameron (ed): Current Surgical Therapy, 2nd ed. Toronto, BC Decker, 1986.

HPIM21e_Part10_p2381-p2670.indd 2507 20/01/22 10:04 PM

 2508 Additional diagnostic modalities that can be useful in diagnosis but performed with resection of compromised bowel. Second-look lapar-
that should not delay surgical therapy include an electrocardiogram otomy after 24–48 h should be attempted as anticoagulation can help
(ECG), echocardiogram, and abdominal radiographs. Patients with prevent resection of viable bowel. Hypercoagulability testing should
AMI should be given a heparin bolus and started on a therapeutic hep- be performed, and if underlying inherited disorders are diagnosed,
arin drip. Correction of electrolyte abnormalities and empiric broad- lifelong anticoagulation is recommended.
spectrum antibiotic therapy should also be initiated immediately.
If the CTA verifies the acute embolic occlusion of SMA, surgical Acknowledgments
exploration should not be delayed. The goal of operative exploration is We thank Cory Sandore for providing the illustration for this chapter.
to resect the compromised bowel and restore blood supply. The entire Susan Gearhart contributed to this chapter in the 18th edition, Rizwan
length of the small and large bowel beginning at the ligament of Treitz Ahmed contributed to the 19th edition and Satinderjit Locham to the
should be evaluated. The SMA artery should be localized, typically at 20th edition.
the mesocolon of the transverse colon. A transverse arteriotomy of the
SMA should be made with the removal of the embolus with a Fogarty ■■FURTHER READING
catheter passed in a retrograde and antegrade manner to restore blood Deng QW et al: Risk factors for postoperative acute mesenteric ische-
flow. In the case of SMA occlusion where the embolus usually lies just mia among adult patients undergoing cardiac surgery: A systematic
proximal to the origin of the middle colic artery, the proximal jejunum review and meta-analysis. J Crit Care 42:294, 2017.
is often spared, while the remainder of the small bowel up to the trans- Salsano G et al: What is the best revascularization strategy for
verse colon may become ischemic. Nonviable bowel should be resected. acute occlusive arterial mesenteric ischemia: Systematic review and
Questionable bowel should undergo a second-look laparotomy in a 24- meta-analysis. Cardiovasc Intervent Radiol 41:27, 2018.
to 48-h period. After revascularization, peristalsis and return of pink Sise MJ: Acute mesenteric ischemia. Surg Clin North Am 94:165, 2014.
color of the bowel wall should be observed. Palpation of major arterial
mesenteric vessels can be performed, as well as applying a Doppler
flowmeter to the antimesenteric border of the bowel wall, but neither
is a definitive indicator of viability.
In the assessment of acute-on-chronic mesenteric ischemia, typically
involvement of the orifice of the SMA is seen. Therefore, the entire
small bowel is compromised. Revascularization using an endovascu-
lar, open, and/or hybrid approach should be individualized based on
330 Acute Intestinal
Obstruction
the patient’s critical status, comorbidities, and anatomy. Endovascular
Danny O. Jacobs
PART 10

stenting, suction thrombectomy, and/or thrombolysis catheter should

be considered for intervention. The bowel should be evaluated for via-
bility, typically via an exploratory laparotomy.
Nonocclusive or vasospastic mesenteric ischemia presents with ■■EPIDEMIOLOGY
generalized abdominal pain, anorexia, bloody stools, and abdominal Morbidity and mortality from acute intestinal obstruction have been
Disorders of the Gastrointestinal System

distention. Often these patients are obtunded, and physical findings decreasing over the past several decades. Nevertheless, the diagnosis
may not assist in the diagnosis or may be obscured by the underlying can still be challenging, and the type of complications that patients suf-
etiology. The presence of leukocytosis, metabolic acidosis, and/or fer has not changed significantly. The extent of mechanical obstruction
lactic acidosis is useful in support of the diagnosis of advanced intes- is typically described as partial, high grade, or complete—generally
tinal ischemia; however, these markers may not be indicative of either correlating with the risk of complications and the urgency with which
reversible ischemia or frank necrosis. the underlying disease process must be addressed. Obstruction is also
Emergent admission to a monitored bed or intensive care unit is rec- commonly described as being either “simple” or, alternatively, “stran-
ommended for resuscitation, broad-spectrum antibiotics, and further gulated” if vascular insufficiency and intestinal ischemia are evident.
evaluation. Anticoagulation is not recommended as the goal of resus- Acute intestinal obstruction occurs either mechanically from block-
citation is to maintain hemodynamics. For select patients, intrame- age or from intestinal dysmotility when there is no blockage. In the
senteric infusion of vasodilators such as papaverine, prostaglandins, latter instance, the abnormality is described as being functional.
and nitroglycerin for reversal of mesenteric ischemia can be used, but Mechanical bowel obstruction may be caused by extrinsic processes,
resuscitation and the treatment of the underlying pathology should be intrinsic abnormalities of the bowel wall, or intraluminal abnormalities
the priority. (Table 330-1). Within each of these broad categories are many diseases
If ischemic colitis is a concern, colonoscopy should be considered that can impede intestinal propulsion. Intrinsic diseases that can cause
to assess the integrity of the colon mucosa. Ischemia of the colonic intestinal obstruction are usually congenital, inflammatory, neoplastic,
mucosa is graded as mild with minimal mucosal erythema or as or traumatic in origin, although intussusception and radiation injury
moderate with pale mucosal ulcerations and evidence of extension to can also be etiologic.
the muscular layer of the bowel wall. Severe ischemic colitis presents Acute intestinal obstruction accounts for ~1–3% of all hospitaliza-
with severe ulcerations resulting in black or green discoloration of the tions and a quarter of all urgent or emergent general surgery admis-
mucosa, consistent with full-thickness bowel-wall necrosis. Laparos- sions. Approximately 80% of cases involve the small bowel, and about
copy can also be employed for assessment. Ischemic colitis is optimally one-third of these patients show evidence of significant ischemia. The
treated with resection of the ischemic bowel and the formation of a mortality rate for patients with strangulation who are operated on
proximal stoma. within 24–30 h of the onset of symptoms is ~8% but triples shortly
Onset of mesenteric venous thrombosis can be acute or subacute thereafter.
based on the location of thrombosis in the splanchnic circulation. Extrinsic diseases most commonly cause mechanical obstruction of
Patients often present with vague abdominal pain associated with nau- the small intestine. In the United States and Europe, almost all cases
sea and vomiting. Physical examination findings include abdominal are caused by postoperative adhesions, carcinomatosis, or herniation
distention with mild to moderate tenderness and signs of dehydration. of the anterior abdominal wall. Carcinomatosis most often originates
Findings on CT venous phase include diffuse bowel-wall thickening from the ovary, pancreas, stomach, or colon, although rarely, metastasis
and thrombus within the splanchnic system. IV therapeutic anticoagu- from distant organs like the breast and skin can occur. Adhesions are
lation, broad-spectrum antibiotics, and correction of electrolyte abnor- responsible for the majority of cases of early postoperative obstruction
malities should be performed. Surgical intervention is not performed that require intervention. It is important to note many patients who
unless there is evidence of peritonitis and/or bowel perforation. If there are successfully treated for adhesive small-bowel instruction will expe-
is evidence of bowel compromise, an exploratory laparotomy should be rience recurrence. Approximately 20% of patients who were treated

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 2509
TABLE 330-1 Most Common Causes of Acute Intestinal Obstruction TABLE 330-3 Most Common Causes of Ileus (Functional or
Extrinsic Disease Pseudo-Obstruction of the Intestine)
Adhesions (especially due to previous abdominal surgery), internal or external Intraabdominal procedures, lumbar spinal injuries, or surgical procedures on the
hernias, neoplasms (including carcinomatosis and extraintestinal malignancies, lumbar spine and pelvis
mostly commonly ovarian), endometriosis or intraperitoneal abscesses, and Metabolic or electrolyte abnormalities, especially hypokalemia and
idiopathic sclerosis hypomagnesemia, but also hyponatremia, uremia, and severe hyperglycemia
Intrinsic Disease Drugs such as opiates, antihistamines, and some psychotropic (e.g., haloperidol,
tricyclic antidepressants) and anticholinergic agents
Congenital (e.g., malrotation, atresia, stenosis, intestinal duplication, cyst
formation, and congenital bands—the latter rarely in adults) Intestinal ischemia
Inflammation (e.g., inflammatory bowel disease, especially Crohn’s disease, Intraabdominal or retroperitoneal inflammation or hemorrhage
but also diverticulitis, radiation, tuberculosis, lymphogranuloma venereum, and Lower lobe pneumonias
schistosomiasis)
Intraoperative radiation (likely due to muscle damage)
Neoplasia (note: primary small-bowel cancer is rare; obstructive colon cancer
Systemic sepsis
may mimic small-bowel obstruction if the ileocecal valve is incompetent)
Hyperparathyroidism
Traumatic (e.g., hematoma formation, anastomotic strictures)
Pseudo-obstruction (Ogilvie’s syndrome)
Other, including intussusception (where the lead point is typically a polyp or
tumor in adults), volvulus, obstruction of duodenum by superior mesenteric Ileus secondary to hereditary or acquired visceral myopathies and neuropathies
artery, radiation or ischemic injury, and aganglionosis, which is Hirschsprung’s that disrupt myocellular neural coordination
disease Some collagen vascular diseases such as lupus erythematosus or scleroderma
Intraluminal Abnormalities
Bezoars, feces, foreign bodies including inspissated barium, gallstones (entering is often the most common reason why hospital discharge is delayed.
the lumen via a cholecystoenteric fistula), enteroliths Pseudo-obstruction of the colon, also known as Ogilvie’s syndrome, is
a relatively rare disease. Some patients with Ogilvie’s syndrome have
colonic dysmotility due to abnormalities of their autonomic nervous
conservatively and between 5 and 30% of patients who were managed
system that may be inherited.
operatively will require readmission within 10 years.
Open operations of the lower abdomen, including appendectomy ■■PATHOPHYSIOLOGY
and colorectal and gynecologic procedures, are especially likely to cre-

CHAPTER 330 Acute Intestinal Obstruction

The manifestations of acute intestinal obstruction depend on the
ate adhesions that can cause bowel obstruction (Table 330-2). The risk nature of the underlying disease process, its location, and changes in
of internal herniation is increased by abdominal procedures such as blood flow (Fig. 330-1). Increased intestinal contractility, which occurs
laparoscopic or open Roux-en-Y gastric bypass. Although laparoscopic proximally and distal to the obstruction, is a characteristic response.
procedures may generate fewer postoperative adhesions compared Subsequently, intestinal peristalsis slows as the intestine or stomach
with open surgery, the risk of obstructive adhesion formation is not proximal to the point of obstruction dilates and fills with gastroin-
eliminated. testinal secretions and swallowed air. Although swallowed air is the
Volvulus, which occurs when bowel twists on its mesenteric axis, primary contributor to intestinal distension, intraluminal air may also
can cause partial or complete obstruction and vascular insufficiency. accumulate from fermentation, local carbon dioxide production, and
The sigmoid colon is most commonly affected, accounting for approx- altered gaseous diffusion.
imately two-thirds of all cases of volvulus and 4% of all cases of large- Intraluminal dilation also increases intraluminal pressure. When
bowel obstruction. The cecum and terminal ileum can also volvulize, luminal pressure exceeds venous pressure, venous and lymphatic
or the cecum alone may be involved as a cecal bascule. Risk factors drainage is impeded. Edema ensues, and the bowel wall proximal to
include institutionalization, the presence of neuropsychiatric condi- the site of blockage may become hypoxemic. Epithelial necrosis can be
tions requiring psychotropic medication, chronic constipation, and identified within 12 h of obstruction. Ultimately, arterial blood supply
aging; patients typically present in their seventies or eighties. may become so compromised that full-thickness ischemia, necrosis,
Colonic volvulus is more common in Eastern Europe, Russia, and and perforation result. Stasis increases the bacteria counts within the
Africa than it is in the United States. It is rare for adhesions or hernias jejunum and ileum. Bacteria, such as Escherichia coli, Streptococcus
to obstruct the colon. Cancer of the descending colon and rectum faecalis, and Klebsiella, and other pathogens may be recovered from
is responsible for approximately two-thirds of all cases, followed by intestinal cultures, mesenteric lymph nodes, the bloodstream, and
diverticulitis and volvulus. other sites.
Functional obstruction, also known as ileus and pseudo-obstruction, Other manifestations depend on the degree of hypovolemia, the
is present when dysmotility prevents intestinal contents from being patient’s metabolic response, and the presence or absence of associated
propelled distally and no mechanical blockage exists. Ileus that occurs intestinal ischemia. Inflammatory edema eventually increases the
after intraabdominal surgery is the most commonly identified form production of reactive oxygen species and activates neutrophils and
of functional bowel obstruction, but there are many other causes macrophages, which accumulate within the bowel wall. Their accumu-
(Table 330-3). Although postoperative ileus is most often transient, it lation, along with changes in innate immunity, disrupts secretory and
neuromotor processes. Dehydration is caused by loss of the normal
TABLE 330-2 Acute Small-Intestinal and Colonic intestinal absorptive capacity as well as fluid accumulation in the gas-
Obstruction Incidences tric or intestinal wall and intraperitoneally.
CAUSE INCIDENCE Anorexia and emesis tend to exacerbate intravascular volume
Postoperative adhesions >50%
depletion. In the worst-case scenario that is most commonly identi-
fied after high-grade distal obstruction, emesis leads to losses of gas-
Neoplasms ~20%
tric potassium, hydrogen, and chloride, while dehydration stimulates
Hernias (especially ventral or internal types, where the ~10% proximal renal tubule bicarbonate reabsorption. Intraperitoneal fluid
risk of strangulation is increased) accumulation, especially in patients with severe distal bowel obstruc-
Inflammatory bowel disease, other inflammation ~5% tion, may increase intraabdominal pressure enough to elevate the dia-
(obstruction may resolve if acute inflammation and phragm, inhibit respiration, and impede systemic venous return and
edema subside)
promote vascular instability. Severe hemodynamic compromise may
Intussusception, volvulus, other miscellaneous <15% elicit a systemic inflammatory response and generalized microvascu-
diseases
lar leakage.

HPIM21e_Part10_p2381-p2670.indd 2509 20/01/22 10:04 PM

 2510

Abnormal Inflammatory
bacteria mediators
colonization released

Fluid and air

accumulate; bacteria
overgrowth may occur
Air

Epithelial
necrosis
Fluid
Proximal
bowel
Inflammatory dilatation
wall edema

Point of obstruction
from extrinsic, intrinsic,
or intraluminal disease

Collapsed
bowel distal
to obstruction
PART 10

Patients with distal

obstruction may still
discharge intraluminal
Disorders of the Gastrointestinal System

contents
Note: intraluminal obstruction is displayed
FIGURE 330-1 Pathophysiologic changes of small-bowel obstruction.

Closed-loop obstruction results when the proximal and distal when there is bacterial overgrowth. Patients with more proximal
openings of a given bowel segment are both occluded, for example, obstruction commonly present with less abdominal distention but
due to volvulus or a hernia. It is the most common precursor for stran- more pronounced vomiting. Elements of the history that might be
gulation, but not every closed loop strangulates. The risk of vascular helpful include any prior history of surgery, including herniorrhaphy,
insufficiency, systemic inflammation, hemodynamic compromise, as well as any history of cancer or inflammatory bowel disease.
and irreversible intestinal ischemia is much greater in patients with Most patients, even those with simple obstruction, appear to be crit-
closed-loop obstruction. Pathologic changes may occur more rapidly, ically ill. Many may be oliguric, hypotensive, and tachycardic because
and emergency intervention is indicated. Irreversible bowel ischemia of severe intravascular volume depletion. Fever is worrisome for stran-
may progress to transmural necrosis even if obstruction is relieved. gulation or systemic inflammation. Bowel sounds and bowel functional
It is also important to remember that patients with high-grade distal activity are notoriously difficult to interpret. Classically, many patients
colonic obstruction who have competent ileocecal valves may present with early small-bowel obstruction will have high-pitched, “musical”
with closed-loop obstruction. In the latter instance, the cecum may tinkling bowel sounds and peristaltic “rushes” known as borborygmi.
progressively dilate such that ischemic necrosis results in perforation Later in the course of disease, the bowel sounds may be absent or
especially when the cecal diameter exceeds 10–12 cm, as informed by hypoactive as peristaltic activity decreases. This is in contrast to the
Laplace’s law. Patients with distal colonic obstruction whose ileocecal common findings in patients with ileus or pseudo-obstruction where
valves are incompetent tend to present later in the course of disease and bowel sounds are typically absent or hypoactive from the beginning.
mimic patients with distal small-bowel obstruction. Lastly, patients with partial blockage may continue to pass flatus and
stool, and those with complete blockage may evacuate bowel contents
■■HISTORY AND PHYSICAL FINDINGS present downstream beyond their obstruction.
Even though the presenting signs and symptoms can be misleading, All surgical incisions should be examined, and the presence of a
many patients with acute obstruction can be accurately diagnosed after tender abdominal or groin mass strongly suggests that an incarcerated
a thorough history and physical examination is performed. However, hernia may be the cause of obstruction. The presence of tenderness
small-bowel obstruction with strangulation can be especially difficult should increase the concern about the presence of complications such
to diagnosis promptly. Early recognition allows earlier treatment that as ischemia, necrosis, or peritonitis. Severe pain with localization or
decreases the risk of progression or other excess morbidity. signs of peritoneal irritation is suspicious for strangulated or closed-
The cardinal signs are colicky abdominal pain, abdominal disten- loop obstruction. It is important to remember that the discomfort may
tion, emesis, and obstipation. More intraluminal fluid accumulates in be out of proportion to physical findings mimicking the complaints of
patients with distal obstruction, which typically leads to greater dis- patients with acute mesenteric ischemia. Patients with colonic volvulus
tention, more discomfort, and delayed emesis. This emesis is feculent present with the classic manifestations of closed-loop obstruction:

HPIM21e_Part10_p2381-p2670.indd 2510 20/01/22 10:04 PM

 severe abdominal pain, vomiting, and obstipation. Asymmetrical 2511
abdominal distension and a tympanic mass may be evident.
Patients with ileus or pseudo-obstruction may have signs and
symptoms similar to those of bowel obstruction. Although abdominal
distention is present, colicky abdominal pain is typically absent, and
patients may not have nausea or emesis. Ongoing, regular discharge of
stool or flatus can sometimes help distinguish patients with ileus from
those with complete mechanical bowel obstruction.
■■LABORATORY AND IMAGING STUDIES
Laboratory testing should include a complete blood count and serum
electrolyte and creatinine measurements. Serial assessments are often
useful. Mild hemoconcentration and slight elevation of the white blood
cell count commonly occur after simple bowel obstruction. Emesis and
dehydration may cause hypokalemia, hypochloremia, elevated blood
urea nitrogen–to–creatinine ratios, and metabolic alkalosis. Patients
may be hyponatremic on admission because many have attempted
to rehydrate themselves with hypotonic fluids. The presence of
guaiac-positive stools and iron-deficiency anemia are strongly sugges-
tive of malignancy.
Higher white blood cell counts with the presence of immature forms
or the presence of metabolic acidosis are worrisome for severe volume
depletion or ischemic necrosis and sepsis. Presently, there are no lab-
oratory tests that are especially useful for identifying the presence of
simple or strangulated obstruction, although increases in serum d-lac-
tate, creatine kinase BB isoenzymes, or intestinal fatty acid binding
protein levels may be suggestive of the latter.
Recommendations for diagnostic imaging continue to evolve. In

CHAPTER 330 Acute Intestinal Obstruction

all cases, the key is not to delay operative intervention unnecessarily
when the patient’s signs or symptoms strongly suggest that high-grade
or complete obstruction or bowel compromise is present. Abdominal
radiography, which must include upright or cross-table lateral views,
can be completed quickly and may indicate the need for emergency
surgical intervention in patients who are not in the immediate post-
operative period. A “staircasing” pattern of dilated air and fluid-filled
small-bowel loops >2.5 cm in diameter with little or no air seen in the
colon are classical findings in patients with small-bowel obstruction,
although findings may be equivocal in some patients with documented
disease. Little bowel gas appears in patients with proximal bowel
obstruction or in patients whose intestinal lumens are filled with
fluid. Upright plain films of the abdomen of patients with large-bowel
obstruction typically show colon dilatation. Small-bowel air-fluid lev-
els may not be obvious if the ileocecal valve is incompetent. Although
it can be difficult to distinguish from ileus, small-bowel obstruction is
more likely when air-fluid levels are seen without significant colonic
distension. Free air suggests that perforation has occurred in patients
who have not recently undergone surgical procedures. A gas-filled,
“coffee bean”–shaped dilated shadow may be seen in patients with
volvulus.
More sophisticated imaging, which may be unnecessarily time con-
suming and expensive, can nevertheless be beneficial when the diagno-
sis is unclear. Computed tomography (CT) is the most commonly used
imaging modality. Its sensitivity for detecting bowel obstruction is ~95% FIGURE 330-2 Computed tomography with oral and intravenous contrast
(78–100%) in patients with high-grade obstruction, with a specificity of demonstrating (A) evidence of small-bowel dilatation with air-fluid levels consistent
96% and an accuracy of ≥95%. Its accuracy in diagnosing closed-loop with a small-bowel obstruction; (B) a partial small-bowel obstruction from an
obstruction is much lower (60%). CT may also provide useful informa- incarcerated ventral hernia (arrow); and (C) decompressed bowel seen distal to
tion regarding location or to identify particular circumstances where the hernia (arrow). (Reproduced with permission from D Longo et al: Harrison’s
Principles of Internal Medicine, 18th ed. New York: McGraw-Hill; 2012.)
surgical intervention is needed urgently. Patients who have evidence
of contrast appearing within the cecum within 4–24 h of oral adminis-
tration of water-soluble contrast can be expected to improve with high pregnant or for whom x-ray exposure is otherwise contraindicated or
sensitivity and specificity (~95% each). For example, contrast studies inappropriate.
may demonstrate a “bird’s beak,” a “c-loop,” or “whorl” deformity on CT CT imaging with enteral and IV contrast can also identify ischemia.
imaging at the site where twisting obstructs the lumen when a colonic Altered bowel wall enhancement is the most specific early finding, but
volvulus is present. Although abdominal radiography is usually the ini- its sensitivity is low. Mesenteric venous gas, pneumoperitoneum, and
tial examination, unlike CT imaging, it may not accurately distinguish pneumatosis intestinalis are late findings indicating the presence of
obstruction from other causes of colonic dysmotility. Examples of some bowel necrosis. CT scanning after a water-soluble contrast enema may
CT images are reproduced in Fig. 330-2. help distinguish ileus or pseudo-obstruction from distal large-bowel
Ultrasonographic evaluations are especially difficult to interpret but obstruction in patients who present with evidence of small-bowel
may be sensitive and appropriate studies to evaluate patients who are and colonic distention. CT enteroclysis, though rarely performed, can

HPIM21e_Part10_p2381-p2670.indd 2511 20/01/22 10:04 PM

 2512 accurately identify neoplasia as a cause of bowel obstruction. Contrast nonoperatively if possible. In most circumstances, early consul-
enemas or colonoscopies are almost always needed to identify causes tation with a surgeon is prudent when there is concern about
of acute colonic obstruction. strangulation obstruction or other abnormality that needs to be
Barium studies are generally contraindicated in patients with firm addressed urgently. Deterioration signifies a need for intervention.
evidence of complete or high-grade bowel obstruction, especially when At this time, the decision as to whether the patient can continue to
they present acutely. Barium should never be given orally to a patient be treated nonoperatively can only be based on clinical judgment,
with possible obstruction until that diagnosis has been excluded. In although, as described earlier, imaging studies can sometimes be
every other case, such investigations should only be performed in helpful. The frequency of major complications after operation
exceptional circumstances and with great caution because patients with ranges from 12 to 47%, with greater risk being attributed to resec-
significant obstruction may develop barium concretions as an additional tion therapies and the patient’s overall health. Risk is increased for
source of blockage and some who would have otherwise recovered will patients with American Society of Anesthesiologists (ASA) physical
require operative intervention. Barium opacification also renders cross- status of class III or higher.
sectional imaging studies or angiography uninterpretable. At operation, dilation proximal to the site of blockage with distal
collapse is a defining feature of bowel obstruction. Intraoperative
TREATMENT strategies depend on the underlying problem and range from lysis
of adhesions to resection with or without diverting ostomy to
Acute Intestinal Obstruction primary resection with anastomosis. Resection is warranted when
there is concern about the bowel’s viability after the obstructive pro-
An improved understanding of the pathophysiology of bowel cess is relieved. Laparoscopic approaches can be useful for patients
obstruction and the importance of fluid resuscitation, electrolyte with early obstruction when extensive adhesions are not expected
repletion, intestinal decompression, and the selected use of antibi- to be present. Some patients with high-grade obstruction secondary
otics has likely contributed to a reduction in mortality from acute to malignant disease that is not amendable to resection will benefit
bowel obstruction. Every patient should be stabilized as quickly from bypass procedures.
as possible. Nasogastric tube suction decompresses the stomach,
minimizes further distention from swallowed air, improves patient ADULT INTUSSUSCEPTION AND GALLSTONE ILEUS
comfort, and reduces the risk of aspiration. Urine output should Primary resection is prudent. Careful manual reduction of any
be assessed using a Foley catheter. In some cases, for example, in involved bowel may limit the amount of intestine that needs to be
patients with cardiac disease, central venous pressures should be removed. A proximal ostomy may be required if unprepped colon
monitored. The use of antibiotics is controversial, although prophy- is involved. The most common site of intestinal obstruction in
lactic administration may be warranted if operation is anticipated. patients with gallstone “ileus” is the ileum (60% of patients). The
PART 10

Complete bowel obstruction is an indication for intervention. Stent- gallstone enters the intestinal tract most often via a cholecysto-
ing may be possible and warranted for some patients with high- duodenal fistula. It can usually be removed by operative entero-
grade obstruction due to unresectable stage IV malignancy. Stenting lithotomy. Addressing the gallbladder disease during urgent or
may also allow elective mechanical bowel preparation before sur- emergent surgery is not recommended.
Disorders of the Gastrointestinal System

gery is undertaken. Because treatment options are so variable, it POSTOPERATIVE BOWEL OBSTRUCTION
is helpful to make as precise a diagnosis as possible preoperatively.
Early postoperative mechanical bowel obstruction is that which
ILEUS occurs within the first 6 weeks of operation. Most are partial and
Patients with ileus are treated supportively with intravenous fluids can be expected to resolve spontaneously. It tends to respond
and nasogastric decompression while any underlying pathology is and behave differently from classic mechanical bowel obstruction
treated. Pharmacologic therapy is not yet proven to be efficacious and may be very difficult to distinguish from postoperative ileus.
or cost-effective. However, peripherally active μ-opioid receptor A higher index of suspicion for a definitive site of obstruction is
antagonists (e.g., alvimopan and methylnaltrexone) may accelerate warranted for patients who undergo laparoscopic surgical proce-
gastrointestinal recovery in some patients who have undergone dures. Patients who first had ileus and then subsequently develop
abdominal surgery. obstructive symptoms after an initial return of normal bowel func-
COLONIC PSEUDO-OBSTRUCTION (OGILVIE’S DISEASE) tion are more likely to have true postoperative small-bowel obstruc-
tion. The longer it takes for a patient’s obstructive symptoms to
Neostigmine is an acetylcholinesterase inhibitor that increases cho- resolve after hospitalization, the more likely the patient is to require
linergic (parasympathetic) activity, which can stimulate colonic surgical intervention.
motility. Some studies have shown it to be moderately effective
in alleviating acute colonic pseudo-obstruction. It is the most
common therapeutic approach and can be used once it is certain Acknowledgment
that there is no mechanical obstruction. Cardiac monitoring is The wisdom and expertise of Dr. William Silen are gratefully
required, and atropine should be immediately available. Intrave- acknowledged.
nous administration induces defecation and flatus within 10 min in ■■FURTHER READING
the majority of patients who will respond. Sympathetic blockade by Catena F et al: Adhesive small bowel adhesions obstruction: Evolu-
epidural anesthesia can successfully ameliorate pseudo-obstruction tions in diagnosis, management and prevention. World J Gastrointest
in some patients. Surg 27:222, 2016.
VOLVULUS Ferrada P et al: Surgery or stenting for colonic obstruction: A practice
Patients with sigmoid volvulus can often be decompressed using a management guideline from the Eastern Association for the Surgery
flexible tube inserted through a rigid proctoscope or using a flexible of Trauma. J Trauma Acute Care Surg 80:659, 2016.
sigmoidoscope. Successful decompression results in sudden release Jaffe T, Thompson WM: Large-bowel obstruction in the adults:
of gas and fluid with evidence of decreased abdominal distension Classic radiographic and CT findings, etiology and mimics. Radiol-
and allows definitive correction to be scheduled electively. Cecal ogy 275:651, 2015.
volvulus most often requires laparotomy or laparoscopic correction. Paulson EK, Thompson WM: Review of small-bowel obstruction:
The diagnosis and when to worry. Radiology 275:332, 2015.
INTRAOPERATIVE STRATEGIES Perry H et al: Relative accuracy of emergency CT in adults with non-
Approximately 60–80% of selected patients with mechanical bowel traumatic abdominal pain. Brit Inst Rad 89:20150416, 2016.
obstruction can be successfully treated conservatively. Indeed, most Taylor MR, Lalani N: Adult small bowel obstruction. Acad Emerg
cases of radiation-induced obstruction should also be managed Med 20:528, 2013.

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 2513
TABLE 331-1 Some Conditions That Mimic Appendicitis

331 and
Acute Appendicitis
Peritonitis
Crohn’s disease
Cholecystitis or other gallbladder
disease
Meckel’s diverticulitis
Mittelschmerz
Mesenteric adenitis
Diverticulitis Omental torsion
Danny O. Jacobs
Ectopic pregnancy Pancreatitis
Endometriosis Lower lobe pneumonia
Gastroenteritis or colitis Pelvic inflammatory disease
ACUTE APPENDICITIS Gastric or duodenal ulceration Ruptured ovarian cyst or other cystic
■■INCIDENCE AND EPIDEMIOLOGY Hepatitis disease of the ovaries
Appendicitis occurs more frequently in westernized societies, but Kidney disease, including Small-bowel obstruction
its incidence is decreasing for uncertain reasons. Nevertheless, acute nephrolithiasis Urinary tract infection
appendicitis remains the most common emergency general surgi- Liver abscess
cal disease affecting the abdomen, with a rate of ~100 per 100,000
person-years in Europe and the Americas or ~11 cases per 10,000 Increasingly it appears that there are two broad categories of patients
people annually. Approximately 9% of men and 7% of women will with appendicitis—those with complicated disease like gangrene or
experience an episode during their lifetime. Appendicitis occurs most perforation and those without. When perforation occurs, the resultant
commonly in 10- to 19-year-olds; however, the average age at diag- leak may be contained by the omentum or other surrounding tissues
nosis appears to be gradually increasing. Overall, 70% of patients are to form an abscess. Free perforation normally causes severe peritonitis.
<30 years old, and most are men. These patients may also develop infective suppurative thrombosis
One of the more common complications and most important of the portal vein and its tributaries along with intrahepatic abscesses.
causes of excess morbidity and mortality is perforation, whether it is The prognosis of the very unfortunate patients who develop this rare
contained and localized or unconstrained within the peritoneal cav- but dreaded complication is very poor.
ity. The incidence of perforated appendicitis (~20 cases per 100,000
person-years) may be increasing. The explanation for this trend is ■■CLINICAL MANIFESTATIONS
unknown. Approximately 20% of all patients will present with evidence Improved diagnosis, supportive care, and surgical interventions are
of perforation, but the percentage risk is much higher in patients <5 or likely responsible for the remarkable decrease in the risk of mortality

CHAPTER 331 Acute Appendicitis and Peritonitis

>65 years of age. from simple appendicitis to currently <1%. Nevertheless, it is still
important to identify patients who might have appendicitis as early
■■PATHOGENESIS OF APPENDICITIS AND as possible. Patients who have persistent symptoms that have not
APPENDICEAL PERFORATION improved over 48 h may be more likely to perforate or develop other
Appendicitis was first described in 1886 by Reginald Fitz. Its etiology is complications.
still not completely understood. Fecaliths, incompletely digested food Appendicitis should be included in the differential diagnosis of
residue, lymphoid hyperplasia, intraluminal scarring, tumors, bacteria, abdominal pain for every patient in any age group unless it is certain
viruses, and inflammatory bowel disease have all been associated with that the organ has been previously removed (Table 331-1).
inflammation of the appendix and appendicitis with potentially differ- The appendix’s anatomic location, which varies, may directly influ-
ent outcomes depending on pathogenesis. ence how the patient presents. Where the appendix can be “found”
Although not proven, obstruction of the appendiceal lumen is ranges from local differences in how the appendiceal body and tip
believed to be an important step in the development of appendicitis— lie relative to its attachment to the cecum (Figs. 331-1 and 331-2), to
at least in some cases. Here, obstruction leads to bacterial overgrowth where the appendix is actually situated in the peritoneal cavity—for
and luminal distension, with an increase in intraluminal pressure that example, from its typical location in the right lower quadrant, to the
can inhibit the flow of lymph and blood. Then, vascular thrombosis pelvis, right flank, right upper quadrant (as may be observed during
and ischemic necrosis with perforation of the distal appendix may pregnancy), or even the left side of the abdomen for patients with mal-
occur. Therefore, perforation that occurs near the base of the appendix rotation or who have severely redundant colons.
should raise concerns about another disease process. Most patients Because the differential diagnosis of appendicitis is so extensive,
who will perforate do so before they are evaluated by surgeons. deciding if a patient has appendicitis can be difficult (Table 331-2).
Appendiceal fecaliths (or appendicoliths) are found in ~50% of Many patients may not present with the classically described history or
patients with gangrenous appendicitis who perforate but are rarely
identified in those who have simple disease. As mentioned earlier,
the incidence of perforated, but not simple, appendicitis appears to
be increasing. The rate of perforated and nonperforated appendicitis
is correlated in men but not in women. Together these observations
suggest that the underlying pathophysiologic processes are different 0.5%
and that simple appendicitis does not always progress to perforation.
It appears that at least some cases of simple acute appendicitis may
resolve spontaneously or with antibiotic therapy with limited risk of
recurrent disease. The use of antibiotics to treat uncomplicated appen-
dicitis continues to be studied intensively. Some data indicate that 64%
some patients who present with uncomplicated appendicitis based on
computed tomography (CT) and who are treated with antibiotics alone
will not experience a recurrence within a year. These findings highlight 1%
the importance of clinical decision-making and risk assessment when
deciding and discussing treatment options with patients who presum-
ably have simple disease, for example, deciding who is an appropriate 32%
candidate for nonoperative management and who is not. The latter
is especially pertinent given the difficulty in assessing which patients 2%
might progress to perforation and which will not. FIGURE 331-1 Regional anatomic variations of the appendix.

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 2514
TABLE 331-3 Relative Frequency of Some Presenting Signs
SIGNS FREQUENCY
Abdominal tenderness >95%
Right lower quadrant tenderness >90%
Rebound tenderness 30–70%
Rectal tenderness 30–40%
Cervical motion tenderness 30%
Rigidity ~10%
Psoas sign 3–5%
Obturator sign 5–10%
Rovsing’s sign 5%
Palpable mass <5%

to answer expeditiously is whether the patient has appendicitis or

some other condition that requires immediate operative intervention.
A major concern is that the likelihood of a delay in diagnosis is greater
if the appendix is unusually positioned. All patients should undergo a
rectal examination. An inflamed appendix located behind the cecum
or below the pelvic brim may prompt very little tenderness of the ante-
rior abdominal wall.
Patients with pelvic appendicitis are more likely to present with
dysuria, urinary frequency, diarrhea, or tenesmus. They may only
experience pain in the suprapubic region on palpation or on rectal
or pelvic examination. A pelvic examination in women is mandatory
to rule out conditions affecting urogynecologic organs that can cause
abdominal pain and mimic appendicitis such as pelvic inflammatory
disease, ectopic pregnancy, and ovarian torsion. Interest in the ability
PART 10

FIGURE 331-2 Locations of the appendix and cecum.

of various clinical scoring systems to predict appendicitis or the need
physical findings, and some may not have any abdominal discomfort for imaging studies continues. However, none of the currently available
early in the disease process. Soliciting an appropriate history requires decision tools yet appear to be able to circumvent or obviate the need
detecting and evaluating symptoms that might suggest alternative for expert clinical opinion. The relative frequencies of some presenting
signs are displayed in Table 331-3.
Disorders of the Gastrointestinal System

diagnoses.
What is the classic history? Nonspecific complaints occur first. Patients with simple appendicitis normally only appear mildly ill
Patients may notice changes in bowel habits or malaise and vague, with a pulse and temperature that are usually only slightly above nor-
perhaps intermittent, crampy abdominal pain in the epigastric or peri- mal. The provider should be concerned about other disease processes
umbilical region. The pain subsequently migrates to the right lower beside appendicitis or the presence of complications such as perfora-
quadrant over 12–24 h, where it is sharper and can be definitively local- tion, phlegmon, or abscess formation if the temperature is >38.3°C
ized as transmural inflammation when the appendix irritates the pari- (~101°F) and if there are rigors.
etal peritoneum. Parietal peritoneal irritation may be associated with Patients with appendicitis will be found to lie quite still to avoid
local muscle rigidity and stiffness. Patients with appendicitis will most peritoneal irritation caused by movement, and some will report dis-
often observe that their nausea, if present, followed the development of comfort caused by a bumpy car ride on the way to the hospital or clinic,
abdominal pain, which can help distinguish them from patients with coughing, sneezing, or other actions that replicate a Valsalva maneuver.
gastroenteritis, for example, in whom nausea occurs first. Emesis, if The entire abdomen should be examined systematically starting in an
present, also occurs after the onset of pain and is typically mild and area where the patient does not report discomfort if possible. Clas-
scant. Thus, timing of the onset of symptoms and the characteristics sically, maximal tenderness is identified where the appendix is most
of the patient’s pain and any associated findings must be rigorously often located—in the right lower quadrant at or near McBurney’s point,
assessed. Anorexia is so common that the diagnosis of appendicitis which is approximately one-third of the way along a line originating at
should be questioned in its absence. the anterior iliac spine and running to the umbilicus. Gentle pressure
Arriving at the correct diagnosis is even more challenging when in the left lower quadrant may elicit pain in the right lower quadrant
the appendix is not located in the right lower quadrant, in women of if the appendix is located there. This is Rovsing’s sign (Table 331-4).
childbearing age, and in the very young or elderly. Because the dif- Evidence of parietal peritoneal irritation is often best elicited by gentle
ferential diagnosis of appendicitis is so broad, often the key question abdominal percussion, jiggling the patient’s gurney or bed, or mildly
bumping the feet.
TABLE 331-2 Relative Frequency of Common Presenting Symptoms
SYMPTOMS FREQUENCY TABLE 331-4 Classic Signs of Appendicitis in Patients with
Abdominal pain >95% Abdominal Pain
Anorexia >70% MANEUVER FINDINGS
Constipation 4–16% Rovsing’s sign Palpating in the left lower quadrant causes pain in
the right lower quadrant
Diarrhea 4–16%
Obturator sign Internal rotation of the hip causes pain, suggesting
Fever 10–20% the possibility of an inflamed appendix located in
Migration of pain to right lower 50–60% the pelvis
quadrant Iliopsoas sign Extending the right hip causes pain along
Nausea >65% posterolateral back and hip, suggesting retrocecal
Vomiting 50–75% appendicitis

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 Atypical presentation and pain patterns are common, especially in 2515
the very old or the very young. Diagnosing appendicitis in children can
be especially challenging because they tend to respond so dramatically
to stimulation and obtaining an accurate history may be difficult. In
addition, it is important to remember that the smaller omentum found
in children may be less likely to wall off an appendiceal perforation.
Observing the child in a quiet surrounding may be helpful.
Signs and symptoms of appendicitis can be subtle in the elderly
who may not react as vigorously to appendicitis as younger people.
Pain, if noticed, may be minimal and have originated in the right lower
quadrant or, otherwise, where the appendix is located. It may never
have been noticed to be intermittent, or there may only be significant
discomfort with deep palpation. Nausea, anorexia, and emesis may be
the predominant complaints. The rare patient may even present with
signs and symptoms of distal bowel obstruction secondary to appendi-
ceal inflammation and phlegmon or abscess formation.

■■LABORATORY TESTING
Laboratory testing does not identify patients with appendicitis. The
white blood cell count is only mildly to moderately elevated in ~70%
of patients with simple appendicitis (with a leukocytosis of 10,000– FIGURE 331-3 Computed tomography with oral and intravenous contrast of acute
18,000 cells/μL). A “left shift” toward immature polymorphonuclear appendicitis. There is thickening of the wall of the appendix and periappendiceal
leukocytes is present in >95% of cases. A sickle cell preparation may stranding (arrow).
be prudent to obtain in those of African, Spanish, Mediterranean, or
Indian ancestry. Serum amylase and lipase levels should be measured.
Urinalysis is indicated to help exclude genitourinary conditions that that should not be used to rule out the presence of appendiceal or
may mimic acute appendicitis, but a few red or white blood cells may periappendiceal inflammation.
be present as a nonspecific finding. However, an inflamed appendix ■■SPECIAL PATIENT POPULATIONS

CHAPTER 331 Acute Appendicitis and Peritonitis

that abuts the ureter or bladder may cause sterile pyuria or hematuria. Appendicitis is the most common extrauterine general surgical emer-
Every woman of childbearing age should have a pregnancy test. Cer- gency observed during pregnancy. Early symptoms of appendicitis
vical cultures are indicated if pelvic inflammatory disease is suspected. such as nausea and anorexia may be overlooked. Diagnosing appen-
Anemia and guaiac-positive stools should raise concern about the dicitis in pregnant patients may be especially difficult because as the
presence of other diseases or complications such as cancer. uterus enlarges the appendix may be pushed higher along the right
flank even to the right upper quadrant or because the gravid uterus
■■IMAGING may obscure typical physical findings. Ultrasonography may facilitate
Plain films of the abdomen are rarely helpful and so are not routinely early diagnosis. A high index of suspicion is required because of the
obtained unless the clinician is worried about other conditions such as effects of unrecognized and untreated appendicitis on the fetus. For
intestinal obstruction, perforated viscus, or ureterolithiasis. Less than example, the fetal mortality rate is four times greater (from 5 to 20%)
5% of patients will present with an opaque fecalith in the right lower in patients with perforation.
quadrant. The presence of a fecalith is not diagnostic of appendicitis, Immunocompromised patients may present with only mild tender-
although its presence in an appropriate location where the patient com- ness and may have many other disease processes in their differential
plains of pain is suggestive and is associated with a greater likelihood diagnosis, including atypical infections from mycobacteria, Cytomeg-
of complications. alovirus, or other fungi. Enterocolitis is a concern and may be present
The effectiveness of ultrasonography as a tool to diagnosis appen- in patients who present with abdominal pain, fever, and neutropenia
dicitis is highly operator dependent. Even in very skilled hands, the due to chemotherapy. CT imaging may be very helpful, although it is
appendix may not be visualized. Its overall sensitivity is 0.86, with a
specificity of 0.81. Ultrasonography, especially intravaginal techniques,
appears to be most useful for identifying pelvic pathology in women.
Ultrasonographic findings suggesting the presence of appendicitis
include wall thickening, an increased appendiceal diameter, and the
presence of free fluid. Current practice in many institutions is to first
perform ultrasonography and progress to other imaging studies only if
the findings are equivocal.
The sensitivity and specificity of CT are at least 0.94 and 0.95,
respectively. Thus, CT imaging, given its high negative predictive value,
may be helpful if the diagnosis is in doubt, although studies performed
early in the course of disease may not have any typical radiographic
findings. In patients where the diagnosis is uncertain, delaying oper-
ation at the time of presentation to obtain CT does not appear to
increase the risk of perforation. CT scanning is a superior method for
assessing the severity of acute appendicitis in the absence of peritoneal
findings indicative of perforation, abscess, or suspicion of an associated
malignancy.
Suggestive findings on CT examination include dilatation >6 mm
with wall thickening, a lumen that does not fill with enteric contrast,
and fatty tissue stranding or air surrounding the appendix, which sug-
gests inflammation (Figs. 331-3 and 331-4). The presence of luminal
air or contrast is not consistent with a diagnosis of appendicitis. Fur-
thermore, nonvisualization of the appendix is a nonspecific finding FIGURE 331-4 Appendiceal fecalith (arrow).

HPIM21e_Part10_p2381-p2670.indd 2515 20/01/22 10:04 PM

 2516 important not to be overly cautious and delay operative intervention TABLE 331-5 Conditions Leading to Secondary Bacterial Peritonitis
for those patients who are believed to have appendicitis. Bowel perforation Perforation or leakage of other organs
 Appendicitis trauma (blunt or  Biliary leakage (e.g., after liver
TREATMENT penetrating) biopsy)
Anastomotic leakage Cholecystitis
Acute Appendicitis Adhesion Intraperitoneal bleeding
In the absence of contraindications, most patients who have Diverticulitis Pancreatitis
strongly suggestive medical histories and physical examinations  Iatrogenic (including endoscopic Salpingitis
with supportive laboratory findings are candidates for appendec- perforation)  Traumatic or other rupture of urinary
tomy. In many instances, imaging studies are not required but are Ingested foreign body bladder
often obtained before surgical consultation is requested. Certainly, Inflammation Loss of peritoneal integrity
imaging and further study are appropriate in patients whose evalu- Intussusception Intraperitoneal chemotherapy
ations are suggestive but not convincing. Neoplasms  Iatrogenic (e.g., postoperative
CT may accurately indicate the presence of appendicitis or other Obstruction foreign body)
intraabdominal processes that warrant intervention. Whenever Peptic ulcer disease Perinephric abscess
the diagnosis is uncertain, it is prudent to observe the patient and Strangulated hernia  Peritoneal dialysis or other
repeat the abdominal examination over 6–8 h. Any evidence of  Vascular (including ischemia or
indwelling devices
progression is an indication for operation. Narcotics can be given embolus) Trauma
to patients with severe discomfort.
All patients should be fully prepared for surgery and have any
fluid and electrolyte abnormalities corrected. Either laparoscopic inflammatory bowel disease, and intestinal obstruction or volvulus.
or open appendectomy is a satisfactory choice for patients with Conditions that may cause secondary bacterial peritonitis and their
uncomplicated appendicitis, although most procedures are now mechanisms are listed in Table 331-5. Over 90% of the cases of primary
performed in a minimally invasive fashion to the patient’s benefit or spontaneous bacterial peritonitis occur in patients with ascites or
in terms of recovery time and complications. Management of those hypoproteinemia (<1 g/L).
who present with a mass representing a phlegmon or abscess can Aseptic peritonitis is most commonly caused by the abnormal
be more difficult. Such patients are best served by treatment with presence of physiologic fluids such as gastric juice, bile, pancreatic
broad-spectrum antibiotics, drainage if there is an abscess >3 cm enzymes, blood, or urine. It can also be caused by the effects of nor-
in diameter, and parenteral fluids and bowel rest if they appear
PART 10

mally sterile foreign bodies such as surgical sponges or instruments.

to respond to conservative management. The appendix can then More rarely, it occurs as a complication of systemic diseases such as
be more safely removed 6–12 weeks later when inflammation has lupus erythematosus, porphyria, and familial Mediterranean fever. The
diminished. chemical irritation caused by stomach acid and activated pancreatic
Laparoscopic appendectomy now accounts for the majority of all enzymes is extreme, and secondary bacterial infection may occur.
Disorders of the Gastrointestinal System

appendectomies performed in Western cultures and is associated

with less postoperative pain, shorter lengths of stay, faster return to ■■CLINICAL FEATURES
normal activity, and likely fewer superficial wound complications, The cardinal signs and symptoms of peritonitis are acute, typically
although the risk of intraabdominal abscess formation may be severe, abdominal pain with tenderness and fever. How patients’
higher. complaints of pain are manifested depends on their overall physical
A laparoscopic approach may also be useful when the exact health and whether the inflammation is diffuse or localized. Elderly
diagnosis is uncertain. A laparoscopic approach may also facilitate and immunosuppressed patients may not respond as aggressively to
exposure in those who are very obese. Absent complications, most the irritation. Diffuse, generalized peritonitis is most often recognized
patients can be discharged within 24–40 h of operation. The most as diffuse abdominal tenderness with local guarding, rigidity, and other
common postoperative complications are fever and leukocytosis. evidence of parietal peritoneal irritation. Physical findings may only
Continuation of these findings beyond 5 days should raise concern be identified in a specific region of the abdomen if the intraperitoneal
for the presence of an intraabdominal abscess. The mortality rate inflammatory process is limited or otherwise contained as may occur
for uncomplicated, nonperforated appendicitis is 0.1–0.5%, which in patients with uncomplicated appendicitis or diverticulitis. Bowel
approximates the overall risk of general anesthesia. The mortality sounds are usually absent to hypoactive.
rate for perforated appendicitis or other complicated disease is Most patients present with tachycardia and signs of volume deple-
much higher, ranging from 3% overall to as high as 15% in the tion with hypotension. Laboratory testing typically reveals a significant
elderly. leukocytosis, and patients may be severely acidotic. Radiographic stud-
ies may show dilatation of the bowel and associated bowel wall edema.
Free air or other evidence of leakage requires attention and could
ACUTE PERITONITIS represent a surgical emergency. In stable patients in whom ascites is
Acute peritonitis, or inflammation of the visceral and parietal perito- present, diagnostic paracentesis is indicated, where the fluid is tested
neum, is most often but not always infectious in origin, resulting from for protein and lactate dehydrogenase and the cell count is measured.
perforation of a hollow viscus. This is called secondary peritonitis, as
opposed to primary or spontaneous peritonitis, when a specific intraab- ■■THERAPY AND PROGNOSIS
dominal source cannot be identified. In either instance, the inflamma- Whereas mortality rates can be <10% for reasonably healthy patients
tion can be localized or diffuse. with relatively uncomplicated, localized peritonitis, mortality rates
>40% have been reported for the elderly or immunocompromised.
■■ETIOLOGY Successful treatment depends on correcting any electrolyte abnormali-
Infective organisms may contaminate the peritoneal cavity after ties, restoration of fluid volume and stabilization of the cardiovascular
spillage from a hollow viscus, because of a penetrating wound of the system, appropriate antibiotic therapy, and surgical correction of any
abdominal wall, or because of the introduction of a foreign object like underlying abnormalities.
a peritoneal dialysis catheter or port that becomes infected. Secondary
peritonitis most commonly results from perforation of the appen- Acknowledgment
dix, colonic diverticula, or the stomach and duodenum. It may also The wisdom and expertise of Dr. William Silen is gratefully acknowl-
occur as a complication of bowel infarction or incarceration, cancer, edged in this updated chapter on acute appendicitis and peritonitis.

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 ■■FURTHER READING men and ~1800 kcal/d for American women, although these estimates 2517
Andersson RE: Short-term complications and long-term morbidity vary with body size and activity level. Formulas for roughly estimating
of laparoscopic and open appendicectomy in a national cohort. Br J REE are useful in assessing the energy needs of an individual whose
Surg 101:1135, 2014. weight is stable. Thus, for males, REE = 900 + 10m, and for females,
Buckius MT et al: Changing epidemiology of acute appendicitis in REE = 700 + 7m, where m is mass in kilograms. The calculated REE is
the United States: Study period 1993–2008. J Surg Res 175:185, 2012. then adjusted for physical activity level by multiplying by 1.2 for seden-
CODA Collaborative: A randomized trial comparing antibiotics tary, 1.4 for moderately active, or 1.8 for very active individuals. The final
with appendectomy for appendicitis. N Engl J Med 383:1907, 2020. figure, the estimated energy requirement (EER), provides an approxima-
Di Saverio S et al: Diagnosis and treatment of acute appendicitis: tion of total caloric needs in a state of energy balance for a person of a
2020 update of the WSES Jerusalem guidelines. World J Emerg Surg certain age, sex, weight, height, and physical activity level. For further
15:27, 2020. discussion of energy balance in health and disease, see Chap. 334.
Drake FT et al: Time to appendectomy and risk of perforation in acute
appendicitis. JAMA Surg 149:837, 2014. Protein Dietary protein consists of both essential and nonessential
Flum DR: Acute appendicitis—appendectomy of the “antibiotics first” amino acids that are required for protein synthesis. The nine essential
strategy. N Engl J Med 372:1937, 2015. amino acids are histidine, isoleucine, leucine, lysine, methionine/
Ohle R et al: The Alvarado score for predicting acute appendicitis: cystine, phenylalanine/tyrosine, threonine, tryptophan, and valine.
A systematic review. BMC Med 9:139, 2011. Certain amino acids, such as alanine, can also be used for energy and
Talan DA, DiSaverio S: Treatment of acute uncomplicated appendicitis. gluconeogenesis. When energy intake is inadequate, protein intake
N Engl J Med 385:1116, 2021. must be increased, because ingested amino acids are diverted into
Vons C et al: Amoxicillin plus clavulanic acid versus appendicectomy pathways of glucose synthesis and oxidation. In extreme energy depri-
for treatment of acute uncomplicated appendicitis: An open-label, vation, protein-calorie malnutrition may ensue (Chap. 334).
non-inferiority, randomised controlled trial. Lancet 377:1573, 2011. For adults, the recommended dietary allowance (RDA) for protein
is ~0.8 g/kg desirable body mass per day, assuming that energy needs
are met and that the protein is of relatively high biologic value. Current
recommendations for a healthy diet call for at least 10–14% of calories
from protein. Most American diets provide at least those amounts. Bio-
logic value tends to be highest for animal proteins, followed by proteins
from legumes (beans), cereals (rice, wheat, corn), and roots. Combina-
Section 2 Nutrition

CHAPTER 332 Nutrient Requirements and Dietary Assessment

tions of plant proteins that complement one another in their essential
amino acid profiles or combinations of animal and plant proteins can
increase biologic value and lower total protein intakes necessary to

332 and
meet requirements. In healthy people with adequate diets, the timing
Nutrient Requirements of protein intake over the course of the day has little effect.
Dietary Assessment Protein needs increase during growth, pregnancy, lactation, and
rehabilitation after injury or undernutrition. Tolerance to dietary pro-
Johanna T. Dwyer tein is decreased in renal insufficiency (with consequent uremia) and
in liver failure. Usual protein intakes can precipitate encephalopathy in
patients with cirrhosis of the liver.
Nutrients are substances that are not synthesized in sufficient amounts Fat and Carbohydrate Fats are a concentrated source of energy
in the body and therefore must be supplied by the diet. Nutrient require- and constitute, on average, 34% of calories in U.S. diets. However, for
ments for groups of healthy persons have been determined experimen- optimal health, fat intake should total no more than 30% of calories.
tally. The absence of essential nutrients leads to growth impairment, Saturated fat and trans fat should be limited to <10% of calories and
organ dysfunction, and failure to maintain nitrogen balance or adequate polyunsaturated fats to <10% of calories, with monounsaturated fats
status of protein and other nutrients. For good health, we require energy- accounting for the remainder of fat intake. At least 45–55% of total cal-
providing nutrients (protein, fat, and carbohydrate), vitamins, minerals, ories should be derived from carbohydrates. The brain requires ~100 g
and water. Requirements for organic nutrients include 9 essential amino of glucose per day for fuel; other tissues use ~50 g/d. Some tissues (e.g.,
acids, several fatty acids, glucose, 4 fat-soluble vitamins, 10 water-soluble brain and red blood cells) rely on glucose supplied either exogenously
vitamins, dietary fiber, and choline. Several inorganic substances, includ- or from muscle proteolysis. Over time, during hypocaloric states,
ing 4 minerals, 7 trace minerals, 3 electrolytes, and the ultratrace elements, adaptations in carbohydrate needs are possible. Like fat (9 kcal/g), car-
must also be supplied by diet. bohydrate (4 kcal/g), and protein (4 kcal/g), alcohol (ethanol) provides
The amounts of essential nutrients required by individuals differ by energy (7 kcal/g). However, it is not a nutrient.
their age and physiologic state. Conditionally essential nutrients are not
required in the diet but must be supplied to certain individuals who do not Water For adults, 1–1.5 mL of water per kilocalorie of energy expen-
synthesize them in adequate amounts, such as those with genetic defects; diture is sufficient under usual conditions to allow for normal variations
those with pathologies such as infection, disease, or trauma with nutri- in physical activity, sweating, and solute load of the diet. Water losses
tional implications; and developmentally immature infants. For example, include 50–100 mL/d in the feces; 500–1000 mL/d by evaporation or
inositol, taurine, arginine, and glutamine may be needed by premature exhalation; and, depending on the renal solute load, ≥1000 mL/d in the
infants. Many other organic and inorganic compounds that are present urine. If external losses increase, intakes must increase accordingly to
in foods and dietary supplements, including pesticides, lead, phytochem- avoid underhydration. Fever increases water losses by ~200 mL/d per
icals, zoochemicals, and microbial products, may also have health effects. °C; diarrheal losses vary but may be as great as 5 L/d in severe diarrhea.
Heavy sweating, vigorous exercise, and vomiting also increase water
■■ESSENTIAL NUTRIENT REQUIREMENTS losses. When renal function is normal and solute intakes are adequate,
the kidneys can adjust to increased water intake by excreting up to 18 L
Energy For weight to remain stable, energy intake must match energy of excess water per day (Chap. 381). However, obligatory urine outputs
output. The major components of energy output are resting energy can compromise hydration status when there is inadequate water intake
expenditure (REE) and physical activity; minor components include or when losses increase in disease or kidney damage.
the energy cost of metabolizing food (thermic effect of food, or specific Infants have high requirements for water because of their large sur-
dynamic action) and shivering thermogenesis (e.g., cold-induced ther- face area to volume ratios, their inability to communicate their thirst,
mogenesis). The average energy intake is ~2600 kcal/d for American and the limited capacity of the immature kidney to handle high renal

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 2518 solute loads. Increased water needs during pregnancy are ~30 mL/d. The risk of dietary inadequacy increases as one’s intake falls below
During lactation, milk production increases daily water requirements so the RDA. However, the RDA is an overly generous criterion for evalu-
that ~1000 mL of additional water is needed, or 1 mL for each milliliter ating nutrient adequacy. For example, by definition, the RDA exceeds
of milk produced. Special attention must also be paid to the water needs the actual requirements of all but ~2–3% of the population. Therefore,
of the elderly, who have reduced total-body water and blunted thirst many people whose intake falls below the RDA are still getting enough
sensation and are more likely to be taking medications such as diuretics. of the nutrient. On food labels, the nutrient content in a food is stated
by weight or as a percentage of the daily value (DV), a variant of the
Other Nutrients See Chap. 333 for detailed descriptions of vita- RDA used on the nutrition facts panel that, for an adult, represents the
mins and minerals. highest RDA for an adult consuming 2000 kcal.
■■DIETARY REFERENCE INTAKES AND RDAS Adequate Intake (AI) It is not possible to set an RDA for some
Fortunately, human life and well-being can be maintained within a nutrients that lack an established EAR. In this circumstance, the AI is
fairly wide range with most nutrient intakes. However, the capacity based on observed or experimentally determined approximations of
for adaptation is not infinite—too much, as well as too little, intake nutrient intakes in healthy people. In the DRIs, AIs rather than RDAs
of a nutrient can have adverse effects or alter the health benefits con- are proposed for nutrients consumed by infants (up to age 1 year) as
ferred by another nutrient. Therefore, benchmark recommendations well as for chromium, fluoride, manganese, sodium, potassium, panto-
regarding nutrient intakes have been developed to guide clinical prac- thenic acid, biotin, choline, and water consumed by persons of all ages.
tice. These quantitative estimates of nutrient intakes are collectively
referred to in the United States and Canada as the dietary reference Tolerable Upper Levels (UL) Healthy individuals gain no estab-
intakes (DRIs). The DRIs supplanted the RDAs—the single reference lished benefit from consuming nutrient levels above the RDA or AI.
values used in the United States until the early 1990s. DRIs include an In fact, excessive nutrient intake can disturb body functions and cause
estimated average requirement (EAR) for nutrients as well as other ref- acute, progressive, or permanent disabilities. The tolerable UL is the
erence values used for dietary planning: the RDA, the adequate intake highest level of chronic (usually daily) nutrient intake that is unlikely to
(AI), the chronic disease risk reduction intake (CDRR), and the tolera- pose a risk of adverse health effects for most of the population. Data on
ble upper level (UL). The DRIs also include acceptable macronutrient the adverse effects of large amounts of many nutrients are unavailable
distribution ranges (AMDRs) for protein, fat, and carbohydrate. The or too limited to establish a UL. Therefore, the lack of a UL does not
current DRIs for vitamins and elements are provided in Tables 332-1 mean that the risk of adverse effects from high intake is nonexistent.
and 332-2, respectively. Table 332-3 provides DRIs for water and Nutrient levels in commonly eaten foods rarely exceed the UL. How-
macronutrients. EERs are discussed in Chap. 334 on energy balance ever, very highly fortified foods and dietary supplements provide more
in health and disease. concentrated amounts of nutrients per serving and thus pose a poten-
PART 10

tial risk of toxicity. Dietary supplements are labeled with Supplement

Estimated Average Requirement (EAR) When florid manifes- Facts that express the amount of nutrients present in absolute units or
tations of the classic dietary-deficiency diseases such as rickets (defi- as the percentage of the DV provided per recommended serving size.
ciency of vitamin D and calcium), scurvy (deficiency of vitamin C), Total nutrient intakes, including that in foods, supplements, and over-
xerophthalmia (deficiency of vitamin A), and protein-calorie malnutri- the-counter medications (e.g., antacids), should not exceed RDA levels.
Disorders of the Gastrointestinal System

tion were common, nutrient adequacy was inferred from the absence
of their clinical deficiency signs. Later, biochemical and other changes Chronic Disease Risk Reduction Intake (CDRR) This is the
were used that became evident long before the deficiency was clini- level above which a reduction in intake is expected to lower chronic
cally apparent. Consequently, criteria of adequacy are now based on disease risk. For example, the sodium CDRR for adults is 2300 mg/d,
biologic markers when they are available. Priority is given to sensitive and this is the lowest level of intake for which there is sufficiently
biochemical, physiologic, or behavioral tests that reflect early changes strong evidence to characterize a CDRR. Three is no CDRR for potas-
in regulatory processes; maintenance of body stores of nutrients; or, if sium or other nutrients, but the AI for potassium has been reduced to
available, the amount of a nutrient that minimizes the risk of chronic 2500 mg/d from a higher prior level. At present, population recom-
degenerative disease. Current efforts focus on this last variable, but mendations for CDRR are not available for other nutrients.
relevant markers often are not available, and the long time lags between Acceptable Macronutrient Distribution Ranges (AMDRs)
intake and disease outcomes further complicate the picture. AMDRs are not experimentally determined; rather, they are rough
The types of evidence and criteria used to establish nutrient require- ranges for energy-providing macronutrient intakes (protein, carbo-
ments vary by nutrient, age, and physiologic group. The EAR is the hydrate, and fat) that the National Academy of Medicine’s (formerly
amount of a nutrient estimated to be adequate for half of the healthy Institute of Medicine [IOM]) Food and Nutrition Board considers to
individuals of a specific age and sex. It is not an effective estimate of be healthful. These ranges are 10–35% of calories for protein, 20–35%
nutrient adequacy in individuals because it is a median requirement for of calories for fat, and 45–65% of calories for carbohydrate. Alcohol,
a group; 50% of individuals in a group fall below the requirement and which also provides energy, is not a nutrient; therefore, no recommen-
50% fall above it. Thus, a person with a usual intake at the EAR has a dations are provided.
50% risk of inadequate intake. For these reasons, the other standards
described below are more useful for clinical purposes. ■■FACTORS ALTERING NUTRIENT NEEDS
Recommended Dietary Allowances The RDA, the nutrient The DRIs are affected by age, sex, growth rate, pregnancy, lactation,
intake goal for planning diets of individuals, is the average daily dietary physical activity level, concomitant diseases, drugs, and dietary compo-
intake level that meets the nutrient requirements of nearly all healthy sition. If requirements for nutrient sufficiency are close to intake levels
persons of a specific sex, age, life stage, or physiologic condition (e.g., indicating excess of a nutrient, dietary planning is difficult.
pregnancy or lactation). It is defined statistically as two standard devi- Physiologic Factors Growth, strenuous physical activity, preg-
ations above the EAR to ensure that the needs of any given individual nancy, and lactation all increase needs for energy and several essential
are met. An online tool, available at https://www.nal.usda.gov/fnic/ nutrients. Energy needs rise during pregnancy due to fetal growth
dri-calculator/, allows health professionals to calculate individual- demands and increased energy required for milk production during
ized daily nutrient recommendations for dietary planning based on lactation. Energy needs decrease with loss of lean body mass, the major
the DRIs. The RDAs are used to formulate food guides such as the determinant of REE. The energy needs of older persons, especially
U.S. Department of Agriculture (USDA) MyPlate Plan for individu- those aged >70 years, tend to be lower than those of younger persons
als (https://www.choosemyplate.gov/resources/MyPlatePlan), to create because lean tissue, physical activity, and health often decline with age.
food-exchange lists for therapeutic diet planning, and as a standard
for describing the nutritional content of foods and nutrient-containing Dietary Composition Dietary composition affects the biologic
dietary supplements on labels. availability and use of nutrients. For example, iron absorption may be

HPIM21e_Part10_p2381-p2670.indd 2518 20/01/22 10:04 PM

HPIM21e_Part10_p2381-p2670.indd 2519

TABLE 332-1 Dietary Reference Intakes (DRIs): Recommended Dietary Allowances and Adequate Intakes for Vitamins
VITAMIN A VITAMIN C VITAMIN D VITAMIN E VITAMIN K THIAMIN RIBOFLAVIN NIACIN VITAMIN B6 FOLATE VITAMIN B12 PANTOTHENIC BIOTIN CHOLINE
LIFE-STAGE GROUP (lg/d)a (mg/d) (lg/d)b,c (mg/d)d (lg/d) (mg/d) (mg/d) (mg/d)e (mg/d) (lg/d)F (lg/d) ACID (mg/d) (lg/d) (mg/d)G
Infants
Birth to 6 mo 400* 40* 10 4* 2.0* 0.2* 0.3* 2* 0.1* 65* 0.4* 1.7* 5* 125*
6–12 mo 500* 50* 10 5* 2.5* 0.3* 0.4* 4* 0.3* 80* 0.5* 1.8* 6* 150*
Children
1–3 y 300 15 15 6 30* 0.5 0.5 6 0.5 150 0.9 2* 8* 200*
4–8 y 400 25 15 7 55* 0.6 0.6 8 0.6 200 1.2 3* 12* 250*
Males
9–13 y 600 45 15 11 60* 0.9 0.9 12 1.0 300 1.8 4* 20* 375*
14–18 y 900 75 15 15 75* 1.2 1.3 16 1.3 400 2.4 5* 25* 550*
19–30 y 900 90 15 15 120* 1.2 1.3 16 1.3 400 2.4 5* 30* 550*
31–50 y 900 90 15 15 120* 1.2 1.3 16 1.3 400 2.4 5* 30* 550*
51–70 y 900 90 15 15 120* 1.2 1.3 16 1.7 400 2.4h 5* 30* 550*
>70 y 900 90 20 15 120* 1.2 1.3 16 1.7 400 2.4h 5* 30* 550*
Females
9–13 y 600 45 15 11 60* 0.9 0.9 12 1.0 300 1.8 4* 20* 375*
14–18 y 700 65 15 15 75* 1.0 1.0 14 1.2 400i 2.4 5* 25* 400*
19–30 y 700 75 15 15 90* 1.1 1.1 14 1.3 400i 2.4 5* 30* 425*
31–50 y 700 75 15 15 90* 1.1 1.1 14 1.3 400i 2.4 5* 30* 425*
51–70 y 700 75 15 15 90* 1.1 1.1 14 1.5 400 2.4h 5* 30* 425*
>70 y 700 75 20 15 90* 1.1 1.1 14 1.5 400 2.4h 5* 30* 425*
Pregnant Women
14–18 y 750 80 15 15 75* 1.4 1.4 18 1.9 600j 2.6 6* 30* 450*
19–30 y 770 85 15 15 90* 1.4 1.4 18 1.9 600j 2.6 6* 30* 450*
31–50 y 770 85 15 15 90* 1.4 1.4 18 1.9 600j 2.6 6* 30* 450*
Lactating Women
14–18 y 1200 115 15 19 75* 1.4 1.6 17 2.0 500 2.8 7* 35* 550*
19–30 y 1300 120 15 19 90* 1.4 1.6 17 2.0 500 2.8 7* 35* 550*
31–50 y 1300 120 15 19 90* 1.4 1.6 17 2.0 500 2.8 7* 35* 550*
Note: This table (taken from the DRI reports; see www.nap.edu) presents recommended dietary allowances (RDAs) in bold type and adequate intakes (AIs) in ordinary type followed by an asterisk (*). An RDA is the average daily dietary
intake level sufficient to meet the nutrient requirements of nearly all healthy individuals (97–98%) in a group. The RDA is calculated from an estimated average requirement (EAR). If sufficient scientific evidence is not available to establish
an EAR and thus to calculate an RDA, an AI is usually developed. For healthy breast-fed infants, an AI is the mean intake. The AI for other life-stage and sex-specific groups is believed to cover the needs of all healthy individuals in those
groups, but lack of data or uncertainty in the data makes it impossible to specify with confidence the percentage of individuals covered by this intake.
a
As retinol activity equivalents (RAEs). 1 RAE = 1 μg retinol, 12 μg β-carotene, 24 μg α-carotene, or 24 μg β-cryptoxanthin. The RAE for dietary provitamin A carotenoids is twofold greater than the retinol equivalent (RE), whereas the RAE for
preformed vitamin A is the same as the RE. bAs cholecalciferol. 1 μg cholecalciferol = 40 IU vitamin D. cUnder the assumption of minimal sunlight. dAs α-tocopherol. α-Tocopherol includes RRR-α-tocopherol, the only form of α-tocopherol
that occurs naturally in foods, and the 2R-stereoisomeric forms of α-tocopherol (RRR-, RSR-, RRS-, and RSS-α-tocopherol) that occur in fortified foods and supplements. It does not include the 2S-stereoisomeric forms of α-tocopherol (SRR-,
SSR-, SRS-, and SSS-α-tocopherol) also found in fortified foods and supplements. eAs niacin equivalents (NEs). 1 mg of niacin = 60 mg of tryptophan; 0–6 months = preformed niacin (not NE). fAs dietary folate equivalents (DFEs). 1 DFE =
1 μg food folate = 0.6 μg of folic acid from fortified food or as a supplement consumed with food = 0.5 μg of a supplement taken on an empty stomach. gAlthough AIs have been set for choline, there are few data to assess whether a dietary
supply of choline is needed at all stages of the life cycle, and it may be that the choline requirement can be met by endogenous synthesis at some of these stages. hBecause 10–30% of older people may malabsorb food-bound B12, it is
advisable for those >50 years of age to meet their RDA mainly by consuming foods fortified with B12 or a supplement containing B12. iIn view of evidence linking inadequate folate intake with neural tube defects in the fetus, it is recommended
that all women capable of becoming pregnant consume 400 μg of folate from supplements or fortified foods in addition to intake of food folate from a varied diet. j It is assumed that women will continue consuming 400 μg from supplements
or fortified food until their pregnancy is confirmed and they enter prenatal care, which ordinarily occurs after the end of the periconceptional period—the critical time for formation of the neural tube.
20/01/22 10:04 PM

Source: National Academies of Sciences, Engineering, and Medicine. 2019. Dietary Reference Intakes for Sodium and Potassium. https://doi.org/10.17226/25353. Adapted and reproduced with permission from the National Academy of
Sciences, Courtesy of the National Academies.

2519
CHAPTER 332 Nutrient Requirements and Dietary Assessment
HPIM21e_Part10_p2381-p2670.indd 2520

Disorders of the Gastrointestinal System PART 10

2520
TABLE 332-2 Dietary Reference Intakes (DRIs): Recommended Dietary Allowances and Adequate Intakes for Elements
LIFE-STAGE CALCIUM CHROMIUM COPPER FLUORIDE IODINE IRON MAGNESIUM MANGANESE MOLYBDENUM PHOSPHORUS SELENIUM ZINC POTASSIUM SODIUM CHLORIDE
GROUP (mg/d) (lg/d) (lg/d) (mg/d) (lg/d) (mg/d) (mg/d) (mg/d) (lg/d) (mg/d) (lg/d) (mg/d) (g/d) (g/d) (g/d)
Infants
Birth to 6 mo 200* 0.2* 200* 0.01* 110* 0.27* 30* 0.003* 2* 100* 15* 2* 0.4* 0.12* 0.18*
6–12 mo 260* 5.5* 220* 0.5* 130* 11 75* 0.6* 3* 275* 20* 3 0.7* 0.37* 0.57*
Children
1–3 y 700 11* 340 0.7* 90 7 80 1.2* 17 460 20 3 3.0* 1.0* 1.5*
4–8 y 1000 15* 440 1* 90 10 130 1.5* 22 500 30 5 3.8* 1.2* 1.9*
Males
9–13 y 1300 25* 700 2* 120 8 240 1.9* 34 1250 40 8 4.5* 1.5* 2.3*
14–18 y 1300 35* 890 3* 150 11 410 2.2* 43 1250 55 11 4.7* 1.5* 2.3*
19–30 y 1000 35* 900 4* 150 8 400 2.3* 45 700 55 11 4.7* 1.5* 2.3*
31–50 y 1000 35* 900 4* 150 8 420 2.3* 45 700 55 11 4.7* 1.5* 2.3*
51–70 y 1000 30* 900 4* 150 8 420 2.3* 45 700 55 11 4.7* 1.3* 2.0*
>70 y 1200 30* 900 4* 150 8 420 2.3* 45 700 55 11 4.7* 1.2* 1.8*
Females
9–13 y 1300 21* 700 2* 120 8 240 1.6* 34 1250 40 8 4.5* 1.5* 2.3*
14–18 y 1300 24* 890 3* 150 15 360 1.6* 43 1250 55 9 4.7* 1.5* 2.3*
19–30 y 1000 25* 900 3* 150 18 310 1.8* 45 700 55 8 4.7* 1.5* 2.3*
31–50 y 1000 25* 900 3* 150 18 320 1.8* 45 700 55 8 4.7* 1.5* 2.3*
51–70 y 1200 20* 900 3* 150 8 320 1.8* 45 700 55 8 4.7* 1.3* 2.0*
>70 y 1200 20* 900 3* 150 8 320 1.8* 45 700 55 8 4.7* 1.2* 1.8*
Pregnant Women
14–18 y 1300 29* 1000 3* 220 27 400 2.0* 50 1250 60 12 4.7* 1.5* 2.3*
19–30 y 1000 30* 1000 3* 220 27 350 2.0* 50 700 60 11 4.7* 1.5* 2.3*
31–50 y 1000 30* 1000 3* 220 27 360 2.0* 50 700 60 11 4.7* 1.5* 2.3*
Lactating Women
14–18 y 1300 44* 1300 3* 290 10 360 2.6* 50 1250 70 13 5.1* 1.5* 2.3*
19–30 y 1000 45* 1300 3* 290 9 310 2.6* 50 700 70 12 5.1* 1.5* 2.3*
31–50 y 1000 45* 1300 3* 290 9 320 2.6* 50 700 70 12 5.1* 1.5* 2.3*
Note: This table (taken from the DRI reports; see www.nap.edu) presents recommended dietary allowances (RDAs) in bold type and adequate intakes (AIs) in ordinary type followed by an asterisk (*). An RDA is the average daily dietary
intake level sufficient to meet the nutrient requirements of nearly all healthy individuals (97–98%) in a group. The RDA is calculated from an estimated average requirement (EAR). If sufficient scientific evidence is not available to establish
an EAR and thus to calculate an RDA, an AI is usually developed. For healthy breast-fed infants, an AI is the mean intake. The AI for other life-stage and sex-specific groups is believed to cover the needs of all healthy individuals in those
groups, but lack of data or uncertainty in the data makes it impossible to specify with confidence the percentage of individuals covered by this intake.
Sources: National Academies of Sciences, Engineering, and Medicine. 2019. Dietary Reference Intakes for Sodium and Potassium. https://doi.org/10.17226/25353. Adapted and reproduced with permission from the National Academy of
Sciences, Courtesy of the National Academies.
20/01/22 10:04 PM
 2521
TABLE 332-3 Dietary Reference Intakes (DRIs): Recommended Dietary Allowances and Adequate Intakes for Total Water and Macronutrients
LIFE-STAGE TOTAL WATER a
CARBOHYDRATE LINOLEIC ACID `-LINOLENIC ACID
GROUP (L/d) (g/d) TOTAL FIBER (g/d) FAT (g/d) (g/d) (g/d) PROTEINb (g/d)
Infants
Birth to 6 mo 0.7* 60* NDc 31* 4.4* 0.5* 9.1*
6–12 mo 0.8* 95* ND 30* 4.6* 0.5* 11.0
Children
1–3 y 1.3* 130 19* ND 7* 0.7* 13
4–8 y 1.7* 130 25* ND 10* 0.9* 19
Males
9–13 y 2.4* 130 31* ND 12* 1.2* 34
14–18 y 3.3* 130 38* ND 16* 1.6* 52
19–30 y 3.7* 130 38* ND 17* 1.6* 56
31–50 y 3.7* 130 38* ND 17* 1.6* 56
51–70 y 3.7* 130 30* ND 14* 1.6* 56
>70 y 3.7* 130 30* ND 14* 1.6* 56
Females
9–13 y 2.1* 130 26* ND 10* 1.0* 34
14–18 y 2.3* 130 26* ND 11* 1.1* 46
19–30 y 2.7* 130 25* ND 12* 1.1* 46
31–50 y 2.7* 130 25* ND 12* 1.1* 46
51–70 y 2.7* 130 21* ND 11* 1.1* 46
>70 y 2.7* 130 21* ND 11* 1.1* 46

CHAPTER 332 Nutrient Requirements and Dietary Assessment

Pregnant Women
14–18 y 3.0* 175 28* ND 13* 1.4* 71
19–30 y 3.0* 175 28* ND 13* 1.4* 71
31–50 y 3.0* 175 28* ND 13* 1.4* 71
Lactating Women
14–18 3.8* 210 29* ND 13* 1.3* 71
19–30 y 3.8* 210 29* ND 13* 1.3* 71
31–50 y 3.8* 210 29* ND 13* 1.3* 71
Note: This table (taken from the DRI reports; see www.nap.edu) presents recommended dietary allowances (RDAs) in bold type and adequate intakes (AIs) in ordinary type
followed by an asterisk (*). An RDA is the average daily dietary intake level sufficient to meet the nutrient requirements of nearly all healthy individuals (97–98%) in a group.
The RDA is calculated from an estimated average requirement (EAR). If sufficient scientific evidence is not available to establish an EAR and thus to calculate an RDA, an AI
is usually developed. For healthy breast-fed infants, an AI is the mean intake. The AI for other life-stage and sex-specific groups is believed to cover the needs of all healthy
individuals in those groups, but lack of data or uncertainty in the data make it impossible to specify with confidence the percentage of individuals covered by this intake.
a
Total water includes all water contained in food, beverages, and drinking water. bBased on grams of protein per kilogram of body weight for the reference body weight
(e.g., for adults: 0.8 g/kg body weight for the reference body weight). cNot determined.
Source: National Academies of Sciences, Engineering, and Medicine. 2019. Dietary Reference Intakes for Sodium and Potassium. https://doi.org/10.17226/25353. Adapted
and reproduced with permission from the National Academy of Sciences, Courtesy of the National Academies.

impaired by large amounts of calcium or lead; likewise, non-heme iron production, although in healthy individuals eating adequate diets, the
uptake may be impaired by a lack of ascorbic acid and amino acids in distribution of protein intake over the course of the day has little effect
the meal. Bodily protein may be decreased when essential amino acids on health.
are not present in sufficient amounts—a rare scenario in U.S. diets.
Animal foods, such as milk, eggs, and meat, have high biologic values, Disease Dietary deficiency diseases include protein-calorie mal-
with most of the needed amino acids present in adequate amounts. nutrition, iron-deficiency anemia, goiter (due to iodine deficiency),
Plant proteins in corn (maize), soy, rice, and wheat have lower biologic rickets and osteomalacia (vitamin D deficiency), xeropthalmia
values and must be combined with other plant or animal proteins or (vitamin A deficiency), megaloblastic anemia (vitamin B12 or folic
fortified with the amino acids that are deficient to achieve optimal use acid deficiency), scurvy (vitamin C/ascorbic acid deficiency), beriberi
by the body. (thiamin deficiency), and pellagra (niacin and tryptophan deficiency)
(Chaps. 333 and 334). Each deficiency disease is characterized by
Route of Intake The RDAs apply only to oral intakes. When nutri- imbalances at the cellular level between the supply of nutrients or
ents are administered parenterally, similar values can sometimes be energy and the body’s nutritional needs for growth, maintenance, and
used for amino acids, glucose (carbohydrate), fats, sodium, chloride, other functions. Imbalances and excesses in nutrient intakes are rec-
potassium, and most vitamins because their intestinal absorption rate ognized as risk factors for certain chronic degenerative diseases, such
is nearly 100%. However, the oral bioavailability of most mineral ele- as saturated fat and cholesterol in coronary artery disease; sodium in
ments may be only half that obtained by parenteral administration. For hypertension; obesity in hormone-dependent cancers (endometrial
some nutrients that are not readily stored in the body or that cannot be and breast); and ethanol in alcoholism. Diet is only one of many risk
stored in large amounts, timing of administration may also be impor- factors because the etiology and pathogenesis of these disorders are
tant. For example, amino acids cannot be used for protein synthesis if multifactorial. Osteoporosis, for example, is associated with calcium
they are not supplied together; instead, they will be used for energy deficiency, sometimes secondary to vitamin D deficiency, as well as

HPIM21e_Part10_p2381-p2670.indd 2521 20/01/22 10:04 PM

 2522 with environment-related risk factors (e.g., smoking, sedentary life- how much and what kinds of food the patient has consumed with the
style), physiology (e.g., estrogen deficiency), genetic determinants (e.g., diet that has been provided. Major deviations in intakes of energy, pro-
defects in collagen metabolism), and drug use (chronic steroids and tein, fluids, or other nutrients of special concern for the patient’s illness
aromatase inhibitors) (Chap. 411). should be noted and corrected, especially for long-staying patients.
Nutritional monitoring is especially important for patients who are
■■DIETARY ASSESSMENT very ill and who have extended lengths of hospital stay. Patients who
Nutrition assessment in clinical situations is an iterative process that are fed by enteral and parenteral routes also require special nutritional
involves (1) screening for malnutrition, (2) assessing the diet and other assessment and monitoring by physicians and/or dietitians with certi-
data to establish either the absence or the presence of malnutrition and fication in nutritional support (Chap. 335).
its possible causes, (3) planning and implementing the most appropri-
ate nutritional therapy, and (4) reassessing intakes to make sure that Ambulatory Settings The aim of dietary assessment in the
they have been consumed. Some disease states affect the bioavailability, outpatient setting is to determine whether or not the patient’s usual
requirements, use, or excretion of specific nutrients. In these circum- diet is a health risk in itself or if it contributes to existing chronic
stances, specific measurements of various nutrients or their biomarkers disease–related problems. Dietary assessment also provides the basis
may be required to ensure adequate replacement (Chap. 333). for planning a diet that fulfills therapeutic goals while ensuring patient
Most health care facilities have nutrition-screening processes in adherence. The outpatient’s dietary assessment should review the
place for identifying possible malnutrition after hospital admission. adequacy of present and usual food intakes, including vitamin and
Nutritional screening is required by The Joint Commission, which mineral supplements, oral nutritional supplements, medical foods,
accredits and certifies health care organizations in the United States. other dietary supplements, medications, and alcohol, because all of
However, no universally recognized or validated standards exist. The these may affect the patient’s nutritional status. The assessment should
factors that are usually assessed include abnormal weight for height focus on the dietary constituents that are most likely to be involved or
or body mass index (e.g., BMI <19 or >25); reported weight change compromised by a specific diagnosis as well as on any comorbidities
(involuntary loss or gain of >5 kg in the past 6 months) (Chap. 47); that are present. More than 1 day’s intake should be reviewed to pro-
diagnoses with known nutritional implications (e.g., metabolic disease, vide a better representation of the usual diet, upon which personalized
any disease affecting the gastrointestinal tract, alcoholism); present dietary recommendations can be based.
therapeutic dietary prescription; chronic poor appetite; presence of There are many ways to assess the adequacy of a patient’s habitual
chewing and swallowing problems or major food intolerances; need for diet. These include use of a food guide, a food-exchange list, a diet his-
assistance with preparing or shopping for food, eating, or other aspects tory, or a food-frequency questionnaire. A commonly used food guide
of self-care; and social isolation. The nutritional status of hospitalized for healthy persons is the USDA’s Choose My Plate, which is useful as
patients should be reassessed periodically—at least once every week. a rough guide for avoiding inadequate intakes of essential nutrients as
PART 10

A more complete dietary assessment is indicated for patients who well as likely excesses in the amounts of fat (especially saturated and
exhibit a high risk of or frank malnutrition on nutritional screening. trans fats), sodium, sugar, and alcohol consumed (Table 332-4). The
The type of assessment varies with the clinical setting, the severity of Choose My Plate graphic emphasizes a balance between calories and
the patient’s illness, and the stability of the patient’s condition.
Disorders of the Gastrointestinal System

Acute-Care Settings In acute-care settings, anorexia, various TABLE 332-4 Choose My Plate: A Guide to Individualized
other diseases, test procedures, and medications can compromise Dietary Planning
dietary intake. Under such circumstances, the goal is to identify EXAMPLES OF STANDARD PORTION SIZES AT
and avoid inadequate intake and to assure appropriate alimentation. INDICATED ENERGY LEVEL
Dietary assessment focuses on what patients are currently eating, DIETARY FACTOR, UNIT LOWER: MODERATE: HIGHER:
whether or not they are able and willing to eat, and whether or not OF MEASURE (ADVICE) 1600 kcal 2200 kcal 2800 kcal
they experience any problems with eating. Dietary intake assessment is Fruits, cups (Focus on 1.5 2 2.5
based on information from observed intakes; medical records; history; fruits.)
clinical examination; and anthropometric, biochemical, and functional Vegetables, cups (Vary 2 3 3.5
status evaluations. The objective is to gather enough information to vegetables.)
establish the likelihood of malnutrition due to poor dietary intake or Grains, oz eq (Make 5 7 10
other causes in order to assess whether nutritional therapy is indicated at least half of grains
(Chap. 335). whole.)a
Simple observations may suffice to suggest inadequate oral intake. Protein foods, oz eq 5 6 7
These include dietitians’ and nurses’ notes; observation of a patient’s (Go lean with protein.)b
frequent refusal to eat or the amount of food eaten on trays; the fre- Dairy, cups or ozc (Choose 3 3 3
quent performance of tests and procedures that are likely to cause calcium-rich foods.)
meals to be skipped; adherence to nutritionally inadequate diet orders “Empty” calories, kcald 120 260 400
(e.g., clear liquids or full liquids) for more than a few days; the occur- Sodium, mg <2300 at all
rence of fever, gastrointestinal distress, vomiting, diarrhea, or a coma- energy levels
tose state; and the presence of diseases or use of treatments that involve Physical activity, min At least 150 min vigorous physical activity per week
any part of the alimentary tract. Acutely ill patients with diet-related at all energy levels
diseases such as diabetes need assessment because an inappropriate Note: Oils (formerly listed with portions of 5, 6, and 8 teaspoons for the lower,
diet may exacerbate these conditions and adversely affect other ther- moderate, and higher energy levels, respectively) are no longer singled out in
apies. Abnormal biochemical values (serum albumin levels <35 g/L Choose My Plate, but rather are included in the empty calories/added sugar
[<3.5 mg/dL]; serum cholesterol levels <3.9 mmol/L [<150 mg/dL]) are category with SOFAS (calories from solid fats and added sugars). The limit is
the remaining number of calories in each food pattern above after intake of the
nonspecific but may indicate a need for further nutritional assessment. recommended amounts of the nutrient-dense foods.
Most therapeutic diets offered in hospitals are calculated to meet a
For example, 1 serving equals 1 slice bread, 1 cup ready-to-eat cereal, or 0.5 cup
individual nutrient requirements and the RDA if they are eaten. Excep- cooked rice, pasta, or cooked cereal. bFor example, 1 serving equals 1 oz lean meat,
tions include clear liquids, some full-liquid diets, and test diets (such as poultry, or fish; 1 egg; 1 tablespoon peanut butter; 0.25 cup cooked dry beans; or
0.5 oz nuts or seeds. cFor example, 1 serving equals 1 cup milk or yogurt, 1.5 oz
those adhered to in preparation for gastrointestinal procedures), which natural cheese, or 2 oz processed cheese. dFormerly called “discretionary calorie
are inadequate for several nutrients and should not be used, if possible, allowance.” Portions are calculated as the number of calories remaining after all of
for >24 h. However, because as much as half of the food served to hos- the above allotments are accounted for.
pitalized patients is not eaten, it cannot be assumed that the intakes of Abbreviation: oz eq, ounce equivalent.
hospitalized patients are adequate. Dietary assessment should compare Source: Data from U.S. Department of Agriculture (http://www.Choosemyplate.gov).

HPIM21e_Part10_p2381-p2670.indd 2522 20/01/22 10:04 PM

 nutritional needs, encouraging increased intake of fruits and vege- Marriott BP et al: Present knowledge, in Nutrition Vol 1: Basic Nutri- 2523
tables, whole grains, and low-fat milk in conjunction with reduced tion and Metabolism, Vol 2: Clinical and Applied Topics in Nutrition.
intake of sodium and high-calorie sugary drinks. The Web version London, Academic Press, 2020.
of the guide provides a calculator that tailors the number of servings National Academy of Sciences, Engineering, and Medicine:
suggested for healthy patients of different weights, sexes, ages, and Guiding Principles for Developing Dietary Reference Intakes Based
life-cycle stages to help them to meet their needs while avoiding excess on Chronic Disease. Washington DC, National Academies Press,
(https://www.myplate.gov/myplate-plan and www.ChooseMyPlate.gov). 2017.
Patients who follow ethnic or unusual dietary patterns may need extra National Academy of Sciences, Engineering, and Medicine:
instruction on how foods should be categorized and on the appropriate Global Harmonization of Methodological Approaches to Nutrient
portion sizes that constitute a serving. The process of reviewing the Intake Recommendations: Proceedings of a Workshop. Washington
guide with patients helps them transition to healthier dietary patterns DC, National Academies Press, 2018.
and identifies food groups eaten in excess of recommendations or in National Academy of Sciences, Engineering, and Medicine:
insufficient quantities. For persons on therapeutic diets, assessment Dietary Reference Intakes for Sodium and Potassium. Washington
against food-exchange lists may be useful. These include, for example, DC, National Academies Press, 2019.
American Diabetes Association food-exchange lists for diabetes and National Academy of Sciences, Engineering, and Medicine:
the Academy of Nutrition and Dietetics food-exchange lists for renal Advancing Nutrition and Food Science: 80th Anniversary of the
disease. Food and Nutrition Board: Proceedings of a Symposium. Washington
DC, National Academics Press, 2020.
■■NUTRITIONAL STATUS ASSESSMENT National Academy of Sciences, Engineering, and Medicine:
Full nutritional status assessment is reserved for seriously ill patients Harmonizing the Process for Establishing Nutrient Reference Values:
and those at very high nutritional risk when the cause of malnutri- A Tool Kit. Washington DC, National Academies Press, 2020.
tion is still uncertain after the initial clinical evaluation and dietary Report of the Subcommittee on Interpretation and Uses of
assessment. It involves multiple dimensions, including documentation Dietary Reference Intakes and Upper Reference Levels of
of dietary intake, anthropometric measurements, biochemical mea- Nutrients, and the Steering Committee on the Scientific
surements of blood and urine, clinical examination, health history Evaluation of Dietary Reference Intakes, Food and Nutri-
elicitation, and functional status evaluation. Therapeutic dietary pre- tion Board: Dietary Reference Intakes: Applications in Dietary
scriptions and menu plans for most diseases are available from most Assessment. Washington, DC, National Academies Press, 2008.
hospitals and from the Academy of Nutrition and Dietetics. For fur- Stover PJ, King JC: More nutrition precision, better decisions for the

CHAPTER 333 Vitamin and Trace Mineral Deficiency and Excess

ther discussion of nutritional assessment, see Chap. 334. health of our nation J Nutr 150:3058, 2020.
Yaktine A et al: Why the derivation of nutrient reference values
■■GLOBAL CONSIDERATIONS should be harmonized and how it can be accomplished. Adv Nutr
The DRIs (e.g., the EAR, the UL, and energy needs) are estimates of 11:1112, 2020.
physiologic requirements based on experimental evidence. Assum- Yetley EA et al: Options for basing Dietary Reference Intakes (DRIs)
ing that appropriate adjustments are made for age, sex, body size, on chronic disease endpoints report from a joint US-/Canadian-
and physical activity level, these estimates should be applicable to sponsored working group. Am J Clin Nutr 105:249S, 2017.
individuals in most parts of the world. However, other values are not
transportable. The AIs are based on customary and adequate intakes
in U.S. and Canadian populations, which appear to be compatible
with good health, rather than on a large body of direct experimental
evidence. Similarly, the AMDRs represent expert opinion regard-
ing the approximate intakes of energy-providing nutrients that are
healthful in these North American populations, and the CDRR may
also vary in other populations. Thus, these measures should be used
333 Mineral
Vitamin and Trace
Deficiency and
with caution in other settings. Nutrient-based standards like the DRIs
have also been developed by the World Health Organization/Food and Excess
Agricultural Organization of the United Nations and are available on
Paolo M. Suter
the Web (https://www.who.int/activities/establishing-global-nutrient-
requirements). The European Food Safety Authority (EFSA) Panel on
Dietetic Products, Nutrition, and Allergies periodically publishes its
recommendations in the online EFSA Journal (https://efsa.onlinelibrary. Vitamins are required constituents of the human diet because they are
wiley.com/journal/18314732). Other countries have promulgated sim- synthesized inadequately or not at all in the human body. Only small
ilar recommendations. The different standards have many similarities amounts of these substances are needed to carry out essential bio-
in their basic concepts, definitions, and nutrient recommendation chemical reactions (e.g., by acting as coenzymes or prosthetic groups).
levels, but there are some differences from the DRIs as a result of the Overt vitamin or trace mineral deficiencies are rare in Western coun-
functional criteria chosen, environmental differences, the timeliness of tries because of a plentiful, varied, and inexpensive food supply; food
the evidence reviewed, and expert judgment. There is a growing trend fortification; and use of supplements. However, multiple nutrient
toward global harmonization of these recommendations. deficiencies may appear together in persons who are chronically ill,
alcoholic, or living in poverty. After bariatric surgery, patients are
■■FURTHER READING at high risk for multiple nutrient deficiencies. Moreover, subclinical
Brannon PM et al: Scanning for new evidence to prioritize updates to vitamin and trace mineral deficiencies (often designated as “hidden
the Dietary Reference Intakes: Case studies for thiamin and phospho- hunger”), as diagnosed by laboratory testing, are quite common in the
rus. Am J Clin Nur 104:1366, 2016. normal population, especially in the geriatric age group and socioeco-
Forster H et al: Personalized nutrition: The role of new dietary assess- nomically deprived individuals due to the lack of nutrient-dense foods.
ment methods. Proc Nutr Soc 75:96, 2016. Conversely, because of the widespread use of nutrient supplements and
Gibson RS: Principles of Nutritional Assessment, 2nd ed. Oxford, food fortification, nutrient toxicities are gaining pathophysiologic and
Oxford University Press, 2005. clinical importance.
Lewis JL, Dwyer JT: Establishing nutrient intake values, in Present Victims of famine, emergency-affected and displaced populations,
Knowledge in Nutrition, Vol 2. BP Marriott, DF Birt, VA Stallings, AA refugees, and camp populations are at increased risk for protein-energy
Yates, eds. London, Academic Press, 2020, pp 267–289. malnutrition and classic micronutrient deficiencies (vitamin A, iron,

HPIM21e_Part10_p2381-p2670.indd 2523 20/01/22 10:04 PM

 2524 zinc, iodine) as well as for overt deficiencies in thiamine (beriberi), heat-labile thiaminases (raw fish, shellfish), which destroy the vitamin,
riboflavin, vitamin C (scurvy), and niacin (pellagra). or heat-stable polyhydroxyphenols (tannins; in coffee, tea, Brussels
Body stores of vitamins and minerals vary tremendously. For exam- sprouts, or betel nuts), which inactivate the vitamin. Thus, drinking
ple, stores of vitamins B12 and A are large, and an adult may not become large amounts of tea or coffee could theoretically lower thiamine body
deficient until ≥1 year after beginning to eat a deficient diet. However, stores.
folate and thiamine may become depleted within weeks among those
eating a deficient diet. Therapeutic modalities can deplete essential Deficiency Most dietary deficiency of thiamine worldwide is the
nutrients from the body; for example, hemodialysis or diuretics remove result of poor dietary intake due to the lack of food or dispropor-
water-soluble vitamins, which must be replaced by supplementation. tionate reliance on highly processed staple crops. Food processing
Vitamins and trace minerals play several roles in diseases: (1) defi- removes thiamine, and high-heat or long-duration cooking destroys
ciencies of vitamins and minerals may be caused by disease states such it. In Western countries, the primary causes of thiamine deficiency
as malabsorption; (2) either deficiency or excess of vitamins and min- are alcoholism and chronic illnesses such as cancer. Alcohol interferes
erals can cause disease in and of itself (e.g., vitamin A intoxication and directly with the absorption of thiamine and with the synthesis of
liver disease); and (3) vitamins and minerals in high doses may be used thiamine pyrophosphate, and it increases urinary excretion. Thiamine
as drugs (e.g., niacin for hypercholesterolemia). Since they are covered should always be replenished when a patient with alcoholism is being
elsewhere, the hematologic-related vitamins and minerals (Chaps. 97 refed, as carbohydrate repletion without adequate thiamine can pre-
and 99) either are not considered or are considered only briefly in this cipitate acute thiamine deficiency with lactic acidosis. Other at-risk
chapter, as are the bone-related vitamins and minerals (vitamin D, populations are women with prolonged hyperemesis gravidarum and
calcium, phosphorus, magnesium; Chap. 409). anorexia, patients with overall poor nutritional status who are receiving
parenteral glucose, patients who have had bariatric/metabolic surgery
(bariatric Wernicke), and patients receiving chronic diuretic therapy
VITAMINS (e.g., in hypertension or systolic heart failure) due to increased urinary
See also Table 333-1 and Fig. 333-1. thiamine losses. Different drugs (e.g., metformin, verapamil) could
■■THIAMINE (VITAMIN B1) inhibit intestinal thiamine transporters (ThTR-2), thereby increasing
Thiamine was the first B vitamin to be identified and therefore is the risk of deficiency for this vitamin. Maternal thiamine deficiency
referred to as vitamin B1. Thiamine functions in the decarboxylation of can lead to infantile beriberi in breast-fed children. Thiamine defi-
α-ketoacids (e.g., pyruvate α-ketoglutarate) and branched-chain amino ciency could be an underlying factor in motor vehicle accidents and
acids and thus is essential for energy generation. In addition, thiamine could be overlooked in the setting of head injury.
pyrophosphate acts as a coenzyme for a transketolase reaction that medi- Thiamine deficiency in its early stage induces anorexia and non-
specific symptoms (e.g., irritability, decrease in short-term memory).
PART 10

ates the conversion of hexose and pentose phosphates. It has been postu-
lated that thiamine plays a role in peripheral nerve conduction, although Prolonged thiamine deficiency causes beriberi, which is classically
the exact chemical reactions underlying this function are not known. categorized as wet or dry, although there is considerable overlap
between the two categories. In either form of beriberi, patients may
Food Sources The median intake of thiamine in the United States complain of pain and paresthesia. Wet beriberi presents primarily
Disorders of the Gastrointestinal System

from food alone is ~2 mg/d. Primary food sources for thiamine include with cardiovascular symptoms that are due to impaired myocardial
yeast, organ meat, pork, legumes, beef, whole grains, and nuts. Milled energy metabolism and dysautonomia; it can occur after 3 months of a
rice and grains contain little thiamine. Thiamine deficiency is there- thiamine-deficient diet. Patients present with an enlarged heart, tachy-
fore more common in cultures that rely heavily on a milled polished cardia, high-output congestive heart failure, peripheral edema, and
rice-based diet. Certain foods contain antithiamine factors such as peripheral neuritis. Patients with dry beriberi present with a symmetric

TABLE 333-1 Principal Clinical Findings of Vitamin Malnutrition

DIETARY LEVEL PER DAY ASSOCIATED
NUTRIENT CLINICAL FINDING WITH OVERT DEFICIENCY IN ADULTS CONTRIBUTING FACTORS TO DEFICIENCY
Thiamine Beriberi: neuropathy, muscle weakness and wasting, <0.3 mg/1000 kcal Alcoholism, chronic diuretic use, bariatric
cardiomegaly, edema, ophthalmoplegia, confabulation surgery, hyperemesis, thiaminases in food
Riboflavin Magenta tongue, angular stomatitis, seborrhea, cheilosis, <0.4 mg Alcoholism, individuals with poor diets and
ocular symptoms, corneal vascularization low intake of milk products
Niacin Pellagra: pigmented rash of sun-exposed areas, bright red <9.0 niacin equivalents Alcoholism, vitamin B6 deficiency,
tongue, diarrhea, apathy, memory loss, disorientation riboflavin deficiency, tryptophan deficiency
Vitamin B6 Seborrhea, glossitis, convulsions, neuropathy, depression, <0.2 mg Alcoholism, isoniazid
confusion, microcytic anemia
Folate Megaloblastic anemia, atrophic glossitis, depression, <100 μg/d Alcoholism, sulfasalazine, pyrimethamine,
↑ homocysteine triamterene
Vitamin B12 Megaloblastic anemia, loss of vibratory and position sense, <1.0 μg/d Gastric atrophy (pernicious anemia),
abnormal gait, dementia, impotence, loss of bladder and terminal ileal disease, strict vegetarianism,
bowel control, ↑ homocysteine, ↑ methylmalonic acid acid-reducing drugs (e.g., H2 blockers),
metformin
Vitamin C Scurvy: petechiae, ecchymosis, coiled hairs, inflamed and <10 mg/d Smoking, alcoholism
bleeding gums, joint effusion, poor wound healing, fatigue
Vitamin A Xerophthalmia, night blindness, Bitot’s spots, follicular <300 μg/d Fat malabsorption, infection, measles,
hyperkeratosis, impaired embryonic development, immune alcoholism, protein-energy malnutrition
dysfunction
Vitamin D Rickets: skeletal deformation, rachitic rosary, bowed legs; <2.0 μg/d Aging, lack of sunlight exposure, fat
osteomalacia malabsorption, deeply pigmented skin
Vitamin E Peripheral neuropathy, spinocerebellar ataxia, skeletal Not described unless underlying Occurs only with fat malabsorption
muscle atrophy, retinopathy contributing factor is present or genetic abnormalities of vitamin E
metabolism/transport
Vitamin K Elevated prothrombin time, bleeding <10 μg/d Fat malabsorption, liver disease,
antibiotic use

HPIM21e_Part10_p2381-p2670.indd 2524 20/01/22 10:04 PM

 peripheral neuropathy of the motor and sensory systems, with dimin- is an additional loss of memory and a confabulatory psychosis, the 2525
ished reflexes. The neuropathy affects the legs most markedly, and syndrome is known as Wernicke-Korsakoff syndrome. Despite the
patients have difficulty rising from a squatting position. typical clinical picture and history, Wernicke-Korsakoff syndrome is
Alcoholic patients with chronic thiamine deficiency also may have underdiagnosed.
central nervous system (CNS) manifestations known as Wernicke’s The laboratory diagnosis of thiamine deficiency usually is made by
encephalopathy, which consists of horizontal nystagmus, ophthal- a functional enzymatic assay of transketolase activity measured before
moplegia (due to weakness of one or more extraocular muscles), and after the addition of thiamine pyrophosphate. A >25% stimulation
cerebellar ataxia, and mental impairment (Chap. 453). When there in response to the addition of thiamine pyrophosphate (i.e., an activity

Active derivative or Principal

Vitamin cofactor form function

Thiamine (B1) Thiamine pyrophosphate Coenzyme for

NH2 cleavage of
CH3 carbon-carbon
N N
bonds; amino
N S CH2CH2OH acid and
carbohydrate
metabolism

Riboflavin (B2) Flavin mononucleotide Cofactor for

O (FMN) and flavin oxidation,
N adenine dinucleotide reduction
NH
(FAD) reactions,
N N O and covalently
Ribityl attached
prosthetic groups
for some
enzymes

CHAPTER 333 Vitamin and Trace Mineral Deficiency and Excess

Niacin Nicotinamide adenine Coenzymes for
O dinucleotide phosphate oxidation and
C O (NADP) and nicotinamide reduction
+ adenine dinucleotide reactions
N
H (NAD)

Vitamin B6 Pyridoxal phosphate Cofactor for

CH2OH enzymes of amino
HO CH2OH acid metabolism

Folate Polyglutamate forms of Coenzyme for one

n
O COOH (5, 6, 7, 8) carbon transfer in
H
O N C N CH tetrahydrofolate with nucleic acid and
H carbon unit amino acid
N CH2
CH2
attachments metabolism
CH2 COOH
H2N N N
C N CH
H
O CH2

CH2

C OH

Vitamin B12 Methylcobalamine Coenzyme for

CH2CH2CONH2 Adenosylcobalamin methionine
CONH2 HC synthase
CH3 3 CH2CH2CONH2
CH2 and
CH2CH2CONH2 L-methylmalonyl-
H3C N N
CONH2
H3C Co
+
CoA mutase
N N CH3
CH2
CH3
NHCOCH2CH2 CH3 CH3 CH2CH2CONH2
CH2 CHCH3 N CH3
O O–
N CH3
P
O O HO

O
HOCH2
OH Cbl

FIGURE 333-1 Structures and principal functions of vitamins associated with human disorders.

HPIM21e_Part10_p2381-p2670.indd 2525 20/01/22 10:04 PM

 2526 Active derivative or Principal
Vitamin cofactor form function

Vitamin C Ascorbic acid and Participation as a

O redox ion in many
O C C C C C CH2OH
dehydroascorbic acid
biologic
OH OH OH oxidation and
hydrogen transfer
reactions

Vitamin A Retinol, retinaldehyde, Formation of

and retinoic acid rhodopsin (vision)
and glycoproteins
(epithelial cell
(β-Carotene) function); also
CH2OH regulates gene
transcription
(Retinol)

Vitamin D 1,25-Dihydroxyvitamin D Maintenance of

blood calcium
OH and phosphorus
levels;
antiproliferative
hormone
CH2

HO OH

Vitamin E Tocopherols and Antioxidants

CH3
PART 10

O tocotrienols
CH2[CH2 CH2 CH CH2]3H

HO

Vitamin K Vitamin K hydroquinone Cofactor for

Disorders of the Gastrointestinal System

O
posttranslation
carboxylation of
many proteins
R
including essential
O
clotting factors

FIGURE 333-1 (Continued)

coefficient of 1.25) is interpreted as abnormal. Thiamine or the phos- Enzymes that contain flavin adenine dinucleotide (FAD) or flavin
phorylated esters of thiamine in serum or blood also can be measured mononucleotide (FMN) as prosthetic groups are known as fla-
by high-performance liquid chromatography to detect deficiency. voenzymes (e.g., succinic acid dehydrogenase, monoamine oxidase,
glutathione reductase). FAD is a cofactor for methyltetrahydrofolate
TREATMENT reductase and therefore modulates homocysteine metabolism. The
vitamin also plays a role in drug and steroid metabolism, including
Thiamine Deficiency detoxification reactions.
Although much is known about the chemical and enzymatic reac-
In acute thiamine deficiency with either cardiovascular or neu-
tions of riboflavin, the clinical manifestations of riboflavin deficiency
rologic signs, 200 mg of thiamine three times daily should be
are nonspecific and are similar to those of other deficiencies of B vita-
given intravenously until there is no further improvement in acute
mins. Riboflavin deficiency is manifested principally by lesions of the
symptoms; oral thiamine (10 mg/d) should subsequently be given
mucocutaneous surfaces of the mouth and skin. In addition, corneal
until recovery is complete. Cardiovascular and ophthalmoplegic
vascularization, anemia, and personality changes have been described
improvement occurs within 24 h. Other manifestations gradually
with riboflavin deficiency.
clear, although psychosis in Wernicke-Korsakoff syndrome may
be permanent or may persist for several months. Other nutrient Deficiency and Excess Riboflavin deficiency almost always is due
deficiencies should be corrected concomitantly. In view of the to dietary deficiency. Milk, other dairy products, and enriched breads
widespread, often unrecognized (subclinical) deficiency, a more and cereals are the most important dietary sources of riboflavin in the
generous supplementation of this vitamin in the emergency care United States, although lean meat, fish, eggs, broccoli, and legumes are
setting is warranted. also good sources. Riboflavin is extremely sensitive to light, and milk
should be stored in containers that protect against photodegradation.
Toxicity Although hypersensitivity/anaphylaxis has been reported Laboratory diagnosis of riboflavin deficiency can be made by deter-
after high intravenous doses of thiamine, no adverse effects have been mination of red blood cell or urinary riboflavin concentrations or by
recorded from either food or supplements at high doses. measurement of erythrocyte glutathione reductase activity, with and
without added FAD. Because of the limited capacity of the gastrointes-
■■RIBOFLAVIN (VITAMIN B2) tinal tract to absorb riboflavin (~27 mg after one oral dose) as well as
Riboflavin is important for the metabolism of fat, carbohydrate, and the instantaneous urinary excretion, riboflavin toxicity has not been
protein, acting as a respiratory coenzyme and an electron donor. described.

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 ■■NIACIN (VITAMIN B3) headache. Flushing is subject to tachyphylaxis and often improves 2527
The term niacin refers to nicotinic acid and nicotinamide and their with time; premedication with aspirin may alleviate these symptoms.
biologically active derivatives. Nicotinic acid and nicotinamide serve Nausea, vomiting, and abdominal pain also occur at similar doses of
as precursors of two coenzymes, nicotinamide adenine dinucleotide niacin. Hepatic toxicity is the most serious toxic reaction caused by
(NAD) and NAD phosphate (NADP), which are important in numer- sustained-release niacin and may present as jaundice with elevated
ous oxidation and reduction reactions in the body. In addition, NAD aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
and NADP are active in adenine diphosphate–ribose transfer reactions levels. A few cases of fulminant hepatitis requiring liver transplantation
involved in DNA repair and calcium mobilization. have been reported at doses of 3–9 g/d. Other toxic reactions include
glucose intolerance, hyperuricemia, macular edema, and macular
Metabolism and Requirements Nicotinic acid and nicotinamide cysts. The combination of nicotinic acid preparations for dyslipidemia
are absorbed well from the stomach and small intestine. The bioavail- plus 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase
ability of niacin from beans, milk, meat, and eggs is high; bioavailability inhibitors may increase the risk of rhabdomyolysis. The upper limit for
from cereal grains is lower. Since flour is enriched with “free” niacin daily (nontherapeutic) niacin intake has been set at 35 mg.
(i.e., the non-coenzyme form), bioavailability is excellent. Median
intakes of niacin in the United States considerably exceed the recom- ■■PYRIDOXINE (VITAMIN B6)
mended dietary allowance (RDA). Vitamin B6 refers to a family of compounds that includes pyridoxine,
The amino acid tryptophan can be converted to niacin with an pyridoxal, pyridoxamine, and their 5′-phosphate derivatives. 5′-Pyri-
efficiency of 60:1 by weight. Thus, the RDA for niacin is expressed in doxal phosphate (PLP) is a cofactor for >100 enzymes involved in
niacin equivalents. A lower-level conversion of tryptophan to niacin amino acid metabolism. Vitamin B6 also is involved in heme and
occurs in vitamin B6 and/or riboflavin deficiencies and in the presence neurotransmitter synthesis and in the metabolism of glycogen, lipids,
of isoniazid. The urinary excretion products of niacin include 2- steroids, sphingoid bases, and several vitamins, including the conver-
pyridone and 2-methyl nicotinamide, measurements of which are used sion of tryptophan to niacin.
in the diagnosis of niacin deficiency.
Dietary Sources Plants contain vitamin B6 in the form of pyridox-
Deficiency Niacin deficiency causes pellagra, which is found ine, whereas animal tissues contain PLP and pyridoxamine phosphate.
mostly among people eating corn-based diets in parts of China, The vitamin B6 contained in plants is less bioavailable than that in
Africa, and India. Pellagra in North America is found mainly among animal tissues. Rich food sources of vitamin B6 include legumes, nuts,
alcoholics; among patients with congenital defects of intestinal and wheat bran, and meat, although it is present in all food groups.
kidney absorption of tryptophan (Hartnup disease; Chap. 420); and

CHAPTER 333 Vitamin and Trace Mineral Deficiency and Excess

among patients with carcinoid syndrome (Chap. 84), in which there is Deficiency Symptoms of vitamin B6 deficiency include epithelial
increased conversion of tryptophan to serotonin. The antituberculosis changes, as seen frequently with other B vitamin deficiencies. In
drug isoniazid is a structural analogue of niacin and can precipitate addition, severe vitamin B6 deficiency can lead to peripheral neurop-
pellagra. In the setting of famine or population displacement, pellagra athy, abnormal electroencephalograms, and personality changes that
results from the absolute lack of niacin but also from the deficiency include depression and confusion. In infants, diarrhea, seizures, and
of micronutrients required for the conversion of tryptophan to niacin anemia have been reported. Microcytic hypochromic anemia is due
(e.g., iron, riboflavin, and pyridoxine). The early symptoms of pellagra to diminished hemoglobin synthesis, since the first enzyme involved
include loss of appetite, generalized weakness and irritability, abdomi- in heme biosynthesis (aminolevulinate synthase) requires PLP as a
nal pain, and vomiting. Bright red glossitis then ensues and is followed cofactor (Chap. 97). In some case reports, platelet dysfunction has
by a characteristic skin rash that is pigmented and scaling, particularly been reported. Since vitamin B6 is necessary for the conversion of
in skin areas exposed to sunlight. This rash is known as Casal’s necklace homocysteine to cystathionine, it is possible that chronic low-grade
because it forms a ring around the neck; it is seen in advanced cases. vitamin B6 deficiency may result in hyperhomocysteinemia, which has
Vaginitis and esophagitis also may occur. Diarrhea (due in part to proc- been associated with vascular dysfunction and an increased risk of car-
titis and in part to malabsorption), depression, seizures, and dementia diovascular disease; however, so far, there is only limited randomized
are also part of the pellagra syndrome. The primary manifestations of controlled trial evidence (Chap. 420). Independent of homocysteine,
this syndrome are sometimes referred to as “the four Ds”: dermatitis, low levels of circulating vitamin B6 have been associated with inflam-
diarrhea, and dementia leading to death. Aging is characterized by a mation and elevated levels of C-reactive protein.
decline in cellular NAD+, and it seems plausible that maintaining and/ Certain medications, such as isoniazid, l-dopa, penicillamine, and
or reestablishing cellular NAD+, might favorably modulate the risk of cycloserine, interact with PLP due to a reaction with carbonyl groups.
chronic diseases of aging (e.g., metabolic disorders). Pyridoxine should be given concurrently with isoniazid to avoid
neuropathy. The increased ratio of AST to ALT seen in alcoholic liver
disease reflects the relative vitamin B6 dependence of ALT. Vitamin B6
TREATMENT dependency syndromes that require pharmacologic doses of vitamin B6
are rare; they include cystathionine β-synthase deficiency, pyridox-
Pellagra ine-responsive (primarily sideroblastic) anemias, and gyrate atrophy
Treatment of pellagra consists of oral supplementation with 100– with chorioretinal degeneration due to decreased activity of the mito-
200 mg of nicotinamide or nicotinic acid three times daily for chondrial enzyme ornithine aminotransferase. In these situations,
5 days. High doses of nicotinic acid (2 g/d in a time-release form) 100–200 mg/d of oral vitamin B6 is required for treatment.
are used for the treatment of elevated cholesterol and triglyceride Severe nausea and vomiting in pregnancy might respond to pyr-
levels and/or low high-density lipoprotein cholesterol levels, but idoxine combined with doxylamine. High doses of vitamin B6 have
without proven evidence to prevent cardiovascular disease. Never- been used to treat carpal tunnel syndrome, premenstrual syndrome,
theless, nicotinic acid may be useful in patients with statin intoler- schizophrenia, autism, and diabetic neuropathy but have not been
ance or severe hypertriglyceridemia (Chap. 407). found to be effective.
The laboratory diagnosis of vitamin B6 deficiency is generally based
on low plasma PLP values (<20 nmol/L). Vitamin B6 deficiency is
Toxicity Prostaglandin-mediated flushing due to binding of the treated with 50 mg/d; higher doses of 100–200 mg/d are given if the
vitamin to a G protein–coupled receptor has been observed at daily deficiency is related to medication use. Vitamin B6 should not be given
nicotinic acid doses as low as 30 mg taken as a supplement or as with l-dopa, since the vitamin interferes with the action of this drug.
therapy for dyslipidemia. There is no evidence of toxicity from niacin
that is derived from food sources. Flushing always starts in the face Toxicity The safe upper limit for vitamin B6 has been set at 100 mg/d,
and may be accompanied by skin dryness, itching, paresthesia, and although no adverse effects have been associated with high intakes of

HPIM21e_Part10_p2381-p2670.indd 2527 20/01/22 10:04 PM

 2528 vitamin B6 from food sources only. When toxicity occurs, it causes reasonable to advise patients with a history of kidney stones (especially
severe sensory neuropathy, leaving patients unable to walk; however, oxalate renal stones) and renal insufficiency not to take large doses of
in most cases, this is reversible upon cessation of the high intake. Med- vitamin C. There is also an unproven but possible risk that chronic high
ication safety monitoring suggests a rather high prevalence of vitamin doses of vitamin C could promote iron overload and iron toxicity (e.g.,
B6–induced neuropathy. Accordingly, long-term high-dose vitamin B6 in patients with hemochromatosis or thalassemia major). High doses of
supplementation should be discouraged. Some cases of photosensitiv- vitamin C can induce hemolysis in patients with glucose-6-phosphate
ity and dermatitis have been reported. dehydrogenase deficiency, and doses >1 g/d can cause false-negative
guaiac reactions and interfere with tests for urinary glucose. High
■■FOLATE (VITAMIN B12) doses may interfere with the activity of certain drugs and diagnostic
See Chap. 99. tests (e.g., false-negative results of guaiac-based fecal occult blood
tests).
■■VITAMIN C
Both ascorbic acid (only the l-isomer) and its oxidized product dehy-
■■BIOTIN
droascorbic acid are biologically active. Actions of vitamin C include
Biotin (also known as vitamin B7 or vitamin H) is a water-soluble vita-
antioxidant activity, promotion of nonheme iron absorption, carnitine
min that plays a role in gene expression, gluconeogenesis, and fatty acid
biosynthesis, conversion of dopamine to norepinephrine, tyrosine
synthesis and serves as a carbon dioxide (CO2) carrier on the surface
catabolism, histone and DNA demethylation, and synthesis of many
of both cytosolic and mitochondrial carboxylase enzymes. The vitamin
peptide hormones. Vitamin C is also important for connective tissue
also functions in the catabolism of specific amino acids (e.g., leucine)
metabolism and cross-linking (proline hydroxylation), and it is a com-
and in gene regulation by histone biotinylation. Excellent food sources
ponent of many drug-metabolizing enzyme systems, particularly the
of biotin include organ meat such as liver or kidney, soy and other
mixed-function oxidase systems.
beans, yeast, and egg yolks; however, egg white contains the protein
Absorption and Dietary Sources Vitamin C is almost com- avidin, which strongly binds the vitamin and reduces its bioavailability.
pletely absorbed if <100 mg is administered in a single dose; however, Biotin deficiency due to low dietary intake is rare; rather, deficiency
only ≤50% is absorbed at doses >1 g. Enhanced degradation and fecal is due to inborn errors of metabolism. Biotin deficiency has been
and urinary excretion of vitamin C occur at higher intake levels. induced by experimental feeding of egg white diets and by biotin-free
Good dietary sources of vitamin C include citrus fruits, green veg- parenteral nutrition in patients with short bowels. In adults, biotin
etables (especially broccoli), tomatoes, and potatoes. Consumption of deficiency results in mental changes (depression, hallucinations),
five servings of fruits and vegetables a day provides vitamin C in excess paresthesia, anorexia, and nausea. A scaling, seborrheic, and erythe-
of the RDA of 90 mg/d for men and 75 mg/d for women. In addition, matous rash may occur around the eyes, nose, and mouth as well as
PART 10

~40% of the U.S. population consumes vitamin C as a dietary supple- on the extremities. In infants, biotin deficiency presents as hypotonia,
ment in which “natural forms” of the vitamin are no more bioavailable lethargy, and apathy. In addition, infants may develop alopecia and a
than synthetic forms. Smoking (including “passive” smoking), hemo- characteristic rash that includes the ears. At present, evidence does not
dialysis, pregnancy, lactation, and stress (e.g., infection, trauma) appear support a therapeutic role of high-dose biotin in multiple sclerosis. The
to increase vitamin C requirements. laboratory diagnosis of biotin deficiency can be established on the basis
Disorders of the Gastrointestinal System

Deficiency Vitamin C deficiency causes scurvy. In the United of a decreased concentration of urinary biotin (or its major metabo-
States, this condition is seen primarily among the poor and the elderly, lites), increased urinary excretion of 3-hydroxyisovaleric acid after a
in alcoholics who consume <10 mg/d of vitamin C, and in young leucine challenge, or decreased activity of biotin-dependent enzymes
adults who eat severely unbalanced diets. In addition to generalized in lymphocytes (e.g., propionyl-CoA carboxylase). Treatment requires
fatigue, symptoms of scurvy primarily reflect impaired formation of pharmacologic doses of biotin, that is, up to 10 mg/d. No toxicity is
mature connective tissue and include bleeding into the skin (petechiae, known. High-dose biotin supplements could interfere with different
ecchymoses, perifollicular hemorrhages); inflamed and bleeding gums; immunoassay platforms based on streptavidin-biotin technology (e.g.,
and manifestations of bleeding into joints, the peritoneal cavity, the biotinylated immunoassays), resulting in false-positive (e.g., free T4 or
pericardium, and the adrenal glands. In children, vitamin C deficiency T3) or false-negative tests (e.g., thyroid-stimulating hormone, troponin,
may cause impaired bone growth. Laboratory diagnosis of vitamin C β-human chorionic gonadotropin pregnancy test).
deficiency is based on low plasma or leukocyte levels.
Administration of vitamin C (200 mg/d) improves the symptoms ■■PANTOTHENIC ACID (VITAMIN B5)
of scurvy within several days. High-dose vitamin C supplementation Pantothenic acid is a component of coenzyme A and phosphopanteth-
(e.g., 0.2 g up to several grams per day) may slightly decrease the symp- eine, which are involved in fatty acid metabolism and the synthesis of
toms and duration of upper respiratory tract infections. Vitamin C sup- cholesterol, steroid hormones, and all compounds formed from isopre-
plementation has also been reported to be useful in Chédiak-Higashi noid units. In addition, pantothenic acid is involved in the acetylation
syndrome (Chap. 64) and osteogenesis imperfecta (Chap. 413). Diets of proteins. The vitamin is excreted in the urine, and the laboratory
high in vitamin C have been claimed to lower the incidence of certain diagnosis of deficiency is based on low urinary vitamin levels.
cancers, particularly esophageal and gastric cancers. If proven, this The vitamin is ubiquitous in the food supply. Liver, yeast, egg yolks,
effect may be because vitamin C can prevent the conversion of nitrites whole grains, and vegetables are particularly good sources. Human
and secondary amines to carcinogenic nitrosamines. Emerging evi- pantothenic acid deficiency has been demonstrated only by experi-
dence suggests a therapeutic effect of intravenous parenteral (not oral) mental feeding of diets low in pantothenic acid or by administration
pharmacologic doses of up to 1g/kg body weight of ascorbic acid in the of a specific pantothenic acid antagonist. The symptoms of panto-
treatment of cancers (e.g., metastatic pancreatic, ovarian, glioblastoma, thenic acid deficiency are nonspecific and include gastrointestinal
and non-small-cell lung cancers). The mechanism of pharmacologic disturbance, depression, muscle cramps, paresthesia, ataxia, and hypo-
ascorbate in cancer treatment (as a stand-alone agent or with other glycemia. Pantothenic acid deficiency is believed to have caused the
therapeutic agents) appear to be pro-oxidative, either synergistic (e.g., “burning feet syndrome” seen in prisoners of war during World War II.
gemcitabine, PD-1 inhibitors, radiation) or additive with other agents. No toxicity of this vitamin has been reported.
Toxicity Taking >2 g of vitamin C in a single dose may result ■■CHOLINE
in abdominal pain, diarrhea, and nausea. Since vitamin C may be Choline is a precursor for acetylcholine, phospholipids, and betaine.
metabolized to oxalate, it is feared that chronic high-dose vitamin C Choline is necessary for the structural integrity of cell membranes,
supplementation could result in an increased prevalence of kidney cholinergic neurotransmission, lipid and cholesterol metabolism,
stones. However, except in patients with preexisting renal disease, this methyl-group metabolism, and transmembrane signaling. Recently,
association has not been borne out in several trials. Nevertheless, it is a recommended adequate intake was set at 550 mg/d for men and

HPIM21e_Part10_p2381-p2670.indd 2528 20/01/22 10:04 PM

 425 mg/d for women, although certain genetic polymorphisms can is equivalent to 1 μg of retinol activity, whereas the figure is ≥24 μg 2529
increase an individual’s requirement. Choline is thought to be a “con- for other dietary provitamin A carotenoids (e.g., β-cryptoxanthin, α-
ditionally essential” nutrient in that its de novo synthesis occurs in carotene). The vitamin A equivalency for a β-carotene supplement in
the liver and results in lesser-than-used amounts only under certain an oily solution is 2:1.
stress conditions (e.g., alcoholic liver disease). The dietary require- Metabolism The liver contains ~90% of the vitamin A reserves in
ment for choline depends on the status of other nutrients involved in healthy individuals and secretes vitamin A in the form of retinol, which
methyl-group metabolism (folate, vitamin B12, vitamin B6, and methi- is bound in the circulation to retinol-binding protein. Once binding
onine) and thus varies widely. Choline is widely distributed in food has occurred, the retinol-binding protein complex interacts with a
(e.g., egg yolks, wheat germ, organ meat, milk) in the form of lecithin second protein, transthyretin. This trimolecular complex functions to
(phosphatidylcholine). Choline deficiency has occurred only in exper- prevent vitamin A from being filtered by the kidney glomerulus, thus
imental conditions or in patients receiving parenteral nutrition devoid protecting the body against the toxicity of retinol and allowing retinol
of choline and rarely in specific inborn errors of choline metabolism. to be taken up by specific cell-surface receptors that recognize retinol-
Deficiency results in fatty liver, elevated aminotransferase levels, and binding protein. A certain amount of vitamin A enters peripheral cells
skeletal muscle damage with high creatine phosphokinase values. even if it is not bound to retinol-binding protein. After retinol is inter-
The diagnosis of choline deficiency is currently based on low plasma nalized by the cell, it becomes bound to a series of cellular retinol-bind-
levels, although nonspecific conditions (e.g., heavy exercise) may also ing proteins, which function as sequestering and transporting agents
suppress plasma levels. as well as co-ligands for enzymatic reactions. Certain cells also contain
Toxicity from choline results in hypotension, cholinergic sweating, retinoic acid–binding proteins, which have sequestering functions but
diarrhea, salivation, and a fishy body odor. The upper limit for choline also shuttle retinoic acid to the nucleus and enable its metabolism.
intake has been set at 3.5 g/d. Because of its ability to lower choles- Vitamin A metabolites (retinoids) such as retinoic acid are potent
terol and homocysteine levels, choline treatment has been suggested regulators of gene transcription through nuclear receptor signaling, thus
for patients with dementia and patients at high risk of cardiovascular playing a key role in many cellular and metabolic pathways. Two fami-
disease. However, the benefits of such treatment have not been firmly lies of receptors (retinoic acid receptors [RARs] and retinoid X receptors
documented; recently, signals for an increased cardiovascular risk have [RXRs]) are active in retinoid-mediated gene transcription. Retinoid
been reported. Choline- and betaine-restricted diets are of therapeutic receptors regulate transcription by binding as dimeric complexes to
value in trimethylaminuria (“fish odor syndrome”) or in decreasing the specific DNA sites—the retinoic acid response elements—in target
production of the gut microbiome-derived trimethylamine N-oxide genes (Chap. 377). The receptors can either stimulate or repress gene
(TMAO) as a potential cardiovascular risk modulator. expression in response to their ligands. RARs bind all-trans retinoic

CHAPTER 333 Vitamin and Trace Mineral Deficiency and Excess

acid and 9-cis-retinoic acid, whereas RXRs bind only 9-cis-retinoic acid.
■■FLAVONOIDS The retinoid receptors play an important role in controlling cell
Flavonoids constitute a large family of polyphenols that contribute proliferation and differentiation. RXRs dimerize with other nuclear
to the aroma, taste, and color of fruits and vegetables. Major groups receptors to function as coregulators of genes responsive to retinoids,
of dietary flavonoids include anthocyanidins in berries; catechins in but also to thyroid hormone and calcitriol. RXR agonists induce insulin
green tea and chocolate; flavonols (e.g., quercetin) in broccoli, kale, sensitivity experimentally, perhaps because RXRs are cofactors for the
leeks, onions, and the skins of grapes and apples; and isoflavones peroxisome proliferator-activated receptors, which also mediate fatty
(e.g., genistein) in legumes. Isoflavones have a low bioavailability and acid and carbohydrate metabolism and are targets for different drugs
are partially metabolized by the intestinal flora. The dietary intake of including thiazolidinedione drugs (e.g., rosiglitazone and pioglitazone)
flavonoids is estimated at 10–100 mg/d; this figure is almost certainly (Chap. 404).
an underestimate attributable to a lack of information on their con-
centrations in many foods. Several flavonoids have antioxidant activity Dietary Sources The retinol activity equivalent (RAE) is used to
and affect cell signaling. From observational epidemiologic studies express the vitamin A value of food: 1 RAE is defined as 1 μg of retinol
and limited clinical (human and animal) studies, flavonoids have been (0.003491 mmol), 12 μg of β-carotene, and 24 μg of other provitamin
postulated to play a role in the prevention of several chronic diseases, A carotenoids. In older literature, vitamin A often was expressed in
including neurodegenerative disease, diabetes, and osteoporosis. The international units (IUs), with 1 μg of retinol equal to 3.33 IU of retinol
ultimate importance and usefulness of these compounds against and 20 IU of β-carotene. Although these IUs are no longer in scientific
human disease have not been consistently demonstrated. Nevertheless, use, they can still be found in reports of the food industry and in public
a dietary pattern with high intake of fruits, vegetables, and legumes health interventions in low-income countries.
should be encouraged to assure a higher intake of these and others Liver, fish, and eggs are excellent food sources for preformed vita-
nonnutritive bioactives. min A; vegetable sources of provitamin A carotenoids include dark
green and deeply colored fruits and vegetables. Moderate cooking of
■■VITAMIN A vegetables enhances carotenoid release for uptake in the gut. Carote-
Vitamin A, in the strictest sense, refers to retinol and retinyl esters. noid absorption is also aided by some fat in a meal. Exclusive breast-
However, the oxidized metabolites retinaldehyde and retinoic acid feeding can cover the vitamin A needs of infants if the mother has
are also biologically active compounds. The term retinoids includes an adequate vitamin A status and a large enough volume of milk. If
all molecules (including synthetic molecules) that are chemically the nursing mother has inadequate vitamin A intake or concomitant
related to retinol. Retinaldehyde (11-cis) is the form of vitamin A that diseases or her infant was a preterm delivery, breast milk probably
is required for normal vision, whereas retinoic acid is necessary for will not supply enough vitamin A to prevent deficiency. In developing
normal morphogenesis, growth, and cell differentiation. Retinoic acid countries, chronic dietary deficiency is the main cause of vitamin A
does not function directly in vision and, in contrast to retinol, is not deficiency and is exacerbated by infection. In early childhood, low vita-
involved in reproduction. Vitamin A also plays a role in iron utiliza- min A status results from inadequate intakes of animal food sources
tion, humoral immunity, T cell–mediated immunity, natural killer cell and edible oils, both of which are expensive, coupled with seasonal
activity, and phagocytosis. unavailability of vegetables and fruits and lack of marketed fortified
Vitamin A is found in the human food supply in two forms: pre- food products. Factors that interfere with vitamin A metabolism may
formed as retinyl esters and provitamin A carotenoids. There are >700 also affect status or function. For example, concurrent zinc deficiency
carotenoids in nature, ~50 of which can be metabolized to vitamin A. can interfere with the mobilization of vitamin A from liver stores. Alco-
β-Carotene is the most prevalent carotenoid with provitamin A activity hol interferes with the conversion of retinol to retinaldehyde in the eye
in the food supply. In humans, significant fractions of carotenoids are by competing for alcohol (retinol) dehydrogenase. Drugs that interfere
absorbed intact and are stored in liver and fat. It is estimated that in with the absorption of vitamin A include mineral oil, neomycin, and
healthy humans ≥12 μg (range, 4–27 μg) of dietary all-trans β-carotene bile acid sequestrants (e.g., cholestyramine).

HPIM21e_Part10_p2381-p2670.indd 2529 20/01/22 10:04 PM

 2530 Deficiency Vitamin A deficiency is endemic in areas where diets supplement of 1500 μg (or RAE) three times a week for 4 weeks.
are chronically poor, especially in southern Asia, sub-Saharan Africa, Severe measles in any society can lead to secondary vitamin A
some parts of Latin America, and the western Pacific, including parts deficiency. Children hospitalized with measles should receive two
of China. Vitamin A status is usually assessed by measuring serum 60-mg doses of vitamin A on 2 consecutive days. Vitamin A defi-
retinol (normal range, 1.05–3.50 μmol/L [30–100 μg/dL]) or via ciency most often occurs in patients with malabsorptive diseases
dose-response tests or tests of dark adaptation. To assure a correct (e.g., celiac sprue, short-bowel syndrome) who have abnormal
biochemical assessment of vitamin A status, a simultaneous assessment dark adaptation or symptoms of night blindness without other
of the inflammatory status is needed (in analogy to the assessment of ocular changes. Typically, such patients are diagnosed in advanced
iron status); not doing so may result in an overestimation of vitamin A care settings where they are treated for 1 month with 15 mg/d of a
deficiency. Correction factors to adjust the measured plasma vitamin water-miscible preparation of vitamin A. This treatment is followed
A levels to account for the influence of C-reactive protein and α1-acid by a lower maintenance dose, with the exact amount determined
glycoprotein are available. Stable isotopic or invasive liver biopsy meth- by monitoring serum retinol. Finding application elsewhere in
ods are available to estimate total-body stores of vitamin A. As judged medicine, retinoic acid is useful in the treatment of promyelocytic
by deficient serum retinol (<0.70 μmol/L [20 μg/dL]), vitamin A leukemia (Chap. 104) and also is used in the treatment of cystic
deficiency worldwide is present in 190 million preschool-age children, acne because it inhibits keratinization, decreases sebum secretion,
among whom >5 million have an ocular manifestation of deficiency and possibly alters the inflammatory reaction (Chap. 57).
termed xerophthalmia. This condition includes milder stages of night No specific signs or symptoms result from carotenoid deficiency.
blindness and conjunctival xerosis (dryness) with Bitot’s spots (white It was postulated that β-carotene would be an effective chemopre-
patches of keratinized epithelium appearing on the sclera) that may ventive agent for cancer because numerous epidemiologic studies
affect 1–5% of children in deficient populations as well as rare, poten- had shown that diets high in β-carotene were associated with lower
tially blinding corneal ulceration and necrosis. Keratomalacia (soften- incidences of cancers of the respiratory and digestive systems.
ing of the cornea) leads to corneal scarring that blinds an estimated However, intervention studies in smokers found that treatment with
quarter of a million children each year and is associated with fatality high doses of β-carotene actually resulted in more lung cancers than
rates of 4–25%. However, vitamin A deficiency severe enough to cause did treatment with placebo. Non–provitamin A carotenoids such
any clinical stage poses an increased risk of death from diarrhea, dys- as lutein and zeaxanthin have been suggested to confer protection
entery, measles, malaria, or respiratory disease. This is because vitamin against macular degeneration, and one large-scale intervention
A deficiency can compromise barrier, innate, and acquired immune study did not show a beneficial effect except in those with a low
defenses to infection. In areas where deficiency is widely prevalent, lutein status. The use of the non–provitamin A carotenoid lycopene
vitamin A supplementation can markedly reduce the risk of childhood to protect against prostate cancer has been proposed. However, the
PART 10

mortality (by 23–34%, on average). About 10% of pregnant women effectiveness of these agents has not been proved by intervention
in undernourished settings also develop night blindness (assessed by studies, and the mechanisms underlying these purported biologic
history) during the latter half of pregnancy; this level of moderate actions are unknown.
to severe vitamin A deficiency is associated with an increased risk of Selective plant-breeding techniques that lead to a higher provi-
maternal infection and death. Maternal vitamin A deficiency may also tamin A carotenoid content in staple foods may decrease vitamin
Disorders of the Gastrointestinal System

exacerbate already low vitamin A nutrition and associated risks for A malnutrition in low-income countries. Moreover, a recently
the newborn. In South Asia, where maternal deficiency is prominent, developed genetically modified food (Golden Rice) had a β-
giving infants a single oral dose (50,000 IU) of vitamin A shortly after carotene–to–vitamin A conversion ratio of ~3:1 in children.
birth has reduced infant mortality by ≥10%, whereas in African set-
tings less affected by maternal vitamin A deficiency, no effect has been Toxicity The acute toxicity of vitamin A was first noted in Arctic
noted, revealing differences in risk of deficiency and benefit of supple- explorers who ate polar bear liver and has also been seen after admin-
mentation across regions. However, the World Health Organization istration of 150 mg to adults or 100 mg to children. Acute toxicity
does not recommend high-dose supplementation to newborns. is manifested by increased intracranial pressure, vertigo, diplopia,
bulging fontanels (in children), seizures, and exfoliative dermatitis; it
may result in death. Among children being treated for vitamin A defi-
TREATMENT ciency according to the protocols outlined above, transient bulging of
Vitamin A Deficiency fontanels occurs in 2% of infants, and transient nausea, vomiting, and
headache occur in 5% of preschoolers. Chronic vitamin A intoxication
Vitamin A is commercially available for treatment and prevention is largely a concern in industrialized countries and has been seen in
in esterified forms (e.g., acetate, palmitate), which are more stable otherwise healthy adults who ingest 15 mg/d and children who ingest
than other forms. Any stage of xerophthalmia should be treated 6 mg/d over a period of several months. Manifestations include dry
with 60 mg (or RAE) or 200,000 IU of vitamin A in oily solution, skin, cheilosis, glossitis, vomiting, alopecia, bone demineralization
usually contained in a soft-gel capsule. The same dose is repeated and pain, hypercalcemia, lymph node enlargement, hyperlipidemia,
1 and 14 days later. Doses should be reduced by half for patients amenorrhea, and features of pseudotumor cerebri with increased
6–11 months of age. Mothers with night blindness or Bitot’s spots intracranial pressure and papilledema. Liver fibrosis with portal
should be given vitamin A orally 3 mg daily for at least 3 months. hypertension may also result from chronic vitamin A intoxication.
These regimens are efficacious, and they are far less expensive and Provision of vitamin A in excess to pregnant women has resulted in
more widely available than injectable water-miscible vitamin A. spontaneous abortion and in congenital malformations, including
A common approach to prevention is to provide vitamin A supple- craniofacial abnormalities and valvular heart disease. In pregnancy,
mentation every 4–6 months to young children 6 months to 5 years the daily dose of vitamin A should not exceed 3 mg. Also, topical
of age (both HIV-positive and HIV-negative) in high-risk areas. retinoids should be avoided during pregnancy. Commercially available
For prevention, infants 6–11 months of age should receive 30 mg of retinoid derivatives are also toxic, including 13-cis-retinoic acid, which
vitamin A; children 12–59 months of age should receive 60 mg. For has been associated with birth defects. Thus, contraception should be
reasons that are not clear, although early neonatal vitamin A may continued for at least 1 year and possibly longer in women who have
reduce infant mortality, vitamin A given between 1 and 5 months taken 13-cis-retinoic acid.
of age has not proven effective in improving survival in high-risk In malnourished children, vitamin A supplements (30–60 mg), in
settings. amounts calculated as a function of age and given in several rounds
Uncomplicated vitamin A deficiency is rare in industrialized over 2 years, are considered to amplify nonspecific effects of vaccines.
countries. One high-risk group—extremely low-birth-weight (<1000- However, for unclear reasons, in one African setting, there has been a
g) infants—is likely to be vitamin A deficient and should receive a negative effect on mortality rates in incompletely vaccinated girls.

HPIM21e_Part10_p2381-p2670.indd 2530 20/01/22 10:04 PM

 High doses of supplemental carotenoids do not result in toxic symp- The U.S. National Academy of Sciences recently advised that the 2531
toms but should be avoided in smokers due to an increased risk of lung majority of adult North Americans should receive 600 IU/d of vitamin
cancer. Very high doses of β-carotene (~200 mg/d) have been used to D (RDA = 15 μg/d or 600 IU/d; Chap. 332). However, for people aged
treat or prevent the skin rashes of erythropoietic protoporphyria. Car- >70 years, the RDA is set at 20 μg/d (800 IU/d). The consumption
otenemia, which is characterized by a yellowing of the skin (in creases of fortified or enriched foods as well as suberythemal sun exposure
of the palms and soles) but not the sclerae, may follow ingestion of should be encouraged for people at risk for vitamin D deficiency.
>30 mg of β-carotene daily. Hypothyroid patients are particularly If adequate intake is impossible, vitamin D supplements should be
susceptible to the development of carotenemia due to impaired break- taken, especially during the winter months. Vitamin D deficiency can
down of carotene to vitamin A. Reduction of carotenes in the diet be treated by oral administration of 50,000 IU/week for 6–8 weeks
results in the disappearance of skin yellowing and carotenemia over a followed by a maintenance dose of 800 IU/d (20 μg/d) from food and
period of 30–60 days. supplements once normal plasma levels have been attained. There is
still uncertainty regarding the optimal therapeutic dosage (high vs low)
■■VITAMIN D for elderly at risk of falls. The physiologic effects of vitamin D2 and
The metabolism of the fat-soluble vitamin D is described in detail in vitamin D3 are similar when these vitamins are ingested over long
Chap. 409. The biologic effects of this vitamin are mediated by vita- periods.
min D receptors, which are found in most tissues; binding with these
receptors potentially expands vitamin D actions to many different Toxicity The upper limit of intake has been set at 4000 IU/d. Con-
cell systems and organs (e.g., immune cells, brain, breast, colon, and trary to earlier beliefs, acute vitamin D intoxication is rare and usually
prostate) in addition to the classic endocrine effects on calcium and is caused by the uncontrolled and excessive ingestion of supplements or
phosphate metabolism and bone health. Vitamin D is thought to be by faulty food fortification practices. High plasma levels of 1,25(OH)2
important for maintaining normal function of many nonskeletal tis- vitamin D and calcium are central features of toxicity and mandate
sues such as muscle (including heart muscle), for immune function, discontinuation of vitamin D and calcium supplements; in addition,
and for inflammation as well as for cell proliferation and differen- treatment of hypercalcemia may be required.
tiation. Older studies have shown that vitamin D may be useful as
■■VITAMIN E
adjunctive treatment for tuberculosis, psoriasis, and multiple sclerosis
Vitamin E is the collective designation for all stereoisomers of toco-
or for the prevention of certain cancers. Vitamin D insufficiency may
pherols and tocotrienols, although only the α-tocopherols meet human
increase the risk of type 1 diabetes mellitus, cardiovascular disease
requirements. Vitamin E acts as a chain-breaking antioxidant and
(insulin resistance, hypertension, or low-grade inflammation), or brain
is an efficient peroxyl radical scavenger that protects low-density

CHAPTER 333 Vitamin and Trace Mineral Deficiency and Excess

dysfunction (e.g., depression). However, the exact physiologic roles of
lipoproteins and polyunsaturated fats in membranes from oxidation.
vitamin D in these nonskeletal diseases and the importance of these
A network of other antioxidants (e.g., vitamin C, glutathione) and
roles have so far not been clarified. Recent placebo-controlled studies
enzymes maintains vitamin E in a reduced state. Vitamin E also inhib-
did not show a therapeutic benefit of vitamin D for cancer prevention,
its prostaglandin synthesis and the activities of protein kinase C and
control of cardiovascular disease, or risk of type 2 diabetes, depression,
phospholipase A2.
tuberculosis infection, or other respiratory infections. Presently, it is
not known whether these effects of vitamin D supplements (with or Absorption and Metabolism After absorption, vitamin E is
without calcium) might be different according to the baseline status taken up from chylomicrons by the liver, and a hepatic α-tocopherol
(normal vs severely deficient) of patients. transport protein mediates intracellular vitamin E transport and incor-
The skin is a major source of vitamin D, which is synthesized upon poration into very-low-density lipoprotein. The transport protein has
skin exposure to ultraviolet B radiation (UV-B; wavelength, 290–320 nm). a particular affinity for the RRR isomeric form of α-tocopherol; thus,
Except for fish, food (unless fortified) contains only limited amounts of this natural isomer has the most biologic activity.
vitamin D. Vitamin D2 (ergocalciferol) is obtained from plant sources Requirement Vitamin E is widely distributed in the food supply,
and is the chemical form found in some supplements. with particularly high levels in sunflower oil, safflower oil, and wheat
Deficiency Vitamin D status has been assessed by measuring germ oil; γ-tocotrienols are notably present in soybean and corn oils.
serum levels of 25-dihydroxyvitamin D (25[OH] vitamin D); however, Vitamin E is also found in meats, nuts, and cereal grains, and small
there is no consensus on a uniform assay, on optimal serum levels, or amounts are present in fruits and vegetables. Vitamin E pills containing
on the real benefit of biochemical screening. The optimal level might, doses of 50–1000 mg are ingested by ~10% of the U.S. population. The
in fact, differ according to the targeted disease entity. Epidemiologic RDA for vitamin E is 15 mg/d (34.9 μmol or 22.5 IU) for all adults.
and experimental data indicate that a 25(OH) vitamin D level of Diets high in polyunsaturated fats may necessitate a slightly higher
>20 ng/mL (≥50 nmol/L; to convert ng/mL to nmol/L, multiply by intake of vitamin E.
2.496) is sufficient for good bone health. The latter 25(OH) vitamin D Dietary deficiency of vitamin E does not exist in developed coun-
plasma concentration would cover the requirements of 97.5% of the tries but can occur in developing countries due to inadequate intake.
population. Some experts, however, advocate higher serum levels (e.g., Vitamin E deficiency is seen only in severe and prolonged malabsorp-
>30 ng/mL) for other desirable endpoints of vitamin D action. There tive diseases, such as celiac disease, chronic cholestatic liver disease,
is insufficient evidence to recommend combined vitamin D and cal- or after small-intestinal resection or bariatric surgery. Children with
cium supplementation as a primary preventive strategy (as opposed cystic fibrosis or prolonged cholestasis may develop vitamin E defi-
to secondary prevention) for reduction of the incidence of fractures in ciency characterized by areflexia and hemolytic anemia. Children
healthy men and premenopausal women. with abetalipoproteinemia cannot absorb or transport vitamin E and
Risk factors for vitamin D deficiency are old age, lack of sun expo- become deficient quite rapidly. A familial form of isolated vitamin E
sure, dark skin (especially among residents of northern latitudes), fat deficiency also exists; it is due to a defect in the α-tocopherol transport
malabsorption, and obesity; deficiency can also occur after gastric protein. Vitamin E deficiency causes axonal degeneration of the large
bypass surgery. In addition, in African populations, the prevalence of myelinated axons and results in posterior column and spinocerebellar
vitamin D deficiency might be high (especially in women, newborn symptoms. Peripheral neuropathy is initially characterized by areflexia,
babies, urban populations, and those living in northern African coun- with progression to an ataxic gait, and by decreased vibration and posi-
tries). Rickets represents the classic disease of vitamin D deficiency. tion sensations. Ophthalmoplegia, skeletal myopathy, and pigmented
Signs of deficiency are muscle soreness, weakness, and bone pain. retinopathy may also be features of vitamin E deficiency. A deficiency
Some of these effects are independent of calcium intake. To prevent of either vitamin E or selenium in the host has been shown to increase
glucocorticoid-induced osteoporosis, treatment with calcium (1000– certain viral mutations and, therefore, virulence. The laboratory diag-
1200 mg/d) and vitamin D (600–800 IU/d) through diet and/or supple- nosis of vitamin E deficiency is based on low blood levels of α-toco-
ments in combination with weight-bearing exercise is recommended. pherol (<5 μg/mL, or <0.8 mg of α-tocopherol per gram of total lipids).

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 2532
TREATMENT malabsorption. The assessment of the vitamin K status can be done by
measurement of phylloquinone (vitamin K1) concentration in serum
Vitamin E Deficiency (deficiency <0.15 μg/L); the cellular utilization of vitamin K can be
assessed by the serum or plasma concentration of undercarboxylated
Symptomatic vitamin E deficiency should be treated with 800–1200 prothrombin (protein induced by vitamin K absence/antagonism
mg of α-tocopherol per day. Patients with abetalipoproteinemia [PIVKA-II]). An elevated prothrombin time or activated partial
may need as much as 5000–7000 mg/d. Children with symptomatic thromboplastin time or reduced clotting factors are useful markers in
vitamin E deficiency should be treated orally with water-miscible severe deficiency but are otherwise nonspecific and lack sensitivity.
esters (400 mg/d); alternatively, 2 mg/kg per d may be administered Vitamin K deficiency is treated with a parenteral dose of 10 mg. For
intramuscularly. Vitamin E in high doses may protect against oxy- patients with chronic malabsorption, 1–2 mg/d should be given orally
gen-induced retrolental fibroplasia and bronchopulmonary dyspla- or 1–2 mg per week can be taken parenterally. Patients with liver
sia as well as intraventricular hemorrhage of prematurity. Vitamin disease may have an elevated prothrombin time because of liver cell
E has been suggested to increase sexual performance, treat inter- destruction as well as vitamin K deficiency. If an elevated prothrombin
mittent claudication, and slow the aging process, but convincing time does not improve during vitamin K therapy, it can be deduced that
evidence for these properties is lacking. When given in combina- this abnormality is not the result of vitamin K deficiency.
tion with other antioxidants, vitamin E may help prevent macular
degeneration. Vitamin E may have favorable therapeutic effects in Toxicity Toxicity from dietary phylloquinones and menaquinones
noncirrhotic nondiabetic patients with nonalcoholic steatohepa- has not been described. High doses of vitamin K can impair the actions
titis. High doses (60–800 mg/d) of vitamin E have been shown in of oral vitamin K antagonist anticoagulants.
controlled trials to improve parameters of immune function and
reduce colds in nursing home residents, but intervention studies MINERALS
using vitamin E to prevent cardiovascular disease or cancer have See also Table 333-2.
not shown efficacy, and at doses >400 mg/d, vitamin E may even
increase all-cause mortality rates and prostate cancer risk (espe- ■■CALCIUM
cially in combination with selenium supplements). See Chap. 409.
■■ZINC
Toxicity All forms of vitamin E are absorbed and could contribute Zinc is an integral component of many metalloenzymes in the body;
to toxicity; however, the toxicity risk seems to be rather low as long as it is involved in the synthesis and stabilization of proteins, DNA, and
liver function is normal. High doses of vitamin E (>800 mg/d) may RNA and plays a structural role in ribosomes and membranes. Zinc
PART 10

reduce platelet aggregation and interfere with vitamin K metabolism is necessary for the binding of steroid hormone receptors and several
and are therefore contraindicated in patients taking warfarin and anti- other transcription factors to DNA. Zinc is essential for normal sper-
platelet agents (such as aspirin or clopidogrel). Nausea, flatulence, and matogenesis, fetal growth, and embryonic development.
diarrhea have been reported at doses >1 g/d. Absorption The absorption of zinc from the diet is inhibited by
dietary phytate, fiber, oxalate, iron, and copper as well as by certain
Disorders of the Gastrointestinal System

■■VITAMIN K drugs, including penicillamine, sodium valproate, and ethambutol.

There are two natural forms of vitamin K: vitamin K1, also known as Protein-containing foods, i.e., meat, shellfish, nuts, and legumes, are
phylloquinone, from vegetable sources, and vitamin K2, or menaquino- good sources of bioavailable zinc, whereas zinc in grains and legumes
nes, which are synthesized by bacterial flora and found in hepatic tis- is less available for absorption. Grains and legumes contain phytate that
sue. Phylloquinone can be converted to menaquinone in some organs. binds zinc in the intestine and reduces its availability for absorption.
Vitamin K is required for the posttranslational carboxylation of glu-
tamic acid, which is necessary for calcium binding to γ-carboxylated
Deficiency Mild zinc deficiency has been described in many dis-
eases, including diabetes mellitus, HIV/AIDS, cirrhosis, alcoholism,
proteins such as prothrombin (factor II); factors VII, IX, and X; protein
inflammatory bowel disease, malabsorption syndromes, and sickle
C; protein S; and proteins found in bone (osteocalcin) and vascular
cell disease. In these diseases, mild chronic zinc deficiency can cause
smooth muscle (e.g., matrix Gla protein). However, the importance of
stunted growth in children, decreased taste sensation (hypogeusia), and
vitamin K for bone mineralization and prevention of vascular calcifica-
impaired immune function. Severe chronic zinc deficiency has been
tion is not known. Warfarin-type drugs inhibit γ-carboxylation by pre-
described as a cause of hypogonadism and dwarfism in several Middle
venting the conversion of vitamin K to its active hydroquinone form.
Eastern countries. In these children, hypopigmented hair is also part
Dietary Sources Vitamin K is found in green leafy vegetables such of the syndrome. Acrodermatitis enteropathica is a rare autosomal
as kale and spinach, and appreciable amounts are also present in mar- recessive disorder characterized by abnormalities in zinc absorption.
garine and liver. Vitamin K is present in vegetable oils; olive, canola, Clinical manifestations include diarrhea, alopecia, muscle wasting,
and soybean oils are particularly rich sources. The average daily intake depression, irritability, and a rash involving the extremities, face, and
by Americans is estimated to be ~100 μg/d. perineum. The rash is characterized by vesicular and pustular crusting
with scaling and erythema. Occasional patients with Wilson’s disease
Deficiency The symptoms of vitamin K deficiency are due to hem- have developed zinc deficiency as a consequence of penicillamine
orrhage; newborns are particularly susceptible because of low fat stores, therapy (Chap. 415).
low breast milk levels of vitamin K, relative sterility of the infantile Zinc deficiency is prevalent in many developing countries and usu-
intestinal tract, liver immaturity, and poor placental transport. Intra- ally coexists with other micronutrient deficiencies (especially iron defi-
cranial bleeding as well as gastrointestinal and skin bleeding can occur ciency). Zinc (20 mg/d until recovery) may be an effective adjunctive
in vitamin K–deficient infants 1–7 days after birth. Thus, vitamin K therapeutic strategy for diarrheal disease and pneumonia in children
(0.5–1 mg IM) is given prophylactically at delivery. ≥6 months of age.
Vitamin K deficiency in adults may be seen in patients with The diagnosis of zinc deficiency is usually based on a serum zinc
chronic small-intestinal disease (e.g., celiac disease, Crohn’s disease), level <12 μmol/L (<70 μg/dL). Pregnancy and birth control pills may
in those with obstructed biliary tracts, or after small-bowel resec- cause a slight depression in serum zinc levels, and hypoalbuminemia
tion. Broad-spectrum antibiotic treatment can precipitate vitamin from any cause can result in hypozincemia. In acute stress situations
K deficiency by reducing numbers of gut bacteria, which synthesize (illness, but also postexercise recovery), zinc may be redistributed
menaquinones, and by inhibiting the metabolism of vitamin K. from serum into tissues. Zinc deficiency may be treated with 60 mg
In patients with warfarin therapy, the antiobesity drug orlistat can of elemental zinc taken by mouth twice a day. Zinc gluconate lozenges
lead to changes in international normalized ratio due to vitamin K (13 mg of elemental zinc every 2 h while awake) have been reported to

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 2533
TABLE 333-2 Deficiencies and Toxicities of Metals
TOLERABLE UPPER (DIETARY) INTAKE
ELEMENT DEFICIENCY TOXICITY LEVEL
Boron No biologic function determined Developmental defects, male sterility, testicular atrophy 20 mg/d (extrapolated from animal data)
Calcium Reduced bone mass, osteoporosis Renal insufficiency (milk-alkali syndrome), 2500 mg/d (milk-alkali)
nephrolithiasis, impaired iron absorption,
thiazide diuretics
Copper Anemia, growth retardation, defective Nausea, vomiting, diarrhea, hepatic failure, tremor, 10 mg/d (liver toxicity)
keratinization and pigmentation of hair, psychiatric disturbances, hemolytic anemia, renal
hypothermia, degenerative changes in aortic dysfunction
elastin, osteopenia, intellectual disability
Chromium Impaired glucose tolerance Occupational: Renal failure, dermatitis, pulmonary Not determined
cancer
Fluoride ↑ Dental caries Dental and skeletal fluorosis, osteosclerosis 10 mg/d (fluorosis)
Iodine Thyroid enlargement, ↓ T4, cretinism Thyroid dysfunction, acne-like eruptions 1100 μg/d (thyroid dysfunction)
Iron Muscle abnormalities, koilonychia, pica, Gastrointestinal effects (nausea, vomiting, diarrhea, 45 mg/d of elemental iron
anemia, ↓ work performance, impaired constipation), iron overload with organ damage, acute (gastrointestinal side effects)
cognitive development, premature labor, and chronic systemic toxicity, increased susceptibility to
↑ perinatal maternal death malaria, increased risk association with certain chronic
diseases (e.g., diabetes)
Manganese Impaired growth and skeletal development, General: Neurotoxicity, Parkinson-like symptoms 11 mg/d (neurotoxicity)
reproduction, lipid and carbohydrate Occupational: Encephalitis-like syndrome, Parkinson-
metabolism; upper body rash like syndrome, psychosis, pneumoconiosis
Molybdenum Severe neurologic abnormalities Reproductive and fetal abnormalities 2 mg/d (extrapolated from animal data)
Selenium Cardiomyopathy, heart failure, striated muscle General: Alopecia, nausea, vomiting, abnormal nails, 400 μg/d (hair, nail changes)
degeneration emotional lability, peripheral neuropathy, lassitude,
garlic odor to breath, dermatitis
Occupational: Lung and nasal carcinomas, liver

CHAPTER 333 Vitamin and Trace Mineral Deficiency and Excess

necrosis, pulmonary inflammation
Phosphorus Rickets (osteomalacia), proximal muscle Hyperphosphatemia 4000 mg/d
weakness, rhabdomyolysis, paresthesia,
ataxia, seizure, confusion, heart failure,
hemolysis, acidosis
Zinc Growth retardation, ↓ taste and smell, General: Reduced copper absorption, gastritis, 40 mg/d (impaired copper metabolism)
alopecia, dermatitis, diarrhea, immune sweating, fever, nausea, vomiting
dysfunction, failure to thrive, gonadal atrophy, Occupational: Respiratory distress, pulmonary fibrosis
congenital malformations

reduce the duration and symptoms of the common cold in adults, but X-linked metabolic disturbance of copper metabolism characterized
study results are conflicting. by intellectual disability, hypocupremia, and decreased circulating
ceruloplasmin (Chap. 413). This syndrome is caused by mutations in
Toxicity Acute zinc toxicity after oral ingestion causes nausea, the copper-transporting ATP7A gene. Children with this disease often
vomiting, and fever. Zinc fumes from welding may also be toxic and die within 5 years because of dissecting aneurysms or cardiac rupture.
cause fever, respiratory distress, excessive salivation, sweating, and Aceruloplasminemia is a rare autosomal recessive disease character-
headache. Chronic large doses of zinc (ranging from 150 to 450 mg/d) ized by tissue iron overload, mental deterioration, microcytic anemia,
may depress immune function and cause hypochromic anemia as a and low serum iron and copper concentrations.
result of a secondary copper deficiency. Intranasal zinc preparations The diagnosis of copper deficiency is usually based on low serum
should be avoided because they may lead to irreversible damage of the levels of copper (<65 μg/dL) and low ceruloplasmin levels (<20 mg/
nasal mucosa and anosmia. dL). Serum levels of copper may be elevated in pregnancy or stress con-
ditions since ceruloplasmin is an acute-phase reactant and 90% of cir-
■■COPPER culating copper is bound to ceruloplasmin. It has been suggested that
Copper is an integral part of numerous enzyme systems, including mild or subclinical copper deficiency is more common than expected;
amine oxidases, ferroxidase (ceruloplasmin), cytochrome c oxidase, at-risk individuals include patients with cholestasis or chronic diar-
superoxide dismutase, and dopamine hydroxylase. Copper is also a rheal diseases, dialysis patients, and people on long-term zinc supple-
component of ferroprotein, a transport protein involved in the baso- ments. The role of copper in cardiovascular disease, immune function,
lateral transfer of iron during absorption from the enterocyte. As such, bone health, or neurodegenerative diseases is still unclear.
copper plays a role in iron metabolism, melanin synthesis, energy
production, neurotransmitter synthesis, and CNS function; the syn- Toxicity Copper toxicity is usually accidental (Table 333-2). In severe
thesis and cross-linking of elastin and collagen; and the scavenging of cases, kidney failure, liver failure, and coma may ensue. In Wilson’s
superoxide radicals. Dietary sources of copper include shellfish, liver, disease, mutations in the copper-transporting ATP7B gene lead to
nuts, legumes, bran, and organ meats. accumulation of copper in the liver and brain, with low blood levels
due to decreased ceruloplasmin (Chap. 415). A potential negative role
Deficiency Dietary copper deficiency is relatively rare, although of copper in the pathogenesis of Alzheimer’s disease has been reported.
it has been described in premature infants who are fed milk diets
and in infants with malabsorption (Table 333-2). Copper-deficiency ■■SELENIUM
anemia (refractory to therapeutic iron) has been reported in patients Selenium, in the form of selenocysteine, is a component of the enzyme
with malabsorptive diseases and nephrotic syndrome and in patients glutathione peroxidase, which serves to protect proteins, cell mem-
treated for Wilson’s disease with chronic high doses of oral zinc, which branes, lipids, and nucleic acids from oxidant molecules. As such,
can interfere with copper absorption. Menkes kinky hair syndrome is an selenium is being actively studied as a chemopreventive agent against

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 2534 certain cancers, such as prostate cancer. However, it remains unclear Ota Y et al: Comprehensive review of Wernicke encephalopathy:
whether selenium is effective as a chemopreventive agent or whether Pathophysiology, clinical symptoms and imaging findings. Jpn J
it increases cancer risk (e.g., prostate cancer). Convincing evidence for Radiol 38:809, 2020.
a protective effect of selenium on cognitive decline or cardiovascular Stevens GA et al: Trends and mortality effects of vitamin A deficiency
disease risk is presently lacking. Selenocysteine is also found in the in children in 138 low-income and middle-income countries between
deiodinase enzymes, which mediate the deiodination of thyroxine to 1991 and 2013: A pooled analysis of population-based surveys.
triiodothyronine (Chap. 382). Rich dietary sources of selenium include Lancet Glob Health 3:e528, 2015.
seafood, muscle meat, and cereals, although the selenium content of Tanumihardjo SA et al: Biomarkers of nutrition for development
cereal is determined by the soil concentration. Countries with low soil (BOND): Vitamin A review. J Nutr 146:1816S, 2016.
concentrations include parts of Scandinavia, China, and New Zealand. Vinceti M, Rothman KJ: More results but no clear conclusion on
Keshan disease is an endemic cardiomyopathy found in children and selenium and cancer. Am J Clin Nutr 104:245, 2016.
young women residing in regions of China where dietary intake of World Health Organization: Guideline: Vitamin A supplementa-
selenium is low (<20 μg/d). Concomitant deficiencies of iodine and tion in pregnant women. Geneva, World Health Organization, 2011.
selenium may worsen the clinical manifestations of cretinism. Chronic
ingestion of large amounts of selenium leads to selenosis, character-
ized by hair and nail brittleness and loss, garlic breath odor, skin rash,
myopathy, irritability, and other abnormalities of the nervous system.
■■CHROMIUM
Chromium potentiates the action of insulin in patients with impaired
glucose tolerance, presumably by increasing insulin receptor–medi-
334 Malnutrition and
Nutritional Assessment
ated signaling, although its usefulness in treating type 2 diabetes is
uncertain. In addition, improvement in blood lipid profiles has been Gordon L. Jensen
reported in some patients. The usefulness of chromium supplements
in muscle building has not been substantiated. Rich food sources of
chromium include yeast, meat, and grain products. Chromium in the Malnutrition occurs in 30–50% of hospitalized patients depending on
trivalent state is found in supplements and is largely nontoxic; however, the setting and criteria that are used. Poor wound healing, compro-
chromium-6 is a product of stainless steel welding and is a known pul- mised immune status, impaired organ function, increased length of
monary carcinogen as well as a cause of liver, kidney, and CNS damage. hospital stay, and increased mortality are among the notable adverse
PART 10

■■MAGNESIUM outcomes associated with malnutrition. It is now widely appreciated

See Chap. 409. that acute or chronic inflammation contribute to the pathophysiology
of disease-related or injury-related malnutrition. The presence of
■■FLUORIDE, MANGANESE, AND inflammation can also render historic nutrition assessment indicators,
ULTRATRACE ELEMENTS like albumin and prealbumin, unreliable, and inflammation diminishes
Disorders of the Gastrointestinal System

An essential function for fluoride in humans has not been described, favorable responses to nutrition therapies. In order to guide appropri-
although it is useful for the maintenance of structure in teeth and ate care, it is necessary to properly assess and diagnose malnutrition.
bones. Adult fluorosis results in mottled and pitted defects in tooth Nutrition assessment is a comprehensive evaluation to diagnose a mal-
enamel as well as brittle bone (skeletal fluorosis). nutrition syndrome and to guide intervention and expected outcomes.
Manganese and molybdenum deficiencies have been reported in Patients are often targeted for assessment after being identified at nutri-
patients with rare genetic abnormalities and in a few patients receiv- tional risk based on screening procedures conducted by nursing or
ing prolonged total parenteral nutrition. Several manganese-specific nutrition personnel within 24 h of hospital admission. Screening tends
enzymes have been identified (e.g., manganese superoxide dismutase). to focus explicitly on a few risk variables like weight loss, compromised
Deficiencies of manganese have been reported to result in bone demin- dietary intake, and high-risk medical/surgical diagnoses. Preferably,
eralization, poor growth, ataxia, disturbances in carbohydrate and lipid health professionals complement this screening with a systematic
metabolism, and convulsions. approach to comprehensive nutrition assessment that incorporates an
Ultratrace elements are defined as those needed in amounts appreciation for the contributions of inflammation that serve as the
<1 mg/d. Essentiality has not been established for most ultratrace ele- basis for new approaches to the diagnosis and management of malnu-
ments, although selenium, chromium, and iodine are clearly essential trition syndromes.
(Chap. 382). Molybdenum is necessary for the activity of sulfite and
xanthine oxidase, and molybdenum deficiency may result in skeletal ■■MALNUTRITION SYNDROMES
and brain lesions. Famine and starvation have long been leading causes of malnutrition
and remain so in developing countries. However, with improvements
■■FURTHER READING in agriculture, education, public health, health care, and living stan-
Combs GF Jr, Mcclung JP: The Vitamins: Fundamental Aspects in dards, malnutrition in the settings of disease, surgery, and injury has
Nutrition and Health. 5th ed. London, Academic Press, 2017, p 612. become a prevalent concern throughout the world. Malnutrition now
Imdad A et al: Vitamin A supplementation for preventing morbid- encompasses the full continuum of undernutrition and overnutrition
ity and mortality in children from six months to five years of age. (obesity). For the objectives of this chapter, we will focus upon the for-
Cochrane Database Syst Rev 3:CD008524, 2017. mer. Historic definitions for malnutrition syndromes are problematic
Lassi ZS et al: Zinc supplementation for the promotion of growth in their use of diagnostic criteria that suffer poor sensitivity, sensitivity,
and prevention of infections in infants less than six months of age. and interobserver reliability. Definitions overlap, and confusion and
Cochrane Database Syst Rev 4:CD010205, 2020. misdiagnosis are frequent. In addition, some approaches do not rec-
Mechanick JI et al: Clinical practice guidelines for the perioperative ognize undernutrition in obese persons. While the historic syndromes
nutrition, metabolic, and nonsurgical support of patients undergoing of marasmus, kwashiorkor, and protein-calorie malnutrition remain in
bariatric procedures–2019 update. Surg Obes Relat Dis 16:175, 2020. use, this chapter will instead highlight evolving insights to the diagno-
Namaste SM et al: Methodologic approach for the Biomarkers sis of malnutrition syndromes.
Reflecting Inflammation and Nutritional Determinants of Anemia The Subjective Global Assessment, a comprehensive nutrition
(BRINDA) project. Am J Clin Nutr 106(Suppl 1):333S, 2017. assessment that included a metabolic stress of disease component,
Ngo B et al: Targeting cancer vulnerabilities with high-dose vitamin C. was described and validated in the 1980s. In 2010, an International
Nat Rev Cancer 19:271, 2020. Consensus Guideline Committee incorporated a new appreciation for

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 the role of inflammatory response into their proposed nomenclature and Enteral Nutrition (ASPEN) extended this approach using clinical 2535
for nutrition diagnosis in adults in the clinical practice setting. Starva- characteristics to support diagnosis, including the presence of illness
tion-associated malnutrition is when there is chronic starvation without or injury, poor food intake, weight loss, and physical findings of fat
inflammation, chronic disease–associated malnutrition is when inflam- loss, muscle loss, edema, or reduced grip strength. In 2016, the Euro-
mation is chronic and of mild to moderate degree, and acute disease– or pean Society for Parenteral and Enteral Nutrition (ESPEN) formally
injury-associated malnutrition is when inflammation is acute and of adopted a disease/inflammation-based construct similar to these
severe degree (see Table 334-1 for examples). In 2012, the Academy earlier approaches. Also in 2016, the Global Leadership Initiative on
of Nutrition and Dietetics and the American Society for Parenteral Malnutrition (GLIM), a collaborative effort of ASPEN, ESPEN, the

TABLE 334-1 History and Physical Examination Elements

ELEMENT NOTES
Historical Data
Body weight Ask about usual weight, peak weight, and deliberate weight loss. A 4.5-kg (10-lb) weight loss over 6 months is noteworthy, and a weight loss
of >10% of usual body weight is prognostic of clinical outcomes. Use medical records, family, and caregivers as information resources.
Medical and surgical Look for medical or surgical conditions or chronic disease that can place one at nutritional risk secondary to increased requirements or
conditions; chronic compromised intake or assimilation such as: critical illness, severe burns, major abdominal surgery, multitrauma, closed head injury, previous
disease gastrointestinal surgery, severe gastrointestinal hemorrhage, enterocutaneous fistula, gastrointestinal obstruction, mesenteric ischemia,
severe acute pancreatitis, chronic pancreatitis, inflammatory bowel disease, celiac disease, bacterial overgrowth, solid or hematologic
malignancy, bone marrow transplant, acquired immune deficiency syndrome, and organ failure/transplant—kidney, liver, heart, lung, or gut.
A number of conditions or diseases are characterized by severe acute inflammatory response including critical illness, major infection/sepsis,
adult respiratory distress syndrome, systemic inflammatory response syndrome, severe burns, major abdominal surgery, multitrauma, and
closed head injury.
Many conditions or diseases are more typically associated with mild to moderate chronic inflammatory response. Examples include
cardiovascular disease, congestive heart failure, cystic fibrosis, inflammatory bowel disease, celiac disease, chronic pancreatitis,
rheumatoid arthritis, solid tumors, hematologic malignancies, sarcopenic obesity, diabetes mellitus, metabolic syndrome, cerebrovascular
accident, neuromuscular disease, dementia, organ failure/transplant (kidney, liver, heart, lung, or gut), periodontal disease, pressure wounds,
and chronic obstructive pulmonary disease. Note that acute exacerbations, infections, or other complications may superimpose acute

CHAPTER 334 Malnutrition and Nutritional Assessment

inflammatory response on such conditions or diseases.
Examples of starvation-associated conditions that generally have little or no discernable inflammatory component include anorexia nervosa
or compromised intake in the setting of major depression.
Constitutional signs/ Fever or hypothermia can indicate active inflammatory response. Tachycardia is also common. Anorexia is another manifestation of
symptoms inflammatory response and is also often a side effect of treatments and medications.
Eating difficulties/ Poor dentition or problems swallowing can compromise oral intake. Vomiting, nausea, abdominal pain, abdominal distension, diarrhea,
gastrointestinal constipation, and gastrointestinal bleeding can be signs of gastrointestinal pathology that may place one at nutritional risk.
complaints
Eating disorders Look for distorted body image, compulsive exercise, amenorrhea, vomiting, tooth loss, dental caries, and use of laxatives, diuretics, or Ipecac.
Medication use Many medications can adversely affect nutrient intake or assimilation. Review potential drug–drug and drug–nutrient interactions.
A pharmacist consultant can be helpful.
Dietary practices and Look for dietary practices including therapeutic, weight reduction, vegetarian, macrobiotic, and fad diets. Also record use of dietary
supplement use supplements, including vitamins, minerals, and herbals. Ask about dietary intake. Recall, record, and food frequency tools are available.
It is estimated that 50% or more of adults take dietary supplements.
Influences on Ask about factors such as living environment, functional status (activities of daily living and instrumental activities of daily living),
nutritional status dependency, caregiver status, resources, dentition, alcohol or substance abuse, mental health (depression or dementia), and lifestyle.
Physical Examination Data
Body mass index (BMI) BMI = weight in kg/(height in meters)2
BMI <18.5 kg/m2 proposed screen for malnutrition per National Institutes of Health guidelines. BMI ≤15 kg/m2 or less is associated with
increased mortality.
Comparison with ideal body weight for stature can also be determined from reference tables. Note hydration status and edema at the time
body weight is determined.
Weight loss Look for loss of muscle mass and subcutaneous fat.
Temporal and neck muscle wasting may be readily observed. Anthropometrics including skinfolds and circumferences can be useful but
require training to achieve reliability.
Weakness/loss of Decreased handgrip and leg extensor strength have been related to loss of muscle mass in malnourished states. Lower extremity weakness
strength may be observed in thiamine deficiency.
Peripheral edema Peripheral edema may confound weight measurements and is often observed with reduced visceral proteins as well as inflammatory states.
Edema may also be observed with thiamine deficiency.
Hair examination Hair findings are indicative of certain nutrient deficiencies.
Loss: protein, vitamin B12, folate
Brittle: biotin
Color change: zinc
Dry: vitamins A and E
Easy pluckability: protein, biotin, zinc
Coiled, corkscrew: vitamins A and C
Alopecia is common in severely malnourished persons.
Ask about excessive hair loss on pillow or when combing hair.
(Continued)

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 2536
TABLE 334-1 History and Physical Examination Elements (Continued)
ELEMENT NOTES
Skin examination Skin findings are indicative of certain nutrient deficiencies.
Desquamation: riboflavin
Petechiae: vitamins A and C
Perifollicular hemorrhage: vitamin C
Ecchymosis: vitamins C and K
Xerosis, bran-like desquamation: essential fatty acid
Pigmentation, cracking, crusting: niacin
Acneiform lesions, follicular keratosis, xerosis: vitamin A
Acro-orificial dermatitis, erythematous, vesiculobullous, and pustular: zinc
Characteristic nutritional dermatitis and skin findings may be observed with a number of nutrient deficiencies. Wounds and pressure sores
should also be noted as indicators of compromised nutritional status.
Eye examination Ocular findings are indicative of certain nutrient deficiencies.
Bitot’s spots: vitamin A
Xerosis: vitamin A
Angular palpebritis: riboflavin
Also ask about difficulties with night vision/night blindness; indicates vitamin A deficiency.
Perioral examination Perioral findings are indicative of certain nutrient deficiencies.
Angular stomatitis and cheilosis: B complex, iron, protein
Glossitis: niacin, folate, vitamin B12
Magenta tongue: riboflavin
Bleeding gums, gingivitis, tooth loss: vitamin C
Angular stomatitis, cheilosis, and glossitis are associated with vitamin and mineral deficiencies. Note poor dentition, caries, and tooth loss.
Difficulty swallowing and impairment of gag should also be recognized.
Extremity examination Extremity findings indicate certain nutrient deficiencies
Arthralgia: vitamin C
PART 10

Calf pain: thiamine

Extremities may also exhibit loss of muscle mass and/or peripheral edema. Neurologic findings in the extremities may also result from
deficiencies described below.
Mental status/nervous Mental and nervous system findings indicate certain nutrient deficiencies.
Disorders of the Gastrointestinal System

system examination Ophthalmoplegia and foot drop: thiamine

Paresthesia: thiamine, vitamin B12, biotin
Depressed vibratory and position senses: vitamin B12
Anxiety, depression, and hallucinations: niacin
Memory disturbance: vitamin B12
Hyporeflexia, loss of lower extremity deep tendon reflexes: thiamine, vitamin B12
Conduct formal cognitive and depression assessments as appropriate. Dementia and depression are common causes of malnutrition among
older persons. Wernicke-Korsakoff syndrome may be observed with severe thiamine deficiency.
Functional assessment Observe and test physical performance as indicated: gait, chair stands, stair steps, and balance. These provide complex measures of
integrated neurologic status, coordination, and strength.
Source: Reproduced with permission from GL Jensen: Nutritional Syndromes, In: Korenstein, D (Ed). ACP Smart Medicine [publisher archive]. Philadelphia (PA): American
College of Physicians, 2013.

Latin American Federation of Parenteral and Enteral Nutrition, the ■■NUTRITION ASSESSMENT
Parenteral and Enteral Society of Asia, and other nutrition societies, There is unfortunately no single clinical or laboratory indicator of com-
embarked on an effort to build global consensus around commonly prehensive nutritional status. Assessment therefore requires systematic
used evidence-based criteria for diagnosis of malnutrition in adults in integration of data from a variety of sources. Micronutrient deficiencies
clinical settings. Weight loss, low body mass index, and reduced muscle of clinical relevance may be detected in association with any of the
mass were selected as phenotypic criteria, whereas reduced food intake malnutrition syndromes, but a detailed discussion of their assessment
and disease burden/inflammation were selected as etiologic criteria. is beyond the scope of this chapter (see Chap. 333). Physical findings
One phenotypic criterion and one etiologic criterion were deemed nec- characteristic of micronutrient deficiencies are, however, summarized
essary for the preliminary diagnosis of malnutrition. Where available, in Table 334-1.
this diagnosis should trigger comprehensive nutrition assessment by
a skilled nutrition professional. However, the primary objective is to
Medical/Surgical History and Clinical Diagnosis Knowledge
of a patient’s medical/surgical history and associated clinical diagnoses
offer a simple approach that can be readily used in global settings with
is especially helpful in discerning the likelihood of malnutrition and
limited clinical nutrition resources. Recent studies suggest that these
inflammation. Nonvolitional weight loss is a well-validated nutrition
newer approaches to diagnosis of malnutrition have similar utility in
assessment indicator and is often also associated with underlying dis-
predicting adverse outcomes. This is not surprising since they share
ease or inflammatory condition. The degree and duration of weight
a number of common criteria including a metabolic stress of disease
loss determine its clinical significance. A 10% loss of body weight over
component that is a proxy indicator of inflammation. Irrespective of
6 months is of clinical relevance, whereas a 30% loss of body weight
the approach that is selected, assessment of patients can be facilitated
over the same duration is severe and life-threatening. Since weight loss
using the indicators of malnutrition and inflammation described
history is often unavailable or unreliable, one should query the patient
below.

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 as well as the medical records, family, and caregivers as appropriate to MRI studies that are being done for other clinical purposes to evaluate 2537
secure a valid weight trajectory. musculature.
A number of conditions or diseases are characterized by severe acute
inflammatory response, whereas others are more typically associated Laboratory Indicators Laboratory findings (Table 334-2) are but
with a chronic inflammatory response that is mild to moderate in one part of the comprehensive nutrition assessment and must be used
severity and may be relapsing and remitting (Table 334-1). It is also in combination with other domains of assessment to appropriately
common for acute inflammatory events to be superimposed on those diagnose a malnutrition syndrome. Although serum albumin and pre-
with chronic conditions; for example, a patient with chronic renal dis- albumin are often measured in patients with suspected malnutrition,
ease is admitted to the hospital with sepsis. The inflammatory milieu, their utility is limited due to their poor sensitivity and specificity as
especially when severe, may modify nutrient requirements by elevating indicators of nutritional status. Patients with low albumin or preal-
resting energy expenditure and promoting muscle catabolism and bumin may or may not prove to be malnourished when evaluated by
nitrogen losses. Inflammation also promotes anorexia, decreasing food comprehensive nutrition assessment because these proteins are readily
intake and further compromising nutritional status. A deteriorating reduced by the systemic response to injury, disease, or inflammation.
course may result because the presence of inflammation may reduce C-reactive protein is a positive acute-phase reactant that may be mea-
the benefit of nutritional interventions and the associated malnutrition sured to help discern whether active inflammation is manifest. If C-
may in turn diminish the effectiveness of medical therapies. It is also reactive protein is increased and albumin or prealbumin decreased,
imperative to recognize medical/surgical conditions or diseases that inflammation is likely to be a contributing factor. Since it is recognized
place patients at increased risk to become malnourished because they that C-reactive protein suffers limitations as a point-in-time measure,
have increased nutritional requirements or compromised intake or trends in levels over the clinical course may be helpful. Research sug-
assimilation (Table 334-1). gests that interleukin 6, and perhaps other cytokines, may also offer
Nutrition assessment should also include a review of medications promise as indicators of inflammatory status. Nonspecific laboratory
with attention to undesirable side effects including anorexia, xeros- indicators that are often associated with inflammatory response
tomia, nausea, diarrhea, and constipation. Potential drug–nutrient include leukocytosis and hyperglycemia. Additional tests that may
interactions should also be identified. be obtained to help confirm the presence of inflammatory response
include 24-h urine urea nitrogen and indirect calorimetry. In the set-
Clinical Signs and Physical Examination Nonspecific clinical ting of severe acute systemic inflammatory response, negative nitrogen
indicators of inflammation include fever, hypothermia, and tachycar- balance and elevated resting energy expenditure are anticipated.
dia. The nutrition-focused physical examination should identify edema
Dietary Assessment Dietary assessment can be used to detect

CHAPTER 334 Malnutrition and Nutritional Assessment

as well as signs of weight gain/loss and specific nutrient deficiencies.
Thorough examination should be particularly directed to those parts inadequate or imbalanced food or nutrient intakes. While dietary
of the body where high cell turnover occurs (e.g., hair, skin, mouth, assessment in patient care settings can be quite challenging, 24-h recall
tongue) as they are most likely to exhibit observable signs of nutritional and modified diet history approaches are sometimes used. A modified
deficiencies (Table 334-1). Physical findings of weight loss associated diet history is targeted to query types and frequencies of intake of spe-
with decreased muscle and subcutaneous fat mass should not be over- cific foods of interest. It is often necessary to access diverse resources
looked, but when appreciable edema is present, these changes may not for diet history information including the patient, medical records,
be readily appreciated. family, and caregivers. Consultation of a registered dietitian nutrition-
ist is highly recommended. Dietary practices and supplements should
Anthropometric Data Body weight measurements are recom- be carefully reviewed for potential inadequacies and toxicities. Since
mended with each clinic visit or hospitalization so that a reliable weight patients will often present to health care practitioners with acute medi-
change trajectory may be monitored. Patients should be weighed in a cal events superimposed upon chronic health conditions, it is common
consistent manner without overgarments or shoes. In order to secure for patients to have had decreased food intakes and malnutrition for
valid measurements, calibration of scales and appropriate staff training extended periods prior to assessment. It is therefore imperative that
are essential. Chair or bed scales may be used for those who cannot compromised dietary intake should not be overlooked so that appro-
stand. For those who are able, height should be measured in a standing priate intervention may be undertaken.
position, without shoes, using a stadiometer. If an adult cannot safely Ongoing assessment is indicated when parenteral or enteral feedings
stand, height can be estimated by doubling the arm span measurement are initiated, because it is necessary to discern what amount of formula
(from the patient’s sternal notch to the end of the longest finger). Stat- is actually being administered to and received by the patient. Enteral
ure of frail older persons can also be estimated from measurement of feedings, in particular, are often interrupted or held for procedures,
knee height using a caliper device. tolerance issues, and feeding tube displacements. It is therefore not
Body weight is often standardized for height to obtain an ideal unusual for such patients to be appreciably underfed for extended
weight for comparison, but available reference tables require subjective periods. When a patient is beginning to transition to oral feedings, it
assessment of frame size and offer limited reference data for many rel- is imperative to monitor quantities of food and/or supplements that
evant population groups, including older persons. A simple measure of are actually consumed as well as patient tolerance to feeding. Meals are
body size and an indirect measure of body fatness is provided by body often delayed or missed for tests or procedures. If possible, the patient
mass index (BMI), defined as weight (kg)/height (m2). The National should be queried about intake since tray inspection is notoriously
Institutes of Health BMI categories for adults are as follows: BMI unreliable as an indicator of consumption.
<18.5 = underweight, BMI 18.5–24.9 = desirable, BMI 25.0–29.9 =
overweight, and BMI ≥30 = obese. Note that being overweight or Functional Outcomes Advanced malnutrition is accompanied by
obese does not mean that one cannot be severely malnourished due declines in muscle mass and function that can be detected by strength
to inadequate nutrition intake or assimilation. Underweight status and physical performance measures. Handgrip strength measured with
is not required for the diagnosis of malnutrition. While classical a simple handgrip dynamometer is the most practical routine clinical
anthropometric measurements including skinfolds and circumferences assessment. Physical performance tests such as timed gait, chair stands,
can be helpful, their utility in routine patient care has been limited and stair steps are used in the comprehensive assessment of integrated
because practitioner training is required to achieve suitable reliability. functions in frail older persons.
Body composition assessment methodologies include bioelectrical The decline in overall functional status observed in advanced
impedance analysis (BIA), dual-energy x-ray absorptiometry (DEXA), malnutrition is associated with nutrient deficiencies and impairment
computed tomography (CT), and magnetic resonance imaging (MRI). of organ system functions. Poor wound healing and immune com-
The imaging modalities have become the state of the art for precise promise are examples of such impairments. Improved wound healing
measurements of muscle mass. It is possible to take advantage of CT or parameters and restored responsiveness to recall antigens by delayed

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 2538
TABLE 334-2 Body Composition, Laboratories, and Other Studies
TEST NOTES
Body Composition Studies
Anthropometrics Skinfolds and circumferences require training for reliability. Typical coefficient of variation is ≥10%.
Bioelectrical impedance Based upon differential resistance of body tissues. Equipment easily portable. Good measure of body water. Requires
population-specific validation of regression equations.
Water displacement Impractical for most clinical settings. Weighed in water tank. Historic reference measure.
Whole-body counting and isotope Research methodologies. Naturally occurring 40K isotope to measure body cell mass by whole-body counting. Total-body
dilution techniques water measurement by dilution volume of tritium, deuterium, or 18O-labeled water.
Air plethysmography Subject sits inside moderately sized BodPod chamber. Validated against water displacement and impedance.
Dual energy x-ray absorptiometry Often used for bone density but can be used for soft tissue measurements with appropriate software. Can compare truncal
(DEXA) and appendicular components. Modest x-ray exposure.
Imaging with computed tomography State of the art research methods for visualizing body tissue compartments. Can quantify visceral fat. Costly, and CT entails
(CT) or magnetic resonance imaging x-ray exposure.
(MRI)
Laboratories and Other Studies
Albumin Lacks sensitivity and specificity for malnutrition. Potent risk indicator for morbidity and mortality. Proxy measure for underlying
injury, disease, or inflammation. Half-life is 14–20 days. Also consider liver disease, nephrotic syndrome, and protein-wasting
enteropathy.
Prealbumin Sensitive to short-term changes in inflammation and protein nutrition with half-life of 2–3 days. Otherwise suffers the same
limitations of albumin with limited sensitivity and specificity for malnutrition. Levels may be decreased in liver failure and
increased in renal failure.
Transferrin Acute-phase reactant also altered by perturbation in iron status. Half-life is 8–10 days. Lacks sensitivity and specificity for
malnutrition.
Retinol-binding protein Responds to very-short-term changes in nutritional status, but utility is also limited by response to stress and inflammation.
Half-life is 12 h. Also affected by vitamin A deficiency and renal disease.
C-reactive protein C-reactive protein is a positive acute-phase reactant. It is generally elevated if an active inflammatory process is manifest.
Cholesterol Low cholesterol (<160 mg/dL) is often observed in malnourished persons with serious underlying disease. It is unrelated to
PART 10

dietary intake in many clinical settings. Increased complications and mortality are observed. It appears that low cholesterol is
again a nonspecific feature of poor health status that reflects cytokine-mediated inflammatory condition. Vegans and patients
with hyperthyroidism may also exhibit low cholesterol.
Carotene Nonspecific indicator of malabsorption and poor nutritional intake.
Disorders of the Gastrointestinal System

Cytokines Research is exploring prognostic use of cytokine measurements as indicators of inflammatory status.
Electrolytes, blood urea nitrogen Monitor for abnormalities consistent with under- or overhydration status and purging (contraction alkalosis). BUN may also be
(BUN), creatinine, and glucose low in the setting of markedly reduced body cell mass. BUN and creatinine are elevated in renal failure. Hyperglycemia may
be nonspecific indicator of inflammatory response.
Complete blood count with differential Screen for nutritional anemias (iron, B12, and folate), lymphopenia (malnutrition), and thrombocytopenia (vitamin C and folate).
Leukocytosis may be observed with inflammatory response.
Total lymphocyte count Relative lymphopenia (total lymphocyte count <1200/μL) is a nonspecific marker for malnutrition.
Helper/suppressor T-cell ratio Ratio may be reduced in severely undernourished patients. Not specific for nutritional status.
Nitrogen balance 24-h urine can be analyzed for urine urea nitrogen (UUN) to determine nitrogen balance and give indication of degree of
catabolism and adequacy of protein replacement. Requires accurate urine collection and normal renal function. Nitrogen
balance = (protein/6.25) − (UUN + 4). Generally negative in the setting of acute severe inflammatory response.
Urine 3-methylhistidine Indicator of muscle catabolism and protein sufficiency. Released upon breakdown of myofibrillar protein and excreted without
reutilization. Urine measurement requires a meat-free diet for 3 days prior to collection.
Creatinine height index (CHI) CHI = (24-h urinary creatinine excretion/ideal urinary creatinine for gender and height) × 100. Indicator of muscle depletion.
Requires accurate urine collection and normal renal function.
Prothrombin time/international Nonspecific indicator of vitamin K status. Prolonged in liver failure.
normalized ratio (INR)
Specific micronutrients When suspected, a variety of specific micronutrient levels may be measured: thiamine, riboflavin, niacin, folate, pyridoxine,
vitamins A, C, D, E, B12, zinc, iron, selenium, carnitine, and homocysteine—indicator of B12, folate, and pyridoxine status.
Skin testing—recall antigens Delayed hypersensitivity testing. While malnourished patients are often anergic, this is not specific for nutritional status.
Electrocardiogram Severely malnourished patients with reduced body cell mass may exhibit low voltage and prolonged QT interval. These
findings are not specific for malnutrition.
Video fluoroscopy Helpful to evaluate suspected swallowing disorders.
Endoscopic and x-ray studies of Useful to evaluate impaired function, motility, and obstruction.
gastrointestinal tract
Fat absorption 72-h fecal fat can be used to quantitate degree of malabsorption.
Schilling test Identify the cause for impaired vitamin B12 absorption.
Indirect calorimetry Metabolic cart can be used to determine resting energy expenditure (REE) for accurate estimation of energy needs.
Elevated REE is a sign of systemic inflammatory response.
Source: Reproduced with permission from GL Jensen: Nutritional Syndromes. In: D Korenstein (Ed). ACP Smart Medicine [publisher archive]. Philadelphia (PA): American
College of Physicians, 2013.

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 hypersensitivity testing may be measured to demonstrate improve- composition, and the details of providing it. To follow these steps 2539
ments with nutritional repletion, though it must be appreciated that properly, physicians require a general understanding of nutritional
these are multivariable outcomes for which improved nutritional status physiology, nutrient requirements, and the pathophysiology and diag-
is but one variable. nosis of the nutritional disorders, and familiarity with the indications,
advantages, risks, and administration of the different kinds of SNS.
■■FURTHER READING Because most physicians are incompletely trained in clinical nutrition,
Cederholm T et al: ESPEN guidelines on definitions and terminology they must collaborate with clinical dietitians and specialized pharma-
of clinical nutrition. Clin Nutr 36:49, 2017. cists in this process.
Detsky AS et al: What is Subjective Global Assessment of nutritional
status? J Parenter Enteral Nutr 11:8, 1987. ■■NUTRITIONAL PHYSIOLOGY
Guerra RS et al: Usefulness of six diagnostic and screening measures (See Chaps. 332-334)
for undernutrition in predicting length of hospital stay: A compara-
tive analysis. J Acad Nutr Diet 115:927, 2015.
Energy Total daily energy expenditure (TEE) of a healthy sedentary
adult is ~36 kcal/kg. Resting energy expenditure (REE), which accounts
Jensen GL: Inflammation as the key interface of the medical and nutri-
for ~75% of TEE, may be measured by indirect calorimetry or esti-
tion universes: A provocative examination of the future of clinical
mated using a variety of predictive equations that input weight, height,
nutrition and medicine. J Parenter Enteral Nutr 30:453, 2006.
age, sex, and sometimes, disease-related factors. Fever and some forms
Jensen GL: Malnutrition and inflammation—“Burning down the
of critical illness increase REE, whereas prolonged semi-starvation
house”: Inflammation as an adaptive physiologic response versus
induces an adaptive reduction in REE and voluntary physical activity.
self-destruction? J Parenter Enteral Nutr 39:56, 2015.
Patients’ TEE identifies the amount of dietary energy they must con-
Jensen GL et al: Adult starvation and disease-related malnutrition:
sume and metabolize to maintain their existing store of body fat (and
A proposal for etiology-based diagnosis in the clinical practice setting
protein). The amount of energy a patient requires may be less than TEE
from the International Consensus Guideline Committee. J Parenter
(in obesity therapy or, temporarily, during periods of energy intoler-
Enteral Nutr 34:156, 2010.
ance) or greater than TEE (during recovery from starvation disease).
Jensen GL et al: Adult nutrition assessment tutorial. J Parenter Enteral
Nutr 36:267, 2012. Protein and Amino Acids Dietary protein must be consumed
Jensen GL et al: GLIM Criteria for the diagnosis of malnutrition: throughout life because endogenous protein turnover entails a mini-
A consensus report from the global clinical nutrition community. mum obligatory rate of amino acid catabolism. Amino acid catabolism
J Parenter Enteral Nutr 43:32, 2019. increases and decreases in response to changes in protein intake,

CHAPTER 335 Enteral and Parenteral Nutrition

Keller H et al: Global Leadership Initiative on Malnutrition (GLIM): but it cannot fall below a certain minimum rate that determines an
Guidance on validation of the operational criteria for the diagnosis individual’s minimum dietary protein requirement. The average daily
of protein-energy malnutrition in adults. J Parenter Enteral Nutr minimum protein requirement of a healthy adult is 0.65 g/kg; the “safe”
44:992, 2020. or “recommended” intake is 0.80 g/kg. The average protein consump-
White JV et al: Consensus statement: Academy of Nutrition and tion in wealthy societies is approximately twice the average minimum
Dietetics and American Society for Parenteral and Enteral Nutrition. requirement.
Characteristics recommended for the identification and documenta- Many diseases (or their treatments) increase the protein require-
tion of adult malnutrition (under-nutrition). J Parenter Enteral Nutr ment, by (1) increasing amino acid loss from the body (as in malab-
36:275, 2012. sorption and protein loss via wound exudates, fistulas, or inflammatory
diarrhea), removing amino acids from the circulation (renal replace-
ment therapy), or (2) increasing muscle protein catabolism, as occurs
as a side effect of high-dose glucocorticoid therapy and especially
as part of the metabolic response to systemic inflammation. Highly

335 Enteral
protein-catabolic patients may excrete 15 g N (nitrogen)/d or more in
and Parenteral their urine in the absence of dietary protein provision—this is more
Nutrition than three times faster than during simple fasting. Since 1 g N lost
from the body reflects the loss of 6.25 g formed protein, 15 g N loss/d
L. John Hoffer, Bruce R. Bistrian, indicates the loss of 15 × 6.25 = 94 g protein/d; since the body’s meta-
David F. Driscoll bolically active tissue mass (its body cell mass, 80% of which is skeletal
muscle) is ~20% protein, 94 g protein loss/d indicates the loss from the
body of ~470 g (1 lb) of muscle mass per day! Sufficiently generous
protein provision can reduce this kind of muscle atrophy. The extent
There are three kinds of specialized nutritional support (SNS): to which protein-catabolic illness increases the protein requirement is
(1) optimized voluntary nutritional support, which is indicated when debated, but the most frequent current recommendation for critically
a patient’s barriers to adequate nutrition can be overcome by special ill patients is 1.5 g protein/kg normal body weight per day—close to the
attention to the details of how their food is constituted, prepared, and habitual protein intake of healthy people in wealthy societies.
served and its consumption monitored; (2) forced enteral nutrition
(EN), in which a liquid nutrient formula is delivered through a tube
Protein-Energy Interactions Energy deficiency and systemic
inflammation increase the dietary protein requirement. Systemic
placed in the stomach or small intestine; and (3) parenteral nutrition
inflammation reduces, but does not prevent, the beneficial effect of
(PN), in which a nutritionally complete mixture of crystalline amino
increased protein provision during energy deficiency, so long as there
acids, glucose, lipid emulsions, minerals, electrolytes, and micronutri-
is a minimum supply of energy, such as 50% of TEE. Energy provision
ents is infused directly into the bloodstream.
>50–70% TEE has little further protein-sparing effect in systemic
When does a hospitalized patient need SNS? When SNS is indicated,
inflammation, and the additional amounts of glucose and fluid volume
how should it be provided? This chapter summarizes the physiologic
required to deliver it can have adverse effects.
principles that guide the correct use of SNS and offers practical infor-
mation about the diagnosis and management of nutritional disorders Permissive Underfeeding and Hypocaloric Nutrition These
in adult hospitalized patients. terms have different meanings, and they should not be conflated or
The management of in-hospital nutritional disorders follows three confused. Permissive underfeeding is the deliberate underprovision
steps: (1) screening and diagnosis; (2) determination of the sever- of all nutrients, including protein, whereas hypocaloric nutrition is
ity and urgency of treating a diagnosed nutritional disorder in its energy provision deliberately set less than TEE with a compensatory
overall clinical context; and (3) selection of the modality of SNS, its increase in protein provision.

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 2540 Micronutrients Minimum amounts of the nine water-soluble food; partial obstruction of the esophagus, stomach, or intestinal tract;
vitamins (the B vitamins and vitamin C), four fat-soluble vitamins thrush; intestinal angina; and most commonly, combinations of these
(A, D, E, and K), eight minerals (calcium, phosphorus, potassium, causes.
sodium, chloride, magnesium, zinc, and iron), essential fatty acids,
and several essential trace elements are required to avoid deficiency Chronic Disease–Related Malnutrition and Cachexia These
diseases. Overt deficiencies of potassium, sodium, magnesium, and terms refer to SRM complicated by chronic systemic inflammation.
phosphorus occur so frequently in hospitalized patients that it is stan- CDM is prevalent among patients with chronic infection, inflamma-
dard practice to monitor for and correct them. Certain drugs induce tory autoimmune disease, chronic severe hepatic, renal, cardiac, and
renal potassium, magnesium, or zinc losses that necessitate appropriate pulmonary disease, and neoplastic diseases that induce a systemic
increases in their provision. Gastrointestinal losses from nasogastric inflammatory response or cause tissue injury. CDM causes and is
drainage tubes or intestinal losses from fistulas or diarrhea incur losses worsened by anorexia—a strong disinclination to eat even when there
of potassium, sodium, calcium, magnesium, and zinc that increase is no physical barrier to it—and is characterized by an increased rate
their daily requirement. of muscle protein catabolism, muscle atrophy, weakness, fatigue, and a
Less studied, but common, are subclinical deficiencies of zinc, vita- subverted adaption to starvation, all of which contribute to a vicious
min C, vitamin D, and possibly other micronutrients. Physicians often cycle of worsening disease. Fortunately, the nutritional deficit on the
assume that consumption of a regular hospital diet protects patients input side of this equation (anorexia-driven inadequate food consump-
from these deficiencies. This assumption is not warranted when the tion) is often a stronger driver of the patient’s CDM than increased
patient’s nutritional status was deficient when they were admitted to nutrient loss on the output side (increased amino acid catabolism and,
hospital and remains so during their hospital stay. sometimes, increased energy expenditure). This makes CDM amenable
to a well-organized nutritional intervention while effective treatment
of the primary disease is implemented. The challenge becomes more
■■MACRONUTRIENT MALNUTRITION SYNDROMES
daunting when there is no effective therapy for the primary disease.
The decision to embark on SNS must be justified by a well-formulated
Cachexia is an older term that refers to a disease-induced metabolic
nutritional diagnosis and clearly defined therapeutic goals. This chap-
syndrome characterized by moderate systemic inflammation, unrelent-
ter focuses on the diagnosis, treatment, and prevention of in-hospital
ing and severe generalized muscle atrophy, and the symptoms associ-
starvation-related malnutrition (SRM) and two related conditions:
ated with them; it is, therefore, approximately synonymous with CDM.
chronic disease–related malnutrition (CDM) and acute disease–related
Anyone with cachexia has CDM, but in the view of some clinicians,
(or injury-induced) malnutrition (ADM). As explained in Chap. 334,
CDM that is milder and less sustained does not qualify for the term.
SRM results solely from prolonged semi-starvation. CDM is usefully
understood as SRM (i.e., simple starvation) that is complicated by Acute Disease–Related Malnutrition Other terms for ADM are
PART 10

moderately severe systemic inflammation. SRM and CDM are anatom- “injury-induced malnutrition” and “protein-catabolic critical illness.”
ically (phenotypically) similar but etiologically and metabolically dis- The metabolic-inflammatory response to severe tissue injury and sep-
tinct variations of starvation disease. ADM refers to an injury-induced sis mobilizes muscle amino acids and leads to rapid and severe general-
metabolic condition that creates a high risk of severe body protein defi- ized muscle atrophy and variable increases in REE under conditions in
ciency, rather than to an already-existing anatomic starvation disease. which voluntary food intake is almost always impossible. SRM or CDM
Disorders of the Gastrointestinal System

may or may not be present at the onset of their critical illness, but mus-
Starvation-Related Malnutrition The pathologic features that cle atrophy will rapidly develop or worsen unless the inciting medical
define SRM—and distinguish it from the semi-starvation that precedes or surgical disease is rapidly and effectively treated and SNS provided.
it—emerge when the body cell mass has been depleted enough to The rate of loss of body cell mass in ADM can be three to five times
impair specific physiologic functions. Other terms for SRM are “star- greater than in simple starvation. Death from simple starvation of non-
vation-induced protein-energy malnutrition,” “starvation disease,” and obese adults occurs within ~8 weeks; death due to untreated starvation
“hunger disease.” of patients with sustained ADM will occur correspondingly sooner.
The body normally adapts to starvation by reducing REE and
net protein catabolism, partly by means of hormone- and nervous ■■NUTRITIONAL DIAGNOSIS
system–regulated changes in cellular metabolism and partly by reduc- The cardinal anatomic features of starvation disease (SRM or CDM)
ing its muscle mass. These adaptations allow prolonged survival, but are generalized muscle atrophy and diminished body fat. A routine
survival comes at a cost that includes muscle atrophy (including of the physical examination will reveal these features, but what should be an
cardiac and respiratory muscles), skin thinning, lethargy, a tendency easy diagnosis is often overlooked. This section explains the details and
to hypothermia, and functional disability. The cardinal anatomic pitfalls of diagnosing SRM and CDM.
diagnostic features of SRM—generalized muscle atrophy and subcuta-
neous adipose tissue depletion—are easily identified by simple physical Muscle Mass Generalized muscle atrophy is easy to identify, and its
examination. severity is determinable almost at a glance. Serum creatinine adjusted
SRM always manifests as weight loss, but weight loss alone may for renal function or urinary excretion, adjusted for height and sex,
not reveal its full severity. Semistarvation increases the extracellular may also confirm severe muscle atrophy. A problem with diagnosing
fluid (ECF) volume (and body weight), sometimes seriously enough to SRM and CDM is that muscle atrophy has many causes. They include
cause edema (“starvation edema”). In adults with initially normal body (1) old age–related muscle atrophy (sarcopenia); (2) disuse muscle
composition, starvation-induced weight loss tracks the loss of body atrophy; (3) high-dose glucocorticoid therapy and certain endocrine
cell mass (since weight change due to reductions in adipose tissue and diseases (uncontrolled diabetes mellitus, adrenocortical insufficiency,
increases in ECF volume tend to cancel one another out). A 25% reduc- hyperthyroidism, androgen deficiency, hypopituitarism); and (4) pri-
tion in body weight significantly compromises physiologic function; a mary muscle or neuromuscular diseases. The guiding clinical prin-
50% reduction places otherwise uncompromised young adults on the ciple is that SRM and CDM are extremely common causes of and
cusp of thermodynamic survival; older patients with comorbidities are contributors to muscle atrophy. Whenever generalized muscle atrophy
at even greater risk. People with SRM feel unwell, lack strength, are is observed, its potential causes should be evaluated and the treatable
frail, and are at risk of hypothermia. ones addressed. Old age is irreversible, but adequate protein and energy
The main cause of SRM worldwide is involuntary food deprivation; provision to starving patients, combined with physical rehabilitation
its causes in hospitalized patients are many. They include inadvertent for immobile patients, can be lifesaving.
or physician-ordered food deprivation; psychologic depression or Generalized muscle atrophy of any cause is especially dangerous
distress; anorexia nervosa; poorly controlled pain or nausea; badly in ADM, because patients suffering from ADM and muscle atrophy
presented unappealing food; communication barriers; physical or sen- are closer to the cliff edge of lethal depletion of their body cell mass.
sory disability; dysphagia and other mechanical difficulties ingesting In addition, a diminished muscle mass is less able to release adequate

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 amounts of amino acids into the circulation for protein synthesis at that indicate systemic inflammation. Systemic inflammation induces 2541
sites of tissue injury and healing and to the central protein pool to anorexia and increases muscle catabolism, increasing the risk of
regulate the immunoinflammatory response. CDM, but the disease itself may or not exist at the time and may never
develop. The serum concentrations of acute-phase reactants will not
Subcutaneous Adipose Tissue Severe adipose tissue depletion improve while systemic inflammation persists, even with prolonged
indicates starvation disease, but it need not be present to make the optimal nutritional therapy.
diagnosis. The current obesity epidemic has created a population of
obese patients with SRM or CDM in whom muscle atrophy has out- PROTEIN-CATABOLIC INTENSITY The defining feature of protein-
paced fat loss. A conscientious physical examination easily identifies catabolic disease (which occurs in a moderate form in CDM and
these patients’ atrophic muscles despite their residual subcutaneous fat. severely in ADM) is increased net muscle amino acid catabolism. Con-
ditions that substantially increase body protein loss can be identified
ECF Volume The ECF volume normally represents ~20% of body by measuring body N loss. Most N leaves the body in the urine (almost
weight. SRM moderately increases ECF volume. Patients with CDM all of it in urea, ammonium, and creatinine). Total N is not usually
have additional edema-promoting conditions, especially hypoalbu- measured in hospital laboratories, but the analysis of urinary urea N
minemia. Unless the effect of ECF is accounted for, its increased vol- (which normally accounts for ~85% of urinary N) is routinely avail-
ume may conceal the severity of muscle atrophy in patients with SRM able. A recent, validated formula estimates daily total N loss as follows:
and CDM. N loss (g) = g N in urinary urea/0.85 + 2.
Net muscle protein catabolism follows approximately first-order
Body Mass Index Body mass index (BMI) is defined as body kinetics, such that the rate of N loss from muscle is proportional to
weight (kg) divided by the square of height (m2). BMI normally ranges the existing amount of N available to be lost. Muscle-atrophic, protein-
from 20 to 25 kg/m2; values <19–20 usually indicate reduced muscle catabolic patients lose less body N per day than equivalently catabolic
and fat mass. BMI <15 indicates severe starvation disease; BMI <13 patients whose muscle mass is normal, but they are nevertheless at
is usually thermodynamically incompatible with life, especially in greater risk of succumbing to their critical illness. The interpretation of
older patients with comorbidities. Some guidelines and clinical trial a patient’s rate of N loss should include an evaluation of their existing
enrollment criteria define “malnutrition”—in this context, a synonym muscle mass.
for starvation disease—as a BMI <16 or 17. Using these criteria alone
can lead to serious error. A BMI <17 certainly indicates starvation Instrumental Nutritional Assessment Many nutritional assess-
disease—the body architecture associated with such a BMI can only be ment instruments claim to identify “malnutrition” by enumerating and
created by jettisoning a large fraction of the body cell mass and adipose summing a list of risk factors, laboratory results, and physical findings.

CHAPTER 335 Enteral and Parenteral Nutrition

tissue store. But a BMI >17 does not rule out starvation disease. Many These tools are often hindered by ambiguity about the definition of
patients with starvation disease have a normal or above-normal BMI malnutrition and by failure to distinguish between screening and
despite their muscle atrophy because of residual obesity or an expanded diagnosis. Diagnosis is the process of identifying a known pathologic
ECF volume. entity—SRM or CDM, for example—by considering the patient’s
medical history, pertinent findings on physical examination, and labo-
Visual BMI After some practice and verification, clinicians can ratory or imaging reports. Diagnosis also involves an estimation of the
accurately predict the BMI of nonobese, nonedematous patients by probability that the diagnosis is correct and a judgment of its severity.
attentively examining their muscle groups. Once acquired, this skill By contrast, screening is the application of a simple test that identifies
enables them to interpolate the severity of starvation disease in obese people at sufficiently high risk of a certain disease to warrant definitive
or edematous patients—in whom measured BMI is unreliable—by procedures to establish the diagnosis or rule it out or that identifies
evaluating their muscles while intuitively discounting their subcutane- people at sufficiently high risk of developing the disease to warrant
ous fat and edema. Visual BMI may also be used to estimate a patient’s specific preventive interventions. Screening tools and risk predictors
normalized dry body weight (i.e., weight adjusted for obesity, edema, are useful, but it is a mistake to confuse them with clinical diagnosis.
or ascites). For example, the normalized dry body weight of a 1.75-m
adult with a visual BMI of 17 is 1.752 × 17 = 52 kg. Since protein and ■■SPECIALIZED NUTRITIONAL SUPPORT
energy targets are based on the patient’s body normalized weight, this
calculation is useful when body weight is unreliable or difficult to Optimized Voluntary Nutritional Support When feasible, this
measure. is the approach of choice because it engages and empowers the patient,
encourages mobilization and reconditioning, is consistent with the
Laboratory and Technical Assessment Clinical laboratory objectives of patient-centered medicine, and is risk-free. Its disadvan-
measurements have three main purposes in the evaluation and man- tage is that it is time-consuming and labor-intensive, and it demands
agement of starvation disease. interest in and attention to the specific needs of individual patients.
MUSCLE MASS Bedside ultrasound is a potentially valuable technique
Enteral Nutrition This is nutrition provided through a feeding
for quantifying muscle mass at specific body sites, but it need not, nor tube placed through the nose into the stomach or beyond it into the
should it, replace the comprehensive evaluation provided by the eyes, duodenum, by insertion of a tube through the abdominal wall into the
hands, and discerning mind of a bedside examiner. stomach or beyond it into the jejunum, or by an open surgical approach
SYSTEMIC INFLAMMATION The absence or presence of systemic to access the stomach or small intestine. EN is the treatment of choice
inflammation distinguishes SRM from CDM. The most useful labora- when optimized voluntary nutritional support is impossible or has
tory indicators of systemic inflammation are a reduced serum albumin failed. It is relatively simple, safe, and inexpensive and maintains the
concentration and increased serum C-reactive protein concentration. digestive, absorptive, and immunologic barrier functions of the gastro-
Systemic inflammation increases the permeability of capillary walls to intestinal tract. EN is appropriate when optimized voluntary nutrition
large molecules; the resulting osmotic shift increases the ECF volume. is not feasible or has failed and the patient’s gastrointestinal tract is
Intravascular albumin redistributes into this larger volume, decreasing functioning and can be accessed.
the serum albumin concentration (increased albumin catabolism also
contributes). Dietary protein deficiency and muscle atrophy combine EN Products The most common forms of EN used are commer-
to perpetuate inflammation-induced hypoalbuminemia, because the cially manufactured formulas with defined compositions.
amino acids used for hepatic albumin synthesis are derived from the STANDARD POLYMERIC FORMULAS These are the most widely used
diet and endogenous muscle protein. sources of EN. They are available in a wide variety of formats that
Hypoalbuminemia and reduced serum prealbumin concentra- generally meet the nutritional requirements of a normal, healthy per-
tions are often claimed to diagnose “malnutrition.” This is incorrect. son. Carbohydrates provide most of the energy. The proteins in them
Serum albumin and prealbumin are negative acute-phase reactants (casein, whey, or soy) are intact and require normal pancreatic enzyme

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 2542 function for digestion and absorption. They are isotonic or nearly so oil, a mixture of 80% olive oil and 20% soybean oil, and a mixture of
and provide 1000–2000 kcal and 50–70 g protein/L. 30% soybean oil, 30% medium-chain triglycerides, 25% olive oil, and
POLYMERIC FORMULAS WITH FIBER The addition of dietary fiber to
15% fish oil are available in the United States. (A 10% fish oil emulsion
is approved for intestinal failure–associated liver disease in neonates
formulas sometimes improves bowel function and feeding tolerance.
and infants.) Fish oil (either as a component of a mixed emulsion or
Fermentable (soluble) fibers such as pectin and guar are metabolized
administered separately) may reduce the risk of infections and length
by colonic bacteria, yielding short-chain fatty acids that fuel colono-
of stay in critically ill patients. The complex lipid emulsions are more
cytes. Nonfermentable (insoluble) fibers increase fecal bulk, improve
highly enriched in n-3 fatty acids and/or contain fewer n-6 polyun-
peristalsis, and may improve diarrhea.
saturated fatty acids than soybean lipid, which is more prone to lipid
ELEMENTAL AND SEMI-ELEMENTAL FORMULAS The macronutrients peroxidation and could promote the formation of the proinflammatory
in these formulas are partially or completely hydrolyzed. They are n-6 derivatives. Standard lipid infusion rates should not exceed 8 g/h,
primarily designed for patients with known maldigestion and mal- equivalent to 175 g (1925 kcal)/d in a 70-kg patient; pure fish oil emul-
absorption, but they are sometimes used empirically for patients who sions must be infused at lower rates.
have had prolonged bowel rest or are critically ill without strong evi-
dence of their superiority, or when a patient is intolerant of a standard Minerals, Micronutrients, and Trace Elements The default
polymeric formula. concentrations of electrolytes, minerals, and micronutrients in PN
solutions are designed to meet the requirements of a healthy adult.
IMMUNE-ENHANCING FORMULAS In addition to providing macronu- These starting doses must be adjusted to meet the frequently abnormal
trients and conventional amounts of micronutrients, these EN products and often-changing requirements of individual patients. Being unsta-
contain large amounts of certain nutrients designed to favorably mod- ble, multivitamin mixtures are injected into PN bags just prior to their
ulate the immune response: arginine and n-3 fatty acids especially, but delivery to the medical unit. Parenteral water-soluble vitamin require-
also various combinations of glutamine, nucleotides, and antioxidants. ments are greater than standard oral requirements, because hospital-
PROTEIN-ENRICHED FORMULAS Most EN formulas provide calo- ized patients often have vitamin deficiencies or increased requirements
ries and protein in a ratio appropriate for a healthy person, whereas and because intravenous administration of vitamins increases their loss
protein-enriched formulas provide ~90 g protein and 1000 kcal/L. in the urine. Ascorbic acid degrades spontaneously in PN solutions,
Originally marketed to meet the increased protein requirement of even when light-protected. The amount of vitamin D in currently
weight-reducing obese patients, these products are increasingly used available intravenous vitamin products is inadequate.
to provide protein-catabolic patients with a more generous amount
of protein without energy overfeeding. EN can be further pro- APPROACH TO THE PATIENT
tein-enriched by adding flushes of water-soluble powdered protein
PART 10

supplements. Indications, Selection, and Provision of

OTHER FORMULAS Various disease-specific EN products are available Specialized Nutritional Support
for patients with diabetes and hepatic, renal, or pulmonary disease.
Most hospitalized patients do not require SNS because they can eat
Their use can improve some metabolic endpoints, but there is no defin-
Disorders of the Gastrointestinal System

and will improve with appropriate management of their primary

itive evidence that they improve clinical outcomes.
disease. Others have a terminal disease whose downward course
Parenteral Nutrition PN delivers a complete nutritional regi- will not be slowed by SNS. Patients who cannot eat enough hos-
men directly into the bloodstream in the form of crystalline amino pital food and who have or are at high risk for SRM or CDM are
acids, glucose, triglyceride emulsions, minerals (calcium, phosphate, candidates for optimized voluntary nutrition support. When this
magnesium, and zinc), electrolytes, and micronutrients. Because of most desirable approach is inappropriate or impractical or has been
its high osmolarity (>1200 mOsm/L) and often large volume, PN is properly tried and failed, invasive SNS must be considered. The
infused into a central vein in adults. Ready-to-use PN admixtures decision to provide or withhold EN or PN is based on a synthesis
typically containing 4–7% hydrated amino acids and 20–25% glucose of four factors: (1) the determination that nutrient ingestion will
(with or without electrolytes) are available in two-chamber (amino likely continue to be inadequate for many days; (2) the patient has
acids and glucose) or three-chamber (amino acids, glucose, and lipid) important muscle atrophy (of any cause) or fat depletion; (3) the
bags that are intermixed with vitamins, trace minerals, and additional patient’s nutrient requirements are increased (as from inflammatory
electrolytes then added just prior to infusion. Although convenient diarrhea, enterocutaneous fistulas or exudates, or a pronounced
and cost-effective, these products have fixed nutrient compositions inflammatory protein-catabolic state); and (4) the reasoned judg-
and are dosed according to the volume required to meet a patient’s ment that SNS has a reasonable prospect of improving the patient’s
energy requirement but not necessarily their protein requirement. In clinical outcome or quality of life.
some situations—especially ADM—a more sophisticated approach is EN THERAPY
justified that uses a computer-controlled sterile compounder to create
combinations of amino acids and glucose that meet the precise protein EN is indicated when the patient is unable to eat enough food
and energy requirements of individual patients. and is unlikely to do so for a long time, their gastrointestinal tract
is functional and accessible, and optimized voluntary nutrition
Amino Acids PN amino acid admixtures vary, but all of them pro- is impossible or cannot meet their nutritional requirements. EN is
vide appropriate amounts of the essential amino acids and nonessential commonly used for patients with impaired consciousness, severe
amino acid N. The hydrated state of the mixed free amino acids in PN dysphagia, or severe upper gastrointestinal tract dysfunction or
solutions reduces their energy density from 4.0 (in formed protein) to obstruction or who need mechanical ventilation. Equally com-
3.3 kcal/g, and it reduces the amount of protein substrate they provide monly, situations arise in which a patient’s voluntary food intake is
by 17%. For example, 100 g of free mixed amino acids provides 83 g seriously curtailed by anorexia, unappealing food, nausea, vomit-
protein substrate and 330 kcal. ing, pain, distress, delirium, depression, chewing difficulties, mild
dysphagia, physical and sensory disability (including dysgeusia), or
Carbohydrate and Lipids The glucose in PN is dextrose monohy- undiagnosed thrush. In these complicated and difficult situations,
drate; its hydrated state reduces its energy density from 4.0 (in
the clinical diagnosis of SRM or CDM should tip the decision from
formed carbohydrate) to 3.4 kcal/g. Lipid emulsions provide energy
optimized voluntary nutrition toward EN or PN.
(~10 kcal/g) and the essential n-6 and n-3 fatty acids. Traditional lipid
EN is contraindicated in patients with intestinal ischemia,
emulsions are based solely on soybean oil, but they are giving way to
mechanical obstruction, peritonitis, and gastrointestinal hemor-
mixed emulsions that include medium-chain triglycerides, n-9 mono-
rhage. High-dose pressor therapy is another relative contraindication,
unsaturated fatty acids, and n-3 fatty acids. Emulsions of pure soybean

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 2543
due to the rare but lethal risk of intestinal ischemic injury. Severe hyperglycemia, and, when a patient experiences nausea, vomiting,
coagulopathy, esophageal varices, absent gag reflex, hypotension, or abdominal distention, by the judicious use of antiemetic and
paralytic ileus, pancreatitis, diarrhea, and nausea and vomiting are prokinetic drugs (and sometimes proton pump inhibitors) on a
not absolute contraindications, but they increase the risk of compli- regular—rather than as-needed—basis. Patients with gastroparesis
cations and make it less likely that EN will succeed in achieving its require postpyloric feeding.
nutritional goal. Fluid Volume, Electrolyte, and Blood Glucose Abnormalities
Initiation, Progression, and Monitoring Nasogastric tube feeding EN’s essential purpose is to provide macronutrients at an appro-
may proceed when the patient’s gastrointestinal function is ade- priate rate. EN also provides standard amounts of fluid, electro-
quate with respect to gastric contractility (e.g., nasogastric tube lytes, minerals, and micronutrients. They are not designed to
output <1200 mL/d), intestinal contractility (absence of a known manage abnormal fluid volume, electrolyte, and mineral require-
or suspected intraabdominal pathologic process and presence of ments, which vary considerably among different patients and can
a nondistended abdomen with detectable bowel sounds, although change rapidly. Blood glucose concentrations should be monitored
the absence of bowel sounds is not, in itself, a contraindication), regularly, and additional measures—including intravenous fluid,
and adequate colonic function (passage of stools and flatus). After electrolyte, and insulin therapy—should be taken to maintain
consent has been obtained and the appropriate feeding tube (usu- homeostasis.
ally a nasogastric tube for short-term feeding) has been placed and Failure to Reach the Nutritional Goal EN is frequently
its position verified, the head of the patient’s bed is raised to at least delayed or interrupted by diagnostic tests and procedures (includ-
30° and kept raised to reduce the risk of regurgitation. Clinical ing dialysis), physical or occupational therapy, a clogged or pulled
dietitians ordinarily order the formula and adjust its rate of provi- out tube, and intolerance to EN. The result can be a long delay in
sion. When a standard polymeric formula is infused, it normally the progression of EN and ultimate failure to meet the patient’s
commences at 50 mL/h and is advanced by 25 mL/h every 4–8 h nutrient requirements.
until the goal rate is attained. Elemental formulas are commenced
at a slower rate and progress more slowly. Intragastric bolus feeding EN in the Intensive Care Unit Most critically ill patients cannot
is an option (200–400 mL feeding solution infused over 15–60 min eat anything—they depend entirely on SNS. EN serves two pur-
at regular intervals with verification of residual gastric contents poses in this setting. The first is to meet the patient’s macronutrient
every 4 h). requirements, especially their often dramatically increased protein
requirement. The second purpose is to infuse nutrients into the
Complications and Their Management The most common com- intestines at a rate that sustains normal intestinal barrier and immu-

CHAPTER 335 Enteral and Parenteral Nutrition

plications of EN are aspiration of regurgitated or vomited formula, nologic functions in the face of a systemic inflammatory response
diarrhea, fluid volume and electrolyte derangements, hyperglyce- that threatens intestinal integrity and immune function. Current
mia, nausea, abdominal pain, constipation, and failure to achieve guidelines recommend starting EN soon after a critically ill patient
the nutritional goal. has been fluid resuscitated and stabilized. Once EN is underway,
Aspiration Patients with delayed gastric emptying, impaired the rate of delivery is increased as tolerated until the patient’s nutri-
gag reflex, and ineffective cough are at high risk of aspiration tional goal is achieved. EN often falls far short of the protein pro-
pneumonia. Ventilator-associated pneumonia is mostly caused by vision target, even after a week or longer in the intensive care unit.
aspiration of microbial pathogens in the mouth and throat past Newer, high-protein EN products and the addition of powdered
the cuffs of endotracheal or tracheostomy tubes, but tracheal suc- protein supplements can correct this protein shortfall.
tioning induces coughing and gastric regurgitation. Measures to PN THERAPY
prevent ventilator-associated pneumonia include elevation of the
PN is more resource-intensive, is potentially riskier, and requires
head of the bed, mouth hygiene and gastrointestinal decontami-
more expertise than EN. It is used when invasive SNS is indicated
nation, nurse-directed algorithms for formula advancement, and
and EN is impossible, inappropriate, or insufficient to meet the
sometimes, postpyloric feeding. EN does not have to be suspended
patient’s nutritional needs. The risks of PN are those of inserting
for gastric residual volumes <300–400 mL in the absence of other
and maintaining a central venous catheter (traumatic injury from
signs of gastrointestinal intolerance (nausea, vomiting, severe
the insertion, serious infection, and venous thrombosis); allergy
abdominal pain, abdominal distention). Continuous EN is often
to some of its components; glucose, electrolyte, magnesium, phos-
tolerated better than bolus feeding, and it is the only option during
phate, and acid-base balance abnormalities; and the adverse effects
jejunal feeding.
of the large intravenous fluid volumes. PN that is prolonged for
Diarrhea Diarrhea commonly occurs when the patient’s many weeks—especially when it delivers excess energy—may cause
bowel function is compromised by disease or drugs (most often, or contribute to hepatic dysfunction.
broad-spectrum antibiotics). Once infectious and inflammatory Initiation, Progression, Monitoring, and Discontinuation When
causes have been ruled out, EN-associated diarrhea may be con- indicated, PN should begin as soon as possible after the patient
trolled by using a fiber-containing formula or adding an antidiar- has been hemodynamically resuscitated, glucose, electrolyte, and
rheal agent to it. H2 blockers or proton pump inhibitors may help acid-base homeostasis has been established, and they can tolerate
reduce the net volume of fluid presented to the colon. Since luminal the fluid volume required to deliver it. The high osmolarity of adult
nutrients have trophic effects on the intestinal mucosa, it is often PN solutions and need for strict sterility require their infusion
appropriate to persist with tube feeding despite moderate, tolerable through a dedicated port in a central venous catheter. Jugular or
diarrhea, even if it necessitates supplemental parenteral fluid sup- femoral vein catheters should not be used because of the difficulty
port. Except for patients with markedly impaired small-intestinal maintaining a dry, sterile dressing over the insertion site. The initial
absorptive function, there are no well-established indications for dose of glucose should not exceed 200 g/d to avoid hyperglycemia
elemental formulas, but they may be used empirically when diar- (and—in susceptible patients with adapted SRM—the refeeding
rhea persists despite the use of fiber-enriched formulas and antidi- syndrome). The full dose of amino acids can be administered from
arrheal agents. the very first day—an option that is, unfortunately, unavailable
Gastrointestinal Intolerance Abnormally high gastric residual when premixed PN solutions are used.
volumes, abdominal distention, pain, and nausea are distressing Most non–critically ill patients (e.g., dry body weight 70 kg) do
for patients, increase the nursing workload, and delay the pro- not require >500 g glucose (1700 kcal)/d, and many, if not most,
gression of EN. These problems can be avoided or minimized by patients with ADM do not require >350 g (1200 kcal)/d during the
ensuring normal fluid and electrolyte balance, by preventing severe intense phase of their disease. A glucose infusion rate of ~200 g/d

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 2544
is physiologic and commonly does not have to be exceeded. When benefit from discharge to the security and pleasure of home life and
it eventually becomes appropriate to set the energy goal equal to homemade food; these patients are identified by observing, asking,
TEE, it may be achieved by infusing a lipid emulsion. Even lower and listening.
glucose infusion rates (e.g., 100–200 g/d) are safe during deliberate Drawbacks, Side Effects, and Complications Patients receiving
hypocaloric nutrition and may prevent or minimize hyperglycemia PN are at greater risk of bloodstream infections than other patients
in insulin-resistant patients. with central venous catheters. Rigorously aseptic insertion tech-
We recommend hypocaloric nutrition (high in protein but lim- nique, meticulous dressing care, one port dedicated solely to PN,
ited in glucose, lipid, and fluid volume) for the first 2 weeks of SNS and careful glycemic control reduce this risk.
in fat-sufficient or obese patients with ADM. Energy provision can
increase, if indicated, after the catabolic storm abates. Lipids are Hyperglycemia The most frequent metabolic complication
commonly introduced after the first week of PN and can be used of PN is hyperglycemia in patients with insulin resistance due to
to make up energy shortfalls. Serum triglyceride concentrations are non-insulin-dependent diabetes mellitus, high-dose glucocorti-
measured before commencing lipid infusions to detect preexisting coid therapy, or severe systemic inflammation; the problem is
hypertriglyceridemia (>400 mg/dL)—a relative contraindication. exacerbated by excessively high rates of glucose provision. Glucose
Lipids may be infused daily or two to three times weekly. Lipid concentrations are most easily kept at <140 mg/dL with the least
infusions are not necessary to prevent essential fatty acid deficiency risk of hypoglycemia by infusing hypocaloric amounts of glucose
during hypocaloric nutrition of obese patients, because the mobili- and, when necessary, meeting the patient’s energy requirement
zation of body fat during energy deficiency provides the body with with intravenous lipid. In ADM, the benefits of using the lowest
endogenous essential fatty acids. possible insulin dose—minimal hyperinsulinemia and a reduced
Capillary blood glucose concentrations are monitored several risk of hypoglycemia—almost always outweigh the doubtful goal of
times daily, and subcutaneous regular insulin is added to the PN rapidly matching energy provision to the energy expenditure rate of
admixture as required to maintain average serum glucose concen- patients whose existing fat store is normal.
trations <140 mg/dL and >80 mg/dL. (Upper and lower limits of Hypoglycemia Reactive hypoglycemia is uncommon but may
180 and 100 mg/dL appear to be appropriate for critically ill patients occur when high-glucose, non-insulin-containing PN is abruptly
with diabetes mellitus.) The dose of regular insulin required on discontinued. It is prevented by slowing the PN infusion rate to
a given day can be added to the following day’s PN solution. The 50 mL/h for 1 or 2 h prior to discontinuing it (or replacing it with
insulin dose increases roughly proportionately to the glucose dose. 10% glucose) or, when the oral route is available, providing a snack.
Certain benchmarks are useful. Basal endogenous insulin secre- More often, hypoglycemia occurs when the intensity of the patient’s
tion is ~30 units/d in normal people. When insulin is required metabolic stress (or their glucocorticoid dose) decreases without
PART 10

for nondiabetic, noncatabolic patients, 10 units of regular insulin an appropriate downward adjustment of the insulin dose. This
roughly cover 100 g infused glucose. Patients with non-insulin- problem is avoided by frequent capillary glucose determinations
dependent diabetes require ~20 units/100 g glucose. Noncatabolic and careful attention to medication doses and the patient’s general
patients with insulin-dependent diabetes usually require approxi- condition.
Disorders of the Gastrointestinal System

mately twice the at-home insulin dose, because parenteral glucose

stimulates insulin release more potently than oral carbohydrate and Artefactual Hyperglycemia and Hyperkalemia Blood sam-
because some insulin adheres to the infusion bag. ples must be meticulously collected from a dual-port central venous
catheter. Intermixing of the sample with even a tiny volume of PN
Biochemical Monitoring Serum urea, creatinine, electrolytes, solution will falsely indicate hyperglycemia and hyperkalemia and
glucose, magnesium, phosphate, calcium, and albumin concentra- may trigger a treatment error. The sampling error is identified when
tions are measured prior to starting PN and followed daily for the the patient’s apparent serum glucose (and potassium) concentra-
first few days, then twice weekly or as required. Serum triglycerides tions abruptly increase without reason and the apparently very high
and liver function tests (and often ferritin) are measured at base- glucose concentration is out of keeping with concurrent capillary
line and after PN is underway to confirm that the lipid infusions glucose readings.
are well tolerated. N balance, calculated from 24-h urinary urea N
excretion, is useful at the outset for evaluating the severity of pro- Volume Overload Hypertonic intravenous glucose triggers a
tein catabolism in patients with CDM or ADM, to identify patients more intense insulin response than oral glucose that can increase
who require more generous amino acid provision, and during PN urinary sodium and water retention. In this setting, net fluid reten-
to determine whether the patient’s N balance is improving with tion is likely when total fluid provision exceeds 2 L/d in patients not
therapy. experiencing large gastrointestinal losses. The problem of volume
overload can be minimized by using a compounder to prepare PN
Discontinuation PN is tapered and discontinued when the solutions, infusing glucose at a rate that minimizes the need for
patient can be adequately nourished by the enteral route. The dose exogenous insulin therapy, and avoiding energy overfeeding.
of PN is gradually reduced as food intake increases. Once a patient
Hypertriglyceridemia This complication occurs when the rate
is tolerating one-half to two-thirds of their food requirement by the
of lipid infusion exceeds plasma triglyceride clearance capacity.
enteral route and there is no mechanical or other barrier to further
Sepsis, renal failure, diabetes mellitus, high-dose glucocorticoid
increases in intake, PN should be terminated. The transition to
therapy, and multiple-organ failure reduce triglyceride clearance.
oral nutrition can be slow for patients with CDM. In this situation,
An impaired immune response, increased risk of acute pancreatitis,
optimized voluntary nutrition, although labor-intensive, is much
and altered pulmonary hemodynamics are potential, but not well
preferred to replacing PN with invasive EN because it is safe, effec-
documented, complications of PN-induced severe hypertriglyc-
tive, fosters well-being, and prepares patients for discharge home.
eridemia. Lipid infusion rates should not usually exceed ~50 g
The temptation to discontinue PN to stimulate a patient to eat more
(500 kcal)/d in ADM.
food should, in general, be resisted. PN does not create anorexia,
nor does discontinuing it stimulate appetite. Too-early discontinu- Liver Disease Mild elevations of serum liver enzyme concen-
ation of PN may delay a patient’s progression to full voluntary food trations can occur within 2–4 weeks of initiating PN, but in most
consumption by inducing anxiety and recreating starvation condi- cases, they return to normal even when PN is continued. Clinically
tions. A patient is most successfully weaned from PN by optimizing important hepatic dysfunction, although common in children, is
their voluntary nutrition (including food from home), providing uncommon in adults when energy overfeeding and resultant fatty
emotional support, encouraging physical activity, and being patient. liver are avoided. Intrahepatic cholestasis occasionally occurs after
Some patients, stuck on the cusp of adequate oral nutrition, will many weeks of continuous PN and is most often multifactorial in

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 2545
origin. Cyclic PN—in which PN is infused for only 12 h of the day— it appears to be chemically compatible with aqueous solutions of
may prevent or reduce the severity of this complication. amino acids and glucose, there is realistic concern that interactions
PN in the Intensive Care Unit Current guidelines recommend between iron molecules and certain vitamins and amino acids
starting EN soon after a critically ill patient has been resuscitated, in PN solutions could catalyze the formation of free radicals that
stabilized, and enteral access established to an adequately function- degrade vitamins and exert subtle adverse systemic effects. In prin-
ing gastrointestinal tract. EN is then advanced over the following ciple, all micronutrient deficiency states, including iron deficiency,
days. If the energy goal has not been achieved after 7–10 days, PN should be prevented and corrected. In-hospital iron deficiency
is recommended, especially if the patient’s protein-catabolic state causes and prevents recovery from anemia, and subclinical iron
has not yet abated. Soy-based lipid emulsions should be avoided deficiency could contribute to cognitive and immune dysfunction.
during the first week of PN during critical illness; alternative lipid Serum ferritin concentrations should be determined when PN
emulsions may prove to be safe and beneficial. commences and remeasured at approximately 8-week intervals.
Iron deficiency is strongly suggested by an intermediate serum
SPECIAL CLINICAL SITUATIONS ferritin concentration in the setting of systemic inflammation and
Critical Illness–Nutrition Paradox High-quality evidence now by decreasing mean red cell volumes (even within the low-nor-
confirms what has long been indicated by the biologic evidence, mal range). Intravenous iron should be administered according
physiologic reasoning, formal observational studies, and objective to standard guidelines. A termination order should be written to
clinical observation, namely, that personalized nutritional inter- prevent inadvertent iron overdosing. Parenteral iron therapy should
ventions improve the clinical outcomes of starving, non–critically be avoided in ADM because a substantial rise in the serum iron
ill patients. The case for SNS would appear to be even stronger in concentration could release free iron and increase susceptibility to
ADM—with its rapid, severe muscle atrophy and maintained or gram-negative (and possibly other microbial) infections, as well as
increased energy expenditure under conditions in which patients catalyze the formation of free radicals that increase the intensity of
are almost always unable to eat voluntarily—but well-designed clin- the catabolic response to major tissue injury.
ical trials of nutritional interventions in critical illness have repeat- Zinc One liter of secretory diarrhea contains ~12 mg of zinc.
edly failed to demonstrate that currently prescribed SNS regimens Patients with intestinal fistulas or high-volume chronic diarrhea
improve the clinical outcomes of critically ill patients. The evidence require this amount of zinc in addition to their daily requirement of
does indicate that, unlike in noncritical illness, energy provision 15 mg to avoid zinc deficiency. Zinc may be provided parenterally
that is set at or near the rate of energy expenditure in fat-sufficient, or enterally. Because of its low bioavailability, 12 mg of parenteral

CHAPTER 335 Enteral and Parenteral Nutrition

insulin-resistant critically ill patients does not improve their clinical zinc is equivalent to 30 mg of oral zinc.
outcomes and may be deleterious to some of these patients. The
inability of currently prescribed SNS to improve outcomes in crit- Old Age In addition to their other frailties, elderly people com-
ical illness has several possible explanations: (1) severe prolonged monly suffer from age-related muscle atrophy (sarcopenia) com-
starvation is so harmful to all people, whether critically ill or not, pounded by disuse muscle atrophy. These factors place them at
that ethical considerations preclude using deliberate starvation as high risk of the consequences of starvation disease and make them
a treatment arm in a clinical trial; (2) critical illness is enormously candidates for early SNS.
heterogeneous, and not every critically ill patient is or remains Inactivity Physical activity and adequate nutrition are closely
severely protein-catabolic for long; (3) owing to more generous interdependent. Reduced physical activity reduces appetite, and
admission criteria and thanks to the high quality of modern inten- physical rehabilitation and its associated emotional benefits restore
sive care, many patients admitted to intensive care units improve optimism and appetite. Full nutrient provision will maintain or
and are discharged within a handful of days, whereas others are normalize many physiologic functions in bedridden patients, but
so mortally ill that their clinical outcome is virtually predeter- they will not increase muscle mass.
mined, and proof-of-concept clinical trials that enroll and report
Renal Failure Protein provision should not be reduced in patients
the outcomes of such patients could fail to demonstrate a benefit
with renal failure unless renal replacement therapy is unavailable.
from SNS; and (4) in current practice, the EN-based SNS regimens
Renal replacement therapy removes large amounts of amino acids,
that are prescribed for most critically ill patients commonly fail to
vitamins, and trace elements from the circulation, so protein and
deliver more than one-half the currently recommended amount of
micronutrient provision should be increased to compensate for
protein. The low protein-to-energy ratio of most standard EN and
these losses.
PN products makes it difficult to provide critically ill patients with
a sufficiently generous amount of protein or amino acids while Liver Failure Patients with severe hepatic disease are relatively
avoiding energy overfeeding. (The problem can be exacerbated by intolerant to starvation and commonly have CDM when admitted
use of the sedative drug propofol, which is infused in a solution of to hospital, so they are prime candidates for SNS. Their SNS should
10% lipid that commonly delivers ~500 kcal/d.) For these reasons, be generous both in energy and protein, despite an increased risk of
together with other experts, we continue to recommend EN and hepatic encephalopathy. The risk of encephalopathy can be reduced
PN for critically ill patients with ADM, with the additional advice by meticulous attention to fluid balance, acid-base balance, and
to avoid energy overfeeding during the initial weeks (or as long as electrolyte status and by spreading protein provision over the day
systemic inflammation remains severe) by deliberately erring on to accommodate the liver’s reduced capacity to clear amino acid–
the side of hypocaloric nutrition while simultaneously providing derived ammonia.
suitably generous protein or amino acids, as guided by physiologic Perioperative SNS Patients with SRM or CDM awaiting elective
reasoning and a personalized evaluation of the anatomic and etio- major surgery benefit from 7–10 days of preoperative SNS. When
logic-metabolic condition of each patient. feasible and properly implemented, optimized voluntary nutrition
Iron and PN Iron deficiency is common in hospitalized patients; is greatly to be preferred, but when a patient has been admitted
its usual causes are preexisting deficiency, inadequate in-hospital to hospital in a semi-urgent condition, EN or PN will meet the
dietary provision, macro- or microscopic gastrointestinal blood patient’s nutritional goal more quickly. Preoperative SNS improves
loss, and repeated blood sampling. The diagnosis is often missed immunity and reduces postoperative complications, but it will not
because the anemia of systemic inflammation is much more com- increase serum albumin concentrations, and it should not be pro-
mon, and it increases serum concentrations of ferritin, a positive vided for >7–10 days with that goal in mind. More prolonged preop-
acute-phase reactant. Iron is not routinely added to PN mixtures. erative EN or PN may confer slight additional nutritional benefits,
Iron dextran is incompatible with lipid emulsions, and although but they are counterbalanced by their risks and the consequences

HPIM21e_Part10_p2381-p2670.indd 2545 20/01/22 10:04 PM

 2546 Lambell KJ et al: Nutrition therapy in critical illness: A review of the
of prolonged hospitalization and delayed surgery. Surgery should
not be delayed for starving patients whose muscle mass is normal literature for clinicians. Crit Care 24:35, 2020.
or only mildly depleted and who are not experiencing systemic Schuetz P et al: Economic evaluation of individualized nutritional
inflammation since they tolerate even major uncomplicated sur- support in medical inpatients: Secondary analysis of the EFFORT
gery well. The urgency of surgery often precludes otherwise indi- trial. Clin Nutr 25:25, 2020.
cated preoperative SNS. Early postoperative PN is usually indicated Sharma K et al: Pathophysiology of critical illness and role of nutri-
for these patients, for they are at increased risk of postoperative tion. Nutr Clin Pract 34:12, 2019.
complications and are unlikely to consume an adequate amount of Van Zanten ARH et al: Nutrition therapy and critical illness: Practical
food voluntarily over the next many days. Patients with only mild guidance for the ICU, post-ICU, and long-term convalescence phases.
muscle atrophy, no systemic inflammation, and no postoperative Crit Care 23:368, 2019.
complications do not require postoperative PN unless (1) adequate Yeh DD et al: Advances in nutrition for the surgical patient. Curr Probl
feeding by mouth has not been achieved by day 5–7 after surgery Surg 56:343, 2019.
or (2) there are indications that voluntary feeding will be further
delayed. Perioperative immune-enhancing EN reduces morbidity in
patients undergoing major elective gastrointestinal surgery.
Cancer SNS plays a crucial role in cancer therapy. Many malig-
nant neoplasms (especially those that involve the gastrointestinal
tract or induce systemic inflammation) and their cytotoxic thera-
Section 3 Liver and Biliary Tract Disease
pies create the conditions for starvation and commonly lead to SRM
or CDM. The prevention or treatment of these starvation diseases
will improve patients’ quality of life and their tolerance to antican-
cer therapy. EN and PN are generally not prescribed to patients with
advanced cancer for which there is no effective anticancer therapy
336 Approach to the Patient
with Liver Disease
because the side effects and complications of invasive SNS are not
counterbalanced by an improved disease trajectory. In some cases, Marc G. Ghany, Jay H. Hoofnagle
the disease may be progressing but so slowly that the patient will die
of the complications of starvation disease long before they would
from the cancer. EN or PN is appropriate for these patients. A diagnosis of liver disease usually can be made accurately by careful
elicitation of the patient’s history, physical examination, and applica-
PART 10

Advanced Dementia Optimized voluntary nutrition is the key tion of a few laboratory tests. In some circumstances, radiologic exami-
approach in this situation, and it can be used to deal with problems nations are helpful or, indeed, diagnostic. Liver biopsy is considered
such as disability and dysphagia in patients who get pleasure from the criterion standard in evaluation of liver disease but is now needed
eating. There is no evidence that EN or PN improves quality or less for diagnosis than for grading (activity) and staging (fibrosis) of
length of life in patients who have advanced dementia and show
Disorders of the Gastrointestinal System

disease. Noninvasive means of assessing fibrosis stage have become

little or no interest in food, and the side effects and complications increasingly helpful and may allow for avoidance of biopsy in a pro-
of EN and PN are unpleasant and sometimes dangerous. portion of patients. This chapter provides an introduction to diagnosis
REFEEDING SYNDROME and management of liver disease, briefly reviewing the structure and
The refeeding syndrome can occur in patients with adapted SRM function of the liver; the major clinical manifestations of liver disease;
during the first week of nutritional repletion if carbohydrate and and the use of clinical history, physical examination, laboratory tests,
sodium are introduced too rapidly. Carbohydrate provision stim- imaging studies, and liver biopsy.
ulates insulin secretion, which, owing to its antinatriuretic effect,
expands the ECF volume, especially when excessive sodium is LIVER STRUCTURE AND FUNCTION
provided. Refeeding edema can be minimized by severely limiting The liver is the largest organ of the body, weighing 1–1.5 kg and rep-
sodium provision and increasing carbohydrate provision slowly. resenting 1.5–2.5% of the lean body mass. The size and shape of the
Carbohydrate refeeding may stimulate enough intracellular glu- liver vary and generally match the general body shape—long and lean
cose-6-phosphate and glycogen synthesis to seriously lower serum or squat and square. This organ is located in the right upper quadrant
phosphate concentrations. It also increases the downregulated met- of the abdomen under the right lower rib cage against the diaphragm
abolic rate of patients with adapted SRM and stimulates N reten- and projects for a variable extent into the left upper quadrant. It is held
tion, new cell synthesis, and cellular rehydration. Phosphorus, in place by ligamentous attachments to the diaphragm, peritoneum,
potassium, and magnesium deficiencies occur and are dangerous great vessels, and upper gastrointestinal organs. The liver receives a
during refeeding; their serum concentrations should be measured dual blood supply; ~20% of the blood flow is oxygen-rich blood from
frequently, and appropriate supplements provided. Left heart failure the hepatic artery, and 80% is nutrient-rich blood from the portal vein
may occur in predisposed patients; it has three causes: (1) an abrupt arising from the stomach, intestines, pancreas, and spleen.
increase of intravascular volume due to the administration of fluids The majority of cells in the liver are hepatocytes, which constitute
and of glucose, which stimulates insulin-mediated renal sodium two-thirds of the organ’s mass. The remaining cell types are Kupffer
retention; (2) increased cardiac demand on an atrophic left ventricle cells (members of the reticuloendothelial system), stellate (Ito or
created by an insulin-mediated increase of resting energy expendi- fat-storing) cells, endothelial and blood vessel cells, bile ductular cells,
ture; and (3) myocardial deficiencies of potassium, phosphorus, or and cells of supporting structures. Viewed by light microscopy, the liver
magnesium. Cardiac arrhythmias may occur. Acute thiamine defi- appears to be organized in lobules, with portal areas at the periphery
ciency encephalopathy is a devastating preventable complication of and central veins in the center of each lobule. However, from a func-
refeeding, even with simple glucose infusions. tional point of view, the liver is organized into acini, with both hepatic
arterial and portal venous blood entering the acinus from the portal
areas (zone 1) and then flowing through the sinusoids to the terminal
■■FURTHER READING hepatic veins (zone 3); the intervening hepatocytes constitute zone 2.
Gomes F et al: ESPEN guidelines on nutritional support for polymor- The advantage of viewing the acinus as the physiologic unit of the liver
bid internal medicine patients. Clin Nutr 37:336, 2018. is that this perspective helps to explain the morphologic patterns and
Kondrup J: Nutrition risk screening in the ICU. Curr Opin Clin Nutr zonality of many vascular and biliary diseases not explained by the
Metab Care 22:159, 2019. lobular arrangement.

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 Portal areas of the liver consist of small veins, arteries, bile ducts, and TABLE 336-1 Liver Diseases 2547
lymphatics organized in a loose stroma of supporting matrix and small Inherited hyperbilirubinemia Liver involvement in systemic
amounts of collagen. Blood flowing into the portal areas is distributed diseases
Gilbert syndrome
through the sinusoids, passing from zone 1 to zone 3 of the acinus and Sarcoidosis
draining into the terminal hepatic veins (“central veins”). Secreted bile  Crigler-Najjar syndrome, types I
and II Amyloidosis
flows in the opposite direction—that is, in a countercurrent pattern
Dubin-Johnson syndrome Glycogen storage diseases
from zone 3 to zone 1. The sinusoids are lined by unique endothelial
cells that have prominent fenestrae of variable sizes, allowing the free Rotor syndrome Celiac disease
flow of plasma but not of cellular elements. The plasma is thus in direct Viral hepatitis Tuberculosis
contact with hepatocytes in the subendothelial space of Disse. Hepatitis A   Mycobacterium avium-intracellulare
Hepatocytes have distinct polarity. The basolateral side of the hepa- Hepatitis B infection
tocyte lines the space of Disse and is richly lined with microvilli; it Hepatitis C Cholestatic syndromes
exhibits endocytotic and pinocytotic activity, with passive and active Hepatitis D Benign postoperative cholestasis
uptake of nutrients, proteins, and other molecules. The apical pole of Hepatitis E Jaundice of sepsis
the hepatocyte forms the canalicular membranes through which bile  Others (Epstein-Barr virus  Total parenteral nutrition–induced
components are secreted. The canaliculi of hepatocytes form a fine [mononucleosis] herpesvirus, jaundice
network, which fuses into the bile ductular elements near the portal cytomegalovirus, adenovirus Cholestasis of pregnancy
areas. Kupffer cells usually lie within the sinusoidal vascular space and hepatitis) Cholangitis and cholecystitis
represent the largest group of fixed macrophages in the body. The stel- Cryptogenic hepatitis  Extrahepatic biliary obstruction
late cells are located in the space of Disse but are not usually prominent Immune and autoimmune liver (stone, stricture, cancer)
unless activated, when they produce collagen and matrix. Red blood diseases Biliary atresia
cells stay in the sinusoidal space as blood flows through the lobules, Primary biliary cholangitis Caroli disease
but white blood cells can migrate through or around endothelial cells Autoimmune hepatitis Cryptosporidiosis
into the space of Disse and from there to portal areas, where they can Sclerosing cholangitis Drug-induced liver disease
return to the circulation through lymphatics. Overlap syndromes  Hepatocellular patterns (isoniazid,
Hepatocytes perform numerous and vital roles in maintaining Graft-versus-host disease acetaminophen)
homeostasis and health. These functions include the synthesis of Allograft rejection  Cholestatic patterns
most essential serum proteins (albumin, carrier proteins, coagulation (methyltestosterone)

CHAPTER 336 Approach to the Patient with Liver Disease

Genetic liver diseases
factors, many hormonal and growth factors), the production of bile  Mixed patterns (sulfonamides,
α1 Antitrypsin deficiency
and its carriers (bile acids, cholesterol, lecithin, phospholipids), the phenytoin)
regulation of nutrients (glucose, glycogen, lipids, cholesterol, amino Hemochromatosis
 Micro- and macrovesicular steatosis
acids), and the metabolism and conjugation of lipophilic compounds Wilson disease (methotrexate, fialuridine)
(bilirubin, anions, cations, drugs) for excretion in the bile or urine.  Benign recurrent intrahepatic Vascular injury
Measurement of these activities to assess liver function is complicated cholestasis
Sinusoidal obstruction syndrome
by the multiplicity and variability of these functions. The most com-  Progressive familial intrahepatic
cholestasis, types I–III Budd-Chiari syndrome
monly used liver “function” tests are measurements of serum bilirubin, Ischemic hepatitis
serum albumin, and prothrombin time. The serum bilirubin level is  Others (galactosemia, tyrosinemia,
cystic fibrosis, Niemann-Pick- Passive congestion
a measure of hepatic conjugation and excretion; the serum albumin disease, Gaucher’s disease)
level and prothrombin time are measures of protein synthesis. Abnor- Portal vein thrombosis
Alcoholic liver disease Nodular regenerative hyperplasia
malities of bilirubin, albumin, and prothrombin time are typical of
Acute fatty liver Mass lesions
hepatic dysfunction. Frank liver failure is incompatible with life, and
the functions of the liver are too complex and diverse to be subserved Acute alcoholic hepatitis Hepatocellular carcinoma
by a mechanical pump; a dialysis membrane; or a concoction of infused Laënnec cirrhosis Cholangiocarcinoma
hormones, proteins, and growth factors. Nonalcoholic fatty liver Adenoma
Steatosis Focal nodular hyperplasia
Steatohepatitis Metastatic tumors
LIVER DISEASES Acute fatty liver of pregnancy Abscess
While there are many causes of liver disease (Table 336-1), these
Cysts
disorders generally present clinically in a few distinct patterns and are
usually classified as hepatocellular, cholestatic (obstructive), or mixed. Hemangioma
In hepatocellular diseases (such as viral hepatitis and alcoholic liver
disease), features of liver injury, inflammation, and necrosis predomi- presence of liver injury as well as to rule it out in someone in whom
nate. In cholestatic diseases, such as gallstone or malignant obstruction, liver disease is suspected.
primary biliary cholangitis (previously referred to as primary biliary Evaluation of patients with liver disease should be directed at (1)
cirrhosis), and some drug-induced liver diseases, features of inhibition establishing the etiologic diagnosis, (2) estimating disease severity
of bile flow predominate. In a mixed pattern, features of both hepato- (grading), and (3) establishing the disease stage (staging). Diagnosis
cellular and cholestatic injury are present (such as in cholestatic forms should focus on the category of disease (hepatocellular, cholestatic, or
of viral hepatitis and many drug-induced liver diseases). The pattern mixed injury) as well as on the specific etiologic diagnosis. Grading refers
of onset and prominence of symptoms can rapidly suggest a diagnosis, to assessment of the severity or activity of disease—active or inactive
particularly if major risk factors are considered, such as the age and sex as well as mild, moderate, or severe. Staging refers to estimation of the
of the patient and a history of exposure or risk behaviors. point in the course of the natural history of the disease, whether early
Typical presenting symptoms of liver disease include jaundice, or late; or precirrhotic, cirrhotic, or end-stage. This chapter introduces
fatigue, itching, right-upper-quadrant pain, nausea, poor appetite, general, salient concepts in the evaluation of patients with liver disease
abdominal distention, and intestinal bleeding. At present, however, that help lead to the diagnoses discussed in subsequent chapters.
many patients are diagnosed with liver disease who have no symp-
toms and who have been found to have abnormalities in biochemical ■■CLINICAL HISTORY
liver tests as a part of a routine physical examination or screening for The clinical history should focus on the symptoms of liver disease—
blood donation or for insurance or employment. The wide availability their nature, patterns of onset, and progression—and on potential risk
of batteries of liver tests makes it relatively simple to demonstrate the factors for liver disease. The manifestations of liver disease include

HPIM21e_Part10_p2381-p2670.indd 2547 20/01/22 10:04 PM

 2548 constitutional symptoms such as fatigue, weakness, nausea, poor appe- are no reliable means of prevention. Transmission is more common
tite, and malaise and the more liver-specific symptoms of jaundice, among HIV-co-infected mothers and is also linked to prolonged and
dark urine, light stools, itching, abdominal pain, and bloating. Symp- difficult labor and delivery, early rupture of membranes, internal fetal
toms can also suggest the presence of cirrhosis, end-stage liver disease, monitoring, and a high maternal viral load. A history of injection drug
or complications of cirrhosis such as portal hypertension. Generally, use, even in the remote past, is of great importance in assessing the
the constellation of symptoms and their patterns of onset, rather than risk for hepatitis B and C. Injection drug use is now the single most
a specific symptom, point to an etiology. common risk factor for hepatitis C. Transfusion with blood or blood
Fatigue is the most common and most characteristic symptom of products is no longer an important risk factor for acute viral hepatitis.
liver disease. It is variously described as lethargy, weakness, listlessness, However, blood transfusions received before the introduction of sen-
malaise, increased need for sleep, lack of stamina, and poor energy. sitive enzyme immunoassays for antibody to hepatitis C virus in 1992
The fatigue of liver disease typically arises after activity or exercise and is an important risk factor for chronic hepatitis C. Blood transfusion
is rarely present or severe after adequate rest; that is, it is “afternoon” before 1986, when screening for antibody to hepatitis B core antigen
rather than “morning” fatigue. Fatigue in liver disease is often intermit- was introduced, is also a risk factor for hepatitis B. Travel to a develop-
tent and variable in severity from hour to hour and day to day. In some ing area of the world, exposure to persons with jaundice, and exposure
patients, it may not be clear whether fatigue is due to the liver disease to young children in day-care centers are risk factors for hepatitis A.
or due to other problems such as stress, anxiety, sleep disturbance, or Tattooing and body piercing (for hepatitis B and C) and eating shell-
a concurrent illness. fish (for hepatitis A) are frequently mentioned but are actually types of
Nausea occurs with more severe liver disease and may accompany exposure that rarely lead to the acquisition of hepatitis.
fatigue or be provoked by smelling food odors or eating fatty foods. Hepatitis E is one of the more common causes of jaundice in Asia
Vomiting can occur but is rarely persistent or prominent. Poor appetite and Africa but is uncommon in developed nations. In endemic areas,
with weight loss occurs frequently in acute liver disease but is rare transmission is usually through exposure to fecally contaminated water.
in chronic disease except when cirrhosis is present and advanced. Recently, non-travel-related (autochthonous) cases of hepatitis E have
Diarrhea is uncommon in liver disease except with severe jaundice, in been described in developed countries, including the United States.
which a lack of bile acids reaching the intestine can lead to steatorrhea. These cases appear to be due to strains of hepatitis E virus that are
Right-upper-quadrant discomfort or ache (“liver pain”) occurs in endemic in swine and some wild animals (genotypes 3 and 4). While
many liver diseases and is usually marked by tenderness over the liver occasional cases are associated with eating raw or undercooked pork
area. The pain arises from stretching or irritation of Glisson’s capsule, or game (deer and wild boars), most cases of hepatitis E occur without
which surrounds the liver and is rich in nerve endings. Severe pain is known exposure, predominantly in elderly men without typical risk
most typical of gallbladder disease, liver abscess, and severe sinusoidal factors for viral hepatitis. Hepatitis E infection can become chronic in
PART 10

obstruction syndrome (previously known as veno-occlusive disease) immunosuppressed individuals (such as transplant recipients, patients
but is also an occasional accompaniment of acute hepatitis. receiving chemotherapy, or patients with HIV infection), in whom it
Itching occurs with acute liver disease, appearing early in obstruc- presents with abnormal serum enzymes in the absence of markers of
tive jaundice (from biliary obstruction) or drug-induced cholestasis hepatitis B or C.
and somewhat later in hepatocellular disease (acute hepatitis). Itching A history of alcohol intake is important in assessing the cause of
Disorders of the Gastrointestinal System

also occurs in chronic liver diseases—typically the cholestatic forms liver disease and in planning management and recommendations. In
such as primary biliary cholangitis and sclerosing cholangitis, in which the United States, for example, at least 70% of adults drink alco-
it is often the presenting symptom, preceding the onset of jaundice. hol to some degree, but significant alcohol intake is less common; in
However, itching can occur in any liver disease, particularly once cir- population-based surveys, only 5% of individuals have more than two
rhosis develops. drinks per day, the average drink representing 11–15 g of alcohol. Alcohol
Jaundice is the hallmark symptom of liver disease and perhaps the consumption associated with an increased rate of alcoholic liver disease
most reliable marker of severity. Patients usually report darkening of is probably more than two drinks (22–30 g) per day in women and
the urine before they notice scleral icterus. Jaundice is rarely detectable three drinks (33–45 g) in men. Most patients with alcoholic cirrhosis
with a bilirubin level <43 μmol/L (2.5 mg/dL). With severe cholestasis, have a much higher daily intake and have drunk excessively for
there will also be lightening of the color of the stools and steatorrhea. ≥10 years before onset of liver disease. In assessing alcohol intake, the
Jaundice without dark urine usually indicates indirect (unconjugated) history should also focus on whether alcohol abuse or dependence is
hyperbilirubinemia and is typical of hemolytic anemia and the genetic present. Alcoholism is usually defined by the behavioral patterns and
disorders of bilirubin conjugation, the common and benign form being consequences of alcohol intake, not by the amount. Abuse is defined
Gilbert syndrome and the rare and severe form being Crigler-Najjar by a repetitive pattern of drinking alcohol that has adverse effects on
syndrome. Gilbert syndrome affects up to 5% of the general popula- social, family, occupational, or health status. Dependence is defined by
tion; the jaundice in this condition is more noticeable after fasting and alcohol-seeking behavior, despite its adverse effects. Many alcoholics
with stress. demonstrate both dependence and abuse, and dependence is consid-
Major risk factors for liver disease that should be sought in the clin- ered the more serious and advanced form of alcoholism. A clinically
ical history include details of alcohol use, medication use (including helpful approach to diagnosis of alcohol dependence and abuse is the
herbal compounds, birth control pills, and over-the-counter medica- use of the CAGE questionnaire (Table 336-2), which is recommended
tions), personal habits, sexual activity, travel, exposure to jaundiced or for all medical history-taking.
other high-risk persons, injection drug use, recent surgery, remote or Family history can be helpful in assessing liver disease. Familial
recent transfusion of blood or blood products, occupation, accidental causes of liver disease include Wilson disease; hemochromatosis and
exposure to blood or needlestick, and familial history of liver disease.
For assessing the risk of viral hepatitis, a careful history of sexual
activity is of particular importance and should include the number TABLE 336-2 CAGE Questionsa
of lifetime sexual partners and, for men, a history of having sex with ACRONYM QUESTION
men. Sexual exposure is a common mode of spread of hepatitis B and
C Have you ever felt you ought to cut down on your drinking?
D but is uncommon for hepatitis C. A family history of hepatitis, liver
disease, and liver cancer is also important. Maternal-infant transmis- A Have people annoyed you by criticizing your drinking?
sion occurs with both hepatitis B and C. Vertical spread of hepatitis B G Have you ever felt guilty or bad about your drinking?
can now be prevented by passive and active immunization of the infant E Have you ever had a drink first thing in the morning to steady
at birth. Additionally, antiviral therapy during the third trimester of your nerves or get rid of a hangover (eye-opener)?
pregnancy is now recommended for mothers with levels of HBV DNA a
One “yes” response should raise suspicion of an alcohol use problem, and more
>200,000 IU/mL. Vertical spread of hepatitis C is uncommon, but there than one is a strong indication of abuse or dependence.

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 α1 antitrypsin deficiency; and the less common inherited pediatric equivocal cases. Peripheral edema can occur with or without ascites. In 2549
liver diseases—that is, familial intrahepatic cholestasis, benign recur- patients with advanced liver disease, other factors frequently contribute
rent intrahepatic cholestasis, and Alagille syndrome. Onset of severe to edema formation, including hypoalbuminemia, venous insuffi-
liver disease in childhood or adolescence in conjunction with a family ciency, heart failure, and medications.
history of liver disease or neuropsychiatric disturbance should lead to Hepatic failure is defined as the occurrence of signs or symptoms of
investigation for Wilson disease. A family history of cirrhosis, diabetes, hepatic encephalopathy in a person with severe acute or chronic liver
or endocrine failure and the appearance of liver disease in adulthood disease. The first signs of hepatic encephalopathy can be subtle and
suggest hemochromatosis and should prompt investigation of iron nonspecific—change in sleep patterns, change in personality, irritabil-
status. Abnormal iron studies in adult patients warrant genotyping of ity, and mental dullness. Thereafter, confusion, disorientation, stupor,
the HFE gene for the C282Y and H63D mutations typical of genetic and eventually coma supervene. In acute liver failure, excitability and
hemochromatosis. In children and adolescents with iron overload, mania may be present. Physical findings include asterixis and flapping
other non-HFE causes of hemochromatosis should be sought. A family tremors of the body and tongue. Fetor hepaticus refers to the slightly
history of emphysema should lead to investigation of α1 antitrypsin sweet, ammoniacal odor that can develop in patients with liver failure,
levels and, if levels are low, for protease inhibitor (Pi) genotype. particularly if there is portal-venous shunting of blood around the liver.
Other causes of coma and disorientation should be excluded, mainly
■■PHYSICAL EXAMINATION electrolyte imbalances, sedative use, and renal or respiratory failure.
The physical examination rarely uncovers evidence of liver dysfunc- The appearance of hepatic encephalopathy during acute hepatitis is
tion in a patient without symptoms or laboratory findings, nor are the major criterion for diagnosis of fulminant hepatitis and indicates
most signs of liver disease specific to one diagnosis. Thus, the physical a poor prognosis. In chronic liver disease, encephalopathy is usually
examination complements rather than replaces the need for other triggered by a medical complication such as gastrointestinal bleeding,
diagnostic approaches. In many patients, the physical examination is overdiuresis, uremia, dehydration, electrolyte imbalance, infection,
normal unless the disease is acute or severe and advanced. Neverthe- constipation, or use of narcotic analgesics.
less, the physical examination is important in that it can yield the first A helpful measure of hepatic encephalopathy is a careful mental
evidence of hepatic failure, portal hypertension, and liver decompen- status examination and use of the trail-making test, which consists of
sation. In addition, the physical examination can reveal signs—related a series of 25 numbered circles that the patient is asked to connect as
either to risk factors or to associated diseases or findings—that point rapidly as possible using a pencil. The normal range for the connect-
to a specific diagnosis. the-dot test is 15–30 s; it is considerably longer in patients with early
Typical physical findings in liver disease are icterus, hepatomegaly, hepatic encephalopathy. Other tests include drawing of abstract objects

CHAPTER 336 Approach to the Patient with Liver Disease

hepatic tenderness, splenomegaly, spider angiomata, palmar erythema, or comparison of a signature to previous examples. More sophisticated
and skin excoriations. Signs of advanced disease include muscle wast- testing—for example, with electroencephalography and visual evoked
ing, ascites, edema, dilated abdominal veins, hepatic fetor, asterixis, potentials—can detect mild forms of encephalopathy but are rarely
mental confusion, stupor, and coma. In male patients with cirrhosis, clinically useful.
particularly that related to alcohol use, signs of hyperestrogenemia Other signs of advanced liver disease include umbilical hernia from
such as gynecomastia, testicular atrophy, and loss of male-pattern hair ascites, hydrothorax, prominent veins over the abdomen, and caput
distribution may be found. medusa, a condition that consists of collateral veins radiating from the
Icterus is best appreciated when the sclera is inspected under nat- umbilicus and results from recanulation of the umbilical vein. Wid-
ural light. In fair-skinned individuals, a yellow tinge to the skin may ened pulse pressure and signs of a hyperdynamic circulation can occur
be obvious. In dark-skinned individuals, examination of the mucous in patients with cirrhosis as a result of fluid and sodium retention,
membranes below the tongue can demonstrate jaundice. Jaundice is increased cardiac output, and reduced peripheral resistance. Patients
rarely detectable if the serum bilirubin level is <43 μmol/L (2.5 mg/dL) with long-standing cirrhosis and portal hypertension are prone to
but may remain detectable below this level during recovery from jaun- develop the hepatopulmonary syndrome, which is defined by the triad
dice (because of protein and tissue binding of conjugated bilirubin). of liver disease, hypoxemia, and pulmonary arteriovenous shunting.
Spider angiomata and palmar erythema occur in both acute and The hepatopulmonary syndrome is characterized by platypnea and
chronic liver disease; these manifestations may be especially prominent orthodeoxia: shortness of breath and oxygen desaturation that occur
in persons with cirrhosis but can develop in normal individuals and are paradoxically upon the assumption of an upright position. Measure-
frequently found during pregnancy. Spider angiomata are superficial, ment of oxygen saturation by pulse oximetry is a reliable screening test
tortuous arterioles, and—unlike simple telangiectasias—typically fill for hepatopulmonary syndrome.
from the center outward. Spider angiomata occur only on the arms, Several skin disorders and changes are common in liver disease.
face, and upper torso; they can be pulsatile and may be difficult to Hyperpigmentation is typical of advanced chronic cholestatic diseases
detect in dark-skinned individuals. such as primary biliary cholangitis and sclerosing cholangitis. In these
Hepatomegaly is not a very reliable sign of liver disease because of same conditions, xanthelasma and tendon xanthomata occur as a result
variability in the liver’s size and shape and the physical impediments of retention and high serum levels of lipids and cholesterol. Slate-gray
to assessment of liver size by percussion and palpation. Marked pigmentation of the skin is also seen with hemochromatosis if iron
hepatomegaly is typical of cirrhosis, sinusoidal obstruction syndrome, levels are high for a prolonged period. Mucocutaneous vasculitis with
infiltrative disorders such as amyloidosis, metastatic or primary can- palpable purpura, especially on the lower extremities, is typical of
cers of the liver, and alcoholic hepatitis. Careful assessment of the cryoglobulinemia of chronic hepatitis C but can also occur in chronic
liver edge may also reveal unusual firmness, irregularity of the surface, hepatitis B.
or frank nodules. Perhaps the most reliable physical finding in the Some physical signs point to specific liver diseases. Kayser-Fleischer
liver examination is hepatic tenderness. Discomfort when the liver is rings occur in Wilson disease and consist of a golden-brown copper
touched or pressed upon should be carefully sought with percussive pigment deposited in Descemet’s membrane at the periphery of the
comparison of the right and left upper quadrants. cornea; they are best seen by slit-lamp examination. Dupuytren con-
Splenomegaly, which occurs in many medical conditions, can be a tracture and parotid enlargement are suggestive of chronic alcoholism
subtle but significant physical finding in liver disease. The availability and alcoholic liver disease. In metastatic liver disease or primary
of ultrasound (US) methods for assessment of the spleen allows confir- hepatocellular carcinoma, signs of cachexia and wasting as well as firm
mation of the physical finding. hepatomegaly and a hepatic bruit may be prominent.
Signs of advanced liver disease include muscle wasting and weight
loss as well as hepatomegaly, bruising, ascites, and edema. Ascites ■■DIAGNOSIS OF LIVER DISEASE
is best appreciated by attempts to detect shifting dullness by careful The key diagnostic tests of major causes of acute and chronic liver
percussion. US examination will confirm the finding of ascites in disease are outlined in Table 336-3, and an algorithm for evaluation of

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 2550
TABLE 336-3 Important Diagnostic Tests in Common Liver Diseases antibody), sclerosing cholangitis (peripheral antineutrophil cyto-
plasmic antibody), and autoimmune hepatitis (antinuclear, smooth-
DISEASE DIAGNOSTIC TEST
muscle, and liver-kidney microsomal antibody). A simple delineation
Hepatitis A Anti-HAV IgM of laboratory abnormalities and common liver diseases is given in
Hepatitis B Table 336-3.
Acute HBsAg and anti-HBc IgM The use and interpretation of liver function tests are summarized
Chronic HBsAg and HBeAg and/or HBV DNA in Chap. 337.
Hepatitis C Anti-HCV and HCV RNA
Hepatitis D (delta) HBsAg and anti-HDV
Diagnostic Imaging Great advances have been made in hepato-
biliary imaging, although no method is adequately accurate in demon-
Hepatitis E Anti-HEV IgM and HEV RNA strating underlying cirrhosis in its early stages. Of the many modalities
Autoimmune hepatitis ANA or SMA, elevated IgG levels, and available for imaging the liver, US, computed tomography (CT), and
compatible histology magnetic resonance imaging (MRI) are the most commonly employed
Primary biliary cholangitis Mitochondrial antibody, elevated IgM levels, and are complementary to one another. In general, US and CT are
and compatible histology highly sensitive for detecting biliary duct dilation and are the first-
Primary sclerosing cholangitis P-ANCA, cholangiography line options for investigating cases of suspected obstructive jaundice.
Drug-induced liver disease History of drug ingestion All three modalities can detect a fatty liver, which appears bright on
Alcoholic liver disease History of excessive alcohol intake and imaging studies. Modifications of CT and MRI can be used to quantify
compatible histology liver fat, and this information may ultimately be valuable in monitoring
Nonalcoholic steatohepatitis Ultrasound or CT evidence of fatty liver and response to therapy in patients with fatty liver disease. Advantages,
compatible histology disadvantages, and clinical utility of each modality are presented in
α1 Antitrypsin disease Reduced α1 antitrypsin levels, phenotype PiZZ Table 336-4. Magnetic resonance cholangiopancreatography (MRCP)
or PiSZ and endoscopic retrograde cholangiopancreatography (ERCP) are the
Wilson disease Decreased serum ceruloplasmin and procedures of choice for visualization of the biliary tree. MRCP offers
increased urinary copper; increased hepatic several advantages over ERCP: there is no need for contrast media
copper level or ionizing radiation, images can be acquired faster, the procedure is
Hemochromatosis Elevated iron saturation and serum ferritin; less operator dependent, and it carries no risk of pancreatitis. MRCP
genetic testing for HFE gene mutations is superior to US and CT for detecting choledocholithiasis but is less
Hepatocellular cancer Elevated α-fetoprotein level (to >500 ng/mL); specific. MRCP is useful in the diagnosis of bile duct obstruction and
PART 10

ultrasound or CT image of mass congenital biliary abnormalities, but ERCP is considered more valuable
Abbreviations: ANA, antinuclear antibody; anti-HBc, antibody to hepatitis B core
in evaluating ampullary lesions and primary sclerosing cholangitis.
(antigen); HAV, HBV, HCV, HDV, HEV, hepatitis A, B, C, D, E virus; HBeAg, hepatitis B ERCP permits biopsy, direct visualization of the ampulla and common
e antigen; HBsAg, hepatitis B surface antigen; P-ANCA, peripheral antineutrophil bile duct, and intraductal ultrasonography and brushings for cytologic
cytoplasmic antibody; SMA, smooth-muscle antibody. evaluation of malignancy. It also provides several therapeutic options
Disorders of the Gastrointestinal System

the patient with suspected liver disease is shown in Fig. 336-1. Specifics in patients with obstructive jaundice, such as sphincterotomy, stone
of diagnosis are discussed in later chapters. The most common causes extraction, and placement of nasobiliary catheters and biliary stents.
of acute liver disease are viral hepatitis (particularly hepatitis A, B, and Doppler US and MRI are used to assess hepatic vasculature
C), drug-induced liver injury, cholangitis, and alcoholic liver disease. and hemodynamics and to monitor surgically or radiologically
Liver biopsy usually is not needed for the diagnosis and management placed vascular shunts, including transjugular intrahepatic porto-
of acute liver disease, exceptions being situations where the diagnosis systemic shunts. Multidetector or spiral CT and MRI with contrast
remains unclear despite thorough clinical and laboratory investigation. enhancement are the procedures of choice for the identification and
Liver biopsy can be helpful in diagnosing drug-induced liver disease evaluation of hepatic masses, the staging of liver tumors, and pre-
and acute alcoholic hepatitis. operative assessment. With regard to mass lesions, the sensitivity
The most common causes of chronic liver disease, in general order of hepatic imaging continues to increase; unfortunately, specificity
of frequency, are chronic hepatitis C, alcoholic liver disease, nonalco- remains a problem, and often two and sometimes three studies
holic steatohepatitis, chronic hepatitis B, autoimmune hepatitis, scle- are needed before a diagnosis can be reached. An emerging imag-
rosing cholangitis, primary biliary cholangitis, hemochromatosis, and ing modality for the investigation of hepatic lesions is contrast-
Wilson disease. Hepatitis E virus is a rare cause of chronic hepatitis, enhanced US. This procedure permits enhancement of liver lesions
with cases occurring mostly in persons who are immunosuppressed in a similar fashion as contrast-enhanced, cross-sectional CT or MRI.
or immunodeficient. Strict diagnostic criteria have not been devel- Major advantages are real-time assessment of liver perfusion through-
oped for most liver diseases, but liver biopsy plays an important role out the vascular phases without risk of nephrotoxicity and radiation
in the diagnosis of autoimmune hepatitis, primary biliary cholangitis, exposure. Other advantages are its widespread availability and lower
nonalcoholic and alcoholic steatohepatitis, and Wilson disease (with a cost. Limitations include body habitus of the patient and skill of the
quantitative hepatic copper level in the last instance). operator. US is the recommended modality for hepatocellular car-
cinoma (HCC) screening. Contrast-enhanced US, CT, and MRI are
Laboratory Testing Diagnosis of liver disease is greatly aided appropriate for further investigation of lesions detected on screening
by the availability of reliable and sensitive tests of liver injury and US. The American College of Radiologists has developed a Liver Imag-
function. A typical battery of blood tests used for initial assessment of ing Reporting and Data System (LI-RADS) to standardize the report-
liver disease includes measurement of levels of serum alanine (ALT) ing and data collection of CT, MRI, and contrast-enhanced US imaging
and aspartate (AST) aminotransferases, alkaline phosphatase (AlkP), for HCC. This system allows for more consistent reporting and reduces
direct and total serum bilirubin and albumin, and prothrombin time. imaging interpretation variability and errors.
The pattern of abnormalities generally points to hepatocellular versus Recently, several US-based elastographic techniques have been
cholestatic liver disease and helps determine whether the disease is developed and approved for the measurement of hepatic stiffness,
acute or chronic and whether cirrhosis and hepatic failure are present. providing an indirect assessment of fibrosis and cirrhosis. The most
Based on these results, further testing over time may be necessary. commonly used approaches in clinical practice include transient
Other laboratory tests may be helpful, such as γ-glutamyl transpep- elastography, acoustic radiation force impulse imaging, shear-wave
tidase (γGT) to define whether AlkP elevations are due to liver disease; elasticity imaging, and supersonic shear imaging. These techniques
hepatitis serology to define the type of viral hepatitis; and autoimmune can eliminate the need for liver biopsy if the only indication for the test
markers to diagnose primary biliary cholangitis (antimitochondrial is the assessment of disease stage. Magnetic resonance elastography is

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 more sensitive than US elastography but is also more 2551
Suspected liver disease expensive and requires advanced scheduling and special
equipment. Studies are ongoing to determine whether
hepatic elastography is an appropriate means of mon-
Abnormal liver tests
itoring fibrosis and disease progression in untreated
and treated patients. Finally, interventional radiologic
techniques allow for the biopsy of solitary lesions,
Acute Chronic the radiofrequency ablation and chemoembolization of
<6 months >6 months cancerous lesions, the insertion of drains into hepatic
abscesses, the measurement of portal pressure, and the
creation of vascular shunts in patients with portal hyper-
tension. Which modality to use depends on factors such
Hepatitic: ⇑⇑ALT Cholestatic: Hepatitic: ⇑⇑ALT Cholestatic: as availability, cost, and experience of the radiologist
Mixed: ↑ALT, ⇑⇑AlkP, Mixed: ↑ALT, ⇑⇑AlkP, with each technique.
↑AlkP ⇑⇑gGT, ↑AlkP ⇑⇑gGT,
↑ALT ↑ALT Liver Biopsy Liver biopsy remains the gold standard
in the evaluation of patients with liver disease, particu-
Diagnostic Diagnostic Diagnostic Diagnostic
larly chronic liver disease. Liver biopsy is necessary for
evaluation evaluation evaluation evaluation diagnosis in selected instances but is more often useful
1. IgM Anti-HAV 1. AMA 1. HBsAg 1. Drug history for assessment of the severity (grade) and stage of liver
2. HBsAg 2. Drug history 2. Anti-HCV 2. AMA damage, prediction of prognosis, and monitoring of the
3. IgM Anti-HBc 3. Ultrasound/MRI 3. Fe saturation, 3. P-ANCA
4. Anti-HCV 4. MRCP/ERCP ferritin 4. Ultrasound response to treatment. The size of the liver biopsy sample
5. ANA, SMA 4. Ceruloplasmin 5. MRCP/ERCP is an important determinant of reliability; a length of
6. Monospot, 5. α1AT 1.5–2 cm with 10 portal tracts is necessary for accurate
heterophile 6. ANA, SMA
7. Ceruloplasmin 7. Ultrasound assessment of fibrosis. Because liver biopsy is an invasive
8. Alcohol history 8. Alcohol history procedure and not without complications, it should be
9. Drug history used only when it will contribute materially to decisions
about management and therapy. In the future, noninva-

CHAPTER 336 Approach to the Patient with Liver Disease

sive means of assessing disease activity (batteries of blood
Liver biopsy in acute liver disease: Liver biopsy in chronic liver disease:
Reserved for patients in whom the diagnosis Often valuable for diagnosis as well as
tests) and fibrosis (elastography and fibrosis markers) may
remains unclear despite medical evaluation staging and grading liver disease replace liver biopsy for the staging and grading of disease.

FIGURE 336-1 Algorithm for evaluation of abnormal liver tests. For patients with suspected ■■GRADING AND STAGING OF LIVER
liver disease, an appropriate approach to evaluation is initial routine liver testing—for example, DISEASE
measurement of serum bilirubin, albumin, alanine aminotransferase (ALT), AST, and alkaline Grading refers to an assessment of the severity or activ-
phosphatase (AlkP). These results (sometimes complemented by testing of γ-glutamyl transpeptidase ity of liver disease, whether acute or chronic; active or
[gGT]) will establish whether the pattern of abnormalities is hepatic, cholestatic, or mixed. In addition, inactive; and mild, moderate, or severe. Liver biopsy is
the duration of symptoms or abnormalities will indicate whether the disease is acute or chronic. If
the disease is acute and if history, laboratory tests, and imaging studies do not reveal a diagnosis, the most accurate means of assessing severity, particu-
liver biopsy is appropriate to help establish the diagnosis. If the disease is chronic, liver biopsy can larly in chronic liver disease. Serum aminotransferase
be helpful not only for diagnosis but also for grading of the activity and staging the progression of levels serve as convenient and noninvasive markers for
disease. This approach is generally applicable to patients without immune deficiency. In patients disease activity but do not always reliably reflect disease
with HIV infection or recipients of bone marrow or solid organ transplants, the diagnostic evaluation severity. Thus, normal serum aminotransferase levels in
should also include evaluation for opportunistic infections (e.g., with adenovirus, cytomegalovirus, patients with hepatitis B surface antigen in serum may
Coccidioides, hepatitis E virus) as well as for vascular and immunologic conditions (veno-occlusive
disease, graft-versus-host disease). α1 AT, α1 antitrypsin; AMA; antimitochondrial antibody; ANA, indicate the inactive carrier state or may reflect mild
antinuclear antibody; anti-HBc, antibody to hepatitis B core (antigen); ERCP, endoscopic retrograde chronic hepatitis B or hepatitis B with fluctuating dis-
cholangiopancreatography; HAV, hepatitis A virus; HBsAg, hepatitis B surface antigen; HCV, hepatitis ease activity. Serum testing for hepatitis B e antigen and
C virus; MRCP, magnetic resonance cholangiopancreatography; P-ANCA, peripheral antineutrophil hepatitis B virus DNA can help sort out these different
cytoplasmic antibody; SMA, smooth-muscle antibody. patterns, but these markers can also fluctuate and change

TABLE 336-4 Diagnostic Tests to Assess Liver Fat

IMAGING MODALITY ADVANTAGES DISADVANTAGES CLINICAL UTILITY
Ultrasound No radiation Operator dependent Initial screening test for suspected liver fat
Widely available Imprecise qualitative assessment of fat severity,
particularly mild steatosis
Transient elastography No radiation Requires special software Alternate screening test for suspected liver
with controlled attenuation Point-of-care assessment of liver fat No reliable cutoff for diagnosis of liver fat fat if available
parameter
Provides semiquantitative assessment Imprecise qualitative assessment of fat severity
of fat severity
Computed tomography Rapid assessment Requires radiation Not recommended for clinical assessment of
Non–operator dependent Quantification of fat requires specific protocols liver fat due to need for radiation exposure
and low sensitivity for mild fat
Quantitative assessment of fat severity Imprecise quantitative assessment of fat
severity, particularly mild steatosis
Magnetic resonance Direct assessment of liver fat Relatively limited accessibility Test of choice for quantitative assessment of
imaging–proton density fat Highly sensitive and specific liver fat if available
fraction

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 2552 over time. Similarly, in chronic hepatitis C, serum aminotransferase TABLE 336-6 Child-Pugh Classification of Cirrhosis
levels can be normal despite moderate disease activity. Finally, in both
POINTS TOWARD TOTAL SCORE
alcoholic and nonalcoholic steatohepatitis, aminotransferase levels are
quite unreliable in reflecting severity. In these conditions, liver biopsy FACTOR UNITS 1 2 3
is helpful in guiding management and identifying appropriate therapy, Serum bilirubin μmol/L <34 34–51 >51
particularly if treatment is difficult, prolonged, and expensive, as is mg/dL <2.0 2.0–3.0 >3.0
often the case in chronic viral hepatitis. Of the several well-verified Serum albumin g/L >35 30–35 <30
numerical scales for grading activity in chronic liver disease, the most g/dL >3.5 3.0–3.5 <3.0
commonly used are the METAVIR, histology activity index, and the
Prothrombin time seconds <4 4–6 >6
Ishak fibrosis scale. prolonged
Liver biopsy is also the most accurate means of assessing stage of
INRa <1.7 1.7–2.3 >2.3
disease as early or advanced, precirrhotic, and cirrhotic. Staging of
disease pertains largely to chronic liver diseases in which progression Ascites None Easily Poorly
controlled controlled
to cirrhosis and end-stage disease can occur but may require years
or decades. Clinical features, biochemical tests, and hepatic imaging Hepatic None Minimal Advanced
encephalopathy
studies are helpful in assessing stage but generally become abnormal
only in the middle to late stages of cirrhosis. Noninvasive tests that a
International normalized ratio.
suggest advanced fibrosis include mild elevations of bilirubin, prolon- Note: The Child-Pugh score is calculated by adding the scores for the five factors
gation of prothrombin time, slight decreases in serum albumin, and and can range from 5 to 15. The resulting Child-Pugh class can be A (a score of
5–6), B (7–9), or C (≥10). Decompensation indicates cirrhosis, with a Child-Pugh
mild thrombocytopenia (which is often the first indication of worsen- score of ≥7 (class B). This level has been the accepted criterion for listing a patient
ing fibrosis). Combinations of blood test results that include clinical for liver transplantation.
features, routine laboratory tests, and special laboratory tests such as
serum proteins or small molecules that are affected by or involved with Once cirrhosis develops, other scoring systems are employed to
fibrogenesis have been used to create models for predicting advanced assess compensated versus decompensated disease and prognosis. The
liver disease, but these models are not reliable enough to use on a reg- first staging system used for this purpose was the modified Child-Pugh
ular basis or for repeated measures and only separate advanced from classification, with a scoring system of 5–15: scores of 5 and 6 represent
early disease (Table 336-5). Recently, elastography and noninvasive Child-Pugh class A (consistent with “compensated cirrhosis”),
breath tests using 13C-labeled compounds have been proposed as a scores of 7–9 represent class B, and scores of 10–15 represent class
means of detecting early stages of fibrosis and liver dysfunction, but C (Table 336-6). This scoring system was initially devised to stratify
PART 10

their reliability and reproducibility remain to be proven. A major lim- patients with cirrhosis into risk groups before portal decompressive
itation of noninvasive markers is that they can be affected by disease surgery. The Child-Pugh score is a reasonably reliable predictor of
activity. Even elastography is limited in this regard, in that it measures survival in many liver diseases and predicts the likelihood of major
liver stiffness, not fibrosis per se, and can be affected by inflammation, complications of cirrhosis, such as bleeding from varices and spon-
edema, hepatocyte necrosis, and intrasinusoidal cellularity (inflamma- taneous bacterial peritonitis. This classification scheme was used to
Disorders of the Gastrointestinal System

tory, malignant, or sickled cells). Thus, at present, mild to moderate assess prognosis in cirrhosis and to provide standard criteria for listing
stages of hepatic fibrosis are detectable only by liver biopsy. In the a patient as a candidate for liver transplantation (Child-Pugh class B).
assessment of stage, the degree of fibrosis is usually used as the quanti- More recently, the Child-Pugh system has been replaced by the Model
tative measure. The amount of fibrosis is generally staged on a scale of for End-Stage Liver Disease (MELD) system for the latter purpose. The
0 to 4+ (METAVIR scale) or 0 to 6+ (Ishak scale). The importance of MELD score is a prospectively derived system designed to predict the
staging relates primarily to prognosis, recommendation of therapy, and prognosis of patients with liver disease and portal hypertension. This
optimal management to prevent complications of chronic liver disease. score is calculated using three readily available objective variables:
Patients with cirrhosis are candidates for screening and surveillance for the prothrombin time expressed as the international normalized ratio
esophageal varices and HCC. Patients without advanced fibrosis need (INR), the serum bilirubin level, and the serum creatinine concen-
not undergo screening. tration. The ability of the MELD score to predict outcome after liver
transplantation is regularly monitored and was modified to increase its
TABLE 336-5 Selected Noninvasive Methods of Assessing Hepatic accuracy and improve allocation of donated livers. These modifications
Fibrosis and Cirrhosis include serum sodium concentration as a factor in the model and a
reweighting of the MELD components. A separate scoring system, the
ADVANCED Pediatric End-Stage Liver Disease (PELD) score, is used for children
METHOD PARAMETERS FIBROSIS CIRRHOSIS
(<12 years old). Transient elastography has also been used to stage
APRI AST, platelet count >1 >1.5 (1–2) cirrhosis and has been shown to be useful in predicting complications
ELF Age, hyaluronic acid, MMP-3, TIMP-1 >7.7 >9.3 such as variceal hemorrhage, ascites development, and liver-related
FIB-4 Age, AST, ALT, platelet count >1.45 >3.25 death.
Fibro testa Haptoglobin, α2-macroglobulin, >0.45 >0.63 The MELD system provides a more objective means of assess-
apolipoprotein A1, γGT, total bilirubin ing disease severity and has less center-to-center variation than the
TE Measures speed of a shear wave >7.3 kPa >15 kPa Child-Pugh score as well as a wider range of values. The MELD and
generated by vibration through liver (9–26.5 PELD systems are currently used to establish priority listing for liver
tissue kPa) transplantation in the United States. Convenient MELD and PELD cal-
ARFI Measures speed of shear wave >1.3 m/s >1.87 m/s culators are available via the Internet (https://optn.transplant.hrsa.gov/
generated by acoustic radiation force resources/allocation-calculators/about-meld-and-peld/).
through liver tissue
a
Patented models.
■■NONSPECIFIC ISSUES IN THE MANAGEMENT OF
Note: The cut points presented in the table were mostly derived from patients with
PATIENTS WITH LIVER DISEASE
chronic hepatitis C. The cut points for the noninvasive models and tests presented Specifics on the management of different forms of acute or chronic
in the table vary among different liver diseases and among patients with the same liver disease are supplied in subsequent chapters, but certain issues
disease among different populations. are applicable to any patient with liver disease. These issues include
Abbreviations: ALT, alanine aminotransferase; APRI, AST-to-platelet ratio; ARFI, advice regarding alcohol use, medication use, vaccination, and sur-
acoustic radiation force imaging; AST, aspartate aminotransferase; ELF, enhanced
liver fibrosis panel; γGT, γ-glutamyl transpeptidase; MMP-3, metalloproteinase-3; veillance for certain liver diseases and complications of liver disease.
TIMP-1, tissue inhibitor of metalloproteinase-1; TE, transient elastography. Alcohol should be used sparingly, if at all, by patients with liver

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 disease. Abstinence from alcohol should be encouraged for all patients aminotransferases, alkaline phosphatase, albumin, and prothrombin 2553
with alcohol-related liver disease, patients with cirrhosis, and patients time tests. When more than one of these tests provide abnormal find-
receiving interferon-based therapy for hepatitis B and during anti- ings or the findings are persistently abnormal on serial determinations,
viral therapy of hepatitis C. With regard to vaccinations, all patients the probability of liver disease is high. When all test results are normal,
with liver disease should receive hepatitis A vaccine, and those with the probability of missing occult liver disease is low.
risk factors should receive hepatitis B vaccine as well. Influenza and
pneumococcal vaccination should also be encouraged, with adher- Serum Bilirubin (See also Chap. 49) Bilirubin, a breakdown
ence to the recommendations of the Centers for Disease Control and product of the porphyrin ring of heme-containing proteins, is found in
Prevention (CDC). Patients with liver disease should exercise caution the blood in two fractions—conjugated and unconjugated. The uncon-
in using any medications other than those that are most necessary. jugated fraction, also termed the indirect fraction, is insoluble in water
Drug-induced hepatotoxicity can mimic many forms of liver disease and is bound to albumin in the blood. The conjugated (direct) bilirubin
and can cause exacerbations of chronic hepatitis and cirrhosis; drugs fraction is water-soluble and can therefore be excreted by the kidney.
should be suspected in any situation in which the cause of exacerbation Normal values of total serum bilirubin are reported between 1 and
is unknown. The CDC now recommends universal one-time testing for 1.5 mg/dL with 95% of a normal population falling between 0.2 and
hepatitis C virus among persons aged 18–79 years and screening of all 0.9 mg/dL. If the direct-acting fraction is <15% of the total, the biliru-
pregnant women during each pregnancy except in settings where the bin can be considered to all be indirect. The most frequently reported
prevalence of hepatitis C virus infection (hepatitis C virus RNA posi- upper limit of normal for conjugated bilirubin is 0.3 mg/dL.
tivity) is <0.1%. Finally, consideration should be given to surveillance Elevation of the unconjugated fraction of bilirubin is rarely due to
for complications of chronic liver disease such as variceal hemorrhage liver disease. An isolated elevation of unconjugated bilirubin is seen
and HCC. Cirrhosis warrants upper endoscopy to assess the presence primarily in hemolytic disorders and in a number of genetic conditions
of varices, and the patient should receive chronic therapy with beta such as Crigler-Najjar and Gilbert’s syndromes (Chap. 49). Isolated
blockers or should be offered endoscopic obliteration if large varices unconjugated hyperbilirubinemia (bilirubin elevated but <15% direct)
are found. Moreover, cirrhosis warrants screening and long-term sur- should prompt a workup for hemolysis (Fig. 337-1). In the absence of
veillance for development of HCC. While the optimal regimen for such hemolysis, an isolated, unconjugated hyperbilirubinemia in an other-
surveillance has not been established, an appropriate approach is US of wise healthy patient can be attributed to Gilbert’s syndrome, and no
the liver at 6- to 12-month intervals. further evaluation is required.
In contrast, conjugated hyperbilirubinemia almost always implies
■■FURTHER READING liver or biliary tract disease. The rate-limiting step in bilirubin metab-

CHAPTER 337 Evaluation of Liver Function

Friedman SL et al: Mechanisms of NAFLD development and thera- olism is not conjugation of bilirubin, but rather the transport of conju-
peutic strategies. Nat Med 24:908, 2018. gated bilirubin into the bile canaliculi. Thus, elevation of the conjugated
Seto WK et al: Chronic hepatitis B virus infection. Lancet 392:2313, fraction may be seen in any type of liver disease including fulminant
2018. liver failure. In most liver diseases, both conjugated and unconjugated
Spearman CW et al: Hepatitis C. Lancet 394:1451, 2019. fractions of the bilirubin tend to be elevated. Except in the presence of a
Tapper EB, Lok AS: Use of liver imaging and biopsy in clinical practice. purely unconjugated hyperbilirubinemia, fractionation of the bilirubin
N Engl J Med 377:756, 2017. is rarely helpful in determining the cause of jaundice.
Although the degree of elevation of the serum bilirubin has not been
critically assessed as a prognostic marker, it is important in a number of
conditions. In viral hepatitis, the higher the serum bilirubin, the greater
is the hepatocellular damage. Total serum bilirubin correlates with
poor outcomes in alcoholic hepatitis. It is also a critical component

337 Evaluation
Function
of Liver of the Model for End-Stage Liver Disease (MELD) score, a tool used
to estimate survival of patients with end-stage liver disease, prioritize
patients awaiting liver transplantation, and assess operative risk of
patients with cirrhosis. An elevated total serum bilirubin in patients
Emily D. Bethea, Daniel S. Pratt with drug-induced liver disease indicates more severe injury.
Unconjugated bilirubin always binds to albumin in the serum and is
not filtered by the kidney. Therefore, any bilirubin found in the urine
There are a number of tests that can be used to evaluate liver function. is conjugated bilirubin; the presence of bilirubinuria implies the pres-
These tests include biochemical tests, radiologic tests, and pathologic tests. ence of liver disease or obstructive jaundice. A urine dipstick test can
Serum biochemical tests, also commonly referred to as “liver func- theoretically give the same information as fractionation of the serum
tion tests,” can be used to (1) detect the presence of liver disease, (2) bilirubin. This test is almost 100% accurate. Phenothiazines may give
distinguish among different types of liver disorders, (3) gauge the a false-positive reading with the Ictotest tablet. In patients recovering
extent of known liver damage, and (4) follow the response to treatment. from jaundice, the urine bilirubin clears prior to the serum bilirubin.
However, serum biochemical tests have shortcomings. They lack sensi- Serum Enzymes The liver contains thousands of enzymes, some of
tivity and specificity; they can be normal in patients with serious liver which are also present in the serum in very low concentrations. These
disease and abnormal in patients with diseases that do not affect the enzymes have no known function in the serum and behave like other
liver. Liver tests rarely suggest a specific diagnosis; rather, they suggest serum proteins. They are distributed in the plasma and in interstitial
a general category of liver disease, such as hepatocellular or cholestatic, fluid and have characteristic half-lives, which are usually measured
which then further directs the evaluation. The liver carries out thou- in days. Very little is known about the catabolism of serum enzymes,
sands of biochemical functions, most of which cannot be easily mea- although they are probably cleared by cells in the reticuloendothe-
sured by blood tests. Laboratory tests measure only a limited number lial system. The elevation of a given enzyme activity in the serum is
of these functions. In fact, many tests, such as the aminotransferases thought to primarily reflect its increased rate of entrance into serum
and alkaline phosphatase, do not measure liver function at all. Rather, from damaged liver cells.
they detect liver cell damage or interference with bile flow. Thus, no Serum enzyme tests can be grouped into two categories: (1) enzymes
one biochemical test enables the clinician to accurately assess the liver’s whose elevation in serum reflects damage to hepatocytes and (2)
total functional capacity. enzymes whose elevation in serum reflects cholestasis.
To increase the sensitivity and the specificity of biochemical tests
in the detection of liver disease, it is best to use them as a battery. ENZYMES THAT REFLECT DAMAGE TO HEPATOCYTES The aminotrans-
Tests usually employed in clinical practice include the bilirubin, ferases (transaminases) are sensitive indicators of liver cell injury and

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 2554
Liver Tests

Isolated elevation Cholestatic pattern

of the bilirubin (see Table 337-1) Isolated elevation
of the alkaline
phosphatase
Review drugs
Ultrasound
Fractionate
bilirubin Ducts not Dilated ducts
dilated

>15% Direct <15% Direct Check AMA CT/MRCP/ERCP

AMA AMA positive
Dubin-Johnson or Evaluation for negative
Rotor syndrome hemolysis
ERCP/Liver Bx Liver Bx
W/U
W/U negative
positive
Fractionate the alkaline
Gilbert’s Hemolysis Hepatocellular phosphatase or check
syndrome pattern GGT or 5' nucleotidase
(see Table 337-1) to assess origin of
alkaline phosphatase
Review drug list
Hepatitis C antibody Alkaline phos.
Alkaline phos.
Hepatitis B surface Ag of bone origin
of liver origin
Iron, TIBC, ferritin
ANA, SPEP
Ceruloplasmin Ultrasound Bone Eval
(if patient <40) Review drug list
Ultrasound to look Check AMA
for fatty liver Ducts not dilated Dilated ducts
PART 10

W/U negative and/or AMA positive

R/O Celiac disease

Consider other Liver biopsy MRCP
nonhepatic cause
Disorders of the Gastrointestinal System

W/U negative
Consider liver biopsy

FIGURE 337-1 Algorithm for the evaluation of chronically abnormal liver tests. Ag, antigen; AMA, antimitochondrial antibody; ANA, antinuclear antibody; Bx, biopsy; CT,
computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; GGT, γ-glutamyl transpeptidase; MRCP, magnetic resonance cholangiopancreatography;
R/O, rule out; SPEP, serum protein electrophoresis; TIBC, total iron-binding capacity; W/U, workup.

are most helpful in recognizing acute hepatocellular diseases such as have shown that fatty liver disease is the most likely explanation. Strik-
hepatitis. They include aspartate aminotransferase (AST) and alanine ing elevations—that is, aminotransferases >1000 IU/L—occur almost
aminotransferase (ALT). AST is found in the liver, cardiac muscle, exclusively in disorders associated with extensive hepatocellular injury
skeletal muscle, kidneys, brain, pancreas, lungs, leukocytes, and ery- such as (1) viral hepatitis, (2) ischemic liver injury (prolonged hypoten-
throcytes in decreasing order of concentration. ALT is found primarily sion or acute heart failure), or (3) toxin- or drug-induced liver injury.
in the liver and is therefore a more specific indicator of liver injury. The The pattern of the aminotransferase elevation can be helpful diag-
aminotransferases are normally present in the serum in low concentra- nostically. In most acute hepatocellular disorders, the ALT is higher
tions. These enzymes are released into the blood in greater amounts than or equal to the AST. Whereas the AST:ALT ratio is typically <1
when there is damage to the liver cell membrane, resulting in increased in patients with chronic viral hepatitis and nonalcoholic fatty liver
permeability. Liver cell necrosis is not required for the release of the disease, a number of groups have noted that as cirrhosis develops, this
aminotransferases, and there is a poor correlation between the degree ratio rises to >1. An AST:ALT ratio >2:1 is suggestive, whereas a ratio
of liver cell damage and the level of the aminotransferases. Thus, the >3:1 is highly suggestive, of alcoholic liver disease. The AST in alco-
absolute elevation of the aminotransferases is of no prognostic signifi- holic liver disease is rarely >300 IU/L, and the ALT is often normal. A
cance in acute hepatocellular disorders. low level of ALT in the serum is due to an alcohol-induced deficiency
The normal range for aminotransferases varies widely among labo- of pyridoxal phosphate.
ratories, but generally ranges from 10 to 40 IU/L. The interlaboratory The aminotransferases are usually not greatly elevated in obstructive
variation in normal range is due to technical reasons; no reference stan- jaundice. One notable exception occurs during the acute phase of bil-
dards exist to establish upper limits of normal for ALT and AST. Some iary obstruction caused by the passage of a gallstone into the common
have recommended revisions of normal limits of the aminotransferases bile duct. In this setting, the aminotransferases can briefly be in the
to adjust for sex and body mass index, but others have noted the poten- 1000–2000 IU/L range. However, aminotransferase levels decrease
tial costs and unclear benefits of implementing this change. quickly, and the biochemical tests rapidly evolve into those typical of
Any type of liver cell injury can cause modest elevations in the cholestasis.
serum aminotransferases. Levels of up to 300 IU/L are nonspecific and ENZYMES THAT REFLECT CHOLESTASIS The activities of three
may be found in any type of liver disorder. Minimal ALT elevations in enzymes—alkaline phosphatase, 5′-nucleotidase, and γ-glutamyl
asymptomatic blood donors rarely indicate severe liver disease; studies transpeptidase (GGT)—are usually elevated in cholestasis. Alkaline

HPIM21e_Part10_p2381-p2670.indd 2554 20/01/22 10:04 PM

 phosphatase and 5′-nucleotidase are found in or near the bile cana- cause, as well as protein-losing enteropathies, nephrotic syndrome, and 2555
licular membrane of hepatocytes, whereas GGT is located in the chronic infections that are associated with prolonged increases in levels
endoplasmic reticulum and in bile duct epithelial cells. Reflecting its of cytokines that inhibit albumin synthesis, such as serum interleukin 1
more diffuse localization in the liver, GGT elevation in serum is less and/or tumor necrosis factor. Serum albumin should not be measured
specific for cholestasis than are elevations of alkaline phosphatase or 5′- to screen patients in whom there is no suspicion of liver disease. A
nucleotidase. Some have advocated the use of GGT to identify patients general medical clinic study of consecutive patients in whom no indi-
with occult alcohol use. Its lack of specificity makes its use in this set- cations were present for albumin measurement showed that although
ting questionable. 12% of patients had abnormal test results, the finding was of clinical
The normal serum alkaline phosphatase consists of many distinct importance in only 0.4%.
isoenzymes found in the liver, bone, placenta, and, less commonly, the
small intestine. Patients over age 60 can have a mildly elevated alkaline Serum Globulins Serum globulins are a group of proteins made
phosphatase (1–1.5 times normal), whereas individuals with blood up of γ globulins (immunoglobulins) produced by B lymphocytes and
types O and B can have an elevation of the serum alkaline phosphatase α and β globulins produced primarily in hepatocytes. γ Globulins are
after eating a fatty meal due to the influx of intestinal alkaline phos- increased in chronic liver disease, such as chronic hepatitis and cirrho-
phatase into the blood. It is also elevated in children and adolescents sis. In cirrhosis, the increased serum γ globulin concentration is due
undergoing rapid bone growth because of bone alkaline phosphatase to the increased synthesis of antibodies, some of which are directed
and late in normal pregnancies due to the influx of placental alkaline against intestinal bacteria. This occurs because the cirrhotic liver fails
phosphatase. to clear bacterial antigens that normally reach the liver through the
Elevation of liver-derived alkaline phosphatase is not totally specific hepatic circulation.
for cholestasis, and a less than threefold elevation can be seen in almost Increases in the concentration of specific isotypes of γ globulins
any type of liver disease. Alkaline phosphatase elevations greater than are often helpful in the recognition of certain chronic liver diseases.
four times normal occur primarily in patients with cholestatic liver Diffuse polyclonal increases in IgG levels are common in autoimmune
disorders, infiltrative liver diseases such as cancer and amyloidosis, hepatitis; increases >100% should alert the clinician to this possibility.
and bone conditions characterized by rapid bone turnover (e.g., Paget’s Increases in the IgM levels are common in primary biliary cholangitis,
disease). In bone diseases, the elevation is due to increased amounts of whereas increases in the IgA levels occur in alcoholic liver disease.
the bone isoenzymes. In liver diseases, the elevation is almost always
■■COAGULATION FACTORS
due to increased amounts of the liver isoenzyme.
With the exception of factor VIII, which is produced by vascular endo-
If an elevated serum alkaline phosphatase is the only abnormal
thelial cells, the blood clotting factors are made exclusively in hepato-

CHAPTER 337 Evaluation of Liver Function

finding in an apparently healthy person or if the degree of elevation is
cytes. Their serum half-lives are much shorter than albumin, ranging
higher than expected in the clinical setting, identification of the source
from 6 h for factor VII to 5 days for fibrinogen. Because of their rapid
of elevated isoenzymes is helpful (Fig. 330-1). This problem can be
turnover, measurement of the clotting factors is the single best acute
approached in two ways. First, and most precise, is the fractionation
measure of hepatic synthetic function and helpful in both diagnosis
of the alkaline phosphatase by electrophoresis. The second, best sub-
and assessing the prognosis of acute parenchymal liver disease. Useful
stantiated, and most available approach involves the measurement of
for this purpose is the serum prothrombin time, which collectively mea-
serum 5′-nucleotidase or GGT. These enzymes are rarely elevated in
sures factors II, V, VII, and X. Biosynthesis of factors II, VII, IX, and
conditions other than liver disease.
X depends on vitamin K. The international normalized ratio (INR) is
In the absence of jaundice or elevated aminotransferases, an elevated
used to express the degree of anticoagulation on warfarin therapy. The
alkaline phosphatase of liver origin often, but not always, suggests early
INR standardizes prothrombin time measurement according to the
cholestasis and, less often, hepatic infiltration by tumor or granulo-
characteristics of the thromboplastin reagent used in a particular lab,
mata. Other conditions that cause isolated elevations of the alkaline
which is expressed as an International Sensitivity Index (ISI); the ISI is
phosphatase include primary biliary cholangitis, sclerosing cholangitis,
then used in calculating the INR.
Hodgkin’s disease, diabetes, hyperthyroidism, congestive heart failure,
The prothrombin time may be elevated in hepatitis and cirrhosis as
and amyloidosis.
well as in disorders that lead to vitamin K deficiency such as obstruc-
The level of serum alkaline phosphatase elevation is not helpful
tive jaundice or fat malabsorption of any kind. Marked prolongation of
in distinguishing between intrahepatic and extrahepatic cholestasis.
the prothrombin time, >5 s above control and not corrected by paren-
There is essentially no difference among the values found in obstruc-
teral vitamin K administration, is a poor prognostic sign in acute viral
tive jaundice due to cancer, common duct stone, sclerosing cholangitis,
hepatitis and other acute and chronic liver diseases. The INR, along
or bile duct stricture. Values are similarly increased in patients with
with the total serum bilirubin and creatinine, are components of the
intrahepatic cholestasis due to drug-induced hepatitis, primary biliary
MELD score, which is used as a measure of hepatic decompensation
cholangitis, sepsis, rejection of transplanted livers, and, rarely, alcohol-
and to allocate organs for liver transplantation.
induced steatohepatitis. Values are also greatly elevated in hepatobil-
iary disorders seen in patients with AIDS (e.g., AIDS cholangiopathy ■■OTHER DIAGNOSTIC TESTS
due to cytomegalovirus or cryptosporidial infection and tuberculosis Although tests may direct the physician to a category of liver disease,
with hepatic involvement). additional biochemical testing, radiologic testing, and procedures are
often necessary to make the proper diagnosis, as shown in Fig. 337-1.
■■TESTS THAT MEASURE BIOSYNTHETIC The most commonly used ancillary tests are reviewed here, as are the
FUNCTION OF THE LIVER noninvasive tests available for assessing hepatic fibrosis.
Serum Albumin Serum albumin is synthesized exclusively by Ammonia Ammonia is produced in the body during normal
hepatocytes. Serum albumin has a long half-life: 18–20 days, with ~4% protein metabolism and by intestinal bacteria, primarily those in the
degraded per day. Because of this slow turnover, the serum albumin is colon. The liver plays a role in the detoxification of ammonia by con-
not a good indicator of acute or mild hepatic dysfunction; only minimal verting it to urea, which is excreted by the kidneys. Striated muscle also
changes in the serum albumin are seen in acute liver conditions such plays a role in detoxification of ammonia, where it is combined with
as viral hepatitis, drug-related hepatotoxicity, and obstructive jaundice. glutamic acid to form glutamine. Patients with advanced liver disease
In hepatitis, albumin levels <3 g/dL should raise the possibility of typically have significant muscle wasting, which likely contributes
chronic liver disease. Hypoalbuminemia is more common in chronic to hyperammonemia. Some physicians use the blood ammonia for
liver disorders such as cirrhosis and usually reflects severe liver damage detecting encephalopathy or for monitoring hepatic synthetic function,
and decreased albumin synthesis. However, hypoalbuminemia is not although its use for either of these indications has problems. There
specific for liver disease and may occur in protein malnutrition of any is very poor correlation between either the presence or the severity

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 2556
TABLE 337-1 Liver Test Patterns in Hepatobiliary Disorders
TYPE OF DISORDER BILIRUBIN AMINOTRANSFERASES ALKALINE PHOSPHATASE ALBUMIN PROTHROMBIN TIME
Hemolysis/Gilbert’s Normal to 86 μmol/L (5 mg/dL) Normal Normal Normal Normal
syndrome 85% due to indirect fractions
No bilirubinuria
Acute hepatocellular Both fractions may be elevated Elevated, often >500 IU, Normal to <3× normal Normal Usually normal. If >5× above
necrosis (viral, ischemic, Peak usually follows ALT > AST elevation control and not corrected
and drug- or toxin- aminotransferases by parenteral vitamin K,
induced hepatitis) suggests poor prognosis
Bilirubinuria
Chronic hepatocellular Both fractions may be elevated Elevated, but usually Normal to <3× normal Often Often prolonged
disorders Bilirubinuria <300 IU elevation decreased Fails to correct with
parenteral vitamin K
Alcoholic hepatitis, Both fractions may be elevated AST:ALT >2 suggests Normal to <3× normal Often Often prolonged
cirrhosis Bilirubinuria alcoholic hepatitis or elevation decreased Fails to correct with
cirrhosis parenteral vitamin K
Intra- and extrahepatic Both fractions may be elevated Normal to moderate Elevated, often >4× normal Normal, unless Normal
cholestasis (obstructive Bilirubinuria elevation elevation chronic If prolonged, will correct
jaundice) Rarely >500 IU with parenteral vitamin K
Infiltrative diseases Usually normal Normal to slight elevation Elevated, often >4× normal Normal Normal
(tumor, granulomata) elevation
Fractionate, or confirm liver
origin with 5′-nucleotidase or
γ-glutamyl transpeptidase
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.

of acute encephalopathy and elevation of blood ammonia; it can be has been shown to be accurate for identifying advanced fibrosis in
occasionally useful for identifying occult liver disease in patients with patients with chronic hepatitis C, primary biliary cholangitis, hemo-
PART 10

mental status changes. There is also a poor correlation of the blood chromatosis, nonalcoholic fatty liver disease, and recurrent chronic
serum ammonia and hepatic function. The ammonia can be elevated hepatitis after liver transplantation. MRE has been found to be superior
in patients with severe portal hypertension and portal blood shunting to TE for staging liver fibrosis in patients with a variety of chronic liver
around the liver even in the presence of normal or near-normal hepatic diseases but requires access to a magnetic resonance imaging scanner
function. Elevated arterial ammonia levels have been shown to cor- and is more expensive.
Disorders of the Gastrointestinal System

relate with outcome in fulminant hepatic failure.

Ultrasonography Ultrasonography is the first diagnostic test
Liver Biopsy Percutaneous biopsy of the liver is a safe procedure to use in patients whose liver tests suggest cholestasis, to look for
that is easily performed with local anesthesia and ultrasound the presence of a dilated intrahepatic or extrahepatic biliary tree or
guidance. Liver biopsy is of proven value in the following situations: to identify gallstones. In addition, it shows space-occupying lesions
(1) hepatocellular disease of uncertain cause, (2) prolonged hepatitis with within the liver, enables the clinician to distinguish between cystic and
the possibility of autoimmune hepatitis, (3) unexplained hepatomeg- solid masses, and helps direct percutaneous biopsies. Ultrasound with
aly, (4) unexplained splenomegaly, (5) hepatic lesions uncharacterized Doppler imaging can detect the patency of the portal vein, hepatic
by radiologic imaging, (6) fever of unknown origin, and (7) staging artery, and hepatic veins and determine the direction of blood flow.
of malignant lymphoma. Liver biopsy is most accurate in disorders This is the first test ordered in patients suspected of having Budd-Chiari
causing diffuse changes throughout the liver and is subject to sam- syndrome.
pling error in focal disorders. Liver biopsy should not be the initial
procedure in the diagnosis of cholestasis. The biliary tree should first ■■USE OF LIVER TESTS
be assessed for signs of obstruction. Contraindications to performing As previously noted, the best way to increase the sensitivity and spec-
a percutaneous liver biopsy include significant ascites and prolonged ificity of laboratory tests in the detection of liver disease is to employ
INR. Under these circumstances, the biopsy can be performed via the a battery of tests that includes the aminotransferases, alkaline phos-
transjugular approach. phatase, bilirubin, albumin, and prothrombin time along with the
judicious use of the other tests described in this chapter. Table 337-1
Noninvasive Tests to Detect Hepatic Fibrosis Although liver shows how patterns of liver tests can lead the clinician to a category
biopsy is the standard for the assessment of hepatic fibrosis, noninva- of disease that will direct further evaluation. However, it is important
sive measures of hepatic fibrosis have been developed and show prom- to remember that no single set of liver tests will necessarily provide a
ise. These measures include multiparameter tests aimed at detecting diagnosis. It is often necessary to repeat these tests on several occasions
and staging the degree of hepatic fibrosis and imaging techniques. over days to weeks for a diagnostic pattern to emerge. Figure 337-1 is
FibroTest (marketed as FibroSure in the United States) is the best an algorithm for the evaluation of chronically abnormal liver tests.
evaluated of the multiparameter blood tests. The test incorporates
haptoglobin, bilirubin, GGT, apolipoprotein A-I, and α2-macroglobulin ■■GLOBAL CONSIDERATIONS
and has been found to have high positive and negative predictive values The tests and principles presented in this chapter are applicable world-
for diagnosing advanced fibrosis in patients with chronic hepatitis C, wide. The causes of liver test abnormalities vary according to region. In
chronic hepatitis B, alcoholic liver disease, or nonalcoholic fatty liver developing nations, infectious diseases are more commonly the etiol-
disease and patients taking methotrexate for psoriasis. Transient elas- ogy of abnormal serum liver tests than in developed nations.
tography (TE), marketed as FibroScan, and magnetic resonance elas-
tography (MRE) both have gained U.S. Food and Drug Administration Acknowledgment
approval for use in the management of patients with liver disease. TE This chapter represents a revised version of a chapter in previous editions
uses ultrasound waves to measure hepatic stiffness noninvasively. TE of Harrison’s in which Marshall M. Kaplan was a co-author.

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 ■■FURTHER READING 3. Conjugation: Bilirubin is conjugated with one or two glucuronic 2557
Kamath PS, Kim WR: The Model for End-Stage Liver Disease acid moieties by a specific UDP-glucuronosyltransferase to form
(MELD). Hepatology 45:797, 2007. bilirubin mono- and diglucuronide, respectively. Conjugation dis-
Kaplan M: Alkaline phosphatase. Gastroenterology 62:452, 1972. rupts the internal hydrogen bonding that limits aqueous solubility
Martínez SM et al: Noninvasive assessment of liver fibrosis. Hepatol- of bilirubin, and the resulting glucuronide conjugates are highly
ogy 53:325, 2011. soluble in water. Conjugation is obligatory for excretion of bil-
Prati D et al: Updated definitions of healthy ranges for serum alanine irubin across the bile canalicular membrane into bile. The UDP-
aminotransferase levels. Ann Intern Med 137:1, 2002. glucuronosyltransferases have been classified into gene families
based on the degree of homology among the mRNAs for the various
isoforms. Those that conjugate bilirubin and certain other substrates
have been designated the UGT1 family. These are expressed from
a single gene complex by alternative promoter usage. This gene
complex contains multiple substrate-specific first exons, designated
A1, A2, etc. (Fig. 338-2), each with its own promoter and each

338 The Hyperbilirubinemias

Allan W. Wolkoff
encoding the amino-terminal half of a specific isoform. In addition,
there are four common exons (exons 2–5) that encode the shared
carboxyl-terminal half of all of the UGT1 isoforms. The various
first exons encode the specific aglycone substrate binding sites for
each isoform, while the shared exons encode the binding site for
■■BILIRUBIN METABOLISM the sugar donor, UDP-glucuronic acid, and the transmembrane
The details of bilirubin metabolism are presented in Chap. 49. How- domain. Exon A1 and the four common exons, collectively desig-
ever, the hyperbilirubinemias are best understood in terms of pertur- nated as the UGT1A1 gene (Fig. 338-2), encode the physiologically
bations of specific aspects of bilirubin metabolism and transport, and critical enzyme bilirubin-UDP-glucuronosyltransferase (UGT1A1).
these will be briefly reviewed here as depicted in Fig. 338-1. A functional corollary of the organization of the UGT1 gene is that
Bilirubin is the end product of heme degradation. Some 70–90% of a mutation in one of the first exons will affect only a single enzyme
bilirubin is derived from degradation of the hemoglobin of senescent isoform. By contrast, a mutation in exons 2–5 will alter all isoforms
red blood cells. Bilirubin produced in the periphery is transported to encoded by the UGT1 gene complex.
the liver within the plasma, where, due to its insolubility in aqueous 4. Biliary excretion: It has been thought until recently that bil-

CHAPTER 338 The Hyperbilirubinemias

solutions, it is tightly bound to albumin. Under normal circumstances, irubin mono- and diglucuronides are excreted directly across
bilirubin is removed from the circulation rapidly and efficiently by the canalicular plasma membrane into the bile canaliculus by
hepatocytes. Transfer of bilirubin from blood to bile involves four dis- an ATP-dependent transport process mediated by a canalicular
tinct but interrelated steps (Fig. 338-1). membrane protein called multidrug resistance–associated protein 2
(MRP2, ABCC2). Mutations of MRP2 result in the Dubin-Johnson
1. Hepatocellular uptake: Uptake of bilirubin by the hepatocyte has syndrome (see below). However, studies in patients with Rotor
carrier-mediated kinetics. Although a number of candidate bilirubin syndrome (see below) indicate that after formation, a portion of
transporters have been proposed, the identity of the actual trans- the glucuronides is transported into the portal circulation by a
porter remains elusive. sinusoidal membrane protein called multidrug resistance–associ-
2. Intracellular binding: Within the hepatocyte, bilirubin is kept in ated protein 3 (MRP3, ABCC3) and is subjected to reuptake into
solution by binding as a nonsubstrate ligand to several of the gluta- the hepatocyte by the sinusoidal membrane uptake transporters
thione-S-transferases, formerly called ligandins. organic anion transport protein 1B1 (OATP1B1, SLCO1B1) and
OATP1B3 (SLCO1B3).

■■EXTRAHEPATIC ASPECTS OF BILIRUBIN

DISPOSITION
OATP1B1
Bilirubin in the Gut Following secretion into bile, conjugated
ALB
OATP1B3 bilirubin reaches the duodenum and passes down the gastrointesti-
UCB
BMG UGT1A1 BMG nal tract without reabsorption by the intestinal mucosa. An appre-
BDG
MRP3
ciable fraction is converted by bacterial metabolism in the gut to
GST:UCB
UCB UGT1A1
BMG
the water-soluble colorless compound urobilinogen. Urobilinogen
MRP2
BDG undergoes enterohepatic cycling. Urobilinogen not taken up by the
BT UCB BDG liver reaches the systemic circulation, from which some is cleared by
+
ALB:UCB GST
the kidneys. Unconjugated bilirubin ordinarily does not reach the gut
except in neonates or, by ill-defined alternative pathways, in the pres-
Space ence of severe unconjugated hyperbilirubinemia (e.g., Crigler-Najjar
Sinusoid
of
Disse
syndrome, type I [CN-I]). Unconjugated bilirubin that reaches the gut
is partly reabsorbed, amplifying any underlying hyperbilirubinemia.
FIGURE 338-1 Hepatocellular bilirubin transport. Albumin-bound bilirubin in
sinusoidal blood passes through endothelial cell fenestrae to reach the hepatocyte
surface, entering the cell by both facilitated and simple diffusional processes.
Renal Excretion of Bilirubin Conjugates Unconjugated biliru-
Within the cell, it is bound to glutathione-S-transferases and conjugated by bin is not excreted in urine, as it is too tightly bound to albumin for
bilirubin-UDP-glucuronosyltransferase (UGT1A1) to mono- and diglucuronides, effective glomerular filtration and there is no tubular mechanism for its
which are actively transported across the canalicular membrane into the bile. In renal secretion. In contrast, the bilirubin conjugates are readily filtered
addition to this direct excretion of bilirubin glucuronides, a portion are transported at the glomerulus and can appear in urine in disorders characterized
into the portal circulation by MRP3 and subjected to reuptake into the hepatocyte by increased bilirubin conjugates in the circulation. It should be kept
by OATP1B1 and OATP1B3. ALB, albumin; BDG, bilirubin diglucuronide; BMG,
bilirubin monoglucuronide; BT, proposed bilirubin transporter; GST, glutathione-
in mind that the kidney can serve as an “overflow valve” for conjugated
S-transferase; MRP2 and MRP3, multidrug resistance–associated proteins 2 and bilirubin. Consequently, the level of jaundice in individuals with con-
3; OATP1B1 and OATP1B3, organic anion transport proteins 1B1 and 1B3; UCB, jugated hyperbilirubinemia can be amplified in the presence of renal
unconjugated bilirubin; UGT1A1, bilirubin-UDP-glucuronosyltransferase. failure.

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 2558 5′ 500 kb 3′ novobiocin, and rifampin, as well as var-
ious cholecystographic contrast agents,
Variable (Substrate Specific) First Exons Common Exons have been reported to inhibit biliru-
2 3 4 5 bin uptake. The resulting unconjugated
hyperbilirubinemia resolves with cessa-
tion of the medication.
A13 A12 A11 A10 A9 A8 A7 A6 A5 A4 A3 A2 A1 Impaired Conjugation • PHYSIO-
LOGIC NEONATAL JAUNDICE Bilirubin
~286 AA ~245 AA produced by the fetus is cleared by the
A(TA)6TAA placenta and eliminated by the mater-
nal liver. Immediately after birth, the
TATA Box
neonatal liver must assume responsi-
FIGURE 338-2 Structural organization of the human UGT1 gene complex. This large complex on chromosome 2 contains bility for bilirubin clearance and excre-
at least 13 substrate-specific first exons (A1, A2, etc.). Since four of these are pseudogenes, nine UGT1 isoforms with tion. However, many hepatic physiologic
differing substrate specificities are expressed. Each exon 1 has its own promoter and encodes the amino-terminal
substrate-specific ∼286 amino acids of the various UGT1-encoded isoforms, and common exons 2–5 encode the 245 processes are incompletely developed at
carboxyl-terminal amino acids common to all of the isoforms. mRNAs for specific isoforms are assembled by splicing a birth. Levels of UGT1A1 are low, and
particular first exon such as the bilirubin-specific exon A1 to exons 2 to 5. The resulting message encodes a complete alternative excretory pathways allow pas-
enzyme, in this particular case, bilirubin-UDP-glucuronosyltransferase (UGT1A1). Mutations in a first exon affect only a sage of unconjugated bilirubin into the
single isoform. Those in exons 2–5 affect all enzymes encoded by the UGT1 complex. gut. Since the intestinal flora that con-
vert bilirubin to urobilinogen are also
DISORDERS OF BILIRUBIN METABOLISM undeveloped, an enterohepatic circulation of unconjugated bilirubin
LEADING TO UNCONJUGATED ensues. As a consequence, most neonates develop mild unconjugated
hyperbilirubinemia between days 2 and 5 after birth. Peak levels are
HYPERBILIRUBINEMIA typically <85–170 μmol/L (5–10 mg/dL) and decline to normal adult
■■INCREASED BILIRUBIN PRODUCTION concentrations within 2 weeks, as mechanisms required for bilirubin
disposition mature. Prematurity, often associated with more profound
Hemolysis Increased destruction of erythrocytes leads to increased immaturity of hepatic function and hemolysis, can result in higher lev-
bilirubin turnover and unconjugated hyperbilirubinemia; the hyperbi- els of unconjugated hyperbilirubinemia. A rapidly rising unconjugated
lirubinemia is usually modest in the presence of normal liver function. bilirubin concentration, or absolute levels >340 μmol/L (20 mg/dL),
PART 10

In particular, the bone marrow is only capable of a sustained eightfold puts the infant at risk for bilirubin encephalopathy, or kernicterus.
increase in erythrocyte production in response to a hemolytic stress. Under these circumstances, bilirubin crosses an immature blood-brain
Therefore, hemolysis alone cannot result in a sustained hyperbiliru- barrier and precipitates in the basal ganglia and other areas of the
binemia of more than ∼68 μmol/L (4 mg/dL). Higher values imply con- brain. The consequences range from appreciable neurologic deficits to
Disorders of the Gastrointestinal System

comitant hepatic dysfunction. When hemolysis is the only abnormality death. Treatment options include phototherapy, which converts biliru-
in an otherwise healthy individual, the result is a purely unconjugated bin into water-soluble photoisomers that are excreted directly into bile,
hyperbilirubinemia, with the direct-reacting fraction as measured in a and exchange transfusion. The canalicular mechanisms responsible for
typical clinical laboratory being ≤15% of the total serum bilirubin. In bilirubin excretion are also immature at birth, and their maturation
the presence of systemic disease, which may include a degree of hepatic may lag behind that of UGT1A1; this can lead to transient conjugated
dysfunction, hemolysis may produce a component of conjugated neonatal hyperbilirubinemia, especially in infants with hemolysis.
hyperbilirubinemia in addition to an elevated unconjugated bilirubin ACQUIRED CONJUGATION DEFECTS A modest reduction in bilirubin
concentration. Prolonged hemolysis may lead to the precipitation of conjugating capacity may be observed in advanced hepatitis or cirrho-
bilirubin salts within the gallbladder or biliary tree, resulting in the for- sis. However, in this setting, conjugation is better preserved than other
mation of gallstones in which bilirubin, rather than cholesterol, is the aspects of bilirubin disposition, such as canalicular excretion. Various
major component. Such pigment stones may lead to acute or chronic drugs, including pregnanediol, novobiocin, chloramphenicol, gentami-
cholecystitis, biliary obstruction, or any other biliary tract consequence cin, and atazanavir, may produce unconjugated hyperbilirubinemia by
of calculous disease. inhibiting UGT1A1 activity. Bilirubin conjugation may be inhibited
Ineffective Erythropoiesis During erythroid maturation, small by certain fatty acids that are present in breast milk, but not serum,
amounts of hemoglobin may be lost at the time of nuclear extrusion, of mothers whose infants have excessive neonatal hyperbilirubinemia
and a fraction of developing erythroid cells is destroyed within the (breast milk jaundice). Alternatively, there may be increased entero-
marrow. These processes normally account for a small proportion of hepatic circulation of bilirubin in these infants. The pathogenesis of
bilirubin that is produced. In various disorders, including thalassemia breast milk jaundice appears to differ from that of transient familial
major, megaloblastic anemias due to folate or vitamin B12 deficiency, neonatal hyperbilirubinemia (Lucey-Driscoll syndrome), in which
congenital erythropoietic porphyria, lead poisoning, and various there may be a UGT1A1 inhibitor in maternal serum.
congenital and acquired dyserythropoietic anemias, the fraction of
total bilirubin production derived from ineffective erythropoiesis is ■■HEREDITARY DEFECTS IN BILIRUBIN
increased, reaching as much as 70% of the total. This may be sufficient CONJUGATION
to produce modest degrees of unconjugated hyperbilirubinemia. Three familial disorders characterized by differing degrees of uncon-
Miscellaneous Degradation of the hemoglobin of extravascu- jugated hyperbilirubinemia have long been recognized. The defining
lar collections of erythrocytes, such as those seen in massive tissue clinical features of each are described below (Table 338-1). While these
infarctions or large hematomas, may lead transiently to unconjugated disorders have been recognized for decades to reflect differing degrees
hyperbilirubinemia. of deficiency in the ability to conjugate bilirubin, recent advances in
the molecular biology of the UGT1 gene complex have elucidated their
■■DECREASED HEPATIC BILIRUBIN CLEARANCE interrelationships and clarified previously puzzling features.
Decreased Hepatic Uptake Decreased hepatic bilirubin uptake Crigler-Najjar Syndrome, Type I CN-I is characterized by strik-
is believed to contribute to the unconjugated hyperbilirubinemia of ing unconjugated hyperbilirubinemia of ∼340–765 μmol/L (20–45 mg/
Gilbert’s syndrome (GS), although the molecular basis for this finding dL) that appears in the neonatal period and persists for life. Other con-
remains unclear (see below). Several drugs, including flavaspidic acid, ventional hepatic biochemical tests such as serum aminotransferases

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 2559
TABLE 338-1 Principal Differential Characteristics of Gilbert and Crigler-Najjar Syndromes
CRIGLER-NAJJAR SYNDROME
FEATURE TYPE I TYPE II GILBERT SYNDROME
Total serum bilirubin, μmol/L (mg/dL) 310–755 (usually >345) (18–45 100–430 (usually ≤345) (6–25 [usually Typically ≤70 μmol/L (≤4 mg/dL) in
[usually >20]) ≤20]) absence of fasting or hemolysis
Routine liver tests Normal Normal Normal
Response to phenobarbital None Decreases bilirubin by >25% Decreases bilirubin to normal
Kernicterus Usual Rare No
Hepatic histology Normal Normal Usually normal; increased lipofuscin
pigment in some
Bile characteristics
Color Pale or colorless Pigmented Normal dark color
Bilirubin fractions >90% unconjugated Largest fraction (mean: 57%) Mainly diconjugates but
monoconjugates monoconjugates increased (mean: 23%)
Bilirubin UDP-glucuronosyltransferase Typically absent; traces in some Markedly reduced: 0–10% of normal Reduced: typically 10–33% of normal
activity patients Promoter mutation: recessive
Inheritance (all autosomal) Recessive Predominantly recessive Missense mutations: 7 of 8 dominant;
1 reportedly recessive

and alkaline phosphatase are normal, and there is no evidence of bilirubin concentrations are lower in CN-II; (2) accordingly, CN-II is
hemolysis. Hepatic histology is also essentially normal except for the only infrequently associated with kernicterus; (3) bile is deeply colored,
occasional presence of bile plugs within canaliculi. Bilirubin glucu- and bilirubin glucuronides are present, with a striking, characteristic
ronides are virtually absent from the bile, and there is no detectable increase in the proportion of monoglucuronides; (4) UGT1A1 in liver
constitutive expression of UGT1A1 activity in hepatic tissue. Neither is usually present at reduced levels (typically ≤10% of normal); and (5)
UGT1A1 activity nor the serum bilirubin concentration responds to while typically detected in infancy, hyperbilirubinemia was not recog-

CHAPTER 338 The Hyperbilirubinemias

administration of phenobarbital or other enzyme inducers. Unconju- nized in some cases until later in life and, in one instance, at age 34. As
gated bilirubin accumulates in plasma, from which it is eliminated very with CN-I, most CN-II cases exhibit abnormalities in the conjugation
slowly by alternative pathways that include direct passage into the bile of other compounds, such as salicylamide and menthol, but in some
and small intestine, possibly via bilirubin photoisomers. This accounts instances, the defect appears limited to bilirubin. Reduction of serum
for the small amount of urobilinogen found in feces. No bilirubin is bilirubin concentrations by >25% in response to enzyme inducers
found in the urine. First described in 1952, the disorder is rare (esti- such as phenobarbital distinguishes CN-II from CN-I, although this
mated prevalence, 0.6–1.0 per million). Many patients are from geo- response may not be elicited in early infancy and often is not accom-
graphically or socially isolated communities in which consanguinity is panied by measurable UGT1A1 induction. Bilirubin concentrations
common, and pedigree analyses show an autosomal recessive pattern during phenobarbital administration do not return to normal but are
of inheritance. The majority of patients (type IA) exhibit defects in typically in the range of 51–86 μmol/L (3–5 mg/dL). Although the
the glucuronide conjugation of a spectrum of substrates in addition to incidence of kernicterus in CN-II is low, instances have occurred, not
bilirubin, including various drugs and other xenobiotics. These indi- only in infants but also in adolescents and adults, often in the setting
viduals have mutations in one of the common exons (2–5) of the UGT1 of an intercurrent illness, fasting, or another factor that temporarily
gene (Fig. 338-2). In a smaller subset (type IB), the defect is limited raises the serum bilirubin concentration above baseline and reduces
largely to bilirubin conjugation, and the causative mutation is in the serum albumin levels. For this reason, phenobarbital therapy is widely
bilirubin-specific exon A1. Estrogen glucuronidation is mediated by recommended, a single bedtime dose often sufficing to maintain clini-
UGT1A1 and is defective in all CN-I patients. More than 30 different cally safe serum bilirubin concentrations.
genetic lesions of UGT1A1 responsible for CN-I have been identified, Over 100 different mutations in the UGT1 gene have been identi-
including deletions, insertions, alterations in intron splice donor and fied as causing CN-I or CN-II. It was found that missense mutations
acceptor sites, exon skipping, and point mutations that introduce are more common in CN-II patients, as would be expected in this
premature stop codons or alter critical amino acids. Their common less severe phenotype. Their common feature is that they encode for
feature is that they all encode proteins with absent or, at most, traces of a bilirubin-UDP-glucuronosyltransferase with markedly reduced, but
bilirubin-UDP-glucuronosyltransferase enzymatic activity. detectable, enzymatic activity. The spectrum of residual enzyme activ-
Prior to the use of phototherapy, most patients with CN-I died of ity explains the spectrum of phenotypic severity of the resulting hyper-
bilirubin encephalopathy (kernicterus) in infancy or early childhood. bilirubinemia. Molecular analysis has established that a large majority
A few lived as long as early adult life without overt neurologic damage, of CN-II patients are either homozygotes or compound heterozygotes
although more subtle testing usually indicated mild but progressive for CN-II mutations and that individuals carrying one mutated and
brain damage. In the absence of liver transplantation, death eventually one entirely normal allele have normal bilirubin concentrations.
supervened from late-onset bilirubin encephalopathy, which often fol-
lowed a nonspecific febrile illness. Although isolated hepatocyte trans- Gilbert Syndrome This syndrome is characterized by mild uncon-
plantation has been used in a small number of cases of CN-I, early liver jugated hyperbilirubinemia, normal values for standard hepatic bio-
transplantation (Chap. 345) remains the best hope to prevent brain chemical tests, and normal hepatic histology other than a modest
injury and death at present. It is anticipated that gene replacement increase of lipofuscin pigment in some patients. Serum bilirubin
therapy may be an option in the future. concentrations are most often <51 μmol/L (<3 mg/dL), although
both higher and lower values are frequent. The clinical spectrum of
Crigler-Najjar Syndrome, Type II (CN-II) This condition hyperbilirubinemia fades into that of CN-II at serum bilirubin concen-
was recognized as a distinct entity in 1962 and is characterized by trations of 86–136 μmol/L (5–8 mg/dL). At the other end of the scale,
marked unconjugated hyperbilirubinemia in the absence of abnor- the distinction between mild cases of GS and a normal state is often
malities of other conventional hepatic biochemical tests, hepatic blurred. Bilirubin concentrations may fluctuate substantially in any
histology, or hemolysis. It differs from CN-I in several specific ways given individual, and at least 25% of patients will exhibit temporarily
(Table 338-1): (1) although there is considerable overlap, average normal values during prolonged follow-up. More elevated values are

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 2560 associated with stress, fatigue, alcohol use, reduced caloric intake, to those homozygous for the normal A[TA]6TAA allele. The prevalence
and intercurrent illness, while increased caloric intake or adminis- of the A[TA]7TAA allele in a general Western population is 30%, in
tration of enzyme-inducing agents produces lower bilirubin levels. which case 9% would be homozygotes. This is slightly higher than
GS is most often diagnosed at or shortly after puberty or in adult life the prevalence of GS based on purely phenotypic parameters. It was
during routine examinations that include multichannel biochemical suggested that additional variables, such as mild hemolysis or a defect
analyses. UGT1A1 activity is typically reduced to 10–35% of normal, in bilirubin uptake, might be among the factors enhancing phenotypic
and bile pigments exhibit a characteristic increase in bilirubin monog- expression of the defect.
lucuronides. Studies of radiobilirubin kinetics indicate that hepatic Phenotypic expression of GS due solely to the A[TA]7TAA promoter
bilirubin clearance is reduced to an average of one-third of normal. abnormality is inherited as an autosomal recessive trait. A number of
Administration of phenobarbital normalizes both the serum biliru- CN-II kindreds have been identified in whom there is also an allele
bin concentration and hepatic bilirubin clearance; however, failure containing a normal coding region but the A[TA]7TAA promoter
of UGT1A1 activity to improve in many such instances suggests the abnormality. CN-II heterozygotes, who have the A[TA]6TAA pro-
possible coexistence of an additional defect. Compartmental analysis moter, are phenotypically normal, whereas those with the A[TA]7TAA
of bilirubin kinetic data suggests that GS patients may have a defect in promoter express the phenotypic picture of GS. GS in such kindreds
bilirubin uptake as well as in conjugation, although this has not been may also result from homozygosity for the A[TA]7TAA promoter
shown directly. Defects in the hepatic uptake of other organic anions abnormality. Seven different missense mutations in the UGT1 gene
that at least partially share an uptake mechanism with bilirubin, such that reportedly cause GS with dominant inheritance have been found
as sulfobromophthalein and indocyanine green (ICG), are observed in Japanese individuals. Another Japanese patient with mild unconju-
in a minority of patients. The metabolism and transport of bile acids gated hyperbilirubinemia was homozygous for a missense mutation in
that do not utilize the bilirubin uptake mechanism are normal. The exon 5. GS in her family appeared to be recessive.
magnitude of changes in the serum bilirubin concentration induced
by provocation tests such as 48 h of fasting or the IV administration DISORDERS OF BILIRUBIN METABOLISM
of nicotinic acid has been reported to be of help in separating GS LEADING TO MIXED OR PREDOMINANTLY
patients from normal individuals. Other studies dispute this assertion. CONJUGATED HYPERBILIRUBINEMIA
Moreover, on theoretical grounds, the results of such studies should In hyperbilirubinemia due to acquired liver disease (e.g., acute hep-
provide no more information than simple measurements of the base- atitis, common bile duct stone), there are usually elevations in the
line serum bilirubin concentration. Family studies indicate that GS serum concentrations of both conjugated and unconjugated bilirubin.
and hereditary hemolytic anemias such as hereditary spherocytosis, Although biliary tract obstruction or hepatocellular cholestatic injury
glucose-6-phosphate dehydrogenase deficiency, and β-thalassemia trait may present on occasion with a predominantly conjugated hyperbi-
PART 10

sort independently. Reports of hemolysis in up to 50% of GS patients lirubinemia, it is generally not possible to differentiate intrahepatic
are believed to reflect better case finding, since patients with both GS from extrahepatic causes of jaundice based on the serum levels or
and hemolysis have higher bilirubin concentrations and are more likely relative proportions of unconjugated and conjugated bilirubin. The
to be jaundiced than patients with either defect alone. major reason for determining the amounts of conjugated and uncon-
GS is common, with many series placing its prevalence as high jugated bilirubin in the serum is for the initial differentiation of
Disorders of the Gastrointestinal System

as 8%. Males predominate over females by reported ratios ranging hepatic parenchymal and obstructive disorders (mixed conjugated and
from 1.5:1 to >7:1. However, these ratios may have a large artifactual unconjugated hyperbilirubinemia) from the inheritable and hemo-
component since normal males have higher mean bilirubin levels than lytic disorders discussed above that are associated with unconjugated
normal females, but the diagnosis of GS is often based on comparison hyperbilirubinemia.
to normal ranges established in men. The high prevalence of GS in the
general population may explain the reported frequency of mild uncon- ■■FAMILIAL DEFECTS IN HEPATIC
jugated hyperbilirubinemia in liver transplant recipients. The disposi- EXCRETORY FUNCTION
tion of most xenobiotics metabolized by glucuronidation appears to
be normal in GS, as is oxidative drug metabolism in the majority of Dubin-Johnson Syndrome (DJS) This benign, relatively rare
reported studies. The principal exception is the metabolism of the anti- disorder is characterized by low-grade, predominantly conjugated
tumor agent irinotecan (CPT-11), whose active metabolite (SN-38) is hyperbilirubinemia (Table 338-2). Total bilirubin concentrations are
glucuronidated specifically by bilirubin-UDP-glucuronosyltransferase. typically between 34 and 85 μmol/L (2 and 5 mg/dL) but on occasion
Administration of CPT-11 to patients with GS has resulted in several can be in the normal range or as high as 340–430 μmol/L (20–25 mg/dL)
toxicities, including intractable diarrhea and myelosuppression. Some and can fluctuate widely in any given patient. The degree of hyper-
reports also suggest abnormal disposition of menthol, estradiol ben- bilirubinemia may be increased by intercurrent illness, oral contra-
zoate, acetaminophen, tolbutamide, and rifamycin SV. Although some ceptive use, and pregnancy. Because the hyperbilirubinemia is due to
of these studies have been disputed, and there have been no reports of a predominant rise in conjugated bilirubin, bilirubinuria is charac-
clinical complications from use of these agents in GS, prudence should teristically present. Aside from elevated serum bilirubin levels, other
be exercised in prescribing them or any agents metabolized primarily routine laboratory tests are normal. Physical examination is usually
by glucuronidation in this condition. It should also be noted that the normal except for jaundice, although an occasional patient may have
HIV protease inhibitors indinavir and atazanavir (Chap. 202) can hepatosplenomegaly.
inhibit UGT1A1, resulting in hyperbilirubinemia that is most pro- Patients with DJS are usually asymptomatic, although some may
nounced in patients with preexisting GS. have vague constitutional symptoms. These latter patients have usually
Most older pedigree studies of GS were consistent with autosomal undergone extensive diagnostic examinations for unexplained jaun-
dominant inheritance with variable expressivity. However, studies of dice and have high levels of anxiety. In women, the condition may be
the UGT1 gene in GS have indicated a variety of molecular genetic subclinical until the patient becomes pregnant or receives oral contra-
bases for the phenotypic picture and several different patterns of ceptives, at which time chemical hyperbilirubinemia becomes frank
inheritance. Studies in Europe and the United States found that nearly jaundice. Even in these situations, other routine liver function tests,
all patients had normal coding regions for UGT1A1 but were homozy- including serum alkaline phosphatase and transaminase activities, are
gous for the insertion of an extra TA (i.e., A[TA]7TAA rather than normal.
A[TA]6TAA) in the promoter region of the first exon. This appeared A cardinal feature of DJS is the accumulation of dark, coarsely gran-
to be necessary, but not sufficient, for clinically expressed GS, since ular pigment in the lysosomes of centrilobular hepatocytes. As a result,
15% of normal controls were also homozygous for this variant. While the liver may be grossly black in appearance. This pigment is thought
normal by standard criteria, these individuals had somewhat higher to be derived from epinephrine metabolites that are not excreted nor-
bilirubin concentrations than the rest of the controls studied. Hete- mally. The pigment may disappear during bouts of viral hepatitis, only
rozygotes for this abnormality had bilirubin concentrations identical to reaccumulate slowly after recovery.

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 2561
TABLE 338-2 Principal Differential Characteristics of Inheritable Disorders of Bile Canalicular Function
DJS ROTOR PFIC1 BRIC1 PFIC2 BRIC2 PFIC3
Gene ABCCA SLCO1B1/SLCO1B3 ATP8B1 ATP8B1 ABCB11 ABCB11 ABCB4
Protein MRP2 OATP1B1/1B3 FIC1 FIC1 BSEP BSEP MDR3
Cholestasis No No Yes Episodic Yes Episodic Yes
Serum GGT Normal Normal Normal Normal Normal Normal ↑↑
Serum bile Normal Normal ↑↑ ↑↑ during ↑↑ ↑↑ during ↑↑
acids episodes episodes
Clinical Mild conjugated Mild conjugated Severe cholestasis Recurrent Severe cholestasis Recurrent Severe
features hyperbilirubinemia; hyperbilirubinemia; beginning in episodes of beginning in episodes of cholestasis
otherwise, normal liver otherwise, normal childhood cholestasis childhood cholestasis beginning in
function; dark pigment liver function; liver beginning at any beginning at any childhood;
in liver; characteristic without abnormal age age decreased
pattern of urinary pigmentation phospholipids
coproporphyrins in bile
Abbreviations: BRIC, benign recurrent intrahepatic cholestasis; BSEP, bile salt excretory protein; DJS, Dubin-Johnson syndrome; GGT, γ-glutamyl transferase; MRP2,
multidrug resistance–associated protein 2; OATP1A/1B, organic anion transport proteins 1B1 and 1B3; PFIC, progressive familial intrahepatic cholestasis; ↑↑, increased.

Biliary excretion of a number of anionic compounds is compro- DJS. Although the fraction of coproporphyrin I in urine is elevated, it
mised in DJS. These include various cholecystographic agents, as is usually <70% of the total, compared with ≥80% in DJS. The disorders
well as sulfobromophthalein (Bromsulphalein [BSP]), a synthetic also can be distinguished by their patterns of BSP excretion. Although
dye formerly used in a test of liver function. In this test, the rate of clearance of BSP from plasma is delayed in RS, there is no reflux of
disappearance of BSP from plasma was determined following bolus conjugated BSP back into the circulation as seen in DJS. Kinetic anal-
IV administration. BSP is conjugated with glutathione in the hepato- ysis of plasma BSP infusion studies suggests the presence of a defect
cyte; the resulting conjugate is normally excreted rapidly into the bile in intrahepatocellular storage of this compound. This has never been
canaliculus. Patients with DJS exhibit characteristic rises in plasma demonstrated directly. Recent studies indicate that the molecular
concentrations at 90 min after injection, due to reflux of conjugated basis of RS results from simultaneous deficiency of the hepatocyte

CHAPTER 338 The Hyperbilirubinemias

BSP into the circulation from the hepatocyte. Dyes such as ICG that plasma membrane transporters OATP1B1 (SLCO1B1) and OATP1B3
are taken up by hepatocytes but are not further metabolized prior to (SLCO1B3). This results in reduced reuptake by these transporters of
biliary excretion do not show this reflux phenomenon. Continuous conjugated bilirubin that has been pumped out of the hepatocyte into
BSP infusion studies suggest a reduction in the time to maximum the portal circulation by MRP3 (ABCC3) (Fig. 338-1).
plasma concentration (tmax) for biliary excretion. Bile acid disposition,
including hepatocellular uptake and biliary excretion, is normal in DJS. Benign Recurrent Intrahepatic Cholestasis (BRIC) This
These patients have normal serum and biliary bile acid concentrations rare disorder is characterized by recurrent attacks of pruritus and
and do not have pruritus. jaundice. The typical episode begins with mild malaise and elevations
By analogy with findings in several mutant rat strains, the selective in serum aminotransferase levels, followed rapidly by rises in alkaline
defect in biliary excretion of bilirubin conjugates and certain other phosphatase and conjugated bilirubin and onset of jaundice and itch-
classes of organic compounds, but not of bile acids, that characterizes ing. The first one or two episodes may be misdiagnosed as acute viral
DJS in humans was found to reflect defective expression of MRP2 hepatitis. The cholestatic episodes, which may begin in childhood
(ABCC2), an ATP-dependent canalicular membrane transporter. Sev- or adulthood, can vary in duration from several weeks to months,
eral different mutations in the ABCC2 gene produce the Dubin-Johnson followed by a complete clinical and biochemical resolution. Intervals
phenotype, which has an autosomal recessive pattern of inheritance. between attacks may vary from several months to years. Between
Although MRP2 is undoubtedly important in the biliary excretion of episodes, physical examination is normal, as are serum levels of bile
conjugated bilirubin, the fact that this pigment is still excreted in the acids, bilirubin, transaminases, and alkaline phosphatase. The disorder
absence of MRP2 suggests that other, as yet uncharacterized, transport is familial and has an autosomal recessive pattern of inheritance. BRIC
proteins may serve in a secondary role in this process. is considered a benign disorder in that it does not lead to cirrhosis or
Patients with DJS also have a diagnostic abnormality in urinary end-stage liver disease. However, the episodes of jaundice and pruritus
coproporphyrin excretion. There are two naturally occurring copro- can be prolonged and debilitating, and some patients have undergone
porphyrin isomers, I and III. Normally, ∼75% of the coproporphyrin liver transplantation to relieve the intractable and disabling symptoms.
in urine is isomer III. In urine from DJS patients, total coproporphy- Treatment during the cholestatic episodes is symptomatic; there is no
rin content is normal, but >80% is isomer I. Heterozygotes for the specific treatment to prevent or shorten the occurrence of episodes.
syndrome show an intermediate pattern. The molecular basis for this A gene termed FIC1 was recently identified and found to be mutated
phenomenon remains unclear. in patients with BRIC. Curiously, this gene is expressed strongly in
the small intestine but only weakly in the liver. The protein encoded
Rotor Syndrome (RS) This benign, autosomal recessive disorder by FIC1 shows little similarity to those that have been shown to play
is clinically similar to DJS (Table 338-2), although it is seen even less a role in bile canalicular excretion of various compounds. Rather, it
frequently. A major phenotypic difference is that the liver in patients appears to be a member of a P-type ATPase family that transports
with RS has no increased pigmentation and appears totally normal. aminophospholipids from the outer to the inner leaflet of a variety of
The only abnormality in routine laboratory tests is an elevation of total cell membranes. Its relationship to the pathobiology of this disorder
serum bilirubin, due to a predominant rise in conjugated bilirubin. remains unclear. A second phenotypically identical form of BRIC,
This is accompanied by bilirubinuria. Several additional features differ- termed BRIC type 2, has been described resulting from mutations in
entiate RS from DJS. In RS, the gallbladder is usually visualized on oral the bile salt excretory protein (BSEP), the protein that is defective in
cholecystography, in contrast to the nonvisualization that is typical of progressive familial intrahepatic cholestasis (PFIC) type 2 (Table 338-2).
DJS. The pattern of urinary coproporphyrin excretion also differs. The How some mutations in this protein result in the episodic BRIC phe-
pattern in RS resembles that of many acquired disorders of hepatobil- notype is unknown.
iary function, in which coproporphyrin I, the major coproporphyrin
isomer in bile, refluxes from the hepatocyte back into the circulation Progressive Familial Intrahepatic Cholestasis This name is
and is excreted in urine. Thus, total urinary coproporphyrin excretion applied to three phenotypically related syndromes (Table 338-2). PFIC
is substantially increased in RS, in contrast to the normal levels seen in type 1 (Byler’s disease) presents in early infancy as cholestasis that

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 2562 may be initially episodic. However, in contrast to BRIC, Byler’s disease replicates like a retrovirus. Although these agents can be distinguished
progresses to malnutrition, growth retardation, and end-stage liver dis- by their molecular and antigenic properties, all types of viral hepatitis
ease during childhood. This disorder is also a consequence of an FIC1 produce clinically similar illnesses. These range from asymptomatic
mutation. The functional relationship of the FIC1 protein to the patho- and inapparent to fulminant and fatal acute infections common to all
genesis of cholestasis in these disorders is unknown. Two other types types, on the one hand, and from subclinical persistent infections to
of PFIC (types 2 and 3) have been described. PFIC type 2 is associated rapidly progressive chronic liver disease with cirrhosis and even hepa-
with a mutation in the protein originally named sister of P-glycoprotein, tocellular carcinoma, common to the bloodborne types (HBV, HCV,
now known as bile salt excretory protein (BSEP, ABCB11), which is and HDV), on the other.
the major bile canalicular exporter of bile acids. As noted above, some
mutations of this protein are associated with BRIC type 2, rather than ■■VIROLOGY AND ETIOLOGY
the PFIC type 2 phenotype. PFIC type 3 has been associated with a Hepatitis A HAV is a nonenveloped 27-nm, heat-, acid-, and ether-
mutation of MDR3 (ABCB4), a protein that is essential for normal resistant, single-stranded, positive-sense RNA virus in the Hepatovirus
hepatocellular excretion of phospholipids across the bile canaliculus. genus of the picornavirus family (Fig. 339-1). Quasi-enveloped virus
Although all three types of PFIC have similar clinical phenotypes, only particles encased in host plasma membrane–derived membranous ves-
type 3 is associated with high serum levels of γ-glutamyl transferase icles circulate in the bloodstream. The virion contains four structural
(GGT) activity. In contrast, activity of this enzyme is normal or only capsid polypeptides, designated VP1–VP4, as well as six nonstructural
mildly elevated in symptomatic BRIC and PFIC types 1 and 2. Interest- proteins, which are cleaved posttranslationally from the polyprotein
ingly, mutations in FIC1 or BSEP are not found in approximately one- product of a 7500-nucleotide genome. Inactivation of viral activity can
third of patients with clinical PFIC and normal GGT. Recent studies be achieved by boiling for 1 min, by contact with formaldehyde and
have shown that patients with mutations in NR1H4, the gene encoding chlorine, or by ultraviolet irradiation. Despite nucleotide sequence
the farnesoid X receptor (FXR), a nuclear hormone receptor activated variation of up to 20% among isolates of HAV and despite the recog-
by bile acids, have a syndrome identical to PFIC2 with absent expres- nition of six genotypes (three of which affect humans), all strains of
sion of BSEP. Mutations in tight junction protein 2 (TJP2) have also this virus are immunologically indistinguishable and belong to one
been associated with severe cholestasis with normal GGT levels, likely serotype. Human HAV can infect and cause hepatitis in chimpan-
due to disruption of tight junctions at the bile canaliculus. zees, tamarins (marmosets), and several monkey species. Recently, a
■■FURTHER READING hepatotropic Hepatovirus related to, and likely to have shared com-
Bull LN, Thompson RJ: Progressive familial intrahepatic cholestasis. mon evolutionary ancestry with, human HAV has been identified in
Clin Liver Dis 22:657, 2018. several species of harbor seals, albeit without histologic evidence for
Canu G et al: Gilbert and Crigler Najjar syndromes: An update of the liver injury or inflammation; HAV-like hepatoviruses have also been
PART 10

UDP-glucuronosyltransferase 1A1 (UGT1A1) gene mutation database. identified in small mammals, including bats and rodents. Hepatitis
Blood Cells Mol Dis 50:273, 2013. A has an incubation period of ~3–4 weeks. Its replication is limited
Gomez-Ospina N et al: Mutations in the nuclear bile acid receptor to the liver, but the virus is present in the liver, bile, stools, and blood
FXR cause progressive familial intrahepatic cholestasis. Nat Commun during the late incubation period and acute preicteric/presymptomatic
phase of illness. Despite slightly longer persistence of virus in the liver,
Disorders of the Gastrointestinal System

7:10713, 2016.
Hansen TW: Biology of bilirubin photoisomers. Clin Perinatol 43:277, fecal shedding, viremia, and infectivity diminish rapidly once jaundice
2016. becomes apparent. Detection of HAV RNA by sensitive reverse tran-
Lamola AA: A pharmacologic view of phototherapy. Clin Perinatol scription polymerase chain reaction assays has been reported to persist
43:259, 2016. at low levels in stool, the liver, and serum for up to several months after
Memon N et al: Inherited disorders of bilirubin clearance. Pediatr Res acute illness; however, this does not correlate with persistent infectivity,
79:378, 2016. probably because of the presence of neutralizing antibody. HAV can be
Sambrotta M et al: Mutations in TJP2 cause progressive cholestatic cultivated reproducibly in vitro and in primate models.
liver disease. Nat Genet 46:326, 2014. Antibodies to HAV (anti-HAV) can be detected during acute ill-
Soroka CJ, Boyer JL: Biosynthesis and trafficking of the bile salt ness when serum aminotransferase activity is elevated and fecal HAV
export pump, BSEP: Therapeutic implications of BSEP mutations. shedding is still occurring. This early antibody response is predomi-
Mol Aspects Med 37:3, 2014. nantly of the IgM class and persists for several (~3) months, rarely for
van de Steeg E et al: Complete OATP1B1 and OATP1B3 deficiency 6–12 months. During convalescence, however, anti-HAV of the IgG class
causes human Rotor syndrome by interrupting conjugated bilirubin becomes the predominant antibody (Fig. 339-2). Therefore, the diag-
reuptake into the liver. J Clin Invest 122:519, 2012. nosis of hepatitis A is made during acute illness by demonstrating anti-
van Wessel DBE et al: Genotype correlates with the natural history of HAV of the IgM class. After acute illness, anti-HAV of the IgG class
severe bile salt export pump deficiency. J Hepatol 73:84, 2020. remains detectable indefinitely, and patients with serum anti-HAV
Wolkoff AW: Organic anion uptake by hepatocytes. Compr Physiol are immune to reinfection. Neutralizing antibody activity parallels the
4:1715, 2014. appearance of anti-HAV, and the IgG anti-HAV present in immune
globulin accounts for the protection it affords against HAV infection.
Hepatitis B HBV is a DNA virus with a remarkably compact
genomic structure; despite its small, circular, 3200-bp size, HBV DNA
codes for four sets of viral products with a complex, multiparticle
structure. HBV achieves its genomic economy by relying on an efficient

339 Acute Viral Hepatitis

Jules L. Dienstag
strategy of encoding proteins from four overlapping genes: S, C, P, and
X (Fig. 339-3), as detailed below. Once thought to be unique among
viruses, HBV is now recognized as one of a family of animal viruses,
hepadnaviruses (hepatotropic DNA viruses), and is classified as hepad-
navirus type 1. Similar viruses infect certain species of woodchucks,
Acute viral hepatitis is a systemic infection affecting the liver predomi- ground and tree squirrels, and Pekin ducks, to mention the most care-
nantly. Almost all cases of acute viral hepatitis are caused by one of five fully characterized; genetic evidence of ancient HBV-like virus forbears
viral agents: hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis has been found in fossils of ancient birds, and an HBV-like virus has
C virus (HCV), the HBV-associated delta agent or hepatitis D virus been identified in contemporary fish. Studies of ancient HBV genomes
(HDV), and hepatitis E virus (HEV). All these human hepatitis viruses date an association between HBV and human beings back as long
are RNA viruses, except for hepatitis B, which is a DNA virus but as 21,000 years ago; primate HBV-like viruses date back millions of years,

HPIM21e_Part10_p2381-p2670.indd 2562 20/01/22 10:05 PM

 B surface antigen (HBsAg). The concen- 2563
tration of HBsAg and virus particles in
the blood may reach 500 μg/mL and 10
trillion particles per milliliter, respec-
tively. The envelope protein, HBsAg, is
the product of the S gene of HBV.
Envelope HBsAg subdeterminants
include a common group-reactive antigen,
a, shared by all HBsAg isolates and one
of several subtype-specific antigens—d
or y, w or r—as well as other specific-
ities. Hepatitis B isolates fall into one
of at least 8 subtypes and 10 genotypes
FIGURE 339-1 Electron micrographs of hepatitis A virus particles and serum from a patient with hepatitis B. Left:
27-nm hepatitis A virus particles purified from stool of a patient with acute hepatitis A and aggregated by antibody to (A–J). Geographic distribution of geno-
hepatitis A virus. Right: Concentrated serum from a patient with hepatitis B, demonstrating the 42-nm virions, tubular types and subtypes varies; genotypes A
forms, and spherical 22-nm particles of hepatitis B surface antigen. 132,000×. (Hepatitis D resembles 42-nm virions of (corresponding to subtype adw) and D
hepatitis B but is smaller, 35–37 nm; hepatitis E resembles hepatitis A virus but is slightly larger, 32–34 nm; hepatitis C (ayw) predominate in the United States
has been visualized as a 55-nm particle.) and Europe, whereas genotypes B (adw)
and C (adr) predominate in Asia; how-
suggesting that HBV predated the emergence of modern humans. ever, these geographic distinctions have been blunted by recent-decade
Like HBV, all have the same distinctive three morphologic forms, migration across continents. Clinical course and outcome are inde-
have counterparts to the envelope and nucleocapsid virus antigens pendent of subtype, but genotype B appears to be associated with less
of HBV, replicate in the liver but exist in extrahepatic sites, contain rapidly progressive liver disease and cirrhosis and a lower likelihood,
their own endogenous DNA polymerase, have partially double-strand or delayed appearance, of hepatocellular carcinoma than genotype C or
and partially single-strand genomes, are associated with acute and D. Patients with genotype A are more likely to clear circulating viremia
chronic hepatitis and hepatocellular carcinoma, and rely on a replica- and achieve hepatitis B e antigen (HBeAg) and HBsAg seroconversion,
tive strategy unique among DNA viruses but typical of retroviruses. both spontaneously and in response to antiviral therapy. In addition,
Entry of HBV into hepatocytes is mediated by binding to the sodium “precore” mutations are favored by certain genotypes (see below).

CHAPTER 339 Acute Viral Hepatitis

taurocholate cotransporting polypeptide receptor. Instead of DNA rep- Upstream of the S gene are the pre-S genes (Fig. 339-3), which code
lication directly from a DNA template, hepadnaviruses rely on reverse for pre-S gene products, including receptors on the HBV surface for
transcription (effected by the DNA polymerase) of minus-strand DNA polymerized human serum albumin and for hepatocyte membrane
from a “pregenomic” RNA intermediate. Then, plus-strand DNA proteins. The pre-S region actually consists of both pre-S1 and pre-S2.
is transcribed from the minus-strand DNA template by the DNA- Depending on where translation is initiated, three potential HBsAg
dependent DNA polymerase and converted in the hepatocyte nucleus gene products are synthesized. The protein product of the S gene is
to a covalently closed circular DNA, which serves as a template for HBsAg (major protein), the product of the S region plus the adjacent
messenger RNA and pregenomic RNA. Viral proteins are translated by pre-S2 region is the middle protein, and the product of the pre-S1 plus
the messenger RNA, and the proteins and genome are packaged into pre-S2 plus S regions is the large protein. Compared with the smaller
virions and secreted from the hepatocyte. Although HBV is difficult to spherical and tubular particles of HBV, complete 42-nm virions are
cultivate in vitro in the conventional sense from clinical material, sev- enriched in the large protein. Both pre-S proteins and their respective
eral cell lines have been transfected with HBV DNA. Such transfected antibodies can be detected during HBV infection, and the period of
cells support in vitro replication of the intact virus and its component pre-S antigenemia appears to coincide with other markers of virus rep-
proteins. lication, as detailed below; however, pre-S proteins have little clinical
VIRAL PROTEINS AND PARTICLES Of the three particulate forms relevance and are not included in routine serologic testing repertoires.
of HBV (Table 339-1), the most numerous are the 22-nm particles, The intact 42-nm virion contains a 27-nm nucleocapsid core par-
which appear as spherical or long filamentous forms; these are anti- ticle. Nucleocapsid proteins are coded for by the C gene. The antigen
genically indistinguishable from the outer surface or envelope protein expressed on the surface of the nucleocapsid core is hepatitis B core
of HBV and are thought to represent excess viral envelope protein. antigen (HBcAg), and its corresponding antibody is anti-HBc. A third
Outnumbered in serum by a factor of 100 or 1000 to 1 compared with HBV antigen is HBeAg, a soluble, nonparticulate, nucleocapsid protein
the spheres and tubules are large, 42-nm, double-shelled spherical that is immunologically distinct from intact HBcAg but is a product
particles, which represent the intact hepatitis B virion (Fig. 339-1). The of the same C gene. The C gene has two initiation codons: a precore
envelope protein expressed on the outer surface of the virion and on and a core region (Fig. 339-3). If translation is initiated at the precore
the smaller spherical and tubular structures is referred to as hepatitis region, the protein product is HBeAg, which has a signal peptide that
binds it to the smooth endoplasmic reticulum, the secretory apparatus
of the cell, leading to its secretion into the circulation. If translation
Jaundice
begins at the core region, HBcAg is the protein product; it has no signal
ALT IgG Anti-HAV peptide and is not secreted, but it assembles into nucleocapsid particles,
IgM Anti-HAV which bind to and incorporate RNA, and which, ultimately, contain
Fecal HAV HBV DNA. Also packaged within the nucleocapsid core is a DNA
polymerase, which directs replication and repair of HBV DNA. When
packaging within viral proteins is complete, synthesis of the incomplete
plus strand stops; this accounts for the single-strand gap and for differ-
ences in the size of the gap. HBcAg particles remain in the hepatocyte,
where they are readily detectable by immunohistochemical staining
and are exported after encapsidation by an envelope of HBsAg. There-
fore, naked core particles do not circulate in the serum. The secreted
0 4 8 12 16 20
nucleocapsid protein, HBeAg, provides a convenient, readily detect-
Weeks after exposure able, qualitative marker of HBV replication and relative infectivity.
FIGURE 339-2 Scheme of typical clinical and laboratory features of hepatitis A HBsAg-positive serum containing HBeAg is more likely to be
virus (HAV). ALT, alanine aminotransferase. highly infectious and to be associated with the presence of hepatitis B

HPIM21e_Part10_p2381-p2670.indd 2563 20/01/22 10:05 PM

 2564 Pre-S2 virions (and detectable HBV DNA, see below) than HBeAg-negative
Pre-S1 or anti-HBe-positive serum. For example, HBsAg-positive mothers
who are HBeAg-positive almost invariably (>90%) transmit hepatitis
P B infection to their offspring, whereas HBsAg-positive mothers with
S anti-HBe rarely (10–15%) infect their offspring.
Early during the course of acute hepatitis B, HBeAg appears tran-
siently; its disappearance may be a harbinger of clinical improvement
and resolution of infection. Persistence of HBeAg in serum beyond the
first 3 months of acute infection may be predictive of the development
C
of chronic infection, and the presence of HBeAg during chronic
hepatitis B tends to be associated with ongoing viral replication, infec-
Pre-C tivity, and inflammatory liver injury (except during the early decades
after perinatally acquired HBV infection; see below).
The third and largest of the HBV genes, the P gene (Fig. 339-3),
codes for HBV DNA polymerase; as noted above, this enzyme has
X both DNA-dependent DNA polymerase and RNA-dependent reverse
FIGURE 339-3 Compact genomic structure of hepatitis B virus (HBV). This structure, transcriptase activities. The fourth gene, X, codes for a small, non-
with overlapping genes, permits HBV to code for multiple proteins. The S gene particulate protein, hepatitis B x antigen (HBxAg), that is capable
codes for the “major” envelope protein, HBsAg. Pre-S1 and pre-S2, upstream of of transactivating the transcription of both viral and cellular genes
S, combine with S to code for two larger proteins, “middle” protein, the product of (Fig. 339-3). In the cytoplasm, HBxAg effects calcium release (possibly
pre-S2 + S, and “large” protein, the product of pre-S1 + pre-S2 + S. The largest gene, from mitochondria), which activates signal-transduction pathways
P, codes for DNA polymerase. The C gene codes for two nucleocapsid proteins, that lead to stimulation of HBV reverse transcription and HBV DNA
HBeAg, a soluble, secreted protein (initiation from the pre-C region of the gene),
and HBcAg, the intracellular core protein (initiation after pre-C). The X gene codes replication. Such transactivation may enhance the replication of
for HBxAg, which can transactivate the transcription of cellular and viral genes; its HBV, leading to the clinical association observed between the expres-
clinical relevance is not known, but it may contribute to carcinogenesis by binding sion of HBxAg and antibodies to it in patients with severe chronic
to p53.
PART 10

TABLE 339-1 Nomenclature and Features of Hepatitis Viruses

HEPATITIS VIRUS
TYPE PARTICLE, nm MORPHOLOGY GENOMEa CLASSIFICATION ANTIGEN(S) ANTIBODIES REMARKS
HAV 27 Icosahedral 7.5-kb Hepatovirus HAV Anti-HAV Early fecal shedding
Disorders of the Gastrointestinal System

nonenveloped RNA, Diagnosis: IgM anti-HAV

linear, ss, +
Previous infection: IgG anti-HAV
HBV 42 Double-shelled 3.2-kb Hepadnavirus HBsAg Anti-HBs Bloodborne virus; carrier state
virion (surface and DNA, HBcAg Anti-HBc Acute diagnosis: HBsAg, IgM anti-HBc
core) spherical circular,
ss/ds HBeAg Anti-HBe Chronic diagnosis: IgG anti-HBc, HBsAg
Markers of replication: HBeAg, HBV DNA
Liver, lymphocytes, other organs
27 Nucleocapsid core HBcAg Anti-HBc Nucleocapsid contains DNA and DNA
HBeAg Anti-HBe polymerase; present in hepatocyte nucleus;
HBcAg does not circulate; HBeAg (soluble,
nonparticulate) and HBV DNA circulate—
correlate with infectivity and complete virions
22 Spherical and HBsAg Anti-HBs HBsAg detectable in >95% of patients with
filamentous; acute hepatitis B; found in serum, body fluids,
represents excess hepatocyte cytoplasm; anti-HBs appears
virus coat material following infection—protective antibody
HCV 55 Enveloped 9.4-kb Hepacivirus HCV core Anti-HCV Bloodborne agent, formerly labeled non-A,
RNA, antigen non-B hepatitis
linear, ss, + Acute diagnosis: anti-HCV, HCV RNA
Chronic diagnosis: anti-HCV, HCV RNA;
cytoplasmic location in hepatocytes
HDV 35–37 Enveloped hybrid 1.7-kb Resembles viroids HBsAg Anti-HBs Defective RNA virus, requires helper function
particle with RNA, and plant satellite HDAg Anti-HDV of HBV (hepadnaviruses); HDV antigen (HDAg)
HBsAg coat and circular, viruses (genus present in hepatocyte nucleus
HDV core ss, – Deltavirus) Diagnosis: anti-HDV, HDV RNA; HBV/HDV
co-infection—IgM anti-HBc and anti-HDV; HDV
superinfection—IgG anti-HBc and anti-HDV
HEV 32–34 Nonenveloped 7.6-kb Orthohepevirus HEV antigen Anti-HEV Agent of enterically transmitted hepatitis; rare in
icosahedral RNA, the United States; occurs in Asia, Mediterranean
linear, ss, + countries, Central America
Diagnosis: IgM/IgG anti-HEV (assays not
routinely available); virus in stool, bile,
hepatocyte cytoplasm
ss, single-strand; ss/ds, partially single-strand, partially double-strand; −, minus-strand; +, plus-strand.
a

Note: See text for abbreviations.

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 as those with chronic HBV infection, anti-HBc is predominantly of the 2565
Jaundice IgG class. Infrequently, in ≤1–5% of patients with acute HBV infection,
levels of HBsAg are too low to be detected; in such cases, the presence
ALT
of IgM anti-HBc establishes the diagnosis of acute hepatitis B. When
HBeAg Anti-HBe
isolated anti-HBc occurs in the rare patient with chronic hepatitis B
whose HBsAg level is below the sensitivity threshold of contemporary
IgG Anti-HBc immunoassays (a low-level carrier), anti-HBc is of the IgG class. Gen-
HBsAg erally, in persons who have recovered from hepatitis B, anti-HBs and
anti-HBc persist indefinitely.
The temporal association between the appearance of anti-HBs and
Anti-HBs
resolution of HBV infection as well as the observation that persons
IgM Anti-HBc with anti-HBs in serum are protected against reinfection with HBV
suggests that anti-HBs is the protective antibody. Therefore, strategies
for prevention of HBV infection are based on providing susceptible
persons with circulating anti-HBs (see below). Occasionally, in ~10%
0 4 8 12 16 20 24 28 32 36 52 100 of patients with chronic hepatitis B, low-level, low-affinity anti-HBs
Weeks after exposure can be detected. This antibody is directed against a subtype deter-
FIGURE 339-4 Scheme of typical clinical and laboratory features of acute hepatitis
minant different from that represented by the patient’s HBsAg; its
B. ALT, alanine aminotransferase. presence is thought to reflect the stimulation of a related clone of
antibody-forming cells, but it has no clinical relevance and does not
signal imminent clearance of hepatitis B. These patients with HBsAg
hepatitis and hepatocellular carcinoma. The transactivating activity and such nonneutralizing anti-HBs should be categorized as having
can enhance the transcription and replication of other viruses besides chronic HBV infection.
HBV, such as HIV. Cellular processes transactivated by X include the The other readily detectable serologic marker of HBV infection,
human interferon-γ gene and class I major histocompatibility genes; HBeAg, appears concurrently with or shortly after HBsAg. Its appear-
potentially, these effects could contribute to enhanced susceptibility of ance coincides temporally with high levels of virus replication and
HBV-infected hepatocytes to cytolytic T cells. The expression of X can reflects the presence of circulating intact virions and detectable HBV
also induce programmed cell death (apoptosis). The clinical relevance DNA (with the notable exception of patients with precore mutations
of HBxAg is limited, however, and testing for it is not part of routine

CHAPTER 339 Acute Viral Hepatitis

who cannot synthesize HBeAg—see “Molecular Variants”). Pre-S1
clinical practice. and pre-S2 proteins are also expressed during periods of peak repli-
SEROLOGIC AND VIROLOGIC MARKERS After a person is infected with cation, but assays for these gene products are not routinely available.
HBV, the first virologic marker detectable in serum within 1–12 weeks, In self-limited HBV infections, HBeAg becomes undetectable shortly
usually between 8 and 12 weeks, is HBsAg (Fig. 339-4). Circulating after peak elevations in aminotransferase activity, before the disap-
HBsAg precedes elevations of serum aminotransferase activity and pearance of HBsAg, and anti-HBe then becomes detectable, coincid-
clinical symptoms by 2–6 weeks and remains detectable during the ing with a period of relatively lower infectivity (Fig. 339-4). Because
entire icteric or symptomatic phase of acute hepatitis B and beyond. In markers of HBV replication appear transiently during acute infection,
typical cases, HBsAg becomes undetectable 1–2 months after the onset testing for such markers is of little clinical utility in typical cases of
of jaundice and rarely persists beyond 6 months. After HBsAg disap- acute HBV infection. In contrast, markers of HBV replication provide
pears, antibody to HBsAg (anti-HBs) becomes detectable in serum and valuable information in patients with protracted infections.
remains detectable indefinitely thereafter. Because HBcAg is intracellu- Departing from the pattern typical of acute HBV infections, in
lar and, when in the serum, sequestered within an HBsAg coat, naked chronic HBV infection, HBsAg remains detectable beyond 6 months,
core particles do not circulate in serum, and therefore, HBcAg is not anti-HBc is primarily of the IgG class, and anti-HBs is either undetect-
detectable routinely in the serum of patients with HBV infection. By able or detectable at low levels (see “Laboratory Features”) (Fig. 339-5).
contrast, anti-HBc is readily demonstrable in serum, beginning within
the first 1–2 weeks after the appearance of HBsAg and preceding
detectable levels of anti-HBs by weeks to months. Because variabil-
ity exists in the time of appearance of anti-HBs after HBV infection, ALT
occasionally a gap of several weeks or longer may separate the dis-
appearance of HBsAg and the appearance of anti-HBs. During this
“gap” or “window” period, anti-HBc may represent the only serologic HBeAg Anti-HBe
evidence of current or recent HBV infection, and blood containing
anti-HBc in the absence of HBsAg and anti-HBs has been implicated HBV DNA
in transfusion-associated hepatitis B. In part because the sensitivity of HBsAg
immunoassays for HBsAg and anti-HBs has increased, however, this
window period is rarely encountered. In some persons, years after HBV Anti-HBc
infection, anti-HBc may persist in the circulation longer than anti-HBs.
Therefore, isolated anti-HBc does not necessarily indicate active virus IgM anti-HBc
replication; most instances of isolated anti-HBc represent hepatitis B
infection in the remote past. Rarely, however, isolated anti-HBc rep-
resents low-level hepatitis B viremia, with HBsAg below the detection 0 1 2 3 4 5 6 12 24 36 48 60 120
threshold, and occasionally, isolated anti-HBc represents a cross- Months after exposure
reacting or false-positive immunologic specificity. Recent and remote FIGURE 339-5 Scheme of typical laboratory features of wild-type chronic
HBV infections can be distinguished by determination of the immuno- hepatitis B. HBeAg and hepatitis B virus (HBV) DNA can be detected in serum
globulin class of anti-HBc. Anti-HBc of the IgM class (IgM anti-HBc) during the relatively replicative phase of chronic infection, which is associated
predominates during the first 6 months after acute infection, whereas with infectivity and liver injury. Seroconversion from the replicative phase to the
IgG anti-HBc is the predominant class of anti-HBc beyond 6 months. relatively nonreplicative phase occurs at a rate of ~10% per year and is heralded by
an acute hepatitis–like elevation of alanine aminotransferase (ALT) activity; during
Therefore, patients with current or recent acute hepatitis B, including the nonreplicative phase, infectivity and liver injury are limited. In HBeAg-negative
those in the anti-HBc window, have IgM anti-HBc in their serum. In chronic hepatitis B associated with mutations in the precore region of the HBV
patients who have recovered from hepatitis B in the remote past as well genome, replicative chronic hepatitis B occurs in the absence of HBeAg.

HPIM21e_Part10_p2381-p2670.indd 2565 20/01/22 10:05 PM

 2566 During early chronic HBV infection, HBV DNA can be detected both chronic hepatitis with mutations in the precore region is now the most
in serum and in hepatocyte nuclei, where it is present in free or epi- frequently encountered form of hepatitis B in Mediterranean countries
somal form. This relatively highly replicative stage of HBV infection and in Europe. In the United States, where HBV genotype A (less prone
is the time of maximal infectivity and liver injury; HBeAg is a quali- to G1896A mutation) is prevalent, precore-mutant HBV is much less
tative marker and HBV DNA a quantitative marker of this replicative common; however, as a result of immigration from Asia and Europe,
phase, during which all three forms of HBV circulate, including intact the proportion of HBeAg-negative hepatitis B–infected individuals has
virions. Over time, the relatively replicative phase of chronic HBV increased in the United States, and they now represent ~30–40% of
infection gives way to a relatively nonreplicative phase. This occurs at patients with chronic hepatitis B. Characteristic of such HBeAg-neg-
a rate of ~10% per year and is accompanied by seroconversion from ative chronic hepatitis B are lower levels of HBV DNA (usually
HBeAg to anti-HBe. In many cases, this seroconversion coincides with ≤105 IU/mL) and one of several patterns of aminotransferase activity—
a transient, usually mild, acute hepatitis-like elevation in aminotrans- persistent elevations, periodic fluctuations above the normal range,
ferase activity, believed to reflect cell-mediated immune clearance of and periodic fluctuations between the normal and elevated range.
virus-infected hepatocytes. In this relatively nonreplicative phase of The second important category of HBV mutants consists of escape
chronic infection, when HBV DNA is demonstrable in hepatocyte mutants, in which a single amino acid substitution, from glycine to
nuclei, it tends to be integrated into the host genome. In this phase, arginine, occurs at position 145 of the immunodominant a determi-
only spherical and tubular forms of HBV, not intact virions, circulate, nant common to all HBsAg subtypes. This HBsAg alteration leads to
and liver injury tends to subside. Most such patients would be charac- a critical conformational change that results in a loss of neutralizing
terized as inactive HBV carriers. In reality, the designations replicative activity by anti-HBs. This specific HBV/a mutant has been observed
and nonreplicative are only relative; even in the so-called nonreplicative in two situations, active and passive immunization, in which humoral
phase, HBV replication can be detected at levels of approximately ≤103 immunologic pressure may favor evolutionary change (“escape”) in
virions/mL with highly sensitive amplification probes such as the poly- the virus—in a small number of hepatitis B vaccine recipients who
merase chain reaction (PCR); below this replication threshold, liver acquired HBV infection despite the prior appearance of neutralizing
injury and infectivity of HBV are limited to negligible. Still, the distinc- anti-HBs and in HBV-infected liver transplant recipients treated with
tions are pathophysiologically and clinically meaningful. Occasionally, a high-potency human monoclonal anti-HBs preparation. Although
nonreplicative HBV infection converts back to replicative infection. such mutants have not been recognized frequently, their existence
Such spontaneous reactivations are accompanied by reexpression of raises a concern that may complicate vaccination strategies and sero-
HBeAg and HBV DNA, and sometimes of IgM anti-HBc, as well as logic diagnosis.
by exacerbations of liver injury. Because high-titer IgM anti-HBc can Different types of mutations emerge during antiviral therapy of
reappear during acute exacerbations of chronic hepatitis B, relying on chronic hepatitis B with nucleoside analogues; such YMDD and
PART 10

IgM anti-HBc versus IgG anti-HBc to distinguish between acute and similar mutations in the polymerase motif of HBV are described in
chronic hepatitis B infection, respectively, may not always be reliable; Chap. 341.
in such cases, patient history and additional follow-up monitoring over EXTRAHEPATIC SITES Hepatitis B antigens and HBV DNA have
time are invaluable in helping to distinguish de novo acute hepatitis B been identified in extrahepatic sites, including the lymph nodes, bone
infection from acute exacerbation of chronic hepatitis B infection. marrow, circulating lymphocytes, spleen, and pancreas. Although the
Disorders of the Gastrointestinal System

MOLECULAR VARIANTS Variation occurs throughout the HBV

virus does not appear to be associated with tissue injury in any of
these extrahepatic sites, its presence in these “remote” reservoirs has
genome, and clinical isolates of HBV that do not express typical viral
been invoked (but is not necessary) to explain the recurrence of HBV
proteins have been attributed to mutations in individual or even
infection after orthotopic liver transplantation. The clinical relevance
multiple gene locations. For example, variants have been described
of such extrahepatic HBV is limited.
that lack nucleocapsid proteins (commonly), envelope proteins (very
rarely), or both. Two categories of naturally occurring HBV variants Hepatitis D The delta hepatitis agent, or HDV, the only member
have attracted the most attention. One of these was identified ini- of the genus Deltavirus, is a defective RNA virus that co-infects with
tially in Mediterranean countries among patients with severe chronic and requires the helper function of HBV (or other hepadnaviruses)
HBV infection and detectable HBV DNA, but with anti-HBe instead for its replication and expression. Slightly smaller than HBV, HDV
of HBeAg. These patients were found to be infected with an HBV is a formalin-sensitive, 35- to 37-nm virus with a hybrid structure.
mutant that contained an alteration in the precore region, rendering Its nucleocapsid expresses HDV antigen (HDAg), which bears no
the virus incapable of encoding HBeAg. Although several potential antigenic homology with any of the HBV antigens, and contains the
mutation sites exist in the pre-C region, the region of the C gene virus genome. The HDV core is “encapsidated” by an outer envelope
necessary for the expression of HBeAg (see “Virology and Etiology”), of HBsAg, indistinguishable from that of HBV except in its relative
the most commonly encountered in such patients is a single base compositions of major, middle, and large HBsAg component proteins.
substitution, from G to A in the second to last codon of the pre-C The genome is a small, 1700-nucleotide, circular, single-strand RNA
gene at nucleotide 1896. This substitution results in the replacement of negative polarity that is nonhomologous with HBV DNA (except
of the TGG tryptophan codon by a stop codon (TAG), which prevents for a small area of the polymerase gene) but that has features and
the translation of HBeAg. Another mutation, in the core-promoter the rolling circle model of replication common to genomes of plant
region, prevents transcription of the coding region for HBeAg and satellite viruses or viroids. HDV RNA contains many areas of internal
yields an HBeAg-negative phenotype. Patients with such mutations complementarity; therefore, it can fold on itself by internal base pairing
in the precore region and who are unable to secrete HBeAg may have to form an unusual, very stable, rod-like structure that contains a very
severe liver disease that progresses more rapidly to cirrhosis, or alter- stable, self-cleaving and self-ligating ribozyme. HDV RNA requires
natively, they are identified clinically later in the course of the natural host RNA polymerase II for its replication in the hepatocyte nucleus
history of chronic hepatitis B, when the disease is more advanced. Both via RNA-directed RNA synthesis by transcription of genomic RNA
“wild-type” HBV and precore-mutant HBV can coexist in the same to a complementary antigenomic (plus strand) RNA; the antigenomic
patient, or mutant HBV may arise late during wild-type HBV infec- RNA, in turn, serves as a template for subsequent genomic RNA syn-
tion. In addition, clusters of fulminant hepatitis B in Israel and Japan thesis effected by host RNA polymerase I. HDV RNA has only one
were attributed to common-source infection with a precore mutant. open reading frame, and HDAg, a product of the antigenomic strand,
Fulminant hepatitis B in North America and western Europe, how- is the only known HDV protein; HDAg exists in two forms: a small,
ever, occurs in patients infected with wild-type HBV, in the absence 195-amino-acid species, which plays a role in facilitating HDV RNA
of precore mutants, and both precore mutants and other mutations replication, and a large, 214-amino-acid species, which appears to
throughout the HBV genome occur commonly, even in patients with suppress replication but is required for assembly of the antigen into
typical, self-limited, milder forms of HBV infection. HBeAg-negative virions. HDV antigens have been shown to bind directly to RNA

HPIM21e_Part10_p2381-p2670.indd 2566 20/01/22 10:05 PM

 polymerase II, resulting in stimulation of transcription. Viral assembly hypervariable region, which varies from isolate to isolate and may allow 2567
requires farnesylation of the large HDAg for ribonucleoprotein anchor- the virus to evade host immunologic containment directed at accessible
ing to HBsAg. Both HBV and HDV enter hepatocytes via the sodium virus-envelope proteins. The 3′ end of the genome also includes an
taurocholate cotransporting polypeptide receptor. Although complete untranslated region and contains the genes for seven nonstructural
hepatitis D virions and liver injury require the cooperative helper func- (NS) proteins: p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B. p7 is a
tion of HBV, intracellular replication of HDV RNA can occur without membrane ion channel protein necessary for efficient assembly and
HBV. Genomic heterogeneity among HDV isolates has been described. release of HCV. The NS2 cysteine protease cleaves NS3 from NS2, and
Although pathophysiologic and clinical consequences of this genetic the NS3-4A serine protease cleaves all the downstream proteins from
diversity have not been defined definitively, preliminarily, genotype the polyprotein. Important NS proteins involved in virus replication
2 has been linked to milder disease and genotype 3 to severe acute include the NS3 helicase; NS3-4A serine protease; the multifunctional
disease. The clinical spectrum of hepatitis D is common to all eight membrane-associated phosphoprotein NS5A, an essential component
genotypes identified, the predominant of which is genotype 1. of the viral replication membranous web (along with NS4B); and the
HDV can either infect a person simultaneously with HBV (co- NS5B RNA-dependent RNA polymerase (Fig. 339-6). Because HCV
infection) or superinfect a person already infected with HBV (super- does not replicate via a DNA intermediate, it does not integrate into
infection); when HDV infection is transmitted from a donor with one the host genome. Because HCV tends to circulate in relatively low titer,
HBsAg subtype to an HBsAg-positive recipient with a different sub- 103−107 virions/mL, visualization of the 50- to 80-nm virus particles
type, HDV assumes the HBsAg subtype of the recipient, rather than remains difficult. Still, the replication rate of HCV is very high, 1012
the donor. Because HDV relies absolutely on HBV, the duration of virions per day; its half-life is 2.7 h. The chimpanzee is a helpful but
HDV infection is determined by the duration of (and cannot outlast) cumbersome animal model. Although a robust, reproducible, small
HBV infection. HDV replication tends to suppress HBV replication; animal model is lacking, HCV replication has been documented in
therefore, patients with hepatitis D tend to have lower levels of HBV an immunodeficient mouse model containing explants of human liver
replication. HDV antigen is expressed primarily in hepatocyte nuclei and in transgenic mouse and rat models; in addition, an HCV-related
and is occasionally detectable in serum. During acute HDV infection, rat Hepacivirus has been reported to be a useful surrogate model.
anti-HDV of the IgM class predominates, and 30–40 days may elapse Although in vitro replication is difficult, replicons in hepatocellular
after symptoms appear before anti-HDV can be detected. In self- carcinoma–derived cell lines support replication of genetically manip-
limited infection, anti-HDV is low-titer and transient, rarely remain- ulated, truncated, or full-length HCV RNA (but not intact virions);
ing detectable beyond the clearance of HBsAg and HDV antigen. In infectious pseudotyped retroviral HCV particles have been shown to
chronic HDV infection, anti-HDV circulates in high titer, and both yield functioning envelope proteins. In 2005, complete replication of

CHAPTER 339 Acute Viral Hepatitis

IgM and IgG anti-HDV can be detected. HDV antigen in the liver and HCV and intact 55-nm virions were described in cell culture systems.
HDV RNA in serum and liver can be detected during HDV replication. HCV entry into the hepatocyte occurs via the non-liver-specific CD81
The recent report that, in vitro, HDV can assemble infectious virus receptor and the liver-specific tight junction protein claudin-1. A grow-
particles with envelope glycoproteins from other viruses, both hepato- ing list of additional host receptors to which HCV binds on cell entry
tropic and nonhepatotropic, raises the possibility that HDV can repli- includes occludin, low-density lipoprotein receptors, glycosaminogly-
cate without hepadnaviruses; however, to date, co-infections in nature cans, scavenger receptor B1, and epidermal growth factor receptor,
with other viruses have not been observed. among others. Relying on the same assembly and secretion pathway as
low-density and very-low-density lipoproteins, HCV is a lipoviropar-
Hepatitis C Hepatitis C virus, which, before its identification, ticle and masquerades as a lipoprotein, which may limit its visibility to
was labeled “non-A, non-B hepatitis,” is a linear, single-strand, posi- the adaptive immune system and explain its ability to evade immune
tive-sense, 9600-nucleotide RNA virus, the genome of which is similar containment and clearance. After viral entry and uncoating, translation
in organization to that of flaviviruses and pestiviruses; HCV is the only is initiated by the IRES on the endoplasmic reticulum membrane, and
member of the genus Hepacivirus in the family Flaviviridae. The HCV the HCV polyprotein is cleaved during translation and posttranslation-
genome contains a single, large open reading frame (ORF) (gene) that ally by host cellular proteases as well as HCV NS2-3 and NS3-4A pro-
codes for a virus polyprotein of ~3000 amino acids, which is cleaved teases. Host cofactors involved in HCV replication include cyclophilin
after translation to yield 10 viral proteins. The 5′ end of the genome A, which binds to NS5A and yields conformational changes required
consists of an untranslated region (containing an internal ribosomal for viral replication, and liver-specific host microRNA miR-122.
entry site [IRES]) adjacent to the genes for three structural proteins, At least six distinct major genotypes (and a minor genotype 7), as
the nucleocapsid core protein, C, and two envelope glycoproteins, E1 well as >50 subtypes within genotypes, of HCV have been identified by
and E2. The 5′ untranslated region and core gene are highly conserved nucleotide sequencing. Genotypes differ from one another in sequence
among genotypes, but the envelope proteins are coded for by the homology by ≥30%, and subtypes differ by ~20%. Because diver-
gence of HCV isolates within a geno-
500 1000 1500 2000 2500 3000 type or subtype and within the same
AA host may vary insufficiently to define a
Envelope Serine
Helicase
RNA-dependent distinct genotype, these intragenotypic
Core glycoproteins protease RNA polymerase differences are referred to as quasispecies
and differ in sequence homology by
5' C E1 E2 NS2 NS3 NS4B NS5A NS5B 3' only a few percent. The genotypic and
quasispecies diversity of HCV, result-
p7 NS4A ing from its high mutation rate, inter-
feres with effective humoral immunity.
Conserved Hypervariable Neutralizing antibodies to HCV have
region region been demonstrated, but they tend to
FIGURE 339-6 Organization of the hepatitis C virus genome and its associated, 3000-amino-acid (AA) proteins. The be short-lived, and HCV infection does
three structural genes at the 5′ end are the core region, C, which codes for the nucleocapsid, and the envelope not induce lasting immunity against
regions, E1 and E2, which code for envelope glycoproteins. The 5′ untranslated region and the C region are highly reinfection with different virus isolates
conserved among isolates, whereas the envelope domain E2 contains the hypervariable region. At the 3′ end are seven or even the same virus isolate. Thus,
nonstructural (NS) regions—p7, a membrane protein adjacent to the structural proteins that appears to function as an
ion channel; NS2, which codes for a cysteine protease; NS3, which codes for a serine protease and an RNA helicase; neither heterologous nor homologous
NS4 and NS4B; NS5A, a multifunctional membrane-associated phosphoprotein, an essential component of the viral immunity appears to develop commonly
replication membranous web; and NS5B, which codes for an RNA-dependent RNA polymerase. After translation of the after acute HCV infection. Some HCV
entire polyprotein, individual proteins are cleaved by both host and viral proteases. genotypes are distributed worldwide,

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 2568 whereas others are more geographically confined (see “Epidemiology to merit its own classification as a unique genus, Orthohepevirus,
and Global Features”). In addition, differences exist among genotypes within the family Hepeviridae (which includes similar viruses infecting
in responsiveness to antiviral therapy but not in pathogenicity or clin- mammals, birds, and fish). The virus has been detected in stool, bile,
ical progression (except for genotype 3, in which hepatic steatosis and and liver and is excreted in the stool during the late incubation period.
clinical progression are more likely). Both IgM anti-HEV during early acute infection and IgG anti-HEV
Currently available, third-generation immunoassays, which incor- predominating after the first 3 months can be detected. The presence
porate proteins from the core, NS3, and NS5 regions, detect anti-HCV of HEV RNA in serum and stool accompanies acute infection; viremia
antibodies during acute infection. The most sensitive indicator of resolves as clinical-biochemical recovery ensues, while HEV RNA
HCV infection is the presence of HCV RNA, which requires molec- in stool may outlast viremia by several weeks. Currently, serologic/
ular amplification by PCR or transcription-mediated amplification virologic testing for HEV infection—not approved or licensed by the
(TMA) (Fig. 339-7). To allow standardization of the quantification of U.S. Food and Drug Administration (FDA)—can be done in special-
HCV RNA among laboratories and commercial assays, HCV RNA is ized laboratories (e.g., the Centers for Disease Control and Prevention
reported as international units (IUs) per milliliter; quantitative assays [CDC]) and some commercial laboratories.
with a broad dynamic range are available that allow detection of HCV
RNA with a sensitivity as low as 5 IU/mL. HCV RNA can be detected ■■PATHOGENESIS
within a few days of exposure to HCV—well before the appearance of Under ordinary circumstances, none of the hepatitis viruses is known
anti-HCV—and tends to persist for the duration of HCV infection. to be directly cytopathic to hepatocytes. Evidence suggests that the
Application of sensitive molecular probes for HCV RNA has revealed clinical manifestations and outcomes after acute liver injury associated
the presence of replicative HCV in peripheral blood lymphocytes of with viral hepatitis are determined by the immunologic responses of
infected persons; however, as is the case for HBV in lymphocytes, the the host. Among the viral hepatitides, the immunopathogenesis of
clinical relevance of HCV lymphocyte infection is not known. hepatitis B and C has been studied most extensively.
Hepatitis E Previously labeled epidemic or enterically transmitted Hepatitis B For HBV, the existence of inactive hepatitis B carriers
non-A, non-B hepatitis, HEV is an enterically transmitted virus that with normal liver histology and function suggests that the virus is
causes clinically apparent hepatitis primarily in India, Asia, Africa, and not directly cytopathic. The fact that patients with defects in cellular
Central America; in those geographic areas, HEV is the most common immune competence are more likely to remain chronically infected
cause of acute hepatitis; one-third of the global population appears to rather than to clear HBV supports the role of cellular immune
have been infected. This agent, with epidemiologic features resembling responses in the pathogenesis of hepatitis B–related liver injury. The
those of hepatitis A, is a 27- to 34-nm, nonenveloped, heat-stable, model that has the most experimental support involves cytolytic T cells
HAV-like virus with a 7200-nucleotide, single-strand, positive-sense
PART 10

sensitized specifically to recognize host and hepatitis B viral antigens

RNA genome. Like HAV, HEV also exists in a quasi-enveloped form on the liver cell surface. Nucleocapsid proteins (HBcAg and possibly
enclosed within host-cell-derived membranes. HEV has three over- HBeAg), present on the cell membrane in minute quantities, are the
lapping ORFs (genes), the largest of which, ORF1, encodes nonstruc- viral target antigens that, with host antigens, invite cytolytic T cells to
tural proteins involved in virus replication (the viral replicase, which destroy HBV-infected hepatocytes. Differences in the robustness and
Disorders of the Gastrointestinal System

includes a protease, polymerase, and helicase). A middle-sized gene, broad polyclonality of CD8+ cytolytic T-cell responsiveness; in the
ORF2, encodes the nucleocapsid protein, the major structural protein, level of HBV-specific helper CD4+ T cells; in attenuation, depletion,
and the smallest, ORF3, encodes a small structural phosphoprotein and exhaustion of virus-specific T cells; in viral T-cell epitope escape
involved in virus particle secretion. All HEV isolates appear to belong mutations that allow the virus to evade T-cell containment; and in
to a single serotype, despite genomic heterogeneity of up to 25% and the elaboration of antiviral cytokines by T cells have been invoked to
the existence of four species (A–D) and eight genotypes, only four of explain differences in outcomes between those who recover after acute
which, all within species A, have been detected in humans; genotypes hepatitis and those who progress to chronic hepatitis or between those
1 and 2 (common in developing countries) appear to be more virulent with mild and those with severe (fulminant) acute HBV infection.
anthrotropic variants, whereas genotypes 3 (the most common in the Although a robust cytolytic T-cell response occurs and eliminates
United States and Europe) and 4 (seen in China), endemic in animal virus-infected liver cells during acute hepatitis B, >90% of HBV DNA
species (enzootic variants), are more attenuated, account for subclinical has been found in experimentally infected chimpanzees to disappear
infections, represent a zoonotic reservoir for human infections, and from the liver and blood before maximal T-cell infiltration of the
can cause chronic infection in immunocompromised hosts. Contribut- liver and before most of the biochemical and histologic evidence of
ing to the perpetuation of this virus are the animal reservoirs described liver injury. This observation suggests that components of the innate
above, most notably in swine but also in camels, deer, rats, and rabbits, immune system and inflammatory cytokines, independent of cyto-
among others. No genomic or antigenic homology, however, exists pathic antiviral mechanisms, participate in the early immune response
between HEV and HAV or other picornaviruses; and HEV, although to HBV infection; this effect has been shown to represent elimination
resembling caliciviruses, is sufficiently distinct from any known agent of HBV replicative intermediates from the cytoplasm and covalently
closed circular viral DNA from the nucleus of infected hepatocytes. In
Anti-HCV
turn, the innate immune response to HBV infection is mediated largely
by natural killer (NK) cell cytotoxicity, activated by immunosuppres-
HCV RNA sive cytokines (e.g., interleukin [IL] 10 and transforming growth factor
[TGF] β), reduced signals from inhibitory receptor expression (e.g.,
ALT major histocompatibility complex), or increased signals from acti-
vating receptor expression on infected hepatocytes. In addition, NK
cells reduce helper CD4+ cells, which results in reduced CD8+ cells
and exhaustion of the virus-specific T-cell response to HBV infection.
Adding to the evidence supporting the role of these immunologic
perturbations in the pathogenesis of HBV-associated liver injury are
0 1 2 3 4 5 6 12 24 36 48 60 120 the observations that many of these departures from normal immune
Months after exposure function are restored after successful antiviral therapy. Ultimately,
HBV-HLA–specific cytolytic T-cell responses of the adaptive immune
FIGURE 339-7 Scheme of typical laboratory features during acute hepatitis C
progressing to chronicity. Hepatitis C virus (HCV) RNA is the first detectable system are felt to be responsible for recovery from HBV infection.
event, preceding alanine aminotransferase (ALT) elevation and the appearance of Debate continues over the relative importance of viral and host fac-
anti-HCV. tors in the pathogenesis of HBV-associated liver injury and its outcome.

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 As noted above, precore genetic mutants of HBV have been associated necroinflammatory activity reflecting the level of virus replication) in 2569
with the more severe outcomes of HBV infection (severe chronic and the later decades of life.
fulminant hepatitis), suggesting that, under certain circumstances,
relative pathogenicity is a property of the virus, not the host. The facts Hepatitis C Cell-mediated immune responses and elaboration
that concomitant HDV and HBV infections are associated with more by T cells of antiviral cytokines contribute to the multicellular innate
severe liver injury than HBV infection alone and that cells transfected and adaptive immune responses involved in the containment of infec-
in vitro with the gene for HDV antigen express HDV antigen and then tion and pathogenesis of liver injury associated with hepatitis C. The
become necrotic in the absence of any immunologic influences are also fact that HCV is so efficient in evading these immune mechanisms
consistent with a viral effect on pathogenicity. Similarly, in patients is a testament to its highly evolved ability to disrupt host immune
who undergo liver transplantation for end-stage chronic hepatitis B, responses at multiple levels. After exposure to HCV, the host cell
occasionally, rapidly progressive liver injury appears in the new liver. identifies viral product motifs (pattern recognition receptors) that dis-
This clinical pattern is associated with an unusual histologic pattern tinguish the virus from “self,” resulting in the elaboration of interferons
in the new liver, fibrosing cholestatic hepatitis, which, ultrastructurally, and other cytokines that result in activation of innate and adaptive
appears to represent a choking of the cell with overwhelming quanti- immune responses. Intrahepatic human leukocyte antigen (HLA) class
ties of HBsAg. This observation suggests that, under the influence of 1–restricted cytolytic T cells directed at nucleocapsid, envelope,
the potent immunosuppressive agents required to prevent allograft and nonstructural viral protein antigens have been demonstrated in
rejection, HBV may have a direct cytopathic effect on liver cells, inde- patients with chronic hepatitis C; however, such virus-specific cytolytic
pendent of the immune system. T-cell responses do not correlate adequately with the degree of liver
Although the precise mechanism of liver injury in HBV infection injury or with recovery. Yet a consensus has emerged supporting a role
remains elusive, studies of nucleocapsid proteins have shed light on in the pathogenesis of HCV-associated liver injury of virus-activated
the profound immunologic tolerance to HBV of babies born to moth- CD4+ helper T cells that stimulate, via the cytokines they elaborate,
ers with highly replicative (HBeAg-positive), chronic HBV infection. HCV-specific CD8+ cytotoxic T cells. These responses appear to be
In HBeAg-expressing transgenic mice, in utero exposure to HBeAg, more robust (higher in number, more diverse in viral antigen spec-
which is sufficiently small to traverse the placenta, induces T-cell tol- ificity, more functionally effective, and longer lasting) in those who
erance to both nucleocapsid proteins. This, in turn, may explain why, recover from HCV infection than in those who have chronic infection.
when infection occurs so early in life, immunologic clearance does not Contributing to chronic infection are a CD4+ proliferative defect that
occur, and protracted, lifelong infection ensues. An alternative expla- results in rapid contraction of CD4+ responses, mutations in CD8+
nation proposed to explain why robust liver injury does not accompany T cell–targeted viral epitopes that allow HCV to escape immune-

CHAPTER 339 Acute Viral Hepatitis

neonatal HBV infection but predisposes to chronic infection is defec- mediated clearance, and upregulation of inhibitory receptors on func-
tive priming of HBV-specific T cells during in utero exposure to HBV. tionally impaired, exhausted T cells. Although attention has focused on
adaptive immunity, HCV proteins have been shown to interfere with
“IMMUNOTOLERANT” VERSUS “IMMUNOREACTIVE” CHRONIC innate immunity by resulting in blocking of type 1 interferon responses
HEPATITIS B An important distinction should be drawn between and inhibition of interferon signaling and effector molecules in the
HBV infection acquired at birth, common in endemic areas, such as interferon signaling cascade.
East Asia, and infection acquired in adulthood, common in the West. Several HLA alleles have been linked with self-limited hepatitis
Infection in the neonatal period is associated with the acquisition of C, the most convincing of which is the CC haplotype of the IL28B
what appears to be a high level of immunologic tolerance to HBV and gene, which codes for interferon λ3, a component of innate immune
absence of an acute hepatitis illness but the almost invariable estab- antiviral defense. The IL28B association is even stronger when com-
lishment of chronic, often lifelong infection. Neonatally acquired HBV bined with HLA class II DQB1*03:01. The link between non-CC IL28B
infection can culminate decades later in cirrhosis and hepatocellular polymorphisms and failure to clear HCV infection has been explained
carcinoma (see “Complications and Sequelae”). In contrast, when HBV by a chromosome 19q13.13 frameshift variant upstream of IL28B,
infection is acquired during adolescence or early adulthood, the host the ΔG polymorphism of which creates an ORF in a novel interferon
immune response to HBV-infected hepatocytes tends to be robust, gene (IFN-λ4) associated with impaired HCV clearance. Also shown
an acute hepatitis-like illness is the rule, and failure to recover is the to contribute to limiting HCV infection are NK cells of the innate
exception. After adulthood-acquired infection, chronicity is uncom- immune system that function when HLA class I molecules required
mon, and the risk of hepatocellular carcinoma is very low. Based on for successful adaptive immunity are underexpressed. Both peripheral
these observations, some authorities categorize HBV infection into an cytotoxicity and intrahepatic NK cell cytotoxicity are dysfunctional in
“immunotolerant” phase, an “immunoreactive” phase, and an “inac- persistent HCV infection. Adding to the complexity of the immune
tive” phase. This somewhat simplistic formulation does not apply at response, HCV core, NS4B, and NS5B have been shown to suppress
all to the typical adult in the West with self-limited acute hepatitis B, the immunoregulatory nuclear factor (NF)-κB pathway, resulting in
in whom no period of immunologic tolerance occurs. Even among reduced antiapoptotic proteins and a resultant increased vulnerability
those with neonatally acquired HBV infection, in whom immunologic to tumor necrosis factor (TNF) α–mediated cell death. Patients with
tolerance appears to be established definitively, immunologic responses hepatitis C and unfavorable (non-CC, associated with reduced HCV
to HBV infection have been demonstrated (albeit typically at reduced clearance) IL28B alleles have been shown to have depressed NK cell/
levels), and intermittent bursts of hepatic necroinflammatory activity innate immune function. Of note, the emergence of substantial viral
punctuate the early decades of life during which liver injury appears quasispecies diversity and HCV sequence variation allow the virus to
to be quiescent (labeled by some as the “immunotolerant” phase; evade attempts by the host to contain HCV infection by both humoral
however, it more accurately is a period of dissociation between high- and cellular immunity.
level HBV replication and a paucity of inflammatory liver injury). In Finally, cross-reactivity between viral antigens (HCV NS3 and
addition, even when clinically apparent liver injury and progressive NS5A) and host autoantigens (cytochrome P450 2D6) has been
fibrosis emerge during later decades (the so-called immunoreactive, invoked to explain the association between hepatitis C and a subset
or immunointolerant, phase), the level of immunologic tolerance to of patients with autoimmune hepatitis and antibodies to liver-kidney
HBV remains substantial. More accurately, in patients with neonatally microsomal (LKM) antigen (anti-LKM) (Chap. 341).
acquired HBV infection, a dynamic equilibrium exists between toler-
ance and intolerance, the outcome of which determines the clinical Hepatitis A and E Viral shedding in these acute hepatitides pre-
expression of chronic infection. Persons infected as neonates tend to dates clinical evidence of liver injury, consistent with the absence of a
have a relatively higher level of immunologic tolerance (high replica- relationship between viral replication and target-organ injury. Instead,
tion, low necroinflammatory activity) during the early decades of life as shown for hepatitis B and C, in hepatitis A and E, experimental
and a relatively lower level (but only rarely a loss) of tolerance (and evidence supports a cytolytic CD8+ T-cell response as the instrument

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 2570 of liver cell injury, in concert with or dwarfed by CD4+ helper T cells A more severe histologic lesion, bridging hepatic necrosis, also
or CD4+ interferon γ–secreting cells. HEV has also been shown to termed subacute or confluent necrosis or interface hepatitis, is observed
interfere with host antiviral defenses, such as interferon signaling and occasionally in acute hepatitis. “Bridging” between lobules results
effector function, and to downregulate interferon-stimulated genes. from large areas of hepatic cell dropout, with collapse of the reticu-
The demonstration of an activated innate immune response in patients lin framework. Characteristically, the bridge consists of condensed
with these hepatitides argues for a multitude of immunologic mecha- reticulum, inflammatory debris, and degenerating liver cells that span
nisms in the pathogenesis of the acute liver injury resulting from HAV adjacent portal areas, portal to central veins, or central vein to central
and HEV infection. vein. This lesion had been thought to have prognostic significance; in
many of the originally described patients with this lesion, a subacute
■■EXTRAHEPATIC MANIFESTATIONS course terminated in death within several weeks to months, or severe
Immune complex–mediated tissue damage appears to play a patho- chronic hepatitis and cirrhosis developed; however, the association
genetic role in the extrahepatic manifestations of acute hepatitis B. between bridging necrosis and a poor prognosis in patients with acute
The occasional prodromal serum sickness–like syndrome observed hepatitis has not been upheld. Therefore, although demonstration of
in acute hepatitis B appears to be related to the deposition in tissue this lesion in patients with chronic hepatitis has prognostic significance
blood vessel walls of HBsAg–anti-HBs circulating immune complexes, (Chap. 341), its demonstration during acute hepatitis is less meaning-
leading to activation of the complement system and depressed serum ful, and liver biopsies to identify this lesion are no longer undertaken
complement levels. routinely in patients with acute hepatitis. In massive hepatic necrosis
In patients with chronic hepatitis B, other types of immune-complex (fulminant hepatitis, “acute yellow atrophy”), the striking feature at
disease may be seen. Glomerulonephritis with the nephrotic syndrome postmortem examination is the finding of a small, shrunken, soft liver.
is observed occasionally; HBsAg, immunoglobulin, and C3 deposition Histologic examination reveals massive necrosis and dropout of liver
has been found in the glomerular basement membrane. Whereas cells of most lobules with extensive collapse and condensation of the
generalized vasculitis (polyarteritis nodosa) develops in considerably reticulin framework. When histologic documentation is required in
<1% of patients with chronic HBV infection, 20–30% of patients the management of fulminant or very severe hepatitis, a biopsy can be
with polyarteritis nodosa have HBsAg in serum (Chap. 363). In done by the angiographically guided transjugular route, which permits
these patients, the affected small- and medium-size arterioles contain the performance of this invasive procedure in the presence of severe
HBsAg, immunoglobulins, and complement components. Another coagulopathy.
extrahepatic manifestation of viral hepatitis, essential mixed cryoglob- Immunohistochemical and electron-microscopic studies have local-
ulinemia (EMC), was reported initially to be associated with hepatitis B. ized HBsAg to the cytoplasm and plasma membrane of infected liver
The disorder is characterized clinically by arthritis, cutaneous vas- cells. In contrast, HBcAg predominates in the nucleus, but, occasion-
PART 10

culitis (palpable purpura), and, occasionally, glomerulonephritis and ally, scant amounts are also seen in the cytoplasm and on the cell mem-
serologically by the presence of circulating cryoprecipitable immune brane. HDV antigen is localized to the hepatocyte nucleus, whereas
complexes of more than one immunoglobulin class (Chaps. 314 and HAV and HCV antigens are localized to the cytoplasm. Hepatitis E
363). Many patients with this syndrome have chronic liver disease, but ORF-2 protein staining is distributed in both a cytoplasmic and nuclear
the association with HBV infection is limited; instead, a substantial pattern.
Disorders of the Gastrointestinal System

proportion has chronic HCV infection, with circulating immune com-

plexes containing HCV RNA. Immune-complex glomerulonephritis ■■EPIDEMIOLOGY AND GLOBAL FEATURES
is another recognized extrahepatic manifestation of chronic hepatitis Before the availability of serologic tests for hepatitis viruses, all viral
C (see “Complications and Sequelae,” below). Immune-complex dis- hepatitis cases were labeled either as “infectious” or “serum” hepatitis.
orders have been linked, albeit rarely, with both hepatitis A and E. Modes of transmission overlap, however, and a clear distinction among
In hepatitis E, rare neurologic (including Guillain-Barré syndrome), the different types of viral hepatitis cannot be made solely based on clin-
renal, pancreatic, and hematologic complications have been postulated ical or epidemiologic features (Table 339-2). The most accurate means
to result from both immunologic mechanisms and/or direct extrahe- to distinguish the various types of viral hepatitis involves specific
patic-site infection with the virus. serologic testing.
■■PATHOLOGY Hepatitis A This agent is transmitted almost exclusively by the
The typical morphologic lesions of all types of viral hepatitis are fecal-oral route. Person-to-person spread of HAV is enhanced by poor
similar and consist of panlobular infiltration with mononuclear cells, personal hygiene and overcrowding; large outbreaks as well as spo-
hepatic cell necrosis, hyperplasia of Kupffer cells, and variable degrees radic cases have been traced to contaminated food, water, milk, frozen
of cholestasis. Hepatic cell regeneration is present, as evidenced by raspberries and strawberries, green onions imported from Mexico, and
numerous mitotic figures, multinucleated cells, and “rosette” or “pseu- shellfish (e.g., scallops imported from the Philippines used to make
doacinar” formation. The mononuclear infiltration consists primarily sushi, the culprit identified in a 2016 Hawaiian outbreak). Intrafamily
of small lymphocytes, although plasma cells and eosinophils occasion- and intrainstitutional spreads are also common. Early epidemiologic
ally are present. Liver cell damage consists of hepatic cell degeneration observations supported a predilection for hepatitis A to occur in late
and necrosis, cell dropout, ballooning of cells, and acidophilic degen- fall and early winter. In temperate zones, epidemic waves have been
eration of hepatocytes (forming so-called Councilman or apoptotic recorded every 5–20 years as new segments of nonimmune population
bodies). Large hepatocytes with a ground-glass appearance of the cyto- appeared; however, in developed countries, the incidence of hepatitis
plasm may be seen in chronic but not in acute HBV infection; these A has been declining, presumably as a function of improved sanitation,
cells contain HBsAg and can be identified histochemically with orcein and these cyclic patterns are no longer observed. No HAV carrier state
or aldehyde fuchsin. In uncomplicated viral hepatitis, the reticulin has been identified after acute hepatitis A; perpetuation of the virus in
framework is preserved. nature depends presumably on nonepidemic, inapparent subclinical
In hepatitis C, the histologic lesion is often remarkable for a relative infection, ingestion of contaminated food or water in, or imported
paucity of inflammation, a marked increase in activation of sinusoidal from, endemic areas, and/or contamination linked to environmental
lining cells, lymphoid aggregates, the presence of fat (more frequent reservoirs.
in genotype 3 and linked to increased fibrosis), and, occasionally, bile In the general population, anti-HAV, a marker for previous HAV
duct lesions in which biliary epithelial cells appear to be piled up with- infection, increases in prevalence as a function of increasing age and
out interruption of the basement membrane. Occasionally, microvesic- of decreasing socioeconomic status. In the 1970s, serologic evidence of
ular steatosis occurs in hepatitis D. In hepatitis E, a common histologic prior hepatitis A infection occurred in ~40% of urban populations in
feature is marked cholestasis. A cholestatic variant of slowly resolving the United States, most of whose members never recalled having had
acute hepatitis A also has been described. a symptomatic case of hepatitis. In subsequent decades, however, the

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 2571
TABLE 339-2 Clinical and Epidemiologic Features of Viral Hepatitis
FEATURE HAV HBV HCV HDV HEV
Incubation (days) 15–45, mean 30 30–180, mean 60–90 15–160, mean 50 30–180, mean 60–90 14–60, mean 40
Onset Acute Insidious or acute Insidious or acute Insidious or acute Acute
Age preference Children, young Young adults (sexual and Any age, but more common Any age (similar to HBV) Epidemic cases: young
adults percutaneous), babies, in adults adults (20–40 years);
toddlers sporadic cases: older
adults (>60)
Transmission
Fecal-oral +++ − − − +++
Percutaneous Unusual +++ +++ +++ −
Perinatal − +++ ±a + −
Sexual ± ++ ±a ++ −
Clinical
Severity Mild Occasionally severe Moderate Occasionally severe Mild
Fulminant 0.1% 0.1–1% 0.1% 5–20%b 1–2%c
 Progression to chronicity None Occasional (1–10%) Common (85%) Commond Nonee
Carrier None (90% of neonates) 1.5–3.2% Variableg None
Cancer None 0.1–30%f + (neonatal infection) + ± None
Prognosis Excellent Worse with age, debility Moderate Acute, good; chronic, poor Good
Prophylaxis Ig, inactivated HBIG, recombinant vaccine None HBV vaccine (none for Vaccine
vaccine HBV carriers)
Therapy None Interferonh Pegylated interferon ribavirin,h Pegylated interferon ± Nonej
Lamivudineh telaprevir,h boceprevir,h
simeprevir,h sofosbuvir,
Adefovirh ledipasvir, paritaprevir/
Pegylated interferoni ritonavir,h ombitasvir,h

CHAPTER 339 Acute Viral Hepatitis

Entecaviri dasabuvir,h daclatasvir,h
Telbivudinei velpatasvir, grazoprevir,
elbasvir, glecaprevir,
Tenofovir disoproxil fumaratei pibrentasvir, voxilaprevir
Tenofovir alafenamidei
a
Primarily with HIV co-infection and high-level viremia in index case; more likely in persons with multiple sex partners or sexually transmitted diseases; risk ~5%. bUp
to 5% in acute HBV/HDV co-infection; up to 20% in HDV superinfection of chronic HBV infection. e10–20% in pregnant women. dIn acute HBV/HDV co-infection, the
frequency of chronicity is the same as that for HBV; in HDV superinfection, chronicity is invariable. eExcept as observed in immunosuppressed liver allograft recipients or
other immunosuppressed hosts. fVaries considerably throughout the world and in subpopulations within countries; see text. gCommon in Mediterranean countries; rare in
North America and western Europe. hNo longer recommended or not included in first-line therapy. iFirst-line agents. jAnecdotal reports and retrospective studies suggest
that pegylated interferon and/or ribavirin are effective in treating chronic hepatitis E, observed in immunocompromised persons; ribavirin monotherapy has been used
successfully in acute, severe hepatitis E.
Abbreviation: HBIG, hepatitis B immunoglobulin. See text for other abbreviations.

prevalence of anti-HAV declined in the United States. In developing susceptible to acute hepatitis A acquired during travel to endemic areas
countries, exposure, infection, and subsequent immunity are almost and from contaminated foods, especially those imported from endemic
universal in childhood. As the frequency of subclinical childhood countries. Recognized initially in San Diego, California, in 2016, wide-
infections declines in developed countries, a susceptible cohort of spread person-to-person outbreaks, attributed to fecally contaminated
adults emerges. Hepatitis A tends to be more symptomatic in adults; environments, of acute hepatitis A occurred primarily among homeless
therefore, paradoxically, as the frequency of HAV infection declines, persons and persons who were using injection drugs. Ultimately, this
the likelihood of clinically apparent, even severe, HAV illnesses outbreak extended to at least 32 states (highest number of cases in
increases in the susceptible adult population. Travel to endemic areas Kentucky), and by March 2020, 31,950 cases were reported, resulting in
is a common source of infection for adults from nonendemic areas. 19,548 hospitalizations (61% of cases) and 322 deaths (1% of reported
Important recognized epidemiologic foci of HAV infection include cases, 1.6% of hospitalized cases). The increased clinical severity, rate of
childcare centers, neonatal intensive care units, promiscuous men hospitalization, and death in these outbreaks can be attributed to their
who have sex with men, injection drug users, and unvaccinated close involving an older population (mean age ranging from 36 to 42 years),
contacts of newly arrived international adopted children, most of born before the introduction of universal childhood hepatitis A vacci-
whom emanate from countries with intermediate-to-high hepatitis nation and in whom clinical severity, as noted above, is higher than in
A endemicity. Although hepatitis A is rarely bloodborne, several out- children. Moreover, the affected homeless and drug-using populations
breaks have been recognized in recipients of clotting-factor concen- suffer from multiple comorbidities (including HBV or HCV co-infection)
trates. In the United States, the introduction of hepatitis A vaccination and disparities in access to health care. Addressing this multistate
programs among children from high-incidence states has resulted in outbreak has required a vigorous hepatitis A vaccination effort as well
a >70% reduction in the annual incidence of new HAV infections and as environmental sanitation/hygiene and education among these sus-
has shifted the burden of new infections from children to adults. In the ceptible populations.
2007–2012 U.S. Public Health Service National Health and Nutrition
Examination Survey (NHANES), the prevalence of anti-HAV in the Hepatitis B Percutaneous inoculation has long been recognized
U.S. population aged ≥20 years had declined to 24.2% from the 29.5% as a major route of hepatitis B transmission, but the outmoded desig-
measured in NHANES 1999–2006. While universal childhood vacci- nation “serum hepatitis” is an inaccurate label for the epidemiologic
nation accounted for a high prevalence of vaccine-induced immunity spectrum of HBV infection. As detailed below, most of the hepatitis
in children aged 2–19 years, the lowest age-specific prevalence of anti- transmitted by blood transfusion is not caused by HBV; moreover, in
HAV (16.1–17.6%) occurred in adults in the fourth and fifth decades approximately two-thirds of patients with acute type B hepatitis, no
(aged 30–49 years). This is a subgroup of the population who remain history of an identifiable percutaneous exposure can be elicited. We

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 2572 now recognize that many cases of hepatitis B result from less obvious adoption of safe behaviors in high-risk groups as well as screening and
modes of nonpercutaneous or covert percutaneous transmission. vaccination programs, the incidence of newly reported HBV infections
HBsAg has been identified in almost every body fluid from infected fell by >80% in the United States during the 1990s (with a low of 3050
persons, and at least some of these body fluids—most notably semen reported cases in 2013). Paralleling that trend, the imbalance between
and saliva—are infectious, albeit less so than serum, when adminis- cases in U.S.-born and foreign-born persons widened; currently,
tered percutaneously or nonpercutaneously to experimental animals. imported cases in non-U.S.-born persons outnumber domestic cases
Among the nonpercutaneous modes of HBV transmission, oral by manyfold; in NHANES 1999–2016, the 2016 prevalence of HBV
ingestion has been documented as a potential but inefficient route of infection was 0.24% in foreign-born versus 0.06% in U.S.-born persons;
exposure. By contrast, the two nonpercutaneous routes considered to in Asian persons, the 2016 prevalence of HBV infections was 3.85% in
have the greatest impact are intimate (especially sexual) contact and foreign-born versus 0.79% in U.S.-born persons. The introduction of
perinatal transmission. hepatitis B vaccine in the early 1980s and adoption of universal child-
In sub-Saharan Africa, intimate contact among toddlers is con- hood vaccination policies in many countries resulted in a dramatic,
sidered instrumental in contributing to the maintenance of the high ~90% decline in the incidence of new HBV infections in those coun-
frequency of hepatitis B in the population. Perinatal transmission tries as well as in the dire consequences of chronic infection, including
occurs primarily in infants born to mothers with chronic hepatitis B hepatocellular carcinoma. In the United States, as demonstrated in
or (rarely) mothers with acute hepatitis B during the third trimester of NHANES 2007–2012, following the 1991 implementation of universal
pregnancy or during the early postpartum period. Perinatal transmis- childhood vaccination, HBsAg seropositivity had declined in children
sion is uncommon in North America and western Europe but occurs aged 6–19 years to as low as 0.03%, an ~85% reduction. Populations
with great frequency and is the most important mode of HBV perpet- and groups for whom HBV infection screening is recommended are
uation in East Asia and developing countries. Although the precise listed in Table 339-3.
mode of perinatal transmission is unknown, and although ~10% of
infections may be acquired in utero, epidemiologic evidence suggests Hepatitis D Infection with HDV has a worldwide distribution,
that most infections occur approximately at the time of delivery and are but two epidemiologic patterns exist. In Mediterranean countries
not related to breast-feeding (which is not contraindicated in women (northern Africa, southern Europe, the Middle East), HDV infection is
with hepatitis B). The likelihood of perinatal transmission of HBV endemic among those with hepatitis B, and the disease is transmitted
correlates with the presence of HBeAg and high-level viral replication; predominantly by nonpercutaneous means, especially close personal
90% of HBeAg-positive mothers but only 10–15% of anti-HBe-positive contact. In nonendemic areas, such as the United States (where
mothers transmit HBV infection to their offspring. In most cases, acute hepatitis D is rare among persons with chronic hepatitis B) and northern
infection in the neonate is clinically asymptomatic, but the child is very Europe, HDV infection is confined to persons exposed frequently to
blood and blood products, primarily injection drug users (especially
PART 10

likely to remain chronically infected.

The 250–290 million persons with chronic HBV infection in the in HIV-infected injection drug users) and hemophiliacs. In the United
world constitute the main reservoir of hepatitis B in human beings. States, the prevalence of HDV infection in the national population was
Whereas serum HBsAg is infrequent (0.1–0.5%) in normal populations 0.02% in NHANES 1999–2012 and 0.11% in NHANES 2011–2016;
in the United States and western Europe, a prevalence of up to 5–10% however, among HBsAg-positive persons, the prevalence of HDV
Disorders of the Gastrointestinal System

has been found in East Asia, sub-Saharan Africa, and tropical coun- infection is highest in injection drug users (11–36%) and hemophiliacs
tries; the prevalence can be even higher in certain high-risk groups, (19%). HDV infection can be introduced into a population through
including persons with Down’s syndrome, lepromatous leprosy, leuke- drug users or by migration of persons from endemic to nonendemic
mia, Hodgkin’s disease, polyarteritis nodosa, and chronic renal disease areas. Thus, patterns of population migration and human behavior
on hemodialysis, as well as in injection drug users. facilitating percutaneous contact play important roles in the introduc-
Other groups with high rates of HBV infection include spouses of tion and amplification of HDV infection. Occasionally, the migrating
acutely infected persons; sexually promiscuous persons (especially pro- epidemiology of hepatitis D is expressed in explosive outbreaks of
miscuous men who have sex with men); health care workers exposed severe hepatitis, such as those that have occurred in remote South
to blood; persons who require repeated transfusions especially with American villages (e.g., “Lábrea fever” in the Amazon basin) as well
pooled blood-product concentrates (e.g., hemophiliacs); residents and as in urban centers in the United States. Ultimately, such outbreaks
staff of custodial institutions for the developmentally handicapped;
prisoners; and, to a lesser extent, family members of chronically TABLE 339-3 High-Risk Populations for Whom HBV Infection
infected patients. In volunteer blood donors, the prevalence of anti- Screening Is Recommended
HBs, a reflection of previous HBV infection, ranges from 5 to 10%, Persons born in countries/regions with a high (≥8%) and intermediate (≥2%)
but the prevalence is higher in lower socioeconomic strata, older age prevalence of HBV infection including immigrants and adopted children and
groups, and persons—including those mentioned above—exposed including persons born in the United States who were not vaccinated as infants
to blood products. Because of highly sensitive virologic screening and whose parents emigrated from areas of high HBV endemicity
(antigen, antibody, and nucleic acid testing) of donor blood, the risk Household and sexual contacts of persons with hepatitis B
of acquiring HBV infection from a blood transfusion is 1 in 230,000 Babies born to HBsAg-positive mothers
to 1 in 346,000. Persons who have used injection drugs
Prevalence of infection, modes of transmission, and human behav- Persons with multiple sexual contacts or a history of sexually transmitted disease
ior conspire to mold geographically different epidemiologic patterns Men who have sex with men
of HBV infection. In East Asia and Africa, hepatitis B, a disease of the Inmates of correctional facilities
newborn and young children, is perpetuated by a cycle of maternal- Persons with elevated alanine or aspartate aminotransferase levels
neonatal spread. In North America and western Europe, hepatitis B Blood/plasma/organ/tissue/semen donors
is primarily a disease of adolescence and early adulthood, the time of
Persons with HCV or HIV infection
life when intimate sexual contact and recreational and occupational
percutaneous exposures tend to occur. To some degree, however, this Hemodialysis patients
dichotomy between high-prevalence and low-prevalence geographic Pregnant women
regions has been minimized by immigration from high-prevalence Persons who are the source of blood or body fluids that would be an indication
to low-prevalence areas. For example, in the United States, NHANES for postexposure prophylaxis (e.g., needlestick, mucosal exposure, sexual
assault)
data from 2007 to 2012 revealed an overall prevalence of current HBV
infection (detectable HBsAg) of 0.3%; however, the prevalence in Asian Persons who require immunosuppressive or cytotoxic therapy (including
anti–tumor necrosis factor α therapy for rheumatologic or inflammatory bowel
persons, 93% of whom were foreign-born, was tenfold higher, 3.1%, disorders)
representing 50% of the U.S. national disease burden. As a result of

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 of hepatitis D—either of co-infections with acute hepatitis B or of high prevalences of HCV infection occur in certain countries such as 2573
superinfections in those already infected with HBV—may blur the dis- Egypt, where >20% of the population (as high as 50% in persons born
tinctions between endemic and nonendemic areas. On a global scale, prior to 1960) in some cities is infected. The high frequency in Egypt
HDV infection declined at the end of the 1990s. Even in Italy, an HDV- is attributable to contaminated equipment used for medical procedures
endemic area, public health measures introduced to control HBV and unsafe injection practices in the 1950s to 1980s (during a campaign
infection (e.g., mass hepatitis B vaccination) resulted during the 1990s to eradicate schistosomiasis with intravenous tartar emetic). Thanks to
in a 1.5%/year reduction in the prevalence of HDV infection. Still, the a 2018–2019 Egyptian government program to screen its entire adult
frequency of HDV infection during the first decade of the twenty- population (79% participation among >60 million people) for hepatitis
first century has not fallen below levels reached during the 1990s; the C and treat infected persons (2.2 million, 4.6% of those screened; of the
reservoir has been sustained by survivors infected during 1970–1980 83% with a documented outcome, 99% were cured; the cost to identify
and recent immigrants from still-endemic (e.g., eastern Europe and and cure a person was $130) with generic versions of direct-acting
Central Asia) to less-endemic countries. The current global prevalence antiviral (DAA) therapy (Chap. 341), hepatitis C has been nearly
of HDV infection has been estimated at 62–72 million people. Of the eliminated there.
eight HDV genotypes, genotype 1 is distributed worldwide, while the In the United States, African Americans and Mexican Americans
others are more geographically confined (e.g., genotypes 2 and 4 in have higher frequencies of HCV infection than whites. Data from
the Far East, 3 in South America, and 5–8 in Africa). NHANES showed that between 1988 and 1994, 30- to 40-year-old
men had the highest prevalence of HCV infection; however, in the
Hepatitis C Routine screening of blood donors for HBsAg and the NHANES survey conducted between 1999 and 2002, the peak age
elimination of commercial blood sources in the early 1970s reduced the decile had shifted to those aged 40–49 years; an increase in hepatitis
frequency of, but did not eliminate, transfusion-associated hepatitis. C–related mortality has paralleled this secular trend, increasing since
During the 1970s, the likelihood of acquiring hepatitis after transfusion 1995 predominantly in the 45- to 65-year age group. Thus, despite an
of voluntarily donated, HBsAg-screened blood was ~10% per patient 80% reduction in new reported HCV infections during the 1990s, the
(up to 0.9% per unit transfused); 90–95% of these cases were classified, prevalence of HCV infection in the population was sustained by an
based on serologic exclusion of hepatitis A and B, as “non-A, non-B” aging cohort that had acquired their infections three to four decades
hepatitis. For patients requiring transfusion of pooled products, such earlier, during the 1960s and 1970s, as a result predominantly of self-
as clotting factor concentrates, the risk was even higher, up to 20–30%. inoculation with recreational drugs. Retrospective phylogenetic mapping
During the 1980s, voluntary self-exclusion of blood donors with of >45,000 HCV genotype 1a isolates revealed that the hepatitis C epi-
risk factors for AIDS and then the introduction of donor screening demic emerged in the United States between 1940 and 1965, peaking in

CHAPTER 339 Acute Viral Hepatitis

for anti-HIV reduced further the likelihood of transfusion-associated 1950 and aligning temporally with the post–World War II expansion of
hepatitis to <5%. During the late 1980s and early 1990s, the intro- medical procedures (including reuse of glass syringes). Thus, HCV was
duction first of “surrogate” screening tests for non-A, non-B hepatitis amplified iatrogenically not only in Egypt but also in the United States;
(alanine aminotransferase [ALT] and anti-HBc, both shown to identify in the United States, the seeds sewn by medical procedures in the 1950s
blood donors with a higher likelihood of transmitting non-A, non-B were reaped in the 1960s and 1970s among transfusion recipients and
hepatitis to recipients) and, subsequently, after the discovery of HCV, injection drug users, even those whose drug use was confined to brief
progressively more sensitive immunoassays for anti-HCV and then the adolescent experimentation.
application of automated PCR testing of donated blood for HCV RNA In NHANES 2003–2010, the prevalence of HCV infection (HCV
reduced the risk of transfusion-associated hepatitis C even further, to RNA reactivity) in the United States had actually fallen to 1% (2.7
almost imperceptible levels ranging between 1 in 2.3 million transfu- million persons) from 1.3% (3.2 million) the decade before (NHANES
sions to 1 in 4.7 million transfusions. 1999–2002), attributable to deaths among the HCV-infected popu-
In addition to being transmitted by transfusion, hepatitis C can lation. In NHANES data from 2010–2014, the prevalence of current
be transmitted by other percutaneous routes, such as injection drug HCV infection (HCV RNA reactivity) had fallen even lower, to 0.65%
use. This virus can be transmitted by occupational exposure to blood, (1.7 million persons), coinciding with and attributable to the intro-
and the likelihood of infection is increased in hemodialysis units. Although duction of highly effective, oral DAA drugs (Chap. 341). As deaths
the frequency of transfusion-associated hepatitis C fell as a result of resulting from HIV infection fell after 1999, age-adjusted mortality
blood-donor screening, the overall frequency of reported hepatitis C associated with HCV infection surpassed that of HIV infection in 2007;
cases did not change until the 1990s, when the overall frequency of >70% of HCV-associated deaths occurred in the “baby boomer” cohort
reported cases fell by 80%, in parallel with a reduction in the number born between 1945 and 1965. By 2012, HCV mortality had surpassed
of new cases in injection drug users, the source of most of the HCV deaths from HIV, tuberculosis, hepatitis B, and 57 other notifiable
reservoir. After the exclusion of anti-HCV-positive plasma units from infectious diseases (i.e., all infectious diseases) reported to the CDC. In
the donor pool, rare, sporadic instances occurred of hepatitis C among NHANES 1999–2002, compared to the 1.6% prevalence of HCV infec-
recipients of immunoglobulin preparations for intravenous (but not tion in the population at large, the prevalence in the 1945–1965 birth
intramuscular) use. cohort was 3.2%, representing three-quarters of all infected persons.
Serologic evidence for HCV infection occurs in 90% of patients Therefore, in 2012, the CDC and, in 2013, the U.S. Preventive Services
with a history of transfusion-associated hepatitis (almost all occurring Task Force (USPSTF) recommended that all persons born between
before 1992, when second-generation HCV screening tests were intro- 1945 and 1965 be screened for hepatitis C, without ascertainment of
duced); hemophiliacs and others treated with clotting factors; injection risk, a recommendation shown to be cost-effective and predicted to
drug users; 60–70% of patients with sporadic “non-A, non-B” hepatitis identify 800,000 infected persons. Because of the availability of highly
who lack identifiable risk factors; 0.5% of volunteer blood donors; effective antiviral therapy, such screening would have the potential to
and, in the NHANES survey conducted in the United States between avert 200,000 cases of cirrhosis and 47,000 cases of hepatocellular car-
1999 and 2002, 1.6% of the general population in the United States, cinoma and to prevent 120,000 hepatitis-related deaths; with the avail-
which translated into 4.1 million persons (3.2 million with viremia), ability of the new generation of DAAs (efficacy >95%, see Chap. 341),
the majority of whom were unaware of their infections. Moreover, screening baby boomers and treating those with hepatitis C have been
such population surveys do not include higher-risk groups such as predicted to reduce the HCV-associated disease burden by 50–70%
incarcerated persons, homeless persons, and active injection drug through 2050.
users, indicating that the actual prevalence is even higher (estimated Still, persons with chronic hepatitis C identified by 1945–1965
to add an additional 1 million with anti-HCV antibody and 0.8 million birth-cohort screening are older than 50, and by the time they are iden-
with HCV RNA in a later cohort assessed in 2003–2010). Comparable tified, >20% already have advanced liver disease. In 2020, based on (1)
frequencies of HCV infection occur in most countries around the the 95–99% efficacy of all-oral, well-tolerated, highly effective DAAs;
world, with 71 million persons infected worldwide, but extraordinarily (2) the demonstration that the endpoint of DAA therapy (sustained

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 2574 virologic response) was associated with a marked decrease in liver and TABLE 339-4 High-Risk Populations for Whom HCV-Infection
all-cause mortality, cirrhosis, and hepatocellular carcinoma (Chap. 341); Screening Is Recommended
(3) a reduction in the initially high cost of DAA therapy; (4) the All adults aged 18–79 should be screened, a recommendation that supplants the
demonstration of higher cost-effectiveness of screening all adults earlier focus on persons born between 1945 and 1965
rather than birth-cohort screening; and (5) the shifting demographics Persons who have ever used injection drugs
of HCV infection (see below), especially since 2010, toward a younger Persons with HIV infection
population exposed through injection drug use, the American Associa- Hemophiliacs treated with clotting factor concentrates prior to 1987
tion for the Study of Liver Diseases and the Infectious Diseases Society
Persons who have ever undergone long-term hemodialysis
of America as well as the USPSTF and CDC expanded recommended
hepatitis C screening to all adolescents and adults aged 18–79 (and Persons with unexplained elevations of aminotransferase levels
because of the substantial increase in HCV infections among women Transfusion or transplantation recipients prior to July 1992
of child-bearing age [age 20–39], expanded such screening to pregnant Recipients of blood or organs from a donor found to be positive for hepatitis C
women). Children born to women with hepatitis C
Hepatitis C accounts for 40% of chronic liver disease and, before Health care, public safety, and emergency medical personnel following needle
the introduction of high-efficacy DAA therapy, was the most fre- injury or mucosal exposure to HCV-contaminated blood
quent indication for liver transplantation; hepatitis C is estimated to Sexual partners of persons with hepatitis C infection
account for 8000–10,000 deaths per year in the United States. The Pregnant women
distribution of HCV genotypes varies in different parts of the world.
Worldwide, genotype 1 is the most common. In the United States, of populations excluded from this NHANES analysis, the prevalence
genotype 1 accounts for 70% of HCV infections, whereas genotypes 2 would be even higher, 0.93% (2.27 million persons). This late tem-
and 3 account for the remaining 30%; among African Americans, the poral trend was attributed to the increase of acute cases in injections
frequency of genotype 1 is even higher (i.e., 90%). Genotype 4 pre- drug users, driven by increases in states most affected by the opioid/
dominates in Egypt; genotype 5 is localized to South Africa, genotype injection drug use epidemic. Also, in parallel with this trend, the prev-
6 to Hong Kong, and genotype 7 to Central Africa. Most asymptomatic alence of HCV infection in women aged 15–44 years (of child-bearing
blood donors found to have anti-HCV and ~20–30% of persons with age) doubled between 2016 and 2014; accordingly, screening of preg-
reported cases of acute hepatitis C do not fall into a recognized risk nant women for HCV infection is now recommended as well.
group; however, many such blood donors do recall risk-associated
behaviors when questioned carefully. Hepatitis E This type of hepatitis, identified in India, Asia, Africa,
As a bloodborne infection, HCV potentially can be transmitted the Middle East, and Central America (endemic areas), resembles
PART 10

sexually and perinatally; however, both modes of transmission are hepatitis A in its primarily enteric mode of spread. The commonly
inefficient for hepatitis C. Although 10–15% of patients with acute recognized cases occur after contamination of water supplies such as
hepatitis C report having potential sexual sources of infection, most after monsoon flooding, but sporadic, isolated cases occur. An epi-
studies have failed to identify sexual transmission of this agent. The demiologic feature that distinguishes HEV from other enteric agents is
chances of sexual and perinatal transmission have been estimated to the rarity of secondary person-to-person spread from infected persons
Disorders of the Gastrointestinal System

be ~5% but have shown in a prospective study to be only 1% between to their close contacts. Large waterborne outbreaks in endemic areas
monogamous sexual partners, well below comparable rates for HIV are linked to genotypes 1 and 2, arise in populations that are immune
and HBV infections. Moreover, sexual transmission appears to be con- to HAV, favor young adults, and account for antibody prevalences of
fined to such subgroups as persons with multiple sexual partners and 30–80%. The worldwide annual incidence of acute HEV infections
sexually transmitted diseases; for example, isolated clusters of sexually has been estimated conservatively to be at least 20 million (of which
transmitted HCV infection have been reported in HIV-infected men 3.3 million are symptomatic), rendering HEV infection as the most
who have sex with men. Breast-feeding does not increase the risk of common cause of acute viral hepatitis. In nonendemic areas of the
HCV infection between an infected mother and her infant. Infection world, such as the United States, clinically apparent acute hepatitis E is
of health workers is not dramatically higher than among the general extremely rare; however, during the 1988–1994 NHANES survey con-
population; however, health workers are more likely to acquire HCV ducted by the U.S. Public Health Service, the prevalence of anti-HEV
infection through accidental needle punctures, the efficiency of which was 21%, reflecting subclinical infections, infection with genotypes 3
is ~3%. Infection of household contacts is rare as well. and 4, predominantly in older males (>60 years). A repeat NHANES
Besides persons born between 1945 and 1965, other groups with study in 2009–2010, however, showed a substantial 70% two-decade
an increased frequency of HCV infection are listed in Table 339-4. In reduction in anti-HEV to only 6%, more consistent with the rarity of
immunosuppressed individuals, levels of anti-HCV may be undetect- acute hepatitis E in the United States than the previous NHANES result
able, and a diagnosis may require testing for HCV RNA. Although new would suggest and perhaps a reflection of a more specific anti-HEV
acute cases of hepatitis C are rare outside of the injection drug–using assay used in the second time period. Again, older age was associated
community, newly diagnosed cases are common among otherwise with anti-HEV seropositivity. In nonendemic areas, HEV accounts for
healthy persons who experimented briefly with injection drugs, as only a small proportion of cases of sporadic (labeled “autochthonous”
noted above, four or five decades earlier. Such instances usually remain or indigenous) hepatitis; however, cases imported from endemic areas
unrecognized for years, until unearthed by laboratory screening for have been found in the United States. Evidence supports a zoonotic
routine medical examinations, insurance applications, and attempted reservoir for HEV primarily in swine (but also in deer, camels, and
blood donation. Although, overall, the annual incidence of new rabbits), which may account for the mostly subclinical infections pri-
HCV infections has continued to fall, the rate of new infections has marily of genotypes 3 and 4 in nonendemic areas. A previously unrec-
been increasing since 2002, has accelerated since 2010 (tripling from ognized high distribution of HEV infection, linked to uncooked or
0.3/100,000 to 1.2/100,000 between 2009 and 2018), and has been undercooked pork-product ingestion, has been discovered in western
amplified by the recent epidemic of opioid use in a new cohort of Europe (e.g., in Germany, an estimated annual incidence of 300,000
young injection drug users aged 20–39 years (accounting for a 3.8-fold cases and a 17% prevalence of anti-HEV among adults; in France, a
increase in cases between 2010 and 2017 and for more than two-thirds 22% prevalence of anti-HEV in healthy blood donors).
of all acute cases), who, unlike older cohorts, had not learned to take
precautions to prevent bloodborne infections. Reflecting this emerging ■■CLINICAL AND LABORATORY FEATURES
development, the prevalence of current HCV infection (HCV RNA
reactivity) in the United States rose from 0.65% (1.7 million persons) Symptoms and Signs Acute viral hepatitis occurs after an incu-
in a 2010–2014 NHANES analysis to 0.84% (2.04 million persons) bation period that varies according to the responsible agent. Generally,
in a 2013–2014 NHANES analysis. Moreover, based on an estimate incubation periods for hepatitis A range from 15 to 45 days (mean,

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 4 weeks), for hepatitis B and D from 30 to 180 days (mean, 8–12 weeks), SGPT) increase to a variable degree during the prodromal phase of 2575
for hepatitis C from 15 to 160 days (mean, 7 weeks), and for hepatitis acute viral hepatitis and precede the rise in bilirubin level (Figs. 339-2
E from 14 to 60 days (mean, 5–6 weeks). The prodromal symptoms of and 339-4). The level of these enzymes, however, does not correlate
acute viral hepatitis are systemic and quite variable. Constitutional well with the degree of liver cell damage. Peak levels vary from ~400
symptoms of anorexia, nausea and vomiting, fatigue, malaise, arthral- to ~4000 IU or more; these levels are usually reached at the time the
gias, myalgias, headache, photophobia, pharyngitis, cough, and coryza patient is clinically icteric and diminish progressively during the recov-
may precede the onset of jaundice by 1–2 weeks. The nausea, vomiting, ery phase of acute hepatitis. The diagnosis of anicteric hepatitis is based
and anorexia are frequently associated with alterations in olfaction and on clinical features and on aminotransferase elevations.
taste. A low-grade fever between 38° and 39°C (100°–102°F) is more Jaundice is usually visible in the sclera or skin when the serum bil-
often present in hepatitis A and E than in hepatitis B or C, except when irubin value is >43 μmol/L (2.5 mg/dL). When jaundice appears, the
hepatitis B is heralded by a serum sickness–like syndrome; rarely, a serum bilirubin typically rises to levels ranging from 85 to 340 μmol/L
fever of 39.5°–40°C (103°–104°F) may accompany the constitutional (5–20 mg/dL). The serum bilirubin may continue to rise despite falling
symptoms. Dark urine and clay-colored stools may be noticed by the serum aminotransferase levels. In most instances, the total bilirubin is
patient from 1–5 days before the onset of clinical jaundice. equally divided between the conjugated and unconjugated fractions.
With the onset of clinical jaundice, the constitutional prodromal Bilirubin levels >340 μmol/L (20 mg/dL) extending and persisting late
symptoms usually diminish, but in some patients, mild weight loss into the course of viral hepatitis are more likely to be associated with
(2.5–5 kg) is common and may continue during the entire icteric phase. severe disease. In certain patients with underlying hemolytic anemia,
The liver becomes enlarged and tender and may be associated with however, such as glucose-6-phosphate dehydrogenase deficiency and
right upper quadrant pain and discomfort. Infrequently, patients pres- sickle cell anemia, a high serum bilirubin level is common, result-
ent with a cholestatic picture, suggesting extrahepatic biliary obstruc- ing from superimposed hemolysis. In such patients, bilirubin levels
tion. Splenomegaly and cervical adenopathy are present in 10–20% >513 μmol/L (30 mg/dL) have been observed and are not necessarily
of patients with acute hepatitis. Rarely, a few spider angiomas appear associated with a poor prognosis.
during the icteric phase and disappear during convalescence. During Neutropenia and lymphopenia are transient and are followed by a
the recovery phase, constitutional symptoms disappear, but usually relative lymphocytosis. Atypical lymphocytes (varying between 2 and
some liver enlargement and abnormalities in liver biochemical tests are 20%) are common during the acute phase. Measurement of the proth-
still evident. The duration of the posticteric phase is variable, ranging rombin time (PT) is important in patients with acute viral hepatitis,
from 2 to 12 weeks, and is usually more prolonged in acute hepatitis B because a prolonged value may reflect a severe hepatic synthetic defect,
and C. Complete clinical and biochemical recovery is to be expected signify extensive hepatocellular necrosis, and indicate a worse progno-

CHAPTER 339 Acute Viral Hepatitis

1–2 months after all cases of hepatitis A and E and 3–4 months after the sis. Occasionally, a prolonged PT may occur with only mild increases in
onset of jaundice in three-quarters of uncomplicated, self-limited cases the serum bilirubin and aminotransferase levels. Prolonged nausea and
of hepatitis B and C (among healthy adults, acute hepatitis B is self-lim- vomiting, inadequate carbohydrate intake, and poor hepatic glycogen
ited in 95–99%, whereas hepatitis C is self-limited in only ~15–20%). reserves may contribute to hypoglycemia noted occasionally in patients
In the remainder, biochemical recovery may be delayed. A substantial with severe viral hepatitis. Serum alkaline phosphatase may be normal
proportion of patients with viral hepatitis never become icteric. or only mildly elevated, whereas a fall in serum albumin is uncommon
Infection with HDV can occur in the presence of acute or chronic in uncomplicated acute viral hepatitis. In some patients, mild and
HBV infection; the duration of HBV infection determines the dura- transient steatorrhea has been noted, as well as slight microscopic
tion of HDV infection. When acute HDV and HBV infections occur hematuria and minimal proteinuria.
simultaneously, clinical and biochemical features may be indistinguish- A diffuse but mild elevation of the γ globulin fraction is common
able from those of HBV infection alone, although occasionally, they during acute viral hepatitis. Serum IgG and IgM levels are elevated in
are more severe. As opposed to patients with acute HBV infection, about one-third of patients during the acute phase of viral hepatitis,
patients with chronic HBV infection can support HDV replication but the serum IgM level is elevated more characteristically during
indefinitely, as when acute HDV infection occurs in the presence of acute hepatitis A. During the acute phase of viral hepatitis, antibodies
a nonresolving acute HBV infection or, more commonly, when acute to smooth muscle and other cell constituents may be present, and low
hepatitis D is superimposed on underlying chronic hepatitis B. In such titers of rheumatoid factor, nuclear antibody, and heterophile antibody
cases, the HDV superinfection appears as a clinical exacerbation or an can also be found occasionally. In hepatitis C and D, antibodies to
episode resembling acute viral hepatitis in someone already chronically LKM may occur; however, the species of LKM antibodies in the two
infected with HBV. Superinfection with HDV in a patient with chronic types of hepatitis are different from each other as well as from the
hepatitis B often leads to clinical deterioration (see below). LKM antibody species characteristic of autoimmune hepatitis type 2
In addition to superinfections with other hepatitis agents, acute (Chap. 341). The autoantibodies in viral hepatitis are nonspecific and
hepatitis-like clinical events in persons with chronic hepatitis B may can also be associated with other viral and systemic diseases. In con-
accompany spontaneous HBeAg to anti-HBe seroconversion or spon- trast, virus-specific antibodies, which appear during and after hepatitis
taneous reactivation (i.e., reversion from relatively nonreplicative to virus infection, are serologic markers of diagnostic importance.
replicative infection). Such reactivations can occur as well in thera- As described above, serologic tests are available routinely with
peutically immunosuppressed patients with chronic HBV infection which to establish a diagnosis of hepatitis A, B, D, and C. Tests for fecal
when cytotoxic/immunosuppressive drugs are withdrawn; in these or serum HAV are not routinely available. Therefore, a diagnosis of
cases, restoration of immune competence is thought to allow resump- hepatitis A is based on detection of IgM anti-HAV during acute illness
tion of previously checked cell-mediated immune cytolysis of HBV- (Fig. 339-2). Rheumatoid factor can give rise to false-positive results
infected hepatocytes. Occasionally, acute clinical exacerbations of in this test.
chronic hepatitis B may represent the emergence of a precore mutant A diagnosis of HBV infection can usually be made by detection
(see “Virology and Etiology”), and the subsequent course in such of HBsAg in serum. Infrequently, levels of HBsAg are too low to be
patients may be characterized by periodic exacerbations. Cytotoxic detected during acute HBV infection, even with contemporary, highly
chemotherapy can lead to reactivation of chronic hepatitis C as well, sensitive immunoassays. In such cases, the diagnosis can be established
and treatment with other immunomodulators, such as monoclonal by the presence of IgM anti-HBc.
antibodies against anti-TNF-α and other cytokines and especially the The titer of HBsAg bears little relation to the severity of clinical
B-cell (CD20)–depleting antibody rituximab, can lead to reactivation disease. Indeed, an inverse correlation exists between the serum con-
of both hepatitis B and C. centration of HBsAg and the degree of liver cell damage. For example,
titers are highest in immunosuppressed patients, lower in patients with
Laboratory Features The serum aminotransferases aspartate chronic liver disease (but higher in mild chronic than in severe chronic
aminotransferase (AST) and ALT (previously designated SGOT and hepatitis), and very low in patients with acute fulminant hepatitis.

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 2576 These observations suggest that in hepatitis B the degree of liver cell sensitivity, amplification assays remain reactive well below the current
damage and the clinical course are related to variations in the patient’s 103–104 IU/mL threshold for infectivity and liver injury. These markers
immune response to HBV rather than to the amount of circulating are useful in following the course of HBV replication in patients with
HBsAg. In immunocompetent persons, however, a correlation exists chronic hepatitis B receiving antiviral chemotherapy (Chap. 341).
between markers of HBV replication and liver injury (see below). Except for the early decades of life after perinatally acquired HBV
Another important serologic marker in patients with hepatitis B is infection (see above), in immunocompetent adults with chronic
HBeAg. Its principal clinical usefulness is as an indicator of relative hepatitis B, a general correlation exists between the level of HBV rep-
infectivity. Because HBeAg is invariably present during early acute lication, as reflected by the level of serum HBV DNA, and the degree
hepatitis B, HBeAg testing is indicated primarily in chronic infection. of liver injury. High-serum HBV DNA levels, increased expression of
In patients with hepatitis B surface antigenemia of unknown viral antigens, and necroinflammatory activity in the liver go hand
duration (e.g., blood donors found to be HBsAg-positive) testing for in hand unless immunosuppression interferes with cytolytic T-cell
IgM anti-HBc may be useful to distinguish between acute or recent responses to virus-infected cells; reduction of HBV replication with
infection (IgM anti-HBc-positive) and chronic HBV infection (IgM antiviral drugs tends to be accompanied by an improvement in liver
anti-HBc-negative, IgG anti-HBc-positive). A false-positive test for histology. Among patients with chronic hepatitis B, high levels of
IgM anti-HBc may be encountered in patients with high-titer rheu- HBV DNA increase the risk of cirrhosis, hepatic decompensation, and
matoid factor. Also, IgM anti-HBc may be reexpressed during acute hepatocellular carcinoma (see “Complications and Sequelae”).
reactivation of chronic hepatitis B. In patients with hepatitis C, an episodic pattern of aminotransferase
Anti-HBs is rarely detectable in the presence of HBsAg in patients elevation is common. A specific serologic diagnosis of hepatitis C can
with acute hepatitis B, but 10–20% of persons with chronic HBV infec- be made by demonstrating the presence in serum of anti-HCV. When
tion may harbor low-level anti-HBs. This antibody is directed not contemporary immunoassays are used, anti-HCV can be detected in
against the common group determinant, a, but against the heterotypic acute hepatitis C during the initial phase of elevated aminotransfer-
subtype determinant (e.g., HBsAg of subtype ad with anti-HBs of ase activity and remains detectable after recovery (which is rare) and
subtype y). In most cases, this serologic pattern cannot be attributed during chronic infection (common). Nonspecificity can confound
to infection with two different HBV subtypes but, instead, is thought immunoassays for anti-HCV, especially in persons with a low prior
(based on the clonal selection theory of antibody diversity) to reflect probability of infection, such as volunteer blood donors, or in persons
the stimulation of a related clone of antibody-forming cells and is with circulating rheumatoid factor, which can bind nonspecifically to
not a harbinger of imminent HBsAg clearance. When such antibody assay reagents; testing for HCV RNA can be used in such settings to
is detected, its presence is of no recognized clinical significance (see distinguish between true-positive and false-positive anti-HCV deter-
“Virology and Etiology”). minations. Assays for HCV RNA are the most sensitive tests for HCV
PART 10

After immunization with hepatitis B vaccine, which consists of infection and represent the “gold standard” in establishing a diagnosis
HBsAg alone, anti-HBs is the only serologic marker to appear. The of hepatitis C. HCV RNA can be detected even before acute elevation
commonly encountered serologic patterns of hepatitis B and their of aminotransferase activity and before the appearance of anti-HCV in
interpretations are summarized in Table 339-5. Tests for the detec- patients with acute hepatitis C. In addition, HCV RNA remains detect-
tion of HBV DNA in liver and serum are now available. Like HBeAg, able indefinitely, continuously in most but intermittently in some, in
Disorders of the Gastrointestinal System

serum HBV DNA is an indicator of HBV replication, but tests for HBV patients with chronic hepatitis C (detectable as well in some persons
DNA are more sensitive and quantitative. First-generation hybridiza- with normal liver tests, i.e., inactive carriers). In the very small minor-
tion assays for HBV DNA had a sensitivity of 105−106 virions/mL, a ity of patients with hepatitis C who lack anti-HCV, a diagnosis can be
relative threshold below which infectivity and liver injury are limited supported by detection of HCV RNA. If all these tests are negative and
and HBeAg is usually undetectable. Currently, testing for HBV DNA the patient has a well-characterized case of hepatitis after percutaneous
has shifted from insensitive hybridization assays to amplification exposure to blood or blood products, a diagnosis of hepatitis caused by
assays (e.g., the PCR-based assay, which can detect as few as 10 or an unidentified agent can be entertained.
100 virions/mL); among the commercially available PCR assays, Amplification techniques are required to detect HCV RNA. Cur-
the most useful are those with the highest sensitivity (5–10 IU/mL) rently, such target amplification (i.e., synthesis of multiple cop-
and the largest dynamic range (100–109 IU/mL). With increased ies of the viral genome) is achieved by PCR, in which the viral
RNA is reverse transcribed to complemen-
TABLE 339-5 Commonly Encountered Serologic Patterns of Hepatitis B Infection tary DNA and then amplified by repeated
cycles of DNA synthesis. Quantitative PCR
HBsAg ANTI-HBs ANTI-HBc HBeAg ANTI-HBe INTERPRETATION
assays provide a measurement of relative
+ − IgM + − Acute hepatitis B, high infectivity a
“viral load”; current PCR assays have a
+ − IgG + − Chronic hepatitis B, high infectivity sensitivity of 10 (lower limit of detection)
+ − IgG − + 1. Late acute or chronic hepatitis B, low to 25 (lower limit of quantitation) IU/mL
infectivity and a wide dynamic range (10–107 IU/mL).
2. HBeAg-negative (“precore-mutant”) Determination of HCV RNA level is not a
hepatitis B (chronic or, rarely, acute) reliable marker of disease severity or prog-
+ + + +/− +/− 1. HBsAg of one subtype and heterotypic nosis but is helpful in predicting relative
anti-HBs (common) responsiveness to antiviral therapy. The same
2. Process of seroconversion from HBsAg to is true for determinations of HCV genotype
anti-HBs (rare) (Chap. 341). Of course, HCV RNA monitor-
− − IgM +/− +/− 1. Acute hepatitis Ba ing during and after antiviral therapy is the
2. Anti-HBc “window” sine qua non for determining on-treatment
− − IgG − +/− 1. Low-level hepatitis B carrier and durable responsiveness.
2. Hepatitis B in remote past A proportion of patients with hepatitis C
− + IgG − +/− Recovery from hepatitis B have isolated anti-HBc in their blood, a reflec-
tion of a common risk in certain populations
− + − − − 1. Immunization with HBsAg (after vaccination)
of exposure to multiple bloodborne hepatitis
2. Hepatitis B in the remote past (?) agents. The anti-HBc in such cases is almost
3. False-positive invariably of the IgG class and usually rep-
a
IgM anti-HBc may reappear during acute reactivation of chronic hepatitis B. resents HBV infection in the remote past
Note: See text for abbreviations. (HBV DNA undetectable); it rarely represents

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 current HBV infection with low-level virus carriage. Detectable anti- establish the diagnosis. Absence of all serologic markers is consistent 2577
HCV in the absence of HCV RNA signifies spontaneous or therapeuti- with a diagnosis of “non-A, non-B, non-C” hepatitis (no other proven
cally induced recovery from (“cured”) hepatitis C. human hepatitis viruses have been identified), if the epidemiologic
The presence of HDV infection can be identified by demonstrating setting is appropriate.
intrahepatic HDV antigen or, more practically, an anti-HDV serocon- In patients with chronic hepatitis, initial testing should consist of
version (a rise in titer of anti-HDV or de novo appearance of anti- HBsAg and anti-HCV. Anti-HCV supports and HCV RNA testing
HDV). Circulating HDV antigen, also diagnostic of acute infection, is establishes the diagnosis of chronic hepatitis C. If a serologic diagno-
detectable only briefly, if at all. Because anti-HDV is often undetectable sis of chronic hepatitis B is made, testing for HBeAg and anti-HBe is
once HBsAg disappears, retrospective serodiagnosis of acute self-lim- indicated to evaluate relative infectivity. Testing for HBV DNA in such
ited, simultaneous HBV and HDV infection is difficult. Early diagnosis patients provides a more quantitative and sensitive measure of the
of acute infection may be hampered by a delay of up to 30–40 days in level of virus replication and therefore is very helpful during antiviral
the appearance of anti-HDV. therapy (Chap. 341). In patients with chronic hepatitis B and normal
When a patient presents with acute hepatitis and has HBsAg and aminotransferase activity in the absence of HBeAg, serial testing over
anti-HDV in serum, determination of the class of anti-HBc is helpful time is often required to distinguish between inactive carriage and
in establishing the relationship between infection with HBV and HDV. HBeAg-negative chronic hepatitis B with fluctuating virologic and
Although IgM anti-HBc does not distinguish absolutely between acute necroinflammatory activity. In persons with hepatitis B, testing for
and chronic HBV infection, its presence is a reliable indicator of recent anti-HDV is useful in those with severe and fulminant disease, with
infection and its absence a reliable indicator of infection in the remote severe chronic disease, with chronic hepatitis B and acute hepatitis-like
past. In simultaneous acute HBV and HDV infections, IgM anti-HBc exacerbations, with frequent percutaneous exposures, and from areas
will be detectable, whereas in acute HDV infection superimposed on where HDV infection is endemic.
chronic HBV infection, anti-HBc will be of the IgG class. Assays for
HDV RNA, available in specialized laboratories and yet to be standard- ■■PROGNOSIS
ized, can be used to confirm HDV infection and to monitor treatment Virtually all previously healthy patients with hepatitis A recover com-
during chronic infection. pletely with no clinical sequelae. Similarly, in acute hepatitis B, 95–99%
The serologic/virologic course of events during acute hepatitis E is of previously healthy adults have a favorable course and recover
entirely analogous to that of acute hepatitis A, with brief fecal sheddingcompletely. Certain clinical and laboratory features, however, suggest
of virus and viremia and an early IgM anti-HEV response that predom- a more complicated and protracted course. Patients of advanced age
inates during approximately the first 3 months but is eclipsed thereafter and with serious underlying medical disorders may have a prolonged

CHAPTER 339 Acute Viral Hepatitis

by long-lasting IgG anti-HEV. Diagnostic tests of varying reliability for course and are more likely to experience severe hepatitis. Initial pre-
hepatitis E are commercially available outside the United States; in the senting features such as ascites, peripheral edema, and symptoms of
United States, although tests for HEV infection are not approved by the hepatic encephalopathy suggest a poorer prognosis. In addition, a
FDA, reliable diagnostic serologic/virologic assays can be performed at prolonged PT, low serum albumin level, hypoglycemia, and very high
the CDC or other commercial or academic laboratories. serum bilirubin values suggest severe hepatocellular disease. Patients
with these clinical and laboratory features deserve prompt hospital
Liver biopsy is rarely necessary or indicated in acute viral hepatitis,
except when the diagnosis is questionable or when clinical evidence admission. The case-fatality rate in hepatitis A and B is very low
suggests a diagnosis of chronic hepatitis. (~0.1%) but is increased by advanced age and underlying debilitating
A diagnostic algorithm can be applied in the evaluation of cases of disorders. Among patients ill enough to be hospitalized for acute
acute viral hepatitis. A patient with acute hepatitis should undergo four hepatitis B, the fatality rate is 1%. Hepatitis C is less severe during the
serologic tests: HBsAg, IgM anti-HAV, IgM anti-HBc, and anti-HCV acute phase than hepatitis B and is more likely to be anicteric; fatalities
(Table 339-6). The presence of HBsAg, with or without IgM anti-HBc, are rare, but the precise case-fatality rate is not known. In outbreaks of
represents HBV infection. If IgM anti-HBc is present, the HBV infec- waterborne hepatitis E in India and Asia, the case-fatality rate is 1–2%
tion is considered acute; if IgM anti-HBc is absent, the HBV infection and up to 10–20% in pregnant women. Contributing to fulminant
is considered chronic. A diagnosis of acute hepatitis B can be made in hepatitis E in endemic countries (but only very rarely or not at all in
the absence of HBsAg when IgM anti-HBc is detectable. A diagnosis nonendemic countries) are instances of acute hepatitis E superimposed
of acute hepatitis A is based on the presence of IgM anti-HAV. If IgM on underlying chronic liver disease (“acute-on-chronic” liver disease).
anti-HAV coexists with HBsAg, a diagnosis of simultaneous HAV and Patients with simultaneous acute hepatitis B and D do not necessarily
HBV infections can be made; if IgM anti-HBc (with or without HBsAg) experience a higher mortality rate than do patients with acute hepatitis
is detectable, the patient has simultaneous acute hepatitis A and B, B alone; however, in several outbreaks of acute simultaneous HBV
and if IgM anti-HBc is undetectable, the patient has acute hepatitis A and HDV infection among injection drug users, the case-fatality rate
superimposed on chronic HBV infection. The presence of anti-HCV was ~5%. When HDV superinfection occurs in a person with chronic
supports a diagnosis of acute hepatitis C. Occasionally, testing for HCV hepatitis B, the likelihood of fulminant hepatitis and death is increased
RNA or repeat anti-HCV testing later during the illness is necessary to substantially. Although the case-fatality rate for hepatitis D is not
known definitively, in outbreaks of severe
TABLE 339-6 Simplified Diagnostic Approach in Patients Presenting with Acute Hepatitis HDV superinfection in isolated popula-
SEROLOGIC TESTS OF PATIENT’S SERUM tions with a high hepatitis B carrier rate
(“Lábrea fever”), a mortality rate >20% has
IgM IgM been recorded.
HBsAg ANTI-HAV ANTI-HBc ANTI-HCV DIAGNOSTIC INTERPRETATION
+ − + − Acute hepatitis B ■■COMPLICATIONS AND
+ − − − Chronic hepatitis B SEQUELAE
+ + − − Acute hepatitis A superimposed on chronic hepatitis B A small proportion of patients with hepa-
+ + + − Acute hepatitis A and B titis A experience relapsing hepatitis weeks
− + − − Acute hepatitis A to months after apparent recovery from
acute hepatitis. Relapses are characterized
− + + − Acute hepatitis A and B (HBsAg below detection
threshold) by recurrence of symptoms, aminotrans-
ferase elevations, occasional jaundice, and
− − + − Acute hepatitis B (HBsAg below detection threshold)
fecal excretion of HAV. Another unusual
− − − + Acute hepatitis C variant of acute hepatitis A is cholestatic
Note: See text for abbreviations. hepatitis, characterized by protracted

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 2578 cholestatic jaundice and pruritus. Rarely, liver test abnormalities per- have IgG anti-HBc in serum; anti-HBs is either undetected or detected
sist for many months, even up to 1 year. Even when these complications at low titer against the opposite subtype specificity of the antigen (see
occur, hepatitis A remains self-limited and does not progress to chronic “Laboratory Features”). These patients may (1) be inactive carriers; (2)
liver disease. During the prodromal phase of acute hepatitis B, a serum have low-grade, mild chronic hepatitis; or (3) have moderate to severe
sickness–like syndrome characterized by arthralgia or arthritis, rash, chronic hepatitis with or without cirrhosis. The likelihood of remain-
angioedema, and, rarely, hematuria and proteinuria may develop in ing chronically infected after acute HBV infection is especially high
5–10% of patients. This syndrome occurs before the onset of clinical among neonates, persons with Down’s syndrome, chronically hemo-
jaundice, and these patients are often diagnosed erroneously as having dialyzed patients, and immunosuppressed patients, including persons
rheumatologic diseases. The diagnosis can be established by measuring with HIV infection.
serum aminotransferase levels, which are almost invariably elevated, Chronic hepatitis is an important late complication of acute hepatitis B
and serum HBsAg. As noted above, EMC is an immune-complex dis- occurring in a small proportion of patients with acute disease but
ease that can complicate chronic hepatitis C and is part of a spectrum more common in those who present with chronic infection without
of B-cell lymphoproliferative disorders, which, in rare instances, can having experienced an acute illness, as occurs typically after neonatal
evolve to B-cell lymphoma (Chap. 108). Attention has been drawn as infection or after infection in an immunosuppressed host (Chap. 341).
well to associations between hepatitis C and such cutaneous disorders The following clinical and laboratory features suggest progression of
as porphyria cutanea tarda and lichen planus. A mechanism for these acute hepatitis to chronic hepatitis: (1) lack of complete resolution of
associations is unknown. Related to the reliance of HCV on lipoprotein clinical symptoms of anorexia, weight loss, fatigue, and the persistence
secretion and assembly pathways and on interactions of HCV with of hepatomegaly; (2) the presence of bridging/interface or multilobular
glucose metabolism, HCV infection may be complicated by hepatic hepatic necrosis on liver biopsy during protracted, severe acute viral
steatosis, hypercholesterolemia, insulin resistance (and other manifes- hepatitis; (3) failure of the serum aminotransferase, bilirubin, and
tations of the metabolic syndrome), and type 2 diabetes mellitus; both globulin levels to return to normal within 6–12 months after the acute
hepatic steatosis and insulin resistance appear to accelerate hepatic illness; and (4) the persistence of HBeAg for >3 months or HBsAg for
fibrosis and blunt responsiveness to interferon-based antiviral therapy >6 months after acute hepatitis.
(Chap. 341). Finally, chronic hepatitis C has been linked to multiple Although acute hepatitis D infection does not increase the likeli-
extrahepatic disorders, including cardiovascular and cerebrovascular hood of chronicity of simultaneous acute hepatitis B, hepatitis D has
disease, renal disease, rheumatologic/immunologic disorders, mental the potential for contributing to the severity of chronic hepatitis B.
health and cognitive disorders (many patients describe “brain fog”), Hepatitis D superinfection can transform inactive or mild chronic
and, in addition to hepatocellular carcinoma, nonliver malignancies. hepatitis B into severe, progressive chronic hepatitis and cirrhosis; it
The most feared complication of viral hepatitis is fulminant hepatitis also can accelerate the course of chronic hepatitis B and accelerate
PART 10

(massive hepatic necrosis); fortunately, this is a rare event. Fulminant the risk of hepatocellular carcinoma. Some HDV superinfections in
hepatitis is seen primarily in hepatitis B, D, and E, but rare fulminant patients with chronic hepatitis B lead to fulminant hepatitis. As defined
cases of hepatitis A occur primarily in older adults and in persons with in longitudinal studies over three decades, the annual rate of cirrhosis
underlying chronic liver disease, including, according to some reports, in patients with chronic hepatitis D is 4%. Although HDV and HBV
chronic hepatitis B and C. Hepatitis B accounts for >50% of fulminant infections are associated with severe liver disease, mild hepatitis and
Disorders of the Gastrointestinal System

cases of viral hepatitis, a sizable proportion of which are associated even inactive carriage have been identified in some patients, and the
with HDV infection and another proportion with underlying chronic disease may become indolent beyond the early years of infection.
hepatitis C. Fulminant hepatitis is hardly ever seen in hepatitis C, but After acute HCV infection, the likelihood of remaining chronically
hepatitis E, as noted above, can be complicated by fatal fulminant hep- infected approaches 85–90%. Although many patients with chronic
atitis in 1–2% of all cases and in up to 20% of cases in pregnant women. hepatitis C have no symptoms, cirrhosis may develop in as many
Patients usually present with signs and symptoms of encephalopathy as 20% within 10–20 years of acute illness; in some series of cases
that may evolve to deep coma. The liver is usually small and the PT reported by referral centers, cirrhosis has been reported in as many
excessively prolonged. The combination of rapidly shrinking liver size, as 50% of patients with chronic hepatitis C. Among cirrhotic patients
rapidly rising bilirubin level, and marked prolongation of the PT, even with chronic hepatitis C, the annual risk of hepatic decompensation
as aminotransferase levels fall, together with clinical signs of confu- is ~4%. Although prior to the availability of highly effective DAA
sion, disorientation, somnolence, ascites, and edema, indicates that therapy during the second decade of the twenty-first century chronic
the patient has hepatic failure with encephalopathy. Cerebral edema hepatitis C accounted for at least 40% of cases of chronic liver disease
is common; brainstem compression, gastrointestinal bleeding, sepsis, and of patients undergoing liver transplantation for end-stage liver
respiratory failure, cardiovascular collapse, and renal failure are ter- disease in the United States and Europe, in the majority of patients
minal events. The mortality rate is exceedingly high (>80% in patients with chronic hepatitis C, morbidity and mortality are limited during
with deep coma), but patients who survive may have a complete bio- the initial 20 years after the onset of infection. Progression of chronic
chemical and histologic recovery. If a donor liver can be located in hepatitis C may be influenced by advanced age of acquisition, long
time, liver transplantation may be lifesaving in patients with fulminant duration of infection, immunosuppression, coexisting excessive alco-
hepatitis (Chap. 345). hol use, concomitant hepatic steatosis, other hepatitis virus infection,
Documenting the disappearance of HBsAg after apparent clinical or HIV co-infection. In fact, instances of severe and rapidly progres-
recovery from acute hepatitis B is particularly important. Before lab- sive chronic hepatitis B and C are being recognized with increasing
oratory methods were available to distinguish between acute hepatitis frequency in patients with HIV infection (Chap. 202). In contrast, nei-
and acute hepatitis–like exacerbations (spontaneous reactivations) of ther HAV nor HEV causes chronic liver disease in immunocompetent
chronic hepatitis B, observations suggested that ~10% of previously hosts; however, cases of chronic hepatitis E (including cirrhosis and
healthy patients remained HBsAg positive for >6 months after the end-stage liver disease and even hepatocellular carcinoma) have been
onset of clinically apparent acute hepatitis B. One-half of these persons observed in immunosuppressed organ-transplant recipients, persons
cleared the antigen from their circulations during the next several receiving cytotoxic chemotherapy, and persons with HIV infection.
years, but the other 5% remained chronically HBsAg positive. More Among patients with chronic hepatitis (e.g., caused by hepatitis B or C,
recent observations suggest that the true rate of chronic infection after alcohol, etc.) in endemic countries, hepatitis E has been reported as the
clinically apparent acute hepatitis B is as low as 1% in normal, immu- cause of acute-on-chronic liver failure; however, in most experiences
nocompetent, young adults. Earlier, higher estimates may have been among patients from nonendemic countries, HEV has not been found
confounded by inadvertent inclusion of acute exacerbations in chron- to contribute commonly to hepatic decompensation in patients with
ically infected patients; these patients, chronically HBsAg positive chronic hepatitis.
before exacerbation, were unlikely to seroconvert to HBsAg negative Persons with chronic hepatitis B, particularly those infected in
thereafter. Whether the rate of chronicity is 10% or 1%, such patients infancy or early childhood and especially those with HBeAg and/or

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 high-level HBV DNA, have an enhanced risk of hepatocellular car- Wilson’s disease, α1 antitrypsin deficiency) and nonalcoholic fatty liver 2579
cinoma. The risks of cirrhosis and hepatocellular carcinoma increase disease are confused with acute viral hepatitis. Among patients with
with the level of HBV replication. The annual rate of hepatocellular biochemical evidence for severe liver injury, i.e., aminotransferase lev-
carcinoma in patients with chronic hepatitis D and cirrhosis is ~3%. els of ≥1000 IU/L, the most common causes are ischemic liver injury,
The risk of hepatocellular carcinoma is increased as well in patients drug-induced liver injury (especially caused by acetaminophen), acute
with chronic hepatitis C, almost exclusively in patients with cirrhosis, viral hepatitis, and pancreaticobiliary disorders.
and almost always after at least several decades, usually after three
decades of disease (Chap. 82). Among such cirrhotic patients with
chronic hepatitis C, the annual risk of hepatocellular carcinoma is TREATMENT
~1–4%. Acute Viral Hepatitis
Rare complications of viral hepatitis include pancreatitis, myocar-
ditis, atypical pneumonia, aplastic anemia, transverse myelitis, and Most persons with acute hepatitis (especially hepatitis A, B, and E)
peripheral neuropathy. In children, hepatitis B may present rarely with recover spontaneously and do not require specific antiviral therapy.
anicteric hepatitis, a nonpruritic papular rash of the face, buttocks, and In hepatitis B, among previously healthy adults who present with
limbs, and lymphadenopathy (papular acrodermatitis of childhood or clinically apparent acute hepatitis, recovery occurs in ~99%; there-
Gianotti-Crosti syndrome). fore, antiviral therapy is not likely to improve the rate of recovery
Rarely, autoimmune hepatitis (Chap. 341) can be triggered by a and is not required. In rare instances of severe acute hepatitis B,
bout of otherwise self-limited acute hepatitis, as reported after acute treatment with a nucleoside analogue at oral doses used to treat
hepatitis A, B, and C. chronic hepatitis B (Chap. 341) has been attempted successfully.
Although clinical trials have not been done to establish the efficacy
■■DIFFERENTIAL DIAGNOSIS or duration of this approach, most authorities would recommend
Viral diseases such as infectious mononucleosis; those due to cytomeg- institution of antiviral therapy with a nucleoside analogue (ente-
alovirus, herpes simplex, and coxsackieviruses; and toxoplasmosis may cavir or tenofovir, the most potent and least resistance-prone
share certain clinical features with viral hepatitis and cause elevations agents) for severe, but not mild-moderate, acute hepatitis B. Treat-
in serum aminotransferase and, less commonly, in serum bilirubin ment should continue until 3 months after HBsAg seroconversion
levels. Tests such as the differential heterophile and serologic tests for or 6 months after HBeAg seroconversion.
these agents may be helpful in the differential diagnosis if HBsAg, In typical cases of acute hepatitis C, recovery is rare (~15–20%
anti-HBc, IgM anti-HAV, and anti-HCV determinations are negative. in most experiences), and progression to chronic hepatitis is the

CHAPTER 339 Acute Viral Hepatitis

Aminotransferase elevations can accompany almost any systemic rule. Patients with jaundice, those with HCV genotype 1, women,
viral infection, including the coronavirus SARS-CoV-2 (~10% of all and those with earlier age of infection, lower level of HCV RNA,
cases and up to half of severe cases); other rare causes of liver injury HBV co-infection, and absence of current injection drug use are
confused with viral hepatitis are infections with Leptospira, Candida, more likely to recover from acute hepatitis C, as are persons who
Brucella, Mycobacteria, and Pneumocystis. A complete drug history have genetic markers associated with spontaneous recovery (IL28B
is particularly important because many drugs and certain anesthetic CC haplotype).
agents can produce a picture of either acute hepatitis or cholestasis Because spontaneous recovery can occur and because most cases
(Chap. 340). Equally important is a history of unexplained “repeated of acute hepatitis C are not clinically severe or rapidly progressive,
episodes” of acute hepatitis. This history should alert the physician delaying antiviral therapy of acute hepatitis C for 3–6 months (after
to the possibility that the underlying disorder is chronic hepatitis, for which recovery is unlikely) was a recommended approach during
example, autoimmune hepatitis (Chap. 341). Alcoholic hepatitis must the era of interferon-based therapy; however, in the current era of
also be considered, but usually the serum aminotransferase levels are highly effective (95–100%) oral DAA therapy, waiting for potential
not as markedly elevated, and other stigmata of alcoholism may be spontaneous recovery is no longer advised; instead, early treatment
present. The finding on liver biopsy of fatty infiltration, a neutrophilic with one of the four first-line drug combinations (of polymerase
inflammatory reaction, and “alcoholic hyaline” would be consistent inhibitors, protease inhibitors, and/or NS5A inhibitors) approved
with alcohol-induced rather than viral liver injury. Because acute hep- for treatment of chronic hepatitis C (Chap. 341) is recommended
atitis may present with right upper quadrant abdominal pain, nausea for treatment of patients with acute hepatitis C. Although abbrevi-
and vomiting, fever, and icterus, it is often confused with acute chole- ated treatment courses have been studied, currently, a standard, full
cystitis, common duct stone, or ascending cholangitis. Patients with 8- to 12-week course is recommended.
acute viral hepatitis may tolerate surgery poorly; therefore, it is impor- Because of the vast reservoir of acute HCV infections acquired
tant to exclude this diagnosis, and in confusing cases, a percutaneous four to five decades ago in the 1945–1965 birth cohort, most newly
liver biopsy may be necessary before laparotomy. Viral hepatitis in the recognized HCV infections are chronic. Opportunities to identify and
elderly is often misdiagnosed as obstructive jaundice resulting from treat patients with acute hepatitis C occur in two population subsets:
a common duct stone or carcinoma of the pancreas. Because acute (1) in health care workers who sustain hepatitis C–contaminated
hepatitis in the elderly may be quite severe and the operative mortality needle sticks (occupational accidents), monitoring for ALT eleva-
high, a thorough evaluation including biochemical tests, radiographic tions and the presence of HCV RNA identify acute hepatitis C in
studies of the biliary tree, and even liver biopsy may be necessary to ~3%, and this group should be treated; (2) in injection drug users,
exclude primary parenchymal liver disease. Another clinical constel- the risk of acute hepatitis C has been on the rise during the previ-
lation that may mimic acute hepatitis is right ventricular failure with ous decade, and the epidemic of opioid use has contributed to an
passive hepatic congestion or hypoperfusion syndromes, such as those amplification of HCV infection among drug users. Such patients
associated with shock, severe hypotension, and severe left ventricular are candidates for antiviral therapy, and efforts to combine antiviral
failure. Also included in this general category is any disorder that inter- therapy with drug rehabilitation therapy have been very successful.
feres with venous return to the heart, such as right atrial myxoma, con- Notwithstanding these specific therapeutic considerations, in
strictive pericarditis, hepatic vein occlusion (Budd-Chiari syndrome), most cases of typical acute viral hepatitis, specific treatment gener-
or veno-occlusive disease. Clinical features are usually sufficient to ally is not necessary. Although hospitalization may be required for
distinguish among these vascular disorders and viral hepatitis. Acute clinically severe illness, most patients do not require hospital care.
fatty liver of pregnancy, cholestasis of pregnancy, eclampsia, and the Forced and prolonged bed rest is not essential for full recovery,
HELLP (hemolysis, elevated liver tests, and low platelets) syndrome but many patients will feel better with restricted physical activity.
can be confused with viral hepatitis during pregnancy. Very rarely, A high-calorie diet is desirable, and because many patients may
malignancies metastatic to the liver can mimic acute or even fulminant experience nausea late in the day, the major caloric intake is best
viral hepatitis. Occasionally, genetic or metabolic liver disorders (e.g., tolerated in the morning. Intravenous feeding is necessary in the

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 2580 acute stage if the patient has persistent vomiting and cannot main- globulin preparations purified by cold ethanol fractionation from the
tain oral intake. Drugs capable of producing adverse reactions such plasma of hundreds of normal donors. Currently, for hepatitis A, B,
as cholestasis and drugs metabolized by the liver should be avoided. and E, active immunization with vaccines is the preferable approach
If severe pruritus is present, the use of the bile salt–sequestering to prevention.
resin cholestyramine is helpful. Glucocorticoid therapy has no value
in acute viral hepatitis, even in severe cases, and may be deleterious, Hepatitis A Both passive immunization with immunoglobulin (IG)
even increasing the risk of chronicity (e.g., of acute hepatitis B). and active immunization with killed vaccines are available. All prepara-
Physical isolation of patients with hepatitis to a single room and tions of IG contain anti-HAV concentrations sufficient to be protective.
bathroom is rarely necessary except in the case of fecal inconti- Administration of plasma-derived globulin is safe; all contemporary
nence for hepatitis A and E or uncontrolled, voluminous bleeding lots of IG are subjected to viral inactivation steps and must be free of
for hepatitis B (with or without concomitant hepatitis D) and C. HCV RNA as determined by PCR testing. Administration of IM lots
Because most patients hospitalized with hepatitis A excrete little, if of IG has not been associated with transmission of HBV, HCV, or HIV.
any, HAV, the likelihood of HAV transmission from these patients When administered before exposure or during the early incubation
during their hospitalization is low. Therefore, burdensome enteric period, IG is effective in preventing clinically apparent hepatitis A.
precautions are no longer recommended. Although gloves should be For postexposure prophylaxis of intimate contacts (household, sexual,
worn when the bed pans or fecal material of patients with hepati- institutional) of persons with hepatitis A, the administration of 0.02
tis A are handled, these precautions do not represent a departure mL/kg is recommended as early after exposure as possible; it may be
from sensible procedure and contemporary universal precautions effective even when administered as late as 2 weeks after exposure. Pro-
for all hospitalized patients. For patients with hepatitis B and C, phylaxis is not necessary for those who have already received hepatitis
emphasis should be placed on blood precautions (i.e., avoiding A vaccine, for casual contacts (office, factory, school, or hospital), for
direct, ungloved hand contact with blood and other body fluids). most elderly persons, who are very likely to be immune, or for those
Enteric precautions are unnecessary. The importance of simple known to have anti-HAV in their serum. By the time most common-
hygienic precautions such as hand washing cannot be overempha- source outbreaks of hepatitis A are recognized, it is usually too late in
sized. Universal precautions that have been adopted for all patients the incubation period for IG to be effective; however, prophylaxis may
apply to patients with viral hepatitis. Hospitalized patients may have limited the frequency of secondary cases. For travelers to tropi-
be discharged following substantial symptomatic improvement, cal countries, developing countries, and other areas outside standard
a significant downward trend in the serum aminotransferase and tourist routes, IG prophylaxis had been recommended before a vaccine
bilirubin values, and a return to normal of the PT. Mild aminotrans- became available.
ferase elevations should not be considered contraindications to the Such IG recommendations for postexposure prophylaxis and for
preexposure prophylaxis for international travel were updated in
PART 10

gradual resumption of normal activity.

2018. Currently, hepatitis A vaccine, not IG, is recommended for
all persons aged ≥12 months for postexposure prophylaxis and for
In fulminant hepatitis, the goal of therapy is to support the patient preexposure prophylaxis prior to international travel to HAV-en-
by maintenance of fluid balance, support of circulation and respira- demic areas. For adults aged >40, IG (at an upward revised dose
Disorders of the Gastrointestinal System

tion, control of bleeding, correction of hypoglycemia, and treatment of 0.1 mg/kg) may be added to postexposure hepatitis B vaccina-
of other complications of the comatose state in anticipation of liver tion depending on an assessment of the person’s risk. Even though
regeneration and repair. Protein intake should be restricted, and oral hepatitis A vaccine is indicated for children ≥12 months of age, when
lactulose administered. Glucocorticoid therapy has been shown in infants aged 6–11 months travel internationally to areas with a risk
controlled trials to be ineffective. Likewise, exchange transfusion, plas- of HAV infection, they should receive the vaccine for preexposure
mapheresis, human cross-circulation, porcine liver cross-perfusion, prophylaxis; however, this travel-related dose should not be counted
hemoperfusion, and extracorporeal liver-assist devices have not been toward the universal childhood two-dose hepatitis A vaccine recom-
proven to enhance survival. Meticulous intensive care that includes mendation, which begins at age 12 months. For postexposure pro-
prophylactic antibiotic coverage is the one factor that appears to phylaxis of persons with contraindications to hepatitis A vaccination
improve survival. Orthotopic liver transplantation is resorted to with and infants aged <12 months, the use of IG (0.1 mL/kg) should be
increasing frequency, with excellent results, in patients with fulminant retained. In addition, for postexposure prophylaxis in immunocom-
hepatitis (Chap. 345). Fulminant hepatitis C is very rare; however, in promised adults and persons with chronic liver disease, both hepatitis
fulminant hepatitis B, oral antiviral therapy has been used successfully, A vaccination and IG administration (0.1 mL/kg), at different IM
as reported anecdotally. In clinically severe acute hepatitis E or acute- sites, are recommended. Finally, for infants aged <6 months and for
on-chronic liver failure, successful therapy with ribavirin (600 mg persons with contraindications to hepatitis A vaccination, preexpo-
twice daily, 15 mg/kg) has been reported anecdotally. Unfortunately, sure prophylaxis for travel consists of IG at doses of 0.1 mg/kg for
when fulminant hepatitis E occurs in pregnant women (as it does in up travel durations up to 1 month, 0.2 mg/kg for travel up to 2 months,
to 20% of pregnant women with acute hepatitis E), ribavirin, which is and repeat 0.2 mg/kg every 2 months thereafter for the remainder
teratogenic, is contraindicated. In cases of hepatitis E in organ-transplant of travel. Thus, except for these limited considerations, hepatitis A
recipients, reduction in overall immunosuppressive drug doses and vaccine has supplanted IG in almost all cases for both postexpo-
switching from tacrolimus to cyclosporine A have been shown to be sure prophylaxis and preexposure prophylaxis for travel. Unlike IG
effective, often without antiviral therapy, in achieving eradication of prophylaxis, the protection afforded by active immunization with
HEV. If a change in immunosuppression is inadequate, ribavirin treat- vaccine is durable and simpler to administer.
ment for 3 months has been observed to achieve a sustained virologic Formalin-inactivated vaccines made from strains of HAV attenu-
response in 78% of treated patients; however, the optimal dose and ated in tissue culture have been shown to be safe, immunogenic, and
duration of ribavirin therapy remain to be determined. effective in preventing hepatitis A. Hepatitis A vaccines are approved
for use in persons who are at least 1 year old and appear to provide
adequate protection beginning 4 weeks after a primary inoculation. As
■■PROPHYLAXIS noted above, for travel to an endemic area, hepatitis A vaccine is the
Because application of therapy for acute viral hepatitis is limited and preferred approach to preexposure immunoprophylaxis and provides
because chronic viral hepatitis requires prolonged and costly courses long-lasting protection (protective levels of anti-HAV should last at
of antiviral therapy (Chap. 341), emphasis is placed on preven- least 20 years after vaccination). Shortly after its introduction, hepatitis
tion through immunization. The prophylactic approach differs for A vaccine was recommended for children living in communities with
each of the types of viral hepatitis. In the past, immunoprophylaxis a high incidence of HAV infection; in 1999, this recommendation
relied exclusively on passive immunization with antibody-containing was extended to include all children living in states, counties, and

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 TABLE 339-7 Hepatitis A Vaccination Schedules (Recombivax-HB 1986; Engerix-B 1989), and a third (Heplisav-B) 2581
was licensed in 2017. Current recommendations can be divided into
SCHEDULE,
AGE, YEARS NO. OF DOSES DOSE MONTHS those for preexposure and postexposure prophylaxis.
For preexposure prophylaxis against hepatitis B in settings of fre-
HAVRIX (GlaxoSmithKline)a
quent exposure (health workers exposed to blood; first-responder pub-
1–18 2 720 ELUb (0.5 mL) 0, 6–12 lic safety workers; hemodialysis patients and staff; residents and staff of
≥19 2 1440 ELU (1 mL) 0, 6–12 custodial institutions for the developmentally handicapped; injection
VAQTA (Merck) drug users; incarcerated inmates of correctional facilities; persons
1–18 2 25 units (0.5 mL) 0, 6–18
with multiple sexual partners or who have had a sexually transmitted
disease; men who have sex with men; persons such as hemophiliacs
≥19 2 50 units (1 mL) 0, 6–18
who require long-term, high-volume therapy with blood derivatives;
a
A combination of this hepatitis A vaccine and hepatitis B vaccine, TWINRIX, is household and sexual contacts of persons with chronic HBV infection;
licensed for simultaneous protection against both of these viruses among adults persons living in or traveling extensively in endemic areas; unvac-
(age ≥18 years). Each 1-mL dose contains 720 ELU of hepatitis A vaccine and
20 μg of hepatitis B vaccine. These doses are recommended at months 0, 1, and 6. cinated children aged <18; unvaccinated children who are Alaskan
b
Enzyme-linked immunoassay units. cCombination hepatitis A and typhoid vaccines, natives, Pacific Islanders, or residents in households of first-generation
Hepatyrix (GlaxoSmithKline) and Viatim (Sanofi Pasteur), are available, targeted immigrants from endemic countries; persons born in countries with a
primarily for travelers to endemic areas. Please consult product insert for doses
and schedules prevalence of HBV infection ≥2%; patients with chronic liver disease
[including persons with aminotransferase levels >2 times the upper
communities with high rates of HAV infection. As of 2006, the Advi- limit of normal]; persons aged <60 years with diabetes mellitus [those
sory Committee on Immunization Practices of the U.S. Public Health ≥60 years at the discretion of their physicians]; persons with end-stage
Service recommended routine hepatitis A vaccination of all children. renal disease; and persons with HIV infection), three IM (deltoid, not
Other groups considered being at increased risk for HAV infection gluteal) injections of hepatitis B vaccine are recommended at 0, 1, and
and who are candidates for hepatitis A vaccination include military 6 months (other, optional schedules are summarized in Table 339-8).
personnel, populations with cyclic outbreaks of hepatitis A (e.g., Alas- Pregnancy is not a contraindication to vaccination (but Heplisav-B
kan natives), employees of day-care centers and persons working in is not recommended for pregnant women because of the lack of
facilities for the developmentally delayed, primate handlers, laboratory safety data in this subpopulation; details of the use of Heplisav-B, a
workers exposed to hepatitis A or fecal specimens, and patients with two-injection course a month apart, appear in Table 339-8). In areas of
chronic liver disease (including persons with aminotransferase eleva- low HBV endemicity such as the United States, despite the availability

CHAPTER 339 Acute Viral Hepatitis

tions ≥2 times the upper limit of normal). Because of an increased risk of safe and effective hepatitis B vaccines, a strategy of vaccinating
of fulminant hepatitis A—observed in some experiences but not con- persons in high-risk groups was not effective. The incidence of new
firmed in others—among patients with chronic hepatitis C, patients hepatitis B cases continued to increase in the United States after the
with chronic hepatitis C are candidates for hepatitis A vaccination, as introduction of vaccines; <10% of all targeted persons in high-risk
are persons with chronic hepatitis B and the expanding population of groups were actually vaccinated, and ~30% of persons with sporadic
persons with nonalcoholic liver disease. Other populations whose rec- acute hepatitis B did not fall into any high-risk group category. There-
ognized risk of hepatitis A is increased should be vaccinated, including fore, to have an impact on the frequency of HBV infection in an area of
men who have sex with men, injection or noninjection drug users, low endemicity such as the United States, universal hepatitis B vacci-
persons experiencing homelessness, persons with clotting disorders nation in childhood is recommended. For unvaccinated children born
who require frequent administration of clotting-factor concentrates, after the implementation of universal infant vaccination, vaccination
persons traveling from the United States to countries with high or during early adolescence, at age 11–12 years, is recommended, and
intermediate hepatitis A endemicity, postexposure prophylaxis for this recommendation has been extended to include all unvaccinated
contacts of persons with hepatitis A, and household members and children aged 0–19 years. In HBV-hyperendemic areas (e.g., Asia),
other close contacts of adopted children arriving from countries with universal vaccination of children has resulted in a marked (~70–90%)
high and moderate hepatitis A endemicity. Hepatitis A vaccine is now 30-year decline in complications of hepatitis B, including liver-related
recommended as well for pregnant women at risk of infection or severe mortality and hepatocellular carcinoma.
outcomes from infection during pregnancy. Recommendations for The original two available aluminum-adjuvanted recombi-
dose and frequency differ for the two approved vaccine preparations in nant hepatitis B vaccines are comparable, one containing 10 μg of
the United States and the combination vaccines that include hepatitis HBsAg (Recombivax-HB) and the other containing 20 μg of HBsAg
A (Table 339-7); all injections are IM. Hepatitis A vaccine has been (Engerix-B), and recommended doses for each injection vary for the
reported to be effective in preventing secondary household and day- two preparations (Table 339-8). Combinations of hepatitis B vaccine
care center–associated cases of acute hepatitis A. In the United States, with other childhood vaccines are available as well (Table 339-8).
reported mortality resulting from hepatitis A declined in parallel with In 2017, a third recombinant hepatitis B vaccine with a novel adju-
hepatitis A vaccine–associated reductions in the annual incidence of vant that activates Toll-like 9 receptors was approved for adults aged 18
new infections. or older. In a series of prospective trials, compared to three Engerix-B
injections, two IM doses a month apart yielded higher proportions with
Hepatitis B Until 1982, prevention of hepatitis B was based protective levels of anti-HBs (≥10 mIU/mL): 95% of adults aged 18–55
on passive immunoprophylaxis either with standard IG, containing or 18–70 (vs 81% for Engerix-B), 90% of older adults aged 40–70 (vs
modest levels of anti-HBs, or hepatitis B immunoglobulin (HBIG), 71% for Engerix-B), and 90% of adults aged 18–70 with type 2 diabetes
containing high-titer anti-HBs. The efficacy of standard IG has never (vs 65% for Engerix-B). This two-injection regimen may be useful for
been established and remains questionable; even the efficacy of HBIG, revaccination of persons who failed to respond to the original vaccines.
demonstrated in several clinical trials, has been challenged, and its Another novel recombinant vaccine (PreHevbrio, VBI Vaccines) con-
contribution appears to be in reducing the frequency of clinical illness, taining of all three hepatitis B surface antigens, S, pre-S1, and pre-S2,
not in preventing infection. The first vaccine for active immunization, has been shown in clinical trials (three IM doses at 0, 1, and 6 months)
introduced in 1982, was prepared from purified, noninfectious, 22-nm to achieve higher proportions with protective anti-HBs and higher
spherical HBsAg particles derived from the plasma of healthy HBsAg antibody levels than Engerix-B (which contains S antigen only), includ-
carriers. In 1987, the plasma-derived vaccine was supplanted by a ing in older persons (≥45 years), persons with diabetes, and overweight
genetically engineered vaccine derived from recombinant yeast. The persons (body mass index >30); approved originally outside the United
latter vaccine consists of HBsAg particles that are nonglycosylated but States, this vaccine was approved by the FDA on December 1, 2021 for
are otherwise indistinguishable from natural HBsAg; two recombi- adults age ≥18 years. Availability is expected during the first quarter
nant vaccines were licensed for use in the United States in the 1980s of 2022.

HPIM21e_Part10_p2381-p2670.indd 2581 20/01/22 10:05 PM

 2582
TABLE 339-8 Preexposure Hepatitis B Vaccination Schedules against clinical hepatitis B, hepatitis B surface
antigenemia, and chronic HBV infection.
TARGET GROUP NO. OF DOSES DOSE SCHEDULE, MONTHS
Currently, booster immunizations are not
Recombivax-HB (Merck)a recommended routinely, except in immu-
Infants, children (<1–10 years) 3 5 μg (0.5 mL) 0, 1–2, 4–6 nosuppressed persons who have lost detect-
Adolescents (11–19 years) 3 or 4 5 μg (0.5 mL) 0–2, 1–4, 4–6 or 0, 12, 24 or 0, 1, 2, 12 able anti-HBs or immunocompetent persons
or who sustain percutaneous HBsAg-positive
Adults (≥20 years) 2 10 μg (1 mL) 0, 4–6 (age 11–15) inoculations after losing detectable antibody.
Hemodialysis patientsb 3 10 μg (1 mL) 0–2, 1–4, 4–6 Specifically, for hemodialysis patients, annual
<20 years 3 5 μg (0.5 mL) 0, 1, 6
anti-HBs testing is recommended after vac-
cination; booster doses are recommended
≥20 years 3 40 μg (4 mL) 0, 1, 6
when anti-HBs levels fall to <10 mIU/mL. As
Engerix-B (GlaxoSmithKline)c noted above, for persons at risk of both hepa-
Infants, children (<1–10 years) 3 or 4 10 μg (0.5 mL) 0, 1–2, 4–6 or 0, 1, 2, 12 titis A and B, a combined vaccine is available
Adolescents (10–19 years) 3 or 4 10 μg (0.5 mL) 0, 1–2, 4–6 or 0, 12, 24 or 0, 1, 2, 12 containing 720 enzyme-linked immunoassay
Adults (≥20 years) 3 or 4 20 μg (1 mL) 0–2, 1–4, 4–6 or 0, 1, 2, 12 units (ELUs) of inactivated HAV and 20 μg of
Hemodialysis patientsb recombinant HBsAg (at 0, 1, and 6 months).
<20 years 4 10 μg (0.5 mL) 0, 1, 2, 6 Hepatitis D Infection with hepatitis D
≥20 years 4 40 μg (2 mL) 0, 1, 2, 6 can be prevented by vaccinating susceptible
Heplisav-B (Dynavax)d persons with hepatitis B vaccine. No prod-
Adults (≥18 years) 2 20 μg (0.5 mL) 0, 1 uct is available for immunoprophylaxis to
prevent HDV superinfection in persons with
a
This manufacturer produces a licensed combination of hepatitis B vaccine and vaccines against Haemophilus chronic HBV infection; for these patients,
influenzae type b and Neisseria meningitides, Comvax, for use in infants and young children. Please consult
product insert for dose and schedule. bThis group also includes other immunocompromised persons. cThis avoidance of percutaneous exposures and
manufacturer produces two licensed combination hepatitis B vaccines: (1) Twinrix, recombinant hepatitis B limitation of intimate contact with persons
vaccine plus inactivated hepatitis A vaccine, is licensed for simultaneous protection against both of these who have HDV infection are recommended.
viruses among adults (age ≥18 years). Each 1-mL dose contains 720 ELU (enzyme-linked immunoassay units) of
hepatitis A vaccine and 20 μg of hepatitis B vaccine. These doses are recommended at months 0, 1, and 6. (2) Hepatitis C IG is ineffective in prevent-
Pediarix, recombinant hepatitis B vaccine plus diphtheria and tetanus toxoid, pertussis, and inactivated poliovirus,
is licensed for use in infants and young children. A hexavalent vaccine combining diphtheria, tetanus toxoid, ing hepatitis C and is no longer recom-
PART 10

pertussis, poliovirus, H. influenzae type b, and hepatitis B (Vaxelis, MCM Vaccine Company) was approved by the mended for postexposure prophylaxis in
U.S. Food and Drug Administration in 2018. Please consult product insert for doses and schedules. dHeplisav-B cases of perinatal, needle stick, or sexual
has not been tested for safety and efficacy in children, adolescents, hemodialysis patients, and pregnant women;
it is not approved for these subpopulations. exposure. Although prototype vaccines that
induce antibodies to HCV envelope proteins
have been developed, currently, hepatitis C
Disorders of the Gastrointestinal System

vaccination is not feasible practically. Geno-

For unvaccinated persons sustaining an exposure to HBV, postexpo- type and quasispecies viral heterogeneity, as well as rapid evasion of
sure prophylaxis with a combination of HBIG (for rapid achievement neutralizing antibodies by this rapidly mutating virus, conspire to
of high-titer circulating anti-HBs) and hepatitis B vaccine (for achieve- render HCV a difficult target for immunoprophylaxis with a vaccine.
ment of long-lasting immunity as well as its apparent efficacy in atten- Prevention of transfusion-associated hepatitis C has been accom-
uating clinical illness after exposure) is recommended. For perinatal plished by the following successively introduced measures: exclusion
exposure of infants born to HBsAg-positive mothers, a single dose of of commercial blood donors and reliance on a volunteer blood supply;
HBIG, 0.5 mL, should be administered IM in the thigh immediately screening donor blood with surrogate markers such as ALT (no longer
after birth, followed by a complete course of three injections of recom- recommended) and anti-HBc, markers that identify segments of the
binant hepatitis B vaccines approved for children (see doses above) to blood donor population with an increased risk of bloodborne infec-
be started within the first 12 h of life. For those experiencing a direct tions; exclusion of blood donors in high-risk groups for AIDS and the
percutaneous inoculation or transmucosal exposure to HBsAg-posi- introduction of anti-HIV screening tests; and progressively sensitive
tive blood or body fluids (e.g., accidental needle stick, other mucosal serologic and virologic screening tests for HCV infection.
penetration, or ingestion), a single IM dose of HBIG, 0.06 mL/kg, In the absence of active or passive immunization, prevention of
administered as soon after exposure as possible, is followed by a com- hepatitis C includes behavior changes and precautions to limit expo-
plete course of hepatitis B vaccine to begin within the first week. For sures to infected persons. Recommendations designed to identify
pregnant mothers with high-level HBV DNA (>2 × 105 IU/mL), adding patients with clinically inapparent hepatitis as candidates for medical
antiviral nucleoside analogues (e.g., pregnancy class B tenofovir, see management have as a secondary benefit the identification of persons
Chap 341) during the third trimester of pregnancy reduces perinatal whose contacts could be at risk of becoming infected. A so-called look-
transmission even further. For persons exposed by sexual contact to a back program has been recommended to identify persons who were
patient with acute hepatitis B, a single IM dose of HBIG, 0.06 mL/kg, transfused before 1992 with blood from a donor found subsequently
should be given within 14 days of exposure, to be followed by a com- to have hepatitis C. In addition, anti-HCV testing, once recommended
plete course of hepatitis B vaccine. When both HBIG and hepatitis B for persons born between 1945 and 1965, has now been expanded to
vaccine are recommended, they may be given at the same time but at include all persons 18 year or older, independent of risk factors. Groups
separate sites. Testing adults for anti-HBs after a course of vaccine is at higher risk and for whom testing is recommended include anyone
advisable to document the acquisition of immunity, but because hepa- who received a blood transfusion or a transplanted organ before the
titis B vaccine immunogenicity is nearly universal in infants, postvac- introduction of second-generation screening tests in 1992, those who
cination anti-HBs testing of children is not recommended. ever used injection drugs (or took other illicit drugs by noninjection
The precise duration of protection afforded by hepatitis B vac- routes), chronically hemodialyzed patients, persons with clotting dis-
cine is unknown; however, ~80–90% of immunocompetent adult orders who received clotting factors made before 1987 from pooled
vaccinees retain protective levels of anti-HBs for at least 5 years, and blood products, persons with elevated aminotransferase levels, health
60–80% for 10 years, and protective antibody has been documented workers exposed to HCV-positive blood or contaminated needles,
to last for at least two decades after vaccination in infancy. Thereafter recipients of blood or organs from a donor found to be positive for
and even after anti-HBs becomes undetectable, protection persists hepatitis C, persons with HIV infection, health care and public safety

HPIM21e_Part10_p2381-p2670.indd 2582 20/01/22 10:05 PM

 personnel following a needle stick or other nonpercutaneous exposure Joy JB et al: The spread of hepatitis C virus genotype 1a in North 2583
to HCV-infected material, sexual partners of persons with hepatitis C, America: A retrospective phylogenetic study. Lancet Infect Dis
and children born to HCV-positive mothers (Table 339-4). 16:698, 2016.
For stable, monogamous sexual partners, sexual transmission of Koh C et al: Pathogenesis of and new therapies for hepatitis D. Gas-
hepatitis C is unlikely, and sexual barrier precautions are not recom- troenterology 156:461, 2019.
mended. For persons with multiple sexual partners or with sexually Le MH et al: Chronic hepatitis B prevalence among foreign-born
transmitted diseases, the risk of sexual transmission of hepatitis C is and U.S.-born adults in the United States, 1999-2016. Hepatology
increased, and barrier precautions (latex condoms) are recommended. 71:431, 2020.
A person with hepatitis C should avoid sharing such items as razors, Lee MH et al: Chronic hepatitis C virus infection increases mortality
toothbrushes, and nail clippers with sexual partners and family from hepatic and extrahepatic diseases: A community-based long-
members. No special precautions are recommended for babies born term prospective study. J Infect Dis 206:469, 2012.
to mothers with hepatitis C, and breast-feeding does not have to be Lemon SM et al: Type A viral hepatitis: A summary and update on
restricted. the molecular virology, epidemiology, pathogenesis, and preven-
tion. J Hepatol 68:167, 2018.
Hepatitis E For prevention of hepatitis E, IG derived from HEV- Lin H-H et al: Changing hepatitis D virus epidemiology in a hepatitis
endemic populations does not appear to be effective. Two safe and B virus endemic area with a national vaccination program. Hepa-
effective three-dose (0, 1, and 6 months), recombinant genotype 1 tology 61:1870, 2016.
capsid protein vaccines, which protect against other genotypes as well, Nelson NP et al: Update: Recommendations of the Advisory Com-
have been shown in randomized, placebo-controlled trials to be highly mittee on Immunization Practices for use of hepatitis A vaccine
protective against symptomatic acute hepatitis E. A Chinese vaccine, for postexposure prophylaxis and for preexposure prophylaxis
Hecolin, achieved 100% 12-month efficacy and was licensed in China for international travel. MMWR Morb Mortal Wkly Rep 67:1216,
in 2011; its long-lasting protection (87% efficacy) was documented for 2018.
up to 4.5 years. A second vaccine developed by GlaxoSmithKline and Pan CQ et al: Tenofovir to prevent hepatitis B transmission in moth-
the U.S. Army vaccine achieved a 12-month 96% efficacy. The second ers with high viral load. N Engl J Med 374:2324, 2016.
vaccine was never developed commercially. The Chinese vaccine is Polaris Observatory Collaborators: Global prevalence, treat-
available in China but is not FDA approved or available in the ment, and prevention of hepatitis B virus infection in 2016: A mod-
United States. elling study. Lancet Gastroenterol Hepatol 3:383, 2018.
Polaris Observatory HCV Collaborators: Global prevalence

CHAPTER 339 Acute Viral Hepatitis

■■FURTHER READING and genotype distribution of hepatitis C virus infection in 2015: A
Buckley GJ, Strom BL (eds). Eliminating the Public Health Problem modelling study. Lancet Gastroenterol Hepatol 2:161, 2017.
of Hepatitis B and C in the United States: Phase One Report. Wash- Rizzetto M et al: Hepatitis delta: The rediscovery. Clin Liver Dis
ington DC, National Academies Press, 2016. 17:475, 2013.
Centers for Disease Control and Prevention: Recommenda- Roberts H et al: Prevalence of chronic hepatitis B virus (HBV)
tions for the identification of chronic hepatitis C virus infection infection in U.S. households: National Health and Nutrition Exami-
among persons born during 1945–1965. MMWR Morb Mortal nation Survey (NHANES), 1988–2012. Hepatology 63:388, 2016.
Wkly Rep 61(RR-4):1, 2012. Robinson CL et al: Advisory Committee on Immunization Practices
Chang M-H et al: Long-term effects of hepatitis B immunization of recommended immunization schedule for children and adolescents
infants in preventing liver cancer. Gastroenterology 151:472, 2016. aged 18 years or younger—United States, 2020. MMWR Morb Mor-
Debing Y et al: Update on hepatitis E virology: Implications for clin- tal Wkly Rep 69:130, 2020.
ical practice. J Hepatol 65:200, 2016. Rosenberg ES et al: Prevalence of hepatitis C virus infection in US
Denniston MM et al: Chronic hepatitis C virus infection in the States and District of Columbia, 2013-2016. JAMA Network Open
United States, National Health and Nutrition Examination Survey 1:e186371, 2018.
2003–2010. Ann Intern Med 160:293, 2014. Ryerson AB et al: Vital signs: Newly reported acute and chronic
Ditah I et al: Current epidemiology of hepatitis E virus infection in hepatitis C cases—United States, 2009–2018. MMWR Morb Mortal
the United States: Low seroprevalence in the National Health and Wkly Rep 69:399, 2020.
Nutrition Survey. Hepatology 60:815, 2014. Schillie S et al: Prevention of hepatitis B virus infection in the
Doshani M et al: Recommendations of the Advisory Committee United States: Recommendation of the Advisory Committee on
on Immunization Practices for use of hepatitis A vaccine for per- Immunization Practices. MMWR Morb Mortal Wkly Rep 67:1,
sons experiencing homelessness. MMWR Morb Mortal Wkly Rep 2018.
68:153, 2019. Schillie S et al: CDC recommendations for hepatitis C screening
Douam F et al: The mechanism of HCV entry into host cells. Prog among adults—United States, 2020. MMWR Recommend Rep
Mol Biol Transl Sci 129:63, 2015. 69(No. RR #2):1, 2020.
Edlin BR et al: Toward a more accurate estimate of the prevalence of Schweitzer A et al: Estimations of worldwide prevalence of chronic
hepatitis C in the United States. Hepatology 62:1353, 2015. hepatitis B virus infection: A systematic review of data published
European Association for the Study of the Liver: EASL clin- between 1965 and 2013. Lancet 386:1546, 2015.
ical practice guidelines on hepatitis E virus infection. J Hepatol Sureau C et al: The hepatitis delta virus: replication and pathogene-
68:1256, 2018. sis. J Hepatol 64:S102, 2016.
Foster M et al: Hepatitis A outbreaks associated with drug use and Trépo C et al: Hepatitis B virus infection. Lancet 384:2053, 2014.
homelessness—California, Kentucky, Michigan, and Utah 2017. U.S. Preventive Services Task Force: Screening for hepatitis B
MMWR Morb Mortal Wkly Rep 67:1208, 2018. virus infection in pregnant women: US Preventive Services Task
Freedman M et al: Advisory Committee on Immunization Practices. Force reaffirmation recommendation statement. JAMA 322:349,
Recommended adult immunization schedule, United States, 2020. 2019.
Ann Intern Med 172:337, 2020. U.S. Preventive Services Task Force: Screening for hepatitis C
Goldberg D et al: Changes in the prevalence of hepatitis C virus virus infection in adolescents and adults: US Preventive Services
infection, nonalcoholic steatohepatitis, and alcoholic liver disease Task Force recommendation statement. JAMA 323:970, 2020.
among patients with cirrhosis and liver failure on the waitlist for Waked I et al: Screening and treatment program to eliminate hepati-
liver transplantation. Gastroenterology 152:1090, 2017. tis C in Egypt. N Engl J Med 382:1166, 2020.

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 2584 deathcap mushroom. Acetaminophen, the prime example of a direct

340 Hepatitis
Toxic and Drug-Induced toxin, is discussed below.
In idiosyncratic drug reactions, the occurrence of liver injury is
infrequent (1 in 103–105 patients) and unpredictable; the response
is not as clearly dose-dependent as is injury associated with direct
William M. Lee, Jules L. Dienstag hepatotoxins, and liver injury may occur at any time after exposure to
the drug but typically between 5 and 90 days following its initiation.
Although regarded as not dose-related in the fashion of direct toxins,
Liver injury is a possible consequence of ingestion of any xenobiotic, most agents causing idiosyncratic toxicity are given at relatively high
including industrial toxins, pharmacologic agents, and complementary daily doses, typically exceeding 100 mg, suggesting a role for dose—
and alternative medications (CAMs). Among patients with acute liver drugs with low potency must be given in higher doses that engender
failure, drug-induced liver injury (DILI) is the most common cause, greater chances for “off-target” effects. Likewise, drugs given in mil-
and evidence for hepatotoxicity detected during clinical trials for drug ligram amounts are of high potency and rarely cause liver or other
development is the most common reason for failure of compounds to off-target effects. Adding to the difficulty of predicting or identifying
reach approval status. DILI requires careful history-taking to identify idiosyncratic drug hepatotoxicity is the occurrence of mild, transient,
unrecognized exposure to chemicals used in work or at home, drugs nonprogressive serum aminotransferase elevations that resolve with
taken by prescription or bought over the counter, and herbal or dietary continued drug use. Such “adaptation,” the mechanism of which
supplement medicines. Hepatotoxic drugs can injure the hepatocyte is unknown, is well recognized for drugs such as isoniazid (INH),
directly, for example, via a free-radical or metabolic intermediate that valproate, phenytoin, and HMG-CoA reductase inhibitors (statins).
causes peroxidation of membrane lipids and that results in liver cell Extrahepatic manifestations of hypersensitivity, such as rash, arthral-
injury. Alternatively, a drug or its metabolite may activate compo- gias, fever, leukocytosis, and eosinophilia, occur in a small fraction of
nents of the innate or adaptive immune system, stimulate apoptotic patients with idiosyncratic hepatotoxic drug reactions but are charac-
pathways, or initiate damage to bile excretory pathways (Fig. 340-1). teristic for certain drugs (phenytoin, trimethoprim-sulfamethoxazole)
Interference with bile canalicular pumps can allow endogenous bile and not others. Both primary immunologic injury and direct hepa-
acids, which can injure the liver, to accumulate. Such secondary injury, totoxicity related to idiosyncratic differences in generation of toxic
in turn, may lead to necrosis of hepatocytes; injure bile ducts, produc- metabolites have been invoked to explain idiosyncratic drug reactions.
ing cholestasis; or block pathways of lipid movement, inhibit protein The most current data implicate the adaptive immune system respond-
synthesis, or impair mitochondrial oxidation of fatty acids, resulting in ing to the formation of immune stimulatory compounds resulting from
lactic acidosis and intracellular triglyceride accumulation (expressed phase I metabolic activation of the offending drug. Differences in host
histologically as microvesicular steatosis). In other instances, drug
PART 10

susceptibility may result from varying kinetics of toxic metabolite gen-

metabolites sensitize hepatocytes to toxic cytokines. The differences eration and genetic polymorphisms in downstream drug-metabolizing
observed between susceptible and nonsusceptible drug recipients may pathways or cytokine activation; in addition, certain HLA haplotypes
be attributable to human leukocyte antigen (HLA) haplotypes that have been associated with hepatotoxicity of certain drugs such as
determine binding of drug-related haptens on the cell surface as well amoxicillin-clavulanate and flucloxacillin. Occasionally, however, the
Disorders of the Gastrointestinal System

as to polymorphisms in elaboration of competing, protective cytokines, clinical features of an allergic reaction (prominent tissue eosinophilia,
as has been suggested for acetaminophen hepatotoxicity (see below). autoantibodies, etc.) are difficult to ignore and suggest activation of
Immune mechanisms may include cytotoxic lymphocytes or antibody- IgE pathways. A few instances of drug hepatotoxicity are observed to
mediated cellular cytotoxicity. In addition, a role has been shown for be associated with autoantibodies, including a class of antibodies to
activation of nuclear transporters, such as the constitutive androstane liver-kidney microsomes, anti-LKM2, directed against a cytochrome
receptor (CAR) or, more recently, the pregnane X receptor (PXR), in P450 enzyme. Four agents that specifically have a phenotype of auto-
the induction of drug hepatotoxicity. immune hepatitis with a high likelihood of positive antinuclear anti-
bodies (ANAs) include nitrofurantoin, minocycline, hydralazine, and
■■DRUG METABOLISM α-methyldopa.
Most drugs, which are water-insoluble, undergo a series of metabolic Idiosyncratic reactions lead to a morphologic pattern that is more
steps, culminating in a water-soluble form appropriate for renal or variable than those produced by direct toxins; a single agent is often
biliary excretion. This process begins with oxidation or methylation capable of causing a variety of lesions, although certain patterns tend to
mediated initially by the microsomal mixed function oxygenases, predominate. Depending on the agent involved, idiosyncratic hepatitis
cytochrome P450 (phase I reaction), followed by glucuronidation or may result in a clinical and morphologic picture indistinguishable from
sulfation (phase II reaction) or inactivation by glutathione. Most drug that of viral hepatitis (e.g., INH or ciprofloxacin). So-called hepatocel-
hepatotoxicity is the result of formation of a phase I toxic metabolite, lular injury is the most common form, featuring spotty necrosis in the
but glutathione depletion, precluding inactivation of harmful com- liver lobule with a predominantly lymphocytic infiltrate resembling
pounds by glutathione S-transferase, can contribute as well by ensuring that observed in acute hepatitis A, B, or C. Drug-induced cholestasis
that the toxic compound is not abrogated. ranges from mild to increasingly severe: (1) bland cholestasis with lim-
ited hepatocellular injury (e.g., estrogens, 17,α-substituted androgens);
■■LIVER INJURY CAUSED BY DRUGS (2) inflammatory cholestasis (e.g., amoxicillin-clavulanic acid [the
In general, two major types of chemical hepatotoxicity have been recog- most frequently implicated antibiotic among cases of DILI], oxacillin,
nized: (1) direct toxic and (2) idiosyncratic. As shown in Table 340-1, erythromycin estolate); (3) sclerosing cholangitis (e.g., after intrahe-
direct toxic hepatitis occurs with predictable regularity in individuals patic infusion of the chemotherapeutic agent floxuridine for hepatic
exposed to the offending agent and is dose-dependent. The latent metastases from a primary colonic carcinoma); and (4) disappearance
period between exposure and liver injury is usually short (often several of bile ducts, “ductopenic” cholestasis or vanishing bile duct syndrome,
hours), although clinical manifestations may be delayed for 24–48 h. similar to that observed in chronic rejection (Chap. 345) following
Agents producing toxic hepatitis are generally systemic poisons or are liver transplantation (e.g., carbamazepine, levofloxacin). Cholestasis
converted in the liver to toxic metabolites. The direct hepatotoxins may result from binding of drugs to canalicular membrane transport-
result in morphologic abnormalities that are reasonably characteristic ers, accumulation of toxic bile acids resulting from canalicular pump
and reproducible for each toxin. Examples of rare toxins currently failure, or genetic defects in canalicular transporter proteins. Clinically,
include carbon tetrachloride and trichloroethylene that characteristi- the distinction between a hepatocellular and a cholestatic reaction is
cally produce a centrilobular zonal necrosis. The hepatotoxic octapep- indicated by the R value, the ratio of alanine aminotransferase (ALT) to
tides of Amanita phalloides usually produce massive hepatic necrosis; alkaline phosphatase values, both expressed as multiples of the upper
the lethal dose of the toxin is ~10 mg, the amount found in a single limit of normal. An R value of >5.0 is associated with hepatocellular

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 Six Mechanisms of Liver Injury 2585

B
Membrane

Transport
Hepatocyte pumps (MRP3)
Canaliculus

Heme
P-450 Drug

Endoplasmic
reticulum

CHAPTER 340 Toxic and Drug-Induced Hepatitis

F
Triglycerides
Free fatty
Vesicle
acid
D Enzyme-drug
E Cell death adduct

Other Other Cytokines

caspases caspases

Inhibition of
β-oxidation, respiration, Caspase
or both
Caspase Caspase

DD DD
DD DD

Cytolytic
Mitochondrion TNF-α receptor, T cell
Fas
Lactate

A. Rupture of cell membrane. D. Drug adducts targeted by CTLs/cytokines.

B. Injury of bile canaliculus (disruption of transport pumps). E. Activation of apoptotic pathway by TNFα/Fas.
C. P-450-drug covalent binding (drug adducts). F. Inhibition of mitochondrial function.
FIGURE 340-1 Potential mechanisms of drug-induced liver injury. The normal hepatocyte may be affected adversely by drugs through (A) disruption of intracellular calcium
homeostasis that leads to the disassembly of actin fibrils at the surface of the hepatocyte, resulting in blebbing of the cell membrane, rupture, and cell lysis; (B) disruption
of actin filaments next to the canaliculus (the specialized portion of the cell responsible for bile excretion), leading to loss of villous processes and interruption of transport
pumps such as multidrug resistance–associated protein 3 (MRP3), which, in turn, prevents the excretion of bilirubin and other organic compounds; (C) covalent binding of
the heme-containing cytochrome P450 enzyme to the drug, thus creating nonfunctioning adducts; (D) migration of these enzyme-drug adducts to the cell surface in vesicles
to serve as target immunogens for cytolytic attack by T cells, stimulating an immune response involving cytolytic T cells and cytokines; (E) activation of apoptotic pathways
by tumor necrosis factor α (TNF-α) receptor or Fas (DD denotes death domain), triggering the cascade of intercellular caspases, resulting in programmed cell death; or (F)
inhibition of mitochondrial function by a dual effect on both β-oxidation and the respiratory-chain enzymes, leading to failure of free fatty acid metabolism, a lack of aerobic
respiration, and accumulation of lactate and reactive oxygen species (which may disrupt mitochondrial DNA). Toxic metabolites excreted in bile may damage bile-duct
epithelium (not shown). CTLs, cytolytic T lymphocytes. (From WM Lee: Drug-induced hepatotoxicity. N Engl J Med 349:474, 2003. Copyright © 2003, Massachusetts Medical
Society. Reprinted with permission from Massachusetts Medical Society.)

injury, R <2.0 with cholestatic injury, and R between 2.0 and 5.0 with steatohepatitis. Severe hepatotoxicity associated with steatohepatitis,
mixed hepatocellular-cholestatic injury. most likely a result of mitochondrial toxicity, was recognized with cer-
Morphologic alterations may also include hepatic granulomas tain antiretroviral therapies, although most of these drugs have been
(e.g., sulfonamides) or macrovesicular or microvesicular steatosis or withdrawn (Chap. 202). Another potential target for idiosyncratic drug

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 2586
TABLE 340-1 Some Features of Toxic and Drug-Induced Hepatic Injury
DIRECT TOXIC EFFECTa IDIOSYNCRATICa OTHERa
CARBON AMOXICILLIN- ESTROGENS/
FEATURES TETRACHLORIDE ACETAMINOPHEN CLAVULANATE ISONIAZID CIPROFLOXACIN ANDROGENIC STEROIDS
Predictable and dose- + + 0 0 0 +
related toxicity
Latent period Short Short Delayed onset Variable May be short Variable
Arthralgia, fever, rash, 0 0 0 0 0 0
eosinophilia
Liver morphology Necrosis, fatty Centrilobular Mixed hepatocellular/ Hepatocellular injury Hepatocellular injury Cholestasis without portal
infiltration necrosis cholestatic resembling viral resembling viral inflammation
hepatitis hepatitis
The drugs listed are typical examples.
a

hepatotoxicity is sinusoidal lining cells; when these are injured, such as several separate supportive assessment variables to lead to a high level
by high-dose chemotherapeutic agents (e.g., cyclophosphamide, mel- of certainty, including temporal association (time of onset, time to
phalan, busulfan) administered prior to bone marrow transplantation, resolution), clinical-biochemical features, type of injury (hepatocellu-
veno-occlusive disease can result. Nodular regenerative hyperplasia, lar vs cholestatic), extrahepatic features, likelihood that a given agent
a subtle form of portal hypertension, may also result from vascular is to blame based on its past record, and exclusion of other potential
injury to portal or hepatic venous endothelium following systemic causes. Scoring systems such as the Roussel-Uclaf Causality Assess-
chemotherapy, such as with oxaliplatin, as part of adjuvant treatment ment Method (RUCAM) yield residual uncertainty and have not been
for colon cancer. adopted widely. Currently, the U.S. Drug-Induced Liver Injury Network
Not all adverse hepatic drug reactions can be classified as either (DILIN) relies on a structured expert opinion process requiring
toxic or idiosyncratic. For example, oral contraceptives, which combine detailed data on each case and a comprehensive review by three experts
estrogenic and progestational compounds, may result in impairment who arrive at a consensus on a five-degree scale of likelihood (definite,
of liver tests and, occasionally, jaundice; however, they do not highly likely, probable, possible, unlikely); however, this approach is
produce necrosis or fatty change, manifestations of hypersensitivity not practical for routine clinical application.
are generally absent, and susceptibility to the development of oral Generally, drug hepatotoxicity is not more frequent in persons with
PART 10

contraceptive–induced cholestasis appears to be genetically deter- underlying chronic liver disease, although the severity of the outcome
mined. Such estrogen-induced cholestasis is more common in women may be amplified. Reported exceptions include hepatotoxicity of aspi-
with cholestasis of pregnancy, a disorder linked to genetic defects in rin, methotrexate, INH (only in certain experiences), antiretroviral
multidrug resistance–associated canalicular transporter proteins. therapy for HIV infection, and certain drugs such as conditioning reg-
Any idiosyncratic reaction that occurs in <1:10,000 recipients will imens for bone marrow transplantation in the presence of hepatitis C.
Disorders of the Gastrointestinal System

go unrecognized in most clinical trials, which involve at most several

thousand subjects. The U.S. Food and Drug Administration (FDA) and TREATMENT
pharmaceutical companies have learned to look for even subtle indica-
tions of serious toxicity and monitor regularly the number of trial sub- Toxic and Drug-Induced Hepatic Disease
jects in whom any aminotransferase elevations develop, as a possible
Treatment is largely supportive, except in acetaminophen hepato-
surrogate for more serious toxicity. Even more valid as a predictor of
toxicity (for which N-acetylcysteine is effective, see below). Acute
severe hepatotoxicity is the occurrence of jaundice in patients enrolled
liver failure develops in 10% of patients with DILI; spontaneous
in a clinical drug trial, so-called “Hy’s Law,” named after Dr. Hyman
recovery, once that threshold is reached, occurs in <30%, and
Zimmerman, one of the pioneers of the field of drug hepatotoxicity. He
liver transplantation is performed in >40% of those who reach the
recognized that, if jaundice occurred during a phase 3 trial, more seri-
level of severity of acute liver failure (coagulopathy and hepatic
ous liver injury was likely, with a 10:1 ratio between cases of jaundice
encephalopathy) (Chap. 345). Withdrawal of the suspected agent
and liver failure (i.e., 10 patients with jaundice would result in 1 patient
is indicated at the first sign of an adverse reaction or when
with acute liver failure). Thus, the finding of such Hy’s Law (jaundiced)
aminotransferase levels reach five times the upper limit of normal.
cases during drug development often portends failure of approval, par-
A number of studies have suggested that lethal outcomes follow
ticularly if any of the subjects sustains a bad outcome. Troglitazone, a
continued use of an agent in the face of symptoms and signs of liver
peroxisome proliferator–activated receptor γ agonist, was the first in its
injury. In the case of the direct toxins, liver involvement should not
class of thiazolidinedione insulin-sensitizing agents. Although in retro-
divert attention from renal or other organ involvement, which may
spect, Hy’s Law cases of jaundice had occurred during phase 3 trials, no
also threaten survival. Agents used occasionally but of questionable
instances of liver failure were recognized until well after the drug was
value include glucocorticoids for DILI with allergic features, silibi-
introduced, emphasizing the importance of postmarketing surveillance
nin for mushroom poisoning, and ursodeoxycholic acid for choles-
in identifying toxic drugs and in leading to their withdrawal from use.
tatic drug hepatotoxicity; these medications have been shown to be
Fortunately, such hepatotoxicity is not characteristic of the second-
effective and cannot be recommended. A double-blind, randomized
generation thiazolidinediones rosiglitazone and pioglitazone; in clinical
controlled trial of the use of N-acetylcysteine for nonacetamin-
trials, the frequency of aminotransferase elevations in patients treated
ophen acute liver failure, including cases of DILI, demonstrated
with these medications did not differ from that in placebo recipients,
benefit, particularly for patients with early-stage hepatic encepha-
and isolated reports of liver injury among recipients are extremely rare.
lopathy; however, the drug has not been approved by FDA for this
Since troglitazone was withdrawn from the market in 2001, no fully
indication.
approved drugs have had to be withdrawn from the market by the FDA.
Several agents have received black box warnings indicating that caution
is needed; overall, the industry and FDA in concert have been able to In Table 340-2, several classes of chemical agents are listed together
avert severe toxicity in approved agents over the past 20 years. with examples of the pattern of liver injury they produce. Certain drugs
Proving that an episode of liver injury is caused by a drug (cau- appear to be responsible for the development of chronic as well as acute
sality) is difficult in many cases. DILI is nearly always a presumptive hepatic injury. For example, nitrofurantoin, minocycline, hydralazine,
diagnosis, and many other disorders produce a similar clinicopatho- and methyldopa have been associated with moderate to severe chronic
logic picture. Thus, causality may be difficult to establish and requires hepatitis with autoimmune features. Methotrexate, tamoxifen, and

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 2587
TABLE 340-2 Principal Alterations of Hepatic Morphology Produced by Some Commonly Used Drugs and Chemicalsa
PRINCIPAL MORPHOLOGIC
CHANGE CLASS OF AGENT EXAMPLE
Cholestasis Anabolic steroid Methyl testosterone, many other body-building supplements
Antibiotic Erythromycin estolate, nitrofurantoin, rifampin, amoxicillin-clavulanic acid, oxacillin
Anticonvulsant Carbamazepine
Antidepressant Duloxetine, mirtazapine, tricyclic antidepressants
Anti-inflammatory Sulindac
Antiplatelet Clopidogrel
Antihypertensive Irbesartan, fosinopril
Antithyroid Methimazole
Calcium channel blocker Nifedipine, verapamil
Immunosuppressive Cyclosporine
Lipid-lowering Ezetimibe
Oncotherapeutic Anabolic steroids, busulfan, tamoxifen, irinotecan, cytarabine, temozolomide
Oral contraceptive Norethynodrel with mestranol
Oral hypoglycemic Chlorpropamide
Tranquilizer Chlorpromazineb
Fatty liver Antiarrhythmic Amiodarone
Antibiotic Tetracycline (high-dose, IV)
Anticonvulsant Valproic acid
Antiviral Dideoxynucleosides (e.g., zidovudine), protease inhibitors (e.g., indinavir, ritonavir)
Oncotherapeutic Asparaginase, methotrexate, tamoxifen
Hepatitis Anesthetic Halothane, fluothane
Antiandrogen Flutamide

CHAPTER 340 Toxic and Drug-Induced Hepatitis

Antibiotic Isoniazid,c rifampicin, nitrofurantoin, telithromycin, minocycline,d pyrazinamide,
trovafloxacine
Anticonvulsant Phenytoin, carbamazepine, valproic acid, phenobarbital
Antidepressant Iproniazid, amitriptyline, trazodone, venlafaxine, fluoxetine, paroxetine, duloxetine,
sertraline, nefazodonee
Antifungal Ketoconazole, fluconazole, itraconazole
Antihypertensive Methyldopa,c captopril, enalapril, lisinopril, losartan
Anti-inflammatory Ibuprofen, indomethacin, diclofenac, sulindac, bromfenac
Antipsychotic Risperidone
Antiviral Zidovudine, didanosine, stavudine, nevirapine, ritonavir, indinavir, tipranavir, zalcitabine
Calcium channel blocker Nifedipine, verapamil, diltiazem
Cholinesterase inhibitor Tacrine
Diuretic Chlorothiazide
Laxative Oxyphenisatinc,e
Norepinephrine reuptake inhibitor Atomoxetine
Oral hypoglycemic Troglitazone,e acarbose
Mixed hepatitis/cholestatic Antibiotic Amoxicillin-clavulanic acid, trimethoprim-sulfamethoxazole
Antibacterial Clindamycin
Antifungal Terbinafine
Antihistamine Cyproheptadine
Immunosuppressive Azathioprine
Lipid-lowering Nicotinic acid, lovastatin, ezetimibe
Toxic (necrosis) Analgesic Acetaminophen
Hydrocarbon Carbon tetrachloride
Metal Yellow phosphorus
Mushroom Amanita phalloides
Solvent Dimethylformamide
Granulomas Antiarrhythmic Quinidine, diltiazem
Antibiotic Sulfonamides
Anticonvulsant Carbamazepine
Anti-inflammatory Phenylbutazone
Xanthine oxidase inhibitor Allopurinol
Vascular injury Chemotherapeutic Oxaliplatin, melphalan
a
Several agents cause more than one type of liver lesion and appear under more than one category. bRarely associated with primary biliary cirrhosis–like lesion.
c
Occasionally associated with chronic hepatitis or bridging hepatic necrosis or cirrhosis. dAssociated with an autoimmune hepatitis–like syndrome. eWithdrawn from use
because of severe hepatotoxicity.

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 2588 amiodarone have been implicated in the development of cirrhosis. Portal adducts, which can be measured in serum by high-performance liquid
hypertension in the absence of cirrhosis, termed nodular regenerative chromatography, hold promise as diagnostic markers of acetamino-
hyperplasia, may result from alterations in hepatic architecture pro- phen hepatotoxicity, and a point-of-care assay for acetaminophen-Cys
duced by excessive intake of vitamin A or following chemotherapy adducts is under development. The binding of acetaminophen to
with oxaliplatin. Oral contraceptives have been implicated in the hepatocyte macromolecules is believed to lead to hepatocyte necrosis;
development of focal nodular hyperplasia or hepatic adenoma (both the precise sequence and mechanism are unknown. Hepatic injury
benign lesions) and, rarely, hepatocellular carcinoma and hepatic vein may be potentiated by prior administration of alcohol, phenobarbital,
occlusion (Budd-Chiari syndrome). Another unusual lesion, peliosis INH, or other drugs; by conditions that stimulate the mixed-function
hepatis (blood cysts of the liver), has been observed in some patients oxidase system; or by conditions such as starvation (including inabil-
treated with anabolic or contraceptive steroids. The existence of these ity to maintain oral intake during severe febrile illnesses) that reduce
hepatic disorders expands the spectrum of liver injury induced by hepatic glutathione levels. Alcohol induces cytochrome P450 CYP2E1;
chemical agents and emphasizes the need for a thorough drug history consequently, increased levels of the toxic metabolite NAPQI may
in all patients with liver dysfunction. The comprehensive, authoritative be produced in chronic alcoholics after acetaminophen ingestion,
LiverTox website, which contains up-to-date information on DILI, but the role of alcohol in potentiating acute acetaminophen injury is
is available as a valuable reference through the National Institutes of still debated. Alcohol also suppresses hepatic glutathione production.
Health and the National Library of Medicine (livertox.nih.gov). Therefore, in chronic alcoholics, the toxic dose of acetaminophen may
The following are patterns of adverse hepatic reactions for some be as low as 2 g, and alcoholic patients should be warned specifically
prototypic agents. about the dangers of even standard doses of this commonly used drug.
In a 2006 study, aminotransferase elevations were identified in 31–44%
■■ACETAMINOPHEN HEPATOTOXICITY of normal subjects treated for 14 days with the maximal recommended
(DIRECT TOXIN) dose of acetaminophen, 4 g daily (administered alone or as part of
Acetaminophen represents the most prevalent cause of acute liver fail- an acetaminophen-opioid combination); because these changes were
ure in the Western world; up to 72% of patients with acetaminophen transient and never associated with bilirubin elevation, the clinical
hepatotoxicity in Scandinavia—somewhat lower frequencies in the relevance of these findings remains to be determined. Although under-
United Kingdom and the United States—progress to encephalopathy lying hepatitis C virus (HCV) infection was found to be associated
and coagulopathy. Acetaminophen causes dose-related centrilobular with an increased risk of acute liver injury in patients hospitalized for
hepatic necrosis after single-time-point ingestions, as intentional acetaminophen overdose, generally, in patients with nonalcoholic liver
self-harm, or over extended periods, as unintentional overdoses, disease, acetaminophen taken in recommended doses is well toler-
when multiple drug preparations or inappropriate drug amounts are ated. Acetaminophen use in cirrhotic patients has not been associated
PART 10

used daily for several days, for example, for relief of pain or fever. with hepatic decompensation. On the other hand, because of the link
In these instances, 8 g/d, twice the daily recommended maximum between acetaminophen use and liver injury and because of the limited
dose, over several days can readily lead to liver failure. Use of opioid- safety margin between safe and toxic doses, the FDA has recommended
acetaminophen combinations appears to be particularly harmful, that the daily dose of acetaminophen be reduced from 4 g to 3 g (even
because habituation to the opioid may occur with a gradual increase lower for persons with chronic alcohol use), that all acetaminophen-
Disorders of the Gastrointestinal System

in opioid-acetaminophen combination dosing over days or weeks. A containing products be labeled prominently as containing acetamin-
single dose of 10–15 g, occasionally less, may produce clinical evidence ophen, and that the potential for liver injury be prominent in the
of liver injury. Fatal fulminant disease is usually (although not invari- packaging of acetaminophen and acetaminophen-containing products.
ably) associated with ingestion of ≥25 g. Blood levels of acetaminophen Within opioid combination products, the limit for the acetaminophen
correlate with severity of hepatic injury (levels >300 μg/mL 4 h after component has been lowered to 325 mg per tablet.
ingestion are predictive of the development of severe damage; levels
<150 μg/mL suggest that hepatic injury is highly unlikely). Nausea,
vomiting, diarrhea, abdominal pain, and shock are early manifes- TREATMENT
tations occurring 4–12 h after ingestion. Then 24–48 h later, when Acetaminophen Overdosage
these features are abating, hepatic injury becomes apparent. Maximal
abnormalities and hepatic failure are evident 3–5 days after ingestion, Treatment includes gastric lavage, supportive measures, and oral
and aminotransferase levels exceeding 10,000 IU/L are not uncommon administration of activated charcoal or cholestyramine to prevent
(i.e., levels far exceeding those in patients with viral hepatitis). Renal absorption of residual drug. Neither charcoal nor cholestyramine
failure and myocardial injury may be present. Whether or not a clear appears to be effective if given >30 min after acetaminophen inges-
history of overdose can be elicited, clinical suspicion of acetaminophen tion; if they are used, the stomach lavage should be done before
hepatotoxicity should be raised by the presence of the extremely high other agents are administered orally. The chances of possible, prob-
aminotransferase levels in association with low bilirubin levels that able, and high-risk hepatotoxicity can be derived from a nomogram
are characteristic of this hyperacute injury. This biochemical signature plot (Fig. 340-2), readily available in emergency departments,
should trigger further questioning of the subject if possible; however, as a function of measuring acetaminophen plasma levels 4–8 h
outright denial (or denial of high doses) or altered mentation may after ingestion. In patients with high acetaminophen blood levels
confound diagnostic efforts. In this setting, a presumptive diagnosis is (>200 μg/mL measured at 4 h or >100 μg/mL at 8 h after inges-
reasonable, and the proven antidote, N-acetylcysteine, is both safe and tion), the administration of N-acetylcysteine reduces markedly the
will be effective if given early (within 12 h) but is also used even when severity of hepatic necrosis. This agent provides sulfhydryl donor
injury has evolved. groups to replete glutathione, which is required to render harmless
Acetaminophen is metabolized predominantly by a phase II reac- toxic metabolites that would otherwise bind covalently via sulfhy-
tion to innocuous sulfate and glucuronide metabolites; however, a dryl linkages to cell proteins, resulting in the formation of drug
small proportion is metabolized by a phase I reaction to a hepatotoxic metabolite-protein adducts. Therapy should be begun within 8 h of
metabolite formed from the parent compound by cytochrome P450 ingestion but may be at least partially effective when given as late
CYP2E1. This metabolite, N-acetyl-p-benzoquinone-imine (NAPQI), as 24–36 h after overdose. Routine use of N-acetylcysteine has sub-
is detoxified by binding to “hepatoprotective” glutathione to become stantially reduced the occurrence of fatal acetaminophen hepato-
harmless, water-soluble mercapturic acid, which undergoes renal toxicity. N-acetylcysteine may be given orally but is more commonly
excretion. When excessive amounts of NAPQI are formed, or when used as an IV solution, with a loading dose of 140 mg/kg over 1 h,
glutathione levels are low, glutathione levels are depleted and over- followed by 70 mg/kg every 4 h for 15–20 doses. Whenever a patient
whelmed, permitting covalent binding to nucleophilic hepatocyte with potential acetaminophen hepatotoxicity is encountered, a
macromolecules forming acetaminophen-protein “adducts.” These local poison control center should be contacted. Treatment can be

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 4000 to INH have been detected in INH recipients, but a link to causality 2589
500 Lower limit for high-risk group of liver injury remains unclear. A clinical picture resembling chronic
3000
400 Lower limit for probable-risk group hepatitis has been observed in a few patients. Many public health
Study nomogram line
2000 300 programs that require INH prophylaxis for a positive tuberculin skin
test or blood test (Quantiferon or T-Spot) include monthly monitoring
1300 200 of aminotransferase levels, although this practice has been called into
Plasma acetaminophen concentration

1000 150 question. Even more effective in limiting serious outcomes may be
encouraging patients to be alert for symptoms such as nausea, fatigue,
100 or jaundice, because most fatalities occur in the setting of continued
500 INH use despite clinically apparent illness. The incidence of severe
INH toxicity may be declining as a result of less frequent use and/or
50 better management.
■■SODIUM VALPROATE HEPATOTOXICITY (TOXIC
AND IDIOSYNCRATIC REACTION)
Sodium valproate, an anticonvulsant useful in the treatment of petit
mal and other seizure disorders, has been associated with the devel-
100 opment of severe hepatic toxicity and, rarely, fatalities, predominantly
in children but also in adults. Among children listed as candidates for
10 liver transplantation, valproate is the most common antiepileptic drug
50 implicated. Asymptomatic elevations of serum aminotransferase levels
have been recognized in as many as 45% of treated patients. These
30 5 “adaptive” changes, however, appear to have no clinical importance,
because major hepatotoxicity is not seen in the majority of patients
despite continuation of drug therapy. In the rare patients in whom
µmol/L µg/mL 4 8 12 16 20 24 28 jaundice, encephalopathy, and evidence of hepatic failure are found,
Hours after acetaminophen ingestion examination of liver tissue reveals microvesicular fat and bridging
FIGURE 340-2 Nomogram to define risk of acetaminophen hepatotoxicity according hepatic necrosis, predominantly in the centrilobular zone. Bile duct

CHAPTER 340 Toxic and Drug-Induced Hepatitis

to initial plasma acetaminophen concentration. (Reproduced with permission from injury may also be apparent. Most likely, sodium valproate is not
Pediatrics, 55:871. Copyright © 1975 by the AAP.) directly hepatotoxic, but its metabolite, 4-pentenoic acid, may be
responsible for hepatic injury. Valproate hepatotoxicity is more com-
stopped when plasma acetaminophen levels indicate that the risk mon in persons with mitochondrial enzyme deficiencies and may be
of liver damage is low. If signs of hepatic failure (e.g., progressive ameliorated by IV administration of carnitine, which valproate therapy
jaundice, coagulopathy, confusion) occur despite N-acetylcysteine can deplete. Valproate toxicity has been linked to HLA haplotypes
therapy for acetaminophen hepatotoxicity, liver transplantation (DR4 and B*1502) and to mutations in mitochondrial DNA polymerase
may be the only option. Early arterial blood lactate levels among gamma 1.
such patients with acute liver failure may distinguish patients highly
likely to require liver transplantation (lactate levels >3.5 mmol/L) ■■NITROFURANTOIN HEPATOTOXICITY
from those likely to survive without liver replacement. Acute renal (IDIOSYNCRATIC REACTION)
injury occurs in nearly 75% of patients with severe acetaminophen This commonly used antibiotic for urinary tract infections may cause
injury but is virtually always self-limited. an acute hepatitis leading to fatal outcome or, more frequently, chronic
hepatitis of varying severity but indistinguishable from autoimmune
Survivors of acute acetaminophen overdose rarely, if ever, have hepatitis. These two scenarios may reflect the frequent use and reuse of
ongoing liver injury or sequela but may be subject to repeat overdosing. the drug for treatment of recurrent cystitis in women. Although most
toxic agents manifest injury within 6 months of first ingestion, nitro-
furantoin may have a longer latency period, in part perhaps because of
■■ISONIAZID HEPATOTOXICITY (TOXIC AND its intermittent, recurrent use. Autoantibodies to nuclear components,
IDIOSYNCRATIC REACTION) smooth muscle, and mitochondria are seen and may subside after res-
INH remains central to most antituberculous prophylactic and thera- olution of injury; however, glucocorticoid or other immunosuppressive
peutic regimens, despite its long-standing recognition as a hepatotoxin. medication may be necessary to resolve the autoimmune injury, and
In 10% of patients treated with INH, elevated serum aminotransferase cirrhosis may be seen in cases that are not recognized quickly. Intersti-
levels develop during the first few weeks of therapy; however, these tial pulmonary fibrosis presenting as chronic cough and dyspnea may
elevations in most cases are self-limited, are mild (values for ALT be present and resolve slowly with medication withdrawal. Histologic
<200 IU/L), and resolve despite continued drug use. This adaptive findings are identical to those of autoimmune hepatitis. A similar dis-
response allows continuation of the agent if symptoms and progressive ease pattern can be observed with minocycline, which is used repeat-
enzyme elevations do not follow the initial elevations. Acute hepatoc- edly for the treatment of acne in teenagers, as well as with hydralazine
ellular DILI secondary to INH is evident with a variable latency period and α-methyldopa.
up to 6 months and is more frequent in alcoholics and patients taking
certain other medications, such as barbiturates, rifampin, and pyrazi- ■■AMOXICILLIN-CLAVULANATE HEPATOTOXICITY
namide. If the clinical threshold of encephalopathy is reached, severe (IDIOSYNCRATIC MIXED REACTION)
hepatic injury is likely to be fatal or to require liver transplantation. Currently, the most common agent implicated as causing DILI in the
Liver biopsy reveals morphologic changes similar to those of viral hep- United States and in Europe is amoxicillin-clavulanate (most frequent
atitis or bridging hepatic necrosis. Substantial liver injury appears to be brand name: Augmentin). This medication causes a very specific
age-related, increasing substantially after age 35; the highest frequency syndrome of mixed or primarily cholestatic injury. Because hepatotox-
is in patients over age 50, and the lowest is in patients under the age icity may follow amoxicillin-clavulanate therapy after a relatively long
of 20. Even for patients >50 years of age monitored carefully during latency period, the liver injury may begin to manifest after the drug
therapy, hepatotoxicity occurs in only ~2%, well below the risk esti- has been withdrawn. The high prevalence of hepatotoxicity reflects
mate derived from earlier experiences. Fever, rash, eosinophilia, and in part the very frequent use of this drug for respiratory tract infec-
other manifestations of drug allergy are distinctly unusual. Antibodies tions, including community-acquired pneumonia. The mechanism of

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 2590 hepatotoxicity is unclear, but the liver injury is thought to be caused ■■TRIMETHOPRIM-SULFAMETHOXAZOLE
by amoxicillin toxicity that is potentiated in some way by clavulanate, HEPATOTOXICITY (IDIOSYNCRATIC REACTION)
which itself appears not to be toxic. Symptoms include nausea, anorexia, This antibiotic combination is used routinely for urinary tract infec-
fatigue, and jaundice—which may be prolonged—with pruritus. Rash tions in immunocompetent persons and for prophylaxis against and
is quite uncommon. On occasion, amoxicillin-clavulanate, like other therapy of Pneumocystis jirovecii pneumonia in immunosuppressed
cholestatic hepatotoxic drugs, causes permanent injury to small bile persons (transplant recipients, patients with AIDS). With its increas-
ducts, leading to the so-called “vanishing bile duct syndrome.” In van- ing use, its occasional hepatotoxicity is being recognized with grow-
ishing bile duct syndrome, initially, liver injury is minimal except for ing frequency. Its likelihood is unpredictable, but when it occurs,
severe cholestasis; however, over time, histologic evidence of bile duct trimethoprim-sulfamethoxazole hepatotoxicity follows a relatively
abnormalities is replaced by a paucity and eventual absence of discern- uniform latency period of several weeks and is often accompanied by
ible ducts on subsequent biopsies. eosinophilia, rash, and other features of a hypersensitivity reaction,
including the drug reaction with eosinophilia and systemic symptoms
(DRESS) syndrome. Biochemically and histologically, acute hepatocel-
■■AMIODARONE HEPATOTOXICITY (TOXIC AND
lular necrosis predominates, but cholestatic features are quite frequent.
IDIOSYNCRATIC REACTION) Occasionally, cholestasis without necrosis occurs, and very rarely, a
Therapy with this potent antiarrhythmic drug is accompanied in
severe cholangiolytic pattern of liver injury is observed. In most cases,
15–50% of patients by modest elevations of serum aminotransferase
liver injury is self-limited, but rare fatalities have been recorded. The
levels that may remain stable or diminish despite continuation of the
hepatotoxicity is attributable to the sulfamethoxazole component of the
drug. Such abnormalities may appear days to many months after begin-
drug and is similar in features to that seen with other sulfonamides; tis-
ning therapy. A proportion of those with elevated aminotransferase
sue eosinophilia and granulomas may be seen. The risk of trimethoprim-
levels have detectable hepatomegaly, and clinically important liver dis-
sulfamethoxazole hepatotoxicity is increased in persons with HIV
ease develops in <5% of patients. Features that represent a direct effect
infection. In a recent study, unique HLA associations in European
of the drug on the liver and that are common to the majority of long-
Americans and in African Americans have been identified.
term recipients are ultrastructural phospholipidosis, unaccompanied
by clinical liver disease, and interference with hepatic mixed-function ■■HMG-COA REDUCTASE INHIBITORS (STATINS)
oxidase metabolism of other drugs. The cationic amphiphilic drug and (IDIOSYNCRATIC MIXED HEPATOCELLULAR AND
its major metabolite desethylamiodarone accumulate in hepatocyte CHOLESTATIC REACTION)
lysosomes and mitochondria and in bile duct epithelium. The relatively Between 1 and 2% of patients taking lovastatin, simvastatin, pravas-
common elevations in aminotransferase levels are also considered a tatin, fluvastatin, or one of the newer statin drugs for the treatment of
predictable, dose-dependent, direct hepatotoxic effect. On the other
PART 10

hypercholesterolemia experience asymptomatic, reversible elevations

hand, in the rare patient with clinically apparent, symptomatic liver (greater than threefold) of aminotransferase activity. Acute hepatitis-
disease, liver injury resembling that seen in alcoholic liver disease is like histologic changes, centrilobular necrosis, and centrilobular
observed. The so-called pseudoalcoholic liver injury can range from cholestasis have been described in a very small number of cases. In a
steatosis, to alcoholic hepatitis–like neutrophilic infiltration and Mal- larger proportion, minor aminotransferase elevations appear during
Disorders of the Gastrointestinal System

lory’s hyaline, to cirrhosis. Electron-microscopic demonstration of the first several weeks of therapy. Careful laboratory monitoring can
phospholipid-laden lysosomal lamellar bodies can help to distinguish distinguish between patients with minor, transitory changes, who may
amiodarone hepatotoxicity from typical alcoholic hepatitis. This cate- continue therapy, and those with more profound and sustained abnor-
gory of liver injury appears to be a metabolic idiosyncrasy that allows malities, who should discontinue therapy. Because clinically meaning-
hepatotoxic metabolites to be generated. Rarely, an acute idiosyncratic ful aminotransferase elevations are so rare after statin use and do not
hepatocellular injury resembling viral hepatitis or cholestatic hepatitis differ in meta-analyses from the frequency of such laboratory abnor-
occurs. Hepatic granulomas have occasionally been observed. Because malities in placebo recipients, a panel of liver experts recommended to
amiodarone has a long half-life, liver injury may persist for months the National Lipid Association’s Safety Task Force that liver test moni-
after the drug is stopped. toring was not necessary in patients treated with statins and that statin
therapy need not be discontinued in patients found to have asymp-
■■ANABOLIC STEROIDS (CHOLESTATIC REACTION) tomatic isolated aminotransferase elevations during therapy. Statin
The most common form of liver injury caused by CAMs is the pro- hepatotoxicity is not increased in patients with chronic hepatitis C,
found cholestasis associated with anabolic steroids used by body hepatic steatosis, or other underlying liver diseases, and statins can be
builders. Unregulated agents sold in gyms and health food stores as used safely in these patients.
diet supplements, which are taken by athletes to improve their perfor-
mance, may contain anabolic steroids. In a young male, jaundice that ■■ALTERNATIVE AND COMPLEMENTARY
is accompanied by a cholestatic, rather than a hepatitic, laboratory MEDICINES (IDIOSYNCRATIC HEPATITIS,
profile almost invariably will turn out to be caused by the use of one STEATOSIS)
of a variety of androgen congeners. Such agents have the potential to Herbal medications that are of scientifically unproven efficacy and
injure bile transport pumps and to cause intense cholestasis; the time that lack prospective safety oversight by regulatory agencies account
to onset is variable, and resolution, which is the rule, may require many currently for >20% of DILI in the United States. Besides anabolic
weeks to months. Initially, anorexia, nausea, and malaise may occur, steroids, the most common category of dietary or herbal products is
followed by pruritus in some but not all patients. Serum aminotrans- weight loss agents. Included among the herbal remedies associated
ferase levels are usually <100 IU/L, and serum alkaline phosphatase with toxic hepatitis are Jin Bu Huan, xiao-chai-hu-tang, germander,
levels are generally moderately elevated with bilirubin levels frequently chaparral, senna, mistletoe, skullcap, gentian, comfrey (containing
exceeding 342 μmol/L (20 mg/dL). Examination of liver tissue reveals pyrrolizidine alkaloids), ma huang, bee pollen, valerian root, penny-
cholestasis without substantial inflammation or necrosis. Anabolic ste- royal oil, kava, celandine, Impila (Callilepis laureola), LipoKinetix,
roids have also been used by prescription to treat bone marrow failure. Hydroxycut, OxyElite Pro, Herbalife, herbal nutritional supplements,
In this setting, hepatic centrizonal sinusoidal dilatation and peliosis and herbal teas containing Camellia sinensis (green tea extract). Well
hepatis have been reported in rare patients, as have hepatic adenomas characterized are the acute hepatitis-like histologic lesions following
and hepatocellular carcinoma. Recently, a large series of cases with a Jin Bu Huan use: focal hepatocellular necrosis, mixed mononuclear
uniform phenotype has been described. Unfortunately, no genomic portal tract infiltration, coagulative necrosis, apoptotic hepatocyte
signature has become evident despite the unique features of the injury. degeneration, tissue eosinophilia, and microvesicular steatosis. Mega-
No permanent sequelae are evident besides prolonged jaundice, lasting doses of vitamin A can injure the liver, as can pyrrolizidine alkaloids,
frequently 10 weeks or more. which often contaminate Chinese herbal preparations and can cause a

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 veno-occlusive injury leading to sinusoidal hepatic vein obstruction. Acknowledgment 2591
Because some alternative medicines induce toxicity via active metab- Kurt J. Isselbacher, MD, contributed to this chapter in previous editions
olites, alcohol and drugs that stimulate cytochrome P450 enzymes of Harrison’s.
may enhance the toxicity of some of these products. Conversely, some
alternative medicines also stimulate cytochrome P450 and may result ■■FURTHER READING
in or amplify the toxicity of recognized drug hepatotoxins. In many Ahmad J et al: Sclerosing cholangitis-like changes on magnetic res-
instances, herbal and dietary supplements actually contain chemi- onance cholangiography in patients with drug-induced liver injury.
cals rather than only leaves, roots, and bark. Antirheumatic “herbs” Clin Gastroenterol Hepatol 17:789, 2019.
have been found to contain a nonsteroidal anti-inflammatory drug Björnsson ES, Hoofnagle JL: Categorization of drugs implicated in
(NSAID) such as diclofenac, for example. Given the widespread use causing liver injury: Critical assessment based upon published case
of such poorly defined herbal preparations, hepatotoxicity is likely to reports. Hepatology 63:590, 2016.
be encountered with increasing frequency; therefore, a drug history Chalasani N et al: Features and outcomes of 899 patients with
in patients with acute and chronic liver disease should include use of drug-induced liver injury: The DILIN prospective study. Gas-
“alternative medicines” and other nonprescription preparations sold troenterology 148:1340, 2015.
in so-called health food stores. Cirulli ET et al: A missense variant in PTPN22 is a risk factor for
drug-induced liver injury. Gastroenterology 156:1707, 2019.
■■CHECKPOINT INHIBITOR AND OTHER de Boer YS et al: Features of autoimmune hepatitis in patients with
IMMUNOTHERAPIES FOR CANCER drug-induced liver injury. Clin Gastroenterol Hepatol 15:103, 2017.
The introduction of a new class of immunotherapeutic agents for Kaplowitz N, Deleve LD (eds): Drug-Induced Liver Disease, 3rd ed.
melanoma and other cancers has ushered in a new kind of hepato- London, Elsevier/Academic Press, 2013.
toxicity, that associated with activation of the immune response. The Kleiner DE: Histopathological challenges in suspected drug-induced
three classes of immune-active molecules are cytotoxic T-lymphocyte- liver injury. Liver Int 38:198, 2018.
associated antigen-4 (CTLA-4), programmed cell death receptor 1 Lee WM et al: Intravenous N-acetylcysteine improves transplant-free
(PD-1), and programmed cell death receptor ligand 1 (PD-L1). Within survival in early stage non-acetaminophen acute liver failure. Gas-
weeks of beginning treatment with any one of several agents, including troenterology 137:856, 2009.
ipilimumab (CTLA-4), pembrolizumab (PD-1), or nivolumab (PD-1), Peeraphatdit TB et al: Hepatotoxicity from immune checkpoint
an active hepatitis evolves that is associated with positive ANAs and inhibitors: A systematic review and management recommendation.
appears to respond to glucocorticoid therapy. Histologically, liver Hepatology 72:315, 2020.

CHAPTER 341 Chronic Hepatitis

histology does not resemble autoimmune hepatitis but, instead, a Stolz A et al: Severe and protracted cholestasis in 44 young men tak-
nonspecific hepatic injury, assumed to result from the release of host ing bodybuilding supplements: Assessment of genetic, clinical and
modulation of anti-self-immune responses. Immune-mediated injury chemical risk factors. Aliment Pharmacol Ther 49:1195, 2019.
to thyroid, muscle, and colon is also commonly seen. Few deaths have
been reported related to these immunotherapies; while these novel
agents may need to be halted temporarily, in many cases, they can be
restarted (and are tolerated better on retreatment) if patients are show-
ing a favorable antitumor response.

■■HIGHLY ACTIVE ANTIRETROVIRAL THERAPY

FOR HIV INFECTION (MITOCHONDRIAL TOXIC,
341 Chronic Hepatitis
Jules L. Dienstag
IDIOSYNCRATIC, STEATOSIS; HEPATOCELLULAR,
CHOLESTATIC, AND MIXED)
The recognition of drug hepatotoxicity in persons with HIV infection
is complicated in this population by the many alternative causes of Chronic hepatitis represents a series of liver disorders of varying
liver injury (chronic viral hepatitis, fatty infiltration, infiltrative disor- causes and severity in which hepatic inflammation and necrosis con-
ders, mycobacterial infection, etc.), but drug hepatotoxicity associated tinue for at least 6 months. Milder forms are nonprogressive or only
with highly active antiretroviral therapy (HAART) was a common slowly progressive, while more severe forms may be associated with
type of liver injury in HIV-infected persons in the early days of HIV scarring and architectural reorganization, which, when advanced, lead
therapy; however, it is less frequent now (Chap. 202). Implicated ultimately to cirrhosis. Several categories of chronic hepatitis have been
most frequently are combinations including the nucleoside analogue recognized. These include chronic viral hepatitis, drug-induced chronic
reverse transcriptase inhibitors zidovudine, didanosine, and, to a lesser hepatitis (Chap. 340), and autoimmune chronic hepatitis. In many
extent, stavudine; the protease inhibitors ritonavir and indinavir (and cases, clinical and laboratory features are insufficient to allow assign-
amprenavir when used together with ritonavir), as well as tipranavir; ment into one of these three categories; these “idiopathic” cases are also
and the nonnucleoside reverse transcriptase inhibitors nevirapine believed to represent autoimmune chronic hepatitis. Finally, clinical
and, to a lesser extent, efavirenz. Distinguishing the impact of HAART and laboratory features of chronic hepatitis are observed occasionally
hepatotoxicity in patients with HIV and hepatitis virus co-infection is in patients with such hereditary/metabolic disorders as Wilson’s disease
made challenging by the following: (1) both chronic hepatitis B and (copper overload), α1 antitrypsin deficiency (Chaps. 344 and 415), and
hepatitis C can affect the natural history of HIV infection and the nonalcoholic fatty liver disease (Chap. 343) and even occasionally in
response to HAART, and (2) HAART can have an impact on chronic patients with alcoholic liver injury (Chap. 342). Although all types of
viral hepatitis. For example, immunologic reconstitution with HAART chronic hepatitis share certain clinical, laboratory, and histopathologic
can result in immunologically mediated liver-cell injury in patients features, chronic viral and chronic autoimmune hepatitis are sufficiently
with chronic hepatitis B co-infection if treatment with an antiviral distinct to merit separate discussions. For discussion of acute hepati-
agent for hepatitis B (e.g., nucleoside analogues such as tenofovir) tis, see Chap. 339.
is withdrawn. Infection with HIV, especially with low CD4+ T-cell
counts, has been reported to increase the rate of hepatic fibrosis asso- CLASSIFICATION OF CHRONIC HEPATITIS
ciated with chronic hepatitis C, and HAART therapy can increase levels Common to all forms of chronic hepatitis are histopathologic dis-
of serum aminotransferases and HCV RNA in patients with hepatitis C tinctions based on localization and extent of liver injury. These
co-infection. Didanosine or stavudine should not be used with ribavi- vary from the milder forms, previously labeled chronic persistent
rin in patients with HIV/HCV co-infection because of an increased hepatitis and chronic lobular hepatitis, to the more severe form,
risk of severe mitochondrial toxicity and lactic acidosis. formerly called chronic active hepatitis. When first defined, these

HPIM21e_Part10_p2381-p2670.indd 2591 20/01/22 10:05 PM

 2592 designations were believed to have prognostic implications, which noninvasive approaches have been introduced to provide approxi-
were not corroborated by subsequent observations. Categorization mations of hepatic histologic stage, including serum biomarkers of
of chronic hepatitis based primarily on histopathologic features fibrosis; fibrosis scores such as FIB-4, a validated algorithm based on
has been replaced by a more informative classification based on a such routine lab tests as aspartate and alanine aminotransferase (AST
combination of clinical, serologic, and histologic variables. Classifi- and ALT) levels and platelet counts (PLT) (age [years] × AST/PLT ×
cation of chronic hepatitis is based on (1) its cause; (2) its histologic ALT1/2); and imaging determinations of liver elasticity.
activity, or grade; and (3) its degree of progression based on level of
fibrosis, or stage. Thus, neither clinical features alone nor histologic CHRONIC VIRAL HEPATITIS
features—requiring liver biopsy or noninvasive markers of fibrosis— Both of the enterically transmitted forms of viral hepatitis, hepatitis A
alone are sufficient to characterize and distinguish among the several and E, are self-limited and do not cause chronic hepatitis (rare reports
categories of chronic hepatitis. notwithstanding in which acute hepatitis A serves as a trigger for the
onset of autoimmune hepatitis in genetically susceptible patients or
■■CLASSIFICATION BY CAUSE in which hepatitis E [Chap. 339] can cause chronic liver disease in
Clinical and serologic features allow the establishment of a diagnosis immunosuppressed hosts, for example, after liver transplantation). In
of chronic viral hepatitis, caused by hepatitis B, hepatitis B plus D, or contrast, the entire clinicopathologic spectrum of chronic hepatitis
hepatitis C; autoimmune hepatitis, including several subcategories, I occurs in patients with chronic viral hepatitis B and C as well as in
and II, based on serologic distinctions; drug-associated chronic hepati- patients with chronic hepatitis D superimposed on chronic hepatitis B.
tis; and a category of unknown cause, or cryptogenic chronic hepatitis
(Table 341-1). These are addressed in more detail below.
■■CHRONIC HEPATITIS B
■■CLASSIFICATION BY GRADE The likelihood of chronicity after acute hepatitis B varies as a function
Grade, a histologic assessment of necroinflammatory activity, is based on of age. Infection at birth is associated with clinically silent acute infec-
examination of the liver biopsy. An assessment of important histologic tion but a 90% chance of chronic infection, whereas infection in young
features includes the degree of periportal necrosis and the disruption adulthood in immunocompetent persons is typically associated with
of the limiting plate of periportal hepatocytes by inflammatory cells clinically apparent acute hepatitis but a risk of chronicity of only ~1%.
(so-called piecemeal necrosis or interface hepatitis); the degree of conflu- Most cases of chronic hepatitis B among adults, however, are recognized
ent necrosis that links or forms bridges between vascular structures— in patients who never had a recognized episode of clinically apparent
between portal tract and portal tract or even more important bridges acute viral hepatitis. The degree of liver injury (grade) in patients with
between portal tract and central vein—referred to as bridging necrosis; chronic hepatitis B is variable, ranging from none in inactive carriers
the degree of hepatocyte degeneration and focal necrosis within the to mild to moderate to severe. Among adults with chronic hepatitis B,
PART 10

lobule; and the degree of portal inflammation. Several scoring systems histologic features are of prognostic importance. In one long-term
that take these histologic features into account have been devised, and study of patients with chronic hepatitis B, investigators found a 5-year
the most popular are the histologic activity index (HAI), used com- survival rate of 97% for patients with mild chronic hepatitis, 86%
monly in the United States, and the METAVIR score, used in Europe for patients with moderate to severe chronic hepatitis, and only 55%
for patients with chronic hepatitis and postnecrotic cirrhosis. The
Disorders of the Gastrointestinal System

(Table 341-2). Based on the presence and degree of these features of

histologic activity, chronic hepatitis can be graded as mild, moderate, 15-year survival in these cohorts was 77%, 66%, and 40%, respectively.
or severe. On the other hand, more recent observations do not allow us to be so
sanguine about the prognosis in patients with mild chronic hepatitis;
■■CLASSIFICATION BY STAGE among such patients followed for 1−13 years, progression to more
The stage of chronic hepatitis, which reflects the level of progression severe chronic hepatitis and cirrhosis has been observed in more than
of the disease, is based on the degree of hepatic fibrosis. When fibrosis a quarter of cases.
is so extensive that fibrous septa surround parenchymal nodules and More important to consider than histology alone in patients with
alter the normal architecture of the liver lobule, the histologic lesion is chronic hepatitis B is the degree of hepatitis B virus (HBV) replica-
defined as cirrhosis. Staging is based on the degree of fibrosis as categorized tion. As reviewed in Chap. 339, chronic HBV infection can occur in
on a numerical scale 0−6 (HAI) or 0−4 (METAVIR) (Table 341-2). Several the presence or absence of serum hepatitis B e antigen (HBeAg), and

TABLE 341-1 Clinical and Laboratory Features of Chronic Hepatitis

TYPE OF HEPATITIS DIAGNOSTIC TEST(S) AUTOANTIBODIES THERAPY
Chronic hepatitis B HBsAg, IgG anti-HBc, HBeAg, HBV DNA Uncommon IFN-α, PEG IFN-α
Oral agents:
First-line: entecavir, tenofovir
Second-line: lamivudine, adefovir, telbivudine
Chronic hepatitis C Anti-HCV, HCV RNA Anti-LKM1a PEG IFN-α plus ribavirinb
Direct-acting oral agents:
sofosbuvir, ledipasvir, velpatasvir
ritonavir-boosted paritaprevir, ombitasvir, dasabuvir, elbasvir,
grazoprevir, daclatasvir, simeprevir
Chronic hepatitis D Anti-HDV, HDV RNA, HBsAg, IgG anti-HBc Anti-LKM3 IFN-α, PEG IFN-αc
Autoimmune hepatitis ANAd (homogeneous), anti-LKM1 (±) ANA, anti-LKM1 anti-SLAe Prednisone, azathioprine
Hyperglobulinemia
Drug-associated — Uncommon Withdraw drug
Cryptogenic All negative None Prednisone (?), azathioprine (?)
a
Antibodies to liver-kidney microsomes type 1 (autoimmune hepatitis type II and some cases of hepatitis C). bSupplanted in almost all cases by combinations of the direct-
acting antiviral agents listed (see www.hcvguidelines.org). cEarly clinical trials suggested benefit of IFN-α therapy; PEG IFN-α is as effective, if not more so, and has
supplanted standard IFN-α. dAntinuclear antibody (autoimmune hepatitis type I). eAntibodies to soluble liver antigen (autoimmune hepatitis type III).
Abbreviations: HBc, hepatitis B core; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus;
IFN-α, interferon α; IgG, immunoglobulin G; LKM, liver-kidney microsome; PEG IFN-α, pegylated interferon α; SLA, soluble liver antigen.

HPIM21e_Part10_p2381-p2670.indd 2592 20/01/22 10:05 PM

 TABLE 341-2 Histologic Grading and Staging of Chronic Hepatitis early childhood, as recognized commonly 2593
in Asian countries, a dichotomy is com-
HISTOLOGIC ACTIVITY INDEX (HAI)
a
METAVIR
b
mon between very high levels of HBV
HISTOLOGIC FEATURE SEVERITY SCORE SEVERITY SCORE replication during the early decades of life
Necroinflammatory Activity (grade) (when the level of apparent host immuno-
Periportal necrosis, including piecemeal None 0 None 0 logic tolerance of HBV is relatively high)
necrosis and/or bridging necrosis (BN) Mild 1 Mild 1
and negligible levels of liver injury; dur-
ing this phase of chronic hepatitis B, the
Mild/moderate 2 Moderate 2
level of viral replication does not correlate
Moderate 3 Severe 3 with liver injury or late complications. Yet
Severe 4 Bridging necrosis Yes despite the relatively immediate, appar-
No ently benign nature of liver disease for
many decades in this population, in the
Intralobular necrosis  Confluent —None 0 None or mild 0 middle decades, activation of liver injury
—Focal 1 Moderate 1 emerges as what appears to be the relative
—Zone 3 some 2 Severe 2 tolerance of the host to HBV declines, and
—Zone 3 most 3 these patients with childhood-acquired
—Zone 3 + BN few 4 HBV infection are ultimately at increased
—Zone 3 + BN multiple 5
risk later in life for cirrhosis, hepato-
cellular carcinoma (HCC) (Chap. 82),
—Panacinar/multiacinar 6
and liver-related death; the link between
Focal —None 0 high-level HBV replication and these late
—≤1 focus/10× field 1 liver complications has been demonstrated
—2–4 foci/10× field 2 convincingly in, and confined mostly to,
—5–10 foci/10× field 3 persons in their middle decades, especially
—>10 foci/10× field 4 age ≥40. A discussion of the pathogenesis
Portal Inflammation None 0 of liver injury in patients with chronic
Mild 1 hepatitis B appears in Chap. 339.

CHAPTER 341 Chronic Hepatitis

Moderate 2 HBeAg-negative chronic hepatitis B
Moderate/marked 3
(i.e., chronic HBV infection with active
virus replication and readily detect-
Marked 4
able HBV DNA but without HBeAg
Total 0–18 A0–A3c [anti-HBe-reactive]) is more common
Fibrosis (stage) than HBeAg-reactive chronic hepatitis B
None 0 F0 in Mediterranean and European coun-
Portal fibrosis—some 1 F1 tries and in Asia (and, correspondingly, in
Portal fibrosis—most 2 F1 HBV genotypes other than A). Compared
Bridging fibrosis—few 3 F2 to patients with HBeAg-reactive chronic
hepatitis B, patients with HBeAg-nega-
Bridging fibrosis—many 4 F3
tive chronic hepatitis B have HBV DNA
Incomplete cirrhosis 5 F4
levels several orders of magnitude lower
Cirrhosis 6 F4 (usually no more than 105−106 IU/mL)
Total 6 4 than those observed in the HBeAg-
a
Ishak K, Baptista A, Bianchi L, et al: Histologic grading and staging of chronic hepatitis. J Hepatol 22:696, 1995. reactive subset. Most such cases represent
b
Bedossa P, Poynard T, French METAVIR Cooperative Study Group: An algorithm for grading activity in chronic precore or core-promoter mutations
hepatitis C. Hepatology 24:289, 1996. cNecroinflammatory grade: A0 = none; A1 = mild; A2 = moderate; A3 = severe. acquired late in the natural history of the
disease (mostly early-life onset; age range
generally, for both HBeAg-reactive and HBeAg-negative chronic hep- 40−55 years, older than that for HBeAg-reactive chronic hepatitis B);
atitis B, the level of HBV DNA correlates with the level of liver injury these mutations prevent translation of HBeAg from the precore com-
and risk of progression. In HBeAg-reactive chronic hepatitis B, two ponent of the HBV genome (precore mutants) or are characterized
phases have been recognized based on the relative level of HBV repli- by downregulated transcription of precore mRNA (core-promoter
cation. The relatively replicative phase is characterized by the presence mutants; Chap. 339). Although their levels of HBV DNA tend to be
in the serum of HBeAg and HBV DNA levels well in excess of 103−104 lower than among patients with HBeAg-reactive chronic hepatitis B,
IU/mL, sometimes exceeding 109 IU/mL; by the presence in the liver of patients with HBeAg-negative chronic hepatitis B can have progres-
detectable intrahepatocyte nucleocapsid antigens (primarily hepatitis B sive liver injury (complicated by cirrhosis and HCC) and experience
core antigen [HBcAg]); by high infectivity; and by accompanying liver episodic reactivation of liver disease reflected in fluctuating levels of
injury. In contrast, the relatively nonreplicative phase is characterized aminotransferase activity (“flares”). The biochemical and histologic
by the absence of the conventional serum marker of HBV replication activity of HBeAg-negative disease tends to correlate closely with
(HBeAg), the appearance of anti-HBe, levels of HBV DNA below a levels of HBV replication, unlike the case mentioned above of Asian
threshold of ~103 IU/mL, the absence of intrahepatocytic HBcAg, patients with HBeAg-reactive chronic hepatitis B during the early
limited infectivity, and minimal liver injury. Patients in the relatively decades of their HBV infection. Worth reiterating, the level of HBV
replicative phase tend to have more severe chronic hepatitis, whereas replication is the most important risk factor for the ultimate develop-
those in the relatively nonreplicative phase tend to have minimal or ment of cirrhosis and HCC in both HBeAg-reactive (beyond the early
mild chronic hepatitis or to be inactive hepatitis B carriers. The likeli- decades of “relatively nonreplicative” infection) and HBeAg-negative
hood in a patient with HBeAg-reactive chronic hepatitis B of convert- patients. Although levels of HBV DNA are lower and more readily
ing spontaneously from relatively replicative to nonreplicative infection suppressed by therapy to undetectable levels in HBeAg-negative (com-
is ~10% per year. Distinctions in HBV replication and in histologic pared to HBeAg-reactive) chronic hepatitis B, achieving sustained
category, however, do not always coincide. In patients with HBeAg- responses that permit discontinuation of antiviral therapy is less likely
reactive chronic HBV infection, especially when acquired at birth or in in HBeAg-negative patients (see below). Inactive carriers are patients

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 2594 with circulating hepatitis B surface antigen (HBsAg), normal serum pharmacologic suppression of HBV replication. In addition, res-
aminotransferase levels, minimal or no histologic evidence of liver toration of impaired HBV-specific T-cell function has been shown
injury, undetectable HBeAg, and levels of HBV DNA that are either following successful suppression of HBV replication with antiviral
undetectable or present at a threshold of ≤103 IU/mL. This serologic therapy. To date, eight drugs have been approved for treatment of
profile occurs not only in inactive carriers but also in patients with chronic hepatitis B: injectable interferon (IFN) α and pegylated
HBeAg-negative chronic hepatitis B during periods of relative inac- interferon (long-acting IFN bound to polyethylene glycol, PEG
tivity; distinguishing between the two requires sequential biochemical [PEG IFN]) and the oral agents lamivudine, adefovir dipivoxil,
and virologic monitoring over many months. entecavir, telbivudine, tenofovir disoproxil fumarate (TDF), and
The spectrum of clinical features of chronic hepatitis B is broad, tenofovir alafenamide (TAF).
ranging from asymptomatic infection to debilitating disease or even Antiviral therapy for hepatitis B has evolved rapidly since the
end-stage, fatal hepatic failure. As noted above, the onset of the dis- mid-1990s, as has the sensitivity of tests for HBV DNA. When IFN
ease tends to be insidious in most patients, apart from the very few in and the first oral antiviral lamivudine were evaluated in clinical
whom chronic disease follows failure of resolution of clinically appar- trials, HBV DNA was measured by insensitive hybridization assays
ent acute hepatitis B. The clinical and laboratory features associated with detection thresholds of 105−106 virions/mL; when subsequent
with progression from acute to chronic hepatitis B are discussed in treatments were studied in clinical trials, HBV DNA was mea-
Chap. 339. sured by sensitive amplification assays (polymerase chain reaction
Fatigue is a common symptom, and persistent or intermittent jaundice [PCR]) with detection thresholds of 101−103 viral copies/mL or
is a common feature in severe or advanced cases. Intermittent deep- IU/mL. Recognition of these distinctions is helpful when compar-
ening of jaundice and recurrence of malaise and anorexia, as well as ing results of clinical trials that established the efficacy of these
worsening fatigue, are reminiscent of acute hepatitis; such exacer- therapies (reviewed below in chronologic order of publication of
bations may occur spontaneously, often coinciding with evidence of these efficacy trials). Of the eight approved treatments, PEG IFN,
virologic reactivation; may lead to progressive liver injury; and, when entecavir, and the two tenofovir preparations (TDF and TAF) are
superimposed on well-established cirrhosis, may cause hepatic dec- recommended as first-line agents, and generally, the oral agents are
ompensation. Complications of cirrhosis occur in end-stage chronic favored over injectable PEG IFN.
hepatitis and include ascites, edema, bleeding gastroesophageal varices,
hepatic encephalopathy, coagulopathy, and hypersplenism. Occasion- INTERFERON
ally, these complications bring the patient to initial clinical attention. IFN-α was the first approved therapy (1992) for chronic hepatitis B.
Extrahepatic complications of chronic hepatitis B, similar to those seen Although it is no longer used to treat hepatitis B, standard IFN is
during the prodromal phase of acute hepatitis B, are associated with important historically, having provided important lessons about
PART 10

tissue deposition of circulating hepatitis B antigen–antibody immune antiviral therapy in general. For immunocompetent adults with
complexes. These include arthralgias and arthritis, which are common, HBeAg-reactive chronic hepatitis B (who tend to have high-level
and the rarer purpuric cutaneous lesions (leukocytoclastic vasculi- HBV DNA [>105−106 virions/mL] and histologic evidence of
tis), immune-complex glomerulonephritis, and generalized vasculitis chronic hepatitis on liver biopsy), a 16-week course of subcuta-
(polyarteritis nodosa) (Chap. 363). neous IFN, 5 million units daily or 10 million units thrice weekly,
Disorders of the Gastrointestinal System

Laboratory features of chronic hepatitis B do not distinguish resulted in a loss of HBeAg and hybridization-detectable HBV
adequately between histologically mild and severe hepatitis. DNA (i.e., a reduction to levels below 105−106 virions/mL) in ~30%
Aminotransferase elevations tend to be modest for chronic hepatitis of patients, with a concomitant improvement in liver histology.
B but may fluctuate in the range of 100−1000 units. As is true for Seroconversion from HBeAg to anti-HBe occurred in ~20%, and, in
acute viral hepatitis B, ALT tends to be more elevated than AST; early trials, ~8% lost HBsAg. Successful IFN therapy and serocon-
however, once cirrhosis is established, AST tends to exceed ALT. version were often accompanied by an acute hepatitis-like elevation
Levels of alkaline phosphatase activity tend to be normal or only in aminotransferase activity, postulated to result from enhanced
marginally elevated. In severe cases, moderate elevations in serum cytolytic T-cell clearance of HBV-infected hepatocytes. Relapse
bilirubin (51.3−171 μmol/L [3−10 mg/dL]) occur. Hypoalbumine- after successful therapy was rare (1 or 2%). Responsiveness to IFN
mia and prolongation of the prothrombin time occur in severe or was higher in patients with low-level HBV DNA and substantial
end-stage cases. Hyperglobulinemia and detectable circulating auto- ALT elevations. Therapy with IFN was not effective in immunosup-
antibodies are distinctly absent in chronic hepatitis B (in contrast to pressed persons, persons with neonatal acquisition of infection and
autoimmune hepatitis). Viral markers of chronic HBV infection minimal-to-mild ALT elevations, or patients with decompensated
are discussed in Chap. 339. chronic hepatitis B (in whom such therapy was actually detri-
mental, sometimes precipitating decompensation, often associated
with severe adverse effects). After HBeAg loss during IFN therapy,
TREATMENT 80% experienced eventual loss of HBsAg and ALT normalization
Chronic Hepatitis B over the ensuing decade. In addition, improved long-term and
complication-free survival as well as a reduction in the frequency
Although progression to cirrhosis is more likely in severe than in of HCC were documented among IFN responders, supporting the
mild or moderate chronic hepatitis B, all forms of chronic hepatitis B conclusion that successful antiviral therapy improves the natural
can be progressive, and progression occurs primarily in patients history of chronic hepatitis B.
with active HBV replication. Moreover, in populations of patients Brief-duration IFN therapy in patients with HBeAg-negative
with chronic hepatitis B who are at risk for HCC (Chap. 82), the chronic hepatitis B was disappointing, suppressing HBV replication
risk is highest for those with continued, high-level HBV replica- transiently during therapy but almost never resulting in sustained
tion and lower for persons in whom initially high-level HBV DNA antiviral responses; however, more protracted courses for up to 1.5
falls spontaneously over time. Therefore, management of chronic years resulted in sustained virologic/biochemical remissions docu-
hepatitis B is directed at suppressing the level of virus replication. mented to last for several years in ~20%.
Although clinical trials tend to focus on clinical endpoints achieved Complications of IFN therapy include systemic “flu-like” symptoms;
over 1−2 years (e.g., suppression of HBV DNA to undetectable marrow suppression; emotional lability (irritability, depression,
levels, loss of HBeAg/HBsAg, improvement in histology, nor- anxiety); autoimmune reactions (especially autoimmune thyroiditis);
malization of ALT), these short-term gains translate into reduc- and miscellaneous side effects such as alopecia, rashes, diarrhea,
tions in the risk of clinical progression, hepatic decompensation, and numbness and tingling of the extremities. With the possible
HCC, liver transplantation, and death; regression of cirrhosis and exception of autoimmune thyroiditis, all these side effects are
of esophageal varices has been documented to follow long-term reversible upon dose lowering or cessation of therapy.

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 Although no longer competitive with the newer generation of transcriptase activity of both HIV and HBV and is an effective 2595
antivirals, IFN did represent the first successful antiviral approach, agent for chronic hepatitis B; however, it is now superseded by
set a standard against which to measure efficacy of subsequent newer, more potent, less resistance-prone agents. For a summary
drugs, and demonstrated the benefit of antiviral therapy on the of its virologic, serologic, biochemical, and histologic efficacy,
natural history of chronic hepatitis B. Standard IFN has been sup- as well as its resistance profile, please refer to Table 341-3. In
planted by long-acting PEG IFN (see below), and IFN nonrespond- clinical trials, lamivudine therapy at daily doses of 100 mg for
ers are now treated with one of the newer oral nucleoside analogues. 48−52 weeks suppressed HBV DNA, as measured by sensitive
LAMIVUDINE PCR amplification assays, by a median of ~5.5 log10 copies/mL in
HBeAg-positive chronic hepatitis B and ~4.5 log10 copies/mL in
The first of the nucleoside analogues to be approved (in 1998) HBeAg-negative chronic hepatitis B (baseline HBV DNA levels
for hepatitis B, the dideoxynucleoside lamivudine inhibits reverse

TABLE 341-3 Comparison of Pegylated Interferon (PEG IFN), Lamivudine, Adefovir, Entecavir, Telbivudine, and Tenofovir Therapy for Chronic
Hepatitis Ba
TENOFOVIR
FEATURE PEG IFNb LAMIVUDINE ADEFOVIR ENTECAVIR TELBIVUDINE (TDF) TENOFOVIR (TAF)
Route of administration Subcutaneous Oral Oral (10 mg/d) Oral (0.5 mg/d) Oral (600 mg/d) Oral (300 mg/d) Oral 25 mg/d)
injection (180 μg/ (100 mg/d)
week)
Status First-line No longer No longer First-line No longer First-line First-line
preferred preferred preferred,
withdrawn
Duration of therapyc 48–52 weeks ≥52 weeks ≥48 weeks ≥48 weeks ≥52 weeks ≥48 weeks 48 weeks
Tolerability Poorly tolerated Well tolerated Well tolerated; Well tolerated Well tolerated Well tolerated; Well tolerated
creatinine creatinine
monitoring monitoring
recommended recommended
HBeAg seroconversion

CHAPTER 341 Chronic Hepatitis

1 yr Rx 18–20% 16–21% 12% 21% 22% 21% 10% (14% HBeAg loss)
>1 yr Rx NA up to 50% at 43% at 3 yrsd 31% at 2 yrs 30% at 2 yrs 40% at 5 yrs 18% at yr 2 (HBeAg
5 yrs 44% at 6 yrs loss 22%)
Log10 HBV DNA reduction Not reported in clinical
(mean copies/mL) trials, likely same as
HBeAg-reactive TDF
4.5 5.5 Median 3.5–5 6.9 6.4 6.2
HBeAg-negative 4.1 4.4–4.7 Median 3.5–3.9 5.0 5.2 4.6
HBV DNA PCR negative
(at then current PCR
sensitivitya) at end of yr 1
HBeAg-reactive
10–25% 36–44% 13–21% 67% (91% at 4 yrs) 60% 76% 64%
HBeAg-negative
63% 60–73% 48–77% 90% 88% 93% 94%
ALT normalization at end
of yr 1
HBeAg-reactive 39% 41–75% 48–61% 68% 77% 68% 72%
HBeAg-negative 34–38% 62–79% 48–77% 78% 74% 76% 83%
HBsAg loss, yr 1 3–4% ≤1% 0% 2% <1% 3% 1%
>yr 1 12% 5 yr after No data 5% at yr 5 6% at yr 6 No data 8% at yr 5 1%
1 yr of Rx
Histologic improvement Not included in clinical
(≥2 point reduction in HAI) trials
at yr 1
HBeAg-reactive
38% 6 months 49–62% 53–68% 72% 65% 74%
after 61–66% 64% 70% 67% 72%
HBeAg-negative 48% 6 months
after
Viral resistance None 15–30% at 1 yr None at 1 yr ≤1% at 1 yre Up to 5% at yr 1 0% at yr 1 0% at yr 1
70% at 5 yrs 29% at 5 yrs 1.2% at 6 yrse Up to 22% at 0% through yr 8 0% through yr 2
yr 2
Pregnancy category C Cf C C B B B
a
Generally, these comparisons are based on data on each drug tested individually versus placebo in registration clinical trials; with rare exception, these comparisons are
not based on head-to-head testing of these drugs. In addition, the sensitivity of HBV DNA assays increased in sensitivity over the two decades between the introduction
of the earliest and latest of these approved drugs. Therefore, relative advantages and disadvantages should be interpreted cautiously. bAlthough standard interferon
α administered daily or three times a week is approved as therapy for chronic hepatitis B, it has been supplanted by PEG IFN, which is administered once a week and
is more effective. Standard interferon has no advantages over PEG IFN. cDuration of therapy in clinical efficacy trials; use in clinical practice may vary. dBecause of a
computer-generated randomization error that resulted in misallocation of drug versus placebo during the second year of clinical trial treatment, the frequency of HBeAg
seroconversion beyond the first year is an estimate (Kaplan-Meier analysis) based on the small subset in whom adefovir was administered correctly. e7% during a year of
therapy (43% at year 4) in lamivudine-resistant patients. fDespite its category C designation, lamivudine has an extensive pregnancy safety record in women with HIV/AIDS.
Abbreviations: ALT, alanine aminotransferase; HAI, histologic activity index; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; NA, not
applicable; PEG IFN, pegylated interferon; PCR, polymerase chain reaction; Rx, therapy; yr, year; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.

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 2596 are lower in HBeAg-negative than in HBeAg-positive chronic monitoring after discontinuation of treatment. Many authorities
hepatitis B) and to undetectable levels in ~40% and ~70%, respec- cautioned against discontinuing therapy in patients with cirrhosis,
tively. Lamivudine, which was shown to improve histology, retard in whom posttreatment flares could precipitate decompensation.
hepatic fibrosis, and prevent progression to cirrhosis, was effective Long-term monotherapy with lamivudine was associated
in patients resistant to IFN (e.g., those with high-level HBV DNA) with methionine-to-valine (M204V) or methionine-to-isoleucine
or who had failed prior IFN therapy. As was true for IFN therapy of (M204I) mutations, primarily at amino acid 204 in the tyrosine-me-
chronic hepatitis B, lamivudine-associated HBeAg seroconversion thionine-aspartate-aspartate (YMDD) motif of the C domain of
occurred in ~20%; patients with near-normal ALT activity tended HBV DNA polymerase, analogous to mutations that occur in
not to experience HBeAg responses (despite suppression of HBV HIV-infected patients treated with this drug. During a year of
DNA), while patients with ALT levels ≥5× the upper limit of nor- therapy, YMDD mutations occurred in 15−30% of patients; the fre-
mal could expect 1-year HBeAg seroconversion rates of 50−60%. quency increased with each year of therapy, reaching 70% at year 5.
Generally, HBeAg seroconversions were confined to patients who Ultimately, patients with YMDD mutants experienced degradation
achieved suppression of HBV DNA to <104 copies/mL (equivalent of clinical, biochemical, and histologic responses; therefore, if treat-
to ~103 IU/mL). Lamivudine-associated HBeAg responses were ment was begun with lamivudine monotherapy, the emergence of
accompanied by a delayed posttreatment HBsAg seroconversion lamivudine resistance, reflected clinically by a breakthrough from
rate comparable to that seen after IFN. Among Western patients suppressed levels of HBV DNA and ALT, was managed by adding
who experienced HBeAg responses during a year-long course of another antiviral to which YMDD variants are sensitive (e.g., ade-
therapy and in whom the response was sustained for 4−6 months fovir, tenofovir; see below).
after cessation of therapy, the response was durable thereafter in Currently, lamivudine has been eclipsed by more potent anti-
the vast majority (>80%); therefore, the achievement of an HBeAg virals that have superior resistance profiles (see below); it is
response represented a viable stopping point in therapy. Reduced no longer recommended as first-line therapy. Still, as the first
durability, however, was reported in Asian patients; therefore, to successful oral antiviral agent for use in hepatitis B, lamivudine
support the durability of HBeAg responses, a period of consoli- provided proof of principle that polymerase inhibitors can achieve
dation therapy of ≥6 months in Western patients and ≥1 year in virologic, serologic, biochemical, and histologic benefits, includ-
Asian patients was recommended after HBeAg seroconversion (see ing retardation and reversal of fibrosis and even of cirrhosis. In
treatment guidelines below; a full 12-month consolidation period addition, lamivudine was shown to be effective in the treatment
is recommended currently for treatment extension after oral-agent- of patients with decompensated hepatitis B (for whom IFN is con-
induced HBeAg seroconversion). Close posttreatment monitoring traindicated), in some of whom decompensation can be reversed.
was recommended to identify HBV reactivation promptly and to Moreover, among patients with cirrhosis or advanced fibrosis,
PART 10

resume therapy. If HBeAg was unaffected by lamivudine therapy, lamivudine was shown to be effective in reducing the risk of
lamivudine was continued until an HBeAg response occurred, but progression to hepatic decompensation and, based on subsequent
long-term therapy was required to suppress HBV replication and, in population studies, the risk of HCC. In the half decade following
turn, limit liver injury; HBeAg seroconversions increased to a level the introduction in the United States of lamivudine therapy for
of 50% after 5 years of therapy. After a cumulative course of 3 years hepatitis B, referral of patients with HBV-associated end-stage liver
Disorders of the Gastrointestinal System

of lamivudine therapy, necroinflammatory activity was reduced in disease for liver transplantation fell by ~30%, supporting further
the majority of patients, and even cirrhosis was shown to regress to the beneficial impact of oral antiviral therapy on the natural his-
precirrhotic stages in as many as three-quarters of patients. tory of chronic hepatitis B.
Losses of HBsAg were few during the first year of lamivudine Because lamivudine monotherapy in persons with HIV infec-
therapy, and this observation had been cited as an advantage of tion can result universally in the rapid emergence of YMDD vari-
IFN-based therapy over lamivudine therapy; however, in head-to- ants, testing for HIV infection was recommended for all patients
head comparisons between standard IFN and lamivudine mono- with chronic hepatitis B prior to lamivudine therapy; if HIV infec-
therapy, HBsAg losses were rare in both groups. Trials in which tion was identified, lamivudine monotherapy at the HBV daily dose
lamivudine and IFN were administered in combination failed to of 100 mg was contraindicated. These patients require treatment for
show a benefit of combination therapy over lamivudine monother- both HIV and HBV with an HIV drug regimen that includes or is
apy for either treatment-naïve patients or prior IFN nonresponders. supplemented by at least two drugs active against HBV; antiretro-
Patients with HBeAg-negative chronic hepatitis B (i.e., in those viral therapy (ART) often contains two drugs with antiviral activity
with precore and core-promoter HBV mutations and who lack against HBV (e.g., tenofovir and emtricitabine), but if lamivudine
HBeAg) cannot achieve an HBeAg response to nucleoside analogue was part of the regimen, the 300-mg daily dose was required
therapy—a stopping point in HBeAg-reactive patients; almost (Chap. 202). The safety of lamivudine during pregnancy has not
invariably, when therapy was discontinued, reactivation was the rule. been established; however, the drug is not teratogenic in rodents
Therefore, these patients required long-term lamivudine therapy. and has been used safely in pregnant women with HIV infection
Clinical and laboratory side effects of lamivudine were negligible and with HBV infection. As shown for subsequent nucleoside
and indistinguishable from those observed in placebo recipients; analogues, administration of lamivudine during the last months of
however, lamivudine doses were reduced in patients with reduced pregnancy to mothers with high-level hepatitis B viremia reduced
creatinine clearance. During lamivudine therapy, transient ALT the likelihood of perinatal transmission of hepatitis B.
elevations, resembling those seen during IFN therapy and dur-
ing spontaneous HBeAg-to-anti-HBe seroconversions, occurred ADEFOVIR DIPIVOXIL
in one-fourth of patients. These ALT elevations may result from At an oral daily dose of 10 mg, the acyclic nucleotide analogue ade-
restored cytolytic T-cell activation permitted by suppression of fovir dipivoxil, the prodrug of adefovir (approved for hepatitis B in
HBV replication. Similar ALT elevations, however, occurred at 2002), reduces HBV DNA by ~3.5−4 log10 copies/mL, i.e., it is less
an identical frequency in placebo recipients; however, ALT ele- potent than lamivudine or any of the newer antiviral agents. For
vations associated temporally with HBeAg seroconversion in a summary of its virologic, serologic, biochemical, and histologic
clinical trials were confined to lamivudine-treated patients. When efficacy, as well as its resistance profile, please refer to Table 341-3.
therapy was stopped after a year of therapy, two- to threefold ALT Like IFN and lamivudine, adefovir dipivoxil is more likely to
elevations occurred in 20−30% of lamivudine-treated patients, achieve an HBeAg response in patients with high baseline ALT;
representing renewed liver-cell injury as HBV replication returned. HBeAg responses to it are highly durable and can be relied upon as
Although these posttreatment flares were almost always transient a treatment stopping point, after a period of consolidation therapy;
and mild, rare severe exacerbations, especially in cirrhotic patients, and biochemical, serologic, and virologic outcomes improve over
were observed, mandating close and careful clinical and virologic time with continued therapy.

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 In HBeAg-negative chronic hepatitis B, as was true for lami- comparison arms of lamivudine monotherapy and combination PEG 2597
vudine, because HBeAg responses—a potential stopping point— IFN plus lamivudine. At the end of therapy (48−52 weeks) in the
cannot be achieved, reactivation is the rule when adefovir therapy PEG IFN monotherapy arms, HBeAg loss occurred in ~30%, HBeAg
is discontinued, and indefinite, long-term therapy is required. seroconversion in 22−27%, undetectable HBV DNA (<400 copies/mL
Reported attempts to stop adefovir after 5 years were followed by a by PCR) in 10−25%, and normal ALT in 34−39%, and a mean reduc-
period of maintained suppression of HBV DNA and ALT; however, tion in HBV DNA of 2 log10 copies/mL (PEG IFN-α2b) to 4.5 log10
most such patients had persistent hepatitis B viremia, and most copies/mL (PEG IFN-α2a) was seen. Six months after completing
HBeAg-negative patients were treated indefinitely unless HBsAg PEG IFN monotherapy in these trials, HBeAg losses were present
loss, albeit very rare, was achieved. in ~35%, HBeAg seroconversion in ~30%, undetectable HBV DNA
Adefovir contains a flexible acyclic linker instead of the in 7−14%, and normal ALT in 32−41%, and the mean reduction in
L-nucleoside ring of lamivudine, avoiding steric hindrance by HBV DNA was 2−2.4 log10 copies/mL. Although the combination of
mutated amino acids. In addition, the molecular structure of phos- PEG IFN and lamivudine was superior at the end of therapy in one
phorylated adefovir is very similar to that of its natural substrate; or more serologic, virologic, or biochemical outcomes, neither the
therefore, mutations to adefovir would also affect binding of the combination arm (in both studies) nor the lamivudine monotherapy
natural substrate, dATP. Thus, resistance to adefovir was much arm (in the PEG IFN-α2a trial) demonstrated any benefit compared
less likely than resistance to lamivudine, and no resistance was to the PEG IFN monotherapy arms 6 months after therapy. Moreover,
encountered in 1 year of clinical trial therapy. In subsequent years, HBsAg seroconversion occurred in 3−7% of PEG IFN recipients
however, adefovir resistance began to emerge (asparagine to thre- (with or without lamivudine); some of these seroconversions were
onine at amino acid 236 [N236T] and alanine to valine or threonine identified by the end of therapy, but many were identified during
at amino acid 181 [A181V/T], primarily), occurring in 2.5% after the posttreatment follow-up period. The likelihood of HBeAg loss
2 years but in 29% after 5 years of therapy (reported in in PEG IFN–treated HBeAg-reactive patients was associated with
HBeAg-negative patients). The primary contribution of adefovir, its HBV genotype A > B > C > D (shown for PEG IFN-α2b but not for
effectiveness in lamivudine-resistant, YMDD-mutant HBV, led to PEG IFN-α2a). PEG IFN-α2a was approved in the United States for
its adoption for lamivudine-resistant hepatitis B. When lamivudine hepatitis B in 2005; PEG IFN-α2b, which is not approved for hepa-
resistance occurred, adding adefovir (i.e., maintaining lamivudine titis B in the United States, is used in other countries.
to preempt the emergence of adefovir resistance) was superior to Based on these results, some authorities concluded that PEG
switching to adefovir. Almost invariably, patients with adefovir-in- IFN monotherapy should be the first-line therapy of choice in
duced HBV mutations respond to lamivudine (or newer agents, HBeAg-reactive chronic hepatitis B; however, this conclusion has

CHAPTER 341 Chronic Hepatitis

such as entecavir, see below). When, in the past, adefovir had been been challenged. Although a finite, 1-year course of PEG IFN
evaluated as therapy for HIV infection, doses of 60−120 mg were results in a higher rate of sustained response (6 months after
required to suppress HIV, and, at these doses, the drug was nephro- treatment) than is achieved with oral nucleoside/nucleotide ana-
toxic. Even at 30 mg/d, creatinine elevations of 44 μmol/L (0.5 mg/ logue therapy, the comparison is confounded by the fact that oral
dL) occurred in 10% of patients; however, at the HBV-effective dose agents are not discontinued at the end of 1 year. Instead, taken
of 10 mg, such creatinine elevations were encountered rarely and orally and free of side effects, therapy with oral agents is extended
hardly ever before 6−8 months of therapy. Although renal tubular indefinitely or until after the occurrence of an HBeAg response.
injury was a rare potential side effect, and although creatinine moni- The rate of HBeAg responses after 2 years of oral-agent nucleo-
toring was recommended during treatment, the therapeutic index of side analogue therapy is at least as high as, if not higher than, that
adefovir dipivoxil was high, and the nephrotoxicity observed in clin- achieved with PEG IFN after 1 year; favoring oral agents is the
ical trials at higher doses was reversible. For patients with underly- absence of injections, difficult-to-tolerate side effects, and labora-
ing renal disease, frequency of administration of adefovir had to be tory monitoring as well as lower direct and indirect medical care
reduced, and it could be given only once a week for patients under- costs and inconvenience. The association of HBsAg responses with
going hemodialysis. Adefovir was very well tolerated, and ALT ele- PEG IFN therapy occurs in such a small proportion of patients that
vations during and after withdrawal of therapy were similar to those subjecting everyone to PEG IFN for the marginal gain of HBsAg
observed and described above in clinical trials of lamivudine. An responses during or immediately after therapy in such a very small
advantage of adefovir was its relatively favorable resistance profile; minority is questionable. Moreover, HBsAg responses occur in a
however, it was not as potent as the other approved oral agents, it did comparable proportion of patients treated with early-generation
not suppress HBV DNA as rapidly or as uniformly as the others, it nucleoside/nucleotide analogues in the years after therapy, and,
was the least likely of all agents to result in HBeAg seroconversion, with the newer, more potent nucleoside analogues, the frequency
and 20−50% of patients failed to suppress HBV DNA by 2 log10 of HBsAg loss during the first year of therapy equals that of
(“primary nonresponders”). For these reasons, adefovir, which has PEG IFN and is exceeded during year 2 and beyond (see below).
been supplanted in both treatment-naïve and lamivudine-resistant Of course, resistance is not an issue during PEG IFN therapy, but
patients by the more potent, less resistance-prone tenofovir (see the risk of resistance is much lower with new agents (≤1% up to
below), is no longer recommended as first-line therapy. 3−8 years in previously treatment-naïve, entecavir-treated patients
and 0% in tenofovir-treated patients; see below). Finally, the level of
PEGYLATED IFN HBV DNA inhibition that can be achieved with the newer agents,
After long-acting PEG IFN was shown to be effective in the and even with lamivudine, exceeds that achieved with PEG IFN, in
treatment of hepatitis C (see below), this more convenient IFN some cases by several orders of magnitude.
preparation was evaluated in the treatment of chronic hepatitis B. In HBeAg-negative chronic hepatitis B, a trial of PEG IFN-α2a
Once-a-week PEG IFN is more effective than the more frequently (180 μg weekly for 48 weeks vs comparison arms of lamivudine
administered, standard IFN, and several large-scale trials of PEG monotherapy and of combination therapy) in 564 patients showed
IFN versus oral lamivudine were conducted in patients with chronic that PEG IFN monotherapy resulted at the end of therapy in sup-
hepatitis B. pression of HBV DNA by a mean of 4.1 log10 copies/mL, undetect-
In HBeAg-reactive chronic hepatitis B, two large-scale studies were able HBV DNA (<400 copies/mL by PCR) in 63%, normal ALT in
done. In one study, PEG IFN-α2b (100 μg weekly for 32 weeks, then 38%, and loss of HBsAg in 4%. Although lamivudine monotherapy
50 μg weekly for another 20 weeks for a total of 52 weeks) was eval- and combination lamivudine−PEG IFN therapy were both superior
uated against a comparison arm of combination PEG IFN with oral to PEG IFN at the end of therapy, no advantage of lamivudine
lamivudine in 307 subjects. The other study involved PEG IFN-α2a monotherapy or combination therapy was apparent over PEG IFN
(180 μg weekly for 48 weeks) in 814 primarily Asian patients, three- monotherapy 6 months after therapy—suppression of HBV DNA
fourths of whom had ALT ≥2× the upper limit of normal, with by a mean of 2.3 log10 copies/mL, undetectable HBV DNA in 19%,

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 2598 and normal ALT in 59%. In patients involved in this trial followed 5.1 vs 0.48 log10 copies/mL), undetectable HBV DNA (72 vs 19%),
for up to 5 years, among the two-thirds followed who had been normal ALT (61 vs 15%), HBeAg loss (10 vs 3%), and HBeAg sero-
treated initially with PEG IFN, 17% maintained HBV DNA sup- conversion (8 vs 3%). In this population of lamivudine-experienced
pression to <400 copies/mL, but ALT remained normal in only 22%; patients, however, entecavir resistance emerged in 7% at 48 weeks.
HBsAg loss increased gradually to 12%. Among the half followed Although entecavir resistance requires both a YMDD mutation
who had been treated initially with lamivudine monotherapy, HBV and a second mutation at one of several other sites (e.g., T184A,
DNA remained <400 copies/mL in 7% and ALT normal in 16%; S202G/I, or M250V), resistance to entecavir in lamivudine-resistant
by year 5, 3.5% had lost HBsAg. As was the case for standard IFN chronic hepatitis B was reported to increase progressively to 43%
therapy in HBeAg-negative patients, only a small proportion main- at 4 years and 57% at 6 years; therefore, entecavir is not as attrac-
tained responsiveness after completion of PEG IFN therapy, raising tive a choice (and is not recommended, despite its approval for
questions about the relative value of a finite period of PEG IFN this indication) as adefovir was or as tenofovir is for patients with
versus a longer course with a potent, low-resistance oral nucleoside lamivudine-resistant hepatitis B.
analogue in these patients. Moreover, the value of PEG IFN for In clinical trials, entecavir had an excellent safety profile. In
HBeAg-negative chronic hepatitis B has not been confirmed. In the addition, on-treatment and posttreatment ALT flares are relatively
only other controlled clinical trial of PEG IFN for HBeAg-negative uncommon and relatively mild in entecavir-treated patients. Doses
chronic hepatitis B, the hepatitis C regimen of PEG IFN plus ribavi- should be reduced for patients with reduced creatinine clearance.
rin was compared to PEG IFN monotherapy. In this trial, HBV Entecavir does have low-level antiviral activity against HIV and
DNA suppression (<400 copies/mL) occurred in only 7.5% of the cannot be used as monotherapy to treat HBV infection in HIV/
two groups combined, and no study subject lost HBsAg. HBV co-infected persons.
In patients treated with PEG IFN, HBeAg and HBsAg responses
have been associated with IL28B (now renamed IFN lambda-3, TELBIVUDINE
IFNL3) genotype CC, the favorable genotype identified in trials of Telbivudine, a cytosine analogue (approved in 2006), is similar in
PEG IFN for chronic hepatitis C. Also, reductions in quantitative efficacy to entecavir but slightly less potent in suppressing HBV
HBsAg levels have been shown to correlate with and to be predictive DNA (a slightly less profound median 6.4 log10 reduction in HBeAg-
of responsiveness to PEG IFN in chronic hepatitis B. If HBsAg levels reactive disease and a similar 5.2 log10 reduction in HBeAg-negative
fail to fall within the first 12–24 weeks or to reach <20,000 IU/mL disease). In its registration trial, telbivudine at an oral daily dose
by week 24, PEG IFN therapy is unlikely to be effective and should of 600 mg suppressed HBV DNA to <300 copies/mL in 60% of
be discontinued. (Similar observations of HBsAg levels in oral- HBeAg-positive and 88% of HBeAg-negative patients, reduced ALT
agent-treated patients are of interest but of limited clinical relevance, to normal in 77% of HBeAg-positive and 74% of HBeAg-negative
PART 10

given the very high likelihood of virologic responses during such patients, and improved histology in 65% of HBeAg-positive and
therapy.) While PEG IFN remains one of the recommended first- 67% of HBeAg-negative patients. Although resistance to telbivu-
line agents for hepatitis B, subsequent-generation, injection-free, dine (M204I, not M204V, mutations) was less frequent than resis-
very-well-tolerated, high-barrier-to-resistance, oral agents are used tance to lamivudine at the end of 1 year, resistance mutations after
much more widely. 2 years of treatment occurred in up to 22%. Generally well tolerated,
Disorders of the Gastrointestinal System

telbivudine was associated with a low frequency of asymptomatic

ENTECAVIR creatine kinase elevations and with a very low frequency of periph-
Entecavir, an oral cyclopentyl guanosine analogue polymerase eral neuropathy; frequency of administration had to be reduced for
inhibitor (approved in 2005), appears to be the most potent of patients with impaired creatinine clearance. Its excellent potency
the HBV antivirals and is just as well tolerated as lamivudine. In notwithstanding, the inferior resistance and safety profile of telbi-
a 709-subject clinical trial among HBeAg-reactive patients, oral vudine limited its appeal; telbivudine is neither recommended as
entecavir, 0.5 mg daily, was compared to lamivudine, 100 mg daily. first-line therapy nor widely used.
At 48 weeks, entecavir was superior to lamivudine in suppression
of HBV DNA (mean 6.9 vs 5.5 log10 copies/mL), percentage with TENOFOVIR
undetectable HBV DNA (<300 copies/mL by PCR; 67 vs 36%), Tenofovir disoproxil fumarate (TDF), an acyclic nucleotide ana-
histologic improvement (≥2-point improvement in necroinflam- logue and potent antiretroviral agent used to treat HIV infection
matory HAI score; 72 vs 62%), and normal ALT (68 vs 60%). The (approved for hepatitis B in 2008), is similar to adefovir but more
two treatments were indistinguishable in percentage with HBeAg potent in suppressing HBV DNA and inducing HBeAg responses;
loss (22 vs 20%) and seroconversion (21 vs 18%). Among patients it is highly active against both wild-type and lamivudine-resistant
treated with entecavir for 96 weeks, HBV DNA was undetectable HBV and active in patients whose response to adefovir is slow
cumulatively in 80% (vs 39% for lamivudine), and HBeAg sero- and/or limited. At an oral once-daily dose of 300 mg for 48 weeks,
conversions had occurred in 31% (vs 26% for lamivudine). After tenofovir suppressed HBV DNA by 6.2 log10 (to undetectable
3–6 years of entecavir, HBeAg seroconversions were observed in levels [<400 copies/mL] in 76%) in HBeAg-positive patients and
39–44% and HBsAg loss in 5–6%. Similarly, in a 638-subject clinical by 4.6 log10 (to undetectable levels in 93%) in HBeAg-negative
trial among HBeAg-negative patients, at week 48, oral entecavir, patients; reduced ALT to normal in 68% of HBeAg-positive and
0.5 mg daily, was superior to lamivudine, 100 mg daily, in sup- 76% of HBeAg-negative patients; and improved histology in
pression of HBV DNA (mean 5.0 vs 4.5 log10 copies/mL) and in 74% of HBeAg-positive and 72% of HBeAg-negative patients. In
percentage with undetectable HBV DNA (90 vs 72%), histologic HBeAg-positive patients, HBeAg seroconversions occurred in 21%
improvement (70 vs 61%), and normal ALT (78 vs 71%). No resis- by the end of year 1, 27% by year 2, 34% by year 3, and 40% by year
tance mutations were encountered in previously treatment-naïve, 5 of tenofovir treatment; HBsAg loss occurred in 3% by the end
entecavir-treated patients during 96 weeks of therapy, and in a of year 1, 6% at year 2, and 8% by year 5. After 5 years of tenofo-
cohort of subjects treated for up to 6 years, resistance emerged vir therapy, 87% of patients experienced histologic improvement,
in only 1.2%. Entecavir-induced HBeAg seroconversions are as including reduction in fibrosis score (51%) and regression of cirrhosis
durable as those achieved with other antivirals. Its high barrier to (71%). The 5-year safety (negligible renal toxicity, in 1%, and mild
resistance coupled with its high potency renders entecavir a first- reduction in bone density, in ~0.5%) and resistance profiles (none
line drug for patients with chronic hepatitis B. recorded through 8 years) of tenofovir are very favorable as well;
Entecavir is also effective against lamivudine-resistant HBV therefore, tenofovir has supplanted adefovir both as first-line therapy
infection. In a trial of 286 lamivudine-resistant patients, entecavir, for chronic hepatitis B and as rescue therapy for lamivudine-resistant
at a higher daily dose of 1 mg, was superior to lamivudine, as mea- chronic hepatitis B. Studies of tenofovir and entecavir reviewed in
sured at week 48, in achieving suppression of HBV DNA (mean 2015 showed no difference in long-term risks of renal and bone

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 toxicity; however, among patients treated with tenofovir, instances 0 2599
of acute renal failure and of low blood phosphate levels have been
reported. Thus, in patients receiving tenofovir, monitoring bone den- –1
sity is not recommended, but periodic (at least annual) monitoring –2

Log10 HBV DNA

for renal injury is recommended (serum creatinine and phosphate,
urine glucose and protein). Frequency of tenofovir administration –3
should be reduced for patients with impaired creatinine clearance. –3.5
Tenofovir alafenamide (TAF), a second-generation tenofovir –4
approved in 2016, is a prodrug of tenofovir that requires activation –5 –4.5
to tenofovir in hepatocytes. This targeted delivery to hepatocytes
allows a lower dose to suffice and reduces systemic exposure by –6 –5.5
90%, thereby minimizing TDF-associated proximal tubular renal –6.2
–6.4
injury, its associated phosphate wasting, and the potential con- –7
–6.9
sequent loss of bone mineral density. The dose of TAF is 25 mg, ADV PEG IFN LAM TDF TBV ETV
which is equivalent in antiviral potency to 300 mg of TDF; both
formulations have the same high barrier to resistance, and clini- FIGURE 341-1 Relative potency of antiviral drugs for hepatitis B, as reflected
by median log10 hepatitis B virus (HBV) DNA reduction in HBeAg-positive chronic
cal resistance has not been encountered. Randomized, controlled, hepatitis B. These data are from individual reports of large, randomized controlled
double-blind, phase 3 noninferiority trials, one in HBeAg-positive registration trials that were the basis for approval of the drugs. In most instances,
patients and the other in HBeAg-negative patients, provided the these data do not represent direct comparisons among the drugs, because study
safety and efficacy data to support TAF approval. populations were different, baseline patient variables were not always uniform,
In 873 HBeAg-positive patients treated for 48 weeks, TAF versus and the sensitivity and dynamic range of the HBV DNA assays used in the trials
TDF achieved (1) HBV DNA reductions to <29 IU/mL in 64% varied. ADV, adefovir dipivoxil; ETV, entecavir; LAM, lamivudine; PEG IFN, pegylated
interferon α2a; TBV, telbivudine; TDF, tenofovir disoproxil fumarate. Because
versus 67%; (2) ALT normalization in 72% versus 67% (an unex- of potency and a high barrier to resistance, ETV and tenofovir (either TDF or the
plained TAF biochemical advantage confirmed in other trials); (3) second-generation tenofovir alafenamide) are recommended as first-line therapy.
HBeAg loss in 14% versus 12%; (4) HBeAg seroconversion in 10% While PEG IFN remains a first-line agent, the oral agents developed earlier, LAM,
versus 8%; and (5) a negligible loss of HBsAg in 1% versus 0.3%. ADV, and TBV, are no longer preferred agents.
Compared to TDF, TAF was associated with reduced impairment of
renal function (median reduction in estimated glomerular filtration monotherapy with either drug alone (and is much less likely to be

CHAPTER 341 Chronic Hepatitis

rate of –0.6 mL/min for TAF vs –5.4 mL/min for TDF) and of bone associated with lamivudine resistance), this combination used for
density (in hip measurements, mean reduction of –0.10% for TAF a year is no better than a year of PEG IFN in achieving sustained
vs –1.72% for TDF; adjusted difference, 1.62%). responses. To date, combinations of oral nucleoside/nucleotide
In the parallel trial among 426 HBeAg-negative patients treated agents have not achieved an enhancement in virologic, serologic, or
for 48 weeks, reductions in HBV DNA to <29 IU/mL occurred in biochemical efficacy over that achieved by the more potent of the
94% versus 93% of individuals treated with TAF versus TDF, respec- combined drugs given individually. In a 2-year trial of combination
tively; normalization of ALT occurred in 83% versus 75%, but no entecavir and tenofovir versus entecavir monotherapy, for a small
HBsAg loss occurred in either group. Similar TAF advantages in subgroup of patients with very high HBV DNA levels (≥108 IU/
maintaining renal function and bone density were reported: reduc- mL), a reduction in HBV DNA to <50 IU/mL was higher in the
tion in median estimated glomerular filtration rate (–1.8 mL/min combination group (79 vs 62%); however, no differences in HBeAg
for TAF vs –4.8 mL/min for TDF) and in median bone density (in responses or any other endpoint were observed between the com-
hip measurements, mean reduction of –0.29% for TAF vs –2.16% bination-therapy and monotherapy groups, even in the high-HBV
for TDF; adjusted percentage difference, 1.87%). DNA subgroup. For resistance to lamivudine or adefovir, add-
At week 96, TAF and TDF HBV DNA and ALT reductions ing a second, non-cross-resistant agent was the chosen approach.
(including the TAF advantage observed at 48 weeks) were main- Whereas, initially, in clinical studies of adefovir as rescue therapy
tained. In the original TDF group, when TDF was switched to TAF for lamivudine resistance, adding adefovir to lamivudine (com-
after week 96, all differences observed during the first 96 weeks (in bination therapy) was considered a better strategy than replacing
normalization of ALT and reductions in renal function and bone lamivudine with adefovir monotherapy (to minimize ALT flares
density) had resolved at week 120. Resistance did not emerge to and to avoid adefovir resistance), according to current treatment
either TAF or TDF throughout the trial. recommendations of the AASLD and the EASL, switching from the
Based on these trial outcomes, TAF joined the list of recom- resistant drug to the new drug is preferred. Because the current
mended first-line antiviral agents for chronic hepatitis B. This generation of antivirals is so potent and has such a high barrier to
drug is recommended over TDF by the American Association for resistance, monotherapy with the rescue drug (e.g., tenofovir for
the Study of Liver Diseases (AASLD) and the European Associ- lamivudine resistance) is as effective (as demonstrated in observa-
ation for the Study of the Liver (EASL) for patients with reduced tional reports for up to 5 years) in maintaining viral suppression
renal function (creatinine clearance <50 mL/min), reduced bone without the emergence of resistance as combination therapy with
density, and risk factors for renal injury (including, according the resistant drug and the rescue drug. Generally, in patients treated
to EASL guidelines, decompensated cirrhosis, creatinine clearance with entecavir and tenofovir preparations, antiviral drug resistance
<60 mL/min, poorly controlled hypertension or diabetes, pro- is no longer encountered. For currently rare patients who already
teinuria, active glomerulonephritis, concomitant nephrotoxic have acquired multidrug resistance (to both nucleoside analogues
medications, or solid-organ transplantation); the EASL recom- [lamivudine, entecavir, telbivudine] and nucleotide analogues [ade-
mendation extends to persons >60 years, who are at increased fovir, tenofovir]), treatment with a combination of entecavir and
risk of TDF nephrotoxicity. In patients with creatinine clearances tenofovir has been shown to be highly effective in suppressing HBV
<15 mL/min, neither TDF nor TAF is recommended. DNA and overcoming drug resistance.
A comparison of antiviral therapies for chronic hepatitis B
appears in Table 341-3; their relative potencies in suppressing NOVEL ANTIVIRALS AND STRATEGIES
HBV DNA are shown in Fig. 341-1. In addition to the eight approved antiviral drugs for hepatitis
B, emtricitabine, a fluorinated cytosine analogue very similar to
COMBINATION THERAPY lamivudine in structure, efficacy, and resistance profile, offers no
Although the combination of lamivudine and PEG IFN sup- advantage over lamivudine. A combination of emtricitabine and
presses HBV DNA more profoundly during therapy than does tenofovir is approved for the treatment of HIV infection and is

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 2600 an appealing combination therapy for hepatitis B, especially for EASL. Although the recommendations differ slightly, a consensus
lamivudine-resistant disease; however, neither emtricitabine nor has emerged on most of the important points (Table 341-4). No
the combination is approved for hepatitis B. Several initially prom- treatment is recommended or available for inactive “nonreplicative”
ising antiviral agents have been abandoned because of toxicity (e.g., hepatitis B carriers (undetectable HBeAg with normal ALT and
clevudine, which was linked to myopathy during its clinical devel- HBV DNA ≤103 IU/mL documented serially over time). In patients
opment). The current generation of oral antivirals have been very with detectable HBeAg and HBV DNA levels >2 × 104 IU/mL, treat-
successful in the management of chronic hepatitis B; however, most ment is recommended by the AASLD for those with ALT levels >2×
patients require long-duration, usually indefinite, therapy. Ideally, the upper limit of normal. (The EASL recommends treatment in
an approach to achieving “cure” (eradication of HBV infection) HBeAg-positive patients for HBV DNA levels >2 × 103 IU/mL and
with finite-duration therapy would be welcome. Currently, inno- ALT above the upper limit of normal.) For HBeAg-positive patients
vative approaches being investigated focus on viral-targeting strat- with ALT ≤2× the upper limit of normal, in whom sustained
egies or immunomodulatory strategies. The direct viral approaches responses are not likely and who would require multiyear therapy,
include viral entry inhibitors, nucleocapsid assembly inhibitors, antiviral therapy is not recommended currently. This pattern is
HBV secretion (HBsAg release) inhibitors, covalently closed circular common during the early decades of life among Asian patients
(ccc) DNA silencing/inhibition/cleavage, RNA interference, HBx infected at birth; even in this group, therapy would be considered
inhibitors, and CRISPR/Cas9 gene editing. Immunomodulators for those >40 years of age, patients with extrahepatic manifestations
being studied have included Toll receptor agonists, T-cell vaccines, of HBV infection, patients with a family history of cirrhosis or
programmed cell death 1 (PD-1) blockade, reconstitution of innate HCC, if the liver biopsy or noninvasive testing shows moderate to
and adaptive immune responses, and HBV mRNA recognition and severe necroinflammatory activity or fibrosis, or if the patient has a
activation of innate immune signaling by retinoic acid–inducible history of previous treatment. In this group, when, eventually, ALT
gene-I (RIG-I). While data supporting several of these unconven- becomes elevated later in life, antiviral therapy should be instituted.
tional approaches have begun to appear, some have been abandoned For patients with HBeAg-negative chronic hepatitis B, ALT >2×
for lack of efficacy or for toxicity (e.g., RIG-I and some of the capsid the upper limit of normal (above the upper limit of normal accord-
inhibitors). Even after almost a decade of early clinical trials, none ing to EASL), and HBV DNA >2 × 103 IU/mL, antiviral therapy
has been shown to “cure” hepatitis B, and none is likely to be com- is recommended. If HBV DNA is >2 × 103 IU/mL and ALT is 1
petitive, unless it can be shown to go beyond current antivirals in to >2× the upper limit of normal, the same considerations apply
achieving recovery (HBsAg seroconversion) from HBV infection. as for HBeAg-positive patients with borderline ALT levels—for
those >40 years of age, patients with extrahepatic manifestations
TREATMENT RECOMMENDATIONS of HBV infection, patients with a family history of cirrhosis or
PART 10

Several learned societies and groups of expert physicians have issued HCC, if the liver biopsy or noninvasive testing shows moderate to
treatment recommendations for patients with chronic hepatitis B; severe necroinflammatory activity or fibrosis, or if the patient has
the most authoritative and updated are those of the AASLD and the a history of previous treatment (treatment in this subset would be
Disorders of the Gastrointestinal System

TABLE 341-4 Recommendations for Treatment of Chronic Hepatitis Ba

HBeAg STATUS CLINICAL HBV DNA (IU/mL) ALT RECOMMENDATION
HBeAg-reactive b
>2 × 104 ≤2 × ULNc,d No treatment; monitor, except in patients >40, with family history of cirrhosis
or hepatocellular carcinoma, with extrahepatic manifestations, with a history
of previous treatment, and/or with liver biopsy (or noninvasive fibrosis
determination) evidence for moderate to severe inflammation or fibrosis
Chronic hepatitis >2 × 104d >2 × ULNd Treate
Cirrhosis compensated >2 × 103 < or > ULN Treate with oral agents, not PEG IFN
<2 × 103 >ULN Treatment suggestedf
Cirrhosis decompensated Detectable < or > ULN Treate with oral agentsg, not PEG IFN; refer for liver transplantation
Undetectable < or > ULN Observe; refer for liver transplantation
HBeAg-negative b
≤2 × 103 ≤ULN Inactive carrier; treatment not necessary
Chronic hepatitis >2 × 103 1 to >2 × ULNd No treatment; monitor, except in patients >40, with family history of cirrhosis
or hepatocellular carcinoma, with extrahepatic manifestations, with a history
of previous treatment, and/or with liver biopsy (or noninvasive fibrosis
determination) evidence for moderate to severe inflammation or fibrosis
Chronic hepatitis >2 × 103 >2 × ULNd Treath,i
Cirrhosis compensated >2 × 103 < or > ULN Treate with oral agents, not PEG IFN
<2 × 103 >ULN Treatment suggestedf
Cirrhosis decompensated Detectable < or > ULN Treath with oral agentsg, not PEG IFN; refer for liver transplantation
Undetectable < or > ULN Observe; refer for liver transplantation
a
Based on practice guidelines of the American Association for the Study of Liver Diseases (AASLD). Except as indicated in footnotes, these guidelines are similar to those
issued by the European Association for the Study of the Liver (EASL). bLiver disease tends to be mild or inactive clinically; most such patients do not undergo liver biopsy.
c
This pattern is common during early decades of life in Asian patients infected at birth. dAccording to the EASL guidelines, treat if HBV DNA is >2 × 103 IU/mL and ALT >ULN.
e
One of the potent oral drugs with a high barrier to resistance (entecavir or tenofovir) or PEG IFN can be used as first-line therapy (see text). These oral agents, but not
PEG IFN, should be used for interferon-refractory/intolerant and immunocompromised patients. PEG IFN is administered weekly by subcutaneous injection for a year; the oral
agents are administered daily for at least a year and continued indefinitely or until at least 6 months after HBeAg seroconversion. fAccording to EASL guidelines, patients
with compensated cirrhosis and detectable HBV DNA at any level, even with normal ALT, are candidates for therapy. Most authorities would treat indefinitely, even in HBeAg-
positive disease after HBeAg seroconversion. gBecause the emergence of resistance can lead to loss of antiviral benefit and further deterioration in decompensated cirrhosis,
a low-resistance regimen is recommended—entecavir or tenofovir monotherapy or combination therapy with the more resistance-prone lamivudine (or telbivudine) plus
adefovir. Therapy should be instituted urgently. hBecause HBeAg seroconversion is not an option, the goal of therapy is to suppress HBV DNA and maintain a normal ALT.
PEG IFN is administered by subcutaneous injection weekly for a year; caution is warranted in relying on a 6-month posttreatment interval to define a sustained response,
because the majority of such responses are lost thereafter. Oral agents, entecavir or tenofovir, are administered daily, usually indefinitely or until, as very rarely occurs,
virologic and biochemical responses are accompanied by HBsAg seroconversion. iFor older patients and those with advanced fibrosis, consider lowering the HBV DNA
threshold to >2 × 103 IU/mL.
Abbreviations: ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; PEG IFN, pegylated interferon; ULN,
upper limit of normal.

HPIM21e_Part10_p2381-p2670.indd 2600 20/01/22 10:05 PM

 recommended according to EASL guidelines, because ALT is ele- TABLE 341-5 Pegylated Interferon Versus Oral Nucleoside Analogues 2601
vated). Per current AASLD recommendations, antiviral treatment for the Treatment of Chronic Hepatitis B
with oral agents can be stopped after HBeAg seroconversion in NUCLEOSIDE
noncirrhotics, and the suggested period of consolidation therapy is PEG IFN ANALOGUES
12 months with close monitoring for recurrent viremia (monthly × 6, Administration Weekly injection Daily, orally
then every 3 months for the rest of a year) after cessation of therapy.
For patients with HBeAg-negative chronic hepatitis, the current Tolerability Poorly tolerated, Well tolerated, limited
intensive monitoring monitoring
recommendation with oral agents is for indefinite therapy; stopping
therapy in this group can be considered after HBsAg loss. Duration of therapy Finite 48 weeks ≥1 year, indefinite in most
patients
The potential for stopping antiviral therapy in noncirrhotic
HBeAg-negative patients after protracted (≥2–5 years) antiviral Maximum mean HBV DNA 4.5 log10 6.9 log10
suppression
therapy has been the subject of several studies. After such pro-
longed courses of entecavir or tenofovir, in one study (DARING-B), Effective in high-level HBV No Yes
DNA (≥109 IU/mL)
18-month virologic relapse rates (HBV DNA >2000 IU/mL) in
57 patients were high (in 72%), but only 26% met study criteria for HBeAg seroconversion ~30% ~20%
resumption of therapy (ALT >10× upper limit of normal, ALT >5× During 1 year of therapy Not applicable 30% (year 2) to up to 50%
upper limit of normal with bilirubin >2 mg/mL, ALT >3× upper During >1 year of therapy (year 5)
limit of normal with HBV DNA >105 IU/mL, or ALT >2× upper HBeAg-negative 17% at 5 years 7% at 4 years
limit of normal and HBV DNA >2 × 103 IU/mL on three sequential posttreatment HBV DNA (lamivudine)
visits). Moreover, 25% underwent HBsAg loss. In a similar study suppression
(FINITE), virologic relapse rates were high, but 62% did not meet HBsAg loss 3–4% 0–3%
criteria for retreatment, and 19% lost HBsAg. In contrast, in a During 1 year of therapy Not applicable 3–8% at 5 years of
study among Asian patients, only ~30% had sustained responses During >1 year of therapy 12% at 5 years therapy
for which resumption of therapy was not introduced, and HBsAg    After 1 year of 3.5% at 5 years
responses were negligible. In other reports, including on patients therapy–HBeAg-negative
with 8 years of TDF treatment prior to stopping, only 35–60% had Antiviral resistance None Lamivudine: ~30% year 1,
sustained treatment-free outcomes, and only 5–13% lost HBsAg. ~70% year 5
In the only randomized, controlled trial of stopping therapy versus Adefovir: 0% year 1,

CHAPTER 341 Chronic Hepatitis

continuing therapy in HBeAg-negative patients after prolonged ~30% year 5
antiviral therapy (Toronto STOP study), only 33% had sustained Telbivudine: up to 4%
responses after cessation of therapy, and HBsAg loss occurred with year 1, 22% year 2
equal, small frequencies in both the stop-treatment group (4%) Entecavir: ≤1.2% through
and the continue-treatment group (5%). Generally, then, although year 6
HBsAg loss can be achieved in a small fraction and although a sub- Tenofovir: 0% through
group may not require reintroduction of therapy in the short run, year 8
enthusiasm for this approach is limited, and for most HBeAg-nega- Use in cirrhosis, No Yes
tive patients, recommendations support indefinite treatment, unless transplantation,
they experience HBsAg loss. immunosuppressed
For patients with compensated cirrhosis, because antiviral ther- Cost, 1 year of therapy ++++ + to ++
apy has been shown to retard clinical progression, treatment is Abbreviations: HBV, hepatitis B virus; HBeAg, hepatitis B e antigen; HBsAg,
recommended regardless of HBeAg status and ALT as long as hepatitis B surface antigen; PEG IFN, pegylated interferon.
HBV DNA is detectable at >2 × 103 IU/mL (detectable at any level
according to the EASL); therapy is suggested, however, even for
those with HBV DNA <2 × 103 IU/mL, regardless of ALT level. For with oral agents is usually extended beyond the first year and, by the
patients with decompensated cirrhosis, treatment is recommended end of the second year (of the current generation of potent agents
regardless of serologic and biochemical status, as long as HBV DNA entecavir and tenofovir), yields HBeAg responses (and even HBsAg
is detectable. Patients with decompensated cirrhosis should be responses) comparable in frequency to those achieved after 1 year
evaluated as candidates for liver transplantation. Cirrhotics should of PEG IFN (and without the associated side effects) (Table 341-5).
be treated indefinitely (see considerations for stopping antiviral In a 2016 systematic review of 1716 patients involved in 25 clinical
therapy in noncirrhotics, above). trials, responses after oral-agent therapy were found to be durable.
Among the eight available drugs for hepatitis B, PEG IFN has Among patients with HBeAg-reactive chronic hepatitis B, the
supplanted standard IFN, entecavir has supplanted lamivudine, and pooled rates of durable HBeAg seroconversions maintained after
tenofovir has supplanted adefovir. PEG IFN, entecavir, or tenofovir cessation of nucleoside/nucleotide analogue therapy (including all
(TDF or TAF) is recommended as first-line therapy (Table 341-3). the oral agents) were 92% and 88% at posttreatment months 12 and
PEG IFN requires finite-duration therapy, achieves the highest rate 24, respectively, unaffected by the duration of post-HBeAg-response
of HBeAg responses after a year of therapy, and does not support consolidation therapy (>6 months in all studies evaluated); the
viral mutations, but it requires subcutaneous injections and is asso- pooled rate of durable biochemical remission after therapy in this
ciated with inconvenience, more intensive clinical and laboratory population was 76%. Even for HBeAg-negative chronic hepatitis B,
monitoring, and intolerability. Oral nucleoside analogues require for which most authorities recommend indefinite therapy, pooled
long-term therapy in most patients, and when used alone, lami- rates of virologic remissions maintained after cessation of oral-
vudine and telbivudine foster the emergence of viral mutations, agent therapy were 44%, 31%, and 30% at posttreatment months 12,
adefovir somewhat less so, and entecavir (except in lamivudine- 24, and 36, and the pooled rate of durable biochemical remission in
experienced patients) and tenofovir rarely at all. Oral agents do not this population was 57%.
require injections or cumbersome laboratory monitoring, are very Although adefovir and tenofovir (TDF) are safe, renal moni-
well tolerated, lead to improved histology in 50−90% of patients, toring (e.g., serum creatinine and phosphate, urine glucose and
suppress HBV DNA more profoundly than PEG IFN, and are protein) is recommended (not for TAF). Substantial experience
effective even in patients who fail to respond to IFN-based therapy. with lamivudine during pregnancy (see above) has identified no
Although oral agents are less likely to result in HBeAg responses teratogenicity; although widely used during pregnancy, lamivudine
during the first year of therapy, as compared to PEG IFN, treatment remains classified as pregnancy category C. Although IFNs do not

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 2602 appear to cause congenital anomalies, these have antiproliferative activity against HIV and can result in selection of HIV resistance;
properties and should be avoided during pregnancy. Adefovir dur- therefore, it is not preferable in HBV-HIV co-infection. Tenofovir
ing pregnancy has not been associated with birth defects; however, and the combination of tenofovir and emtricitabine in one pill are
the risk of spontaneous abortion may be increased, and adefovir is approved therapies for HIV and represent excellent choices for
categorized as pregnancy category C. Data on the safety of entecavir treating HBV infection in HBV-HIV co-infected patients. Gener-
during pregnancy have not been published (pregnancy category C). ally, even for HBV-HIV co-infected patients who do not yet meet
Sufficient data in animals and limited data in humans suggest that treatment criteria for HIV infection, treating for both HBV and
telbivudine and tenofovir (both pregnancy category B) can be used HIV is recommended. In HIV-HBV co-infection, TAF is preferable
safely during pregnancy; however, telbivudine is not an acceptable to TDF because of its better safety profile.
first-line drug. In general, then, except for lamivudine and tenofo- Patients with chronic hepatitis B who undergo cytotoxic che-
vir, and until additional data become available, the other antivirals motherapy for treatment of malignancies as well as patients treated
for hepatitis B should be avoided or used with extreme caution dur- with immunosuppressive, anticytokine, or anti–tumor necrosis
ing pregnancy. Tenofovir is the current drug of choice in pregnancy. factor (TNF) therapies (the risk varies, from highest [e.g., B cell–
For children aged 2 to <18 years old with HBeAg-reactive depleting agents, anthracycline derivatives, moderate-/high-dose
hepatitis B (most children will be HBeAg-reactive; no studies have corticosteroids for ≥4 weeks] to moderate [e.g., TNF-α inhibitors,
been done in children with HBeAg-negative chronic hepatitis B), cytokine or integrin inhibitors, tyrosine kinase inhibitors, low-dose
treatment is recommended if HBV DNA is detectable and ALT corticosteroids for ≥4 weeks] to lowest [e.g., immunosuppressive
levels are elevated, but not if ALT levels are normal. Each of the agents like methotrexate and azathioprine, intraarticular corti-
available drugs, except telbivudine, is approved for different child- costeroids, any dose of corticosteroids for ≤1 week]) experience
hood age groups (standard IFN α2b age ≥1 year; PEG IFN α2a enhanced HBV replication and viral expression on hepatocyte
age ≥5 years [approved for hepatitis C, not B, but can be used in membranes during chemotherapy coupled with suppression of cel-
hepatitis B]; lamivudine and entecavir age ≥2 years; adefovir and lular immunity. When chemotherapy is withdrawn, such patients
tenofovir age ≥12 years). Package inserts should be consulted for are at risk for reactivation of hepatitis B, often severe and occa-
childhood doses. sionally fatal. Such rebound reactivation represents restoration of
As noted above, some physicians prefer to begin with PEG IFN, cytolytic T-cell function against a target organ enriched in HBV
while other physicians and patients prefer oral agents as first-line expression. Preemptive treatment with the first of the oral HBV
therapy. For patients with decompensated cirrhosis, the emergence antivirals, lamivudine, prior to the initiation of chemotherapy was
of resistance can result in further deterioration and loss of antiviral shown to reduce the risk of such reactivation substantially; treating
effectiveness. Therefore, in this patient subset, therapy with a very after reactivation has occurred is less effective. The newer, more
PART 10

favorable resistance profile (e.g., entecavir or tenofovir) should be potent oral antiviral agents, entecavir and tenofovir, which are even
used. PEG IFN should not be used in patients with compensated or more effective in preventing hepatitis B reactivation and with a
decompensated cirrhosis. lower risk of antiviral drug resistance, are preferred. The optimal
Several observational studies have suggested that TDF is supe- duration of antiviral therapy after completion of chemotherapy is
rior to entecavir in reducing the risk of HCC. Such studies, however, not known, but a suggested approach is 6 months (12 months for
Disorders of the Gastrointestinal System

sophisticated statistical analyses notwithstanding, are subject to B cell–depleting agents) for inactive hepatitis B carriers and longer-
confounding influences that could favor TDF; in addition, while duration therapy in patients with baseline HBV DNA levels >2 ×
several studies confirm a differential effect of TDF on long-term 103 IU/mL, until standard clinical endpoints are met (Table 341-4).
HCC risk, many others do not. Therefore, currently, the prepon- Such chemotherapy-associated reactivation of hepatitis B is com-
derance of data is insufficient to support this benefit of TDF over mon (4–68%, median 25%, in a meta-analysis) in persons with
entecavir. ongoing HBV infection (HBsAg-reactive); however, such reactiva-
For patients with end-stage chronic hepatitis B who undergo tion can occur, albeit less commonly, in persons who have cleared
liver transplantation, reinfection of the new liver is almost universal HBsAg but express anti-HBc (moderate risk, <10%) and rarely
in the absence of antiviral therapy. The majority of patients become (<5%) even in persons with serologic evidence of recovery from
high-level viremic carriers with minimal liver injury. Before the HBV infection (anti-HBs-reactive, anti-HBc-reactive). Therefore,
availability of antiviral therapy, an unpredictable proportion most authorities (e.g., Centers for Disease Control and Prevention;
experienced severe hepatitis B−related liver injury, sometimes a AASLD; American Gastroenterological Association; EASL) recom-
fulminant-like hepatitis and sometimes a rapid recapitulation of mend HBsAg and anti-HBc (± anti-HBs) screening of all patients
the original severe chronic hepatitis B (Chap. 339). Currently, undergoing such chemotherapy and preemptive antiviral prophy-
however, prevention of recurrent hepatitis B after liver transplan- laxis for HBsAg-reactive persons and anti-HBc-reactive persons
tation has been achieved definitively by combining short-term treated with the most potent immunomodulatory agents (especially
(5–7 days) intravenous hepatitis B immune globulin (HBIG) with B cell–depleting agents like rituximab) and close on-therapy mon-
lifelong low-resistance oral entecavir or TDF or TAF (Chap. 345); itoring of other anti-HBc-reactive/anti-HBs-reactive persons with
in some patients, especially those with a low risk for recurrence, treatment if and when reactivation occurs.
the newer, more potent, and less resistance-prone oral agents
may be used instead of HBIG for posttransplantation therapy. For CHRONIC HEPATITIS D (DELTA HEPATITIS)
patients at high risk for recurrence and progressive disease (e.g., Chronic hepatitis D virus (HDV) may follow acute co-infection
patients with HDV-HBV or HIV-HBV co-infection as well as with HBV but at a rate no higher than the rate of chronicity of acute
for nonadherent patients, lifelong combination HBIG-oral agent hepatitis B. That is, although HDV co-infection can increase the
therapy should be considered. For patients receiving livers from severity of acute hepatitis B, HDV does not increase the likelihood
anti-HBc-positive donors, lifelong oral-agent therapy is recom- of progression to chronic hepatitis B. When, however, HDV super-
mended (without HBIG). infection occurs in a person who is already chronically infected
Patients with HBV-HIV co-infection can have progressive with HBV, long-term HDV infection is the rule, and a worsening
HBV-associated liver disease and, occasionally, a severe exacerba- of the liver disease is the expected consequence. Except for severity,
tion of hepatitis B resulting from immunologic reconstitution fol- chronic hepatitis B plus D has similar clinical and laboratory fea-
lowing ART. Lamivudine should never be used as monotherapy in tures to those seen in chronic hepatitis B alone. Relatively severe
patients with HBV-HIV infection because HIV resistance emerges and progressive chronic hepatitis, with or without cirrhosis, is the
rapidly to both viruses. Adefovir was used successfully in the past to rule, and mild chronic hepatitis is the exception. Occasionally,
treat chronic hepatitis B in HBV-HIV co-infected patients but is no however, mild hepatitis or even, rarely, inactive carriage occurs
longer considered a first-line agent for HBV. Entecavir has low-level in patients with chronic hepatitis B plus D, and the disease may

HPIM21e_Part10_p2381-p2670.indd 2602 20/01/22 10:05 PM

 become indolent after several years of infection. A distinguish- in HDV RNA occurred in all three groups, by 1.67 log10 copies/ 2603
ing serologic feature of chronic hepatitis D is the presence in the mL (in two of eight patients RNA became undetectable), 2.59 log10
circulation of antibodies to liver-kidney microsomes (anti-LKM); copies/mL (in five of eight patients RNA became undetectable), and
however, the anti-LKM seen in hepatitis D, anti-LKM3, are directed 2.17 log10 copies/mL (in two of eight patients RNA became unde-
against uridine diphosphate glucuronosyltransferase and are dis- tectable), respectively. No change occurred, however, in the level of
tinct from anti-LKM1 seen in patients with autoimmune hepatitis HBsAg, which would have been expected. In these two exploratory
and in a subset of patients with chronic hepatitis C (see below). The brief-duration trials, sustained responses were not achieved, and
clinical and laboratory features of chronic HDV infection are toxicities were encountered (e.g., intermittent vomiting and weight
summarized in Chap. 339. loss [lonafarnib] and transient amylase and lipase elevations
[myrcludex B]); however, from these proof-of-principle trials,
more definitive and larger-scale studies of efficacy are awaited.
TREATMENT Additional experimental approaches to the treatment of hepa-
titis D include nucleic acid polymer therapy to inhibit HBsAg
Chronic Hepatitis D release, administered alone or with PEG IFN and/or nucleoside
Management is not well defined, and the host cellular RNA poly- analogues; so far, these studies have been done in one Eastern
merase upon which HDV replication depends cannot be targeted European site, have yielded some promising reductions in HDV
by conventional antiviral agents. Glucocorticoids are ineffective and RNA and HBsAg, but have been plagued by adverse effects, includ-
are not used. Preliminary experimental trials of IFN-α suggested ing marked ALT elevations. PEG IFN lambda has also been studied
that conventional doses and durations of therapy lower levels of in small numbers of patients with hepatitis D; both IFN-associated
HDV RNA and aminotransferase activity only transiently during side effects and elevations of aminotransferase and bilirubin lev-
treatment but have no impact on the natural history of the disease. els accompanied modest on-treatment reductions in HDV RNA.
In contrast, high-dose IFN-α (9 million units three times a week) Follow-up studies in larger numbers of patients have been frustrat-
for 12 months was reported to be associated with a sustained loss of ingly slow to materialize.
HDV replication and clinical improvement in up to 50% of patients. In patients with end-stage liver disease secondary to chronic
Moreover, in anecdotal reports, the beneficial impact of treatment hepatitis D, liver transplantation has been effective. If hepatitis D
has been observed to persist for 15 years and to be associated with recurs in the new liver without the expression of hepatitis B
a reduction in grade of hepatic necrosis and inflammation, rever- (an unusual serologic profile in immunocompetent persons but
sion of advanced fibrosis (improved stage), and clearance of HDV common in transplant patients), liver injury is limited. In fact,

CHAPTER 341 Chronic Hepatitis

RNA in some patients. A suggested approach to therapy has been the outcome of transplantation for chronic hepatitis D is supe-
high-dose, long-term IFN for at least a year and, in responders, rior to that for chronic hepatitis B; in such patients, combination
extension of therapy until HDV RNA and HBsAg clearance; how- HBIG and nucleoside analogue therapy for hepatitis B is indicated
ever, extension of therapy to a second year provided no advantage, (Chap. 345).
and sustained responses after completion of therapy have been rare.
While standard IFN-α is the only approved drug for hepatitis D, ■■CHRONIC HEPATITIS C
PEG IFN has been shown to be more effective but still of limited Regardless of the epidemiologic mode of acquisition of hepatitis C
therapeutic value; after 48 weeks of therapy, durable undetectable virus (HCV) infection, chronic hepatitis follows acute hepatitis C in
HDV RNA for 24 posttreatment weeks has been reported in a quar- 50−70% of cases; chronic infection is common even in those with
ter to just over a half of patients. Disappointingly, loss of virologic a return to normal in aminotransferase levels after acute hepatitis
responses (reappearance of HDV RNA) was observed during long- C, adding up to an 85% likelihood of chronic HCV infection after
term (median 4.5 years) monitoring in a majority of 24-week-post- acute hepatitis C. Few clues had emerged to explain host differences
treatment responders, with durable HDV RNA suppression to associated with chronic infection until recently, when variation in a
undetectable in only 12%. Even extending PEG IFN therapy for single nucleotide polymorphism (SNP) on chromosome 19, IL28B
5 years and driving treatment doses up to 270 μg weekly (of PEG (which codes for IFN-λ3, now renamed IFNL3), was identified that
IFN-α2a), as reported in a small trial among 13 patients, while distinguished between responders and nonresponders to IFN-based
achieving serologic, virologic, histologic, biochemical, and clinical antiviral therapy (see below). The same variants correlated with
improvement, yielded sustained virologic responses (SVRs) in only spontaneous resolution after acute infection: 53% in genotype C/C,
3 patients (58–246 weeks of posttreatment observation). None of 30% in genotype C/T, but only 23% in genotype T/T. The association
the nucleoside analogue antiviral agents for hepatitis B is effective with HCV clearance after acute infection is even stronger when IL28B
in hepatitis D, and adding oral nucleoside agents to PEG IFN is no (IFNL3) haplotype is combined with haplotype G/G of a SNP near
more effective than PEG IFN monotherapy. While recommended, human leukocyte antigen (HLA) class II DBQ1*03:01.
12 months of PEG IFN therapy is far from satisfactory. In patients with chronic hepatitis C followed for 20 years, progres-
Preliminary trials have been performed with an oral prenylation sion to cirrhosis occurs in ~20−25%. Such is the case even for patients
inhibitor, lonafarnib, and with an inhibitor of HBV/HDV viral with relatively clinically mild chronic hepatitis, including those without
entry into hepatocytes, myrcludex B. Prenylation, the posttransla- symptoms, with only modest elevations of aminotransferase activity,
tional covalent addition of the prenyl lipid farnesyl to large HDV and with mild chronic hepatitis on liver biopsy. Even in cohorts of
antigen, is required for this HDV protein to interact and form well-compensated patients with chronic hepatitis C referred for clini-
secreted viral particles with HBsAg. In 14 patients treated twice cal research trials (no complications of chronic liver disease and with
daily for 28 days with 100 or 200 mg of lonafarnib, HDV RNA normal hepatic synthetic function), the prevalence of cirrhosis may
fell by 0.73 log10 IU/mL and 1.54 log10 IU/mL, respectively, before be as high as 50%. Most cases of hepatitis C are identified initially in
rebounding after completion of therapy. HBV entry into hepato- asymptomatic patients who have no history of acute hepatitis C (e.g.,
cytes requires the binding of the myristolated N-terminal pre-S1 those discovered while attempting to donate blood, while undergoing
peptide of large HBsAg to sodium taurocholate co-transporting lab testing as part of an application for life insurance, or as a result
peptide, the functional receptor for HBV into hepatocytes. The of routine laboratory tests). The source of HCV infection in many
application of myrcludex B, a synthetic homologous myristolated of these cases is not defined, although a long-forgotten percutaneous
lipopeptide that competes for binding with HBsAg, was reported exposure (e.g., injection drug use) in the remote past can be elicited
in a study of 24 patients (with a baseline mean of 4.1–4.2 log10 in a substantial proportion and probably accounts for most infections;
copies/mL of HDV RNA) randomized to 24 weeks of treatment most of these infections were acquired in the 1960s and 1970s among
with myrcludex B (2 mg daily subcutaneously) as monotherapy or persons in the 1945–1965 birth cohort (Chap. 339), coming to clinical
combined with PEG IFN compared to PEG IFN alone. A reduction attention decades later.

HPIM21e_Part10_p2381-p2670.indd 2603 20/01/22 10:05 PM

 2604 Approximately one-third of patients with chronic hepatitis C have Perhaps the best prognostic indicator in chronic hepatitis C is liver
normal or near-normal aminotransferase activity; although one-third to histology; the rate of hepatic fibrosis may be slow, moderate, or rapid.
one-half of these patients have chronic hepatitis on liver biopsy, the grade Patients with mild necrosis and inflammation as well as those with
of liver injury and stage of fibrosis tend to be mild in the vast majority. limited fibrosis have an excellent prognosis and limited progression to
In some cases, more severe liver injury has been reported—even, rarely, cirrhosis. In contrast, among patients with moderate to severe necro-
cirrhosis, most likely the result of previous histologic activity. Among inflammatory activity or fibrosis, including septal or bridging fibrosis,
patients with persistent normal aminotransferase activity sustained over progression to cirrhosis is highly likely over the course of 10−20 years.
≥5−10 years, histologic progression has been shown to be rare; however, The pace of fibrosis progression may be accelerated by such factors
approximately one-fourth of patients with normal aminotransferase as concomitant HIV infection, other causes of liver disease, excessive
activity experience subsequent aminotransferase elevations, and his- alcohol use, and hepatic steatosis. Among patients with compensated
tologic injury can be progressive once abnormal biochemical activity cirrhosis associated with hepatitis C, the 10-year survival rate is close
resumes. Therefore, continued clinical monitoring and antiviral therapy to 80%; mortality occurs at a rate of 2−6% per year; decompensation
are indicated, even for patients with normal aminotransferase activity. at a rate of 4−5% per year; and, as noted above, HCC at a rate of 1−4%
Despite this substantial rate of progression of chronic hepatitis C and per year. Estimates of the natural history of chronic hepatitis C have
even though liver failure can result from end-stage chronic hepatitis C, been made, based on data available on the prevalence of HCV infec-
the long-term prognosis over 1–2 decades for chronic hepatitis C in tion in the U.S. population and on the rate of disease progression.
most patients is relatively benign. Mortality over 10−20 years among Weighted primarily by the concentration of chronic hepatitis C in the
patients with transfusion-associated chronic hepatitis C has been shown baby boomer generation, the peak prevalence was estimated to have
not to differ from mortality in a matched population of transfused occurred in 2015. The calculated frequency of cirrhosis in U.S. patients
patients in whom hepatitis C did not develop. Although death in the with hepatitis C was 5% in 1990 and 25% in 2010 and was projected to
hepatitis group is more likely to result from liver failure and although be 37% in 2020. Estimated peak mortality has been predicted to occur
hepatic decompensation may occur in ~15% of such patients over the in 2032. A discussion of the pathogenesis of liver injury in patients
course of a decade, the majority (almost 60%) of patients remain asymp- with chronic hepatitis C appears in Chap. 339.
tomatic and well compensated, with no clinical sequelae of chronic liver Clinical features of chronic hepatitis C are similar to those described
disease. Overall, chronic hepatitis C tends to be very slowly and insid- above for chronic hepatitis B. Generally, fatigue is the most common
iously progressive, if at all, in most patients, whereas in approximately symptom; jaundice is rare. Immune complex–mediated extrahepatic
one-fourth of cases, chronic hepatitis C will progress eventually to complications of chronic hepatitis C are less common than in chronic
end-stage cirrhosis. In fact, because HCV infection is so prevalent, and hepatitis B (despite the fact that assays for immune complexes are often
because a proportion of patients progress inexorably to end-stage liver positive in patients with chronic hepatitis C), with the exception of essen-
PART 10

disease, hepatitis C was the most frequent indication for liver transplan- tial mixed cryoglobulinemia (Chap. 339), which is linked to cutaneous
tation (Chap. 345) in the era prior to the availability of direct-acting anti- vasculitis and membranoproliferative glomerulonephritis as well as
viral (DAA) therapy (see below). In the United States, hepatitis C accounts lymphoproliferative disorders such as B-cell lymphoma and unexplained
for up to 40% of all chronic liver disease; as of 2007, mortality caused by monoclonal gammopathy. In addition, chronic hepatitis C has been
hepatitis C surpassed that associated with HIV/AIDS, and as of 2012, associated with extrahepatic complications unrelated to immune-com-
Disorders of the Gastrointestinal System

reported deaths caused by hepatitis C surpassed those associated with plex injury. These include Sjögren’s syndrome, lichen planus, porphyria
all other notifiable infectious diseases (HIV, tuberculosis, hepatitis B, cutanea tarda, renal injury, type 2 diabetes mellitus, and the metabolic
and 57 other infectious diseases). Moreover, because the prevalence of syndrome (including insulin resistance and steatohepatitis). In addition,
HCV infection is so much higher in the “baby boomer” cohort born a link has been observed between HCV infection and cardiovascular/
between 1945 and 1965, three-quarters of the mortality associated cerebrovascular disease, rheumatologic/immunologic disorders, mental
with hepatitis C occurs in this age cohort. Referral bias may account health and cognitive disorders, and nonliver malignancies.
for the more severe outcomes described in cohorts of patients reported Laboratory features of chronic hepatitis C are similar to those in
from tertiary care centers (20-year progression of ≥20%) versus the patients with chronic hepatitis B, but aminotransferase levels tend to
more benign outcomes in cohorts of patients monitored from initial fluctuate more (the characteristic episodic pattern of aminotransferase
blood-product-associated acute hepatitis or identified in community activity) and to be lower, especially in patients with long-standing dis-
settings (20-year progression of only 4−7%). Still unexplained, how- ease. An interesting and occasionally confusing finding in patients with
ever, are the wide ranges in reported progression to cirrhosis, from 2% chronic hepatitis C is the presence of autoantibodies. Rarely, patients
over 17 years (eventually 19% over 36 years) in a population of Irish with autoimmune hepatitis (see below) and hyperglobulinemia have
women with hepatitis C infection acquired from contaminated anti-D false-positive immunoassays for anti-HCV. On the other hand, some
immune globulin to 30% over ≤11 years in recipients of contaminated patients with serologically confirmable chronic hepatitis C have circu-
intravenous immune globulin. lating anti-LKM. These antibodies are anti-LKM1, as seen in patients
Progression of liver disease in patients with chronic hepatitis C has with autoimmune hepatitis type 2 (see below), and are directed against
been reported to be more likely in patients with older age, longer dura- a 33-amino-acid sequence of cytochrome P450 IID6. The occurrence
tion of infection, advanced histologic stage and grade, more complex of anti-LKM1 in some patients with chronic hepatitis C may result
HCV quasispecies diversity, increased hepatic iron, concomitant other from the partial sequence homology between the epitope recognized
liver disorders (alcoholic liver disease, chronic hepatitis B, hemochro- by anti-LKM1 and two segments of the HCV polyprotein. In addi-
matosis, α1 antitrypsin deficiency, and steatohepatitis), HIV infection, tion, the presence of this autoantibody in some patients with chronic
and obesity. Among these variables, however, duration of infection hepatitis C suggests that autoimmunity may be playing a role in the
appears to be one of the most important, and some of the others prob- pathogenesis of chronic hepatitis C.
ably reflect disease duration to some extent (e.g., quasispecies diver- Histopathologic features of chronic hepatitis C, especially those that
sity, hepatic iron accumulation). No other epidemiologic or clinical distinguish hepatitis C from hepatitis B, are described in Chap. 339.
features of chronic hepatitis C (e.g., severity of acute hepatitis, level of
aminotransferase activity, level of HCV RNA, presence or absence of
jaundice during acute hepatitis) are predictive of eventual outcome. TREATMENT
Despite the relatively benign nature of chronic hepatitis C over time Chronic Hepatitis C
in many patients, cirrhosis following chronic hepatitis C has been
associated with the late development, after several decades, of HCC Therapy for chronic hepatitis C has evolved substantially in the
(Chap. 82); the annual rate of HCC in cirrhotic patients with hepatitis 30 years since IFN-α was introduced for this indication in 1991.
C is 1−4%, occurring primarily in patients who have had HCV infec- The therapeutic armamentarium grew to include PEG IFN with
tion for 30 years or more. ribavirin and, then, in 2011, the introduction of the first protease

HPIM21e_Part10_p2381-p2670.indd 2604 20/01/22 10:05 PM

 inhibitors, telaprevir and boceprevir, used in combination with Treatment with the combination of PEG IFN and ribavirin 2605
PEG IFN and ribavirin in patients with HCV genotype 1. The field increased SVR rates to 55% overall—to >40% in genotypes 1 and 4,
of antiviral therapy for hepatitis C was transformed beginning in requiring 48 weeks of therapy, and to >80% in genotypes 2 and 3,
2013, with the approval of the first nucleoside analogue polymerase requiring only 24 weeks of therapy—and histologic improvement
inhibitor, sofosbuvir. Although several of these combination regi- in approximately three-fourths of patients. After initiation of IFN
mens have been supplanted by better, later-generation drugs, as of treatment, ALT levels fell precipitously, and up to 90% of virologic
2020, five all-oral, highly effective (>95%), low-resistance, pangeno- responses were achieved within the first 12 weeks of therapy. Failure
typic, well-tolerated, short-duration (primarily 8–12 weeks) combi- to achieve an early virologic response (EVR), a ≥2-log10 reduction in
nation regimens of DAA drugs are recommended. The remarkable HCV RNA by week 12, predicted failure to experience a subsequent
historical evolution of antiviral therapy for hepatitis C is instructive. SVR. Similarly, patients in whom HCV RNA became undetectable
THE INTERFERON ERA (1991–2011) within 4 weeks (i.e., who achieve a rapid virologic response [RVR])
had a very high likelihood of achieving an SVR (Fig. 341-2). Sur-
IFN-based therapy has been supplanted by DAA agents introduced prisingly, however, high-dose induction with IFN-based therapy
in the second decade of the twenty-first century; however, many did not yield higher SVR rates.
important lessons about antiviral therapy for chronic hepatitis C Most relapses occurred within the first 12 weeks after treatment,
were learned from the experience with IFN-based treatment, and and absence of HCV RNA 12 weeks after completion of therapy has
many of the limitations of—and disparities in responsiveness to— become the current standard for SVR (SVR12); relapses are very rare
IFN-based therapy have been overcome by current-generation 6 months to a year after SVR and almost unheard of after 2 years.
DAA treatments. Mechanistically, HCV proteins inhibit several Of documented durability decades after successful therapy, an SVR
steps of the JAK-STAT signal transduction pathway, and by acti- to antiviral therapy for chronic hepatitis C is tantamount to a cure
vation of JAK-STAT signaling, exogenous IFN culminates in and and is followed by marked improvements in liver-disease outcomes
restores intracellular expression of IFN-stimulated genes and their (see below).
protein products that have antiviral properties. Patient variables that correlated with IFN-based SVRs included
When first approved, subcutaneous IFN-α three times a week favorable genotype (genotypes 2 and 3 as opposed to genotypes 1
for 6 months achieved an SVR (Fig. 341-2) (defined then as a and 4; genotype 1b as opposed to genotype 1a); low baseline HCV
reduction of HCV RNA to PCR-undetectable levels ≥24 weeks after RNA level (<800,000 IU/mL), low HCV quasispecies diversity,
completion of therapy) in <10%. Doubling the duration of therapy and histologically mild hepatitis and minimal fibrosis, especially
increased the SVR rate to ~20%, and addition to the regimen of absence of cirrhosis; immunocompetence; low liver iron levels;

CHAPTER 341 Chronic Hepatitis

daily ribavirin (ineffective when used alone), an oral guanosine age <40; female gender; and absence of obesity, insulin resistance,
nucleoside, increased the SVR rate to 40% by reducing the likeli- type 2 diabetes mellitus, and hepatic steatosis. High levels of HCV
hood of virologic relapse after completion of treatment (Fig. 341-2). RNA, more histologically advanced liver disease, and high HCV
Although its mechanism of action remains poorly understood, quasispecies diversity all went hand in hand with advanced dura-
ribavirin retains a limited role in supporting DAA agents in several tion of infection and reduced IFN responsiveness. Also associated
subgroups of otherwise refractory patients (see below). with poor responses to IFN-based therapy were African-American
ethnicity (contributed to, but not explained entirely by, a higher
proportion with genotype 1, slower early treatment viral kinetics,
Peginterferon and Ribavirin impaired HCV-specific immunity, and host genetic differences in
7 IL28B [IFNL3] alleles, described below), Latino ethnicity, and poor
6
treatment adherence (<80% of IFN and ribavirin doses and <80% of
prescribed duration of therapy). Ironically, patients whose disease
HCV RNA log10 IU/ml

Null
5 was least likely to progress were the ones most likely to respond to
Nonresponse
4
IFN and vice versa.
Partial As described above in the discussion of spontaneous recovery
Relapse
3 from acute hepatitis C, IFN gene variants discovered in genome-
2
wide association studies were shown to have a substantial impact on
IFN responsiveness of patients with genotype 1 to antiviral therapy.
RVR EVR ETR SVR
1
Undetectable
In studies of patients treated with PEG IFN and ribavirin, variants
0
of the IL28B (now renamed IFNL3) SNP that code for IFN-λ3
–8 –4 –2 0 4 8 12 16 20 24 32 40 48 52 60 72
(a type III IFN, the receptors for which are more discretely distrib-
uted than IFN-α receptors and more concentrated in hepatocytes)
Weeks after start of therapy
correlated significantly with responsiveness. Homozygotes for the C
FIGURE 341-2 Classification of virologic responses based on outcomes during and allele at this locus (C/C) achieved SVRs of ~80%, heterozygotes (C/T)
after a 48-week course of pegylated interferon (PEG IFN) plus ribavirin antiviral SVRs of ~35%, and homozygotes for the T allele (T/T) SVRs of ~25%.
therapy in patients with hepatitis C, genotype 1 or 4 (for genotype 2 or 3, the
course would be 24 weeks). Nonresponders can be classified as null responders Side effects of IFN therapy are described in the section on treat-
(hepatitis C virus [HCV] RNA reduction of <2 log10 IU/mL) or partial responders ment of chronic hepatitis B (see above). Besides ribavirin-associated
(HCV RNA reduction ≥2 log10 IU/mL but not suppressed to undetectable) by week 24 nasal and chest congestion, pruritus, and precipitation of gout, the
of therapy. In responders, HCV RNA can become undetectable, as shown with most pronounced ribavirin side effect is hemolysis, often requiring
sensitive amplification assays, within 4 weeks (rapid virologic response [RVR]); dose reduction or addition of erythropoietin therapy (not shown,
can be reduced by ≥2 log10 IU/mL within 12 weeks (early virologic response however, to increase the likelihood of an SVR); therefore, close
[EVR]; if HCV RNA is undetectable at 12 weeks, the designation is “complete” EVR);
or can be undetectable at the end of therapy, 48 weeks (end-treatment response monitoring of blood counts is crucial, and ribavirin should be
[ETR]). In responders, if HCV RNA remains undetectable for 24 weeks after ETR, week avoided in patients with anemia, hemoglobinopathies, coronary
72, the patient has a sustained virologic response (SVR), but if HCV RNA becomes artery disease or cerebrovascular disease, or renal insufficiency (the
detectable again, the patient is considered to have relapsed. The posttreatment drug is excreted renally) and in pregnancy (the drug is teratogenic,
week-24 SVR (SVR24) has been supplanted by an SVR at week 12 (SVR12), which mandating contraception during, and for several months after, ther-
has been shown to be equivalent to an SVR24. In patients treated with direct-acting apy in women of child-bearing age [because of their antiprolifera-
antiviral therapy, RVR and EVR milestones are largely irrelevant, being met by almost
all patients. (Reproduced with permission from Marc G. Ghany, National Institute of tive properties, IFNs also are contraindicated during pregnancy]).
Diabetes and Digestive and Kidney Diseases, National Institutes of Health and the Overall, combination IFN-ribavirin therapy was more difficult to
American Association for the Study of Liver Diseases. Hepatology 49:1335, 2009.) tolerate than IFN monotherapy and more likely to lead to dose
reductions and discontinuation of therapy.

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 2606 Beginning in 2011, for the treatment of hepatitis C, standard risk of HCC. Fortunately, PEG IFN–ribavirin nonresponders can
IFNs were supplanted by PEG IFNs, which have substantially longer now be retreated with DAAs and experience SVR rates comparable
half-lives, permitting administration once (rather than three times) to those in treatment-naïve persons (see below).
a week. Once-a-week PEG IFN monotherapy was twice as effec-
tive as IFN monotherapy, approached the efficacy of combination FIRST-GENERATION PROTEASE INHIBITORS (2011–2013)
standard IFN plus ribavirin, and was as well tolerated as standard The HCV RNA genome encodes a single polyprotein, which is
IFNs. For most of the decade prior to 2011, when protease inhibi- cleaved during and after translation by host and viral-encoded
tors were introduced for HCV genotype 1 (see below), the standard proteases. One protease involved in the cleavage of the viral poly-
of care was a combination of PEG IFN plus ribavirin for all HCV protein is an NS3/4A viral protein that has serine protease activity.
genotypes. Telaprevir and boceprevir are serine protease inhibitors that target
Two PEG IFNs were available: PEG IFN-α2b, a 12-kD, linear NS3/4A. In 2011, telaprevir and boceprevir used in combination
PEG molecule bound to IFN-α2b, and PEG IFN-α2a, a larger, with PEG IFN and ribavirin were approved by the U.S. Food and
40-kD, branched PEG molecule bound to IFN-α2a; because of its Drug Administration (FDA) as the first oral DAA agents for the
larger size and smaller volume of extravascular distribution, PEG treatment of hepatitis C genotype 1 (not other genotypes) in adults
IFN-α2a could be given at a uniform dose independent of weight, with stable liver disease, both in patients who had not been treated
whereas the dose of the smaller PEG IFN-α2b, which has a much before and in patients who had failed previous treatment. Although
wider volume distribution, had to be weight-based. Between the now replaced by more effective, all-oral regimens, these first-in-
two PEG IFNs, PEG IFN-α2a appeared to be slightly better tolerated class agents represented a breakthrough in the treatment of chronic
and slightly more effective than PEG IFN-α2b in registration trials. hepatitis C and established milestones against which subsequent
The frequency of an SVR to PEG IFN–ribavirin therapy could be therapies could be measured.
increased by tailoring therapy according to baseline variables and Because resistance developed rapidly during monotherapy with
on-treatment virologic responsiveness. For example, in patients telaprevir and boceprevir, these drugs had to be used in combina-
with baseline variables weighing against a response (e.g., high HCV tion with PEG IFN and ribavirin. Ribavirin in particular appeared
RNA, obesity), raising the dose of PEG IFN and/or of ribavirin or to reduce relapse rates significantly in protease-inhibitor-based
extending therapy to 72 weeks for patients with genotype 1 and a regimens, such that those who could not take or were intolerant
slow virologic response, SVR rates could be improved. In contra- to ribavirin were unlikely to benefit from the addition of these
distinction, in the ≤20% of patients with genotype 1 (and 4) who had agents. Telaprevir and boceprevir regimens consisted of periods
a 4-week RVR and low baseline HCV RNA, treatment could be of triple therapy (protease inhibitor plus PEG IFN plus ribavirin)
abbreviated to 24 weeks and SVR rates of ~90% achieved. and periods of dual therapy (PEG IFN plus ribavirin). Telapre-
PART 10

For most of the decade prior to 2011, when protease inhibitors vir regimens began with 12 weeks of triple therapy followed by
were introduced for HCV genotype 1 (see below), the standard of dual therapy of a duration based on HCV RNA status at weeks 4
care was a combination of PEG IFN plus ribavirin (unless ribavi- and 12 (“response-guided therapy”) and prior treatment status.
rin was contraindicated) for all HCV genotypes. Even after the Boceprevir-based regimens consisted of a 4-week lead-in period of
introduction of protease inhibitors for genotypes 1 and 4, however, dual (PEG IFN–ribavirin) therapy followed by triple therapy and, in
Disorders of the Gastrointestinal System

PEG IFN–ribavirin remained the standard of care for patients with some instances, a further extension of dual therapy, with duration
genotypes 2 and 3 until late 2013. Responsiveness to IFN-ribavirin– of response-guided therapy based on HCV RNA status at weeks 4,
based therapy was diminished in immunocompromised patients 8, and 24 and prior treatment status.
and in patients with HIV-HCV co-infection and contraindicated For patients with HCV genotype 1, protease inhibitors improved
in patients with decompensated liver disease or end-stage renal the frequency of RVRs and SVRs significantly as compared to PEG
disease. The cumbersome nature of IFN-ribavirin–based therapy IFN plus ribavirin alone. In treatment-naïve patients, telaprevir-based
(injections, complicated laboratory monitoring, side effects and SVRs were achieved in up to 79% of patients who received
poor tolerability, modest efficacy, variables and patient subsets 12 weeks of triple therapy followed by 12–36 weeks of dual therapy,
associated with poor responsiveness, tailored therapy, futility rules, and among those with EVRs (undetectable HCV RNA at weeks 4
etc.) was supplanted eventually (in 2016) by DAAs for all genotypes and 12) and response-guided therapy stopped at week 24 (12 weeks
(see below). Most of the variables associated with poor responsive- of triple therapy, then 12 weeks of dual therapy), SVRs occurred
ness to IFN-based therapy became irrelevant, and difficult-to-treat in 83–92%. In studies with boceprevir in treatment-naïve patients,
patient subpopulations began to experience responses to DAAs SVRs occurred in 59–66% of patients, and among those with unde-
that were indistinguishable from responses in standard patients tectable HCV RNA at 8 weeks, the SVR rate increased to 86–88%.
(see below). Adding to the complexity of treatment with these protease inhibi-
Persons with chronic HCV infection suffer increased liver- tors were absolute stopping rules for futility, that is, absence of HCV
related mortality, all-cause mortality, and multiple extrahepatic dis- RNA reductions at critical treatment milestones, which were shown
orders (see above). On the other hand, successful antiviral therapy to be invariably predictive of nonresponse (telaprevir: HCV RNA
of chronic hepatitis C resulting in an SVR was shown to improve >1000 IU/mL at weeks 4 or 12, or detectable at week 24; boceprevir:
survival (and to reduce the need for liver transplantation); to lower HCV RNA ≥100 IU/mL at week 12, or detectable at week 24).
the risk of liver failure, liver-related death, and all-cause mortality; In patients previously treated unsuccessfully with PEG IFN plus
to slow the progression of chronic hepatitis C; to reverse fibrosis and ribavirin, telaprevir-based treatment achieved SVRs in 83–88% of
even cirrhosis; and to improve such HCV-associated extrahepatic prior relapsers, 54–59% of partial responders (HCV RNA reduced
disorders as type 2 diabetes and renal disease. Whereas the 10- and by ≥2 log10 IU/mL but not to undetectable levels), and 29–33% of
20-year survival in the absence of an SVR is reduced in cirrhotic null responders (HCV RNA reduced by <2 log10 IU/mL). With
patients with chronic hepatitis C, survival at these intervals after an boceprevir, a similar degradation in SVR rate occurred as a func-
SVR has been found to be indistinguishable from that of the gen- tion of prior responsiveness—in 75% of prior relapsers, in 40–52%
eral population. In cirrhotic patients (and in those with advanced of previous partial responders, and in ~30–40% of null responders.
fibrosis), although successful treatment reduces mortality and liver In a substantial proportion of protease inhibitor nonresponders,
failure (three- to fourfold 10-year reduction) and reduces the need resistance-associated substitutions (RASs, previously referred to
for liver transplantation and the likelihood of HCC (14-fold 10-year as resistance-associated variants [RAVs]) could be identified, but
reduction), the risk of liver-related death and HCC persists, albeit at these variants were not archived, and wild-type HCV reemerged in
a much reduced level, necessitating continued clinical monitoring almost all cases within 1.5–2 years. SVRs to these protease inhibitors
and cancer surveillance after SVR in cirrhotics. On the other hand, were highest in prior relapsers and treatment-naïve patients (white
in the absence of an SVR, IFN-based therapy does not reduce the > black ethnicity), lower in prior partial responders, lower still in

HPIM21e_Part10_p2381-p2670.indd 2606 20/01/22 10:05 PM

 prior null responders, and lowest in cirrhotic prior null responders, involved in synthesis of viral RNA [drug name ending in “-buvir”]), 2607
for whom no benefit accrued over PEG IFN–ribavirin treatment. and NS5A inhibitors (which interfere with a membrane-associated
Responses to protease inhibitor triple-drug regimens were higher phosphoprotein essential to the HVC RNA replication complex
in patients with IL28B (IFNL3) C than non-C genotypes, HCV [drug name ending in “-asvir”]).
genotype 1b than genotype 1a, less advanced than more advanced The first of the new DAA agents (approved in November 2013)
fibrosis stage, whites than blacks, lower body mass index (BMI) was simeprevir, a second-generation protease inhibitor for genotype
than elevated BMI, and, for boceprevir, achievement of a >1 log10 1, followed shortly thereafter (December 2013) by sofosbuvir, a
HCV RNA reduction during 4 weeks of PEG IFN–ribavirin lead-in pangenotypic nucleoside polymerase inhibitor. For genotype 1,
therapy. Age and HCV RNA level were less influential and insulin both of these agents had to be combined with PEG IFN and
resistance was noninfluential on response to these antiviral agents. ribavirin; for genotypes 2 and 3, sofosbuvir was administered with
Both protease inhibitors had substantial toxicities. Telaprevir was ribavirin, without PEG IFN; however, these treatment regimens
associated with a severe, generalized (trunk and extremities), often have been supplanted by combinations of all-oral, IFN-free DAAs,
confluent, maculopapular, pruritic rash in ~6% of treated patients and ribavirin is rarely needed and retained only for very limited
(that required careful dermatologic monitoring in all patients and indications.
systemic corticosteroid therapy in the most severely affected). Simeprevir: When simeprevir was used with PEG IFN, its effi-
Other common side effects included pruritus, rectal burning, nau- cacy (genotype 1b > 1a) was similar to that of first-generation
sea, diarrhea, fatigue, dysgeusia (altered or unpleasant taste), and protease inhibitors but required only once-a-day dosing without
anemia, which required close monitoring, could be relatively refrac- the complexity of response-guided therapy. Similar to first-gen-
tory, and occasionally required transfusion and even hospitalization eration protease inhibitors, simeprevir was hampered by many
(especially in cirrhotic prior nonresponders). Anemia occurred drug-drug interactions and side effects (including photosensitiv-
in half of boceprevir-treated patients, neutropenia in up to 30%, ity, rash, and mild hyperbilirubinemia); moreover, patients, with
and thrombocytopenia in 3–4%. Other side effects of boceprevir HCV NS3 polymorphism Q80K had markedly reduced drug effi-
included fatigue, nausea, headache, dysgeusia, dry mouth, vomit- cacy, necessitating pretreatment genetic testing and disqualifying
ing, and diarrhea. approximately a third of potential treatment candidates. Little about
Both drugs came with an inconveniently high pill burden and simeprevir supported its adoption in combination with PEG IFN
had to be administered every 8 h with food (telaprevir with a 20-g and ribavirin. On the other hand, the combination of simeprevir
fat meal). Use of protease inhibitors was further complicated by (150 mg) along with sofosbuvir (400 mg) for 12 weeks was found to
numerous drug-drug interactions. As telaprevir and boceprevir are be effective in treatment-naïve (97% SVR12) or treatment-experienced

CHAPTER 341 Chronic Hepatitis

both eliminated by and inhibit CYP3A4, these agents could not (95% SVR12) patients without cirrhosis and in treatment-naïve (88%
be administered with other medications that induce CYP3A4 or SVR12) or treatment-refractory (79% SVR12) patients with cirrhosis.
are dependent on CYP3A4 for elimination. Care had to be taken Like first-generation protease inhibitors, however, simeprevir was
to examine for any potential interactions between these protease limited to genotype 1, required pretreatment genotyping that dis-
inhibitors and other medications the patient was taking, and a qualified a third of recipients, usually required concomitant PEG
convenient website became available to check for such drug-drug IFN and ribavirin, had multiple drug-drug interactions and side
interactions (www.hep-druginteractions.org). effects, and was not competitive with the improved combinations
Despite the improvement in SVRs with protease-inhibitor-based that followed; therefore, simeprevir is no longer recommended.
regimens for genotype 1 compared to PEG IFN–ribavirin (e.g., in Sofosbuvir: Sofosbuvir, the first nonprotease inhibitor DAA to
treatment-naïve patients 66–79% vs 38–44%), triple-drug protease be approved, has an excellent profile—high potency, high barrier
inhibitor therapy was hampered by amplified intolerability, the to resistance, pangenotypic activity, very well tolerated with limited
complexity of response-guided regimens and futility stopping rules, adverse effects (most commonly mild fatigue, insomnia, headache,
the inconvenience of thrice-daily dosing with meals and a high and nausea), once-daily oral administration, and relative freedom
pill burden, the need for PEG IFN injections and ribavirin with all from major drug-drug interactions. Sofosbuvir has efficacy in all
their intolerability, and multiple drug-drug interactions. Moreover, genotypes (1–6); in treatment-naïve subjects and prior nonre-
side effects appeared to be more severe and burdensome once these sponders to PEG IFN–based and protease-inhibitor-based therapy;
drugs entered practice, especially in cirrhotic nonresponders, in with PEG IFN–ribavirin or in IFN-free regimens; in combination
whom studies reported from Europe showed serious adverse events with ribavirin or with NS5A inhibitors (see below); and for treat-
in up to 45% and deaths in up to 3%. All these issues, as well as ment periods as brief as 8–12 weeks. Currently, sofosbuvir is used
rapidly accelerating progress on next-generation and all-oral DAA in combination with one of two NS5A inhibitors and is a compo-
therapy (see below), conspired to temper enthusiasm for these new nent of three of the five currently recommended DAA regimens
antivirals; after a brief stint as recommended therapy (2011–2013), (Table 341-6).
these drugs became obsolete and are no longer recommended or Sofosbuvir-ledipasvir: The DAA combination that has had a
available. dominant role in the treatment of hepatitis C is sofosbuvir (400 mg)
plus the NS5A inhibitor ledipasvir (90 mg) in a once-a-day, fixed-
DIRECT-ACTING ANTIVIRAL COMBINATIONS OF SECOND- dose, single pill, approved in October 2014 for genotype 1 and in
GENERATION PROTEASE INHIBITORS, FIRST-GENERATION November 2015 for genotypes 4, 5, and 6. Phase 3 trials were con-
POLYMERASE INHIBITORS, AND FIRST-GENERATION NS5A ducted in treatment-naïve noncirrhotic patients, in treatment-naïve
INHIBITORS (2014–2015) cirrhotic and noncirrhotic patients, and in treatment-experienced
Since late 2013, the number of new antiviral agents for hepati- cirrhotic and noncirrhotic patients treated for 8, 12, or 24 weeks,
tis C has expanded substantially, and currently, PEG IFN–based both with and without ribavirin. In treatment-naïve noncirrhotics,
treatments have been supplanted by five remaining therapeutic an SVR12 was achieved in 97–99% of subjects, and no benefit was
regimens, which are all oral, IFN-free, highly efficacious (>95% observed by extending therapy from 12 to 24 weeks or by add-
SVR), and well tolerated, with high barriers to resistance, simple ing ribavirin. Moreover, for treatment-naïve, noncirrhotic patients
dosing, low pill burdens, treatment durations as brief as 8–12 weeks, with baseline HCV RNA <6 × 106 IU/mL, a treatment duration of
and pangenotypic efficacy (Table 341-6). These drugs are dis- 8 weeks was as effective as one of 12 weeks (94–95% SVR12), which
tributed among three classes of DAAs: NS3/4 protease inhibitors may be a consideration for a proportion of patients. In cirrhotic
(which cleave the single HCV polyprotein into constituent struc- patients, SVR12 was achieved in 97–100% of treatment-naïve sub-
tural and nonstructural proteins [drug name ending in “-previr”]), jects (no advantage of extending therapy from 12 to 24 weeks or
NS5B nucleoside and nonnucleoside polymerase inhibitors (which of adding ribavirin); however, for cirrhotic prior nonresponders to
interfere with the RNA-dependent RNA polymerase [a replicase] IFN-based therapy, 12 weeks of therapy was inferior (86% SVR12)

HPIM21e_Part10_p2381-p2670.indd 2607 20/01/22 10:05 PM

 2608
TABLE 341-6 Indications and Recommendations for Antiviral Therapy of Chronic Hepatitis Ca
Standard Indications for Therapy FAILED PRIOR PEG IFN/RIBAVIRIN THERAPY, NO CIRRHOSISd
All patients with chronic HCV infection (detectable HCV RNA, with or without Genotype 1a and 1b
elevated ALT) except for those with short life expectancies owing to comorbid sofosbuvir + velpatasvir 12 weeks
conditions.
glecaprevir + pibrentasvir 8 weeks
Any stage of fibrosis; pretreatment biopsy is no longer embraced and has
been supplanted by noninvasive measures of fibrosis, e.g., imaging to ledipasvir + sofosbuvir 12 weeks
determine liver elasticity. grazoprevir + elbasvir 12 weeks (without ELB NS5A RASs)
Responsiveness in groups previously refractory to interferon-based Genotype 2
therapy (HIV-HCV co-infection, renal insufficiency, African-American and sofosbuvir + velpatasvir 12 weeks
Latino ethnicity, IL28B non-C haplotype, obesity, insulin resistance, hepatic glecaprevir + pibrentasvir 8 weeks
decompensation, etc.) is not diminished to contemporary direct-acting oral
combination regimens. Genotype 3
Retreatment Recommended sofosbuvir + velpatasvir 12 weeks (for patients without baseline NS5A RAS Y93H for
velpatasvir)
Relapsers, partial responders, or nonresponders after a previous course
of interferon-based therapy or prior direct-acting antiviral therapy (see glecaprevir + pibrentasvir 16 weeks
genotype-specific recommendations below). sofosbuvir + velpatasvir + voxilaprevir 12 weeks for patients with baseline NS5A RAS
Antiviral Therapy Not Recommended Y93H for velpatasvir
Pregnancy: No clinical studies of direct-acting antivirals during pregnancy Genotype 4
are available. Ribavirin is contraindicated during pregnancy; therefore, any sofosbuvir + velpatasvir 12 weeks
regimen including ribavirin should not be used. Sofosbuvir; sofosbuvir + glecaprevir + pibrentasvir 8 weeks
ledipasvir; and paritaprevir-ritonavir + ombitasvir + dasabuvir are classified grazoprevir + elbasvir 12 weeks (for prior relapse)
as pregnancy category B, but the other direct-acting antivirals do not have
a pregnancy classification. Therefore, these therapies are not indicated ledipasvir + sofosbuvir 12 weeks
routinely in pregnancy and should be used, with caution, only if the benefit of Genotypes 5, 6
treatment outweighs the potential for fetal risk. sofosbuvir + velpatasvir 12 weeks
Therapeutic Regimens (based on AASLD-IDSA recommendations, glecaprevir + pibrentasvir 8 weeks
www.hcvguidelines.org)b ledipasvir + sofosbuvir 12 weeks
The European Association for the Study of the Liver (EASL) recommendations
diverge slightly from AASLD-IDSA recommendations.c
PART 10

TREATMENT-NAÏVE OR RELAPSED AFTER PRIOR PEG

IFN–RIBAVIRIN THERAPY FAILED PRIOR PEG IFN–RIBAVIRIN THERAPY, COMPENSATED CIRRHOSISd
Genotype 1a and 1b Genotype 1a
sofosbuvir + velpatasvir 12 weeks sofosbuvir + velpatasvir 12 weeks
glecaprevir + pibrentasvir 8 weeks glecaprevir + pibrentasvir 12 weeks
Disorders of the Gastrointestinal System

ledipasvir + sofosbuvir 12 weeks (consider 8 weeks for noncirrhotic grazoprevir + elbasvir 12 weeks (without ELB NS5A RASs)
HIV-negative patients with HCV RNA <6 × 10 6 IU/mL) ledipasvir + sofosbuvir + RBV 12 weeks
grazoprevir + elbasvir 12 weeks (no cirrhosis or cirrhosis sans ELB NS5A Genotype 1b
RASs)
sofosbuvir + velpatasvir 12 weeks
Genotype 2
glecaprevir + pibrentasvir 12 weeks
sofosbuvir + velpatasvir 12 weeks grazoprevir + elbasvir 12 weeks
glecaprevir + pibrentasvir 8 weeks ledipasvir + sofosbuvir + RBV 12 weeks
Genotype 3 Genotype 2
sofosbuvir + velpatasvir 12 weeks (in cirrhotics, recommended only if sofosbuvir + velpatasvir 12 weeks
without baseline NS5A RAS Y93H for velpatasvir)
glecaprevir + pibrentasvir 12 weeks
glecaprevir + pibrentasvir 8 weeks
Genotype 3
sofosbuvir + velpatasvir 12 weeks + weight-based ribavirin (in cirrhotics with
baseline NS5A RAS Y93H for velpatasvir) sofosbuvir + velpatasvir + voxilaprevir 12 weeks
sofosbuvir + velpatasvir + voxilaprevir 12 weeks (in cirrhotics with baseline glecaprevir + pibrentasvir 16 weeks
NS5A RAS Y93H for velpatasvir) grazoprevir + elbasvir 12 weeks
Genotype 4 sofosbuvir + velpatasvir + RBV 12 weeks
sofosbuvir + velpatasvir 12 weeks Genotype 4
glecaprevir + pibrentasvir 8 weeks (12 weeks for HIV co-infection) sofosbuvir + velpatasvir 12 weeks
ledipasvir + sofosbuvir 12 weeks (consider 8 weeks for noncirrhotic HIV- glecaprevir + pibrentasvir 12 weeks
negative patients with HCV RNA <6 × 10 6 IU/mL) grazoprevir + elbasvir 12 weeks (for prior relapse)
grazoprevir + elbasvir 12 weeks ledipasvir + sofosbuvir 12 weeks
Genotypes 5, 6 Genotypes 5, 6
sofosbuvir + velpatasvir 12 weeks sofosbuvir + velpatasvir 12 weeks
glecaprevir + pibrentasvir 8 weeks glecaprevir + pibrentasvir 12 weeks
ledipasvir + sofosbuvir 12 weeks (except for genotype 6e) ledipasvir + sofosbuvir 12 weeks
FEATURES ASSOCIATED WITH REDUCED RESPONSIVENESS TO DIRECT-ACTING
ANTIVIRAL COMBINATION THERAPY
Genotype and subtype (genotype 1a less responsive than genotype 1b for several drugs)
Treatment experience
Advanced fibrosis (bridging fibrosis, cirrhosis)
Reduced adherence

(Continued)

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 2609
TABLE 341-6 Indications and Recommendations for Antiviral Therapy of Chronic Hepatitis Ca (Continued)
a
Rapidly evolving new recommendations continue to be issued; for up-to-date treatment recommendations, please see www.hcvguidelines.org. For treatment-naïve
b

patients, simplified treatment regimen recommendations are in bold font (based on broad applicability, pangenotypic coverage, and simplicity). For treatment-experienced
patients, recommended regimens are in bold font, and alternative regimens are in standard font. cThe following EASL recommendations differ from those of AASLD-IDSA:
Genotype 1
For genotype 1a, noncirrhotic, prior IFN/RBV nonresponders, sofosbuvir + ledipasvir is not recommended.
For genotype 1b, treatment-naïve or -experienced patients, EASL retains paritaprevir/ritonavir + ombitasvir + dasabuvir for 12 weeks (for 8 weeks in patients with stage
F0–F2 fibrosis).
For genotype 1b, noncirrhotic, treatment-naïve or -experienced patients with stage F0–F2 fibrosis, the recommended duration of grazoprevir + elbasvir is 8 weeks.
Genotype 3
For cirrhotic, treatment-naïve or -experienced patients (IFN-based regimen failures), sofosbuvir + velpatasvir is not recommended. For noncirrhotic patients with genotype 3,
sofosbuvir + ledipasvir + voxilaprevir is not recommended.
Genotype 4
For genotype 4, prior IFN/RBV nonresponders, sofosbuvir + ledipasvir is not recommended. In treatment-naïve noncirrhotics, shorter duration (8 weeks) is not recommended
for patients with HCV RNA ≤6 × 106 IU/mL.
d
For nonresponders to prior direct-acting antiviral therapy (protease, polymerase, or NS5A inhibitors) and for decompensated cirrhosis, please consult www.hcvguidelines
.org.
Abbreviations: AASLD, American Association for the Study of Liver Diseases; ALT, alanine aminotransferase; ELB NS5A RASs, elbasvir NS5A resistance-associated
substitutions; HCV, hepatitis C virus; IFN, interferon; IDSA, Infectious Diseases Society of America; PEG IFN, pegylated interferon; IU, international units (1 IU/mL is
equivalent to ~2.5 copies/mL); RASs, resistance-associated substitutions; RBV, ribavirin.

to 24 weeks of therapy (100% SVR12). This combination, which is treatment-naïve and treatment-experienced patients (100% SVR12),
equally effective in patients with HIV-HCV co-infection and in including those with compensated cirrhosis. In July 2016, the FDA
African-American patients, has been shown to be highly effective approved a long-acting formulation of dasabuvir, allowing once-a-
in patients with decompensated cirrhosis and in patients with day instead of twice-a-day treatment; for genotype 1a, twice-daily
hepatitis C after liver transplantation and after kidney trans- ribavirin dosing remained.
plantation. Initially, sofosbuvir-ledipasvir was not recommended This combination was well tolerated with generally mild side
in patients with advanced renal failure; however, subsequently, effects, for example, fatigue, asthenia, insomnia, headache, and

CHAPTER 341 Chronic Hepatitis

the safety and efficacy of sofosbuvir-ledipasvir in patients with pruritus. Hyperbilirubinemia (primarily unconjugated) and eleva-
advanced renal failure were established, and the DAA was approved tions in alanine aminotransferase activity could occur but resolved
for this indication (November 2019). All sofosbuvir-containing reg- during or shortly after treatment. Because of occasional hyperbil-
imens can be associated with severe bradycardia in patients taking irubinemia and potential hepatotoxicity (FDA warning letter issued
the antiarrhythmic agent amiodarone, especially along with beta October 2015 regarding hepatic failure/decompensation reported
blockers; sofosbuvir-containing combinations are contraindicated in treated cirrhotic patients), this combination (and all subsequently
with amiodarone. Drug-drug interactions are few, but P-glycoprotein introduced protease-inhibitor-containing combinations) was con-
inducers, such as St. John’s wort and rifampin, and proton pump traindicated in patients with decompensated cirrhosis, and treated
gastric acid inhibitors, such as omeprazole, may reduce sofosbu- cirrhotic patients had be monitored closely for decompensation;
vir-ledipasvir concentrations. Generally, responsiveness to sofosbu- however, the safety and efficacy of this combination was demon-
vir-ledipasvir is not reduced in patients with baseline RASs to these strated for patients with advanced renal insufficiency. Similar to
agents, with the exception of treatment-experienced patients who other regimens containing protease inhibitors, drug-drug inter-
have baseline NS5A RASs (see Table 341-6). actions are common with other drugs that induce CYP3A4 or are
Paritaprevir-ritonavir, ombitasvir, and dasabuvir: The combi- dependent on CYP3A4 for elimination. Checking for potential
nation of ritonavir (100 mg)–boosted paritaprevir (150 mg), a drug-drug interactions was important prior to initiating ther-
protease inhibitor; ombitasvir (25 mg), an NS5A inhibitor; and apy with this drug combination (www.hep-druginteractions.org).
dasabuvir (250 mg), a nonnucleoside polymerase inhibitor, with or Responsiveness to this multidrug regimen was not reduced in
without weight-based ribavirin (total of five drugs), was approved patients with baseline RASs to these agents.
in December 2014 for genotypes 1 and 4. Paritaprevir-ritonavir and Compared to sofosbuvir-ledipasvir, this regimen had the disad-
ombitasvir, formulated in a single tablet, are taken once daily, and vantage of requiring twice-a-day ribavirin therapy for genotype 1a
both dasabuvir (a separate pill) and weight-based ribavirin (when and of being contraindicated in decompensated cirrhosis; however,
included in the regimen) are taken twice daily. In clinical trials, this it had the advantage of offering a 12-week, ribavirin-free regimen
combination achieved SVR12 rates of 87–100% in treatment-naïve for prior null responders with cirrhosis and providing an option for
and treatment-experienced patients with genotype 1; without patients with renal failure. Based on regimen simplicity and supe-
ribavirin, this combination in genotype 1a was ~7% less responsive riority, subsequent-generation, ribavirin-free combination DAAs
than in genotype 1b. Therefore, in treatment-naïve patients with have supplanted paritaprevir-ritonavir, ombitasvir, and dasabuvir;
genotype 1a, this combination was administered with ribavirin for this regimen is no longer recommended at all by the AASLD;
12 weeks in the absence of cirrhosis (95–97% SVR12) or for 24 weeks however, it is retained in EASL recommendations as an alternative
in the presence of compensated cirrhosis (94% SVR12), whereas regimen for genotype 1b only.
in patients with genotype 1b, the combination did not require Sofosbuvir and daclatasvir: Daclatasvir, an NS5A inhibitor, along
ribavirin, and the duration of therapy was 12 weeks for both non- with the polymerase inhibitor sofosbuvir, was approved by the FDA
cirrhotics and cirrhotics (99–100% SVR12). In prior nonresponders in July 2015 for genotype 3 and in February 2016 for genotype 1.
without cirrhosis, the combination was administered for 12 weeks, At the time of its approval for genotype 3, daclatasvir filled a need
with ribavirin in genotype 1a (96% SVR12) and without ribavirin in inadequately met by other available combination DAAs; how-
genotype 1b (100% SVR12). In prior nonresponders with cirrhosis, ever, eventually, recommendation of this combination regimen was
the combination was administered for 24 weeks with ribavirin in extended to genotypes 1–4 in the United States and to all genotypes
genotype 1a (SVR12 100% in prior relapsers and partial responders, (1–6) in Europe. Daclatasvir, a 60-mg tablet, and sofosbuvir, a sepa-
95% in prior null responders [in whom treatment without ribavirin rate 400-mg tablet, were taken once a day for 12–24 weeks.
was associated with an 80% SVR12]), but only for 12 weeks and with- In clinical trials among treatment-naïve or treatment-experienced
out ribavirin in genotype 1b (100% SVR12). For genotype 4, the regi- patients, SVR12 rates for 12 weeks of daclatasvir plus sofosbuvir were
men was given for 12 weeks with ribavirin but without dasabuvir in 98% for genotype 1 (comparable results in genotypes 1a and 1b),

HPIM21e_Part10_p2381-p2670.indd 2609 20/01/22 10:05 PM

 2610 92% for genotype 2, and 89% for genotype 3. For noncirrhotic nonresponders (whether to PEG IFN–ribavirin or protease inhib-
patients, the addition of ribavirin or the extension of therapy to itor regimens) was 16 weeks of elbasvir-grazoprevir plus ribavirin.
24 weeks did not improve efficacy. In patients with compensated Now that simpler, improved combination regimens are available,
cirrhosis, limited prospective data and data from observational for patients with NS5A RASs, extending the duration of elbasvir-
cohorts suggested that extending therapy to 24 weeks, with or with- grazoprevir and adding ribavirin have been abandoned (Table 341-6);
out ribavirin, improved efficacy. In cirrhotics, SVR12 was achieved however, elbasvir-grazoprevir is one of the currently recommended
in 93% with Child-Pugh class A and B but in only 56% with class C DAA combinations (Table 341-6).
decompensated cirrhosis. For patients with genotype 3 and cirrhosis, This combination is just as effective in patients with HIV-HCV
the combination was effective in treatment-naïve patients (94% SVR12) co-infection and in patients with advanced renal failure (including
but less so in prior nonresponders (69% SVR12). Outcomes in those requiring hemodialysis), but like all protease-inhibitor-
patients with HIV-HCV co-infection were comparable. including DAA combinations, it is contraindicated in decompensated
Like other sofosbuvir–NS5A inhibitor combinations, daclatasvir cirrhosis. In this vein, like other protease inhibitor regimens, elbasvir-
plus sofosbuvir was well tolerated (mild fatigue, headache, nausea, grazoprevir can be associated with aminotransferase elevations
or diarrhea in 5–14%) but could cause severe bradycardia when and potential hepatotoxicity; because these drugs are excreted by
administered with amiodarone (contraindicated), especially along the liver, plasma drug concentrations may become elevated sub-
with beta blockers. Because daclatasvir is a substrate for CYP3A, stantially in the presence of impaired hepatic function. Therefore,
CYP3A inducers can reduce daclatasvir levels, and CYP3A inhib- all treated patients should have ALT screening periodically during
itors reduce daclatasvir levels. Similarly, daclatasvir, an inhibitor therapy, and the drug should be stopped for elevations exceeding
of P-glycoprotein, OATP1B1 and OATP1B3, and breast cancer tenfold or for elevations of conjugated bilirubin, alkaline phos-
resistance protein (BCRP), can increase the levels of drugs that phatase, or prothrombin time.
are substrates of these transporters. Responsiveness to daclatasvir- Elbasvir-grazoprevir is well tolerated, with only low levels of
containing drug combination therapy was reduced in cirrhotic mild adverse effects (fatigue, headache, or nausea in 5–11%) seen
patients with genotype 1a and in both cirrhotic and noncirrhotic just as frequently in placebo recipients. Both elbasvir and grazopre-
patients with genotype 3 who had baseline daclatasvir-associated vir are substrates for CYP3A and are subject to multiple potential
NS5A RASs. drug-drug interactions. Therefore, this combination should not
As new combination DAAs were introduced, however, be used with potent CYP3A inducers; conversely, CYP3A and
daclatasvir-sofosbuvir was less competitive and no longer filled a OATP1B1 inhibitors can lead to untoward elevations of plasma
niche; it has been supplanted by better, later-generation combina- elbasvir-grazoprevir concentrations. Checking for potential drug-
tion DAAs and is no longer recommended. drug interactions is advisable prior to initiating therapy (www
PART 10

.hep-druginteractions.org).
DIRECT-ACTING ANTIVIRAL COMBINATIONS OF THIRD- Compared to other available regimens for genotypes 1 and 4,
GENERATION PROTEASE INHIBITORS AND SECOND- elbasvir-grazoprevir has the disadvantage/inconvenience of requir-
GENERATION NS5A INHIBITORS (2016) ing baseline NS5A RAS testing but the advantages of a comparable
Elbasvir-grazoprevir: Elbasvir (50 mg), an NS5A inhibitor, com- regimen for cirrhotics and noncirrhotics, for treatment-naïve and
Disorders of the Gastrointestinal System

bined in a single, fixed-dose pill with grazoprevir (100 mg), an treatment-experienced patients, and for patients with normal renal
NS3/4 protease inhibitor, was approved in January 2016 as a function and with renal failure.
once-a-day (with or without food) treatment for genotypes 1 Sofosbuvir-velpatasvir: The combination in a single, fixed-dose
and 4. In clinical trials, a 12-week course was effective in treat- pill of velpatasvir (100 mg), a highly potent, pangenotypic NS5A
ment-naïve and treatment-experienced patients without cirrhosis inhibitor, and the polymerase inhibitor sofosbuvir (400 mg) was
or with compensated cirrhosis. In treatment-naïve patients, this approved in June 2016 for genotypes 1–6 in treatment-naïve and
combination yielded an SVR12 in 92% of patients with genotype treatment-experienced noncirrhotics and cirrhotics. In August
1a, 99% with genotype 1b, and 100% with genotype 4 (very small 2017, approval was extended to include patients with HCV-HIV
numbers, however); 10 patients with genotype 6 were included, co-infection. Ribavirin is not required, including in patients with
but only 80% achieved SVR12. Cirrhotic and noncirrhotic patients genotypes 2 and 3, except in patients with decompensated cirrhosis.
had comparable rates of SVR12, 97% and 94%, respectively. For this In a series of clinical trials, this combination for 12 weeks in
drug combination, however, ~11% of patients with genotype 1a the absence of ribavirin was shown to yield a 99% SVR12 (range
harbor NS5A polymorphisms, that is, RASs, at baseline. If present, 97–100%) in genotypes 1, 2, 4, 5, and 6 and 95% in genotype 3.
these NS5A RASs reduce efficacy of elbasvir-grazoprevir (unlike Baseline NS5A RASs had no impact on responsiveness.
baseline RASs to most of the other combination DAA regimens Prior to the availability of this drug combination, patients with
described above and below) from 99 to 58% in treatment-naïve genotype 3, especially those with cirrhosis and prior null response
patients. Therefore, all patients with genotype 1a require baseline to other therapies, proved to be the most refractory subset of
RAS testing; when these RASs were present, treatment extension to patients. In treatment-naïve patients with genotype 3, 12 weeks
16 weeks and the addition of weight-based ribavirin were docu- of sofosbuvir-velpatasvir (95% SVR12) was superior to 24 weeks
mented to bring SVR12 rates up to expected levels of close to 100%. of sofosbuvir plus ribavirin (80% SVR12). In patients with geno-
In treatment-experienced patients, both extending treatment to type 3, the combination of sofosbuvir-velpatasvir for 12 weeks
16 weeks and adding ribavirin were studied; however, generally, in was comparable in noncirrhotics (97% SVR12) and cirrhotics
the absence of baseline NS5A RASs, SVR12 rates were not increased (91% SVR12) and in treatment-naïve (97% SVR12) and treatment-
over those without ribavirin for 12 weeks (94–97%). For genotype experienced (90% SVR12) patients and was superior in all these
1a, among prior nonresponders to PEG IFN–ribavirin, 12 weeks of categories to 24 weeks of sofosbuvir plus ribavirin (87%, 66%, 86%,
elbasvir-grazoprevir sufficed without ribavirin except for patients and 63%, respectively). In cirrhotic null responders, most avail-
with baseline NS5A RASs, who required 16 weeks of therapy and able IFN-free regimens for genotype 3 (including daclatasvir plus
ribavirin. Among nonresponders to prior protease inhibitor ther- sofosbuvir, which had been approved specifically for this genotype)
apy, even in the absence of baseline NS5A RASs, ribavirin had to achieved SVR12 rates in the range of ~60–75%, while the combina-
be added to a 12-week regimen; in the presence of baseline NS5A tion of PEG IFN, ribavirin, and sofosbuvir could boost SVR12 to the
RASs, treatment was extended to 16 weeks and ribavirin added. For mid-80% range. For treatment-experienced patients with genotype
genotype 1b, NS5A RASs are not an issue, and the only subgroup 3, sofosbuvir-velpatasvir in noncirrhotics and cirrhotics had simi-
requiring modification of a 12-week course of therapy were prior larly high efficacy (91% and 89% SVR12, respectively); this was the
nonresponders to protease inhibitor regimens, for whom ribavirin highest recorded SVR12 for genotype 3 cirrhotic null responders
was added. For genotype 4, the recommended regimen for all prior treated with IFN-free DAA regimens. Finally, in patients with

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 genotypes 1–4 and 6 and with decompensated, class B cirrhosis ~99% for genotypes 1, 2, and 4–6 and of 95–98% for genotype 3. 2611
(55% treatment-experienced), sofosbuvir-velpatasvir plus ribavirin Extended treatment for 12 weeks did not increase efficacy. In trials
for 12 weeks yielded an SVR12 in 94%; this result was better than among treatment-experienced patients, treatment with 12 weeks of
sofosbuvir-velpatasvir without ribavirin for 12 weeks (83% SVR12) this DAA combination was just as effective as 16 weeks for all geno-
or 24 weeks (86% SVR12). types except genotype 3; however, with increasing numbers of prior
Like other all-oral DAAs, sofosbuvir-velpatasvir was very well treatment courses, SVR12 rates fell—100% for patients treated with
tolerated; in noncirrhotic and compensated cirrhotic patients, mild a protease inhibitor only, 88% for patients treated with an NS5A
headache and fatigue were seen in >10% (this occurred in a com- inhibitor only, and 79% for patients treated previously with both a
parable proportion of placebo recipients), and in patients with protease inhibitor and an NS5A inhibitor. Similarly, baseline RASs
decompensated cirrhosis, mild fatigue, headache, nausea, insom- reduced SVR12 rates—from 100% without RASs (or with RASs
nia, diarrhea, and anemia (ribavirin was part of the regimen) were limited to those reflecting protease inhibitor resistance) to 89% for
seen in >10%. Like other sofosbuvir-containing regimens, sofosbu- baseline NS5A RASs.
vir-velpatasvir should not be administered along with amiodarone For retreatment of patients with prior glecaprevir-pibrentasvir
(potential serious bradycardia); in addition, P-glycoprotein inducers failure, 16 weeks of glecaprevir-pibrentasvir plus sofosbuvir are
and moderate-to-potent CYP3A inducers can reduce plasma levels recommended (alternatively, sofosbuvir-velpatasvir-voxilaprevir
of sofosbuvir and/or velpatasvir. Checking for drug-drug interac- for 12 weeks [+ ribavirin in cirrhotics]). Glecaprevir-pibrentasvir
tions prior to therapy is advisable (www.hep-druginteractions.org). for 16 weeks is recommended as well after failure to respond to
Baseline RASs do not influence responsiveness to this combination. the triple-drug combination of sofosbuvir-velpatasvir-voxilaprevir
Sofosbuvir-velpatasvir is one of the currently recommended DAA (see below). For retreatment of patients with sofosbuvir-
combinations for hepatitis C (Table 341-6). Because it is so simple velpatasvir-voxilaprevir failure, 16 weeks of glecaprevir-pibrentasvir
and broadly effective across patient subgroups, sofosbuvir-velpatasvir plus ribavirin is recommended, as is a repeat course of sofosbuvir-
is one of the two combination DAA regimens recommended by the velpatasvir-voxilaprevir plus ribavirin for 24 weeks.
AASLD and EASL as a preferred, simplified treatment algorithm As is the case for any DAA combination containing a protease
(Table 341-6). inhibitor, glecaprevir-pibrentasvir is contraindicated in decom-
pensated cirrhosis; it has been shown to achieve an SVR12 in 98%
DIRECT-ACTING ANTIVIRAL COMBINATIONS OF of patients with stage 4 or 5 renal disease (in treatment-naïve or
THIRD-GENERATION NS5A INHIBITORS AND FOURTH- experienced, cirrhotic or noncirrhotic patients) and is a preferred
GENERATION PROTEASE INHIBITORS—CURRENT treatment for patients with severe renal impairment. This DAA

CHAPTER 341 Chronic Hepatitis

STANDARD OF CARE (SINCE 2017) combination should be taken with food, and drug-drug interactions
Sofosbuvir-velpatasvir-voxilaprevir: Approved in July 2017, the should be considered prior to initiating treatment. Because it is so
pangenotypic, high-barrier-to-resistance protease inhibitor vox- simple and broadly effective across patient subgroups (8 weeks for all
ilaprevir (100 mg) added to the polymerase inhibitor–NS5A noncirrhotic treatment-naïve patients except patients with HIV co-in-
inhibitor combination of sofosbuvir-velpatasvir yields a very fection [12 weeks]; 12 weeks for all treatment-experienced cirrhotics
well-tolerated triple-drug combination with ~97% SVR12 across all and treatment-naïve cirrhotics with genotype 3 [except treatment-
HCV genotypes and patient subgroups. These include the small experienced cirrhotic or noncirrhotic genotype 3 (16 weeks)]),
percentage of patients with genotype 1 and genotype 3 refractory glecaprevir-pibrentasvir is one of the two combination DAA regimens
to previously approved DAA combinations as well as noncirrhotic/ recommended by the AASLD and EASL as a preferred, simplified
cirrhotic, treatment-naïve/treatment-experienced groups, includ- treatment algorithm (Table 341-6).
ing those who had or who had not received prior NS5A treatment. Emerging data on the impact of DAAs on the natural history
Efficacy was independent of the number of prior DAA drug classes of chronic hepatitis C indicated that, as was documented for IFN-
received, and no effects of baseline NS5A RASs were noted. based therapy, successful DAA therapy is associated with a gradual
The potential for abbreviated (8-week) treatment with this reduction in fibrosis progression and a regression of advanced
triple combination was explored in a clinical trial involving fibrosis (cirrhosis), improvement in survival among patients with
treatment-naïve patients; however, the shortened duration was decompensated cirrhosis, a reduction in HCC, and a decline in
inferior to a full 12-week course. The side effect profile for sofosbu- the number of patients with hepatitis C being referred for liver
vir-velpatasvir-voxilaprevir was similar to that in the placebo arm of transplantation. Early observations purported to show an increase
clinical trial patients and included mild and uncommon headache, in HCC after a DAA-associated SVR for chronic hepatitis C. On
fatigue, nausea, and diarrhea. the contrary, HCC rates are reduced dramatically and consistently
Because other DAA regimens are so effective in most patients after successful DAA therapy. Ultimately, the initial observation was
with chronic hepatitis C, recommendations for sofosbuvir-vel- attributed to a cohort bias resulting from the application of simple-
patasvir-voxilaprevir are limited to a small subset of otherwise refractory to-use DAA therapy to an older and sicker population with more
patients: for treatment-naïve cirrhotic patients with genotype 3 and advanced chronic hepatitis C (including decompensated cirrhosis);
baseline NS5A velpatasvir RAS Y93H, for treatment-naïve (according this cohort effect explains why the baseline risk for HCC was higher
to AASLD, not EASL) or IFN-ribavirin–experienced noncirrhotic or in DAA-treated patients than it had been when IFN-based therapy
cirrhosis patients with genotype 3 (Table 341-6), and for patients with was withheld from such patients. Thus, the increased risk in HCC
or without compensated cirrhosis and prior, failed NS5A inhibitor– cases was not linked to DAA treatment but to more advanced liver
containing therapy (consult www.hcvguidelines.org). disease at baseline in patients treated with DAAs. The reports of
This triple-drug combination, like all sofosbuvir-containing HCC after DAA therapy drive home the residual HCC risk after
combinations, is contraindicated in patients taking amiodarone SVR in patients with cirrhosis (advanced hepatic fibrosis) treated
and, like all protease inhibitor-containing combinations, in patients either in the IFN or DAA era; therefore, continued HCC sur-
with decompensated cirrhosis. Concomitant omeprazole, 20 mg, veillance after therapy is recommended for anyone with baseline
can be taken with this sofosbuvir-containing regimen. Prior to initi- advanced fibrosis prior to therapy.
ating therapy, checking for drug-drug interactions is recommended. Based on the known prevalence, natural history, and rate of
Glecaprevir-pibrentasvir: A regimen of 8 weeks of this single-pill, progression of chronic hepatitis C and on the efficacy of DAA ther-
fixed-dose combination of the protease inhibitor glecaprevir apies and their impact on the complications of hepatitis C, modeling
(300 mg) and NS5A inhibitor pibrentasvir (120 mg), two pangeno- estimates have suggested that the availability and application of these
typic, high-potency DAAs with high barriers to resistance (approved therapies have the potential to reduce the hepatitis C–associated dis-
in August 2017), achieves SVR12 in close to 100% of treatment-naïve ease burden, including liver-related death, HCC, decompensated cir-
patients with all genotypes, with or without cirrhosis: SVR12 of rhosis, and liver transplantation, by 50–70% between 2015 and 2050.

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 2612 TREATMENT RECOMMENDATIONS not eliminated, and twice-yearly posttreatment imaging for HCC
Because the pace of new drug development and approval has been surveillance (and endoscopic surveillance for esophageal varices at
so rapid, the AASLD and the Infectious Diseases Society of America intervals of 1–3 years) is indicated even after an SVR. In patients
(IDSA) have been providing a consensus of updated treatment with low-level fibrosis at baseline, achievement of an SVR allows the
recommendations for patients with hepatitis C; these recommen- cessation of such surveillance.
dations, which continue to be revised regularly based on new Patients who have relapsed after, or failed to respond to, a
data, are available online at www.hcvguidelines.org and should be course of IFN-based or DAA agent–based therapy are candi-
consulted before initiating therapy (Table 341-6). The EASL issues dates for retreatment with a DAA therapy regimen (Table 341-6).
similar (but not identical) treatment recommendations annually For patients who have failed to respond to a DAA combination,
for hepatitis C (www.easl.eu), most recently in November 2020. options include increasing the duration of therapy with the failed
Divergences between AASLD-IDSA and EASL recommendations regimen, adding ribavirin, or changing the drug class (e.g., after
are noted in Table 341-6. failed protease and polymerase inhibitors, switching to an NS5A-
Prior to therapy, HCV genotype should be determined, because containing combination). In the presence of cirrhosis or a need
the genotype contributes to decisions about which treatment regi- for urgent retreatment, patients who have failed protease inhibi-
mens are indicated (Table 341-6). Monitoring of serum HCV RNA tor plus polymerase inhibitor combination therapy or who have
levels before, during, and after treatment is crucial in assessing failed an NS5A combination are candidates for RAS testing and
response to therapy; moreover, the baseline level may contribute to tailored therapy based on such resistance testing. If reliable RAS
determining the duration of therapy (e.g., in noncirrhotic patients testing is not available, adding ribavirin or extending the duration
with genotype 1 and HCV RNA <6 × 106 IU/mL, 8 [instead of the of therapy are options. For prior nonresponders to IFN-based
usual 12] weeks of sofosbuvir-ledipasvir may be a consideration). therapy, NS5A inhibitor–containing regimens are highly effective;
The goal of treatment is to eradicate HCV RNA during therapy however, reduced responsiveness can be encountered, especially
and to document that the virus remains undetectable for at least in cirrhotic patients. For this relatively refractory group, ideally,
12 weeks after completion of therapy (SVR12). Several reports have the most potent or effective NS5A regimen should be selected
appeared describing hepatitis B reactivation, often severe, during to give such patients the best chance of responding and to avoid
and after DAA therapy in patients co-infected with HCV and HBV treatment-emergent NS5A RASs. Noted above (see discussion of
who were not being treated for their HBV infections. Therefore, sofosbuvir-velpatasvir-voxilaprevir and of glecaprevir-pibrentasvir)
screening for HBV infection is recommended prior to initiating are potential retreatment approaches after failure of a prior NS5A-
DAA therapy for hepatitis C (which should have been done to containing regimen. Additional details for treatment of such patient
determine HBV immunity status as a prelude to recommended subgroups can be found at www.hcvguidelines.org. It is worth
PART 10

hepatitis B vaccination in patients with chronic hepatitis C), and reiterating that protease inhibitors are contraindicated for patients
therapy for HBV infection (for those meeting HBV treatment cri- with decompensated cirrhosis, and sofosbuvir-containing regimens
teria, see above) should be initiated prior to or simultaneously with are not recommended for patients taking amiodarone (especially
HCV therapy. with beta blockers) for treatment of cardiac arrhythmias. While
Because of their high efficacy and pangenotypic range, two sofosbuvir-containing DAA combinations were not recommended
Disorders of the Gastrointestinal System

DAA regimens, glecaprevir-pibrentasvir (8 weeks) and sofosbuvir- initially for patients with advanced renal failure, subsequent studies
velpatasvir (12 weeks), are recommended as simplified treatment demonstrated safety and efficacy in this subgroup, and sofosbuvir-
algorithms that can be prescribed for all treatment-naïve patients containing DAA combinations are now approved for advanced
with or without cirrhosis (Table 341-6). renal failure.
Persons with acute hepatitis C are also candidates for antiviral
INDICATIONS FOR ANTIVIRAL THERAPY therapy (Chap. 339) with the same pangenotypic combination DAA
Patients with chronic hepatitis C who have detectable HCV RNA agents (and the same duration of treatment) approved for chronic
in serum, whether or not aminotransferase levels are increased, hepatitis C; delaying the initiation of therapy to allow for sponta-
and chronic hepatitis of any grade and stage are candidates for neous recovery is no longer recommended. According to EASL
antiviral therapy with DAA agents. The only exception would be recommendations, patients with acute hepatitis C should be treated
patients with short life expectancies, for whom treating hepatitis C ideally with a currently recommended 8-week DAA regimen. In
would have no influence on longevity. Certainly, for patients with patients with biochemically and histologically mild chronic hepatitis
advanced liver disease, early treatment merits a high priority. C, the rate of progression is slow; however, such patients respond just
Although patients with persistently normal aminotransferase activ- as well to antiviral therapy as those with elevated aminotransferase
ity tend to progress histologically very slowly or not at all, they levels and more histologically severe hepatitis. Because of the high
respond to antiviral therapy just as well as do patients with elevated cost of DAA treatments, in the past, a higher priority was assigned to
aminotransferase levels; therefore, such patients are candidates for patients with advanced fibrosis/cirrhosis; however, this controversial
antiviral therapy. As noted above, antiviral therapy has been shown approach was relied upon by some medical insurers and pharmacy
to improve survival and complication-free survival and to slow benefit management organizations to withhold therapy from patients
progression of and to reverse fibrosis. with low-level fibrosis. Unfortunately, delaying therapy until fibrosis
HCV genotype determines the regimen to be selected becomes advanced misses the opportunity to prevent all the dire con-
(Table 341-6). Similarly, the absence or presence of cirrhosis or sequences of chronic hepatitis C (liver failure, death/transplantation,
advanced fibrosis determines the treatment options from which HCC), which can be reduced, but not eliminated completely, once
to select, including the antiviral agents to be used, the duration of advanced fibrosis is established. Therefore, therapy for patients with
therapy, and the now rare need for ribavirin (Table 341-6). In the mild disease is justified as well as cost-effective.
past, a pretreatment liver biopsy was relied upon to assess histo- Patients with compensated cirrhosis can respond to therapy, and
logic grade and stage as well as to identify such histologic factors their likelihood of a sustained response with DAAs is comparable to
as steatosis, which can influence responsiveness to therapy. As that in noncirrhotics. Patients with decompensated cirrhosis, who
therapy has improved for patients with a broad range of histologic were not candidates for IFN-based antiviral therapy, respond well
severity and as noninvasive measures of the stage of fibrosis (e.g., to DAA therapy regimens consisting of combinations of polymerase
assessment of liver elasticity by imaging, FIB-4 score [see above]) inhibitors and NS5A inhibitors (e.g., sofosbuvir-ledipasvir, sofosbu-
have gained in accuracy and popularity, noninvasive approaches vir-velpatasvir); however, protease-inhibitor-containing combina-
have supplanted histology in almost most cases. As noted above, if tions have been associated with potential hepatotoxicity and hepatic
cirrhosis or advanced fibrosis is present prior to therapy, the risk decompensation and, as noted above, are contraindicated in this
of HCC, although reduced substantially by successful therapy, is patient subset. For decompensated cirrhosis, ribavirin should be

HPIM21e_Part10_p2381-p2670.indd 2612 20/01/22 10:05 PM

 added to a 12-week course of sofosbuvir-NS5A therapy; however, The approved oral DAA combinations are effective in patients 2613
in cases of ribavirin ineligibility, the duration of therapy should with mild-modest renal failure and require no dose adjustments.
be extended to 24 weeks. In cases of prior failure to respond to For patients with severe renal impairment (creatinine clearances
sofosbuvir-NS5A therapy, the sofosbuvir-NS5A regimen should be <30 mL/min), including those undergoing hemodialysis, recom-
repeated but supplemented with ribavirin and extended to 24 weeks mended combinations are 12 weeks of elbasvir-grazoprevir for
(www.hcvguidelines.org). Patients with decompensated cirrhosis genotypes 1 and 4 or 12 weeks of glecaprevir-pibrentasvir for all
should be referred to a liver transplantation center. DAAs are highly genotypes. Both in severe renal impairment and after renal trans-
effective not only for patients with end-stage liver disease awaiting plantation, levels of SVR12 in patients treated with these oral DAA
liver transplantation but also for patients with recurrent hepatitis C combinations have approached 100%. Initially, in patients with
after liver transplantation. Ideally, patients should be treated prior severe renal impairment, sofosbuvir-containing combinations were
to liver transplantation; however, a concern is that eradication of not recommended. Subsequently, however, based on efficacy and
HCV infection will disqualify such patients from accepting donor safety in a series of clinical trials, sofosbuvir-containing regimens
livers from persons with HCV infection, thus contracting the were approved by the FDA in November 2019 for patients with
potential donor pool and limiting accessibility to donor organs and severe renal impairment.
timely transplantation. In addition, responsiveness to DAA therapy No clinical studies of the use of DAAs during pregnancy are
appears to be reduced in patients with decompensated cirrhosis available. Ribavirin is contraindicated during pregnancy; therefore,
and with high Model for End-Stage Liver Disease (MELD) scores; any regimen including ribavirin should not be used. Sofosbuvir;
in this subgroup, responsiveness after liver transplantation would sofosbuvir-ledipasvir; and paritaprevir-ritonavir, ombitasvir, and
be substantially better. Therefore, advocacy has been expressed dasabuvir are classified as pregnancy category B; the other DAAs
for postponing DAA therapy in patients with high-MELD-score do not have a pregnancy classification. Therefore, these therapies
(≥18–20), HCV-associated, end-stage liver disease until after liver are not indicated routinely in pregnancy and should be used, with
transplantation; for patients with MELD scores <18–20, pretrans- caution, only if the benefit of treatment is compelling and justified
plantation DAA therapy is advised. Still, the decision whether to compared to the potential for fetal risk. Currently, screening all
treat pretransplantation or posttransplantation should be individu- pregnant women for HCV infection is recommended. Breast feed-
alized thoughtfully for each patient, based on such factors as MELD ing is not contraindicated in women with HCV infection (unless the
score, time anticipated prior to availability of a donor organ, relative mother has a break in the integrity of the nipples or is co-infected
clinical stability, and comorbidities (Chap. 345). Because DAA with HIV).
therapy is so effective, many transplantation centers, to expand Choosing Among Available Treatment Options Choosing among

CHAPTER 341 Chronic Hepatitis

the donor pool, are accepting organs from HCV-infected donors, the number of all-oral DAA combinations approved since 2013
transplanting them into HCV-uninfected recipients, and treating was daunting to treating clinicians. Currently, however, the num-
recipients with sofosbuvir-velpatasvir for 12 weeks or glecapre- ber of recommended DAA combinations has narrowed to a
vir-pibrentasvir for 8 weeks after transplantation—with excellent very manageable few. The most popular of the regimens have
results. been fixed-dose, single-pill, pangenotypic combinations. Although
The cutaneous and renal vasculitis of HCV-associated essential sofosbuvir-ledipasvir and elbasvir-grazoprevir are among the rec-
mixed cryoglobulinemia (Chap. 339) may respond to antiviral ommended DAA combinations (Table 341-6), for simplicity, two
therapy, but sustained responses were rare after discontinuation of “one-size-fits-all” pangenotypic regimens—sofosbuvir-velpatasvir
therapy in the IFN era, and prolonged, potentially indefinite, ther- and glecaprevir-pibrentasvir—can be used, for 8–12 weeks, mostly
apy was recommended. Now that more effective DAAs are avail- without ribavirin, in almost all treatment-naïve, noncirrhotic and
able, a 12-week course of sofosbuvir-based combination therapy has cirrhotic patients, including those with advanced renal failure
been shown to yield an SVR12 rate exceeding 80% in cryoglobuline- and HCV-HIV co-infection. Applicability of the triple-drug com-
mic vasculitis. Anecdotal reports suggest that IFN-based antiviral bination sofosbuvir-velpatasvir-voxilaprevir is quite limited in
therapy may be effective in porphyria cutanea tarda or lichen planus treatment-naïve patients, reserved primarily for cirrhotic patients
associated with hepatitis C; whether the more appealing DAAs are with genotype 3. As noted above, protease-inhibitor-containing
effective in these groups remains to be documented. DAA regimens (elbasvir-grazoprevir, glecaprevir-pibrentasvir, and
In patients with HCV/HIV co-infection, hepatitis C is more pro- sofosbuvir-velpatasvir-voxilaprevir) are contraindicated in decom-
gressive and severe than in HCV-monoinfected patients. Although pensated cirrhosis.
patients with HCV/HIV co-infection responded less well to IFN-
based antiviral therapy for hepatitis C, they respond as well as
patients with HCV infection alone to DAA combination regimens. AUTOIMMUNE HEPATITIS
For patients with HCV/HIV co-infection, an abbreviated, 8-week
course of sofosbuvir-ledipasvir for low-level HCV RNA is not recom- ■■DEFINITION
mended, and a full 12 weeks should be given; similarly, for patients Autoimmune hepatitis is a chronic disorder characterized by contin-
with genotype 4, a 12-week course of glecaprevir-pibrentasvir is uing hepatocellular necrosis and inflammation, usually with fibrosis,
recommended instead of an 8-week course for treatment-naïve or which can progress to cirrhosis and liver failure. When fulfilling cri-
-experienced patients with or without cirrhosis (Table 341-6). In teria of severity, this type of chronic hepatitis, when untreated, may
HCV/HIV-infected patients, ribavirin can potentiate the toxicity have a 6-month mortality of as high as 40%. Based on contemporary
of didanosine (e.g., lactic acidosis) and the lipoatrophy of stavu- estimates of the natural history of autoimmune hepatitis, the 10-year
dine, and zidovudine can exacerbate ribavirin-associated hemolytic survival is 80−98% for treated and 67% for untreated patients. The
anemia; therefore, these drug combinations should be avoided. prominence of extrahepatic features of autoimmunity and seroimmu-
In HCV/HIV co-infected persons, the list of potential drug-drug nologic abnormalities in this disorder supports an autoimmune process
interactions is extensive and should be consulted carefully before in its pathogenesis; this concept is reflected in the prior labels lupoid
beginning DAA treatment (www.hcvguidelines.org). and plasma cell hepatitis. Autoantibodies and other typical features of
Patients with a history of injection drug use and alcoholism autoimmunity, however, do not occur in all cases; among the broader
can be treated successfully for chronic hepatitis C, preferably in categories of “idiopathic” or cryptogenic chronic hepatitis, many, per-
conjunction with drug and alcohol treatment programs. Moreover, haps the majority, are probably autoimmune in origin. Cases in which
because injection drug users, as a source of transmission to others, hepatotropic viruses, metabolic/genetic derangements (including non-
account disproportionately for perpetuating the spread of HCV alcoholic fatty liver disease), and hepatotoxic drugs have been excluded
infection in the population, the impact of treating active injection represent a spectrum of heterogeneous liver disorders of unknown
drug users is amplified by reducing such transmission. cause, a proportion of which are most likely autoimmune hepatitis.

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 2614 ■■IMMUNOPATHOGENESIS confused with, acute viral hepatitis; a history of recurrent bouts of what
The weight of evidence suggests that the progressive liver injury in had been labeled acute hepatitis is not uncommon. In approximately a
patients with autoimmune hepatitis is the result of a cell-mediated quarter of patients, the diagnosis is made in the absence of symptoms,
immunologic attack directed against liver cells in the setting of a loss based on abnormal liver laboratory tests. A subset of patients with
of, or failed, immunologic tolerance for self-liver antigens. In all like- autoimmune hepatitis has distinct features. Such patients are predom-
lihood, predisposition to autoimmunity is inherited, whereas the liver inantly young to middle-aged women with marked hyperglobulinemia
specificity of this injury is triggered by environmental (e.g., chemical, and high titer circulating ANAs. This is the group with positive lupus
drug [e.g., minocycline], or viral) factors. For example, patients have erythematosus (LE) preparations (initially labeled lupoid hepatitis)
been described in whom apparently self-limited cases of acute hepatitis in whom other autoimmune features are common. Fatigue, malaise,
A, B, or C led to autoimmune hepatitis, presumably because of genetic anorexia, amenorrhea, acne, arthralgias, and jaundice are common.
susceptibility or predisposition. Evidence to support an autoimmune Occasionally, arthritis, maculopapular eruptions (including cutaneous
pathogenesis in this type of hepatitis includes the following: (1) in the vasculitis), erythema nodosum, colitis, pleuritis, pericarditis, ane-
liver, the histopathologic lesions are composed predominantly of cyto- mia, azotemia, and sicca syndrome (keratoconjunctivitis, xerostomia)
toxic T cells and plasma cells; (2) circulating autoantibodies (nuclear, occur. In some patients, complications of cirrhosis, such as ascites and
smooth muscle, thyroid, etc.; see below), rheumatoid factor, and hyper- edema (associated with portal hypertension and hypoalbuminemia),
globulinemia are common; (3) other autoimmune disorders—such as encephalopathy, hypersplenism, coagulopathy, or variceal bleeding
autoimmune thyroiditis, rheumatoid arthritis, autoimmune hemolytic may bring the patient to initial medical attention.
anemia, ulcerative colitis, membranoproliferative glomerulonephri- The course of autoimmune hepatitis may be variable. In patients
tis, juvenile diabetes mellitus, vitiligo, celiac disease, and Sjögren’s with mild disease or limited histologic lesions (e.g., piecemeal necro-
syndrome—occur with increased frequency in patients who have auto- sis [inflammation and erosion of the limiting place of periportal
immune hepatitis and in their relatives; (4) histocompatibility haplo- hepatocytes] without bridging), progression to cirrhosis is limited,
types associated with autoimmune diseases, such as HLA-B1, B8, DR3, but, even in this subset, clinical monitoring is important to identify
and DR4 as well as extended haplotype DRB1*0301 and DRB1*0401 progression; up to half left untreated can progress to cirrhosis over
alleles, are common in patients with autoimmune hepatitis; and (5) this the course of 15 years. In North America, cirrhosis at presentation
type of chronic hepatitis is responsive to glucocorticoid/immunosup- is more common in African Americans than in whites. In those with
pressive therapy, effective in a variety of autoimmune disorders. severe symptomatic autoimmune hepatitis (aminotransferase levels
Cellular immune mechanisms appear to be important in the patho- >10 times normal, marked hyperglobulinemia, “aggressive” histologic
genesis of autoimmune hepatitis. In vitro studies have suggested that lesions—bridging necrosis or multilobular collapse, cirrhosis), the
in patients with this disorder, CD4+ T lymphocytes are capable of 6-month mortality without therapy may be as high as 40%. Such severe
PART 10

becoming sensitized to hepatocyte membrane proteins and of destroy- disease accounts for only 20% of cases; the natural history of milder
ing liver cells. Molecular mimicry by cross-reacting antigens that con- disease is variable, often accentuated by spontaneous remissions and
tain epitopes similar to liver antigens is postulated to activate these T exacerbations. In a 10-year (2006–2016) national Dutch study, mortal-
cells, which infiltrate, and result in injury to, the liver. Abnormalities ity in patients with autoimmune hepatitis was higher than that of the
of immunoregulatory control over cytotoxic lymphocytes (impaired general population only in patients with cirrhosis; for patients without
Disorders of the Gastrointestinal System

regulatory CD4+CD25+ T-cell influences) may play a role as well. cirrhosis, survival was comparable to that of the general population.
Studies of genetic predisposition to autoimmune hepatitis demonstrate Especially poor prognostic signs include the presence histologically of
that certain haplotypes are associated with the disorder, as enumer- multilobular collapse at the time of initial presentation and failure of
ated above, as are polymorphisms in cytotoxic T lymphocyte antigens serum bilirubin to improve after 2 weeks of therapy. Death may result
(CTLA-4) and tumor necrosis factor α (TNFA*2). The precise trigger- from hepatic failure, hepatic coma, other complications of cirrhosis
ing factors, genetic influences, and cytotoxic and immunoregulatory (e.g., variceal hemorrhage), and intercurrent infection. In patients with
mechanisms involved in this type of liver injury remain incompletely established cirrhosis, HCC may be a late complication (Chap. 82) but
defined. occurs less frequently than in cirrhosis associated with viral hepatitis.
Intriguing clues into the pathogenesis of autoimmune hepatitis come Laboratory features of autoimmune hepatitis are similar to those
from the observation that circulating autoantibodies are prevalent in seen in chronic viral hepatitis. Liver biochemical tests are invariably
patients with this disorder. Among the autoantibodies described in abnormal but may not correlate with the clinical severity or histo-
these patients are antibodies to nuclei (so-called antinuclear antibodies pathologic features in individual cases. Many patients with autoim-
[ANAs], primarily in a homogeneous pattern) and smooth muscle mune hepatitis have normal serum bilirubin, alkaline phosphatase,
(so-called anti-smooth-muscle antibodies, directed at actin, vimentin, and globulin levels with only minimal aminotransferase elevations.
and skeletin), antibodies to F-actin, anti-LKM (see below), antibodies Serum AST and ALT levels are increased and fluctuate in the range
to “soluble liver antigen” (directed against a uracil-guanine-adenine of 100−1000 units. In severe cases, the serum bilirubin level is mod-
transfer RNA suppressor protein), antibodies to α-actinin, and anti- erately elevated (51−171 μmol/L [3−10 mg/dL]). Hypoalbuminemia
bodies to the liver-specific asialoglycoprotein receptor (or “hepatic occurs in patients with very active or advanced disease. Serum alkaline
lectin”) and other hepatocyte membrane proteins. Although some of phosphatase levels may be moderately elevated or near normal. In
these provide helpful diagnostic markers, their involvement in the a small proportion of patients, marked elevations of alkaline phos-
pathogenesis of autoimmune hepatitis has not been established. phatase activity occur; in such patients, clinical and laboratory features
Humoral immune mechanisms have been shown to play a role in the overlap with those of primary biliary cholangitis (Chap. 344). The
extrahepatic manifestations of autoimmune and idiopathic hepatitis. prothrombin time is often prolonged, particularly late in the disease or
Arthralgias, arthritis, cutaneous vasculitis, and glomerulonephritis during active phases.
occurring in patients with autoimmune hepatitis appear to be mediated Polyclonal hypergammaglobulinemia (>2.5 g/dL) is common in
by the deposition of circulating immune complexes in affected tissue autoimmune hepatitis, as is the presence of rheumatoid factor. As noted
vessels, followed by complement activation, inflammation, and tissue above, circulating autoantibodies are also prevalent, most characteris-
injury. While specific viral antigen-antibody complexes can be iden- tically ANAs in a homogeneous staining pattern. Smooth-muscle anti-
tified in acute and chronic viral hepatitis, the nature of the immune bodies are less specific, seen just as frequently in chronic viral hepatitis.
complexes in autoimmune hepatitis has not been defined. Because of the high levels of globulins achieved in the circulation of
some patients with autoimmune hepatitis, occasionally the globulins
■■CLINICAL FEATURES may bind nonspecifically in solid-phase binding immunoassays for
Many of the clinical features of autoimmune hepatitis are similar to viral antibodies. This has been recognized most commonly in tests for
those described for chronic viral hepatitis. The onset of disease may antibodies to HCV, as noted above. In fact, studies of autoantibodies
be insidious or abrupt; the disease may present initially like, and be in autoimmune hepatitis have led to the recognition of new categories

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 of autoimmune hepatitis. Type I autoimmune hepatitis is the classic with features of chronic hepatitis long before neurologic manifestations 2615
syndrome prevalent in North America and northern Europe occurring become apparent and before the formation of Kayser-Fleischer rings
in young women, associated with marked hyperglobulinemia, lupoid (copper deposition in Descemet’s membrane in the periphery of the
features, circulating ANAs, and HLA-DR3 or HLA-DR4 (especially cornea). In this age group, serum ceruloplasmin and serum and uri-
B8-DRB1*03). Also associated with type I autoimmune hepatitis are nary copper determinations plus measurement of liver copper levels
autoantibodies against actin and atypical perinuclear antineutrophilic establish the correct diagnosis. Postnecrotic or cryptogenic cirrhosis
cytoplasmic antibodies (pANCA). Included in the spectrum of type I and primary biliary cholangitis (Chap. 344) share clinical features
autoimmune hepatitis is a subset of patients who lack ANA and anti- with autoimmune hepatitis, and both alcoholic hepatitis (Chap. 342)
LKM1 but who have circulating antibodies to soluble liver antigen. and nonalcoholic steatohepatitis (Chap. 343) may present with many
Most of these patients are women and have clinical features similar features common to autoimmune hepatitis; historic, biochemical, sero-
to, or perhaps more severe than, those of other patients with type I logic, and histologic assessments are usually sufficient to allow these
autoimmune hepatitis. entities to be distinguished from autoimmune hepatitis. Of course,
Type II autoimmune hepatitis, often seen in children, more common the distinction between autoimmune and chronic viral hepatitis is
in Mediterranean populations, and linked to HLA-DRB1 and HLA- not always straightforward, especially when viral antibodies occur
DQB1 haplotypes, is associated not with ANA but with anti-LKM. in patients with autoimmune disease or when autoantibodies occur
Actually, anti-LKM represent a heterogeneous group of antibodies. in patients with viral disease. Furthermore, the presence of extrahe-
In type II autoimmune hepatitis, the antibody is anti-LKM1, directed patic features such as arthritis, cutaneous vasculitis, or pleuritis—not
against cytochrome P450 2D6. This is the same anti-LKM seen in some to mention the presence of circulating autoantibodies—may cause
patients with chronic hepatitis C. Anti-LKM2 is seen in drug-induced confusion with rheumatologic disorders such as rheumatoid arthritis
hepatitis, and anti-LKM3 (directed against uridine diphosphate glucu- and systemic LE. The existence of clinical and biochemical features of
ronyltransferases) is seen in patients with chronic hepatitis D. Another progressive necroinflammatory liver disease distinguishes chronic hep-
autoantibody observed in type II autoimmune hepatitis is directed atitis from these other disorders, which are not associated with severe
against liver cytosol formiminotransferase cyclodeaminase (anti-liver liver disease. Rarely, hepatic venous outflow obstruction (Budd-Chiari
cytosol 1). syndrome) may present with features suggestive of autoimmune hep-
Liver biopsy abnormalities are similar to those described for chronic atitis, but painful hepatomegaly, ascites, and vascular imaging provide
viral hepatitis. Expanding portal tracts and extending beyond the plate distinguishing diagnostic clues. Other diagnostic considerations would
of periportal hepatocytes into the parenchyma (designated interface include celiac disease and ischemic liver disease, which would be
hepatitis or piecemeal necrosis) is a mononuclear cell infiltrate that, readily distinguishable by clinical and laboratory features from auto-

CHAPTER 341 Chronic Hepatitis

in autoimmune hepatitis, may include the presence of plasma cells. immune hepatitis.
Necroinflammatory activity characterizes the lobular parenchyma, In patients treated with immune checkpoint inhibitors for malig-
and evidence of hepatocellular regeneration is reflected by “rosette” nancy, the liver may be one of the autoimmune targets of therapy;
formation, the occurrence of thickened liver cell plates, and regenera- the syndrome resembles autoimmune hepatitis in clinical features
tive “pseudolobules.” Septal fibrosis, bridging fibrosis, and cirrhosis are and response to glucocorticoid-based treatment. Finally, occasionally,
frequent. In patients with early autoimmune hepatitis presenting as an features of autoimmune hepatitis overlap with features of autoimmune
acute-hepatitis-like illness, lobular and centrilobular (as opposed to the biliary disorders such as primary biliary cholangitis, primary sclerosing
more common periportal) necrosis has been reported. Bile duct injury cholangitis (Chaps. 344 and 346), or, even more rarely, mitochondrial
and granulomas are uncommon; however, a subgroup of patients antibody-negative autoimmune cholangitis. Such overlap syndromes
with autoimmune hepatitis has histologic, biochemical, and serologic are difficult to categorize, and often response to therapy may be the
features overlapping those of primary biliary cholangitis (Chap. 344). distinguishing factor that establishes the diagnosis.

■■DIAGNOSTIC CRITERIA
An international group has suggested a set of criteria for establish- TREATMENT
ing a diagnosis of autoimmune hepatitis. Exclusion of liver disease Autoimmune Hepatitis
caused by genetic disorders, viral hepatitis, drug hepatotoxicity, and
alcohol is linked with such inclusive diagnostic criteria as hyperglob- The mainstay of management in autoimmune hepatitis is glucocor-
ulinemia, autoantibodies, and characteristic histologic features. This ticoid therapy. Several controlled clinical trials have documented
international group has also suggested a comprehensive diagnostic that such therapy leads to symptomatic, clinical, biochemical, and
scoring system that, rarely required for typical cases, may be helpful histologic improvement as well as increased survival. A therapeutic
when typical features are not present. Factors that weigh in favor of response can be expected in up to 80% of patients. Unfortunately,
the diagnosis include female gender; predominant aminotransferase therapy has not been shown in clinical trials to prevent ultimate
elevation; presence and level of globulin elevation; presence of nuclear, progression to cirrhosis; however, instances of reversal of fibrosis
smooth-muscle, LKM1, and other autoantibodies; concurrent other and cirrhosis have been reported in patients responding to treat-
autoimmune diseases; characteristic histologic features (interface ment, and rapid treatment responses within 1 year do translate into
hepatitis, plasma cells, rosettes); HLA-DR3 or DR4 markers; and a reduction in progression to cirrhosis. Although some advocate
response to treatment (see below). A more simplified, more specific the use of prednisolone (the hepatic metabolite of prednisone),
scoring system relies on four variables: autoantibodies, serum IgG prednisone is just as effective and is favored by most authorities.
level, typical or compatible histologic features, and absence of viral Therapy may be initiated at 20 mg/d, but a popular regimen in
hepatitis markers. Weighing against the diagnosis are predominant the United States relies on an initiation dose of 60 mg/d. This high
alkaline phosphatase elevation, mitochondrial antibodies, markers of dose is tapered successively over the course of a month down to
viral hepatitis, history of hepatotoxic drugs or excessive alcohol, histo- a maintenance level of 20 mg/d. An alternative, but equally effec-
logic evidence of bile duct injury, or such atypical histologic features as tive, more appealing approach is to begin with half the prednisone
fatty infiltration, iron overload, and viral inclusions. dose (30 mg/d) along with azathioprine (50 mg/d). With azathio-
prine maintained at 50 mg/d, the prednisone dose is tapered over
■■DIFFERENTIAL DIAGNOSIS the course of a month down to a maintenance level of 10 mg/d.
Early during the course of chronic hepatitis, autoimmune hepatitis may The advantage of the combination approach is a reduction, over the
resemble typical acute viral hepatitis (Chap. 339). Without histologic span of an 18-month course of therapy, in serious, life-threatening
assessment, severe chronic hepatitis cannot be readily distinguished complications of steroid therapy (e.g., cushingoid features, hyper-
based on clinical or biochemical criteria from mild chronic hepatitis. tension, diabetes, osteoporosis) from 66% down to <20%. Genetic
In adolescence, Wilson’s disease (Chaps. 344 and 415) may present analysis for thiopurine S-methyltransferase allelic variants does not

HPIM21e_Part10_p2381-p2670.indd 2615 20/01/22 10:05 PM

 2616 correlate with azathioprine-associated cytopenias or efficacy and as 35−40% of cases in others; nonetheless, 5-year patient and graft
is not assessed routinely in patients with autoimmune hepatitis. survival exceed 80%.
In combination regimens, 6-mercaptopurine may be substituted Like all patients with chronic liver disease, patients with auto-
for its prodrug azathioprine, but this is rarely required. Azathio- immune hepatitis should be vaccinated against hepatitis A and
prine alone, however, is not effective in achieving remission, nor B, ideally before immunosuppressive therapy is begun, if practi-
is alternate-day glucocorticoid therapy. Limited experience with cal. Patients with autoimmune hepatitis and cirrhosis should be
budesonide in noncirrhotic patients suggests that this steroid side screened for HCC with ultrasound at 6-month intervals and for
effect−sparing drug may be effective; however, the few randomized gastroesophageal varices with upper gastrointestinal endoscopy at
controlled trials of budesonide have not consistently shown effi- intervals of 1–3 years, based on severity of liver disease.
cacy. Although therapy has been shown to be effective for severe
autoimmune hepatitis (AST ≥10× the upper limit of normal or
≥5× the upper limit of normal in conjunction with serum globulin ■■FURTHER READING
greater than or equal to twice normal; bridging necrosis or multi- AASLD/IDSA HCV Guidance Panel: Hepatitis C guidance 2019
lobular necrosis on liver biopsy; presence of symptoms), therapy is update: American Association for the Study of Liver Diseases–
not indicated for mild forms of chronic hepatitis, and the efficacy Infectious Diseases Society of America recommendations for testing,
of therapy in mild or asymptomatic autoimmune hepatitis has not managing, and treating hepatitis C virus infection. Hepatology
been established. 71:686, 2020. Updated regularly and available at http://www.hcvguide-
Improvement of fatigue, anorexia, malaise, and jaundice tends lines.org. Accessed April 20, 2020.
to occur within days to several weeks; biochemical improvement Bersoff-Matcha SJ et al: Hepatitis B virus reactivation associated
occurs over the course of several weeks to months, with a fall in with direct-acting antiviral therapy for chronic hepatitis C virus: A
serum bilirubin and globulin levels and an increase in serum albu- review of cases reported to the U.S. Food and Drug Administration
min. Serum aminotransferase levels usually drop promptly, but Adverse Event Reporting System. Ann Intern Med 166:792, 2017.
improvements in AST and ALT alone do not appear to be reliable Bourliere M et al: Sofosbuvir, velpatasvir, and voxilaprevir for previ-
markers of recovery in individual patients; histologic improvement, ously treated HCV infection. N Engl J Med 376:2134, 2017.
characterized by a decrease in mononuclear infiltration and in Buti M et al: Tenofovir alafenamide versus tenofovir disproxil fuma-
hepatocellular necrosis, may be delayed for 6−24 months. Still, if rate for the treatment of HBeAg-negative chronic hepatitis B virus
interpreted cautiously, aminotransferase levels are valuable indi- infection: A randomized, double-blind, phase 3 non-inferiority trial.
cators of relative disease activity, and, although recommended, Lance Gastroenterol Hepatol 1:196, 2017.
many authorities do not advocate for serial liver biopsies to assess Butt AA et al: Direct-acting antiviral therapy for HCV infection is
PART 10

therapeutic success or to guide decisions to alter or stop therapy. associated with a reduced risk of cardiovascular disease events. Gas-
Rapidity of response is more common in older patients (≥69 years) troenterology 156:987, 2019.
and those with HLA DBR1*04; although rapid responders may Carbone M, Neuberger JM: Autoimmune liver disease, autoimmu-
progress less slowly to cirrhosis and liver transplantation, they are nity and liver transplantation. J Hepatol 60:210, 2014.
no less likely than slower responders to relapse after therapy. Ther- Carrat F et al: Clinical outcomes in patients with chronic hepatitis C
Disorders of the Gastrointestinal System

apy should continue for at least 12−18 months. After tapering and after direct-acting antiviral treatments: A prospective cohort study.
cessation of therapy, the likelihood of relapse is at least 50%, even if Lancet 393:1453, 2019.
posttreatment histology has improved to show mild chronic hepa- Chan HLY et al: Tenofovir alafenamide versus tenofovir disproxil
titis, and most patients require therapy at maintenance doses indef- fumarate for the treatment of HBeAg-positive chronic hepatitis B
initely. Continuing azathioprine alone (2 mg/kg body weight daily) virus infection: A randomized, double-blind, phase 3 non-inferiority
after cessation of prednisone therapy has been shown to reduce trial. Lancet Gastroenterol Hepatol 1:185, 2017.
the frequency of relapse. Long-term maintenance with low-dose European Association for the Study of the Liver: EASL 2017
prednisone (≤10 mg daily) has also been shown to keep autoim- clinical practice guidelines on the management of hepatitis B virus
mune hepatitis in check without the theoretical risk of azathioprine infection. J Hepatol 67:370, 2017.
marrow suppression and, in young women of child-bearing age, European Association for the Study of the Liver: EASL recom-
teratogenicity; however, maintenance azathioprine is more effective mendations on treatment of hepatitis C 2018. J Hepatol 69:461, 2018.
in preserving remission. European Association for the Study of the Liver: EASL recom-
In medically refractory cases, an attempt should be made to mendations on treatment of hepatitis C: Final update of the series. J
intensify treatment with high-dose glucocorticoid monotherapy Hepatol 73:1170, 2020.
(60 mg daily) or combination glucocorticoid (30 mg daily) plus Forns X et al: Glecaprevir plus pibrentasvir for chronic hepatitis C
high-dose azathioprine (150 mg daily) therapy. After a month, virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated
doses of prednisone can be reduced by 10 mg a month, and doses cirrhosis (EXPEDITION-1): A single-arm, open-label, multicentre
of azathioprine can be reduced by 50 mg a month toward ultimate, phase 3 trial. Lancet Infect Dis 17:1062, 2017.
conventional maintenance doses. Patients refractory to this regimen Jacobson IM et al: American Gastroenterological Association Institute
may be treated with cyclosporine, tacrolimus, or mycophenolate clinical practice update-expert review: Care of patients who have
mofetil. Similarly, in exploratory studies, infusions of monoclo- achieved a sustained virologic response after antiviral therapy for
nal antibodies directed at tumor necrosis factor (infliximab) and chronic hepatitis C infection. Gastroenterology 152:1578, 2017.
against the B-lymphocyte antigen CD20 (rituximab) have been Kwo PY et al: Glecaprevir and pibrentasvir yield high response rates in
reported to be of clinical benefit (improved aminotransferase levels, patients with HCV genotype 1-6 without cirrhosis. J Hepatol 67:263,
immunoglobulin G levels, histologic inflammatory activity) as res- 2017.
cue therapy for refractory autoimmune hepatitis. To date, however, Liem KS et al: Limited sustained response after stopping nucleos(t)ide
only limited, often anecdotal, data in small numbers of patients analogues in patients with chronic hepatitis B: Results from a ran-
support these alternative approaches. If medical therapy fails, or domized controlled trial (Toronto STOP study). Gut 68:2206, 2019.
when chronic hepatitis progresses to cirrhosis and is associated Lok ASG et al: Antiviral therapy for chronic hepatitis B viral infection
with life-threatening complications of liver decompensation, liver in adults: A systematic review and meta-analysis. Hepatology 63:284,
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after 2 weeks of therapy should prompt early consideration of the suppressive and biological modifier therapies: Current concepts,
patient for liver transplantation. Recurrence of autoimmune hepati- management strategies, and future directions. Gastroenterology
tis in the new liver occurs rarely in most experiences but in as many 152:1297, 2017.

HPIM21e_Part10_p2381-p2670.indd 2616 20/01/22 10:05 PM

 Mcglynn EA et al: Assessing the safety of direct-acting antiviral agents Liver cirrhosis is the eleventh leading cause of mortality worldwide, 2617
for hepatitis C. JAMA Open Network 2(6):e194765, 2019. causing 1.16 million deaths annually; 48% of cases of cirrhosis can be
Papatheodoridis GV et al: Eight-year survival in chronic hepatitis attributed to alcohol. Among patients with alcohol use disorder, 18%
B patients under long-term entecavir or tenofovir is similar to the had fibrosis, 26% had cirrhosis, and 7% had acute alcoholic hepatitis
general population. J Hepatol 68:1129, 2018. without underlying cirrhosis. In the European population, the annual
Papatheodoridis GV et al: DARING-B: Discontinuation of effective incidence rate for acute alcoholic hepatitis is between 24 and 27 per
entecavir or tenofovir disoporxil fumarate long-term therapy before million persons in women and between 46 and 65 per million persons
HBsAg loss in non-cirrhotic HBeAg-negative chronic hepatitis B. in men.
Antivir Ther 23:677, 2018.
Pawlotsky J-M et al: From non-A, non-B hepatitis to hepatitis C virus ■■PATHOGENESIS
cure. J Hepatol 62:S87, 2015. Alcohol in the form of ethanol is rapidly absorbed in the upper gas-
Perrillo RP et al: American Gastroenterological Association Institute trointestinal tract and predominantly metabolized in the liver. Ethanol
technical review on prevention and treatment of hepatitis B virus reaches the liver through the portal vein, and the majority of ethanol
reactivation during immunosuppressive drug therapy. Gastroenter- is oxidized via alcohol dehydrogenase 1 (ADH1) into acetaldehyde
ology 148:221, 2015. in hepatocytes. Chronic alcohol consumption induces the expression
Reddy KJ et al: American Gastroenterological Association Institute of a second ethanol-metabolizing enzyme, cytochrome P450 family
guideline on the prevention and treatment of hepatitis B virus reac- 2 subfamily E member 1 (CYP2E1), which also converts ethanol into
tivation during immunosuppressive drug therapy. Gastroenterology acetaldehyde. In addition to the direct cellular toxic effects of acetal-
148:215, 2015. dehyde, metabolism of ethanol into acetaldehyde causes the genera-
Rossi C et al: Sustained virologic response from interferon-based tion of reactive oxygen species (ROS), resulting in further injury of
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oral direct-acting antivirals for chronic hepatitis C infection and leads to acetaldehyde accumulation after alcohol consumption. These
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antiviral therapy in patients with chronic hepatitis C: A systematic (CoA), which contributes to fatty acid and triglyceride synthesis.

CHAPTER 342 Alcohol-Associated Liver Disease

review and meta-analysis. Clin Gastroenterol Hepatol 16:27, 2018. Alcohol, in part through epigenetic changes, increases the expression
Spearman CW et al: Hepatitis C. Lancet 394:1451, 2019. of genes involved in lipogenesis, while genes involved in fatty acid
Tang LS et al: Chronic hepatitis B infection: A review. JAMA 319:1802, transport and oxidation are suppressed. Alcohol also increases the ratio
2018. of reduced nicotinamide adenine dinucleotide (NAD)/oxidized NAD
Terrault N et al: Update on prevention, diagnosis, and treatment of (NADH/NAD+) in hepatocytes, which further reduces mitochondrial
chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology β-oxidation. Alcohol can increase fatty acid mobilization in adipose
67:1560, 2018. tissue and the intestine, which will lead to hepatic accumulation of fatty
Van Den Brand FF et al: Increased mortality among patients with acids and increased hepatic steatosis. Overall, the net effect of these
vs without cirrhosis and autoimmune hepatitis. Clin Gastroenterol processes contributes to fat accumulation in the liver.
Hepatol 17:940, 2019.
Yurdaydin C et al: Treating chronic hepatitis delta: The need for sur- ■■RISK FACTORS FOR PROGRESSION OF ALD
rogate markers of treatment efficacy. J Hepatol 70:1008, 2019. Daily alcohol consumption or heavy drinking results in hepatic steato-
sis, but only 10–20% of such individuals will develop progressive liver
disease and cirrhosis. Therefore, other cofactors such as behavioral,
environmental, and genetic factors play important roles in progression
of ALD (Table 342-1). There is a dose-dependent increase, with regard
to the amount of alcohol consumed, in the likelihood of developing
liver cirrhosis. Women develop ALD at a lower daily alcohol intake.

342 Alcohol-Associated
Liver Disease
Cigarette smoking is an independent risk factor for alcohol-associated
cirrhosis. The drinking pattern, in particular binge drinking and
excessive alcohol drinking outside meals, increases the risk of devel-
oping progressive ALD. Obesity and other chronic liver diseases such
Bernd Schnabl as viral hepatitis, hemochromatosis, and nonalcoholic steatohepatitis
(NASH), are frequent cofactors contributing to progression of ALD.
Twin studies demonstrated a genetic predisposition to alcohol-associ-
Alcohol-associated liver diseases (ALD) comprise a spectrum of dis- ated liver cirrhosis that is independent from the genetic predisposition
eases associated with chronic alcohol consumption ranging from to alcohol use disorder. Gene polymorphisms conferring increased
alcohol-associated fatty liver disease and steatohepatitis to more risk of alcohol-associated liver cirrhosis have been found in three
advanced liver disease including fibrosis and cirrhosis. Acute alcoholic genes, patatin-like phospholipase domain-containing 3 (PNPLA3),
hepatitis is an acute-on-chronic form of ALD that is associated with
liver failure and high mortality.
TABLE 342-1 Factors for Progression of Alcohol-Associated Liver
■■EPIDEMIOLOGY Disease
Approximately 5.8% of adults in the United States have an alcohol use • Alcohol dose (>1 drink per day for women, >2 drinks per day for men)
disorder, defined as >2 drinks per day in women and >3 drinks per day • Drinking pattern (drinking without meal, binge drinking)
in men, or partake in binge drinking, defined as 4 drinks for women • Genetic factors, especially PNPLA3 polymorphism
and 5 drinks for men in ~2 h (1 drink equals ~14 g of ethanol, which • Female gender
is 1 beer, 4 oz of wine, or 1 oz of 80% spirits). Prevalence of ALD cor- • Smoking
relates with the amount of alcohol consumption in different regions. • Increased body mass index and chronic liver diseases
Prevalence of alcohol-associated fatty liver disease is 4.7% of the general
• Intestinal microbiota
population in the United States, and 1.5% has stage 2 or greater fibrosis.

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 2618 TABLE 342-2 Symptoms and Signs Associated with Alcohol-Associated with large lipid droplets (macrovesicular steatosis) around pericentral
Cirrhosis and Alcoholic Hepatitis veins (zone 3). Morphologic features of alcohol-associated steatohep-
• Tiredness atitis include hepatocyte injury and ballooning with Mallory-Denk
• Malnutrition and sarcopenia bodies, necrosis, and lobular inflammation with mononuclear and
• Abdomen: abdominal discomfort, hepatomegaly, splenomegaly, caput
neutrophilic granulocytes.
medusae, ascites with weight gain, abdominal pain, and shortness of breath Progression of alcohol-associated steatohepatitis to fibrosis can be
• Skin: spider angioma, palmar erythema, jaundice, ecchymoses diagnosed using liver stiffness measurement by techniques such as
transient elastography (e.g., FibroScan). Liver stiffness <6 kPa indicates
• Eyes: icteric sclerae
normal liver, whereas cutoffs for each stage of alcohol-associated liver
• Hands: Dupuytren contracture
fibrosis have been validated (>8 kPa indicates ≥F3 advanced fibrosis;
• Face: rhinophyma >12.5 kPa indicates F4 cirrhosis). Histology shows initially periven-
• Reproductive system: gynecomastia, gonadal atrophy, loss of libido, ular fibrosis with subsequent extension of collagen fibers into hepatic
amenorrhea lobules, described as septal fibrosis. Patients with cirrhosis show liver
• Neurologic: nodularity on imaging with ultrasound, MRI, or CT scan. Radiologic
• Peripheral neuropathy signs of portal hypertension include ascites, splenomegaly, and portal-
• Alcohol withdrawal: tachycardia, agitation, tremor, seizures, delirium systemic collateral vessels. Prognosis and risk of mortality are assessed
• Hepatic encephalopathy: asterixis (flapping tremor), forgetfulness, inversion using Child-Pugh-Turcotte (CPT) or Model for End-Stage Liver Dis-
of sleep/wake pattern, altered consciousness, confusion, lethargy, coma ease (MELD; or sodium-MELD) scores (Chap. 344).
• Wernicke-Korsakoff syndrome In patients presenting with features suggestive of alcoholic hepatitis,
imaging is obtained to exclude biliary obstruction and hepatocellular
carcinoma (HCC). In addition, other causes of liver disease such as
membrane bound O-acyltransferase domain-containing 7 (MBOAT7), viral hepatitis, Wilson’s disease, and severe autoimmune liver disease
and transmembrane 6 superfamily member 2 (TM6SF2), although should be ruled out. Histology shows macrovesicular steatosis, hepa-
the molecular mechanism is not well understood. A subset of patients tocyte ballooning with Mallory-Denk bodies, megamitochondria,
with alcohol use disorder develop changes in the gut microbiome and neutrophil infiltration, bilirubinostasis, and chicken wire fibrosis. The
increased intestinal permeability resulting in activation of hepatic majority of patients with alcoholic hepatitis have underlying cirrhosis
inflammation, hepatocyte death, and activation of fibrotic pathways. (80%) (Chap. 344), and 10–20% of patients with a clinical diagnosis of
Ongoing fibrosis due to continued alcohol consumption can result in alcoholic hepatitis will have other liver diseases on biopsy. Therefore, in
the development of cirrhosis with portal hypertension (Chap. 344). the presence of potential confounding factors, including possible ische-
PART 10

mic hepatitis (in the setting of, e.g., hypotension, massive gastrointes-
■■CLINICAL FEATURES tinal bleeding, recent cocaine use, septic shock), drug-induced liver
The development of alcohol-associated steatosis, steatohepatitis, and injury (DILI), autoimmune liver disease, uncertain alcohol use assess-
cirrhosis is most often clinically silent. Symptoms arise once the patient ment, or atypical laboratory tests (AST <50 IU/L or >400 IU/L, AST/ALT
with alcohol-associated liver cirrhosis decompensates or develops ratio <1.5), a transjugular liver biopsy is recommended to confirm the
Disorders of the Gastrointestinal System

alcoholic hepatitis (Table 342-2). Patients with alcoholic hepatitis have diagnosis of alcoholic hepatitis. Infections need to be assessed routinely
been drinking heavily for typically >5 years and until at least 8 weeks with chest x-ray and blood, urine, and ascites cultures in patients pre-
before onset of symptoms. They present with rapid onset of jaundice senting with alcoholic hepatitis.
(serum bilirubin >3 mg/dL), often accompanied by fever, malaise,
tender hepatomegaly, and clinical signs of hepatic decompensation,
such as ascites, bacterial infection, variceal bleeding, and hepatic TREATMENT
encephalopathy. Infections occur in 12–26% of patients with severe Alcohol-Associated Liver Disease (Fig. 342-1)
alcoholic hepatitis at the time of admission. Alcoholic hepatitis is often
accompanied by systemic inflammatory response syndrome (SIRS) and To date, the most effective therapy to reduce the progression of and
acute kidney injury (AKI) secondary to hepatorenal syndrome. reverse ALD is prolonged alcohol abstinence. In particular, alcohol-
associated hepatic steatosis and steatohepatitis are reversible with
■■LABORATORY FINDINGS cessation of alcohol consumption. Thus, treatment of the underly-
Patients with simple hepatic steatosis can present with normal liver ing alcohol use disorder is an integral part for therapy of ALD. There
function tests. Steatohepatitis is characterized by elevated levels of are currently no approved drugs for treatment of alcohol-associated
aspartate aminotransferase (AST) and γ-glutamyl transferase (GGT). steatosis and steatohepatitis with or without fibrosis.
Characteristic laboratory parameters for ALD include a ratio of AST Patients with alcohol-associated cirrhosis and ongoing alcohol
to alanine aminotransferase (ALT) of >1, and serum AST is rarely consumption are at risk for decompensation and development
>300 IU/L. Serum bilirubin and international normalized ratio (INR) of hepatic encephalopathy, ascites, variceal bleeding, hepatorenal
are typically normal. Elevated bilirubin and INR and low serum albu- syndrome, and HCC (Chap. 344). Patients with cirrhosis should
min and platelet count are common laboratory finings in patients with undergo an upper gastrointestinal endoscopy to screen for varices.
cirrhosis. Patients with alcoholic hepatitis have AST and ALT eleva- HCC screening is recommended using ultrasonography every 6
tions that do not exceed 400 IU/L, with AST/ALT ratio of >1.5 and months in patients with cirrhosis. Management of complications of
serum bilirubin >3 mg/dL. cirrhosis such as variceal bleeding, ascites, hepatic encephalopathy,
and HCC does not differ from patients with cirrhosis due to a dif-
■■DIAGNOSIS ferent etiology (Chap. 344). Liver transplantation for patients with
The Alcohol Use Disorders Inventory Test (AUDIT) is a validated tool alcohol-associated decompensated cirrhosis or HCC is a definitive
for identifying patients with alcohol use disorder (Chap. 453). Diagno- therapy and is currently the leading indication for liver transplan-
sis of ALD requires exclusion of other liver diseases in heavy drinkers. tation in the United States. Liver transplantation evaluation should
Alcohol-associated steatosis can be diagnosed by simple ultrasound, be taken into consideration for patients with end-stage liver disease
magnetic resonance imaging (MRI), or computed tomography (CT). (Chap. 345).
Noninvasive quantification of hepatic fat can be achieved with the In patients diagnosed with alcoholic hepatitis, short-term mor-
ultrasound technique of controlled attenuation parameter (CAP) or tality can be predicted using the Maddrey discriminant function
with magnetic resonance proton density fat fraction (MR-PDFF). Liver (MDF; calculated as 4.6 × [the prolongation of the prothrombin
biopsy is rarely indicated for diagnosing alcohol-associated hepatic time above control {seconds}] + serum bilirubin [mg/dL]), MELD
steatosis or steatohepatitis. Liver biopsy typically shows hepatocytes score (Chap. 344), or age-bilirubin-INR-creatinine (ABIC) score.

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 alcohol abstinence and underlying cirrhosis. Patients with severe 2619
Alcoholic Hepatitis (AH) Confounding alcoholic hepatitis that is nonresponsive to medical therapy have
Clinical diagnosis with diagnostic high 30-day mortality and are therefore unable to fulfill a minimum
laboratory findings factors
of 6 months of alcohol abstinence, which is required in many cen-
ters for liver transplantation evaluation. Early liver transplantation
can be successfully performed in highly selected patients with an
Moderate AH Severe AH excellent psychosocial profile (Chap. 345). If a nonresponder is
MDF <32 MDF ≥32 TJ liver biopsy ineligible for early liver transplantation, supportive or palliative
or MELD ≤20 or MELD >20
care should be considered for patients with multiple-organ failure.

■■FURTHER READING
Crabb DW et al: Standard definitions and common data elements for
- Alcohol Oral prednisolone 40 mg/d
abstinence (unable to take oral medications:
Contraindications clinical trials in patients with alcoholic hepatitis: Recommendation
- Nutritional methylprednisolone 32 mg/d IV)
for corticosteroids from the NIAAA Alcoholic Hepatitis Consortia. Gastroenterology
support 150:785, 2016.
Crabb DW et al: Diagnosis and treatment of alcohol-associated liver
7 days diseases: 2019 practice guidance from the American Association for
the Study of Liver Diseases. Hepatology 71:306, 2020.
Lille score <0.45 Lille score ≥0.45 Louvet A et al: Corticosteroids reduce risk of death within 28 days for
patients with severe alcoholic hepatitis, compared with pentoxifylline
or placebo-a meta-analysis of individual data from controlled trials.
Continue prednisolone Stop prednisolone Gastroenterology 155:458, 2018.
for 28 days total Seitz HK et al: Alcoholic liver disease. Nat Rev Dis Primers 4:16, 2018.
Singal AK et al: ACG clinical guideline: Alcoholic liver disease. Am J
Gastroenterol 113:175, 2018.
- If eligible, early liver transplantation (LT)
- If not eligible for LT: Supportive/palliative care

CHAPTER 343 Nonalcoholic Fatty Liver Diseases and Nonalcoholic Steatohepatitis

FIGURE 342-1 Treatment algorithm for alcoholic hepatitis. In patients with a
clinical diagnosis of alcoholic hepatitis, confounding factors (see text) need to
be ruled out, if necessary, by transjugular (TJ) liver biopsy. Patients with severe

343 Nonalcoholic Fatty Liver

alcoholic hepatitis (AH), defined as Maddrey discriminant function (MDF) ≥32 or
Model for End-Stage Liver Disease (MELD) score >20, without contraindications
for glucocorticoids (see text) are candidates for such treatment. Nonresponders or
patients with contraindications for treatment should be considered for early liver Diseases and Nonalcoholic
transplantation (LT) or supportive or palliative care, as clinically appropriate.
Steatohepatitis
Patients with MDF <32 or MELD ≤20 are defined as having moder- Manal F. Abdelmalek, Anna Mae Diehl
ate alcoholic hepatitis. Currently, patients with moderate alcoholic
hepatitis are treated under a multidisciplinary team including an
alcohol use disorder specialist, dietitian for nutritional supplemen- ■■INCIDENCE, PREVALENCE,
tation for patients with markedly reduced intake, and hepatologist AND NATURAL HISTORY
for managing liver disease complications. Enteral nutrition with a Nonalcoholic fatty liver disease (NAFLD) is the most common cause
goal of >21 kcal/kg and supplementation of micronutrients (in par- of chronic liver disease in the United States, as well as worldwide. The
ticular zinc) and vitamin supplementation (in particular vitamin B1) global prevalence of NAFLD is estimated to be as high as one billion.
are recommended for patients with alcoholic hepatitis. Intravenous In the United States, NAFLD is estimated to effect between 80 and
albumin is preferred for volume expansion. MDF ≥32 or MELD 100 million individuals. NAFLD is strongly associated with insulin
>20 identifies patients with severe alcoholic hepatitis and high resistance, overweight/obesity, and metabolic syndrome. However, it
short-term mortality who will have a survival benefit with gluco- can also occur in lean individuals and is particularly common in those
corticoid treatment. Contraindications for glucocorticoid treatment with a paucity of adipose depots (i.e., lipodystrophy). Ethnic/racial
include uncontrolled infections or sepsis, AKI and hepatorenal syn- factors also appear to influence liver fat accumulation; the documented
drome, uncontrolled upper gastrointestinal bleeding, concomitant prevalence of NAFLD is lowest in African Americans (~25%), high-
diseases (including viral hepatitis, HCC, pancreatitis, DILI, active est in Americans of Hispanic ancestry (~50%), and intermediate in
tuberculosis, and HIV), multiorgan failure, and shock. Glucocorti- American whites (~33%).
coids can be used once infection, sepsis, and gastrointestinal bleed- NAFLD encompasses a spectrum of liver pathology with different
ing are adequately controlled. Glucocorticoid use reduces the risk clinical prognoses (Fig. 343-1). The simple accumulation of triglyc-
of death in patients with severe alcoholic hepatitis within 28 days eride within hepatocytes (hepatic steatosis) is on the most clinically
of treatment but not in the following 6 months. Oral prednisolone, benign extreme of the spectrum. On the opposite, most clinically
40 mg/d for a total duration of 4 weeks, is preferred. For patients ominous extreme, are cirrhosis (Chap. 344) and primary liver can-
unable to take oral medications, methylprednisolone, 32 mg/d IV, cer (Chap. 82). The risk of developing cirrhosis is extremely low in
is used. The combination of glucocorticoids with N-acetylcysteine individuals with isolated steatosis (nonalcoholic fatty liver [NAFL])
infusion might add short-term survival benefit at 1 month. Failure but increases as steatosis becomes complicated by liver-cell injury and
of improvement of Lille score (≥0.45) after 7 days of glucocorticoid death and the accumulation of inflammatory cells (i.e., nonalcoholic
treatment will determine patients with severe alcoholic hepatitis steatohepatitis [NASH]). At least a quarter of adults with NAFLD are
who will unlikely benefit from continued treatment with glucocor- presumed to have NASH. NASH itself is also a heterogeneous condi-
ticoids. Glucocorticoids should be stopped in nonresponders, and tion; it can improve to steatosis or normal histology, remain relatively
early liver transplantation should be considered. Although short- stable for years, or cause progressive accumulation of fibrous scar that
term prognosis is dependent on liver disease severity at the time eventuates in cirrhosis (stage 4 fibrosis). Advanced hepatic fibrosis is
of presentation, long-term prognosis (>1 year) largely depends on the primary predictor of eventual liver-related morbidity and mortality

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 2620

A B C D
Healthy liver Steatosis (NAFL) Steatohepatitis (NASH) Cirrhosis

Dynamic process

FIGURE 343-1 Histopathologic spectrum of nonalcoholic fatty liver disease (NAFLD). NAFLD encompasses a dynamic spectrum of liver pathology. A. Healthy liver.
B. Simple steatosis (nonalcoholic fatty liver [NAFL]); arrow shows fatty hepatocyte. C. Nonalcoholic steatohepatitis (NASH); ballooned hepatocyte (arrow) near central vein
with adjacent blue-stained pericellular fibrosis (arrowheads). D. Cirrhosis with blue-stained bridging fibrosis surrounding micronodules of liver parenchyma.

in NAFLD. Once NAFLD-related cirrhosis develops, the annual inci- ALT elevations increases with body mass index, it is presumed that
dence of primary liver cancer can be as high as 1–2% per year. they are due to NASH. Hence, at any given point in time, NASH is
Abdominal imaging is not able to determine which individuals present in ~25% of individuals who have NAFLD (i.e., ~6–8% of the
with NAFLD have associated liver-cell death and inflammation (i.e., general U.S. adult population has NASH). Smaller cross-sectional
NASH), and specific blood tests to diagnose NASH are not yet avail- studies in which liver biopsies have been performed on NASH patients
able. However, population-based studies that have used elevated serum at tertiary referral centers consistently demonstrate advanced fibrosis
alanine aminotransferase (ALT) as a marker of liver injury indicate or cirrhosis in ~25% of those cohorts. By extrapolation, therefore,
that ~6–8% of American adults have serum ALT elevations that cannot
PART 10

be explained by excessive alcohol consumption, other known causes TABLE 343-2 Medications Associated with Hepatic Steatosis
of fatty liver disease (Table 343-1), viral hepatitis, or drug-induced or
• Cytotoxic and cytostatic drugs
congenital liver diseases. Because the prevalence of such “cryptogenic”
• 5-Fluorouraci
• l-Asparaginase
Disorders of the Gastrointestinal System

TABLE 343-1 Alternative Causes of Hepatic Steatosis • Azacitidine

• Alcoholic liver disease • Azaserine
• Hepatitis C (particularly genotype 3) • Bleomycin
• Inborn errors of metabolism • Methotrexate
• Abetalipoproteinemia • Puromycin
• Cholesterol ester storage disease • Tetracycline
• Galactosemia • Doxycycline
• Glycogen storage disease • Metals
• Hereditary fructose intolerance • Antimony
• Homocystinuria • Barium salts
• Systemic carnitine deficiency • Chromates
• Tyrosinemia • Phosphorus
• Weber-Christian syndrome • Rare earths of low atomic number
• Wilson’s disease • Thallium compounds
• Wolman’s disease • Uranium compounds
• Medications (see Table 343-2) • Other drugs and toxins
• Miscellaneous • Amiodarone
• Industrial exposure to petrochemical • 4,4’-Diethylaminoethoxyhexesterol
• Inflammatory bowel disease • Ethionine
• Lipodystrophy • Ethyl bromide
• Bacterial overgrowth • Estrogens
• Starvation • Glucocorticoids
• Parenteral nutrition • Highly active antiretroviral therapy
• Surgical procedures • Hydralazine
• Bilopancreatic diversion • Hypoglycin
• Extensive small-bowel resection • Orotate
• Gastric bypass • Perhexiline maleate
• Jejunoileal bypass • Safrole
• Reye’s syndrome • Tamoxifen
• Acute fatty liver of pregnancy • Valproic acid
• HELLP syndrome (hemolytic anemia, elevated liver enzymes, low platelet • Acetylsalicylic acid intoxication
count) • Apo-B inhibitors: Mipomersen and lomitapide

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 cirrhosis develops in ~6% of individuals with NAFLD (i.e., in ~1.5–2% the morphologic manifestation of lipotoxicity and resultant wound 2621
of the general U.S. population). The risk for advanced liver fibrosis is healing responses. Because the severity and duration of lipotoxic liver
highest in individuals with NASH who are aged >45–50 years and over- injury dictate the intensity and duration of repair, the histologic fea-
weight/obese or afflicted with type 2 diabetes. Having a first-degree tures and outcomes of NASH are variable. Cirrhosis and liver cancer
relative with cryptogenic hepatitis or cirrhosis also increases the risk are potential outcomes of chronic NASH. Cirrhosis results from futile
for developing cirrhosis. repair, i.e., progressive accumulation of wound healing cells, fibrous
Heritable factors clearly impact susceptibility to hepatic steatosis, matrix, and abnormal vasculature (scarring), rather than efficient
NASH, liver fibrosis, and liver cancer. Genetic variants on or near reconstruction/regeneration of healthy hepatic parenchyma. Primary
TM6SF2 or MBOAT7 (genes involved in lipid homeostasis) and liver cancers develop when malignantly transformed liver cells escape
palatin-like phospholipase domain-containing 3 gene (PNPLA3, a gene mechanisms that normally control regenerative growth. The mecha-
that encodes an enzyme involved in intracellular trafficking of lipids) nisms responsible for futile repair (cirrhosis) and liver carcinogenesis
may increase the heritability of NAFLD. A recent meta-analysis showed are not well understood. Because normal liver regeneration is a very
that PNPLA3 exerts a strong influence not only on hepatic fat accu- complex process, there are multiple opportunities for deregulation
mulation but also on the severity of NASH and liver fibrosis. Indeed, and, thus, pathogenic heterogeneity. To date, this heterogeneity has
recent twin studies suggest that inheritance accounts for about half the confounded development of both diagnostic tests and treatments for
risk for developing cirrhosis. Epigenetic factors (i.e., heritable traits defective/deregulated liver repair (i.e., cirrhosis and cancer). Hence,
that do not result from direct changes in DNA) may also influence current strategies focus on circumventing misrepair by preventing and/
NAFLD pathogenesis and/or progression based on evidence that intra- or reducing lipotoxic liver injury.
uterine exposures influence susceptibility to obesity and the metabolic
syndrome in adolescence. Studies of families with adult-onset obesity ■■DIAGNOSIS
have identified genome-wide epigenetic alterations that dysregulate Diagnosing NAFLD requires demonstration of increased liver fat in
metabolic pathways controlling adiposity, insulin sensitivity, and tissue the absence of hazardous levels of alcohol consumption. Thresholds
generation or regeneration. Whether such epigenetic mechanisms for potentially dangerous alcohol ingestion have been set at more than
influence susceptibility to NASH and cirrhosis is being investigated. one drink per day in women and two drinks per day in men based on
NAFLD is currently the leading indication for liver transplantation epidemiologic evidence that the prevalence of serum aminotransferase
in the United States. Similar to cirrhosis caused by other liver diseases, elevations increases when alcohol consumption habitually exceeds
cirrhosis caused by NAFLD increases the risk for primary liver cancer. these levels. In those studies, one drink was defined as having 10 g
Both hepatocellular carcinoma and intrahepatic cholangiocarcinoma of ethanol and, thus, is equivalent to one can of beer, 4 oz of wine,

CHAPTER 343 Nonalcoholic Fatty Liver Diseases and Nonalcoholic Steatohepatitis

(ICC) have also been reported to occur in NAFLD patients without or 1.5 oz (one shot) of distilled spirits. Other causes of liver fat accu-
cirrhosis, suggesting that NAFLD per se may be a premalignant condi- mulation (particularly exposure to certain drugs; Table 343-2) and
tion. NAFLD, NASH, and NAFLD-related cirrhosis are not limited to liver injury (e.g., viral hepatitis, autoimmune liver disease, iron or copper
adults. All have been well documented in children. As in adults, obesity overload, α1 antitrypsin deficiency) must also be excluded. Thus, estab-
and insulin resistance are the main risk factors for pediatric NAFLD. lishing the diagnosis of NAFLD does not require invasive testing: it can be
Thus, the rising incidence and prevalence of childhood obesity sug- accomplished by history and physical examination, liver imaging (ultra-
gests that NAFLD will be a major contributor to society’s burden of sound is an acceptable first-line test; computed tomography [CT] or mag-
liver disease in the future. netic resonance imaging [MRI] enhances sensitivity for liver fat detection
but adds expense), and blood tests to exclude other liver diseases.
■■PATHOGENESIS It is important to emphasize that, in individuals with NAFLD, the
The mechanisms underlying the pathogenesis and progression of liver may not be enlarged and serum aminotransferases and liver
NAFLD are not entirely clear. The best-understood mechanisms function tests (e.g., bilirubin, albumin, prothrombin time) may be
pertain to hepatic steatosis. This is proven to result when hepatocyte completely normal. Because there is yet no one specific blood test for
mechanisms for triglyceride synthesis (e.g., lipid uptake and de novo NAFLD, confidence in the diagnosis of NAFLD is increased by identi-
lipogenesis) overwhelm mechanisms for triglyceride disposal (e.g., fication of NAFLD risk factors. The latter include increased body mass
degradative metabolism and lipoprotein export), leading to accu- index, insulin resistance/type 2 diabetes mellitus, and other parameters
mulation of fat (i.e., triglyceride) within hepatocytes. Obesity stimu- indicative of the metabolic syndrome (e.g., systemic hypertension,
lates hepatocyte triglyceride accumulation by altering the intestinal dyslipidemia, hyperuricemia/gout, cardiovascular disease; Chap. 408)
microbiota to enhance both energy harvest from dietary sources and in the patient or family members. Individuals who have, or have had,
intestinal permeability. Reduced intestinal barrier function increases pituitary or hypothalamic neoplasms and women with polycystic ovary
hepatic exposure to gut-derived products, which stimulate liver cells syndrome are also at increased risk for NAFLD. Hypothyroidism and
to generate inflammatory mediators that inhibit insulin actions. Obese obstructive sleep apnea may also increase NAFLD, presumably by pro-
adipose depots also produce excessive soluble factors (adipokines) that moting obesity and/or exacerbating the metabolic syndrome.
inhibit tissue insulin sensitivity. Insulin resistance promotes hypergly- Establishing the severity of NAFLD-related liver injury and related
cemia, which drives the pancreas to produce more insulin to maintain scarring (i.e., staging NAFLD) is more difficult than simply diagnosing
glucose homeostasis. However, hyperinsulinemia also promotes lipid NAFLD. Staging is critically important, however, because it is necessary
uptake, fat synthesis, and fat storage. The net result is hepatic triglycer- to define prognosis and thereby determine treatment recommenda-
ide accumulation (i.e., steatosis). tions. The goal of staging is to distinguish patients with NASH from
Triglyceride per se is not hepatotoxic. However, its precursors (e.g., those with simple steatosis and to identify which of the NASH patients
fatty acids and diacylglycerols) and metabolic by-products (e.g., reac- have advanced fibrosis. The 10-year probability of developing liver-
tive oxygen species) may damage hepatocytes, leading to hepatocyte related morbidity or mortality in steatosis is negligible, and hence, this
lipotoxicity. Lipotoxicity also triggers the generation of other factors subgroup of NAFLD patients tends to be managed conservatively (see
(e.g., inflammatory cytokines, hormonal mediators) that deregulate below). In contrast, more intensive follow-up and therapy are justified
systems that normally maintain hepatocyte viability. The net result is in NASH patients, and the subgroup with advanced fibrosis merits the
increased hepatocyte death. Dying hepatocytes, in turn, release vari- most intensive scrutiny and intervention because their 10-year risk of
ous factors that trigger wound healing responses that aim to replace liver-related morbidity and mortality is clearly increased.
(regenerate) lost hepatocytes. Such repair involves transient expansion Staging approaches can be separated into noninvasive testing
of other cell types, such as myofibroblasts and progenitor cells, that (i.e., blood testing, physical examination, and imaging) and invasive
make and degrade matrix, remodel the vasculature, and generate approaches (i.e., liver biopsy). Blood test evidence of hepatic dysfunc-
replacement hepatocytes, as well as the recruitment of immune cells tion (e.g., hyperbilirubinemia, hypoalbuminemia, prothrombin time
that release factors that modulate liver injury and repair. NASH is prolongation) or portal hypertension (e.g., thrombocytopenia) and

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 2622 stigmata of portal hypertension on physical examination (e.g., spider sleep apnea, thyroid dysfunction, polycystic ovary syndrome, and
angiomata, palmar erythema, splenomegaly, ascites, clubbing, enceph- chronic pain syndrome. NAFLD is an independent risk factor for meta-
alopathy) suggest a diagnosis of advanced NAFLD. Liver biopsy has bolic syndrome (Chap. 408). Longitudinal studies suggest that patients
been the gold standard for establishing the severity of liver injury and with NASH are at two- to threefold increased risk for the development
fibrosis because it is both more sensitive and more specific than these of metabolic syndrome. Similarly, studies have shown that patients
other tests for establishing NAFLD severity. Further, although invasive, with NASH have a higher risk for the development of hypertension and
liver biopsy is seldom complicated by serious adverse sequelae such as diabetes mellitus. The presence of NAFLD is also independently associ-
significant bleeding, pain, or inadvertent puncture of other organs and ated with endothelial dysfunction, increased carotid intimal thickness,
thus is relatively safe. However, biopsy suffers from potential sampling and the number of plaques in carotid and coronary arteries. Such data
error unless tissue cores of 2 cm or longer are acquired. Also, exami- indicate that NAFLD has many deleterious effects on health in general.
nation of tissue at a single point in time is not reliable for determining
whether the pathologic processes are progressing or regressing. The ■■TREATMENT OF NAFLD
risk of serial liver biopsies within short time intervals is generally Treatment of NAFLD can be divided into three components: (1) specific
deemed as unacceptable outside of research studies. These limita- therapy of NAFLD-related liver disease; (2) treatment of NAFLD-
tions of liver biopsy have stimulated efforts to develop noninvasive associated comorbidities; and (3) treatment of the complications of
approaches to stage NAFLD. advanced NAFLD. The subsequent discussion focuses on specific
As is true for many other types of chronic liver disease, in NAFLD, therapies for NAFLD, with some mention of their impact on major
the levels of serum aminotransferases (aspartate aminotransferase NAFLD comorbidities (insulin resistance/diabetes, obesity, and dyslip-
[AST] and ALT) do not reliably reflect the severity of liver cell injury, idemia). Treatment of the complications of advanced NAFLD involves
extent of liver-cell death, or related liver inflammation and fibrosis. management of the complications of cirrhosis and portal hyperten-
Thus, they are imperfect for determining which individuals with sion, including primary liver cancers. Approaches to accomplish these
NAFLD have NASH. This has prompted efforts to identify superior objectives are similar to those used in other chronic liver diseases and
markers of NASH and, particularly, liver fibrosis, because fibrosis stage are covered elsewhere in the textbook (Chaps. 344 and 82).
predicts eventual liver outcomes and mortality in NASH. Algorithms At present, there are no U.S. Food and Drug Administration (FDA)–
that combine various laboratory tests (e.g., Enhanced Liver Fibrosis approved therapies for the treatment of NAFLD. Thus, the current
[ELF] score, BARD score, AST to Platelet Ratio Index [APRI] score, approach to NAFLD management focuses on treatment to improve
NAFLD fibrosis score, and Fibrosis-4 [FIB-4] score) are somewhat the risk factors for NASH (i.e., obesity, insulin resistance, metabolic
helpful in separating NASH patients with advanced versus mild liver syndrome, dyslipidemia). Based on our understanding of the natu-
fibrosis. The NAFLD fibrosis score (NFS) and FIB-4 score, two of ral history of NAFLD, only patients with NASH or hepatic fibrosis
are considered currently for targeted pharmacologic therapies. This
PART 10

the most commonly employed noninvasive tests to assess severity of

hepatic fibrosis, can be calculated from a few readily available clini- approach may change as our understanding of disease pathophysiology
cal variables (age, body mass index, glucose, platelet count, albumin, improves and potential targets of therapy evolve.
AST, ALT) using published formulas that are readily accessed via an Diet and Exercise Lifestyle changes and dietary modifications
online calculator. Both scores are helpful for gauging the severity of that result in weight loss and/or improve insulin sensitivity are the pri-
Disorders of the Gastrointestinal System

NASH and liver fibrosis. Combining these tests with new imaging mary treatments for NAFLD. Many studies indicate that loss of 3–5%
approaches that permit noninvasive quantification of liver fat (e.g., of body weight improves steatosis and that greater weight loss (i.e.,
MRI using proton density fat fraction [MRI-PDFF]) and liver stiffness, ≥7–10%) improves steatohepatitis and hepatic fibrosis. The benefits
a surrogate marker of liver fibrosis (e.g., magnetic resonance elastog- of modifying dietary macronutrient contents (e.g., low-carbohydrate
raphy [MRE], and transient elastography [FibroScan]), improves their vs low-fat diets, saturated vs unsaturated fat diets) generally parallel
predictive power (Chap. 337). Transient elastography in particular changes in calorie consumption, suggesting that diet modifications
has become widely available and is relatively inexpensive. It is most are mainly beneficial because they reduce energy intake and improve
useful for excluding advanced liver fibrosis as cirrhosis is extremely obesity. However, a Mediterranean-type diet has been reported to
unlikely when the liver stiffness score is low. However, higher stiffness improve NASH and liver fibrosis independently of weight loss. Exclud-
scores must be interpreted with caution since several factors (obesity, ing foods and beverages high in added fructose and increasing coffee
nonfasting state, hepatic inflammation, iron overload, and/or hepatic consumption are also recommended because high-fructose diets have
congestion) decrease the specificity of the test. Increasingly, these new been shown to exacerbate hepatic steatosis, steatohepatitis, and fibro-
serologic and imaging tools are being used serially or in combination sis, and consuming two or more cups of coffee per day is associated
to monitor fibrosis progression and regression in NAFLD patients. As with reduced risk of liver fibrosis. Changes in diet composition partic-
a result, liver biopsy staging is becoming restricted to patients who ularly merit consideration in lean individuals with NAFLD, although
cannot be stratified reliably using these noninvasive assessments. Inde- available data are insufficient to determine if this improves their liver
terminant or discordant results of noninvasive testing should prompt histology. Modifying lifestyle to increase physical activity (i.e., energy
referral to a liver specialist and consideration of liver biopsy. expenditure) complements dietary caloric restriction and, thus, expe-
dites weight loss. Exercise also improves muscle insulin sensitivity,
■■CLINICAL FEATURES OF NAFLD which improves the metabolic syndrome independent of weight loss.
Most subjects with NAFLD are asymptomatic. The diagnosis is often Both aerobic exercise and resistance training effectively reduce liver
made when abnormal liver aminotransferases or features of fatty liver fat. At least 30 min of moderate-intensity aerobic exercise or resistance
are noted during an evaluation performed for other reasons. NAFLD training five times per week is recommended. The choice of training
may also be diagnosed during the workup of vague right upper should be tailored to patients’ preferences and functional capacity to
quadrant abdominal pain, hepatomegaly, or an abnormal-appearing enable long-term maintenance. Any activity is better than remaining
liver at time of abdominal surgery. Obesity is present in 50–90% of sub- sedentary. Unfortunately, most NAFLD patients cannot sustain long-
jects. Most patients with NAFLD also have other features of the meta- term compliance with diet and lifestyle modifications and, thus, fail
bolic syndrome (Chap. 408). Some have subtle stigmata of chronic liver to maintain a healthier weight. Although pharmacologic therapies to
disease, such as spider angiomata, palmer erythema, or splenomegaly. facilitate weight loss, such as orlistat, topiramate, phentermine, and
In a small minority of patients with advanced NAFLD, complications GLP-1 receptor agonists, are available, their role in the treatment of
of end-stage liver disease (e.g., jaundice, features of portal hypertension NAFLD remains experimental.
such as ascites or variceal hemorrhage) may be the initial findings.
The association of NAFLD with obesity, diabetes, hypertriglyceri- Pharmacologic Therapies Several drug therapies have been
demia, hypertension, and cardiovascular disease is well known. Other tried in both research and clinical settings. There are currently no
associations include chronic fatigue, mood alterations, obstructive FDA-approved drugs for the treatment of NAFLD. Hence, at present,

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 NAFLD patients without NASH or fibrosis should receive only coun- risk-to-benefit ratio and long-term therapeutic efficacy of vitamin 2623
seling for healthy diet and physical activity. Consideration of additional E in NASH. Ursodeoxycholic acid (a bile acid that improves certain
specific pharmacotherapy for liver disease is restricted to NAFLD cholestatic liver diseases) and betaine (a metabolite of choline that
patients with more serious liver damage (i.e., NASH or liver fibrosis). raises S-adenosylmethionine [SAM] levels and decreases cellular
A number of large clinical trials designed to identify effective and safe oxidative damage) offer no histologic benefit over placebo in patients
treatments for these conditions are in progress. Because NAFLD is with NASH. Experimental evidence to support the use of omega-3 fatty
strongly associated with the metabolic syndrome and type 2 diabetes acids in NAFLD exists; however, a recent large, multicenter, placebo-
(Chaps. 403 and 404), the efficacy of various insulin-sensitizing agents controlled study failed to demonstrate a histologic benefit.
has been examined. Metformin, an agent that mainly improves hepatic Many other pharmacotherapies that target dysregulated energy
insulin sensitivity, has been evaluated in several small, open-label homeostasis, lipotoxicity, cell death, and liver inflammation, processes
studies in adults and a recent larger, prospectively randomized trial that are critically involved in the pathogenesis and/or progression of
in children (dubbed the TONIC study). Although several of the adult NASH and liver fibrosis, are currently in clinical trials (e.g., probiotics,
NASH studies suggested improvements in aminotransferases and, less farnesoid X receptor agonists, fibroblast growth factor agonists, anti-
consistently, liver histology, metformin did not improve liver histology apoptotic agents, anticytokine agents, dipeptidyl IV antagonists, PPAR
in the TONIC study of children with NASH. Thus, it is not currently modulators, thyroid hormone receptor β-selective agonists, stearyl-CoA
recommended as a treatment for NASH. Thiazolidinediones (pioglita- desaturase-1 inhibitors, DGAT inhibitors, acyl-CoA carboxylase inhib-
zone and rosiglitazone), drugs known to improve systemic insulin resis- itors, and direct modulators of liver fibrosis). Sufficient data do not yet
tance, have been studied in adults with NASH. Both agents reduced exist to justify their use as NASH treatments in clinical practice. Given
aminotransferases and improved some of the histologic features of that liver disease outcomes in NASH patients are highly heterogeneous,
NASH in small, uncontrolled studies. A large, randomized, placebo- optimal treatment of NASH may need to be individualized by tailoring
controlled clinical trial sponsored by the National Institutes of Health, therapy based on clinical or histologic phenotypes of NASH and/or
the PIVENS Study (Pioglitazone vs Vitamin E vs Placebo for the genetic susceptibility for disease progression.
Treatment of 247 Nondiabetic Adults with NASH), demonstrated Statins are an important class of agents to treat dyslipidemia and
that resolution of histologic NASH occurred more often in subjects decrease cardiovascular risk. There is no evidence to suggest that
treated with pioglitazone (30 mg/d) than with placebo for 18 months statins cause liver failure in patients with any chronic liver disease,
(47 vs 21%, p = .001). However, many subjects in the pioglitazone group including NAFLD. The incidence of liver enzyme elevations in NAFLD
gained weight, and liver fibrosis did not improve. Five-year follow-up of patients taking statins is also no different than that of healthy controls
subjects who were treated with rosiglitazone for up to 2 years demon- or patients with other chronic liver diseases. Moreover, several studies

CHAPTER 343 Nonalcoholic Fatty Liver Diseases and Nonalcoholic Steatohepatitis

strated that extending treatment and follow-up duration did not further have suggested that statins may improve aminotransferases and his-
improve NASH or liver fibrosis, and rosiglitazone has been associated tology in patients with NASH. Yet there is continued reluctance to
with increased long-term risk for cardiovascular mortality. Pioglitazone use statins in patients with NAFLD. The lack of evidence that statins
may be safer than rosiglitazone, however, because in a recent large harm the liver in NAFLD patients, combined with the increase risk for
meta-analysis it was associated with reduced overall morality, myocar- cardiovascular morbidity and mortality in NAFLD patients, justifies
dial infarction, and stroke. Caution is still warranted, however, because the use of statins to treat dyslipidemia in patients with NAFLD/NASH.
long-term use of thiazolidinediones has been associated with weight
gain, increased risk for bladder cancer, and bone fractures in women.
Bariatric Surgery Although interest in bariatric surgery as a
treatment for NAFLD exists, a recently published Cochrane review
Incretin mimetics, drugs that act on the pancreas to optimize insulin
concluded that lack of randomized clinical trials or adequate clinical
and glucagon release, have improved liver enzyme elevations. A small
studies prevents definitive assessment of benefits and harms of bariat-
pilot trial of daily injections of liraglutide and phase 2 studies of semag-
ric surgery as a treatment for NASH. Most studies of bariatric surgery
lutide demonstrated remission of NASH without worsening liver fibro-
have shown that bariatric surgery is generally safe in individuals with
sis. Agents that improve hyperglycemia by blocking renal reabsorption
well-compensated chronic liver disease and improves hepatic steatosis
of glucose, sodium glucose cotransporter (SGLT2) inhibitors, have been
and necroinflammation (i.e., features of NAFLD/NASH); however,
observed to improve serum liver enzymes in diabetic patients with
effects on hepatic fibrosis have been variable. Concern lingers because
and are also under formal evaluation as treatments for NASH. Both
some of the largest prospective studies suggest that hepatic fibrosis
incretin mimetics and SGLT2 inhibitors can be used in NASH patients
might progress after bariatric surgery. Thus, the Cochrane review
with type 2 diabetes or obesity (conditions for which the drugs have
deemed it premature to recommend bariatric surgery as a primary
an FDA-registered indication for use); however, they are not currently
treatment for NASH. This opinion was challenged by a recently study
approved specifically for the treatment of NASH.
that demonstrated that fibrosis stage had improved by 5 years after
Antioxidants have also been evaluated for the treatment of NAFLD
surgery in about half the patients in one large bariatric surgery cohort.
because oxidant stress is thought to contribute to the pathogenesis of
However, most of those individuals had relatively mild fibrosis initially,
NASH. Vitamin E, an inexpensive yet potent antioxidant, has been
and thus, it is unclear if similar outcomes would occur in individuals
examined in several small pediatric and adult studies with varying
with more advanced liver disease. Indeed, there is general agree-
results. In all of those studies, vitamin E was well tolerated, and most
ment that patients with NAFLD-related cirrhosis and, particularly,
studies showed modest improvements in aminotransferase levels,
those with portal hypertension should be excluded as candidates for
radiographic features of hepatic steatosis, and/or histologic features of
bariatric surgery. However, given growing evidence for the benefits of
NASH. Vitamin E (800 IU/d) was compared to placebo in the PIVENS
bariatric surgery on metabolic syndrome complications in individuals
and TONIC studies. In PIVENS, vitamin E was the only agent that
with refractory obesity, it is not contraindicated in otherwise eligible
achieved the predetermined primary endpoint (i.e., improvement
patients with NAFLD or NASH.
in steatohepatitis without worsening of fibrosis). This endpoint was
met in 43% of patients in the vitamin E group (p = .001 vs placebo), Liver Transplantation Patients with NAFLD in whom end-stage
34% in the pioglitazone group (p = .04 vs placebo), and 19% in the liver disease develops should be evaluated for liver transplantation
placebo group. Vitamin E also improved NASH histology in pediatric (Chap. 345). The outcomes of liver transplantation in well-selected
patients with NASH (TONIC trial). However, recent population-based patients with NAFLD are generally good, but comorbid medical con-
studies suggest that chronic vitamin E therapy may increase the risk ditions associated with NAFLD, such as diabetes mellitus, obesity, and
for cardiovascular mortality, hemorrhagic stroke, and prostate cancer. cardiovascular disease, often limit transplant candidacy. NAFLD may
Thus, vitamin E should only be considered as a first-line pharmaco- recur after liver transplantation. The risk factors for recurrent or de
therapy for nondiabetic, noncirrhotic NASH patients who are at low novo NAFLD after liver transplantation are multifactorial and include
risk for cardiovascular disease or prostate cancer. Further studies are hypertriglyceridemia, obesity, diabetes mellitus, and immunosuppres-
needed before firm recommendations can be made regarding the sive therapies, particularly glucocorticoids.

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 2624 ■■GLOBAL HEALTH CONSIDERATIONS TABLE 344-1 Causes of Cirrhosis
Obesity is an accelerating global disease. The worldwide prevalence Alcohol Cardiac cirrhosis
of obesity has more than doubled since 1980, and there are now >1
Chronic viral hepatitis Inherited metabolic liver disease
billion overweight adults, of whom at least 300 million are obese. In
the wake of the obesity epidemic follow numerous comorbidities, Hepatitis B Hemochromatosis
including NAFLD. NAFLD is the most common liver disease identified Hepatitis C Wilson’s disease
in Western countries and the fastest rising form of chronic liver disease Autoimmune hepatitis α1 Antitrypsin deficiency
worldwide. The economic burden directly attributable to NAFLD is Nonalcoholic steatohepatitis Cystic fibrosis
already enormous (estimated direct medical costs of ~$103 billion/year Biliary cirrhosis Cryptogenic cirrhosis
in the United States and €35 billion/year in the Europe-4 countries: Primary biliary cholangitis
Germany, France, Italy, and United Kingdom) and predicted to increase
tenfold by the year 2025. Present understanding of NAFLD’s natural Primary sclerosing cholangitis
history is based mainly on studies in whites who became overweight/ Autoimmune cholangiopathy
obese and developed the metabolic syndrome in adulthood. The
impact of the global childhood obesity epidemic on NAFLD pathogen-
distortion with the formation of regenerative nodules. This results in a
esis/progression is unknown. Emerging evidence demonstrates that
decrease in hepatocellular mass, and thus function, and an alteration of
advanced NAFLD, including cirrhosis and primary liver cancer, can
blood flow. The induction of fibrosis occurs with activation of hepatic
occur in children, prompting concerns that childhood-onset NAFLD
stellate cells, resulting in the formation of increased amounts of col-
might follow a more aggressive course than typical adult-acquired
lagen and other components of the extracellular matrix.
NAFLD. Some of the most populated parts of the world are in the
Clinical features of cirrhosis are the result of pathologic changes
midst of industrial revolutions, and certain environmental pollutants
and mirror the severity of the liver disease. Most hepatic pathologists
seem to exacerbate NAFLD. Some studies also suggest that the risk for
provide an assessment of grading and staging when evaluating liver
NASH and NAFLD-related cirrhosis may be higher in certain ethnic
biopsy samples. These grading and staging schemes vary between
groups such as Asians, Hispanics, and Native Americans, and lower in
disease states and have been developed for most conditions, including
others such as African Americans, compared with whites. Although
chronic viral hepatitis, nonalcoholic fatty liver disease, and primary
all of these variables confound efforts to predict the net impact of
biliary cholangitis. Advanced fibrosis usually includes bridging fibrosis
this obesity-related liver disease on global health, it seems likely that
with nodularity designated as stage 3 and cirrhosis designated as stage 4.
NAFLD will remain a major cause of chronic liver disease worldwide
Patients who have cirrhosis have varying degrees of liver function, and
for the foreseeable future.
clinicians need to differentiate between those who have stable, compen-
PART 10

■■FURTHER READING sated cirrhosis and those who have decompensated cirrhosis. Patients
Chalasani N et al: The diagnosis and management of nonalcoholic who have developed ascites, hepatic encephalopathy, or variceal bleed-
fatty liver disease: Practice guidance from the American Association ing are classified as decompensated. They should be considered for
for the Study of Liver Diseases. Hepatology 67:328, 2018. liver transplantation, particularly if the decompensations are poorly
controlled. Many of the complications of cirrhosis will require specific
Disorders of the Gastrointestinal System

Diehl AM, Day CSC: Cause, pathogenesis, and treatment of nonalco-

holic steatohepatitis. N Engl J Med 377:2063, 2017. therapy. Portal hypertension is a significant complicating feature of
European Association for the Study of the Liver (EASL) et al: decompensated cirrhosis and is responsible for the development of
EASL-EASD-EASO Clinical Practice Guidelines for the management ascites and bleeding from esophagogastric varices, two complications
of non-alcoholic fatty liver disease. J Hepatol 64:1388, 2016. that signify decompensated cirrhosis. Loss of hepatocellular function
Vos MB et al: NASPGHAN clinical practice guideline for the diagnosis results in jaundice, coagulation disorders, and hypoalbuminemia and
and treatment of nonalcoholic fatty liver disease in children: Recom- contributes to the causes of portosystemic encephalopathy. The com-
mendations from the Expert Committee on NAFLD (ECON) and the plications of cirrhosis are basically the same regardless of the etiology.
North American Society of Pediatric Gastroenterology, Hepatology Nonetheless, it is useful to classify patients by the cause of their liver
and Nutrition (NASPGHAN). J Pediatr Gastroenterol Nutr 64:319, disease (Table 344-1); patients can be divided into broad groups,
2017. including those with alcohol-associated cirrhosis, cirrhosis due to
chronic viral hepatitis, biliary cirrhosis, nonalcoholic fatty liver disease,
and other, less common causes, such as cardiac cirrhosis, cryptogenic
cirrhosis, and other miscellaneous causes.
ALCOHOL-ASSOCIATED CIRRHOSIS

344 Complications
Cirrhosis and Its Excessive chronic alcohol use can cause several different types of
chronic liver disease, including alcohol-associated fatty liver, alco-
holic hepatitis, and alcohol-associated cirrhosis. Furthermore, use of
excessive alcohol can contribute to liver damage in patients with other
Alex S. Befeler, Bruce R. Bacon liver diseases, such as hepatitis C, hemochromatosis, and fatty liver
disease related to obesity. Chronic alcohol use can produce fibrosis in
the absence of accompanying inflammation and/or necrosis. Fibrosis
can be centrilobular, pericellular, or periportal. When fibrosis reaches
Cirrhosis is a condition that is defined histopathologically and has a
a certain degree, there is disruption of the normal liver architecture
variety of clinical manifestations and complications, some of which
and replacement of liver cells by regenerative nodules. In alcohol-
can be life-threatening. In the past, it has been thought that cirrhosis
associated cirrhosis, the nodules are usually <3 mm in diameter; this
was never reversible; however, it has become apparent that when the
form of cirrhosis is referred to as micronodular. With cessation of alco-
underlying insult that has caused the cirrhosis has been removed, there
hol use, larger nodules may form, resulting in a mixed micronodular
can be reversal of fibrosis. This is most apparent with the successful
and macronodular cirrhosis.
treatment of chronic hepatitis C; however, reversal of fibrosis is also
seen in patients with hemochromatosis who have been successfully Pathogenesis Alcohol is the most commonly used drug in the
treated and in patients with alcohol associate liver disease who have United States, and >70% of adults drink alcohol each year. Twenty
discontinued alcohol use. percent have had a binge within the past month, and >7% of adults
Regardless of the cause of cirrhosis, the pathologic features consist regularly consume more than four or five drinks five or more times
of the development of fibrosis to the point that there is architectural a month. Unfortunately, >14 million adults in the United States meet

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 the diagnostic criteria for alcohol use disorder. In the United States, 2625
chronic liver disease is the tenth most common cause of death in
adults, and alcohol-associated cirrhosis accounts for ~48% of deaths
due to cirrhosis.
Ethanol is mainly absorbed by the small intestine and, to a lesser
degree, through the stomach. Gastric alcohol dehydrogenase (ADH)
initiates alcohol metabolism. Three enzyme systems account for
metabolism of alcohol in the liver. These include cytosolic ADH, the
microsomal ethanol oxidizing system (MEOS) utilizing the inducible
cytochrome P450 CYP2E1, and peroxisomal catalase. Normally the
majority of ethanol oxidation occurs via ADH to form acetaldehyde,
which is a highly reactive molecule that may have multiple effects. The
MEOS pathway in chronic alcohol use causes induction of CYP2E1,
which leads to generation of reactive oxygen species and produces
more acetaldehyde. Ultimately, acetaldehyde is metabolized to acetate
by aldehyde dehydrogenase (ALDH). Intake of ethanol increases intra-
cellular accumulation of triglycerides by increasing fatty acid uptake
and by reducing fatty acid oxidation and lipoprotein secretion. Protein FIGURE 344-2 Spider angioma. This figure shows a spider angioma in a patient with
hepatitis C cirrhosis. With release of central compression, the arteriole fills from the
synthesis, glycosylation, and secretion are impaired. Oxidative damage center and spreads out peripherally.
to hepatocyte membranes occurs due to the formation of reactive oxy-
gen species; acetaldehyde is a highly reactive molecule that combines parotid gland enlargement, digital clubbing, muscle wasting, edema, and
with proteins and nucleic acids to form acetaldehyde adducts. These ascites. Men may have decreased body hair and gynecomastia as well
adducts may interfere with specific enzyme activities, including micro- as testicular atrophy, which may be a consequence of hormonal abnor-
tubular formation and hepatic protein trafficking. With acetaldehyde- malities or a direct toxic effect of alcohol on the testes. In women with
mediated hepatocyte damage, certain reactive oxygen species can result advanced alcohol-associated cirrhosis, menstrual irregularities usually
in Kupffer cell activation. As a result, profibrogenic cytokines are pro- occur including amenorrhea. These changes are often reversible following
duced that initiate and perpetuate stellate cell activation, with the resul- cessation of alcohol ingestion.
tant production of excess collagen and extracellular matrix. Connective Laboratory tests may be completely normal in patients with early

CHAPTER 344 Cirrhosis and Its Complications

tissue appears in both periportal and pericentral zones and eventually compensated alcohol-associated cirrhosis. Alternatively, in advanced
connects portal triads with central veins forming regenerative nodules. liver disease, many abnormalities usually are present. Patients may be
Hepatocyte loss occurs, and with increased collagen production and anemic from chronic GI blood loss, nutritional deficiencies, or hyper-
deposition, together with continuing hepatocyte destruction, the liver splenism or as a direct suppressive effect of alcohol on the bone marrow.
contracts and shrinks in size. This process generally takes from years A unique form of hemolytic anemia (with spur cells and acanthocytes)
to decades to occur and requires repeated insults. called Zieve’s syndrome can occur in patients with severe alcoholic hep-
atitis. Platelet counts are often reduced early in the disease, reflective of
Clinical Features The diagnosis of alcohol associate liver disease portal hypertension with hypersplenism. Serum total bilirubin can be
requires an accurate history regarding both amount and duration of normal or elevated with advanced disease. Prothrombin times are often
alcohol consumption. Patients with alcohol associate liver disease can prolonged and usually do not respond to administration of parenteral
present with nonspecific symptoms such as vague right upper quadrant vitamin K. Serum sodium levels are usually normal unless patients have
abdominal pain, fever, nausea and vomiting, diarrhea, anorexia, and ascites and then can be depressed, largely due to ingestion of excess free
malaise. Alternatively, they may present with more specific complications water. Serum alanine and aspartate aminotransferases (ALT, AST) are
of chronic liver disease, including ascites, edema, upper gastrointestinal typically elevated, particularly in patients who continue to drink, with
(GI) hemorrhage, jaundice, or encephalopathy. Many cases present inci- AST levels being higher than ALT levels, usually by a 2:1 ratio.
dentally at the time of autopsy or elective surgery. The abrupt onset of
any of these complications may be the first event prompting the patient to Diagnosis Patients who have any of the above-mentioned clinical
seek medical attention. Other patients may be identified in the course of features, physical examination findings, or laboratory studies should be
an evaluation of routine laboratory studies that are found to be abnormal. considered to have alcohol associate liver disease. The diagnosis, how-
On physical examination, the liver and spleen may be enlarged, with the ever, requires accurate knowledge that the patient is continuing to use
liver edge being firm and nodular. Other frequent findings include scleral or has recently stopped alcohol. Furthermore, other forms of chronic
icterus, palmar erythema (Fig. 344-1), spider angiomas (Fig. 344-2), liver disease (e.g., chronic viral hepatitis or metabolic or autoimmune
liver diseases) must be considered or ruled out, or if present, an esti-
mate of relative causality along with the alcohol use should be deter-
mined. Liver biopsy can be helpful to confirm a diagnosis but generally
is not performed unless there is a suspicion of an alternative diagnosis.
In patients who have had complications of cirrhosis and who
continue to drink, there is a <50% 5-year survival. In contrast, in
patients who are able to remain abstinent, the prognosis is significantly
improved, particularly when they have resolution of liver complica-
tions; however, some individuals who remain abstinent do not improve
and liver transplantation is a viable option.

TREATMENT
Alcohol-Associated Cirrhosis and Alcoholic Hepatitis
Abstinence is the cornerstone of therapy for patients with alcohol
associate liver disease. In addition, patients require good nutrition
FIGURE 344-1 Palmar erythema. This figure shows palmar erythema in a patient with and long-term medical supervision to manage underlying complica-
alcohol-associated cirrhosis. The erythema is peripheral over the palm with central pallor. tions that may develop. Complications such as the development of

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 2626 ascites and edema, variceal hemorrhage, or portosystemic encepha- Southeast Asia, sub-Saharan Africa), up to 15% of the population
lopathy all require specific management and treatment. Liver trans- may be infected, having acquired the infection vertically at the time of
plantation can be an effective long-term treatment in those who birth. Thus, >300–400 million individuals are thought to have hepatitis
have been deemed a low enough risk for alcohol relapse and do not B worldwide. Approximately 25% of these individuals may ultimately
respond to other treatments. develop cirrhosis.
Glucocorticoids are occasionally used in patients with severe
alcoholic hepatitis in the absence of infection. Short-term survival Clinical Features and Diagnosis Patients with cirrhosis due to
has been shown to be improved in certain studies and meta-analysis, either chronic hepatitis C or B can present with the usual symptoms
although 6-month survival is more dependent on abstinence. Treat- and signs of chronic liver disease. Fatigue, malaise, vague right upper
ment is restricted to patients with a discriminant function (DF) quadrant pain, and laboratory abnormalities are frequent presenting
value of >32. The DF is calculated as the serum total bilirubin plus features. Diagnosis requires a thorough laboratory evaluation, includ-
the difference in the patient’s prothrombin time compared to upper ing quantitative HCV RNA testing and analysis for HCV genotype, or
limit of control (in seconds) multiplied by 4.6. Failure to improve hepatitis B serologies to include HBsAg, anti-HBs, HBeAg (hepatitis B
total bilirubin after 7 days predicts treatment failure, and glucocor- e antigen), anti-HBe, and quantitative HBV DNA levels.
ticoids can be stopped; otherwise, they are continued for 28 days.
There is modest evidence that intravenous N-acetylcysteine plus TREATMENT
glucocorticoids may have survival benefit in alcoholic hepatitis if Cirrhosis due to Chronic Viral Hepatitis B or C
the DF is >32. Other therapies including oral pentoxifylline, par-
enterally administered inhibitors of tumor necrosis factor (TNF) α Management of complications of cirrhosis revolves around specific
such as infliximab or etanercept, anabolic steroids, propylthiouracil, therapy for treatment of whatever complications occur (e.g., esoph-
antioxidants, colchicine, and penicillamine have not shown clear- ageal variceal hemorrhage, development of ascites and edema, or
cut benefits and are not recommended. A variety of nutritional encephalopathy). In patients with chronic hepatitis B, numerous
therapies have been tried, both parenteral and enteral feedings; studies have shown beneficial effects of antiviral therapy, which is
however, there is no clear evidence of improved survival. There effective at viral suppression, as evidenced by reducing aminotrans-
is evidence that persons who consume >21.5 kcal/kg body weight ferase levels and HBV DNA levels and improving histology by
per day have better survival, so achieving better caloric intake is reducing inflammation and fibrosis. Several clinical trials and case
recommended. Finally, in highly selected patients with good social series have demonstrated that patients with decompensated liver
support structure who fail other treatments for alcoholic hepatitis, disease can become compensated with the use of antiviral therapy
early liver transplant can be an effective treatment. directed against hepatitis B. Currently available therapy includes
PART 10

The cornerstone to treatment is cessation of alcohol use. Recent lamivudine, adefovir, telbivudine, entecavir, and tenofovir, with the
experience with medications that reduce craving for alcohol, such latter two being preferred because of reduced risk of viral resistance.
as acamprosate calcium and baclofen, have been favorable. Patients Interferon α can also be used for treating hepatitis B, but it should
may take other necessary medications even in the presence of cir- not be used in cirrhotics (see Chap. 341).
rhosis. Acetaminophen use is often discouraged in patients with Treatment of patients with cirrhosis due to hepatitis C used to be
Disorders of the Gastrointestinal System

liver disease; however, if no more than 2 g of acetaminophen per more difficult because the side effects of pegylated interferon and
day are consumed, there generally are no problems unless there is ribavirin therapy were difficult to manage. Over the past several
active alcohol use. years, interferon-based regimens have been replaced by direct-
acting antiviral protocols that are highly successful (>95% cure
rate), well tolerated, and usually of short duration (8–12 weeks), but
■■CIRRHOSIS DUE TO CHRONIC VIRAL costly. These medications have truly revolutionized the treatment of
HEPATITIS B OR C hepatitis C (see Chap. 341).
Of patients exposed to the hepatitis C virus (HCV), ~80% develop
chronic hepatitis C, and of those, ~20–30% will develop cirrhosis over
20–30 years. Many of these patients have had concomitant alcohol CIRRHOSIS FROM AUTOIMMUNE
use, and the true incidence of cirrhosis due to hepatitis C alone is HEPATITIS AND NONALCOHOLIC FATTY
unknown. It is expected that an even higher percentage will go on to LIVER DISEASE
develop cirrhosis over longer periods of time. In the United States, Other causes of posthepatitic cirrhosis include autoimmune hepatitis
~5–6 million people have been exposed to HCV, and ~4–5 million are (AIH) and cirrhosis due to nonalcoholic steatohepatitis. Many patients
chronically viremic. Worldwide, ~170 million individuals have hep- with AIH present with cirrhosis that is already established. Typically,
atitis C, with some areas of the world (e.g., Egypt) having up to 15% these patients will not benefit from immunosuppressive therapy with
of the population infected. HCV is a noncytopathic virus, and liver glucocorticoids or azathioprine because the AIH is “burned out.” In
damage is probably immune-mediated. Progression of liver disease this situation, liver biopsy does not show a significant inflammatory
due to chronic hepatitis C is characterized by portal-based fibrosis with infiltrate. Diagnosis in this setting requires positive autoimmune
bridging fibrosis and nodularity developing, ultimately culminating in markers such as antinuclear antibody (ANA) or anti-smooth-muscle
the development of cirrhosis. In cirrhosis due to chronic hepatitis C, antibody (ASMA). When patients with AIH present with cirrhosis and
the liver is small and shrunken with characteristic features of a mixed active inflammation accompanied by elevated liver enzymes, there can
micro- and macronodular cirrhosis seen on liver biopsy. In addition be considerable benefit from the use of immunosuppressive therapy.
to the increased fibrosis that is seen in cirrhosis due to hepatitis C, an Patients with nonalcoholic steatohepatitis are increasingly being
inflammatory infiltrate is found in portal areas with interface hepatitis found to have progressed to cirrhosis. With the epidemic of obesity
and occasionally some lobular hepatocellular injury and inflammation. that continues in Western countries, more and more patients are
In patients with HCV genotype 3, steatosis is often present. identified with nonalcoholic fatty liver disease (Chap. 343). Of these,
Similar findings are seen in patients with cirrhosis due to chronic a significant subset has nonalcoholic steatohepatitis and can progress
hepatitis B. Of adult patients exposed to hepatitis B, ~5% develop to increased fibrosis and cirrhosis. Over the past several years, it has
chronic hepatitis B, and ~20% of those patients will go on to develop been increasingly recognized that many patients who were thought to
cirrhosis. Special stains for hepatitis B core (HBc) and hepatitis B have cryptogenic cirrhosis in fact have nonalcoholic steatohepatitis.
surface (HBs) antigen will be positive, and ground-glass hepatocytes As their cirrhosis progresses, they become catabolic and then lose the
signifying HBs antigen (HBsAg) may be present. In the United States, telltale signs of steatosis seen on biopsy. Management of complications
there are ~2 million carriers of hepatitis B, whereas in other parts of cirrhosis due to either AIH or nonalcoholic steatohepatitis is similar
of the world where hepatitis B virus (HBV) is endemic (i.e., Asia, to that for other forms of cirrhosis.

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 ■■BILIARY CIRRHOSIS cholesterol metabolism. Hyperpigmentation is evident on the trunk 2627
Biliary cirrhosis has pathologic features that are different from either and the arms and is seen in areas of exfoliation and lichenification
alcohol-associated cirrhosis or posthepatitic cirrhosis, yet the manifes- associated with progressive scratching related to the pruritus. Bone
tations of end-stage liver disease are the same. Cholestatic liver disease pain resulting from osteopenia or osteoporosis is occasionally seen at
may result from necroinflammatory lesions, congenital or metabolic diagnosis.
processes, or external bile duct compression. Thus, two broad categories
reflect the anatomic sites of abnormal bile retention: intrahepatic and Laboratory Findings Laboratory findings in PBC show choles-
extrahepatic. The distinction is important for obvious therapeutic reasons. tatic liver enzyme abnormalities with an elevation in γ-glutamyl trans-
Extrahepatic obstruction may benefit from surgical or endoscopic biliary peptidase and alkaline phosphatase (ALP) along with mild elevations
tract decompression, whereas intrahepatic cholestatic processes will not in aminotransferases (ALT and AST). Immunoglobulins, particularly
improve with such interventions and require a different approach. IgM, are typically increased. Hyperbilirubinemia usually is seen once
The major causes of chronic cholestatic syndromes are primary cirrhosis has developed. Thrombocytopenia, leukopenia, and anemia
biliary cholangitis (PBC), autoimmune cholangitis (AIC), primary may be seen in patients with portal hypertension and hypersplenism.
sclerosing cholangitis (PSC), and idiopathic adulthood ductopenia. Liver biopsy shows characteristic features as described above and should
These syndromes are usually clinically distinguished from each other be evident to any experienced hepatopathologist. Up to 10% of patients
by antibody testing, cholangiographic findings, and clinical presenta- with characteristic PBC will have features of AIH (moderate to severe
tion. However, they all share the histopathologic features of chronic interphase hepatitis on biopsy, elevated ALT >5× the upper limit of nor-
cholestasis, such as cholate stasis; copper deposition; xanthomatous mal, and elevated IgG levels) as well and are defined as having “overlap”
transformation of hepatocytes; and irregular, so-called biliary fibrosis. syndrome. These patients are usually treated as PBC patients and may
In addition, there may be chronic portal inflammation, interface activ- progress to cirrhosis with the same frequency as typical PBC patients.
ity, and chronic lobular inflammation. Ductopenia is a result of this Some patients require immunosuppressive medications as well.
progressive disease as patients develop cirrhosis. Diagnosis PBC should be considered in patients with chronic
cholestatic liver enzyme abnormalities. AMA testing may be negative
■■PRIMARY BILIARY CHOLANGITIS in as many as 5–10% of patients with PBC. These patients usually are
PBC is seen in about 100–200 individuals per million, with a strong positive for other PBC-specific autoantibodies including sp100 or
female preponderance and a median age of ~50 years at the time of gp210, although these tests are not universally available. Liver biopsy is
diagnosis. The cause of PBC is unknown; it is characterized by portal most important in this setting of AMA-negative PBC. In patients who
inflammation and necrosis of cholangiocytes in small- and medium- are AMA negative with cholestatic liver enzymes, PSC should be ruled

CHAPTER 344 Cirrhosis and Its Complications

sized bile ducts. Cholestatic features prevail, and biliary cirrhosis is out by way of cholangiography.
characterized by an elevated bilirubin level and progressive liver fail-
ure. Liver transplantation is the treatment of choice for patients with
decompensated cirrhosis due to PBC. Ursodeoxycholic acid (UDCA) is TREATMENT
the first-line treatment that has some degree of efficacy by slowing the Primary Biliary Cholangitis
rate of progression of the disease.
Antimitochondrial antibodies (AMAs) are present in ~95% of Treatment of the typical manifestations of cirrhosis is no differ-
patients with PBC. These autoantibodies recognize lipoic acid on the ent for PBC than for other forms of cirrhosis. UDCA has been
inner mitochondrial membrane proteins that are enzymes of the pyru- shown to improve both biochemical and histologic features of
vate dehydrogenase complex (PDC), the branched-chain 2-oxoacid the disease, thus slowing but not reversing or curing the disease.
dehydrogenase complex, and the 2-oxogluterate dehydrogenase com- Improvement is greatest when therapy is initiated early; the like-
plex. These autoantibodies are not pathogenic, but rather are useful lihood of significant improvement with UDCA is low in patients
markers for making a diagnosis. with PBC who present with manifestations of cirrhosis. UDCA
is given in doses of 13–15 mg/kg per d; the medication is usually
Pathology Histopathologic analyses of liver biopsies of patients well tolerated, although some patients have worsening pruritus
with PBC have resulted in identifying four distinct stages of the disease with initiation of therapy. A small proportion of patients may have
as it progresses. The earliest lesion is termed chronic nonsuppurative diarrhea or headache as a side effect of the drug. About 30–40% of
destructive cholangitis and is a necrotizing inflammatory process of the patients with PBC do not have a satisfactory response to UDCA;
portal tracts. Medium and small bile ducts are infiltrated with lympho- about half of these patients will have significant improvement with
cytes and undergo duct destruction. Mild fibrosis and sometimes bile obeticholic acid. Patients with PBC require long-term follow-up by
stasis can occur. With progression, the inflammatory infiltrate becomes a physician experienced with the disease. Certain patients may need
less prominent, but the number of bile ducts is reduced and there is to be considered for liver transplantation should their liver disease
proliferation of smaller bile ductules. Increased fibrosis ensues with the decompensate.
expansion of periportal fibrosis to bridging fibrosis. Finally, cirrhosis, The main symptoms of PBC are fatigue and pruritus, and
which may be micronodular or macronodular, develops. symptom management is important. Several therapies have been
Clinical Features Currently, most patients with PBC are middle- tried for treatment of fatigue, but none of them has been suc-
aged women diagnosed well before the end-stage manifestations of cessful; frequent naps should be encouraged. Pruritus is treated
the disease are present, and as such, most patients are asymptomatic. with antihistamines, narcotic receptor antagonists (naltrexone),
When symptoms are present, they most prominently include a sig- and rifampin. Cholestyramine, a bile salt–sequestering agent, has
nificant degree of fatigue out of proportion to either the severity of been helpful in some patients but is somewhat tedious and difficult
the liver disease or the age of the patient. Pruritus is seen in ~50% of to take. Plasmapheresis has been used rarely in patients with severe
patients at the time of diagnosis, and it can be debilitating. It might be intractable pruritus. There is an increased incidence of osteopenia
intermittent and usually is most bothersome in the evening. In some and osteoporosis in patients with cholestatic liver disease, and bone
patients, pruritus can develop toward the end of pregnancy and can density testing should be performed. Oral calcium and vitamin D
be mistaken for cholestasis of pregnancy. Pruritus that presents prior are also recommended. Treatment with a bisphosphonate should be
to the development of jaundice indicates severe disease and a poor instituted when bone disease is identified.
prognosis.
Physical examination can show jaundice and other complications ■■PRIMARY SCLEROSING CHOLANGITIS
of chronic liver disease including hepatomegaly, splenomegaly, ascites, As in PBC, the cause of PSC remains unknown. PSC is a chronic
and edema. Other features that are unique to PBC include hyperpig- cholestatic syndrome that is characterized by diffuse inflammation and
mentation, xanthelasma, and xanthomata, which are related to altered fibrosis involving the entire biliary tree, resulting in chronic cholestasis.

HPIM21e_Part10_p2381-p2670.indd 2627 20/01/22 10:05 PM

 2628 This pathologic process ultimately results in obliteration of both the ■■CARDIAC CIRRHOSIS
intra- and extrahepatic biliary tree, leading to biliary cirrhosis, portal
hypertension, and liver failure. The cause of PSC remains unknown Definition Patients with long-standing right-sided congestive heart
despite extensive investigation into various mechanisms related to bac- failure may develop chronic liver injury and cardiac cirrhosis. This is
terial and viral infections, toxins, genetic predisposition, and immuno- an increasingly uncommon, if not rare, cause of chronic liver disease
logic mechanisms, all of which have been postulated to contribute to given the advances made in the care of patients with heart failure.
the pathogenesis and progression of this syndrome. Etiology and Pathology In the case of long-term right-sided
Liver biopsy changes in PSC are not pathognomonic, and estab- heart failure, there is an elevated venous pressure transmitted via the
lishing the diagnosis of PSC must involve imaging of the biliary tree. inferior vena cava and hepatic veins to the sinusoids of the liver, which
Pathologic changes occurring in PSC show bile duct proliferation as become dilated and engorged with blood. The liver becomes enlarged
well as ductopenia and fibrous cholangitis (pericholangitis). Periductal and swollen, and with long-term passive congestion and relative ische-
fibrosis is occasionally seen on biopsy specimens and can be quite help- mia due to poor circulation, centrilobular hepatocytes can become
ful in making the diagnosis. As the disease progresses, biliary cirrhosis necrotic, leading to pericentral fibrosis. This fibrotic pattern can extend
is the end-stage manifestation of PSC. to the periphery of the lobule outward until a unique pattern of fibrosis
Clinical Features The usual clinical features of PSC are those found causing cirrhosis can occur.
in cholestatic liver disease, with fatigue, pruritus, steatorrhea, deficien- Clinical Features Patients typically have signs of congestive heart
cies of fat-soluble vitamins, and the associated consequences. As in PBC, failure and will manifest an enlarged firm liver on physical examina-
the fatigue is profound and nonspecific. Pruritus can often be debilitat- tion. ALP levels are characteristically elevated, and aminotransferases
ing and is related to the cholestasis. The severity of pruritus does not may be normal or slightly increased, with AST usually higher than
correlate with the severity of the disease. Metabolic bone disease, as seen ALT. It is unlikely that patients will develop variceal hemorrhage or
in PBC, can occur with PSC and should be treated (see above). encephalopathy.
Laboratory Findings Patients with PSC typically are identified Diagnosis The diagnosis is usually made in someone with clear-cut
during an evaluation of abnormal liver enzymes. Most patients have cardiac disease who has an elevated ALP and an enlarged liver. Liver
at least a twofold increase in ALP and may have elevated aminotrans- biopsy shows a pattern of fibrosis that can be recognized by an experi-
ferases as well. Albumin levels may be decreased, and prothrombin enced hepatopathologist. Differentiation from Budd-Chiari syndrome
times are prolonged in a substantial proportion of patients at the time (BCS) can be made by seeing extravasation of red blood cells in BCS,
of diagnosis. Some degree of correction of a prolonged prothrombin but not in cardiac hepatopathy. Veno-occlusive disease, now termed
time may occur with parenteral vitamin K. A small subset of patients sinusoidal obstructive syndrome, can also affect hepatic outflow and
PART 10

has aminotransferase elevations >5× the upper limit of normal and has characteristic features on liver biopsy. Sinusoidal obstructive syn-
may have features of AIH on biopsy indicating an overlap syndrome drome can be seen under the circumstances of conditioning for bone
between PSC and AIH. Autoantibodies are frequently positive in marrow transplant with radiation and chemotherapy; it can also be
patients with the overlap syndrome but are typically negative in seen with the ingestion of certain herbal teas as well as pyrrolizidine
patients who only have PSC. One autoantibody, the perinuclear anti- alkaloids. This is typically seen in Caribbean countries and rarely in
Disorders of the Gastrointestinal System

neutrophil cytoplasmic antibody (pANCA), is positive in ~65% of the United States. Treatment is based on management of the underlying
patients with PSC. Sixty to eighty percent of patients with PSC have cardiac disease.
inflammatory bowel disease, predominately ulcerative colitis (UC);
thus, a colonoscopy is recommended at diagnosis.
OTHER TYPES OF CIRRHOSIS
Diagnosis The definitive diagnosis of PSC requires cholangio- There are several other less common causes of chronic liver disease that
graphic imaging. Over the past several years, magnetic resonance can progress to cirrhosis. These include inherited metabolic liver dis-
imaging (MRI) with magnetic resonance cholangiopancreatography eases such as hemochromatosis, Wilson’s disease, α1 antitrypsin (α1AT)
(MRCP) has been used as the imaging technique of choice for initial deficiency, and cystic fibrosis. For these disorders, the manifestations
evaluation. Endoscopic retrograde cholangiopancreatography (ERCP) of cirrhosis are similar, with some minor variations, to those seen in
should be performed if the MRCP provided suboptimal images or if other patients with other causes of cirrhosis.
there is clinical (newly elevated total bilirubin or worsening pruritus) Hemochromatosis is an inherited disorder of iron metabolism that
or MRCP evidence of a dominant stricture. Typical cholangiographic results in a progressive increase in hepatic iron deposition, which, over
findings in PSC are multifocal stricturing and beading involving both time, can lead to a portal-based fibrosis progressing to cirrhosis, liver
the intrahepatic and extrahepatic biliary tree. These strictures are typi- failure, and hepatocellular cancer. While the frequency of hemochro-
cally short and with intervening segments of normal or slightly dilated matosis is relatively common, with genetic susceptibility occurring in
bile ducts that are distributed diffusely, producing the classic beaded 1 in 250 individuals, the frequency of end-stage manifestations due to
appearance. The gallbladder and cystic duct can be involved in up to the disease is relatively low, and <5% of those patients who are geno-
15% of cases. Gradually, biliary cirrhosis develops, and patients will typically susceptible will go on to develop severe liver disease from
progress to decompensated liver disease with all the manifestations of hemochromatosis. Diagnosis is made with serum iron studies showing
ascites, esophageal variceal hemorrhage, and encephalopathy. an elevated transferrin saturation and an elevated ferritin level, along
with abnormalities identified by HFE mutation analysis. Treatment is
TREATMENT straightforward, with regular therapeutic phlebotomy.
Wilson’s disease is an inherited disorder of copper homeostasis with
Primary Sclerosing Cholangitis failure to excrete excess amounts of copper, leading to an accumulation
There is no specific proven treatment for PSC. Some clinicians in the liver. This disorder is relatively uncommon, affecting 1 in 30,000
use UDCA at “PBC dosages” of 13–15 mg/kg per d with anecdotal individuals. Wilson’s disease typically affects adolescents and young
improvement, although no study has shown convincing evidence of adults. Prompt diagnosis before end-stage manifestations become
clinical benefit. A study of high-dose (28–30 mg/kg per d) UDCA irreversible can lead to significant clinical improvement. Diagnosis
found it to be harmful. Endoscopic dilatation of dominant strictures requires determination of ceruloplasmin levels, which are low; 24-h
can be helpful, but the ultimate treatment is liver transplantation urine copper levels, which are elevated; typical physical examination
when decompensated cirrhosis develops. Episodes of cholangitis findings, including Kayser-Fleischer corneal rings; and character-
should be treated with antibiotics. A dreaded complication of PSC istic liver biopsy findings. Treatment consists of copper-chelating
is the development of cholangiocarcinoma, which is a relative con- medications.
traindication to liver transplantation. α1AT deficiency results from an inherited disorder that causes abnor-
mal folding of the α1AT protein, resulting in failure of secretion of that

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 protein from the liver. It is unknown how the retained protein leads to TABLE 344-3 Classification of Portal Hypertension 2629
liver disease. Patients with α1AT deficiency at greatest risk for develop- Prehepatic
ing chronic liver disease have the ZZ phenotype, but only ~10–20% of
Portal vein thrombosis
such individuals will develop chronic liver disease. Diagnosis is made
by determining α1AT levels and phenotype. Characteristic periodic Splenic vein thrombosis
acid–Schiff (PAS)–positive, diastase-resistant globules are seen on liver Massive splenomegaly (Banti’s syndrome)
biopsy. The only effective treatment is liver transplantation, which is Hepatic
curative. Presinusoidal
Cystic fibrosis is an uncommon inherited disorder affecting whites   Schistosomiasis
of northern European descent. A biliary-type cirrhosis can occur, and
   Congenital hepatic fibrosis
some patients derive benefit from the chronic use of UDCA.
Sinusoidal
MAJOR COMPLICATIONS OF CIRRHOSIS   Cirrhosis—many causes
These include gastroesophageal variceal hemorrhage, splenomegaly,   Alcoholic hepatitis
ascites, hepatic encephalopathy, spontaneous bacterial peritonitis Postsinusoidal
(SBP), hepatorenal syndrome (HRS), and hepatocellular carcinoma    Hepatic sinusoidal obstruction (veno-occlusive syndrome)
(Table 344-2). There are also more rare complications in the pulmo-
Posthepatic
nary system including hepatopulmonary syndrome and portopulmo-
nary hypertension. Budd-Chiari syndrome
Inferior vena caval webs
■■PORTAL HYPERTENSION Cardiac causes
Portal hypertension is defined as the elevation of the hepatic venous   Restrictive cardiomyopathy
pressure gradient (HVPG) to >5 mmHg. Portal hypertension is caused
  Constrictive pericarditis
by a combination of two simultaneously occurring hemodynamic
processes: (1) increased intrahepatic resistance to the passage of blood    Severe congestive heart failure
flow through the liver due to cirrhosis, regenerative nodules, and
microthrombi, and (2) increased splanchnic blood flow secondary to
disease, whereas presinusoidal causes include congenital hepatic fibro-
vasodilation within the splanchnic vascular bed. In more advanced
sis and schistosomiasis. Sinusoidal causes are related to cirrhosis from

CHAPTER 344 Cirrhosis and Its Complications

stages, there is also activation of neurohumoral responses and vaso-
various causes.
constrictive systems resulting in sodium and water retention, increased
Cirrhosis is the most common cause of portal hypertension in the
blood volume, and hyperdynamic circulatory system producing more
United States, and clinically significant portal hypertension is present
portal hypertension. There is usually an initial stage of compensated
in >60% of patients with cirrhosis. Portal vein obstruction may be
cirrhosis with HVPG between 5 and 10 mmHg that can be asymptomatic
idiopathic or can occur in association with cirrhosis or with infection,
and last for ≥10 years, but when clinically significant portal hypertension
pancreatitis, or abdominal trauma.
develops (defined as a HVPG ≥10 mmHg), there is substantial risk of
Coagulation disorders that can lead to the development of portal
decompensation with variceal bleeding, ascites, or hepatic encephalopa-
vein thrombosis include polycythemia vera; essential thrombocytosis;
thy. With decompensation, median mortality is <2 years. Variceal hemor-
deficiencies in protein C, protein S, antithrombin III, and factor V
rhage is an immediate life-threatening problem with a 20–30% mortality
Leiden; and abnormalities in the gene-regulating prothrombin produc-
rate associated with each episode of bleeding. The portal venous system
tion. Some patients may have a subclinical myeloproliferative disorder.
normally drains blood from most of the GI tract including the stomach,
small and large intestines, spleen, pancreas, and gallbladder. Clinical Features The three primary complications of portal
The causes of portal hypertension are usually subcategorized as hypertension are gastroesophageal varices with hemorrhage, ascites,
prehepatic, intrahepatic, and posthepatic (Table 344-3). Prehepatic and hypersplenism. Thus, patients may present with upper GI bleed-
causes of portal hypertension are those affecting the portal venous sys- ing, which, on endoscopy, is found to be due to esophageal or gastric
tem before it enters the liver; they include portal vein thrombosis and varices; with the development of ascites along with peripheral edema;
splenic vein thrombosis. Posthepatic causes encompass those affect- or with an enlarged spleen with associated reduction in platelets and
ing the hepatic veins and venous drainage to the heart; they include white blood cells on routine laboratory testing.
BCS and chronic right-sided cardiac congestion. Intrahepatic causes ESOPHAGEAL VARICES Over the past decade, it has become com-
account for >95% of cases of portal hypertension and are represented mon practice to screen known cirrhotics with endoscopy to look for
by the major forms of cirrhosis. Intrahepatic causes of portal hyper- esophageal varices. Such screening studies have shown that approx-
tension can be further subdivided into presinusoidal, sinusoidal, and imately one-third of patients with histologically confirmed cirrhosis
postsinusoidal causes. Postsinusoidal causes include veno-occlusive have varices. Approximately 5–15% of cirrhotics per year develop
varices, and it is estimated that the majority of patients with cirrhosis
TABLE 344-2 Complications of Cirrhosis will develop varices over their lifetimes. Furthermore, it is anticipated
Portal hypertension Coagulopathy that roughly one-third of patients with varices will develop bleeding.
Gastroesophageal varices Factor deficiency Several factors predict the risk of bleeding, including the severity of cir-
Portal hypertensive gastropathy Fibrinolysis rhosis (Child-Pugh class, Model for End-Stage Liver Disease [MELD]
score); the height of wedged-hepatic vein pressure; the size of the varix;
Splenomegaly, hypersplenism Thrombocytopenia
the location of the varix; and certain endoscopic stigmata, including
Ascites Bone disease red wale signs, hematocystic spots, diffuse erythema, bluish color,
Spontaneous bacterial peritonitis Osteopenia cherry red spots, or white-nipple spots. Patients with tense ascites are
Hepatorenal syndrome Osteoporosis also at increased risk for bleeding from varices.
Type 1 Osteomalacia Diagnosis In patients with cirrhosis who are being followed chroni-
Type 2 Hematologic abnormalities cally, the development of portal hypertension is usually revealed by the
Hepatic encephalopathy Anemia presence of thrombocytopenia; the appearance of an enlarged spleen;
Hepatopulmonary syndrome Hemolysis or the development of ascites, encephalopathy, and/or esophageal
Portopulmonary hypertension Thrombocytopenia
varices with or without bleeding. In previously undiagnosed patients,
any of these features should prompt further evaluation to determine
Malnutrition Neutropenia
the presence of portal hypertension and liver disease. Varices should

HPIM21e_Part10_p2381-p2670.indd 2629 20/01/22 10:05 PM

 2630 be identified by endoscopy. Contrasted-enhanced abdominal imag- shunt. Encephalopathy can occur in as many as 20% of patients
ing, either by computed tomography (CT) or MRI, can be helpful after TIPS and is particularly problematic in elderly patients and in
in demonstrating a nodular liver and in finding changes of portal patients with preexisting encephalopathy. TIPS is usually reserved
hypertension with intraabdominal collateral circulation. Rarely, the for individuals who fail or are unable to receive endoscopic therapy,
HVPG is measured by interventional radiology. Patients with a gradient although there is emerging evidence that patient who are highly
>12 mmHg are at risk for variceal hemorrhage. selected to be at high risk for rebleeding may also benefit. TIPS can
sometimes be used as a bridge to transplantation, and all patients
requiring TIPS should be considered for transplant evaluation.
TREATMENT Some gastric varices are associated with a splenorenal shunt and
Variceal Hemorrhage can be effectively treated with a balloon occluded retrograde trans-
venous obliteration (BRTO) of varices sometimes in combination
Treatment for esophageal varices as a complication of portal hyper- with a TIPS. Prevention of further bleeding is usually accomplished
tension is divided into two main categories: (1) primary prophylaxis with repeated variceal band ligation until varices are obliterated in
and (2) prevention of rebleeding once there has been an initial combination with NSBB. If recurrent variceal bleeding occurs, then
variceal hemorrhage. Primary prophylaxis requires routine surveil- TIPS should be performed for long-term prevention of bleeding.
lance by endoscopy of all patients with cirrhosis. Upper endoscop- Once a TIPS has been performed, there is no need for further endo-
ies are recommended at diagnosis of compensated cirrhosis and scopies for variceal surveillance; however, the TIPS should be period-
then every 2 years if the liver disease is active or every 3 years if ically monitored with Doppler ultrasound for stenosis. (Fig. 344-3).
inactive (alcohol cessation, viral hepatitis eradication). Endoscopy
is also recommended at the time of hepatic decompensation. Once ■■PORTAL HYPERTENSIVE GASTROPATHY
varices that are at increased risk for bleeding are identified, usually Portal hypertensive gastropathy can cause both acute clinical GI
defined as medium or large varices or small varices with high-risk bleeding and chronic bleeding resulting in iron-deficiency anemia. It
stigmata or in decompensated cirrhosis, primary prophylaxis can be is associated with all causes of portal hypertension and is diagnosed by
achieved either through nonselective beta blockade (NSBB) titrated characteristic endoscopy findings showing a snake skin–like mosaic
with a goal heart rate of 55–60 beats/min with systolic blood pres- pattern of gastric mucosa often with central red or brown spots. When
sure >90 mmHg or by variceal band ligation. Numerous placebo- there is bleeding, treatment is with NSBB and iron repletion. Refrac-
controlled clinical trials of either propranolol or nadolol show a tory bleeding may respond to TIPS.
lower risk of variceal hemorrhage and mortality related to variceal
hemorrhage but no clear benefit on overall survival. ■■SPLENOMEGALY AND HYPERSPLENISM
PART 10

Endoscopic variceal ligation (EVL) has been compared to NSBB Congestive splenomegaly with hypersplenism is common in patients
for primary prophylaxis against variceal bleeding, and EVL appears with portal hypertension and is usually the first indication of portal
to have equivalent efficacy. Two more recent trials comparing EVL hypertension. Clinical features include the presence of an enlarged
to carvedilol, a drug with NSBB and anti–α1-adrenergic properties, spleen on physical examination and the development of thrombocy-
showed similar efficacy. Thus, either NSSB or EVL is effective for topenia and leukopenia in patients who have cirrhosis. Some patients
Disorders of the Gastrointestinal System

primary prophylaxis of bleeding, and the choice should be based will have significant left-sided and left upper quadrant abdominal pain
on patient and physician preference and tolerability. Once primary
prophylaxis has been initiated, repeat endoscopy for surveillance of
varices is unnecessary.
Recurrent acute bleeding
The approach to patients once they have had a variceal bleed is
first to treat the acute bleed, which can be life-threatening, and then
to prevent further bleeding. Treatment of acute bleeding requires Endoscopic therapy
both fluid and red blood cell replacement to stabilize hemodynam- +
ics. A recent randomized trial of restricted transfusion starting when Pharmacologic therapy
hemoglobin is <7 g/dL with a goal hemoglobin of 7–9 g/dL, com-
pared to a more liberal strategy, resulted in reduced early rebleeding
and mortality. This strategy is recommended, although adjustments Control of bleeding
should be made based on cardiac risks and hemodynamics. Correct-
ing an elevated prothrombin time with fresh frozen plasma is not
recommended unless there is evidence of coagulopathy (bleeding Compensated cirrhosis Decompensated cirrhosis
at other sites such as IV lines). The use of vasoconstricting agents, Child’s class A Child’s class B or C
usually somatostatin or octreotide, has been shown to improve initial
bleeding control and reduce transfusion requirements and all-cause
mortality. Prophylactic antibiotics, usually with ceftriaxone, started TIPS Transplant evaluation
prior to endoscopy result in reduced infections, recurrent bleeding,
and mortality. Balloon tamponade (Sengstaken-Blakemore tube or Endoscopic therapy or
Minnesota tube) can be used in patients who need stabilization prior Consider liver beta blockers
to endoscopic therapy or as a bridge to transjugular intrahepatic por- transplantation
tosystemic shunt (TIPS) after endoscopic failure. Control of bleeding evaluation
can be achieved in the vast majority of cases; however, bleeding Consider TIPS
recurs in the majority of patients if definitive endoscopic therapy has
not been instituted. Upper endoscopy is used as first-line treatment Liver transplantation
to diagnose the cause of the bleeding and to control bleeding acutely
with EVL. When esophageal varices extend into the proximal stom-
ach or the bleeding varices are entirely within the stomach, band FIGURE 344-3 Management of recurrent variceal hemorrhage. This algorithm
ligation is often unsuccessful. In these situations, consideration for a describes an approach to management of patients who have recurrent bleeding
from esophageal varices. Initial therapy is generally with endoscopic therapy often
TIPS should be made. This technique creates a portosystemic shunt supplemented by pharmacologic therapy. With control of bleeding, a decision
by a percutaneous approach using an expandable metal stent, which needs to be made as to whether patients should go on to transjugular intrahepatic
is advanced under angiographic guidance to the hepatic veins and portosystemic shunt (TIPS; if they are Child’s class A) or if they should have TIPS
then through the substance of the liver to create a direct portocaval and be considered for transplant (if they are Child’s class B or C).

HPIM21e_Part10_p2381-p2670.indd 2630 20/01/22 10:05 PM

 may have a fluid wave, or may have the presence of shifting dullness. 2631
Cirrhosis This is determined by taking patients from a supine position to lying
on either their left or right side and noting the movement of the
dullness to percussion. Subtle amounts of ascites can be detected by
Portal hypertension
ultrasound or CT scanning. Hepatic hydrothorax is more common on
the right side and implicates a rent in the diaphragm with free flow of
Splanchnic vasodilation ascitic fluid into the thoracic cavity.
When patients present with ascites for the first time, it is recom-
mended that a diagnostic paracentesis be performed to characterize
the fluid. This should include the determination of total protein and
↑ Splanchnic pressure Arterial underfilling albumin content, blood cell counts with differential, and cultures. In
the appropriate setting, amylase may be measured and cytology per-
Lymph formation
Activation of
formed. In patients with cirrhosis, the protein concentration of the
vasoconstrictors and ascitic fluid is low, usually <2.5 g/dL. The serum ascites-to-albumin
Formation of ascites
antinatriuretic factors* gradient (SAAG), calculated by subtracting the fluid albumin level
from the serum albumin level, has replaced the description of exu-
Plasma volume dative or transudative fluid. When the SAAG is >1.1 g/dL, the cause
Sodium retention of the ascites is most likely due to portal hypertension; this is usually
expansion
in the setting of cirrhosis. Cardiac ascites can be identified by SAAG
FIGURE 344-4 Development of ascites in cirrhosis. This flow diagram illustrates the
>1.1 g/dL and ascites protein >2.5g/dL. When the SAAG is <1.1 g/dL,
importance of portal hypertension with splanchnic vasodilation in the development infectious or malignant causes of ascites should be considered. When
of ascites. *Antinatriuretic factors include the renin-angiotensin-aldosterone ascitic fluid protein is very low, <1.5 g/dL, patients are at increased risk
system and the sympathetic nervous system. for developing SBP. A high level of red blood cells in the ascitic fluid
usually signifies a traumatic tap but can also rarely occur with hepato-
related to an enlarged spleen. Splenomegaly itself usually requires no cellular cancer or a ruptured omental varix. When the absolute level of
specific treatment. polymorphonuclear leukocytes is >250/μL, infection is likely.
■■ASCITES TREATMENT

CHAPTER 344 Cirrhosis and Its Complications

Definition Ascites is the accumulation of fluid within the peri- Ascites
toneal cavity. Overwhelmingly, the most common cause of ascites is
portal hypertension related to cirrhosis; however, clinicians should Patients with small amounts of ascites can usually be managed
remember that malignant, infectious, and cardiac causes of ascites can with dietary sodium restriction alone. Most average diets in the
be present as well, and careful differentiation of these other causes is United States contain 6–8 g of sodium per day, and if patients eat at
obviously important for patient care. restaurants or fast-food outlets, the amount of sodium in their diet
can exceed this amount. Thus, it is often extremely difficult to get
Pathogenesis The presence of portal hypertension contributes to patients to change their dietary habits to ingest 2 g of sodium per
the development of ascites in patients who have cirrhosis (Fig. 344-4). day, equivalent to slightly more than three-quarters of a teaspoon
There is an increase in intrahepatic resistance, causing increased portal of salt, which is the recommended amount. Sodium educational
pressure, but there is also vasodilation of the splanchnic arterial system, pamphlets are helpful. Often, a simple recommendation is to eat
which, in turn, results in an increase in portal venous inflow. Both fresh or frozen foods, avoiding canned or processed foods. When
abnormalities result in increased production of splanchnic lymph. a moderate amount of ascites is present, diuretic therapy is usually
Vasodilating factors such as nitric oxide are responsible for the vaso- necessary. Traditionally, spironolactone at 100 mg/d as a single dose
dilatory effect. There is activation of the renin-angiotensin-aldosterone is started, and furosemide may be added at 40 mg/d, particularly in
system with the development of hyperaldosteronism and activation of patients who have peripheral edema. Failure of the diuretics sug-
the sympathetic nervous system as a consequence of a homeostatic gests that patients may not be compliant with a low-sodium diet.
response caused by underfilling of the arterial circulation secondary to If compliance is confirmed and ascitic fluid is not being mobilized,
arterial vasodilation in the splanchnic vascular bed. The renal effects there should be incremental increases in spironolactone to a maxi-
of increased aldosterone and activation of the sympathetic nervous sys- mum of 400 mg/d and furosemide to 160 mg/d. If a large amount of
tem lead to sodium retention causing fluid accumulation and expan- ascites is still present on diuretics in patients who are compliant with
sion of the extracellular fluid volume, resulting in peripheral edema a low-sodium diet, then they are defined as having refractory ascites,
and ascites. Because the retained fluid is constantly leaking out of the and alternative treatment modalities including repeated large-
intravascular compartment into the peritoneal cavity, the sensation of volume paracentesis (LVP) or a TIPS procedure should be consid-
vascular filling is not achieved, and the process continues. Hypoalbu- ered (Fig. 344-5). After LVP of ≥5 L, IV 25% albumin at a dose of
minemia from decreased synthetic function in a cirrhotic liver results ~8 g/L of removed ascites should be given to prevent circulatory
in reduced plasma oncotic pressure and contributes to the loss of fluid dysfunction. Multiple studies have shown that TIPS, although
from the vascular compartment into the peritoneal cavity. effective at managing the ascites, does not improve survival. Unfor-
Clinical Features Patients typically note an increase in abdomi- tunately, TIPS is often associated with an increased frequency of
nal girth that is often accompanied by the development of peripheral hepatic encephalopathy and must be considered carefully on a case-
edema. The development of ascites is often insidious, and it is surpris- by-case basis. The prognosis for patients with cirrhosis with ascites
ing that some patients wait so long and become so distended before is poor, and some studies have shown that <50% of patients survive
seeking medical attention. Patients usually have at least 1–2 L of fluid 2 years after the onset of ascites. Thus, there should be consider-
in the abdomen before they are aware that there is an increase. If ascitic ation for liver transplantation in patients with ascites. Patients with
fluid is massive, respiratory function can be compromised, causing cirrhosis and ascites are at increased risk for renal failure from cer-
dyspnea. Hepatic hydrothorax may also contribute to respiratory tain medications including nonsteroidal anti-inflammatory drugs
symptoms. Patients with massive ascites are often malnourished and and aminoglycosides; therefore, these medications should gener-
have muscle wasting and excessive fatigue and weakness. ally be avoided. Angiotensin-converting enzyme inhibitors and
angiotensin receptor blockers should be used cautiously with close
Diagnosis Diagnosis of ascites is by physical examination and is monitoring of blood pressure and renal function.
often aided by abdominal imaging. Patients will have bulging flanks,

HPIM21e_Part10_p2381-p2670.indd 2631 20/01/22 10:05 PM

 2632 HRS requires exclusion of other causes of acute renal failure,
Symptomatic ascites most notably volume depletion. Diuretics should be stopped, and
infusion of albumin 1 g/kg per day is recommended. Treatment is
with vasoconstrictors such as terlipressin (not currently available in
Large-volume paracentesis (LVP) + albumin North America) or low-dose norepinephrine (requires intensive care
unit monitoring). Midodrine, an α-agonist, along with octreotide and
Dietary sodium restriction + diuretics
intravenous albumin are also commonly used in the United States.
The best therapy for HRS is liver transplantation; recovery of renal
function is typical in this setting. In patients with either type 1 or type
Ascites reaccumulation 2 HRS, the prognosis is poor unless transplant can be achieved within
a short period of time.
■■HEPATIC ENCEPHALOPATHY
Consider TIPS Continue LVP with Consider liver Portosystemic encephalopathy is a serious complication of chronic
albumin as needed transplantation
liver disease and is broadly defined as an alteration in mental status and
cognitive function occurring in the presence of liver failure. In severe
FIGURE 344-5 Treatment of refractory ascites. In patients who develop azotemia acute liver injury, the development of encephalopathy is a requirement
in the course of receiving diuretics in the management of their ascites, some will for a diagnosis of acute liver failure and can be seen in association with
require repeated large-volume paracentesis (LVP), some may be considered for life-threatening brain edema, which is not a feature in chronic liver
transjugular intrahepatic portosystemic shunt (TIPS), and some would be good disease. Encephalopathy is much more commonly seen in patients with
candidates for liver transplantation. These decisions are all individualized.
chronic liver disease. Gut-derived neurotoxins that are not removed
by the liver because of vascular shunting and decreased hepatic mass
■■SPONTANEOUS BACTERIAL PERITONITIS reach the brain and cause the symptoms known as hepatic enceph-
SBP is a common and severe complication of ascites characterized by alopathy. Ammonia levels are typically elevated, but the correlation
spontaneous infection of the ascitic fluid without an intraabdominal between severity of liver disease and height of ammonia levels is often
source. In hospitalized patients with cirrhosis and ascites, SBP can poor, and most hepatologists do not rely on ammonia levels to make
occur in up to 30% of individuals and can have a 25% in-hospital a diagnosis or follow clinical progress. Other compounds and metabo-
mortality rate. Bacterial translocation is the presumed mechanism lites that may contribute to the development of encephalopathy include
for development of SBP, with gut flora traversing the intestine into certain false neurotransmitters and mercaptans.
mesenteric lymph nodes, leading to bacteremia and seeding of the
PART 10

ascitic fluid. The most common organisms are Escherichia coli and Clinical Features In acute liver failure, changes in mental status
other gut bacteria; however, gram-positive bacteria, including Strep- can occur rapidly. Brain edema can be seen in these patients, with
tococcus viridans, Staphylococcus aureus, and Enterococcus spp., can severe encephalopathy associated with swelling of the gray matter.
also be found. If more than two organisms are identified, secondary Cerebral herniation is a feared complication of brain edema in acute
liver failure, and treatment to decrease edema is with mannitol and
Disorders of the Gastrointestinal System

bacterial peritonitis due to a perforated viscus should be considered.

The diagnosis of SBP is made when the fluid sample has an absolute judicious use of intravenous fluids.
neutrophil count >250/μL. Bedside cultures should be obtained by In patients with cirrhosis, encephalopathy is often found as a
direct injection of ascitic fluid into blood culture bottles. Patients with result of certain precipitating events such as hypokalemia, infection,
ascites may present with fever, altered mental status, elevated white an increased dietary protein load, or volume depletion. Patients may
blood cell count, abdominal pain or discomfort, and acute kidney be confused or exhibit a change in personality. They may actually be
injury, or they may present without any of these features. Therefore, it quite violent and difficult to manage; alternatively, patients may be
is necessary to have a high degree of clinical suspicion, and peritoneal very sleepy and difficult to rouse. Precipitating events are common, so
taps are recommended for most cirrhosis patients hospitalized with they should be sought carefully. If patients have ascites, this should be
ascites and cirrhosis complications or signs of infection. Treatment is tapped to rule out infection. Evidence of GI bleeding should be sought,
commonly with intravenous third-generation cephalosporin for 5 days. and patients should be appropriately hydrated. Electrolytes should be
In addition, intravenous albumin (1.5 g/kg body weight on day and measured and abnormalities corrected. In patients presenting with
1.0 g/kg on day 3) has been shown to reduce the risk of renal failure encephalopathy, asterixis is often present. Asterixis can be elicited by
and to improve survival. In patients with variceal hemorrhage, the fre- having patients extend their arms and bend their wrists back. Patients
quency of SBP is significantly increased, and prophylaxis against SBP who are encephalopathic have a “liver flap”—that is, a sudden forward
is recommended when a patient presents with upper GI bleeding. Fur- movement of the wrist. This requires patients to be able to cooperate
thermore, in patients who have had an episode (or multiple episodes) with the examiner. Alternative causes for altered mental status should
of SBP and recovered, quinolone antibiotic prophylaxis should be given also be considered.
to prevent recurrent SBP. The diagnosis of hepatic encephalopathy is clinical and requires
an experienced clinician to recognize and put together all the various
features. Often when patients have encephalopathy for the first time,
■■HEPATORENAL SYNDROME they (and/or their caregivers) are unaware of what is transpiring, but
HRS is a form of functional renal failure without renal pathology once they have been through the experience, they can identify when
that occurs in ~10% of patients with advanced cirrhosis or acute liver this is developing in subsequent situations and can often self-medicate
failure. There are marked disturbances in the arterial renal circulation to prevent the development or worsening of encephalopathy.
in patients with HRS; these include an increase in vascular resistance
accompanied by a reduction in systemic vascular resistance. The rea-
son for renal vasoconstriction is most likely multifactorial and is poorly TREATMENT
understood. The diagnosis is made usually in the presence of a large
amount of ascites in patients who have a stepwise progressive increase
Hepatic Encephalopathy
in creatinine. Type 1 HRS is characterized by a progressive impairment Treatment is multifactorial and includes management of the above-
in renal function and a significant reduction in creatinine clearance mentioned precipitating factors. Sometimes hydration and cor-
within 1–2 weeks of presentation. Type 2 HRS is characterized by a rection of electrolyte imbalance are all that is necessary. In the
reduction in glomerular filtration rate with an elevation of serum crea- past, restriction of dietary protein was used; however, the negative
tinine level, but it is stable and is associated with a better outcome than impact of that maneuver on overall nutrition is thought to outweigh
that of type 1 HRS. the benefit, and it is thus strongly discouraged. The mainstay of

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 treatment for encephalopathy is to use lactulose, a nonabsorb- is diminished in patients with chronic cholestatic syndromes because 2633
able disaccharide, which results in colonic acidification. Catharsis absorption of vitamin K requires good bile flow. Intravenous or intra-
ensues, contributing to the elimination of nitrogenous products in muscular vitamin K can quickly correct this abnormality. Overall, the
the gut that are responsible for the development of encephalopathy. status of coagulation in a cirrhotic patient needs to be judged clinically
The goal of lactulose therapy is to promote two to three soft stools rather than relying on current laboratory tests.
per day. Patients are asked to titrate their amount of ingested lac-
tulose to achieve the desired effect. Lactulose is usually continued ■■BONE DISEASE IN CIRRHOSIS
after the initial episode of encephalopathy. Poorly absorbed antibi- Osteoporosis is common in patients with chronic cholestatic liver
otics are often used as adjunctive therapies for patients who have disease because of malabsorption of vitamin D and decreased calcium
a difficult time with lactulose. The alternating administration of ingestion. The rate of bone resorption exceeds that of new bone forma-
neomycin and metronidazole has been used in the past to reduce tion in patients with cirrhosis, resulting in bone loss. Dual-energy x-ray
the individual side effects of each: neomycin for renal insufficiency absorptiometry (DEXA) is a useful method for determining osteopo-
and ototoxicity and metronidazole for peripheral neuropathy. More rosis or osteopenia. When a DEXA scan shows osteoporosis, treatment
recently, rifaximin at 550 mg twice daily has been very effective with bisphosphonates is effective.
in preventing recurrent encephalopathy. Zinc supplementation is
sometimes helpful and is relatively harmless. The development ■■HEMATOLOGIC ABNORMALITIES IN CIRRHOSIS
of encephalopathy in patients with chronic liver disease is a poor Numerous hematologic manifestations of cirrhosis are present, includ-
prognostic sign, but this complication can be managed in the vast ing anemia from a variety of causes including hypersplenism, hemoly-
majority of patients. sis, iron deficiency, and perhaps folate deficiency from malnutrition.
Macrocytosis is a common abnormality in red blood cell morphology
seen in patients with chronic liver disease, and neutropenia may be a
■■LIVER-LUNG SYNDROMES result of hypersplenism.
Hepatopulmonary syndrome (HPS) is characterized by arterial hypox-
emia in a patient with cirrhosis without significant lung disease. The ■■FURTHER READING
liver disease causes intrapulmonary vascular dilations resulting in AASLD/IDSA HCV Guidance Panel: Hepatitis C guidance 2019
blood shunting past alveoli and significant ventilation-perfusion mis- update: AASLD-IDSA recommendations for testing, managing, and
match. Clinical symptoms include dyspnea and platypnea. HPS is com- treating hepatitis C virus infection. Hepatology 71:686, 2020.
mon, occurring in 4–32% of patients with cirrhosis; however, it is often Biggins SW et al: Diagnosis, evaluation and management of ascites
mild. Diagnosis involves demonstrating hypoxemia, without evidence and hepatorenal syndrome: 2021 Practice guidance by the American

CHAPTER 345 Liver Transplantation

of significant lung disease, and shunt on bubble echocardiography. Association for the Study of Liver Diseases. Hepatology 74:1014,
Treatment is with oxygen supplementation and liver transplantation. 2021.
Portopulmonary hypertension (PPHT) is pulmonary hypertension Garcia-Tsao G et al: Portal hypertensive bleeding in cirrhosis: Risk
in a patient with portal hypertension. The portal hypertension results stratification, diagnosis and management: 2016 practice guidance by
in the production of vasoconstrictor substances that affect the pul- the American Association for the Study of Liver Diseases. Hepatology
monary artery. Many patients are asymptomatic, especially early in 65:310, 2017.
the disease; however, they later can develop dyspnea on exertion and Terrault NA et al: Update on prevention, diagnosis and treatment of
fatigue. PPHT is rare, occurring in ~5% of patients with advanced chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology
cirrhosis. Diagnosis includes initial identification on echocardiogram 67:1560, 2018.
and confirmation on right heart catheterization showing elevated mean Vilstrup H et al: Hepatic encephalopathy in chronic liver disease:
pulmonary artery pressure, elevated pulmonary vascular resistance, 2014 Practice Guideline by the American Association for the Study
and normal pulmonary capillary wedge pressure. Prognosis is poor, of Liver Diseases and the European Association for the Study of the
although liver transplantation after effective reduction in pulmonary Liver. Hepatology 60:715, 2014.
artery pressure with vasodilatory medications can be effective.
■■MALNUTRITION IN CIRRHOSIS
Because the liver is principally involved in the regulation of protein
and energy metabolism in the body, it is not surprising that patients
with advanced liver disease are commonly malnourished. Once
patients become cirrhotic, they are more catabolic, and muscle pro-
tein is metabolized. There are multiple factors that contribute to the
345 Liver Transplantation
Raymond T. Chung, Jules L. Dienstag
malnutrition of cirrhosis, including poor dietary intake, alterations in
gut nutrient absorption, and alterations in protein metabolism. Close
attention to food intake is helpful in preventing patients from becom-
ing catabolic. General recommendations include multiple small meals
including a late evening snack with total calories of 25–30 kcal per kg Liver transplantation—the replacement of the native, diseased liver by
of ideal body weight per day and 1.2–1.5 g of protein per kg of ideal a normal organ (allograft)—has matured from an experimental pro-
body weight per day. cedure reserved for desperately ill patients to an accepted, lifesaving
operation applied more optimally in the natural history of end-stage
■■ABNORMALITIES IN COAGULATION liver disease. The preferred and technically most advanced approach
Coagulation disorders in cirrhosis are poorly understood, and typical is orthotopic transplantation, in which the native organ is removed and
clinical measures of coagulation, such as the prothrombin time and the donor organ is inserted in the same anatomic location. Pioneered
international normalized ratio, are not reliable measures of clotting in the 1960s by Thomas Starzl at the University of Colorado and, later, at
ability. There is decreased synthesis of both pro- and anticoagulant fac- the University of Pittsburgh and by Roy Calne in Cambridge, England,
tors and thus some rebalancing in coagulation; however, the coagula- liver transplantation is now performed routinely worldwide. Success
tion cascade can easily tip toward thrombosis or bleeding. In addition, measured as 1-year survival has improved from ~30% in the 1970s to
patients may have thrombocytopenia from hypersplenism due to portal >90% today. These improved prospects for prolonged survival resulted
hypertension and some platelet dysfunction, which is counterbalanced from refinements in operative technique, improvements in organ pro-
with increased von Willebrand factor. Adequate thrombin formation curement and preservation, advances in immunosuppressive therapy,
can occur with platelet levels from cirrhosis patients >50,000–60,000/L. and, perhaps most influentially, more enlightened patient selection and
Synthesis of vitamin K–dependent clotting factors II, VII, IX, and X timing. Despite the perioperative morbidity and mortality, the technical

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 2634 and management challenges of the procedure, and its costs, liver trans- indication for transplantation in children and adolescents. In Crigler-
plantation has become the approach of choice for selected patients Najjar disease type I and in certain hereditary disorders of the urea
whose chronic or acute liver disease is progressive, life-threatening, cycle and of amino acid or lactate-pyruvate metabolism, transplan-
and unresponsive to medical therapy. Based on the current level of suc- tation may be the only way to prevent impending deterioration of
cess, the number of liver transplants has continued to grow each year; central nervous system function, despite the fact that the native liver
in 2020, 8906 patients received liver allografts in the United States. Still, is structurally normal. Combined heart and liver transplantation has
the demand for new livers continues to outpace availability; as of 2021, yielded dramatic improvement in cardiac function and in cholesterol
11,710 patients in the United States were on a waiting list for a donor levels in children with homozygous familial hypercholesterolemia;
liver. In response to this drastic shortage of donor organs, many trans- combined liver and kidney transplantation has been successful in
plantation centers supplement deceased-donor liver transplantation patients with primary hyperoxaluria type I. In hemophiliacs with
with living-donor transplantation. transfusion-associated hepatitis and liver failure, liver transplantation
has been associated with recovery of normal factor VIII synthesis.
INDICATIONS ■■TRANSPLANTATION IN ADULTS
Potential candidates for liver transplantation are children and adults
who, in the absence of contraindications (see below), suffer from Liver transplantation is indicated for end-stage cirrhosis of all causes
severe, irreversible liver disease for which alternative medical or sur- (Table 345-1). In sclerosing cholangitis and Caroli’s disease (multiple
gical treatments have been exhausted or are unavailable. Timing of the cystic dilatations of the intrahepatic biliary tree), recurrent infections
operation is of critical importance. Indeed, improved timing and better and sepsis associated with inflammatory and fibrotic obstruction
patient selection are felt to have contributed more to the increased of the biliary tree may be an indication for transplantation. Because
success of liver transplantation in the 1980s and beyond than all the prior biliary surgery complicates and is a relative contraindication
impressive technical and immunologic advances combined. Although for liver transplantation, surgical diversion of the biliary tree has
the disease should be advanced, and although opportunities for been all but abandoned for patients with sclerosing cholangitis. In
spontaneous or medically induced stabilization or recovery should be patients who undergo transplantation for hepatic vein thrombosis
allowed, the procedure should be done sufficiently early to give the (Budd-Chiari syndrome), postoperative anticoagulation is essential;
surgical procedure a fair chance for success. Ideally, transplantation underlying myeloproliferative disorders may have to be treated but are
should be considered in patients with end-stage liver disease who are not a contraindication to liver transplantation. If a donor organ can
experiencing or have experienced a life-threatening complication of be located quickly, before life-threatening complications—including
hepatic decompensation or whose quality of life has deteriorated to cerebral edema—set in, patients with acute liver failure are candidates
unacceptable levels. Although patients with well-compensated cirrho- for liver transplantation. Currently, alcohol-associated liver disease,
chronic hepatitis C, and nonalcoholic fatty liver disease (NAFLD) are
PART 10

sis can survive for many years, many patients with quasi-stable chronic
liver disease have much more advanced disease than may be apparent. the most common indications for liver transplantation, accounting
As discussed below, the better the status of the patient prior to trans- for >40% of all adult candidates who undergo the procedure. Patients
plantation, the higher will be its anticipated success rate. The decision with alcohol-associated cirrhosis can be considered as candidates for
about when to transplant is complex and requires the combined judg- transplantation if they meet strict criteria for abstinence and reform;
Disorders of the Gastrointestinal System

ment of an experienced team of hepatologists, transplant surgeons, however, these criteria still do not prevent recidivism in up to a quarter
anesthesiologists, and specialists in support services, not to mention of cases. In highly selected cases in a limited but growing number of
the well-informed consent of the patient and the patient’s family. centers, transplantation for severe acute alcohol-associated hepatitis
has been performed with success; however, because patients with acute
■■TRANSPLANTATION IN CHILDREN alcohol-associated hepatitis are still actively using alcohol and because
Indications for transplantation in children are listed in Table 345-1. continued alcohol abuse remains a concern, acute alcohol-associated
The most common is biliary atresia. Inherited or genetic disorders hepatitis is not a routine indication for liver transplantation. Patients
of metabolism associated with liver failure constitute another major with chronic hepatitis C have early allograft and patient survival
comparable to those of other subsets of patients after transplanta-
tion; however, reinfection in the donor organ is universal, recurrent
hepatitis C had been insidiously progressive, with allograft cirrhosis
TABLE 345-1 Indications for Liver Transplantation and failure occurring at a higher frequency beyond 5 years. Fortu-
CHILDREN ADULTS nately, with the introduction of highly effective direct-acting antiviral
Biliary atresia Primary biliary cholangitis (DAA) agents targeting hepatitis C virus (HCV), allograft outcomes
Neonatal hepatitis Secondary biliary cirrhosis have improved substantially. In patients with chronic hepatitis B, in
Congenital hepatic fibrosis Primary sclerosing cholangitis the absence of measures to prevent recurrent hepatitis B, survival after
transplantation is reduced by ~10–20%; however, prophylactic use of
Alagille’s syndromea Autoimmune hepatitis
hepatitis B immune globulin (HBIg) during and after transplantation
Byler’s diseaseb Caroli’s diseasec increases the success of transplantation to a level comparable to that
α1 Antitrypsin deficiency Cryptogenic cirrhosis seen in patients with nonviral causes of liver decompensation. Spe-
Inherited disorders of metabolism Chronic hepatitis with cirrhosis cific oral antiviral drugs (e.g., entecavir, tenofovir disoproxil fumarate,
Wilson’s disease Hepatic vein thrombosis tenofovir alafenamide) (Chap. 341) can be used both for prophylaxis
Tyrosinemia Fulminant hepatitis against and for treatment of recurrent hepatitis B, facilitating further
Glycogen storage diseases Alcohol-associated cirrhosis
the management of patients undergoing liver transplantation for end-
stage hepatitis B; most transplantation centers rely on antiviral drugs
Lysosomal storage diseases Chronic viral hepatitis with or without HBIg to manage patients with hepatitis B. Issues of
Protoporphyria Primary hepatocellular malignancies disease recurrence are discussed in more detail below. Patients with
Crigler-Najjar disease type I Hepatic adenomas nonmetastatic primary hepatobiliary tumors—primary hepatocellular
Familial hypercholesterolemia Nonalcoholic steatohepatitis carcinoma (HCC), cholangiocarcinoma, hepatoblastoma, angiosar-
Primary hyperoxaluria type I Familial amyloid polyneuropathy coma, epithelioid hemangioendothelioma, and multiple or massive
Hemophilia
hepatic adenomata—have undergone liver transplantation; however,
for some hepatobiliary malignancies, overall survival is significantly
a
Arteriohepatic dysplasia, with paucity of bile ducts, and congenital malformations, lower than that for other categories of liver disease. Most transplan-
including pulmonary stenosis. bIntrahepatic cholestasis, progressive liver failure,
and mental and growth retardation. cMultiple cystic dilatations of the intrahepatic tation centers have reported 5-year recurrence-free survival rates in
biliary tree. patients with unresectable HCC for single tumors <5 cm in diameter

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 or for three or fewer lesions all <3 cm comparable to those seen in in selected HIV-positive persons who have excellent control of HIV 2635
patients undergoing transplantation for nonmalignant indications. infection. Selected patients with CD4+ T-cell counts >100/μL and
Consequently, liver transplantation is currently restricted to patients with pharmacologic suppression of HIV viremia have undergone
whose hepatic malignancies meet these criteria. Expanded criteria for transplantation for end-stage liver disease. HIV-infected persons who
patients with HCC continue to be evaluated. Because the likelihood have received liver allografts for end-stage liver disease resulting from
of recurrent cholangiocarcinoma is very high, only highly selected chronic hepatitis B have experienced survival rates comparable to those
patients with limited disease are being evaluated for transplantation of HIV-negative persons undergoing transplantation for the same indi-
after intensive chemotherapy and radiation. cation. In contrast, recurrent HCV in the allograft has until recently
limited long-term success in persons with HCV-related end-stage
CONTRAINDICATIONS liver disease. Again, the availability of DAA agents targeting HCV (see
Absolute contraindications for transplantation include life-threatening below and Chap. 341) is expected has improved allograft outcomes
systemic diseases, uncontrolled extrahepatic bacterial or fungal infec- significantly.
tions, preexisting advanced cardiovascular or pulmonary disease, mul-
tiple uncorrectable life-threatening congenital anomalies, metastatic TECHNICAL CONSIDERATIONS
malignancy, and active drug or alcohol abuse (Table 345–2). Because
carefully selected patients in their sixties and even seventies have ■■DECEASED-DONOR SELECTION
undergone transplantation successfully, advanced age per se is no lon- Deceased-donor livers for transplantation are procured primarily from
ger considered an absolute contraindication; however, in older patients, victims of head trauma. Organs from brain-dead donors up to age 60
a more thorough preoperative evaluation should be undertaken to are acceptable if the following criteria are met: hemodynamic stability,
exclude ischemic cardiac disease and other comorbid conditions. adequate oxygenation, absence of bacterial or fungal infection, absence
Advanced age (>70 years), however, should be considered a relative of abdominal trauma, absence of hepatic dysfunction, and serologic
contraindication—that is, a factor to be considered with other relative exclusion of hepatitis B virus (HBV), HCV, and HIV. Occasionally,
contraindications. Other relative contraindications include portal vein organs from donors with hepatitis B and C are used, particularly for
thrombosis, preexisting renal disease not associated with liver dis- recipients with prior hepatitis B and C, respectively. Organs from
ease (which may prompt consideration of combined liver and kidney donors with antibodies to hepatitis B core antigen (anti-HBc) can also
transplantation), intrahepatic or biliary sepsis, severe hypoxemia (Po2 be used when the need is especially urgent, and recipients of these
<50 mmHg) resulting from right-to-left intrapulmonary shunts, porto- organs are treated prophylactically with antiviral drugs. Increasingly,
pulmonary hypertension with high mean pulmonary artery pressures with the early administration of highly effective DAA agents, organs

CHAPTER 345 Liver Transplantation

(>35 mmHg), previous extensive hepatobiliary surgery, any uncon- from donors with hepatitis C have been used successfully in previously
trolled serious psychiatric disorder, and lack of sufficient social sup- uninfected recipients. Cardiovascular and respiratory functions are
ports. Any one of these relative contraindications is insufficient in and maintained artificially until the liver can be removed. Transplanta-
of itself to preclude transplantation. For example, the problem of portal tion of organs procured from deceased donors who have succumbed
vein thrombosis can be overcome by constructing a graft from the to cardiac death can be performed successfully under selected cir-
donor liver portal vein to the recipient’s superior mesenteric vein. Now cumstances, when ischemic time is minimized and liver histology
that combination antiretroviral therapy has dramatically improved the preserved. Encouraging improvements in normothermic ex vivo liver
survival of persons with HIV infection (Chap. 202), and because end- perfusion techniques may make broader use of these organs possible.
stage liver disease caused by chronic hepatitis C and B has emerged Compatibility in ABO blood group and organ size between donor and
as a serious source of morbidity and mortality in the HIV-infected recipient are important considerations in donor selection; however,
population, liver transplantation has now been performed successfully ABO-incompatible, split-liver, or reduced-donor-organ allografts can
be performed in emergencies or marked donor scarcity. Tissue typing
for human leukocyte antigen (HLA) matching is not required, and
TABLE 345-2 Contraindications to Liver Transplantation preformed cytotoxic HLA antibodies do not preclude liver transplan-
ABSOLUTE RELATIVE tation. Following perfusion with cold electrolyte solution, the donor
Uncontrolled extrahepatobiliary Age >70 liver is removed and packed in ice. The use of University of Wisconsin
infection (UW) solution, rich in lactobionate and raffinose, has permitted the
Active, untreated sepsis Prior extensive hepatobiliary surgery
extension of cold ischemic time up to 20 h; however, 12 h may be a
more reasonable limit. Improved techniques for harvesting multiple
Uncorrectable, life-limiting congenital Portal vein thrombosis
anomalies
organs from the same donor have increased the availability of donor
livers, but the availability of donor livers is far outstripped by the
Active substance abuse Renal failure not attributable to
liver disease (consider dual organ
demand. Currently in the United States, all donor livers are distributed
transplantation) through a nationwide organ-sharing network (United Network for
Advanced cardiopulmonary disease Previous extrahepatic malignancy (not
Organ Sharing [UNOS]) designed to allocate available organs based
including nonmelanoma skin cancer) on regional considerations and recipient acuity. Recipients who have
the highest disease severity generally have the highest priority, but
Extrahepatobiliary malignancy (not Severe obesity
including nonmelanoma malignancy allocation strategies that balance highest urgency against best out-
skin cancer) comes continue to evolve to distribute deceased-donor organs most
Metastatic malignancy to the liver Severe malnutrition/wasting effectively. Allocation based on the Child-Turcotte-Pugh (CTP) score,
which uses five clinical variables (encephalopathy stage, ascites, bil-
Cholangiocarcinoma (except those Medical noncompliance
tumors that fit into protocols) irubin, albumin, and prothrombin time) and waiting time, has been
replaced by allocation based on urgency alone, calculated using the
AIDS HIV seropositivity with failure to control
HIV viremia or CD4 <100/μL Model for End-Stage Liver Disease (MELD) score. The MELD score is
based on a mathematical model that includes bilirubin, creatinine, and
Life-threatening systemic diseases Intrahepatic sepsis
prothrombin time expressed as international normalized ratio (INR)
Severe hypoxemia secondary to right- (Table 345-3). Neither waiting time (except as a tie breaker between
to-left intrapulmonary shunts (Po2 <50
mmHg) two potential recipients with the same MELD scores) nor posttrans-
plantation outcome is taken into account, but use of the MELD score
Severe pulmonary hypertension (mean
pulmonary artery pressure >35 mmHg) has been shown to reduce waiting list mortality, to reduce waiting time
prior to transplantation, to be the best predictor of pretransplantation
Uncontrolled psychiatric disorder
mortality, to satisfy the prevailing view that medical need should be the

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 2636
TABLE 345-3 United Network for Organ Sharing (UNOS) small-bowel obstruction, and incisional hernias in 9–19%; and even, in
Liver Transplantation Waiting List Criteria 0.2–0.4%, death) as well as the increased frequency of biliary (15–32%)
Status 1 Fulminant hepatic failure (including primary graft nonfunction and vascular (10%) complications in the recipient. Potential donors
and hepatic artery thrombosis within 7 days after transplantation must participate voluntarily without coercion, and transplantation
as well as acute decompensated Wilson’s disease)a teams should go to great lengths to exclude subtle coercive or inappro-
The Model for End-Stage Liver Disease (MELD)-Na score, on a continuous priate psychological factors as well as outline carefully to both donor
scale,b determines allocation of the remainder of donor organs. This model is and recipient the potential benefits and risks of the procedure. Donors
based on the following calculation: for the procedure should be 18–60 years old; have a compatible blood
MELD = 3.78 × loge bilirubin (mg/100 mL) + 11.2 × loge international normalized ratio type with the recipient; have no chronic medical problems or history of
(INR) + 9.57 × loge creatinine (mg/100 mL) + 6.43.c,d,e major abdominal surgery; be related genetically or emotionally to the
MELD-Na = MELD + 1.32 * (137 – Na [meq/L]) – [0.033 * MELD * (137 – Na [meq/L]) recipient; and pass an exhaustive series of clinical, biochemical, and
Online calculators to determine MELD scores are available, such as the following: serologic evaluations to unearth disqualifying medical disorders. The
https://optn.transplant.hrsa.gov/resources/allocation-calculators/meld-calculator/ recipient should meet the same UNOS criteria for liver transplantation
a
For children <18 years of age, status 1 includes acute or chronic liver failure plus
as recipients of a deceased donor allograft.
hospitalization in an intensive care unit or inborn errors of metabolism. Status 1 is
retained for those persons with fulminant hepatic failure and supersedes the MELD ■■SURGICAL TECHNIQUE
score. bThe MELD scale is continuous, with 34 levels ranging between 6 and 40 (scores Removal of the recipient’s native liver is technically difficult, particu-
above 40 are categorized as 40). Donor organs usually do not become available unless
the MELD score exceeds 20. cPatients with stage T2 hepatocellular carcinoma receive larly in the presence of portal hypertension with its associated collat-
22 disease-specific points. dCreatinine is included because renal function is a validated eral circulation and extensive varices and especially in the presence
predictor of survival in patients with liver disease. For adults undergoing dialysis twice of scarring from previous abdominal operations. The combination of
a week, the creatinine in the equation is set to 4 mg/100 mL. eFor children <18 years of
age, the Pediatric End-Stage Liver Disease (PELD) scale is used. This scale is based portal hypertension and coagulopathy (elevated prothrombin time and
on albumin, bilirubin, INR, growth failure, and age. Status 1 is retained. thrombocytopenia) may translate into large blood product transfusion
requirements. After the portal vein and infrahepatic and suprahepatic
decisive determinant, and to eliminate both the subjectivity inherent inferior vena cava are dissected, the hepatic artery and common bile
in the CTP scoring system (presence and degree of ascites and hepatic duct are dissected. Then the native liver is removed and the donor
encephalopathy) and the differences in waiting times among different organ inserted. During the anhepatic phase, coagulopathy, hypogly-
regions of the country. Data indicate that liver recipients with MELD cemia, hypocalcemia, and hypothermia are encountered and must
scores <15 experienced higher posttransplantation mortality rates than be managed by the anesthesiology team. Caval, portal vein, hepatic
similarly classified patients who remained on the waiting list. This artery, and bile duct anastomoses are performed in succession, the last
PART 10

observation led to the modification of UNOS policy to allocate donor by end-to-end suturing of the donor and recipient common bile ducts
organs to candidates with MELD scores exceeding 15 within the local (Fig. 345-1) or by choledochojejunostomy to a Roux-en-Y loop if the
or regional procurement organization before offering the organ to local recipient common bile duct cannot be used for reconstruction (e.g., in
patients whose scores are <15. In 2016, the MELD score was modified sclerosing cholangitis). A typical transplant operation lasts 8 h, with a
to incorporate serum sodium, another important predictor of survival range of 6–18 h. Because of excessive bleeding, large volumes of blood,
Disorders of the Gastrointestinal System

in liver transplantation candidates (the MELD-Na score). blood products, and volume expanders may be required during surgery;
The highest priority (status 1) continues to be reserved for patients however, blood requirements have fallen sharply with improvements in
with fulminant hepatic failure or primary graft nonfunction. Because surgical technique, blood-salvage interventions, and experience.
candidates for liver transplantation who have HCC may not be suffi- As noted above, emerging alternatives to orthotopic liver transplan-
ciently decompensated to compete for donor organs based on urgency tation include split-liver grafts, in which one donor organ is divided
criteria alone and because protracted waiting for deceased-donor and inserted into two recipients, and living-donor procedures, in which
organs often results in tumor growth beyond acceptable limits for part of the left (for children), the left (for children or small adults), or
transplantation, such patients are assigned disease-specific MELD
points (Table 345–3). Other disease-specific MELD exceptions include
portopulmonary hypertension, hepatopulmonary syndrome, familial
amyloid polyneuropathy, primary hyperoxaluria (necessitating liver- Suprahepatic
kidney transplantation), cystic fibrosis liver disease, and highly selected vena cava
cases of hilar cholangiocarcinoma.
■■LIVING-DONOR TRANSPLANTATION
Donor
Occasionally, especially for liver transplantation in children, one liver
deceased-donor organ can be split between two recipients (one adult
and one child). A more viable alternative, transplantation of the right
lobe of the liver from a healthy adult donor into an adult recipient, has
gained increased popularity. Living-donor transplantation of the left
lobe (left lateral segment), introduced in the early 1990s to alleviate Hepatic artery
the extreme shortage of donor organs for small children, accounts
currently for approximately one-third of all liver transplantation pro-
cedures in children. Driven by the shortage of deceased-donor organs,
living-donor transplantation involving the more sizable right lobe is
Portal vein
being considered with increasing frequency in adults; however, living- Common bile duct
donor liver transplantation cannot be expected to solve the donor Infrahepatic vena cava
organ shortage; 524 such procedures were done in 2019, representing
only ~4% of all liver transplant operations done in the United States.
Living-donor transplantation can reduce waiting time and cold
ischemia time; is done under elective, rather than emergency, circum- FIGURE 345-1 The anastomoses in orthotopic liver transplantation. The anastomoses
are performed in the following sequence: (1) suprahepatic and infrahepatic vena
stances; and may be lifesaving in recipients who cannot afford to wait cava, (2) portal vein, (3) hepatic artery, and (4) common bile duct-to-duct anastomosis.
for a deceased donor. The downside, of course, is the risk to the healthy (From JL Dienstag, AB Cosimi: Liver transplantation—a vision realized. N Engl J Med
donor (a mean of 10 weeks of medical disability; biliary complica- 367:1483, 2012. Copyright © 2012 Massachusetts Medical Society. Reprinted with
tions in ~5%; postoperative complications such as wound infection, permission from Massachusetts Medical Society.)

HPIM21e_Part10_p2381-p2670.indd 2636 20/01/22 10:05 PM

 the right (for adults) lobe of the liver is harvested from a living donor hirsutism or gingival hyperplasia. Because of overlapping toxicity 2637
for transplantation into the recipient. In the adult procedure, once the between cyclosporine and tacrolimus, especially nephrotoxicity, and
right lobe is removed from the donor, the donor right hepatic vein is because tacrolimus reduces cyclosporine clearance, these two drugs
anastomosed to the recipient right hepatic vein remnant, followed by should not be used together. Because 99% of tacrolimus is metabolized
donor-to-recipient anastomoses of the portal vein and then the hepatic by the liver, hepatic dysfunction reduces its clearance; in primary graft
artery. Finally, the biliary anastomosis is performed, duct-to-duct if nonfunction (when, for technical reasons or because of ischemic dam-
practical or via Roux-en-Y anastomosis. Heterotopic liver transplanta- age prior to its insertion, the allograft is defective and does not func-
tion, in which the donor liver is inserted without removal of the native tion normally from the outset), tacrolimus doses have to be reduced
liver, has met with very limited success and acceptance, except in a very substantially, especially in children. Both cyclosporine and tacrolimus
small number of centers. In attempts to support desperately ill patients are metabolized by the cytochrome P450 IIIA system, and therefore,
until a suitable donor organ can be identified, several transplantation drugs that induce cytochrome P450 (e.g., phenytoin, phenobarbital,
centers are studying extracorporeal perfusion with bioartificial liver carbamazepine, rifampin) reduce available levels of cyclosporine and
cartridges constructed from hepatocytes bound to hollow fiber systems tacrolimus, and drugs that inhibit cytochrome P450 (e.g., erythromy-
and used as temporary hepatic-assist devices, but their efficacy remains cin, fluconazole, ketoconazole, clotrimazole, itraconazole, verapamil,
to be established. Areas of research with the potential to overcome diltiazem, danazol, metoclopramide, the HIV protease inhibitor
the shortage of donor organs include hepatocyte transplantation and ritonavir, and the HCV protease inhibitors glecaprevir [cyclosporine
xenotransplantation with genetically modified organs of nonhuman only] and grazoprevir) increase cyclosporine and tacrolimus blood
origin (e.g., swine). levels. Indeed, itraconazole is used occasionally to help boost tacroli-
mus levels. Like azathioprine, cyclosporine and tacrolimus appear to
POSTOPERATIVE COURSE AND be associated with a risk of lymphoproliferative malignancies (see
MANAGEMENT below), which may occur earlier after cyclosporine or tacrolimus than
after azathioprine therapy. Because of these side effects, combinations
■■IMMUNOSUPPRESSIVE THERAPY of cyclosporine or tacrolimus with prednisone and an antimetabo-
The introduction in 1980 of cyclosporine as an immunosuppressive lite (azathioprine or mycophenolic acid, see below)—all at reduced
agent contributed substantially to the improvement in survival after doses—are preferable regimens for immunosuppressive therapy.
liver transplantation. Cyclosporine, a calcineurin inhibitor, blocks Mycophenolic acid, a nonnucleoside purine metabolism inhibitor
early activation of T cells and is specific for T-cell functions that result derived as a fermentation product from several Penicillium species, is
from the interaction of the T cell with its receptor and that involve another immunosuppressive drug being used for patients undergoing

CHAPTER 345 Liver Transplantation

the calcium-dependent signal transduction pathway. As a result, the liver transplantation. Mycophenolate has been shown to be better than
activity of cyclosporine leads to inhibition of lymphokine gene acti- azathioprine, when used with other standard immunosuppressive
vation, blocking interleukins 2, 3, and 4, tumor necrosis factor α, and drugs, in preventing rejection after renal transplantation and has been
other lymphokines. Cyclosporine also inhibits B-cell functions. This adopted widely as well for use in liver transplantation. The most com-
process occurs without affecting rapidly dividing cells in the bone mon adverse effects of mycophenolate are bone marrow suppression
marrow, which may account for the reduced frequency of posttrans- and gastrointestinal complaints.
plantation systemic infections. The most common and important side In patients with pretransplantation renal dysfunction or renal dete-
effect of cyclosporine therapy is nephrotoxicity. Cyclosporine causes rioration that occurs intraoperatively or immediately postoperatively,
dose-dependent renal tubular injury and direct renal artery vasospasm. tacrolimus or cyclosporine therapy may not be practical; under these
Following renal function is therefore important in monitoring cyclo- circumstances, induction or maintenance of immunosuppression with
sporine therapy and is perhaps even a more reliable indicator than antithymocyte globulin (ATG; thymoglobulin) or monoclonal anti-
blood levels of the drug. Nephrotoxicity is reversible and can be man- bodies to T cells, OKT3, may be appropriate. Therapy with these agents
aged by dose reduction. Other adverse effects of cyclosporine therapy has been especially effective in reversing acute rejection in the post-
include hypertension, hyperkalemia, tremor, hirsutism, glucose intol- transplantation period and is the standard treatment for acute rejection
erance, and gingival hyperplasia. that fails to respond to methylprednisolone boluses. Available data sup-
Tacrolimus, a macrolide lactone antibiotic isolated from a Japanese port the use of thymoglobulin induction to delay calcineurin inhibitor
soil fungus, Streptomyces tsukubaensis, has the same mechanism of use and its attendant nephrotoxicity. IV infusions of thymoglobulin
action as cyclosporine but is 10–100 times more potent. Initially may be complicated by fever and chills, which can be ameliorated by
applied as “rescue” therapy for patients in whom rejection occurred premedication with antipyretics and a low dose of glucocorticoids.
despite the use of cyclosporine, tacrolimus was shown to be associated Infusions of OKT3 may be complicated by fever, chills, and diarrhea
with a reduced frequency of acute, refractory, and chronic rejection. or by pulmonary edema, which can be fatal. Because OKT3 is such a
Although patient and graft survival are the same with these two drugs, potent immunosuppressive agent, its use is also more likely to be com-
the advantage of tacrolimus in minimizing episodes of rejection, reduc- plicated by opportunistic infection or lymphoproliferative disorders;
ing the need for additional glucocorticoid doses, and reducing the therefore, because of the availability of alternative immunosuppressive
likelihood of bacterial and cytomegalovirus (CMV) infection has sim- drugs, OKT3 is now used sparingly.
plified the management of patients undergoing liver transplantation. Sirolimus, an inhibitor of the mammalian target of rapamycin
In addition, the oral absorption of tacrolimus is more predictable than (mTOR), blocks later events in T-cell activation and is approved for
that of cyclosporine, especially during the early postoperative period use in kidney transplantation, but it is not formally approved for use
when T-tube drainage interferes with the enterohepatic circulation of in liver transplant recipients because of the reported association with
cyclosporine. As a result, in most transplantation centers, tacrolimus an increased frequency of hepatic artery thrombosis in the first month
has now supplanted cyclosporine for primary immunosuppression, after transplantation. In patients with calcineurin inhibitor–related
and many centers rely on oral rather than IV administration from the nephrotoxicity, conversion to sirolimus has been demonstrated to be
outset. For transplantation centers that prefer cyclosporine, a better- effective in preventing rejection with accompanying improvements in
absorbed microemulsion preparation is available. renal function. Because of its profound antiproliferative effects, siroli-
Although more potent than cyclosporine, tacrolimus is also more mus has also been suggested to be a useful immunosuppressive agent
toxic and more likely to be discontinued for adverse events. The in patients with a prior or current history of malignancy, such as HCC.
toxicity of tacrolimus is similar to that of cyclosporine; nephrotox- Side effects include hyperlipidemia, peripheral edema, oral ulcers,
icity and neurotoxicity are the most commonly encountered adverse and interstitial pneumonitis. Everolimus is a hydroxyethyl derivative
effects, and neurotoxicity (tremor, seizures, hallucinations, psychoses, of sirolimus that, when used in conjunction with low-dose tacroli-
coma) is more likely and more severe in tacrolimus-treated patients. mus, also provides successful protection against acute rejection, with
Both drugs can cause diabetes mellitus, but tacrolimus does not cause decreased renal impairment compared to that associated with standard

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 2638 tacrolimus dosing. Everolimus and sirolimus share a similar adverse TABLE 345-5 Hepatic Complications of Liver Transplantation
events profile. The most important principle of immunosuppression is
Hepatic Dysfunction Common after Major Surgery
that the ideal approach strikes a balance between immunosuppression
and immunologic competence. In general, given sufficient immuno- Prehepatic Pigment load
suppression, acute liver allograft rejection is nearly always reversible. Hemolysis
On one hand, incompletely treated acute rejection predisposes to the Blood collections (hematomas, abdominal
development of chronic rejection, which can threaten graft survival. collections)
On the other hand, if the cumulative dose of immunosuppressive ther- Intrahepatic
apy is too large, the patient may succumb to opportunistic infection. Early Hepatotoxic drugs and anesthesia
In hepatitis C, pulse glucocorticoids or OKT3 use accelerates recurrent Hypoperfusion (hypotension, shock, sepsis)
allograft hepatitis, although the routine use of DAA therapy to clear
Benign postoperative cholestasis
the allograft of HCV should remove this concern. Further complicating
matters, acute rejection can be difficult to distinguish histologically Late Transfusion-associated hepatitis
from recurrent hepatitis C. Therefore, immunosuppressive drugs must Exacerbation of primary hepatic disease
be used judiciously, with strict attention to the infectious consequences Posthepatic Biliary obstruction
of such therapy and careful confirmation of the diagnosis of acute ↓ Renal clearance of conjugated bilirubin (renal
rejection. In this vein, efforts have been made to minimize the use dysfunction)
of glucocorticoids, a mainstay of immunosuppressive regimens, and Hepatic Dysfunction Unique to Liver Transplantation
steroid-free immunosuppression can be achieved in some instances.
Primary graft nonfunction
Patients who undergo liver transplantation for autoimmune diseases
such as primary biliary cholangitis, autoimmune hepatitis, and pri- Vascular compromise Portal vein obstruction
mary sclerosing cholangitis are less likely to achieve freedom from Hepatic artery thrombosis
glucocorticoids. Anastomotic leak with intraabdominal bleeding
Bile duct disorder Stenosis, obstruction, leak
■■POSTOPERATIVE COMPLICATIONS
Complications of liver transplantation can be divided into nonhepatic Rejection
and hepatic categories (Tables 345-4 and 345-5). In addition, both Recurrent primary
immediate postoperative and late complications are encountered. As a hepatic disease
rule, patients who undergo liver transplantation have been chronically
ill for protracted periods and may be malnourished and wasted. The
PART 10

impact of such chronic illness and the multisystem failure that accom- during the operation, patients may remain fluid overloaded during the
panies liver failure continue to require attention in the postoperative immediate postoperative period, straining cardiovascular reserve; this
period. Because of the massive fluid losses and fluid shifts that occur effect can be amplified in the face of transient renal dysfunction and
pulmonary capillary vascular permeability. Continuous monitoring
Disorders of the Gastrointestinal System

TABLE 345-4 Nonhepatic Complications of Liver Transplantation of cardiovascular and pulmonary function, measures to maintain the
CATEGORY COMPLICATION integrity of the intravascular compartment and to treat extravascu-
lar volume overload, and scrupulous attention to potential sources
Cardiovascular instability Arrhythmias
and sites of infection are of paramount importance. Cardiovascular
Congestive heart failure instability may also result from the electrolyte imbalance that may
Cardiomyopathy accompany reperfusion of the donor liver as well as from restoration
Pulmonary compromise Pneumonia of systemic vascular resistance following implantation. Pulmonary
Pulmonary capillary vascular permeability function may be compromised further by paralysis of the right hem-
Fluid overload idiaphragm associated with phrenic nerve injury. The hyperdynamic
Renal dysfunction Prerenal azotemia
state with increased cardiac output that is characteristic of patients
with liver failure reverses rapidly after successful liver transplantation.
Hypoperfusion injury (acute tubular necrosis) Other immediate management issues include renal dysfunction.
Drug nephrotoxicity Prerenal azotemia, acute kidney injury associated with hypoperfu-
↓ Renal blood flow secondary to ↑ intraabdominal sion (acute tubular necrosis), and renal toxicity caused by antibiotics,
pressure tacrolimus, or cyclosporine are encountered frequently in the post-
Hematologic Anemia secondary to gastrointestinal and/or operative period, sometimes necessitating dialysis. Hemolytic-uremic
intraabdominal bleeding syndrome can be associated with cyclosporine, tacrolimus, or OKT3.
Hemolytic anemia, aplastic anemia Occasionally, postoperative intraperitoneal bleeding may be sufficient
Thrombocytopenia to increase intraabdominal pressure, which, in turn, may reduce renal
Infection Bacterial: early, common postoperative infections blood flow; this effect is rapidly reversible when abdominal distention
is relieved by exploratory laparotomy to identify and ligate the bleeding
Fungal/parasitic: late, opportunistic infections
site and to remove intraperitoneal clot.
Viral: late, opportunistic infections, recurrent Anemia may also result from acute upper gastrointestinal bleeding
hepatitis
or from transient hemolytic anemia, which may be autoimmune, espe-
Neuropsychiatric Seizures cially when blood group O livers are transplanted into blood group A
Metabolic encephalopathy or B recipients. This autoimmune hemolytic anemia is mediated by
Depression donor intrahepatic lymphocytes that recognize red blood cell A or B
Difficult psychosocial adjustment antigens on recipient erythrocytes. Transient in nature, this process
Diseases of donor Infectious resolves once the donor liver is repopulated by recipient bone marrow–
Malignant
derived lymphocytes; the hemolysis can be treated by transfusing
blood group O red blood cells and/or by administering higher doses
Malignancy B-cell lymphoma (posttransplantation of glucocorticoids. Transient thrombocytopenia is also commonly
lymphoproliferative disorders)
encountered. Aplastic anemia, a late occurrence, is rare but has been
De novo neoplasms (particularly squamous cell reported in almost 30% of patients who underwent liver transplanta-
skin carcinoma)
tion for acute, severe hepatitis of unknown cause.

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 Bacterial, fungal, or viral infections are common and may be Hepatic complications unique to liver transplantation include primary 2639
life-threatening postoperatively. Early after transplant surgery, com- graft failure associated with ischemic injury to the organ during har-
mon postoperative infections predominate—pneumonia, wound infec- vesting; vascular compromise associated with thrombosis or stenosis
tions, infected intraabdominal collections, urinary tract infections, of the portal vein or hepatic artery anastomoses; vascular anastomotic
and IV line infections—rather than opportunistic infections; these leak; stenosis, obstruction, or leakage of the anastomosed common bile
infections may involve the biliary tree and liver as well. Beyond the first duct; recurrence of primary hepatic disorder (see below); and rejection.
postoperative month, the toll of immunosuppression becomes evident,
and opportunistic infections—CMV, herpes viruses, fungal infections ■■TRANSPLANT REJECTION
(Aspergillus, Candida, cryptococcal disease), mycobacterial infections, Despite the use of immunosuppressive drugs, rejection of the trans-
parasitic infections (Pneumocystis, Toxoplasma), and bacterial infec- planted liver still occurs in a proportion of patients, beginning 1–2
tions (Nocardia, Legionella, Listeria)—predominate. Rarely, early infec- weeks after surgery. Clinical signs suggesting rejection are fever, right
tions represent those transmitted with the donor liver, either infections upper quadrant pain, and reduced bile pigment and volume. Leukocy-
present in the donor or infections acquired during procurement tosis may occur, but the most reliable indicators are increases in serum
processing. De novo viral hepatitis infections acquired from the donor bilirubin and aminotransferase levels. Because these tests lack specific-
organ or, almost unheard of now, from transfused blood products ity, distinguishing among rejection, biliary obstruction, primary graft
occur after typical incubation periods for these agents (well beyond nonfunction, vascular compromise, viral hepatitis, CMV infection,
the first month). Obviously, infections in an immunosuppressed host drug hepatotoxicity, and recurrent primary disease may be difficult.
demand early recognition and prompt management; prophylactic Radiographic visualization of the biliary tree and/or percutaneous
antibiotic therapy is administered routinely in the immediate postop- liver biopsy often help to establish the correct diagnosis. Morphologic
erative period. Use of sulfamethoxazole with trimethoprim reduces the features of acute rejection include a mixed portal cellular infiltrate,
incidence of postoperative Pneumocystis jirovecii pneumonia. Antiviral bile duct injury, and/or endothelial inflammation (“endothelialitis”);
prophylaxis for CMV with ganciclovir should be administered in some of these findings are reminiscent of graft-versus-host disease,
patients at high risk (e.g., when a CMV-seropositive donor organ is primary biliary cholangitis, or recurrent allograft hepatitis C. As soon
implanted into a CMV-seronegative recipient). as transplant rejection is suspected, treatment consists of IV methyl-
Neuropsychiatric complications include seizures (commonly associated prednisolone in repeated boluses; if this fails to abort rejection, many
with cyclosporine and tacrolimus toxicity), metabolic encephalopathy, centers use thymoglobulin or OKT3. Caution should be exercised
depression, and difficult psychosocial adjustment. Rarely, diseases when managing acute rejection with pulse glucocorticoids or OKT3
are transmitted by the allograft from the donor to the recipient. In in patients with HCV infection, because of the high risk of triggering

CHAPTER 345 Liver Transplantation

addition to viral and bacterial infections, malignancies of donor ori- recurrent allograft hepatitis C. The availability of DAAs for HCV has
gin have occurred. Posttransplantation lymphoproliferative disorders, effectively obviated this concern.
especially B-cell lymphoma, are a recognized complication associated Chronic rejection is a relatively rare outcome that can follow repeated
with immunosuppressive drugs such as azathioprine, tacrolimus, and bouts of acute rejection or that occurs unrelated to preceding rejection
cyclosporine (see above). Epstein-Barr virus has been shown to play episodes. Morphologically, chronic rejection is characterized by pro-
a contributory role in some of these tumors, which may regress when gressive cholestasis, focal parenchymal necrosis, mononuclear infiltra-
immunosuppressive therapy is reduced. De novo neoplasms appear at tion, vascular lesions (intimal fibrosis, subintimal foam cells, fibrinoid
increased frequency after liver transplantation, particularly squamous necrosis), and fibrosis. This process may be reflected as ductopenia—
cell carcinomas of the skin. Routine screening should be performed. the vanishing bile duct syndrome, which is more common in patients
Long-term complications after liver transplantation attributable undergoing liver transplantation for autoimmune liver disease. Revers-
primarily to immunosuppressive medications include diabetes melli- ibility of chronic rejection is limited; in patients with therapy-resistant
tus and osteoporosis (associated with glucocorticoids and calcineurin chronic rejection, retransplantation has yielded encouraging results.
inhibitors) as well as hypertension, hyperlipidemia, and chronic
renal insufficiency (associated with cyclosporine and tacrolimus). OUTCOME
Monitoring and treating these disorders are routine components of
posttransplantation care; in some cases, they respond to changes in ■■SURVIVAL
immunosuppressive regimen, while in others, specific treatment of the The survival rate for patients undergoing liver transplantation has
disorder is introduced. Data from a large U.S. database showed that the improved steadily since 1983. One-year survival rates have increased
prevalence of renal failure was 18% at year 5 and 25% at year 10 after from ~70% in the early 1980s to 85–90% from 2003 to the present time.
liver transplantation. Similarly, the high frequency of diabetes, hyper- Currently, the 5-year survival rate exceeds 60%. An important obser-
tension, hyperlipidemia, obesity, and the metabolic syndrome renders vation is the relationship between clinical status before transplantation
patients susceptible to cardiovascular disease after liver transplanta- and outcome. For patients who undergo liver transplantation when
tion; although hepatic complications account for most of the mortality their level of compensation is high (e.g., still working or only partially
after liver transplantation, renal failure and cardiovascular disease are disabled), a 1-year survival rate of >85% is common. For those whose
the other leading causes of late mortality after liver transplantation. level of decompensation mandates continuous in-hospital care prior
to transplantation, the 1-year survival rate is ~70%, whereas for those
■■HEPATIC COMPLICATIONS who are so decompensated that they require life support in an intensive
Hepatic dysfunction after liver transplantation is similar to the hepatic care unit, the 1-year survival rate is ~50%. Since the adoption by UNOS
complications encountered after major abdominal and cardiothoracic in 2002 of the MELD system for organ allocation, posttransplantation
surgery; however, in addition, hepatic complications include primary survival has been found to be affected adversely for candidates with
graft failure, vascular compromise, failure or stricture of the biliary MELD scores >25, considered high disease severity. Thus, irrespective
anastomoses, and rejection. As in nontransplantation surgery, postoper- of allocation scheme, high disease severity before transplantation cor-
ative jaundice may result from prehepatic, intrahepatic, and posthepatic responds to diminished posttransplantation survival. Another impor-
sources. Prehepatic sources represent the massive hemoglobin pigment tant distinction in survival has been drawn between high- and low-risk
load from transfusions, hemolysis, hematomas, ecchymoses, and other patient categories. For patients who do not fit any “high-risk” desig-
collections of blood. Early intrahepatic liver injury includes effects of nations, 1- and 5-year survival rates of 85 and 80%, respectively, have
hepatotoxic drugs and anesthesia; hypoperfusion injury associated been recorded. In contrast, among patients in high-risk categories—
with hypotension, sepsis, and shock; and benign postoperative choles- cancer, fulminant hepatitis, age >65, concurrent renal failure, respi-
tasis. Late intrahepatic sources of liver injury include exacerbation of rator dependence, portal vein thrombosis, and history of a portacaval
primary disease. Posthepatic sources of hepatic dysfunction include shunt or multiple right upper quadrant operations—survival statistics
biliary obstruction and reduced renal clearance of conjugated bilirubin. fall into the range of 60% at 1 year and 35% at 5 years. Survival after

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 2640 retransplantation for primary graft nonfunction is ~50%. Causes of lowering of the risk of HBV reinfection from ~75 to 35% and a reduc-
failure of liver transplantation vary with time. Failures within the first tion in mortality from ~50 to 20%.
3 months result primarily from technical complications, postoperative As a result of long-term HBIg use following liver transplantation
infections, and hemorrhage. Transplant failures after the first 3 months for chronic hepatitis B, similar improvements in outcome have been
are more likely to result from infection, rejection, or recurrent disease observed in the United States, with 1-year survival rates between 75
(such as malignancy or viral hepatitis). and 90%. Currently, with HBIg prophylaxis, the outcome of liver trans-
plantation for chronic hepatitis B is indistinguishable from that for
chronic liver disease unassociated with chronic hepatitis B; essentially,
■■RECURRENCE OF PRIMARY DISEASE medical concerns regarding liver transplantation for chronic hepatitis B
Features of autoimmune hepatitis, primary sclerosing cholangitis, and have been eliminated. Passive immunoprophylaxis with HBIg is begun
primary biliary cholangitis overlap with those of rejection or post- during the anhepatic stage of surgery, repeated daily for the first 6
transplantation bile duct injury. Whether autoimmune hepatitis and postoperative days, and then continued with infusions that are given
sclerosing cholangitis recur after liver transplantation is controversial; either at regular intervals of 4–6 weeks or, alternatively, when anti–
data supporting recurrent autoimmune hepatitis (in up to one-third hepatitis B surface (HBs) levels fall below a threshold of 100 mIU/mL.
of patients in some series) are more convincing than those supporting The current approach in most centers is to continue HBIg indefinitely,
recurrent sclerosing cholangitis. Similarly, reports of recurrent primary which can add ~$20,000 per year to the cost of care; some centers are
biliary cholangitis after liver transplantation have appeared; however, evaluating regimens that shift to less frequent administration or to IM
the histologic features of primary biliary cholangitis and chronic administration in the late posttransplantation period or, in low-risk
rejection are virtually indistinguishable and occur as frequently in patients, maintenance with antiviral therapy (see below) alone. Still,
patients with primary biliary cholangitis as in patients undergoing “breakthrough” HBV infection occasionally occurs.
transplantation for other reasons. The presence of a florid inflamma- Further improving the outcome of liver transplantation for chronic
tory bile duct lesion is highly suggestive of the recurrence of primary hepatitis B is the current availability of such antiviral drugs as entecavir,
biliary cholangitis, but even this lesion can be observed in acute rejec- tenofovir disoproxil fumarate, and tenofovir alafenamide (Chap. 341).
tion. Hereditary disorders such as Wilson’s disease and α1 antitrypsin When these drugs are administered to patients with decompensated
deficiency have not recurred after liver transplantation; however, liver disease, a proportion improves sufficiently to postpone immi-
recurrence of disordered iron metabolism has been observed in some nent liver transplantation. In addition, antiviral therapy can be used
patients with hemochromatosis. Hepatic vein thrombosis (Budd- to prevent recurrence of HBV infection when administered prior to
Chiari syndrome) may recur; this can be minimized by treating under- transplantation; to treat hepatitis B that recurs after transplantation,
lying myeloproliferative disorders and by anticoagulation. Because including in patients who break through HBIg prophylaxis; and to
cholangiocarcinoma recurs almost invariably, few centers now offer
PART 10

reverse the course of otherwise fatal fibrosing cholestatic hepatitis.

transplantation to such patients; however, a few highly selected patients Clinical trials have shown that entecavir or tenofovir antiviral therapy
with operatively confirmed stage I or II cholangiocarcinoma who reduces the level of HBV replication substantially, sometimes even
undergo liver transplantation combined with neoadjuvant chemoradi- resulting in clearance of hepatitis B surface antigen (HBsAg); reduces
ation may experience excellent outcomes. In patients with intrahepatic alanine aminotransferase (ALT) levels; and improves histologic fea-
Disorders of the Gastrointestinal System

HCC who meet criteria for transplantation, 1- and 5-year survivals are tures of necrosis and inflammation. Currently, most liver transplanta-
similar to those observed in patients undergoing liver transplantation tion centers combine HBIg plus one of the high-barrier-to-resistance
for nonmalignant disease. Finally, metabolic disorders such as NAFLD oral nucleoside (entecavir) or nucleotide analogues (tenofovir). In
recur frequently, especially if the underlying metabolic predisposition low-risk patients with no detectable hepatitis B viremia at the time of
is not altered. The metabolic syndrome occurs commonly after liver transplantation, a number of clinical trials have suggested that antiviral
transplantation as a result of recurrent NAFLD, immunosuppressive prophylaxis can suffice, without HBIg or with a finite duration of HBIg,
medications, and/or, in patients with hepatitis C related to the impact to prevent recurrent HBV infection of the allograft. In patients docu-
of HCV infection on insulin resistance, diabetes and fatty liver. mented at the time of liver transplantation to have undetectable HBV
Hepatitis A can recur after transplantation for fulminant hepatitis DNA in serum and covalently closed circular DNA in the liver (i.e.,
A, but such acute reinfection has no serious clinical sequelae. In ful- with low risk for recurrence of HBV infection), a preliminary clinical
minant hepatitis B, recurrence is not the rule; however, in the absence trial suggested that, after receipt of 5 years of combined therapy, both
of any prophylactic measures, hepatitis B usually recurs after trans- HBIg and oral-agent therapy can be withdrawn sequentially (over two
plantation for end-stage chronic hepatitis B. Before the introduction of 6-month periods) with a success rate, as monitored over a median of
prophylactic antiviral therapy, immunosuppressive therapy sufficient 6 years after withdrawal, of 90% and an anti-HBs seroconversion rate
to prevent allograft rejection led inevitably to marked increases in of 60% (despite transient reappearance of HBV DNA and/or HBsAg in
hepatitis B viremia, regardless of pretransplantation levels. Overall some of these patients).
graft and patient survival were poor, and some patients experienced a Antiviral prophylactic approaches applied to patients undergoing
rapid recapitulation of severe injury—severe chronic hepatitis or even liver transplantation for chronic hepatitis B are being used as well
fulminant hepatitis—after transplantation. Also recognized in the era for patients without hepatitis B who receive organs from donors
before availability of antiviral regimens was fibrosing cholestatic hepatitis, with antibody to hepatitis B core antigen (anti-HBc) but do not have
rapidly progressive liver injury associated with marked hyperbiliru- HBsAg. Patients who undergo liver transplantation for chronic hepa-
binemia, substantial prolongation of the prothrombin time (both out titis B plus D are less likely to experience recurrent liver injury than
of proportion to relatively modest elevations of aminotransferase activ- patients undergoing liver transplantation for hepatitis B alone; still, such
ity), and rapidly progressive liver failure. This lesion has been suggested co-infected patients would also be offered standard posttransplantation
to represent a “choking off ” of the hepatocyte by an overwhelming prophylactic therapy for hepatitis B.
density of HBV proteins. Complications such as sepsis and pancreatitis Until recently, the most common indication for liver transplantation
were also observed more frequently in patients undergoing liver trans- was end-stage liver disease resulting from chronic hepatitis C. For
plantation for hepatitis B prior to the introduction of antiviral therapy. patients undergoing liver transplantation for hepatitis C, because of
The introduction of long-term prophylaxis with HBIg revolutionized an aggressive natural history of recurrent allograft hepatitis C, graft
liver transplantation for chronic hepatitis B. Preoperative hepatitis B and patient survival were diminished substantially compared to other
vaccination, preoperative or postoperative interferon (IFN) therapy, indications for transplantation.
or short-term (≤2 months) HBIg prophylaxis has not been shown to The approval over the last decade of several DAA agents and of
be effective, but a retrospective analysis of data from several hundred IFN-free DAA regimens against HCV has had a major impact on the
European patients followed for 3 years after transplantation has shown management and outcome of both pretransplantation and posttrans-
that long-term (≥6 months) prophylaxis with HBIg is associated with a plantation HCV infection. Such therapeutic approaches (1) permit

HPIM21e_Part10_p2381-p2670.indd 2640 20/01/22 10:05 PM

 the clearance of viremia in a substantial proportion of decompensated 2020. (Updated regularly, available at http://www.hcvguidelines.org.) 2641
cirrhotics, thereby preventing recurrent allograft infection and even Accessed August 24, 2021.
improving the clinical status of most of these patients, delaying or Cotter TG et al: Improved graft survival after liver transplantation
obviating the need for liver replacement; and (2) achieve sustained for recipients with hepatitis C virus in the direct-acting antiviral era.
virologic responses in a much higher proportion of persons with allog- Liver Transpl 25:598, 2019.
raft HCV infection, because of improvements in antiviral treatment European Association for the Study of the Liver: EASL clinical
efficacy and tolerability. Ideally, patients should be treated prior to practice guidelines: Liver transplantation. J Hepatol 64:433, 2016.
liver transplantation. This approach has already reduced the numbers Fung J et al: Outcomes including liver histology after liver transplan-
of patients referred for liver transplantation and led to delisting of tation for chronic hepatitis B using oral antiviral therapy alone. Liver
others. A concern, however, is that eradication of HCV infection will Transpl 21:1504, 2015.
reduce the MELD score and lower the priority for a donor organ in Goldberg D et al: Changes in the prevalence of hepatitis C virus
some patients who still require transplantation because of continued infection, nonalcoholic steatohepatitis, and alcoholic liver disease
hepatic decompensation and profound reduction in quality of life. In among patients with cirrhosis or liver failure on the waitlist for liver
addition, elimination of HCV infection prior to transplantation would transplantation. Gastroenterology 152:1090, 2017.
disqualify such patients from accepting donor livers from persons Kwo PY et al: An interferon-free antiviral regimen for HCV after liver
with HCV infection, contracting the potential donor pool and limiting transplantation. N Engl J Med 371:2375, 2014.
accessibility to donor organs and timely transplantation. Therefore, Lenci I et al: Complete hepatitis B virus prophylaxis withdrawal in
consideration should be given to postponing DAA therapy in patients hepatitis B surface antigen-positive liver transplant recipients after
with high-MELD HCV-associated end-stage liver disease until after long-term minimal immunosuppression. Liver Transpl 22:1205,
liver transplantation; however, a distinct threshold at which to treat 2016.
pretransplantation or posttransplantation has not yet been estab- Lucey MR et al: Long-term management of the successful adult liver
lished. Regardless, the approach to treatment should be individualized transplant: 2012 practice guideline by the American Association for
thoughtfully for each patient, based on such factors as MELD score, the Study of Liver Diseases and the American Society of Transplanta-
time anticipated prior to availability of a donor organ, relative clinical tion. Liver Transpl 19:3, 2013.
stability, and comorbidities. Manns M et al: Ledipasvir and sofosbuvir plus ribavirin in patients
DAA combinations that have been used successfully against allog- with genotype 1 or 4 hepatitis C virus infection and advanced liver
raft HCV include ledipasvir, sofosbuvir, and ribavirin; velpatasvir, disease: A multicentre, open-label, randomised, phase 2 trial. Lancet
sofosbuvir, and ribavirin; and grazoprevir and pibrentasvir. (For Infect Dis 16:685, 2016.

CHAPTER 346 Diseases of the Gallbladder and Bile Ducts

updated guidelines, see www.hcvguidelines.org.) In patients with recur- Martin P et al: Evaluation for liver transplantation in adults: 2013
rent HCV infection after liver transplantation, each of these regimens practice guideline by the American Association for the Study of Liver
has yielded response rates approaching those seen in compensated Diseases and the American Society of Transplantation. Hepatology
nontransplant patient populations. 59:1145, 2014.
A small number of allograft recipients have historically succumbed Reau N et al: Glecaprevir/pibrentasvir treatment in liver or kidney
to early HCV-associated liver injury, and a syndrome reminiscent of transplant patients with hepatitis C virus infection. Hepatology
fibrosing cholestatic hepatitis (see above) has been observed rarely. 68:1298, 2018.
Currently, however, the routine use of DAA regimens early after trans-
plantation, before the onset of these variant presentations, has already
had a profound impact on the frequency of severe recurrent allograft
hepatitis C.
Patients who undergo liver transplantation for end-stage alco-
hol-associated cirrhosis are at risk of resorting to drinking again after
transplantation, a potential source of recurrent alcohol-associated liver
injury. Currently, alcohol-associated liver disease is the most common
346 Diseases of the
Gallbladder and Bile Ducts
indication for liver transplantation, accounting for 30% of all liver
transplantation procedures, and most transplantation centers screen Norton J. Greenberger*, Gustav Paumgartner,
candidates carefully for predictors of continued abstinence. Recidivism Daniel S. Pratt
is more likely in patients whose sobriety prior to transplantation was
<6 months. For abstinent patients with alcohol-associated cirrhosis,
liver transplantation can be undertaken successfully, with outcomes
comparable to those for other categories of patients with chronic liver PHYSIOLOGY OF BILE PRODUCTION
disease, when coordinated by a team approach that includes substance AND FLOW
abuse counseling.
■■BILE SECRETION AND COMPOSITION
■■POSTTRANSPLANTATION QUALITY OF LIFE Bile formed in hepatocytes is secreted into a complex network of cana-
Full rehabilitation is achieved in most patients who survive the early liculi, small bile ductules, and larger bile ducts that run with lymphatics
postoperative months and escape chronic rejection or unmanageable and branches of the portal vein and hepatic artery in portal tracts situ-
infection. Psychosocial maladjustment interferes with medical com- ated between hepatic lobules. These interlobular bile ducts coalesce to
pliance in a small number of patients, but most manage to adhere to form larger septal bile ducts that join to form the right and left hepatic
immunosuppressive regimens, which must be continued indefinitely. ducts, which in turn, unite to form the common hepatic duct. The
In one study, 85% of patients who survived their transplant operations common hepatic duct is joined by the cystic duct of the gallbladder to
returned to gainful activities. In fact, some women have conceived and form the common bile duct (CBD), which enters the duodenum (often
carried pregnancies to term after transplantation without demonstra- after joining the main pancreatic duct) through the ampulla of Vater.
ble injury to their infants. Hepatic bile is an isotonic fluid with an electrolyte composition
resembling blood plasma. The electrolyte composition of gallbladder
■■FURTHER READING
bile differs from that of hepatic bile because most of the inorganic
AASLD/IDSA HCV Guidance Panel: Hepatitis C guidance 2019
anions, chloride, and bicarbonate have been removed by reabsorption
update: American Association for the Study of Liver Diseases-Infectious
across the gallbladder epithelium. As a result of water reabsorption,
Diseases Society of America recommendations for testing, man-
total solute concentration of bile increases from 3–4 g/dL in hepatic
aging, and treating hepatitis C virus infection. Hepatology 71:686,
bile to 10–15 g/dL in gallbladder bile.
*
Deceased.

HPIM21e_Part10_p2381-p2670.indd 2641 20/01/22 10:05 PM

 2642 Major solute components of bile by moles percent include bile Bile acids are detergent-like molecules that in aqueous solutions
acids (80%), phospholipids (lecithins, cephalins, and sphingomyelin) and above a critical concentration of ~2 mM form molecular aggre-
(16%), and unesterified cholesterol (4.0%). In the lithogenic state, the gates called micelles. Cholesterol alone is sparingly soluble in aqueous
cholesterol value can be as high as 8–10%. Other constituents include environments, and its solubility in bile depends on both the total
conjugated bilirubin; proteins (all immunoglobulins, albumin, metab- lipid concentration and the relative molar percentages of bile acids
olites of hormones, and other proteins metabolized in the liver); elec- and lecithin. Normal ratios of these constituents favor the formation
trolytes; mucus; heavy metals; and, often, drugs and their metabolites. of solubilizing mixed micelles, while abnormal ratios promote the
The total daily basal secretion of hepatic bile is ~500–600 mL. Many precipitation of cholesterol crystals in bile via an intermediate liquid
substances taken up or synthesized by the hepatocyte are secreted into crystal phase.
the bile canaliculi. The canalicular membrane forms microvilli and is In addition to facilitating the biliary excretion of cholesterol, bile
associated with microfilaments of actin, microtubules, and other con- acids facilitate the normal intestinal absorption of dietary fats, mainly
tractile elements. Prior to their secretion into the bile, many substances cholesterol, and fat-soluble vitamins, via a micellar transport mecha-
are taken up into the hepatocyte, while others, such as phospholipids, nism (Chap. 325). Bile acids also serve as a major physiologic driving
a portion of primary bile acids, and some cholesterol, are synthesized force for hepatic bile flow and aid in water and electrolyte transport in
de novo in the hepatocyte. Three mechanisms are important in reg- the small bowel and colon.
ulating bile flow: (1) active transport of bile acids from hepatocytes Bile acids also function as hormones binding to nuclear (farnesoid X
into the bile canaliculi, (2) active transport of other organic anions, receptor [FXR]) and G protein–coupled (TGR5) receptors that regulate
and (3) cholangiocellular secretion. The last is a secretin-mediated and bile acid metabolism and their enterohepatic circulation.
cyclic AMP–dependent mechanism that results in the secretion of a
bicarbonate-rich fluid into the bile ducts. ■■ENTEROHEPATIC CIRCULATION
Active vectorial trans-hepatocellular movement of bile acids from Bile acids are efficiently conserved under normal conditions. Uncon-
the portal blood into the bile canaliculi is driven by a set of trans- jugated, and to a lesser degree also conjugated, bile acids are absorbed
port systems at the basolateral (sinusoidal) and the canalicular apical by passive diffusion along the entire gut. Quantitatively much more
plasma membrane domains of the hepatocyte. Two sinusoidal bile salt important for bile salt recirculation, however, is the active transport
uptake systems have been cloned in humans, the Na+/taurocholate mechanism for conjugated bile acids in the distal ileum (Chap. 325).
cotransporter (NTCP, SLC10A1) and the organic anion–transporting The reabsorbed bile acids enter the portal bloodstream and are taken
proteins (OATP1B1/1B3), which also transport a large variety of non– up rapidly by hepatocytes, reconjugated, and resecreted into bile
bile salt organic anions. Several ATP-dependent canalicular transport (enterohepatic circulation).
systems, “export pumps” (ATP-binding cassette transport proteins, The normal bile acid pool size is ~2–4 g. During digestion of a meal,
PART 10

also known as ABC transporters), have been identified, the most the bile acid pool undergoes at least one or more enterohepatic cycles,
important of which are the bile salt export pump (BSEP, ABCB11); depending on the size and composition of the meal. Normally, the bile
the anionic conjugate export pump (MRP2, ABCC2), which mediates acid pool circulates ~5–10 times daily. Intestinal reabsorption of the
the canalicular excretion of various amphiphilic conjugates formed by pool is ~95% efficient; therefore, daily fecal loss of bile acids is in the
phase II conjugation (e.g., bilirubin mono- and diglucuronides and range of 0.2–0.4 g. In the steady state, this fecal loss is compensated
Disorders of the Gastrointestinal System

drugs); the multidrug export pump (MDR1, ABCB1) for hydropho- by an equal daily synthesis of bile acids by the liver, and thus, the size
bic cationic compounds; and the phospholipid export pump (MDR3, of the bile acid pool is maintained. Bile acids in the intestine stimulate
ABCB4). Two hemitransporters, ABCG5/G8, functioning as a couple, the release of fibroblast growth factor 19 (FGF19), which suppresses
constitute the canalicular cholesterol and phytosterol transporter. F1C1 the hepatic synthesis of bile acids from cholesterol by inhibiting the
(ATP8B1) is an aminophospholipid transferase (“flippase”) essential rate-limiting enzyme cytochrome P450 7A1 (CYP7A1). FGF19 also
for maintaining the lipid asymmetry of the canalicular membrane. The promotes gallbladder relaxation. While the loss of bile salts in stool is
canalicular membrane also contains ATP-independent transport sys- usually matched by increased hepatic synthesis, the maximum rate of
tems such as the Cl/HCO3 anion exchanger isoform 2 (AE2, SLC4A2) synthesis is ~5 g/d, which may be insufficient to replete the bile acid
for canalicular bicarbonate secretion. For most of these transporters, pool size when there is pronounced impairment of intestinal bile salt
genetic defects have been identified that are associated with various reabsorption.
forms of cholestasis or defects of biliary excretion. F1C1 (ATP8B1) is The expression of ABC transporters in the enterohepatic circulation
defective in progressive familial intrahepatic cholestasis type 1 (PFIC1) and of the rate-limiting enzymes of bile acid and cholesterol syn-
and benign recurrent intrahepatic cholestasis type 1 (BRIC1) and thesis are regulated in a coordinated fashion by nuclear receptors,
results in ablation of all other ATP-dependent transporter functions. which are ligand-activated transcription factors. The hepatic BSEP
BSEP (ABCB11) is defective in PFIC2 and BRIC2. Mutations of MRP2 (ABCB11) is upregulated by the FXR that also represses bile acid
(ABCC2) cause the Dubin-Johnson syndrome, an inherited form synthesis. The expression of the cholesterol transporter, ABCG5/G8,
of conjugated hyperbilirubinemia (Chap. 338). A defective MDR3 is upregulated by the liver X receptor (LXR), which is an oxysterol
(ABCB4) results in PFIC3. ABCG5/G8, the canalicular half transport- sensor.
ers for cholesterol and other neutral sterols, are defective in sitoster-
olemia. The cystic fibrosis transmembrane regulator (CFTR, ABCC7), ■■GALLBLADDER AND SPHINCTERIC FUNCTIONS
located on bile duct epithelial cells but not on canalicular membranes, In the fasting state, the sphincter of Oddi (SOD) offers a high-pressure
is defective in cystic fibrosis, which is associated with impaired cholan- zone of resistance to bile flow from the CBD into the duodenum. Its
giocellular pH regulation during ductular bile formation and chronic tonic contraction serves to (1) prevent reflux of duodenal contents into
cholestatic liver disease, occasionally resulting in biliary cirrhosis. the pancreatic and bile ducts and (2) promote filling of the gallblad-
der. The major factor controlling the evacuation of the gallbladder is
■■THE BILE ACIDS the peptide hormone cholecystokinin (CCK), which is released from
The primary bile acids, cholic acid and chenodeoxycholic acid the duodenal mucosa in response to the ingestion of fats and amino
(CDCA), are synthesized in hepatocytes from cholesterol, conjugated acids. CCK produces (1) powerful contraction of the gallbladder, (2)
with glycine or taurine, and secreted into the bile canaliculus. Second- decreased resistance of the SOD, and (3) enhanced flow of biliary con-
ary bile acids, including deoxycholate and lithocholate, are formed in tents into the duodenum.
the colon as bacterial metabolites of the primary bile acids. However, Hepatic bile is “concentrated” within the gallbladder by energy-
lithocholic acid is much less efficiently absorbed from the colon than dependent transmucosal absorption of water and electrolytes. Almost
deoxycholic acid. Another secondary bile acid, found in low concen- the entire bile acid pool may be sequestered in the gallbladder follow-
tration, is ursodeoxycholic acid (UDCA), a stereoisomer of CDCA. In ing an overnight fast for delivery into the duodenum with the first meal
healthy subjects, the ratio of glycine to taurine conjugates in bile is ~3:1. of the day. The normal capacity of the gallbladder is ~30 mL.

HPIM21e_Part10_p2381-p2670.indd 2642 20/01/22 10:05 PM

 DISEASES OF THE GALLBLADDER ABCG5/G8 CYP7A1 MDR3 (ABCB4) 2643

■■CONGENITAL ANOMALIES
Anomalies of the biliary tract are not uncommon and include abnor- I.
malities in number, size, and shape (e.g., agenesis of the gallbladder,
duplications, rudimentary or oversized “giant” gallbladders, and diver- Cholesterol Normal cholesterol Normal cholesterol
ticula). Phrygian cap is a clinically innocuous entity in which a partial Normal bile acids Bile acids Normal bile acids
or complete septum (or fold) separates the fundus from the body. Normal lecithin Normal lecithin Lecithin
Anomalies of position or suspension are not uncommon and include
left-sided gallbladder, intrahepatic gallbladder, retrodisplacement of
the gallbladder, and “floating” gallbladder. The latter condition predis-
II. Supersaturation
poses to acute torsion, volvulus, or herniation of the gallbladder.

■■GALLSTONES Promote nucleation Inhibit nucleation

Mucous glycoproteins Apolipoproteins
Epidemiology and Pathogenesis Gallstones are quite prevalent Heat-labile proteins Lecithin vesicles
in most Western countries. Gallstone formation increases after age 50.
In the United States, the prevalence is highest in Native Americans
followed by Hispanics, non-Hispanic whites, and black Americans. The III. Nucleation
prevalence is higher in women than men across all ages.
Gallstones form because of abnormal bile composition. They are
divided into two major types: cholesterol stones and pigment stones.
Cholesterol stones account for >90% of all gallstones in Western industri-
alized countries. Cholesterol gallstones usually contain >50% cholesterol
monohydrate plus an admixture of calcium salts, bile pigments, proteins, IV. Microstone
and fatty acids. Pigment stones are composed primarily of calcium biliru-
binate; they contain <20% cholesterol and are classified into “black” and
“brown” types, the latter forming secondary to chronic biliary infection.

CHAPTER 346 Diseases of the Gallbladder and Bile Ducts

CHOLESTEROL STONES AND BILIARY SLUDGE Cholesterol is essen-
tially water-insoluble and requires aqueous dispersion into either
micelles or vesicles, both of which require the presence of a second
lipid to solubilize the cholesterol. Cholesterol and phospholipids are Gallstone
secreted into bile as unilamellar bilayered vesicles, which are converted
into mixed micelles consisting of bile acids, phospholipids, and cho-
lesterol by the action of bile acids. If there is an excess of cholesterol FIGURE 346-1 Scheme showing pathogenesis of cholesterol gallstone
in relation to phospholipids and bile acids, unstable, cholesterol-rich formation. Conditions or factors that increase the ratio of cholesterol to bile
vesicles remain, which aggregate into large multilamellar vesicles from acids and phospholipids (lecithin) favor gallstone formation. ABCB4, ATP-binding
which cholesterol crystals precipitate (Fig. 346-1). cassette transporter; ABCG5/8, ATP-binding cassette (ABC) transporter G5/G8;
There are several important mechanisms in the formation of CYP7A1, cytochrome P450 7A1; MDR3, multidrug resistance protein 3, also called
lithogenic (stone-forming) bile. The most important is increased phospholipid export pump.
biliary secretion of cholesterol. This may occur in association with
obesity, the metabolic syndrome, high-caloric and cholesterol-rich the initial step in cholesterol catabolism and bile acid synthesis. The
diets, or drugs (e.g., clofibrate) and may result from increased activity homozygous state is associated with hypercholesterolemia and gall-
of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, the stones. Because the phenotype is expressed in the heterozygote state,
rate-limiting enzyme of hepatic cholesterol synthesis, and increased mutations in the CYP7A1 gene may contribute to the susceptibility to
hepatic uptake of cholesterol from blood. In patients with gallstones, cholesterol gallstone disease in the population. Mutations in the MDR3
dietary cholesterol increases biliary cholesterol secretion. This does not (ABCB4) gene, which encodes the phospholipid export pump in the
occur in non-gallstone patients on high-cholesterol diets. In addition canalicular membrane of the hepatocyte, may cause defective phospho-
to environmental factors such as high-caloric and cholesterol-rich lipid secretion into bile, resulting in cholesterol supersaturation of bile
diets, genetic factors play an important role in gallstone disease. A and formation of cholesterol gallstones in the gallbladder and in the
large study of symptomatic gallstones in Swedish twins provided strong bile ducts. Thus, an excess of biliary cholesterol in relation to bile acids
evidence for a role of genetic factors in gallstone pathogenesis. Genetic and phospholipids is primarily due to hypersecretion of cholesterol,
factors accounted for 25%, shared environmental factors for 13%, and but hyposecretion of bile acids or phospholipids may contribute. An
individual environmental factors for 62% of the phenotypic variation additional disturbance of bile acid metabolism that is likely to contrib-
among monozygotic twins. A single nucleotide polymorphism of the ute to supersaturation of bile with cholesterol is enhanced conversion
gene encoding the hepatic cholesterol transporter ABCG5/G8 has of cholic acid to deoxycholic acid, with replacement of the cholic
been found in 21% of patients with gallstones, but only in 9% of the acid pool by an expanded deoxycholic acid pool. It may result from
general population. It is thought to cause a gain of function of the enhanced dehydroxylation of cholic acid and increased absorption of
cholesterol transporter and to contribute to cholesterol hypersecretion. newly formed deoxycholic acid. An increased deoxycholate secretion is
A high prevalence of gallstones is found among first-degree relatives of associated with hypersecretion of cholesterol into bile.
gallstone carriers and in certain ethnic populations such as American While supersaturation of bile with cholesterol is an important pre-
Indians, Chilean Indians, and Chilean Hispanics. A common genetic requisite for gallstone formation, it is generally not sufficient by itself
trait has been identified for some of these populations by mitochon- to produce cholesterol precipitation in vivo. Most individuals with
drial DNA analysis. In some patients, impaired hepatic conversion of supersaturated bile do not develop stones because the time required
cholesterol to bile acids may also occur, resulting in an increase of the for cholesterol crystals to nucleate and grow is longer than the time bile
lithogenic cholesterol/bile acid ratio. Although most cholesterol stones remains in the gallbladder.
have a polygenic basis, there are rare monogenic (Mendelian) causes. An important mechanism is nucleation of cholesterol monohydrate
Mutations in the CYP7A1 gene have been described that result in a crystals, which is greatly accelerated in human lithogenic bile. Acceler-
deficiency of the enzyme cholesterol 7-hydroxylase, which catalyzes ated nucleation of cholesterol monohydrate in bile may be due to either

HPIM21e_Part10_p2381-p2670.indd 2643 20/01/22 10:05 PM

 2644 an excess of pronucleating factors or a deficiency of antinucleating factors. study involving 600 patients who completed a 3-month, 520-kcal/d
Mucin and certain nonmucin glycoproteins, principally immunoglob- diet, UDCA in a dosage of 600 mg/d proved highly effective in
ulins, appear to be pronucleating factors, while apolipoproteins A-I preventing gallstone formation; gallstones developed in only 3% of
and A-II and other glycoproteins appear to be antinucleating factors. UDCA recipients, compared to 28% of placebo-treated patients. In
Pigment particles may possibly play a role as nucleating factors. In a obese patients treated by gastric banding, 500 mg/d of UDCA reduced
genome-wide analysis of serum bilirubin levels, the uridine diphos- the risk of gallstone formation from 30 to 8% within a follow-up of
phate-glucuronyltransferase 1A1 (UGT1A1) Gilbert’s syndrome gene 6 months.
variant was associated with the presence of gallstone disease. Because To summarize, cholesterol gallstone disease occurs because of several
most gallstones associated with the UGT1A1 variant were cholesterol defects, which include (1) bile supersaturation with cholesterol, (2)
stones, this finding points to the role of pigment particles in the patho- nucleation of cholesterol monohydrate with subsequent crystal retention
genesis of gallbladder stones. Cholesterol monohydrate crystal nucle- and stone growth, and (3) abnormal gallbladder motor function with
ation and crystal growth probably occur within the mucin gel layer. delayed emptying and stasis. Other important factors known to pre-
Vesicle fusion leads to liquid crystals, which, in turn, nucleate into solid dispose to cholesterol-stone formation are summarized in Table 346-1.
cholesterol monohydrate crystals. Continued growth of the crystals PIGMENT STONES Black pigment stones are composed of either
occurs by direct nucleation of cholesterol molecules from supersatu- pure calcium bilirubinate or polymer-like complexes with calcium
rated unilamellar or multilamellar biliary vesicles. and mucin glycoproteins. They are more common in patients who
A third important mechanism in cholesterol gallstone formation is have chronic hemolytic states (with increased conjugated bilirubin
gallbladder hypomotility. If the gallbladder emptied all supersaturated in bile); cirrhosis, especially related to alcohol; Gilbert’s syndrome;
or crystal-containing bile completely, stones would not be able to grow. or cystic fibrosis. Gallbladder stones in patients with ileal diseases,
A high percentage of patients with gallstones exhibits abnormalities ileal resection, or ileal bypass generally are also black pigment stones.
of gallbladder emptying. Ultrasonographic studies show that gallstone
patients display an increased gallbladder volume during fasting and
after a test meal (residual volume) and that fractional emptying after TABLE 346-1 Predisposing Factors for Cholesterol and
gallbladder stimulation is decreased. The incidence of gallstones is Pigment Gallstone Formation
increased in conditions associated with infrequent or impaired gall- Cholesterol Stones
bladder emptying such as fasting, parenteral nutrition, or pregnancy
1. Demographic/genetic factors: Prevalence highest in North American Indians,
and in patients using drugs that inhibit gallbladder motility. Chilean Indians, and Chilean Hispanics, greater in Northern Europe and North
Biliary sludge is a thick, mucous material that, upon microscopic America than in Asia, lowest in Japan; familial disposition; hereditary aspects
examination, reveals lecithin-cholesterol liquid crystals, cholesterol 2. Obesity, metabolic syndrome: Normal bile acid pool and secretion but
PART 10

monohydrate crystals, calcium bilirubinate, and mucin gels. Biliary increased biliary secretion of cholesterol
sludge typically forms a crescent-like layer in the most dependent 3. Rapid weight loss: Mobilization of tissue cholesterol leads to increased
portion of the gallbladder and is recognized by characteristic echoes biliary cholesterol secretion while enterohepatic circulation of bile acids is
on ultrasonography (see below). The presence of biliary sludge implies decreased
two abnormalities: (1) the normal balance between gallbladder mucin 4. Female sex hormones
Disorders of the Gastrointestinal System

secretion and elimination has become deranged, and (2) nucleation a. Estrogens stimulate hepatic lipoprotein receptors, increase uptake of
of biliary solutes has occurred. That biliary sludge may be a precursor dietary cholesterol, and increase biliary cholesterol secretion
form of gallstone disease is evident from several observations. In one b. Natural estrogens, other estrogens, and oral contraceptives lead to
study, 96 patients with gallbladder sludge were followed prospectively decreased bile salt secretion and decreased conversion of cholesterol to
by serial ultrasound studies. In 18%, biliary sludge disappeared and did cholesteryl esters
not recur for at least 2 years. In 60%, biliary sludge disappeared and 5. Pregnancy: Impaired gallbladder emptying caused by progesterone
reappeared; in 14%, gallstones (8% asymptomatic, 6% symptomatic) combined with the influence of estrogens, which increase biliary cholesterol
secretion
developed; and in 6%, severe biliary pain with or without acute pan-
creatitis occurred. In 12 patients, cholecystectomies were performed, 6 6. Increasing age: Increased biliary secretion of cholesterol, decreased size of
bile acid pool, decreased secretion of bile salts
for gallstone-associated biliary pain and 3 in symptomatic patients with
sludge but without gallstones who had prior attacks of pancreatitis; the 7. Gallbladder hypomotility leading to stasis and formation of sludge
latter did not recur after cholecystectomy. It should be emphasized that a. Total parenteral nutrition
biliary sludge can develop with disorders that cause gallbladder hypo- b. Fasting
motility; that is, surgery, burns, total parenteral nutrition, pregnancy, and c. Pregnancy
oral contraceptives—all of which are associated with gallstone formation. d. Drugs such as octreotide
However, the presence of biliary sludge implies supersaturation of bile 8. Clofibrate therapy: Increased biliary secretion of cholesterol
with either cholesterol or calcium bilirubinate. 9. Decreased bile acid secretion
Two other conditions are associated with cholesterol-stone or a. Genetic defect of the CYP7A1 gene
biliary-sludge formation: pregnancy and rapid weight reduction 10. Decreased phospholipid secretion: Genetic defect of the MDR3 gene
through a very-low-calorie diet. There appear to be two key changes 11. Miscellaneous
during pregnancy that contribute to a “cholelithogenic state”: (1) a a. High-calorie, high-fat diet
marked increase in cholesterol saturation of bile during the third
b. Spinal cord injury
trimester and (2) sluggish gallbladder contraction in response to a
standard meal, resulting in impaired gallbladder emptying. That these Pigment Stones
changes are related to pregnancy per se is supported by several studies 1. Demographic/genetic factors: Asia, rural setting (presumed due to increased
that show reversal of these abnormalities quite rapidly after delivery. prevalence of parasitic biliary infections; the incidence has been dropping
During pregnancy, gallbladder sludge develops in 20–30% of women with time)
and gallstones in 5–12%. Although biliary sludge is a common finding 2. Chronic hemolysis (example: sickle cell disease)
during pregnancy, it is usually asymptomatic and often resolves spon- 3. Alcohol related liver cirrhosis
taneously after delivery. Gallstones, which are less common than sludge 4. Ineffective erythropoiesis (example: pernicious anemia)
and frequently associated with biliary colic, may also disappear after 5. Cystic fibrosis
delivery because of spontaneous dissolution related to bile becoming 6. Chronic biliary tract infection, parasite infections
unsaturated with cholesterol postpartum. 7. Increasing age
Approximately 10–20% of persons with rapid weight reduction 8. Ileal disease, ileal resection or bypass
achieved through very-low-calorie dieting develop gallstones. In a

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 Enterohepatic recycling of bilirubin in ileal disease states contributes The plain abdominal film may detect gallstones containing suffi- 2645
to their pathogenesis. Brown pigment stones are composed of calcium cient calcium to be radiopaque (10–15% of cholesterol and ~50% of
salts of unconjugated bilirubin with varying amounts of cholesterol pigment stones). Plain radiography may also be of use in the diagnosis
and protein. They are caused by the presence of increased amounts of emphysematous cholecystitis, porcelain gallbladder, limey bile, and
of unconjugated, insoluble bilirubin in bile that precipitates to form gallstone ileus.
stones. Deconjugation of an excess of soluble bilirubin mono- and OCG was historically a useful procedure for the diagnosis of gall-
diglucuronides may be mediated by endogenous β-glucuronidase but stones but has been replaced by ultrasound and is now regarded as
may also occur by spontaneous hydrolysis. Sometimes, the enzyme is obsolete. It may be used to assess the patency of the cystic duct and
also produced when bile is chronically infected by bacteria, and such gallbladder emptying function. Further, OCG can also delineate the
stones are brown. Pigment stone formation is frequent in Asia and is size and number of gallstones and determine whether they are calci-
often associated with parasitic infections in the gallbladder and biliary fied, useful information if medical dissolution is being considered.
tree (Table 346-1). Radiopharmaceuticals such as 99mTc-labeled N-substituted iminodi-
acetic acids (HIDA and DISIDA) are rapidly extracted from the blood
Diagnosis Procedures of potential use in the diagnosis of cholelith- and are excreted into the biliary tree in high concentration even in
iasis and other diseases of the gallbladder are detailed in Table 346-2. the presence of mild to moderate serum bilirubin elevations. Failure
Ultrasonography of the gallbladder is very accurate in the identifica- to image the gallbladder in the presence of biliary ductal visualization
tion of cholelithiasis and has replaced oral cholecystography (OCG) may indicate cystic duct obstruction, acute or chronic cholecystitis,
(Fig. 346-2A). Stones as small as 1.5 mm in diameter may be con- or surgical absence of the organ. Such scans have application in the
fidently identified provided that firm criteria are used (e.g., acoustic diagnosis of acute cholecystitis and may play a role in the detection of
“shadowing” of opacities that are within the gallbladder lumen and that a postcholecystectomy bile leak.
change with the patient’s position [by gravity]). In major medical cen-
ters, the false-negative and false-positive rates for ultrasound in gall-
Symptoms of Gallstone Disease Gallstones usually produce
stone patients are ~2–4%. Biliary sludge is material of low echogenic symptoms by causing inflammation or obstruction following their
activity that typically forms a layer in the most dependent position of migration into the cystic duct or CBD. The most specific and charac-
the gallbladder. This layer shifts with postural changes but fails to pro- teristic symptom of gallstone disease is biliary colic that is a constant
duce acoustic shadowing; these two characteristics distinguish sludges and often long-lasting pain (see below). Obstruction of the cystic
from gallstones. Ultrasound can also be used to assess the emptying duct or CBD by a stone produces increased intraluminal pressure and
function of the gallbladder. distention of the viscus that cannot be relieved by repetitive biliary
contractions. The resultant visceral pain is characteristically a severe,

CHAPTER 346 Diseases of the Gallbladder and Bile Ducts

steady ache or fullness in the epigastrium or right upper quadrant
(RUQ) of the abdomen with frequent radiation to the interscapular
TABLE 346-2 Diagnostic Evaluation of the Gallbladder area, right scapula, or shoulder.
DIAGNOSTIC DIAGNOSTIC Biliary colic begins quite suddenly and may persist with severe
ADVANTAGES LIMITATIONS COMMENT intensity for 30 min to 5 h, subsiding gradually or rapidly. It is steady
Ultrasound rather than intermittent, as would be suggested by the word colic,
Rapid Bowel gas Procedure of choice for
which must be regarded as a misnomer, although it is in widespread
detection of stones use. An episode of biliary pain persisting beyond 5 h should raise
Accurate identification of Massive obesity
gallstones (>95%) the suspicion of acute cholecystitis (see below). Nausea and vomiting
Ascites
Simultaneous scanning
frequently accompany episodes of biliary pain. An elevated level of
of GB, liver, bile ducts, serum bilirubin and/or alkaline phosphatase suggests a common duct
pancreas stone. Fever or chills (rigors) with biliary pain usually imply a com-
“Real-time” scanning plication, that is, cholecystitis, pancreatitis, or cholangitis. Complaints
allows assessment of GB of short-lasting, vague epigastric fullness, dyspepsia, eructation, or
volume, contractility flatulence, especially following a fatty meal, should not be confused
Not limited by jaundice, with biliary pain. Such symptoms are frequently elicited from patients
pregnancy with or without gallstone disease but are not specific for biliary calculi.
May detect very small Biliary colic may be precipitated by eating a fatty meal, by consumption
stones of a large meal following a period of prolonged fasting, or by eating a
Plain Abdominal X-Ray normal meal; it is frequently nocturnal, occurring within a few hours
Low cost Relatively low yield Pathognomonic findings of retiring.
Readily available Contraindicated in in: calcified gallstones, Natural History Gallstone disease discovered in an asymptomatic
pregnancy limey bile, porcelain GB,
emphysematous
patient or in a patient whose symptoms are not referable to cholelithiasis
cholecystitis, is a common clinical problem. Sixty to 80% of persons with asymp-
gallstone ileus tomatic gallstones remain asymptomatic over follow-up periods of up
Cholescintigraphy (HIDA, DISIDA, etc.)
to 25 years. The probability of developing symptoms within 5 years
after diagnosis is 2–4% per year and decreases in the years thereafter to
Accurate identification of Contraindicated in Indicated for 1–2%. The yearly incidence of complications is about 0.1–0.3%. Patients
cystic duct obstruction pregnancy confirmation of
suspected acute remaining asymptomatic for 15 years were found to be unlikely to
Simultaneous Serum bilirubin >103–205 develop symptoms during further follow-up, and most patients who did
assessment of bile ducts μmol/L (6–12 mg/dL) cholecystitis; less
sensitive and less develop complications from their gallstones experienced prior warning
Cholecystogram of low
resolution
specific in chronic symptoms. Similar conclusions apply to diabetic patients with silent
cholecystitis; useful gallstones. Decision analysis has suggested that (1) the cumulative risk
in the diagnosis of death due to gallstone disease while on expectant management is
of acalculous
cholecystopathy, small, and (2) prophylactic cholecystectomy is not warranted.
especially if given Complications requiring cholecystectomy are much more common
with CCK to assess GB in gallstone patients who have developed symptoms of biliary pain.
emptying Patients found to have gallstones at a young age are more likely to
Abbreviations: CCK, cholecystokinin; DISIDA, diisopropyl iminodiacetic acid; GB, develop symptoms from cholelithiasis than are patients >60 years at the
gallbladder; HIDA, hydroxyl iminodiacetic acid. time of initial diagnosis. Patients with diabetes mellitus and gallstones

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 2646

A B C D
FIGURE 346-2 Examples of ultrasound and radiologic studies of the biliary tract. A. An ultrasound study showing a distended gallbladder (GB) containing a single large
stone (arrow), which casts an acoustic shadow. B. Endoscopic retrograde cholangiopancreatogram (ERCP) showing normal biliary tract anatomy. In addition to the
endoscope and large vertical gallbladder filled with contrast dye, the common hepatic duct (CHD), common bile duct (CBD), and pancreatic duct (PD) are shown. The arrow
points to the ampulla of Vater. C. Endoscopic retrograde cholangiogram (ERC) showing choledocholithiasis. The biliary tract is dilated and contains multiple radiolucent
calculi. D. ERCP showing sclerosing cholangitis. The CBD shows areas that are strictured and narrowed.

may be somewhat more susceptible to septic complications, but the good results within a reasonable time period, this therapy should
magnitude of risk of septic biliary complications in diabetic patients is be limited to radiolucent stones <5 mm in diameter. The dose of
incompletely defined. UDCA should be 10–15 mg/kg per d. Stones >10 mm in size rarely
dissolve. Pigment stones are not responsive to UDCA therapy. Prob-
PART 10

TREATMENT ably ≤10% of patients with symptomatic cholelithiasis are candidates

for such treatment. However, in addition to the vexing problem of
Gallstones recurrent stones (30–50% over 3–5 years of follow-up), there is also
the factor of taking a drug for up to 2 years and perhaps indefinitely.
SURGICAL THERAPY
Disorders of the Gastrointestinal System

The advantages and success of laparoscopic cholecystectomy have

In asymptomatic gallstone patients, the risk of developing symp- largely reduced the role of gallstone dissolution to patients who
toms or complications requiring surgery is quite small (see above). wish to avoid or are not candidates for elective cholecystectomy.
Thus, a recommendation for cholecystectomy in a patient with However, patients with cholesterol gallstone disease who develop
gallstones should probably be based on assessment of three factors: recurrent choledocholithiasis after cholecystectomy should be on
(1) the presence of symptoms that are frequent enough or severe long-term treatment with UDCA.
enough to interfere with the patient’s general routine; (2) the pres-
ence of a prior complication of gallstone disease, that is, history
of acute cholecystitis, pancreatitis, gallstone fistula, etc.; or (3) the ■■ACUTE AND CHRONIC CHOLECYSTITIS
presence of an underlying condition predisposing the patient to Acute Cholecystitis Acute inflammation of the gallbladder wall
increased risk of gallstone complications (e.g., a previous attack usually follows obstruction of the cystic duct by a stone. Inflammatory
of acute cholecystitis regardless of current symptomatic status). response can be evoked by three factors: (1) mechanical inflammation
Patients with very large gallstones (>3 cm in diameter) and patients produced by increased intraluminal pressure and distention with
harboring gallstones in a congenitally anomalous gallbladder might resulting ischemia of the gallbladder mucosa and wall, (2) chemical
also be considered for prophylactic cholecystectomy. Although inflammation caused by the release of lysolecithin (due to the action
young age is a worrisome factor in asymptomatic gallstone patients, of phospholipase on lecithin in bile) and other local tissue factors, and
few authorities would now recommend routine cholecystectomy in (3) bacterial inflammation, which may play a role in 50–85% of patients
young patients with silent stones. Laparoscopic cholecystectomy with acute cholecystitis. The organisms most frequently isolated by
is a minimal-access approach for the removal of the gallbladder culture of gallbladder bile in these patients include Escherichia coli,
together with its stones. Its advantages include a markedly short- Klebsiella spp., Streptococcus spp., and Clostridium spp.
ened hospital stay, minimal disability, and decreased cost, and it Acute cholecystitis often begins as an attack of biliary pain that pro-
is the procedure of choice for most patients referred for elective gressively worsens. Approximately 60–70% of patients report having
cholecystectomy. experienced prior attacks that resolved spontaneously. As the episode
From several studies involving >4000 patients undergoing progresses, however, the pain of acute cholecystitis becomes more
laparoscopic cholecystectomy, the following key points emerge: generalized in the right upper abdomen. As with biliary colic, the pain
(1) complications develop in ~4% of patients, (2) conversion to of cholecystitis may radiate to the interscapular area, right scapula, or
laparotomy occurs in 5%, (3) the death rate is remarkably low (i.e., shoulder. Peritoneal signs of inflammation such as increased pain with
<0.1%), and (4) the rate of bile duct injuries is low (i.e., 0.2–0.6%) jarring or on deep respiration may be apparent. The patient is anorectic
and comparable with open cholecystectomy. These data indicate and often nauseated. Vomiting is relatively common and may produce
why laparoscopic cholecystectomy has become the “gold standard” symptoms and signs of vascular and extracellular volume depletion.
for treating symptomatic cholelithiasis. Jaundice is unusual early in the course of acute cholecystitis but may
MEDICAL THERAPY—GALLSTONE DISSOLUTION occur when edematous inflammatory changes involve the bile ducts
In carefully selected patients with a functioning gallbladder and and surrounding lymph nodes.
with radiolucent stones <10 mm in diameter, complete dissolution A low-grade fever is characteristically present, but shaking chills
can be achieved in ~50% of patients within 6 months to 2 years. For or rigors are not uncommon. The RUQ of the abdomen is almost

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 invariably tender to palpation. An enlarged, tense gallbladder is palpa- ACALCULOUS CHOLECYSTOPATHY Disordered motility of the gall- 2647
ble in 25–50% of patients. Deep inspiration or cough during subcostal bladder can produce recurrent biliary pain in patients without gall-
palpation of the RUQ usually produces increased pain and inspiratory stones. Infusion of an octapeptide of CCK can be used to measure the
arrest (Murphy’s sign). Localized rebound tenderness in the RUQ is gallbladder ejection fraction during cholescintigraphy. The surgical
common, as are abdominal distention and hypoactive bowel sounds findings have included abnormalities such as chronic cholecystitis,
from paralytic ileus, but generalized peritoneal signs and abdominal gallbladder muscle hypertrophy, and/or a markedly narrowed cystic
rigidity are usually lacking, in the absence of perforation. duct. Some of these patients may well have had antecedent gallbladder
The diagnosis of acute cholecystitis is usually made on the basis disease. The following criteria can be used to identify patients with
of a characteristic history and physical examination. The triad of acalculous cholecystopathy: (1) recurrent episodes of typical RUQ
sudden onset of RUQ tenderness, fever, and leukocytosis is highly pain characteristic of biliary tract pain, (2) abnormal CCK cholescin-
suggestive. Typically, leukocytosis in the range of 10,000–15,000 tigraphy demonstrating a gallbladder ejection fraction of <40%, and
cells per microliter with a left shift on differential count is found. (3) infusion of CCK reproducing the patient’s pain. An additional clue
The serum bilirubin is mildly elevated (<85.5 μmol/L [5 mg/dL]) in would be the identification of a large gallbladder on ultrasound exami-
fewer than half of patients, whereas about one-fourth have modest nation. Importantly, it should be noted that SOD dysfunction can also
elevations in serum aminotransferases (usually less than a fivefold give rise to recurrent RUQ pain and CCK-scintigraphic abnormalities.
elevation). Ultrasound will demonstrate calculi in 90–95% of cases EMPHYSEMATOUS CHOLECYSTITIS So-called emphysematous
and is useful for detection of signs of gallbladder inflammation cholecystitis is thought to begin with acute cholecystitis (calculous or
including thickening of the wall, pericholecystic fluid, and dilatation acalculous) followed by ischemia or gangrene of the gallbladder wall
of the bile duct. The radionuclide (e.g., HIDA) biliary scan may be and infection by gas-producing organisms. Bacteria most frequently
confirmatory if bile duct imaging is seen without visualization of cultured in this setting include anaerobes, such as Clostridium
the gallbladder. welchii or C. perfringens, and aerobes, such as E. coli. This condition
Approximately 75% of patients treated medically have remission occurs most frequently in elderly men and in patients with diabetes
of acute symptoms within 2–7 days following hospitalization. In 25%, mellitus. The clinical manifestations are essentially indistinguishable
however, a complication of acute cholecystitis will occur despite con- from those of nongaseous cholecystitis. The diagnosis is usually
servative treatment (see below). In this setting, prompt surgical inter- made on plain abdominal film by finding gas within the gallbladder
vention is required. Of the 75% of patients with acute cholecystitis who lumen, dissecting within the gallbladder wall to form a gaseous ring,
undergo remission of symptoms, ~25% will experience a recurrence of or in the pericholecystic tissues. The morbidity and mortality rates
cholecystitis within 1 year, and 60% will have at least one recurrent bout with emphysematous cholecystitis are considerable. Prompt surgical

CHAPTER 346 Diseases of the Gallbladder and Bile Ducts

within 6 years. In view of the natural history of the disease, acute chole- intervention coupled with appropriate antibiotics is mandatory.
cystitis is best treated by early surgery whenever possible. Mirizzi’s syn-
drome is a rare complication in which a gallstone becomes impacted in Chronic Cholecystitis Chronic inflammation of the gallbladder
the cystic duct or neck of the gallbladder causing compression of the wall is almost always associated with the presence of gallstones and is
CBD, resulting in CBD obstruction and jaundice. Ultrasound shows thought to result from repeated bouts of subacute or acute cholecys-
gallstone(s) lying outside the hepatic duct. Endoscopic retrograde titis or from persistent mechanical irritation of the gallbladder wall
cholangiopancreatography (ERCP) (Fig. 346-2B), percutaneous tran- by gallstones. The presence of bacteria in the bile occurs in >25% of
shepatic cholangiography (PTC), or magnetic resonance cholangio- patients with chronic cholecystitis. The presence of infected bile in a
pancreatography (MRCP) will usually demonstrate the characteristic patient with chronic cholecystitis undergoing elective cholecystectomy
extrinsic compression of the CBD. Surgery consists of removing the probably adds little to the operative risk. Chronic cholecystitis may be
cystic duct, diseased gallbladder, and impacted stone. The preoperative asymptomatic for years, which may progress to symptomatic gallblad-
diagnosis of Mirizzi’s syndrome is important to avoid CBD injury. der disease or to acute cholecystitis or may present with complications
(see below).
ACALCULOUS CHOLECYSTITIS In 5–14% of patients with acute chole-
cystitis, calculi obstructing the cystic duct are not found at surgery. Complications of Cholecystitis • EMPYEMA AND HYDROPS
In >50% of such cases, an underlying explanation for acalculous Empyema of the gallbladder usually results from progression of acute
inflammation is not found. An increased risk for the development of cholecystitis with persistent cystic duct obstruction to superinfection
acalculous cholecystitis is especially associated with prolonged fasting, of the stagnant bile with a pus-forming bacterial organism. The clin-
with serious trauma or burns, in the postpartum period following pro- ical picture resembles that of cholangitis with high fever; severe RUQ
longed labor, and with orthopedic and other nonbiliary major surgical pain; marked leukocytosis; and often, prostration. Empyema of the
operations in the postoperative period. It may possibly complicate gallbladder carries a high risk of gram-negative sepsis and/or perfora-
periods of prolonged parenteral hyperalimentation. For some of these tion. Emergency surgical intervention with proper antibiotic coverage
cases, biliary sludge in the cystic duct may be responsible. Other pre- is required as soon as the diagnosis is suspected.
cipitating factors include vasculitis, obstructing adenocarcinoma of Hydrops or mucocele of the gallbladder may also result from pro-
the gallbladder, diabetes mellitus, torsion of the gallbladder, “unusual” longed obstruction of the cystic duct, usually by a large solitary calcu-
bacterial infections of the gallbladder (e.g., Leptospira, Streptococcus, lus. In this instance, the obstructed gallbladder lumen is progressively
Salmonella, or Vibrio cholerae), and parasitic infestation of the gallblad- distended, over a period of time, by mucus (mucocele) or by a clear
der. Acalculous cholecystitis may also be seen with a variety of other transudate (hydrops) produced by mucosal epithelial cells. A visible,
systemic disease processes (e.g., sarcoidosis, cardiovascular disease, easily palpable, nontender mass sometimes extending from the RUQ
tuberculosis, syphilis, actinomycosis). into the right iliac fossa may be found on physical examination. The
Although the clinical manifestations of acalculous cholecystitis are patient with hydrops of the gallbladder frequently remains asymptom-
indistinguishable from those of calculous cholecystitis, the setting of atic, although chronic RUQ pain may also occur. Cholecystectomy is
acute gallbladder inflammation complicating severe underlying ill- indicated, because empyema, perforation, or gangrene may complicate
ness is characteristic of acalculous disease. Ultrasound or computed the condition.
tomography (CT) examinations demonstrating a large, tense, static GANGRENE AND PERFORATION Gangrene of the gallbladder results
gallbladder without stones and with evidence of poor emptying over from ischemia of the wall and patchy or complete tissue necrosis.
a prolonged period may be diagnostically useful in some cases. The Underlying conditions often include marked distention of the gall-
complication rate for acalculous cholecystitis exceeds that for calculous bladder, vasculitis, diabetes mellitus, empyema, or torsion resulting
cholecystitis. Successful management of acute acalculous cholecystitis in arterial occlusion. Gangrene usually predisposes to perforation of
appears to depend primarily on early diagnosis and surgical interven- the gallbladder, but perforation may also occur in chronic cholecys-
tion, with meticulous attention to postoperative care. titis without premonitory warning symptoms. Localized perforations

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 2648 are usually contained by the omentum or by adhesions produced by eliminated, nasogastric suction may be indicated, extracellular vol-
recurrent inflammation of the gallbladder. Bacterial superinfection of ume depletion and electrolyte abnormalities are repaired, and analge-
the walled-off gallbladder contents results in abscess formation. Most sia is provided. Intravenous antibiotic therapy is indicated in patients
patients are best treated with cholecystectomy, but some seriously ill with severe acute cholecystitis, even though bacterial superinfection
patients may be managed with cholecystostomy and drainage of the of bile may not have occurred in the early stages of the inflammatory
abscess. Free perforation is less common but is associated with a mor- process. Antibiotic therapy is guided by the most common organ-
tality rate of ~30%. Such patients may experience a sudden transient isms likely to be present including E. coli, Klebsiella, Enterococcus,
relief of RUQ pain as the distended gallbladder decompresses; this is Enterobacter, and Streptococcus. Effective antibiotics include piper-
followed by signs of generalized peritonitis. acillin plus tazobactam, imipenem, meropenem, ceftriaxone plus
FISTULA FORMATION AND GALLSTONE ILEUS Fistula formation into metronidazole, and levofloxacin plus metronidazole (Chap. 161).
an adjacent organ adherent to the gallbladder wall may result from Postoperative complications of wound infection, abscess formation,
inflammation and adhesion formation. Fistulas into the duodenum are and sepsis are reduced in antibiotic-treated patients.
most common, followed in frequency by those involving the hepatic SURGICAL THERAPY
flexure of the colon, stomach or jejunum, abdominal wall, and renal The optimal timing of surgical intervention in patients with acute
pelvis. Clinically “silent” biliary-enteric fistulas occurring as a compli- cholecystitis depends on stabilization of the patient. The clear trend
cation of acute cholecystitis have been found in up to 5% of patients is toward earlier surgery, and this is due in part to requirements for
undergoing cholecystectomy. Asymptomatic cholecystoenteric fistulas shorter hospital stays. Urgent (emergency) cholecystectomy or per-
may sometimes be diagnosed by finding gas in the biliary tree on plain cutaneous cholecystostomy is probably appropriate in most patients
abdominal films. Barium contrast studies or endoscopy of the upper in whom a complication of acute cholecystitis such as empyema,
gastrointestinal tract or colon may demonstrate the fistula. Treatment emphysematous cholecystitis, or perforation is suspected or con-
in the symptomatic patient usually consists of cholecystectomy, CBD firmed. Patients with uncomplicated acute cholecystitis should
exploration, and closure of the fistulous tract. undergo early elective laparoscopic cholecystectomy, ideally within
Gallstone ileus refers to mechanical intestinal obstruction resulting 48–72 h after diagnosis. The complication rate is not increased in
from the passage of a large gallstone into the bowel lumen. The stone patients undergoing early as opposed to delayed (>6 weeks after
customarily enters the duodenum through a cholecystoenteric fistula at diagnosis) cholecystectomy. Delayed surgical intervention is prob-
that level. The site of obstruction by the impacted gallstone is usually ably best reserved for (1) patients in whom the overall medical
at the ileocecal valve, provided that the more proximal small bowel is condition imposes an unacceptable risk for early surgery and (2)
of normal caliber. Most patients do not give a history of either prior patients in whom the diagnosis of acute cholecystitis is in doubt.
biliary tract symptoms or complaints suggestive of acute cholecystitis Thus, early cholecystectomy (within 72 h) is the treatment of
PART 10

or fistula formation. Large stones, >2.5 cm in diameter, are thought to choice for most patients with acute cholecystitis. Mortality figures
predispose to fistula formation by gradual erosion through the gall- for emergency cholecystectomy in most centers range from 1 to
bladder fundus. Diagnostic confirmation may occasionally be found 3%, whereas the mortality risk for early elective cholecystectomy
on the plain abdominal film (e.g., small-intestinal obstruction with gas is ~0.5% in patients under age 60. Of course, the operative risks
in the biliary tree [pneumobilia] and a calcified, ectopic gallstone) or
Disorders of the Gastrointestinal System

increase with age-related diseases of other organ systems and with

following an upper gastrointestinal series (cholecystoduodenal fistula the presence of long- or short-term complications of gallbladder
with small-bowel obstruction at the ileocecal valve). Laparotomy with disease. Seriously ill or debilitated patients with cholecystitis may
stone extraction (or propulsion into the colon) remains the procedure be managed with percutaneous drainage (a cholecystostomy tube),
of choice to relieve obstruction. Evacuation of large stones within the transpapillary drainage (an endoscopically placed transpapillary
gallbladder should also be performed. In general, the gallbladder and drainage catheter via the cystic duct), or transmural drainage (an
its attachment to the intestines should be left alone. endoscopically placed covered, lumen-apposing stent). Elective
LIMEY (MILK OF CALCIUM) BILE AND PORCELAIN GALLBLADDER Cal- cholecystectomy may then be done at a later date.
cium salts in the lumen of the gallbladder in sufficient concentration
may produce calcium precipitation and diffuse, hazy opacification of Postcholecystectomy Complications Early complications fol-
bile or a layering effect on plain abdominal roentgenography. This lowing cholecystectomy include atelectasis and other pulmonary
so-called limey bile, or milk of calcium bile, is usually clinically disorders, abscess formation (often subphrenic), external or internal
innocuous, but cholecystectomy is often performed, especially when it hemorrhage, biliary-enteric fistula, and bile leaks. Jaundice may indi-
occurs in a hydropic gallbladder. In the entity called porcelain gallblad- cate absorption of bile from an intraabdominal collection following a
der, calcium salt deposition within the wall of a chronically inflamed biliary leak or mechanical obstruction of the CBD by retained calculi,
gallbladder may be detected on the plain abdominal film. In the past, intraductal blood clots, or extrinsic compression.
cholecystectomy was advised in all patients with porcelain gallbladder Overall, cholecystectomy is a very successful operation that pro-
because there was felt to be a high incidence of carcinoma of the gall- vides total or near-total relief of preoperative symptoms in 75–90% of
bladder associated with this condition, an association challenged by a patients. The most common cause of persistent postcholecystectomy
number of studies. Two patterns of gallbladder wall calcification have symptoms is an overlooked symptomatic nonbiliary disorder (e.g.,
now been appreciated: complete intramural calcification and selective reflux esophagitis, peptic ulceration, pancreatitis, or—most often—
mucosal calcification. The incidence of cancer in those with selective irritable bowel syndrome). In a small percentage of patients, however,
intramural calcification is higher than those with complete mucosal a disorder of the extrahepatic bile ducts may result in persistent symp-
wall calcification, but the risk is very small. As such, the need for chole- tomatology. These so-called postcholecystectomy syndromes may be
cystectomy for porcelain gallbladder is not absolute; close surveillance due to (1) biliary strictures, (2) retained biliary calculi, (3) cystic duct
in these patients is also acceptable. stump syndrome, (4) stenosis or dyskinesia of the SOD, or (5) bile
salt–induced diarrhea or gastritis.
TREATMENT CYSTIC DUCT STUMP SYNDROME In the absence of cholangiographi-
cally demonstrable retained stones, symptoms resembling biliary pain
Acute Cholecystitis or cholecystitis in the postcholecystectomy patient have frequently
been attributed to disease in a long (>1 cm) cystic duct remnant
MEDICAL THERAPY (cystic duct stump syndrome). Careful analysis, however, reveals
Although surgical intervention remains the mainstay of therapy that postcholecystectomy complaints are attributable to other causes
for acute cholecystitis and its complications, a period of in-hospital in almost all patients in whom the symptom complex was originally
stabilization may be required before cholecystectomy. Oral intake is thought to result from the existence of a long cystic duct stump.

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 Accordingly, considerable care should be taken to investigate the pos- Cholesterolosis is characterized by abnormal deposition of lipid, espe- 2649
sible role of other factors in the production of postcholecystectomy cially cholesteryl esters, within macrophages in the lamina propria of
symptoms before attributing them to cystic duct stump syndrome. the gallbladder wall. In its diffuse form (“strawberry gallbladder”), the
SOD STENOSIS, SOD DYSKINESIA, AND BILIARY DYSKINESIA Symp- gallbladder mucosa is brick red and speckled with bright yellow flecks of
toms of biliary colic accompanied by signs of recurrent, intermittent lipid. The localized form shows solitary or multiple “cholesterol polyps”
biliary obstruction may be produced by acalculous cholecystopathy, studding the gallbladder wall. Cholesterol stones of the gallbladder are
SOD stenosis, or SOD dyskinesia. SOD stenosis is thought to result found in nearly half the cases. Cholecystectomy is only indicated in ade-
from acute or chronic inflammation of the papilla of Vater or from nomyomatosis or cholesterolosis when biliary symptoms are present.
glandular hyperplasia of the papillary segment. Five criteria have been The prevalence of gallbladder polyps in the adult population is
used to define SOD stenosis: (1) upper abdominal pain, usually RUQ 1–4% with a marked male predominance. Types of gallbladder polyps
or epigastric; (2) abnormal liver tests; (3) dilatation of the CBD upon include cholesterol polyps, adenomyomas, inflammatory polyps, and
MRCP or ERCP examination; (4) delayed (>45 min) drainage of con- adenomas (rare). No significant changes have been found over a 5-year
trast material from the duct; and (5) increased basal pressure of the period in asymptomatic patients with gallbladder polyps <6 mm and
SOD. After exclusion of acalculous cholecystopathy, treatment consists few changes in polyps 7–9 mm. Cholecystectomy is recommended in
of endoscopic or surgical sphincteroplasty to ensure wide patency of symptomatic patients as well as in asymptomatic patients >50 years
the distal portions of both the bile and pancreatic ducts. The greater the whose polyps are >10 mm or associated with gallstones or polyp
number of the preceding criteria present, the greater is the likelihood growth on serial ultrasonography.
that a patient does have a degree of SOD sufficient to justify correc-
tion. The factors usually considered as indications for sphincterotomy DISEASES OF THE BILE DUCTS
include (1) prolonged duration of symptoms, (2) lack of response to ■■CONGENITAL ANOMALIES
symptomatic treatment, (3) presence of severe disability, and (4) the
patient’s choice of sphincterotomy over surgery (given a clear under- Biliary Atresia and Hypoplasia Atretic and hypoplastic lesions
standing on his or her part of the risks involved in both procedures). of the extrahepatic and large intrahepatic bile ducts are the most com-
Biliary SOD disorders are characterized by three criteria: (1) biliary mon biliary anomalies of clinical relevance encountered in infancy.
pain, (2) absence of bile duct stones or other abnormalities, and (3) The clinical picture is one of severe obstructive jaundice during the
elevated liver enzymes or a dilated CBD, but not both. In this setting, first month of life, with pale stools. When biliary atresia is suspected
either hepatobiliary scintigraphy or SOD manometry can support the on the basis of clinical, laboratory, and imaging findings, the diag-
diagnosis. Importantly, the presence of both elevated liver enzymes nosis is confirmed by surgical exploration and operative cholangi-

CHAPTER 346 Diseases of the Gallbladder and Bile Ducts

and a dilated CBD should raise the question of obstruction. Pro- ography. Approximately 10% of cases of biliary atresia are treatable with
posed mechanisms to account for SOD dysfunction include spasm of Roux-en-Y choledochojejunostomy, with the Kasai procedure (hepatic
the sphincter, denervation sensitivity resulting in hypertonicity, and portoenterostomy) being attempted in the remainder in an effort to
abnormalities in the sequencing or frequency rates of the sphincteric- restore some bile flow. Most patients, even those having successful
contraction waves. When thorough evaluation has failed to demon- biliary-enteric anastomoses, eventually develop chronic cholangitis,
strate another cause for the pain and when cholangiographic and extensive hepatic fibrosis, and portal hypertension.
manometric criteria suggest a diagnosis of SOD dyskinesia, medical Choledochal Cysts Cystic dilatation may involve the free portion
treatment with nitrites or anticholinergics to attempt pharmacologic of the CBD, that is, choledochal cyst, or may present as diverticulum
relaxation of SOD has been proposed but not evaluated in detailed formation in the intraduodenal segment. In the latter situation, chronic
studies. Endoscopic biliary sphincterotomy (EBS) or surgical sphinc- reflux of pancreatic juice into the biliary tree can produce inflamma-
terotomy may be indicated in patients who fail to respond to a 2- to tion and stenosis of the extrahepatic bile ducts, leading to cholangitis
3-month trial of medical therapy, especially if SOD pressures are ele- or biliary obstruction. Because the process may be gradual, ~50% of
vated. Approximately 45% of such patients have long-term pain relief patients present with onset of symptoms after age 10. The diagnosis
after EBS. EBS has become the procedure of choice for removing bile may be made by ultrasound, abdominal CT, MRCP, or cholangiog-
duct stones and for other biliary and pancreatic problems. raphy. Only one-third of patients show the classic triad of abdominal
BILE SALT–INDUCED DIARRHEA AND GASTRITIS Postcholecystectomy pain, jaundice, and an abdominal mass. Ultrasonographic detection
patients may develop symptoms of dyspepsia, which have been attrib- of a cyst separate from the gallbladder should suggest the diagnosis
uted to duodenogastric reflux of bile. However, firm data linking these of choledochal cyst, which can be confirmed by demonstrating the
symptoms to bile gastritis after surgical removal of the gallbladder are entrance of extrahepatic bile ducts into the cyst. Surgical treatment
lacking. Cholecystectomy induces persistent changes in gut transit, and involves excision of the “cyst” and biliary-enteric anastomosis. Patients
these changes effect a noticeable modification of bowel habits. Chole- with choledochal cysts are at increased risk for the subsequent devel-
cystectomy shortens gut transit time by accelerating passage of the fecal opment of cholangiocarcinoma.
bolus through the colon with marked acceleration in the right colon,
thus causing an increase in colonic bile acid output and a shift in bile Congenital Biliary Ectasia Dilatation of intrahepatic bile ducts
acid composition toward the more diarrheagenic secondary bile acids, may involve either the major intrahepatic radicles (Caroli’s disease),
that is, deoxycholic acid. Diarrhea that is severe enough, that is, three the inter- and intralobular ducts (congenital hepatic fibrosis), or both.
or more watery movements per day, can be classified as postcholecys- In Caroli’s disease, clinical manifestations include recurrent cholangitis,
tectomy diarrhea, and this occurs in 5–10% of patients undergoing abscess formation in and around the affected ducts, and, often, brown
elective cholecystectomy. Treatment with bile acid–sequestering agents pigment gallstone formation within portions of ectatic intrahepatic
such as cholestyramine or colestipol is often effective in ameliorating biliary radicles. Ultrasound, MRCP, and CT are of great diagnostic
troublesome diarrhea. value in demonstrating cystic dilatation of the intrahepatic bile ducts.
Treatment with ongoing antibiotic therapy is usually undertaken in an
■■THE HYPERPLASTIC CHOLECYSTOSES effort to limit the frequency and severity of recurrent bouts of cholangi-
The term hyperplastic cholecystoses is used to denote a group of dis- tis. Progression to secondary biliary cirrhosis with portal hypertension,
orders of the gallbladder characterized by excessive proliferation of extrahepatic biliary obstruction, cholangiocarcinoma, or recurrent
normal tissue components. episodes of sepsis with hepatic abscess formation is common.
Adenomyomatosis is characterized by a benign proliferation of
■■CHOLEDOCHOLITHIASIS
gallbladder surface epithelium with glandlike formations, extramural
sinuses, transverse strictures, and/or fundal nodule (“adenoma” or Pathophysiology and Clinical Manifestations Passage of gall-
“adenomyoma”) formation. stones into the CBD occurs in ~10–15% of patients with cholelithiasis.

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 2650 The incidence of common duct stones increases with increasing age The alkaline phosphatase level usually falls slowly, lagging behind the
of the patient, so up to 25% of elderly patients may have calculi in decrease in serum bilirubin.
the common duct at the time of cholecystectomy. Undetected duct PANCREATITIS The most common associated entity discovered in
stones are left behind in ~1–5% of cholecystectomy patients. The over- patients with nonalcoholic acute pancreatitis is biliary tract disease.
whelming majority of bile duct stones are cholesterol stones formed in Biochemical evidence of pancreatic inflammation complicates acute
the gallbladder, which then migrate into the extrahepatic biliary tree cholecystitis in 15% of cases and choledocholithiasis in >30%, and the
through the cystic duct. Primary calculi arising de novo in the ducts common factor appears to be the passage of gallstones through the
are usually brown pigment stones developing in patients with (1) hepa- common duct. Coexisting pancreatitis should be suspected in patients
tobiliary parasitism or chronic, recurrent cholangitis; (2) congenital with symptoms of cholecystitis who develop (1) back pain or pain to
anomalies of the bile ducts (especially Caroli’s disease); (3) dilated, the left of the abdominal midline, (2) prolonged vomiting with para-
sclerosed, or strictured ducts; or (4) an MDR3 (ABCB4) gene defect lytic ileus, or (3) a pleural effusion, especially on the left side. Surgical
leading to impaired biliary phospholipids secretion (low phospholipid– treatment of gallstone disease is usually associated with resolution of
associated cholesterol cholelithiasis). Common duct stones may remain the pancreatitis.
asymptomatic for years, may pass spontaneously into the duodenum,
or (most often) may present with biliary colic or a complication. SECONDARY BILIARY CIRRHOSIS Secondary biliary cirrhosis may
complicate prolonged or intermittent duct obstruction with or with-
Complications • CHOLANGITIS Cholangitis may be acute or out recurrent cholangitis. Although this complication may be seen
chronic, and symptoms result from inflammation, which usually is in patients with choledocholithiasis, it is more common in cases of
caused by at least partial obstruction to the flow of bile. Bacteria are prolonged obstruction from stricture or neoplasm. Once established,
present on bile culture in ~75% of patients with acute cholangitis early secondary biliary cirrhosis may be progressive even after correction of
in the symptomatic course. The characteristic presentation of acute the obstructing process, and increasingly severe hepatic cirrhosis may
cholangitis involves biliary pain, jaundice, and spiking fevers with chills lead to portal hypertension or to hepatic failure and death. Prolonged
(Charcot’s triad). Blood cultures are frequently positive, and leukocy- biliary obstruction may also be associated with clinically relevant defi-
tosis is typical. Nonsuppurative acute cholangitis is most common and ciencies of the fat-soluble vitamins A, D, E, and K.
may respond relatively rapidly to supportive measures and to treatment
with antibiotics. In suppurative acute cholangitis, however, the presence Diagnosis and Treatment The diagnosis of choledocholithiasis
of pus under pressure in a completely obstructed ductal system leads is made by cholangiography (Table 346-3), either preoperatively by
to symptoms of severe toxicity—mental confusion, bacteremia, and endoscopic retrograde cholangiogram (ERC) (Fig. 346-2C) or MRCP
septic shock. Response to antibiotics alone in this setting is relatively or intraoperatively at the time of cholecystectomy. As many as 15% of
poor, multiple hepatic abscesses are often present, and the mortality patients undergoing cholecystectomy will prove to have CBD stones.
PART 10

rate approaches 100% unless prompt endoscopic or surgical relief of the When CBD stones are suspected prior to laparoscopic cholecystec-
obstruction and drainage of infected bile are carried out. Endoscopic tomy, preoperative ERCP with endoscopic papillotomy and stone
management of bacterial cholangitis is as effective as surgical interven- extraction is the preferred approach. It not only provides stone clear-
tion. ERCP with endoscopic sphincterotomy is safe and the preferred ance but also defines the anatomy of the biliary tree in relationship to
the cystic duct. CBD stones should be suspected in gallstone patients
Disorders of the Gastrointestinal System

initial procedure for both establishing a definitive diagnosis and provid-

ing effective therapy. who have any of the following risk factors: (1) a history of jaundice or
pancreatitis, (2) abnormal tests of liver function, and (3) ultrasono-
OBSTRUCTIVE JAUNDICE Gradual obstruction of the CBD over a
graphic or MRCP evidence of a dilated CBD or stones in the duct.
period of weeks or months usually leads to initial manifestations of Alternatively, if intraoperative cholangiography reveals retained stones,
jaundice or pruritus without associated symptoms of biliary colic or postoperative ERCP can be carried out. The need for preoperative
cholangitis. Painless jaundice may occur in patients with choledocho- ERCP is expected to decrease further as laparoscopic techniques for
lithiasis but is much more characteristic of biliary obstruction secondary bile duct exploration improve.
to malignancy of the head of the pancreas, bile ducts, or ampulla of The widespread use of laparoscopic cholecystectomy and ERCP
Vater. has decreased the incidence of complicated biliary tract disease and
In patients whose obstruction is secondary to choledocholithiasis, the need for choledocholithotomy and T-tube drainage of the bile
associated chronic calculous cholecystitis is very common, and the ducts. EBS followed by spontaneous passage or stone extraction is the
gallbladder in this setting may be unable to distend. The absence of treatment of choice in the management of patients with common duct
a palpable gallbladder in most patients with biliary obstruction from stones, especially in elderly or poor-risk patients.
duct stones is the basis for Courvoisier’s law, that is, that the presence
of a palpably enlarged gallbladder suggests that the biliary obstruction ■■TRAUMA, STRICTURES, AND HEMOBILIA
is secondary to an underlying malignancy rather than to calculous Most benign strictures of the extrahepatic bile ducts result from surgical
disease. Biliary obstruction causes progressive dilatation of the intra- trauma and occur in about 1 in 500 cholecystectomies. Strictures may
hepatic bile ducts as intrabiliary pressures rise. Hepatic bile flow is present with bile leak or abscess formation in the immediate postoper-
suppressed, and reabsorption and regurgitation of conjugated bilirubin ative period or with biliary obstruction or cholangitis as long as 2 years
into the bloodstream lead to jaundice accompanied by dark urine (bil- or more following the inciting trauma. The diagnosis is established by
irubinuria) and light-colored (acholic) stools. percutaneous or endoscopic cholangiography. Endoscopic brushing of
CBD stones should be suspected in any patient with cholecystitis biliary strictures may be helpful in establishing the nature of the lesion
whose serum bilirubin level is >85.5 μmol/L (5 mg/dL). The maximum and is more accurate than bile cytology alone. When positive exfoliative
bilirubin level is seldom >256.5 μmol/L (15.0 mg/dL) in patients with cytology is obtained, the diagnosis of a neoplastic stricture is estab-
choledocholithiasis unless concomitant hepatic or renal disease or lished. This procedure is especially important in patients with primary
another factor leading to marked hyperbilirubinemia exists. Serum sclerosing cholangitis (PSC) who are predisposed to the development of
bilirubin levels ≥342.0 μmol/L (20 mg/dL) should suggest the possi- cholangiocarcinomas. Successful operative correction of non-PSC bile
bility of neoplastic obstruction. The serum alkaline phosphatase level duct strictures by a skillful surgeon with duct-to-bowel anastomosis is
is almost always elevated in biliary obstruction. A rise in alkaline usually possible, although mortality rates from surgical complications,
phosphatase often precedes clinical jaundice and may be the only recurrent cholangitis, or secondary biliary cirrhosis are high.
abnormality in routine liver function tests. There may be a two- to Hemobilia may follow traumatic or operative injury to the liver or
tenfold elevation of serum aminotransferases, especially in association bile ducts, intraductal rupture of a hepatic abscess or aneurysm of the
with acute obstruction. Following relief of the obstructing process, hepatic artery, biliary or hepatic tumor hemorrhage, or mechanical
serum aminotransferase elevations usually return rapidly to normal, complications of choledocholithiasis or hepatobiliary parasitism. Diag-
while the serum bilirubin level may take 1–2 weeks to return to normal. nostic procedures such as liver biopsy, PTC, and transhepatic biliary

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 2651
TABLE 346-3 Diagnostic Evaluation of the Bile Ducts
DIAGNOSTIC ADVANTAGES DIAGNOSTIC LIMITATIONS CONTRAINDICATIONS COMPLICATIONS COMMENT
Ultrasound
Rapid Bowel gas None None Initial procedure of choice in
Simultaneous scanning of GB, liver, Massive obesity investigating possible biliary tract
bile ducts, pancreas obstruction
Ascites
Accurate identification of dilated Barium
bile ducts
Partial bile duct obstruction
Not limited by jaundice, pregnancy
Poor visualization of distal CBD
Guidance for fine-needle biopsy
Computed Tomography
Simultaneous scanning of GB, liver, Extreme cachexia Pregnancy Reaction to iodinated contrast, Indicated for evaluation of
bile ducts, pancreas Movement artifact if used hepatic or pancreatic masses or
Accurate identification of dilated for assessing for complications
Ileus related to gallstones
bile ducts, masses
Partial bile duct obstruction (pancreatitis)
Not limited by jaundice, gas,
obesity, ascites Procedure of choice in
investigating possible biliary
High-resolution image obstruction if diagnostic
Guidance for fine-needle biopsy limitations limit US
Magnetic Resonance Cholangiopancreatography
Noninvasive modality for Cannot offer therapeutic Claustrophobia None First choice to assess for
visualizing pancreatic and biliary intervention Certain metals (iron) choledocholithiasis given
ducts High cost comparable sensitivity and
Has excellent sensitivity for bile specificity to ERCP
duct dilatation, biliary stricture,
and intraductal abnormalities

CHAPTER 346 Diseases of the Gallbladder and Bile Ducts

Can identify pancreatic duct
dilatation or stricture, pancreatic
duct stenosis, and pancreas
divisum
Endoscopic Retrograde Cholangiopancreatography
Simultaneous pancreatography Gastroduodenal obstruction Pregnancy Pancreatitis Cholangiogram of choice if there
Best visualization of distal biliary Roux-en-Y biliary-enteric Acute pancreatitis Cholangitis, sepsis is believed to be a need for
tract anastomosis intervention:
Severe cardiopulmonary Infected pancreatic pseudocyst
Bile or pancreatic cytology disease Diagnosed or high clinical
Perforation (rare) probability of choledocholithiasis
Endoscopic sphincterotomy and Hypoxemia, aspiration
stone removal Biliary stricture requiring
sampling and stenting
Biliary manometry
Need for sphincterotomy such as
Sphincter of Oddi dysfunction
Percutaneous Transhepatic Cholangiogram
Best when bile ducts dilated Nondilated or sclerosed ducts Pregnancy Bleeding Indicated for the drainage of
Best visualization of proximal Uncorrectable Hemobilia obstructed and infected ducts
biliary tract coagulopathy when ERCP is contraindicated
Bile peritonitis or failed
May be used to obtain bile Massive ascites Bacteremia, sepsis
cytology/culture Hepatic abscess
Allows for percutaneous
transhepatic drainage
Endoscopic Ultrasound
Most sensitive method to detect Excellent for detecting
ampullary stones and exclude choledocholithiasis
pathology in the head of the
pancreas
Abbreviations: CBD, common bile duct; ERCP, endoscopic retrograde cholangiopancreatography; GB, gallbladder; US, hepatobiliary ultrasound.

drainage catheter placement may also be complicated by hemobilia. obstructive jaundice is carcinoma of the head of the pancreas. Biliary
Patients often present with a classic triad of biliary pain, obstructive obstruction may also occur as a complication of either acute or chronic
jaundice, and melena or occult blood in the stools. The diagnosis is pancreatitis or involvement of lymph nodes in the porta hepatis by
sometimes made by cholangiographic evidence of blood clot in the lymphoma or metastatic carcinoma. The latter should be distinguished
biliary tree, but selective angiographic verification may be required. from cholestasis resulting from massive replacement of the liver by
Although minor episodes of hemobilia may resolve without interven- tumor.
tion, arteriography and transcatheter embolization or surgical ligation
of the bleeding vessel may be required. ■■HEPATOBILIARY PARASITISM
Infestation of the biliary tract by adult helminths or their ova may pro-
■■EXTRINSIC COMPRESSION OF THE BILE DUCTS duce a chronic, recurrent pyogenic cholangitis with or without multiple
Partial or complete biliary obstruction may be produced by extrinsic hepatic abscesses, ductal stones, or biliary obstruction. This condition
compression of the ducts. The most common cause of this form of is relatively rare but does occur in inhabitants of southern China and

HPIM21e_Part10_p2381-p2670.indd 2651 20/01/22 10:05 PM

 2652 elsewhere in Southeast Asia. The organisms most commonly involved may be used as initial therapy to help prevent the loss of bone mass
are trematodes or flukes, including Clonorchis sinensis, Opisthorchis frequently seen in patients with chronic cholestasis. In cases where
viverrini or Opisthorchis felineus, and Fasciola hepatica. The biliary high-grade biliary obstruction (dominant strictures) has occurred,
tract also may be involved by intraductal migration of adult Ascaris balloon dilatation is preferred over stenting due to the higher com-
lumbricoides from the duodenum or by intrabiliary rupture of hydatid plication rate associated with stenting including pancreatitis and
cysts of the liver produced by Echinococcus spp. The diagnosis is made cholangitis. Only rarely is surgical intervention indicated. PSC is a
by cholangiography and the presence of characteristic ova on stool progressive disease with a median survival of 12–18 years following
examination. When obstruction is present, the treatment of choice is the diagnosis, regardless of therapy. Four variables (age, serum
laparotomy under antibiotic coverage, with common duct exploration bilirubin level, histologic stage, and splenomegaly) predict survival
and a biliary drainage procedure. in patients with PSC and serve as the basis for a risk score. PSC is a
common indication for liver transplantation.
■■SCLEROSING CHOLANGITIS
PSC is characterized by a progressive, inflammatory, sclerosing, and
■■FURTHER READING
obliterative process affecting the extrahepatic and/or the intrahepatic
Baron TH et al: Interventional approaches to gallbladder disease.
bile ducts. PSC is strongly associated with inflammatory bowel disease,
N Engl J Med 373:357, 2015.
especially ulcerative colitis.
Lindor K et al: American College of Gastroenterology (ACG) guide-
Immunoglobulin G4 (IgG4)–associated cholangitis is a biliary dis-
lines: Primary sclerosing cholangitis. Hepatology 51:660, 2010.
ease of unknown etiology that presents with biochemical and cholangi-
Ryl JK et al: Clinical features of acute acalculous cholecystitis. J Clin
ographic features indistinguishable from PSC, is often associated with
Gastroenterol 36:166, 2003.
autoimmune pancreatitis and other fibrosing conditions, and is charac-
Strasberg S: Clinical practice. Acute calculous cholecystitis. N Engl J
terized by elevated serum IgG4 and infiltration of IgG4-positive plasma
Med 358:2804, 2008.
cells in bile ducts and liver tissue. All patients diagnosed with sclero-
sing cholangitis should have a serum IgG4 level checked to rule out
IgG4 disease as a cause of secondary sclerosing cholangitis, particularly
if they do not have inflammatory bowel disease. Glucocorticoids are
the initial treatment of choice. Relapse is common after steroid with-
drawal, especially with proximal strictures. Long-term treatment with Section 4 Disorders of the Pancreas
glucocorticoids and/or steroid-sparing agents such as azathioprine may
be needed after relapse or for inadequate response (Chap. 348).
Patients with PSC often present with signs and symptoms of
347 Approach
PART 10

chronic or intermittent biliary obstruction: RUQ abdominal pain, to the Patient

pruritus, jaundice, or acute cholangitis. Late in the course, complete
biliary obstruction, secondary biliary cirrhosis, hepatic failure, or with Pancreatic Disease
portal hypertension with bleeding varices may occur. The diagnosis is
Somashekar G. Krishna,
Disorders of the Gastrointestinal System

established by finding multifocal, diffusely distributed strictures with

intervening segments of normal or dilated ducts, producing a beaded Darwin L. Conwell, Phil A. Hart
appearance on cholangiography (Fig. 346-2D). The cholangiographic
techniques of choice in suspected cases are MRCP and ERCP. When
a diagnosis of sclerosing cholangitis has been established, causes of ■■GENERAL CONSIDERATIONS
secondary sclerosing should be considered. Patients with PSC should Globally, pancreatic disorders, including acute and chronic pancreati-
undergo testing for associated diseases, especially inflammatory bowel tis, pancreatic cysts, and pancreatic cancer, are challenging to manage
disease, if that diagnosis has not already been established. and associated with a high burden on health care resources. The rela-
Small duct PSC is defined by the presence of chronic cholestasis and tionships between these diseases continues to be poorly understood,
hepatic histology consistent with PSC in a patient with IBD, but with but there is encouraging progress. Acute pancreatitis is one of the most
normal findings on cholangiography. Small duct PSC is found in ~5% common reasons for hospitalizations in gastroenterology, and there is
of patients with PSC and may represent an earlier stage of PSC asso- increasing evidence of long-term sequelae including diabetes, exocrine
ciated with a significantly better long-term prognosis. However, such pancreas insufficiency, and pancreas cancer. Chronic pancreatitis, an
patients may progress to classic PSC and/or end-stage liver disease with irreversible disease of the pancreas, is associated with poor quality of
consequent necessity of liver transplantation. life, largely related to abdominal pain, and associated exocrine insuffi-
In patients with AIDS, cholangiopancreatography may demon- ciency. Pancreatic cysts, mostly incidental, are increasingly detected on
strate a broad range of biliary tract changes as well as pancreatic duct cross-sectional abdominal imaging studies. Although a small number
obstruction and occasionally pancreatitis (Chap. 202). Further, biliary and specific types of pancreatic cysts can progress to pancreatic cancer,
tract lesions in AIDS include infection and cholangiopancreatographic diagnostic uncertainty can introduce unwanted anxiety to patients
changes of sclerosing cholangitis. Changes noted include (1) diffuse and treating physicians. Meanwhile, with persistently high mortality
involvement of intrahepatic bile ducts alone, (2) involvement of both rates, the incidence of pancreatic adenocarcinoma is increasing and is
intra- and extrahepatic bile ducts, (3) ampullary stenosis, (4) stricture the seventh leading cause of cancer-related death in the industrialized
of the intrapancreatic portion of the CBD, and (5) pancreatic duct world and the third most common in the United States.
involvement. Associated infectious organisms include Cryptosporid- As emphasized in Chap. 348, the etiologies and clinical manifesta-
ium, Mycobacterium avium-intracellulare, cytomegalovirus, Microspo- tions of pancreatitis are quite varied. Although it is well-appreciated
ridia, and Isospora. ERCP sphincterotomy can provide significant pain that acute pancreatitis is frequently secondary to biliary tract disease
reduction in patients with AIDS-associated papillary stenosis. and alcohol abuse, it can also be caused by drugs, genetic muta-
tions, and trauma. In ~30% of patients with acute pancreatitis and
TREATMENT 25–40% of patients with chronic pancreatitis, the etiology is initially
unexplained.
Primary Sclerosing Cholangitis The global pooled incidence of acute pancreatitis is ~33.7 cases
There is no proven medical therapy for PSC. Therapy to treat pru- (95% confidence interval [CI], 23.3–48.8) with 1.16 deaths (95%
ritus associated with PSC includes cholestyramine, rifampin, and CI, 0.85–1.6) per 100,000 person-years. The global pooled incidence
naltrexone. Antibiotics are useful when bacterial cholangitis compli- of chronic pancreatitis is ~9.6 cases (95% CI, 7.9–11.8) with 0.09
cates the clinical picture. Vitamin D and calcium supplementation attributable deaths (95% CI, 0.02–0.5) per 100,000 person-years. In the

HPIM21e_Part10_p2381-p2670.indd 2652 20/01/22 10:05 PM

 United States, the number of patients admitted to the hospital with ■■TESTS USEFUL IN THE DIAGNOSIS OF 2653
acute pancreatitis is increasing, with estimated rates of almost 300,000 PANCREATIC DISEASE
annually, whereas the number of patients hospitalized for chronic pan- Several tests are of value in the evaluation of pancreatic disease. Exam-
creatitis is decreasing, with recent estimates of ~13,000 admissions per ples of specific tests and their usefulness in the diagnosis of acute and
year. Chronic pancreatitis has an annual prevalence of 42–73 cases per chronic pancreatitis are summarized in Table 347-1 and Fig. 347-2.
100,000 adults in the United States, although higher prevalence rates At some institutions, pancreatic function tests are available and per-
(0.04–5%) have been noted among adults at autopsy. Together, acute formed if the diagnosis of chronic pancreatitis remains a possibility
and chronic pancreatic disease costs an estimated $3 billion annually after noninvasive tests (i.e., ultrasound, CT Scan, MRI with magnetic
in health care expenditures. resonance cholangiopancreatography [MRCP]) or invasive tests (i.e.,
The diagnosis of acute pancreatitis is generally clearly defined endoscopic retrograde cholangiopancreatography [ERCP], endoscopic
based on a combination of laboratory, imaging, and clinical symp- ultrasound [EUS]) have given normal or inconclusive results. In this
toms. The diagnosis of chronic pancreatitis, especially in mild disease, regard, tests using direct stimulation of the pancreas with secretin are
is hampered by the relative inaccessibility of the pancreas to direct the most sensitive.
examination and the nonspecificity of the abdominal pain associated Pancreatic Enzymes in Body Fluids The serum amylase and
with chronic pancreatitis. Many patients with chronic pancreatitis do lipase levels are widely used as screening tests for acute pancreatitis
not have elevated blood amylase or lipase levels. Some patients with in the patient with acute abdominal pain or back pain. Lipase is very
chronic pancreatitis develop signs and symptoms of exocrine pancre- specific for the pancreas, and values greater than three times the upper
atic insufficiency (EPI), and thus, objective evidence for pancreatic limit of normal (3× ULN) in combination with epigastric pain strongly
disease can be demonstrated. However, there is a very large reservoir suggest the diagnosis of acute pancreatitis. In acute pancreatitis, the
of pancreatic exocrine function. More than 90% of the pancreas must serum amylase and lipase are usually elevated within 24 h of onset and
be damaged before maldigestion of fat and protein is manifested. remain so for 3–7 days. Levels usually return to normal within 7 days
Noninvasive, indirect tests of pancreatic exocrine function (e.g., fecal unless there is pancreatic ductal disruption, ductal obstruction, or
elastase) are much more likely to give abnormal results in patients pseudocyst formation. Approximately 85% of patients with acute pan-
with obvious advanced pancreatic disease (i.e., pancreatic calcification, creatitis have threefold or greater elevated serum lipase and amylase
steatorrhea, or diabetes mellitus) than in patients with occult disease. levels. The values may be normal if (1) there is a delay (2–5 days) before
Invasive, direct tests of pancreatic secretory function (e.g., secretin blood samples are obtained, (2) the underlying disorder is chronic
stimulation test) are the most sensitive and specific tests to detect early pancreatitis rather than acute pancreatitis, or (3) hypertriglyceridemia
chronic pancreatic disease when imaging is equivocal or normal. is present. Patients with hypertriglyceridemia and acute pancreatitis

CHAPTER 347 Approach to the Patient with Pancreatic Disease

The increasing utilization of cross-sectional imaging modalities have been found to have spuriously low levels of amylase and perhaps
with their improved resolution has contributed to a high prevalence lipase activity. In the absence of objective evidence of pancreatitis by
(2–5% with computed tomography [CT] scans, 20–30% with magnetic abdominal ultrasound, contrast-enhanced CT scan, MRI with MRCP,
resonance imaging [MRI]) of incidentally detected pancreatic cysts. or EUS, mild to moderate elevations of amylase and/or lipase are not
The most common cyst type encountered is an intraductal papillary helpful in making a diagnosis of chronic pancreatitis.
mucinous neoplasm (IPMN), which is classified as a precancerous It should be noted that the serum amylase can be elevated in other
mucinous cyst. In the absence of high-risk features, radiographic conditions (Table 347-2), in part because the enzyme is found in many
surveillance is typically recommended (Fig. 347-1). Mucinous cystic organs. In addition to the pancreas and salivary glands, small quantities
neoplasms (MCNs) are a less commonly encountered mucinous cyst. of amylase are found in the tissues of the fallopian tubes, lung, thyroid,
Among the neoplastic cysts, serous cystadenomas have a negligible and tonsils and can be produced by various tumors (carcinomas of the
risk of progression to malignancy. Other infrequent neoplastic cysts lung, esophagus, breast, and ovary). Isoamylase determinations do not
include neuroendocrine tumors and solid pseudopapillary neoplasms. accurately distinguish elevated blood amylase levels from pancreatic
The most commonly encountered benign cyst is a pseudocyst, which or nonpancreatic sources. In patients with unexplained hyperamy-
can occur in patients with a history of acute or chronic pancreatitis. lasemia, the measurement of macroamylase can avoid numerous tests
It is often difficult to accurately predict the risk of malignant trans- in patients with this rare disorder.
formation of precancerous pancreatic cysts, and there is an increasing Elevation of ascitic fluid amylase occurs in acute pancreatitis as well
number of patients on imaging surveillance protocols burdening the as in (1) ascites due to disruption of the main pancreatic duct or a leaking
health care systems in the industrialized world. pseudocyst and (2) other abdominal disorders that simulate pancreatitis

A B C
FIGURE 347-1 A. Side-branch intraductal papillary mucinous neoplasm (magnetic resonance imaging [MRI] with magnetic resonance cholangiopancreatography [MRCP]).
T2-weighted MRCP image demonstrates a dominant, lobulated, hyperintense cystic structure (arrow) within the posterior body of the pancreas. The pancreatic duct
upstream from the cyst is dilated and irregular. Endoscopic ultrasound and fine-needle aspiration of cyst fluid were consistent with a mucinous cyst. Surgical histopathology
revealed an infiltrating moderately differentiated adenocarcinoma, 0.3 cm, arising in a background of an intraductal papillary mucinous neoplasm (IPMN). B. Mucinous
cystic neoplasm (computed tomography [CT] scan). In the tail of the pancreas, there is a well-circumscribed hypodense cyst (arrow) without any nodular enhancing
components. Endoscopic ultrasound and fine-needle aspiration of cyst fluid were suggestive of a mucinous cyst. Surgical histopathology revealed a mucinous cystic
neoplasm (3.4 cm) with low-grade dysplasia. The stroma of the cyst demonstrated diffuse positivity for progesterone receptor and focal positivity for CD10 (ovarian stroma),
confirming the diagnosis. C. Serous cystadenoma (MRI). A lobulated microcystic cyst (arrow) is observed in the tail of the pancreas. Neither a communication with the main
pancreatic duct nor intracystic soft tissue enhancing nodular components were observed. However, the cyst continued to increase in size and a distal pancreatectomy
was performed. Histopathology revealed a serous microcystic adenoma. (Courtesy of Dr. Z.K. Shah, The Ohio State University Wexner Medical Center; with permission.)

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TABLE 347-1 Tests Useful in the Diagnosis of Acute and Chronic Pancreatitis and Pancreatic Neoplasms
TEST PRINCIPLE COMMENT
Pancreatic Enzymes in Body Fluids
Serum lipase Pancreatic inflammation leads to increased serum enzyme Enzyme measurement of choice for the diagnosis of acute pancreatitis;
levels increased specificity if the level is more than three times the upper limit
of normal (3× ULN)
Amylase
1. Serum Pancreatic inflammation leads to increased serum enzyme Simple; increased specificity if the level is >3× ULN; may be falsely
levels normal in patients with hypertriglyceridemic pancreatitis
2. Urine Renal clearance of amylase is increased in acute Infrequently used
pancreatitis
3. Ascitic fluid Disruption of gland or main pancreatic duct leads to Can help establish source of ascites; false positives occur with intestinal
increased amylase concentration obstruction and perforated ulcer; can also measure lipase
4. Pleural fluid Exudative pleural effusion with pancreatitis False positives occur with carcinoma of the lung and esophageal
perforation
Studies Pertaining to Pancreatic Structure
Radiologic and radionuclide tests
1. Plain film of the abdomen or Can demonstrate large calcifications in chronic Infrequently used
upper gastrointestinal x-rays pancreatitis
2. Ultrasonography (US) Can provide limited information on edema, inflammation, Simple, noninvasive; sequential studies quite feasible; useful in diagnosis
calcification, pseudocysts, and mass lesions of gallstones; pancreas visualization limited by interference from
overlying bowel gas
3. Computed tomography Permits detailed visualization of pancreas and Useful in the diagnosis of pancreatic calcification, dilated pancreatic
(CT) scan surrounding structures, pancreatic fluid collection, ducts, and pancreatic tumors; may not be able to distinguish between
pseudocyst; assessment of necrosis or interstitial disease inflammatory and neoplastic mass lesions; multiphasic CT scans are the
preferred imaging modality for staging pancreatic cancer; IV contrast is
needed for characterization of most features
4. Magnetic resonance Permits noninvasive detailed evaluation of the pancreatic Has mostly replaced ERCP for diagnostic assessment of the pancreatic
imaging (MRI) and parenchyma, biliary and pancreatic ducts, adjacent soft duct; more sensitive than CT scan for detection of mild pancreatitis,
PART 10

cholangiopancreatography tissues, and vascular structures. necrosis, choledocholithiasis, pancreatic ductal abnormalities, and
(MRCP) cystic neoplasms; no exposure to ionizing radiation
5. Endoscopic ultrasonography High-frequency transducer used with EUS produces very- Can be used to assess gallstones, choledocholithiasis, chronic
(EUS) and fine-needle high-resolution images permitting focused evaluation of pancreatitis, pancreatic masses, and cystic neoplasms; FNA/B facilitates
aspiration/biopsy (FNA/B) pancreatic parenchyma and biliary and pancreatic ducts, diagnostic and therapeutic management of pancreatic diseases
Disorders of the Gastrointestinal System

and FNA/B provides targeted tissue acquisition

6. Endoscopic retrograde Cannulation of pancreatic and/or common bile duct Primarily a therapeutic procedure; invasive with risks for iatrogenic
cholangiopancreatography permits visualization of pancreaticobiliary ductal system complications
(ERCP)
Tests of Exocrine Pancreatic Function
Direct stimulation of the pancreas with analysis of duodenal contents
1. Secretin test Secretin leads to increased output of pancreatic juice and Sensitive to detect occult disease; poorly defined normal enzyme
HCO3–; pancreatic secretory response is related to the response; large secretory reserve capacity of the pancreas; rarely
functional mass of pancreatic tissue; involves duodenal performed
intubation and fluoroscopic placement of gastroduodenal
tube
2. Endoscopic pancreatic Secretin-stimulated collection of pancreatic juice Sensitive to detect occult disease; high negative predictive value for
function test (ePFT) performed during upper endoscopy; replaces need for chronic pancreatitis; requires sedation
tube placement in the duodenum
3. EUS-ePFT Combines endosonographic evaluation of the pancreas Single endoscopic evaluation of pancreatic structure and function
and endoscopic collection of pancreatic juice
4. Secretin-stimulated MRCP Combines imaging evaluation of the pancreas and a Improved visualization of pancreatic ductal anatomy; functional
semiquantitative estimation of pancreatic juice output in evaluation is less accurate than ePFT; noninvasive
the duodenum
Measurement of intraluminal digestion products
1. Stool fat determination Lack of lipolytic enzymes brings about impaired fat Reliable reference standard for defining severity of fat malabsorption;
digestion; quantitative 72-h stool collection and estimation does not distinguish between pancreatic and nonpancreatic cause of
are more reliable than qualitative analysis of a random malabsorption
stool sample
Measurement of pancreatic enzymes in feces
1. Fecal elastase Pancreatic secretion of proteolytic enzymes; not degraded Diagnostic accuracy is highest when the pretest probability is high
in intestine and the value is <100 μg/g; false positives will occur in patients with
nonformed stools

(e.g., intestinal obstruction, intestinal infarction, or perforated peptic elevated in the setting of renal disease, so determining whether a patient
ulcer). Elevation of pleural fluid amylase can occur in acute pancreatitis, with renal failure and abdominal pain has pancreatitis remains a chal-
chronic pancreatitis, carcinoma of the lung, and esophageal perforation. lenging clinical problem. One study found that serum amylase levels
Lipase is the single best enzyme to measure for the diagnosis of acute were elevated in patients with renal dysfunction only when creatinine
pancreatitis. It is important to acknowledge that levels are often mildly clearance was <0.8 mL/s (<50 mL/min). In such patients, the serum

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 2655
• Clinical signs and symptoms suggestive of chronic pancreatic disease: abdominal pain,
nausea, weight loss, steatorrhea, malabsorption, history of alcohol abuse, recurrent
pancreatitis, fatty-food intolerance
• Perform history, physical examination, review of laboratory studies; consider fecal elastase
measurement
Step 1 • Contrast-enhanced CT scan
• CP diagnostic criteria: calcifications in combination with atrophy and/or dilated duct
• Diagnostic criteria met; no further imaging needed
• Inconclusive or nondiagnostic results; continue to step 2
Step 2 • MRI and MRCP, with or without secretin enhancement (sMRCP)
• CP diagnostic criteria: Cambridge class III,a dilated duct, atrophy of gland, filling
defects in duct suggestive of stones
• Diagnostic criteria met; no further imaging needed
• Inconclusive or nondiagnostic results; continue to step 3
Step 3 • EUS with quantification of parenchymal and ductal criteria
• CP diagnostic criteria: ≥5 EUS CP criteria
• Diagnostic criteria met; no further imaging needed
• Inconclusive or nondiagnostic results; continue to step 4
Step 4 • Pancreas function test (with secretin)—endoscopic (ePFT) collection method
preferred; consider combining ePFT with EUS
• CP diagnostic criteria: peak [bicarbonate] <80 mEq/L
• Diagnostic criteria met; no further imaging needed
• Inconclusive or nondiagnostic results require monitoring of signs and symptoms and repeat
testing in 6 months–1 year

FIGURE 347-2 A stepwise diagnostic approach to the patient with suspected chronic pancreatitis (CP). Endoscopic ultrasonography (EUS) and magnetic resonance
imaging (MRI) with secretin-stimulated magnetic resonance cholangiopancreatography (sMRCP/MRCP) are appropriate diagnostic alternatives to endoscopic
retrograde cholangiopancreatography (ERCP). CT, computed tomography; ePFT, endoscopic pancreas function test. aCambridge classification of pancreatic duct findings:
class 0: normal—visualization of complete normal ductal anatomy; class I: equivocal—normal main duct, 1–3 abnormal side branches; class II: mild—normal main duct,

CHAPTER 347 Approach to the Patient with Pancreatic Disease

>3 abnormal side branches; class III—dilated and irregular main duct, >3 abnormal side branches, small (<10 mm) cysts; class IV—irregular main duct, intraductal calculi,
strictures, obstruction with dilation, or large (> 10 mm) cysts.

amylase level was invariably <500 IU/L in the absence of objective pancreatic necrosis. The major benefit of CT scan in acute pancreatitis
evidence of acute pancreatitis. In that study, serum lipase and trypsin is the diagnosis of pancreatic necrosis in patients not responding to
levels paralleled serum amylase values. With these limitations in mind, conservative management within 72 h. It may take 48–72 h to develop
the recommended screening test for acute pancreatitis in renal disease perfusion defects indicative of pancreatic necrosis. Therefore, if acute
is serum lipase, but a high index of clinical suspicion is needed based on pancreatitis is confirmed with serology and physical examination find-
symptoms. Elevations in serum lipase >3× ULN due to nonpancreatic ings, CT scan in the first 3 days is not recommended to minimize risk
etiology can be observed in hepatobiliary or gastrointestinal malignan- of contrast-induced nephropathy and unnecessary health care costs.
cies, septicemia, liver cirrhosis, systemic lupus erythematosus, severe Improved imaging technology and increased resolution are facilitated
head injury, chronic alcoholism, diabetes mellitus, and post-ERCP by multiphasic CT scans using multidetector technology (MDCT)
without any associated evidence of pancreatitis. in which a pancreas protocol consisting of dual-phase scanning with
Studies Pertaining to Pancreatic Structure • RADIOLOGIC intravenous contrast is utilized for the detection and staging of pan-
TESTS Plain films of the abdomen rarely provide useful informa- creatic cancers. While the sensitivity of MDCT for detecting smaller
tion related to pancreatic disease and have been superseded by more (≤2 cm) lesions is lower, the reported overall sensitivity for pancreatic
detailed imaging studies (ultrasound, EUS, CT, and MRI with MRCP). cancers is 76–97%. The contraindications to using intravenous contrast
Ultrasonography (US) can provide important information in the include renal failure (serum creatinine >2 mg/dL) and a history of
initial emergency ward evaluation of patients with acute pancreatitis, severe allergic reaction to iodinated contrast agents. In situations where
chronic pancreatitis, pseudocysts, and pancreatic adenocarcinoma. EUS is not available, CT-guided percutaneous aspiration or biopsy of a
Sonographic changes can indicate the presence of edema, inflamma- pancreatic mass can be performed. Prior to the major advance of EUS-
tion, and calcification (not obvious on plain films of the abdomen), guided fine-needle aspiration (FNA), CT-guided biopsy was utilized in
as well as gallstones, biliary dilation, pseudocysts, and mass lesions. In the preceding decades and is regarded as a safe procedure.
acute pancreatitis, the pancreas is characteristically enlarged. In pan- MRI and MRCP provide excellent imaging of the bile duct, pan-
creatic pseudocyst, the usual appearance is primarily that of a smooth, creatic duct, and pancreas parenchyma in both acute pancreatitis and
round fluid collection. Pancreatic adenocarcinoma distorts the usual chronic pancreatitis. MRI is better than transabdominal US and CT
landmarks, and mass lesions >3.0 cm are usually detected as localized, scans and comparable to EUS in the detection of choledocholithiasis.
solid lesions. US is often the initial investigation for most patients with Similar to CT, MRI can evaluate for the severity of acute pancreatitis.
suspected pancreatic disease. However, obesity and excess intestinal Moreover, T2-weighted MRI of fluid collections can differentiate
bowel gas can interfere with pancreatic imaging, limiting its sensitivity. necrotic debris from fluid in suspected walled-off necrosis, and T1
CT with intravenous contrast is the best imaging study for the imaging can diagnose hemorrhage in suspected pseudoaneurysm
assessment of complications of acute and chronic pancreatitis. It is rupture. In chronic pancreatitis, secretin-enhanced MRCP is a method
especially useful in the detection of pancreatic and peripancreatic to enhance the evaluation of major and minor ductal changes. While
acute fluid collections, fluid-containing lesions such as pseudocysts, imaging is comparable to CT for evaluating pancreatic mass lesions,
walled-off necrosis (see Chap. 348, Figs. 348-1, 348-2, and 348-4), MRI with MRCP is the preferred imaging modality for evaluating
and pancreatic neoplasms. Acute pancreatitis is characterized by (1) pancreatic cystic lesions. Nephrogenic systemic fibrosis has been
enlargement of the pancreas, (2) distortion of the pancreatic contour described in patients with chronic renal failure following exposure to
with peripancreatic stranding of adjacent fat tissue, and/or (3) the the gadolinium contrast, but incidence rates are extraordinarily low
presence of pancreatic fluid that has a different attenuation coeffi- with contemporary contrast agents.
cient than normal pancreas. When possible, CT scans should ideally EUS produces high-resolution images of the bile duct, pancre-
be performed with oral and intravenous contrast to detect areas of atic parenchyma, and pancreatic duct with a transducer fixed to an

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 2656
TABLE 347-2 Causes of Hyperamylasemia and Hyperamylasuria TABLE 347-3 Endoscopic Ultrasonographic Criteria for Chronic
Pancreatic Disease Pancreatitis (Total Criteria = 9)
I. Pancreatitis DUCTAL PARENCHYMAL
A. Acute Stones Echogenic strands
B. Chronic: ductal obstruction Hyperechoic main duct margins Echogenic foci
C. Complications of pancreatitis Main duct irregularity Lobular contour
1. Pancreatic pseudocyst Main duct dilatation Cysts
2. Ascites caused by pancreatic duct disruption Visible side branches
3. Pancreatic necrosis
II. Pancreatic trauma
III. Pancreatic adenocarcinoma Although a pancreatogram during ERCP is the most specific and
Nonpancreatic Disorders sensitive test for evaluating the ductal anatomy, EUS and MRI/MRCP
I. Renal insufficiency have largely replaced ERCP in the diagnostic evaluation of pancreatic
disease to avoid the risk of complications. Therefore, ERCP is primarily
II. Salivary gland lesions
of therapeutic value after CT, EUS, or MRI and MRCP has detected
A. Mumps
abnormalities requiring endoscopic treatment. ERCP is the most
B. Calculus sensitive modality for the detection of bile duct stones. In the manage-
C. Irradiation sialadenitis ment of acute biliary pancreatitis, ERCP should not be unduly delayed
D. Maxillofacial surgery in patients with high clinical suspicion of biliary obstruction. In
III. “Tumor” hyperamylasemia chronic pancreatitis, ERCP abnormalities in the main pancreatic duct
A. Carcinoma of the lung, esophagus, breast, or ovary and side branches have been outlined by the Cambridge classification
IV. Macroamylasemia (Fig. 347-2). The presence of ductal stenosis and irregularity can make
V. Burns it difficult to distinguish chronic pancreatitis from pancreatic adeno-
VI. Diabetes mellitus, particularly when ketoacidosis is present carcinoma. It is important to be aware that ERCP changes interpreted
VII. Pregnancy as indicating chronic pancreatitis actually may be due to the effects
VIII. Renal transplantation
of aging on the pancreatic duct, sequelae of a recent attack of acute
pancreatitis, or changes secondary to placement of pancreatic duct
IX. Cerebral trauma
stent. Although aging may cause impressive ductal alterations, it does
PART 10

X. Drugs: opiates not affect the results of pancreatic secretin function tests. Pancreatic
Other Abdominal Disorders adenocarcinoma is characterized by stenosis or obstruction of either
I. Biliary tract disease: cholecystitis, choledocholithiasis the pancreatic duct or the common bile duct; both ductal systems are
II. Intraabdominal disease often abnormal (double-duct sign). When indicated, ERCP permits
Disorders of the Gastrointestinal System

A. Perforated or penetrating peptic ulcer acquisition of diagnostic tissue as in biopsy of ampullary lesions or
B. Intestinal obstruction or inflammation biliary brushings for distal bile duct strictures. Elevated serum amy-
C. Ruptured ectopic pregnancy
lase levels after ERCP have been reported in the majority of patients,
and clinical pancreatitis has been reported in 5–10% of patients. Until
D. Peritonitis
recently, pancreatic duct stents were commonly placed to prevent post-
E. Aortic aneurysm ERCP pancreatitis. However, recent data suggest that periprocedural
F. Postoperative hyperamylasemia administration of rectal indomethacin can decrease the incidence of
post-ERCP pancreatitis. Studies are currently underway comparing
endoscope that can be directed onto the surface of the pancreas through rectal indomethacin alone versus combination with prophylactic pan-
the stomach or duodenum. EUS is not beneficial for the evaluation of creatic duct stents to prevent post-ERCP pancreatitis.
pancreas during acute pancreatitis. It is preferable to perform EUS after ■■TESTS OF EXOCRINE PANCREATIC FUNCTION
the resolution of acute pancreatitis (~4 weeks) to detect any predis- Pancreatic function tests (Table 347-1) can be divided into the
posing factors, including malignancy, choledocholithiasis, pancreatic following:
divisum, or ampullary lesions. EUS can be combined with ERCP in a
single session and is increasingly preferred for the diagnosis and man- 1. Direct stimulation of the pancreas by IV infusion of secretin followed
agement of choledocholithiasis in acute pancreatitis and pancreatic by collection and measurement of duodenal contents: The secretin
neoplasm with biliary obstruction. EUS has been studied as a diag- test, used to detect diffuse pancreatic disease, is based on the phys-
nostic modality for chronic pancreatitis. Criteria for abnormalities on iologic principle that the pancreatic secretory response is directly
EUS in severe chronic pancreatic disease have been developed. There is related to the functional mass of pancreatic tissue. In the standard
general agreement that the presence of five or more of the nine criteria assay, secretin is given IV in a dose of 0.2 μg/kg of synthetic human
listed in Table 347-3 is highly predictive of chronic pancreatitis in the secretin as a bolus. Normal values for the standard secretin test are
correct clinical context. The sensitivity of EUS (81%; 95% CI, 70–89%) (1) volume output >2 mL/kg per h, (2) bicarbonate (HCO3–) concen-
to diagnose chronic pancreatitis is comparable to that of MRI/MRCP tration >80 mmol/L, and (3) HCO3– output >10 mmol/L in 1 h. The
(78%; 95% CI, 69–85%) and better than CT (75%; 95% CI, 66–83%); most reproducible measurement, giving the highest level of discrim-
however, nonspecific changes are commonly seen in the pancreas that ination between normal subjects and patients with chronic pancreas
may be attributable to cigarette smoking, diabetes, or normal aging. dysfunction, appears to be the maximal bicarbonate concentration.
EUS also facilitates the delivery of nerve-blocking agents via fine- A cutoff point <80 mmol/L is considered abnormal and suggestive
needle injection in patients suffering from pancreatic pain from of reduced secretory function that is most commonly observed in
chronic pancreatitis (celiac plexus block) or cancer (celiac plexus early chronic pancreatitis.
neurolysis). When clinically suspected, EUS imaging is more sensitive 2. There may be a dissociation between the results of the secretin test
than MDCT for the detection of pancreatic malignancy and permits and other tests of absorptive function. For example, patients with
fine-needle aspiration/biopsy (FNA/B). Currently, EUS-guided FNA/B chronic pancreatitis often have abnormally low outputs of HCO3–
is the diagnostic modality of choice for the acquisition of diagnostic after secretin but have normal fecal fat excretion. The secretin test
tissue and cyst fluid in patients with pancreatic masses and cystic directly measures the secretory capacity of ductular epithelium,
lesions, respectively. whereas fecal fat excretion indirectly reflects intraluminal lipolytic

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 activity. Steatorrhea does not occur until intraluminal levels of (tryptophan, phenylalanine, valine, methionine), and gastric acid 2657
lipase are markedly reduced, underscoring the fact that only small itself. CCK evokes an enzyme-rich secretion from acinar cells in the
amounts of enzymes are necessary for intraluminal digestive activ- pancreas. The parasympathetic nervous system (via the vagus nerve)
ities. It must be emphasized that an abnormal secretin test result exerts significant control over pancreatic secretion, particularly during
suggests that pancreatic ductal secretory function is abnormal. This the cephalic phase. Secretion evoked by secretin and CCK depends on
is an early abnormality in chronic pancreatitis but should not be the permissive roles of vagal afferent and efferent pathways. This is
considered diagnostic and must be interpreted within the proper particularly true for enzyme secretion, whereas water and bicarbonate
clinical context (for example, a patient with recurrent attacks of pan- secretions are heavily dependent on the hormonal effects of secretin
creatitis and persistent abdominal pain and Cambridge 2 changes and to a lesser extent CCK. Also, vagal stimulation affects the release
on imaging) of vasoactive intestinal peptide (VIP), a secretin agonist. Pancreatic
3. Measurement of fecal pancreatic enzymes such as elastase: Measure- exocrine secretion is also influenced by inhibitory neuropeptides
ment of intraluminal digestion products (i.e., undigested muscle including somatostatin, pancreatic polypeptide, peptide YY, neuro-
fibers, stool fat, and fecal nitrogen) is discussed in Chap. 325. The peptide Y, enkephalin, pancreastatin, calcitonin gene–related peptides,
amount of human elastase in stool reflects the pancreatic output glucagon, and galanin. Pancreatic polypeptide and peptide YY may act
of this proteolytic enzyme. Decreased fecal elastase-1 (FE-1) activ- primarily on nerves outside the pancreas, while somatostatin acts at
ity in stool is a test to detect severe EPI in patients with chronic multiple sites.
pancreatitis and cystic fibrosis. FE-1 levels >200 μg/g are normal,
levels of 100–200 μg/g are considered mild-moderate EPI, and levels ■■WATER AND ELECTROLYTE SECRETION
<100 μg/g are severe EPI. Although the test is simple and noninva- Bicarbonate is the ion of primary physiologic importance within pan-
sive, it can yield false-positive results if stools are not formed and creatic secretion. The ductal cells secrete bicarbonate predominantly
should not generally be used for the evaluation of a patient with derived from plasma (93%) more than from intracellular metabolism
diarrhea. False-positive results have also been observed in diabetes (7%). Bicarbonate enters the duct lumen through the sodium bicar-
and irritable bowel syndrome. bonate cotransporter with depolarization caused by chloride efflux
through the cystic fibrosis transmembrane conductance regulator
Tests useful in the diagnosis of EPI and the differential diagnosis (CFTR). Secretin and VIP bind at the basolateral surface and cause an
of malabsorption are also discussed in Chaps. 325 and 348. increase in secondary messenger intracellular cyclic AMP and act on
■■FURTHER READING the apical surface of the ductal cells opening the CFTR, which promotes
Conwell DL et al: American Pancreatic Association practice guide- secretion. CCK, acting as a neuromodulator, markedly potentiates the

CHAPTER 348 Acute and Chronic Pancreatitis

lines in chronic pancreatitis: Evidence-based report on diagnostic stimulatory effects of secretin. Acetylcholine also plays an important
guidelines. Pancreas 43:1143, 2014. role in ductal cell secretion. Intraluminal bicarbonate secreted from the
Hart PA et al: Endoscopic pancreas fluid collection: Methods and rel- ductal cells helps neutralize gastric acid, increases the solubility of fatty
evance for clinical care and translational science. Am J Gastroenterol acids and bile acids, maintains an optimal pH for pancreatic and brush
111:1258, 2016. border enzymes, and prevents intestinal mucosal damage.
Petrov MS, Yadav D: Global epidemiology and holistic prevention of
pancreatitis. Nat Rev Gastroenterol Hepatol 16:175, 2019. ■■ENZYME SECRETION
Singh VK et al: Diagnosis and management of chronic pancreatitis: A The acinar cell is highly compartmentalized for the production and
review. JAMA 322:2422, 2019. secretion of pancreatic enzymes. Proteins synthesized by the rough
endoplasmic reticulum are processed in the Golgi and then targeted
to the appropriate site: zymogen granules, lysosomes, or other cell
compartments. The zymogen granules migrate to the apical region of
the acinar cell awaiting the appropriate neural or hormonal stimulatory
response. The pancreas secretes amylolytic, lipolytic, and proteolytic

348 Acute
enzymes into the duct lumen. Amylolytic enzymes, such as amylase,
and Chronic hydrolyze starch to oligosaccharides and to the disaccharide maltose.
Pancreatitis The lipolytic enzymes include lipase, phospholipase A2, and cholesterol
esterase. Bile salts inhibit lipase in isolation, but colipase, another
Phil A. Hart, Darwin L. Conwell, constituent of pancreatic secretion, binds to lipase and prevents this
Somashekar G. Krishna inhibition. Bile salts activate phospholipase A and cholesterol esterase.
Proteolytic enzymes include endopeptidases (trypsin, chymotrypsin),
which act on internal peptide bonds of proteins and polypeptides;
exopeptidases (carboxypeptidases, aminopeptidases), which act on
BIOCHEMISTRY AND PHYSIOLOGY OF the free carboxyl- and amino-terminal ends of peptides, respectively;
PANCREATIC EXOCRINE SECRETION and elastase. The proteolytic enzymes are secreted as inactive zymogen
precursors. Ribonucleases (deoxyribonucleases, ribonuclease) are also
■■GENERAL CONSIDERATIONS secreted. Enterokinase, an enzyme found in the duodenal mucosa
The pancreas secretes 1500–3000 mL of isosmotic alkaline (pH >8) (“brush border”), cleaves the lysine-isoleucine bond of trypsinogen to
fluid per day containing ~20 enzymes. Pancreatic secretions provide form trypsin. Trypsin then activates the other proteolytic zymogens
the enzymes and bicarbonate needed to perform the major digestive and phospholipase A2 in a cascade. The nervous system initiates pan-
activity of the gastrointestinal tract and provide an optimal pH for the creatic enzyme secretion. The neurologic stimulation is cholinergic,
function of these enzymes. involving extrinsic innervation by the vagus nerve and subsequent
innervation by intrapancreatic cholinergic nerves. The stimulatory
■■REGULATION OF PANCREATIC SECRETION neurotransmitters are acetylcholine and gastrin-releasing peptides.
Secretions from the exocrine pancreas are highly regulated by neuro- These neurotransmitters activate calcium-dependent secondary mes-
hormonal systems in a phasic manner (cephalic, gastric, and intestinal senger systems, resulting in the release of zymogens into the pancreas
phases). Gastric acid is the stimulus for the release of secretin from the duct. VIP is present in intrapancreatic nerves and potentiates the
duodenal mucosa (S cells), which stimulates the secretion of water and effect of acetylcholine. In contrast to other species, there are no CCK
electrolytes from pancreatic ductal cells. Release of cholecystokinin receptors on acinar cells in humans. CCK in physiologic concentra-
(CCK) from the duodenal and proximal jejunal mucosa (Ito cells) tions stimulates pancreatic secretion by stimulating afferent vagal and
is largely triggered by long-chain fatty acids, essential amino acids intrapancreatic nerves.

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 2658 ■■AUTOPROTECTION OF THE PANCREAS TABLE 348-1 Causes of Acute Pancreatitis
Autodigestion of the pancreas is prevented by (1) the packaging of
Common Causes
pancreatic proteases in the precursor (proenzyme) form, (2) intracel-
lular calcium homeostasis (low intracellular calcium in the cytosol of Gallstones (including microlithiasis)
the acinar cell promotes the destruction of spontaneously activated Alcohol (acute and chronic alcoholism)
trypsin), (3) acid-base balance, and (4) the synthesis of protective Hypertriglyceridemia
protease inhibitors (pancreatic secretory trypsin inhibitor [PSTI] or Endoscopic retrograde cholangiopancreatography (ERCP), especially after
SPINK1), which can bind and inactivate ~20% of intracellular trypsin biliary manometry
activity. Chymotrypsin C can also lyse and inactivate trypsin. These Idiopathic
protease inhibitors are found in acinar cells, pancreatic secretions, and
Uncommon Causes
the α1- and α2-globulin fractions of plasma. Loss of any of these four
protective mechanisms leads to premature enzyme activation, autodi- Drugs (azathioprine, 6-mercaptopurine, sulfonamides, estrogens, tetracycline,
gestion, and ultimately acute pancreatitis. valproic acid, 5-aminosalicylic acid [5-ASA])
Connective tissue disorders and thrombotic thrombocytopenic purpura (TTP)
■■ENTEROPANCREATIC AXIS AND Pancreatic cancer
FEEDBACK INHIBITION Hypercalcemia
Pancreatic enzyme secretion is controlled, at least in part, by a negative Periampullary diverticulum
feedback mechanism induced by the presence of active serine proteases Pancreas divisuma
in the duodenum and nutrients in the distal small intestine. For exam-
Hereditary pancreatitis
ple, perfusion of the duodenal lumen with phenylalanine (stimulates
early digestion) causes a prompt increase in plasma CCK levels as well Cystic fibrosis
as increased secretion of chymotrypsin and other pancreatic enzymes. Renal failure
However, simultaneous perfusion with trypsin (stimulates late diges- Infections (mumps, coxsackievirus, cytomegalovirus, echovirus, parasites)
tion) blunts both responses. Conversely, perfusion of the duodenal Autoimmune (e.g., type 1 and type 2)
lumen with protease inhibitors actually leads to enzyme hypersecre- Trauma (especially blunt abdominal trauma)
tion. Available evidence supports the concept that the duodenum con-
Postoperative (abdominal and nonabdominal operations)
tains a peptide called CCK-releasing factor (CCK-RF) that is involved
in stimulating CCK release. It appears that serine proteases inhibit Causes to Consider in Patients with Recurrent Bouts of Acute
pancreatic secretion by inactivating a CCK-releasing peptide in the Pancreatitis without an Obvious Etiology
PART 10

lumen of the small intestine. Thus, the integrative result of both bicar- Occult disease of the biliary tree or pancreatic ducts, especially microlithiasis,
bonate and enzyme secretion depends on a feedback process for both biliary sludge
bicarbonate and pancreatic enzymes. Acidification of the duodenum Alcohol abuse
releases secretin, which stimulates vagal and other neural pathways to Metabolic: Hypertriglyceridemia, hypercalcemia
activate pancreatic duct cells, which secrete bicarbonate. This bicar- Anatomic: Pancreas divisuma
Disorders of the Gastrointestinal System

bonate then neutralizes the duodenal acid, and the feedback loop is Pancreatic cancer
completed. Dietary proteins bind proteases, thereby leading to an
Intraductal papillary mucinous neoplasm (IPMN)
increase in free CCK-RF. CCK is then released into the blood in phys-
iologic concentrations, acting primarily through the neural pathways Hereditary pancreatitis
(vagal-vagal). This leads to acetylcholine-mediated pancreatic enzyme Cystic fibrosis
secretion. Proteases continue to be secreted from the pancreas until Idiopathic
the protein within the duodenum is digested. At this point, pancreatic a
Pancreas divisum is not believed to cause acute pancreatitis in isolation of another
protease secretion is reduced to basic levels, thus completing this step disease precipitant.
in the feedback process. Additional hormonal feedback inhibition of
pancreatic enzyme secretion occurs via peptide YY and glucagon-like
peptide-1 following lipid or carbohydrate exposure to the ileum. pancreatitis in most series (30–60%). The risk of acute pancreatitis
in patients with at least one gallstone <5 mm in diameter is four-
ACUTE PANCREATITIS fold greater than that in patients with larger stones. Alcohol is the
second most common cause, responsible for 15–30% of cases in the
■■GENERAL CONSIDERATIONS United States. The incidence of pancreatitis in alcoholics is surprisingly
Recent U.S. estimates indicate that acute pancreatitis is the most low (5/100,000), indicating that in addition to the amount of alcohol
common inpatient principal gastrointestinal diagnosis, responsi- ingested, other factors affect a person’s susceptibility to pancreatic
ble for >250,000 hospitalizations per year. The annual incidence injury, such as cigarette smoking and genetic predisposition. Acute
ranges from 15–45/100,000 persons, depending on the distribu- pancreatitis occurs in 5–10% of patients following endoscopic retro-
tion of etiologies (e.g., alcohol, gallstones, metabolic factors, drugs grade cholangiopancreatography (ERCP); however, this risk can be
[Table 348-1]) and country of study. The median length of hospital stay is decreased with proper patient selection and the use of a prophylactic
4 days, with a median hospital cost of ~$6000 and a mortality of ~1%. pancreatic duct stent and/or rectal nonsteroidal anti-inflammatory
The estimated cost annually approaches $3 billion. Hospitalization drugs (NSAIDs; indomethacin). Risk factors for post-ERCP pancre-
rates increase with age and are higher among blacks and men. The atitis include minor papilla sphincterotomy, suspected sphincter of
age-adjusted rate of hospital discharges with an acute pancreatitis diag- Oddi dysfunction, prior history of post-ERCP pancreatitis, age <60
nosis increased by 62% between 1988 and 2004. From 2000 to 2009, years, more than two contrast injections into the pancreatic duct, and
the rate increased by 30%. Thus, the incidence of acute pancreatitis endoscopist experience.
continues to rise and is associated with substantial health care costs. Hypertriglyceridemia is the cause of acute pancreatitis in 1–4%
of cases; serum triglyceride levels are usually >1000 mg/dL. Most
■■ETIOLOGY AND PATHOGENESIS patients with hypertriglyceridemic pancreatitis have undiagnosed or
There are many causes of acute pancreatitis (Table 348-1), and the uncontrolled diabetes mellitus. An additional subset has an underlying
mechanisms by which each of these conditions triggers pancreatic derangement in lipid metabolism, probably unrelated to pancreatitis.
inflammation have not been fully elucidated. Gallstones and alcohol Such patients are prone to recurrent episodes of pancreatitis. Any factor
account for 80–90% of identified cases of acute pancreatitis in the (e.g., alcohol or medications, such as oral contraceptives) that causes an
United States. Gallstones continue to be the leading cause of acute abrupt increase in serum triglycerides can potentially precipitate a bout

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 of acute pancreatitis. Patients with a deficiency of apolipoprotein CII modifiers. Investigations of other genetic variants are currently under- 2659
have an increased incidence of pancreatitis; apolipoprotein CII acti- way, and new genes will be added to this list in the future.
vates lipoprotein lipase, which is important in clearing chylomicrons
from the bloodstream. Although frequently entertained, <2% of cases
of acute pancreatitis are drug related. Drugs cause pancreatitis either by
APPROACH TO THE PATIENT
a hypersensitivity reaction or by the generation of a toxic metabolite, Abdominal Pain
although in some cases, it is not clear which of these mechanisms is
operative (Table 348-1). Abdominal pain is the major symptom of acute pancreatitis. Pain
Pathologically, acute pancreatitis ranges from interstitial pancreatitis may vary from mild discomfort to severe, constant, and incapacitat-
(pancreas blood supply maintained), which is generally self-limited, ing distress. Characteristically, the pain, which is steady and boring
to necrotizing pancreatitis (pancreas blood supply interrupted). Auto- in character, is located in the epigastrium region and may radiate to
digestion is a currently accepted pathogenic theory resulting when the back, chest, flanks, and lower abdomen. Nausea, vomiting, and
proteolytic enzymes (e.g., trypsinogen, chymotrypsinogen, proelastase, abdominal distention due to gastric and intestinal hypomotility are
and lipolytic enzymes such as phospholipase A2) are activated in the also frequent complaints.
pancreas acinar cell compartment rather than the intestinal lumen. A Physical examination frequently reveals a distressed and anxious
number of factors (e.g., endotoxins, exotoxins, viral infections, ische- patient. Low-grade fever, tachycardia, and hypotension are com-
mia, oxidative stress, lysosomal calcium, direct trauma) are believed mon. Shock is not unusual and may result from (1) hypovolemia
to facilitate premature activation of trypsin. Activated proteolytic secondary to exudation of blood and plasma proteins into the
enzymes, especially trypsin, not only digest pancreatic and peripan- retroperitoneal space; (2) increased formation and release of kinin
creatic tissues but can also activate other enzymes, such as elastase and peptides, which cause vasodilation and increased vascular permea-
phospholipase A2. Spontaneous activation of trypsin also can occur, bility; and (3) systemic effects of proteolytic and lipolytic enzymes
resulting in autodigestion. released into the circulation. Jaundice occurs infrequently; when
present, it may be a consequence of extrinsic compression due to
■■ACTIVATION OF PANCREATIC ENZYMES IN THE peripancreatic edema or a pancreatic head mass or of intraductal
PATHOGENESIS OF ACUTE PANCREATITIS obstruction from a common bile duct stone or sludge. Erythema-
Several studies have suggested that pancreatitis is a disease that evolves tous skin nodules due to subcutaneous fat necrosis rarely occur. In
in three phases. The initial phase is characterized by intrapancreatic 10–20% of patients, there are pulmonary findings, including basilar
digestive enzyme activation and acinar cell injury. Trypsin activation rales, atelectasis, and pleural effusion, the latter most frequently

CHAPTER 348 Acute and Chronic Pancreatitis

appears to be mediated by lysosomal hydrolases such as cathepsin left-sided. Abdominal tenderness and muscle rigidity are present
B that become colocalized with digestive enzymes in intracellular to a variable degree, but compared with the intense pain, these
organelles; it is currently believed that acinar cell injury is the conse- signs may be less impressive. Bowel sounds are usually diminished
quence of trypsin activation. The second phase of pancreatitis involves or absent. An enlarged pancreas from an acute fluid collection,
the activation, chemoattraction, and sequestration of leukocytes and walled-off necrosis, or a pseudocyst may be palpable in the upper
macrophages in the pancreas, resulting in an enhanced intrapancre- abdomen later in the course of the disease (i.e., 4–6 weeks). A faint
atic inflammatory reaction. Neutrophil depletion induced by prior blue discoloration around the umbilicus (Cullen’s sign) may occur
administration of an antineutrophil serum has been shown to reduce as the result of hemoperitoneum, and a blue-red-purple or green-
the severity of experimentally induced pancreatitis. There is also evi- brown discoloration of the flanks (Turner’s sign) reflects tissue
dence to support the concept that neutrophils can activate trypsinogen. breakdown of hemoglobin from severe necrotizing pancreatitis
Thus, intrapancreatic acinar cell activation of trypsinogen could be a with hemorrhage; both findings are rare but reflect an increased
two-step process (i.e., an early neutrophil-independent and a later neu- clinical severity.
trophil-dependent phase). The third phase of pancreatitis is due to the
effects of activated proteolytic enzymes and cytokines, released by the ■■LABORATORY DATA
inflamed pancreas, on distant organs. Activated proteolytic enzymes, Serum amylase and lipase values threefold or more above normal are
especially trypsin, not only digest pancreatic and peripancreatic tissues strongly supportive of the diagnosis if alternate etiologies, including
but also activate other enzymes such as elastase and phospholipase gut perforation, ischemia, and infarction, are excluded. However, it
A2. The active enzymes and cytokines then digest cellular mem- should be noted that there is no correlation between the severity of
branes and cause proteolysis, edema, interstitial hemorrhage, vascular pancreatitis and the degree of serum lipase and amylase elevations or
damage, coagulation necrosis, fat necrosis, and cellular necrosis in serial trends. After 3–7 days, even with continuing evidence of pan-
the parenchyma. Cellular injury and death result in the liberation of creatitis, total serum amylase values tend to return toward normal.
bradykinin peptides, vasoactive substances, and histamine that can However, pancreatic lipase levels may remain elevated for 7–14 days.
produce vasodilation, increased vascular permeability, and edema with It should be recognized that amylase elevations in serum and urine
profound effects on other organs. The systemic inflammatory response occur in many conditions other than pancreatitis (see Chap. 347,
syndrome (SIRS) and acute respiratory distress syndrome (ARDS), as Table 347-2). Importantly, patients with acidemia (arterial pH ≤7.32)
well as multiorgan failure, may occur as a result of this cascade of local may have spurious elevations in serum amylase. This finding explains
and distant effects. why patients with diabetic ketoacidosis may have marked elevations in
A number of genetic factors can increase the susceptibility and/or serum amylase without any other evidence of acute pancreatitis. On the
modify the severity of pancreatic injury in acute pancreatitis, recurrent other hand, serum amylase levels can be spuriously low in the setting of
acute pancreatitis, and chronic pancreatitis. All the major genetic sus- severe hypertriglyceridemia. Serum lipase activity increases in parallel
ceptibility factors center on the control of trypsin activity within the with amylase activity and is more specific than amylase, making it the
pancreatic acinar cell, in part because they were identified as candidate preferred test. A serum lipase measurement can be instrumental in dif-
genes linked to intrapancreatic trypsin control. Six genetic variants ferentiating a pancreatic or nonpancreatic cause for hyperamylasemia.
have been identified as being associated with susceptibility to pancre- Leukocytosis (15,000–20,000 leukocytes/μL) occurs frequently.
atitis. The genes that have been identified include (1) cationic trypsino- Patients with more severe disease may show hemoconcentration with
gen gene (PRSS1), (2) pancreatic secretory trypsin inhibitor (SPINK1), hematocrit values >44% and/or prerenal azotemia with a blood urea
(3) the cystic fibrosis transmembrane conductance regulator gene nitrogen (BUN) level >22 mg/dL resulting from loss of plasma into the
(CFTR), (4) the chymotrypsin C gene (CTRC), (5) the calcium-sensing retroperitoneal space and peritoneal cavity.
receptor (CASR), and (6) claudin-2 (CLDN2). Among these variants, Hemoconcentration may be the harbinger of more severe dis-
only PRSS1 mutations are sufficient to precipitate acute pancreatitis in ease, whereas azotemia is a significant risk factor for mortality.
the absence of other risk factors, whereas the other variants are disease Hyperglycemia is common and is due to multiple factors, including

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 2660
TABLE 348-2 Revised Atlanta Definitions of Morphologic Features of Acute Pancreatitis
DEFINITION COMPUTED TOMOGRAPHY FEATURES
Types of Acute Pancreatitis
Interstitial pancreatitis Acute inflammation of the pancreatic parenchyma and Pancreatic parenchyma enhancement by IV contrast agent and without
peripancreatic tissues, but without recognizable tissue peripancreatic necrosis
necrosis
Necrotizing Inflammation associated with pancreatic parenchymal Lack of pancreatic parenchymal enhancement by IV contrast agent and/or presence
pancreatitis and/or peripancreatic necrosis of findings of peripancreatic necrosis (see below—ANC and WON)
Morphologic Features
Acute pancreatic fluid Peripancreatic fluid associated with interstitial Occurs in the setting of interstitial pancreatitis
collection edematous pancreatitis with no associated Homogeneous collection with fluid density
peripancreatic necrosis. This term applies only to areas
of peripancreatic fluid seen within the first 4 weeks after Confined by normal peripancreatic fascial planes
onset of interstitial edematous pancreatitis and without No definable wall encapsulating the collection
the features of a pseudocyst. Adjacent to pancreas (no intrapancreatic extension)
Pancreatic An encapsulated collection of fluid with a well-defined Well circumscribed, usually round or oval
pseudocyst inflammatory wall usually outside the pancreas Homogeneous fluid density
with minimal or no necrosis. This entity usually
occurs >4 weeks after onset of interstitial edematous No solid component
pancreatitis. Well-defined wall; that is, completely encapsulated
Maturation usually requires >4 weeks after onset of acute pancreatitis; occurs after
interstitial pancreatitis
Acute necrotic A collection containing variable amounts of both fluid Occurs in the setting of acute necrotizing pancreatitis
collection (ANC) and necrosis associated with necrotizing pancreatitis; Heterogeneous and nonliquid density of varying degrees in different locations (some
the necrosis can involve the pancreatic parenchyma appear homogeneous early in their course)
and/or the peripancreatic tissues.
No definable wall encapsulating the collection
Location—intrapancreatic and/or extrapancreatic
Walled-off necrosis A mature, encapsulated collection of pancreatic and/ Heterogeneous with liquid and nonliquid density with varying degrees of loculations
(WON) or peripancreatic necrosis that has developed a (some may appear homogeneous)
PART 10

well-defined inflammatory wall. WON usually occurs Well-defined wall; that is, completely encapsulated
>4 weeks after onset of acute necrotizing pancreatitis.
Location—intrapancreatic and/or extrapancreatic
Maturation usually requires >4 weeks after onset of acute necrotizing pancreatitis
Source: Data from P Banks et al: Gut 62:102, 2013.
Disorders of the Gastrointestinal System

decreased insulin release, increased glucagon release, and increased ■■DIAGNOSIS

output of adrenal glucocorticoids and catecholamines. Hypocalcemia Any severe acute pain in the abdomen or back should suggest the pos-
occurs in ~25% of patients, and its pathogenesis is incompletely under- sibility of acute pancreatitis. The diagnosis is established by two of the
stood. Although earlier studies suggested that the response of the para- following three criteria: (1) typical abdominal pain in the epigastrium
thyroid gland to a decrease in serum calcium is impaired, subsequent that may radiate to the back, (2) threefold or greater elevation in serum
observations have failed to confirm this phenomenon. Intraperitoneal lipase and/or amylase, and (3) confirmatory findings of acute pancre-
saponification of calcium by fatty acids in areas of fat necrosis occurs atitis on cross-sectional abdominal imaging. Although not required for
occasionally, with large amounts (up to 6.0 g) dissolved or suspended diagnosis, markers of severity may include hemoconcentration (hema-
in ascitic fluid. Such “soap formation” may also be significant in tocrit >44%), admission azotemia (BUN >22 mg/dL), SIRS, and signs
patients with pancreatitis, mild hypocalcemia, and little or no obvious of organ failure (Table 348-3).
ascites. Hyperbilirubinemia (serum bilirubin >4.0 mg/dL) occurs in The differential diagnosis should include the following disorders:
~10% of patients. However, jaundice is transient, and serum bilirubin (1) perforated viscus, especially peptic ulcer; (2) acute cholecystitis
levels return to normal in 4–7 days. Serum alkaline phosphatase and and biliary colic; (3) acute intestinal obstruction; (4) mesenteric
transaminase levels may also be transiently elevated and parallel serum vascular occlusion; (5) renal colic; (6) inferior myocardial infarction;
bilirubin values. Elevations of alanine aminotransferase (ALT) >3× the (7) dissecting aortic aneurysm; (8) connective tissue disorders with
upper limit of normal are strongly associated with a gallstone etiology vasculitis; (9) pneumonia; and (10) diabetic ketoacidosis. It may be
in patients with acute pancreatitis. Approximately 5–10% of patients difficult to differentiate acute cholecystitis from acute pancreatitis,
have hypoxemia (arterial Po2 ≤60 mmHg), which may herald the onset because an elevated serum amylase may be found in both disorders.
of ARDS. Finally, the electrocardiogram is occasionally abnormal in Pain of biliary tract origin is more right sided or epigastric than
acute pancreatitis with ST-segment and T-wave abnormalities simulat- periumbilical or left upper quadrant and can be more severe; ileus is
ing myocardial ischemia. usually absent. Ultrasound is helpful in establishing the diagnosis of
An abdominal ultrasound is recommended in the emergency ward cholelithiasis and cholecystitis. Intestinal obstruction due to mechan-
as the initial diagnostic imaging modality and is most useful to evaluate ical factors can be differentiated from pancreatitis by the history of
for gallstones and common bile duct dilation. crescendo-decrescendo pain, findings on abdominal examination,
The Revised Atlanta Criteria have clearly outlined the morpho- and CT of the abdomen showing changes characteristic of mechanical
logic features of acute pancreatitis on computed tomography (CT) obstruction. Acute mesenteric vascular occlusion is usually suspected
scan as follows: (1) interstitial pancreatitis, (2) necrotizing pancre- in elderly debilitated patients with leukocytosis, abdominal disten-
atitis, (3) acute pancreatic fluid collection, (4) pancreatic pseudocyst, tion, and bloody diarrhea, confirmed by CT or magnetic resonance
(5) acute necrotic collection (ANC), and (6) walled-off necrosis angiography. Vasculitides secondary to systemic lupus erythematosus
(WON) (Table 348-2 and Fig. 348-1). Radiologic studies useful in and polyarteritis nodosa may be confused with pancreatitis, especially
the diagnosis of acute pancreatitis are discussed in Chap. 347 and because pancreatitis may develop as a complication of these diseases.
listed in Table 347-1. Diabetic ketoacidosis is often accompanied by abdominal pain and

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 TABLE 348-3 Severe Acute Pancreatitis Severity of Acute Pancreatitis Three classes of severity have 2661
been defined: mild, moderately severe, and severe. Mild acute pancreatitis
Risk Factors for Severity
is without local complications or organ failure. Most patients with
• Age >60 years interstitial acute pancreatitis have mild pancreatitis. In mild acute pan-
• Obesity, BMI >30 kg/m2 creatitis, the disease is self-limited and subsides spontaneously, usually
• Comorbid disease (based on Charlson comorbidity index) within 3–7 days after onset. Oral intake can be resumed if the patient
Markers of Severity at Admission or within 24 h is hungry, has normal bowel function, and is without nausea and
• SIRS—defined by presence of 2 or more criteria:
vomiting. Typically, a clear or full liquid diet has been recommended
for the initial meal; however, a low-fat solid diet is a reasonable choice
• Core temperature <36° or >38°C
following recovery from mild acute pancreatitis.
• Heart rate >90 beats/min Moderately severe acute pancreatitis is characterized by transient
• Respirations >20/min or Pco2 <32 mmHg organ failure (i.e., it resolves in <48 h) or local or systemic complica-
• White blood cell count >12,000/μL, <4000/μL, or 10% bands tions in the absence of persistent organ failure. These patients may or
• APACHE II (≥8 at 24 h) may not have necrosis but may develop a local complication such as
• Hemoconcentration (hematocrit >44%) a fluid collection that requires a prolonged hospitalization >1 week.
• Admission BUN (>22 mg/dL) As with mild acute pancreatitis, the mortality rate for these patients
• BISAP score (≥3 present) remains low.
• (B) BUN >25 mg/dL Severe acute pancreatitis is characterized by persistent organ failure
• (I) Impaired mental status (>48 h), involving one or more organs. A CT scan or magnetic reso-
• (S) SIRS: ≥2 of 4 present nance imaging (MRI) should be obtained to assess for necrosis and/
or complications. If a local complication is encountered, management
• (A) Age >60 years
is dictated by clinical symptoms, evidence of infection, the maturity
• (P) Pleural effusion
of fluid collection, and clinical stability of the patient. Prophylactic
• Organ failure (Modified Marshall score) (≥1 present): antibiotics are no longer recommended for severe acute pancreatitis.
• Cardiovascular: systolic BP <90 mmHg, heart rate >130 beats/min
• Pulmonary: Pao2 <60 mmHg
Imaging in Acute Pancreatitis Two types of pancreatitis are
recognized on imaging as interstitial or necrotizing based on pancreatic
• Renal: serum creatinine >2.0 mg/dL
perfusion. CT imaging with IV contrast is best evaluated 3–5 days
Markers of Severity during Hospitalization into hospitalization if patients are not responding to supportive care

CHAPTER 348 Acute and Chronic Pancreatitis

• Persistent organ failure (≥48 h) to assess for local complications such as necrosis. Recent studies
• Pancreatic or extrapancreatic necrosis report the overutilization of CT imaging within 72 h for acute pan-
creatitis, including those with a mild severity of disease. The Revised
Abbreviations: APACHE II, Acute Physiology and Chronic Health Evaluation II; BISAP,
Bedside Index of Severity in Acute Pancreatitis; BMI, body mass index; BP, blood Atlanta Criteria also outline the terminology for local complications
pressure; BUN, blood urea nitrogen; SIRS, systemic inflammatory response syndrome. and fluid collections along with a CT imaging template to guide
reporting of findings. Local morphologic features are summarized in
elevated total serum amylase levels, thus closely mimicking acute Table 348-2. Interstitial pancreatitis occurs in 90–95% of admissions
pancreatitis; however, the serum lipase level is often not elevated in for acute pancreatitis and is characterized by diffuse gland enlarge-
diabetic ketoacidosis, and pancreas imaging is normal. ment, homogenous contrast enhancement, and mild inflammatory
changes or peripancreatic stranding. Symptoms generally resolve with
■■CLINICAL COURSE, DEFINITIONS, a week of hospitalization. Necrotizing pancreatitis occurs in 5–10% of
AND CLASSIFICATIONS acute pancreatitis admissions and may not evolve until several days
The Revised Atlanta Criteria define (1) phases of acute pancreatitis, of hospitalization. It is characterized by lack of pancreatic parenchy-
(2) severity of acute pancreatitis, and (3) radiographic definitions, as mal enhancement by intravenous contrast agent and/or presence of
outlined below. findings of peripancreatic necrosis. The natural history of pancreatic
and peripancreatic necrosis is variable because it may remain solid
Phases of Acute Pancreatitis Two phases of acute pancreatitis or liquefy, remain sterile or become infected, and persist or disappear
have been defined, early (<2 weeks) and late (>2 weeks), which pri- over time. Importantly, those with only extrapancreatic necrosis have
marily describe the hospital course of the disease. In the early phase of a more favorable prognosis than patients with pancreatic necrosis
acute pancreatitis, which lasts 1–2 weeks, severity is defined by clinical (with or without extrapancreatic necrosis). CT identification of local
parameters rather than morphologic findings. Most patients exhibit complications, particularly necrosis, is critical in patients who are
SIRS, and if this persists, patients are predisposed to organ failure. not responding to therapy because patients with infected and sterile
Three organ systems should be assessed to define organ failure: respi- necrosis are at greatest risk of mortality (Figs. 348-1 and 348-2). The
ratory, cardiovascular, and renal. Organ failure is defined as a score median prevalence of organ failure is >50% in necrotizing pancreatitis,
of 2 or more for one of these three organ systems using the modified and is perhaps slightly higher in infected versus sterile necrosis. With
Marshall scoring system. Persistent organ failure (>48 h) is the most single-organ system failure, the mortality is 3–10%, but increases to
important clinical finding regarding severity of the acute pancreatitis nearly 50% with multiorgan failure.
episode. Organ failure that affects more than one organ is considered
multisystem organ failure. CT imaging is usually not needed or recom- ■■ACUTE PANCREATITIS MANAGEMENT
mended during the first 48 h of admission in acute pancreatitis. The management of patients with acute pancreatitis from the time
The late phase is characterized by a protracted course of illness and of diagnosis in the emergency ward to hospital discharge is briefly
may require imaging to evaluate for local complications. The critical reviewed, highlighting salient features based on severity and complica-
clinical parameter of severity, as in the early phase, is persistent organ tions. It is important to recognize that 85–90% of cases of acute pancre-
failure. These patients may require supportive measures such as renal atitis are self-limited and subside spontaneously, usually within 3–7 days
dialysis, ventilator support, or need for supplemental nutrition via a after onset, and do not exhibit organ failure or local complications.
nasojejunal or parenteral route. The radiographic feature of greatest The management of acute pancreatitis begins in the emergency
importance to recognize in this phase is the development of necrotiz- ward. After a diagnosis has been confirmed, early and aggressive fluid
ing pancreatitis on CT imaging. Necrosis is associated with prolonged resuscitation is critical. Additionally, intravenous analgesics are admin-
hospitalization and, if infected, may require intervention (percutane- istered, severity is assessed, and a search for etiologies that may impact
ous, endoscopic, and/or surgical). acute care is begun. Patients who do not respond to aggressive fluid

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 2662

A B
PART 10

C D
FIGURE 348-1 Evolution of changes of acute necrotizing pancreatitis on computed tomography (CT). A. CT scan of the abdomen without IV contrast performed on admission
for a patient with acute gallstone pancreatitis, showing mild peripancreatic stranding. B. Contrast-enhanced CT scan of the abdomen performed on the same patient 1
Disorders of the Gastrointestinal System

week after admission shows extensive intrapancreatic necrosis, evidenced by the lack of contrast enhancement in the pancreatic body with very minimal enhancement
noted at the distal most aspect of the pancreatic tail. C. Contrast-enhanced CT scan of the abdomen performed on the same patient 2 weeks after admission demonstrates
a semiorganized, heterogeneous fluid collection, referred to as an acute necrotic collection. On this image, a small area of viable pancreatic parenchyma is seen at the tail
of the pancreas. D. Contrast-enhanced CT scan of the abdomen performed on the same patient 5 weeks after admission demonstrates a well-encapsulated fluid collection,
essentially replacing the pancreas, referred to as walled-off necrosis.

resuscitation in the emergency ward should be considered for admis- the pancreas and is given intravenous narcotic analgesics to control
sion to a step-down or intensive care unit for aggressive fluid resuscita- abdominal pain and supplemental oxygen (as needed).
tion, hemodynamic monitoring, and management of any organ failure. Intravenous fluids of lactated Ringer’s or normal saline are initially
Fluid Resuscitation and Monitoring Response to Therapy The bolused at 15–20 mL/kg (1050–1400 mL), followed by 2–3 mL/kg
most important treatment intervention for acute pancreatitis is early, per hour (200–250 mL/h), to maintain urine output >0.5 mL/kg per
aggressive intravenous fluid resuscitation to prevent systemic complica- hour. Serial bedside evaluations are required every 6–8 h to assess vital
tions from the secondary systemic inflammatory response. The patient signs, oxygen saturation, and change in physical examination to opti-
is initially made NPO to minimize nutrient-induced stimulation of mize fluid resuscitation. Lactated Ringer’s solution has been shown to

A B C
FIGURE 348-2 Imaging features of a pancreaticopleural fistula secondary to acute pancreatitis. A. Pancreaticopleural fistula: pancreatic duct leak on endoscopic
retrograde cholangiopancreatography. Pancreatic duct leak (arrow) demonstrated at the time of retrograde pancreatogram in a patient with exacerbation of alcohol-
induced acute pancreatitis. B. Pancreaticopleural fistula: computed tomography (CT) scan. Contrast-enhanced CT scan (coronal view) with arrows showing fistula tract
from pancreatic duct disruption in the pancreatic pleural fistula. C. Pancreaticopleural fistula: chest x-ray. Large pleural effusion in the left hemithorax from a disrupted
pancreatic duct. Analysis of pleural fluid revealed elevated amylase concentration. (Courtesy of Dr. K.J. Mortele, Brigham and Women’s Hospital; with permission.)

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 decrease systemic inflammation (lower C-reactive protein levels from plasmapheresis, but there is no compelling evidence these measures 2663
admission) and may be a better crystalloid than normal saline. A improve clinical outcomes. Outpatient therapies include control of
targeted resuscitation strategy with measurement of hematocrit and diabetes if present, administration of lipid-lowering agents, weight loss,
BUN every 8–12 h is recommended to ensure adequacy of fluid resus- and avoidance of drugs that elevate lipid levels.
citation and monitor response to therapy, noting that a less aggressive Other potential etiologies that may impact acute hospital care
resuscitation strategy may be needed in milder forms of pancreatitis. include hypercalcemia and post-ERCP pancreatitis. Treatment of hyper-
A rising BUN during hospitalization is not only associated with inade- parathyroidism or malignancy is effective at reducing serum calcium.
quate hydration but also higher in-hospital mortality. Pancreatic duct stenting and rectal indomethacin administration are
A decrease in hematocrit and BUN during the first 12–24 h is strong effective at decreasing pancreatitis after ERCP. Drugs that cause pan-
evidence that sufficient fluids are being administered. Serial measure- creatitis should be discontinued. Multiple drugs have been implicated,
ments and bedside assessment for fluid overload are continued, and but only about 30 have been rechallenged (Class 1A) and found to be
fluid rates are maintained at the current rate. Adjustments in fluid causative.
resuscitation may be required in patients with cardiac, pulmonary, or
renal disease. A rise in hematocrit or BUN during serial measurement Nutritional Therapy A low-fat solid diet can be administered to
should be treated with a repeat volume challenge with a 2-L crystalloid subjects with mild acute pancreatitis once they are able to eat. Enteral
bolus followed by increasing the fluid rate by 1.5 mg/kg per hour. If the nutrition should be considered 2–3 days after admission in subjects
BUN or hematocrit fails to respond (i.e., remains elevated or does not with more severe pancreatitis instead of total parenteral nutrition
decrease) to this bolus challenge and increase in fluid rate, consider- (TPN). Enteral feeding maintains gut barrier integrity, limits bacterial
ation of transfer to an intensive care unit is strongly recommended for translocation, is less expensive, and has fewer complications than TPN.
hemodynamic monitoring. Gastric feeding is safe; the benefits of nasojejunal enteral feeding over
gastric feeding remains under investigation.
Assessment of Severity and Hospital Triage Severity of acute
pancreatitis should be determined in the emergency ward to assist in Management of Local Complications (Table 348-4) Patients
patient triage to a regular hospital ward or step-down unit or direct exhibiting signs of clinical deterioration despite aggressive fluid resus-
admission to an intensive care unit. The Bedside Index of Severity citation and hemodynamic monitoring should be assessed for local
in Acute Pancreatitis (BISAP) incorporates five clinical and labo- complications, which may include necrosis, pseudocyst formation,
ratory parameters obtained within the first 24 h of hospitalization pancreas duct disruption, peripancreatic vascular complications,
(Table 348-3)—BUN >25 mg/dL, impaired mental status (Glasgow and extrapancreatic infections. A multidisciplinary team approach
is recommended, including gastroenterology, surgery, interventional

CHAPTER 348 Acute and Chronic Pancreatitis

coma scale score <15), SIRS, age >60 years, and pleural effusion on
radiography—that can be useful in assessing severity. The presence radiology, and intensive care specialists, and consideration should also
of three or more of these factors was associated with substantially be made for transfer to a tertiary pancreas center of excellence.
increased risk for in-hospital mortality among patients with acute pan- NECROSIS The management of necrosis requires a multidisciplinary
creatitis. In addition, an elevated hematocrit >44% and admission BUN team approach. Percutaneous fine-needle aspiration of necrosis with
>22 mg/dL are also associated with more severe acute pancreatitis. Gram stain and culture was previously performed to evaluate for
Incorporating these indices with the overall patient response to initial infected pancreatic necrosis in those with sustained leukocytosis, fever,
fluid resuscitation in the emergency ward can be useful at triaging or organ failure. However, the current use of this technique varies
patients to the appropriate hospital acute care setting. depending on institutional preference, with many abandoning this
In general, patients with lower BISAP scores, hematocrits, and diagnostic test to avoid potentially contaminating an otherwise sterile
admission BUNs tend to respond to initial management and can be collection, particularly when culture results will not lead to a clinical
safely triaged to a regular hospital ward for ongoing care. If SIRS is decision to de-escalate antimicrobial therapy. Even though there is
not present at 24 h, the patient is unlikely to develop organ failure or currently no role for prophylactic antibiotics in necrotizing pancreatitis,
necrosis. Therefore, patients with persistent SIRS at 24 h or underly- empiric antibiotics should be considered in those with clinical decom-
ing comorbid illnesses (e.g., chronic obstructive pulmonary disease, pensation. Prophylactic antibiotics do not lead to improved survival
congestive heart failure) should be considered for a step-down unit and may promote the development of opportunistic fungal infections.
setting if available. Patients with higher BISAP scores and elevations Repeated CT or MRI imaging should also be considered with any
in hematocrit and admission BUN who do not respond to initial fluid change in clinical course to monitor for complications (e.g., thrombo-
resuscitation and exhibit evidence of respiratory failure, hypotension, ses, hemorrhage, abdominal compartment syndrome).
or organ failure should be considered for direct admission to an inten- In general, sterile necrosis is most often managed conservatively
sive care unit. unless complications arise. Once a diagnosis of infected necrosis is
Special Considerations Based on Etiology A careful history, established and an organism identified, targeted antibiotics should be
review of medications, selected laboratory studies (liver profile, serum instituted. Pancreatic drainage and/or debridement (necrosectomy)
triglycerides, serum calcium), and an abdominal ultrasound are rec- should be considered for definitive management of infected necrosis,
ommended in the emergency ward to assess for etiologies that may but clinical decisions are ultimately influenced by the clinical response
impact acute management. An abdominal ultrasound is the initial since almost two-thirds of patients respond to antibiotic treatment with
imaging modality of choice and will evaluate the gallbladder, common or without percutaneous drainage. Symptomatic local complications
bile duct, and pancreatic head. as outlined in the Revised Atlanta Criteria typically require definitive
therapy.
GALLSTONE PANCREATITIS Patients with evidence of ascending
A step-up approach (percutaneous or endoscopic transgastric/trans-
cholangitis (rising white blood cell count, increasing liver enzymes) duodenal drainage followed, if necessary, by surgical necrosectomy)
should undergo ERCP within 24–48 h of admission. Patients with gall- has been successfully reported by some pancreatic centers. One-third
stone pancreatitis are at increased risk of recurrence, and consideration of the patients successfully treated with the step-up approach did not
should be given to performing a cholecystectomy during the same require major abdominal surgery. A randomized trial reported advan-
admission in mild acute pancreatitis. An alternative for patients who tages to an initial endoscopic approach compared to an initial surgical
are not surgical candidates would be to perform an endoscopic biliary necrosectomy approach in select patients requiring intervention for
sphincterotomy before discharge. symptomatic WON. Taken together, a more conservative approach to
HYPERTRIGLYCERIDEMIA Serum triglycerides >1000 mg/dL are asso- the management of infected pancreatic necrosis has evolved under the
ciated with acute pancreatitis. Initial therapy should focus on treatment close supervision of a multidisciplinary team. If conservative therapy
of hyperglycemia with intravenous insulin, which often corrects the can be safely implemented, it is recommended to do so for 4–6 weeks
hypertriglyceridemia. Adjunct therapies may also include heparin or to allow the pancreatic collections to either resolve or evolve to develop

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 2664 PANCREATIC DUCT DISRUPTION Pancreatic duct disruption may
TABLE 348-4 Complications of Acute Pancreatitis
present with symptoms of increasing abdominal pain or shortness of
Local breath in the setting of an enlarging fluid collection resulting in pan-
Pancreatic/peripancreatic fluid collections: creatic ascites (ascitic fluid has high amylase level). Diagnosis can be
Acute necrotic collection (sterile or infected) confirmed on magnetic resonance cholangiopancreatography (MRCP)
Walled-off necrosis (sterile or infected) or ERCP. Placement of a bridging pancreatic stent for at least 6 weeks
Pancreatic pseudocyst is >90% effective at resolving the leak with or without parenteral nutri-
Disruption of main pancreatic duct or secondary branches tion and octreotide. Nonbridging stents are less effective (25–50%) but
Pancreatic ascites should be considered with parenteral nutrition and octreotide prior to
Chylous ascites (secondary to disruption of lymphatic ducts)
surgical intervention.
Involvement of contiguous organs by necrotizing pancreatitis (e.g., colon PERIVASCULAR COMPLICATIONS Perivascular complications may
perforation) include splenic vein thrombosis with gastric varices and pseudoaneu-
Splanchnic thromboses (splenic vein, superior mesenteric vein, rysms, as well as portal and superior mesenteric vein thromboses. Gastric
and/or portal vein) varices rarely bleed but can be life-threatening. Similarly, life-threatening
Bowel infarction/perforation bleeding from a ruptured pseudoaneurysm can be diagnosed and
Gastric outlet obstruction treated with mesenteric angiography and embolization.
Biliary obstruction (jaundice) EXTRAPANCREATIC INFECTIONS Hospital-acquired infections occur
Systemic in up to 20% of patients with acute pancreatitis. Patients should be con-
Pulmonary tinually monitored for the development of pneumonia, urinary tract
Pleural effusion
infection, and line infection. Continued culturing of urine, monitoring
of chest x-rays, and routine changing of intravenous lines are important
Atelectasis
during hospitalization.
Mediastinal fluid
Pneumonitis Follow-Up Care Hospitalizations for moderately severe and severe
Acute respiratory distress syndrome acute pancreatitis can be prolonged and last weeks to months and often
Hypoxemia (unrecognized) involve periods of intensive care unit admission and outpatient rehabil-
Cardiovascular itation or subacute nursing care. Follow-up evaluation should assess for
Hypotension
development of diabetes, exocrine pancreatic insufficiency, recurrent
cholangitis, or infected fluid collections. As mentioned previously,
Hypovolemia
PART 10

cholecystectomy should be performed during the initial hospitalization

 Nonspecific ST-T changes in electrocardiogram simulating myocardial for acute gallstone pancreatitis with mild clinical severity. For patients
infarction
with necrotizing gallstone pancreatitis, the timing of cholecystectomy
Pericardial effusion
needs to be individualized.
Hematologic
Disorders of the Gastrointestinal System

Disseminated intravascular coagulation ■■RECURRENT ACUTE PANCREATITIS

Gastrointestinal hemorrhage Approximately 25% of patients who have had an attack of acute pan-
Peptic ulcer disease creatitis have a recurrence. The two most common etiologic factors
Erosive gastritis are alcohol and cholelithiasis. In patients with recurrent pancreatitis
Hemorrhagic pancreatic necrosis with erosion into major blood vessels without an obvious cause, the differential diagnosis should encompass
Variceal hemorrhage secondary to splanchnic thrombosis occult biliary tract disease, including microlithiasis, hypertriglyceri-
Renal demia, pancreatic cancer, and hereditary pancreatitis (Table 348-1).
Oliguria (<300 mL/d) In one series of 31 patients diagnosed initially as having idiopathic or
Azotemia
recurrent acute pancreatitis, 23 were found to have occult gallstone dis-
ease. Thus, approximately two-thirds of patients with recurrent acute
Renal artery and/or renal vein thrombosis
pancreatitis without an obvious cause actually have occult gallstone
Acute tubular necrosis disease due to microlithiasis. Genetic defects as in hereditary pancre-
Metabolic atitis and cystic fibrosis mutations can result in recurrent pancreatitis.
Hyperglycemia Other diseases of the biliary tree and pancreatic ducts that can cause
Hypertriglyceridemia acute pancreatitis include choledochocele; ampullary tumors; pancreas
Hypocalcemia divisum; and pancreatic duct stones, stricture, and tumor. Approx-
Encephalopathy imately 2–4% of patients with pancreatic cancer present with acute
Sudden blindness (Purtscher’s retinopathy) pancreatitis.
Central nervous system
■■PANCREATITIS IN PATIENTS WITH AIDS
Psychosis
The incidence of acute pancreatitis is theoretically increased in patients
Fat emboli with AIDS for two reasons: (1) the high incidence of infections involv-
Fat necrosis ing the pancreas such as infections with cytomegalovirus, Cryptospo-
Subcutaneous tissues (erythematous nodules) ridium, and the Mycobacterium avium complex; and (2) the frequent
Bone use by patients with AIDS of medications such as pentamidine, trime-
Miscellaneous (mediastinum, pleura, nervous system) thoprim-sulfamethoxazole, and protease inhibitors. The incidence
has been markedly reduced due to advances in therapy, including the
disuse of didanosine (Chap. 202).
a more organized boundary (i.e., to “wall off ”) so that surgical or endo-
scopic intervention is generally safer and more effective. CHRONIC PANCREATITIS AND EXOCRINE
PSEUDOCYST The incidence of pseudocyst is low, and most acute PANCREATIC INSUFFICIENCY
collections resolve over time. Less than 10% of patients have persis-
tent fluid collections after 4 weeks that would meet the definition of ■■PATHOPHYSIOLOGY
a pseudocyst. Only symptomatic collections require intervention with Chronic pancreatitis is a disease process characterized by irreversible
endoscopic or surgical drainage. damage to the pancreas, in contrast to the reversible changes noted

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 in acute pancreatitis (Table 348-4). The events that initiate and then normal pancreatic architecture that shifts toward fibrogenesis in those 2665
perpetuate the inflammatory process in the pancreas are becoming who develop chronic pancreatitis. It is believed that alcohol or addi-
more clearly understood. Irrespective of the mechanism of injury, tional stimuli lead to matrix metalloproteinase–mediated destruction
it is becoming apparent that stellate cell activation leads to cytokine of normal collagen in pancreatic parenchyma, which later allows for
expression and production of extracellular matrix proteins that con- pancreatic remodeling. Proinflammatory cytokines, tumor necrosis
tribute to acute and chronic inflammation and collagen deposition in factor α (TNF-α), interleukin 1 (IL-1), and interleukin 6 (IL-6), as well
the pancreas. This condition is defined by the presence of histologic as oxidant complexes, can induce PSC activity with subsequent new
abnormalities, including chronic inflammation, fibrosis, and progres- collagen synthesis. In addition to being stimulated by cytokines, oxi-
sive destruction (atrophy) of both exocrine and endocrine tissue. A dants, or growth factors, PSCs also possess transforming growth factor
number of etiologies have been associated with chronic pancreatitis β (TGF-β)–mediated self-activating autocrine pathways that may
resulting in the cardinal manifestations of the disease such as abdominal explain disease progression in chronic pancreatitis even after removal
pain, steatorrhea, weight loss, diabetes mellitus, and, less commonly, of noxious stimuli.
pancreatic cancer (Table 348-5).
Even in individuals in whom alcohol is believed to be the primary ■■ETIOLOGIC CONSIDERATIONS
cause of chronic pancreatitis, other factors are likely required for the Among adults in the United States, alcoholism is the most common
development and progression of disease, which explains why not all cause of clinically apparent chronic pancreatitis, whereas cystic fibrosis
heavy consumers of alcohol develop pancreatic disease. There is also a is the most frequent cause in children. As many as 25% of adults in
strong association between smoking and chronic pancreatitis. Cigarette the United States with chronic pancreatitis have the idiopathic form,
smoke leads to an increased susceptibility to pancreatic autodigestion including a subset of patients who do not develop clinical manifes-
and predisposes to dysregulation of duct cell CFTR function. Smoking tations until later in life (idiopathic late-onset chronic pancreatitis).
is an independent, dose-dependent risk factor for chronic pancreatitis Recent investigations have indicated that up to 15% of patients with
and recurrent acute pancreatitis. Both continued alcohol and smoking chronic pancreatitis previously classified as having idiopathic pancre-
exposure are associated with disease progression, including pancreatic atitis may have an underlying genetic predisposition (Table 348-5).
fibrosis and calcifications. The prototypical genetic defect was identified in the cationic
Characterization of pancreatic stellate cells (PSCs) has added insight trypsinogen gene (PRSS1) by studying several large families with
into the underlying cellular responses behind development of chronic chronic pancreatitis. Additional pathogenic and nonpathogenic muta-
pancreatitis. Specifically, PSCs are believed to play a role in maintaining tions have been identified in this gene. The defect prevents the destruc-
tion of prematurely activated trypsin and allows it to be resistant to the

CHAPTER 348 Acute and Chronic Pancreatitis

TABLE 348-5 Classification of Chronic Pancreatitis: The TIGAR-O intracellular protective effect of trypsin inhibitor. It is hypothesized
System that this continual activation of digestive enzymes within the gland
leads to acute injury and, finally, chronic pancreatitis. Since the initial
Toxic-metabolic discovery of the PRSS1 mutation defect, other genetic disease modifiers
Alcoholic have been identified (Table 348-5).
Tobacco smoking The CFTR gene functions as a cyclic AMP–regulated chloride
Hypercalcemia channel. In patients with cystic fibrosis, the high concentration of
Hyperlipidemia (hypertriglyceridemia) macromolecules can block the pancreatic ducts. It must be appreci-
ated, however, that there is a great deal of heterogeneity in relationship
Chronic renal failure
to the CFTR gene defect. More than 1700 putative mutations of the
Idiopathic CFTR gene have been identified. Attempts to elucidate the relationship
Early onset between the genotype and pancreatic manifestations have been ham-
Late onset pered by the large number and different classes of CFTR mutations.
Tropical The ability to detect CFTR mutations has led to the recognition that
the clinical spectrum of the disease is broader than previously thought.
Genetic Two studies have clarified the association between mutations of the
Cationic trypsinogen (PRSS1) CFTR gene and another monosymptomatic form of cystic fibrosis (i.e.,
Cystic fibrosis transmembrane conductance regulator gene (CFTR)a chronic pancreatitis). It is estimated that in patients with idiopathic
Calcium-sensing receptor (CASR)a pancreatitis, the frequency of a single CFTR mutation is 11 times the
Chymotrypsin C gene (CTRC)a expected frequency and the frequency of two mutant alleles is 80 times
the expected frequency. In these studies, patients were adults when the
Pancreatic secretory trypsin inhibitor gene (SPINK1)a
diagnosis of pancreatitis was made; none had any clinical evidence of
Autoimmune pulmonary disease, and sweat test results were not diagnostic of cystic
Type 1 autoimmune pancreatitis (associated with IgG4-related disease) fibrosis. The prevalence of such mutations is unclear, and further stud-
Type 2 autoimmune pancreatitis (idiopathic duct-centric chronic pancreatitis) ies are needed. In addition, the therapeutic and prognostic implication
Recurrent and severe acute pancreatitis
of these findings with respect to managing pancreatitis remains to be
determined. CFTR mutations are common in the general population,
Postnecrotic (severe acute pancreatitis) so it is unclear whether the CFTR mutation alone can lead to pancre-
Recurrent acute pancreatitis atitis as an autosomal recessive disease. A study evaluated 39 patients
Vascular diseases/ischemia with idiopathic chronic pancreatitis to assess the risk associated with
Radiation induced these mutations. Patients with two CFTR mutations (compound hete-
Obstructive
rozygotes) demonstrated CFTR function at a level between that seen
in typical cystic fibrosis and cystic fibrosis carriers and had a fortyfold
Pancreas divisuma increased risk of pancreatitis. The presence of a separate genetic muta-
Duct obstruction (e.g., tumor) tion (N34S SPINK1) increased the risk twentyfold. A combination of
Preampullary duodenal wall cysts two CFTR mutations and an N34S SPINK1 mutation increased the risk
Posttraumatic pancreatic duct strictures of pancreatitis 900-fold. Knowledge of the genetic defects and down-
stream alterations in protein expression has led to the development of
a
These conditions are believed to be disease modifiers that require additional
factors to cause chronic pancreatitis. novel therapies in children with cystic fibrosis that potentiate the CFTR
Abbreviations: TIGAR-O, toxic-metabolic, idiopathic, genetic, autoimmune, recurrent channel, resulting in improvement in lung function, quality of life, and
and severe acute pancreatitis, obstructive. weight gain. Some studies have shown that use of CFTR modulators

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 2666
TABLE 348-6 Comparison of the Autoimmune Pancreatitis (AIP) a pancreas-specific disorder that is associated with inflammatory bowel
Subtypes disease in ~10% of patients. AIP is not a common cause of idiopathic
TYPE 1 AIP TYPE 2 AIP
recurrent acute pancreatitis.
Jaundice, weight loss, and new-onset diabetes are the most common
Age at diagnosis, mean Seventh decade Fifth decade
presenting symptoms. Elevated serum IgG4 levels are supportive of the
Male sex 75% 50% diagnosis (elevated in two-thirds of patients with type 1 AIP) but have
Serum IgG4 elevation ~66% ~25% a low positive predictive value when used in isolation of other clinical
Other organ involvement 50% Noa findings. CT imaging demonstrates abnormalities in the majority of
Histologic findings: patients with either diffuse or focal enlargement during active disease,
Lymphoplasmacytic ++ ++ unless the gland is atrophic due to previous disease (Fig. 348-3). The
Infiltration presence of an inflammatory rim, termed a capsule sign, is highly
Periductal inflammation ++ ++
specific (but not sensitive) for AIP. ERCP or MRCP reveals strictures
in the bile duct in more than one-third of patients with AIP, including
Storiform fibrosis ++ +
some patients with isolated intrahepatic bile duct strictures (type 1
Obliterative phlebitis ++ + AIP only), which can mimic primary sclerosing cholangitis, and is
Granulocytic epithelial – +++ referred to as IgG4-related sclerosing cholangitis (previously termed
lesion (GEL) IgG4-associated cholangitis).
IgG4 tissue staining Abundant Scant The Mayo Clinic HISORt criteria provide a helpful mnemonic
(≥10 cells/hpf) (<10 cells/hpf) to remember the key diagnostic features of this disease, including
Response to steroids ~100% ~100% (1) histology; (2) imaging; (3) serology (elevated serum IgG4 levels);
Risk for relapse High (20–60%) Low (<10%) (4) other organ involvement; and (5) response to glucocorticoid
Associated with IgG4-RD Yes No
therapy. These diagnostic criteria have been harmonized with those
from other countries to develop the International Consensus Diagnos-
a
Inflammatory bowel disease is seen in ~10–20% of patients with idiopathic duct- tic Criteria for AIP, which are the most widely utilized criteria. Gluco-
centric chronic pancreatitis but may also occur in type 1 AIP.
corticoids have shown efficacy in alleviating symptoms, decreasing the
Abbreviation: IgG4-RD, IgG4-related disease.
size of the pancreas, and reversing histopathologic features in patients
Source: Reproduced with permission from PA Hart: Reviews in basic and clinical with AIP. Patients typically respond dramatically to glucocorticoid
gastroenterology and hepatology. Gastroenterology 149:39, 2015.
therapy within a 2- to 4-week period. Prednisone is usually adminis-
may reduce the frequency of acute pancreatitis in heterozygous carri- tered at an initial dose of 40 mg/d for 4 weeks followed by a taper of the
PART 10

ers. Table 348-5 lists other recognized causes of chronic pancreatitis. daily dosage by 5 mg per week based on monitoring of clinical param-
eters. Relief of symptoms, liver biochemistries, and abnormal imaging
■■AUTOIMMUNE PANCREATITIS (TABLE 348-6) of the pancreas and bile ducts are followed to assess for treatment
Autoimmune pancreatitis (AIP) refers to a form of chronic pancre- response. A poor response to glucocorticoids should raise suspicion
atitis with distinct histopathology and several unique differences in of an alternate diagnosis, such as pancreatic cancer. A recent multi-
Disorders of the Gastrointestinal System

the clinical phenotype. Currently, two subtypes of AIP are recognized, center international study examined >1000 patients with AIP. Clinical
type 1 AIP and idiopathic duct-centric chronic pancreatitis (IDCP, remission was achieved in 99% of type 1 AIP and 92% of type 2 AIP
also referred to as type 2 AIP). Type 1 AIP is identified as the pancre- patients with steroids. However, disease relapse occurred in 31 and 9%
atic manifestation of a multiorgan syndrome currently referred to as of patients with type 1 and type 2 AIP, respectively. Patients with
IgG4-related disease (Chap. 368). The characteristic histopathologic multiple relapses may be managed with an immunomodulator (e.g.,
findings of type 1 AIP include lymphoplasmacytic infiltrate, storiform azathioprine, 6-mercaptopurine, or mycophenolate mofetil) or B-cell
fibrosis, and abundant IgG4 cells. IDCP is histologically defined by depletion therapy (e.g., rituximab). The appearance of interval cancers
the presence of granulocytic infiltration of the duct wall (termed a following a diagnosis of AIP is uncommon.
granulocytic epithelial lesion [GEL]) but without IgG4-positive cells.
Type 1 AIP is often associated with involvement of other organs in Clinical Features of Chronic Pancreatitis Patients with chronic
the setting of IgG4-related disease, including bilateral submandibular pancreatitis primarily seek medical attention due to abdominal pain or
gland enlargement, characteristic renal lesions, retroperitoneal fibrosis, symptoms of maldigestion. The abdominal pain may be quite vari-
and stricturing of the suprapancreatic biliary tree. In contrast, IDCP is able in location, severity, and frequency. The pain can be constant or

A B
FIGURE 348-3 Imaging features of the pancreatic parenchyma in a patient with type 1 autoimmune pancreatitis on computed tomography (CT). A. Contrast-enhanced CT
scan of the abdomen demonstrates diffuse pancreatic enlargement and a hypoechoic rim (capsule sign) in a patient who presented with jaundice. The serum IgG4 level
was elevated to 942 mg/dL (reference range 4–86 mg/dL), so the patient was diagnosed with definitive type 1 autoimmune pancreatitis. B. Contrast-enhanced CT scan of the
abdomen following a treatment course with high-dose steroids demonstrates return to normal size of the pancreas, reappearance of normal lobulations along the margin,
and absence of the hypoechoic rim.

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 intermittent with pain-free intervals. Eating may exacerbate the pain, imaging (Fig. 348-4) is the initial modality of choice, followed by MRI, 2667
leading to a fear of eating with consequent weight loss. The spectrum of endoscopic ultrasound, and pancreas function testing. In addition to
abdominal pain ranges from mild to quite severe, with narcotic depen- excluding a pseudocyst and pancreatic cancer, CT imaging may show
dence as a frequent consequence. There is often a disparity between calcifications, dilated pancreatic or biliary ducts, or an atrophic pan-
the reported severity of abdominal pain and the physical findings, creas. Although abdominal CT scanning and MRCP greatly aid in the
which primarily consist of nonfocal abdominal tenderness. Patients diagnosis of pancreatic disease, the diagnostic test with the best sensi-
with chronic abdominal pain may or may not experience symptoms tivity is the hormone stimulation test using secretin. The secretin test
of maldigestion, such as chronic diarrhea, steatorrhea, and/or weight becomes abnormal when ≥60% of the pancreatic exocrine function has
loss. Fat-soluble vitamin deficiencies are increasingly recognized. been lost. This usually correlates well with the onset of chronic abdom-
Importantly, there is an exceedingly high prevalence of metabolic bone inal pain. The role of endoscopic ultrasonography (EUS) in diagnosing
disease in chronic pancreatitis, with ~65% of patients having either early chronic pancreatitis is still evolving. A total of nine endoso-
osteopenia or osteoporosis. Patients with chronic pancreatitis have nographic features have been described in chronic pancreatitis. The
impaired quality of life and develop significant morbidity, requiring presence of five or more features is considered diagnostic of chronic
frequent use of health care resources. pancreatitis. EUS is not a specific enough test for detecting early
The diagnosis of early or mild chronic pancreatitis can be challeng- chronic pancreatitis alone (Chap. 347) and may show positive features
ing because there is no accurate biomarker for the disease. In contrast in patients with diabetes, patients with a history of cigarette smoking,
to acute pancreatitis, the serum amylase and lipase levels are usually or even in normal aging individuals. Recent data suggest that EUS can
not strikingly elevated in chronic pancreatitis. Rather, low serum pan- be combined with endoscopic pancreatic function testing (EUS-ePFT)
creatic enzyme levels are moderately specific for a diagnosis of chronic during a single endoscopy to screen for chronic pancreatitis in patients
pancreatitis but have poor sensitivity. Elevation of serum bilirubin and with chronic abdominal pain. Diffuse calcifications noted on plain film
alkaline phosphatase may indicate cholestasis secondary to common of the abdomen usually indicate significant damage to the pancreas and
bile duct stricture caused by chronic inflammation or fibrosis. The are pathognomic for chronic pancreatitis. Although alcohol is by far
cumulative prevalence of exocrine pancreatic insufficiency is >80%. the most common cause of pancreatic calcification, such calcification
The presence of overt steatorrhea in a patient with chronic pancreati- may also be noted in hereditary pancreatitis, posttraumatic pancreati-
tis is highly suggestive of this complication. However, in those with tis, idiopathic chronic pancreatitis, and tropical pancreatitis.
milder symptoms, additional testing, such as a random fecal elastase-1
level (on a formed stool specimen) may be needed to confirm the Complications of Chronic Pancreatitis There are a number
diagnosis of exocrine pancreatic insufficiency. The radiographic of disease-related complications from chronic pancreatitis in addi-

CHAPTER 348 Acute and Chronic Pancreatitis

evaluation of a patient with suspected chronic pancreatitis usually pro- tion to the aforementioned abdominal pain and exocrine pancre-
ceeds from a noninvasive to more invasive approach. Abdominal CT atic insufficiency (Table 348-7). The lifetime prevalence of chronic

A B

C D
FIGURE 348-4 Distribution of imaging features of chronic pancreatitis on computed tomography (CT). Distinct features of chronic pancreatitis are seen on selected
images from contrast-enhanced CT scans of the abdomen from four unique patients, including the following. A. Numerous punctate calcifications involving the pancreatic
parenchyma in the head and body. B. A moderate-sized calculus visualized in the pancreatic duct with associated ductal dilation. C. Significant pancreatic duct dilation
and adjacent parenchymal atrophy secondary to a pancreatic duct stricture (which is not well seen on this scan). D. A large unilocular, encapsulated cyst in the tail of the
pancreas consistent with a pseudocyst from prior pancreatitis. Note adjacent pancreatic parenchymal atrophy.

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 2668
TABLE 348-7 Complications of Chronic Pancreatitis pancreatic duct would seem to be most appropriate in the setting of
Chronic abdominal pain Biliary stricture and/or biliary cirrhosis a dominant stricture, especially if there is an obstructing intraduc-
Exocrine pancreatic insufficiency Pancreatic duct stricture
tal stone. The use of endoscopic stenting for patients with chronic
pain, but without a dominant stricture, has not been subjected to
Diabetes mellitus Pseudocyst
controlled trials. It is now appreciated that significant complica-
Splanchnic venous thrombosis Pancreatic cancer tions can occur from stenting (e.g., stent migration, stent occlusion,
Metabolic bone disease (osteoporosis) and stent-induced pancreatic duct strictures). Recent guidelines
recommend considering celiac plexus block for treatment of pain
pancreatitis–related diabetes exceeds 80%. Although most patients in chronic pancreatitis, but recommendations were conditional
develop hyperglycemia due to insulin deficiency caused by loss of with very low quality of evidence. Celiac plexus block has not been
islet cells, diabetic ketoacidosis and diabetic coma are uncommon. rigorously studied for chronic pancreatitis and does not provide
Likewise, end-organ damage (retinopathy, neuropathy, nephropathy) durable pain relief. It can provide relive in some selected patients,
is also uncommon. Nondiabetic retinopathy may be due to vitamin A but the a priori identification of those who will respond is difficult.
and/or zinc deficiency. Osteoporosis and osteopenia are increasingly In patients with pancreatic duct dilation, ductal decompression
recognized in chronic pancreatitis and likely related to a combination with surgical therapy has been the therapy of choice. Among such
of shared risk factors (e.g., alcohol use, cigarette smoking), vitamin D patients, 80% seem to obtain immediate relief; however, at the end
deficiency, and detrimental effects on the bone from chronic inflam- of 3 years, one-half of the patients have recurrence of pain. Two
mation. Gastrointestinal bleeding may occur from peptic ulceration, randomized prospective trials comparing endoscopic to surgical
gastritis, a pseudocyst eroding into the duodenum, arterial bleeding therapy for chronic pancreatitis demonstrated that surgical therapy
into the pancreatic duct (hemosuccus pancreaticus), or ruptured was superior to endoscopy at decreasing pain and improving quality
varices secondary to splenic vein thrombosis. Jaundice, cholestasis, and of life in selected patients with dilated ducts and abdominal pain.
biliary cirrhosis may occur from the chronic inflammatory reaction This would suggest that chronic pancreatitis patients with dilated
around the intrapancreatic portion of the common bile duct. Twenty ducts and pain should be considered for surgical intervention.
years after the diagnosis of chronic calcific pancreatitis, the cumulative The role of preoperative stenting prior to surgery as a predictor of
risk of pancreatic cancer is 4%. Patients with hereditary PRSS1 or trop- response has yet to be proven.
ical pancreatitis have an increased risk for pancreatic cancer compared Total pancreatectomy with or without autologous islet cell trans-
to other forms of chronic pancreatitis. plantation has been used in highly selected patients with chronic
pancreatitis and abdominal pain refractory to conventional therapy.
However, some patients will continue to have pain postoperatively,
TREATMENT
PART 10

illustrating the complex nature of pain in patients with chronic pan-

Chronic Pancreatitis creatitis. Patients who benefit most from total pancreatectomy have
a shorter duration of symptoms and lower pain medication require-
There are currently no therapies to reverse or delay the disease ments. The role of this procedure remains to be fully defined but
progression of chronic pancreatitis, so management is primar- may be an option in lieu of ductal decompression surgery or partial
Disorders of the Gastrointestinal System

ily focused on screening for and management of disease-related pancreatic resection in patients with intractable, painful, small-duct
complications. disease or hereditary pancreatitis and particularly as the standard
STEATORRHEA surgical procedures tend to decrease islet cell yield.
The treatment of steatorrhea with pancreatic enzyme replacement
therapy is conceptually straightforward, yet complete correction of ■■HEREDITARY PANCREATITIS
steatorrhea is uncommon. Enzyme therapy usually brings diarrhea Hereditary pancreatitis (PRSS1) is a rare form of pancreatitis with early
under control and restores absorption of fat to an acceptable level age of onset that is typically associated with familial aggregation of
and affects weight gain. Thus, pancreatic enzyme replacement is the cases. A genome-wide search using genetic linkage analysis identified
cornerstone of therapy. In treating steatorrhea, it is important to the hereditary pancreatitis gene on chromosome 7. Mutations in ion
use a potent pancreatic formulation that will deliver sufficient lipase codons 29 (exon 2) and 122 (exon 3) of the cationic trypsinogen gene
into the duodenum to correct maldigestion and decrease steator- (PRSS1) cause an autosomal dominant form of pancreatitis. The codon
rhea. For adult patients with exocrine pancreatic insufficiency, it is 122 mutations lead to a substitution of the corresponding arginine
generally recommended to start at a dosage of 25,000–50,000 units with another amino acid, usually histidine. This substitution, when it
of lipase taken during each meal; however, the dose may need to be occurs, eliminates a fail-safe trypsin self-destruction site necessary to
increased up to 100,000 units of lipase depending on the response eliminate trypsin that is prematurely activated within the acinar cell.
in symptoms, nutritional parameters, and/or pancreas function These patients have recurring episodes of acute pancreatitis. Patients
test results. Additionally, some may require acid suppression with frequently develop pancreatic calcification, diabetes mellitus, and
proton pump inhibitors to optimize the response to pancreatic steatorrhea; in addition, they have an increased incidence of pancreatic
enzymes. Monitoring nutritional parameters such as fat-soluble cancer with a cumulative incidence of ~10%. A previous natural history
vitamins, zinc levels, body weight, and periodic bone mineral den- study of hereditary pancreatitis in >200 patients from France reported
sity measurement should be considered. that abdominal pain started in childhood at age 10 years, steatorrhea
ABDOMINAL PAIN developed at age 29 years, diabetes at age 38 years, and pancreatic can-
cer at age 55 years. Abdominal complaints in relatives of patients with
The management of pain in patients with chronic pancreatitis is
hereditary pancreatitis should raise the question of pancreatic disease.
challenging due to the complex mechanisms of pancreatitis-related
pain. Recent meta-analyses have shown no consistent benefit of ■■PANCREATIC ENDOCRINE TUMORS
enzyme therapy at reducing pain in chronic pancreatitis. Pain relief Pancreatic endocrine tumors are discussed in Chap. 84.
experienced by patients treated with pancreatic enzymes may be
due to improvements in the dyspepsia from maldigestion. One OTHER CONDITIONS
short-term randomized trial showed that pregabalin could decrease
pain in chronic pancreatitis and lower pain medication require- ■■ANNULAR PANCREAS
ment. Other studies using antioxidants have yielded mixed results. When the ventral pancreatic anlage fails to migrate correctly to make
Endoscopic treatment of chronic pancreatitis pain may involve contact with the dorsal anlage, the result may be a ring of pancre-
sphincterotomy, pancreatic duct stenting, stone extraction, and atic tissue encircling the duodenum. Such an annular pancreas may
drainage of a pancreatic pseudocyst. Therapy directed to the cause intestinal obstruction in the neonate or the adult. Symptoms of

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 postprandial fullness, epigastric pain, nausea, and vomiting may be ■■MACROAMYLASEMIA 2669
present for years before the diagnosis is entertained. The radiographic In macroamylasemia, amylase circulates in the blood in a polymer
findings are symmetric dilation of the proximal duodenum with bulg- form too large to be easily excreted by the kidney. Patients with this
ing of the recesses on either side of the annular band, effacement but condition demonstrate an elevated serum amylase value and a low uri-
not destruction of the duodenal mucosa, accentuation of the findings nary amylase value. The presence of macroamylase can be documented
in the right anterior oblique position, and lack of change on repeated by chromatography of the serum. The prevalence of macroamylasemia
examinations. The differential diagnosis should include duodenal is 1.5% of the nonalcoholic general adult hospital population. Usually,
webs, tumors of the pancreas or duodenum, duodenal ulcer, regional macroamylasemia is an incidental finding and is not related to disease
enteritis, and adhesions. Patients with annular pancreas have an of the pancreas or other organs. Macrolipasemia has now been docu-
increased incidence of pancreatitis and peptic ulcer. Because of these mented in patients with cirrhosis or non-Hodgkin’s lymphoma. In these
and other potential complications, the treatment is surgical even if the patients, the pancreas appeared normal on ultrasound and CT exami-
condition has been present for years. Retrocolic duodenojejunostomy nation. Lipase was shown to be complexed with immunoglobulin A.
is the procedure of choice, although some surgeons advocate Billroth II Thus, the possibility of both macroamylasemia and macrolipasemia
gastrectomy, gastroenterostomy, and vagotomy. should be considered in patients with elevated blood levels of these
enzymes.
■■PANCREAS DIVISUM
Pancreas divisum is present in 7–10% of the population and occurs Acknowledgment
when the embryologic ventral and dorsal pancreatic anlagen fail to This chapter represents a revised version of chapters by Drs. Norton J.
fuse, so that pancreatic drainage is accomplished mainly through Greenberger (deceased), Phillip P. Toskes (deceased), Peter A. Banks, and
the accessory minor papilla. Pancreas divisum is the most common Bechien Wu that were in previous editions of Harrison’s.
congenital anatomic variant of the human pancreas. Current evidence
indicates that this anomaly does not predispose to the development ■■FURTHER READING
of pancreatitis in the majority of patients who harbor it. However, the Crockett SD et al: American Gastroenterological Association Insti-
combination of pancreas divisum and a small accessory orifice could tute guideline on initial management of acute pancreatitis. Gas-
result in dorsal duct obstruction. The challenge is to identify this sub- troenterology 154:1096, 2018.
set of patients with dorsal duct pathology. Cannulation of the dorsal Forsmark CE et al: Acute pancreatitis. N Engl J Med 375:1972, 2016.
duct by ERCP is technically challenging and associated with a very Gardner TB et al: ACG clinical guideline: Chronic pancreatitis. Am J
high risk of post-ERCP pancreatitis, so patients with pancreatitis and Gastroenterol 115:322, 2020.

CHAPTER 348 Acute and Chronic Pancreatitis

pancreas divisum should likely be treated with conservative measures. Hart PA, Conwell DL: Chronic pancreatitis: Managing a difficult
In many of these patients, pancreatitis is idiopathic and unrelated to disease. Am J Gastroenterol 115:49, 2020.
the pancreas divisum. Endoscopic or surgical intervention is indicated Hart PA et al: Recent advances in autoimmune pancreatitis. Gas-
only if pancreatitis recurs and no other cause can be found. It should troenterology 149:39, 2015.
be stressed that the ERCP/MRCP appearance of pancreas divisum (i.e., Petrov MS, Yadav D: Global epidemiology and holistic prevention of
a small-caliber ventral duct with an arborizing pattern) may be mis- pancreatitis. Nat Rev Gastroenterol Hepatol 16:175, 2019.
taken as representing an obstructed main pancreatic duct secondary Yadav D, Lowenfels AB: The epidemiology of pancreatitis and pan-
to a mass lesion. creatic cancer. Gastroenterology 144:1252, 2013.

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