Audio File: Day 1: Cellular Injury 1 (Med Ess. Page.

146)

CHAPTER 1: CELLULAR REACTION TO INJURY

Key issues hypoxia, cyanide poisoning, free radicals, apoptosis (cell destruction), growth
alternations (Ex.

I. HYPOXIA = inadequate oxygenation of tissue (same definition as shock). Need O2 for Oxidation
Phosphorylation pathway this process is where you get ATP from Inner Mitochondria membrane
(electron transport system, called oxidative phosphorylation). This is the last reaction where O2
receive the electrons. Protons are being kicked off from Electron Transport System and go back into
the mitochondria membrane and form ATP.

A. Terms:
1. Oxygen content = Hb (hemoglobin) x O2 saturation + partial pressure of arterial oxygen
(These are the 3 main things that carry O2 in our blood)

In Hb (hemoglobin), the O2 attaches to heme group (O2 saturation)

The Partial Pressure of O2 is O2 dissolved in plasma.

In Hb = RBC (red blood cells), four heme groups, (Fe (iron) must be +2 to bind ; if Fe+ is +3, it
cannot carry O2) Therefore, when all four heme groups have an O2 on it, the O2 saturation is
100%.

2. O2 saturation is the O2 in the RBC attached to the heme group = (measured by a pulse
oximeter)

3. Partial Pressure O2 (pO2): is O2 dissolved in PLASMA

O2 flow: from alveoli through the interphase, then dissolves in plasma, and increases the
partial pressure of O2, diffuses through the RBC membrane and attaches to the heme groups
on the RBC on the Hb, which is the O2 saturation.

Therefore if partial pressure of O2 is decreased, O2 saturation HAS to be decreased

(Because, O2 came from amount that was dissolved in plasma)

B. Causes of tissue hypoxia: High Yield for the Board!!!

1. Ischemia (decrease in ARTERIAL blood flow leading to low oxygenation in organs and
tissues) (MCC) Most common cause of death in USA is Ischemia due to thrombus in
muscular artery.

Best Example: 1. (In Myocardial Infarction (MI) - the thrombus is blocking arterial blood flow,
producing tissue hypoxia).

Example 2. (Decrease in Cardiac Output) leads to hypovolemia and cardiogenic shock)

because there is a decrease in arterial blood flow.

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 2. 2nd Most Common Cause of tissue hypoxia = HYPOXEMIA

Hypoxemia = cause of hypoxia (they are not the same); deals with the (PaO2) partial pressure
of arterial O2 (O2 dissolved in arterial plasma, therefore, when the partial pressure of O2 is
decreased, this is called hypoxemia). Deficient oxygenation of blood.

Causes of hypoxemia:

a. Respiratory Acidosis low PH (in terms of hypoxemia)

sum of the partial pressure of gas must = 760 at atmospheric pressure that have O2, CO2,
and nitrogen; nitrogen remains constant. When you increase CO2 (Carbon Dioxide) =
Respiratory Acidosis). When CO2 increase, pO2 has to decrease because must have to
equal 760.

Every time you have respiratory acidosis, from ANY cause, you have hypoxemia
because low arterial pO2; increase CO2= decrease pO2, and vice versa like:
Respiratory Alkalosis (increase pO2 = low CO2).

b. Ventilation Defects Best Example: Respiratory Distress Syndrome (Hyaline

Membrane Disease in children). In adults, this is called Adult RDS, and has a ventilation
defect. Lost ventilation to the alveoli but have perfusion (deliver fluid through an organ or
tissue) called intrapulmonary shunt.

Board Question: Pt with hypoxemia, given 100% of O2 for 20 minutes, and pO2 did not
increase? Indicates a SHUNT, massive ventilation defect.

c. Perfusion Defects knock off blood flow

Most common perfusion defect = pulmonary embolus, especially in prolonged flights,

with sitting down and not getting up. Stasis in veins of the deep veins, leads to propagation
of a clot and 3-5 days later an embolus develops and embolizes. In this case, you have
ventilation, but no perfusion; therefore there is an increase in dead space. If you give
100% O2 for a perfusion defect, pO2 will go UP (way to distinguish ventilation from
perfusion defect), because not every single vessel in the lung is not perfused.

To tell the difference, give 100% O2 and see whether the pO2 stays the same, it does not
go up = (shunt), if increases (increase in dead space). Perfusion defect.

d. Diffusion defect there is something in the interphase or membrane that O2 cannot get
through.

Best 1 example Sarcoidosis (a restrictive lung disease); O2 have trouble getting through
the membrane due fibrosis.

2 example: Pulmonary edema; O2 cannot cross.

3 example is plain old fluid from heart failure leads to dyspnea, because the
stimulation of the J reflex, initiated by CN X (vagus) innervation; activation of CN X,

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 leads to dyspnea of fluid in interstium of the lung,
and the J receptor is irritated.

CENTRAL CYANOSIS: is due by the four causes of hypoxemia (respiratory acidosis,

ventilation defects, perfusion defects, and diffusion defects).

3. Hemoglobin related with hypoxia: There is NO hypoxemia in anemia, there is normal

gas exchange (normal respiration), normal pO2 and normal O2 saturation. Anemia is:
decrease in Hb. If you have 5 gm of Hb, there is not a whole lot of O 2 that gets to tissue,
(decreace oxygen content); therefore get tissue hypoxia and the patient has exertional
dyspnea with anemia, exercise intolerance.

Cause of anemia related with hypoxia:

a. Carbon monoxide (CO): classic In a closed space with a heater (heater have many
combustable materials; automobile exhaust and house fire. In the house fire scenario,
two things cause tissue hypoxia: 1) CO poisoning (smoke) and 2) Cyanide poisoning
because upholstery (furniture material) is made of polyurethrane products.

CO is very diffusible and has a high affinity for Hb, therefore the O2 saturation will be
decreased because sitting on the heme group, instead of O2 (remember that CO has a
210X affinity for Hb and oxygen saturation is oxygen attached to heme). (If Hemoglobine
and pO2 is normal, too

When O2 diffuses into the RBC, CO already sitting there, and CO has a higher affinity for
heme. Tx: give 100% O2. The Clinical evidence for Decrease of O2 saturation is
cyanosis CO poisoning because cherry red pigment MASKS it,
therefore makes the diagnosis hard to make. Most common symptom of CO poisoning
= headache.

b. Methemoglobin is (Iron) with 3 = Fe3+ on heme group and O2 CANNOT bind. In

methemoglobin poisoning, the only thing screwed up is O 2 saturation (because the iron is
+3, instead of +2) O2 bind with Fe2+.

Example: pt that has drawn (extract) blood, which is chocolate colored because there is no
O2 on heme groups (normal pO2, Hb concentration is normal, but the O2 saturation is not
normal t, because That why
methemoglobin reductase system in glycolytic cycle (reduction of Fe +3 to Fe+2).

Tx: IV methylene blue (Drug of Choice) and Vitamin C (a reducing agent).

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 Question: Pt from Rocky Mountains was cyanotic; they gave him 100% O2, and he was still
cyanotic. What is the Treatment to cyanosis?

Drinking water in minutes water has nitrites. Nitrites are oxidizing agents that oxidize Hb so
the irons become +3 instead of +2. So giving 100% oxygen will not correct the cyanosis, instead
give methylene blue and vitamin C.

Most recent drug, Dapsone (used to Treatment leprosy) is a sulfa, and nitrites drug
which produces:

1) Methemoglobin (methemoglobinemia)
2) Hemolytic anemia in glucose 6 phosphate dehydrogenase deficiencies. The
hemolysis in G6PD deficiency is referring to oxidizing agents, causing an increase in
peroxide, which destroys the RBC; the same drugs that produce hemolysis in G6PD
Deficiency are sulfa and nitrites. These drugs also produce methemoglobin.

Therefore, exposure to dapsone, primaquine, and TMP-SMX (trimethoprim), or nitrites drugs

(nitroglycerin/nitroprusside), there can be a combo of hemolytic anemia in G6PD Deficiency and
methemoglobinemia because they are oxidizing agents.

Common to see methemoglobinemia in HIV patients because this pt is on TMP-SMX

for Treatment of PCP (PNEUMOCYSTIC CARINII PNEUMONIA).

c. Curves: left and right shifts

Right Shift: means Hb with a low affinity for O2, so it can release O2 to tissues.

Right Shift Causes: INCREASE: 2,3 bisphosphoglycerate (BPG), Temperature

(fever=hyperthermia), PCo2, and DECREASE low pH (acidosis).

Left Shift Causes: DECREASE: PCO2, Temperature (cold=Hypothermia),

methemoglobin, HbF (fetal Hb), 2,3-BPG and INCREASE pH (alkalosis)

*In high altitude (as a respond; you have a respiratory alkalosis, therefore have to
hyperventilate because you will decrease the CO 2, leading to an increase in pO2, but
(leading to a right shift JUST to increase in synthesis of 2,3 BPG).

4. Problems related to OXIDATIVE PATHWAY.

a. Most important: Cytochrome Oxidase (last enzyme before it transfers the electrons to
O2). Remember cytochrome oxidase, cyanide, CO all inhibit cytochrome
oxidase.

3 functions for CO:

(1) Decrease in O2 saturation (hypoxia)

(2) Left shifts (because have affinity with Hb)
(3) It blocks cytochrome oxidase, so the entire system shuts down.

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 b. Uncoupling ability for inner mitochondria membrane to synthesize ATP. Inner
mitochondria membrane is permeable to protons. You only want protons to go through a

random influx of protons and that is what uncoupling agents do.

Examples: dinitrylphenol (chemical for preserving wood), alcohol and salicylates.

Uncoupling agents causes protons to go right through the membrane; therefore you are
draining (filter) all the protons, and very little ATP being made. Because our body is in total
equilibrium with each other, reactions that produce protons increase (reaction that make
NADH and FADH, these were the protons that were delivered to the electron transport
system).

Therefore, any reaction that makes NADH and FADH that leads to proton production will
stimulate reactions making NADH and FADH and make more protons. With increased rate
of reactions, leads to an increase in temperature (HYPERTHERMIA=hot).

Complication of salicylate toxic = hyperthermia (because it is an uncoupling agent).

Another example: alcoholic on hot day will lead to heat stroke=hyperthermia because
already have uncoupling of oxidative phosphorylation (because mitochondria are already
messed up).

These are all the causes of tissue hypoxia (ischemia, Hb related, cytochrome
oxidase block, uncoupling agents).

What happens when there is Respiratory Acidosis pH low?

Hb stays same, O2 saturation decreased, because (pO2) partial pressure of O2 is decreased.

What happens when there is Anemia low Hb? (Normal O2 saturation and pO2)

What happens when there is CO/methemoglobin?

Hb normal, pO2 normal and O2 saturation decreased.

Tx. 1. CO poisoning 100% O2

2. Methemoglobin IV methylene blue (Drug of choice) or Vitamin C (ascorbic acid)

c. Consequenses of hypoxic cell injury: (Med Ess. Page.147)

1. Decreased of ATP (as a result of tissue hypoxia)

Most important: ATP has to go into anaerobic glycolysis and the end Product is
lactic acid (pyruvate is converted to lactate because of increased NADH); this process
need to make NAD, so that the NAD can feedback into the glycolytic cycle to make 2
more ATP.

Why do we have to use anaerobic glycolysis with tissue hypoxia? Because with anaerobic
glycolysis, you can make 2 ATP without going into the mitochondria.

Every ce
therefore surviving on 2 ATP per glucose, if you have tissue hypoxia because
Mitochondrial system is totally shut down (if you don O2 at the end of the electron
transport system in the cell, you can only get 2 ATP with anaerobic glycolysis.
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 *Good news get 2 ATP
*Bad news increase lactic acid in the cell and outside the cell (increased anion- Gap
metabolic acidosis with tissue hypoxia) due to lactic acidosis from anaerobic glycolysis.

However, causes havoc (wide destruction) inside the cell because increase of lactic
acid within a cell will denature proteins (with structural proteins messed up (damage),
the configuration will be altered); enzymes will be denatured, too. As a result, cells
cannot autodigest anymore because enzymes are destroyed due to increase lactic acid
in cell. Tissue hypoxia will therefore lead to COAGULATION NECROSIS (infarction).

2. 2nd problem of lacking ATP: all ATP pumps are screwed up because they run on
ATP. ATP is the power, anything that needs energy needs ATP.

Na/K ATPase pump is blocked by digitalis to allow Na to go into cardiac muscle, so

Ca channels open to increase force of contraction. With no ATP, produce diffusion of
Na and H20 into the cell, which leads to cellular swelling (which is reversible).
Therefore, with tissue hypoxia there will be swelling of the cell due to decreased ATP (If
O2 is availble, all that reactions are REVERSABLE).

In RBC, anaerobic glycolysis is the main energy source because they do not have
mitochondria; not normal in other tissues (want to utilize Fatty Acids, TCA, etc)

3. Cell without O2 leads to irreversible changes.

Ca changes with irreversible damage Ca/ATPase pump. With decrease in ATP,

Ca has easy access into the cell. Within the cell, it activates many enzymes (Ex.
phospholipases in the cell membranes, enzymes in the nucleus, leading to nuclear
pyknosis (so the chromatin disappears), goes into the mitochondria and destroys it.

Ca activates enzymes; hypercalcemia leads to acute pancreatitis because enzymes in

the pancreas have been activated. Therefore, with irreversible changes, Ca has a major
role. Of the two that get damaged (mitochondria and cell membrane), cell membrane is
damaged a lot worse, resulting in bad things from the outside to get into the cell.

However, to add insult to injury, knock off mitochondria (energy producing factory), it is
a very bad situation (cell dies).

Enzyme Test to prove damage:

1. (CK-MB) Creatine Kinase MB indicator for heart damage for Miocardial Infarction.

2. (SGOT) Serum Glutamic Oxaloacetic Transaminase, an enzyme present in liver

and heart and is released into blood when and alanine
transaminase (ALT) and aspartate transaminase (AST), may be an indicator of liver
damage. Transaminases for hepatitis.

3. Amylase in pancreatitis.

II. FREE RADICALS (mechanism of cell injury (Med Ess. Page. 146)
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 A. Definition of free radical compound with unpaired electron that is out of orbit, therefore
ll damage things.

B. Types of Free Radicals:

1. Oxygen: We are breathing O2, and O2 can give free radicals. If give a person 50% O2 for a
period of time, will get superoxide free radicals, which lead to reperfusion injury, especially
after giving tPA (alteplase=thrombolytic) when trying to rid a damaged thrombus.

Oxygentated blood goes back into the damaged cardiac muscle=reperfusion injury. Kids with
respiratory distress syndrome can get free radical injury and go blind because they destroy
the retina called retinopathy prematurity; also leads to bronchopulmonary dysplasia, which
leads to damage in the lungs and a crippling lung disease.

2. Water in tissues is converted to hydroxyl free radicals, leading to mutations in tissues.

Complication of radiation therapy is CANCER (Most Common cancer from radiation is
leukemia, due to hydroxyl free radicals). Fe2+ produces hydroxyl free radicals because of
the fenton reaction. This is what makes Fe overload diseases so dangerous, because
wherever Fe is overloaded, leads to hydroxyl free radicals which will damage that tissue
(therefore, in liver leads to cirrhosis, in heart leads to restrictive cardiomyopathy, in pancreas
leads to failure, and malabsorption, along with diabetes).

Audio file 2: Cell Injury 2

3. Tylenol (acetaminophen):
Most common cause drug induced fulminant hepatitis because free radicals (especially
targets the liver, but also targets the kidneys). Cytochrome P450 in liver metabolizes
drugs, and can change drugs into free radicals. Drugs are often changed in the liver to the
active metabolite, example: phenytoin.

Where in the liver does acetaminophen toxicity manifest itself? Right around central vein.

Treatment: N-Acetylcysteine (mucamist); how? Superoxide free radicals can be neutralized

with superoxide dismutase (SOD). Glutathione is the end product of the hexose/pentose
phosphate shunt and this shunt also generates NADPH. Glutathione Main function is
neutralize free radicals (especially free radicals drugs, and free radicals derived from
peroxide).N-Acetylcysteine is converted to glutathione which neutralizes free radicals
produced by the drug.

4. Carbon tetrachloride: In liver CCl4 can be converted to a free radical (CCl3) and a free
radical can be formed out of that (seen in dry cleaning industry).

5. Aspirin + Tylenol = very bad for kidney (takes a long time for damage to be seen). Free
radicals from acetaminophen are destroying the renal medulla *only receives 10% of the blood
supply-relatively hypoxic) and renal tubules. Aspirin is knocking off the vasodilator PGE2
(prostaglandin E2), which is made in the afferent arteriole.

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 Therefore, Angiotensin II (a vasoconstrictor) is left in charge of renal blood flow at the efferent
arteriole. Either sloughing (change site) of medulla or destroyed ability to concentrate/dilute
your urine, which is called analgesic nephropathy (due mainly to acetaminophen).

C. Clinica Association: Lipofuscin is the end products of free radical damage are
lipofuscin because certain things are not digestible (include lipids). Liver with brownish
pigment.

LIVER BIOPSY: LIPOFUSCIN

III. APOPTOSIS: Programmed cell death. Apoptotic genes

(Med Ess. Page. 147)

*Apoptosis have normal functions like: (Med Ess. Page.148)

(1) Embryo small bowel got lumens from apoptosis.

(2) King of the body (For Men) Y chromosome is a Mullerian Inhibitory Factor (MIF) with
these all mullerian structures (uterus, cervix, upper 1/3 of vagina) are gone. MIF is a signal
working with apoptosis, via caspases enzymes. They destroy everything, by apoptotic bodies
and lipofuscin gone.

(3)For woman X chromosome; only have one functioning one because the other is a barr
body. Absence of Y chromosome caused germinal ridge and go to the ovarian route, therefore
apoptosis knocked off the wolffian structures (epidydymis, seminal vesicles, and vas
deferens).

(4) Thymus in anterior mediastinum In X-Rays it seem large in kids; if thymus is absent =
DiGeorge syndrome (absent thymic shadow), and would also have tetany; cause of thymus to
involve is apoptosis.

CEREBRAL CORTEX APOPTOSIS: Describes by red

neurons and the spaces are cerebral edema.

(5) Apoptosis is the major cancer killing mechanism.

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 (6) Process of atrophy, reduced cell or tissue mass is due to apoptosis. Ex. Hepatitis

LIVER: VIRAL HEPATITIS WITH APOPTOSIS

Councilman body (looks like eosinophilic cell without a nucleus, individual cell death without
inflammation around it). Just needs a signal (hormonal or chemical) which activates the caspases
to destroy cell. Apoptosis of neurons loss brain mass and brain atrophy, and leads to ischemia.
Atherosclerotic plaque. Therefore, apoptosis is involved in embryo, pathology, and knocking off
cancer cells.

IV. TYPE OF NECROSIS manifestations of tissue damage.

(Med Ess. Page. 147)

*A. Coagulation Necrosis: Results often from a sudden cut off of blood supply to an organ,
example: Ischemia (decrease arterial blood flow). In ischemia, there is no oxygen therefore
lactic acid builds up, and leads to coagulation necrosis. Gross manifestation of
coagulation necrosis is infarction. Under microscope, cardiac muscle present: no striations, no
nuclei, bright red, no inflammatory infiltrate, all due by the increase of lactic acid that has
denatured and destroyed all the enzymes and these cells or tissues cannot be broken down, in
this case neutrophils need to come in from the outside to breakdown.

HEART: COAGULATION NECROSIS (micro view)

1. (Pale vs hemorrhagic) Colors of tissue infarctions: look at consistency of tissue.

(a) Good consistency = grossly looks PALE color:

HEART: PALE INFARCTION WITH COAGULATION NECROSIS (macro view)

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 Prevent Red Blood Cells diffuse through necrotic tissue. Example: infarcts in heart, kidney,
spleen, liver (rarest of the organ to infarct because dual blood supply); Example:
coagulation necrosis.

Pathogenesis of Miocardial Infarction: coronary thrombosis overlying the atheromatous

plaque, leading to ischemia, and lumen is blocked due to thrombosis.

¿What is the pathogenesis of Miocardial Infarction? Coronary Thombosis, because if have

atheromatous plaque in coronary artery have small lumen.

Example of a pale infarction of the spleen, most

likely due to emboli from left side of heart; causes of emboli: vegetations (rarely
embolize in acute rheumatic fever), in mitral stenosis (heart is repeatedly attacked by group
A beta hemolytic streptococcus); and clots/thrombi.

*Important to the Boards: The worst arrhythmia associated with embolization in the systemic
circulation is atrial fibrillation because produce stasis (slow flow) in the atria making clots, then it
vibrates (it pieces of clot embolize).

Dry Gangrene: Gangrenous Necrosis, but this in particular is a good example of

Coagulative Necrosis. Picture of a dry gangrene . Occurs in diabetics with
atherosclerosis in popliteal artery, possible thrombosis; (dry gangrene related to
coagulation necrosis related with ischemia is due to atherosclerosis of the popliteal artery.

Most common cause nontraumatic amputation in lower extremities in USA =

diabetes, because enhanced atherosclerosis in (popliteal artery = dangerous artery).
Popliteal artery is next to the coronary artery is probably of the most dangerous artery

PROBLEM!!!!

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 (b) Loose consistency of tissue= HEMORRAGIC Color: Allows Red Blood Cells diffuse
through necrosis tissue. Infarcts in bowel, in testes (torsion of the testes)*IMPORTANT
QUESTION FOR THE BOARDS, and especially in the lungs because is has a loose
out (flow in a thin
gentle stream), leading to a hemorrhagic appearance.

Example: Most common cause of bowel infarction is adhesions from previous

surgery. 2nd Most common cause of bowel infarction is getting a piece of small
bowel trapped in indirect hernial sac.

Example: In the Lung

Hemorrhagic infarction, wedge shaped, went to pleural surface, therefore have
effusion and exudates; neutrophils in it; have pleuritic chest pain (knife-like pain on
inspiration) and Pulmonary embolus leads to hemorrhagic infarction.

*B. Liquefactive Necrosis: In wet gangrene, ve heterolysis and

consequent liquefactive necrosis.

INFARCTION IN BRAIN

BRAIN: OLD ARTHEROSCLEROTIC STROKE WITH CYSTIC CAVITY.

Most common site of brain infarction is in carotid artery why we listen for a bruit (hearing
for a noise that is going thru a vessel that has a narrow lumen place with thrombus
develops over atherosclerotic plaque and leads to stroke); leads to transient ischemic
attacks is little atherosclerotic plaques going to little vessels of the brain, producing motor
and sensory abnormalities, that go away in 24 hrs.

Brain with in brain, astrocytes is analogous to the fibroblasts because of

protoplasmic processes gives some structure to the brain. Therefore, infarction of the brain
basically liquefies, it has no structure, leaves a hole and you see a cystic cavity liquefactive
necrosis.

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BRAIN: CEREBRAL ABSCESS

Cerebral abscess and old atherosclerotic stroke -both are liquefactive necrosis. Liquefactive
liquefies; think in neutrophil, because
liquefactive necrosis is with neutrophils involved in (usually acute infection producing an
abscess or an inflammatory condition, which liquefies tissue). Therefore, liquefactive
necrosis usually applies to acute inflammation, related to neutrophils damaging the tissue. (Slide
shows liquefactive necrosis due to infection in the brain). So, if you infarct the brain, have an
infection, or have an abscess = liquefactive necrosis.

WRIST ABSCESS DUE STAPHYLOCOCCO AUREUS

Example: Abscess
which leads to abscesses with staphylococco aureus. Coagulase converts fibrinogen into
fibrin, so it localizes the infection, neutrophils
resulting in an abscess.

Streptococco: releases hyaluronidase, which breaks down Glycosaminoglycans in tissue, and

infection spreads through the tissue leading in (cellulitis).

Example: Abscess in Lung yellowish areas, high fever and

streptococco pneumonia = most common cause of
bronchopneumonia. Not hemorrhagic because pale and wedged shaped necrosis at the
periphery, which leads to pleuritic chest pain.

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*C. Caseous (cheesy consistency) Necrosis: either have mycobacterial infection (any
infections, including atypicals, or systemic fungal infection); these are the ONLY things that will
produce caseation in a granuloma. It is the lipid in the cell wall of the organism leads to cheesy
appearance.

Sarcoidosis get granulomas, but is not caseous because is not related to mybacterium or
systemic fungi.

get granulomas, but not caseous because not related to.

Example: pt with fever, night sweats, weight loss Most Common Tuberculosis (TB) by
Mycobacterium Tuberculosis, which has granulomatous (caseous) necrosis. Pathogenesis
of granuloma (involves IL-12 and activate Helper T cel

(Micro) (Macro view)

LYMPH NODE: LOCALIZED GRANULOMA IN PT WITH TUBERCULOSIS

*D. Fat Necrosis:

1. Enzymatic Fat Necrosis: unique to pancreas.

Example: pt with epigastric distress with pain radiating to the back pancreatitis
(pancreas is retroperitoneal)

PANCREAS: ACUTE PANCREATITIS WITH ENZIMATIC FAT NECROSIS.

Enzymatic fat necrosis is unique to the pancreas because enzymes are breaking down fats
into Fatty Acids, which combine with Ca and salts, forming chalky white areas of enzymatic
fat necrosis (chalky white areas due to calcium bound to Fatty Acids saponification
(soap/like salt formation); It can be seen on x-rays because have calcium in them.

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 Example: A pt with pain constently penetrating into the back, show x-ray of Right Upper
Quadrant. What is the Dx? Pancreatitis and especially seen in alcoholics.

HISTOPATOLOGY SLIDE ON ENZYMATIC FAT NECROSIS IN ALCOHOLIC WITH ACUTE

PANCREATITIS: BLUISH (BLUE) DISCOLORATION AND DYSTROPHIC CALCIFICATION
OF TISSUE.

What enzyme would be elevated? Amylase and Lipase (LIPASE is more specific
because amylase is also in the parotid gland, small bowel, and fallopian tubes). Alcohol
produces a thick secretion that will lead to activation of enzymes; which leads to pancreatitis.
Therefore, whenever you see blue discoloration and atherosclerotic plaque in a pancreas, it
will be calcium.

2. Traumatic Fat Necrosis: Example: woman with damage to breasts is TRAUMATIC FAT
necrosis (not enzymatic); it can calcify, can look like cancer on mammogram.

Difference between traumatic fat necrosis vs. Cancer.

(Cancer = painless). Traumatic fat tissue usually occurs in breast tissue or other adipose tissue.

*E. Fibrinoid necrosis: oid means: looks like, but ) Therefore, looks like fibrin, but is not
s the necrosis of immunologic disease:

Examples of immunologic disease: Palpable purpura = small vessel vasculitis (immune

complex type III Hypersensitivity). Fibrinoid necrosis has immune complex deposition of small
vessel.

Pathogenesis of immune complex: damage of type III Hypersensitivity (an immune complex is
an Antigen-Ab circulating in the circulation; it deposits wherever circulation takes it. Example:
glomerulus, small vessel, wherever). The immune complex activates the complement system (the
alternative system), which produces C5a, which is chemotactic to neutrophils. Therefore,
damage done as a result of type III Hypersensitivity is done by neutrophils. (Neutrophils do
eventual damage)

ARTERIOLE: FIBRINOID NECROSIS

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 Henoch-Scholein purpura le purpura (due to type III
Hypersensitivity).

Rhematic fever (vegetations off the mitral valve) have fibrin like (fibrinoid necrosis) materials
(necrosis of immunologic disease).

Morning stiffness = in rheumatoid arthritis, you see fibrinoid necrosis because immunologic
Damage. Therefore, fibrinoid necrosis is necrosis of immunologic damage (in vessel = a
vasculitis, in kidney = lomerulonephritis, and in lupus = glomerulonephritis
involving immune complexes).

LIVER

IN LIVER: HAVE FATTY CHANGE SECONDARY WITH

ALCOHOLISM: REVERSEBLY REACTION.

Triad area: portal vein, hepatic artery, bile duct. Liver is unique because it has dual blood supply.
Hepatic artery and portal vein will dump blood into sinusoids (examples of sinusoid organs are Bone
Marrow and Spleen).

Characteristic of sinusoids: gaps between endothelial cells, with nothing there so things can fit
through (things like RBC Glomerular Basement Membrane is
fenestrated = (have little tiny pores for filtration). Sinusoids have gaps so large cells can get
through them.

*(Communication between right heart and liver) = Portal vein blood and hepatic artery blood go
through sinusoids, and eventually taken up by central vein, which becomes the hepatic vein. The
hepatic vein dumps into the inferior vena cava, which goes to the right side of the heart.

Right Heart Failure (blood fills behind failed heart), therefore the liver becomes congested with
blood, leading to nutmeg liver (congestive hepatomegaly). Blockage of hepatic vein leads to
budd chiari and liver becomes congested.

If you block the portal vein, nothing happens to the liver, because, it is BEFORE the liver.

Which part of liver is most susceptible to injury normally? Around central vein, because it gets
first little O2 coming out of the sinusoids Zone 1.

Zone 2 is where yellow fever will hit (midzone necrosis) due to Aedes aegypti.

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 Central vein
Zone 3, around portal vein, which will have least O2 (analogous to renal medulla, which only
receives 10% of the blood supply, and the cortex receives 90%). Fatty change is around zone 3
(part around central vein).

About acetaminophen toxicity, which part is most susceptible? Around the central vein because
it gets the least amount O2, and therefore cannot combat free radical injury.

1. Alcohol related liver damage:

(a) Most common cause fatty change: ALCOHOL

(b) Metabolism of alcohol: *NADH and *Acetyl CoA (acetate is a Fatty Acid, and acetyl CoA
can be converted to Fatty Acid in the cytosol).

Biochemical reaction: What causes pyruvate to form lactate in anaerobic glycolysis?

NADH.

NADH NAD+

PYRUVATE LACTATE

In alcoholics have lactic acidosis (metabolic acidosis) because increased *NADH by

pyruvate-lactate reaction. Also, in fasting state, alcoholic will have trouble making
glucose by gluconeogenesis because need pyruvate to start it off. They have lactate,
therefore, alcoholics will have fasting hypoglycemia.

*Acetyl CoA increases the production of ketone bodies (acetoacetyl CoA, HMG CoA, and
beta hydroxybutyric acid ). (Metabolic acidosis)

CIRRHOTIC LIVER WITH FATTY CHANGE

*Big time board question: Why does it produce fatty change?

In glycolysis, around reaction 4, get intermediates (DHAP) dihydroxyacetone phoshphate (NADH
reaction) and is forced to become glycerol 3-phosphate.

Also important to carbohydrates molecules for making tryglycerides (add 3 Fatty Acid + 1
glycerol + phosphate to make union and produce =Triglycerides). The liver have VLDL (very
low density lipoprotein), is an endogenous Triglycerides synthesized in the liver from
glycerol 3 phosphate derived from glycolysis).
** VLDL: ??
When you have restriction Fat, decrease sythesis of VLDL? NO
When you have restriction of Carb's, decrease synthesis of VLDL? YES
Because VLDL it's made from Glycerol-3-phosphate and G-3-P is a product of 16
glycolysis, Producing Fatty liver.
Drink alcohol increase NADH (cheating the body, saying that have enough energy) = inhibit
gluconeogenesis (stimulating fatty acid synthesis) and glycolysis (producing hydrolysis of
Triglicerides divide in Fatty Acids and Glycerol = inhibit glycerol 3 phospate synthesis= inhibit
VLDL synthesis and accumulation of fatty acid in liver) producing FATTY LIVER.

Audio file Day 1: Inflammation 1

2. Kwashiorkor In kwashiorkor, there is decreased protein intake; they have adequate

number of calories, but its all carbs.

The mechanism: when you make VLDL, and to be able to get it out of the liver, the VLDL must
be surrounded by apoproteins , they cannot get VLDL that they
made in the liver out because there are no apolipoproteins to cover it and put it out in the
bloodstream and solubilize it in water. Lipid and water do not mix; therefore it is necessary to
put proteins around the lipid to dissolve it in water.

The protuberant abdomen in these pts is there for two reasons:

1) Decreased protein intake which decreases oncotic pressure, leading to ascites.
2) Huge liver (Fatty Change) is a lack of protein to put around the VLDL and export it out of the
liver. **different mechanism than alcohol (in alcohol ^ VLDL v.s Kwashiorkor decrease apolipoprotein synthesis) ??

3. Hemosiderin and Ferrtin: *Ferritin = soluble form of circulating iron (Fe), and is a good
marker for Fe in Bone Marrow. Ferritin is the test of choice in diagnosting any Fe related
problem Fe deficiency anemia, or Anemia of Chronic Disease or Fe overload diseases such as
hemochromatosis and hemosiderosis (would be elevated). Ferritin is a soluble form of Fe, while
*Hemosiderin is an insoluble form of Fe storage, and is stored in macrophages and Bone
Marrow. Stain it with Prussian blue.

LUNG CHRONIC PULMONARY CONGESTION WITH HEMOSIDERIN LANDEN ALVEOLAR

MACROPHAGES.

17
V. TYPE OF CALCIFICATIONS: dystrophic and metastatic.

A. Dystrophic calcification: means abnormal calcification. The damaged tissue gets calcified
with normal serum calcium level.

1. Example: Seen in enzymatic fat necrosis (chalky white areas on x-ray are a result of
dystrophic calcification).
2. Example: football player with hematoma in foot, that becomes calcified dystrophically (Ca
binds and co-produces dystrophic Ca deposits). Serum Ca is normal, but damaged tissue
becomes calcified. Occurs in atheromatous plaques (causes serious tissue damage),
therefore, they are difficult to dissolve (need to be on the ornish diet a vegan diet).

AORTA WITH ATHEROMATOUS PLAQUES

BAD

3. Example: Congenital Bicuspid Aortic Valve = dystrophic calcification leading to Aortic

Stenosis and also Hemolytic Anemia).

*MCC of aortic stenosis and hemolytic anemia?

Dystrophic Calcification

Slide: the aorta has only 2 valves doing the job of three, and
gets damaged, leading to dystrophic calcification which narrows orifice of valve, leading to
aortic stenosis.

B. Metastatic calcification:

MUSCLE: METASTASIC CALCIFICATION

In cases of Hypercalcemia or hyperphosphatemia, Calcium is actually made to deposit in
normal tissues, non-damaged tissues.
18
*Most common cause of hypercalcemia (outside of hospital) = primary hyperparathyroidism.

*Most common cause of hypercalcemia (inside the hospital) = malignancy induced

hypercalcemia.

Because with hypercalcemia, you put Ca in NORMAL tissues; this is called metastatic
calcification. Metastatic calcification is when there are high Ca or phosphorus serum levels
(actually when Ca is deposited into bone, it is the phosphorus part of solubility product that
drives Ca into bone).

High phosphate levels (very dangerous) will take Ca and drive it into normal tissue. This
is why have to put a pt with renal failure on dialysis (have high phosphorus serum levels) and
therefore, need to dialyze the phosphate because the phosphate will drive Ca into normal
tissue Ex. heart, conduction system, renal tubules, basement membrane
(nephrocalcinosis) all lead to damage.

VI. CELL MEMBRANE DEFECTS

A. RBC membrane defect: Spherocytosis is an absence of spectrin within RBC cell

membrane.

Characteristic is an Absence of central area of pallor

spherocyte. Absence of spectrin with in the RBC does not allow the RBC to form a biconcave
disk; it is defective, and therefore forms a sphere.

PERIFERAL BLOOD SMEAR: SPHEROCYTOSIS

B. Ubiquitin stress protein. High ubiquitin levels are associated with high levels of stress.
Some of the intermediate filaments (keratin, desmin, vimentin) are part of the superstructure of our
ce
damaged, the ubiquitin marks then for destruction. The intermediate filaments have been tagged
(ubiquinated) and marked for destruction.

19
 *Example of ubiquinited products:

First example: IN LIVER BIOPSY: MALLORY BODIES IN ALCOHOLIC HEPATITIS.

There are open spaces within the liver tissue, these spaces are fat and they are probably
due to alcohol. The ubiquinited products of the liver are called Mallory bodies. These are
the result of ubiquinated filaments called keratin and these are seen in alcoholic hepatitis.

Second example: Silver stain of neurofibilary tangles in Jacob crutzfelt and alzheimers
disease. Tau protein is associated with neurofibrilary tangles; this is an example of an
ubiquinated neurofilament.

Third example: In the substantia nigra in Parkinson disease include inclusions called Lewy
bodies, the neurotransmitter deficiency is dopamine. Lewy bodies are ubiquinated
neurofilaments.

VII. CELL CYCLE- IMPORTANT TO THE BOARD!!! Med Ess. Page 149

A. Different types of cells:

1. Labile cells (cell division via a stem cell). Three tissues that has stem cells: bone
marrow, basement membrane of skin, and the base of crypts in the intestine. Cells
divide continuously and usually undergo hyperplasia. These cells have the tendency of
being in the cell cycle a lot. In pharmacology: there are cell cycle specific and cell cycle
nonspecific drugs. The cells that are most affected by these drugs are the labile cells because
they are in the cell cycle. Complications of these drugs are Bone Marrow suppression,
diarrhea, mucocidis, and rashes on the skin (there are stem cells in all these tissues!).

2. Stable cells (are in resting phase or act in Go phase). Cells that divide infrequently
may undergo hyperplasia and hyperthrophy. Example: Smooth Muscle hyperplasia /
hypertrophia in gravid uterus. Most of parenchymal organs (liver, spleen, and kidney)
and smooth muscle are stable cells. Stable cells can undergo division, but most of the time
they are resting, and something must stimulate them to get into the cell cycle and divide.

Example: a hormone or a growth factor. (Estrogen) In woman will help in the proliferative
phase of the menstrual cycle. The endometrial cells are initially in the G o phase and then the
estrogen stimulated the cells to go into the the cell cycle.

3. Permanent cells (non-replicating): highly specialized cells (neuronal, cardiac and

striated muscle) only undergo hypertrophy.

20
 Example: left ventricular hypertrophy (LVH). Can no longer get into the cell cycle, and have
been permanently differentiated. Only muscle that is NOT a permanent tissue = smooth
muscle.

*Would a permanent cell be able to undergo hyperplasia? NO, because that means more copies
of it.
*Can permanent cell go under hypertrophy? YES. A smooth muscle cell can undergo hyperplasia
AND hypertrophy.

B. Different phases of cell cycle: Med Ess. Page. 81

1. G1 phase: Is the most variable phase. Making a comparison in menstrual cycle: The
most variable phase is the proliferative phase (not the secretory phase) and varies with stress.
But, in ovulation has occurred, it is 14 days. Therefore, proliferative phase is analogous to
G1 phase of the cell cycle because it can be shorter or lengthened.

The other phases (S, G2, and M phase) changes, they stay the same. Therefore, in cancer
cells, ones with a longer cell cycle will have a longer G1 phase, and cancer cells with a shorter
cell cycle will have a shorter G1 phase.

G1 phase is the mastermind of everything. Cyclin Dependent Kinase (kinase =

phosphorylation = activation). Phosphorylation usually involves sending a message to
activate something. Glucagon phosphorylate (activate) protein kinase and insulin
dephosphorylate (inactivate) protein kinase.

G1 to S phase: G1 phase makes Cyclin D. Cyclin D activates the enzyme Cyclin Dependent
Kinase. Key area to control in cell cycle: is the transition from G1 to S phase. Because
if you have a mutation and it goes into S phase, it then becomes duplicated, then you have the
potential for cancer.

Two suppressor genes that control the transition:

(1) (Retinoblastoma Protein) Rb Tumor suppressor gene: located on chromosome 13,

Rb inhibits excesive the cell growth going from the G1 to the S phase. To go from G1
to S, the active cyclin dependent kinase phosphorylates the Retinoblastoma protein.
Retinoblastoma Protein goes from the G1 phase to the S phase.

*If there is a mutation, the enzyme cyclin dependent kinase is checked by p53
suppressor gene.

(2) p53 suppressor gene : located on

chromosome 17. If the damage is minor, p53 stop the cell division, makes a protein
that inhibits the cyclin dependent kinase. Therefore, it cannot go into the S phase until
the damage is repaired. If the damage is major and cannot be repaired, p53 stimulate
the cell to commit suicide by apoptosis. P53 gives the cell an opportunity to clean its
DNA before going into the S phase.

21
 Example: HPV (Human Papiloma Virus) inactivates Rb suppressor gene and p53
suppressor gene. HPV makes two genes products (E6 -inhibit p53) and (E7 - inhibit
Rb suppressor gene).

If Rb suppressor gene is inhibit: the cell will progress to the S phase. This mutation in
the Rb suppressor gene predisposing to many cancers, such as retinoblastoma, osteogenic
sarcoma (Ex. kid with pain around knees = sunburst appearance
on x-rays), and breast cancer (Rb suppressor can be involved). Depending on the age
bracket, it hits in different areas.

If p53 suppressor gene is inhibit: Cyclin Dependent Kinase will be active,

phosphorylate the Rb protein and go into the S phase, THIS IS BAD!!! p53 gene
makes a protein to inhibit the Cyclin Dependent Kinase, then prevents the Rb protein from
being phosphorylated, and stays in the G1 phase. Therefore, when you inhibit the
supressors, Cyclin Dependent Kinase maintain activated, and Rb is constantly
phosphorylated and go to S phase = keeps the cell dividing, and then has the potential to
lead to cancer.

2. S phase = synthesis phase, where everything is doubled, includes DNA and chromosomes

elements.

Drugs acting on S phase: Med Ess. 166

a) Ergot alkaloids work on the mitotic spindle in S phase.
b) Methotrexate (inhibit the synthesis of DNA, RNA, thymidilate and proteins) is used in
Cancer and Autoimmune disease and works in S phase. Example: pt with rheumatoid
arthiritis has macrocytic anemia. Drug responsible for this is in what phase of the cell
cycle? S phase. Because, it is methotrexate blocking dihydrofolate reductase to inhibit
folate (tetrahydrofolate) metabolism.

3. G2 phase = where tubulin is made (important to microtubule of the mitotic spindle); it is

blocked by etoposide and bleomycin.

Drugs that block G2 phase:

a) Etoposide
b) Bleomycin

4. M phase = mitosis; where the cell divides into two 2N cells. The cell can either go into
the Go resting phase, or can continue dividing in the cycle, or can be permanently
differentiated.

22
 Drugs acting on M phase:
a) Gresiofulvin
b) Paclitaxel - This drug is a chemotherapy agent made from a yew tree.
c) Vincristine and Vinblastine
d) Colchicine - used to be used for the treatment of acute gouty arthritis but because of all
the side effects is no longer used.

Clinical scenario that does not work on the cell cycle person with dyspnea and white out
of the lung, on a drug; ends up with cyanosis; which drug? Dapsone

VII. ADAPTATIONS TO ENVIROMENTAL STRESS: GROWTH ALTERATIONS Med Ess. 148

A. Atrophy: Diagnosis: the decrease in tissue mass and the cell decreases in size. The cell
has just enough organelles to survive.

1. Example: KIDNEY ATROPHY: due the compression

atrophy is causing increase the pressure because of the thinning of cortex and medulla.

Most Common Cause hydronephrosis is stone in the ureter (the pelvis is dilated).

What kind of growth alteration can occur here? ATROPHY, because of the increased pressure on
the cortex and the medulla and produces to ischemia, blood flow decreases and can produce
atrophy of renal tubules.

2. Example: BRAIN ATROPHY: due to atherosclerosis

in Internal Carotid Artery, see the lost brain mass and the division of the gyri and sulci.

Most Common or degeneration of neurons are Alzheimers (related to beta amyloid protein,
which is toxic to neurons).

23
3. Example: MUSCLE ATROPHY
Example: Lou (amylateral sclerosis = loss nerve stimulation) and Duchene
Muscular Dystrophy.

4. Example: Endocrine related:

a) Hypopituitarism will lead to atrophy of adrenal cortex: the zona fasiculata and zona
retiucularis layers of the adrenal cortex; The fasiculata is where glucocorticoids (cortisol)
are made, while reticularis is where sex hormones are made (17 ketosteroids and
testosterone). NOT the zona glomerulosa because ACTH has nothing to with stimulating
aldosterone release. ACTH is responsible for stimulating these, therefore zona fasiculata
and zona reticularis are atrophied.

b) Thyroid hormone will lead to atrophy of thyroid gland. This is due to a decrease of
TSH and therefore nothing is stimulating the thyroid gland which leads to atrophy.

5. Example: PANCREAS ATROPHY DUE CYSTIC FIBROSIS.

What is growth alteration? Atrophy, because the

Cistic Fibrosis Transmembrane Regulator (CFTR) on chromosomes 7 is defective and has
problems with secretions. The secretions become thicker and as a result, it blocks the ducts
and the glands that were making the fluids (the exocrine part of the gland) cannot make fluids
because of the back pressure blocking the lumen of the duct, which leads to atrophy of the
glands, which then leads to malabsorption in all children with cystic fibrosis.

24
 6. Example: Atherosclerotic plaque in Aorta, leads to:

KIDNEY ATROPHY and secondary HYPERTENSION

(renovascular HYPERTENSION, leading to high renin level coming out of the kidney). In
the other kidney, it is overworked, therefore there is hypertrophy (renin level coming out of this
vein is decreased and suppressed).

B. Hypertrophy (increase of the SIZE of cell)

Scenario: A cell biology question: what is the N of this?

HYPERTROPHY OF CARDIAC MUSCLE: the left is normal

and the right has hypertrophied (permanent muscle), suppose there is a block just before the G2
phase. What is the number of chromosomes? Answer: the number of chromosome is 4N,
because it already underwent synthesis: already doubled.

1 N = sperm (23 chromosomes)

2 N = normal (diploid cell)
3 N = trisomy
4 N = double the number

C. Hyperplasia (Increase in the number of cells) In normal proliferative gland, there are
thousands of mitoses, therefore see more glands with hyperplasia.

1. Example leading to cancer:

ENDOMETRIAL MUCOSA: WITH UNOPPOSED ESTROGEN STIMULATION. I
have progesterone, you will get CANCER. The cells will go from hyperplasia, to atypical
hyperplasia to endometrial cancer.

25
One exception:
PROSTATE GLAND WITH BENING PROSTATIC HYPERPLASIA (note the nodular area
throughout the gland, that hyperplasia) and does NOT lead to cancer; just urinary
incontinence.

2. Example: GRAVID UTERUS ry). This

is an example of 50% hypertrophy of the smooth muscle cells in the wall of the uterus, and
50% related to hyperplasia.

3. Example: BONE MARROW: RED BLOOD CELLS HYPERPLASIA

I = RBC hyperplasia.
This is not expected to be seen in Iron deficiency anemia or in thalassemias because in those,
there a defect in Hemoglobin (Hb) production. It is expected to be seen in chronic
obstructive pulmonary disease (COPD) because the hypoxemia causes the release of
hormone EPO (erythropoietin); which is made in the endothelial cells of the peritubular
capillaries. So in the slide this is an example of EPO stimulated Bone marrow.

26
4. Example: PSORIASIS (ON ELBOWS)

HISTOLOGIC PSORIASIS
(Unregulated proliferation of squamous cells in the skin), leading to red skin, and raised red
plaque, because excessive stratum corneum. This is why methotrexate works here, because,

5. Example: PROSTATE GLAND AND BLADDER MUSCLE HYPERPLASIA

It a hormone related hyperplasia; all hormone stimulated

glands undergo hyperplasia. The wall of the bladder is too thick; because urine has to go
out thru a narrow opening in the urethra, therefore the muscle has to work harder which leads
to hypertrophy of smooth muscle cells of the bladder wall (more urine must go out against a
greater force because of an increase in after load).

27
 D. Metaplasia replacement of one adult cell type by another.

1. Example: GASTRO ESOPHAGEAL REFLUX DISEASE

(GERD) is the number 1 precursor to squamous cell carcinoma of mid-esophagus and
(adenocarcinoma) is the Most Common cancer of the esophagus.

The ulcerative area (reddened area) is due incompetence of the lower esophageal sphincter
and reflux acid to the distal portion. On a section surrounding the ulcer (right at the edge of the
muscosa) there are mucous secreting cells and goblet cells (these are grandular cells).
These cells are not supposed to be present in lower esophagus; squamous cells should be
there (not glandular cells).

Metastatic grandular: DISTAL ESOPHAGUS:

GLANDULAR METAPLASIA SECONDARY TO ACID REFLUX BARRET ESOPHAGUS is a
precursor for adenocarcinoma.

Audio file 4: Inflammation 2

2. Example: Lining of mainstem bronchus ciliated columnar, pseudostatified columnar. In

smokers, this would be an example of metaplasia would be squamous.

3. Example: There are increased goblet cells within mainstem bronchus of an old smoker,
also see goblet cells in the terminal bronchial. Normally there are goblet cells in the
mainstem bronchus but there are no goblet cells in the terminal bronchus, therefore this is an
example of hyperplasia.

4. Example: Goblet cells in the stomach are abnormal (should be in the intestines, only).
This is a glandular metaplasia, which is a precursor for adenocarcinoma of the stomach.
Most Common cause of adenocarcinoma in stomach? Helicobacter Pylori. H. pylori
causes damage to pylorus and antral mucosa because it is a chronic gastritis which intestinal
Which predisposed to
glandular metaplasia.
Adenocarcinoma.
*Endometrial hyperplasia is the most common precursor lesion for Endometrial Adenocarcinma.
** The only exeption is prostate hyperplasia, which not predispose to prostate cancer.

28
 5. Example: Cases where metaplasia causes an increased risk to cancer:

(1) In lung, ciliated columnar epithelium BECOMES squamous, therefore, this is called
SQUAMOUS metaplasia; this will lead to squamous dysplasia, which then proceeds to
cancer (squamous carcinoma).

(2) In distal esophagus, went from squamous to glandular epithelium because squamous
epithelium cannot handle the acid, therefore it needs mucous secreting epithelium as a
defense against cellular injury. However, the glandular metaplasia can go on to an
atypical metaplasia, predisposing to adenocarcinoma of the distal esophagus.

(3) 2 parasites produce cancer: clonorchis sinensis leads to cholangiocarcinoma

(Chinese liver fluke); and shistosoma hematobium.

BLADDER BIOPSY: SQUAMOUS METAPLASIA

SECONDARY TO SCHISTOSOMIAS HEMATOBIUM.

The schistosomias hematobium causes bladder cancer by causing the transitional

epithelium to undergo squamous metaplasia. This leads to squamous dysplasia, and then
on to squamous cancer. Transitional epithelium leads to squamous epithelium (called
metaplasia), then dysplasia, then on to cancer. (Type 2 Hypersensitivity reaction).

E. Dysplasia is really an atypical hyperplasia. Abnormal proliferation of cell: change cell size,
shape and loss cellular organization, becoming a premalignant cell.

1. Example: CERVICAL BIOPSY: SEVERAL DYSPLASIA.

Slide of a squamous epithelium is disorganized, with nuclei that are larger near the surface
and the basal cell layer is responsible for the dividing; cells at top are bigger than the ones that
are dividing, it has lack orientation. If it was found during a cervical biopsy in pt with HPV
infection, or if it was found in the mainstem bronchus biopsy, you should be able to tell that it is
dysplastic. Therefore dysplasia, whether glandular or squamous, is a precursor for
cancer.

29
2. Example: There was a farmer with lesion on the back of his neck (can grow on any part of
the body, due to sun exposure), which could be scraped off and grew back actinic
keratosis (aka solar keratosis is a precursor for squamous cell carcinoma of the skin. UV-
b light damages the skin. Actinic keratosis does not predispose to basal cell carcinoma,
even though basal cell carcinoma is the most common skin cancer.

30
 Chapter Two: Inflammation
I. ACUTE INFLAMMATION FA. Page. 211

A. Cardinal signs of inflammation:

BEE STING: ACUTE INFLAMMATION

* Redness (Rubor). The king of vasodilators is histamine and it vasodilates the arterioles.
Therefore, histamine is responsible for the (REDNESS) of acute inflammation (Ex. bee
sting), and is working on arterioles. Now if we felt the area, it will be warm (HEAT), this is due
to vasodilating the arterioles, which is caused by histamine. For example in endotoxic and
septic shock, the skin is warm because you are vasodilated.

BEE STING IN FACE: TYPE I HYPERSENSITIVITY REACTION.

*(Tumor) is a raised structure caused by release of histamine from mast cells lead to
increased vessel permeability in the venules; is arterial thicker than venules? Yes. The
venules are very thin; they basically have an endothelial cell with a basement membrane, all
you have to is drill a hole through the Basement Membrane and you are out.

31
 ACUTE INFLAMMATION: STASIS = normal flow of a
body liquid stops. (see small venul ue histamine
making an adhesion of neuthrophils to endothelial cells, increasing vessel permeability
producing an exudate = (the material composed of serum, fibrin, and white blood cells
that escapes from blood vessels into a superficial lesion or area of inflammation) , and
swelling of tissue, hence tumor of acute inflammation.)

*The area may hurt (PAIN) but histamine does not have anything to do with this. Bradykinin is
part of the kininogen system between factor 11 and Hageman factor 12. So when you activate
the intrinsic pathway, you automatically activate the kininogen system. When you activate
factor 12 (Hageman factor), it will activate 11 and the whole kininogen system. The end
product is bradykinin. ACE degrades bradykinin. Complication of ACE inhibitor is
angioedema. Also inhibit metabolism of bradykinin, which increases vessel permeability,
producing the angioedema (swelling of the tissues). How bradykinin produces cough is not
really understood. Bradykinin and PGE2 cause pain and is the only one out of the four Latin
terms of acute inflammation that is not due to histamine release.

B. Steps involved in Acute inflammation (this the normal sequence in acute inflammation):

1. Emigration: includes margination, paveenting, rouleau, adhesion, and transmigration

Neutrophils in circulation start to become sticky because of adhesion molecule synthesis.
Endothelial cells begin to synthesize adhesion molecules Eventatually, neutrophils will stick to
endothelial cells, and these steps are called:

(PAVMENTING OR MARGINATION)

32
Then, it cause increased of erythrocytes sedimentation rate called:

(ROULEAU)
Then neutrophils look for bare basement membrane on the venules and then they drill a hole

metastasize. Cancer cells attach to endothelial via adhesion molecules, usually against
laminin in Basement Membrane, and they have collagensae to get through the Base
Membrane, therefore, cancer cells are pretty much like a neutrophil when invading tissue.

2. Chemotaxis:

NEUTHROPHIL IN ACUTE INFLAMMATION

When they pass Basement Membrane of small venules, they emigrate but they have to know
what direction to go. They get directions in a process called directed chemotaxis. C3a, C5a
and LT-B4 (leukotriene B4) are the chemotactic agents. These chemotactic agents are
also involved in making adhesion molecules on neutrophils). Therefore, they make adhesion
molecules AND give direction by acting like chemotactic agents.

3. Phagocytosis via opsonization:

a) Example: in an acute inflammation with staphylococcos aureus, the bacteria are being
processed by opsonins, which immobilize the particles on the surface of the phagocyte.
The two main opsonins are IgG and C3b. They help with phagocytosis.

b) Example of an opsonization defect: Brutons agammaglobinemia: an x-linked

recessive disease. Most common cause of death in these pts is due to infection
because cannot opsonize things. It produces hypogamma-globinemia, but the
mechanism of infection is due to Deficiency of IgG and C3b to opsonize bacteria,
therefore cannot phagocytose it.

33
 Bacteria are opsonized by IgG and C3b, which means that neutrophils must have receptors
for those. In acute inflammation the main cell is NEUTROPHIL.

And in chronic inflammation the main cell is monocyte/macrophage,

(MONOCYTES become

MACROPHAGES)

These cells have to have receptors for these opsonins (IgG and C3b). Then they become
phagocytosed or become phagolysomes. When they are phagocytosed, the lysosomes go
to microtubules and empty their enzyme into this.

c) Example: I-cell disease: In this disease, mannose residues cannot be

phosphorylate in Golgi apparatus therefore the enzymes are not marked with
phosphorus, and the lysosome are empty.

4. Intracellular microbial killing: IMPORTANT TO BOARDS!!!

a) Examples:

(1) Staphylococcos Aureus in hot tub surrounded by enzymes.

(2) Chlamydia can get out of phagolysosome, mechanism unknown, but sometimes
they have mucous and all kinds of things around them.

34
b) O2 dependent myeloperoxidase system:
Molecular O2 is converted by NADPH oxidase, which is in the cell membrane of neutrophils
and monocytes, but not macrophages. The most important cofactor is NADPH, which
is synthesized in the pentose phosphate shunt. The enzyme responsible is glucose 6
phosphate dehydrogenase, which converts G6Phosphate into 6-phosphogluconate,
generating NADPH and a neutralizing factor for free radicals (glutathione).

It is converting O2 into a free radical, superoxide. Superoxide has an unpaired electron

giving off energy, which is called a respiratory burst, which can be measured by radiation
detectors; and by a negative NBT dye test.

In the NBT test, you have a test tube, add the colorless NBT dye; and if neutrophils and
monocytes are working normally, they will phagocytose it, will have a respiratory burst, and
the free radical O2 will cause the color to change to blue, indicating that the respiratory
burst is working. If there is no color change, there is not a respiratory burst indication
of chronic granulomatous disease of childhood.

Free radical O2 is converted by Superoxide dismutases into peroxide. (SOD is enzymes

neutralizer. Peroxide itself could kill bugs, but it is used for another reason. Within the
neutrophils and monocytes are reddish granules which are lysosomes, and are seen in the
peripheral blood. Myeloperoxidase (one of the many enzymes in the granules) will catalyze
the reaction. It will combine peroxide with chloride to from bleach. This is the most
potent bactericidal mechanism O2 dependent - myeloperoxidase system, which is in
NEUTROPHILS and MONOCYTES but NOT in macrophages, because macrophages lose
the system when they convert from monocytes to macrophages and they use lysosomes to
kill. Macrophages in CNS are microglial cells, so the reservoir cell for CNS/AIDS is the
microbial cell. Out of CNS, macrophage are the dendritic cell; it is a macrophage
located in the lymph nodes.

c) In Glucose 6 Phospate Dehydrogenase deficiency: Infection is the Most Common

precipitation of hemolysis because there is no NADPH, therefore there is no functioning O2
dependent myeloperoxidase system, and therefore you are susceptible to infection, which
.

d) Chronic granulomatous diseases of childhood = X linked recessive disease where

the mom gives the disease to the boy, and is an asymptomatic carrier, and they will
transmit the disease to , there is a deficient activity of
NADPH oxidase, and the NBT dye test is negative
NO RESPIRATION BURST. Do they have Myeloperoxidase? Yes. Chloride? Yes.
Therefore, if they phagocytosed a bacteria that could make peroxide, and add it inside the
phagolysosome, this is what the kid would need to kill the bacteria. These kids are
missing PEROXIDE because there is no NADPH oxidase. ALL living organisms make
peroxide (including ALL bacteria). However, not all bacteria contain catalase, which is an
enzyme that breaks down peroxide. So, in chronic granulomatous disease, what can
aphylococcos, but can kill streptococos. Why?
Because staphylococcus Aureus is ;
staphylococcos Aureus and when it makes peroxide, it will also make catalase and
neutralize it; therefore the child cannot kill staphylococcos, and will kill the kid.

35
 If it was a streptococcus organism that makes peroxide (does not have catalase therefore
peroxide can be used by the child), it adds what kid really needed to make bleach, and the
bacteria is then wiped out.

e) Myeloperoxidase deficiency: Do they have a respiratory burst? Yes, because they

have NADPH oxidase. They have peroxide, superoxide free radicals and chloride.
But NO myeloperoxidase. They have a normal respiratory burst and a normal NBT dye
test, but because they cannot make bleach. This is called a
myeloperoxidase defect. The inheritance is Autosomal Recesive.

all off when it should. When it was removed and

looked at histologically, they did not see neutrophils in the tissue or neutrophils lining the
small vessels. This is an adhesion molecule defect or beta 2 integrin defect. Umblilcal
cord needs to have an inflammatory reaction involving neutrophils; they have to stick in

this is a classic adhesion molecule defect.

C. Chemical mediators:

1. Histamine: is the king of chemical mediators of acute inflammation

a) What does it do to arterioles? Vasodilates
b) What does it do to Venules? Increased vessel permeability

2. Serotonin:
a) What amino acid makes serotonin? Tryptophan
b) Is serotonin a neurotransmitter? Yes
c) Serotonin Deficiency cause? Depression (also decreased NE)

3. Complement system: Anaphylatoxins C3a, C5a. Function: stimulate mast cells

to release histamine, leading to vasodilation and increased vessel permeablility.
They also play a role in shock, because when there is inflammation the complement
system is activated.

4. Nitric oxide made mainly in endothelial cells, and is a potent vasodilator. It is used
for treating pulmonary hypertension. It has a big time role in septic shock.

5. IL-1 associated with a fever, it is a pyrogen, therefore stimulates the hypothalamus to

make Prostaglandins, which stimulate thermoregulatory system to produce fever.
Aspirin works by inhibiting the synthesis of prostaglandins thereby reducing the fever.

6. Arachidonic acid metabolites:

a) Corticosteroids:

First function: inhibits Phospholipase A2, therefore do not release arachidonic acid
from phospholipids, therefore not making Prostaglandins or leukotrienes.

36
 This is the supreme antiflammatory agent because BOTH Prostaglandins and
leukotrienes are blocked by blocking phospholipase A 2. Arachidonic acids make linoleic
acid (omega 3), which is found in fish oils and walnuts. It is very good for you because

your heart.

Second function: decreases adhesion molecule synthesis, along with other steroids
like epinephrine and NE. These will lead to increased neutrophils on CBC test; in
immuno, 50% neutrophils are stuck to the endothelial vessels, and the other 50% are
circulating, therefore, decreasing adhesion molecule synthesis will lead to doubled
White Blood Cell WBC (because the 50% of neutrophils that were stuck are now
circulating). Corticosteroids destroy B-cells because they are lymphocytotoxic.

*Mechanism
are the signal to activate the caspasases.

Eosinophils, mainly seen in type I Hypersensivity reaction, corticosteroids decrease

them. When on corticosteroids, the only thing that is increased is neutrophils, via
decreased adhesion molecule synthesis. Lymphocytes and eosinophils are decreased.

Example: If have Addisons Disease, do not have cortisol, therefore the neutrophil
count decreases and the eosinophil count will increase.

Example: a person with Miocardial Infarction with an 18,000 CBC most of which are
neutrophils. Mechanism: Epinephrine decreases adhesion molecule sythesis and
neutrophil count goes up.

b) Lipoxygenase pathway: Zileuton blocks 5-lipoxgenase, other drugs act by

blocking the receptors, example: zirkufulast, ect. These block Leukotriene (LT) C4,
D4, E4 (the slow reactor substances of anaphylaxis) seen in bronchial asthma.
Leukotrienes are potents bronchoconstrictors; therefore it can be seen why zileuton
works well in asthma because it blocks the leukotrienes, including these (LT-C4, D4,
and E4). LT B4 is an adhesion molecule in chemotaxis.

c) Cyclooxygenase pathway: Aspirin blocks cycloxygenase, irreversibly in platelets.

Prostaglandin H2 (PGH2): where everything seems to be derived from.
Prostaglandin I2 (PGI2): prostacyclin
synthase; is a vasodilator and inhibits platelet aggregation.

Thrombaxane A2 vasoconstrictor, a
bronchoconstrictor, and promotes platelet aggregation.

What drug blocks thrombaxane A2 synthase and is used to stress testing for Coronary Artery
Disease (CAD)? Dipyramidal blocks TxA2 synthase enzyme, therefore does not have to perform
a treadmill stress test, all you have to do is use the drug dipyrramidal.

PGE2: vasodilator in kidney; keeps patent ductus open in baby heart; makes the
mucous barrier in GI (stomach) thereby preventing ulcers; can cause dysmenorrhea in
woman and increased uterine contractility, and its an abortifactant, to get rid of
fetal material.
37
 d) COX 2-make sure you know how this works!

D. Electron microscopy of inflammatory cells:

1. In lung, type II pneomocyte (black dots are lysosomes).

Lamellar bodies structures where lecithin and phosphotidyl choline is located; if ask
where macrophage, is, will ask which makes surfactant.

2. Monocyte: single nucleus with a grayish cytoplasm has scavaged; can form foam cell
in atherosclerotic plaque because
radical); Vit E neutralizes oxidized LDL.

3. Lymphocyte all nucleus and scant cyptoplasm,

probably a T cell (60% of peripheral blood lymphocytes are T cells); ratio of helper to
suppressor: CD4:CD8 is (2:1), therefore, more likely to be a Helper T cell, then a
suppressor T-cell, and B cells (20%) are least likely.

ELECTRON MICROSCOPY OF LYMPHOCYTE

4. Rough Endoplasmic Reticulum looks like a thumbprint, have ribosomes on it, and
has
eccentrically located nucleus, cytoplasm is always sky blue, making plasma cells ez to
recognize. Plasma cells are derived from B cells, and located in the germinal follicle.

5. Granules eosinophil (have a red col

ELECTRON MICROSCOPY OF EOSINOPHIIL.

38
 1. EOSINOPHIL AND 2. BASOPHIL
1. EOSINOPHIL- has granules that are more purplish and darker. Eosinophils are the
only inflammatory cell that has crystals in the granules. They are called Charcot-
Leiden crystals . They are
degenerated eosinophils in sputum of asthmatic, and have formed crystals that
look like spear heads.

2. BASOPHIL - have darker colors.

6. Mechanism for killing invasive helminthes Type II Hypersensitivity major basic

protein is involved. Remember that shistotosome eggs are coated by IgE Antibodies.
Eosinophils have IgE receptors; therefore, eosinophils hook into the IgE antibody and
release chemicals (chemotactic factors); the main one released is major basic protein,
which destroys the helminth, which is type II HPY, because it is a cell hooking into an
Antibodies on the target cell. The effector cell is Type II HPY reaction is the
eosinophils Type I HPY reaction where the effector cell is the
MAST CELL, and they release histamine, therefore they are invited to area of type I HPY
because they have histaminase and arylsulfatase, which neutralizes leukotrienes. The
purpose of eosinophils in type I HPY is to knock off chemical mediators produced in
reaction; however, when an eosinophil kills an invasive helminth, it does so via type II HPY.

E. Cluster designations:
*Helper T cell = CD4
*Cytotoxic T cell = CD8
*Marker for Antigen recognition site for all T cells is CD3
* CD1
*Marker for Most Common leukemia in children = CD10 (+CALLA Antigen); positive B-cell
lymphoma.
*CD15 and 30 = Red Stember cell
*CD21, Only on B cells Epstein barr virus; hooks into CD21 on B cells, and actually the
atypical lymphocytes are not B-cells but T-cells reacting to the infected B-cells.
*Burkitts is a B cell lymphoma.
*CD45 is found on all leukocytes, is a common antigen on everything.

F. Fever IL-1 is responsible and PGE2 (this is what the hypothalamus is making) which
stimulates the thermoregulatory center. Fever is good! It right shifts the O2 dissociative curve.
Why do we want more O2 in the tissues with an infection? Because of O2 dependent
myeloperoxidase system. Therefore, with antipyretics, lack the mechanism of
getting O2 to neutrophils and monocytes to do what they do best. Also, hot temperature in the
body is not good for reproduction of bacteria/viruses.

39
 II. TYPES OF INFLAMMATION (scenarios)

A. Post partum woman, with pus coming out of lactiferous duct. Cause: Staphylococco Aureus
suppurative inflammation.

OSTEOMYELITIS with suppurative inflammation cause by:

Staphylococcos Aureus. Bone of child with sepsis, on top of the bone, was a yellowish area,
and it was an abscess; if the kid had sickle cell anemia the cause of Osteomyelitis is:
Salmonella.

Why at metaphysis of bone? Because most of blood supply goes here. This mechanism of
spread is hematogenous (therefore, comes from another source, and then it gets to bone).

40
B. CELULLITIS cause by: Streptococco group A Pyogenes
Hot, spread over face (called erysipilis, , another name for cellulitis).

C. UPPER AIRWAY (OROPHARYNX) DIPHTHERIA due:

CORYNEBACTERIUM DIPHTHERIAE, a gram + rod, which makes an exotoxin, messing up
ribosylation of protiens via elongation factor 2, the toxin damages mucosa/submucosa, producing
a pseudomembrane inflamation.

COLON: PSEUDOMEMBRANOUS COLITIS DUE CLOSTRIDIUM DIFFICILE.

It also produces a pseudomembrane and a toxin, which we measure in stool to make the
diagnostic.

toxin that damages the membrane? Clostridium Difficile.

41
D. FIBRINOUS PERICARDITIS (HEART)
Usually with increased vessel permeability; seen in (1) lupus, leading to friction rub; (2) the first
week of Miocardial Infarction s syndrome, (3) in
Coxsackie.

E. Most Common organism producing infection in third degree burns = Pseudomonas

Aeuriginosa. Color of pus: green due to pyocyanin.

F. Healing Tissue Process: Collagen Synthesis FA84-ME66

1. First day of healing: Fibrilin clots develop in wound. Increases a Basal cell layer on both
sides of clot, proliferate, and go underneath it to clot.

2. Second day: usually sealed off in 48 hrs, macrophages migrate to

the wound (Ex. appendectomy).

3. Third day: Key to wound healing is prescence of granulation tissue (angiogenesis),

macrophages replace neutrophils, Initial deposition of type III collagen. Initial Wound
Repair.

Fibronectin is a very important proteoglycan and is involved in the healing of the

wound. Fibronectin is an important adhesion agent and chemotactic agent, inviting fibroblast
in helping healing process. The granulation tissue starts at day 3 and is on its prime by day 5.

If you ever picked at a scar (granulation tissue), it going to bleed like mad and you try to stop it,
but it still bleed like mad No granulation tissue means no healing of a wound.

At the End of the First Month:

*Type 3 Collagen is in initial stage of wound repair.

*Type 4 Collagen is seen in Basement Membrane.
*Type 1 Collagen very strong tensile strength; seen in bone, skin, tendons, ligaments.
42
 After a few months, the collagen type 3 is broken down by collagenases, and a metallic
enzyme converts type 3 into type 1. Zinc is part of the metallic enzyme; this is why in a pt
with zinc deficiency has poor wound healing because it screws up the collagenase
(must replace type 3 with type 1). Maximal tensile strength after 3 months = 80%.

Most Common Cause poor wound healing = infection.

G. Ehlers Danlos defect in collagen due to syndrome/breaking down; have poor wound
healing. Collagen III more affected.

H. Marfan Syndrome defects in the mutation of fibrilin; also have poor wound healing.

I. Pt with scurvy defect in hydroxylation of two Amino Acid proline and lysine via
ascorbic acid (Vitamin C).
together and increase tensile strength? Crossbridges. When you crossbridge things, they anchor
into areas where you have hydroxylated proline and lysine. Therefore have weak abnormal
collagen in scurvy because there are no crossbridges to attach, leading to not being able to heal
en has weak tensile strength because cannot
crossbridge.

Audio file 5: Fluid and hemodyn1

J. Granulation tissue with a lot of blood vessels due to lot of FGF (fibroblast growth factor),
with inflammatory cells from plasma cells and lymphocytes. Granulation Tissue is necessary for
wound healing (rich vascular tissue, which is absolutely essential for normal wound healing).

K. Keloid (hypertrophic scar) = excess in type 3 collagen deposition; which causes a tumor
looking lesions, especially in blacks.

Ex.1. White kid keloid to due to third degree burns.

Ex.2. in a chronically draining sinus tract of the skin, they tried to put antibiotics on it
, there was an ulceration lesion at the orifice of this chronically draining
tract, and nothing worked. What is it? Is squamous cell carcinoma due to a lot of
turnover; type 3 converted to type 1, and fibroblasts are involved. A lot of cell division
occurring. Squamous cell cancer is important because chronically draining sinus tracts
predisposes to squamous cell carcinoma. Hyperplasia predisposes to squamous cell
carcinoma.

III. CHRONIC INFLAMMATION

A. Difference in Immunoglobulins:

1. Acute Inflammation:

-IgM = main Ig first produced. IgM is the most potent activator of complement pathway
(all the way for 1-9); IgM has 10 activating sites (pentamer). IgM need a lot of complement
components in healing process.

43
 -IgG can activate the classical system, but does NOT go passed C3. It stops and does
not go onto C5-9. After 10 days, there is isotype switching, and the mu heavy chain is
spliced out (mu heavy chain defies specificity of an Ig); it splices in a gamma heavy chain,
and IgG is made via isotype switching.

2. Chronic inflammation: IgG (IgM is coverted to IgG immediately)

B. Difference in Cell Types:

1. Acute (short) inflammations = neutrophil (increased vessel permeability, and increased

emigration of neutrophils into interstitial tissue, a protein rich fluid with >3 grams/dL = pus
exudative).

2. Acute allergic reactions= eosinophils (mast cells are in tissues too).

3. Viral infections = lymphocytes are the main inflammatory cells.

4. Chronic (long) inflammations = monocytes/macrophages are important. And see a lot of

plasma cells and lymphocytes. Example: Cholecystis.

C. Type IV Hypersensitivity Reaction (Delay):

Ex. Granuloma = chronic inflammation; Ex. Caseous

Necrosis in someone with TB; roundish, pink, multinucleated giant cells = granulomas;
pathogenesis = type IV hypersentistivity reaction delayed hypersentistivity.

The main actors are CD8 cytoxic T cells (inside cell pathogen); when they kill neoplastic, virally
infected cells, these are also type IV Hypersentistivity (no Antibodies involved).

Poison ivy = type IV Hypersentistivity. Back to TB infection, alveovlar macrophage phagocytoses

it, and there is lymphohemotogenous spread (lymphocytes around the granuloma);
meanwhile the macrophage is processing the Antigen. Then after weeks, it presents it to Helper T
cells. Therefore, the key players in Type IV Hypersensitivity reaction are macrophages which
process that Antigen and present that Antigen via MHC class II sites to the CD4 helper T cells.

These helper T-cells release cytokines: Interferon Gamma (IFN) and macrophage inhibitory factor.
IFN Gamma will activate the macrophage to kill the TB, Cryptococcus, histoplasmosis, etc.
Therefore the IFN gamma is the trigger to active the macrophage; macrophage cannot kill
without the activation from IFN Gamma because of systmemic fungi and TB have lipid in the cell
wall, this leads to caseous necrosis.

44
 All the pink stainin epthiloid
activated by IFN gamma); when they die, they die in style they fuse together and form
multinucleated giant cells ed
macrophages; black dots are Helper T cells.

There are two types of Helper T-cell: CD4/MACROPHAGES

a. Subset 1: involved in Type IV (delayed type) Hypersentistivity reaction; macrophages

have IL-12; when it is secreted, the subset 1 CD4-Helper T cells are presented with the
antigen; then, subset 1 become MEMORY T cells. IL-12 is involved in activating the memory
of subset 1 CD4 Helper T cells. Most people in their primary disease usually recover with no
problems, but the granulomas can calcify, as seen on x-ray. A calcified granuloma is not dead
because they are resistant to dying. Therefore, most cases of secondary TB are due to
reactivation TB. Granulomas necrosis is due to reactivation.

test injected into the skin; the macrophage of the skin

is a:

(histocyte) (marker: CD1) which have birbeck granules-

look like tennis rackets on Electron Microscopy. They phagocyotose the Antigen (the PPD),
and process it very quickly; they present it to subset 1 CD4 Helper T Cell, which has memory
of previous exposure. Therefore, it hooks in the MHC class II Antigen sites (as all immune cells
do), and once the Antigen (PPD processed by ) is presented, the CD4 Helper T
cell releases the cytokines producing the inflammatory reaction
PPD.

*Correlation: older people usually n:

test on them. In pt with
elper T-
granuloma formation. Macrophage inhibitory factor keeps macrophages in that area;
therefore, with HIV, because the Helper T cell count is decreased, you d
at all. Therefore, they will have MAI (organisms) all over the body without granulomas
because H

IV. TISSUES REPAIR: Scar tissue (its permanent tissue, fibrous tissue) does not contract;
therefore, if you have more scar tissue to free wall of left vetricle will lead to decreased ejection
fraction (which is stroke volume divided by EDV).

A. Response of Kidneys to Injury: Kidney will form scar tissue; medulla is most susceptible to
ischemia (because least amount of blood supply).

45
 What part of nephron is most susceptible to tissue hypoxia?

1. Straight portion of proximal tubule because most of oxidative metabolism is located

there, with brush borders this is where most of reabsorption of Na, and reclaiming of
bicarbonate is there.
2. Medullary segment of thick ascending limb where the Na/K-2Cl pump is which is
where loop diuretics block. The Na/K-2Cl pump generates free water. The two type of water
in urine: obligated and free. Obligated water: to go out with every Na, K, and Cl
(concentrated urea). Basically 20 ml
Na/K/2Cl pump. The ADH hormone absorbs free water because the pump generates free
water.

20 ml; then
reabsorbed another K, that is another 20, so its up to 40; another 2 Cl are reabsorbed which is
another 40; therefore, for absorbing one Na, one K, and 2 Cl, you have taken 80 ml of free
water from the urine this is free water that is generated; its is this pump that loop diuretics
block, which is in the thick ascending limb of the medullary segment.

B. Lung repair cell is type II pneumocyte: Can repair type I pneumocytes and synthesizes
surfactant.

C. CNS Central Nervous System have oligodendrocytes (make myelin) and the repair cell
is the astrocyte; the astrocyte proliferates (because uron), that can
proliferate and produces protoplasmic processes called gliosis= (injury in the brain due to
astrocyte proliferation); this is analogous to fibroblasts laying down collagen type 3 in the wound.

D. PNS Periferal Nervous System wallarian degeneration is the mechanism of axonal

regeneration. In PNS, have Schwann cells (make myelin).

What is the analogous cell in CNS to PNS Schwann cell? Oligodendrocyte (both make myelin)

What is the name of the Tumor Schwann cell? Schwannoma

What its call if shwannoma involves CN VIII (Vestibulococlear)? Acoustic Neuroma

What genetic disease that is autosomal dominant has association with acoustic neuroma?
Neurofibromatosis.

(Side note: myasthenia gravis tensilon injection will increase Ach in synapses in eyelids, and
myasthenic crisis will end)

46
V. Extra Side notes and Review of Inflammation:

A. ESR-(Erythrocytes Sedimentation Rate) putting whole blood into cylinder and see when it
settles. The higher density or weight, therefore settle pretty quickly and therefore have an
increase sedimentation rate.

*When increase in fibrinogen and decrease in RBC negative charge and stuck together and
looks like coins = Rouleaux.

*When aggregated together = increased sedimentation rate. Which is increased IgG and
fibrinogen (includes every acute and chronic inflammation)

What (compact mass)? IgM, because the negative charge normally

.

The IgM antibodies can cause cold agglutinins, leading to ischemia. This is why in cold weather;
you get (lips, nose, ears, toes, and fingers turn blue).

Another type of clumping of IgM are Cryoglobulins Inmunoglobulins congeal in cold weather;
IgM antibodies do the same thing. (Associated of Hepatitis C).

Multiple Myleoma = increased erythrocyte sedimentation rate, increased IgG; with

= increased IgM.

B. Acute appendicitis get CBC and want to see absolute neutrophilic leukocytosis,
meaning that you have an increase of neutrophils (WBC) in the peripheral blood; also looking for
toxic granulation, and a LEFT SHIFT ---- . Assuming you
start from myeloblast on the left, and eventually form a segmented neutrophil on the right;
normally go left to right on maturation; therefore, with a left shift, its means that we go back to
immature neutrophils; the definitions is greater than 10% band neutrophils is considered a
LEFT SHIFT (all the neutrophils are bands); if you have just one metamyelocyte or one
myelocyte, its is automatically considered a LEFT SHIFT. In acute appendicitis, there is an
absolute increase in neutrophils, with toxic granulation and a left shift.

C. Most potent system for killing bugs = O2 dependent myeloperoxidase system;

Myeloperoxidase is located in azurophilic granules, which are lysosomes. Want a lot of lysosome
in an acute inflammatory reaction. Therefore there is more myeloperoxidase around for killing
bugs this is toxic granulation. Therefore, toxic granulation ensures that there is enough
myeloperoxidase to work that potent system to kill bugs (O2 dependent myeloperoxidase
system).

47
 CHAPTER 3: Fluid and hemodynamics
I. EDEMA excess fluid in the interstitial space = extracellular fluid (ECF); this is outside the
vessel.

A. Types of Edema:

1. Non-Pitting edema:

*Exudates - increased vessel permeability with pus in the interstial space.

*Lymphedema: due to lymphatic obstruction, leads to lymphatic fluid in the interstial

space.

2. Pitting edema transudate (no protein). It sees in right heart failure, swelling of the lower
extremities, fluid in the interstial space.

So there are three things that cause edema: exudates, lymphedema and transudate.

B. Transudate/Pitting Edema: Transudate deals with starling forces:

1. What keeps fluid in our blood vessels? Albumin and this is called oncotic pressure
( c). 80% of our oncotic pressure is related to the serum albumin levels. Anytime there is
hypoalbuminemia then we will have a leaking of a transudate (protein of less than 3 g/dL)
leaking into interstial space via capillaries and venules (pitting edema);

2. Normally, hydrostatic pressure (Pc) is trying to push fluid out of the vessel. Therefore,
in a normal person, oncotic pressure is winning. Therefore, a decrease in oncotic pressure
and an increase in hydrostatic pressure will lead to transudate (pitting edema).

Pc
(Push out)

c (Pull in)
(pull in)

3. Albumin is made in the liver. With chronic liver (cirrhosis), have a decreased albumin
level. Can you vomit it out? No. Can crap it out (malabsorption syndrome), or can pee it out
(nephrotic syndrome), can come off our skin (3rd degree burn because losing plasma), another
possibility of low protein count (low-intake) is seen in kids Kwashiorkor kid has fatty liver
and decreased protein intake, leading to low albumin level.

48
4. Examples:
A. (TRANSUDATE) LUNG: PULMONARY EDEMA

SECOND CAUSE DUE LEFT HEART

FAILURE
Person with Miocardial Infarction 24 hrs ago, he died and has fluid coming out is transudate
because increased hydrostatic pressure and left Heart Faliure due to Miocardial
Infarction so things backed up into the lungs. Because the CO decreased, the (EDV)
End Diastolic Volume increases and pressure on left ventricle increases, and the
pressure is transmitted into the left atrium, to the pulmonary vein, keeps backing up,
and the hydrostatic pressure in the lung approaches the oncotic pressure, and a transudate
starts leaking into the interstitial space, which leads to activation of the J receptor, which
will cause dyspnea. Leads to full blown in alveoli and pulmonary edema.

B. BEE STING IN ARM: TYPE I

HYPERSENSITIVITY REACTION, leads to exudate due to anaphylactic reaction (face
swelled), produced by histamine being the propagator, and type I Hypersensitivity, causing
tissue swelling. Tx airway, Intravenous 1:1000 aqueous epinephrine subcutaneously.

49
C. LIVER: CIRRHOSIS, with swelling of the legs:
transudate, mechanism: decreased oncotic pressure because cannot synthesized albumin,
and increased hydrostatic pressure because portal Hypertension; there is cirrhosis of the
liver, and the portal vein empties into the liver; in this case, it cannot, and there is an
increase in hydrostatic pressure, pushing the fluid out into the peripheral cavities (so there
are 2 mechanism for acites). Pitting edema in legs: decreased in oncotic pressure.

D. Pt with dependent pitting edema: pt has right heart failure, and therefore an increase in
hydrostatic pressure; with right heart failure, the blood behind the failed right heart is in the
venous system; cirrhosis of liver is due to decrease in oncotic pressure.

E.
LYMPHEDEMA IN ARM: ASSOCIATED WITH RADIATION STATUS BY RADICAL
MASTECTOMY OF BREAST. (TRANSUDATE)

Most Common Cause lymphedema = postradical mastectomy; can also run risk of
lymphangiosarcoma. Other causes Wuchereria bancrofti or Filaria, is a parasitic filarial
nematode worm spread by a mosquito vector. Lymphogranulomon venarium (subtype of
chylamdia trachomata scarring tissure and lymphatics, leading to lymphedema of scrotum
lymphatic). Also, Inflam
deals with dermal lymphatics plug with tumor; excess leads to dimpling, and looks like the
surface of an orange.

50
 II. RENAL PHYSIOLOGY

A. EXTRACELLULAR FLUID AND INTRACELLULAR FLUID

ICF ECF

INTERSTICIAL
INTRACELLULAR FLUID FLUID PLASMA=
2/3 2/3 VASCULAR
1/3

*ECF (1/3) = extracellular fluid of two compartments vascular (1/3) and interstitial (2/3)
*ICF (2/3) = intracellular fluid compartment

How many liters of isotonic saline do you have to infuse to get 1 liter into the plasma? 3
Liters (2/3:1/3 relationship); 2 liters in interstial space, and 1 L would go to the vascular
space; it equilibrates with interstial/vascular compartments.

B. Osmolality = measure of solutes in a fluid; due to three things: Na, glucose, and blood
urea nitrogen (BUN) urea cycle is located in the liver, partly in the cytosol and partly in the
mitochondria; usually multiply Na times 2 (because one Na and one Cl).

Audio file 6: Fluid and hemodyn 2

Normal Na is 135-140 range, x 2 that 280. For glucose, normal is 100 /18 =
contributing much. BUN: located in the liver, part of the cycle is in the cytosol and part of it is in
mitochondria. The urea comes from am is gotten rid of, by urea. Because
the end product of the urea cycle is urea. The normal is about 12/3 =4. Therefore, in a normal
person Na is controlling the plasma osmolality. To measure serum osmolality: double the serum
Na and add 10.

C. Osmosis
2 of these 3 are limited to the ECF compartment. Which one can equilibrate between ECF and
ICF across the cell membranes? Urea increase; it can equilibrate equally on both sides to it
will be equal on both sides; this is due to osmosis. Because Na and glucose are limited to the
ECF compartment, then changes in its concentration will result in the movement of WATER from
low to high concentration (opposite of diffusion (Ex. in lungs, 100 mmHg in alveoli of O2, and
returning from the tissue is 40 mmHg pO2; 100 vs. 40, which is bigger, 100 is bigger, so via
diffusion, O2 moves through the interspace into the plasma to increase O 2 to about 95mm Hb).
Therefore, in diffusion, it goes from high to low, while in osmosis, it goes from low to high
concentration.

51
 1. Example: In the case with hyponatremia water goes from ECF into the ICF, because
the lower part is in the ECF (hence HYPOnatremia); therefore is expanded by osmosis. Now
make believe that the brain is a single cell, what will we see? Cerebral edema and mental
status abnormalities via law of osmosis (the intracellular compartment of all the cells in the
brain would be expanded)

2. Example: hypernatremia water goes out of the ICF into the ECF, therefore the ICF will
be contracted. So in the brain, it will lead to contracted cells, therefore mental status
abnormalities; therefore, with hyponatremia and hypernatremia, will get mental status
abnormalities of the brain.

3. Example: Diabetes Ketoacidosis (DKA) have (1000mg) large amount blood sugar.
Remember that both Na and glucose are limited to the ECF compartment. You would think

therefore glucose in the ICF (again its not) because to order to get into the cell (intracellular),
glucose must bind to phosphorus, generating G6P
fructose and galactose, which are also metabolized immediately, therefore, there is NO
glucose, fructose, or galactose intracellularly). So, with hyperglycemia=high glucose in
the ECF, so water will move from ICF to ECF. Therefore, the serum Na concentration will go
down this is called dilutional hyponatremia (which is what happens to the serum sodium
with hyperglycemia).

Therefore the two things that control water in the ECF are Na and glucose; but a normal
situation, Na controls. Urea does not control water movements because its permeable, and
can get through both compartments to have equal concentrations on both sides.

D. Tonicity isotonic state, hypotonic state, and hypertonic state.

We have all different types of saline: Isotonic saline, hypotonic saline (1/2 normal saline, ! normal
saline, 5% dextrose in water), and hypertonic saline (3%, 5%); normal saline is 0.9%. We are
referring to normal tonicity of the plasma, which is controlled by the serum Na. These are the
three types of tonicity (iso, hypo, and hyper). Serum Na is a reflection of total body Na divided by
total body H20. For example: hypernatremia is not just caused by increased total body Na; it can
also be caused by decreasing total body water with a normal total body Na, therefore there is an
increase in serum Na concentration. It is really a ratio of total body Na to total body H20. To
determine serum Na, just look at serum levels. With different fluid abnormalities, can lose or gain
a certain tonicity of fluid.

1. Isosmotic Volume Contraction=Isotonic loss fluid

ECF

Look at ratio of total body Na and water; in this case, you are losing equal amounts of water
and Na, hence ISOtonic. This fluid is mainly lost from the ECF. The serum Na concentration
is normal when losing isotonic fluid. ECF would look contracted.

52
There would be no osmotic gradient moving into or out of the ECF. Clinical conditions
where there is an isotonic loss of fluid: hemorrhage, diarrhea.

2. Isosmotic Volume Expansion=Isotonic gain fluid

C
O
N ECF
C
E
N
T
R
A
T
I
O
N
Volume
We have in equal increase in salt and water; Ex. someone getting too much isotonic saline;
normal serum Na, excess isotonic Na would be in the ECF, and there would be no osmotic
gradient for water movement.

3. Hypotonic solutions = hyponatremia. Hypoglycemia will not produce a hypotonic

condition. Most Common Cause of low osmolality in plasma is hyponatremia. How?
Lose more salt than water, therefore, serum Na would be decreased. If losing more salt than
water, kidney is probably the location of where/why it is happening. Main place to deal with
sodium (either to get rid of it or to get it back) is in kidney, especially when dealing with
diuretics (furosemides and HCTZ). The tonicity of solution you lose in your urine is
HYPERt ECF
concentration is low with hyponatremia, therefore the water will move into the ICF
compartment. (Osmosis-remember low to high).
HYPOSMOTIC VOLUME CONTRACTION=LOSS NA
C
O
N
C ICF ECF
E
N
T
R
A
T
I
O
N
Volume

53
 HYPOSMOTIC VOLUME EXPANSION=GAIN WATER
C
O
N
C ICF ECF
E
N
T
R
A
T
I
O
N
Volume
If you gained pure water, and no salt, you have really lowered your serum Na: Hyponatremia.
Most Common Cause = SIADH in small cell carcinoma of the lung; you gain pure water
because ADH renders the distal and the collecting tubule permeable to free water. With ADH
present, will be reabsorbing water back into the ECF compartment, diluting the serum Na, and
the ECF and ICF will be expanded. The ECF is expanded due to water reabsorption, and the
ICF is expanded because it has a high concentration levels (its levels are not diluted).

This can lead to mental status abnormalities. Therefore, the more water you drink, the lower
your serum Na levels would be. The treatment is by restricting water
because the Na levels are normal. When ADH is present, you will CONCENTRATE your urine
because taking free water out of urine; with absent ADH, lose free water and the urine is
diluted. Therefore, for with SIADH, water stays in the body, goes into the ECF compartment,
and then move into the ICF compartment via osmosis. The lowest serum sodium will be in
SIADH.

On the boards, when serum Na is less than 120, the answer is always SIADH. Example:
pt with SIADH, not a smoker (therefore not a small cell carcinoma), therefore, look at
drugs she was on chlorpropramide, oral sulfylureas produce SIADH.

Example: Gain both water and salt, but more water than salt, leading to hyponatremia these
are the pitting edema states Ex. Right Heart Failure, Cirrhosis of the liver. When total body
Na is increased, it always produces pitting edema. What compartment is the total body Na in?
ECF. What is the biggest ECF compartment? Interstial compartment. Therefore, increase in
total body Na will lead to expansion of interstial compartment of the ECF, water will follow the
Na, therefore you get expansion via transudate and pitting edema; seen in Right Heart
Failure and Cirrhosis.

Example: hypertonic loss of salt (from diuretic) leads to hyponatremia

Example: SIADH (gaining a lot of water) leads to hyponatremia

Example: gaining more water than salt will lead to hyponatremia: pitting edema.
54
4. Hypertonic state have too much Na (hypernatremia) or have (hyperglycemia) (Ex. pt
with Diabetes Ketoacidosis has a hypertonic condition, which is more common than
hypernatremia). With hypernatremia, what does ICF look like? It will always be contracted or
shrunken. Primary aldosteronsim gain more salt and water.

HYPEROSMOTIC VOLUME EXPANSION=GAIN NA

C
O
N
C
E
N
T
R
A
T
ICF ECF
I
O
N

Volume
Diabetes insipidus Lose pure water (vs. gaining pure salt in SIADH). If you lose more
water than salt in the urine, you have osmotic diuresis mixture. When there is glucose and
losing hypotonic salt solution in urine.

HYPEROSMOTIC VOLUME EXPANSION=GAIN NA

C
O
N
C
E
N
T ICF ECF
R
A
T
I
ON

Volume
Example: Baby diarrhea = hypotonic salt solution (adult diarrhea is isotonic), therefore, if
baby has no access to water and has a rotavirus infection, serum sodium should be high
because losing more water than salt, leading to hypernatremia. However, most moms give the
baby water to correct the diarrhea; therefore the baby will come in with normal serum Na or
even hyponatremia because the denominator (H2O) is increased. Treatment is pedialyte and
Gatorade hypotonic salt solution (just give them back what they lost). What has to be
in pedialyte and what has to be in Gatorade to order to reabsorb the Na in the GI tract?
Glucose because of the co-transport. With the co-transport, the Na HAS to be reabsorbed with
glucose or galactose.

55
 Example: cholera, in oral replacement, need glucose to reabsorb Na because co-
transport pump located in the small intestine. Gatorade has glucose and sucrose
(which is converted to fructose and glucose).

Sweat = hypotonic salt solution; if you are sweating in a marathon, you will have
hypernatremia.

E. Volume Compartments
Arterial blood volume is same as stroke volume and CO (cardiac output). When CO decreases,
all physiologic processes occur to restore volume. With decrease CO (Ex. hypovolemia),
oxygenated blood will not get to tissues, and we can die. Therefore, volume is essential to our
bodies.

We have baroreceptors (low and high pressure ones). The low pressure ones are on the venous
side, while the high pressure ones are on the arterial side (ie the carotids and arch of aorta). They
are usually innervated by CN 9 and 10 (the high pressure ones).

When there is a decrease in arterial blood volume (decreased SV or CO), it will under fill the arch
vessels and the carotid; instead of 9th or 10th nerve response, you have a sympathetic Nervous
System response, therefore catecholamines are released. This is good because they will constrict
the venous system, which will increase blood returning to the right side of the heart (do not want
venodilation b/c it will pool in your legs). Catecholamines will act on the beta adrenergic receptors
on the heart, which will increase the force of contraction, there will be an increase in stroke
tropic effect on the heart, increase in
systolic Blood Pressure). Arterioles on the systemic side: stimulate beta receptors in smooth
muscle. Diastolic pressure is really due to the amount of blood in the arterial system, while you
heart is filling with blood. Who controls the amount of blood in arteriole system, while your heart is
filling in diastole? Your peripheral resistance arterioles that maintains your diastolic blood
pressure. So, when they are constricted, very little blood is going to the tissues (bad news); good
news: keep up diastolic pressure this is important because the coronary arteries fill in
diastoles. This is all done with catecholamines. Renin system is activated by catecholamines,
too; angiotensin II can vasoconstrictor the peripheral arterioles (therefore it helps the
catecholamines). AG II stimulates 18 hydroxylase, which converts corticosterone into
aldosterone, and stimulates aldosterone release, which leads to reabsorption of salt and water to
get cardiac output up.

With decreased Sroke Volume, renal blood flow to the kidney is decreased, and the RAA can be
stimulated by this mechanism, too. Where exactly are the receptors for the juxtaglomerlur
apparatus? Afferent arteriole. There are sensors, which are modified smooth muscle cells that
sense blood flow. ADH will be released from a nerve response, and pure water will increase but
that does not help with increasing the cardiac output. Need salt to increase CO.

Example of fluid how can you keep BP up? Give

normal saline is isotonic therefore the saline will stay in the ECF compartment. Normal saline is
plasma without the protein. Any time you have hypovolemic shock, give normal saline to increase
Blood Pressure because it stays in the ECF compartment.
Cannot raise Blood Pressure with " normal saline or 5% dextrose; have to give something that
resembles plasma and has the same tonicity of plasma. Normal saline is 0.9%.

56
Peritubular capillary pressures: you reabsorb most of the sodium in the proximal tubule (60-
80%). Where is the rest absorbed?; in the distal and collecting tubule by aldosterone. The Na is
reabsorbed into the peritubular capillaries. Starling forces in the capillaries must be amenable to
it. Two starling forces: oncotic pressure (keeps fluids in the vessel) and hydrostatic (pushes fluids
out of vessel).

Example: When renal blood flow is decreased (with a decreased SV and CO), what happens to
the peritubular capillary hydrostatic pressure? It decreases. Therefore, the peritubular oncotic
pressure is increasing (Ex. the force that keeps fluids in the vessel), and that is responsible for
reabsorption of anything into the blood stream from the kidney. This is why PO (peritubular
oncotic pressure) > PH (hydrostatic pressure of peritubular capillary), allows absorption of salt
containing fluid back into blood stream into the kidney.

Tonicity of fluid reabsorbing out of proximal tubule is isotonic (like giving normal saline). ADH is
reabsorbing isotonic salt solution, but not as much as the proximal tubule. ADH contributes pure
water, therefore, with all this reabsorption you have an isotonic solution add the ADH effect and
the pt becomes slightly hyponatremic and hypotonic, therefore absorbs into the ECF compartment
when there is a decreased CO.

Opposite Example: increased SV, and increase arterial volume, will lead to stretch of
baroreceptors (innervated by 9th and 10th nerve), and a parasympathetic response will be elicited,
instead of a sympathetic response. There will not be any venuloconstriction nor any increase in
the force of contraction of the heart. This is fluid overload; therefore we need to get rid of all the
volume. There is increased renal blood flow, so the ADH will not be activated. Fluid overload
does not ADH be released. The peritubular hydrostatic pressure is greater than the oncotic. Even

pt is losing hypotonic salt solution with increased in arterial blood volume.

Need to know what happens if there is decreased CO, what happens when ANP is released from
the atria, and give off diuretic effect; it wants to get rid salt. ANP is only released in volume
overloaded states.

Pt given 3% hypertonic saline: what will happen to osmolality? Increase. What will that do
to serum ADH? Increase increase of osmolality causes a release of ADH.

What happens in a pt with SIADH? Decreased plasma osmolality, high ADH levels.

What happens in a pt with Diabetis Insipitus? No ADH, therefore, serum Na increases, and
ADH is low.

57
How to tell total body Na in the pt:

1. DIABETIC KETOACIDOSIS PATIENT with dry tongue = there is a

decrease in total body Na, and the pt with indentation of the skin, there is an increase in total body
Na. Dehydration: Skin turgur is preformed by pinching the skin, and when the skin goes down,
this tells you that total body Na is normal in interstial space. Also look in mouth and at mucous
membranes.

2. LEG: DEPENDENT PITTING EDEMA that means that there is

an increase in total body Na.

SIADH gaining pure water, total body sodium is normal, but serum Na is low; have to restrict
water.

Right Heart Failure and dependent pitting edema fluid kidney reabsorbs is hypotonic salt
solution with a decreased CO (little more water than salt), therefore serum Na will low. Numerator
is increased for total body sodium, but denominator has larger increase with water.

What is nonpharmalogical Rx of any edema states? (Ex. Right Heart Failure /liver Disease)
restrict salt and water.

What is the Rx for SIADH = restrict H2O

What is the Rx for any pitting edema state? Restrict salt and water
Pharmacological Rx for pitting water diuretics (also get rid of some salt).

58
III. SHOCK

A. Causes of hypovolemic shock diarrhea, blood loss, cholera, sweating, NOT Diabetis
Insipidus (because losing pure water, and not losing Na, total body Na is NORMAL! when you
lose salt, show signs of dehydration).

Example: lady with hypovolemic shock when she was lying down, her Blood Pressure and
pulse were normal; when they sat her up, the Blood Pressure decreased and pulse went up.
What does this indicate? That she is volume depleted. This is called the TILT test. When
Normal Blood Pressure lying down is because there is no effective gravity, therefore normal blood
returning to the right side of the heart, and normal CO. However, when you sit the patient up, and
impose gravity, you decrease the venous return to right heart. So, if you are hypovolemic, it will
show up by a decrease in Blood Pressure and an increase in pulse. Cardiac output is decreased,
and the catecholamine effect causes this scenario. How would you Rx? Normal saline.

Audio file 7: Fluid and hemodyn 3

Example: pt collapses, and you do a tilt test: 100/80 Blood Pressure and pulse of 120 while
lying down. Sitting up, it was 70/60 and pulse of 150. The pt is severely hypovolemic,
therefore Rx is normal saline. Treatment: One liter in, showed no signs, put another liter and the
Blood Pressure becomes normal, and is feeling better, but still signs of volume depletion (dry
mouth). We have the Blood Pressure stabilized, but the pt lost hypotonic salt solution, therefore
we need to replace this. So on IV, give hypotonic salt solution (because was losing hypotonic salt
solution). We do not give 5% dextrose and water because
will give " normal saline. The treatment protocol is: when a pt loses something, you replace
what they lost. And when pt is hypovolemic, always give isotonic saline.

Example: Diabetic Ketoacidosis (DKA) have osmotic diuresis; tonicity of fluid in the urine that
has excess glucose is hypotonic. Hypotonic fluid has a little more fluid than salt. So the pt is
severely hypovolemic; therefore the first step in management is correction of volume depletion.
Some people are in hypovolemic shock from all that salt and water loss. Therefore need to
correct hypovolemia and then correct the blood sugar levels (DKA pts lose hypotonic solution).
Therefore, first step for DKA pt is to give normal saline because you want to make them
normo-tensive. Do not put the pt on insulin because
hypovolemia. It can take 6-8 liters of isotonic saline before the blood pressure starts to stabilize.
After pt is feeling better and the pt is fine volume wise. Now what are we going to do? The pt is
still losing more water than salt in urine, therefore still losing a hypotonic salt solution, therefore
need to hang up an IV with " normal saline (Ex. the ratio of solutes to water) and insulin (because
the pt is loosing glucose).

So, first thing to do always in a pt with hypovolemic shock is normal saline, to get the Bloor
Pressure normal. Then to correct the problem that caused the hypovolemia. It depends on what
is causing the hypovolemia (Ex. if pt is sweating, give hypotonic salt solution, if diarrhea in an
adult give isotonic salt solution (Ex. normal saline), if pt with Diabetis Insipidus (Ex. Stable Blood
Pressure, pt is lucid) give water (they are losing water, therefore give 5% dextrose (Ex. 50%
glucose) and water).

59
 B. Four kinds of shock:

1. Hypovolemic shock: blood loss, diarrhea (adult or child), basically whenever you are lose
salt, you could end up with hypovolemic shock

2. Cardiogenic shock: Most Common due to Miocardial Infarction

3. Neurogenic shock: associated with spinal cord injuries

4. Septic shock: Most Common due to E. coli; also Most Common Cause sepsis in
hospital and is due to an indwelling of the urinary catheter. Gran Negatives bacteria have
Endotoxin (lipids) in cell wall is a lipopolysacharide. SO if you have E.Coli sepsis, you will
have big time problems, and is called septic shock.

5. Classical clinical presentations:

a) Hypovolemic and cardiogenic shock: you would see cold and clammy skin, because
of vasoconstriction of the peripheral vessels by catecholamines (release is due to the
decrease in Stroke Volume and Cardiac Output) and AG II. These will vasoconstrict the
skin and redirect the blood flow to other important organs in the body, like brain and
kidneys, leading to a cold clammy skin. Blood Pressure is decreased, pulse is increased.

b) : is a concept that teaches you about peripheral resistance of arterioles

which control the diastolic blood pressure.

TPR = Total peripheral resistance of the arterioles

V = Viscosity
r = radius of the vessel to the 4th power

The main factor controlling TPR? Radius to the 4th power

What controls the viscosity in the blood? Hemoglobin.

So if you are anemic, viscosity of blood is decreased (Ex. low hemoglobin), and if you have
polycythemia (high hemoglobin), viscosity will be increased. Therefore, TPR in anemia will
decrease, and in polycythemia will increase.

c) Septic shock There is a release of endotoxins which activates the alternative complement
system. The complement will eventually release C3a and C5a which are anaphylatoxins, which will
stimulate the mast cells to release histamine. The histamine causes vasodilation of arterioles (the
same ones of the peripheral resistance arterioles). Therefore blood flow is increased throughout the
peripheral resistance arterioles and the skin feels warm. The endotoxins also damage the endothelial
cells; as a result, two potent vasodilators (Nitride Oxide and Prostaglandin2) are released. Therefore,
2 or 3 vasodilators are released, and affect the TPR to the fourth power. Therefore, the TPR will
decrease (due to vasodilation).

TPR arterioles control your diastolic Blood Pressure because when they are constricted; they control
the amount of blood that remains in the arterial system while your heart is filling up in diastole.
Therefore, when the TPR arterioles are dilated, the diastolic Blood Pressure will pan out.

60
Think of a dam (with gates): if all the gates are wide open all that water will come gushing (emit
sudden copious flow) through. This is what happens to the arterioles when they are dilated. The
blood gushes out and goes to the capillary tissues, supposedly feeding all the tissues with O 2. Think
in the context of fishing: when the dam wall opens, all the water rushes thru causing turbulent waters,
therefore this would be a bad time to go fishing. The fishes would be trying to save themselves. That
is what the O2 is doing. Therefore, with all this blood going by, the tissues cannot extract O 2 because
it is going too fast and because
Therefore, the blood is coming back to the right side of the heart faster than usual, because all the
arterioles are widely dilated. Due to the blood going back to the heart faster, the cardiac output is
increased. This is seen in septic shock and the skin feels warm because the vessels are dilated.
Therefore, with septic shock, there is a HIGH output failure, with warm skin.

However, in hypovolemic and cardiogenic shock, the cardiac output is decreased (because the
vessels are constricted by catecholamines and angiotensin II), and the skin feels cold and clammy.

C. Swan ganz catheter is inserted in the right side of the heart and it measures all parameter that is
taught in physiology. All of these things are measured in a swan ganz catheter.

1. Cardiac Output: measured by swan ganz

2. Systemic vascular resistance: this is a calculation. The basically measures the TPR. (Ex.
measures what arterioles are doing)

3. Mixed venous O2 content. You know normally that the O2 content is equal to = 1.34 x Hb x O2
saturation + pO2. Measured in Right Atrium with swan ganz catheter; this is the BEST TEST for
evaluating tissue hypoxia.

Cardiac output in cardiogenic and hypovolemic shock is low, therefore, blood not being pushed ahead
with a great deal of force. So, tissue will have a lot of time to extract O2 from what little blood that is
being delivered. As a result, mixed venous O 2 content in hypovolemic and cardiogenic shock will be
decreased ie very low because the blood going through the vessels is very slow (no force is helping
to push it through). Therefore, it extracts more O2 than normal. Mixed venous O2 content in septic
shock (when blood is passing through vessels at a very fast rate) will lead to a HIGH mixed venous
content (because tissues unable to extract O2).

4. Pulmonary capillary wedge pressure measures Left ventricular end diastolic volume and End
Diastolic Pressure (EDV and EDP). Catheter in right heart will tell you what the pressure is in the left
ventricle.

5. It can distinguish the differences between Hypovolemic, Cardiogenic, and Septic Shock using
swan ganz catheter:

CO in hypovolemic and cardiogenic? Both decreased CO in septic shock? Increased

Systemic vascular resistance (TPR) is a measure of what the ARTERIOLES are doing.

What is TPR in hypovolemic and cardiogenic shock? Increased due to vasoconstriction

TPR in septic shock? Decreased due to vasodilation.

61
Mixed venous in hypovolemic and cardiogenic? Low. Mixed venous in septic shock?
High.

How do we separate hypovolemic and cardiogenic? Pulmonary capillary wedge pressure

(measures left ventricular EDV)

In Hypovolemic, what is Left Ventricle End Diastolic Pressure? Low.

In Cardiogenic, what is Left Ventricle EDP? High.

In Endotoxic

D. Examples:

1. Example:
KIDNEY: ISCHEMIC ACUTE TUBULAR NECROSIS

Of all organs in the body, which suffers the greatest due to decreased Blood Pressure? Kidneys.
What part? Medulla. Not the brain because with decreased CO, the circle of Willis will distribute
blood flow to certain areas in the brain, especially the areas where there are neurons. Someone with
hypovolemic, or cardiogenic, or septic shock: Oliguria and an increased in BUN/Creatine causes
sugars in the body. This occurs because the patient is going into acute tubular necrosis (ATN).
Nephrologists want to correct the renal blood flow, so that you can prevent ATN because a pt can die.
What type of necrosis? Coagulation necrosis. The dead renal tubules will slough off and produce
renal tubular casts in the urine which will block urine flow, thereby producing oliguria, decrease in
GFR, leading to Acute Tubular Necrosis (chances of survival are zero). So it is the kidneys that are
the most affected when the cardiac output is decreased, (Ex. decreased blood flow). Brain
would be a close second to necrosis. The heart has a bit of a collateral circulation as well.

2. Example: Pt with the Sickle Cell Trait = (Some red blood cells tend to sickle but usually not
enough to produce anemia) can get kidney disease; because 2 tension is low
enough to induce sickling. Therefore if you have a young black woman with microscopic hematuria
coming to the office, what is first test you should do? Sickle cell screen, because she probably has
the sickle cell trait. Therefore, sickle cell trait has problems, because O2 tension in renal medulla is
low enough to induce sickling in peritubular capillaries, which produces microinfarctions in the
(aka Acute Tubular Necrosis)

IV. ACID BASE AND BLOOD GAS

62
 pH
_ 7.4 +

ACIDOSIS ALKALOSIS
Increase in H+ ions Decrease in H+ ions

Decrease in bicarbonate HCO3 Increase in bicarbonate (HCO3)

Metabolic acidosis Metabolic alkalosis

Increase pCO2 Decrease pCO2

Respiratory acidosis Respiratory alkalosis

A. New equation for acid/base physio by Goljan: pH = [HCO3-] / pCO2

B. Compensation = bodies attempt to try to maintain a normal pH (which it never does). So if

you want to keep pH roughly normal (assuming you could).

1. Example: if you have metabolic alkalosis (increase in HCO3: which is in the numerator), then have
to increase denominator (pCO2) to keep it normal, therefore, compensation is due to respiratory
(pCO2) acidosis. A nice way of memorizing it is what is the opposite of metabolic? Respiratory and
what is the opposite of acidosis? Alkalosis, and vice versa.

2. Example: if you have metabolic acidosis (decrease bicarb) what do we have to do with the pCO 2?
We have to get rid of it. If we decrease the nominator, we have to decrease the dominator in order
for the equation to stay the same. Therefore, we have to blow off the CO 2 (hyperventilation).

3. Ventilation is a CO2 term!

Hyperventilation = Increase in respiratory rate allows for the blowing off of CO2, therefore results in
respiratory alkalosis. For the treatment of respiratory alkalosis is to give the pt a paper bag and ask to
breath in it, because then they are re-breathing their own CO2.

Hypoventilation = Decrease in respiratory rate allows for the retention of CO2, therefore results in
respiratory acidosis.

Full compensation does not exist; you never bring back the pH to the normal range. There is one
exception: chronic respiratory alkalosis in high altitude; Ex. mountain sickness (Places like peru).

C. Respiratory conditions: acidosis and alkalosis

1. Things that deal with CO2:

a) Respiratory center is in medulla oblongata, which controls the breathing rate.

b) Upper airways if obstructed, there will be a problem getting rid of CO2.

63
c) Chest bellows most important muscle of respiration is diaphragm. On inspiration: the
diaphragm goes down, the negative intrathroacic pressure increases, and air is sucked into the lungs
and blood is sucked into the right side of the heart (this is why neck veins collapse on inspiration).

pressure, pushing things out. It helps the left heart to push blood out and it also helps the lungs by
pushing out air.

2. Examples:

(a) Barbiturates or any drug that depresses the respiratory center will leads to respiratory
acidosis

(b) CNS injury to medulla oblongata respiratory acidosis

(c) Anxiety = Most Common Cause respiratory alkalosis. When you take a test, sometimes you
feel strange, and get numb and tingly, especially around mouth and on the tips of fingers, and
become twitchy (because you are in tetany) its all caused by being alkalotic and ionizing calcium level
gets lower and you really are getting tetany. Therefore you become twitchy and paresthesias (ie
l due to tetany because of breathing
too fast from anxiety.

(d) Pregnant woman have respiratory alkalosis because estrogen and progesterone over stimulate
the respiratory center. Located in the lungs are spider angiomas due to Atrial Venuses fistulas
related to high estrogen, therefore clear more CO2 per breath than a normal woman. A lot of shunting
occurring within lungs. These spider angiomas go away after delivery of the baby.

(e) Endotoxins over stimulate the system. All pts in endotoxic shock have respiratory alkalosis.
They are also in anaerobic metabolism, producing lactic acid, therefore are also in metabolic
acidosis. Therefore, endotoxic respiratory alkalosis due to overstimulation, and metabolic acidosis
due with normal pH.

(f) Salicylate overdose overstimulate respiratory center, leading to respiratory alkalosis.

Salicylic acid is an acid, hence metabolic acidosis, and pH will be normal because they balance each
other out. (Tinnitus in salicylate OD also a MIXED disorder!)

(g) 6 y/o child with inspiratory strider do a lateral x-ray, and see thumbprint sign, with a
swollen epiglottis. The diagnosis is acute epiglottitis, due to H. influenza; vaccination has
e any ids with H. meningitis because of the vaccination. The
Most Common of meningitis in 1 month 18 yrs = Neisseria meningitis.

(h) 3 month old croup = (inflammation, edema, and subsequent obstruction of the larynx, trachea,
and bronchi especially of infants and young children that is typically caused by a virus and is marked
by episodes of difficult breathing and hoarse metallic cough), a larygiotracheobronchitis disease
due to parainfluenza virus. Want to do a lateral x-ray and see a steeple sign. Where is the
obstruction in croup? Trachea

(i) Pt shoving (push) food in their mouth (café coronary) Heimlich maneuver; if they can talk,
leave alone and let them cough it out.

64
(j) Diaphragm innervated by the phrenic nerve Ex. Erb Duchene palsy, with brachial plexus
injury, and child has respiratory difficulty, and diaphragm on right side is elevated. Paralysis of the
diaphragm will lead to increased CO2.

(k) isease amyotrophic lateral sclerosis disease, a Lower Motor Neuron

Upper Motor Neuron gone therefore cannot breath because no innervation to the diaphragm (Ex.
diaphragm and intercostals are paralyzed)

(l) Guillain-Barre ascending paralysis in a patient who a week ago had a respiratory infection. The
spinal fluid shows increased protein, slight increase in lymphocytes, and a gram stain negative.
Disease: Guillain-Barre, demyelinating disease.

(o) Polio destroys Lower Motor Neuron pper Motor Neuron

anything that paralyzes muscle of respiration will lead to respiratory acidosis.

(p) LUNGS: obstructive and restrictive lung diseases

Obstructive lung disease problem getting air out, compliance increased and elasticity is
decreased, therefore, have a respiratory acidosis.
Restrictive lung disease - Ex. Sarcoidosis and pneumonocionioses, there is a problem in getting air
in therefore has a respiratory alkalosis.

Audio File 1: Day2 Nutrition1

Underwater: for every 30 ft, increase 1 atmosphere, (Ex. 760 at level, but 30 ft
lower it will be 2 atm); the reverse is true when you go to high altitudes Ex. at top of mt everst, the
atmospheric pressure is 200 atm; still breathing 21% O 2; breathing the same, but atmospheric
pressure is different, depending on where you are.

Formula for calculating: alveolar O2 = (0.21 x atmospheric pressure) PCO2 / .8

High Altitude: (.21 x 200) 40mmHb/.8 = 2mmHg of air in alveoli, therefore will have to
hyperventilate at high altitudes, because lower pCO2= increased PO2 (you HAVE to hypverventilate
otherwise you die).

However, when you go under, the atmosphere pressure increases, and the nitrogen gases are
dissolved in your tissues, leading to an increase in pressure. Ex. 60 ft below, want to get up fast; like
shaking a soda bottle; as you ascend, the gas comes out of fat in bubbles; the bubbles get into
tissues and Bloof Vessels; this is called the bends; leads to pain, and quadriplegia, loss of bladder
control. Rx = hyperbaric O2 chamber.

65
 CHAPTER 4: NUTRITION
I. EATING DISORDERS

A. Anorexia

Distorted body image; women with anorexia can have distorted image; control issue; they have lost
control of everything in their life, and the only thing that they can control over is what they put in their
mouth. With a decrease of body fat and weight, GnRH decreases, therefore FSH and LH also
decrease, leading to low estrogen = amenorrhea and predisposes to osteoporosis, as if pt is
postmenopausal. Anorexic people will eventually develop osteoporosis.

Rx convince person to gain enough weight to bring period back; not birth control. (Ex. first step in
management of Hypertension/diabetes = weight loss; as you lose adipose, you upregulate insulin
resistance). In anorexia, usually die to cardiac disease (heart failure: heart just stops).

B. Bulimia

1. Metabolic Alkalosis they can be obese, normal or thin (no

weight issue); however, they binge (eat a lot), then force themselves to vomit. Picture: from
vomiting, wear down enamel on teeth; so, brownish stuff seen on teeth is just dentine
(erosions seen on teeth). Metabolic alkalosis from forced vomiting will be seen. Metabolic alkalois
is bad b.c there is a left shift curve, and the compensation is respiratory acidosis, which decrease
pO2, therefore will get hypoxia with metabolic alkalosis, and the heart do not like that. The heart
already with low O2 will get PVC (pre-mature ventricular contractions), RRT phenom, then Ventricular-
fibrilation, then death. Therefore, met alkalosis is very dangerous in inducing cardiac arrythmias, and
this commonly occurs in bulimics due to forced vomiting. Pt can also vomit out blood Mallory Weiss
Syndrome tear in distal esophagus or proximal stomach.

2. Borhave syndrome, which is worse. In the syndrome, there is a rupture and air and secretions
from the esophagus get into the pleural cavity; the air will dissect through subcutaneous tissue, come
around the anterior mediastinum, which leads to Hemimans crunch

up into the mediastinum, indicating that

a rupture occurred in the esophagus; this is another common thing in bulimics.
So, there are 2 things imp in bulimics: 1) Metabolic alkalosis from vomiting (which can induce

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C. Obesity: With obesity, using a diff method: Body Mass Index
(BMI) eigh ater, you are obese; if your
BMI is 40 or greater, you are morbidly obese. Main complication of obesity = Hypertension and leads
to Left Ventricular Hypertrophy, and potentially heart failure. Most Common Cause death in HTN =
cardiac disease. Other complications of obesity include: gallbladder disease, cancers with a lot of
adipose, you aromatize many 17-ketosteroids like androstenedione into estrogens. Therefore, will
hyperestrinism (all obese women have hyperestrinism), you are at risk for estrogen related cancers
Ex. breast cancer, endometrial carcinoma, colon cancer.

II. MALNUTRITION

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1. MARASMUS Energy Malnutrition: Total calories deposition, and wasting away
of muscle; however, high chance of survival if they get food.

2. KWASHIORKOR Protein Malnutrition; also have anemias, cellular

immunity problems (Ex. no reaction to antigens), low albumin levels, ascites, fatty livers.These
kids are apathetic and need to be force-fed; therefore, kid with kwashiorkor is more likely to die than
child with Marasmus. Example: kid with edema, Swollen Belly, flaky dermatitis, reddish hair (Cooper
deficiency) kwashiorkor.

III. VITAMINS

A. Difference between fat and water soluble vitamins:

1. Fat soluble vitamins dissolve in fats, indicating that they are taken up by chymlomicrons. The
chymlomicron have vitamin A, D, E, and, K = fat soluble vitamins. Fat soluble are more likely to be
stored in fat, so the toxicity is much greater, because if it is water soluble, we just pee it out.

Most Common Cause of bright yellow urine = vitamins

2. Water soluble vitamins are all cofactors for biochemical reactions.

B. Fat soluble vitamins:

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 1. Vitamin A:

a. Function: Is very important in children for growth and can have failure to thrive in Vit. A deficiency.
Very important in iodopsin/rhodopsin within the eye and the first sign of vit. A deficiency is
night blindness which is called nictolopia. Vit. A also prevents squamous metaplasia.

b. Example of Vit A deficiency:

GOOSE BUMPS: BACK OF THE ARM called: follicular hyperkeratois.

Eye is lined with cuboidal epithelium; when you

get squamous metaplasia, will get white spots on the eye.

69
 If become extensive, grow over eye, and can lead to softening of
the cornea (keratomalacia), and leads to blindness.

2nd Most Common Cause blindness globally = vit A def.

Most Common Cause blindness globally = Trachoma due Chlamydia Trachomatis

Most Common Cause blindness in USA = diabetes.

Therefore, vit A will prevent squamous metaplasia, if you are Vit. A deficient and a nonsmoker, a
person can end up with squamous metaplasia in mainstem bronchus and bronchogenic carcinoma.

c. Toxicity: Hypervitaminosis A ex. big game hunter that eats bears liver and has headaches.
Increased vit A causes cerebral edema, also get papilloedema (which causes the headache), can
also lead to herniation and death. There is also an increase of retinoic acid (used from treating
acne and acute progranulocytic anemia). The retinoic acid toxicity can lead to severe liver toxicity.
Therefore, hypervitaminosis of vit A affects 2 areas: 1) cerebral edema (brain) 2) liver. Example: if
have young lady pt on retinoic acid for acne, need to check liver enzymes and ask for headaches
(can be developing papilloedema or cerebral edema related to vit A toxicity).

2. Vitamin D = VERY imp on the boards; Most Common source of Vit. D is from sunlight.
a. Cholesterol is the:
1. Main component of our cell membranes
2. Starting point for making bile salts and bile acids
3. First compound that starts the synthesis of steroid hormones in the adrenal cortex
4. And the 7-dehydrocholesterol in the skin is photoconverted to vitamin D.

Therefore we need cholesterol! (Makes bile salts, hormones, cell membranes, and vit D).

b. Source: Sun is the most important source of vit D. take baby out to expose to sunlight (no vit D or
vit K in breast milk, therefore must be supplemented expose to sun for vit D).

c. Synthesis of Vitamin D: Reabsorbed in the jejunum. Undergoes 2 hydroxylation steps; first is in

the liver, where it is 25 hydroxylated and the 2 nd is in the kidney and its 1 alpha hydroxylase. What
hormone puts 1-alpha hydroxylase in the proximal tubule? Parathyroid Hormone (PTH).
PTH is responsible for synthesis of 1-a-hydroxylase and is synthesized in the proximal tubule. (ACE
is from the endothelial cells of the pulmonary capillary, EPO is from the endothelial cells of the
peritubular capillary). 1-a-hydroxylase is the 2nd hydroxylation step, and now it is active (the first was
in the kidney).

d. Vit D function: reabsorb Ca and phosphorus from the jejunum. It HAS to reabsorb both of
these, because its main job is mineralizing bone and cartilage. Have to have appropriate solubility
product to be able to do that; Ca and phosphorus are necessary to mineralize cartilage and bone
(like the osteoid making bone).
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e. Parathyroid Hormone (PTH) Functions:

(1) PTH is related to Vitamin D metabolism, it helps last step for hydroxylation of Vit. D synthesis.

(2) PTH lead the reabsorption of Ca in the early distal tubule (this is also where Na is reabsorbed,
and thiazides block this channel). At that location, there is a Ca channel; PTH helps reabsorption of

to sneak through channel, with help of PTH. Therefore, with thiazides, Na is blocked, leaving the Ca
channel completely open, and the thiazides will lead to hypercalcemia. Therefore, use in Ca stone
formers most of stone formers have hypercalciurea; these pts have too much Ca in their urine;
when they are on thiazides, the drug takes Ca OUT of the urine, so they do not form stones.

(3) PTH decrease reabsorption of phosphorus in the proximal tubule

(4) PTH decreases the reaccumulation of bicarbonate.

f. Vitamin D and PTH and how they work together:

main function is mineralizing bone, and osteoblasts (bone builders) are involved with this
process, therefore the receptor for Vit D is located on the osteoblast. When vit D hooks into the
receptor, it causes the release of alkaline phosphatase enzyme. So, when you are growing bone or
rehealing of a fracture, you expect to see an increase in alkaline phosphatase, which makes the
appropriate solubility product to mineralized cartilage and bone. Knowing that PTH breaks down
bone (maintains Ca levels in the blood stream) you would think that its receptor would be on the
osteoclast (cell normally breaks bone down). However, only one hormone has a receptor on
ostoeclasts and that is calcitonin. When calcitonin hooks into the osteoclast receptor, it inhibits
the osteoclast, and therefore is used to treat hypercalcemia. Calcitonin also used in treating
osteoporosis. The receptor for PTH is on the osteoblast, but not sharing the same one as vit D.
When PTH hooks on the osteoblast, it releases IL-1.
Another name for IL-1 is osteoclast activating factor (other functions of IL-1 are also involved in fever,
stimulates Antibodies synthesis, and B cell stimulation).

So, IL-1 (released from the osteoblast) activates osteoclasts via IL-1 release from osteoblast,
and osteoclast is signaled to break down bone to maintain Ca levels in our bloodstream. Sex
hormones keep IL-1 in check; in women, estrogen levels keep a check on IL-1 (do not want too much
osteoclast activation); in men, it is testosterone that keeps IL-1 in check (puts inhibitory effect on IL-1
release from the osteoblast after PTH hooks in). Therefore, in women, can see why they get
osteoporosis lack of estrogen = IL-1 not in check and breaking more bone down than
making (this is the mechanism of postmenopausal osteoporosis).

PTH is more involved in maintaining Ca levels in our blood, while Vit D is more involved in
mineralizing our bones and cartilage.

g. Vitamin D deficiency: Many reasons: lack of sun, poor diet, liver disease, renal disease.

Example: Pt on phenytoin and pt has hypocalcemia, why? Phenytoin, alcohol, barbiturates, rifampin
all induce the cytochrome p450 system located in the SER. Therefore, get Smooth Endoplasmic
Reticulum (SER) hyperplasia; therefore, you metabolize drugs and other things made in the liver,

71
including 25-hydroxyvitamin D. Therefore, Cytochrome p450 enzymes will cause a decrease in vit
D, and any other drugs being taken.

Example: woman on birth control pills and taking phenytoin, and she got pregnant, why? The
phenytoin increases the p450 system, which increased the metabolism of estrogen and progesterone
in the birth control pills, therefore not enough levels to prevent pregnancy.

What enzyme increase in the SER when increase Cytochrome p450?

Gamma glutamyl transferase (GGT) enzyme of SER! (Look at in alcoholics)

Example: Most Cause Cause chronic renal disease in USA: diabetes mellitus tubular damage,
so no 1-a-hydroxylase, therefore inactive vit D. Therefore, pts with chronic renal failure are put on 1-
25-vit D.

If someone gets over the counter (OTC) vit D, what steps does it go through to become
metabolically active?
25 hydroxylated in liver, and 1-a-hydroxylated in your kidney (it is NOT 1, 25 vit D this is a
prescription drug, and extremely dangerous). Many people have the misconception that the
vitamin D is already working. This is not the case; pt must have a functioning liver and kidney.

Vitamin D deficiency in adults = osteomalacia (soft bones).

cannot mineralize cartilage, and they will both be soft, therefore pathologic fractures are common.

Vitamin D deficiency in kids = rickets

Kids have different a few things that are different in rickets Ex.craniotabes, soft skulls (can actually
press in and it will recoil). They can also get ricketic rosaries, because the osteoid is located in the
costochondral junctions, and because they are vit D deficiency, there is a lot of normal osteoid waiting
to be mineralized, but not an appropriate Calcium/phosphorus solubility product; will have excess
osteoid with little bumps, which is called ricketic rosary they are
getting fused.

h. Toxicity/Hypervitaminosis of vit D: hypercalcemia, therefore risk of having too many stones in

the urine, and toxicity stones is a Most Common Cause complication.
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Type 1 rickets missing the 1-a-hydroxylase
Type 2 rickets missing the receptor for vit D

3. Vitamin E

a. Main function:

1. It protects the cell membranes from being broken down by phospholipase A (lipid
peroxidation, which is free radical damage on the cell membrane, and is prevented with vit E).

2. Oxidizes free LDL (this is the LDL that macrophages phagocytose to produce foam cells, and
leads to atherosclerotic plaques). Is a cardioprotectant.

b. Deficiency of vitamin E: Is seen but is very uncommon, and if seen in kids with cystic fibrosis;
from birth, kids have respiratory problems and pancreas problems. A kid that has cystic fibrosis
will have malabsorption problems; therefore what four vitamins should you give him? Cystic fibrosis
pt has a malabsorption of fat; therefore they will have malabsorption of fat soluble vitamins
A, D, E, and K. Vit E def in USA is usually seen in cystic fibrosis patients.

c. Clinical presentations: One of the features of vit E deficiency is hemolytic anemia (vit E
normally maintains the integrity of the membrane); this pt is now susceptible to free radical
damage, damaged mem of RBC leads to hemolysis of RBC and hemolytic anemia. Another feature
of vit E are things related to myelin: posterior column disease, spinal cerebellar problems. Therefore,
with vit E def, have neurological problems and hemolytic anemia.

d. Vitamin E toxicity: anything more than 1100 units (average capsule is 400 units, therefore, if take
3 pills, already toxic). Vitamin E toxicity will inhibit synthesis of Vit K dependent Coagulation factors
(2, 7, 9, 10, protein C, protein S); in other words, you are antiCoagulated.

Example: pt with MI take antioxidants, and aspirin; with anterior Miocardial Infarction, they
antiCoagulate the pt, and pt goes home on three months of warfarin. Normal INR ratio, and takes lots
and lots of vit E and other vitamins. Take a lot of vit E and will help warfarin, leading to over
antiCoagulated state, (remember that warfarin blocks gamma carboxylation of vitamin K dependent
factors). Vit E will prevent the SYNTHESIS of these factors. Therefore, vit E toxicity is synergistic in
activity with warfarin.

Pt on warfarin, came home from Miocardial Infarction, INR ratio is huge; why? Taking vit E.

4. Vitamin K
a. Sources: Can come from what we eat, but most is synthesized by our colonic bacteria (our
anaerobes in our gut) this is why we give vit K injections to our baby when they are born; they only
have 3 days worth of vit K from mom, but aft its not in breast
milk; therefore, a very low level of vit K between days 3-
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vit K. Therefore, can get hemorrhagic disease of the newborn (this is why we give vit k when they are
born); after 5 days, the bacteria colonize, and vit is made by the baby.

b. Metabolism: Bacteria make vit K in an inactive form K2. K2 (inactive form must be converted
by epoxide reductase to K1 (K1 is the active form of vitamin K). K1 will gamma carboxylates the
vit K dependent factors (2, 7, 9, 10, protein C and S). Gamma carboxylates requires the same
prolyne and lysine then the crosslinks
are weaker (anchor pt). Gamma carboxylation of vit K dep factors actually activates them to become
functional.

Vit K dependent factors all have something in common:

(1) Have to be activated by vit K1

(2) They are the only Coagulation factors that are bound to a clot by Calcium (Ca); so they have to be

That is what gamma carboxylation: glutamic acid residues are gamma carboxylated on the vit K
dependent factors (which is done with K1), and allows Ca to bind the factors; therefore, it keeps them
together and you are able to form a clot; therefore, if they are not gammacarboxylated, they are
useless because grab them to form a clot (so, gammacarboxylation is the anchor pt, so Ca
can bind to form a clot, similar to hydroxylation of proline and lysine in collagen synthesis).

PATIENT WITH PERIORBITAL HEMORRAGE DUE WARFARIN TOXICITY.

Warfarin blocks epoxide reductase, so all the vit K pt has is K2 and no gammacarboxylation will
occur. Therefore, the patient is anticoagulated.

c. Vitamin K deficiency:
Most Common Cause vit K deficiency in hospital=broad spectrum Antibodies.
2nd Most Common Cause = poor diet, being a newborn, malabsorption.

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 NEWBORN BRAIN WITH HEMORRAGIC DISEASE
DUE VITAMIN K DEFICIENCY
Deficiency of Vit K = hemorrhagic diathesis (bleeding into skin or brain). Know why newborn has
vit K deficiency: Example: kid with rat poison rat poison is warfarin; when rats eat it, they get
antiCoagulated and die. Treat with intramuscular Vitamin K. Example: kid lived with grandparents
and developed hemorrhagic diathesis: why? Because the elderly were on warfarin and kid ate the
warfarin, and led to toxic levels.
C. Water Soluble Vitamins: all are cofactors in major biochemical pathways.

1. Vitamin C:

a) Vitamin C deficiency: SCURVY

Vit C is responsible for hydroxylation of proline and lysine, and this

occurs in the Golgi apparatus because that -translational modification occurs. Pts have
weak Type I collagen because cannot crossbridge it; therefore, Blood Vesselss are unstable:
smooth and red tongue (glossitis) and gums bleed. Get bleeding of the gums, inflammation,
and may loose teeth. Older person on tea and toast diet = malnourished leading to = scurvy Vit C
deficiency.

What complication is associated with severe hemophilia A? Hemearthroses, and caused by Vit
C deficiency (because the Blood Vessels are unstable and they rupture).

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c) Physical diagnosis of Vitamin C deficiency:

PERIFOLLICULAR HEMORRHAGE (hemorrhage around the hair follicles). See ring sideroblast
(nucleated RBC, and has too much iron in the mitochondria), ring around the hair follicle and also see
cork screw hairs due to vit C deficiency.

d) Excess vitamin C: very common because pts take way too much vit C (6-8gm), main
complication is Renal stones (increased uric acid stones, and other kinds of stones). Vitamin C
and D both have toxicity stones.

e) Vitamin C is used in ancillary Rx for methemoglobinuria; it is a reducing agent and a great

scavenger hunter for free radicals (knocks them off).

f) Cofactor in biochemical pathway: Vit C is a cofactor for converting the catecholamine NE into
Epi.

2. Vitamin B1 (Thiamine):

a) Involved in many biochemical reactions:

1. Vit B1 work with transketolase reaction in the pentose phosphate shunt (HMP SHUNT); and
pyruvate dehydrogenase;

2. Alpha keto glutarate dehydrogenase; and alpha keto acid dehydrogenase. All the dehydrogenase
reaction requires thiamine as a cofactor.

3. Pyruvate dehydrogenase is the main reaction that converts pyruvate into acetyl CoA.
Pyruvate can also be converted to OAA with a carboxylase enzyme. When you combine acetyl
CoA with OAA, you make citrate, and you are in the TCA cycle.

b) So, if thiamine deficiency, because it is involved in the pyruvate dehydrogenase reaction (which

much citrate around

Therefore, the problem with thiamine deficiency is ATP depletion. When you go from pyruvate to
chondria, you get 6 ATP (so, just from
going from pyruvate to acetyl-Coa=6 ATP and then with TCA= 24 ATP). 6 + 24 = 30 ATP; the total
you can get from completely metabolizing glucose is 38 ATP. With Vit. B1 Thiamine deficiency, you
are out 30.
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c) In Vitamine B1-Thiamine deficiency. How does this explain wet/dry beriberi?

1) Dry beriberi = FOOT DROP

It takes a lot of ATP for synthesis of myelin; without myelin (Demyelization), you will get
peripheral neuropathy, refers to ( encephalopathy is confusion, ataxia, and
nystagmus). d new things like an exam
Ex. Foot drop (due to common
peroneal palsy), can get wrist drop (radial nerve palsy), and claw hand (ulnar nerve palsy).

2) Wet beriberi = heart failure; Most Common Cause Thiamine deficiency = alcohol (not
polished rice). Alcoholics are the MC people with thiamine deficiency. Wet beriberi is referring to
cardiomyopathy cause: Left Heart Failure went into Right Heart Failure which lead to pitting edema.
Heart needs ATP to function, therefore, the pt with have congestive cardiomyopathy; their heart will
have biventricular enlargement (the whole chest will be heart), with left and Right Heart Failure

PITTING EDEMA is a sign of right Heart Failure due to increased hydrostatic

to toxicity of alcohol, and cannot work.

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Pt. in ER given IV of 5% dextrose and normal saline; all of sudden, pt develops confusion,
nystagmus, and ataxia, and opthalmaplegia. Dx: subclinical thiamine Vit B1 deficiency. As
soon as the glucose was hung up, the pyruvate went to acetyl CoA and used the rest of

give IV thiamine before hanging up IV glucose, especially in ER.

f) When people come in comatose or semicomatose, several things you always do: 1) 50% glucose if
a hypoglycemia problem 2) naloxone (OD) 3) IV thiamine

3. Vitamin B3 (Niacin): PELLAGRA (dermatitis)

Rash in sun exposed area due to niacin deficiency (also diarrhea, dermatitis, dementia);
hyperpigmentation in sun-exposed areas =

PELLAGRA (dermatitis)
NAD/NADP reaction (N stands for nicotinamide, and the nicotinamide was derived from niacin).
Therefore, all the oxidation reaction reactions are niacin dependent. Example: pyruvate to acetyl CoA
= went from NAD to NADH and niacin is involved here.

Tryptophan can used in synthesizing niacin and serotonin mino acid); but

Nicotinic acid = least expensive lipid lowering drug; see the flushing association with it; supposed to
take aspirin with it to remove the flushing related to nicotinic acid (used in treating familial
hyperlipidemia), it is the Drug Of Choice for elevated hyperlipidemia and cholesterol combined.

4. Vitamin B2 (Riboflavin):
FAD/FMN reactions are riboflavin cofactor reaction (therefore, whenever you have FAD and FMN
reaction, these are riboflavin cofactor reaction). (Niacin for NAD/NADP reaction, and riboflavin for
FAD/FMN reaction). Also, the first reaction: glutathione reductase converts oxidized glutathione
into glutathione which riboflavin is a cofactor for.

5. Vitamin B6 (Pyridoxine):
ut microcytic anemia. First reaction in the synthesis of heme involves succinyl
Coa, plus glycine. The enzyme is ALA synthase, and the cofactor is B6. Therefore, it is important
to the synthesis of hemoglobin and heme proteins. The cytochrome system is the heme system, too.
Myoglobin is different from Hb (has one heme group), while Hb has four heme groups. There is also
heme in the liver, in the cytochrome system. Pyridoxine is involved in the synthesis of heme, which is
in porphyrin.

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Pyridoxine is in the transaminases reaction. Most abundant substrate from making glucose in the
fasting state = alanine (amino acid from muscle
gluconeogenesis). How can an amino acid be used to make glucose? Transamination.
Transaminations (SGOT, SGPT) from the liver can take transaminases; they take amino groups out
and put them into other things; if you take the amino group out of alanine, this produces pyruvate (an
alpha keto acid). If you take aspartate and take the amino acid out, you have OAA, which is a
substrate for gluconeogenesis. If you take pyruvate, and add an amino group, can synthesize
alanine. If you take OAA, and add an amino group, you can make aspartate. This is what the
transaminases do, with B6 as a cofactor. B6 is also involved in the synthesis of neurotransmitters.
Therefore, a child that is B6 deficient, they end up with severe neurological problems because no
neurotransmitters (B6 is important to synthesizing the neurotransmitters). Important in
transamination, neurotransmitter, and heme synthesis.

Most Common Cause def B6 deficiecy = isoniazid; without B6, will develop neurologic
problems and sideroblastic anemia related to heme problem.

D. Other important co-factors

1. Pantothenic acid is related to FA synthase; not the rate limiting reaction, but important in making
palmitic acid (a 16 Carbon Fatty Acid), and helps in making CoA (Ex. acetyl CoA, HMG CoA);
pantothenic acid is the cofactor for these reactions.

2. Biotin
Cofactor for other reaction of pyruvate to acetyl CoA via pyruvate dehydrogenase = thiamine
is the cofactor, while biotin is the cofactor for Pyruvate decarboxylase to OAA. Therefore,
thiamine helps form acetyl CoA from pyruvate, while biotin helps form OAA from pyruvate.
If you are deficent, need to eat 20 raw eggs/day.
Deficiency: get a rash and go bald (alopecia). If biotin deficiency, cannot form OAA=cannot from
citrate either (this is the first step in gluconeogenesis, therefore you can end up with fasting
hypoglycemia). If you build pyruvate, it will be forced to go to lactic acid.

3. Trace elements
a) Chromium = glucose tolerance factor, and helps insulin do its job.
Oatmeal can also decrease glucose with all the fiber; good for a type II diabetic to be on chromium.

b) Copper lysl oxidase puts crossbridge between collagen fibrils and elastic tissue. Therefore, if
Cu deficiency, have weak collagen and weak elastic tissue, predisposing to dissecting aortic
aneurysm. Red hair in kwashiorkor also due to Cu deficiency.

c) Fluorine needed to prevent dental carries; too much fluorine leads to white, chalky teeth, also in
Colorado because water has too much fluorine. It will also get calcification of the ligaments, where
ligaments go into bone; the calcified ligaments are subject to rupture; any good radiologist can detect
fluorine toxicity.

d) Selenium In pentose phosphate shunt (HMP Shunt) form glutathione, and have riboflavin
helping that enzyme. Glutathione can neutralize peroxide, and this requires glutathione
peroxidase; selenium is the cofactor for this reaction. Therefore, in other words, it is an
antioxidant because if you are def in it; the glutathione cannot breakdown the peroxide. (Vit E usually
comes with selenium so one works on glutathione, while the other protects the lipid membrane from
free radical damage and scavenges oxidized LDL).
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e) Zinc Example: older person with dysgusia (abnormal taste) and anosmia (lack of smell);
smell and taste are both def in zinc def. Zinc is a metalloenzyme; therefore it has a trace metal as a
cofactor. Collagenase is a metalloenzyme because it has zinc in it, and it breaks down the type 3
collagen, so you can form type 1 collagen. Therefore, if deficient in it, will have poor wound healing,
and you get a rash on the face. So, rash on face, dysgusia, anosmia, poor wound healing = zinc
deficiency!!! Diabetics are zinc deficient, unless taking supplements.

4. Dietary fiber (insoluble and soluble) soluble fiber can lower cholesterol (not the insoluble
fiber). How it works (Ex. oatmeal
water into it from the colon, and also suck up bad things lipopolic acid. 95% of bile acids and bile
salts are reabsorbed in the terminal ileum. The 5% are lipopolic acids, which are carcinogenic
(produces colon cancer). So, fiber (insoluble and soluble), it sucks the lipopolic acid up, into the
interior of the stool, so it has no contact with the bowel mucosa. Plus, defecate more often and
therefore lipopolic acids have even less contact with the stool. Women are lucky because they
recycle estrogens; main way of excreting estrogens is in bile and out of your stool, but a small % of
estrogens are recycled back into the system. You may not necessarily need that, so, when on fiber,
increased estrogen is passed out, therefore, decreasing chance of breast cancer, ovarian cancer, and
uterine cancer because fiber in the diet.

IV. SPECIAL DIET

What 2 dIseases would you restrict protein in?

1) Chronic Renal failure because excess protein broken down to ammonia and other things the
ammonia is metabolized in the urea cycle, will have increase urea and the kidney will have to get rid
of more urea.

2) Cirrhosis of the liver defective urea cycle therefore cannot metabolize ammonia; most of the
ammonia that we have in our bodies comes from bacteria in our colon that have urease in them (H.
pylori); and they breakdown urea to ammonia in our colon. Ammonia is reabsorbed, and supposed to
go back to our liver and go into the urea cycle, become urea and get rid of it. But with cirrhosis, no
urea cycle, so the ammonia levels increase in the blood, leading to hepatic encephalopathy, mental
status abnormalities, asterixis; also caused by octpaneme, benzoic acid, neurotransmitters.

So, two situations to restrict protein: cirrhosis and chronic renal failure.

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 Chapter 5. NEOPLASIA
I. NOMENCLATURE: B9 vs. malignant

A. Main difference B9 = not metastasize contrary to Malignant = metastasize. Exception: Only

B9 tumor that metastasize: invasive mole (metastasize to lungs, but goes away).

B. Slides:
a) Most Common skin cancer INVADES but does not metastasize: Basal cell carcinoma.
b) Most Common B9 tumor in woman is Leiomyoma in Uterus

c) Fibroids smooth muscle; become very hard

d) Most Common B9 tumor in male (yellow) = Lipoma

LIPOMA
e) B9 tumor of glands = adenomas

ADRENAL ADENOMA
Thin adrenal cortex because it is functional; it could be making cortisol, therefore suppressing ACTH,

mineralocorticoids ome, causing atrophy of the zone glomerulosa (Glomerulosa-

salty, Fasiculata-sweet, Reticularis-sex).

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f) Tubular adenoma
Most Common precursor lesion for colon cancer (looks like strawberry on a stick)

C. Carcinoma vs. sarcoma

1. Carcinoma malignancy of epithelial tissue (3 epithelial tissues squamous, glandular, and
transitional)

a) Squamous cell carcinoma

How to recognize? Little swirls of increased redness (bright red) called squamous pearls.

b) Adenocarcinoma (Glandular Carcinoma) Round glands, with something in the middle.

ADENOCARCINOMA ADENOCARCINOMA OF RIGHT LUNG

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c) Transitional cell carcinoma in Urinary Bladder

Include: ureter, renal pelvis (from genital urinary tract) all with transitional epithelium

Therefore 3 carcinomas = squamous cell carcinoma, adenocarcinoma, and transitional cell

carcinoma.

d) Malignant Melanoma first step in management? Excision (B9 version = nevus), both are
derived from melanocytes. Most rapidly increasing cancer in the USA. They are S-100 Antigen
(aput tumors)

e) Aput Tumors: S- aput tumors; aput is precursor uptake decarboxylation,

meaning that they are of neurosecretory cell or neural crest origin. Therefore, on Electron
Microscopy, have neurosecretory granules. S-100 Antigen is used to stain things of aput origin or
neural crest origin (most, not all, will take up that Antigen).

Examples of aput tumors: melanoma; small cell carcinoma of the lung; bronchial carcinoid;
carcinoid tumor at the tip of the appendix; neuroblastoma (secretory tumor), Ex. 2 y/o with tumors
all over skin, and on biopsy, it is S- adrenal medulla, metastasize to skin.

2. Sarcomas are malignancy of MESENCHYMAL tissue (not epithelial).

*Sarcoma of smooth muscle = leioymyosarcoma
*Striated muscle = rhabdomyosarcoma
*Fat = liposarcoma; (these are malignancies of mesenchymal tissue,
epithelial tissue).

Examples:
a) B sunburst appearance on x-ray because this
tumor actually makes bone. Dx = osteogenic sarcoma (bone marrow Embryonal rhabdomyosarcoma
king sarcoma).

Biopsy from girl having necrotic mass coming out of her --

? Embryonal rhabdomyosarcoma. This is the Most
Common sarcoma of children (vagina in little girls and penis in little boys)

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c) Movable mass at angle of jaw = MIXED TUMOR (in parotid)

Mixed two histologically have two different types of

tissue but derived from SAME cell layer (not a teratoma, which is from three cell layers), Most
Common overall salivary gland tumor (usually B9 = mixed tumor)

d) Teratoma = tooth, hair, derived from all three cell layers (ectoderm, mesoderm, and endoderm)
germ cell tumors because they are totipotential, and stay midline. Ex. anterior mediastinum, or
pineal gland; therefore, teratomas are germ cell, midline tumors.

e) Cystic teratoma of the ovaries:

66 y/o girl with sudden onset of Right Left Quadrant
disease, ectopic pregnancy, follicular cyst). On x-ray, see calcifications of the pelvic area! Cystic
teratoma (the calcifications can be bone or teeth). Usually develop in midline germ cell tumor.

II. NOMENCLATURE: Leukemia and lymphoma

Most Common on the boards: ACUTE MYELOBLASTIC ANEMIA

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 AUER rod from myeloblast, and hypersegmented neutrophil
from B12 and folate deficiency.

A. Leukemia = malignancy derived from stem cells in the Bone Marrow, and they can metastasize to
lymph nodes, leading to generalized lymphadenopathy and hepatosplenomegaly.

B. Malignant lymphoma: arise from LYMPH nodes, and can

metastasize anywhere, include Bone Marrow.

The Most Common site in body for lymphoma NOT developing (extranodal=outside lymph
node) in lymph node: Stomach by H. Pylory.

2nd Most Common Cause location (lymphoid organ in the GI tract) =

in the terminal ileum).

Most Common lymphoma = follicular B cell lymphoma. This is an example of knocking off
apoptosis gene -14:18 translocation of a heavy chain; when you get the translocation, B cells will
make bcl-2, which inactivates apoptotic gene in the B cell, therefore, the apoptotic gene is immortal,
leads to cancer.

III. Nomenclature of Trophoblastic Tumors

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A. Hydatidiform mole , is a B9 tumor of the WHOLE chorionic
villus, pr It manifests in the first trimester with
signs of preeclampsia (Hypertension, proteinuria, edema in the first trimester). On ultrasound,
will see uterus too large for its gestational age, with a snowstorm appearance = classic complete
mole; and can progress to choriocarcinoma.

B. Choriocarcinoma mole is a malignancy of the lining of the chorionic

villus: the synctiotrophoblast and the cytotrophoblast (not the actual chorionic villus). Chorionic villi
are formed with cytotrophoblastic cells, including synctiotrophoblast on the outside (has
contact with the blood, from which O2 is extracted); under the synctiotrophoblast is the
cytotrophoblast, then have in the chorionic villus, then have vessel that
becomes the umbilical vein, which has the most O2 in the vessels of the fetus.

Which makes hormones? The syncytiotrophoblast synthesizes B-HCG and human placental
lactogen (growth hormone of pregnancy it gives amino acids and glucose from mom to
baby).
So, when gestationally derived, and even when they metastasize to the lungs, they respond well to
chemotherapy (methotrexate, chlabucil). Therefore, these are highly malignant tumors, but go away
with chemotherapy.

Audio File 1: Day2 Neoplasia 2

IV. THING THAT END IN OMA

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Everything that end in oma is not necessarily B9 Ex.melanoma (malignant tumor of
melanocytes), lymphoma (malignant tumor of lymph nodes)

Also, all that ends in oma is not necessarily a neoplasm Ex. hamartoma = overgrowth of tissue
that is normally present in that area.

Example: BRONCHIAL HARMATOMA seen lung. Which is B9

The polyp in PEUTZ JEGHERS syndrome is a hamartoma

se in risk of poly cancer.

Most Common polyp in Gastric Intestine:

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 Hyperplastic polyp lace it
is not suppose to be (Ex. pancreatic tissue in the stomach) this is called a:

choristoma, or heterotopic

Most Common = BLEEDING from a gastric mucosa that

is ulcerated, or pancreatic tissue that is ulcerated. Should gastric mucosa be in th
diverticulum? No, because it is in the small bowel (about 2 ft from the ileocecal valve).
Hemartomas are non-neoplastic, and therefore do not have cancer producing potential.

V. MALIGNANT CELLS

Increased mitotic rate does not mean cancer. What makes mitosis malignant is having an atypical
mitotic spindle (they are (aneuploid) = have more than the normal 46 chromosomes. Key thing that
determines if it is malignant is its ability to metastasize. Malignant cells usually have a longer
cell cycle than the cells they derived from. How many doubling times does it take to get a tumor
that can be detected clinically? 30 doubling times means that the tumor goes through the cell
cycle 30 times, and a tumor of one sonometer in size is produced; 10 9 in mass. Malignant cells are
immortal adhesion; if they were stuck to each other, they would
have problems infiltrating tissue. Malignant cells have simple biochemical systems, typically
anaerobic metabolism, and have many enzymes such as proteases (used to break through
tissue), collagenases (used to break through Basement Membrane). This is what makes a
malignant cell malignant.

VI. MECHANICS OF METASTASIS: lymphatic, hematogenous, seeding

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A. Lymphatic metastasizes:

How do carcinomas usually metastasize?

LYMPH NODE METASTASIS IN PAPILLARY

CARCINOMA IN THYROID

Lymph nodes drain to their regional lymph nodes; Ex. breast cancer goes to axillary nodes or
internal mammary nodes. For colon cancer, go to nodes around them (the local lymph nodes); same
with carcinoma of the esophagus. What part of the lymph node do metastases go to? Subcapsular
sinus. If they can get through the lymph node, they go to the efferent lymphatics which drains into the
thoracic duct, and then into the subclavian, and then they become hematogenous. Therefore,
carcinoma can become hematogenous, this means that they 1st went through the lymph nodes;

LYMPHAGITIC SPREAD IN ADENOCARCINOMA now, they

can spread to other organs (Ex. bone, liver, etc). This is better than sarcoma because can feel the
lymph nodes by clinical exam and pick up before it spreads.

B. Hematogenous metastasizes: MORE DANGEROUS!!!

On the other hand, Sarcomas go right through Blood Vessels and are characterized by
hematogenous spread lungs and bones are common sites of sarcomas.
Therefore, they are a little worse because they immediately go hematogenous, and do not give a clue
that they are spreading. Example: have angiosarcoma of the breast; would you do a radical
dissection of the axilla? No, because angiosarcoma does not go to the lymph nodes, therefore, do a
simple mastectomy. If it is breast carcinoma, take breast and lumpectomy and local axillary lymph
nodes and complete the dissection.

Examples:
*Follicular carcinoma of the thyroid

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 Goes to Blood Vessels, and takes the
hematogenous route.
*Renal adenocarcinoma goes to renal veins (also determines prognosis)
*Hepatocellular carcinoma like to attack the blood vessels.

C. Seeding: OMENTAL SEEDING cancers that are in cavities and

have a potential of seeding, like little malignant implants. Most ovarian cancers are surface
derived cancers, therefore derived from lining around the ovary, and they seed like little implants.
Therefore, easy to throw out these implants and for it to metastasize to the omentum, and into the
pouch of Douglas. The pouch of Douglas is posterior to the uterus and anterior to the rectum and is
felt by digital rectal exam. The pouch of Douglas is to a woman, as the prostate gland is to the man.
If you do a rectal on a man, and push forward, you will feel the prostate. If you do a rectal on a
woman and push forward, this is the pouch of Douglas.
This is an important area because
go here clotted blood in a rupture ectopic pregnancy, where endometrial implants go in
endometriosis, and where seeding goes in ovarian cancers (pouch of Douglas). So, seeding of
ovarian cancer to the omentum and can actually invade. Can also seed in the pleural cavity, for
example: peripherally located lung cancer that can seed into the pleural cavity. Glioblastoma
Multiforme GBM (Most Common primary malignancy of the brain in adults) can seed into the
spinal fluid and implant into the entire spinal cord, as can a medulloblastoma in a child.

VII. MOST COMMON (MC) CANCERS

The first question is to ask: ¿

90
In most cases, metastasis is the Most Common cancer in an organ (not a primary cancer).
Exception: renal adenocarcinoma (which is more common than metastasis to it).

Lung: Most Common cancer is metastasis from the breast cancer. Therefore, Most Common
cancer in the lung is breast cancer. Therefore, women are more likely to get lung cancer.

Bone: Most Common cancer is metastasis to bone is breast cancer because the batsom
system; it is a venous complex going from base of the skull down to the sacrum, and has no valves
in it. The little tributaries communicate with the vena cava and also go right into the vertebral bodies.
Then they collect around the spinal cord and go up.

Example: a lady has a little plug of tumor in the intercostal vein, and bends down to pick up
something off the ground, which causes the cancer to be dislodged from the vein to the vena cava to
the batson plexus in the vertebral bodies, and 3 months later she is complaining of lower back pain.
All of a sudden, she is stage four cancers.

Most Common bone metastasis = VERTEBRAL COLUMN. 2nd Most Common cancer in the
head of the femur (in a woman, this is due to breast cancer Ex. breast cancer in head of femur,
when they thought it was degenerative arthritis).

Most Common organ metastasis to = lymph nodes (carcinomas are more common than
sarcomas, and carcinomas like to go to lymph nodes, meaning it is the Most Common metastasis to)

Liver: Most Common cancer of liver = metastasis from lung into liver.

Testicular Cancer: Where would testicular cancer metastasize first? Paraortic lymph nodes;
NOT the inguinal lymph nodes because it derived from the abdomen, and then descended. Example:
seminoma (malignant) will metastasize to paraortic nodes because that is where it came from.

Left supraclavicular node ( ) The Most Common primary metastasize to

stomach cancer! There is a mass in the left supraclavicular nodes along with wt
loss and epigastric distress.

Bone: Best test looking for bone metastatis? Radionucleide scan. Example: everywhere that is
black in a woman is mets from breast cancer. Most Common bone metastasis to = vertebral column!

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Metastasis that are lytic (break bone down) and are blastic
(metastasis go into bone and induce osteoblastic response).

A. Lytic Metastasis: they can lead to pathologic fractures and hypercalcemia. Multiple myeloma
with punched out lesions b/c all malignant plasma cells have IL-1 in them (aka osteoclast activating
factor)

B. Blastic metastasis: alkaline phosphatase will be elevated. Example: this is a male with prostate
cancer (prostate cancer is blastic); it is making bone (OSTEOBLASTIC METASTASIS) and will
release alkaline phosphatase

Example: 80 y/o man with lower lumbar pain with pt tenderness; what is first step in management?
Digital rectal exam would be the first thing to do because this would be stage four disease, and the
prostate is palpable; so, this is the easiest and cheapest test (not PSA, or radionucleide bone scan to
make sure its not mets).

Lytic metastasis have lucency (absence of bone) Ex. vertebrae collapse

Blastic metastasis have entity on x ray.

If you see any specimen with multiple lesions in it, it is METASTASIS (primary cancers are confined
to one area of the organ).

WHITE=BRAIN, BROWN=LIVER, RED=BONE

Most Common cancer site metastasis in lung = breast

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Most Common primary site for metastasis in brain: Lung
Most Common site for metastasis in Liver: Lung
Most Common location for metastatsis = lumbar vertebrae
Most Common site for metastasis in bone: Prostate Cancer
Most Common cancer killer in men and women = lung cancer
Most Common metastasis to adrenal = lung therefore they always do a CT of the hilar lymph
nodes, and adrenal glands in the staging of all lung cancers.

VIII. STAINS AND Electron Microscopy USED TO HELP DIAGNOSTIC DISEASE:

Stains: Desmin good stain for muscle Ex. used for rhabdomyosarcoma
Stain for Keratin (most carcinomas have keratin in it, therefore stain for that)
Stains help to identify different types of tumors.
Vimentin- mesenchymal cells

Electron Microscopy: Used when nothing else helps

*Auput tumor see neurosecretory granules.
*Histiocyte tumor (Ex. histiocytosis X) see birbeck granules, with CD 1
*Muscle see actin and myosin filaments
*Vascular malignancy Wibble palad bodies (have vWF in them); they are of endothelial origin.
*Gap junctions (which communic

IX. ONCOGENESIS: IMPORTANT TO THE BOARD!!!!

A. Definitions of oncogenesis:
1) Initiation (mutation Ex. within the cell cycle)
2) Promotion (where multiple copies of the mutation are made)
3) Progression (sub-specializing) differents types of cancer cells have differents functions
malignant cells with one purpose to kill you. Some stay where they are; some invade (and are
given special things for it to be able to invade); some have special receptors to home in to specific
organs; some resist chemo, some spread, some make enzymes to penetrate tissues.

Final Points: 2 sets of genes involved with cancer:

1) Involved in growth process (cell cycle related)
2) Genes that suppress things (suppressor genes)

B. Things that are involved in trying to get a cell to divide:

Growth Factors (GF) (epidermal derived Growth Factors); protooncogenes normal genes, which

oncogenes, which are bad and become cancerous. Certain protooncogenes code for growth factors
Ex. SIS, whose function

make
receptors Ex. erb-B2 = breast cancer, which codes for a receptor and ret = seen in
Multiple Endocrine Neoplasia syndrome (MEN I and IIa and IIb).

We have to send a message to the nucleus, so have another set of genes, whose job is to send the
message; some located in the cell membrane. Example: ras protooncogene sends a GTP (a
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Another example: abl protooncogene which lives in the cytosol, very close to the nuclear
membrane and also is involved in messages.

Who is the messenger sent to? The message is sent to a group of protooncogenes in the nucleus.
Once that message is sent to them, there is stimulation of nuclear transcription of that message; in
other words, the cell divides and makes whatever it is supposed to make. Classic protooncogenes
there are myc protooncogenes = n-myc and c-myc (n-myc is for neuroblastoma, and c-myc
is for Burkitts lymphoma).

often phosphorylated proteins). Example Ex. insulin hooks into receptor on adipose and activated
tyrosine kinase (located right on the receptor), which makes a phosphorylated product, goes to the
nucleus (to divide), and also goes to Golgy Apparatus and attaches to GLUT-4, which is made from

messages go to nuclear transcribers in the nucleus and these are myc oncogenes.

The suppressor genes are controlling the cell cycle. The 2 most important are Rb suppressor
gene and p53 suppressor gene. Normally, they control the cell cycle and do not let cell cycle

How do we initiate a cell? Mutations mechanisms: usually a point mutation Ex.substitutes aa for each
other. The p53 suppressor gene and the ras oncogenes is a point mutation. All suppressor genes
are due to point mutation.

Other mutations include:

Amplification make multiple copies (erb-2 is an amplification system).

Translocation ChronicMyelogenous

Leukemia translocation of abl (non receptor tyrosine kinase activity from chromosome 9 to 22.
On chrosome 22), it fuses on a cluster region of the fusion gene, and because of the tyrosine kinase
activity, it sends a message and stem cells keep dividing; Ex. Philly chromosome. Another example:
Cancer associated with Epstein Barr virus translocation of myc nuclear transcriber gene from
chromosome 8 and puts it on chromo :

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 BURKITTS LYMPHOMA
Receptor for Epstein barr virus on all B cells CD 21; when it hooks on to receptor, it causes B cells
to become plasma cells and make Antibody (therefore, this virus is an amazing stimulating of
Antibody synthesis, as is the Cellular Medullar Virus.) The more a cell divides, the worse it is if
something happens to it; Ex.EBV virus , 8,14 translocation of myc oncogenes from 8 to 14 and all of a
sudden you are making multiple copies, and leads to lymphoma (greater chance that you do
something, the greater chance that you will screw up).

Follicular B cell lymphoma translocation of 14:18; inactivation of suppressor gene.

Translocation 15:17 = acute progranulocytic leukemia; Rx Vit A (retinoic acid) b/c it matures the
blasts, therefore the malignant cell becomes B9.

C. Tumor Suppressor genes

Suppressor genes suppress, therefore if knocked off, whatever they were suppressing keeps on
going. Key suppressor genes: p53, Rb gene, APC adenomatos polyposis coli (familial polyposis),
neurofibromatosis NF-1, 2, WT-1, , BRCA1 and 2 (both involved in DNA repair, and
one is on chromosome 13 while the other is on chromosome 17); BRCA1 can be breast cancer,
ovarian cancer, or others; BRCA2 is TOTALLY related to breast cancer. Only 15% of breast
cancers have genetic associated with these genes, therefore, most cases are sporadic.

X. COMMON THINGS THAT PREDISPOSE MUTATIONS:

Protooncogenes are activated, while suppressor genes are inactivated and

3 main ways this occurs: chemicals, viruses, radiation

A. Chemicals: Which of the three is most common in initiating a cell producing a mutation?
Chemicals smoking = Most Common Cause death in USA due to polycyclic hydrocarbons.

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By itself, smoking is Most Common than virally induced or radiation induced cancers. Smoking

#1 cause

Most Common Cause papillary tumor of the bladder = transitional cancer (smoking)
What if you worked in a dye industry? Aniline

ria, did cytology and

saw cells, what drug is pt on? Cyclophosphamide (hemorrhagic cystitis); prevent with mesna, and
can cause transitional cell carcinoma (therefore acts as a carcinogen!)

Most Common Cause of Lung Cancer = polycyclic hydrocarbons from smoke; most often
associated with smoking is small cell and squamous;

B. Viruses:
Virus associated cancer: a virus with nonpruritic raised red lesions. Dx?

K (due to Human Herpes Virus- HHV 8)

Burkitts; due to Epstein barr varies which also causes nasopharyngeal carcinoma, especially in
Chinese.

Liver Hepatocellular carcinoma due to hepatitis B from Asia; also due to a mold aflatoxin B;
combo of hep B, cirrhosis, plus aflatoxin makes is common in Asia; can also be caused by hep C.

HIV is associated with primary CNS lymphoma. They will ask: the rapidly increasing incidence
of primary CNS lymphoma can be directly attributed to what? HIV
HPV causes squamous cancer of cervix, vagina, and vulva, and anus of homosexuals due to
unprotected intercourse; due to HPV 16, 18, 31. This virus causes anal squamous cell carcinoma
in homosexuals. The virus works by making two proteins, E6 which knocks off p53, while E7
knocks of Rb.

C. Radiation
Most Common cancer associated with radiation = leukemia
Most Common leukemia associated with radiation = CML (9, 22 translocation of abl gene)

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Papillary carcinoma of thyroid is also commonly seen as a
result of radiation. Example: pt had radiation in head and neck, and has nontender nodular masses
in cervical region = metastatic papillary carcinoma of the thyroid related to ionizing radiation.

Example: osteogenic sarcoma

Example: which medical profession is most subject to leukemia? Radiologist, leukemias are
e radiologists that are commonly involved with this.

Example: if you have Jacob Crutzfelt disease, what dr are you? Neuro-Pathologist (because work
with brains and prions)

Example: basal cell carcinoma (pearly gray papules), multifocal;

this is non ionizing radiation (ionizing radiation is the bad stuff). This is UV B light (b is bad); UV A

sclerosis (therefore used by dermatologists), aka black light. UV B light is what you protect yourself
from to prevent getting skin cancers (basal cell = Most Common, then squamous cell, then
melanoma). UV D = thymidine dimmers

Example: lesion in sun exposed areas that is scraped off and grows back aka solar (actinc)
keratosis; it predisposes to squamous dysplasia. Arsenic is a metal that is associated with skin
cancer. Bangladesh has bad water supply which contains arsenic, therefore they have a high
number of squamous skin cancers, and with time it can lead to cancer of the lung, and
angiosarcoma of the liver.

Example: kid with white eye reflex RETINOBLASTOMA

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 Chromosome 13. This disease is sporadic and familial. It takes
the sporadic disease 2 separate mutatio 13).
If it is familial, which is Autosomal dominant it takes just one mutation, because you are born with one
already inactivated, therefore only need one more mutation on the other chromosome in order to
develop retinoblastoma.

White eye reflex is not most common due to retinoblastoma the Most Common Cause is
congenital cataract (which can be due to CMV, rubella, or any congenital infections). Which
drug predisposes to cataracts? Corticosteroids; ther
may develop cataracts.

Audio File 1: Day2 Neoplasia3-Hematology 1

XI. GENETIC DISEASE

Xeroderma pigmentosa sun exposed areas, auto recessive,

can cause all skin cancers (Basal Cell Carcinoma, Squamous Cell Carcinoma, and melanomas), and
the defect is in DNA repair enzymes. Other DNA repair defects are associated with BRCA1 and
BRCA2, p53, they splice out the defects, this group is called the chromosomal instability syndromes
lems with DNA repair.

Basic rule of thumb for Basal Cell Carcinoma and Squamous Cell Carcinoma:
*Upper lip and up is basal cell carcinoma;
*lower lip and down is squamous cell

(therefore, lesion on lower lip , associated with pipe smoking and sun exposure=
SQUAMOUS CELL CARCINOMA
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Example: keloid squamous cell carcinomas and 3rd degree burns and squamous cell carcinoma

So, wherever there is constant irritation, and division of cells related to irritation, there is an increase
susceptibility to cancer. This does not hold true for scar cancer tissue related cancers of the lungs or
adenocarcinoma (just applies to things on the skin Ex. burns and draining of sinus tracts).

Only bacteria associated with 2 cancers? 1. H. pylori adenocarcinoma and 2. Low grade
malignant lymphomas.

XII. GRADE vs. STAGES

A. Grade = what does it look like? When the cell is well differentiated (low grade) = means that
the tumor is making something like keratin or glands, and . When the cells is
anaplastic (high grade) = is poorly differentiated under the microscope, and you cannot tell what it
is.
Example: squamous cell carcinoma can see keratin pearls; can IDENTIFIED
cancer.
Example: see gland like spaces, can IDENTIFIED so its low grade.

B. Stage = (TNM) Most Common staging system; goes from least important to most important (TNM).

T = size of tumor; if tumor is over 2 centimeters, it has a chance of metastasis.

N = nodes (next most important for prognosis).
M = metastasis outside of nodes (most important prognostic factor)
indicates that cancer has spread to other organs like bone, etc.

Example: pt with prostate cancer, which of following has it the worst?

A. were cancer limited to prostate.

B. it went into seminal vesicles.
C. it involved the wall of bladder.
D. went to lymph nodes, or bone.

Answer = bone (bone represents the tem. Ex. stage 4 by definition=metastasis)

Example: a slide of a liver, colon and a lymph node cancer: what is most important size of
tumor or lymph node involvement? Lymph node.
XIII. HOST DEFENCES most important is Cytotoxic CD8 T cell
Others NK cells, Antibodies, macrophages, type 2 Hypersensitivity.
In hospital, they look for altered MHC class I Antigens in the cancer pt, because cancer wants to kill T
cells; they do this by putting in perforins, which activate caspasases, and this leads to apoptosis (the

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signal, from the perforins, activate the caspasases, which have proteases, which break down the
nucleus and mitochondria, and cell dies, without any inflammatory infiltrate).

XIV. OTHER DISEASES SEEN IN MALIGNANCY:

A. Cachexia cause is TNF @; it is irreversible.

Once you see a pt with disseminated cancer about to go into catabolic state, can give then total
-alpha)

B. Many hematologic causes of anemia seen in malignancy:

*Most Common anemia in malignancy is Anemia of chronic disease (this is the overall most common)

*Colon cancer: left side obstructs with right side bleeds; if you have Right side bleed in colon cancer,
Fe (iron) deficiency anemia is very common.

*Metastasis to Bone Marrow and replace Bone Marrow. Or, use chemotherapy drugs that are cell
cycle specific or cell cycle nonspecific they wipe out (destruct) the bone marrow.

C. Associations with disseminated cancers:

1. Most pts with disseminated cancers are hypercoagulable (they have a tendency for forming
clots).

Classic Example: a pt with painless jaundice, left supraclavicular node (this is a distracter), had light
color stools, lesions that jump from one part of body to next tro
thrombophlebitis due to carcinoma of the head of the pancreas). *Pancreatic cancers can ALSO
mets to left supraclavicular node ( node), and
vascular problem in the veins that jumps from one place to the next.

2. Another common thing seen is disseminated cancers is thrombocytosis an elevated platelet

count. Other causes of thrombocytosis: Fe deficiency, splenectomy (Ex. see scar on abdomen),
Tuberculosis, anemias. If you cannot find any obvious cause of thrombocytosis then the cause
is cancer. 40% of disseminated cancers are thrombocytosis. Or a do a stool guaic for colon cancer.

D. Most Common Cause fever in malignancy = due gram negative infection or gram positive
(Staphylococcos Aureus). An E. coli-if you have an indwelling catheter (Pseudomonas)-if you have
a respirator.

Most Common Cause of death in cancer = infection

XV. PARANEOPLASTIC SYNDROMES:

These are signs and sometimes symptoms saying that you may have an underlying cancer present.
important because when you recognize the signs and symptoms, then you can catch the cancer
before it metastasize.

Most Common Paraneoplastic syndrome = HYPERCALCEMIA

2 mechanisms for hypercalcemia in malignancy:

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1) Metastasis to bone, produce a chemical (IL-1, PGE2, both
that produces lytic lesions in bone, and you get hypercalcemia.

2) Renal adenocarcinoma or squamous carcinoma of mainstem bronchus that sits there and makes
PTH-like peptide and causes hypercalcemia because it acts like Parathyroid Hormone (PTH) and

Example: 2 black lesions both are markers for gastric adenocarcinoma:

1. Under the arm: ACANTHOSIS NIGRICANS

2. SEBORRHEIC KERATOSIS
(These are not neoplasms); however, when these suddenly develop overnight, you get multiple
outcroppings (lesserr tree-ar sign), and the outcroppings is a phenotypic marker for
gastroadenocarcinoma; this is easy to remember because 2 black lesions are markers from
gastroadenocarcinoma.

Example: clubbing periostitis; inflammation of underlying bone causes proliferation of the soft

tissue around it, which leads to clubbing (called

HYPERTROPHIC OSTEOARTHROPATHY: look the ends of the fingers and toes are enlarged and
the nails are shiny and abnormally curved). Clubbing is associated with primary lung cancer.

Example: least common collagen vascular disease, but the most often associate with a certain
cancer. They have an elevation of serum CK; this is dermatomyositis; raccoon eyes, so you see
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inflammation of skin and muscle; high associate with leukemias, lymphomas and lung cancer.
patches of knuckles s (seen in dermatomyositis).

Example: vegetations (sterile) on the mitral valve MARANTIC ENDOCARDITIS Ex. nonbacterial
thrombotic endocarditis. Associated with mucous producing cancers such as colon cancer. Not
infectious.

Can they embolize? Yes. You will need history to separate from rheumatic fever, but history will
relate more to colon cancer (Ex. polyarthritis)

Example: - LUNG CANCER = SMALL CELL CARCINOMA

Which is secreting either ADH or ACTH; also, for small cell, they are aput tumors, S-100 Antigen
positive, neural crest origin, and neural secretory granules on electron microscopy.

amyloid (calcitonin) =

MEDULLARY CARCINOMA OF THE THYROID.

Example: Hypercalcemia or secondary polycythemia: renal adenocarcinoma (can make PTH like
peptide or (erythropoietin) EPO).

Example: Hypoglycemia or secondary polycythemia: Hepatocellular carcinoma

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(They can make EPO (erythropoietin) or insulin-like factor).

XVI. TUMOR MARKERS

A. 2 markers associated with Testicular cancer alpha feto protein (AFP) (which is really the
albumin of a fetus) and HCG. AFP is a maker for yolk sac tumor (endodermal sinus tumor). So
the tumors in kids are yolk sac tumors (alpha feto protein)

AFP is also associated with Hepatocellular carcinoma, increased in neural tube defects (must be

Marker for malignancy in bone, associate with monoclonal spike: Bence Jones Proteins (light
chain Ig), associated with Multiple Myeloma.

Tumor marker for prostate cancer: Prostate Specific Antigen (PSA); not special for cancer
because, it can be also increased in hyperplasia; it is sensitive but not specific. If you do a rectal
exam, it is not increased. PSA is NOT an enzyme; it is an Antigen and is within the actual cell. It will
not increase with a rectal exam.

Tumor marker for Breast cancer (surface derived) =CA-15, 3.

Tumor marker for Ovarian cancer = (carcinoembrionic antigen) CA 125
CEA Antigen for colon cancer; and sometimes used for small cell, and breast cancer.

CEA can be a part of an immune complex, and will get CEA: anti-CEA immune complexes which
deposit in the kidney, and lead to nephrotic syndrome this is diffuse membranous
glomerulonephritis = Most Common overall cause of nephrotic syndrome. Many of these are related
to malignancy because CEA can be the Ag that is deposits in the glomeruli.
woman with a trophoblastic mole, what would you get? Beta HCG

What is Most Common primary tumor of the brain in kids? Cerebellar cystic astrocytoma (B9).

primary tumor, and then the answer is medulloblastoma, which derives from cerebellum). MC actual
tumor of the brain cerebellar tumor derived from astrocytes;

Most Common childhood cancer = ALL leukemia (other childhood tumors include CNS tumors,
neuroblasto
embryonal rhabdomyosarcoma.)

Adults: incidence:

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*Woman: 1st. breast, 2nd. Lung, 3rd.colon *Men: 1st. prostate, 2nd. Lung, 3rd.
colon

*Cancer Killers: lung is #1 in both (followed by prostate/breast and colon)

*2nd Most Common cancer and cancer killer in men and women combined = COLON CANCER

Therefore, from age 50 and on, you should get a rectal exam and a stool guaic.
After 50, Most Common Cause guaic is colon cancer.

Most Common GYN cancer: 1st. Endometrial (the best prognosis), 2nd. Ovarian, 3rd. Cervix.

Cervix is least common because Pap smear. When you do a cervical pap, picking up cervical

Because cervical pap smears; the incidence of cervical cancer has gone down significantly because
the detection of the precursor lesion, cervical dysplasia. Therefore, cervical Pap smear, incidence of
cervical cancer has gone down dramatically (picking up the precursor lesion); with mammography,
the incidence of breast cancer decreases, like with PSA.

Most Common Gyn cancer killer: 1st. ovarian, 2nd. Cervical, 3rd. endometrial.

What is the only known existing tumor vaccine? Hepatitis B Virus

Why? Because, Hepatitis B is the Most Common infection transmitted by accidental needle
stick in hospitals. Because viral burden (charge) of Hepatitis B in blood is greater than any
infection, even more so than HIV.

So, with the He (1) Hepatitis B, (2) Hepatitis D (requires

Hep B), and (3) hepatocellular carcinoma (related to Hepatitis B related cirrhosis).

How do you eradicate hepatocellular carcinoma? Vaccination (Ex. in the Far East).

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 CHAPTER 6: HEMATOLOGY
BIG PICTURE!!!!!

I. RED BLOOD CELLS (RBC) MCV (MEAN CORPUSCULAR VOLUME) First Aid-pag. 332

A. MCV < 80: Microcytic (hypochromic) anemia: Fe (Iron) deficiency, decrease serum iron,
decrease ferritin (intracellular iron stores) and increases Total Iron Binding Capacity. Most
Common of Anemia. Thalassemias alfa y beta (target cells), Anemia of Chronic Disease
(ACD), Sideroblastic anemias (chronic alcoholism and lead poisoning).

B. MCV > 100: Macrocytic anemia: B12/Folate deficiency (Megaloblastic Anemia). Most
Common see folate deficiency in an alcoholic. Drugs that blocks DNA synthesis and produce that
anemia are (sulfa, phenytoin, azidothymidine (AZT).

C. MCV 80-100: Normocytic (Normochromic) anemia:

Causes:
1. Acute hemorrhage - Blood loss
2. Enzyme defects: G6PD deficiency (Xlinked) or Pyruvate Kinase deficiency (Autosomal
Recessive)
3. RBC membrane defect: hereditary spherocytosis
4. Bone Marrow disorder: aplastic anemia, leukemia.
5. Hemoglobinopathies: Sickle Cell anemia.
6. Autoimmune hemolytic anemia.
7. Early Iron deficiency or Anemia of chronic disease (ACD): low Total Iron Binding Capacity,
hight ferritin, high iron storage in marrow macrophages.

*low reticulocyte count corrected: aplastic anemia, renal disease

*high corrected reticulocyte count: hemolytic anemias hereditary spherocytosis, sickle cell,
G6PD deficiency, autoimmune hemolytic anemia, microangiopathic.

II. RETICULOCYTE COUNT: Before CBC, Reticulocyte Count is the first step in the work up of any
anemias. What is reticulocyte? Young Red Blood Cell. In 24 hrs, a reticulocyte will become a

MATURE RED BLOOD CELL with a biconcave disk.

If you have an anemia, the reticulocyte count is important because it tells you where the problem
is: Out or in the Bone Marrow. To determine this, look at reticulocyte count.

105
*If the Bone Marrow was the problem, then the reticulocyte count would not have an
appropriate response. What is an appropriate response? You would have a Bone Marrow with

prematurely, therefore working correctly to correct the anemia. Therefore, it tells whether the
Bone Marrow is responding appropriately or not.

If you have blood loss right now, it takes at least 5-7 days to get the response of making more
reticulocytes (like the kidney making bicarbonate, which takes a few (3-4 days).

If nothing is wrong with the Bone Marrow, then it should have a normal reticulocyte response; if
there is something wrong, will not have a normal response (this is important because might decide
whether you have to do a Bone Marrow exam or not). Therefore, if you have a normal reticulocyte
count, do not do a Bone Marrow exam.

*Have to correct the reticulocyte count for the degree of anemia. (Formula):
Corrected reticulocyte count = Hematocrits (Hct) of the pt ÷ 45 # reticulocyte count that you are
given.

Example ount that was

initially measured is 9% (which is increased anything over 3% is increased).

This one Marrow is responding correctly because the reticulocyte count is 9% (but
have to correct for the degree of anemia). 15/45 X 9 is 3; so, when we correct for the anemia, we
therefore, 3% or greater = good response; 3% or less =
bad response; so, this figure is saying that it is a reasonable response occurring in the pt.

RETICULOCYTE need to do a special giemsa stain to see the

black filaments (which are RNA filaments); So, in about 24 hrs, 25% the normal Hb is being
synthesized and need RNA filaments; cannot see these without doing a special stain (look like
little black worms in the RBC).

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 RETICULOCYTES using right giemsa stain with bluish stain
polychromasia. These are younger blood cells than the 24 hr old reticulocytes. They still have
the basophilia, which is not normally present in the peripheral blood; so, when we see
them, it means that the Bone Marrow is really responding, and pushing even the younger
ones out.

When polychromasia
take 2-3 days before they become a mature RBC. Why is this important? Because we have
to make an additional correction why? When we are working up an anemia, we do a
corrected reticulocyte count and want to know how the Bone Marrow is responding right
now at this day.

Not interested about what will happen in 2-3 days, but what will
problem: when they do a reticulocyte stain, these guys will also have RNA filaments and will be
counted in the reticulocyte count and it will show a falsely elevated reticulocyte c
want these because they take 2-3 days before they become a mature RBC) instead we want the
normal guys there.

So, how do we factor them out? Divide by 2. So, make the first correction for the degree of
anemia (did it with 3% in this case), look at CBC and see nothing that says poly
say the CBC coun then have to make an additional correction by
dividing by 2.

All of a sudden, it is now 1.5% and this is not a good reticulocyte response! So, when you see
n you have to make an additional correction by dividing by 2.

Example: reticulocyte cannot see with right giemsa stain; use special giemsa stain to see RNA
filaments, and ribosomes (look like dots BASOPHILIC STIPPLING, seen in lead poisoning).

III. SIDE NOTES:

When looking at CBC you can make many diagnoses.

Rule of 3 is good: Hb x 3 should roughly equal the Hct (hematocrits).
Example: for previous Ex, had 15% Hct, therefore, 15/3= Hb was a 5.

for every unit transfused increase the Hb by 1 and the Hct by 3%.
Example
grams grams of Hb,
with Hct of 24. (5+3=8Hbx3=24Hct.) the pt has a GI track is bleeding.

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 *Most Common Cause of anemia worldwide = Fe (iron) deficiency anemia (microcytic)
*Most Common Cause of Fe deficiency (overall) = GI bleed
*Most Common fter transfusion? Because blood loss,
Most Common due to GI tract bleeding.

IV. RED BLOOD CELLS (RBC) indices MCV

How big is the cell? Best way to classify is with MCV (mean corpuscular volume). The machine
d sizes it. And then takes an average; this is the best
way for classifying an anemia

MCV: < 80 = Microcytic-hypochromic anemia (Fe deficiency)

MCV (normal): 80 -100 = Normocytic-normochromic anemia
MCV: >100 = Macrocytic-Megaloblastic anemia (Vit. B12 or folate deficiency)

, it will be Normocytic
(Like the metabolic acidosis, and respiratory alkalosis, but normal pH).

How could you have a Fe deficiency anemia and a folate deficiency anemia at the same
time?
*Know where these things are reabsorbed Fe reabsorbed in the duodenum, Folate is
reabsorbed in the jejunum, and B12 is reabsorbed in the terminal ileum. So if you have all
these, you have small bowel diseases (Ex. celiac diseases).

Pt has malabsorption that affects different areas of the bowel. Example: celiac sprue (Most
Common Cause of malabsorption) involves duodenum and jejunum, therefore will have
deficiency of Fe and folate, and will have small cells and large cells. Example: if it involves the
jejunum and terminal ileum, you will have folate and B12 deficiency.

V. RDW DISTRIBUTION WIDTH

,
uniformly small, normal, macrocytic, or different in size. So, the RDW detects a change in size
.

Example: microcytic anemia, with an increased RDW; this tells us that is microcytic, and there are
different sized microcytic cells.

If you develop microcytic anemia overnight and all the cells are Fe deficiency, the cells
t become microcytic immediately? NO!!! They are normocytic first before they
become microcytic, and there will be a size variation picked up by the RDW.

What is if you look at the CBC, and it shows decreased MCV with an increased RDW?
Is Microcytic anemia = Fe deficiency (not thalassemias because that is genetic and ALL the
cells are microcytic).

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 HIGH RDWhas large and small cells. Another slide with spherocyte cells

Spherocyte Cell
Target Cell

(have too little membrane, and therefore cannot hold a biconcave disk - an anorexic cell), and
target cell (has too much membrane and too much Hb collects in there and looks like a -eye
an obese cell).

Target cells are important markers for alcoholics because they have altered cell membrane
due to an altered cholesterol concentration of the membrane and markers for hemoglobinopathies
(Ex. thalassemias, Sickle Cell Disease, HbC).

RED BLOOD CELL WITH MICROCITYC ANEMIA looks like

biconcave disk and is thin in the middle because there is less Hb there, and more is concentrated
at the edges; this is why there is a central area of pallor in a normal RBC when it lying flat. All
microcytic anemias have one thing in common: decreased Hb synthesis; with less Hb, the
redness of the cell with decrease and see greater area of pallor will increase (and if you play odd
). Spherocyte too little membrane NO central area of
pallor! (All red, no central area of pallor). Microcytic anemias all have a PALE, blank color to
them; therefore, it is very easy to identify spherocyte and microcytic cells with hypochromia and
identify of chronic disease.

Audio Day 3: Hematology File 2

VI. Normocytic Anemia:

For normocytic anemia, you need to look at the reticulocyte count. First, you have to correct for
the degree of anemia (Hct/45 X reticulocyte count). Then look to see if there is polychromasia, if
there is polychromasia (then divide by 2); 3% or higher = Bone Marrow responding normally,
and 2% or lower = not responding properly.

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Physical signs of anemia:

*SPOON NAILS= iron (Fe) deficiency, Ex.Kelosis.

*PARLLOR OF CONJUNTIVA = have 6 grams or less of Hemoglobin.

*PALMER CREASE works for white people .

Ex. (women, often due to Fe deficiency.)

*LEAD LINE discoloration in gums due to lead poisoning.

Neurologic exam very important in B12 deficiency because the posterior columns and lateral
corticospinal tract are knocked off, therefore have propioception abnormalities and
decreased vibration sensation and babinski (lateral cortical).

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VII. Microcytic anemias

A. Fe (iron) studies:

1. Serum Fe (normal = 100, like the alveolar O2),

2. Serum ferritin (Is the best screening test) this is a soluble, circulating form of Fe
storage; it represent the amount of Fe stored in the Bone Marrow.
3. TIBC (Total Iron Binding Capacity); transferrin is the carrying protein for Fe.
(Trans = carry) in the LIVER. (normal TIBC=300).
4. % saturation= serum Fe ÷ TIBC.

B. 3 rules:

1. Transferrin and the TIBC is the SAME! (Remember transferrin is what carries Fe).
2. There is a relationship of Fe stores in Bone Marrow with the transferrin synthesized in the
liver will also be increased in Fe deficiency. Therefore:

*Low Fe stores = increased transferrin synthesis and TIBC in liver.

*High Fe stores = transferrin and TIBC decrease (Ex. Fe overload hemochromatosis or
transfusions)

3. % saturation is a calculation = serum Fe ÷ TIBC (normal serum Fe is 100 and normal

TIBC is 300, therefore, the % saturation is normally 100/300 = 33% - therefore, 1/3 of the
binding sites are occupied with Fe.

These are the terms and Fe studies we use, especially for microcytic anemias (related to Fe
problems).

C. Pathogenesis of microcytic anemias

All microcytic anemias are microcytic because they have a problem making Hb. When the
e RBC that determines the
number of cell divisions. Therefore, if the Hb synthesis is decreased, it is a signal in the
marrow to increase the number of mitoses. When cells mitoses, they go from something
originally big to something small. So because of the decrease in Hb synthesis, there are
extra divisions (mitoses) and therefore the cell is smaller.

All four groups of microcytic anemias have a decrease in Hb.

Heme = Fe + protoporphyrin
Globin is made in the body by alpha ( ), beta , delta ( ), gamma ( )
Hb = heme + globin
HbA 2 2
HbA2 2 2
HbF 2 2 .

We can dispense 2 of the 4 microcytic anemias immediately:

Fe deficiency = no Fe = no protoporphyrin to form heme = no Hb

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D. Pathogenesis of Anemia of chronic disease

When we have inflammation, our bodies respond to inflammation as if it is an infection. In

microbiology: increase Fe = more bugs production. Same concept: with anemia of chronic
inflammation and body assumes it is subject to a bacterial infection, the object is to keep Fe
away from the bacteria.

Fe in
Macrophages
in Bone marrow
How does it do that? like a safety deposit box , and you have the key Fe
is normally stored in macrophages in the Bone Marrow this is where transferrin goes (to the
macrophage) to pick up the Fe
access to the Fe, it will be locked away in the macrophages in the Bone Marrow
to the macrophages will be lost; therefore, there is lots of Fe in the macrophages of the Bone
Marrow, but Fe cannot get it out.

*G
*Bad news a decrease in Hb synthesis.
However, unlike Fe deficiency, (where there is no Fe in the macrophages of the Bone Marrow),
there is PILES of Fe
that, your serum Fe is decreased because
have enough Fe to make iciency, but for
different reasons: (1) you have no Fe (Iron Deficiency Anemia) and (2) you have lots of it, but
locked in the safety deposit box and you cannot get it so, either way, you cannot make
heme and therefore you cannot make hemoglobin.

To distinguish: Iron Deficiency Anemia (IDA) = High TIBC levels and Low Ferritin
Anemic Chronic Disease (ACD) = High Ferritin levels and Low TIBC

E. Heme synthesis (First Aid pag. 333) - 3 reactions in biochemistry occur in the cytosol and the
inner mitochondria.
1. (Oxidative phosphorilation) in mitochondria membrane.
2. (Beta oxidation of Fatty Acid
3. (Gluconeogenesis, which starts in the mitochondria and ends up in the cytosol) in cytosol
AND the mitochondria.
4. (Heme synthesis and urea synthesis starts in mitochondria, then cytosol, and then again in
the mitochondria).

First part of heme synthesis begins in the mitochondria.

1. Succinyl Coa + Glycine Protoporphyrin + Iron (Fe)

ALA Synthase with Vit B6 reaction due Ferrochelatase
and form HEMOGLOBINE

Mitochondria Mitochondria

Cytosol Cytosol

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 First reaction is Succinyl CoA + Glycine

Succinyl Coa (substrate in TCA cycle and substrate for gluconeogenesis) and glycine (which
is an inhibitory neurotransmitter of muscle, blocked by tetanus toxin rhesus sardonicus and
tetanic contraction so when glycine is inhibited, the muscles are in a tonic state of
contraction).

Know all RATES hemical reaction. (RLE in

cholesterol synthesis = HMG CoA reductase).

RLE in heme synthesis = ALA synthase with cofactor (Vit. B6 = pyridoxine). So,
protoporphyrin is made and goes back to the mitochondria. So you have protoporphyrin plus
Fe , so you have a metal
plus protoporphyrin. Ferrochelatase puts these together; so, it is called, with combines Fe
with protoporphyrin and forms heme.

Heme has a feedback mechanism with ALA synthase (all RLE have a feedback mechanism).
So, with increased heme, it will decrease synthesis of ALA synthase, and when heme is
decreased, it will increase ALA synthase synthesis.

F. Pathogenesis of Sideroblastic anemias (least common of the microcytic anemias).

Sidero sideroblastic anemias; they have 3 causes:

1. Alcohol - Alcohol is a mitochondrial poison and uncouples

oxidative phosphorilaton, and damages inner mitochondria membrane, allowing protons to go
in and drain them off. On Electron Microscope of the mitochondria of an alcoholic is huge
because they are damaged (called megamitochondria). Therefore, any process that occurs in
the mitochondria is screwed up. This, therefore, includes heme synthesis. So, Fe is delivered
Some is stored as ferritin, while most
of it goes to the mitochondria, which is BAD news! Why? Because it can get in, but CANNOT
get out. So, there is damaged mitochondria that were damaged by alcohol, Fe goes in and
now cannot go out. So, there will lots of Fe caught and Fe builds up within the
mitochondria. Mitochondria is located around the nucleus of an RBC in the Bone
Marrow, leading to a ringed sideroblast (marker cell for sideroblastic anemia); also in Fe
overload disease will excess iron, and will not get heme because mitochondria destroyed.

Most Common Cause of sideroblastic anemia = Alcohol

Most Common anemia overall = Anemia Chronic Disease, followed by folate deficiency

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 2) G6PD (Glucose 6 phosphate dehydrogenase) deficiency X-linked deficiency (hexose
monophosphate shunt) pyridoxine (Vit B6) deficiency; Ex. not taking Vit B6 during
Treatment of TB = no heme, and the first reaction will not happen.
and goes to the mitochondria, waiting for porphyrin, leading to ringed sideroblast.)

3) Lead poisoning - Lead is a denaturer. All heavy metals denature proteins (enzymes are
proteins). Ferrochelatase is denaturated by lead = no heme = no Hb, leading to
microcytic anemia. Less of inhibitory effect, but does have a little one on aminolevulinic acid
dehydratase. But is MOST commonly knocks off ferrochelatase. So, when Fe comes into
mitochondria, it cannot bind to protoporphyrin to form heme. No heme = decreased Hb =
microcytic anemia.

Example: Ferrochelatase decreased or inhibited = heme decreases = protoporphyrin

increases in RBC.

I Anemic Chronic Disease/Fe deficiency, what will happen

to the protoporphyrin in the mitochondria? It will increase. So Blood lead level is the
screening and confirmatory test for lead poisoning.

G. Pathogenesis of Thalassemias: Autosomal recessive disease. First Aid pag. 334

1. Alpha thalassemias See in Asians (Far eastern) and African (blacks).

(All genetic hematologic disease is seen in the black population alpha/beta

thalassemia, G6PD deficiency and Sickle Cells Disease).

a. Hb electrophoresis separates things based on size and charge, therefore you can
clearly separate HbA, HbF, and HbA2 clearly on cellulose acetate because they have
different migrations. So, they fluoresence it, and HbA, HbF and HbA2 all settle down
(ordered and stable). Then they stain the cellulose acetate to see how much is there.
Then, it produces density, and the density correlates with the concentration of each of the
ey know the percent? With a densitometer (it converts the density of the
stain to the percentage.) It turns out that HbA (2 2 ) is the predominant Hb in an adult
(95-96%). HbA2 is 1-2%; HbF = 1%. These are the normal, which are expressed as a
percentage.

b. Thalassemias, autosomal recessive: has a problem in making alpha globin

chains. Do HbA2 and HbF require HbA to be made? Yes. Therefore, all will be equally
decreased. This will NOT show up on an electrophoresis, because all are equally
decreased, therefore, it shows to be totally normal. There are 4 genes that control alpha
globin synthesis:

*Deletion of 1 globin-gene: not cause anemia.

*Deletion of 2 globin-genes = mild anemia. It is microcytic because the globin part is
decreased, meaning you will get a microcytic anemia (decrease in Hb concentration,
which will be the stimulus). This called alpha thalassemia minor, seen in the far eastern
population and black population.

114
 *Deletion of 3 globin-genes: The beta chains get irritated that there is no alpha
chains around, so they from their own beta globin chains. So, four beta chains get together
and form HbH. If you do an electrophoresis, there will be a different result.
HbH is a different Hb, and therefore will not migrate to
you can diagnost this alpha thalassemia with Hb electr HbH
disease).
*Deletions of 4 globin-genes: produced spontaneous abortions (usually, therefore
not usually born alive (Intrauterine dead and hydrops fetalis). Gamma chains form
together (like the beta chains did earlier) and form an Hb with 4 globin-genes, which is
called Hb Barts. This will show up on elect baby is
dead already.

What is the spontaneous abortion rate in (Asia) Far East? High because this is where
alpha thalassemia is most commonly located.

If the incidence of spontaneous abortions is increased, what cancer risk is

increased? Choriocarcinoma (increased hydatidiform moles, which leads to
choriocarcinoma). So, there is a high incidence of choriocarcinoma in the Far East
because of alpha thalassemia. Rx DO NOT give Fe (will Fe overload them).

(2nd Most Common Cause of isease especiallecially with lack

of food).

2. Thalassemia common in blacks, Greeks and Italians (Mediterranean population).

B (by itself) = making normal beta chains; B (with a
Beta thalassemia is autosomal recesive, and
has to do with splicing defects and stop codons.

The most severe form is due to stop codon (therefore, terminate synthesis of beta chains, and
Mild (minor) B thalassemia: slightly decreased beta chains,
probably due to a splicing defect; beta chains are slightly decreased, alpha chains are okay,
delta chains are okay, gamma chains fine (confined to fetus). So, HbA will decrease, and delta
will get together (hence increase in HbA2) and gamma chains get together (hence increase in
HbF). Therefore, see a decrease in HbA and an increase in HbA2 and HbF; this WILL
show up on electrophoresis. This happened because beta chain is decreased, and it
showed a decreased HbA. It is just a mild thalassemia and is very common. So, only way to
diagnosed Beta thalassemia is with Hb electrophoresis.

In Severe (Mayor) B Thalassemia: not making any beta chains Ex. and
will not live past 30 years old. Will have a constant transfusion requirement; many of these pts
die from Fe overload, or Hepatitis C or multiple transfusions or HIV.

Most Common in black population Beta-Delta thalassemia (decreased beta chains and
l the
electrophoresis show? HbF. This called hereditary persistence of HbF. No anemia, just
dominant HbF.

For thalassemias, know they are genetic, what groups of people they are in and that you
ecially giving Fe because all their Fe studies are normal.
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H. Iron Deficiency Anemia (IDA):

1. Causes of Fe deficiency anemia look at age brackets:

a) Prematurity everyday a baby is not in utero, it is losing Fe (all their Fe stores are
decreased, so baby must be given Fe supplements).

b) Newborn can be
swallowed. This is done with the Apt test (most commonly used in cases of vaginal
bleeding late during pregnancy to determine if the bleeding is from the mother or the fetus.)
Most of blood that comes out of is blood the baby swallowed from
mom, and it has HbA in it.=Mom blood.

However, if it was HbF blood that came out, of

baby stool due of bleeding by =Baby blood.

Most Common Cause Fe deficiency in a newborn and child =

diverticulum.

c) Most Common Cause of Fe deficiency in Woman under 50 = menorrhagia

(abnormally heavy and prolonged menstrual period at regular intervals), therefore
need to get a good menstrual history (hx); due to anovulatory cycles (between 20-40
years old, due to ovulatory cycles, inadequate luteal phase, pregnancy related bleeds,
endometrial polyp that is bleeding).

d) Most Common Cause of Fe deficiency in Men under 50 years = Peptic

Ulcer Disease (usually duodenal ulcer).

e) Most Common Cause of Fe deficiency Men and women over 50 = Colon cancer.

2. Lab Test in the Iron (fe) Deficiency

*Serum Fe = low
*TIBC = high
*(% saturation) = low. Fe, saturation is decreased because Transferrin
on it.
*Serum ferritin level = low.

116
I. Anemia Chronic Disease related to inflammation. Fe is locked in safety deposit box (in
macrophages and in Bone Marrow, so you have plenty, but cannot get it out.

*Serum Fe=low
*TIBC=low (high Fe STORES = decrease transferrin synthesis)
*% saturation = Transferrin low
*Serum ferritin = high, because Fe is storage in the box.

Main test to distinguish Anemic Chronic Disease from Fe deficiency = serum Ferritin

J. Mild alpha and beta thalassemia NORMAL Fe studies, because nothing to do with Fe, but
globin chains.

K. Sideroblastic Ex. smear without appropriate amount of Hb in the cells, therefore, they are
more than likely to be a microcytic anemia like (Fe deficiency, Anemic Chronic Disease,
thalassemia, lead poisoning).

Slide: (only seen in Bone Marrow, and is stained with

Prussian blue, which stains Fe because mitochondria around the nucleus, all filled up with
Fe called a RINGED SIDEROBLAST this is pathognomonic of a sideroblastic anemia). So if
you think that Vit B6 or alcohol is causing the anemia, need to get Bone Marrow test.

L. Lead poisoning: If you suspect lead poisoning; just do a lead level exam. In lead poisoning
the enzyme affected are ferrochelatase and ALA Synthase.

Cells with blue spots called basophilic stippling; great

marker in the peripheral blood to see denatures ribonuclease. (Shows up on giemsa stain). The
purpose of ribonuclease is to break down ribosomes
ribosome persists.
persistent ribosome = lead poisoning.

117
On x-ray on the BOARDS!!!! Epiphyses of finger of child; the only heavy
metal that can deposit in the epiphysis of bone is Lead. This is why they have failure to grow.
If you screw up the epiphyses of the kid, they will not be able to grow properly.

Clinical scenario child eating paint/plaster leads to lead poisoning, have severe abdominal
colic, problem with cerebral edema, convulsions, severe microcytic anemia, see three things Fe,
lead, and mercury in intestines (flat plate). Also, there is a failure to thrive.

Mechanism of cerebral edema? Increased vessel permeability of brain and buildup of -

aminolevulynic acid. If you block ferrochelatase, everything distal to the block will increase
(protoporphyrin and -aminolevulynic acid) this is toxic to neurons, leading to cerebral
edema.

Example: guy at an automobile shop, complains of abdominal colic and diarrhea. This is lead
poisoning because exposure to batteries. In plants, there is exposure to incineration of
batteries, and pts are exposed to lead in auto factories.

Example: moonshine (illegal liquor) make alcohol in old radiators, leads to lead
poisoning.

Example: pottery painter pottery is commonly painted with lead based paints. A lot times they
lick the tip of the brush, and leads to lead poisoning.

Example: LEAD LINE THROUGH THE GUMS DUE LEAN

POISONING. In certain country, they use lead-based pottery for dishes, which leads to lead
poisoning. In Adults lead poisoning will get the neuropathies slapping gait (perineal palsy),
wrist drop (radial palsy), claw hand (ulnar palsy), lead lines in gums and teeth (usually get with
colic and diarrhea).

118
 Fe TIBC %saturation Ferritin
Fe deficiency: low high low low
Anemic Chronic Disease: low low low high
Alpha/beta thalassemia: normal normal normal normal
Lead poisoning: high low high high
(And sideroblastic anemias Fe overload like Hemochromatosis): (TIBC is low because Fe
stores are high!) In Fe overload everything is high, TIBC is LOW.

Audio Day 2: Hematology File 3

VIII. Macrocytic anemias

B12 and folate are involved in DNA synthesis; therefore, if you are B12 or folate deficiency, you
cannot make DNA, specifically because you have a problem with making dTMP (deoxythymidine
monophosphate). Therefore, if you cannot make that, you cannot mature the nucleus (in which you
make more DNA, the nuclei become more matured, and the nucleus becomes smaller and more
condensed). In immature nuclei do not have a lot of DNA in them and DNA cannot be made, then you
have large nucleus, and all nucleated the cells in your body are big, this is called MEGAloblastic
anemias. A good pathologist can diagnosed B12 and folate deficiency in a cervical pap smear, when
looking at the squamous cells (cells look big ALL nucleated cells in the body are big Ex. GI,
squamous cells)

Vit. B12 (Cobalamin): B12 has cobalt in it. Circulating form of folate is methyltetrahydrofolate (tetra
= four). Function of cobalamin (B12) is to take the methyl group off of methyltetrahydrofolate. Then
folate, you will not make DNA. So,
if you are B12 deficiency If you are
deficiency

Cobalamin adds a methyl to group homocysteine; when you add a methyl group to homocysteine, it
becomes methionine. Methionine = amino acid for 1 carbon transfer reaction. (Methyl = CH3).

If you are B12 or folate deficiency, what are the serum homocysteine levels? High
*Most Common Cause of increased homocysteine = Folate deficiency (increased incidence of
thrombosis and Miocardial Infarction) more than B12 deficiency. This is why cardiologists order
serum homocysteine levels.

*In folate deficiency, no methyl group to add to homocysteine = homocysteine increases.

*In Vit. B12 deficiency, no methyl group to add to homocysteine to make methionine = homocysteine
increases.

Tetrahydrofolate is the start of the cycle, and leads to production of thymidilate synthase this is
where DNA is made. dUMP is converted to dTMP, making DNA. Therefore, this substrate is
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necessary to make DNA. So, it is used in the making of DNA by an enzyme called dihydrofolate
reductase which converts oxidized dihydrofolate to tetrahydrofolate.

Many drugs block dihydrofolate reductase methotrexate, TMP-SMX. The drugs block DNA
synthesis (Ex. decreasing DNA synthesis) leading to macrocytic anemia.

So, the functional B12 takes the methyl group from tetrahydrofolate and gives it to homocysteine to
make methionine. And tetrahydrofolate will start the cycle for making DNA.

A. VITAMIN B12 (COBALAMIN)

1. B12 Reactions: B12 is humiliated by having to transfer methyl groups. This is an odd request
so whoever he asked said that they can take care of even chained Fatty Acid, but we have a problem
with ODD chained Fatty Acid because we can only break down to proprionyl CoA, which leads to
dementia and proprioception loss. B12 helps in odd chain Fatty Acid metabolism. Therefore, it is
involved in proprionate metabolism, which is metabolism of an odd chain Fatty Acid. Proprionate
forms methylmalonyl CoA, where B12 comes in and helps convert methylmalonyl CoA to succinyl
CoA, which can go into the TCA cycle.

In B12 deficiency, certain things will build up, such as proprionate and methylmalonyl CoA.
Methylmalonyl CoA becomes methylmalonlylic acid, which is a sensitive and specific test for
B12 deficiency. So, with B12 deficiency, get a methylmalonlylic acid test (increased).

Neurological problems is proprionate metabolism; without B12, cannot convert odd chain Fatty Acid
into succinyl CoA, and they increase, and cannot synthesized myelin = to demyelination of
posterior columns, and damage of the lateral corticospinal tract. Because of that, you will have
problems with proprioception, vibration; you will get Upper Motor Neuron lesions (spasticity,
babinski), and then dementia.

*Folate Deficiency = hematologic problems

*B12 deficiency = problems (
with dementia, get a TSH level (to rule out hypothyroidism), and a B12 level to rule out B12
deficiency because these are REVERSIBLE causes of dementia.

Pure vegan vs. ovo-lactovegan:

*Ovo-lactovegan eat dairy products (which are animal products), therefore, do not have to take
B12 supplements.

*Pure vegan - does have to take B12 supplements.

2. Normal sequence of B12 absorption: Have to eat meats or dairy products to get B12.

1. The first thing B12 does is binds to R factor in saliva. R factor protects B12 from destruction by
acid in the stomach.

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2. Intrinsic factor (IF) made by parietal cells in the body fundus; they also make acid. Intrinsic Factor
is not destroyed by acid, therefore does not need anything to protect it.
3. B12/R factor complex goes into the duodenum, where there is Intrinsic Factor waiting for it.
4. R factor must be separated by B12, which is done with enzymes from the functioning pancreas.

5. Intrinsic Factor and B12 bind to each other and take a long trip and go terminal ileum, where
there are receptors for Intrinsic Factor, and it is reabsorbed. This is the same place bile salts are
reabsorbed, and the hits. Therefore, with , you
also have bile salt reabsorption problems and B12 deficiency.

3. Causes of B12 deficiency:

a) Most Common Cause B12 deficiency = Pernicious Anemia; this is an autoimmune disease with
destruction of the parietal cells; autoAntibodies attack the parietal cells and there are
autoAntibodies against Intrinsic Factor and destroys the parietal cells which are located in the body
and fundus. Everything gets destroyed leading to an atrophic gastritis of the body and fundus.

In pernicious anemia = No parietal cells = no acid = achyloridria, and no Intrinsic Factor.

Achyloridria is a major predisposing factor for gastric adenocarcinoma.

b) Causes of B12 deficiency: *pure vegan; *chronic pancreatitis seen in alcoholics (this leads
to B12 deficiency because *D. latum Diphyllobothriu (fish
tapeworm that eats B12 (rarest) from fish in lake trout in lakes of Chicago); terminal ileum disease
*peristalsis problem (diverticular pouches or stasis
(stop movement). ll get bacterial infection (also bladder infection);
bacteria love B12 and bile salts with bacterial overgrowth. All of these will lead to B12 deficiency.

B. Folate (FOLIC ACID)

Folate is seen in animal and plant products (NOT seen in vegans). Folate has many pharm ties
(Ex. dihydrofolate reductase).
cannot reabsorb it in the jejunum; therefore it has to be converted to a monoglutamate form by
Intestinal conjugase enzyme in the small intestine.

What drug blocks intestinal conjugase? Phenytoin.

Pt on Phenytoin, with macrocytic anemia, hypersegmented neutrophils, neurological effects

are NOT present, what is the deficiency? Folate deficiency (because there are no neurological
problems, this r/o Vit. B12 deficiency.)

Now you have monoglutamate, which is absorbed in the jejunum. There are 2 things that inhibit its
absorption:
(1) Birth control pills
(2) Alcohol (Most Common Cause folate deficiency = alcoholism). Folate only has 3-4 month
supply. Even you have an excellent diet, you can have folate deficiency, if you are taking one of
these two things.

Summary:
1. Folate circulating form = methyltetrahydrofolate.
2. B12 takes the folate, and gives it to homocysteine.
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3. Homocysteine becomes methionine.
4. Methyltetrahydrofolate becomes tetrahydrofolate.
5. Tetrahydrofolate with the help of dihydrofolate reductase made DNA.

*CHOICE BY BOARDS HYPERSEGMENTED NEUTROPHILS (definition: 5 or more lobes!).

Hypersegmented neutrophil indicates B12 or folate deficency,

It is the first thing that comes up before anemia. And if the
iciency. Test for proprioception: Romberg test if you
have post column disease, problem with proprioception because do not know where your joints are;
does not show cerebellar ataxia (will have these with eyes opened AND closed). Use vibrating
tuning fork to see if pt has proprioception on the malleous.

BONE MARROW WITH MEGALOBLASTIC RBC/WBC.

Hematopoetic cells are made outside the sinusoids in the Bone Marrow cords of
bilroth in the spleen = (
get back into the sinusoids and circulate through holes. They get through, and are in sinusoids). The
same thing occurs in the Bone Marrow they have a place equivalent to the cords of bilroth and that
is where they are made. To get into the circulations, they have to fit through lil, narrow holes to get
into the sinusoids in the Bone Marrow and into the blood stream. Something very big will not be able
to get through the lil holes and into the sinusoids. Therefore, macrophages will want to feast on the
elets) that cannot get into the sinusoids. So, the macrophages
kill them all. So in the peripheral blood, will see NOTHING Pancytopenia; severe macrocytic
anemia, neutropenia, thrombocytopenia which is characteristic of B12 /folate deficiency.
(Everything in the marrow is too big and cannot get out into the circulation).

good test for localizing B12 deficiency

and we want to know what caused it. Steps for schilling test: Give radioactive B12 by mouth; they
then collect the 24 hr urine to see if any comes out in the urine and nothing comes out, therefore
prove that they have a problem absorbing B12.

1st step: give radioactive B12 and Intrinsic Factor, collect urine for 24 hrs, and piles in the urine
= Pernicious anemia; because added what was missing (Intrinsic Factor
EXCLUDE pernicious anemia.
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2nd step: give 10 days worth of broad spectrum antibiotic; pt comes back and again you give them
radioactive B12; see piles of radioactive B12 in the urine, what is diagnosis? Bacterial
overgrowth because knocked off the bugs eating B12.

3rd step: pancreatic extract, swallow pills, then give radioactive B12; 24 hrs later, see what
happens; if there is radioactivity in urine, pt has chronic pancreatitis.

, etc.

Summary:

If B12 malabsorption was corrected by adding Intrinsic Factor, pt has pernicious

anemia.

If B12 corrected by adding an antibiotic, pt has bacterial overgrowth

If B12 is corrected by adding pancreatic extract, pt has chronic pancreatitis.

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IX. Normocytic anemias

When you do the corrections for the anemia and look for polychromasia; if correction is less than 2%,
it is a bad response (Bone Marrow not responding correctly).

First two things you see: early Iron Deficiency Anemia and Anemic Chronic Disease remember
that you have to have a normocytic anemia first to become microcytic.
Therefore, with a decreased reticulocyte count (Ex.
in the differential, and you need to get a ferritin level.

Iron Deficiency Anemia goes through differents stages: first thing that happens decreased ferritin,
then Fe decreases, TIBC increased, % saturation
words, all Fe studies are ABNORMAL before you have anemia. Then you get mild normocytic
anemia, and eventually microcytic anemia.

A. Causes:
1. Blood loss less than a week = normocytic anemia; no increase in reticulocyte response
because nothing wrong with the Bone Marrow, and not enough time (need 5-7 days for Bone Marrow
so, after one week, would get an appropriate response.
2. Aplastic anemia no marrow; if that is true, the peripheral blood will show pancytopenia (all
hematopoetic cells are destroyed in the marrow); have normocytic anemia, thrombocytopenia, and
neutropenia.
3. Most Common known Cause = drugs: chloramphenical used in Rocky Mountain spotted
fever, indomethacin, phenylbutazone, and thyroid related drugs.
4. 2nd Most Common Cause = infections especially Hepatitis C (wipes out everything); aplasia
of RBC = parvovirus.
5. Radiation and malignancy
6. Early Iron Deficiency Anemia and Anemic Chronic Disease (need to have serum ferritin
levels)
7. Mechanism of normocytic anemia with less then 2% reticulocyte count renal failure, and
decreased Erythropoietin (can be given exogenously) decreased in hepatitis B, C, and HIV.
to allow more O2 delivery to body.

B. Mechanisms of hemolysis 2 ways to kill an RBC:

Normocytic anemias with corrective reticulocyte count about 3%:

1. Extravascularly (outside of the Blood Vessel).

They are killed by macrophages, usually in cords of bilroth in the spleen, sometimes in liver sinusoids.
Every RBC must go to the cords of bilroth a few times per day and get examined by a macrophage
if the cell picked up an IgG or C3b, it is marked for destruction via phagocytosis because the
ve IgG or C3b, can still die because the
cell is in bad shape abnormal shape: Ex. sphere will not be able to fit through a 2 micron hole to get
to the sinusoids therefore, spherocytes are removed extravascularly because they cannot
get out; sickle cells cannot get out either because they have a bad shape.
Another reason for their destruction is because
a piece of nucleus; what is this called? Howell jolly body; macrophage will get rid of it.

There are autoimmune hemolytic anemias, and can be due to IgG or C3b on the surface of the
RBC, or extravascular hemolytic anemias is where you have abnormal shape (Ex. sphere, Sickle
cell will not make it out of the spleen because removed by macrophages).
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End product of phagocytosing an RBC: unconjugated bilirubin. When the RBC is broken down,
you have hemoglobin, and there is an enzyme that splits heme from globin and the globin is broken
into amino acid and therefore goes to the amino acid pool. Then, takes the heme, splits it open, and
saves the Fe. Now you have protoporphyrin, and spit it out; end result is unconjugated bilirubin in the
macrophage within the spleen. Then, the macrophage spits out the unconjugated bilirubin into blood
stream (which is insoluble because in
and goes to the liver and is conjugated.

What clinical finding will you see in pts with extravascular hemolytic anemia? Jaundice

Does that bilirubin get into the urine? No.

Why? 2 reasons:
(1) Lipid soluble
(2) Bound to albumin (albumin does not get into the urine)
get into the urine

2. Intravascular (within the Blood Vessels)

Intravascular is less common meaning that you die within the Blood Vessels. How does that
happen? You die within the vessel if you bump into something. Example: congenital bicuspid aortic
valve with calcium there if you bump into that, you would damage yourself and die. Example: if you
have IgM on the surface of the RBC (IgM is the most potent activator of the complement system); this
will go from 1-9, meaning that it will sit on the RBC, activate the complement and dies intravascularly;
so, anything that is IgM mediated = intravascular hemolysis.

What will you release into the bloodstream if you are killing the RBC? Hb

want to lose all of it and need to retreat it by getting back the amino acid and retrieving the Fe.
Specific protein that is made in the liver that is released when there is intravascular hemolysis
haptoglobin (suicide protein because forms complex with Hb and is phagocytosed by the
macrophage), therefore giving life to retrieve the Hb, therefore in pts with intravascular hemolysis,
the haptoglobin levels decrease. Is it possible to get jaun
macrophage is phagocytosing. Intravascular hemolysis: hemoglobinuria, and low haptoglobin levels.

Summary:

Extravascular = macrophages remove = unconjugated bilirubin is the end product = jaundice

is the clinical manifestation.

Intravascular = Hb in urine, decreased haptoglobin.

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 Audio Day 2: Hematology File 4
C. Intrinsic vs. Extrinsic Hemolytic anemia:
1. Intrinsic something wrong with RBC, causing it to hemolyze: such as no spectrin, or not
decay accelerating factor to neutralize complement, no G6PD enzyme in pentose phosphate shunt,
or abnormal Hb (Ex. HbS).

2. Extrinsic nothing wrong with the RBC, just at the wrong place at the wrong time; Ex. it just
happened to smash (destroy) into the calcified valve (nothing was wrong with RBC, until it hit the
valve). Then it will be dreading (fear) and going to the cords of bilroth with destroy it because it has
been marked with IgG and C3b for phagocytosis.

D. Something intrinsically wrong with the RBC causing it to hemolyze

with the Bone Marrow, and the corrective reticulocyte count is greater than 3%.

Most Common intrinsic problems are: Membrane defect (spherocytosis, paroxysmal nocturnal
hemoglobinuria), Abnormal Hb (Sickle Cell trait Disease), Deficiency of enzyme (G6PD
deficiency).
1. Membrane Defects:

(a) Spherocytosis: do no see a central area of pallor therefore

must be a spherocyte and must be removed extravascularly. Clinically manifest with jaundice from
unconjugated bilirubin. Spectrin defect and Autosomal Dominant Disorder disease;
splenomegaly always seen over a period of time. Gallbladder (GB) disease is common because
there is a lot more unconjugated bilirubin presented to the liver and more conjugation is occurring and
more bilirubin is in the bile than usual. So, whenever you supersaturate anything that is a liquid, you
run the risk of forming a stone; if you supersaturate urine with Ca, you run the risk of getting a Ca
stone; if you supersaturate bile with cholesterol, you will get a cholesterol stone; if you
supersaturate with bilirubin, you will get a

Ca-bilirubinate stone.

Therefore, pts have Gall Bladder disease related to gallstone disease and then do a CBC with
normocytic anemia and a corrected reticulocyte count that is elevated, and see congenital
spherocytosis.

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 therefore have an increased osmotic fragility).
Rx: splenectomy (need to remove organ).

(b) Paroxysmal Nocturnal Hemoglobinuria = defect in decay accelerating factor. So when we

sleep, we have a mild respiratory acidosis because we breathe slowly (if you have obstructive sleep
apnea, the acidosis is worse). When you have acidosis that predisposes th
on ALL cells circulating in peripheral blood. RBCs, WBCs, and platelets all have complement sitting
on it. There is no complement destruction of these cells because in our membranes we have delay
accelerating factor.

This f ortunity to drill

and thrombocytopenia. So, if you are missing decay accelerating factor, the complement will be
activated and goes from C1-9, leading to intravascular hemolysis. Think about the name
(paroxysmal nocturnal hemoglobinuria): occurs at night, and when you wake up in the
morning, you pee out hemoglobin. So, when you do a CBC, not only have a severe anemia, but
also a neutropenia and a thrombocytopenia: pancytopenia).

2. Abnormal Hb: Sickle Cell Trait/Disease

With sickle cell trait, there is NO anemia and NO sickled cells in the peripheral blood. You can
have sickled cells in a certain part of your body in the renal medulla within the peritubular capillaries
(decreased O2 tension), but not in the peripheral blood. This is because in Sickle Cell Disease, the
amount of sickled Hb in the RBC determines whether it sickles or not. Magic # = 60%; if you have
60% or more, HbS can spontaneously sickle. Oxygen tension in the blood also determines
whether a cell will sickle or not. At lower O2 tensions, cells are more likely to sickle. This is an
autosomal recesive disease, meaning that both parents must have abnormal gene on their
chromosome (so its 2 traits); therefore, 25% complete normal, 50% heterozygous asymptomatic
carrier, 25% complete disease (same with cystic fibrosis).

Sickle Cell Trait vs. Sickle Cell Disease:

(a) Sickle cell trait, black individual with normal Phisical Exam (PE) and normal CBC, but
microscopic hematuria, the first step is sickle cell screen because microscopic hematuria is ALWAYS
abnormal and must be worked up but in blacks = 1/8 people have the trait. So, Sickle Cell trait is
what you are thinking of; not renal stones, or IgA glomerulonephritis, but is Sickle Cell trait normally.

(b) Sickle Cell Disease 2 things are happening: Hemolytic anemia (usually extravascular)
can be very severe and commonly requires a transfusion and Occlusion of small Blood Vessels by
the sickle cells (blockage of circulation) lead to vasoocclusive crisis, and this ischemia leads to
pain. Therefore, they are painful crisis (occur anywhere in the body lungs, liver, spleen, Bone
Marrow, hands/feet (dactilytis). Over time, it leads to damage of organs kidneys, spleen
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autoinfarcted (autosplenectomy) in first 10 years of life, pt will have splenomegaly because trapped
autosplenectomy around age 19 (spleen will be the size of a thumb).

After 2 years, it is nonfunctional

How will you know what that has happened? Howell Jolly body (RBC with a piece of nucleus that
should not be in the spleen if the spleen were working, a fixed macrophage would have taken care
of it). This occurs at about 2 yrs of age. This is fortunate because this is about the age where you
can get pneumovax.

With a nonfunctional spleen what infection is guaranteed? Streptococco pneumoniae sepsis.

Most Common Cause of death in child with Sickle Cell Disease = streptococco pneumoniae
sepsis.
They try to cover with antibiotics and pneumovax pneumovax can be given at the age of 2 and
about the time when the spleen stops working (start to see Howell jolly bodies).

BOARD SLIDE with Howell jolly body and sickled cells,

Howell jolly would have been
removed if the spleen is functional.

When do they get their first sickle cell crisis?

When little kids gets painful hands, and are swollen up (called dactilytis)
does not occur at birth, because HbF inhibits sickling and newborns in newborns, 70-80% of their
HbF. In Sickle Cell Disease, 60-

replaced, the HbF decreases and HbS increases, and by 6-9 months of age, there is a high enough
concentration to induce sickling and their first vasooclusive crisis, producing dactilytis. So, dactilytis
d -9 months because HbF inhibits the sickling.
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*Bone infarctions occur from sickling the Bone Marrow:

Osteomyelitis pts are susceptible to osteomyelitis from salmonella due to a dysfunctional

spleen. Salmonella is destroyed by macrophages. The spleen normally filters out salmonella, but is
dysfunctional.

Most Common Cause of osteomyelitis is staphylococco, but Most Common Cause of

osteomyelitis in Sickle Cell Disease = salmonella.

What drug is used to decrease the incidence of vasooclusive crises? Hydroxyurea. How does
it work? It increases HbF synthesis.

3. Deficiency of enzyme: G6PD deficiency is X-linked recessive.

Most enzyme deficiencies are autosomal recessive (Ex. PKU, albinism, homocystinuria). What are
the two X-linked recessive enzyme deficiencies? G6PD def and Lesch-Nyhan syndrome =
(involves purine metabolism with mental retardation, self mutilation, increased uric acid,
deficiency of Hypoxanthine- ).

Glucose 6 phosphate has several functions: (1) to make glutathione, (2) to make ribose 5 carbon
sugars for making DNA, and (3) to make glycogen from G6P (converted to G1P, UDP-glucose
and glycogen).
Key: with this enzyme, we can make NADPH, which is the main factor for making anabolic types of
biochemical reactions (Ex. steroid synthesis). NADPH will reduce oxidized glutathione to glutathione;
its job is to neutralize peroxide to water.

Which vitamin catalyzes this reaction? Vit B2 - Riboflavin.

Which enzyme helps glutathione neutralize peroxide? Glutathione peroxidase.
Which trace metal is involved? Selenium.

Every living cell makes peroxide as an end product, therefore every cell must a way to handle it.
Catalase
peroxisomes. Other way to neutralize peroxide is with glutathione (only thing av
because t

If you are deficient in this enzyme, there is a problem. So, peroxide increases to the point of
hemolyzing , if you had an Infection, or if you took an oxidizing
drug (Ex. sulfa drug, nitryl drug), which will lead to a lot more peroxide lying around. Peroxide will not
be able to be neutralized if you are deficient in catalase. So, what will happen is the peroxide will
affect the Hb. The peroxide will cause the Hb to clump and form Heinz bodies (Hb clumped up
together). Will also affect the RBC membrane because, it damages the membrane so much that is
the primary mechanism of destruction is intravascular. Little element is extravascular,

It is precipitated by infections and/or drugs. 2 Most Common drugs:

1) primaquine missionary got malaria, received a drug, and 2-3 days later the got hemoglobinuria,
chills, and a hemolytic anemia (this is primaquine induced hemolysis).

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2) Dapsone is used in treating leprosy; every person with leprosy is given a screen for G6PD
deficiency because of the high incidence of producing hemolysis. See this disease in the same
population as Beta thalassemia blacks, Greeks, Italians.

Slide: G6PD deficiency smear with actively hemolyzing blood

cells Heinz bodies when it goes into the cords of bilroth, the macrophage will take a big bite out
of it and sometimes, is a small bite out of the membrane, and the cell goes to the peripheral
(RBC with little membrane). Need to do special stains to
identified Heinz bodies.

In Greeks or Italians with severe forms of G6PD deficiency, when they eat fava beans which can
precipitate an episode (favism).
Dx when you have an acute hemolytic episode, NEVER use enzyme assays for active hemolysis.
Need to special stain to identify the Heinz body. When the hemolytic ep
diagnosed is confirmed, this is done with a G6PD assay.

In the exam you will get a question on G6PD deficiency, either dapsone related or primaquine
related.

X. AUTOIMMUNE HEMOLITIC ANEMIAS

Warm reacting antibodies are IgG and cold reacting is IgM.

*Most Common autoimmune hemolytic anemia = warm; Most Common Cause of it = Lupus

*2nd Most Common Cause of autoimmune hemolytic anemia = drug induced

When you have autoimmune disease in your family, you have certain HLA types that predispose you
to that autoimmune disease. Therefore, you should not be surprised if you have one autoimmune
disease, y to have another. So, pts with lupus commonly also have autoimmune hemolytic
anemia, autoimmune thrombocytopenia, autoimmune neutropenia, and autoimmune lymphopenia.

For example: the Most Common Cause pts

commonly have other autoimmune diseases (Ex. pernicious anemia, vitiligo, autoimmune
destruction of melanocytes).

This is because of the (HLA) human leukocyte antigen relationship. Therefore, if you have a family
that has an autoimmune disease, what would be the single best screening test to use? HLA (Ex. if
they have the HLA type specific for lupus erents diseases).
Therefore, HLA is the best way to see if pt is predisposed to something.

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Most Common Cause of autoimmune anemia = Lupus; it has IgG and C3b on the surface of the
RBC, so it will be removed by the macrophage. This is an extravascular hemolytic anemia. How
: detect
DIREC The test of choice if you

*Indirect coombs is what the women get, when they are pregnant and they do an Antibody screen
on you (looking for any kind of Antibody); so, when you look for Antibody in the SERUM
indirect Coombs = Antibody screen.

*Direct coomb we are detecting IgG and/or C3b on the

. You

A. Drug induced autoimmune hemolytic anemias:

1. PENICILLIN (PCN) mechanism: the bpo group of PCN attaches to RBC (Piece of PCN is
attached on RBC membrane). This is bad if an IgG Antibody develops against it because if it does,
than the IgG attaches to the bpo group, goes to the spleen and is removed extravascularly; this is a
type II HPY.

Pt on Penicillin develops a rash, what type of HPY? Type I

Pt on Penicillin develops a hemolytic anemia, what type of HPY? Type II

2. Methyldopa (Ex.aldomet) Use: anti-hypertension (HTN) for pregnant woman. Complications:

Methyldopa can cause a hemolytic anemia. Methyldopa works differently from PCN: methyldopa
messes (mixed) with Rh Antigen on surface of RBC and alters them. They are altered so much that
IgG Antibodies are made against the Rh Antigen (our OWN Rh Antigen). So, the drug is not sitting
on the membrane, it just causes formation of IgG Antibodies and they attach to RBC to have
macrophage kill it.

Hydralazine - anti-HTN used in pregnancy. Hydralazine can lead to drug-induced lupus (2nd to
procainamide for drug induced lupus).

What type of HPY are Methildopa and PCN? HPY type II for hemolytic anemia.

3. Quinidine: this immune complexes are formed. Quinidine

acts as the hapten and the IgM Antibodies attaches; so, the drug and IgM are attached together,
circulating in the bloodstream. This is a HPY type III, and will die a different way, because this is
IgM. When IgM sees the immune complex, it will sit it, and activate the classical pathway 1-9,

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leading to intravascular hemolysis, and haptoglobin will be decreased, and in the urine, Hb
will be present.

XI. MICROANGIOPATHIC HEMOLITIC ANEMIA (chronic intravascular hemolysis)

ented schistocytes (schisto means split). Most Common Cause chronic

intravascular hemolysis = aortic stenosis.

In this disease, the cells hit something; therefore have

intravascular hemolysis, Hb in the urine and haptoglobin is down.

*In chronic intravascular hemolysis = losing Hb in the urine.

*What does Hb have attached to it? Fe
*What is another potential anemia you can get from these pts? Iron deficiency anemia.

Causes of Chronic Intravascular Hemolysis (schistocytes):

1. Aortic stenosis findings: (systolic ejection murmur, 2nd Inter Costal Space, radiates to the carotids,
S4, increased on expiration, prominent Pulse of Maximal Impulse in apex and they have the
following CBC findings: low MCV an chronic intravascular hemolysis d present
(schistocytes) this is a microangiopathic hemolytic anemia related to aortic stenosis.

2. Disseminated Intravascular Cuagulation

(Fibrin strands split RBCs right apart because RBC is very fragile);

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In thrombotic thrombocytopenic purpura

Autoimmune disorder with IgG Antibodies against a platelet antigen (HPY TYPE II) Petechial in
skin and Hemolytic-uremic syndrome (HUS) you see schistocytes. When you have platelet
plugs everywhere in the body, the RBCs are banging into these things causing schistocytes and
microangiopathic hemolytic anemia. Example in long distance
marathon it; to
prevent, use bathroom before start the marathon.

3. Hemolytic anemia: falciparum Malaria

Have multiple ring forms gametocyte (comma shaped and ringed form). It produces a hemolytic
anemia, which correlates with the fever. The fever occurs when the cells rupture (intravascular
hemolysis).

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White Blood Cells (WBC)*NORMAL VALUES: 4000-6500
I. Non-neoplastic Lymphoid Proliferations:

Cell 1= Normal mature Lymphocytes. Cell 2 = Eosinophil.

A. Neutrophils when you have acute inflammation = Ex. appendicitis, neutrophilic leukocytosis,
left shift, toxic granulation, and leukamoid reaction (
). Usually involves any of cell lines. What causes leukamoid reactions? Tuberculosis and
sepsis. You see greater than 30-50,000 cells in the blood. Kids get these a lot (Ex. otitis media -
30,000 exaggerated). Adult with otitis media = 12,000; lymphosytosis is common in infections.
Bordetella Pertussus (Paroxysms of whooping cough and lymphocytosis (60,000)

Pediatricians are worried about Acute Lymphoblastic Leukemia

ALL

In atypical lymphocytosis
presented to and Antigen ntigen by dividing and getting bigger, so basically
atypical lymphocyte, the absolute first
thing that pops into the mind is: mononucleolosis Eibstern Barr Virus (EBV) called the
kissing disease because the virus holds up in the salivary glands. EBV affects B cells and CD
21. EBV is Mono causes viremia, generalized painful lymphadenopathy, very commonly get
exudative tonsillitis, jaundice (hardly ever seen), increased transaminases (off the chart), and spleen

avoid contact sports usually for 6-8 weeks. Also causes macrocytic anemia via inhibiting intestinal
conjugase). Other disease that are seen with large, beautifully staining bluish cells: CitomegaloVirus,
toxoplasmosis, any cause of viral hepatitis, phenytoin.

Audio Day 2: Hematology File 5

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Example: the boards will give you a classic history of mono, and ask which tests you run, but
monospot test is not on the choices because
(hetero = different phile = loving). Heterophile Antibodies are anti-horse RBC Antibodies (or anti-
sheep); they are d ntibodies. Once you have mono, you always have it
and will have 3-4 recurrences over your lifetime Ex. reactivation consists of swollen glands, very
tired, etc. Eibstern Barr Virus lives in B cells; the atypical lymphs in mono are T cells reacting against
the infected B cells.

B. Monocyte = king of chronic inflammation, therefore expect monocytosis in pts with chronic
infections Ex. .

Worthy board question:

What serum test is markedly elevated in someone taking creatine for their muscles?
Creatinine. Because, creatine metabolism final product is Creatinine. The BUN is normal in
this person. Creatine gives energy, it binds to phosphate, and that is the phosphate you get from
making ATP.

C. Eosinophilia - Only invasive helminthes produces eosinophilia

You would see eosinophilia in Hay fever, rash in pt with Penicillin, strongyloidiasis.
Protozoa infections DOES NOT produce eosinophilia, therefore it rules out amabiasis
(pinworm), giardia, malaria and ascariasis. Adult ascariasis does NOT cause eosinophilia
because all they do is obstructing bowels; lungs
that cause eosinophilia. So anything that is Type I HPY causes eosinophilia.

II. MYELOPROLIFERATIVE DISEASE: Polycythemia increased RBC count, increased Hb and

Hct.

Difference between serum Na and total body Na:

*Serum Na is milliequavalents per liter of plasma.

*Total body Na is milliliters per kg body weight (the total amount you have).

Similarly:

RBC mass in body weight.

RBC count = Number , therefore its how many you have in a certain
volume of blood.

Why is this big deal? Example: went running and volume depleted RBC count would be
hemoconcentrated, therefore would look like more RB you
depleted the plasma volume), but what would the RBC mass be? Normal (not actually synthesizing

So, there are 2 types of

Relative = decrease in plasma volume causing an increase in RBC count, but the RBC mass is
normal.
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Absolute = increase (appropriate or inappropriate)

When would it be appropriate? Synthesis of RBC tissue hypoxia, so, any source of tissue
hypoxia would be an appropriate response. Example of appropriate polycythemias: lung disease,
hypoxemia, Congestive Obstructive Pulmonary Disease or high altitude.

What if we have normal blood gases, but di tissue hypoxia? This is inappropriate
polycythemia (have normal blood gases and no evidence of tissue hypoxia and have an
increase in RBC mass).

What increased RBC mass?

1) Polycythemia rubivera, which is an Ex. of a stem cell proliferative disease of the Bone Marrow,
meaning that the stem cells are dictators and nothing keeps them in check a neoplastic disease;
they can become leukemias.
2) Tumor or cyst with an excess production of Erythropoietin (EPO): renal adenocarcinoma
making EPO, causing an increase in RBC mass this is inappropriate because a tumor is
inappropriately making it.

In summary: polycythemia is relative or absolute. Relative means that you just lost plasma vol (ie
from running) with RBC ct increased, and mass is normal. Absolute increase: is it appropriate or
inappropriate? Appropriate
hypoxic condition causing the EPO production, then you are ectopically making EPO from a tumor or
cyst or you have polycythemia rubivera (a myeloproliferative disease).

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III. Myeloproliferative disease neoplastic stem cell disease that has lost all regulation and nothing
can inhibit it anymore.

There 4 diseases that fit under this definition:

1. Polycythemia rubra vera
2. Chronic myelogenous leukemia (CML) (only leukemia in this category)
3. Agnogenic myeloid metaplasia Bone Marrow is replaced by fibrous tissue.
4. Essential thrombocythemia where a stem cell that makes platelets goes crazy and make 1
million, 600 platelets for microliter, Myelodysplastic syndrome.

A. Polycythemia rubra
4
1. Hyperviscosity ). With polycythemia, it will
have an increased resistance and TPR will go up; it will predispose to thrombosis, which kills you
thrombosis of anything Ex. dural sinuses; Most Common Cause Budd chiari = hepatic vein
thrombosis; coronary artery, Superior Mesenteric Vein, anything can be thrombosed because blood
slugging around and this is why phlebotomy is done. Phlebotomy is performed to make you Fe
deficiency they want to make you Fe deficiency why? If you make them Fe deficiency, because

2. Hypervolemia only polycythemia that has an increase in plasma volume that matches the
increase in RBC mass; none of the other causes have an increase in plasma volume (these are
measured with radioactive techniques). So, it is very rare to see an increase in plasma volume with
polycythemia, except for this case. Why? Myeloproliferative disease takes years and years to
develop. Therefore, plasma volume is able to keep up; therefore both increase together over time.

3. Histaminemia all cells are increas

basophils. Example: Classic Clinical history: pt takes a shower and gets itchy all over body this is
a tip off for polycythemia rubivera why? Mast cells and basophils are located in the skin and
temperature changes can degranulate mast cells, causing a release of histamine, leading to
generalized itching (very few things cause generalized itching bile salt deposition in the skin in pts

with obstructive jaundice, and pts with mast cell degranulation), face is red
looking (plethoric face) due of histamine because vasodilatation, leading to migraine-like
headaches.

4. Hyperuricema because nucleated hematopoetic cells are elevated, they then die, and the nuclei
have purines in them. The purines will go into purine metabolism and become uric acid. Example: pt
on chemotherapy must also be put on allupurinol to prevent urate nephropathy and prevent renal
failure from uric acid. (Allupurinol leasing
millions of purines when the nucleated cells are killed and the tubules are filled with uric acid, leading
to renal failure. Must put them on allupurinol. This called tumor lysis syndrome. The same thing

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occurs in polycythemia rubra vera because there is an increase in number of cells that eventually dies
and you run the risk of hyperuricemia.

B.
RBC mass Plasma Vol O2 sa Erythropoietin
Polycythemia Rubi Vera: high high normal (inappropriate) low
COPD, tetra of fallot, high alt: high normal low (appropriate) high
Renal Adenocarcinoma/Cyst: high normal normal high
Relative Polycythemia: normal low normal normal

Polycythemia rubivera (have too much O2 because you have piles of RBCs and therefore suppress

COPD, tetralogy of fallot, high altitude (appropriate polycythemia because

hypoxia)

Renal adenocarcinoma, hepatocellar carcinoma, any cyst (renal, especially Ex. hydronephrosis,
(even with normal gas studies because ectopically produced)

IV. LEUKEMIAS - They are a malignancy of the Bone Marrow and mets anywhere it wants.

A. General characteristics of Leukemia; therefore will always have:

1. Generalized lymphadenopathy, hepatosplenomegaly

2. Abnormal cells in the peripheral blood BLASTS (myeloblasts, lymphoblasts, monoblasts,
megakaryoblasts)
3. Becase it is arising in the Bone Marrow, will always crowd out the normal hematopoetic cells,
and will ALWAYS have an anemia, usually normocytic.

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4. Usually Thrombocytopenia because crowding out the normal megakaryocytes from making
platelets.
5. Usually an increase in WBCs counts with abnormal cells present.
6. Acute vs. chronic Do a bone marrow test and look at blasts if blasts are <30% = chronic; if the
% blasts is >30% = acute. Therefore the blast count tells if its acute vs chronic.

B. Age brackets: Know age brackets

*0-14 years = Acute Lymphoblastic Leukemia (ALL)

*15-39 = 25 years 32 year Acute

Myelogenous Leukemia (AML) myeloblast with Auer rods in peripheral blood.

*40-59 =AML, Chronic Myelogenous Leukemia (CML) (separate with Bone Marrow AML with
>30% and CML with <30%, 9, 22, Philly chromosome test)

60+= 70 years
Most Common overall leukemia regardless of age = Chronic Lymphocytic Leukemia (CLL)
Most Common Cause generalized nontender lymphadenopathy in pt 60+ = CLL; because
mets to lymph nodes).

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 C. Different Types of Leukemia:

Question: Peripheral smear of 49 years, 150,000 WBC

count, 1% myeloblast in peripheral blood and Bone Marrow, generalized nontender
lymphadenopathy, hepatosplenomegaly, thrombocytopenia, and normal anemia. What is the
diasnostic? Chronic Mielogenous Leukemia (look at age bracket and % blasts).

To prove CML, get 9, 22 Philly chromosome test (abl protooncogene with nonreactor tyrosine kinase
activity and goes from 9 to 22 and fuses with the cluster fusion gene) and (LAP) leukocyte alkaline
phosphatase stain can also be used. Look at which neutrophils take it up mature neutrophils all
have LAP in them; neoplastic neutrophils do not why? Because they are neoplastic. So, if no stain,
know its neoplastic (normal cells take up stain). Called a LAP score always low in CML. So, the
two tests: Philly chromosome and LAP score, which is always low for Chronic Myelogenous
Leukemia (CML).

Example: TEAR DROP CELL because there was a dictator in

Bone Marrow, and cells have to move to the spleen, so there is a migration of hematopoetic cells
from the Bone Marrow to the spleen. When you take up hematopoesis anywhere other than the bone
marrow, this is called extramedullary hematopoesis. So, the spleen in huge especially in
agnogenic myeloid metaplasia. Some of the megakaryocytes go back to the marrow to lay
down collagen; and megakaryocytes go back. Fibrosis of the Bone Marrow occurs (used to be
called myelofibrosis metaplasia). So, not everyone left the Bone Marrow, and stay in the fibrotic
marrow. For them to get to the spleen, they have to work their way through strands of fibrotic tissue,

fibrous tissue and getting into the sinusoids, they are tear drop cells in the peripheral blood).

Question: Too many platelets?

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 ESSENTIAL THROMBOCYTHEMIA (makes too many
platelets)

Question: 4 years pt that presents with sternal tenderness,

fever, generalized nontender lymphadenopathy, hepatosplenomegaly, normocytic anemia,
50,000 WBC counts many of which had an abnormal appearance cells. What is the diagnosis?
ALL (acute lymphoblastic leukemia).

Most Common cancer in kids; the most common type is: ALL Antigen B cell leukemia. CD10+;
calla+ Ag B-cell ALL, associated with syndrome.

Example:= 65 years, normal criteria, smudge cells and normocytic

anemia. They also have hypogammaglobinemia because they are neoplastic B cells and cannot
change to plasma cells to make Igs. Therefore, Most Common Cause of death in CLL = infection
related to hypogammaglobinemia. What is the Diagnostic? Chronic Lymphocytic Leukemia.

Example: 62 years, normal criteria, special stain of (TRAP)=tartrate

resistant acid phosphatase stain hairy cell leukemia (know the TRAP stain)

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Example: 35 years pt, with normal criteria, with 50,000 abnormal
WBCs and Auer rods (abnormal lysosomes), 70% blast cells in the Bone Marrow. What is the
Diasgnostic? Acute Myelogenous Leukemia. Know what Auer rods look like, know the leukemia
that infiltrates gums (acute monocytic anemia M5), and acute progranulocytic anemia (M3)
they always have Disseminated Intravascular Coagulation, has a translocation 15, 17. Rx =
retinoic acid (vit A causes blasts to mature into b9 cells).
V. LYMPH NODES

A. General Characteristics:

1. Painful vs painless: Painfull lymphadenopathy: not malignant; mean that you have
inflammation causing it (does not always mean infection) In Lupus you are stretching the capsule,
and that produces pain. When you have non-tender, think malignant,
either (1) mets or 2) primary lymphoma originating from it. Painless lymphoadenopathy:
Metastasis (Cancer).

2. Localized vs. generalized lymphadenopathy: Localized infection (Ex. exudative tonsillitis

goes to local nodes; breast cancer goes to local nodes. Generalized painful (systemic disease
Ex. HIV, EBV, Lupus).

3. Examples: Disease and what affect

germinal follicle absent: B-cell

(b) DiGeorge syndrome paratrabeculae messed up: T-cell country
(c) Histiocytes (Han shculler Christian/letterman sieve disease) involves sinuses.
(d) Severe Combine Immunodeficiency Disease (SCID) = (adenine deaminase deficiency) B and T
cell deficiency, therefore no germinal follicle and no paratrabeculae but will have sinuses.
(e) Reactive lymphadenopathy: Macrophage takes Antigen, and presents to germinal follicles and
they spit out a plasma cell, making Antibodies.

B. Non-Hodgk

FOLLICULAR LYMPHOMA

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Most Common primary cancer of lymph nodes? Non- : Follicular
lymphoma, B-cell; translocation 14,18; and apoptosis gene knocked off, so the cells are
immortal.

What 2 tissues are resistant to invasion by cancer cells?

See that the lymphoma do not damage the Cartilage and elastic tissue.

Example: BURKITTS caused EBV; Translocation 8, 14, myc oncogenes,

STARRY SKY; normal Macrophages looking like sky at night, #3

Most Common Cause cancer in kids, it can cure and Most Common lymphoma in Africa kids,
usually in the abdomen (Ex. payers patches, paraortic lymph nodes, also but rarely in the jaw, or
testes)

Example: plaque like lesions, no teeth, is actually the inflammatory cells are
really neoplastic; so the helper T cell in mycosis fungoides T cell
malignancy.

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Involves the skin and lymph nodes vs. SEZARY CELL which is
seen in peripheral blood (malign helper T cell that is in peripheral blood, in mycosis
fungoides)

Example: kid with Electron Microscopy of eczematous rash

all over generalized nontender hepatosplenomegaly, , EM of monomorphic cells which were CD 1+
cells histiocytosis X complex is part of (letterer Siwe disease) (birbeck granules, look like
tennis racket also clostridium tetani which has a spore looks like a tennis racket )

Audio Day 3: Hematologies file 6

C. isease fever, night

sweats, and weight loss (usually TB unless proven otherwisasd e). It is usually localized, nontender
lymphadenopathy.
On micro: the malignant cell is REED STERNBERG CELLS:

Characterizes by: owl eyes - common on boards (also giardia,

CMV, ashoff nodule in rheumatic fever). Less # = better prognosis; more = worse.

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The Most Common important Hodgkin Disease is Nodular Sclerosis:

It is nodular (hence the name), and has lots of sclerosis

non-painful node). You would see in woman with lymph node
involvement in 2 places: 1) anterior mediastinum and 2) somewhere above the diaphragm-
Example: Painless Cervical Lymphoadenopathy Lymph node biopsy(see the Reed Sternberg
present)

CERVICAL NODES, superclavicular nodes in neck. This

combination of mass in neck and anterior mediastinum = nodular sclerosis.

LYMPH NODE WITH NODULAR SCLEROSIS IN HIGHER

MAGNIFICATION (see the lacunar cells)

1. Terms: polyclonal and monoclonal (this will help to understand the difference from multiple
myeloma and other things that increase gamma globulin). On serum protein electrophoresis, albumin
migrates the farthest because it has the most negative charge, whereas gamma globulin just sits
there.

(A) Polyclonal: plasma cells, therefore you have many clones of plasma
cells because -a-
the order of most abundant/greatest number of globulin. Therefore, on electrophoresis, you see a little
peak, this is an increase in IgG because ndant IgG this makes sense because for
chronic inflammation, the main Ig is IgG, and for acute inflammation the main Ig is IgM. So, in
chronic inflammation (Ex. lcerative Colitis) there is an increase in IgG

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 which will show a large diffuse elevation (a nice round mtn). This is called polyclonal
gammopathy because many benign plasma cells are making IgG. Polyclonal gammopathy
always means benign and chronic inflammation. Will not have polyclonal gammopathy with acute
inflammation (ie acute appendicitis); this not any rise in the gamma gobulin region for acute
inflammation the main Ig is IgM for acute.

(B) Monoclonal = ; other plasma cells are not making

Ig
malignancy of plasma cells. Meanwhile, all other plasma cells are suppressed by immunologic
mechanisms. The malignant clone makes its own Ig; most of the time it is an IgG malignancy.

Immunoglobulin and light chain are abnormal in the slide.

They are making many light chains and get into the urine these
are called Bence Jones proteins. Monoclonal usually means malignancy and always means multiple
myeloma.

(C) Peaks (in order): albumin, alpha 1, alpha 2, beta, gamma have a pt 25 years, non-smoker,
had emphysema of the lower lungs, no alpha 1 peak what is Diagnosise? Alpha 1 antitrypsin
deficiency.

VI. PLASMA CELL DISORDER:

A. Multiple Myeloma (MM)

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Multiple Mieloma is a very bad disease incurable, and unless you get Bone Marrow transplant, you

is Ig kappa, which is abundant. Plasma cells have IL-1 (Ex. osteoclast activating factor);

this is why you see lots of lytic lesions in the skull or bones.
The lytic regions are round, and nicel , the lytic regions are fuzzy
and not sharply cut). While in Multiple Mieloma lesions have a fine, sharp (cookie cutter cut) border,
because IL-1 activates osteoclasts, leading to the punched out lesions.

If there was a lytic lesion in the ribs and pt coughed, what would potentially happen?
Pathologic fractures and these are extremely common.

Elderly woman coughs and develops severe pain and you see lytic lesion of the rib, so what
does the pt have? Multiple myeloma

Multiple Mieloma plasma cell has bright blue cytoplasm and

nucleus is eccentrally located (around the nucleus are clear areas present). On Electron Microscopy,
will see layer and layers of RER, because they are constantly making protein (ribosomes are where
ribosomal RNA sits on). Must know what plasma cell looks like on EM and giemsa stain.

Summary: Multiple Myeloma lytic lesions, Bence Jones proteins, and seen in elderly pts.

1. Amyloidosis: is a clinical
characteristic of Multiple Myeloma.

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Amyloid on Electron Microscopy is a non-branching, linear compound with a hole on the center of it.
They always ask a question on amyloidosis because it ends up in the differential diagnostic for multi-
system disease
different proteins can be transformed and converted into amiloid Ex. pre-albumin, calcitonin (tumor
marker for medullary carcinoma of the thyroid), light chains in Multiple Myeloma, and trisomy 21.

In , the chromolsome 21 codes for beta amyloid, and if you have

three of these, you will make more beta amyloid protein. And beta amyloid protein is toxic to
neurons; so, if you have trisomy 21 are making more beta amyloid protein, then you will be losing
more neurons because you are losing more of this protein that is toxic to neurons.

Question: Pt dying at forty and on autopsy, you see atrophy of the brain and it reveals senile
plaques in frontal and temporal lobes. What is the diagnostic? .

(1) Endocardial cushion defects which leads to heart defects and an Atrial Septal Defect
(in childhood) and a Ventricular Septal D
(2) (death because chromosome 21 is making too much beta amyloid
protein). Example: 40 has downs syndrome. Beta amyloid is most
important protein.

VII. LYSOSOMAL STORAGE DISEASE

Two different cells that they like to ask questions about.

1. Gaucher disease:

there is a macrophage with a crinkled paper like appearance

in the cytoplasm. There are lysosomes filled with glucocerebroside, therefore pt has Gaucher
disease with a missing glucocerebrosidase enzyme.

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2. Niemann-Pick disease:

bubbly cytoplasm, severe mental retardation, buildup of

sphingomyelin in the lysosomes, therefore the pt has Niemann-Pick disease, missing
sphingomyelinase enzyme.

3. isease: only glycogen storage diseas

glycogen storage disease that is lysosomal because they are missing an enzyme to break glycogen
down in the lysosomes. How does pt die? Die from cardiac failure because excess deposition
of normal glycogen in the heart.

Summary:
*Bubbly cytoplasm = Niemann-Pick disease
*Crinkled paper = Gaucher Disease both are lysosomal storage disease.

I. THROMBOGENESIS: THE COAGULATION SYSTEM

Hemostasis: things in our body that prevents clots from developing in Blood Vessel. If these
clots were not prevented, the pt has: Disseminated Intravascular Coagulation (DIC), thrombotic
thrombocytopenic purpura (TTP), or Hemolitic Uremic Syndrome (HUS), and all of them lead to
death. What are our small Blood Vessels? [Small blood vessels include arterioles, venules, and
capillaries, while small airways include terminal bronchioles, respiratory bronchioles, alveolar duct,
and alveolus].

Because we have coagulation factors such as: heparin, PGI 2,

Protein C and Protein S, and tissue plasminogen activator. So all of these things are used to prevent
little clots occurring in our small blood vessels.

1. Heparin (is a Glucosaminoglycans (GAG) = mucopolysaccharide). It is normally found in the body

and helps prevent formation of clots. How does heparin work? It ENHANCES antithrombin III.
Antithrombin III is made In the Liver (like all other proteins). Therefore, heparin gets the credit for
anticoagulating you, but its antithrombin III does all the work. Antithrombin III neutralizes most of
the coagulation factors and can only inhibit serine proteases. So, we have a little bit of heparin in
our small vessels, which prevents clotting from occurring.

2. PGI2, prostacyclin, made from endothelial cells, PGI2 is a vasodilator. When the vessel is
vasodilated blood flows faster and it is more difficult for a thrombus and other things to stick. PGI2
also prevents platelet aggregation.

3. Protein C and S are Vit K dependent factors (as are factors 2, 7, 9, 10). Functions of protein C
and S: they INACTIVATE (Ex. neutralize or get rid of) inhibit factors 5 and 8 in our body.

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4. t-PA (tissue plasminogen activator) this is what we use to dissolve a
clot in a pt with coronary thrombosis t-PA activates plasminogen = produces plasmin= eats
everything in site.

B. Deficiency in any of the anticoagulants: Deficiency in any of these things (heparin, PGI2, protein
C and S, and t-PA), clots would form. In other words pt will be thrombogenic.

Why are pts on birth control thrombogenic? Birth control pills (estrogen) are blocking heparin by
inhibiting AntiThrombin III and increases the synthesis of 5 and 8, increases synthesis of
fibrinogen. The result is the assisting in the formation of clots. Deadly duo: woman on birth
control and smoking = bad; smoking is thrombogenic = damages endothelial cells (so both are
thrombogenic).
C. Formation of a stable clot
For example: a pt is shaving and cut himself. How do we stop bleeding when you cut a small Blood
Vessel (not talking about muscular arteries need to plug that)
injury/cut/damage of a small vessel (Ex. arteriole, venule, capillary.

What will stop the bleeding? To determine this we use bleeding time as Ex: bleeding time is
used to evaluate platelet function.

Example: If pt has hemophilia A and has no factor 8, the pt will still have a NORMAL bleeding time
because bleeding time has NOTHING to do with coagulation factors. Bleeding time is purely a
PLATELET thing.

1. How do they perform the test?

Cut the pt (inflict wound), start stop watch, and dab (gentle touch) wound every thirty sec; when the
normally it is 7-9 mins.

2. The pathway of bleeding time:

a. When the vessel is cut.

b. Tissue thromboplastin is released (which activates the extrinsic coagulation system, but has
nothing to do with bleeding time). The cut exposes collagen and of course Hageman factor (factor
12) is activated by the exposed collagen; hence the intrinsic pathway is activated, but this has nothing
to do with bleeding time, either.

c. Endothelial cells and megakaryocytes make an adhesion product (a type of glue) whose special
purpose is to stick to platelets Von Willebrand factor (vWF). vWF is part of the factor 8 molecule
and is made in 2 places megakaryocytes in the Bone Marrow and endothelial cells.
from megakaryocytes? Platelets; which carry a little bit of glue with them in their granules. Also,
platelets are made in the endothelial cells.
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d. When you damage the small Blood Vessel, Von Willebrand factor (vWF) is exposed and platelets
have receptors for vWF which is basically an adhesion molecule (just like neutrophils had receptors
for the endothelial cell made by the endothelial cell. If neutrophils cannot stick to venules, then they
cannot get out killing bugs). Same concept here platelets have to stick to before they can do their
thing so vWF is the adhesion molecule that allows them to do that.

e. The platelet sticks called platelet adhesion. When the platelet sticks, it causes the platelet to
release chemicals most important chemical is ADP this is a potent aggregating agent, and
causes platelets to stick together. They start to help form a thrombus to begin to stop the
bleeding. However this is not enough to complete the process. So, this is called the release
reaction when the platelet sticks, it causes the platelet to release chemicals, and the most
important chemical is ADP. When platelets come by, they will stick together (because of the ADP)
and the bleeding will go down.

f. As soon as the platelet has the release reaction, it starts synthesizing its produce another unique
substance Thromboxane A2; platelets make it because they are the only cell in the body that
has thromboxane synthase. So, Platelets can convert PgA2 into TxA2, potent vasoconstrictor.
This is important in stopping bleeding, because if you slow rate of blood flow, it will make it easier for
ed away. As opposed to prostacyclin,
which is a vasodilator the platelets cannot stick because the blood flow has increased.
TxA2 it has
affects in asthmatics because it helps LT C4, D4, and E4. So, TxA2 is a vasoconstrictor, a
bronchoconstrictor, and a platelet aggregator. It puts the finishing touches on it and causes the
platelets to really aggregate, and blocks the injured vessels, and bleeding time has just ended.

3. Integration: Platelets do two things:

(1) release reaction, where chemical were already made in it were released so, preformed
chemicals were released.
(2) it makes its own chemical called Thromboxane A2.

This is analogous to MAST CELLS. In immunology: f

pollen bridged the gap. This caused the mast cells to have a release reaction (release of preformed
chemicals: histamine, serotonin, and eosinophil chemotactic factor). These chemicals then started
the inflammatory reaction in a type I HPY reaction. The mast cell released arachidonic acid from its
membrane and we ended up making Prostaglandins and leukotrienes. They were released 30
minutes to an hour later and furthered/enhanced type I HPY (inflammatory) reactions.
So the mast cell had a release reaction of preformed elements and it made its own
Prostaglandins/leukotrienes. That is what platelets did: released its preformed chemicals and made
its own chemical: TxA2.

Plug is temporary it is a bunch of platelets stuck together and held together by fibrinogen, and is
enough to prevent bleeding (to stop bleeding time), but if you scratch or try to open the wound, it

4. Conditions that arise with increased or decreased bleeding time: Lets screw up bleeding
time:

Disease that has a problem with adhesion molecule defect and would be an obvious mess up
of bleeding time?
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 *Thrombocytopenia: decreased platelet count therefore if you have less than 90,000 platelets,
you will have a prolonged bleeding time because you will not have enough to aggregate.

* Von Willebrand (vWB) disease (Most Common genetic hereditary disease, Autosomal
Dominant)
Most Commoon Cause prolonged bleeding time = aspirin.

Mechanism? Aspirin blocks platelet Cyclooxygenase (COX) (blocked by Dipyrramidal).

2?
The platelet COX vs the endothelial COX reacts differently to aspirin. Different compounds act
differently to non-
cannot neutralize both would be bad. So, aspirin is irreversible and other NSAIDs are reversible
for 48 hrs. So, if you took an aspirin, it prevents platelets from aggregating, and therefore they do
not work, so if you cut yourself, the bleeding time will be increased. Aspirin inhibits platelets from
aggregating;

5. Continuation of Clotting: Recall that the release of t-PA which will activate extrinsic system
and it also activates the Hageman factor 12 because of collagen being exposed therefore the
intrinsic system is also activated. End product of coagulation is thrombin, and thrombin
converts fibrinogen into fibrin. So, we have pile of platelets stuck together and they are bound
with fibrinogen. What will happen right after the bleeding time ends? The activated thrombin
(produced by the extrinsic and intrinsic pathways) will convert the fibrinogen (which is holding the
platelets together loosely) into fibrin, making a more stable platelet plug that you are not able to
dislodge. So, who will remove that platelet plug from the vessel? Plasmininogen, and when it is
activated and plasmin are formed; plasmin will drill a hole through it and recanalize, so the vessel is
normal again.

D. Platelet deficiency vs Coagulation deficiency

So, with bleeding time, the platelets (which are held together with fibrinogen) form a temporary

makes thrombin, it converts fibrinogen into fibrin, making a strong platelet plug. This difference is
very imp b/c it distinguishes a difference between a platelet abnormality vs coagulation factor
deficiency

1. Platelet problem, what will happen to bleeding time? Prolonged, because if the pt cuts a vessel,
what will happen? It will continue to bleed (therefore a platelet prob). Therefore, in platelet
abnormalities, you see bleeding from superficial scratches or cuts (pt continues to bleed because you

platelets are messed up, leading to petechia (hemorrhage only see in a platelet abnormality
pinpoint area of hemorrhage), echymoses (purpura), epistaxis (nose bleed, which is the Most
Common manifestations in platelet problem).

2. Coagulation deficiency:

*Pt with hemophilia A (deficiency in factor 8)

What is bleeding time? Normal. What type of problems do these pts run into? LATE re-
bleeding.

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 Appendectomy everything went fine, pt woke up, starting moving around and blood started
coming out (massive amounts of blood came out of the wound and pt bled to death). Because the
only thing that was holding the blood in was sutures and temporary hemostatic plugs. If you have a
Coagulation factor deficiency, you cannot convert fibrinogen into fibrin, and the platelets will
fall away, leading to late re-bleeding. Pt is able to handle superficial scratches/cuts. However, will
not hold vessel closed for too long because late re-bleeding will take place.

Example: If pt had a Molar or wisdom tooth extracted, and had hemophilia A,

pt had no problems with bleeding; however, what is the ONLY thing holding the wound shut? Little
temporary platelet plugs that are held together by fibrinogen (not fibrin). Dentist tells you to wash
mouth out (with salt or a little bit of peroxide) when you get home; bad because you will bleed to
death and suffocate on your own blood (all hemostatic plugs are gone and pt bleeds to death). This is
LATE rebleeding; not from superficial scratches. If after extraction of a wisdom tooth no bleeding
occurred, then they have normal Coagulation factors. Other conditions of coagulation deficiency:
Menorrhagia more of Coagulation deficiency, than a platelet problem, and the potential for
Hemearthroses: where you bleed into closed spaces.

Summary: So, platelet problem (epistaxis, echymoses, petechia, bleeding from superficial
scratches) vs coagulation problem (late re-bleed, Menorrhagia, GI bleeds, hemarthroses). This
is all based on knowing what happens to small vessels.

E. Tests for platelet abnormalities:

1. First do platelet count: if you took an aspirin you still have a normal # of

2. Secondly do Bleeding time assesses platelet function

3. Test for vWF? Ristocetin cofactor assay - if missing vWF, ristocetin

cause platelets to clump (most sensitive test for diagnost vWF disease).

So, three tests that assess platelets: platelet count, bleeding time, ristocedin cofactor assay (for vWB
Disease)

Older man with osteoarthritis prostate was resection and massive bleeds: if have
osteoarthritis, you have pain, and if you have pain, you will be on pain medication, an NSAIDS,
and will give test results PT/PTT/platelet count all normal bleeding time is longer. Rx
platelet pack transfusion when you give from a donor, it
normal). So, if taking NSAIDs, platelets not working and if you have a problem during
surgery, give pt platelets from donor.

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Audio Day 3: hematology files 7
F. Extrinsic vs. Intrinsic system:

1. Factors involved: *Extrinsic = factor 7; *Intrinsic = factors 12, 11, 9, 8

Both share the same final common pathway factor 10.

(What is another system that has a final common pathway? Complement whether by the
classical pathway, the alternate pathway, or by the MAC pathway, all includes C3)

What do we have left? 10, 5, 2 (Prothrombin), 1 (fibrinogen) and then the clot.

2. Tests involved:

a) Prothrombin time (PT): Evaluates the extrinsic system all the way down to the formation of a
clot so it only deals with 7, 10, 5, 2, and 1. End stage of the test is a clot in the test tube. INR =
standardized way of doing it standardization technique (same everywhere in world).

b) Partial thromboplastin time (PTT): Evaluates the intrinsic system all the way down to a clot
so it deals with 12, 11, 9, 8, 10, 5, 2, and 1.

Example: PT is prolonged, but PTT is normal, what is the factor deficiency? Factor 7 Because
the prothrombin was prolonged; this includes 7, 10, 5, 2, or 1. And the PTT are normal, meaning that
12, 11, 9, 8, 10, 5, 2, 1 are all normal. So the only one responsible is 7.

Example PTT is prolonged, but PT is normal, what is the factor deficiency? Factor 8 (play odds).
Why? If PTT is prolonged, it is 12, 11, 9, 8, 10, 5, 2, and 1 that is the problem. However the PT is
normal, therefore 7, 10, 5, 2, and 1 are normal. Therefore, its one the PTT factors (12, 11, 9, 8). We
know what hemophilia A (next to vWB Disease) is the Most Common factor deficiency, therefore, if
or 8 deficiency.

Example: What did the anticuagulant warfarin block? Epoxide reductase. So, that prevented the
gamma carboxylation of Factors: 2, 7, 9, and 10.

What do you follow with warfarin? PT. What is the only factor you are not evaluating to when
you are doing a PT time for a person on warfarin? Factor 9 because its part of the intrinsic
system.

What is the PTT in a person on warfarin? Prolonged because factors 2 and 10 are vit K
dependent factors in the final common pathway. However, PT does a better job in evaluating
warfarin because
and PTT are prolonged when you are on warfarin, but PT is better diagnostic tool.

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Example: What do you follow the anticuagulante heparin therapy with? PTT (evaluates the
intrinsic pathway). Factors that antithrombin III knocks off: 12, 11, 7, 10, 2, 1 are all neutralized by
antithrombin III.

Pt on heparin, PTT is prolonged, what is the PT? Prolonged. the PTT does a better
job at evaluating heparin (many factors antithrombin III involved with).
II. FIBRINOLYTIC SYSTEM: PLASMIN

Plasmin leaves crumbs its breaks down things (fibrinogen, fibrin, coagulation factors) think
fibrinoLYTIC system. When it breaks down a clot, there are many pieces (Ex. fibrin) left around,
which are fibrin degradation products.

*What is the single best screening test for Disseminated Intravascular Cuagulation? D-dimers
(better answer) or fibrin split products.

*What plasmin does is breaks things apart, leaving crumbs behind and you have degradation
products? D dimers are the absolute best test for DIC (di- means 2).

*When you form a fibrin clot, factor 13 (fibrin stabilizing factor) makes the clot stronger.

*How do you stabilize strands? Link them; factor 13 put crossbridge in fibrin connections between
them to make them stronger increase the tensile strength.

*What does this absolutely prove? That there is a fibrin clot. Do you see this in Disseminated
Intravascular Coagulation? Yes.

*Would you see it if you broke apart a platelet thrombus in a coronary artery? (Remember a platelet
thrombus is a bunch of platelets held together by fibrin). So, what would the D dimer assay be if you
broke apart that clot? You would see increased D dimers with little fibrin strands held together by
cross linking. They often do that to see if you have recanalized or if you got rid of your thrombus.

*If you have a pulmonary embolus, one test is a D dimer because you will form a clot that will
activate the fibrinolytic system, and it will try to start breaking it down and there will be a release of D
dimers. Single best test for Disseminated Intravascular Coagulation. Good test for picking up
pulmonary embolus, along with ventilation/perfusion scans. Excellent test to see if you have
reperfusion after given t-PA because it proves that if D dimers were present, a fibrin clot must be
present (fibrin was there so it proves it).

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III. VESSEL ABNORMALITIES

A. Senile purpura: Seen on the back of hands of an old

person. Vessels get unstable as you get older and subcutaneous tissue thins. When you hit
yourself, Blood Vessels rupture and you get echymoses (age dependent findings). Senile
purpura is the cause of echymoses only presents in places those normal hit things: on the back of the
and the shin. Everyone will get this.

Example: Mom was put in old age home and the children were gonna sue the old age home for
abuse. Do the children have a case? No, because it has nothing to do with abuse and is an age
dependent finding. But, if they also saw echymoses on buttocks and back, this is not a normal
place to get trauma related to just bumping into things that would be abuse.

B. Osler Weber Rendu Disease (hereditary telangiectasias): Most Common genetic vascular
disease. Many of these pts have chronic Iron (Fe) deficiency anemia, related to persistent GI bleeds.
You can make the diagnoses with Phisical Examination of the pt.

The pt will have small red dots called telangiectasias and if you
look on the lips and tongue you will see telangiectasias, and if you do endoscopy, you will see the
little red dots throughout the GI tract. What does this pt have? Osler Weber Rendu Disease
(hereditary telangiectasias). Therefore, you can see why you get chronic Fe deficiency and bleeds
because the telangiectasias will rupture. It is kind of like the angiodysplasia of the skin.

C. Scurvy (Vit. C Deficiency)

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IV. PLATELET ABNORMALITIES: Findings of platelet problems: all have a problem in making a
hemostatic plug, epistaxis = nose bleed (Most Common), petechia, echymoses, and bleeding from
superficial scratches/cuts.

Example: 12 years kid, with Upper Respiratory Infection one week

ago, presents with epistaxis. Perform Physical Exam, and you see lesions that do NOT blanch (need
to know the difference between petechia and spider angiomas: petechias do not blanch = (pale)
because bleeding into the skin; spider angioma WILL blanch because rterial Venous fistula).
Platelet count is 20,000. What is your dx? Idiopathic thrombocytopenic purpura. Mechanism:
IgG against the platelet with type of HPY II. Who is removing the platelet? Macrophages in the
spleen (because IgG marked the platelet for destruction by the macrophage). This is similar to
autoimmune hemolytic anemia, but this is autoimmune THROMBOcytopenia. Rx if they are very
symptomatic, give corticosteroids; if not, leave alone and it will go away.

The same reaction: MARROW EXHIBIT CLUMPS WITH

MEGAKARYOCYTES in ntibodies test, epistaxis, petechia, generalized
tender lymphadenopathy, and splenomegaly. Pt has LUPUS, autoimmune thrombocytopenia, same
mechanism: IgG auto-antibodies against platelets, a type II HPY reaction, with macrophage
related removal.

A. TTP (thrombotic thrombocytopenic purpura) and HUS (hemolytic uremic

syndrome)
Both have similar pathophysiology. These are NOT Disseminated Intravascular Coagulation,
therefore you are not consuming coagulation factors; the PT and PTT are totally and
unequally normal.

*Have a formation of a temporary hemostatic plug of small blood vessels (bleeding time) and
the coagulation system converting fibrinogen to fibrin to form a strong platelet plug. So in
TTP and HUS, something in the plasma damages small vessels throughout your body, so that
platelets stick and platelets aggregate and eventually form firm platelet plugs in all the vessels
of the entire body.

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 You consume all the platelets with all that sticking going on and because of that you will bleed. To
make the diagnostic of hemolytic anemia you have to see schistocytes in the peripheral blood
on RBC. Therefore you will have a microangiopathic hemolytic anemia. Pts will have
thrombocytopenia, fever; renal failure is because glomerular capillaries will have these platelet
plugs in them.
B. 2 causes of HUS:

a) 0157:H7 serotype of E. coli (toxin producing E. coli that can be present in undercooked beef)
and that toxin damage the vessels. One of the Most Common causes of acute renal failure in
children = HUS.

b) Shigella toxin (very potent) that leads to shigellosis and then HUS.
In TTP/HUS will see low platelet count, prolonged bleeding time, and normal PT/PTT because
not consuming coagulation factors, but only consuming platelets.

V. COAGULATION DEFICIENCY

In Coagulation deficiency have ms, such as: delayed bleeding Ex. go through
operation with no problem When pt has an
operation and they start bleeding out of the wound, the Most Common Cause is due to suture
slipped or a bleed. When you have a coagulation deficiency, the Treatment is TIE IT OFF.

Example: molar extraction with constant oozing (pass flow) of blood is because nothing holding those
small vessels together except a temperature hemostatic plug need a tight fibrin bond to plug it up.

Example: It is showing hemorrhage into the fascial compartment of the thigh. In the knee, there are
repeated hemarthroses and the pt has hemophilia A. Will not see hemarthroses or bleeding into
spaces with platelet abnormalities, but only coagulation factor deficiency.

A. Hemophilia A Vs. vWB Disease (these are the key coagulation deficiencies)
VON WILLEBRAND DISEASE (vWBD) HEMOFILIA A

Autosomal dominant, and only one of the X linked recessive disease, therefore males get the
parents have to have the abnormality and 50% of disease.
the kids will have the potential to get the disease.
1. platelet adhesion defect and have all the signs 1. Coagulation factor 8 Deficiency
and symptoms of a PLATELET deficiency.
2. Coagulation factor 8 deficiencies (mildly
decreased). This is why they can have
menorrhagia and GI bleedings (this the
coagulation part of it); will also see history of
epistaxis and they bruise easy.
3. vWF decrease
4. 8 Antigen decrease

There are 3 parts of the factor 8 molecule:

*vWF
*Factor 8 coagulate (part of intrinsic system)
* 8 Antigen (It carries proteins vWF and factor 8
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coagulant bloo All 3 of
these can be measured.

B. What drug can increase the synthesis of all three of these factor 8 molecules? The drug
comes from ADH and is called desmopressin (ddadp). = increase the synthesis of all three factor
8 molecules. It will help treat mild hemophilia A, and is the Drug of Choice (DOC) for vWD.

In woman, if they have menorrhagia and normal everything else, you have vWDz. They put you on
birth control and that took the bleeding away. In one of the cases, the Dr. ordered PT, PTT, and
bleeding time tests. The tests for PT and PTT were normal and the bleed time was normal. The
sensitivity for these tests is only 50%, so do not depend on these. The ristocedin cofactor assay is
the test of choice for vWD, and will be abnormal. So, Anticonceptive pill is the Drug of Choice
to treatment women in vWD = Estrogen increases the synthesis of all factor 8 molecules.

C. USMLE Step 2: Anti-phospholipids syndrome (one of the causes of spontaneous abortion)

includes:

1. Lupus anticoagulant antibodies (not an anticoagulant, but the opposite: thrombogenic).

2. Anti-cardiolipin antibodies.

That two are part of the syndrome that cause Vessel Thrombosis. Also seen in HIV pt. Anti-
cardiolipin antibodies have a history of having a biological false + syphilis serology. So, here you
are with Venereal Disease Research Laboratory (VDRL) and Rapid Plasma Reagin (RPR) being
positive. To confirm, Fluorescent treponemal antibody absorption (FT-ABS (the test antigen is beef
cardiolipin) would be negative. Therefore makes the VDRL and RPR false positive, because the
confirmatory test was negative. So why was the RPR positive in the first place, because the test
antigen is beef cardiolipin. Therefore syphilis antibodies react to against that beef cardiolipin, and
producing a positive reaction. But so the anti-cardiolipin antibodies. Therefore you get a biological

If you have a woman with a biol

get? Serum anti ANA antibody because she can develop lupus. Anti-cardiolipin antibodies are a
very common feature of LUPUS. Matter of fact, a erology is a
criteria for diagnosing Lupus.

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D. Disseminated Intravascular Coagulation (DIC)
Disseminated = all over the body
Intravascular = within the vessel
Coagulation = clotting (forming clots throughout the body)

What is consumed in a clot? Fibrinogen, 5, 8, prothrombin, platelets

In clot tube form a clot on top is serum and the serum is missing. What is consuming in a clot?
(fibrinogen, 5, 8, prothrombin, platelets). This is what you have in DIC consuming these
coagulation factors, including platelets, in those clots throughout the body.

DIC cause a hemorrhagic thrombosis syndrome is very unusual and two things are happening at
the same time:

(a) Thrombi in vessels

(b) Anticoagulated because all you have circulating around is serum; you
because you consumed the coagulation factors

What started all this off? The intravascular coagulation is responsible for consuming all these
things.

*Most Common Cause of DIC = Septic shock

*Most Common Cause of septic shock = E. coli, snake bite (rattlesnakes=cascabel), and Acute
Respiratory Distress Syndrome (ARDS).

Very simple to recognize they bleed from every orifice or scratch, and even if there is a puncture
wound.

Classic Disseminated Intravascular Coagulation = Diagnostic is easy, because if you consuming all
The
test for Diagnost is D-dimer test.

Example: pt with abruptio placenta and had amniotic fluid embolism. Amniotic fluid gets into
circulation of the mom, which contains thromboplastin, so, death is from DIC, not from the amniotic
embolism. Because the thromboplastin within the amniotic fluid precipitated DIC.

Example: hereditary thrombosis = young person with Deep Venous Thrombosis (DVT), it is not
normal and family history.

Example: factor 5 Leiden abnormal factor 5 that protein C and S cannot breakdown, therefore
there is an increase in factor 5, which predisposing to thromboses.

Example: Antithrombin III deficiency Most Common Cause in woman is birth control pills. It
can also be genetic Ex. pt with DVT, put on warfarin and heparin (anticuagulants), and do a PTT is
normal after heparin, so you give more heparin, and the PTT is still normal. So, pt with DVT, give
heparin, PTT remains normal = Antithrombin III deficiency. Because heparin works on Antithrombin
III. Normally, the heparin facilitates antithrombin III thereby increasing the PTT. In this case, no
matter how much heparin is injected, there is no change in PTT, therefore there is no Antithrombin III
for the heparin to work on (this is how diagnostic is usually made by mistake)

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 Platelet
Disease Bleeding Time PT PTT
Count
Aspirin Normal HIGH (prolonged) Normal Normal
Idiopathic thrombocytopenic purpura
LOW HIGH (prolonged) Normal Normal
(MCC of thrombocytopenia in kids): ITP
TTP
(thrombotic thrombocytopenic purpura)
LOW HIGH (prolonged) Normal Normal
HUS
(hemolytic uremic syndrome)
HIGH
Hemophilia A Normal Normal Normal (prolonge
d)
HIGH
Von Willebrand Disease (vWBD) Normal HIGH (prolonged) Normal (prolonge
d)
HIGH (W) HIGH (H)
Warfarin/Heparin (anticuagulants) Normal Normal (prolonged (prolonge
) d)
Disseminated Intravascular Coagulation LOW HIGH (prolonged) HIGH HIGH
(DIC) (prolonged (prolonge
) d)

VI. BLOOD GROUP

A. Different blood groups and what is floating around in the serum:

Most Common: O: have anti-A IgM, anti-B IgM, anti-AB IgG

2nd Most Common: A: anti B IgM
3rd Most Common: B: anti A IgM
Rarest: AB: nothing

Newborn: nothing, after 2-

3 months do they start synthesizing IgG.

Elderly: nothing Example: Old person who is blood group A and by mistake received blood
group B, but did not develop a hemolytic transfusion reaction. Why happened that? Because
their levels of Antibodies
attack those cells.

B. Associated Diseases:

*Which is associated with gastric cancer? A

*Which is associated with duodenal ulcer? O
*Universal donor? O (can give their blood to anyone because have NO anti-A or anti-B Antigen).
*What is the only blood group O can get? O
*Universal recipient? AB because they have no Antibodies to attack those cells.

C. Other Antigens:
1. Rh + D antigen.
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2. Duffy Antigen is missing in black population; therefore not as likely to get plasmodium vivax
(malaria) because the Antigen ntigen and if
ntigen iciency, thalassemias, Sickle Cell
Diseas pts protected from falciparum they are protected because
lifespan so, the parasite cannot live out their cycle, and R

D. Major crossmatch: pt gonna get blood; their serum is in a test tube, with the blood of the donor
unit and they mix the 2 together
compatible; looking for an

before mixing (remember that it detects the ANTIBODY). If this test is negative, the crossmatch is
compatible (so, there no Antibodies This does
not prevent a transfusion reaction, or that Antibodies will develop later against the donor.

What is the chance that anyone has the same Antigen makeup as another? Zero. So, even if I get a
ntibodies attack. Moral of the

Audio Day 3: hematology 8 and Cardiovascular 1

VII. SIDE NOTES

A. Questions asked during the break about hypersensitivity:

*Lupus (not everything is type III)

*Post streptococco (not everything is type III) post streptococco produce Rheumatic fever cause
HPY type II fever and glomerulonephritis cause HPY type III
*Thrombocytopenia and Hemolytic anemia = HPY type II
*Penicillin (PCN) rash = type I
*Penicillin (PCN) hemolytic anemia = type II (IgG Antibodies against the Penicillin (PCN) group
attached to the RBC membrane)

Most Common Antibodies in the USA is Anti-Cytomegalo virus (CMV) (everyone has been
exposed).

You are safest from getting HIV from blood transfusion than from all the other infections
(1/625,000 per unit of blood chance of getting HIV therefore uncommon get to get HIV from blood).
This is due to all the screening tests that they perform. They do the Elisa test which looks for
anti-gp120 Antibodies -120 Ag that attaches to helper T cell (CD4)
molecule). On western blot, looking for more (3 or 4) Antibodies, making it more specific, so if you

.
What is the Most Common infection transmitted by blood transfusion? Cytomegalo Virus
(CMV),
Which is the Most Common overall infection? CMV. That is why this antibody is the most
common.

What is Most Common Cause post transfusion hepatitis? Hepatitis C (1/3000)

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In newborn, want to prevent graft vs. host disease and Cytomegalo Virus (CMV) because
have immune defenses, therefore, need to irradiate the blood. The irradiation kills off the
lymphocytes and since the CMV lives in lymphocytes, we kill off the CMV virus also. This is why we
radiate blood before giving to newborns.

What is the Most Common infection you can get by an accidental needle stick? Hepatitis B.

1/300

What do you do about it? You go on therapy as if you are HIV+. Go on to triple therapy (2
Reverse Transcripts Inhibitors AZT and a protease inhibitor) for six months and get
constant checks do PCR test looking for RNA in the virus (most sensitive), do Elisa test. In
fact, the Most Common mechanism of a healthcare worker getting HIV = accidental needle
stick.

Do not transfuse anything into a person unless they are symptomatic in what they are deficient in.
Example: If you have 10 grams of Hb, and have no symptoms in the pt, do not transfuse. You
should transfuse the pt if they have Congestive Obstructive Pulmonary Disease (COPD) and are
starting to have angina related to the 10 grams. Example: 50,000 platelet count no epistaxis = do
not treat them; if they do have epistaxis, treat the pt.

Every blood product is dangerous because you can get infections from it.

B. Fresh frozen plasma should never be used to expand a pts plasma volume to raise Blood
Pressure use normal saline (it is too expensive and you run the risk of transmitting disease). Use
fresh frozen plasma for multiple coagulation factor deficiencies Ex. would be legitimate to give
frozen plasma to replace consumed factors, as in Disseminated Intravascular Coagulation.

Example: pt with warfarin is over anticoagulation and bleeding to death not to give Intramuscular vit
K will take to long to work (takes 6-8 hrs to work), so the treatment of choice is fresh frozen
plasma to immediately replace it. So, fresh frozen plasma is limited to use of multiple factor
deficiencies (Ex. cirrhosis of the liver and you are bleeding since most of the factors are made in the
liver, they are deficient in all proteins).

Drug of Choice for heparin overdose is protamine sulfate.

C. Know the diffirents transfusion reaction.

1. Most Common transfusion reaction = allergic reaction (itching, hives , anaphylaxis

). Allergic Reaction is a type I HPY reaction Ex. have unit of blood, and in their
plasma you are allergic to something (Ex. Penicillin= PCN); Treatment = benadryl, antihistamines.

2. 2nd transfusion reaction = febrile reaction; it is due to HLA Antibodies; pt has HLA Antibodies
against leukocytes of donor Antigen. So, when the unit of blood is transfused into me, and there are
some leukocytes with HLA Antibodies on them, my Antibodies will react against it, destroy the cell
and release the pyrogenes from neutrophil, leading to fever.
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 ntibodies against anything? No
Who is most at risk for having a febrile reaction with transfusion? Woman because she is
has been pregnant

Every woman that has had a baby has had a fetal maternal bleed, so some of the babies leukocytes
got into the bloodstream, and the woman developed an anti HLA Antibodies
husband, that have been passed on to the woman). So, the more pregnancies a woman has had, the
more anti HLA Antibodies she will develop because of her previous pregnancies. This is also true for
spontaneous abortions you can still get HLA Antibodies. So, women are more likely to have
transfusion induced febrile reaction because they are more likely to have anti-HLA Antibodies (we

Who has the greatest risk in developing febrile reaction?

A. Newborn
B. 12 years without transfusion
C. Woman with one pregnancy
D. Woman with spontaneous abortion
E. Man.

The answer is woman with spontaneous abortion because that is a pregnancy and there is a
potential for HLA antibodies to leak out of the fetus into the mother.

3. Hemolytic transfusion reaction is very rare.

Example: If you are blood group A, and given group B by stupidity because the pt has anti-B IgM
(remember that IgM is the most potent complement activator and that cell will not last only about 1
msec) this is because the IgM will attack it, C1-C9: MAC, anaphylatoxins are released, and shock will
ensue very serious Ex. clerical error).

Example: pt has Antibodies against Antigens you would think that this
the crossmatch said it is compatible; and did an Antibodies screen that
was negative (Indirect Coombs). However, some Antibodies are not present, and you have memory
B cells. Suppose if I got blood transfusion 30 years ago, there are no Antibodies titers now because
however, there are memory B cells; these antibodies will be way below
the sensitivity of an Antibodies screen, come out compatible from a crossmatch, and will have
negative indirect coomb; however, after transfusion, memory B cells would detect the foreign Antigen.
After the B cell detects the Antigen, it will start dividing in the germinal follicle and start dividing and
become a plasma cell, which would make anti-calla Antibodies. This can occur in a few hours or
may occur in a week depending on the Antibodies
delayed hemolytic transfusion reaction.

Example: woman postpartum, difficult delivery (abruptio placenta) was transfused 3 units of blood.
When she left the hospital, she had an Hb of ten. One week later, she is jaundice and weak, and has
an unconjugated hyperbilirubinemia and has an Hb of 8. What is the diagnosis? Hb was less than
what she left the hospital, and they will not mention the coombs test) What is most likely cause?
delayed hemolytic transfusion reaction so, they might ask what test would you get? Indirect
coombs test to prove it because you will see the Antibodies Coating the RBC. Moral of the story?
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Transfused with certain level of Hb, 1 week later have jaundice and less Hb = delayed
hemolytic transfusion reaction = type II HPY.

VIII. ABO/Rh incompatibility

A. ABO incompatibility:
If blood group O woman have a baby, the mom will have a problem with ABO incompatibility because
mom already have an Antibodies that can cross the placenta (blood group O people have anti A IgM,
anti B IgM and anti AB IgG, normally). Normally, there is an anti AB IgG Antibodies which can cross
the placenta, and attack an A or B RBC. So, there could be a problem in the very first pregnancy.

Example: mom is blood group O negative and baby is blood group A negative. Is there an
incompatibility of blood groups? Yes. Is there an incompatibility in Rh groups? No. Just the blood
groups, since the mom is O while baby is A. The mom is O, she has anti AB IgG, which will cross the
placenta; the A part of the Antibodies
macrophages of the spleen will destroy it, which is Type II HPY, mild anemia, and unconjugated
lems with jaundice in the baby
because
mild anemia and jaundice. Most Common Cause jaundice in the first 24 hrs for a newborn =
ABO incompatibility (not physiologic jaundice of the newborn that starts on day 3). Why did
the baby develop jaundice? Because
unconjugated bilirubin on its own now, so it builds up. This is an exchange transfusion reaction for
ABO incompatibility most of the time is b9, and put under UV B light. How does UV B light work? It
converts the bilirubin in the skin into di-pyrol, which is water soluble and they pee it out (Treatment for
jaundice in newborn). Anemia is mild because it is not a strong Antigen
hemolytic anemia. If you do a coomb
always an O mom with a blood group A or AB baby. This can occur from the first pregnancy (not like
Rh sensitization where the first pregnancy is not a problem). In any pregnancy, if mom is blood group
O, and she has a baby with blood group A or B, there will be a problem (blood group O = no
problem).

B. Rh incompatibility
Mom is Rh negative and baby is Rh positive.

Example: mom is O negative and baby is O positive (not ABO

incompatible, but Rh incompatible). In the first pregnancy: deliver baby without going to a Dr, and
there is a fetal maternal bleed, some of the babies O positive Antibodies got into my bloodstream,
which is not good (pale cells=mom Hgb A/Normal Staining cell-baby HgbF). So, mom will develop
an anti B Antibodies against it. So, mom is sensitized which means that there is an Antibody against
that D Antigen and now mom is anti D. 1 year later, mom is pregnant again, and still O negative, and
have anti D and the baby again is O positive. This is a problem because it is an IgG Antibodies,
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which will cross the placenta, attach to the babies D Antigen positive cells (of the entire Antigen, the
D Antigens hosts the worst hemolytic anemia). So, the baby will be severely anemic with Rh than will
ABO incompatibility. The same thing happens though baby

anemia occurs, and there is an excellent chance that an exchange transfusion will be necessary
(99% chance), so take all the blood out (gets rid of all the bilirubin and se
transfuse because baby is anemic). So, they will usually always have an exchange transfusion.

Therefore, for the first pregnancy, the baby is not affected, and this is when the mother gets
sensitized. In future pregnancies, the baby will a lot worse.

How do we prevent? Mom will do an Antibodies screen test and she is Rh negative. Around the 28th
week, give her Rh Ig, which is prophylactic. This is anti D, which comes from woman; it has been
sensitized and heat treated and cannot cross the placenta. Why do they give at 28 weeks? Pt may
get fetal maternal bleeds before the pregnancy or a car accident or fall can cause babies blood to get
ntibodies to sit on the D positive cells and destroy them,
itive). Do a
dentify (if any
them; they can say how much is in there. Depending on that, that will determine how many viles of
allergen Ig you give the mom to protect her further (anti D only last three months, and need to give
more at birth, especially if the baby is Rh positive).

Example: If Mom: O negative and Baby: A positive 2 problems: ABO incompatible and Rh
incompatible. But, there is not going to be problems with sensitization. No Why? After delivery of
lood (which mom has anti A
IgM); those cells will be destroyed so fast, that in most cases the mom cannot generate Antibodies
against those cells because they have been destroyed. So, ABO incompatibility protects against
Rh sensitization. You still would give Rh Immunoglobulin. So if you are ABO and Rh
incompatible, Rh sensitization will be protected against.

Kid with HYDROP FETALIS will have Rh incompatibility what do

they die of? Heart failure severe anemias will decrease viscosity of blood, so they get a high output
failure: Left Heart Failure, then Right Heart Failure, big livers because extramedullary
hematopoesis because they are so severe anemic.

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For Board: cross section of brainstem from kid what is the
cause of color change? yellowish due to kernicterus problem from a baby that had Rh
because
and lipid soluble; liver cannot synthesis it; goes to brain and is very toxic leading to severe debilitating
disease or death.

CHAPTER 7 CARDIOVASCULAR PATHOLOGIES

I. SUMMARY OF PHYSICAL DIAGNOSTIC SIGNS IN CARDIOVASCULAR DISEASE:
Abbreviations used: MV: mitral valve, TV: tricuspid valve, AV: aortic valve, PV: pulmonic valve.

1. Valve locations for auscultation:

A. mitral valve (MV) at cardiac apex.
B. tricuspid valve (TV) along left sternal border.
C. pulmonic valve (PV) in the left 2nd and 3rd intercostal space (ICS).
D. aortic valve (AV) - in the left sternal border or right 2nd ICS.

2. Jugular venous pulse is use to make a cardiac diagnosis by physical diagnosis:

S1: first heart sound =!identify by C wave ascending (positive), which is produced by a bulging of
the tricuspid valve into the right atrium during right ventricular isovolumic systole. Beginning at
systole.!

S3 heart sound: Early Filling is the most clinically significant extra heart sound

*physiologic S3: can be heard in normal children and young adults

*pathologic S3:

a. due to sudden rush of blood entering a volume overloaded left or right ventricle
b. volume overloaded left or right ventricle in left-sided heart failure/right-sided heart failure.
(Ventricular dilatation)
c. AV/MV regurgitation or PV/TV regurgitation: all regurgitation (insufficiency) valve diseases overload
their respective ventricles:

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1. LEFT SIDE S3 increases in intensity on EXPIRATION: positive intrathoracic pressures assists the
Left Ventricle emptying of blood, hence all abnormal heart sounds and murmurs increase in intensity
on expiration.
2. RIGHT SIDE S3 increases on INSPIRATION: more blood in the right heart on inspiration-
accentuates all abnormal heart sounds and murmurs.

3. S4 heart sound:
A. identify by a wave ascending (positive) = atrial contraction in late diastolic filling.
B. due to increased resistance to ventricular filling (decreased compliance) following vigorous atrial
contraction.
C. decreased ventricular compliance may be due to:
(1) Ventricular hypertrophy (leff/right) or
(2) Already volume overloaded ventricle (leff/right).
D. S4 is absent normally

Pt with irregular pulse at mitral stenosis, which wave is affected? A wave disappears due
atrial contraction (atrial fibrillation.)

If this heart sound is present, when usually is absent, what heart sound would be absent? S4
absent A wave because atrial contraction.

In tricuspid stenosis what you see? HUGE A wave

V wave = In Jugular Venous Pressure V wave (positive) ascending results from the increase in blood
volume in the venae cavae and the right atrium during ventricular systole when the tricuspid valve is
closed. Beginning of diastole (positive).

In Tricuspid regurgitation what you see? Giant C-V wave

X wave = (negative) occur due decrease jugular venous pressure forming the normal descending X
wave (combination of atrial relaxation, the downward displacement of the tricuspid valve during right
ventricular systole, and the ejection of blood from both the ventricles.)
Y wave = (negative) initial "y" wave normal descent corresponds to the right ventricular rapid filling
phase in early diastole.

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 4. Heart murmur characteristics
A. occur in systole and/or diastole
B. mechanisms:
(1) structural valve disease: Ex. Previous Rheumatic fever
(2) stretching of the valve annulus: Ex.mitral/tricuspid valve regurgitation in left
and right-sided heart failure due to volume overload stretching the ring, respectively
C. murmurs radiate:
(1) AV stenosis radiates into the neck
(2) MV regurgitation radiates into the axilla
D. murmur/heart sound intensity with respirations:
(1) right-sided murrnurs and abnormal heart sounds increase on inspiration: more blood enters the
right heart on inspiration due to the increase in negative intrathoracic pressure when the diaphragm
moves down
(2) left-sided heart murmurs/abnormal heart sounds increase on expiration: related to
positive intrathoracic pressures aiding expulsion of blood from the left heart

5. Mid-systolic clicks in MV/TV prolapsed

A. click is due to ballooning (prolapse) of excess valve tissue into the atrium during
systole: when the valve suddenly stops its movement into the atria, it produces a click

C. maneuvers that cause click/murmur to come closer to S1 are those that decrease volume in the
left/right ventricle (decrease preload) resulting in a shorter systole:
(1) standing-up: decreases venous return to the heart.
(2) Anxiety: increased heart rate decreased filling of ventricle in diastole.

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(3) Vasalva maneuver.
D. Maneuvers that cause click/murmur to come closer to S2 are those that increase the
Volume of blood in the ventricles (increased preload) so systole takes longer to occur:
1. Lying down or leg lifting in the supine position: increase venous return to the heart.
2. Sustained clenching of fist: increase of systemic vascular resistant (afterload), the ventricle have to
contract against, hence increasing preload.
3. Squatting: increase of systemic vascular resistant (afterload), the ventricle have to contract against,
hence increasing preload.

6. Opening snap in MV/TV stenosis

A. occurs-MV/TV (less common) stenosis.
B. due to nonpliable valve which has difficulty in opening in diastole until atrial
contraction forces it open.
C. opening, snap early in diastote indicates severe disease: correlates with intense atrial contraction
that is necessary to open the non-pliable valve.
D. opening snap that occurs later in diastole indicates less severe stenosis: correlates with less
intense atrial contraction to open the valve.

7. Stenosis murmurs
A. problems with opening valves
B. valves opening in systole: AV/PV
C. valves opening in diastole: MV/TV
D. AV/PV stenosis:
(1) Ejection type
(2) crescendo/decrescendo due to blood forcibly moving through constricted opening
(3) Produce concentric hypertrophy of leff/right ventricle, respectively
E. M/V stenosis with mid-diastolic mumur occurs after openings nap

8. Regurgitation (insufficiency) murmurs

A. problem with closing valves or stretching of the valve ring (arurulus) valve leaks
B. valves closing in systole: MV/TV
C. valves closing in diastole: AV/PV
D. MV/TV regurgitation:
(1) Even intensity pansystolic (holosistolic) murmur due to blood refluxing into atria throughout systole
(2) Volume overload of atria and ventricles (hypertrophy/dilation)
E. AV/PV regurgitation:
(1) High pitched blowing murmur directly after S2
(2) Volume overload of ventricles

II. LYPID DISORDERS

A. Lipoprotein fractions
1. Chylomicrons: tryglicerides that you eat in Mck Donalds. Carry diet-derived TG (surfaced by apo
B 48); it happens when someo ; form a creamy
layer on top of plasma (supranate) in a test tube

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CHYLOMICRION PRESENCE: RIGHT SIDE; TYPE II HYPERLIPOPROTEINEMIA

2. Very-low density lipoproteins (VLDL): Make in liver from glycerol 3 phospate which came from
glucose. Transports liver-synthesized Tryglicerol; plasma turbidity occurs throughout the sample
(infranate) PINKISH STAINING

CHYLOMICRONS AND VLDL PRESENSE: TYPE V

HYPERLIPOPROTEINEMIA IN DIABETIC KETOACIDOSIS (TYPE IV HYPERLIPOPROTEINEMIA
= VLDL ONLY PRESENT)

3. Low-density lipoprotein (LDL): carries H (surfaced by apo Bl00); derived from

complete hydrolysis of VLDL by capillary lipoprotein lipase.

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4. High-density lipoproteins (HDL): "good CH"; carriesa polipoproteinsa nd removes CH from
plaques;increased by exercise, red wine, estrogen.

B. Acquired and genetic lipoprotein disorders

1. Type II: Ex.familial hypercholesterolemia (autosomal dominant disorder)
a. Pathogenesis of familial hypercholesterolemia: absent or defective LDL
receptors; increase in serum CH; Iower with 'statin" drugs
o Plaques can be reversed if LDL is lowered to < 70 ms/dl
b. Lipid deposits: Achille's tendon xanthoma (diagnostic of familial
hypercholesterolemia)

XANTHELASMAS (yellow (ch)plaque on the eyelid)

c. Acquired causes: hypothyroidism (decreased LDL receptor synthesis)
2- Type III: Ex. familial dysbetalipoproteinemia "remnant disease".
a. Pathogenesism: mutant form of apo E; accumulation of hydrolyzed chylomicron remnants and
intermediate-densitlyip oproteinr emnants (derived from VLDL) in the blood.
b. Increase in serum CH and TG.
3. Type IV: Ex.familial hypertriglyceridemia: alcohol excess
a. Pathogenesis: most common hyperlipoproteinemia; High VLDL due increased synthesis or
decreased catabolism of VLDL; HYPERLIPOPROTEINEMIA = (hypertrygliceridemia)
b. Clinical findings: eruptive xanthomas (yellow, papular lesions); lower TG with fibric acid derivatives
and reduced carbohydrate in take.
c. Acquired causes: alcohol excess, increased carbohydrates in diet.
4. Type V: Hypertriglyceridemia have VLDL with chylomicrons.

C. Apo-B deficiency (abetalipoproteinemia) Pathogenesis deficiency of apo B 48 and 100

leading to deficiency of chylomicrons VLDL and LDL.
*Clinical Findings:
a. Lipid profile: very low CH and TG levels.
b. Malabsorption: chylomicrons accumulate in villi and prevent reabsorption of micelles.
c. other: CNS disease (ataxia; retinitis pigmentosa); hemolytic anemia which respond to megadoses
of vitamin E

III. ARTHEROSCLEROSIS

*Atherosclerosis in an aorta reaction to injury theory = injury to endothelial cells lining the elastic
arteries and muscular arteries what is injuring it? Ammonia in cigarrete smoke, CO in cigarrets
smoke; so, poisons damage the endothelial cells; LDL damages it, and if its oxidized, it damages it
worse; viral infections damage it, too. (2nd Most Common Cause atypical pneumonia: Chlamydia

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pneumoniae); pts with Miocardial Infarction most had Antibodies against Chlamydia
pneumonia, homocysteine all these things damage endothelial cells

What happens when you damage endothelial cells? Platelets stick to it and PDGF is released into the
artery and PDGF causes smooth muscle cells within the media to proliferate and they undergo
hyperplasia and then, they chemotactically migrate to the subintimal level. They have all these
smooth muscle cells migrating to the intima of the vessel. Monocytes have access into the vessel
because it has been injured and monocytes also have GFs. As the LDL increases, the macrophages
phagocytose them. Macrophages and smooth cells have LDL w/in them; the LDL becomes oxidized
and a fatty streak is produced. Over time, a fibrofatty plaque develops, which is pathognomonic of
atherosclerosis. It can be complicated by dystrophic calcification, fissuring, thrombosis and a
complicated atherosclerosis.

Audio File day 3 Cardiovascular 2

In atherosclerosis you see Cells involved: platelets, monocytes, macrophages, cytotoxic T cells with
cytokines (Neutrophils not involved).

IV. Arterial Disorders:

A. Atherosclerosis is a primary factor for certain diseases

Coronary Artery Disease; atherosclerotic stroke relates to plaques; abdominal aneurysm due to
weakening of the vessel; nontraumatic amputation of lower extremity (peripheral vascular diseases);
mesenteric angina, small bowel infarction, renovascular atherosclerosis of the renal arteries.
Atherosclerosis only involves muscular arteries and elastic arteries. Can small vessel, such as
arterioles get hardened? Yes. Example: look at the spleen hyaline arteriolar sclerosis and
hyperplastic arteriolar sclerosis (onion skinning).

1. Hyaline arteriosclerosis is a small vessel disease; lumen is

narrow; whenever there is a lot of pink staining stuff, this is hyaline. Example: small vessel disease
of diabetes and Hypertension two major diseases that produces a small vessel diseases with
different mechanisms:

a. Diabetes: nonenzymatic glycosylization Ex. HbA1c; glycoslyzation is glucose attaching to amino

acid and protein. For HbA, its glucose attaching to amino acid and HbA, and the HbA is glycosylated.
HbA1c levels correlate with the blood glucose levels of the last 6-8 weeks, so this is the best way of
looking at long term glucose levels. All the damage seen in diabetes is due to glucose. For a
diabetic, you should be under 6%, meaning that you are in a normal glucose range. There is nothing
unique about diabete
have diabetes. The only two pathologic processes are this: nonenzymatic glycosylation of
small Blood Vessel osmotic damage. Those tissues that

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contain aldose reductase lens, pericytes in the retina, schwann cells all have aldose reductase
and can convert glucose into sorbitol and sorbitol is osmotically active sucks water into it and those
cells die, leading to cataracts, microaneurysms in the eye because the pericytes are destroyed and
weakened and the retinal vessels get aneurysms, and you get peripheral neuropathy because
schwann cells are destroyed. They all related to excess glucose. So, tight glucose control = normal
life.
What does nonenzymatic glycosylation to do the basement membrane of small vessels? Its
renders them permeable to protein, so the protein in the plasma leaks through the Basement
Membrane and goes into the vessel wall, produces a hyaline change and narrows the lumen.

What if there is nonenzymatic glycosylation of the Glomerular Basement Membrane? It will

render it permeable to protein called microalbuminuria. This is the first change to be seen in
diabetic nephropathy. So, what is the mechanism? Nonenzymatic glycosylation.

b. Hypertension
It just uses bruit force and drives (because of increase in diastolic pressure) the proteins through the
Basement Membrane and produces the effect. When we look at a kidney in Hypertension, it is
shrunken, has a cobblestone appearance this is because there is hyaline arteriolosclerosis of the
arterioles in the cortex, ischemia, and is wasting away with fibrosis and atrophy of tissue. Lacunaer
strokes (tiny areas of infarction that occur in the internal capsule) are a hyaline arteriosclerosis
problem related to Hypertension.

2. Hyperplastic arteriosclerosis
Seen in malignant Hypertension; more common in blacks then whites, mainly becauses hypertension
is more common in blacks than whites. Mainly see this vessel disease in malignant Hypertension
(Ex. when pt has Blood Pressure of 240/160).

B. Aneurysm
1. Definition: area of outpouching of a vessel due to weakening of the vessel wall. Atherosclerosis
can cause weakening of the abdominal aorta leading to an aneurysm.

What would be the analogous lesion in the lungs with weakening and outpouching?
Bronchiectasis due to cystic fibrosis with infection, destruction of elastic tissue leading to
outpouching and dilatation of the bronchi.

What is the Gastro Intestinal aneurysm? Diverticular disease have a weakening and
outpouching of mucosa and submucosa

2. Law of Laplace the wall stress increases as radius increases. In terms of this, once you start
as you dilate something, you increase the wall stress and
eventually it ruptures. So, in other words, all aneurysms will rupture .

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3. Abdominal Aorta Aneurysm:

Why is the abdominal aorta the Most Common area of aneurysm? Because there is no vasa
vasorum or blood supply to the aorta below the renal arteries.

So, the only way Abdominal Aorta So,

part furthest from it gets screwed. Therefore, apart from the part that is not getting much O2 and
nutrients, it will be more susceptible to injury, therefore atherosclerosis leads to weakening of the wall
and aneurysm/injury occurs. Most Common complication abdominal aortic aneurysm = rupture.
These are three things (Triad) that always occur when there is a ruptured aortic abdominal
aneurysm: a sudden onset of severe left flank pain because the aorta is retroperitoneal organ and
so it does not bleed into the peritoneal cavity, but into the peritoneal tissue; Hypotension, and
pulsatile mass on Physical Examination.

Most Common complication of any aneurysm = rupture

4. Aneurysm of the arch of the aorta/SYPHILITIC ANEURYSM

Most Common Cause = tertiary syphilis.

Pathology of syphilis is vasculitis of arterioles. Chancre, too. painless because if you
section it, you will see little arterioles surrounded by plasma cells and the lumen of the vessel
is completely shut, so it is ischemic necrosis.

In other words, it is ischemia of the overlying tissue undergoing necrosis. Because nerves are next to
vessels, they are knocked off, too, and it is painless. All of syphilis is a vasculitis. That is what the
Treponema infects small vessels and arterioles. What are they affecting in the arch of the aorta?
The vasa vasorum; the richest supply of vasa vasorum is in the arch, so its logical that the
Treponema will pick it leads to endarteritis obliterans (they are obliterating the lumen),
ischemia, weakening under systolic pressures, leads to depression in the arch of the aorta (looks like

What will that do to the aortic valve ring? It will stretch it which murmur will this lead to?
Aortic regurgitation.
Murmurs can occur because there is valvular damage or because the valvular ring is stretched. So,
there can be stretching of the ring and nothing wrong with the valves, and have a murmur, or you can
have damage to the valves and have a murmur. Syphilis is an example of stretching of the aortic
valve ring leading to a murmur and aortic regurgitation.
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Aorta should be closing during diastole as you pump the blood out, and the Strove Volume goes
down, and because the aortic cannot close properly, only some of the blood will drip back in. So you
will have more volume of blood in the left ventricle in someone with aortic regurgitation. Frank-
starling forces will be working. As you stretch cardiac muscle, you increase the force of contraction.
jection Fraction is 80/120 =66%.
say you have 200 mls of blood in the Left Ventricle because blood is dripping back in, and frank-
starling force gets out 100 mls of blood, which has an Ejection Fraction
efficient. Therefore, frank-starling occurs in a pathologic condition.

If you have 100 mls of blood coming out of their head is

wobbling, and when they open their mouth you can see uvula pulsating, can take their nail
and lift it up and see pulsations of the vessels under the nail (Water-hammer pulse), and when

due to the increase in Stroke Volume coming out related to the fact that there is more blood in
the Left Ventricle. Syphilitic aneurysm of the abdominal aorta is the classic example of this.
Anatomy correlation: the Left Recurrent Laryngeal Nerve wraps around the arch and therefore
can get hoarseness. Again the Most Common complication is rupture.

5. Dissecting aortic aneurysm/AORTIC ARCH:

a. Key factor that causes a tear in the aorta is Hypertension because it imposes stress on the
wall of the vessel. There must be weakening the elastic artery and is caused by elastic tissue
fragmentation. Cystic medial necrosis licosaminoglycans mix together and
when adding a little bit of
Hypertension leads to a tear. Wherever the area of weakness in the elastic artery is where the blood
will dissect and tear blood can go to the pericardial sac, leading to cardiac tamponade. This is
called (Most Common is proximal dissection). Most of the tears up in the arch; therefore you
would think the pt may have an absent pulse; this is very common in pts with tears that are proximal.
When it dissects, it
closes lumen to subclavian artery and it usually dissects on the left and causes an absent pulse on
left.

b. Chest pain in Miocardial Infarction is different than the chest pain in a dissecting aneurysm.
Miocardial Infaction has chest tightness radiating to left arm and jaw; in aortic dissection, there is a
tearing pain radiates to the back; and is a retrosternal pain. Pulse on left is diminished vs. the
one on the right. On chest x-ray, widening of the aortic knob. With blood there, diameter of aorta will
be enlarged, as seen on x-ray, and this test is 85% sensitive in detecting it, therefore it is the
screening test of choice; see widening of the proximal aortic knob. To prove, do transesophageal
ultrasound or angiography to confirm diagnosis.

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c. Many disease can predispose to aortic dissections:

(1) Marfan syndrome

(Eunochoid proportions high of pelvic brim to feet is greater than from pelvic brim to the head. Also,
another definition is that arm span is greater than the height. Autosomal Dominant inheritance,
chromosome 15, defect in fibrillin, which is a component in elastic tissue. Due to the defect in

fibrillin, the elastic tissue is weak this is why they have high arched
palate, dislocated lenses and dissected aortic aneurysms (Most Common Cause death in
marfans is Mitral Valve Prolapse).

(2) Ehler Danlos has a collagen defect; Most Common Cause of death is Dissecting Aortic
Aneurysm.

(3) Pregnant women are susceptible to dissecting aortic aneurysms because in pregnancy they have
twice the amount of plasma volume vs. a non-pregnant woman. There is an increase of plasma vol
ume to RBC mass; which
decreases the Hb concentration.
usually around 11.5 is their cutoff for anemia and the cutoff is 12.5 for normal women. This is

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because of dilutional effect with excess in plasma volume. Apparently in some women, the excess
plasma volume for 9 months can cause weakening of the aorta and thereby causing an aneurysm.

V. VENOUS DISORDER:

A. Superior vena caval syndrome:

A smoker with primary lung cancer, now complaining of headache and blurry vision look at
his retina and see retinal vein engorgement, and congested, diagnostic? Superior vena caval
syndrome.

Usually due to primary lung cancer knocking off the superior vena cava, leading to backup of venous
blood into the jugular venous system and to the dural sinuses; this is a very bad disease, and will lead
to death. Usually treat with radiation to shrink the tumor to get normal blood flow.

B. Varicose Veins

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 Varicose vein in lower extremities.

Primariy varicosities involving the saphenous veins.

VI. Tumors of Blood Vessels:

A. Sturge Weber syndrome looks like a mini map on their face a vascular
m stribution (making it easy to disease).
However, on the rterial Venous malformation, predisposing
to bleeding. So, not only a vascular malformation of the face, but also an Arterial Venous
malformation in the same side of the brain, which predisposes to bleeding. Also, these pts are a little
mentally retarded. (Some pts show it on the entire side of the face).

B. Osler Weber Rendu (Hereditary hemorrhagic telangiectasia)

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Small telangiectasia in Gastro Intestinal. Autosomal Dominant inheritance characterized by
localized telangiectases of the skin and mucous membranes and by recurrent hemorrhage from these
lesions.

C. Spider angioma/spider telangiectasia: If you press down

on this, the little tentacles will go away (therefore it blanches ) called spider angioma. It is due
to hyperestrinism. This is normal in pregnancy. If a male has spider angioma, he has cirrhosis
(Most Common Cause of cirrhosis = alcohol). Why would a male have a spider angioma?
Because if you have cirrhosis, you cannot metabolize estrogen so it builds up, leading to
gynecomastia, warm skin, palmer erythema, and spider angioma related to hyperestrinism. Another
reason would be because they cannot metabolize 17 ketosteroids either, therefore they will be
aromatized those in the adipose tissue into estrogen. So, they are 2 ways of getting hyperestrinism in
cirrhosis. So, how is this different from petechia? It looks different; also, it will blanch when you press
it in because rterial Venous fistula in other words, the blood goes directly from arteriole to a
venule and is bypassing the capillaries.

D. Capillary Hemangioma: child with red lesion (not bilateral wide eye
lesion so its not retinoblastoma); what do you do? Leave it alone; do not surgically remove
because by 8 years, it will be gone.

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E. Kaposi Sarcoma: caused by the HSV 8 organisms. If there
was another lesion seen only in AIDs
bacillary angiomatosis due to bartenella hensilai seen with silver stain.
Treatment? Sulfa drug. This organism also causes Cat Scratch Disease.

F. Angiosarcoma of the liver common causes = Vinyl chloride (people who work with
plastics and rubber), Arsenic (part of pesticides, contaminated water), and Thorotrast (a radioactive
diagnostic agent thorium dioxide).

VII. VASCULITIS SYNDROMES

A. Concept of Vasculitis: Vasculitis of small vessels (arterioles, venules, capillaries), muscular

arteries, and elastic arteries. All of these vasculitis present with different signs and symptoms (Ex.
like coagulation disorders vs. platelet disorders).

1. Small vessel vasculitis - 99% of the time it is due to a type III HPY, meaning it is involves
immune complex deposition, that will deposit in the small vessel, activate complement and
attract neutrophils (C5a), and will get fibrinoid necrosis and damage to the small vessel and
PALPABLE PURPURA; (remember the old person with purpura on the back of the hand that was
not palpable and was due to hemorrhage into the skin, there was no inflammatory problem it just
ruptured into the skin) but if it was palpable, it would be considered a SMALL VESSEL vasculitis not a
platelet problem.

Example: Near Dust, Henoch-Shonlein purpura and

LEUKOCYTOCLASTIC VASCULITIS (hypersensitivity vasculitis) !!

;
So, SMALL VESSEL vasculitis = PALPABLE purpura.

2. Muscular artery vasculitis These will get THROMBOSIS of the vessel. Will have
INFARCTION.

Example: isease coronary artery vasculitis, rash, infarction,

myocardial infarction, swelling get coronary artery vasculitis.

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Most Common Cause of Miocardial Infarction in children =

because part of the syndrome, in addition to mucocutaneous

inflammation, desquamation of skin, and lymphadenopathy, there is a coronary artery vasculitis
thrombosis occurs and little child will have an infarction. So, infarction is what you see with a
muscular artery vasculitis. Examples: Polyarteritis Nodosa, Wegener g
disease in kids.

3. Elastic artery vasculitis When you knock off an elastic artery, then you deal with arch vessels,
and they will get pulseless disease = the vasculitis will block off the lumen of
one of the arch vessels, leading to STROKES and can knock off the internal carotid.

Example: Arteritis young, far eastern lady with

absent pulse.

*Palpable purpura = small vessel vasculitis

*Infarction = muscular vasculitis
*Involves pulse/stroke = elastic artery vasculitis

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B. Temporal Arteritis unilateral headache, aches and pains
all over body, loss of vision of same side of headache, hurts when pt chews in temporal area. This is
a granulomatous (have multinucleated giant cell) vasculitis of the temporal artery, a type of giant
cell arteritides. It can involve other portions of the artery including the ophthalmic branch and

arteritis. Why? Not that it is specific, but because this is an arteritis, (an inflammation) the
sedimentation rate should be elevated. If the sedimentation rate is NOT elevated, it could be a
transient ischemic attack. This is good screen because it takes time to take a biopsy and look at it,
and the pt could go blind. So, you must put the pt on corticosteroids immediately (right there and
then) just based on history alone.

C. Buerger disease (Ex. thromboangiitis obliterans disease)

Occur in males, young, digital vessel thrombosis, leading to autoinfarction of their fingers, AND toes.
to medium-sized arteries.

D. Henoch-Schonlein purpura:
Patient with (butt, joints, git, renal,skin) (palpable purpura on butt and legs, joint problems,
and kidney problems) 14 years, Upper Respiratory Infection one week ago, presents with
polyarthritis, joint pains, hematuria, with RBC casts and palpable purpura of buttocks and
lower extremity,diagnose? Henoch-Schonlein purpura = Most Common vasculitis in children
immune complex (as is all small vessel vasculitis) anti IgA immune complex, and the RBC casts
are due to glomerulonephritis. Do not confuse with IgA glomerulonephritis

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E. Wegener granulomatosis
Pt with saddle nose deformity (not congenital syphilis) also problemss with sinus infections,
Upper Respiratory Infection, lung problems with nodular masses, and glomerular disease,
diagnosis? Wegener granulomatosis (Most Common Cause of saddle nose deformity).

This is a granulomatous inflammation AND vasculitis. Therefore, it involves the upper airways, lungs,
and kidneys; also, there is an Antibody that is highly specific for it (c-ANCA (anti-neutrophil
cytoplasmic Antibodies). Treatment: Cyclophosphamide (which can lead to hemorrhagic cystitis
and bladder cancer and how can you prevent the hemorrhagic cystitis? Mesna).

F. Polyarteritis Nodosa is male dominant disease that involves muscular arteries, therefore
infarction is a part of it. Have p-ANCA Antibodies and a high association with Hepatitis B
surface Antigenimia.

Patient has Intravenous Drug Abuse with chronic Hepatitis B who has a nodular inflamed
mass on the lower extremity and hematuria (due to kidney infarct); what does the pt have?
Polyarteritis Nodosa because the pt has a chronic hepatitis B infection therefore has hepatitis B
surface antigens. So, remember p-ANCA and Hepatitis B surface Antigen in blood.

G. Bacterial infections: vessel in Rocky Mountain spotted fever. The rickettsial organisms infect
endothelial cells; the spots are petechia; unlike other rickettsial diseases with rash, this starts on the
extremities and goes to the trunk (whereas others start on the trunk and to the extremities). Also
have to remember the vector: tick. Other tick born disease: Lyme disease (borrelia burgdorferi
borrelia. recurentis is relapsing fever, and has antigenic shifts; it is a spirochete (Leptospira and
syphilis are also spirochetes). So, 3 spirochetes BLT

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H. Fungus that is wide angle, nonseptate, pt has Diabetes Ketoacidosis, and cerebral abscesses

related to fungus mucormycosis

(Know relationship of this fungus and DKA); Diabetics commonly have mucor in their frontal sinuses;
so when they go into ketoacidosis and start proliferating, they go through the cribiform plate into the
frontal lobes where they infarct it and infect it with the disease.

VIII. Functional Vascular Disorders: Raynaud Disease

There are many causes this:

1. Some involve cold reacting Antibodiess and cold reacting globulins. People who go outside in
the cold weather will get Ray
IgM cold agglutinin disease or cryoglobinemia in old man with Hepatitis C.

2. Diseases that are collagen vascular diseases

digital vasculitis and eventually a fibrosis progressive systemic sclerosis (scleroderma), and its
similar CREST syndrome. Vasculitis of fingers and leads to fibrosis will eventually auto-amputate

CREST syndrome Calcinosis (dystrophic calcification) and Centromere Antibody (specific for
crest syndrome), , Esophageal dysmotility, Sclerodactyly (finger that is very narrow),
Telangiectasia (very similar to the pin point hemorrhages also seen in Osler Weber Rendu).

3. Vasoconstriction common in pts that take drugs for migraine drugs for migraines cause
; Buerger disease,
too.

on, vasculitis of the digits (Ex. CREST

and scleroderma), and cold reacting Antibodiess and globulins.

IX. HYPERTENSION (HTN)

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Most Common Cause of death with Hypertension = Miocardial Infarction
(2nd = stroke) (3rd = renal failure)

Essential Hypertension= Most Common

A. Multifactorial Inheritance:

What racial group has highest incidence of Hypertension? Blacks. Why? Multifactorial
inheritance (polygenic inheritance; other disease include: gout, Coronary Arterial Disease, Type II
diabetes, affective disorders, congenital pyloric stenosis, and essential hypertension). This means
that you have a tendency to FOR the disease ecessarily get the disease. Why? Because

Example: I am black, what should I do to prevent from getting it? I cannot get rid of genetics, and my
genetics are that I cannot get rid of salt in my urine - retaining too much salt (which is the basic
mechanism of essential Hypertension in blacks and elderly). So, cannot control genetics.

Black population can control hypertension with 3 things:

(1) Weight has a direct correlation with HTN

(2) Reduce salt intake
(3) Exercise.

Example: family history of gout, what can I do so I avoid gout? Avoid red meet, no alcohol (which will
decrease purine metabolism).

Example: If you had a family history of Diabetes Mellitus type II be skinny (lean and mean) as
you lose adipose, upregulate insulin receptor synthesis and that alone could prevent you from having
the disease.

B. Mechanism that produce Hypertension:

Retain salt ost Common one). When you retain salt, what
compartment will the salt be retained in? Extra Cellular Fluid if that is true, what will be the plasma
volume if you have excess salt in your vascular and interstitial compartment? Increased if your
plasma volume is increased, your stroke volume will be increased which is your systolic
Hypertension (because increase in PLASMA volume).

When you have excess salt, salt wants to go into smooth muscle cells (into peripheral resistance
arterioles). When sodium enters muscle, it opens certain channels for Ca to go in; Ca goes in and
smooth muscle will contract, so the peripheral resistance arterioles are vasoconstricting.

TPR = viscosity/radius4; we are decreasing radius, increasing resistance, and retaining more blood
in the arteriole system (that registers as an increase in diastolic pressure). Treatment of
choice for essential Hypertension in blacks and elderly = hydrochlorothiazide because you rid
salt and water to decrease Blood Pressure; however, do not use if pt has hyperlipidemia, so use ACE
inhibitors.

Is this a high or low renin type of Hypertension? Low renin because increased plasma volume
= increased blood flow to the renal artery = decreased renin.
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C. Complications: Hypertension is a major risk factor for Coronary Arterial Diseases, leading to
Miocardial Infarction (Most Common Cause of death); Stroke = #2. Blood is located in brain
(globus pallidus or putamen) this is where almost all of the Hypertensives bleed.

This is because the lenticulostriate vessels (which are small vessels of the middle cerebral artery)
under increased pressure form aneurysms called Charcot Bouchard aneurysms, and they rupture.
This is not a good place to rupture. Therefore, this is not an infarct it is a hematoma
clot right there. Neurosurgeons can suck these out. Therefore the 2nd Most Common Cause of
death in Hypertension is Hypertensive Bleed by Hematoma. Example: kidney that is too small
with a pebbly surface due to hyaline arteriolosclerosis a small vessel disease is causing ischemia of
the kidney, atrophy of tubules, destruction of glomeruli, shrinkage of kidney, and leads to:

Kidney failure (3rd Most Common Cause of death in Hypertension.

Most Common overall abnormality in HTN = Left Ventricular Hypertrophy (mech: afterload problem
because the heart has to contract against increased resistance and if it remains over a period of time
it will eventually lead to heart failure.

Audio File Day 3: Cardiovascular 3

I. HYPERTROPHY OF THE HEART:

Concentric (thick) HYPERTROPHY (HPY) heart vs. Dilated HYPERTROPHY heart: 2 different
etiologies and they involve work. It requires a lot of work to contract and push blood thru a stenotic
aortic valve, or increased TPR from Hypertension.

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 Increased afterload = CONCENTRIC HYPERTROPHY (RIGHT)
*Concentric Hypertrophy = afterload problem.

*Dilated Hypertrophy: If you have a valvular problem, and have excess volume of blood in the
ventricles increased preload = increased work. Therefore, the frank starling goes into effect
because stretching and increasing preload in there, and you have to work harder to increase the force
of contraction this produces dilated HPY. Dilated Hypertrophy = volume overload = preload
problem (increased volume)

II. HEART SOUNDS

S1 heart sound = beginning of Systole = mitral and tricuspids close (mitral closes before the
tricuspid because higher pressures) C wave ascending +.

S2 heart sound = beginning of Diastole = pulmonic and aortic close (variation with respiration as
diaphragm goes down they increase the intrathoracic pressure. Blood is being sucked into the right
side of the heart, and the pulmonic valve will close later than the aortic valve. So, the second heart
sound has a variation with inspiration the P2 separates away from A2 because more blood coming
into the right heart, so the valve closes a little bit later.

S3 heart sound = normal under 35 years. After that, it is pathologic. S3 = early diastole. S3 is due
to blood, in early diastole, going into a chamber that is volume overloaded. So, blood from the left
atrium is going into overloaded chamber, causing turbulence, which is the S3 heart sound. Only hear
S3 heart sound in volume overloaded chamber. It could be from Left Heart Failure (left ventricle
overloaded) or Right Heart Failure (right ventricle
it means volume overload in the chamber. Analogy: rivers going into ocean leads to
turbulence (ocean is the ventricle with a lot of fluid in it and the river is the blood coming in during
diastole; the river hits this large mass of fluid in the ventricle, causing turbulence and an S3 heart
sound).

S4 heart sound = late diastole this is when the atrium is contracting and you get the last bit of
blood out of the atrium into the ventricles, leading to S4 sound. filling
problem (compliance problem).

So, . The left atrium is

contracting, trying to get blood into a thick ventricle; the ventricle is noncompliant, and therefore
resistance will occur. This will create a vibration, leading to an S4 heart sound. An S4 heart sound
is due to a problem with compliance. The left atrium is encountering a problem in putting blood in
to fill up anymore.

This could be due to 2 reasons:

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(1) Its restricting filling up)
(2) Its already filled up and has to put more blood in an already overfilled chamber.

Summary: Slides:

If the heart is volume overloaded? S3. So can it have an S4? Yes.

If you have Hypertension, which type of heart will you have? Concentric Hypertrophy.

In Hypertension, which type of heart sound will you have? S4.

With Hypertension the hearth is Volume overloaded? Yes. So can it have an S3? Yes
Can it also have an S4? Yes. Why? Because

Analogy: turkey dinner all filled up, but always room for desert little vibration that occurs
when it fills is an S4 heart sound. So you have both S3 and S4 heart sound = gallop rhythm
(they have S1, 2, 3, and 4).

How do you know if from the left or right? It is breathing. When you breathe in, you are sucking
blood to the right side of the heart. All right sided heart murmurs and abnormal heart sounds
(Ex. S3, S4) increase in intensity on inspiration this is more obvious because there is more
blood in there, and it emphasizes those abnormal sounds. Probably get them on expiration with
positive intrathoracic pressures that are helping the left ventricle push blood out of the heart this
is when abnormal heart sounds and abnormal murmurs will increase in intensity on expiration. So, all
you have to do is figure out that there is an S3 heart sound. *****Then, you have to figure out which
side it is coming from. Louder on expiration, therefore from the right side.

Example: essential Hypertension = left; Mitral regurgitation = right; and Mitral stenosis = middle.

III. MURMURS

Stenosis = probably in opening, that is when the valve is opening, and that is when the murmur
occurs.
Regurgitation = probably in closing the valve, that is when the valve is closing, and that is when the
murmur occurs.

Need to know where valves are heard best right 2nd ICS (aortic valve), left 2nd ICS (pulmonic), left
parasternal border (tricuspid), apex (mitral)
noise is heard the best.

A. Stenosis:

1. Systolic Murmurs: Who is opening in systole = aortic and pulmonic valves = therefore,
murmurs of aortic stenosis and pulmonic stenosis are occurring in systole. This is when they are
opening; they have to push the blood through a narrow stenotic valve.

a. Aortic Stenosis Left Ventricle contracts and it is encountering resistance - intensity of the
murmur goes up; as it is pushing and pushing, it gets to a peak and this is diamond shape
configuration this is why it is called an ejection murmur. So, they often have diagrams of the
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configurations on these murmurs. With an ejection murmur (aortic stenosis), it will have a crescendo-
decrescendo (hence, diamond shaped configuration). So, with aortic stenosis, there is an ejection
murmur in systole, heard best at the right 2nd ICS, which radiates to the carotids, and the
murmur intensity increases on expiration, and will probably hear an S4.

b. Pulmonic Stenosis heard best on left 2nd ICS, ejection murmur, and increases on expiration.

2. Diastolic murmurs: Occur in diastole, mitral and tricuspid valves are opening.

a. Mitral Stenosis (problem in opening the valve)

who has the problem? Left atrium.

left
atrium will get strong because it has an afterload to deal with it becomes dilated and hypertrophied
(the atrium) which predisposes to atrial fibrilation, thrombosis, and stasis of blood. So, the atrium is
dreading diastole because it has to get the buildup of blood into the left ventricle. With the build up of
pressure, the mitral valv
in the atrium comes gushing out into the ventricle, causing a mid-diastolic rumble. So, you have an
opening snap followed by a rumbling sound (due to excess blood gushing into LV). With mitral
stenosis, there is a problem with opening the valve, and therefore you are under filling the left
ventricle, and therefore will be NO Hypertrophy. If you are having trouble getting blood into it, you
are not overworking the ventricle; the left atrium has to do most of the work. Heard best at the apex
and will increase in intensity on expiration. (Same concept with tricuspid stenosis, just a different
valve).

B. Regurgitation problem in closing the valve.

1. Systolic Murmurs: mitral and tricuspid are closing in systole.

a) Mitral Regurgitation: If they are incompetent and mitral valve cannot close properly.
Example: 80 mls of blood = normal stroke volume; lets say 30 mls into the left atrium and only 50 mls
leaves the aorta. So, an extra 30 mls of blood in the left atrium, plus trying to fill up and have excess
blood there way more blood ends up in the left ventricle and it becomes volume overloaded. So,
how would the murmur characteristics be if there is a problem in closing the valve? It will not be an

systole is going through the incompetent mitral valve, back into the left atrium therefore it is
pansystolic or almost pansystolic
S2. So, is an apical murmur, pansystolic, S3 and S4 (because a problem with compliance and
volume overload increased in intensity on expiration.)

b. Tricuspid Regurgitation: it will be pansystolic, S3 and S4, left parasternal border, and
increases on intensity on inspiration).

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Intravenous Drug Abuse with fever, pansystolic murmur along parasternal border, S3 and S4
heart sound, accentuation of the neck veins, what is the most likely diagnosis?

Infective endocarditis of tricuspid valve, which is the Most Common infection.

So, it was extremely important to know if the murmur increased on inspiration (which is right sided). If
the question said that the murmur had increased on expiration, it would be Infective
endocarditis of the mitral valve (which is left sided).

2. Diastolic Murmurs: want the aortic and pulmonic valves to close (what you just pumped out

Aortic Regurgitation (as seen in syphilis aneurysm but this is due to the stretching of the ring). In
systole the blood goes out and the valve should be closing properly
trickle (dropping) back in. Example: 80 cc went out initially and 30 cc is dripped back in. As blood
keeps dripping back in, you will get a volume overloaded chamber. Eventually you will have and
EDV of 200 mls (instead of 120). So, for aortic regurgitation, when you hear the murmur? After the 2nd
heart sound because it i that makes the sound of a high
pitched blowing diastolic murmur into the right second ICS, increases on expiration, S3 and
S4 heart sounds, volume overloaded, and bounding pulses.

What valve leaflet (part) is dripping blood? Anterior leaflet of mitral valve. This is one side of
the outflow tract out of the aorta. What murmur does that create? Austin flint murmur. If you have
aortic regurgitation with an Austin flint murmur, you have to perform surgery. Need to replace the
valve because you are significantly dripping blood.

IV. HEART FAILURE: LEFT OR RIGHT HEART FAILURE

*Left Heart Failure = lungs and Paroxysmal nocturnal dyspnea/pillow orthopnea

*Right Heart Failure = Liver

A. Left heart failure = Is when c because the Left Ventricle fails.

Therefore your left ventricle has to push against an afterload and fails; or it has to deal with excess
longer muscle but now
fibrous tissue and this reduces contractility and it fails. ou are

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having problems getting blood outside of the heart. This means that EDV increase because you
cannot get all the blood out because you cannot push it out.

The pressure and volume will go back in to the left atrium, back into the pulmonary vessels, increase
the hydrostatic pressure, and then pulmonary edema. With chronic left heart failure, this will lead
to hemorrhage and alveolar macr
sputum.

On cytology slide: Pulmonary Edema sees heart failure cells,

which are alveolar macrophages that have
Pulmonary edema is always left heart failure. Left heart failure is a diagnosis of symptoms,
because the main symptom in Left Heart Failure is dyspnea (Short of Breath = SOB), have
trouble breathing because fluid in there.

Examples of Left Heart Failure: When you lie down to go to sleep, you can reabsorb up to 1 liter of
fluid because it will go from the interstium to the venous side because
Therefore, there is extra blood going back to the right heart and into the left heart. However, what if
you had left Heat Failure
you were standing up) and the left heart is having trouble getting blood out, with even more
blood coming back in. Then the heart cannot handle it and goes back to the lungs, leading to
dyspnea and continues for the next 30 minutes this is paroxysmal nocturnal dyspnea. Eventually
it settles down, you go back to sleep, wake up again, and it occurs again. Pt realizes that after you
stand up, then it eventually goes away therefore they put a pillow under the head to decrease the
dyspnea when they wake. This is called pillow orthopnea. If its one pillow orthopnea, its not that
bad; however, if you have to sit up, you have serious left heart failure because you are imposing
gravity. Just by putting head on one pillow will decrease venous return back to the heart. If you put 2
pillows under, it will decrease the dyspnea even more because of effective gravity. So, pillow
orthopnea and paroxysmal nocturnal dyspnea are signs of LEFT heart failure.

B. Right Heart Failure: Diagnosis of signs: It get blood into the heart. Right Heart Failure
is a problem of the right heart getting blood through the pulmonary vessels to the left heart.
So, if it fails, blood builds up behind it, and it is a backward failure. Because if it cannot get blood
through pulmonary vessels into the heart, blood will build up behind it, and hydrostatic pressures will
build in the venous circuit. This leads to neck vein distension; also, will get hepatomegaly (which
is painful), and:

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! nutmeg liver because of the increased pressures in the vena
cava are transmitted to the hepatic vein, which empties into it, then back into the liver and the central
vein, then will get red dots all over liver, which looks like a nutmeg. Most Common Cause of
congested hepatomegaly = Right Heart Failure. What caused the increased in hydrostatic
pressure also going to produce pitting edema and ascites therefore its more signs than it is
symptoms. So, neck vein distension, pitting edema, hepatomegaly, nut Meg liver and ascites.

C. Treatment:
If you have heart failure (right or left), what is the best nonpharmacologic treatment? Restrict
water and salt.

What the king of Treatment of Heart Failure? ACE inhibitor because it decreases afterload
AND preload at the same time.

ACE inhibitors increase longevity by (1) decreased aldosterone, therefore decreased salt and water
reabsorption which decreases preload and (2) by blocking Angiotensin II, will lead to a decrease in
vasoconstrictor effect on peripheral resistance arterioles, which will decrease afterload.

Pts with spironolactone + ACE inhibitor did better because aldosterone will eventually break
through and become elevated again, therefore ACE inhibitor acting against aldosterone is not a
permanent suppression. So spironolactone which specifically blocks aldosterone, plus the ACE
treatment to put the pt on
spironolactone and ACE inhibitor because it will increase longevity.

D. High output failure

One cause is endotoxic shock peripheral resistance arterioles are dilated, therefore an
increase in C3a, C5a, NO, leading to increased venous return to the heart and the heart eventually
give viscosity/radius to
the fourth power. So, if you vasodilate the peripheral resistance arterioles, and you decrease TPR,
more blood returns to the right heart, the left heart has to deal with it, too, and pt runs the risk of high
output failure. So, one cause of the vasodilatation is septic shock, while the other is thiamine
deficiency. Problem in thiamine deficiency: ATP depletion. Smooth muscle cells and peripheral
resistance arterioles need ATP, therefore they do not work as well, and there is vasodilatation of the
peripheral arterioles, leading to high output failure. So, thiamine def can produce high out put failure
because vasodilatation of those vessels. Examples:

*Grave isease hyperthyroidism thyroid hormone increases the synthesis of beta receptors in
the heart. Get an increase in force of contraction, and more blood. Systolic pressures are higher,
and go into high output failure.

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*Arterial Venous fistulas Ex. get stabled in the leg; and develop an Arterial Venous malformation,
where there is arteriole blood bypassing the microcirculation going directly to the venous circulation
and the blood comes back faster to the heart than normal; a bruit can be heard over the mass and it
these
are all signs of Arterial Venous fistula, leading to high output failure.

So, 3 examples of high output failure are endotoxic shock, graves, and AV fistulas

V. CONGENITAL HEART DISEASE

A. Fetal circulation

(Which vessels have the least/most O2); remember that the baby is NOT exchanging blood with O 2 in
the lungs. Pulmonary vessels in the fetus look like they have pulmonary Hypertension they are so
thick that it is extremely hard to get blood through the pulmonary artery into the Left Ventricle
because very little blood can go there this is why baby needs a patent ductus to get blood out.
Where is O2 coming from? Coming from chorionic villus dipping into lake of blood, this derives from
Have chorionic villi dipping into blood and extracting O 2 from it. Obviously,
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this is not as good an O2 source as the lungs; therefore, you want a high affinity Hb to be able to get
what little O2 is down in the area this is why babies have HbF, because of its high affinity to grab O2
from the blood. Bad news is that it gets the O 2 it left
shifts the curve. What is compensatory response? This left shift causes tissue hypoxia, which will
cause Erythropoietin (EPO) to be released and the kid will have an 18 gram Hb because of this, all
affinity for O2 more
2.

Order of O2 passing: O2 goes through (Placenta componentes) = syncytiotrophoblast of chorionic

villus, into the cytotrophoblast, then through the myxomatous stroma of the chorionic villus, then into
the blood vessel. The blood vessels of the chorionic villis all coalesce to form the umbilical vein.
This has the highest O2 content.

It goes to the liver and it can go two ways:

1) Into the hepatic sinusoids and recollects into the hepatic vein and gets dumped into the Inferior
Vena Cava
2) Ductus venosus and straight into the Inferior Vena Cava. Then it goes up the right side of the
heart; the foramen ovale is open in all fetuses ( not closed) so all this blood is coming up the
Inferior Vena Cava.

Will it go straight across, through the foramen ovale and into the left atrium, or into the
Inferior Vena Cava into the right atrium, down through the tricuspid valve, and into the right
ventricle? Foramen ovale.

So, all this oxygenated blood will go directly from the right atrium of the foramen ovale into
the left atrium, then the left ventricle and out the aorta. Deoxygenated blood from the Superior
Vena Cava is expelled into the pulmonary artery and ductus arteriosus to the lower body of
the fetus.What about Superior Vena Cava blood valve? It is coming from the superior part of the right
atrium (its not gonna make a left turn and go through the foramen ovale). It will go straight down,
through the tricuspid valve into the right ventricle.

Now, it will go out the pulmonary artery. This is a PROBLEM because the pulmonary vessels are too

patent ductus open (which is kept open by the PGE2, a vasodilator, made by the placenta) so,
there is a right to left shunt and blood can get out of the pulmonary artery and dumped back into the
aorta. Then, when the baby is born and takes its first breath, the pulmonary vessels (that were all
shut), all open within a millisecond, and blood is going through those pulmonary arteries and gas
exchange is occurring through the lungs in literally seconds. Also, the patent ductus closes and
forms the ligamentum arteriosum. This is normal fetal circulation. Vessels with the least O2 are
the 2 umbilical arteries, and with the most O2 is the one umbilical vein.

B. Shunts:

To the Boards look at O2 saturations (this is how they diagnosed them they catheterize,
measure O2 saturations in different chambers, and know which direction the shunts are going.

Need to get used to two terms step up and step down.

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*Left to right shunt, and have oxygenated blood going into deoxigenated blood, what is happening
to O2 saturation on the right side? Step up because mixing Oxigenated with deoxigenated blood.

*Right to left shunt with deoxigenated blood going into the Oxigenated blood? Step down.
The O2 saturation on the right side of the heart in blood returning from the body is 75%. The O 2
saturation on the left side is 95%.

C. Ventricular Septal Defects (VSD) (Most Common)

stronger - left or right ventricle? Left, therefore the direction of the shunt is left to right. So,
oxygenated blood will be dumped into the right ventricle, leading to step up. Also, it will pump it out of
the pulmonary artery, leading to step up. So, you have a step up of O2 in right ventricle and
pulmonary artery.

What if this is not corrected? With this mechanism: you are volume overloading the right side of the
heart because of all that blood coming over. The outcome of this will be pulmonary Hypertension
(the pulmonary artery has to deal with more blood and must contract more leading to pulmonary
Hypertension) Once pulmonary Hypertension occurs, right ventricle will have a problem contracting
and it will get hypertrophied. Suddenly, you run the risk of reversing a shunt because then right
ventricle could eventually be stronger than the left. So, it will be a right to left shunt this is
called drome. After reversal of the shunt occurs, pt will have cyanosis
(cyanosis tardive). Most Ventricular Septal Defect close spontaneously and some need to be
patched.

D. Atrial Septal Defect (ASD)

Normal for a fetus to have a patent foramen ovale but not once they are born. Which direction will
blood go through the foramen ovale? Left to right (because the left side is always stronger than the
right). Therefore, what will happen to the right atrium? Step up so it will go from 75 to 80%. What
will happen to the right ventricle and pulmonary artery? Step up.

What is the main difference in O2 saturations in VSD vs ASD? ASD is step up of O2 also in
the right atrium.

Are you volume overloading the right heart? Yes. So, do you run a risk for Eis
Yes.

What else are at increased risk for? Paradoxical embolization.

What if you (DVT) Deep Venous Thrombosis in the leg, and it

embolize up and the pressures of the right side of the heart are increasing, and you have a
patent foramen ovale will there be an embolus that can go from the right atrium to the left
atrium and will have a venous clot in arterial circulation? Yes this occurs in pts with Atrial
Septal Defect.

Most Common teratogen that has Atrial Septal Defect associated with it? Fetal alcohol
syndrome (1/5000)

E. Patent Ductus Arterous (PDA)

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 Connection between the aorta and pulmonary
artery. Which is stronger? Aorta. So, oxygenated blood goes from left and gets dumped in the
pulmonary artery before going into the lungs. So, what happens in the pulmonary artery? Step up.
So, now its 80% O2 saturation the pulmonary artery is the only thing that has a step up of O2.
Then will go under the lungs and the pulmonary vein will have the normal 95% O2 saturation.
Because there is an opening between these, there is blood going back and forth during systole and
diastole machinery murmur where is it heard well? Between shoulder blades
(Scapula=Omoplato). Can you volume overload the right heart? Yes. Pulmonary
Hypertension? Yes.

Now which way will the shunt go? Will go the same way when it was a fetus; you will have
deoxigenated blood dumping into the aorta. Where does the ductus empty? Distal to the subclavian
artery so, the baby will have pink on top and blue on bottom because dumping deoxigenated blood
below the subclavian artery therefore will have differential cyanosis pink on top, cyanotic on
bottom.

What is the teratogen association with Patent Ductus Arterious? Congenital Rubella.

If you had a PDA, can you close it off without surgery? Yes. How? Indomethacin - this is a
potent NSAID, which would inhibit PGE2, and therefore would start constricting and close on
its own.

F. Tetralogy of Fallot !

Most Common cyanotic congenital disease overriding aorta: its straddling the
septum; pulmonic stenosis below the valve, Right Ventricular Hypertrophy, membranous septal
defect (VSD).

What determines whether you get cyanosis or not? Degree of pulmonic stenosis; not all
babies have cyanosis and are acyanotic called acyanotic tetralogy.

Why does this occur? Lets say the degree of pulmonic stenosis is not that bad when the right vent
contracts, a lot of the blood goes up the pulmonary artery to get Oxigenated and less blood gets into
the left ventricle, and therefore probably will not have cyanosis at birth. What if it was a severe
stenosis and when the right ventricle contracts, little blood got up there? Most will be shunted right to
left and there will be a step DOWN in O2 in the left ventricle and baby will be cyanotic. So, it is the
degree of pulmonic stenosis that determines whether you have cyanosis or not.

Which of the groups of shunts is cardio-protective in a pt with tetralogy of fallot? PDA, ASD
good say there is an ASD; therefore blood will go left to right because we get Oxigenated blood
emptying into the right atrium. This would cause a step up of blood into the right atrium (this is good).
How about a PDA? Lets make believe this occurs so, deoxigenated blood pushed from left from
the aorta down to the pulmonary artery to get O2; some of the deoxigenated blood put back into the
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pulmonary artery, where it gets Oxigenated and more gets out good to have PDA and ASD
(foramen of ovale) with tetralogy of fallot.

Right to left leads to polycythemia and a real risk for infective endocarditis because shunts
going into left side therefore can get vegetations going into the brain and other systemic organs. All
congenital heart defects lead to infective endocarditis.

G. Transposition of Great vessels

Examp have a normal heart that is on the right side. So, there is NOT a
complete transposition of vessels, but a normal heart on the right side (called sinus inversus).

Not the right atrium it is still getting unoxygenated blood. not the left
atrium it is still getting 95% O2 saturated blood from the pulmonary vein. The problem is in the
ventricles the right ventricle is being emptied by the aorta; and the left is being emptied by
the pulmonary artery. So, the thing that is transposed is the ventricles (the atria are fine). This is
incompatible with life unless you have shu
work?

Start at the atrial side have 95% O2 coming into left atrium and it is going from the left to right;
there will be a step up of O2 in the right atrium and therefore also a step up of O2 in the right
ventricle. Some will go out the aorta and rest will go to the left ventricle. This is good because the
left ventricle is being emptied by the pulmonary artery, so the blood will be taken to the lungs to be
oxygenated. So, these shunts are necessary for life.

Otherwise, the right ventricle being emptied by the aorta would be all oxygenated blood and the left
ventricle being emptied with the pulmonary artery would not be okay. So, by having the shunts can
get around these defects. An Atrial Septal Defect is necessary so you can get Oxigenated blood
into the right atrium, and from the right atrium there will be a step up of O2 in the right ventricle, which
is why
there is cyanosis in these patients. At least some blood can get out of the aorta and have some O2
to the pt and they can survive for a little while. Because of the right to left shunt, that blood is
being emptied by the pulmonary artery and that is going to the lungs and being oxygenated.

H. Coarctation have preductal = before patent ductus and postductal = after patent ductus (after
the ligamentum arteriosum).
.
Preductal occur in Turner syndrome and go straight into failure, therefore must be corrected
immediately.

Postductal ife. Important to

recognize because they are a surgically correctable cause of Hypertension.

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 Note the area of constriction just distal to the ligamentum arterosusm
extending of transected pulmonary artery .

Stenosis in aorta what is happening proximal? There is trouble getting blood through that,
therefore there will be a murmur heard best between the shoulder blades a systolic murmur. There
is a lot of pressure built up proximally, so the proximal aorta will be dilated and there will be a lot of
pressure going into the vessels the subclavian, internal carotids therefore the Blood Pressure in
the upper extremities will be higher than it is in the lower extremities. Also, with increased
blood flow into the brain, at the junction where the communicating branches hit the main cerebral
branches, we have no internal elastic lamina and no smooth muscle there, therefore it is a weak area
(for ALL people); therefore, everybody has the potential to develop berry aneurysms.

What would exacerbate, or make the berry aneurysm a realistic thing? Hypertension (any
cause of Hypertension can cause berry aneurysms Ex. Adult Polycystic Kidney Disease (ADPKD),
essential Hypertension, the bottom line is Hypertension, and ALL hypertensive pts run the risk of
berry aneurysms we all have the same defect at the junction form any cause of Hypertension its
not unique to ADPKD, its in all cases of HTN other relations to HTN = subarachnoid bleeds,
stretch/dilatation of aortic valve ring and therefore a murmur of aortic regurgitation.

All the pressure on the wall of the proximal aorta can also predispose to dissecting aortic
aneurysm. What is distal to this? Decreased blood flow, claudication (angina of peripheral vessels
so when they walk, they will get calf pain, buttock pain, then they stop and it goes away, they walk it
hurts) this is all due to ischemia, and the muscle development to the lower extremities will not be
too good, either. Muscle mass will be decreased, Bloop Pressure difference between upper and
lower extremities, and the blood flow to the renal arteries is decreased, leading to activation of the
Renin Angiotensine will lead to Hypertension. So the HTN in pts with Coarctation is due to
activation of Renin Angiotensin so it is a high renin HTN. So, if you can correct it the HTN will
go away. When there is a problem (Ex. a roadblock), we have to go around it Ex. need collaterals.

However, the aorta is not a good place to have a roadblock because only have two ways to get
around the block:

1) (Rarest) superficial epigastric artery, with the internal mammary artery can get around this; this is
at the lateral border of hasselbach (the superficial epigastric artery). So, when you stick your finger in

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the canal and have an indirect inguinal hernia. Right through the medial side will feel a pulsation
(where the superficial epigastric artery is).

*2) Intercostals on the undersurface of the ribs and getting extra blood through them leading to
notching of ribs (visualized on x-ray).

VI. MAJOR RISK FACTORS FOR CORONARY ARTERY DISEASE: Know the risk factors!

*Age is the most important risk factor (cannot control) -45 for males; 55 for women

Why? Higher estrogen levels, which affect HDL levels.

Risk factor for Coronary Artery Disease is HDL. HDL visits fatty streaks, sucks LDL out, takes it to
the liver to be metabolized. 55 in women becauethat is the age of menopause; not taking estrogens
and that is the age when estrogens go down; HDL levels go down and risk goes up.

Family history of premature artery disease, cigarretes smoking, Hypertension, HDL<35, diabetes,
LDL (cholesterol is not a risk factor, LDL is) because all therapeutic decisions are based on LDL
levels, not cholesterol levels. HDL is a negative risk factor: if your HDL is greater than 60, you can
subtract one from your major risk factor Ex. 58 years, but HDL is above 60, can subtract the age
risk factor and will have no risk factors.

VII. ISCHEMIC HEART DISEASE:

4 types: Angina, Myocardial Infarct, Sudden Cardiac Death Syndrome, Chronic Ischemic Heart
Disease

A. Sudden cardiac death syndrome = death within the last hour what will you see at autopsy?
Will see severe coronary artery atherosclerosis. !

Leading to ischemia, Premature Ventricular Contractions, ventricular fibrillation (die of ventricular

arrhythmia just like in Miocardial Infarction); die so fast that there are no changes in the heart (Ex.
pallor/Coagulation necrosis); see severe coronary artery disease and the diagnosis sudden cardiac
death. Very high risk in smokers.

B. Chronic ischemia heart diseases unts who have coronary

artery disease with little infarcts, or had a small heart attack, basically talking about subendocardial
infarctions. What happens is that the muscle gets replaced by fibrous tissue and eventually the poor
Left Ventricle is all fibrous tissue, with no muscle therefore the ejection fraction is very low. Its 0.2
instead of the normal 0.66 and they die from heart failure. Fibrous tissue does not have contractility;
this disease is the 2nd Most Common indication for a heart transplant.

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C. Angina (Most Common type of heart disease)

3 types exertional, prinzmetal, unstable (resting) angina

1. Exertional chest pain on exertion (effort), goes away within 5-10 minutes of resting; ST
depression on EKG (1-2 mm depression) therefore a candidate for coronary angiogram to see

2. seen in women, occurs in morning; due to vasospasm of the coronary arteries. In

some people, Thromboxane A2 (TxA2) is implicated for the vasospasm. ST depression means
subendocardial ischemia. Coronary arteries penetrate the outside of the heart and go in, so the
subendocardial tissue get screwed because its furtherest (far) from the blood supply. Therefore, with
coronary artery atherosclerosis, and decreased blood flow, who gets screwed? Subendocardium and
it reacts to it with pain and ST depression. With vasospasm of coronary artery, get transmural
ischemia therefore there is ischemia throughout the entire thickness of the muscle this
produces ST elevation. So, Prinzmet transmural
ischemia.

3. Unstable or pre-infarction angina get angina on resting. Classic hstory: initially had stable
angina, now pt just get it when they are sitting. This means that they will need angioplasty and put
into the hospital. Do not put on treadmill, they will die.

What veins do they use? Saphenous vein over 10 years will become
arterialized (it will look exactly like an artery). If you take a vein, and put arterial pressures into it, it
will change its histology and look exactly like an artery. They have a high tendency for fibrosing off
after 10 years because they are veins.

Internal mammary is an artery, therefore it is used to those

pressures. They will remain patent, but cannot do four vessel bypass with one internal mammary
artery. So, they use the saphenous vein, which has the tendency to undergo fibrosis over time
because they are arterialized under pressure. They can also use the internal mammary.

D. Acute Miocardial Infarction

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Thrombus composed of group of platelet cells bound together with fibrin. Tissue Plasmin Activated
does plasmin just breaks the fibrin bonds to destroy the clot. It
has a much bigger problem with the breakdown of a venous clot because those have more fibrin.
The thromboses/clots in the heart do not have that much fibrin. Another factor to deal with is
reperfusion injury Oxigenated blood goes into injured tissue, superoxide free radicals form, Ca form,
and a few of the injured myocardial cells will die. Once those die, it will still improve longevity.

1. Complications of Miocardial Infarction:

a) Left Artery Disease (LAD): coronary artery is Most

Common vessel thrombosed, and supplies entire anterior part of your heart and the anterior 2/3 parts
of the interventricular septum. So, there will be paleness, with the anterior 2/3 parts knocked off.
Where are most of the conduction bundles? Anterior 2/3 parts. So, if you have complete heart
block that requires ectopic pacemaker, what is the most likely vessel thrombosed? Left Artery
Disease. When you have LAD occlusion, you have classical signs pain radiating the jaw, pain
down the left arm, substernal chest pain.

b) Right Coronary Artery = 2nd Most Common Thrombosed artery which supplies the entire
posterior part of the heart and the posterior 1/3 of the ventricular septum and the entire right ventricle.
So, it supplies the post heart, post 1/3 of the septum and the entire right ventricle. The mitral valve
has two valves with papillary muscles posteromedial papillary muscle and posteromedio
papillary muscle. So, what supplies the posterior? Right Coronary Artery. Also have the Sino
Atrial node and Atrial Ventricular node. The Sino Atrial node has an equal distribution between left
and right. However, the Atrio Ventricular node has a 95% supply from the branches of the Right
Coronary Artery this brings up interesting complications. Example: pt with mitral regurgitation
murmur, which is related to posteromedial papillary muscle dysfunction, or may break what is the
problem? Thrombosis of the RCA because the RCA supplies that papillary muscle. So, mitral
regurgitation murmur that occurs during Miocardial Infarction would be due to RCA. If you knock off
the Atrio Ventricular node, this is sinus bradycardia, and atypical chest pain. The RCA is
dangerous because sometimes pt will get epigastric pain, which is an atypical pain. This simulates
Gastro Esophageal Reflux Disease (GERD); Ex. pt sent home with pepto bismol, and ends up dying
at home (because of missed diagnostic). They should have been sent to hospital. Therefore, elderly
pt with epigastric pain could be GERD or coronary artery thrombosis of the RCA.

2. Gross/microscopic features
Need to know when the heart is softest and has a chance for rupturing this is between 3-7 days.
When do you see gross manifestation of being a pale infarct? 24 hrs begin seeing paleness.

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Early Miocardial Infarction: coagulation necrosis 4-6 hours.

Old Miocardial Infarction: coagulation necrosis 3 days.

Example: Rupture of Anteori Wall.

Left Artery Disease thrombosis because see pale anterior 2/3 of heart. Rupture pericardium filled
with blood (hemopericardium) most are interior, and therefore is from the Left Artery Disease
thrombosis how does this manifest itself? Day 3 or day 4 complain of chest pain, have muffled heart
sounds, neck vein distension, and know they have ruptured.

*Example: rupture of post medial papillary muscle

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 And it was infracted, therefore the Right Coronary Artery is
the cause of the rupture so, what would the murmur be? Mitral regurgitation On day 3 pt goes
into heart failure, have a pansystolic murmur, increases on expiration, and S3 and S4 heart sound. It
meaning the posterior medial papillary muscle was dysfunctional because
arises
between days 3-7. Will go into heart failure because massive volume overload and go right back to
the lungs.

Example: rupture of anterior wall

Example: rupture of papillary muscle, and the posteromedial one is Most Common.
Example: Coagulation necrosis
Example: interventricular septum ruptures, therefore a left to right shunt and a step up. Most
interventricular ruptures are Left Arteries Disease thromboses.

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Example: mural thrombus (mural = wall) in this case, mural is a
thrombus, on the wall. They are almost always Left Artery Disease thrombi because need a place to
stick. With anterior Miocardial Infarcition, always give aspirin and put pt on warfarin/heparin why do
they do that? To prevent mural thrombus from forming. So, when you have an anterior problem, they
will anticoagulate you. Mural thrombi are mixed clots they are not a pure venous like clot or a
platelet like clot, they are mixed.

: you have a transmural infarction and therefore injury to endothelial cells of the
heart, therefore platelets will stick so platelets are the first things that stick and then because the
muscle is not contracting that well (because infracted muscle does not contract), there is stasis, and
so on top of the platelets is a venous like clot, which Coagulation factor 5, 8 ts mixed
(platelets with fibrin and venous clot from stasis). With aspirin, you not only preventing a coronary
thrombus with decreasing platelet aggregation, but also preventing a mural thrombus from initially
forming b/c it inhibits the platelets from aggregating. Also, by putting on warfarin and heparin, you
prevent the other part of the clot fro it can embolize and
therefore are very dangerous.

3. Fibrinous pericarditis can occur 2 times in a person with

Micardial Infarction:

1) 1st week get a friction rub, chest pain (relieved when leaning forward and worse when
leaning back -
vessel permeability. Not autoimmune.

2) History of transmural infarct, comes in 6 weeks later with fever, muscle aches and pains,
and a 3 component friction rub in the chest = , which is an autoimmune
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pericarditis. When had infarct, damage of the pericardial surface led to autoAntibodies against
pericardial tissue. This took 6 weeks to build up, and they start attacking the pericardium leading to
systemic symptoms related to immunologic reaction Autoimmune. Basically treat with
NSAIDS.

4. Later complications

Most Common complication of Miocardial Infaction is ventricular aneurysm:

Example: pt 3 weeks out of Miocardial Infarction chest bulges what under there? Massive
pectoralis major Ex. systolic bulge of pericardium is ventricular aneurysm. Blood is collecting
in the aneurysm and making the chest bulge out. This is a late manifestation ricular
aneurysm; this aneurysm is lined by scar tissue. Most Common Cause of death in a ventricular
aneurysm = heart failure. Most of heart has scar tissue, which leads to decreased ejection fraction,
therefore, die of HEART FAILURE.

Fibrous tissue (scar) in old Acute Miocardial Infaction is

whiter and more patchy and it can be anywhere from 3 weeks to 10 years. We must look at EF
(ejection fra
low EF, you had a big infarct, with a lot of muscle that was destroyed. Therefore, EF is the biggest
prognostic factor. If ut if your 0.4, very bad.

5. How do we diagnose Miocardial Infarction? CK-MB is Gold Standard diagnoses of choice.

CK-MB is an isoenzyme of creatinine kinase have CK-MM, MB, and BB. CK MB is primarily in
cardiac muscle. Therefore, when you infarct the muscle, you will see a primary increase in cardiac
muscle, and when the muscle is infracted, will see an increase in that enzyme. Starts to go up at 6
hrs. Peaks in 24 hrs, and gone in 3 days because if CK MB is present after 3 days defines
REinfarction. So, the reappearance of CK-MB = REinfarction.

Troponin I elevates a few hrs earlier than CK MB its goes up at about 4 hrs, and peaks in about 24
hrs, too. It lasts 7 days, which is good. However, cannot diagnose reinfarction. So, after day 3

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Troponin will still be there and therefore, you cannot diagnose reinfarction. CK-MB replaces LDH
isoenzymes.

LDH isoenzyme: Normally, LDH2 is higher than LDH1. However, LDH1 is in cardiac muscle.
So, when you have an infarct, you release LDH1, and 1 becomes higher than 2 which is called the
flip. When you infarct through the muscle, 1 will be higher than 2, and that is the flip. This occurs in
about 18 hours and peaks in about 3 days and last for a week. Most of the time, we use LDH
enzymes if the pt came in 2-3 days after symptoms: chest pain and CK-MB will have been gone by
then. Then, look at LDH isoenzymes, and recognize that there is a flip and realize that there was a
Miocardial Infarction few days ago. This will be replaced by Troponin 1 because elevated during
this time period.

VIII. VALVULAR HEART DISEASE

A. Mitral Valve Prolapse Most Common mitral valve

lesion more common in women; too much valve and looks like a parachute (air goes under
a parachute and fills it up same with blood) blood will prolapse into left atrium, and when it
stops, it causes a click. Prolapse means that something is coming out Ex. rectal prolapse.

So, with mitral valve prolapse, it is extending into the left atrium. When it stops, and cannot go
in anymore, it stops and causes a click, and it followed by a short mitral regurgitation murmur.
So, it goes . What is the pathology? Myxomatous degeneration. What
Glycosaminoglycocides makes up the valve? Dermatan sulfate, therefore its an excess
of dermatan sulfate in the mitral valve, and it becomes redundant (too much of it), blood
goes under it and causes a click and murmur.
(Next information is in the next audio file Day 3 Cardio 4 before tricuspid regurgitation, Dr. Golgian talked more about (Mitral valve prolapsed
topic) and I organized the script.)

Mitral valve prolapse is being prolapsed into atrium,

because it is so redundant, and, chordae tendinae will rupture, leading to acute mitral
insufficiency. This is not common in Mitral Valve Prolapse most of the time it is
asymptomatic. Most Common symptom in Mitral Valve Prolapse = palpitations.

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2 genetic disease with Mitral Valve Prolapse association
syndrome. Marfan pt and pt died suddenly, why? NOT dissecting aortic aneurysm (do not die
immediately with dissections get pain, radiation and cardiac tamponade) answer is MVP
and conduction defects. So, pt with marfan and dies suddenly, this is due to MVP and
conduction defects (not dissecting aortic aneurysm).

Audio File Day 3: Cardiovascular 4

Is it closer to S1 or S2? It deals with preload. If we increased vol of blood in the left ventricle,
then the click and murmur will come closer to S2 because it takes longer for all the events to
get blood out. If we decrease the amount of blood coming into the left ventricle (decrease
preload), the click and murmur come closer to S1. So, when standing and have Mitral Valve
Prolapse, what is preload vs. lying down? It is less. Less preload = less blood in the ventricle
click and murmur closer to S2
because increasing preload.

What will happen to click and murmur with anxiety? What will happen to heart rate with
anxiety? Increase. Therefore, will have less time to fill ventricles, therefore will come
closer to S1.

Queston American tourist came back from Saint Petersburt with

giardisis

B. Aortic Stenosis
*Most Common valvular cause of syncope with exercise
*Most Common Cause angina with exercise.
*Most Common Cause microangiopathic hemolytic anemia

This will an ejection murmur, right 2nd ICS, radiation into the neck, systolic, increases in
intensity on expiration. Intensity of murmur with different positions: what will increase the
intensity of the murmur (what will make it worse and therefore louder)? Increasing preload
in the ventricle. With decreased blood in the ventricle, it will decrease the intensity of the
ejection murmur because it has to go out the stenotic valve. If you are putting more blood into
the LV and need to get it out, it will increase the intensity - this is important because it
differentiates it from hypertrophic cardiomyopathy.

Aortic Valve orifice is stenotic due dystrophic calcification.

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 Aortic Stenosis with Left Ventricular Hypertrophy.

Why do they get angina with exercise? Pulse is diminished and therefore the stroke volume
will decrease. So, when do the coronary arteries fill up? Diastole. With less blood there
(because
less blood going to the heart, leading to angina. So, this is the Most Common valvular
lesion leading to angina. Also, with syncope with exercise, because you have decreased
cardiac output, you will faint.

C. Mitral stenosis

When Mitral stenosis is due a Thrombi, left atrium is dilated; murmur in diastole (stenosis
problem in opening and this valve opens in diastole, leading to snap and rumble), heard at
apex and increases in intensity on expiration.

Most Common Cause of mitral stenosis rheumatic fever (acute) due to group A beta
hemolytic streptococcal infection. Usually occurs as post-pharyngitis. As opposed to
post streptococcal glomerulonephritis, this can be pharyngitis or a skin infection. Most
of time rheumatic fever is from a previous tonsillitis. When you culture blood in pts with
rheumatic fever, it will be negative. Will not be able to grow the organisms because not an
infective endocarditis. It is an immunologic mechanism. With streptococco, M protein is the
pathogenic factor for group A streptococco. Certain strains have Antigens similar to the
heart and joints. So, when we make Antibodie against the group A streptococoo, we are also
making Antigen against the heart (our own tissue) therefore we attack our own heart, joints,
basal ganglia and elsewhere. This is called mimicry because we are developing Antibodies
against our own tissue, because there are similar Antigens in the M protein of the bacteria, so
it is all immunologic! Most Common valve involved is the mitral valve. The vegetations are
sterile and line along the closure of the valve. The vegetations usually do not embolize.

Jones criteria for diagnose of acute rheumatic fever:

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*Young person
* With exudative tonsillitis prior to next symptoms.
*Polyarthritis-Most common symptom
*Joint pain and swelling.
*Dyspnea
*Rales in the lung (abnormal sound with normal respiration sound)
*Pansystolic murmur, apex, and increases in intensity on expiration, S3 and S4 heart
sound.

*Erythema marginatum (skin zit) !

*Subcutaneous nodules (like rheumatic nodules on the extensor surfaces they are
exactly the same). Rh nodules and nodules associated with acute rheumatic fever are
exactly the same. They are both immunologic disease.

Late manifestation of Jones criteria is abnormal movements called .

Most Common symptom is polyarthritis. They like this question because in children, there
is a limited diferencial diagnosis for polyarthritis it includes juvenile rheumatic
arthritis, Henoch Schonlein purpura, rubella, acute rheumatic fever. However, none of
these have symptoms of heart failure and mitral insufficiency except for acute
rheumatic fever. So, if they ask you the Most Common valvular lesion in acute rheumatic
fever.

It takes 10 years to have a stenotic valve (mitral stenosis). So, the murmur that you hear is
mitral REGURGITATION, because all parts of the heart are inflamed, leading to friction rub,
myocarditis (inflamed myocardium), and endocarditis (these are the valves with the
vegetations). So, will get mitral regurgitation murmur with acute rheumatic fever.

Example: pt with acute rheumatic fever (grade 3, pansystolic, apex, rales, S3 and S4, nodules,
erythema marginatum) -

ASO titer is important, too because tococco infection and its

elevated.

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 Aschoff nodules reactive histocytes in the myocardium; only find with bx on death.
Summary: immunologic dz, will not culture out group A streptococco in the blood, Jones
criteria (polyarthritis, Most Common carditis, subcutaneous nodules, erythema marginatum,

Ex. mitral stenosis, looking from left atrium, down to

the ventricle looks like a fishmouth (fishmouth appearance).

Example: what is the most posteriorly located chamber of you heart? Left atrium. Seen
best on transesophageal ultrasound. Because it is posteriorly located and enlarged when
dilated, it can press on the esophagus, leading to dsyphagia with solids (not liquids). Also, it
can stretch the left recurrent laryngeal nerve and cause hoarseness. This is called
syndrome.

Example: if they have an irregular irregular pulse, what does that mean? Atrial fibrillation.
There is a lot of stasis (reduction of motility) because blood is having trouble getting through,
leading to stasis and thromboses. So, have to anticoagulate the pts, which is a bad combo.

Atrial fibrilation + thrombus = bad combo. When you picture atrial fibrilation, like a vibrator
and little chips can come off and embolize this is very common in patients with MITRAL
STENOSIS.

D. Tricuspid regurgitation know about Intravenous Drug Abuse with infective endocarditis.
Turned to Carcinoid syndrome in order to have carcinoid syndrome, must have metasis to
liver of carcinoid tumor. Serotonin and the tumor nodules gets into hepatic vein tributaries
and gets into the venous blood and bathes the right side of the heart, and serotonin produces
a fibrous tissue response of the valves. So, will get tricuspid insufficiency and pulmonic
stenosis (TIPS). These are the 2 valvular lesions associated with carcinoid syndrome.

IX. INFECTIVE ENDOCARDITIS

in Mitral Valve due Staphylococco Aureus.

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Mitral valve with vegetations and rupture chordae tendinae; vegetations are big and bulky and
destroying the valve (hence, infective).

What is Most Common Cause? Streptococco viridians; 2nd Most Common Cause =
Staphylococco Aureus.

While brushing teeth, have a transient streptococco viridians infection. If you have an
underlying cardiac disease, then you run the risk of developing a bacterial endocarditis
because just brushing your teeth can cause it to get into the bloodstream; with damaged
valves, it can seed into it and produce vegetations.

Staphylococco aureus can affect a NORMAL valve OR a damaged valve.

*Most Common valve involved in infective endocarditis = mitral valve

2nd Most Common valve = aortic valve

*If you are an Intravenous Drug Abuser (who inject into veins), Most Common valve
involved = Tricuspid valve; involved = Murmur of tricuspid regurgitation, pansystolic,
increased on inspiration.

2nd Most Common is aortic valve; involved: aortic regurgitation, high pitched diastolic after S2.

*Staphylococcos is #1 (Most Common Cause) for Intravenous Drug Abuser.

If you have colon cancer/ulcerative colitis (any type of ulceration of the colonic mucosa),
there is a unique type of infective endocarditis this is streptococco bovis = group D
streptrococco commonly involved with disease that produce ulceration of the colonic
mucosa.

If you have a patient with Ulcerative Colitis or colon cancer and in the history have
infective endocarditis organism is streptococco bovis.

Aortic valve close relationship of membranous portion of the septum with the aortic valve.
So, why did pt get vegetations of the aortic valve? Because they got Ventricular Septal Defect
that was not picked up. If you have congenital heart disease, you have an increased risk for
infective endocarditis. Ventricular Septal Defect that someone did not pick up caused aortic
valve to get infective and cause aortic regurgitation.

Aortic Valve infective endocarditis with Ventricular Septal Defect

*In the board will be mitral valve infective endocarditis, or aortic valve infective
endocarditis with a Ventricular Septal Defect.
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Splinter hemorrhages: Signs in Infective Endocarditis:

1. Painful = nodes

2. Painless = janeway lesion

;

3. Roth spot in the eye (red with white center just like
Koplik spots in measles, which are red with a white center). This is why it is called the Koplik
spot of the eye.

What do they all have in common? (aside from the fact that they are seen in infective
endocarditis)

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 glomerulonephritis? All are Immuno complex type III Hypersensitivity. All these lesions are
immune complex vasculitis.

Vegetations all over surface of the valve and is the second Most
Common cause of non-bacterial endocarditis DIAGNOSIS? Libman sacs endocarditis.
Immunologic Damage and fibrinoid necrosis (like in Acute Reumathic Fever)

Libman sacs commonly seen in Systemic Lupus Erythematous.

X. MYOCARDITIS vs. PERICARDITIS

On the test, if you have an infection question, it is Coxsackie virus.

*Most Common Cause of myocarditis and pericarditis = Coxsackie virus
*Most Common Cause of viral meningitis = Coxsackie virus.
*Cause of hand, foot and mouth disease? Coxsackie virus
*Herpangina (ulcer in skin-blister)

Example: Pt with heart failure did an endomyocardial biopsy and it had lymphocytic infiltrate in
there, and it was due to . To diagnose, need to do a biopsy of
subendocardial tissue, and will see lymphocytic infiltrate (as expected with ANY virus).
Therefore, if pt in heart failure, with a biopsy of myocardium has lymphocytes =
arditis.
(Following this Audio File the other part is in XI Cardiomyopathies)

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Chest x-ray Myocarditis and Pericarditis due Coxsackie see
water bottle configuration this pt as muffled heart sounds (cannot hear anything), when the
pt breaths in, neck veins distend when you breath in and
increase negative intrathoracic pressure, the neck veins should collapse on inspiration), radial
pulse is decreased on inspiration, when you take Blood Pressure there is a drop of 10mmHg
during inspiration. Diagnosis? Pericardial effusion

What the name of the triad? What is the name of the sign? .
What is the drop of 10 mm Hb on inspiration? Pulsus paradoxus. How does all this occur?
Because there is an effusion of the pericardial sac, meaning that that heart cannot fill up
(because there is fluid around it) leading to muffled heart sounds. So, when you breath in
and blood is supposed to get into the right side of your heart, it cannot expand. So, the neck
veins

What ever happens to right side of the heart affects the left side of the heart because the left
side receive blood from the right side. So, there is no blood going into the right heart, and
therefore, no blood is going out of the left heart, either. So, on inspiration, blood cannot get out
of left side (because blood is not coming out of the right heart), leading to a drop in pulse
hence pulsus paradoxus. Always see these things together: neck vein distension, drop
in pulse magnitude, and drop in Blood Pressure
pericardial effusion. However, this is not what they will ask you they will ask what first
step in work management is? Echocardiogram shows that they have fluid (proves it
because need to call surgeon to do pericardiocentesis).

What is it Most Common due to? Pericarditis. What is the Most Common Cause of
pericarditis? Coxsackie.

* (SLE). Any young woman that

has an unexplained pericardial or pleural effusion is lupus until proven otherwise.
Why? Serositis = inflame serosal membranes its gonna leak fluid, leading to effusions.
And is a feature of Lupus.

E. CONSTRICTIVE PERICARDITIS

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 ! In third world countries, Tuberculosis is Most Common.
In USA, due to previous cardiac surgery because have to go through pericardium. Slide of a
heart and thickened pericardium, no fluid, so when you breathe in blood goes to right heart,
fills up and hits wall called pericardial knock therefore to differentiate pericardial
effusion from constrictive pericarditis, have muffled heart sounds in effusion with no
knock in pericardial effusion, and in have some filling up with a pericardial knock in
constrictive pericarditis. White stuff in pericardium is dystrophic calcification, and can see it
on x-ray. Pt goes to Russia and gets diarrhea = giardiasis)

XI. CARDIOMYOPATHIES (these topic is in Audio File Day 3 Cardio 4 after paragraph 2 in X. Myocarditis vs. Pericarditis topic)
Large left ventricle and right ventricle

A. Congestive cardiomyopathy (Dilated cardiomyopathy)

Example: woman 6 weeks postpartum, and do a chest

x-ray and she has a generalized cardiomegaly heart is huge, has effusions at both lung
bases diagnosis? Congestive cardiomyopathy; this is a disease of the cardiac muscle and
has many causes. Pt has both left and right heart failure. Causes: Why? 6 weeks postpartum
but s; Most Common Causte of
transplants is due to congestive cardiomyopathy. Cardiotoxic drugs daunorubicin,
tricyclics = drug induced cardiomyopathies = congestive cardiomyopathy. Alcoholic with big
heart due to thiamine deficiency = congestive cardiomyopathy.

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 B. Hypertrophic cardiomyopathy

Most Common Cause sudden death in a young athlete = hypertrophic cardiomyopathy.

Hypertrophy of Left and Right ventricles: Note the

thickness of septum very thick with an asymmetric
Hypertrophy; why? Because the interventricular septum
is thicker. Blood flow of left ventricle goes through
narrow opening (anterior leaflet of mitral valve so, if
you have aortic regurgitation, blood will hit anterior leaflet
of mitral valve and produce Austin flint murmur).

Why is this a narrow opening? Because it is too thick. If

we took a laser to burn it off, could open it up; so, where is the obstruction in hypertrophic
cardiomyopathy? Its not at the level of the aortic valve, but below it. Why does it obstruct?
Venturi phenomenon things go through a narrow opening quickly and there is a
negative pressure behind it. When blood, under increased force of contraction is forced
through, the negative pressure behind it sucks the anterior leaflet behind the septum
and stops the blood, leading to obstruction of blood flow.

What can we do to make this better (what can we do to reduce the intensity of the murmur and
have the pt have better Cardiac Output)? Put more blood into the ventricle increase preload
and decrease obstruction because it would pull it away because there is more blood in it. All
these things that increase preload will make the intensity of the murmur less and improve the
pt. So, if you are standing up, will that improve the disease? No, because would decrease
preload, leading to a harsh systolic murmur. However, if lying down, there is increased venous
return to the right heart, and increased blood in the ventricle, this would decrease intensity of
murmur.

Digitalis would be contraindicated because it would increase force of contraction, make it go

faster and make it obstruct quicker. A beta blocker would be good; Ca channel blocker
would also be good b/c it would decrease force of contraction, slow the heart rate, and
increase preload.

If you took a section of the septum, in the slide it s not a normal septum its disorganized,
and the conduction bundles are messed up, leading to conduction defects - with conduction
defects, run the risk of Ventricular tachicardia and death at any time. This abnormal
conduction system and asymmetric septum is responsible.

Ex. 16 years basketball player that died suddenly what do you see at autopsy? Hypertrophic
cardiomyopathy. What is the Mechanism? Abnormal conduction.

C. Endocardial Fibroelastosis (Restricted cardiomyopathy) !!

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 If it is restrictive, something is preventing the ventricle from filling up. This is the Most
Common disease causing restrictive cardiomyopathy in children also called
endocardial Fibroelastosis. Is the Most Common reason why a child needs a heart
transplant. If the child does not get a transplant, they will die. Other causes of restrictive
cardiomyopathy Disease, Fe overload and amyloid.

D. Cardiac myxoma
85% in the left atrium, 15% in right
It a benign tumor B9, movable can move over and block orifice of mitral valve, leading to
syncope. They can embolize (they are very soft and have bits and pieces inside them). Have
a lot of junk inside them, which leaks out. It can lead to fever, and other signs and symptoms.
Syncope cannot figure it out; then get a transesophageal ultrasound and see it. So, this is the
Most Common primary bening b9 tumor of the heart in adults.

They describe tumor in heart of kid this is rhabdomyoma (bening b9 tumor of cardiac
muscle) they are associated with autosomal dominant disease, which one? Tuberous
sclerosis.

So, if they talk a tumor in a heart of Kid

tuberous sclerosis.

(Following the Audio File the other part continue in X. Myocarditis vs. Pericarditis, 2nd. paragraph)

Audio File Day 3: 8 Respiratory 1

CHAPTER 8: RESPIRATORY
I. Alveolar-arterial gradient know how to calculate:

Alveolar O2 and arterial pO2 are never the same. The difference between the two is called Alveolar-
arterial gradient. Reasons for it:

*Ventilation and perfusion are not evenly matched in the lungs. When standing up the ventilation is
better than perfusion in the apex, whereas perfusion is better than ventilation at lower lobes. This
explains why almost all pulmonary infarctions are in the lower lobes perfusion is greater there.
Also, this explains why reactivation Tuberculosis (TB) is in the apex TB is a strict aerobe and needs
as more O2, and there is more ventilation in the upper lobes (higher O2 content).

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Normally, alveolar O2 is 100 and the arterial pO2 is 95. So, normally, the gradient is 5 mmHg. As you
get older, the gradient expands, but not that much. Most people use their upper limit of normal in
other words, have a very very high specificity of 30 mmHg. If you have prolongued an A-a gradient
of 30 mmHg or higher there is a problem. It is very high specificity (Positive Predicted Value (PPV)
truly have something wrong).

The concept is easy you would expect the gradient between the alveolar O2 and the arterial O2 to
be greater if you have primary lung disease. What will do this? Ventilation defects (produces
hypoxemia, and therefore prolongs the A-a gradient decrease the PO2 and subtracting, and
therefore a greater difference between the two), perfusion defect increase A-a gradient (Ex.
pulmonary embolus), and diffusion defect increase A-a gradient. But the depression of the
medullary respiratory center by barbiturates does not cause a difference in A-a gradient.

So, prolonged A-a gradient tells you the hypoxemia is due to a problem in the lungs
(ventilation, perfusion and diffusion defect). A normal A-a gradient tells you that something
outside the lungs that is causing hypoxemia (respiratory acidosis in respiratory acidosis,
PO2 will go down).

Causes of respiratory acidosis: pulmonary problems: Congestive Obstructive Pulmonary

Disease (COPD), depression of respiratory center (obstruction upper airway from epiglottitis,
larygiotracheobronchitis, café coronary (paralyzed muscles of respiration), Guillain Barre
syndrome, amyotrophic lateral sclerosis, and paralysis of diaphragm. These all produce
respiratory acidosis and hypoxemia, but the A-a gradient will be NORMAL. So, prolonged A-a
gradient, something is wrong with the lungs. If A-a gradient is normal, there is something OUTSIDE
of the lungs that is causing a respiratory problem. Few things must always be calculated: anion gap
(with electrolytes) and A-a gradient for blood gases all you need to do is calculated alveolar O2.

Calculation the A-a gradient:

(0.21 is the atmospheric O2; and 760 minus the water vapor=713, and 40 is normal pCO2). The
calculation is like this:

0.21 x 713 = 150

40 ÷ 0.8 = 50 (respiratory quotient) 150 - 50 = 100 (given in the blood gas)

So, now that I have calculated the alveolar O2, just subtract the measured arterial pO2 and you have
the A-a gradient. This is very simple and gives a lot of information when working up hypoxemia.

II. Upper Respiratory Disease:

A. Nasal Polyps:
3 differents types of nasal polyps:
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 Most common is an allergic polyp. Allergic polyps develop in adults after a long term
allergies such as allergic rhinitis.

5 years child with nasal polyp and respiratory defects, what is the first step in management?
Sweat test because if you have a polyp in the nose of the kid = cystic fibrosis. NOT Allergic
Polyp.

B. Triad Asthma take an aspirin or Non Steroid Anti-Inflammatory Drug (NSAID), have
nasal polyps and of
has a polyp. The aspirin or NSAID is the answer but this is how they will ask the question:

35 years woman with chronic headaches or fibromyalgia. Pt has some type of chronic pain
syndrome and will not tell you that the pt is on medication and she develops occasional bouts of
asthma what is the mech She is taking an NSAID.

however, if a pt is in
pain or has chronic pain, it is safe to assume the pt is on pain medication (Ex. an NSAID, Motrin
or aspirin).

Mechanism of asthma from pain medication: what do aspirin/NSAIDs block? COX, therefore
arachidonic acid cannot forms Prostaglandins but the Lipoxygenase pathway is left open. Some
people are very sensitive to this and LT C4, D4, and E4 are formed, which are potent
bronchoconstrictors, leading to asthma. It is a chemical mediated non type I HPY reactionn. So,
chronic pain can lead to asthma because of aspirin sensitivity.

In BOARDS they like to assume any well built male is on anabolic steroids (Ex. football player,
wrestler) with intraperitoneal hemorrhage. Anabolic steroids produce benign liver cell
adenomas which have the tendency of rupturing = intraperitoneal hemorrhage.

C. Laryngeal carcinoma (a squamous cell carcinoma)

Concept of synergism:

*Most Common Cause = Smoking

2nd Most Common Cause = alcohol.

Alcohol and smoking have a SYNERGISTIC effect which leads to laryngeal carcinoma.
(this is true for any squamous cancer from the esophagus to the mouth to the larynx).

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Most Common Cause of cancer in mouth, upper esophagus and larynx = Smoking. Alcohol
can do the same thing, so if you are smoker and alcohol consumer, you can double your risk.
Most Commmon symptom associated = hoarseness of the throat.

What can infect epiglottis? Haemofilous influenza what is the

symptom? Inspiratory strider.

3 month old child died with inspiratory strider, what is the diagnostic?
Croup due parainfluenza; this is a TRACHEAL inflammation. Whereas epiglottitis is
elsewhere. Both produce upper airway obstruction.

III. Respiratory Distress Syndromes (RDS):

A. Hyaline membrane disease (Neonatal Respiratory distress syndrome)

If something has a lot of pink in it, what is it? Hyaline

Key to understanding this disease is massive atelectasis

1. What is atelectasis? Collapse of airways. Why did these airway collapse? No

surfactant (lecithin/phosphotidyl choline/phosphotidyl glycerol they are all
surfactant). So, deficient of surfactant causes atelectasis because:

Collapsing pressure in the airways = surface tension/radius of airway. Normally,

on expiration the airway will be smaller because there is a positive intrathoracic
pressure. Decrease the radius = increase the collapsing pressure in the airways.
Therefore, on normal expiration (in all of us), we have to decrease surface tension
(which is what surfactant does) by doing this, it keeps the airways open on
expiration, preventing atelectasis.

2. Three causes of Respiratory Distress Syndrome:

*Prematurity: surfactant begins synthesis early, but it peaks at 32-35 week, so if you
are born prematurely, you will not have enough surfactant, and baby will develop
increased risk of developing RDS. Sometimes mother has no choice and must deliver
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 baby, or else it will die, and there is something you can do to the mom so the baby has
more surfactant: give mother glucocorticoids because they stimulate surfactant
synthesis.

W
choices) thyroxine (thyroid hormone) and prolactine; Give cortisol or glucocorticoids.

*Diabetes: gestational diabetes pregnant,

and then obtains glucose intolerance after delivery so if a diabetic gets pregnant, this
is not called gestational diabetes, but a diabetic that got pregnant. It s important that a
woman in pregnancy has good glucose control because if she is hyperglycemic, baby
will be, too. Because baby is hyperglycemic, it will stimulate insulin synthesis, and
insulin has a negative effect on surfactant synthesis and will decrease its synthesis.

*C section because the baby is not delivered vaginally, there is no stress. Because
the baby has not been stressed, the ACTH and cortisol are not released, and
surfactant is not made. Whereas a child that is delivered vaginally has a lot of stress
and therefore a lot of ACTH and cortisol is being released, which stimulates surfactant
release. So, C section predisposes to Respiratory Distress Syndrome.

So, these are the three main causes (prematurity, diabetes, and C section).

3. Complications and associated conditions:

a. Why are the babies of poor glycemic control big (macrosomial)?

insulin is increased to keep the glucose down. Insulin will increase storage of
triglyceride in adipose (it increases fat storage). Where is most of the adipose
located? Centrally. So, one of the reasons why they have macrosomia is
because insulin stimulates synthesis of Triglyceride and deposition of fat.
Also, insulin increases uptake of amino acids in muscle (like growth
hormone). So, it will increase muscle mass. So, the reason for macrosomia is
increased adipose and muscle mass, both due to insulin. This also explains

coming into the baby, causing the baby to release insulin; the moment insulin is
made and the cord is cut, and no more increase in glucose, glucose goes down,
and leads to hypoglycemia.

b. Superoxide free radical damage seen in retinopathy of prematurity and

blindness and bronchopulmonary dysplasia.

c. Why do babies with Respiratory Distress Syndrome commonly have

Patent Ductus Arterious? Because they have hypoxemia. When a normal
baby takes a breath, it starts the process of functional closure of the ductus.
However, with hypoxemia after they are born, it remains open, and they have a
machinery murmur.

d. Hyaline membranes are due to Degeneration of type II pneumocytes and

leakage of fibrinogen, and it congeals to form the membrane. So, they will give a

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 classic history for Respiratory Dystress Syndrome, and then will ask for the
pathogenesis of hypoxemia in the baby.

This is a massive ventilation defect because everything is collapsing. This is a

SHUNT problem, which leads to a massive interpulmonary shunt.
Treatment=PEEP (positive end expiratory pressure) because these airways are
collapsed and you need to get O2 into them and surfactant. So, give O2 and at
the end of expiration, pump in pressure, which keeps airways open on expiration,
so you can keep O2 in them.

Example: Type II pneumocyte (with lamellar

bodies look like onion). These lamellar bodies contain surfactant. This
would identify it as a type II pneumocyte. They commonly give Electron
Microscope
the cytoplasm. The type II pneumocyte is the repair cell of the lung and
synthesizes surfactant.

B. Adult Respiratory Distress Syndrome (ARDS)

In terms of ARDS, essentially it is the same as RDS in pathophys, but is NEUTROPHIL
related injury. ARDS because you have too much inflammation.

Most Common Cause of Adult Respiratory Distress Syndrome (ARDS) = septic shock .

Most Common Cause septic shock = E coli from sepsis from an indwelling catheter;

Most Common Cause Disseminated Intravascular Coagulation (DIC) = septic shock.

Example: In the Intensive Care Unit (ICU) if a pt come in with dyspnea and it s within 24 hrs
of having septic shock, pt has ARDS. If pt is in septic shock and within 48 hrs of admission
and is bleeding from every orifice, he has Disseminated Intravascular Coagulation. So, first
day = septic shock, second day = ARDS, third day = DIC.

Pathogenesis: Neutrophils get into the lung in septic shock and start destroying all the
cells of the lung (type I and II pneumocytes). So surfactant production decreases and
result is massive atelectasis (collapse). However, this is neutrophil related (the
neutrophils are destroying the type II pneumocyte. The reason why they get hyaline
membranes in the ARDS is because the neutrophils have to get in the lungs by going
through the pulmonary capillaries, so they put holes in them as they get out of the
bloodstream and into the lungs (this is why it is called leaky capillary syndrome). All the
protein and fibrinogen get in and produce hyaline membranes. Therefore, you can
actually see hyaline membranes are in ARDS. So, there is massive collapse and the

223
 pathophys is intrapulmonary shunting. This is the same in RDS, but ARDS is neutrophil
related, which is a bad prognosis.

IV. Pneumothorax

A. Spontaneous pneumothorax:

Most Common Cause spontaneous = ruptured subpleural bleb have pleura and right
underneath is a bleb (air pocket). The bleb (air pocket) ruptures causing a hole in the pleura,
so that part of the lung collapses. Because ative
intrathoracic pressure, which keeps the lungs expanded. So, if you put a hole in the pleura,
then the atmospheric pressure is not negative, but is the same as the air you are breathing.
So, there is nothing to hold it open and therefore it collapses.

When parts of the lung collapse, there are things that will take up the slack (negligence). The
diaphragm will go up on that side to take up the open space on that has been left. If there is a
collapse on one side, the trachea will go to the side that there is space. So, will have tracheal
deviation to the side of the collapse, and the diaphragm is up, leading to spontaneous
pneumothorax. Usually seen in tall male they have blebs that rupture and lead to
spontaneous pneumothorax. Can also get in scuba divers because they come up too quickly,
which leads to rupture of the blebs.

B. Tension pneumothorax

Most Common Cause is due to knife injuries into the lung

space when you breathe in the flap goes up and on expiration it closes. So, the air stays in the
pleural cavity. So, every time you breathe, the flap goes up, air stays in, and on expiration it
closes. So, for every breath you take, it keeps increasing and the pressure in the lung. The
The increase in pressure starts pushing the lung and the
mediastinum to the opposite side. When it pushes it, it compresses the lung and it leads to
compression atelectasis (
expiration, and that pos pleural pressure is pushing everything over to the opposite
side). This compression will push on the Inferior Vena Cava, Superior Vena Cava, right
ventricle, and left atrium on the opposite side. This will compromise blood return and
breathing, leading to a medic
out. Air is filling pleural cavity and cannot get out. It keeps building up and starts
pushing everything to the opposite side. With a positive intrathoracic pressure, the
diaphragm will go down (goes up in spontaneous pneumothorax).

V. Pulmonary Infection

A. Pneumonia

1. 2 kinds of pneumonia:

Typical wake in the morning feeling normal, and then suddenly develop a fever,
productive cough.

Atypical slow, insidious onset (feel bad over few days)

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 2. Types of Pneumonia: Community vs. Nosocomial (hospital acquired):

If you get pneumonia in the community and typical (Streptococco pneumonia).

G Treatment = Penicillin G. The Most

Common pneumonia adquired (community and typical)

If you get pneumonia in the community and atypical (Mycoplasma pneumonia).

Most Common Cause atypical pneumonia = mycoplasma pneumoniae; 2 nd Most
Common Cause = Chlamydia pneumoniae; which are all interstitial pneumonias.

Organisms in the hospital (nosocomial) = E coli, Pseudomonas, Staphylococcos

aureus.

3. Productive cough in typical pneumonia.

Reason for productive cough in typical pneumonia: have exudate (pus) and signs of
consolidation in the lung.

Slide: Bronchopneumonia: Most Common Cause = streptococco pneumonia, in

community acquired. Yellow areas with microabcesses which are consolidation in the
lung.

225
 (The same lung in the slides)
Ex. Lobar pneumonia = Pus in the alveoli, pale consolidation in the entire upper lung.

Therefore, with typical = you see consolidation and pus in the lung. Physical diagnostic
tools of lung consolidation: decreased percussion, increased Talk Feel Vibratiion (when
the person talks, feel vibrations in chest if have consolidation in Ex. the Right upper lobe, will
have increased TVF because it is a consolidation, compared to the other side so, increased
TVF = consolidation), (egophony sign) = (pt says E and you hear A), whispered
(pectoriloquy sing) = (pt whisper
stethoscope). Therefore, decreased percussion, increased TVF, egophony, and
pectoriloquy = consolidation.

In BOARDS: What if there is a pleural effusion overlying the lung? Only thing you would have
is decreased percussion (this separates pleural effusion from pneumonia).

4. Atypical pneumonias

They have inflammation of the interstitium Atypical pneumonia has an insidious onset,
relatively nonproductive cough, no hight temperature, no signs of consolidation.

a) Viral pneumonias

1) Rhinovirus = Most Common Cause of cold; they are acid labile meaning
stroenteritis in the stomach because is destroyed by the
acid in the stomach. Never will have a vaccine because 100 serotype.

2) Respiratory Syncytial Virus (RSV) Most Common Cause bronchiolitis

whenever you inflame small airways, its leads to wheezing. This is a small
airway disease and bronchiolitis is most common due to RSV and
pneumonia in children.

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 3) Influenza drift and shift have hemagglutinins, which help attach the virus
to the mucosa. Have neuraminidase bore a hole through the mucosa.
Antigenic drift = minor change/mutation in either hemagglutinins or
neuraminidase; do not need a new vaccine; antigenic shift= major
change/mutation in either hemagglutinins or neuraminidase need a vaccine.
The vaccine is against A Antigen.

b) Bacterial pneumonias

1) Chlamydia psittacosis from birds (Ex. parrots, turkeys).

*2) Chlamydia trachomatis In BOARDS!!!

A little kid was born and a week later he was wheezing (big time), pneumonia, increased AP
diameter, tympanic percussion sounds, no fever, eyes are crusty (both sides), staccato cough
(short coughs). Is due Chlamidia Trachomatis. fected cervix.

(Most Common Cause conjunctivitis in 2nd week in a newborn = Chlamydia trachomatis).

(Most Common overall of conjunctivitis is inflammation of erythromycin drops).

c) Hospital-acquired gram-negative pneumonias

1) Pseudomonas water loving bacteria, therefore see in pt in Intensive Care

Unit (ICU) when on a RESPIRATOR. pt water unit with green productive cough
with.

2) Klebsiella famous in the alcoholic; however, alcoholic can also get

streptococcos pneumonia. So, how will you know strep vs. Klebsiella? Alcoholic
with high spiking fevers, productive cough of MUCOID appearing sputum the
capsule of Klebsiella is very thick. Lives in the upper lobes and can cavitate,
therefore can confuse with Tuberculosis.

3) Legionella atypical cough, nonproductive cough, very sick can kill you, from
water coolers (water loving bacteria), seen in mists (particles) in groceries or at
restaurants.

Classic atypical pneumonia, then pt had hyponatremia, what is the cause? Legionella.

Legionell other organs such as liver disease, interstial

nephritis and knocks off the juxtaglomerlur cells, and kills the renin levels, low aldosterone and
therefore lose salt in the urine, leads to hyponatremia (low renin levels with low aldosterone).
Treatment = erythromycin

B. Fungal Infections
The two systemic funguses are Candida and Histoplasmosis.

1. Candida seen in indwelling catheters (usually in subclavian). And get Candida

sepsis.

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 2. Histoplasmosis = Midwest (Ohio/Tennessee
valley) carried by (feces) dung of starlings (bird consider a pest) and bats often seen
in cave explorers, or spelunkers. They develop non-productive cough.
Histoplasmosis is the only systemic fungus that has yeasts phagocytosed by
alveolar macrophages.

3. Cryptococcus = Pigeons looks like Mickey Mouse yeast forms are narrow based
buds.

Example: NY executive in a building with pigeons roosting in air conditioner and

developed non productive cough.

Example: painter developed respiratory infection worked on Brooklyn Bridge with

pigeons, how do you treat? Amphotericin B. Actinomycin.

4. Blastomycosis = Southern USA = skin and lung infections; broad based bud.

5. *Coccidioidomycosis: South West USA (New

Mexico, Arizona, southern Cal. = coccidiomycose has spherule endospores.

Example: in LA earthquake, a number of people had nonproductive cough the arthrospore are
inhaled (the infectious form) in dust. With the earthquake, dust comes up, breathe it in.

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 Example: man that is an Indian artifact explorer in the sonaran desert, which is in Arizona, and is a
CAVE explorer that developed nonproductive cough this is COCCIOMYCOSIS (not Histo because
not the Midwest).
Audio File Day 4: 1Respiratory 2

6. Aspergillus 3 different manifestations/diseases:

1) Loves to inhabit abandoned Tuberculosis fungus cavities fungus ball

(aspergilloma, a very common cause of massive hemoptysis, potential
complication). This is a left upper lobe cavitary lesion and aspergillus love to live
in there = fungus ball.

2) Vessel invader; therefore will invade the vessels in lung, leading to

thrombosis and infarction in vessels.
3) Allergies the mold, leading to extrinsic asthma and type I Hypersensitivity.

So, three manifestations: fungus ball, invasive vascular disease producing

hemorrhagic infarctions of the lung, and asthma.

Example: Corona component of Aspergillus

(looks like a crown) Aspergillus has narrow angles

Septate is very characteristic (mucormycosis

is nonseptate and has wide angles.

7. PCP (Pneumocystitis carinii pneumonia)

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Fungus (used to be a protozoa) because more things in the cell wall that look like a
fungus.
*I Most Common AIDs
defining lesion of infection, (as soon as the
helper T cell count is 200, it usually shows up).
Used to be Most Common Cause death in AIDs
pt, but now has gone down, because as soon as
your CD4 ct is 200, will put pt on prophylactic
therapy with TMP-SMX.

When taking TMP-SMX and protecting against PCP, would other organism is the pt
protected from? Toxoplasmosis. (So, you get 2 for 1). Most Common Cause space
occupying lesion within the brain in a pt with AIDs= Toxoplasmosis.

Seen with silver stain: cysts of PCP can be seen

look like ping pong balls, seen in alveoli, leading to alveolar infiltrate, leading to
dyspnea, tachypnea, foamy bubbly infiltrate, on chest x-ray, looks all white out because
of the involvement of the lung however, not only seen in lungs, can be seen in any
part of the body

Other organisms that are only seen with silver stain: bartenella henselae (bacillary
angiomatosis), Legionella (not visualized with gram stain, therefore use silver stain)

8. Tuberculosis (TB)
Organism in Right Upper Lobe of lungs see cavitary lesion, which is reactivation TB
(not primary). Primary TB is the lower part of the upper lobe or the upper part of the
lower lobe and close to the pleura (kind of in the middle of the lobe). Primary TB
has a Ghon focus and a Ghon complex. Most people recover; when pt is
immunocompromised, it leads to reactivation and goes into the apex and produces a
cavitary lesion. There is no Ghon focus or complex in reactivation TB, only
primary TB.
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 Other things that cavitate in upper lobes:
*Which systemic fungus is kind a like uberculosis Histoplasmosis

*Which cancers can cavitate in the lung? Squamous Cell carcinoma of the lung

*Which bacteria (that has a big mucous wall around it) can also produce cavitations in the
upper lobe? Klebsiella pneumoniae.

*What is acid fast stain staining? Mycolic acids.

So, just because something is cavitating the upper lobe, it is not necessarily
Tuberculosis.

C. Foreign Bodies

*If you are standing or sitting up, foreign bodies will go to posterobasal segment of the
right lower lobe. This is the most posterior segment of the right lower lobe.

*Lying down (Most Common way to aspirate things), foreign body will go to superior
segment of the right lower lobe.

*Lying on the right side, can go to 2 places 1) middle lobe 2) posterior segment of right
upper lobe (this is the ONLY one that is in the upper lobe.

*Lying down on your left, and aspirate, it will go to the lingula.

Summary:
Sitting/standing = posterobasal segment of right lower lobe
Back: superior segment of right lower lobe
Right: middle or superior segment of right lower lobe
Left: lingula

D. Abscess - Most Common Cause of abscess = aspiration of oropharyngeal material.

Seen commonly in street people that do not have good dentition, may be drunk and fall and
oropharyngeal material will be aspirated. Aspirate consists of aerobes and anaerobes, leading
to putrid/stanchy smell. The aspirate is a mixture of all these organisms: Mixed aerobes and
anaerobes, fusobacterium, bacteroides. Can get absecces in the lung from pneumonia:
staphylococcos aureus, Klebsiella (however, Most Common Cause is aspiration), see fluid
cavities in lung on x-ray.

VI. Pulmonary Vascular Disease:

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A. Pulmonary Embolus:
2 types of emboli:

1. Tiny ones that produce wedge shaped hemorrhagic infaction of the lung.

Hemorrhagic emboli or can chip off large ones.

Most Common SITE for thrombosis is the deep veins of the lower leg. The most
common site for embolization; it is the femoral vein. Makes sense because venous
clots propagate toward the heart (deep veins to the femoral vein, and the femoral vein is
a larger vessel, therefore it is more likely to chip off). So, the femoral vein is the Most
Common site for embolization to the lung.

The deep veins are the Most Common site where deep venous thrombosis begins.
(When it get to the femoral vein, it is dangerous for embolization). So, small ones
produces hemorrhagic infarct that is only if you have an underlying lung disease. If I
have a small embolus, prob
However, if you have preexisting lung disease you will infarct. 85% of the time embolus
will not produce infarct. However, in the 15%, most of the pts with infarcts have
preexisting lung disease (like they are smokers). The other type of embolus is a saddle

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 embolus (it is huge) and blocks off the orifices of
the pulmonary vessels and pulmonary arteries. If you knock off at least 3 out of the 5
orifices, you are dead in a millisecond, so there is no infarction because
time to infarct. It produces acute right heart strain and immediate death.

Initial Screening test of choice to Pulmonary Embolus: Ventilation perfusion

scan- will have ventilation, no perfusion; confirmatory test is pulmonary
angiogram.

VII. Restrictive Pulmonary Disease

Before start the discution of the topic learn this term: (this is not in the audio)

TIDAL VOLUME (TV): Volume inspired or expired with each normal breath.

INSPIRATORY RESERVE VOLUME (IRV): Maximum volume that can be inspired over the
inspiration of a tidal volume/normal breath. Used during exercise/exertion.

EXPIRATORY RESERVE VOLUME (ERV): Maximal volume that can be expired after the
expiration of a tidal volume/normal breath.

RESIDUAL VOLUME (RV): Volume that remains in the lungs after a maximal expiration.
CANNOT be measured by spirometry.
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 INSPIRATORY CAPACITY (IC): Volume of maximal inspiration:

IRV + TV

FUNCTIONAL RESIDUAL CAPACITY (FRC): Volume of gas remaining in lung after normal
expiration cannot be measured by spirometry because it includes residual volume:

ERV + RV

VITAL CAPACITY (VC): Volume of maximal inspiration and expiration:

IRV + TV + ERV = IC + ERV

TOTAL LUNG CAPACITY (TLC): The volume of the lung after maximal inspiration. The sum
of all four lung volumes cannot be measured by spirometry because it includes residual
volume:

IRV+ TV + ERV + RV = IC + FRC

DEAD SPACE: Volume of the respiratory apparatus that does not participate in gas exchange,
approximately 300 ml in normal lungs.

ANATOMIC DEAD SPACE: Volume of the conducting airways, approximately 150 ml

PHYSIOLOGIC DEAD SPACE: The volume of the lung that does not participate in gas
exchange. In normal lungs, is equal to the anatomic dead space (150 ml). May be greater in
lung disease.

FORCED EXPIRATORY VOLUME in 1 SECOND (FEV1):

(Continuation of the audio)

Restrictive something is restricting it from filling. Example: restricted filling of the heart = restrictive
cardiomyopathy. Or restriction in filling up of the lungs with air.

Have 2 terms:

*Compliance (filling term, inspiration term)

*Elasticity (recoil, expiration term);

For restrictive lung disease, picture a hot rubber bottle for restrictive lung disease. The hot rubber
compliance is decreased and it is hard to fill the lung up with
osis (interstial fibrosis, Most commonly). If you get
the hot water rubber bottle filled with air and let the air out, what happens to the elasticity? Increases.
So, compliance is decreased and cannot fill it up, but once you do fill the lung up, it comes out quickly
(elasticity increases).

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Example: pt with sarcoid difficult to fill lungs, but get it out fast (due to fibrosis). So, all TLC, RV,
TV(all lung capacities have all equally decreased). FEV1/Force Vital Capacity on spirometer take a
deep breath (Ex. pt with sarcoid) FEV1 (amount you get out in one second normally it is 4 liters) is
decreased, FVC (total that got out after deep inspiration) is decreased (because increased elasticity)
this is the same as FEV1, so the ratio is often 1. Normally, the FVC is 5 liters, and the FEV1 is
normally 4 liters so, the normal FEV1/FVC ratio is 4/5 =80%. Because the elasticity is increased,
the FVC is the same as FEV1, and therefore the ratio is increased to 1 instead of 0.8.

Examples of restrictive lung diseases:

1. Pneumoconiosis airborne/dustborne diseases

famous in big cities (LA, NY). Cole worker pneumoconiosis especially in west
Virginia/Pennsilvania, have an anthrocotic pigment that causes a fibrous reaction in the lung,
leading to restrictive lung disease. Have an increased incidence of TB.

2. Silicosis Sandblasters get graffiti off things, or work

in foundries and deal with rocks (Ex. quartz), and break them down, and breathe in dust,
leading to silicoses). Have nodules in the lung that are hard has rock (literally) because there
is quartz in them and it looks like metastatic disease in the lung (silica dioxide which is sand
in the lung) again, increased incidence in TB. If pt happens to have rheumatoid arthritis,
and also has one of these pneumoconiosis (Ex. Cole workers), have a potential for a
syndrome, which is called caplan syndrome. Caplan syndrome consists of rheumatoid
nodules in the lung (same as extensor surfaces in the arm). Rheumatoid arthritis commonly
involves the lung with fibrosis. And rheumatoid nodules can form in the lung. The combo of
rheumatoid arthritis (rheumatoid nodules) in the lung, plus pneumoconiosis
(silicosis/asbestosis/Cole workers) = caplan syndrome.

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3. Asbestos asbestos fibers look like dumbbells (dumb
person). These are called ferruginous bodies. Asbestos fibers coated with iron, therefore can
call them either asbestos bodies or ferruginous bodies. Most Common pulmonary lesion
associated with asbestosis is a fibrous plaque with a pleura, which is b9 benign (not a
precursor for mesothelioma). Most Common cancer associated with asbestos = primary
lung cancer,

2nd Most Common Cause = mesothelioma , which is a

malignancy of the serosal lining of the lungs.

If you are a smoker and have asbestos exposure, you have an increased chance of
getting primary lung cancer. This is a good example of synergism (other causes of lung
cancer (SCC) include smoking, alcohol). Asbestos + smoker = will get cancer. There is no
increased incidence of mesothelioma with smoking (not synergistic).

Board Question: Roofer for 25 years, nonsmoker (you had to know that 25 years
working with roofing material that had asbestos in it; in other parts of NY, many
buildings were torn down, and there was asbestos in the roofing of those buildings,
which was inhaled by many people, and 10-30 years later they developed primary lung
cancer or another complication of asbestosis). What would he most likely get? Primary
lung cancer (primary pleural plaque was not there). If he was a smoker? Primary lung
cancer. Mesothelioma takes 25-30 years to develop. Lung cancers take about 10 years
to develop. Lung cancers are more common, and you die earlier. What is the main cause of
asbestos exposure? Roofers or people working in a naval shipyard (because all the pipes in
the ship are insulated with asbestos), also in brake lining of cars and headgear.

4. Sarcoidosis =2nd Most Common Cause restrictive lung disease.

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Example: Classic Sarcoidosis X-Ray lymph
nodes (hilar lymph nodes are big), haziness seen, too, which is interstial fibrosis. Sarcoid
is a granulomatous dz that has NO relationship to infection (cause = unknown).

Causes a noncaseating granuloma (not caseating

because no relationship to Tuberculosis and systemic fungal infections). The lungs are
ALWAYS involved (lungs are the primary target organ), and more common in blacks.

Example: black person, 35 years, with dyspnea, see hilar nodes on x-ray, uviitis (blurry vision
this is inflammation of the uveal tract this diseas always affects something in the face, and
the face the 2nd Most Common site a lesion will occur with this disease, can also involve
salivary glands or lacrimal glands something in the head/neck/face area (behind the lungs).

This disease is a diagnosis of exclusion, therefore must rule out anything that causes
granuloma (TB, Histo), along with the correct physical presentation = Sarcoidosis. Rx =
steroids. ACE enzymes are very high in these pts because granulomas in kidney;
hypercalcemia macrophages (epitheloid cells) make 1-alpha-hydroxylase. If they are
making 1-alpha-hydroxylase, what is the mechanism of hypercalcemia? Hypervitaminosis D.
You are second hydroxylation more vit D and therefore have excess vitamin D, and vitamin D
promotes reabsorption of calcium and phosphorus, leading to hypercalcemia. This is the
Most Common noninfectious cause of granulomatous hepatitis (TB is the Most
Common Cause of infectious hepatitis, 2nd Most Common = pneumoconiosis).

5. Hypersensitivity pneumoniti lung, silofillers disease, bysinosis)

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 These are restrictive lung disease fillers disease they
are BOTH seen in farmers. So, remember one, the other is the other!

*Silofillers disease put things in silos, which is a closed space, and fermentation of gas
occurs, the gas is nitrogen dioxide Example: farmer went into a room in his barn and
suddenly developed wheezing and dyspnea, why? Because he took in nitrogen dioxide,
which is a fermenting problem. (silo can explode because gas from fermentation).

* thermophilic actinomyces (a mold).

Example: on tractor, dust being blown up in the air and thermophilic actinomyces
(which is a mold) is inhaled; leading to Hypersensitivity pneumonitis and they end up
with a restrictive lung disease.

*Bysinosis worker in textile industry, and they get dyspnea. These are the
Hypersensitivity and restrictive lung diseases.

Goodpasture syndrome
Begins in the lungs with a restrictive lung disease (with coughing up blood hemoptysis), and
ends up very shortly with renal disease (therefore, it starts in the lung and ends in the kidneys).
This is a restrictive lung disease.

VIII. Obstructive lung Disease

A. Deals with compliance/elasticity concept

In obstructive lung disease, have a problem in getting the air out. ave a
problem getting it in? Because the elastic tissue support is destroyed, so it is very easy to fill
up the lungs. However, because the elastic tissue support is destroyed, it is very difficult hard
to get it out because it collapses on expiration, so you can get air in, but cannot get air out.

So, something is left over in the lung cannot get all the air out, therefore the residual volume
is increased (whenever something is l
air out, then the residual volume increases, which means that the TLC will increase, which
means that the diaphragm will go down because as the lungs are over inflated, and the AP
diameter will go out. So, with obstructive lung disease, you have increased Antero Posterior
diameter and diaphragms go down (depressed). There is only a certain amount of expansion
your chest can go. Eventually, the chest starts to compress other volumes (as you trap air and
residual volumes go up). So, tidal volume starts decreasing, vital capacity goes down because
the residual volume is increasing and you are compressing other volumes. So, TLC and RV
increases, everything else decreases. On spirometer, FEV1 is very low (usually 1
normally it is 4). In other words, you have a better FEV1 with restrictive lung disease because
you can get air in. The FVC (total amt they can get out) is 3 liters (vs. 5 liters). When you do
a ratio of FEV1/FVC, the ratio has decreased, hence distinguishing restrictive from
obstructive disease.

Classic COPD x-ray: hard to see the heart, with depressed diaphragms (at level of umbilicus),
increased AP diameter dx? Classic obstructive dz x-ray prob getting air out, therefore the
diaphragm is down and AP diameter is increased. Example: 3 month old can have this same
finding due to RSV
Example: Newborn with Chlamydia trachomatis pneumonia b/c he is trapping air.
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B. There are 4 type of obstructive lung disease: chronic bronchitis, bronchiectasis,
emphysema, asthma. The ones associated with smoking are bronchitis and emphysema.

1. Chronic Bronchitis

Purely a clinical diagnosis = Pt has productive cough for 3 months out of the year
for 2 consecutive years. Where is the disease? Terminal bronchioles (you have
main stem bronchus, segmental bronchi, terminal bronchioles, respiratory bronchioles,
alveolar ducts, alveoli). As soon as you hit the terminal bronchioles, these are small
airway; it is all turbulent air up to terminal bronchioles. After that, it is parallel branching
of the airways. The turbulent air hits the terminal bronchioles and then hits a massive
cross sectional airway where you can go differents pathologies because parallel
branching of the small airways. So, the airflow changes from turbulent to laminar
airflow. By the time you hit the respiratory unit, it is not moving the air. Most small
airway disease is inflammation of the terminal bronchioles, leads to wheeze.

Terminal bronchioles are the site of chronic bronchitis. This is the same area as asthma
and bronchiolitis. More proximal to the terminal bronchioles, in bronchitis, you will get a

The actual area of obstruction is the terminal bronchiole. Have goblet cell metaplasia
and mucous plugs. Think about having one terminal bronchiole and one mucous plug
this is affecting a major cross sectional area of lung because all the parallel branches
that derive from here will not have CO2 in them, and they are trying to get air past the
mucous plug, but cannot. So, there is a HUGE ventilation-perfusion mismatch. This
is why they are called blue boaters they are cyanotic (Right side).

They have mucous plugs in the terminal bronchioles and cannot rid CO2.

2. Emphysema
It is in the respiratory unit: (respiratory unit is where gas exchange occurs cannot
exchange gas in the terminal bronchioles like nonrespiratory bronchiole); it is the
primary place for expiratory wheeze and small airway disease, however. Gas
exchange occurs in the resp bronchiole, resp alveolar duct and alveoli. Only need
to know 2 emphysemas: centrolobular and panacinar. Emphysema affects gas
exchange and where it affects the airway is more distal, compared to chronic bronchitis
(proximal). So, when you have emphysema with all the inflammation associated with it,
not only destroy the resp unit, but also the vasculature associated with it. Therefore,
there is an even loss of ventilation and perfusion. So, will NOT have retention of
CO2 in these pts. When you have a problem with a mucous plug in the terminal
bronchiole, which is way more proximal and a great cross sectional area of the lung is
239
affected, there is gonna be a problem there; however when you are out this far (in
emphysema) and also destroying the vessels, you will not have an increase in CO2.

This is why they are called pink puffers (Left

Side), and this is why many of them have respiratory alkalosis.

a) Centrilobular Emphysema
Most associated with smoking and involved with the upper lobes. So, it is
upper lobe emphysema, and the primary portion of the respiratory unit that is
destroyed is the respiratory bronchiole (this is the very first thing that smokes
hits). Neutrophils will damage it because all people that smoke have more
neutrophils in their lungs, and smoke is chemotactic for neutrophils. ALL
smokers have increased neutrophils in their lungs.

What does alpha- urpose is to

destroy elastases produced by neutrophils that is its function. If you are a
smoker, that is denatured. So, you also have an acquired alpha-1 antitrypsin
deficiency -1 antitrypsin, and have too many
neutrophils in the lungs. This is a terrible combo.

This why neutrophils have no problem in destroying the elastic tissue support of
the respiratory bronchioles. So, you breath air in, which is no problem; but you
try to get it out, and there is no elastic tissue support and leads to lung expansion
this is why blebs are found there are big cystic spaces in the lung it has
trapped air in there because there is no elastic tissue, so when it tries to get by, it
just expands. This is centrolobular emphysema of the UPPER lobes.

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 b) Panacinar Emphysema (remember
Ex. in pancytopenia, ALL the cells decreased). So,
panacinar means that the ENTIRE resp unit is decreased because it is
associated with NO alpha 1 antitrypsin. This is a genetic disease autosomal
recesive the LIVER does not make it. So, at a young age, you develop
destruction of entire respiratory unit of the LOWER lobes, so this is a LOWER
lobe emphysema. So, you can see that the respiratory bronchioles are knocked
out, the alveolar ducts are knocked out, alveoli knocked out. So, you breathe in,
and this entire respiratory unit catches it this is in the lower lobes.

Smokers, which have an acquired alpha-1 antitrypsin deficiency, can get an

element of panacinar emphysema in the lower lobes, too. So, smokers can get 2

the respiratory bronchiole) and in the lower lobes, get a panacinar type of
pattern. Therefore, can get upper AND lower lobe emphysema, and 2 diff types
of emphysema.

3. Bronchiectasis

Have bronchiectasis see bronchi going out to the

pleura (abnormal). When you see bronchi going out further than the hilum, this is
bronchiectasis.

Mechanism: infection, destruction of the elastic tissue support, dilatation of the

airways. Segmental bronchi; fill with pus.

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 In Board l t just a tablespoon) of pus,
because they are trapped.

Audio File Day 4: 2Respiratory 3

a) Causes:
1) Most Common Cause bronchiectasis in USA = cystic fibrosis. If parent
with child has cystic fibrosis, will see huge pus coming out of bronchi, a
couple times per day.
2) Most Common Cause bronchiectasis in 3rd world countries =
Tuberculosis

3) (like immotile cilia syndrome). 9+2 configuration

arrangement with cilia and microtubules. The problem with immotile cilia
syndrome is an absent dynein arm. The 9 microtubules on the outside
have arms that keep them together these dynein arms are missing.

So, when these arms are missing, the cilia cannot move. So, the places with
cilia not moving are affected: these places are sinuses (why sinusitis is a
problem), bronchiectasis (because there is cilia psuedostratified columnar
epithelium is affected).

Males are Infertile (because the tail on the sperm cannot move the tail is a
modified cilia they head is moving, but the tail is weak.

Women are Infertile (because the fallopian tube needs cilia to carry the egg
down.) Organs are located on the opposite side (dextrocardia, withOUT
transposition of great vessels).

4. Asthma

Can be extrinsic (type 1 Hypersensitivity) and intrinsic:

1. Involves chemicals people in the workplace can get triad asthma, which
involves people taking NSAIDs.

2. Many people, ex. athletes will get exertional asthma and wheeze cromolyn
Na is the Drug of Choice for these patients.

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 3. Cold temperatures can cause asthma. Type I HPY has nothing to do with
these causes of asthma.

Increasing anteroposterior diameter of chest, The

wheezing is due to inflammation of the terminal bronchioles it is not due to
smoking, but because factors like LT C4, D4, E4, Prostaglandins causing
inflammation and narrowing of the airways.

IX. Lung Cancer

A. Peripherally located vs. centrally located:

1. Centrally located (mainstem bronchus):

Have the highest association with smoking. Include squamous cell carcinoma and small
cell carcinoma. These are generally centrally located, hence mainstem bronchus types
of locations. Squamous cell are more common than small cell carcinomas.

2. Peripherally located:
Adenocarcinomas (the most common primary lung cancer, more common than
squamous) are more peripheral than central. Shifted to the periphery because of the
filters of the cigarettes. The filters prevented the large carcinogens from passing in, but
the small carcinogens still passed through, and they are not trapped in the main stem,
but trapped in the periphery.

There are at least 3 or 4 types of adenocarcinoma. One obviously does have a

smoking relationship, while the others do not. The ones that do not have a smoking
relationship include bronchiolar alveolar carcinoma, and large cell adenocarcinoma of
the lung (scar cancers).

B. Cytology: know what squamous cancer looks like with a pap smear. A lot of people think
that the Papanicolaou stain is only done for cervical carcinoma. This is not the case. This is a

243
famous stain (pap smear) used for all cytological
specimens on for all organs. s keratin bright red.

Slide: pt that is a smoker with a centrally located mass.

Showing sputum sample with a Papanicolaou (pap smear) stain has red keratin, which is
squamous cell carcinoma. If this were a cervical pap smear from a woman that is 40 years of
age, this is squamous cell carcinoma. The keratin is staining bright red! (bright red cytoplasm
= keratin = squamous cell carcinoma). Papanicolaou stains keratin bright red.

Example: small cells that look like lymphocytes this is

small cell carcinoma. This is more difficult to diagnosis, because sometimes difficult to tell
the difference from lymphocytes. Slide shows malignant cells. Small cell carcinoma is the
most malignant cancer of the lung. Treatment? Radiation and chemotherapy (not surgery).
These are auput tumors with neurosecretory granules and S-100 Ag positive. They can
make ADH and ACTH.

A slightly less malignant tumor with auput origin is the bronchiocarcinoid. It is a low grade
malignancy of the same types of cells that produce small cell carcinoma. So, they can invade,

have to mets to produce carcinoid syndrome it just goes straight into the bloodstream. It is
very uncommon.

C. Cancer:

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Most Common cancer of lung = metastasis see many
metastatic nodules all over lung.

What is the primary cancer? Breast (which the Most Common met to the lung, or in other
words, it is the Most Common cancer of the lung)

Most Common primary cancer = primary adenocarcinoma of the lung, followed by

squamous and small cell carcinoma.

Worst cancer (worst prognosis): small cell carcinoma.

pancoast tumor/superior sulcus tumor tumors that are in the

upper lobe posteriorly (in post mediastinum); most of the time is caused by squamous

the lower trunk of the brachial plexus, so can get lower trunk brachial plexus like findings, and
can also affect the superior cervical ganglion. This is in the posterior mediastinum, therefore
knocking OFF sympathetic
activity ptosis (lid is lower), anhydrous (lack of sweating),

miosis (in sympathetic, which is fight or flight, normally

have mydriasis, which dilates the pupil with fight or flight, want as much light as possible,
therefore dilating pupil, but this is cut off, leading to miosis).

Myasthenia Gravis has to do with thymoma, which is located in the anterior mediastinum.

245
Exudate vs. transudate (< 3 grams, without many cells in it)

Most Common Cause pleural effusion due to transudate = Heart Failure

Exudate = protein > 3 grams, and has cells in it (Ex. y infarction)

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 CHAPTER 9: GastroIntestinal Track
I. Diseases of the Mouth

A. Herpes simplex; Herpes labialis-(fever blisters and

cold sores); primary herpes is a systemic infection. Have fever, viremia, generalized
lymphadenopathy, and goes away; it stays in the sensory ganglia (dormant in the sensory
ganglia) every now and then it can come out with stress, menses, whatever, and will form
vesicles. Recurrent herpes is no longer systemic there is no more fever, and no more
lymphadenopathy. Other virus that remain latent herpes zoster remains latent in the
sensory ganglia; can involve the skin, lips, dermatomes. So, primary herpes is systemic,
recurrent herpes is not. (No fever = no lymphadenopathy).If we enroot and stain, will see
inclusion in herpes it is a multinucleated cell with internuclear inclusions.

B. Hairy Leukoplakia
This is a preAIDs type of infection as is thrush, shingles. Located on the lateral boarder of
the tongue. Has nothing to do with dysplasia (leukoplakia). It is a result of an infection from
EBV. So, do not get the idea that it is a preneoplastic lesion. Start seeing this before the
helper T cell count get to 200. Rx - Acyclovir

C. Thrush (oral candidiasis)

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In an adult therefore can assume that it is in an immunocompromised patient, where there
is a defect in cellular immunity.

In kids (newborns), they can get it from the mom on the way out. However, it is not a sign of
immunocompromise.

D. Exudative tonsillitis
30% chance that it is group A beta hemolytic streptococco. 70% chance that it is a
virus; adenovirus, Eibstain Barr Virus. So, when you see exudative tonsillitis immediately
give Penicillin.

How do you prove it is group A streptococco? Latex agglutination test. So, most pus
tonsils are not bacteria.

Question: It is group A streptococco, and 3 weeks later, has bilateral rales, pansystolic
murmur apex radiating into the axilla, polyarthritis diagnostic? Rheumatic fever.
When you do a blood culture what would you find? Nothing
endocarditis.
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E. Leukoplakia (right side) invasive Squamous cancer
(left side)

White lesion, plaque like, try to scrap off, of leukoplakia

what is the first step in management? Bipsy

True in the vulva/penis area white or reddish-white plaque like lesion that does not scrape off
first step in management? Biopsy Why? Rule out dysplasia and/or invasive cancer.

F. Cancer of the mouth

*Most Common Cause squamous dysplasia and cancer = smoking

*2nd Most Common Common = alcohol

If you do both, you increase the risk of both.

Invasive squamous cancer = color change

*Lower lip cancer? Squamous cell carcinoma

*Upper lip? Basal cell carcinoma

Verrucous carcinoma from chewing tobacco (squamous carcinoma); also has a Human
Papiloma virus associated with it.

G. Hyperpigmentation diagnosis?

stimulating properties); very first place you see hyperpigmentation is in the Buccal mucosa.

H. Peutz-Jeghers
Blotchy (not diffuse) areas of hyperpigmentation. Polyps in small intestine. Polyps of
Peutz Jeghers are located in the small intestine and they are hamartomas, therefore they
are not neoplastic, and their ability to change to cancer is ZERO.

249
II. Diseases of the Salivary Glands

Pleomorphic adenoma aka Mumps / mixed tumor ( NOT a teratoma, but a mixed tumor it has
two diffiferents types of tissues, same cell layer). It is the Most Common salivary gland tumor and
the Most Common location? The parotid.

Mumps See Bilaterial parotiditis paramxyovirus, increase in

amylase; is the incidence of orchitis high? No; does it cause infertility? No, why? Because its
unilateral if it were bilateral then it would a much greater chance to be steril. Usually in older
teenage males or male adults is where orchitis will occur. Can also occur in females - oophoeritis
the Most Common unilateral parotiditis, therefore infertility is rare.

III. Diseases of the esophagus

A. Dysphagia and odynophgia = difficulty swallowing

Most of the time, there will be 5-6 clues per question.

*A pt has problem swallowing foods, is it solids or liquids?

If the pt can take down liquids and not solids (difficulty in swallowing solids), is due to
obstruction can be due to esophageal web in Plummer Vinson syndrome, Iron Deficiency
Anemia with glossitis and cheilosis and an esophageal web, esophageal cancer

If pt difficulty swallowing solids AND liquids, is due peristalsis problem, which is very
bad.

* upper 1/3 of the esophagus is due myasthenia gravis (because it affects

striated muscle).

* the middle 1/3 (combo of smooth and striated muscle).

*If the lower 1/3 (smooth muscle) e to Scleroderma (like progressive systemic
sclerosis and CREST syndrome = (calcinosis, Raynaud phenomenon, esophageal
dysmotility, sclerodactyly, and telangiectasia) syndrome) and achalasia. So, they will tell

250
you immediately if they can swallow liquids and/or solids, or neither (which is a peristalsis
problem).

*How can you distinguish Progressive Systemic Sclerosis/CREST from achalasia? In

achalasia, they vomit up the food they ate when they go to bed at night; or they will tell you pt

Helpful hints with other diseases:

*Palpable purpura = immune HPY type III = Most Common Henoch Schonlein

Epistaxis = platelet problem

*Pansystolic murmur increases on inspiration = tricuspid regurgitation

*Pansystolic murmur increases on expiration = mitral regurgitation

Odynophgia = PAINFUL swallowing; always abnormal

In HIV pt = Candida esophagitis is it AIDs defining? Yes.

*Most Common fungal infection in HIV = Candida

When it gets into the esophagus, it is AIDs defining

When it is a thrush = PRE AIDS lesion (not aids defining)

B. Tracheoesophageal fistula

Blindly ending esophagus (proximal esophagus ends blindly) distal esophagus arrives
from the trachea.

Pregnant women have obstruction in the esophagus, or proximal portions of the duodenum.
What does the mom have? Polyhydramnios amniotic fluid is baby urine, so have to recycle
251
it, or mom will have big belly. So, the baby swallows it and it is reabsorbed in the small
intestine. So, there are 2 answers:

1) Tracheoesophageal fistula

these 2 are associated with

polyhydramnios. They block the ability to reabsorb amniotic fluid, leading to
polyhydramnios. Also, when these kids eat, food gets caught and kids cough and
sputter (spit) because the distal esophagus arises from the trachea and leads to
distension of the stomach. This is very characteristic.

Area of weakness cricopharyngeous muscle. It has a little slit in between the fibers of it.
Not the whole area is cut (which would be a true diverticulum this is a false diverticulum). It
goes out and gets a pouch. The pouch collects food and leads to halitosis (profund exhale).
They have a tendency of regurgitating undigested food out of the nose.

D. Achalasia
Peristalsis problem problem with relaxation of the Lower Esofageal Sphincter (LES),
therefore it is in spasm all the time. Why? If you biopsy that area, this means that the ganglion
cells are missing.

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What disease does this remind you of? Hirschsprung disease. What is in those ganglion
cells? Vasointestinal peptide (VIP). What is its function? To relax the Lower Esophageal
Sphincter.

So, when you destroy those ganglionic cells, not only do you destroy the movement of the
lower esophagus, but you also reduce Vaso Intestinal Peptide levels. So, you have constant
constriction of the Lower Esophageal Sphincter, leading to bird beak appereance (pico
de pajaro). Proximal portion is dilated.

E. Parasites

Disease of South America, where the leishmania forms invades the ganglion cells of the
Lower Esophageal Sphincter and the rectum produce acquired achalasia and
Hirschsprung disease = isease, vector = reduvid bug (like kissing bug); swelling
of the eye sign?

What does it do in the heart? Causes myocarditis and chronic heart failure congestive
cardiomyopathy. This is one of the most common causes of heart disease in South
America.

F. Barrett esophagus
Ulcerated mucosa in the distal esophagus. Biopsy: see glandular metaplasia; therefore see
t be there). They are there because the
esophagus cannot protect itself from esophageal injury. Therefore, run the risk of
adenocarcinoma of the distal esophagus. Example: If the lesion in esophagus, dsyphagia
of solids, but not liquids, lesion in noted in distal esophagus do NOT pick squamous cell
carcinoma this is in the MID esophagus. If it is distal, it is adenocarcinoma, and the

253
G. Esophageal varices
Dilated submucosal esophageal veins = therefore pt has cirrhosis, who was an alcoholic.
Pt also has portal Hypertension the left gastric vein is involved (one of the branches off
the portal vein is left gastric vein). The left gastric vein drains the distal esophagus and
proximal stomach.

What drains into the left gastric vein? Azygous vein.

Where does the left gastric vein drain into? Portal vein. However, because of cirrhosis,
portal vein cannot empty blood sufficiently into it, the hydrostatic pressure increases; you
reverse blood flow into the left gastric vein, splenic vein, and other veins, and end up
producing varices which rupture.

*Hematemisis = vomiting blood

*Hemoptysis = coughing up blood
*Hematochezia = blood pouring out of anus (actual dripping of blood not Melena= coating
of stool with blood, that is seen in anus). Most Common Cause of hematochezia =
diverticulosis; not diverticlulitis because the vessel is next to the diverticular sac, so if it were
- -osis, it is intact, and just have to erode it, leading to 600
mL bleed.

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H. Mallory Weiss Syndrome

Tear at esophago-gastric junction. Example what

does her have? Bulimia. Classic Example: alcoholic with retching (trying to vomit, but
nothing is coming out causes tremendous pressures, leading to tear (hematemisis) or
Syndrome- this is when the air gets into the pleural cavity, and leads to
So, seen that in bulimia and leads to instead
more than an anorexic alcoholic).

I. Esophageal cancer

Squamous cancer (mid-esophagus); Most Common Cause = Smoking and (2nd Most
Common Cause = Alcohol).

Dysphagia seen in this pt - initially, pt cannot swallow solids, but can take down liquids.

Classic on Boards: 50 years, male, alcoholic, weight loss, problem swallowing foods,
not liquids diagnosis? Esophageal cancer squamous cell carcinoma of the mid-
esophagus.

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 Example: Trachea and see cartilage rings, and elastic
artery (esophageal in middle) this is esophageal cancer.

IV. Diseases of the Stomach

A. Congenital Pyloric Stenosis

Example: Kid, 3 weeks old and started vomiting non bile stained fluid at 3 weeks; palpated
the abdomen and felt a knot in Right Upper Quadrant and see hyperperistalsis. This is NON
bile stain fluid at 3 weeks. What is the diagnosis? Congenital Pyloric Stenosis.

What if it is duodenal atresia in a down Syndrome kid? That would be at birth vomiting of
bile stained fluid. And double bubble sign atresia (lack of development of the lumen) is distal
to where the bile duct comes in, so bile can still enter the proximal portion of the duodenum
this is why it is bile staining because there is no movement, there will be air trapped in there,
and air is trapped in the stomach, therefore there is air in the stomach and proximal duodenum
a double bubble sign. Also, mom will have polyhydramnios. So, do not confuse congenital

It does have multifactorial inheritance; therefore it can be increased in future children. Can see
pyloric stenosis, as it has thickened, the treatment split the muscle (called pyloroplasty).

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B. NSAID ulcers

Non steroidal will block PGE2, which is responsible for the mucous barrier of the stomach, and
vasodilatation of the vessels, mucous secretion, and secretion of bicarbonate into the mucous
barrier. So, when you take NSAIDS for a period of time, the whole thing is destroyed. Leads
to multiple ulcers and significant blood loss over time. They are punched out.

C. Helicobacter pylori
Silver stain (as is pneumocystis carinii pneumonia (PCP), Legionella, bartenella
hensilai). Comma shaped organisms (like campylobacter), but found out that they have
different cell walls and etc.

Nasty bug because it make lots of cytokines and urease which converts urea to ammonia,
and is one of the reasons why they can burrow through the mucous layer ammonia is very
toxic. Slide: Helicobacter Pylori with Gastritis

When we take biopsy of gastric mucosa, we do a urease test on it and if it s positive, know
Helicobacter pylorus is in it. Can also use serological tests Antibodies
good for the first time. Why? Because the Antibodies do not go away and, therefore cannot
diagnosis reactivation or recurren
will always be positive because Antibodies stick around.

Where does pernicious anemia hit? Body and fundus. That is where the parietal cells have
autoAntibodies destroying them, and Intrinsic Factor leading to atrophic gastritis.
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 Helicobacter pylori affects the pylorus and antrum. It
destroys the mucosa, leading to atrophic gastritis of the pylorus and antrum. This is where
cancers are. Most cancers are along the lesser curvature of the pylorus and antrum (exact
same place where gastric ulcers are). The Helicobacter pylori live in a mucous barrier and
therefore are protected. Most Common Cause of stomach cancer = Helicobacter pylori.
Helicobacter pylori can also cause malignant lymphomas of the stomach (low grade).

a duodenal ulcer? Because they are never malignant.

Gastric ulcers have a chance of becoming malignant therefore need to biopsy gastric
and not duodenal ulcers. Only reason they biopsy a gastric ulcer is because they are trying to
rule out whether it is cancer (malignant) or not ulcer and it has a 3% of
been malignant. Never have to biopsy a duodenal ulcer, so just leave alone. H pylori is more
commonly associate with duodenal Peptic Ulcer Disease than gastric.

Why do you get melena with upper Gastro Intestinal bleeds? Upper Gastro Intestinal Track =
anything that is a bleed from the ligamentum of trietz where the duodenum hits the jejunum
and up.

Why the melena is it black?

Acid converts Hb to hematin. Hematin is black pigment, leading to melena. This is

important to know, because if you have black tarry stools, and its 95% chance that is
an upper GI bleed, and if you play odds, it is probably a duodena ulcer (vs. a gastric
ulcer).

Vomiting of coffee ground material = blood clots acted upon by acid and changes to
hematin.

Example: Pt, an executive under great stress, and sudden onset of severe epigastric pain that
radiates into the left shoulder.

First step in work up? Flat plate of the abdomen; see air under diaphragm. What you think?
Duodenal ulcer.

Why did he have shoulder pain? Air got out, settled (stay) under the diaphragm, irritated nerve
#4 (phrenic), and got referred pain to the dermatome (which is the same dermatomes).

Audio File: Day4 3Gastrointestinal1

D. Linitis Plastica: Adenocarcinoma of the stomach

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 Example: 52 years female with weight loss and epigastric distress. She had an upper
gastrointestinal series, noted that stomach did not move (no peristalsis), and then she
died. Dx? Linitis plastica cells that are invading the wall of the entire stomach, called

signet ring cells (which are stained with mucocarnine

cells, are pink signet ring cells are like a diamond ring, and the diamond has been pushed to
the periphery). The mucous is inside, making the cell look empty, and pushing the nucleus to
the side (just like fatty change of the liver). However, these are malignant neoplastic glandular
cells, and are characteristic of rhinitis plastica type of gastric adenocarcinoma.

Misconception: Krukenberg tumor.

This tumor is due to hematogenous spread to the ovary. The signet ring cells came
from stomach cancer that has metastasize to ovaries = Krukenberg tumor.

Most are ulcerative tumors in the lesser curvature of the pylorus and antrum. Leather bottle
stomach very hard due to all of the cancer cells and the fibrous response to it.

Gastric cancer is a primary cancer - Japan, because smoked products. Other ethnic cancers:
nasopharyngeal carcinoma = china; stomach cancer and HTLV 1 = Japan; Burkitts lymphoma
= Africa.

Pt with a nontender mass in left supraclavicular area and pt with epigastric distress one week
ago dx? Metastatic gastric adenocarcinoma.

Cervical cancer can also metastasize here. Left supraclavicular node drains abdominal
organs; therefore pancreatic cancers but mostly the stomach cancers metastasize there. The
right supraclavicular node mets are from lung cancer.

V. Malabsorption - Means bad absorption of everything: fats, carbs, and proteins. Diagnosis point
of view we look for increased fat in the stool = steatorrhea = screening test for malabsorption.

A. Fat Digestion: We need:

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 1) Need lipases to break down fat into 2 monoglycerides and Fatty Acids, so you
need a functioning pancreas.

2) Need villi of the small intestine because

have to be a mile long. Villi increase the overall absorptive surface without

surface, and will lose the monoglycerides and Fatty Acids. Therefore, you need a
functioning Small Intestine with villi.

3) Need bile salts to emulsify the fat and break it down to micelles (tiny
particles that are 1 micron in diameter) and chymlomicrons. Emulsifying agents are
many times in dishwashers because need to get fat off plates. Fat will come to the
surface and break up into micelles, which are easier to absorb.

So, need functioning pancreas, bile salts, small intestine that has villi in order to
reabsorb fat.

Bile salts are made in the liver from cholesterol. Cholesterol cannot be degraded;
it either solubilized in bile (therefore run the risk of cholesterol stones) or is converted to
bile acids. Cannot break down cholesterol.

Bile salt deficiency is seen in:

a) Liver disease.
b) Anything that obstructs bile flow will produce bile salt deficiency.
c) Bacterial overgrowth can eat and breakdown bile.
d) Terminal ileal disease, ex. cannot recycle.
e) Cholestyramine: resins used for treatment of hyperlipidemia, can produce bile salt
deficiency. This is the MOA of resins, by binding and then excreting them, because if
you are not recycling them, you will make more.
Upregulation of LDL receptors synthesis, because need to make more bile salts,
therefore need to suck more out of the blood to regulate and will make more LDL
receptors. These drugs will eventually take more cholesterol out of the blood and

people taking medications, because you will lose these medications in the stool, along
with bile salts.

Diseases: screening test is looking for fat in stool (steatorrhea)

So, we have to figure which if the 3 areas is the cause of the malabsorption pancreatic
deficiency, bile salt deficiency, or something wrong with the small bowel (Most
Common).

B. Celiac Disease (sprue)

Celiac Disease is an autoimmune disease against gluten wheat, especially gliadin.

It is the Most Common Cause of malabsorption in this country. So, when you eat wheat
products, the gluten is reabsorbed into the villi and there are Antibodies against gliadin, and
leads to destruction of the villi (just like Antibodies against parietal cells or intrinsic factors,

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 which destroy everything around it). So, the Antibodies attack gluten that has just been
reabsorbed by the food, which will cause destruction of the villus.

And there are no villi here it is flattened; blunting of villus

so you are not able to reabsorb fat, proteins, or carbs. There is no villus surface. The
glands underneath are fine, however. The villi are absent. .

Dermatitis herpetiformis associated with Celiac Disease.

There is a 100% chance of dermatitis herpetiformis association with underlying celiac
disease Dermatitis herpetiformis is an autoimmune disease, and it is a vesicular lesion
of the skin looks like herpes of the skin. But NOT is herpes!!!

In the exam they will show you a picture of a dermatitis herpetiformis, and will ask what the
cause of diarrhea is? Antibodies against gluten (gliadin).

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 disease

An infection of the small infection due to an organism that you cannot gram stain called:

Trophermyma Whippelii, only seen with Electron Macroscopy;

cannot be cultured.

See flat blunted villi and foamy macrophages in the

lamina propia in the small bowel (look like bubbly macrophages). The macrophages have
distinctive PAS-positive stains.

HIV positive pt and acid fast stain pt with helper T

cell count of 100. Have an acid fast stain with the foamy macrophages due to
*Mycobacterium Avium Intracellulare (this is more common that TB), and can cause
Whipple disease with malabsorption.

be treated with antibiotics.

So, there are 2 diseases that cause malabsorption: Celiac disease and
disease and another suggested is chronic pancreatitis (Most Common in alcoholics 2
reasons for malabsorption in alcoholics a lipase deficiency related to chronic pancreatitis, or
bile salt deficiency due to cirrhosis, or both in an alcoholic).

D. Diarrhea: Best way to classify is to subdivide into 3 types:

1. Invasive: bacteria invade.

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 2. Secretory: the bacteria produce toxins and that will stimulate cAMP (or other
mechanisms) causing the small bowel to secrete small amounts of ISOTONIC fluid,
which is NaCl.

3. Osmotic: lactase deficiency. Also produced by laxatives, and other inborn errors
of metabolism.

Secretory and osmotic diarrheas are high volume diarrheas and you go frequently,
whereas invasive diarrhea is a small volume diarrhea. Best/cheapest test to get in a
pt with diarrhea = fecal smear for leukocytes. If there are NOT neutrophil = not
invasive. If there are inflammatory cells then you must do fecal smear test for
campylobacter or shigella.

a) Osmotic diarrhea (fits in with osmotic water movement) is when there is some
osmotically active substance in the bowel lumen that is sucking water out of the
bowel, causing a high volume, hypotonic loss of fluid.

Example: lactase deficiency = due brush border enzyme (digestive enzyme

or disaccharidase deficiency.

*T iciency ase
deficiency or even a brush border enzyme deficiency.

iciency, it means that any dairy products which contain

will go to the colon, and act as desserts to the anaerobic bacteria which will eat the
lactose and produces hydrogen gas, and other gases, and acids, and get acidic
stools. The hydrogen gases cause the bloating, distention, and incredible explosive
diarrhea.

b) Secretory diarrhea: two things to know, Vibrio cholerae and Enterotoxicgenic

Encherichia Coli Therefore when you do a bowel biopsy
there will not be sign
activates a pump either cAMP (Vibrio) or some other pump: guanylate cyclase (E.
coli).

Treatment: when you give fluid replacement to patients with vibrio Cholerae, you
need to give glucose along with the fluids. This is because you need glucose to co-
transport Na that was in the fluids. Side note: Need to know the other E. coli related
toxins: EHEC: O157:H7; EIEV; and EaggEC.

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 c) Invasive diarrhea: the most common in US is caused by campylobacter

jejuni, and shigella is a close second.

Classic case: a person with low vine (?) diarrhea, with some blood in it, and on gram stain there were
comma shaped or S-
produce pseudomembranes. Therefore all pseudomembranes does not necessarily mean you will
see C. difficile.

d) Parasites that causes diarrhea:

Giardia: owl eyes that move. This is the MCC

of diarrhea due to a parasite in the US. Treatment: metronidazole.

Cryptosporidium parvi: MCC of AIDS diarrhea

is a partially acid-fast organism. It sticks to the wall of the colon.

Classic case: there is a pt that has AIDS and has diarrhea, and when they stain it, there are oocysts
that are partially acid-fast. What is the diagnosis? Cryptosporidium Parvi. It will kill if you are
immunocompromised. The treatment is almost worthless. It comes at the end when the helper T-
ycobacteria
Intracellulary, cryptosporidium, toxoplasmosis, and Cytomegalovirus all comes in at the end. P.
carinii comes in around 200 helper T-cells.

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 Clostridium difficile: This is
an autopsy picture of an older woman who was in the hospital with pneumonia, and
she developed diarrhea. What was found on autopsy? Well, it is safe to say that if
she had pneumonia, then she was taking antibiotics. So this is
pseudomembranous colitis, caused by clostridium difficile.

This occurs when taking antibiotics that wipe off the good organisms, leaving behind
c. difficile. Everybody has clostridium difficile in their stools, but Encherichia. coli,
enterobacter fragilis are keeping it in check. But when taking antibiotics such as
ampicillin (Most Common), clindomycin (2nd Most Common) for a period of time, you
knock off the good guys, giving clostridium difficile a chance to proliferate and make
toxins that damage the superficial layers of the colon.

hat do. This is analogous to

corynebacterium diphtheria, which also has a toxin that damages and produces
pseudomembranes but the organism does not invade. The ribosylation thing, and
the Elongation factor 2 (EF-2 allows for protein elongation) are messed up,
therefore cannot elongate proteins. The first step in management is to do a toxin
assay of stools, The screening test of choice is toxin assay of stool! The
treatment is to give metronidazole, used to give vancomycin because clostridium
difficile became resistant and is expensive. Metronidazole itself can produce
pseudomembranous colitis but you take that chance.

VI. Diseases of the Small Intestine

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A. Small bowel obstruction:
Characdteristic: Classic Step ladder appearance of air-fluid levels: air, fluid, air .

When you have a hollow viscous that peristalsis, you get a certain characteristically pain,
called COLICKY pain= TOTAL small bowel obstruction. Colicky pain is when you have pain,
a painfree interval, pain, and then a painfree interval. The intervals are not consistent,
sometimes you have a 15 minutes painfree interval, and other times if may be longer or shorter.

You have to have peristalsis = colicky pain

move against that obstruction a you cannot peristalse you
get stagnation of the food proximal to wherever the obstruction is, and get air-fluid levels. Distal
to the area of obstruction there is no air.

In obstruction, there are two things that can happen: constipation or obstipation:

1. Constipation is where you have a problem with stooling, which does not necessarily mean
obstruction.

2. Obstipation means that do you have constipation and problem passing gas that means
you have complete obstruction. So you have to ask the pt whether they have passed any
stools or gas.

Most Common Cause of obstruction: adhesions from previous surgeries.

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 Slide: those are watermelon pits, with a narrow lumen. But
if the case read that this pt did not have pervious surgeries and had colicky pain, this is due to
the bowel being trapped in the indirect inguinal hernia.

Example: there was a weight lifter who developed colicky pain in the Right Lower Quadrant
area, had no previous surgery, the most likely cause is indirect inguinal hernia. Weight lifters
often times create indirect inguinal hernias.

Side note: there was a picture of kid. Trisomy 21 (abnormal number of

chromosomes) is due to nondisjunction (unequal separation during the first stage of meiosis I)
es, this is due to
Robertsonian translocation. In this case, they would have 46 chromosomes but on one of
those chromosomes 21, will be another chromosome attached to it. They will have three
functional chromosomes 21. The two Gastrointestinal diseases that are most commonly seen
duodenal atresia (double bubble sign) and Hirschsprung disease.

B. Hirschsprung Disease:
Depict= describe Ganglion Cells (left slide)

(Right slide) Absence of the ganglion cell of the rectosigmoid)

The ne
the rectum, the stools cannot get by, even when there is an opening, because there is no
peristalsis. So the stools just stay there. So, the dilation of the proximal colon has ganglionic

means that the rectal ampulla has no stools in it.

Example ectal exam was

performed. If there were NO stools that came out on exam it means Hirschsprung
disease. If on rectal exam, there were stools on the finger, it means tight sphincter. This is a
disease of the colon.

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C. Intussusception:

Most occur in
cecum.

There will be colicky pain because you are obstructing, and are compromising blood flow,
so you get the bleeding. They will say: a 2 years kid, with colicky pain and bloody stools.
They might way there is an oblong mass in the Right Upper Quadrant. In some kids, it
spontaneously comes out, but if not, then the radiologists will do barium enema, and put a little
pressure there, and he reverts it. So you get complete bowel obstruction and infarctions.

D. Volvulus: Twisting of the colon around the

mesentery because complete obstruction and infractions due
to compromising blood flow.

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 E. Gallstone ileus: usually seen in older people, more
women, and have signs of colicky pain, and obstruction. The gallbladder stone falls thru the
fistula and settles into the ileocecal valve and causes obstruction.

See a flat plane of the abdomen that produced air in the biliary tree. Diagnostic? Gallstone of
Ileus. There is a fistula that is communicating the gallbladder with the small bowel therefore air can
get in the small bowel and the biliary tree. Air in the biliary tree with colicky pain is gallstone
ileus. This is a gallbladder disease.

F. Meconium Ileus = cystic fibrosis

VII: Diseases of the Colon

A. Vascular diseases of the colon:

1. Ischemic (infarct) Bowel Disease:

The small bowel infarct more because has only one blood supply. The entire small
bowel, the ascending colon, and the transverse colon are all supplied by the SMA
(superior mesenteric artery).

Ischemic Colitis stricture (restriction) at splenic flexure

What is the main difference in a small bowel infarct vs. an ischemic ulcer causing bloody
diarrhea in the splenic flexure? They both can have bloody diarrhea, but:

The small bowel infarction will DIFFUSE abdominal pain (all abdomen hurt).

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 The ischemic colitis, is a localize infarction and it will point to specific area on left side of
abdomen. This differentiates between a small bowel infarct from a small infarct in the colon (can
pinpoint area).

Audio File: Day4 4Gastrointestinal 2

2. Angiodysplasia of Cecum
2nd Most Common Cause of Hematochezia e cecum because law of Laplace
(wall stress and radius). The diameter of the cecum is bigger than any other part of the
colon. Because the diameter is greater, the wall stress is greater. Therefore, putting
stress on the vessels in the wall of the cecum, it actually pulls them apart and produces
telangiectasias. As a result, it predisposes to angiodysplasia because increased wall
stress. If one of them ruptures to the surface, you can end up with significant loss
bright red blood per rectum (profuse bleeding). A very common cause of
Hematochezia in older people. So, if diverticulosis is ruled out, angiodysplasia is
probably it. Associated with von Willebrand's disease and aortic stenosis.

Diverticulum/ Small Intestine Disease:

2% of population; 2 inches from terminal ileum; 2 feets from the

iliocecal valve; 2 cm in length; 2 years or younger; and 2% of carcinoid tumors occur in

Most Common complication = bleeding. Because it is a diverticulum, it can be

inflamed, and leads to diverticulitis. Example: hematemisis, pain in Right Lower
Quadrant area, melena diagnosis? Diverticulum (involved melena AND
hematemisis definitely not Ulcerative Colitis

Example: newborn with a sinus and umbilicus was draining poop (feces)
diagnosis? Persistent vitelline duct sometimes it is open all the
way through, therefore there is a communication between the small bowel and
umbilicus, so feces coming out of umbilicus, which is persistence of the vitelline duct. If
you have urine coming out of the vitelline duct, this is persistence of the uracus.

C. Sigmoid Colon

*Most Common location for cancer in the entire Gastrointestinal tract = sigmoid colon
*Most Common location for polyps in the entire Gastrointestinal tract = sigmoid colon
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*Most Common location for diverticula in the entire Gastrointestinal tract = sigmoid colon

The area of weakness is where the blood vessels penetrate the valve. The mucosa and
submucosa will herniate right next to the vessel. This is very bad.

When feces are stuck (fecalith), can

erode that vessel, and see a diverticulitis (complication of diverticulosis) with
hematochezia = massive lower Gastrointestinal bleed. These extend outside of the
lumen, which is diverticulosis. If you see polyps in the lumen, do not confuse with
polyposis polyps go INTO the lumen, not out.

D. Diverticulosis:

Diverticulosis known as "diverticular disease," Which have diverticula = an

outpocketings of the colonic mucosa and submucosa through weaknesses of muscle
layers in the colon wall. Usually in a sigmoid colon.

Most Common complication = diverticulitis which produce Hematochezia (bright

blood in stools)

Diverticulitis = Left side appendicitis (appendicitis diagnosis? Right Lower

Quadrant philic
leukocytosis) this is the same presentation but, diverticulitis occurs in the Left Lower
Quadrant area, in an elderly person.

Most Common Cause fistulas communications in the Gastrointestinal =

diverticulosis. With a fistula, there is communication between 2 hollow organs.

colon and the bladder, leading to neumaturia air in the urine.

Most Common Cause of colovesicle fistula is diverticular disease. They can

rupture, and the rupture can cause peritonitis.

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 Barium enema with diverticulosis

Diverticulum in colon: Does not have all layers in colon wall.

Development of diverticuli where the artery penetrate the muscular wall of the
colon.

VIII. Inflammatory Bowel Diseases lcerative Colitis

Disease:

1. Like (ANUS) involved the terminal ileum 80% of the time or sometimes it
just involves the colon or just terminal ileum and colon at the same time.

2. Produce fistulas and fissures of the anus.

3. Jumps around, transmural, noncaseating granulomas.

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 Slide: This is ileocecal valve, ascending colon, terminal ileum a
transmural inflammation with a very narrow lumen.

will presented colicky, Right Lower Quadrant pain, with diarrhea in young
person.

In the third world countries, it produces presentation same as what is it?

Intestinal Tuberculosis due by (the most common cause of tuberculosis in that
countries: mycobacterium bovis), this have . This occurs because they do
not have pasteurization. In America, if we get intestinal Tuberculosis from swallowing it from
the primary in the lungs.

String sign on barium study, looks like a string see

that it is transmural and that it is segmental. The proximal valve is dilated have to push stool

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disease. Linear ulcers are apthus ulcers.

Ulcerative Colitis:

1. Likes (RECTUM), always begins in the rectum.

2, Produce bloody diarrhea.

3. Involves the mucosa/submucosa and you

see Pseudopolyps are residual polyps that are inflamed, it is inflamed bloody mucosa.
Everything is ulcerated off, and you see the submucosa of the colon.

4. Non caseating granuloma can stay

there, or can move up in continuity and involved the whole colon called pancolitis, but
it never involves the terminal ileum. So, the more involvement and greater duration =
greater chance of cancer related to Ulcerative Colitis.

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 Ulcerative Colitis has the highest incidence with cancer, HLA B27 anklyosis spondylitis,
and is the Most Common Cause of sclerosing pericholangitis (sclerosis/fibrosis around
common bile duct, producing obstructive jaundice and high incidence of cholangiocarcinoma).

IX. Tumors of the Colon Polyps

1. Most common Cause of polyp in entire Gastrointestinal track = hyperplastic polyp

It is a little nubbin like hemartomas (therefore not neoplastic), usually in sigmoid colon.

1. Tubular adenoma: looks like a strawberry on stick,

therefore has a stalk with strawberry, which is the precursor lesion for colon cancer.

2. Juvenile Polyp:
kid with polyp in rectum; all juvenile polyps located in the rectum and are hamartomas
(no precancerous).

Lets say it is an adult and the polyp is sticking out (a reddish mass) dx? Internal
hemorrhoids. Rule: internal hemorrhoids bleed, external hemorrhoids thrombose.
Therefore, when you have blood coating the stool, it is internal hemorrhoid. Internal
hemorrhoids are NOT painful, but they do prolapse.

*Adult with something reddish sticking out of their butt = prolapsed internal hemorrhoid
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(Internal hemorrhoids bleed and painless, while external hemorroids thrombose and are
painful.)

3. Sessile Polyp (villous adenoma)

Histologically: looks like the villous surface of the small

intestine (hence name villous adenoma); these are little finger-like excrenses of the small
intestine, hence the name villous adenoma.

These have the greatest malignant potential,

and are usually in the rectal sigmoid. Because they are villous/finger like they have a lot of
mucous coating the stool; mucous secreting villous. They have a 50% chance of becoming
malignant.
So, tubular adenomas are precursors for cancer (size determines malignant potential if they
are above 2 sonometers, they are very dangerous) and villous adenomas lead to cancer, too.

4. Familial polyposis need to have over 100 polyps to

have familial polyposis. This disease is autosomal dominant, uses APC suppressor
gene, ras, and p53; APC is the major one. Will always get cancer in them, usually
between 35-40. Therefore, will need to prophylactically remove the bowel.

Autosomal Dominant disease famous for late manifestations, penetrance, and variable
expressivity (as are all other Autosomal Dominant diseases). They will not be born with

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 polyps at birth (they start developing between the ages of 10-20; in Autosomal
Dominant Polycystic Kidney Disease (ADPKD), they do not have cysts are birth, they
start developing between 10-20; in , do not have chorea at birth, but
around 35-40 years, and they have late manifestations.

Another disease that affected colon has polyps and brain tumors = Turcot syndrome have a
polyposis syndrome with brain tumor; this disease is autosomal recesive.

: Have multiple polyps in there, plus b9 salt tissue tumors: desmoids

and osteomas in the jaw.

X. Carcinoid Tumors

Along with auput tumors. All carcinoid tumors are malignant, but have low grade potential. A
lot of it depends on their size and if they are going to metastasis. Depends on their size in
sonometers if they are greater than 2 sonometers they have the ability to metastasis.

Most Common location for carcinoid tumor = tip of the appendix have a bright yellow
color, but they are NEVER the cause of carcinoid syndrome why? Because the tip of the
appendix will never be greater than 2 sonometers.

So, where is the Most Common location of carcinoid tumor that CAN be associated with
carcinoid syndrome? Terminal Ileum they are always greater than 2 sonometers.
What do all carcinoid tumors make? Serotonin. Because the appendix and terminal ileum
are drained by the portal vein, the serotonin made goes to the portal vein, goes to the
hepatocyte, is metabolized into 5 hydroxyindoleacetic acid and is pee out; therefore it is not in
the bloodstream.

Therefore, there are no signs of flushing and diarrhea because there is no contact with the
systemic circulations. However, if you metastasis to the liver, then those metastasic
nodules that are making serotonin can dump some of it into the hepatic vein tributaries. This
does have access to the systemic circulation because goes to Inferior Vena Cava to Right side
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 heart, and this is why you get right sided lesions
stenosis.

Serotonin is a vasodilator in some cases, but a vasoconstrictor in other cases. However, in

terms of serotonin syndrome (which is the Most
nd
Common symptom of carcinoid), followed by diarrhea (2 Most Common). If it has
access to systemic circulation, it has high levels of which are the screening test 5
hydroxyindoleacetic acid of choice because it is the metabolite of serotonin. So, because
making and LOSING a lot of serotonin, what amino acid can be deficient? Tryptophan,
therefore the vitamin B3 (Niacin) is deficient = pellagra. You using up all the Tryptophan
and making serotonin instead of niacin.

XI. Colon cancer

Neurosecretory granules on Electron Microscopy colon cancer; left side obstructs, right
side bleeds.

In the left side of colon has a smaller diameter. So, when the cancer develops in the left
colon and wants to form a polyp, it goes around

Annular (napkin ring), and produces constriction. Open

bowel in left colon, see one edge of the cancer on each side of the bowel and bowel is
constricted have signs of obstruction by constipation or diarrhea.

In the right colon, because of there is a bigger diameter;

it has a bigger chance of going out and forming a polyp. Therefore, it is sitting in the stool,
leading to a bleeding and anemia (Fe Deficiency) (therefore left side obstructs, right side
bleeds).

*Which is side is more likely to have Fe deficiency? Right colon side lesion.

*Which is more likely to have alteration in bowel habits (constipation/diarrhea)? Left

colon side.

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 Tumor marker for colon cancer = CEA (carcinoembryonic Antigen). Not used to
diagnosted colon cancer, but used to follow it for REOCCURRENCE.

*Risk factors:

Most Common Cause relates to diet (*lack of fiber in stool therefore, more fiber you
have, the less chance of colon cancer because you are getting rid of lipocolic acid). *Age is
also a risk factor (pts over 50); *smoking is a risk factor that is associated with colon cancer.
*Polyposis coli syndrome also has

XII. Diseases of the Appendix: Appendicitis

Appendicitis covered with pus

Most Common Cause of appendicitis in adults = fecalith = impacted stool

. So when you impact stool it presses on the sides

of the appendix, and leads to ischemia, then get a breakdown of the mucosa, E. coli gets in
there and acute appendicitis occurs. This is the SAME mechanism for diverticulitis (the
diverticular sacs also get fecaliths in them and the same exact thing happens the
pathogenesis of acute diverticulitis and acute appendicitis is exactly the same). So, fecalith,
ischemia along the wall, inflammation, E coli.

Another analogy: acute cholecystitis is a stone in the cystic duct pushes on the side, leads
to ischemia, acute cholecystitis, E coli. So, there is a concept there we have acute
cholecystitis, diverticulitis, and appendicitis all related to something obstructing the
lumen, causing mucosal damage, and E coli inflammation.

What the Most Common Cause of appendicitis in children? Measles and/or adenovirus
infection.

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 In Review: ACUTE APENDICITIS:

In adults occurs because there is lymphoid tissue in the appendix, by a felalith produce
diverticulitis and obstruct the lumen and set up inflammation for mucosal injury and
leads to acute appendicitis.

In childrens occur with measles or adenovirus infection, get hyperplasia of lymphoid tissue
in the appendix, and can obstruct the lumen and set up inflammation for mucosal injury
and leads to acute appendicitis. So, in children, it usually follows a viral infection.

Chapter 10. Liver

I. Bilirubin metabolism:

Most of the bilirubin in our blood is unconjugated and derived from the Red Blood Cells when
they are old, phagocytosed and destroyed.
(99%), which is all unconjugated. None of this is in the urine because it is lipid soluble.

The Unconjugated bilirubin is the end product, goes to the bloodstream and binds with
albumin, goes to the liver, taken up and conjugated by cytochrome p450.

Any time the cytochrome p450 conjugates bilirubin, or metabolizes any drug, it renders (give) it
water soluble. So, we have a lipid soluble unconjugated bilirubin is converted to conjugated
bilirubin (direct bilirubin), which is water soluble. One of the purposes of the liver is to give
lipid soluble drugs water soluble, so you can pee them out. So, we conjugate it and have
water soluble bilirubin.

Once bilirubin is taken up by the liver, it is never close to a vessel. So, there is no way it can
get into a vascular channel (once it is taken up by the liver). So, if direct conjugated
bilirubin is in our urine, this is because something happened (either in the liver or bile
duct) to have caused it to get there because
stream. So, it is taken up in the liver, conjugated, and pumped into the bile ductules; which go
into the triad, goes up the common bile duct, some is stored in the Gallbladder and goes into
the small intestine through the common bile duct. Therefore, bile contains conjugated bilirubin.
Its also contains bile salts, cholesterol and estrogen, but has conjugated bilirubin that we will
get rid of.

So, this conjugated bilirubin takes a long trip down to the colon and the bacterial have been
waiting for the conjugated bilirubin and will break it down back into unconjugated bilirubin.
Then, it continues to break it down. *The bacteria breaks it down to stercobilinogen (what it
used to be called). Stercobilinogen oxidizes to stercobilin produces the color of stool.
This term is no longer used. Now, it is called urobilinogen (which makes the color of the
pigment). It is easier to understand the concept. So, the unconjugated bilinogen is broken
down to urobilinogen - ound;
however, when you oxidize them, they have color. So, urobilinogen, when it becomes
oxidized in the stool becomes urobilin, which is the color of stool.
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 A small portion of urobilinogen is reabsorbed out of the colon. Most of it goes back to the liver.
A little of it goes to the kidney and ends up in the urine, where it get oxidized into urobilin. This
is the cause of the color of urine. So, the same pigment that colors stool is responsible for
coloring urine.

We were taught that stercobilinogen is in the stool and urobilinogen is in the urine; however,
sterco = uro, so the same compound is responsible for color change in feces and urine. They
are not differents pigments, they are the same.

If you have obstructed bile flow (in the liver or Common Bowel Duct), what should the color of
the stool be? Light colored because the urobilinogen would not have access to the stool to
color it. Also, would not have urobilinogen in the urine. This leads to jaundice.

II. Jaundice
To calculate jaundice, they take the total bilirubin and find out the percentage of bilirubin that is
conjugated (direct bilirubin).

Example: total is 10, conjugated = 5, therefore conjugated bilirubin = 50%. So, they subdivide
jaundice into 3 types conjugated bilirubin less than 20% (therefore most of it is
unconjugated), between 20-50% (therefore some is conjugated and unconjugated), and
greater than 50% (most of it is conjugated bilirubin). Its also means that you have
obstruction.

If it is under 20%, this primary unconjugated hyperbilirubinemia.

What can increase unconjugated bilirubin? Hemolytic anemias, spherocytosis, Sickle Cell
Anemia Disease, ABO hemolytic disease of the newborn, Rh hemolytic disease of the
newborn, physiologic jaundice of the newborn (because they cannot conjugate it). So, there is
increased unconjugated bilirubin because breaking down more Red Blood Cell, have problems
with conjugating enzymes either too immature or they are missing enzymes (Craigler Najjar
syndrome). So, we are either making too much because we are breaking down too many
Red Blood Cell or we have a problem with conjugating enzymes which is little babies with
physiologic jaundice disease of the newborn, or rare diseases where we are deficient in the
enzyme (Craigler Najjar).

The diseases between 20- 50% are hepatitis. Hepatitis = inflammation of the liver (not just
some of it, all of it). So, because
unconjugated bilirubin. Unconjugated liver builds up behind the liver. Inflammation in
the liver will maybe destroy the architecture in the liver and break open bile ducts that
have conjugated bilirubin in them. Now, because you have disrupted the architecture,
there is a possibility of water soluble bilirubin to get into the blood stream (because there is
necrosis of liver cells and bile ducts so you will get conjugated bilirubin in there, too) -
leading to 20-50%. This includes all the hepatitis (including alcoholic).

If it is greater than 50%, this is an obstruction of bile. We have intrahepatic obstruction

(intrahepatic cholestasis), meaning that you are blocking bile flow in the liver (triad is
blocked). Also have extrahepatic cholestasis (outside of the liver). There is only one thing
outside the liver that can lead to this CBD (common bile duct). Therefore, something is
obstructing that a stone in the common bile duct that came from the Gallbladder (play odds).
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 Can also have carcinoma of the head of the pancreas because ducts go through the head
of the pancreas. As a result, you have complete bile duct obstruction. So, there is intrahepatic
cholestasis and extrahepatic cholestasis.

So, what will happen is like water behind a dam (reservior). If you block bile flow, it will back
up = where it was made (the liver cells remember this is an excess of conjugated, direct
bilirubin). In the liver cells, it bubbles outside, and has access to the sinusoids and now is in
the blood stream. So, the predominant factor in the blood stream is CONJUGATED bilirubin,
which is water soluble. So, will have very dark yellow urine and the stool will be LIGHT
colored.

This combo high conjugated bilirubin, bilirubin in the urine (HAS to be conjugated
because e), and light colored stools =
OBSTRUCTION (nothing else can do this, and it is either intrahepatic or extrahepatic).

A. Congenital Unconjugated hyperbilirubinemias

Seen if you fast for over 24 hours and get jaundice, Autosomal Dominant, b9
(therefore do not need a biopsy). Mechanism: problem in taking up bilirubin and
problem in conjugating bilirubin, therefore it is predominantly an unconjugated
hyperbilirubinemia. So, if you want to see if pt has it, do 24 hr fasting test. So, get

er fasting
test and is 2.5.

(Most Common cause of jaundice = Hepatitis A), 2nd Most Common Cause of jaundice = Gilberts
syndrome

stick = he has because

was fasting (enzyme levels are normal, high unconjugated bilirubin levels). Treatment? Nothing

2. Criggler Najjar

B. Congenital Conjugated hyperbilirubinemias

1. Dubin Johnson AND Rotor syndromes: Genetic disease involving problem

getting rid of CONJUGATED bilirubin in the bile ducts. So, this is predominantly a
conjugated hyperbilirubinemia. In Dublin Johnson, have a black colored pigment that
builds in the liver and get black liver.

III. Liver Function Test (LFTs)

Transaminases = indices of liver cell necrosis (hepatitis). (SGPT) ALT is more specific
because it is only found in the liver; (SGOT) AST

In Viral hepatitis, with massive liver cell necrosis, which would be the predominant
transaminases elevated? ALT. I Ex: 2500 ALT and 2200 AST. So ALT will
be the main liver cell enzyme elevated in diffuse liver cell necrosis.
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 In alcoholic hepatitis, this is not what happens. There is a reason: AST is present in the
mitochondria of hepatocytes. Alcohol is a mitochondria poison (remember that it uncouples).
AST is predominantly in mitochondria, and when pt has alcoholic hepatitis, AST is higher
than ALT (forget the 2:1 relationship).

AST ALT = alcoholic liver disease or fatty change or alcoholic cirrhosis, and alcoholic
hepatitis.

ALT AST = Viral Hepatitis

So, what are the enzymes of obstruction of bile ducts? Alkaline phosphatase and
Gamma glutamyl transferase. Transaminases will also be up, but not to the same degree.

Gamma glutamyl transferase is located in the Smooth Endoplasmic Reticulum. When

the SER is stimulated, it undergoes hyperplasia (Ex. due to drugs: alcohol, barbiturates,
rifampin, and phenytoin); you not only increase the metabolism of the drug, but also increase
the synthesis of gamma glutamyl transferase.

What would the classic thing you would see in any alcoholic liver disease? AST>ALT, along
with INCREASED gamma glutamyl transferase.

There is a problem: alkaline phosphatase is in oth in bone

(osteoplastic activity) and in placenta.

How will you know where the alkaline phosphatase comes from (Ex.
obstruction vs. other things)? Look at gamma glutamyl transferase because it is specific for the
liver. If the gamma glutamyl transferase IS elevated along with alkaline phosphatase, this is
BILE DUCT OBSTRUCTION.

Albumin protime = marker of severity of liver damage. It is made in the liver, therefore if
you have severe liver disease (Ex. cirrhosis), it will be decreased. Even better than that is
prothrombin time because coagulation factors are made in the liver (most are made there
von Willebrand Factor is not). So, if you have liver damage, the production of coagulation
factors will be decreased, and PT will be prolonged (increased). So, albumin levels and PT
are the 2 best tests for liver severity (PT is a little better than albumin).

There is only one autoAntibodies that is important: anti mitochondria Antibodies in primary
biliary cirrhosis.

Tumor markers: alpha feto protein is a marker for hepatocellular carcinoma. Can also
use alpha-1 antitrypsin because it is made in the liver (it is increased in hepatocellular
carcinoma).

If you have fractionation of bilirubin (less than 20%, 20-50%, and 50+ %), can start differential
diagnosis; then give transaminase levels see how it correlates with liver disease:
transaminases correlate with viral hepatitis and conjugated bilirubin of 20-50, or obstructive

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 liver disease (alkaline phosphatase, gamma glutamyl transferase) and conjugated bilirubin
over 50%.

Audio File: Day4 5Hepatobilliary-Pancreas1

IV. Viral Hepatitis

A. MC on hepatitis:
Most Common hepatitis = A (followed by B, C, D, E in that order)
Hepatitis A and E = transmitter by fecal oral; all the others are transmitted parentally.
Hepatitis A = No produce chronic carrier state.
Hepatitis E = produces a chronic carrier state only if you are pregnant, leading to
chronic liver disease.
Hepatitis D = Requires Hepatitis B to infection.
Hepatitis A = Get in a Daycare centers (therefore should get vaccine to prevent;
outbreaks can occur in daycare centers).
Hepatitis A = get in Jail.
Hepatitis B = Intravenous Drug Abuser
Hepatitis C = Post transfusion Hepatitis.
Hepatitis B = Most Common infection by accidental needle stick.

B. Serology:

HAV (Hepatitis A Virus): antibody Hepatitis A IgM= have hepatitis A (acute); antibody
hepatitis A IgG (protect you long time) = had hepatitis .

HCV (Hepatitis C Virus): antibody Hepatitis C IgG is NOT protective and means that
you have the disease; there are no known protective Antibodies.

HDV (Hepatitis D Virus): (same as HCV) antibody Hepatitis D IgG = have the
disease, and no known Antibodies will help cure; if you are antibody Hepatitis D IgG
positive it means you have the active disease now.

So, only protective Antibodies are HAV, HBV (surface Antibody) and HEV.

Hepatitis B Virus (HBV)

1. First marker is surface Antigen (HBsAg). It comes up about 1 month after you
hav
studies are normal.

2. The next thing that comes up is the bad guys: E Antigen (HBeAg) and HBV DNA,
because these are only ones that are infective.

3. Then the first Antibody comes up a little after the DNA and E Antigen, which is core
Antibody IgM (Anti-HBc) or (HBcAb) (this is expected because the first Antibody
against acute inflammation is IgM).

The majority of people with Hepatitis B recover (about 90%); those with HIV+ never
recover and will have chronic cases because they have no immune response to knock it
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 off. If you do recover the first things to go away are E Antigen (HBeAg) and HBV
DNA and the last of the Antigen that goes away is surface Antigen (HBsAg).

So, surface Antigen

look at the chart and will see that Surface Antigen is the big house and E
Antigen and HBV DNA are the little houses under big house).

In other words, it is IMPOSSIBLE to be E Antigen positive and Surface Antigen negative

(E Antigen and HBV DNA come up after Surface Antigen and leave before).

Surface Antibody IgG Surface Antigen is

gone, so there is this gap, which window period with nothing elevated (only has
one Antibody there; Surface Antigen, E Antigen, HBV DNA are all gone, and Surface
Antibody not there yet).

How do you know the pt HAD Hepatitis B? Core Antibody it

stays there and becomes IgG over time. So, the marker for that window period when
all the bad guys are gone and surface Antibody IgG the marker is
core Antibody IgM (which tells you that you HAD Hepatitis B and are in the process of
recovery). There is no way you are infected during this period why? Because E
Antigen and HBV DNA are not there. Therefore, you are not infective it just means
that you HAD Hepatitis B and are in the process of recovering. YOU ARE NOT
INFECTIVE this is between the 5th and 6th month.

So, if you had Hepatitis B, there should be 2 Antibodies that you have: core Antibody
IgG and surface Antibody IgG.

If you have been vaccinated, cannot have anything because you had yeast make
surface Antigen IgG, which is what the vaccine consists of. The only bad Antibody you
can get from injecting surface Antigen is Antibodies against it. So, only Antibody you
will have if you were vaccinated is Surface Antibody IgG. NOT core Antibody IgG
because were not injected with that. Core Antibody is not a protective Antibody.

C. Chronic hepatitis

D How long have you had surface Antigen ,

you have chronic Hepatitis B.

So, are you infective or not? are you an infective carrier or healthy carrier? You
automatically know if you are an infective chronic carrier if you have HBV DNA. This
means that you are a patient with chronic Hepatitis
walking hazard, and your intimate contacts need to be immunized because the diease
can be transmitted sexually to those people, or by Intravenous Drug Addicted

If you are negative for E Antigen and HBV DNA but are surface Antigen positive,
(this does not mean you are healthy you are
still a chronic carrier of Hep B). If you are a healthy carrier, however, the chances of
recovery are excellent because in about one year, Surface Antigen will disappear and
will come up. Will also have core Antibody IgG at this time this means that you have a
good chance of total recovery. Also have a good chance of recovery with E Antigen
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 because pt is a candidate for Alpha Interferon IFN therapy (Drug of choice).
Never give corticosteroids to any chronic viral infections.

D. Review:

What we expect in acute hepatitis B (what would the markers be)? Surface Antigen, E
Antigen, HBV DNA, and core Antibody IgM.

What if the pt is in the window period? Core Antibody IgM.

What if had Hepatitis B, but have recovered from it? Core Antibody IgG and surface
Antibody IgG.

What if pt was vaccinated (what is the ONLY thing you should have)? Surface Antibody
IgG.

What if you have at the end of 6 months Surface Antigen, core antibody IgM, with
everything else negative? Healthy carrier.

What if you have after 6 months surface Antigen, E Antigen, HBV DNA and core
Antibody IgM? Infective carrier.

V. Inflammatory Liver Disorders

A. Amebiasis: Entamoeba histolytica

Organism is resistant to acid swallow it and will not die in presence of acid. It ex-cysts in
the cecum, within an alkaline environment. Has a chemical that can drill a hole through the
mucosa, leading to flask shaped ulcers, and leads to bloody diarrhea. Unfortunately,
because the cecum is drained by the portal vein, and is forming an ulcer, there is a chance
that it can drill and hole, get into the portal vein tributary and get to the right lobe of the
liver, where it will produce an abscess. It will start dissolving the liver hence term
anchovy paste abscess because it looks like anchovy paste (a brownish liquid). If it
wants to, it can drill a hole through the right diaphragm, go to the lungs, and produce an
effusion, and go anywhere it wants in the systemic circulation brain. Treatment
metronidazole. Trophozoites ( The
only protozoa that can phagocytose is Entamoeba histolytica (no other amoeba can
phagocytose Red Blood Cells) this is a very characteristic finding. Metronidazole is
used in the treatment of giardiasis, Entamoeba histolytica, vaginosis, clostridium difficile,
and trichinosis.

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B. Hydatid Cyst disease

1. Definitive vs. intermediate host

*Definitive host = sexually active worms that have the ability to mate and lay eggs.

*Intermediate host = only have the larval form; do not have sexually active adults.

These are the stages: Adult, egg, larva. Adult lays eggs, and the eggs develop into
larva. If you have the larva form in you, it will stay there because
stage form. If
go anywhere else. If you have the adult form in you, it will give an egg, which
changes to larva. Larva form cannot go anywhere it is the end stage form.

(gonococcus vermicularis or unilicularis (?))

The sheep dog eats some sheep meat (there are larval forms in the sheep;
therefore, the sheep is the intermediate host). Dog eats sheep, and has larva in the
dog. The larva form develops into an adult within the dog, and the dog becomes the
definitive host. The dog has sexually active worms inside it and the worms lay eggs
within the dog. Dog is petted, gets eggs on their hand and into pts food, which is
eaten. So, now, the pt has the egg, which develops in the larva (cannot go any
farther because larval form is end stage), and the pt (human) becomes the
intermediate host. So, the sheep is an intermediate host, the dog is the definitive
host and the sheep herder is an intermediate host. Do not want to rupture these
cysts, because if the fluid gets into the abdominal cavity, leads to anaphylactic
shock.

C. Tenias Solium (pig tapeworm)

You go to a barbecue and eat undercooked pork (larva in the pig meat, which is
eaten). The larva develop into the adult form within the pt (so, there is a sexually
active worm inside). So, pt becomes definitive host, while the pig was the
intermediate host. Now you have a family member that is a definitive host (has
sexually active worms inside them) lets say this family member is making salad

pt eats the salad with the eggs in it. What is the egg going to form inside me? Larva.
What is this called cystocerci. Do they form adults? No, stops there. Therefore, pt
has cystocercosis. What are the larvae going to do? They like the eye and the
brain (where they form a cyst in the brain, calcify and lead to seizure activity
. So, in this disease, the pt can have two forms of it. If
pt ate the infected pig, they can be the definitive host. If you get the egg in your

287
 mouth, you become an intermediate host, and the egg can become larva, which will
go on to cystocercosis. So the larvae form is the dangerous form in Tenia Solium.

(Most Common complicartion of glucocorticoids therapy = cataracts)

VI. Nutmeg Liver

*Most Common Cause of nutmeg liver = Right Heart Failure

Thrombus in portal vein will NOT lead to nutmeg liver because portal vein is before emptying
into the liver. Would you have ascites? Yes. Portal Hypertension? Yes. Varices? Yes. But is
liver big and congested? No.

Thrombus in hepatic vein: is called Budd Chiari syndrome (the Most Common Cause of
buddy chiary syndrome is polycythemia Rubivera, 2nd Most Common Cause = birth control
pills. In this condition, would you have a nutmeg liver? Yes hepatic vein empties the liver.

You get a huge liver, and are a surgical emergency and die
pre/post hepatic thromboses
(Prehepatic = portal vein, posthepatic = hepatic vein).

VII. Alcoholic liver disease

Most Common manifestation is fatty change (steatosis).

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 Because
acetate, and acetyl CoA. h pyruvate and convert it into lactate leading
to fasting hypoglycemia, and metabolic acidosis. Acetyl CoA can make Fatty Acid and
glycerol 3 phosphate and Tryclicerides and fatty change, or can be converted into ketone
bodies, which causes an increased anion gap: metabolic acidosis. Fatty change is reversible if
the alcoholic stops drinking.

Alcoholic hepatitis is very bad; can have hepatic encephalopathy, ascites, etc. Alcoholic
hepatitis is different from fatty change because there is fever, neutrophilic leukocytosis,
very high AST>ALT, and gamma glutamyl transferase is up.
you do not stop drinking you will die. It is very serious systemic disease. If pt hospitalized for
alcoholic hepatitis, is released and takes alcohol, they will die.

See Mallory bodies (ubiquinated keratin microfilaments).

Toxic compound that causes cirrhosis is acetaldehyde bound to a protein, not acetaldehyde by
itself. Ito cell normally is the cell that stores Vit A. In an alcoholic the acetaldehyde protein
complex stimulates the Ito cell to make fibrous tissue and collagen. The Ito cell, which is
responsible for storing vit A, is now putting down collagen tissue and is responsible for causing
fibrosis. Fibrous tissue is a big part of alcoholic tissue disease.

VIII. Cholestasis

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Cholestasis = obstruction to bile flow, due to a stone in the Common Bower Duct. Ex:

have a cholesterol stone with a deep green colored liver.

Bile is blocked, which has conjugated bilirubin in it and is backed up into the liver. The
conjugated bilirubin will eventually reflux into the sinusoids, and leads to bilirubin in the urine
and light color stools, with NO urobilinogen in the urine. The yellow urine is due to water
soluble conjugated bilirubin in the urine.

What enzymes are elevated? Alkaline phosphatase and gamma glutamyl transferase.

What is the mechanism for getting rid of cholesterol? Bile. So, you reflux cholesterol,
bilirubin and bile salts (they are all recycled). Would it surprise you that they have
hypercholesterolemia, too? No because it is recycled. The bile salts deposit in the skin,
leading to itching.

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 2 other causes of cholestasis:

*Bile duct radical, surrounded by fibrous tissue, bloody diarrhea with Left Lower
Quadrant crampy pain, jaundice what is the Inflammatory Bower Disease? Ulcerative
Colitis.

*Common bile duct surrounded by fibrous tissue diagnosis? Primary sclerosing

cholangitis.

*Most Common Cause of primary sclerosing cholangitis = Ulcerative Colitis.

*What cancer can develop because it involves the bile duct? Cholangiocarcinoma (Most
Common Cause of cancer in bile duct in this country), in 3rd world countries, it is due to
Clonorchis sinensis Chinese liver fluke).

IX. Primary Biliary cirrhosis

50 years woman with generalized itching, find enlarged liver

on Physical Examination, normal bilirubin (no jaundice),
alkaline phosphatase and gamma glutamyl transferase are
huge (obstructive type of enzymes), transaminases are
elevated diagnosis? Primary biliary cirrhosis, which is an
autoimmune disease that leads to granulomatous destruction
of the bile ducts in the portal triad.

W because pt has a reserve of triad that can handle the

bilirubin. Therefore, there is no reason to have jaundice early and it comes late. What is the
Antibody to order in this pt? Anti-mitochondrial antibodies

X. Drug effects
Birth control oral contraceptic pills (OCP) and anabolic steroid have the same effect on
the liver.

The OCP and anabolic steroids both produce intrahepatic cholestasis. Ex. weight lifter
aline
phosphatase and gamma glutamyl = due to steroids (not hepatitis).

One of the Most Common Causes of jaundice in pregnancy is b9 intrahepatic

cholestasis. This is because of the estrogen during pregnancy, causes intrahepatic
cholestasis. Treatment? Deliver baby (goes away after delivering baby). Lets say woman
takes OCP and gets jaundice; when she become pregnant, she will develop jaundice, too
because of the estrogen effect.

Both of
these drugs also predispose to a b9 liver tumor, called liver cell adenoma (hepatic
adenoma.) It has a nasty habit it likes to rupture, leading to intraperitoneal hemorrhage
(which can kill you).

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 Board Question: Weigh
suddenly becomes hypotensive and collapses. Find abnormal liver/cavity what is
most likely cause? Ruptured liver cell adenoma because pt is on anabolic steroids.

intrahepatic cholestasis (which goes away if you stop the drug) and liver cell adenoma
which is susceptible to rupture.

For women, if they are on birth control, then get off it to get pregnant
liver cell adenoma they did not know about (that developed with OCP use), then get pregnant,
then get an intraperitoneal hemorrhage, and then what is differencial diagnosis? Ruptured
ectopic pregnancy or rupture intraperitoneal hemorrhage. Step 2: pregnant women have the
tendency to have splenic artery aneurysm = rupture.

XI. Hemochromatosis

Example: hyperpigmented pt adult that is diffusely

hyperpigmented and has diabetes (type I diabetic) = bronze diabetes = hemochromatosis =
Iron (Fe) overload, autosomal recessive, reabsorb too much Fe.

Hemosiderosis is acquired iron overload by being an alcoholic. Iron supplements are

contraindicated in the elderly because it will create hemosiderosis and have iron overload.

Back to hemochromatosis: isease and what happens is that

instead of reabsorbing 10-15% of iron from foods, you are absorbing 100% of iron. Target
organ is the liver. Whenever Fe is absorbed into cells, it produces hydroxyl free radicals. So,
droxyl free radicals Fenton
reaction). If you are damaging liver cells, will lead to fibrosis and cirrhosis. They ALL have
cirrhosis in Fe overload, either by hemosiderosis or hemochromatosis.

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 In cirrhosis Kupffer Cellls with prussian blue staining iron, next
you see liver with brownish pigment, Prussian blue stain (to see Fe), and a VERY HIGH
incidence of hepatocellular carcinoma.

Pancreas therefore can have EXOcrine

and ENDOcrine dysfunction, leading to malabsorption. Destruction of islet cells leads to
very brittle type I diabetes. Also deposits in skin and lead to hyperpigmentation (bronze look).
This is a combo of Fe depositing there and by stimulating melanocytes, therefore there is Fe
pigmentation and melanin. Can go into joints and lead to polyarthritis, can go to pituitary,
leading to hypopituitarism, can go to heart and produce restrictive cardiomyopathy. How you
do screen for iron overload? Serum ferritin. Serum Fe = high. Excess Fe stores, therefore
decreased syn of transferrin. The TIBC is decreased. % saturation is increased, serum ferritin
is increased. Treatment? Phlebotomy. Do not use chelation therapy. They purposely make
you Fe deficiency. This disease is the next to the most common autosomal recessive disease.
Hemosiderosis = ACQUIRED Fe overload from alcohol.

Kayser Fleischer ring: brown ring around cornea. What is

degeneration called? Hepatolenticular degeneration. Pt with abnormal movement (chorea)
disorder, dementia, and cirrhosis. Auto recessive. Defect in secreting Cooper (Cu) in
bile and synthesis of ceruloplasmin (binding protein of copper). So, the Cu builds up and
accumulates in the liver. Very toxic. So, over a period of months to years, you go from chronic
active hepatitis to cirrhosis.
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 When you get a total Cu level, what does it include? Free Cu and binding protein for Cu. The
binding protein is called ceruloplasmin. So, some Cu is attached to ceruloplasmin. So, the
total Cu measured includes bound and free. 95% of a normal total Cu level is related to Cu
attached to ceruloplasmin. So, most of the total Cu level is bound to ceruloplasmin, not the Cu
that is free.

So, 95% in a normal person the total copper is Cu that is bound and inactive to
ceruloplasmin. So, is ceruloplasmin a protein? Yes. So, with cirrhosis, are you synthesizing
ceruloplasmin? No. Therefore, there is a decrease of binding protein for Cu. So, free cu
increased. So, the total Cu level is decreased (because decrease ceruloplasmin), but the
free Cu is increased in blood (more unbound). Treatment? Penicillamine (Cu binder).
Lenticular nucleus messed up (caudate nucleus in Hepatic Disease).

Audio File: Day4 6Hepatobilliary-Pancreas2

XIII. Cirrhosis

Never focal, always diffuse. The bumps all over it are called
regenerative nodules.
and something has to stimulate it to go into the cell cycle to divide. The liver has an amazing
regenerative capacity. Regeneration of liver cells is hepatocytes with no triad, no central
vein, and no sinusoids. Just wall to wall hepatocytes which are worthless. Bumps are
regenerative nodules; there are just wall to wall hepatocytes surrounded by fibrous tissue
and inflammation. This is a combination Micro and Macronodular Cirrhosis.

Starts off as micronodular (less then 3 mm) and ends up

macronodular (over 3 mm). So, have liver, but cells not working. How is a portal vein gonna
portal
Hypertension.

Complications: Pitting edema, ascites, esophageal varices, and metabolic problems (cannot
metabolize estrogen, leads to gynecomastia). Cannot look at gynecomastia, have to feel it.

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Side effects of problems of estrogen metabolism:

Side note: There are 3 times in a lifetime where males can

develop gynecomastia.

1. Newborns males have boobs because estrogen from mom; newborn girls with
periods because estrogen from, then drop off (decrease), leads to bleeding.

2. Males also get boobs in teens (puberty).

3. Males also get boobs when they turn old because testosterone goes down and
estrogen goes down, leading to gynecomastia so, get boobs (gynecomastia) three
times throughout life, and this is normal.

Board Question: 13 years boy unilateral subareolar mass, what is management? Leave
it alone. Gynecomastia is not always bilateral, it is usually unilateral. Women have
different size breasts because each breast has different susceptibility to estrogen,
progesterone, and prolactin. Men do not have breast tissue, therefore more likely that
one will enlarge, the other will not.

Palmer erythema (related to estrogen),

spider angioma

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 Vitamins deficiencies like Folate Deficiency (Glossitis
in alcoholic) and dupatron (fibromatosis increased fibrous
tissue around the tendon sheaths, causing fingers to coil in, commonly associated with
alcoholics) these are all estrogen abnormalities.

Complication of Ascites:

*Adult with ascites and spontaneous peritonitis is due to E coli.

*Child with nephrotic syndrome and get ascites and spontaneous peritonitis, due
what is the organism? Streptococco pneumoniae.

XIV. Hepatocellular carcinoma Multiple Metastasic Nodules

Nodularity; Cancer in hepatitis vein tributary .

This cancer almost always develops in the background of cirrhosis, look the right side
large mass on the corner. It is very rare for hepatocellular carcinoma to develop
without cirrhosis present.

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Most Common Cause of cirrhosis: Alcohol

Most Common Cause of hepatocellular carcinoma = pigment cirrhosis in

hemochromatosis; hepatitis B and C.

This cancer can produce ectopic hormones:

1. Erythropoietin (EPO) (leads to 2ndary polycythemia)

2. Insulin - like factor (leads to hypoglycemia). Tumor marker: alpha feto protein.

Example: pt with underlying cirrhosis, and is stable. But suddenly the pt begins to lose
weight and ascites is getting worse. Do a peritoneal tap and it is hemorrhagic (do not
assume it is traumatic from the needle, unless they say it). If there is blood in the
acidic fluid it is pathologic bleeding. It is hepatocellular carcinoma, but will ask what
test do you do? Alpha feto protein.

*Key for the exam:

If they say multiple things or many tumors = metastasis.

If they say what is the primary cancer to nonsmoker? Colon cancer, so

the 2nd Most Common Cause is colon cancer
smoking like (Polyp).

Remember, The Most Common Cause of small bowel obstruction is adhesion from
previous surgery, but if the pt did not have any surgeries then the 2nd cause is indirect
inguinal hernia.

Gallbladder Diseases

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I. Ask about pathogenesis of stone too much cholesterol in bile or too little bile salts. You

will have a supersaturated stone with cholesterol will get Yellow

cholesterol stone (Most Common stone). Or, too little bile salts, both lead to stones. Anything
that causes bile salt deficiency from (cirrhosis, obstruction, Cholestyramine, C
can lead to gallstones because too little bile salts.

II. Pigment stones

Board Question: 25 years female, Right Upper Quadrant crampy pain, fever, point
tenderness, neutrophilic leukocytosis, stones revealed on ultrasound. CBC showed a
mild normocytic anemia and a corrected reticulocyte count of 8%. Splenomegaly on
Physical Examination and family history of splenectomy.

Diagnosis? Congenital spherocytosis; because she has been hemolyzing Red Blood
Cell all her life, she puts a lot of bilirubin into conjugated bilirubin and therefore has
supersaturated bile with bilirubin, and forms Calcium (Ca) bilirubinate stones that are
jet black.

What is the screening test of choice for stones? Ultrasound. (can tell diameter of
Common Bile Duct to tell if there is a stone in it).

Ultrasound showing a stone following by white arrows.

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 Pancreas
*Screening test of choice in the pancreas = CT Scans reason why is because bowel overlies
pancreas and messes up ultrasound, therefore not as sensitive. Always put CT for pancreas.

I. Cystic Fibrosis dilated ducts filled with pink material.

Growth alteration because mucous in ducts of the pancreas. See atrophy because block
lumen of exocrine ducts, and pressure goes back to the glands and that pressure atrophies the
glands, leading to malabsorption.

Can cystic fibrosis also lead to diabetes? Yes because eventually fibrose off the islet
cells, leading to type I diabetes, too.

Biochemistry: Cystic Fibrosis = chromosome 7 with 3 nucleotide deletion, and those 3

nucleotides codes for phenylalanine. So, you are deficiency of phenylalanine in the cystic
fibrosis transmembrane regulator protein (CFTR). So, all its missing is phenylalanine.

Most things, after Protein are made in the ribosome in the RER, have posttranslational
modifications in the Golgi apparatus, which is where the real defect is. The real problem is
when it gets to the Golgi apparatus
cell surface. It ends up being degraded in the cell, and you end up not having the
Cystic Fibrosis transmembrane regulator protein and develop Cystic Fibrosis. So, the
problem is in the Golgi apparatus it screws it up, and never makes it to the surface, therefore
has no function.

So, what does it do? In the sweat glands, normally, it would reabsorb Na and Cl out of the
sweat gland. Because they are deficiency in this, they are losing salt, which is the basis of the
sweat test.

3 years kid, failure to thrive, chronic diarrhea, respiratory infection, mom states that the baby
ystic Fibrosis, because they
lose considerable salt and become salt depleted when they are overheated.

Why are all the secretions so thick in the lungs, pancreas, and bile ducts? Cystic Fibrosis
Transmambrane Regulator protein.

What does Cystic Fibrosis Transmembrane Regulator do? In lungs, need to have salt
and secretions in the lumens of the respiratory tract to keep it viscous (to keep it nice
and loose); if you are missing Cystic Fibrosis Transmembrane Regulator protein, *Na is
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 reabsorbed OUT of the secretions in the airway (dehydrated). And, *chloride
cannot be pumped into the lumen of the airway so you are taking away the 2
importants ingredients with this pump: taking Na out and not putting Chloride in.
Therefore these secretions are thick like concrete. The same is true for secretions in
the pancreas (Na pumped out and Cl not put in).

Most Common Cause of death in cystic fibrosis is = infection due pseudomonas

aeruginosa.

Fertility: what is chance of male and females with cystic fibrosis having children?

Male - 0-5% (most are infertile)

Females - They can get pregnant, but only have 30% chance of getting pregnant. The
problem is that the cervical mucous is as thick as concrete and therefore the sperm
cannot penetrate, and that is one of the reasons why they are infertile.

II. Acute pancreatitis

Most Common due to alcohol; 2nd Most Common Cause = stone caught in accessory
ducts of the pancreas. Amylase is elevated. Characteristic pain: Epigastric pain with
radiation into the back (because

Have a history of acute pancreatitis; after 10 days, have a mass in the abdomen and they ask
what do you do? CT Scan what is it? Pancreatic pseudocyst - a lot of fluid accumulates
around an inflamed pancreas and forms a false capsule and has a potential to rupture (not
good to have amylase in peritoneal cavity).

Right Upper Quadrant with dystrophic calcification (dots

on x-ray); what do you think it is? Pancreatitis.

*Is it acute or chronic? Chronic, because there are so

many.

*Is this pt likely to be an alcoholic? Yes.

*Which of the following you expect? Steatorrhea (one
of the causes of malabsorption need enzymes), or
hemorrhagic diathesis (because of Vitamin K deficiency

*Most Common Cause of Carcinoma of the head of the pancreas = smoker

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 Both with local invation in duodenal wall.

*2nd Most Common Cause of Carcinoma of the head of pancrea = chronic pancreatitis,
painless jaundice (mainly conjugated bilirubin), light colored stools, palpable
Gallbladder C sign permanently indenting the duodenum,
do barium study, also a sign of pancreatic cancer.

Board Case: Patient with Acute pancreatitis with inflammation

How does the bowel react to the presence of inflammation next to it? It stops peristalsing
(not through the entire bowel, just there).

If this is true, th what is this

called? Sentinel sign (sentinel is someone that is supposed to keep watch) keep watch of
what? Inflammation (so, the sentinel sign keeps watch of inflammation); the classic area is
t called: localized ileus (lack of peristalsis). Whenever the bowel lacks
peristalsis, will see air accumulate and will get distension.

What if you have a segment of bowel that is distended in the Right Lower Quadrant?
Has to be inflammation, the cecum is in the Right Lower Quadrant and appendix could be the

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 Chapter 11: Kidney
I. Cast mold of whatever is going on in the nephron/tubule. It is a protein that is congealing around
whatever is present in the tubule at that time; there is a mold made, and is passed into the urine and
we can see it under the microscope. This is important because, now we do not have to do a
renal biopsy of the renal tubules because the cast will tell you what is going on.

Example: if you have glomerulonephritis

(inflammation of the glomerulus), you have damaged the capillaries and get hematuria, so the
Red Blood Cells Red Blood
Cells cast that tells you there is a glomerulonephritis occurring.

Example: With renal tubule necrosis, the tubules are sloughing

off (take off the skin) with coagulation necrosis. This will form a cast and is called
Pigmented tubular cast, and will tell you there is renal tubular necrosis.

Example: man/woman with acute pyelonephritis with neutrophils

invading the interstitium and the tubules, there are cast of neutrophils (White Blood Cell
casts), telling me there is infection of the kidney.

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 Example: spilling lipid in urine in nephrotic syndrome and form cast
of fat and a fatty cast that you can see and polarize in the urine.

II. Urinalysis

Most common test order. The first thing that disappears in renal failure is the ability of
the kidney to concentrate urine. This occurs before Creatine/BUN think about increasing, or
even having renal tubular casts.

Example: taking urine in the morning and doing the specific gravity of the urine and seeing
what it is. Because, specific gravity can tell you if it is concentrated or dilute urine. If the
specific gravity is greater than 1.023, this means that the pt is concentrating urine and that
the kidneys are ABSOLUTELY NORMAL (this is a CHEAP test).

Example of urine overnight and it is 1.010 this is very

hypotonic urine, and it means that the pt could not concentrate, and that the pt is in renal
failure. (BUN/Cr will not help determine this). The urine that should be concentrated is from a
pt that is sleeping overnight.

* Hyaline cast cast of a protein; mostly b9/harmless

(all other casts have pathological significance). Means nothing.

III. Crystals:

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 Uric acid crystal looks like a star; pH of the urine has to be
acidic to form a uric acid crystal. Pt with gout want to stop crystals from forming, and you
know they form in low pH, what do you want to do with the urine? Alkalinize it. How can you
do that? Carbonic Anhidrase inhibitor (acetazolamide). By blocking bicarbonate
reclamation will alkalinize the urine, and prevent stones from forming. So, simple manipulation
of the pH can prevent urate nephropathy.

Calcium Oxalate crystal look like the back of an envelope; why is this
important to know?

Example: street person comes in, stupurous, has increased anion gap metabolic acidosis. Do
a urinalysis, and see bunch of calcium oxalate stones what did he drink? Ethylene glycol.
What is the Most Common stone we pass? Ca oxalate. So if you have a Ca Oxalate stone,
you will have crystals associated with it.

Horse shoe kidney joined at their lower poles.

Associated with Turner Syndrome.

BOARD QUESTION: Will ask what is restricting the movement of the kidney? Inferior
Mesentery Artery it traps the kidney.

IV. Cystic diseases of the kidney

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A. Infantile polycystic kidney disease
Which is autosomal recessive; therefore it is present at birth. Do you think this baby is
urinating? No, therefore has oligohydramnios (decreased amniotic fluid). So, baby is in an
amniotic sac, with hardly any amniotic fluid around it, and therefore have malformation due to
pressure.

Look at the nose and ears; this is called Potters

face, which is a sign of oligohydramnios in polycystic kidney disease: flattened nose,
low-set ears, and recessed chin). T , and when it tried to
they never fully developed because the kid

with life.

B. Adult polycystic kidney disease (APKD)

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 CT Scans of Adult Polycystic Kidney (bilateral enlargement)

Adult Polycystic Kidney Disease is an autosomal dominant disease that is not present
at birth because Autosomal Disease have delayed manifestations.

Adult Polycystic Kidney Disease is an incomplete penetrance. (normal parents,

they do not express the gene, but passed on to child.)

Some autosomal dominant disease show Penetrance have the abnormality when
they look for it on the gene, but do not express it. (So you have the genetic abnormality,
but have never expressed it in your life). The bad news is that you can transmit it to
your child, therefore it is difficult to recognize on the pedigree.

Example of penetrance: familial polyposis = 100% penetrance if you have the gene,
you have the disease.

Example of incomplete penetrance: marfan abnormality on chromosome 15.

See cysts by 10-12 years of age, always get *Hypertension

which will then predisposes 2 types of bleeds:

(1) Charcot-Bouchard aneurysms (a blood clot).

(2) See blood all over the brain, due to subarachnoid hemorrhage; therefore the
blood is due to rupture berry aneurysm. Subarachnoid hemorrhage

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 *MVP (mitral valve prolapse): Example: history of Hypertension, abnormality of
ultrasound in the renal pelvis, and had click murmur (therefore Mitral Valve
Prolapse) diagnosis? Adult Polycystic Kidney Disease. There is a high association
of Mitral Valve Prolapse with this.

*Diverticulosis also has a high incidence. Example: pt with Hypertension,

abnormality on ultrasound in renal area, lost 600 mls of blood all of a sudden,
leading to hematochezia (Most Common Cause of hematochezia = diverticulosis),
Diagnosis? Adult Polycystic Kidney Disease.

V. Glomerular stuff

A. Nomenclature of the Kidney disease:

(glomerulonephritis).

Example: IgA glomerulonephritis, diffuse membranous glomerulonephritis? Yes

*When we say = EVERY glomerulus has something wrong with it on renal

biopsy.

*What is ? Not all glomeruli involved.

*What if disease is focal and disease in the glomerulus is focal? Have a problem this
is called Focal Segmental Glomerulus.

*What does proliferative mean? Have lots of them. So, you have many nuclei. If all the
glomeruli have a lot of nuclei, this is diffuse proliferative glomerulonephritis

*If you just see thick membranes, its membranous glomerulonephritis

*If you see both increased cell and thickened membrane? Membranoproliferative
glomerulonephritis

Audio File: Day4 7Renal1

B. Anatomy/schematic

The order is: blood, endothelial cells of the

capillaries, underneath there is a Basement Membrane, and then the visceral epithelial
cells (looks like feet = podocytes); which have spaces in between them called slit
)

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 pores) that line the capsule. Who makes/synthesizes the Glomerular
Basament Membrane? Visceral epithelial cells (podocytes).

What keeps Albumin out of the urine normally? Strong negative charge of the
Glomerular Basement Membrane. Who is responsible for strong negative charge of the
Basement Membrane? A Glycosaminogycan GAG called heparan sulfate, which has
a strong negative charge.

If we immunologically damage the visceral epithelial cell, what do we

automatically also damage? The Basament Membrane
spill a lot of protein in the urine, which means you potentially can have nephrotic
syndrome if you spill >3.5 grams in 24 hours).

C. Test on Renal Biopsy

Stains routine H & E hemotoxylin stains, silver stains. Immunofluorescent stain
pattern can be linear or granular (like lumpy bumpy), which are the only 2 patterns.

These patterns are immune complexes or patterns/Antibodies that they are detecting.
Take biopsy, and have Antibodies with a fluorescent tag on them. Ex. want to see IgA
in the glomerulus and have anti IgA Antibody with a fluorescent tag if there are any, it
will attach to it and make a fluorescent tag.

There are also tags for IgG, C3, fibrinogen

glomerulus and an idea of what pattern it is in (like linear vs. lumpy bumpy granular
pattern).

ell us where these things are, it just tells us that they are there. What tells us
where immune deposits and immune complexes are located are Electron Microscopy

. So, we do stains, fluorescence, and Electron Microscopy.

How can we tell that the podocytes are fused? Can only tell by Electron Microscopy
because its so small.

VI. Difference between Antibody recognition vs. immune complexes

Detect with Antibody which have 2 Antigen recognition sites on the Antibody.

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 Goodpasture syndrome is an IgG anti Basement
Membrane Antibody. So, they get in the blood they get into the glomerular capillary and are
directed against the Basement Membrane. Wherever there was a spot on the Basement
Membrane you will see an IgG Antibody the Basement
Membrane without IgG. So, what if we do a fluorescent tag for IgG overlying the glomerulus
what would you see? Would see outlines of all the Basement Membrane of the entire
glomerulus. It is linear.

Most Common Cause of linear pattern on immunufluorescence = Goodpastures.

Immune complexes Antigen with Antibody attached and is circulating in the bloodstream,
hence Antigen-Antibody complex Ex. lupus = immune complex disease: Antigen =
DNA, Antibody = anti-DNA they attach to each other and float around and deposit in certain
places; in this case it will deposit in the glomerular capillary; type III Hypersensitivity
(because immune complex). Because they are immune complexes, they are larger than
individual Antibody because they are Antigen and Antibody attached together therefore they
are bigger, have different solubilities, have different charges
the glomerulus. So, depending on the size and charge will depend on where they locate
themselves. Ex. if too big, will locate under the endothelial nucleus.

So, this would be called a subendothelial membrane they are so big that they fit under a
podocyte (they cannot get through the Basement Membrane). Lupus is like this, too they
cannot get passed the Basement Membrane and hangout under the endothelial cells.
Post streptococco Glomerular Nephrytis bacterial Antigen with Antibody against
(immune complex), which is very small, and very soluble. They can go all the way past
the Basement Membrane and deposit under the epithelial side this is a subepithelial
deposit.

So, how do you find out where the deposits are? Cannot see with immunufluorescence, but will
be able to see with Electron Microscopy because they are electron dense (meaning that they
increase the density wherever they are). So, immune complexes have diff solubilities, diff
charges, and randomly go underneath the endothelium, under the subepithelial surface; they
will not have a nice smooth linear pattern like anti basement membrane Antibody.

Example: disease s not Goodpastures) it could be any immune

complex disease lupus, post streptococco, IgA glomerulonephritis. Can get a hint of
what the disease is, depending on what is in there.

What is the only glomerular nephritis that you can only diagnosed with
immunufluorescence? IgA glomerulonephris. The only way to accurately diagnosed IgA
glomerulonephritis is to prove that it is IgA and nothing else.

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 Granular/lumpy bumpy pattern when you see this,
what does it mean? Immunocomplex type III disease; remember anti Basement
Membrane and anti Basement Membrane Antibody against the Basement Membrane is
not a type III, but a type II. Whereas, immune complexes are type III.

VII. Nephritic vs. Nephrotic Glomerulonephritis

There are 2 types of glomerulonephritis: nephritic or nephrotic (cannot be both at same

time; however, it can start out nephritic and become nephrotic)

A. Nephritic Syndrome:

Has unique cast that is red, and looks like biconcave disk (Red Blood Cell casts)
(unique to nephritic disease); because you have inflammation you will spill protein, but
not greater than 3.5 grams in a 24 hour period (because if it did, it would be nephrotic)
so it is mild to moderate proteinuria.

You are spilling protein, but not to the same level as nephritic. If are inflaming the
glomerulus, will you have oliguria? Yes all the glomerular capillaries have swollen
up, Glomerular Filtration Rate (GFR) would decrease, and this would lead to oliguria.

Are you decreasing the absorption or not filtering Na? yes.

Does the Na build up? Yes therefore run the risk of Hypertension.

Classically, what you see in nephritic disease (hemat

Hypertension, and mild/moderate proteinuria (this is the definition)

B. Nephrotic Syndrome:

Has a different cast (fatty cast), have greater than 3.5 grams of protein in a 24 hours
urine sample. Will also have pitting edema.

So, if you started out nephritic (RBC casts, mild/moderate proteinuria) and all of a
sudden you start seeing pitting edema and ascities, start seeing over 3.5 grams of
protein in the urine over 24 hrs, and fatty casts then nephritic has become
nephrotic.

VIII. Nephritic Syndromes

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A. Acute Diffuse Proliferative Glomerulonephritis
All the glomeruli are diffuse, too many nuclei

B. Post streptococco Glomerulonephritis

Example: scarlet fever 2 weeks ago, presents with hematuria, RBC casts, mild to
moderate proteinuria, Hypertension, periorbital puffiness.

Electron Microscopy: lumen of capillary, bump on lumen

is endothelial cell, underneath is Basement Membrane (grayish), and epithelial cells
under. Has boulders that are denser than the normal glomerular Basement Membrane
these are immune complexes. In this case, it the bacteria is the Antigen-Antibody
immune complexes. Which side are they closer to? Closer to epithelial side, therefore
they are subepithelial deposits hence post streptococco Glomerular Nephritis.

C. Lupus Glomerularnephritis

35 years (meaning you have anti

DNA Antibody present), diagnosis? Lupus. Lupus almost always involves the
kidney. There are 6 types, and the important one to know is Lupus type IV, which
is a diffuse proliferative glomerulonephritis, which is the Most Common overall one
seen in Lupus. Has many nuclei, therefore proliferative; has wire loops.

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 (Electron Microscopy) deposits in Basement
Membrane are anti DNA deposits. Would you agree that they are in the endothelial
cell? Yes. So what is this location? Subendothelial deposits. Podocytes with slit
pores in between are not fused because if they were, it would be nephrotic syndrome.
Also see lumen, endothelial cells and deposits. Immune complexes are so big they
asement Membrane.

D. Crescentic Glomerulonephritis

Glomerulus surrounded by proliferating cells that are parietal cells because not in the
glomerulus, and has crescent shape, hence the name crescentic glomerular nephritis.
This is the WORST glomerular nephritis to have because in 3 months; pts will go
into acute renal failure and die unless pt is on dialysis. Many diseases have a
crescentic glomerulonephritis, but the only one I need to know is Goodpastures;

this is a NEPHRITIC disease; this disease has

crescentic glomerulonephritis on biopsy (therefore a BAD diagnosis).

IX. Nephrotic Syndromes:

Pt with casts (fatty casts), polarized specimen with Maltese cross

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 This is cholesterol in the urine. When cholesterol is
polarized, it looks like a maltese cross. These fatty casts are pathonognomic for
nephrotic syndrome. Greater than 3.5 grams protein for 24 hours, fatty casts in the
urine, ascites, pitting edema, risk of spontaneous peritonitis if you are a child.
Organism? Streptococco pneumonia in kids, E. coli in adults.

A. Lipoid nephrosis (Minimal Change Disease):

Example: Electron Microscopy of 8 year old boy that had

an Upper Respiratory Infection one week ago, and now is all swollen, has pitting
edema throughout body (anasarca) and ascites, normo-tensive; saw nothing on
renal biopsy; but then did a Electron Microspy see Red Blood Cell in glomerular
capillary lumen. So, see endothelial cells, see Basement Membrane (without electron
dense deposits), podocytes (fused) fusion of podocytes is ALWAYS seen in any
cause of nephrotic syndrome. Maltese crosses in urine. Diagnosis? Lipoid
nephrosis.

All pt with nephrotic syndrome have hypercholesteremia. Since they have

glomerular disease and some of the cholesterol can get into the urine, some can form
casts in the urine. Like minimal change disease. Why is this happening? Has lost
negative charge in Glomerular Basement Membrane, therefore albumin can get
through. These pts have a select proteinuria the only protein in this
albumin, and it is greater than 3.5 grams per 24 hrs. Treatment corticosteroids
(usually goes away in 1 year never to come back again). The Most Common Cause of
nephrotic syndrome in kids.

B. Focal Segmental Glomerulosclerosis

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 Example: pitting edema
therefore look at urine and note that is greater than 3.5 grams over 24 hours. Has fatty
casts in urine and has Hypertension. Do biopsy, and already know what you are gonna
see because it the Most Common Cause of nephrotic syndrome in AIDs pt. On
biopsy, some of the glomeruli are abnormal and others are normal, but only a part of the
glomerulus is messed up. Therefore, it is focal segmental. Because the renal
biopsy with Electron Microscopy and immunofluorence did NOT show deposits,
focal segmental
glomerulosclerosis. This is the Most Common lesion in AIDs pts and Intravenous
Drug Abuser. Next to rapidly progressive crecentric glomerulonephritis, this is the next
worse glomerular disease

C. Diffuse membranous glomerulonephritis

Example: adult with pitting edema, over 3.5 gram per 24 yrs, fatty casts. Do a biopsy
and see isease. However the Basement
Membrane is thicker. Diagnosis? Diffuse membranous glomerulonephritis = Most
Common Cause of nephrotic syndrome in adults. This is subepithelial deposit.

Epimembranous spikes spike like lesion on the outside of

Glomerular Basement Membrane seen with silver stain = diffuse membranous
glomerulonephritis (only one that looks like that).

Many things can cause this (drugs, cancer, nothing, infections); some the drugs include
NSAIDs, Hepatitis B, captopril (king of treatment of diabetic nephropathy and heart
failure), malaria, syphilis, colon cancer (immune complex is anti-CEA Antibody).
Eventually leads to renal failure and can die unless you get a renal transplant.

D. Type I and II Membranoproliferative Glomerulonephritis

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 (Ends - it is type III HPY immune complex!)

1. Type I has a relationship with Hepatitis C how do you remember? Membranous =

Hepatitis B (also remember the vasculitis Polyarteritis Nodosa),
Membranoproliferative = Hepatitis C (also remember cryoglobinemia). So, type I is a
subendothelial deposit that produces nephrotic syndrome.

2. Type II is less common, and has an Auto

Antibody against C3, called C3 nephritic factor. It causes C3 convertase to become
overactive and is constantly breaking complement down. So, the lowest complement
levels you will see are in type II glomerular nephritis this is called dense deposit
disease because the entire Basement Membrane an immune complex.

tram tracks mesangial cell (structural component of the glomerular capillary) the
mesangial cell is extending itself between the Basement Membrane and the endothelial
etween the Basement
Membrane and endothelial cell tram track Membranoproliferative disease.

E. Diabetic Glomerulosclerosis

Classic sign: big round balls on H and E stain.

When there is excess red in the cell, think hyaline arteriolosclerosis; this is a small
vessel disease of diabetes and Hypertension. The very first vessel that is hyalinized is
s say it is hyalinized. So, because the lumen is narrow in the
efferent arteriole, the Glomerular Filtration Rate (GFR) will increase. So, what is the
Creatine (Cr) clearance? Increased.

So, in early diabetic nephropathy, there is an increased GFR and Cr clearance. Why?
Because the efferent arteriole is hyalinized and obstructed. Is this bad? Yes as a
result the glomerulus will take a pounding for the next ten years leading injury called
hyperfiltration damage.

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 What is the process? where glucose attaches to an amino acid in a protein)?
Nonenzymatic glycosylation. Lets say this is also going on because the pt is not
watching himself too well, therefore we are nonenzymatically glycosylating the
Glomerular Basement Membrane.

What would happen when you glycosylate a Basement Membrane what is it

permeable to? Protein.

So, have all this pressure on the glomerular capillary due the efferent arteriole and also
nonenzymatically glycosylating the Glomerular Basement Membrane, so it s permeable
to protein. So, tons of protein going into the urine.

When you initially start seeing it, is called microalbuminuria. Will the standard dipstick
for protein detect that? No. There are special dipsticks that are available to detect this
called microalbuminuria dipsticks.

microalbuminuria? Have to give pt ACE inhibitor because you want to stop

progression of this.

How will it work? Afferent arteriole is controlled by PGE 2; the efferent arteriole is
controlled by Angiotension II (which constricts it). So, when you give an ACE
inhibitor, what happens to Angiotension II level? It decreases.

So, because of Angiotensin II decreased, you take off the vasoconstrictive element it
has on it. Even though it was hyalinized, it will open then lumen, taking pressure off the
glomerulus, and decrease the Glomerular Filtration Rate. So, the constant pounding on
the glomerulus is taken away. Need to get glycosylated Hb (HbA1c) under 6%, but the
ACE inhibitor can t do it all, so must have perfect glycemic control, otherwise will go into
chronic renal disease. If they can do this, the ACE inhibitor will prevent the disease.
The ACE inhibitor also helps Hypertension. Pink stuff is type IV collagen in the
mesangium. It builds up, easy to see big circle (big balls/golf balls/Christmas
balls) like Kimmelstiel-Wilson nodules this is nodular glomerular sclerosis.

F. Amyloid

Like to deposit in the kidneys. Its a special protein. Stain with Congo
red, and after you polarize it, it has a (granny smith) apple green birefringence.
Light green is what the amyloid is supposed to look like when you polarize it with a
Congo Red stain. Amyloid and diabetic glomerular sclerosis are nephrotic syndromes.

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 X. Combo of Nephritic and Nephrotic Syndrome

A. IgA )

IgA glomerulonephritis is a VARIANT of Henoch Schonlein purpura because it is an immune

complex disease, anti IgA Antibodies (so is Henoch Schonlein palpable purpura in buttocks
of legs, polyarthritis, Gastro Intestinal bleed, hematuria (RBC casts)

On immunofluorence, everything shows up in the mesangium. Example: in kids, presents

with episodes of gross hematuria, goes away, comes back a few years later; in adults,
presents with episodic bout of microscopic hematuria. So, have a lil hematuria, goes away,
and comes again. Little proteinuria, no Hypertension. When it starts getting worse (10 years
hen it will be bad (so its not b9). It is the Most Common of all
glomerulonephritis and is type III Hypersensitivity.

Audio File: Day4 8Renal 2

XI. BUN/Creatine Prerenal Azotemia

You can separate prerenal azotemia vs. renal failure with BUN/Creatine Ratio.

BUN = blood urea nitrogen

Creatine = end product of creatine metabolism. Urea can be filtered and reabsorbed in the
proximal tubule (so its not a perfect clearance substance); Creatine is only filtered in the kidney
and is reabsorbed or secreted. (lnulin clearance is better).

If you take the normal BUN level (10), and normal Creatine level (1mg/dL), will have the
normal ratio of 10:1.

In Prerenal azotemia, there is an increase in BUN (this is what azotemia means). Pre =
before, theref in other words, there is nothing
wrong with the kidney, but the CO is decreased (from any cause Ex. Congestive Heart
Failure, Miocardial Infarction, hypovolemia, cardiomyopathy, etc). Anything that decreases
CO will lead to prerenal azotemia because the Glomerular Filtration Rate (GFR) will
decrease. If you have less renal blood flow, you will filter less and the GFR will decrease. So,
when it decreases, it gives the proximal tubule more time to reabsorb little bit more urea than
normal. So, there is increase proximal tubule reabsorption of urea.

What about Creatine? We know that it is not reabsorbed, but you do have to get rid of it
through the kidneys. So, even though it is not reabsorbed, the GFR is decreased, there is a
back up of Creatine and will not be able to clear it as fast. Therefore, there will be an increase
in serum Creatine. There is little more of an increase is urea because it is being reabsorbed
than with Creatine. So, there is a disproportionate increase of BUN/Creatine. All you have to
remember is greater than a 15:1 BUN/Creatine ratio = prerenal azotemia.

Example: the pt has Congestive Heart Failure, BUN is 80 and Creatine is 2. So, both are
elevated, but the BUN/Creatine ratio is 40:1, indicating that it is prerenal azotemia.

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 say pt truly has renal failure oliguria, renal tubular casts, and acute renal failure.
This will affect urea and Creatine EQUALLY because something is wrong with the kidney;
therefore the same effect on the BUN is the same on Creatine. For both, urea has to be filtered
out of the kidney and it has failed both increased proportionate to each other because both
rid of
creatinine, so they increase in proportion to each other because the urea is not being
reabsorbed anymore because the kidney is in shock.

Example: BUN = 80, Creatine = 8, therefore the BUN/Creatine ratio is 10:1, and pt is in
renal failure. So, even though the 10:1 is maintained, still have renal failure because it has
increased so much. If the ratio is 15:1, it is prerenal azotemia; if it is increased and still
10:1, its renal failure.

XII. Acute Renal Failure: Acute Tubular Necrosis:

A. Ischemic Acute Tubular Necrosis: Pigmented Renal Tubular Cast

Most Common Cause of Acute Renal Failure = Ischemic Acute Tubular Necrosis
this is what you worry about the most when the CO decreases, pt develops oliguria.

prerenal azotemia, you have a decrease in

Glomerular Filtration Rate, which is another cause of the oliguria. So, decrease in CO and
oliguria is VERY BAD, and start to see BUN/Creatine go up need to know if its prerenal
azotemias, or renal azotemia to distinguish, get a BUN/Creatine. It its 15:1, still
prerenal. But it can progress to renal failure ischemic acute tubular necrosis.

Most Common Cause of ischemic acute tubular necrosis = not treating prerenal
azotemia. So, ischemic Acute Tubular Necrosis is the worst the get and the
BUN/Creatine ratio will be normal, but increased in values (Ex. 80/8)

*Coagulation necrosis: Sloughs off, blocks lumen

and contributes to oliguria, and see casts in the urine. The casts are renal tubule casts.

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 So, combo of renal tubular casts, oliguria, BUN/Creatine of 10:1 = Acute Tubular
Necrosis.

Why does this have such a bad prognosis? When pt has ischemic necrosis, not only are
you killing the tubular cells, but the Basement Membrane also gets damaged, so the
structural integrity of the tubule is being taken away, which is not good.

When you have liver damage, and damage liver cells, and the cells regenerate, the cells
are not regenerating sinusoids and triads, but only themselves. If the Basement Membrane
cute Tubular Necrosis or is in the process
of doing that, can you regenerate a tubular cell without a Basement Membrane? No. So,
the more necrosis, the more Basement Membrane are destroyed, the worse the prognosis
because cannot regenerate and cannot get back normal function.

There are 2 parts of the nephron that are most susceptible to ischemia

1. Straight portion of the proximal tubule.

2. Thick ascending limb of the medullary segment (where the Na/K/2 Cl co-
transport pump is).

These two parts undergo coagulation necrosis and sloughing off. So, will see these fall off
in the proximal tubule and also in the thick ascending limb of the medullary segment.

B. Nephrotoxic Acute Tubular Necrosis:

Gentamycin, intravenous pyelograms and

Aminoglycosides = nephrotoxic, what is the first thing they will filter from the glomerulus?
Proximal tubule.

So, nephrotoxic tubular necrosis related to drugs involves the proximal tubule. And,
the Basement Membrane remains intact.

The prognosis of nephrotoxicity is better for 2 reasons:

1. Only affecting the proximal tubules.

2. Not affecting the Basement Membrane.

*Most Common Cause of nephrotoxicity = Aminoglycosides.

(2nd Most Common Cause of nephrotixicity = intravenous pyelograms dyes).

What is Glormerular Filtration Rate in 80 years old person? It is decreased the

Creatine is 4 mls/min; which is normal in older people. Creatine clearance decreases
along with Glomerular Filtration Rate as they get older; so, if you are giving a drug without
nephrotoxicity the same dose as a young person, you will be killing the older person. This
is obviously occurring because Aminoglycosides are the Most Common Cause of Acute
Tubular Necrosis and doctors are not decreasing the dose of the drug to decrease
nephrotoxicity.

XIV. Tubular and Interstitial Disorders of the Kidney

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 A. Acute Pyelonephritis:

*Most Common Cause of Acute pyelonephritis is Ascending Infection of short

urethra in women.

How do you separate it from a lower Urinary Track Infection? Very easily.

*Acute pyelonephritis is a systemic infection and is an infection of the kidney proper.

How does it get into the kidney? At the uretovesicular junction, the muscle squeezes so
there is no reflux of urine from the bladder into the ureter. This is true in normal people.
However, not all people have a normal vesicoureteral junction.

So, what happens in a pt with a bladder infection and the junction is incompetent, it leads to
vesicouretal reflux, and the infected urine refluxes up into ureters, and leads to ascending
infection that goes all the way up to the kidneys.

Board Question: hat is the mechanism of ALL Urinary Track Infection Urethritis, cystitis,
pelvitis, or pyelonephritis) Due to ascending infection from the beginning of the urethra.

Every woman (has nothing to do with cleanliness) has the same E coli serotype in her stool
at the introutus of the urethra and her vagina. So, with trauma or certain serotypes of E
coli, it can ascend up the urethra into the bladder. If the pt has an incompetent
uretovesicular junction, up the ureters into the kidneys.

Fever, flank pain, and White Blood Cell casts = ACUTE PYELONEPHRITIS. So, it s an
ascending infection due to incompetent vesicouretal junction. This usually shows up in
newborn girls (and will be a problem for rest of lives).

Example: kidney with white spots = abscesses seen in

pyelonephritis. If you have constant acute attacks of pyelonephritis, can become chronic.
Therefore have increased risk of Hypertension and renal failure.

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B. Chronic Pyelonephritis

Example: scarred eosinophil protein cast in kidney (on cortex), blunting of the calyces
(occurs under the scar), seen on intravenous pyelograms Diagnosis? CHRONIC
pyelonephritis.

blunting of the calyces = CHRONIC pyelonephritis.

C. Acute Drug-induced interstitial nephritis

Can drugs produce a nephritis involving the interstitium and tubules? Yes can be
acute and chronic and easy to diagnose.

Why? Because will have Fever + Rash (obviously due to drug, because started after
taking the drug and activated type I and IV Hypersensitivity.), oliguria,
eosinophiliuria (eosinophils in the urine pathognomonic). When have that
combination STOP the medication!!!

This is called acute drug induced interstitial nephritis. This is more and more common,
and is a Most common cause of chronic renal failure = Acute drug induced.

*Analgesic nephropathy:

Example: discoloration in renal medulla, pale infarct, renal

papilla sloughed off ringed signed; and on pyelograms
there will be nothing there just an empty space. Diagnosis?
Analgesic nephropathy. This from combo of acetaminophen
and aspirin over a long period of time.

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Acetaminophen is producing free radicals. Because of the poor circulation in the medulla,
there is free radical damage on the tubular cells of the medulla. Aspirin will block
Prostaglandin 2 (a vasodilator), therefore angiotensin II (a vasoconstrictor) is in charge of
the renal blood flow. Vasoconstrictor of the efferent arteriole. The peritubular capillaries
arise from the efferent arteriole. So, with vasoconstriction of the efferent arteriole, pt is
affecting peritubular capillaries going around collecting tubules and renal medulla. So, is
that producing ischemia? Yes.

So, pt has free radical damage and ischemia leading to analgesic nephropathy. This
is why the renal papilla necroses, sloughs off, and leads to renal papillary necrosis.

This is a Renal Papillary Necrosis due larges quantities of acetaminophen and aspirin
for chronic pain.

So, aspirin and acetaminophen toxicity. Diabetic nephropathy (because causes

ischemia), acute pyelonephritis (because abscess formation), Sickle Cell Disease
and trait, can all lead to analgesic nephropathy but with different mechanism.

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XV. Chronic renal Failure

Definition: Pt has BUN/Creatine ratio 10:1 for more than 3 months.

If both kidneys failed:

1. Will not be able to excrete the things we normally get rid of (so those things will
build up Ex. salt)

2. Erythropoietin (EPO) production will decrease, leading to normocytic anemia

with a corrected reticulocyte count of less than 2%.

3. Will not be able to get rid of organic acids, leading to metabolic acidosis, increased
anion gap. With metabolic acidosis, bones try to buffer all the acid. Because the bones
are buffering for the extra H ion (acidosis) and wearing away bone matrix, leading to
osteoporosis.

4. The proximal tubules are messed up in the renal tubules, and 1-alpha
hydroxylase decrease (this responsible is hydroxylating Vitamin D) having
hypovitaminosis D (vitamin D deficiency). This means that there will be
hypocalcemia and hypophosphatemia, leading to another bone disease:
osteomalacia. PTH is reacting to chronic hypocalcemia and leads to secondary
hyperparathyroidism (also affects the bone).

The bun/Creatine ratio is 80/8. So, if you know normal renal function you know what
happens.

XVI. Other Problems related to kidneys:

Example: pt has essential Hypertension over 10 yrs,

and pt is not compliant with medication kidney with cobblestone appearance =
nephrosclerosis. Underlying disease causing it: hyaline arteriolosclerosis because
there is decreased blood flow, tubular atrophy, glomeruli are fibrosing off, renal
function is going down, and leads to renal failure.

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Example: Pt wakes up with a big headache and blurry
vision. Pt is getting dizzy, goes to the doctor, and pressure is 240/140, in the retina,
dude has papilloedema with flame hemorrhages and hard and soft exudates, grade 4
hypertensive retinopathy, BUN/Creatine are 80/8 Diagnosis? Malignant Hypertension
(like flea bitten kidney petechia visible on surface of kidney due by blood vessels
rupture. They can also ask Treatment: Intravenous nitroprusside to get the Blood
Pressure down. So, they have CNS edema with papilloedema, and if the Blood Pressure
lowered, they are gonna die.

Example: kidney with abnormal areas that are pale and

depressed so, if you take a section through one of these, and you see an irregular
irregular pulse, will see pale infarction with coagulation necrosis because what you are
looking at are infarcts. Irregular irregular pulse is from atrial fibrilation, and atrial fibrilation is
most dangerous for embolization. So, these infarcts are from multiple emboli, leading to
multiple pale infarcts of the kidney. Has microabcesses.

*Example: atrophy due to dilatation of the renal pelvis,

leading to hydronephrosis. So, if you have hydronephrosis and increased pressure pressing
on the cortex and medulla, what happens to that? Get ischemia and atrophy which is
called compression atrophy. This is very similar to cystic fibrosis ducts filled with mucous
the pressure is impacted back to the glands, and they undergo compression atrophy. Cortex
and medulla are very thin, along with very dilated renal pelvices. Most Common Cause of
hydronephrosis = stone.

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 *Example: staghorn calculus urine pH is alkaline and
smells like ammonia; therefore, there must be a urease producer, and this is Proteus.
Because it is a urease producer, they break urea down to ammonia, and get an alkaline pH.
This is why a staghorn calculus is Mg ammonium phosphate, and only develops in
infections in pts that have urease producers. E coli are not urease producer and proteus
species are and they predispose to these stones. Do not pass these stones (too big),
therefore need to extract these (surgery). So, urease producer, alkaline pH, ammonia smell
to the urine.

XVII. Tumors of the kidney

If you see a mass in a kidney, and its an adult = renal

adenocarcinoma.

kid = W . So, if you see a mass in the kidney, its problably not metastasis
(because not many things go there), its not b9, pick cancer.

They derived from the proximal tubule and the Most Common Cause of
renal adenocarcinoma = smoking; they make lot of ectopic hormones: EPO, parathyroid
hormone (leads to hypercalcemia), invade the renal vein.
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 Cells are clear, full of glycogen.

Example: flank mass in child, Hypertension = Wilms

tumor; Hypertension occurs because renin; usually unilateral.

Histology: cancer where pt is duplicating embryogenesis of

a kidney everything is primitive mesenchyme. Can see rhabdomyblasts; likes to metastasis
to lung.

If Autosomal Dominant, from chromosome 11, and have 2 classic findings:

1. *aniridia (absent iris)

2. Hemihypertrophy of an extremity (one extremity is bigger than another) this is a

sign that the wilms tumor has a genetic basis.

XVIII. Urinary Tract Infection

Most Common urine abnormality seen in the lab

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Example: arrow pointing to neutrophils in
urine; Red Blood Cells in it, too, bacteria = E coli (play odds). So, see neutrophils,
and bacteria. The dipstick will pick up all three of these things.

ed Blood Cells. Hematuria is very frequent and sometimes a

lot of blood comes out (hemorrhagic cystitis) and most of the time its E coli, but sometimes it
can be from adenovirus.

Also, the dipstick has leukocyte esterase

Most urinary pathogens are nitrate reducers, meaning that they convert nitrate to nitrite. On a
dipstick, they have a section for nitrites. Because E coli is a nitrate reducer, there should be

So, you have a pt, woman or man, who has dysuria, increased frequency, suprapubic
pain and have a urine sediment of neutrophils, R
Urinary Track Infection.

How to know is it lower or upper infection? If the pt has fever, flank pain, White Blood
Cell casts its upper = Urinary track infection in UPPER PART.

Example:
ative, and sexually active person,
diagnosis? Chlamydia normal urine cultures do not pick up Chlamydia trachomatis.

Most Common Sexual Transmitted Disease = Chlamydia trachomatis

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 In men, called nonspecific urethritis, in woman, called
acute urethral syndrome.

Chlamidia is also called: sterile pyuria o have

neutrophil present. On routine stool culture, it s negative. So, one cause of sterile pyuria is
Chlamydia infection and the other one is Tuberculosis.

Most Common organ that military Tuberculosis goes to = kidney, therefore will have
Tuberculosis in the urine, and it will be sterile because urine cultures do not pick up
Tuberculosis. So, remember Chlamydia and Tuberculosis as causes of sterile pyuria.

Papillary lesion in the bladder = transitional cell carcinoma (TCC).

*Most Common Cause transitional cell carcinoma of the bladder? Smoking

*Dye use to look transitional cell carcinoma of the bladder? Aniline dye.

* Cyclophosphamide.
*What are the complications of Cyclophosphamide? Hemorrhagic cystitis and
transitional cell carcinoma.
*How do you prevent this? Mesna.

Penis
Embryo:

What is the embryology of hypospadias? Opening on the undersurface (you pee and it goes
on your shoes) failure of closure of urethral fold.

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What is the embryology of Epispadias? Opening on upper surface (pee and goes in face);
defect in genital tubercle.

: .

Priapism permanent erection, seen commonly in Sickle Cell Disease because of the Red
Blood Cell and sickle cells trapped in the vascular channels.

Most Common cancer of the penis = squamous because lack of circumcision. It is more
commonly seen in an uncircumscribed pt they usually do not clean (poor hygiene)
predisposes the smegma is carcinogenic.

Testicle
*Cryptorchid testis down.

There are two phases in the decent of a testicle:

1st. Phase - Transabdominal migration down to inguinal canal. Mullarian Inhibitory

Factor is responsible for this.

2nd. Phase - Androgen dependent. This includes testosterone and

dihydrotestosterone.

All men need testicle down by two years of age old because if not, has a risk of seminomas.

Still at risk if you get it down. Lets say you went in, and it look atrophic and other testicle looks
normal, have to take normal one out, too because it is also at risk. So, must have testes
In women is called: dysgerminomas.

Analogy: in Turner syndrome, they are infertile and have menopause before menarche,
because by two years of ages, they have no follicles in their ovaries, and this is called a streak
gonad (ovary without any follicles)

So, in pts woman diagnosed they surgically remove both ovaries

because of the great risk. lead to cancer.

*Orchitis mumps.

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*Epididymitis less than 35 years= Neisseria gonorrhea/chlamydia, greater than 35 years =
pseudomonas

*Varicocele on left side because spermatic vein connected to left renal vein, wheras the
spermatic vein on the right is connected to the Inferior Vena Cava; because of this, the pressures
increase, and a varicocele on the left, leads to increased heat and is one of the most common
causes of infertility: Varicocele.

Board Question: What would happen if you blocked the left renal vein? Would develop a
varicocele. So, if you block the left renal vein, you will increase the pressure in the spermatic
vein and will lead to a varicocele.

*Torsion spermatic cord twisting.

1. Torsion spermatic cord twistin = spermatic cord shortens it. This means that the testicle
will go up into the inguinal canal.

2. This is painful.

3. You will lose your cremasteric reflex (in normal male, if you scatch the scrotum, it will
contract, which is lost in torsion of the testicle).

*Hydrocele persistence of tunica vaginalis; when you have big scrotum, y

its big because there is fluid in it, or its big because there is a testicle in it. So, what do you do?
Transilluminate. If it transilluminates = hydrocele. Differential diagnosis
for painless enlargement of testicle: cancer, cancer, cancer!! (They iopsy, just
remove)

Seminoma histologically

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Most Common (best prognosis); huge cells with lymphocyctic infiltrate. This is the same the
have little beta hcG;
metastasis to paraortic lymph nodes why? Because they came from
they will go.

Most Common testicular tumor in child? Yolk sac tumor; What is the tumor marker?
Alpha feto protein

What is worst testicular cancer? choriocarcinoma not the same prognosis of a

gestationally derived choriocarcinma in a woman .

Example:: 25 years male with unilateral gynecomastia and dyspnea. Chest xray reveals
multiple nodular masses in the lung. So, gynecomastia and metastasis, -

What is the primary cancer? testicle choriocarcinoma. Source of gynecomastia: Beta hCG is
like LH, and therefore it stimulates progesterone in the male, which increases duct
growth and breast tissue and leads to gynecomastia.

Example: same scenario, but older man with testicular cancer will lead to metastasis
malignant lymphoma.

So, older pts get malignant lymphoma (from metastasis); the testes metastasis a lot, especially
in leukemia and lymphomas.

Prostate

Nodular Protate Hyperplasia occurs in the periurethral portion of

the prostate gland. This is why you get dribbling and urinary retention as the most common
symptom.

Prostate cancer is in the periphery of the prostate gland

within the periphery of your finger. So, when you press on it, you feel hardness.

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 Example 75 yo man with urinary retention and bladder is up the umbilicus and has dribbling
what is the most likely cause? Prostate Hyperplasia why? Because for prostate cancer to do
that, it has to invade all the way through the prostate gland to the urethra/bladder neck. This
is prostate HYPERPLASIA because it is already around the urethra.

What male hormone is totally responsible for prostate? Dihydrotestosterone in

embryogenesis, this hormone fuses the labia to form a scotrum, extends the clitoris to form a penis
and makes a prostate gland.

So, prostate Hyperplasia and Prostate cancer are dihydrotesterone dependent cancers. If you
use a 5 alpha reductase inhibitor, that will increase testosterone. This drug will decrease
DIHYDROTESTOSTERONE.

Most Common cancer in men = prostate cancer (osteoblastic metastatis.)

Audio file: Day 5 1GYN1

*Hirsutism and Virilization

Hirsutism = increased hair in normal hair in bearing (no

relation) areas.

Virilization = hirstuism + male secondary sexual characteristics (zits, acne, deeper voice),
clitoromegaly (pathognomonic)

Testosterone is predominantly synthesized in the ovary. Most testosterone in a woman

is from the ovary.

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 DHEA sulfate (Dehydroepiandrosterone sulfate) is 95% from adrenals, and is an androgen.

If you have a patient with hirstuism, do two tests to see where it come from:

*Testosterone level have to fractionate it because sometimes the total can be

normal, but the free test can be increased.
*DHEA sulfate test.

So, if testeterone is predominantly elevated, it is coming from the ovary and if DHEA is
elevated, it is coming from the adrenals.

Histuism is from adrenal orgin is due hydroxylase deficiency (adrogenital syndrome),

Cushings, etc.

Hirstuism from the ovaries is a common phenomenon and the most common cause of
hirstuism due polycystic ovarian syndrome.

So, when you are evaluating hirsutism, look at DHEA levels (adrenal origin) and testosterone
levels (ovarian origin).

*Polycystic ovarian syndrome Cyst devoid (without) of

follicules

Most Common Cause of Hirstuism = polycystic ovarian syndrome (or idiopathic)

(Also due to stromal hyperplasia stroma of the ovary can make testosterone, or tumors
others ovary)

This disease is a hypothalamic-pit abnormality where FSH is decrease (suppressed) and

LH is increased.

*LH function: In a woman, LH is responsible for synthesis of theca interna (which is

around the developing follicle). During the proliferative phase of the cycle, what is
predominantly being synthesized is the 17 ketosteroids, DHEA and androstenedione.

The androstenedione is converted by oxydoreductase into testosterone. Then, the

testosterone goes across the membrane of the developing follicle into the granulosa cells,
where there is aromatase. FSH is put in there.

Then, the aromatase in the granulosa cell converts testosterone into estradiol and this is
where the woman gets her estradiol (from the aromatization process).

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 LH is responsible for synthesis of 17 ketosteroids and testosterone in the ovaries. This
is why we will see hirstuism in a woman with polycystic ovarian syndrome (because increase
of 17 ketosteroids, DHEA, androstendione, and testosterone).

*Obesity is a common correlation with this disease due excess adipose = more aromatase, so
the sex hormones test and androstenedione can be converted to estrogens in these pts.

Androstenedione is aromatized into estrone (a weak estrogen). Testosterone is aromatized into

estradiol, which is a strong estrogen. So, we have a paradox have a woman with signs of
excess androgens (hirsutism, acne not signs of virulization). At the same time, these
are being converted to estrogens so will have endometrial hyperplasia and therefore
have a risk of endometrial caricinoma. So, there is a combo of increased androgens and
increased estrogens. It is the increased estrogen that causes suppression of FSH via
negative feedback, while there is a POSITIVE feedback on LH. So, because increased
estrogens, pt is constantly suppressing FSH and constantly increasing LH, so the cycle repeats
itself.

So, you can break the cycle with an Oral Contraceptive Pills because the progestin in it will
block LH. So, why do they have cysts? Function of FSH is to prepare the follicle. Also, they
increase the aromatase activity. If the FSH is constantly suppressed, the follicle
degenerates and leaves behind a cystic space where the follicle used to be. So, pt has
POLYcytic ovarian syndrome related to chronic FSH suppression. Can feel these by
pelvic exam and seen with ultrasound.

*Menstrual dysfunction

1. Dysmenorrhea = painful menses

*Most Common Cause of primary dysmenorrhea is too much PGF (Prostaglandin

that increases contraction of the uterine musculature).

*Most Common cause of secondary dysmenorrhea cause is endometriosis).

There are also problems with dysfunctional uterine bleeding this type of bleeding is
a hormone imbalance (HORMONE RELATED) that causes abnormality in
bleeding.

Most Common Causes of abnormal bleeding in young lady from menarche to 20

years = anovulatory bleeding. So, if a young lady is bleeding, irregulatory period that
is the usual cause in ovulatory cycle.

What is occurring? There is a persistent estrogen stimulation that is occurring on

the mucosa, and not enough progesterone stimulation. So, they develop a little
hyperplasia, there is a build up of mucosa as the month progresses, and then eventually
the stroma sloughs off and leads to significant bleeding.

2. Amenorrhoea

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 *It can be Primary amenorrhea (no menses by 14 years) or Secundary
amenorrhea (when have already menses )
due:

1. It can be a problem with the hypothalamus/pituitary. In other words, is the

hypothalamus putting out GnRH or not? Is the pit putting out FSH/LH or not?

2. May be it a hypothalamic-pit abnormality? If pt has hypothalamic-pit prob, what

would FSH and LH be Low. May be is it an ovarian problem? If had a primary
ovarian problem, what would they be? FSH and LH High. Maybe the ovary is not
making enough estrogen. Is it s an end organ problem? If you have an end organ
defect, what would FSH and LH levels be? Normal.

(ANATOMICALLY RELATED) maybe she -

Rokitansky-Kuster-Hauser syndrome , or maybe she has

an imperforate hymen ong, and has blood built up
behind it, or cervical stenosis or (DES exposure).

4. secondary amenorrhea, woman has repeated

dilatation and synechiaes, where the stratum basalis is scraped away; have to
leave something behind from which you can proliferate endometrial mucosa if you
scrape all the way down the the muscle, will not be able to menstruate again, and
will scar everything off, leading to an infertile woman.

What is the first step in the workup of any case of amenorrhea? Pregnancy test.

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 5. Primary cause of
amenorrhea. The most common recognize sex chromosome disease at birth.
Majority are XO, therefore do not have a barr body. Defects in lymphatics.

Can make diagnosis at birth via Physical Examination:

*Swelling of hand and feet (lymphedema).

*Short 4th. Metacarpal (knuckle knuckle dimple knuckle sign).
*Webbed neck is due to lymphatic abnormalities called: Cystic hygromas,
which are dilated lymphatics in the neck area and fill with lymphatic fluid and
stretch the skin because they stretch the skin, looks like webbing.
*Preductal coarctations. Some cases are mosaics XOXX and there is a
remote possibility that they may be fertile. There
mosaics. Have menopause before menarche. All of there follicles are gone by
the age of 2, and this is the streak ovaries (gonad). Therefore, they are
susceptible to dysgerminomas (seminomas are in males are analogous).

3. Uterine Disorders

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 a. Adenomyosis glands and stroma inside in the
myometrium very common cause of dysmenorrheal, dyspyrunia, menorragiah,
hysterectomy.

Adenomyosis

b. Endometriosis functioning glands and stroma that implant outside the confines
of the uterus. Most Common location = ovary, causes bleeding in the ovary see
chocolate cyst (endometriosis of the ovary). Most common cause due = Reverse
menses. Only in a reproductive life.

Good question to ask if pt has endometriosis:

*Does it hurt when you defecate? Yes.

* No, it goes away this is endometriosis because
induration of pouch of Douglas, producing bleeding in rectal pouch (there is endometriosis there).
The rectum is filled with stools, and streches the pouch of Douglas, leading to pain. So, pain on
defecation during the period leads to endometriosis.

c. Endometrial Hyperplasia

Always dangerous to have unopposed estrogen, meaning no progesterone effect,

because then pt runs risk for endometrial cancer.

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 Most Common Cause of endometrial cancer = endometrial Hyperplasia due to
unopposed estrogen.

Endometrial Adenocarcinoma

Pouch of Douglas can collect seeding from ovarian cancer, pus from PID, unclotted
blood from ruptured ectopic pregnancy

d. Endometrial cancer: Posible causes:

*Early vs late menarche early is worse because longer time for estrogen to
circulate.
*Early vs Late menopause late is worse because more estrogen exposure.
*Obese vs not obese obese because the estrogen factor in adipose (more
aromatase), therefore, obese woman are more susceptible to cancers related to
estrogen - breast cancer, endometrial cancer, ovarian cancer.
*Type II diabetics are at increased risk because 80% of type II pts are obese (so, the
obesity is the cause of increased risk of endometrial cancer).

*Cancer and age brackets

45 = cervical cancer
55 = endometrial cancer
65 = ovarian cancer

55 years, postmenopausal is when you usually see endometrial carcinoma. Any woman that
has been in menopause for over 1 year, and then has rebleeding has endometrial cancer until
proven otherwise. 1st step in management? Endometrial Biopsy.

e. Leiomyoma Most Common b9 (benign) tumor in a woman

Most Common sarcoma of the uterus

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 Big bulky tumors (as are all sarcomas); leiomyoma
is NOT a precursor for leiomyosarcoma and is a mitosis problem.

Example: young woman sudden onset of severe

lower abdominal pain must do a pregnancy (look at beta hCG level) test to rule
out ectopic pregnancy.

4. Ovarian masses

Surface derived derived from the surface of the ovary

Germ cell types - dysgerminomas (men have these, too)
Sex chord stromal tumors make estrogens (ex. granulosa cell tumors - therefore
can have hyperestrinism which leads to bleeding and endo carcinomas), some make
androgens (sertoli leydig cell tumors of the ovary associated with virulization and
hirstuism). (Males just have germ cell tumors)

a. Follicular cyst

Most Common Cause of ovarian mass in a young woman = follicular cyst

Follicle that ruptured, not neoplastic, accumulates fluid and leads to peritonitis. It
is bad if it s on the right side because it can be either ruptured follicular cyst,
appedicitus, ectopic pregnancy (ruptured), Pelvic Inflamatory Disease; look at
with ultrasound.

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 Under 35 years, most ovarian masses are b9 benign.
Over 35 years, most ovarian masses have a greater potential of being malignant.

b. Surfaced derived (overall Most Common)

Most Common surfaced derived ovarian tumor = serous cystadenoma
benign (B9)

Serous cystadenocarcinoma (malignant)

(These are the Most Common overall benignant b9 and malignant ovarian tumors)

These are also the Most Common that are bilateral, and the
cystadenocarcinoma has:

Psommoma bodies (Bluish colored due to

apoptosis, destruction of the tumor cell and replacement with dystrophic
calcification). Also seen in papillary carcinoma of the thyroid and in meningioma.

Example:: 65 years, bilateral ovarian enlargement (remember they tend to arise

at this age)

Any woman that is over 55 and has palpable ovaries is cancer until proven
otherwise because a postmenopausal woman should be have ovaries that
are atrophying.

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 Example:: 62 years woman with ovarian mass on the right already know its bad
because

c. Cystic teratoma
Tooth, sebaceous glands, cartilage, skin, thyroid,

Most Common overall germ cell tumor, usually B9-benign.

If it is making thyroid, it is called struma ovary.

d. Sex chord stromal tumors

Most Common = fibromas (B9)

Meigs syndrome: ovarian fibroma, ascites, and right side pleural effusion
goes away when you take the ovary out.

Granulosa cell tumor of ovary: low grade

malignant tumor; what does the granulosa cell normally do? It aromatizes
androgens and estrogens, so a granulosa cell tumor is more than likely an
estrogen producing tumor.

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 Signet ring cells is this a primary cancer,
or metastasis from another site? Site is from stomach called a krukenburg
tumor; there is NO primary ovarian cancer that has signet ring cells.

*Gestational Disorders:

1. Placenta

a. Chorionic villus outside layer =

syncytiotrophoblast, clear cells under the outside layer = cytotrophoblast; which is making
hormones? Syncytiotrophoblast.

What hormones is it making? Beta-hcG and Human Placental Lactogen (HPL) growth
hormone of pregnancy. Has myxomatous stroma. Vessels coalesce into umbilical vein,
which has the highest o2 content.

Neoplasms of chorionic villus:

*Hydatidiform mole can be complete (46,

XX, both X chromosomes come from father called androgenesis) or partial
(triploid, 69 chromosomes, can have a fetus present). The complete moles have a
greater propensity to moving on to choriocarcinoma.

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 Causes of choriocarcinoma:
15% of choriocaricnomas are from preexisting hyadiform mole
25% from spontaneous abortion
25% from normal pregnancy
Hyatidiform moles are b9 tumors of the chorionic villus; choriocarcinomas are a
malignancy of the trophoblastic tissue (do not see chorionic villi). Loves to go to the
lungs and responds well to chemotherapy (can even go away in the presence of
metastasis)

*Breast

Breast lesion location:

Nipple = Pagets disease of the breast

Lactiferous duct = Intraductal papilloma (Most

Common Cause of bloody nipple discharge of woman under 50) b9 papillary tumor, if
you press on it, blood will come out of the areola

Major ducts = where most of the cancers arise from invasive ductal cancers, medullary
carcinomas, mucinous carcinomas

Terminal lobules (where milk is made) Most Common tumor = lobular carnicoma, is
famous be BILATERAL (so, lobular tumors are to the breast as serous tumors are to the ovary
in terms of their bilaterallity); mammog up lobular cancers.

Most Common Cause of mass in breast of woman over 50 = cancer: infiltrating ductal
carcinoma (not intraductal this means that we are not picking up the cancer early enough by
mammography and picking up in the intraductal phase, and our techniques are insensitive so
we are missing the ductal stage and we are picking up the cancer when it has invaded to
pick up early, need to get at 5mm or less). So, if they are intraductal, has a good
prognosis.

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 Example: ductal hyperplasia cannot see; precursor lesion for cancer that are estrogen
sensitive epithelial cells in the ducts (just like the endometrial glands are estrogen sensitive,
the glands lining the ducts are estrogen sensitive).

Fibroadenoma

Example: 35 years woman with movable mass in breast

that gets bigger as the cycle progresses = fibroadenoma
These are the most commons in terms of age and location.

Most Common tumor that moves around in the breast in a woman under 35 =
fibroadenoma is the as it
grows, it compresses the ductstems, so they have slit like spaces; very common. Even if you
s a fibroadenoma, still get a biopsy.

Slide: fibrocystic change cysts, lumpy bumpy in breast,

more painful as the cycle progresses because they are hormone sensitive.

Most Common Cause of mass in breast of woman under 50 = fibrocystic change

Sclerosing adenosis in terminal lobules, b9 part of fibrocystic change (see cysts)

Breast Cancer

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 Slide: Orange appearance. How do you know its
breast cancer? Nipple is hard as a rock when breast cancers invade the stroma, they elicit a
fibroblastic and elastics tissue response, making it hard this is good because it makes it
palpable. This is why a woman over 50, that has a painless palpable mass, its cancer.

If it s painful and under 50, it s rarely cancer (fat necrosis, fibrocystic change). So, the
magic word is painless.

The Most Common site for breast cancer is in the Outer Quadrant of the breast because is
where are most of the breast tissue. The 2nd Most Common site is around the areola.

Slide: nipple being sucked in, whitish mass, stellate

(classic for invasive cancer); on mammography, see density with spicules coming out and has
calcified. This is highly predictive for cancer.

What is the first step in management of a palpable mass? Fine Niddle Aspiration because can
make a diagnosis and tell if it s solid or cystic (this is also the first step in management of cold nodule
in thyroid).

Slide: intraductal cancer net like arrangement, called

comedocarcinoma, junk that comes out (like caseous necrosis); has erb-2 oncogene
(aggressive cancers).

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Slide: invasive cancer, see tumor cells invading stroma;
see Indian filing sign of invasive lobular cancer; seen more often in infiltrating ductal
carcinoma.

Slide: eczematous
disease around the nipple = pagaets disease of the breast rash around nipple cancer of
the duct that has spread to the skin.

Slide: inflammatory carcinoma worst, red, dimpled

skin because the lymphatics are plugged with cancer underneath and the lymphatic fluid
leaked out, but the ligaments are still attached, but increasing the fluid in the interstium, and as
it expands out, it dimples so, inflammatory carcinoma looks like that
because its lymphatic filled with tumor, and is the worst of the worst.

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 Slide: lymphedema is a woman that is postradical
masectectomy; when you are doing a modified radical mastectomy, what are you removing?
The entire breast including a nipple, leaving behind pectoralis major, axillary resection, and
taking pectoralis minor.

Most Common complication of masectomy= winged scapula (becuase cut the long thoracic
nerve)

The lumpectomy removes the underlying tumor with a good border of normal tissue around it,
take a few nodes from the axilla (because have to use for staging because they go to lower
axillary first), and then you do radiation of the breast (good for breast conservation same
prognosis as mastectomy)

Example:: ERA-PRA = estrogen receptor/progesterone receptor assay

What does it mean? Relationship betwn estrogen and its receptor synthesis. So, if you
are in a reproductive period of your life when estrogen is abundant, the receptors will be
downregulated. This is why in women that is young, in the reproductive period of their life,
have breast cancer and are ERPRA negative because this is what we would expect because
estrogen would down regulate receptor synthesis.

Whereas, if you are postmenopausal, it leads to up regulation of the receptors and those
women are ERPRA positive. But what does this mean? It means that the tumor is responding
to estrogen and need to take away that estrogen affect because it is feeding the tumor.

How can you take it away? Tamoxifen this is weak estrogen, so it hooks into the receptor

e receptor.

Complications? Menopausal type symptoms; also, it is an estrogen so you have the risk of
endometrial cancer. A benefit in the postmenopausal state with an ERA PRA positive woman
is that it does prevent osteoporosis. So, cannot give estrogen to a woman that is ERA PRA
positive, but is a candidate for tamoxifen and will prolong recurrence.

Audio file: Day5 3Endocrine1

Endocrine Disorders
Primary vs Secondary vs Tertiary

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 *Hashimotos = destruction of the thyroid gland = PRIMARY hypothyroidism (the gland screws
up the hormone)

*Hypopituitarism and hypothyroidism = SECONDARY hypothyroidism (no Thyroid Stimulator

Hormone (TSH) to stimulate)

*Hypothalamic Disease = Sarcoidosis destroying Thyroid Releasing Hormone (TRH): TERTIARY

(no TRH)

Example: adenoma on parathyroid producing Parathyroid Hormone (PTH) leading to

hypercalcemia = primary hyperparathyroidism

Example: have hypocalcemia/vit D deficiency, and asked the parathyroid to undergo hyperplasia,
that is called SECONDARY hyperparathyroidism

Example: what if after a long time Parathyroide Hormone (PTH) keeps being made = tertiary
hyperparathryroidism (rare)

*Overactivity vs underactivity of glands

Stimulation test: if pt has underactive gland, would use stimulation test to see if the gland is
working.

Supression test: if pt has overactive gland, would use suppression test to see if gland will stop
working.

Most of the time, things that cause overactivity, we CANNOT suppress them.

There are 2 exceptions where we suppress them, and they deal with overactivity in the pituitary
gland

1) Prolactinoma can be suppressed because it can prevent the tumor from making prolactin;
bromocriptine suppresses prolactine. What is bromocriptine? (Dopamine analog), normally,
women do not have galactorrhea because they are releasing dopamine, which is inhibiting
prolactin (therefore dopamine is an inhibitory substance bromocriptine is also used for
ecause bromocriptine is a dopamine analog (which is what is missing in
parkinsons disease)

2) Pituitary Cushings: b9 tumor in the pitiuitary that is making Adrenocorticotropic Hormone

(ACTH) you CAN suppress it with a high dose of dexamethasone. These are the only two
exceptions for a tumor making too much stuff.

(There is no way to suppress a parathyroid adenoma making Parathyroid Hormone (PTH), or

an adrenal ademona making cortisol, or an adrenal tumor from synthesizing aldosterone
these are AUTONOMOUS).

Example: pt with hypocortisolism lets do an ACTH stimulation test will hang up an

Intravenous drip and put in some ACTH; collecting urine for 17 hydroxycorticoids (metabolic
end product of cortisol) and nothing happens so what is the hypocortisol due to? Addison

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disease gland was destroyed therefore, even if you keep stimulating it, you will not be
making cortisol.

cause of hypocortisolism? Hypopituitarism ecause it s not

being stimulated by ACTH, but when you gave it ACTH over a period of time, it was able to
regain its function. So, with that single test, you are able to find cause of hypocortisalism.

Ex. High
Ex. if you have hypopituitarism causing hypocortisalism, what would ACTH be? Low

*Hypopituitarism

Most Common Cause of hypopituitarism in adults = nonfunctioning pituitary adenoma

(within sella turcica in the sphenoid bone, hence surgery

is transphenoidal surgery, where the expanded sella turcica is). Pituitary Adenoma usually
nonfunctioning and destroys the normal pituitary over time as it grows, leading to hypopituitarism.

Sheehans (postpartum necrosis)

Example:: have a pregnant woman, has abruptio placenta and goes in to hypovolemic
shock, but get out; doing fine and breast feading baby at home, but suddently stops
breast milk production diagnostic? Postpartum necrosis therefore she has infarcted her
pituitary (coagulation necrosis), and this is residual pitiuatary.

(This is not liquefactive necrosis because the pituitary is not part of the brain).
Mechanism is ischemia and coagulation necrosis. Pregnant woman have a pituitary gland two
times the normal size. Prolactin is being synthesized but a pregnant woman does not have
galatorrhea because the estrogen and progesterone inhibit release. So, the moment you give
birth, the inhibitory effects are released and start having galactorrhea. This is the 2nd Most
Common Cause of hypopituitarism in adult.

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 Most Common in kids = craniopharnygioma
this is part of the embryological development of the pituitary gland
pieces of it remain and can become neoplastically transformed into a craniopharygioma. It
benign b9 tumor in a bad place. It is Most Common supra-sellar (above the sella) and it
goes down and destroys the pituitary, but likes to go forward and presses into optic
chiasm, leading to bitemporal hemianopsia, leading to visual field defect.

Example: child with headaches and visual field defect do a schematic of it and will ask what the
cause is craniopharyngioma

*Growth Hormone (GH)

When you have a tumor that is expanding in the sella turcica, different releasing factors or
(hormones) decrease in a certain succession. The first thing that is destroyed is gonadotropin.
So, in a woman, what would happen? She would have (secondary amenorrhea). What if I were
a man (what is the analogous condition)? Impotence; impotence is to a male as amenorrhea is to
a female. Impotence = failure to sustain an erection during attempted intercourse.
Growth hormone has 2 functions:

1) Increases amino acids uptake

2) involved in gluconeogenesis (hormone that produces bone and tissue growth is insulin
like growth factor-1 (IGF-1), which is present in the liver like somatomedins; Growth
Hormone release will stimulate the liver to release IGF-1 to cause growth of bones
linearly and soft tissue); an adult with the loss of growth hormone will not get smaller, but will
have the effects of lack of growth hormone: will start to lose muscle mass and will have fasting
hypoglycemia because GH is normally gluconeogenic.

So, its not there and not contributing is function to glucogngeogenesis, leading to
hypoglycemia. What would you see in a child? Pituitary Dwarfism. Would see hypoplasia
(incomplete development of something). So, pituitary dwarfisim is an incompletely developed
child, but everything looks normal. What is the best stimulation test to see if you are GH or
Insuline like growth factor (IGF-1) defecient? Sleep. You grow when you sleep exactly at
5 a.m. rowth Hormone comes out). So, the best test is sleeping, and then
checking blood at 5 a.m. icient).

Why is histidine and arginine deficient? They are essential to normal growth of a child
because they stimulate growth hormone. These are basic amino acids. This is why weight
lifters buy arginine/histidine supplements to build up muscles. So, best test is sleep, followed
by measuring arginine and histidine levels.

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*Thyroid Stimulated Hormone, which leads to hypothyroidism (therefore low Thyroid Stimulated
Hormones and low T4 cold intolerance, brittle hair, fatigue, delayed reflexes).

*Adrenalcorticotropic Hormone (ACTH), leading to hypocortisolism. Will be fatigue will a low

cortisol level. Will also lead to hypoglycemia because cortisol is gluconeogenic. That last thing to
lose is prolactin.

*Diabetes Insipidus: Central (lacking Antidiuretic Hormone-ADH) vs.

respond to Antidiuretic Hormone-ADH)

1. Central: one of the common causes is car accident, leading to head trauma. The head is
shifted and stalk is severed. One of the first things that go is ADH because it is made in the
supraopitic paraventricular nucleus of the hypothalamus. In the same nerve it is made in, it goes
down the stalk and is stored in the POSTERIOR pituitary. So, if you sever that stalk, you sever
the connection and leads to Antidiuretic Hormone (ADH) deficiency. Also deficiency in all the
releasing factors that are made in the hypothalamus that stimulate the pituitary, leading to
hypopituitarism (eventually but initially will have signs/simptoms of Diabetes Insipidus =
polyurea and thrist).

2. Nephrogenic: have Antidiuretic Hormone (ADH)

tubule to make it permeable to free water. Other iabetes Mellitus mechanism
= osmotic diuresis, polydipisia mechanism = drink too much water (psychological
problem), hypercalcemia leads to polyurea).

Constantly diluting, but will never be able to concentrate urine; Syndrome Inappropiate
Antidiuretic Hormone (SIADH) is the exact opposite, where Antidiuretic Hormone (ADH) is
always there, and will constantly concentrating, and will not be able to dilute. In Diabetes
Insipidus, constantly diluting urine, losing free water, and will never be able to concentrate the
urine. So, you are losing all the water, and serum Na will go up, correlating with an increased
plasma osmolality (because most of plasma osmolality is Na).

To test: restrict water in a normal person, if you restrict water, the plasma osmolality will go
up to 292 (the upper limit of normal for the osmolality), 750 urine osmolality - what does
that mean? Pt is concentrating the urine. So, if you are depriving a normal pt of water, it
should concentrate the urine; water is being retained get into the Extracellular Fluid (ECF) to get
the serum Na into normal range.

Example: pt restricted water and have a 319 and 312 plasma osmolality (which is elevated). So,
they have hypernatremia. If you look at urine osmolality, it is 110 and 98. So you know that have
Diabetes Insipidus.

How do you distinguish central from nephrogenic? Give them ADH (like vasopressin). So, you
give it to them and see what happens to urine osmolality.

*
* So, gave ADH to first guy and it urine osmolality change
to 550, indicating that he has central Diabetes Insipidus. For the second pt, ADH was given, but
only a little increase in urine osmalality, indicated nephrogenic Diabetes Insipidus.

*Acromegaly
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What is cheapest way for screening for acromegaly? Ask for an old picture of the pt 10 years ago.

Gigantism in kid because rowth Hormone and

Insuline like growth factor-1 (IGF-1) lead to an increase in linear growth. Bad disease because
can die from cardiomyopathy. So, they have excess GH and excess IGF-
adult with acromegaly? Will not get taller because the epiphyses have fused, but bones will grow
wider

One of the bones in the head that does that is the frontal bones, so they stick out. So, get a gorilla
like increase in the frontal lobe (because it increases size of the sinuses), so the hat size will
increase. (Left hand-

Your hands get bigger, feet get bigger, and every organ in the body gets bigger. Also, you
produce a cardiomyopathy, which leads to death.

*Galactorrhea/Prolactinoma

Men do not get galactorrhea because

So, if a male has a prolactinoma, do not expect him to have galactorrhea.

*Causes: When woman comes in with it, make sure you ask what drug they are on - because
there are many drugs that can stimulate prolactin synthesis.

1. Oral Contraceptic Pills (OCP), hydralazine, Ca channel blockers, psychotropic drugs

increase prolactine synthesis.

In Primary hypothyroidism can also be a cause, therefore get a TSH level. Why? Because, if you
TRH increased. TRH is used as a stimulation test for
prolactin. So, you must rule out hypothyroidism in a woman with galactorrhea (so in this case,
there is nothing wrong with the pituitary, but the thyroid, leading to galactorrhea). So, must rule
out hypothyroidism.

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 If all this is ruled out and pt has high prolactin level, diagnosis is prolactinoma (any time there is a
prolactin level over 200 it is always a prolactinoma). When pts have prolactinoma, why do they
develop amenorrhea? Because prolactin has a negative feedback and Inhibit on
Gonadotropin Releasing Hormone (GnRH). So, this is a cheap birth control pill for the first
three months after pregnancy because mom is breast feeding, and the high prolactin levels are
feeding back on the pituitary on GnRH.

THYROID GLANDS

Thyroid studies 3 things need to know: T4, Thyroid Stimulated Hormone (TSH), I 131
uptakes.

*If TSH is normal = thyroid is normal.

*If TSH is decreased = hyperthyroidism or hypopituitarism.
*If TSH is increased = high primary hypothyroidism.

Thyroid binding globulin (TBG) is the binding protein for thyroid hormone

What is the binding protein for cortisol? Transcortin

What is the binding protein for calcium? Albumin
What is the binding protein for Fe? Transferrin
What is the binding protein for Cu? Ceruloplasmin; what % of binding sites occupied? 30%).

3 of 9 binding sites on Thyroid Binding Globulin are occupied by thyroid hormone.

Free T4 level. When we measure total T4 level, there is free T4 and bound T4. The free T4 is
the part that is metabolically active and is converted to T3. This part is doing all the work (that
part that is bound is not).

What happens if you are on an OCP with an increase of estrogen? Thyroid Binding
Globulin and transcortin increase. So, increased synthesis Thyroid Binding Globulin, and is
immediately 1/3 occupied (9 sites on Thyroid Binding Globulin, and 1/3 occupied by T4, so that is
3 sites occupied by ecause everything is in equilibrium, the thyroid senses that it lost 3
TSH?
Normal. What is the T4? Increased (but the free hormone level and TSH not altered). So, an
increase T4 with a normal TSH means the pt is on estrogens. This is true for any woman on
estrogen or any pregnant women. So, the total T4 is elevated becausec increased TBG (not be
increased free hormone level) and it automatically has 3 sites occupied by T4). Same is true for
cortisol if pt is pregnant or on OCP, cortisol is elevated but do not have signs of cushings. Why?
Because transcortin is increased because estrogen increasing the synthesis of it, so there is more
cortisol bound to it, but the free cortisol levels are still normal.

Example: if football player/wt lifter, assume pt is on anabolics. They work the opposite. Anabolics
break down proteins that you normally would use for other things to build up and put them into
muscle. The protein it likes to go after is binding proteins. So, when they are on anabolics,
thyroid binding globulin is decreased because the amino acids that you would have used

work if you are not working amino acids supplements.

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 Example: pt on anabolics, so less Thyroid Binding Globulin being synthesize becausec proteins
being used elsewhere (muscles). The same number of site is occupied, but missing Thyroid
Binding Globulin. So, free T4 is the same, but missing Thyroid Binding Globulin.

*If a person has a low T4 with a TSH, they are on anabolic steroids.
*If a woman has a high T4 and a normal TSH, what is she on? Estrogen.
*If a person has high T4 and low TSH, what do they have? Hyperthyroidism.
*If pt has low T4 and increased TSH, what do they have? Primary hypothyroidism.

*I 131 uptake is a radioactive test

Board Question: (What is thyroid hormone? tyrosine with iodine on it). (What are other things
involved with tyrosine? Melanin, tyrosine, tyrosinase, dopamine goes into the Golgi apparatus
and becomes melanin, phenylalanine, dopamine, dopa, Norepinephrine (NE), epinephine
(catecholamines), if you put iodides on tyrosine you have thyroid hormone).

So, with hyperthyroidism (Ex. graves), thyroid gland will be making more thyroid hormone. Would
we need more iodide to do this? Yes. So, if you gave a pt radioactive iodide, will there be
increased uptake of radioactive iodide in that overactive gland? Yes. So, will have increased
I131 uptake.

What if I were taking excess thyroid hormone to lose weight? What would that do to my
TSH level? Suppress it. So, when that pt is taking too much hormone, the gland has atrophied.
So, if you have a radioactive I 131, would there be an increased uptake? No, because is has
atrophied. So, radioactive I 131 is the main way to distinguish whether a person has true evidence
of hyperthyroidism (GLAND is making too much thyroid hormone) vs someone that is
surreptitiously/purposely/unknowingly taking too much thyroid hormone and producing
hyperthyroidism.

I 131 is the best test to distinguish these two types of hyperthyroidism. So, if its increased, pt
has graves (gland is using it); if its decreased, pt is taking thyroid hormone.

Example:: pt from wt loss clinic they are taking thyroid hormone, so they will lose wt at the
expense of hyperthyroidism.

Slide: midline cyst diagnosis? Thyroglossal cyst.

Remember that the thyroid gland was originally at the base of the tongue and migrates down the
midline to the current location.

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 Slide: cyst in anterolateral portion of neck
diagnosis? Branchial cleft cyst (know all branchiocleft derivatives especially the one in the
head area).

* Disease exophalmos
Disease excess Glucoaminoglycosides deposited in orbital fat, and pushing the eye out
(pathonomognic for graves); apathetic graves. OLD people with graves disease have heart
problem with atrial fibrilation. They get heart manifestations. So, any pt with atrial fibrilation must get
a TSH level to rule out graves.

Signs/Simptoms of hyperthyroidism:

Heat intolerance, sinus tachycardia, atrial fibribilation, brisk reflexes, diarrhea, systolic
Hypertension, hypercalcemia, increased bone turnover (all symptoms are adrenergic
they are all catecholamine things why? Because T4 increases the synthesis of beta
receptors (catecholamines are cousins of Thyroid hormone and they work together. All the
symptoms are adrenergic.

What is the INITIAL treatment of graves? Beta blockers (blocking adrenergic response, then
give Propilphiouracil (PTU) to stop the gland from making it can stop all the symptoms with
beta blocker except one sweating)

so, thyroid studies on graves pt: T4 is high, TSH is low, I 131 is HIGH

Audio File: Day5 4Endocrine2

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*Hyperthyroidism, want to always look at the face and will
see periorbital puffiness, which is seen a lot because of Glycosaminoglycan (also in vocal cords,

leading to hoarseness, pretibial area leading to nonpitting myxedema).

Mitral Valve Prolapse also has an increase in Glycosaminoglycan because dermatan sulfate is
responsible for causing excess and redudency of the valve). Also seen in Hashimotos.

Graves is due to IgG Antibody against TSH receptor, causing it to synthesize too much.
What type of Hypersensitivity reaction is this? Type II (Antibody against the receptor);

Myastenia Gravis is also type II Hypersensitivity (have Antibody against receptor which is
destroying the receptor).

, they also have an IgG against the receptor, except instead of

activating the gland, it raves, these are both autoimmune

inhibibitory one. So, an overlying symptom that they both have is pretibial myxedema and
GAG deposition.

Where do you see a decrease in Glycoaminoacidglycans (ex. metabolism of

Glycoaminoacidglycan)? Lysosomal storage diseases Hurlers, Hunters need

-Signs/Simptoms in hypothyroidism

Weakness (Most Common) because all pts with hypothyroidism have proximal muscle
myopathy, so they cannot get up out of chairs
hair, coarse skin, slow mentation, periorbital puffiness, delayed reflex, diastolic
Hypertension.

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 Slide: biopsy of thy no
follicle, but do see germinal follicle because there is autoimmune destruction of the gland. There
are cytotoxic T cells that destroying it, and are synthesizing Antibodies (IgG Antibodies, hence
you see the germinal follicles), and therefore looks like a lymph node). Will see a low T4, high
TSH, low I 131 (not necessary to do this test).

Example: pt on estrogen what will happen to T4? Increase TSH? Normal (no need for I
131 this is bad because babies thyroid would take it up and its thyroid would take it up and
leads to cretinism) Thyroid hormone is responsible for brain growth in the first year, so it
important to do thyroid hormone screens to avoid cretinism (will be severly Mental
Retardation because brain depends on thyroid hormone for development).

Example: T4 high, TSH, low, I 131 high

Example: pt on anabolic steroids T4 low, TSH normal

Example: Hashimotos T4 low, TSH high, I 131 low

Example: factitious (taking too much thyroid hormone and have hyperthyroidism) T4
high, TSH low, I 131 low (main factor that distinguishes from graves)

*Goiter
Anytime thyroid is big. Lots cysts.

Most Common Cause of goiter = Iodine deficiency

Most often due to low iodide levels, so they have hypothyroidism or borderline hypothyroidism, so

then not, then it is, etc..).

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 Treatment of choice thyroxine

Sometimes have a nodule nodules that develop in the thyroid gland get hemorrhaged.

There is sudden increase in hemorrhage due to cyst.

Diagnostic with Fine Niddle Aspiration. Then, give thyroid hormone and many times these
things will get smaller.

wever, some places people have iodine

poor diets Ex. Great Lakes in Chicago area, Britain; when they get graves disease, due to
increase in T3 because they are iodide deficiency and do not have enough iodine.

*Cold nodule vs Hot Nodule

Means if nodule is taking up I 131 or not. If it does not, there is an area of lucency, and therefore
cold. If it is hot, there will be a black dot. Why? Because if the nodule is autonomously making
thyroid hormone, what is the TSH? Decreased. If the TSH is decreased, would that suppress the
normal portion of the thyroid? Yes, so it undergo atrophy and not take it up, leading to black dot
What is chance that a cold nodule is malignant in a woman?
15-20%.

Most cold nodules in an older woman are benign. Most are

cysts. A small % is follicular adenoma.

Any cold nodule in a MAN is cancer until proven otherwise. Any cold nodule in a child is cancer
until proven otherwise. Any PERSON that has been exposed to radiation and has a cold nodule
has CANCER (papillary carcinoma of the thyroid radiation exposure in head/neck area).

*Cancers of the thyroid

Need to biopsy (cannot tell if malignant just by looking at it) this is true for follicular adenoma,
something b9, multinodular goiter. Done with Fine Niddle Aspiration.

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1. Papillary cancer would show up with a cold nodule, and
has Psammoma bodies. Papillary carcinomas metastasis to cervical lymph nodes next to
them. They commonly do this, and have a good prognosis. This is the only association with
radiation. Annie orphan nuclei.

2. Follicular cancer 2nd Most Common type, invades

vessels. Do not go to lymph nodes. Spread hematogenously, therefore often go to lungs and
bone.

3. Medullary carcinoma some cases are sporadic and

other cases have Autosomal Dominant relationship; associated with MEN syndromes (multiple
endocrine neoplasia I, IIa, IIb). Pink stain stain with Congo red and see polarized apple
green birefringence = amyloid A (which came from calcitonin); what is the tumor marker?
Calcitonin (which is the screening test of choice)

Where would the cancer be located in the body where the tumor marker is converted into
amyloid? Medullary carcinoma of the thyroid

MEN I pituitary tumor, parathyroid adenoma, pancreatic tumor (usually Zolinger Ellison, leading
to peptic ulcer).
MEN IIa medullary carcinoma, parathyroid adenoma, pheochromocytoma
MEN IIb medullary carcinoma, pheochromocytoma, mucosal neuroma
How do you screen? Ret protooncogene (unique to coding for receptors in this syndrome).

Prognosis (best to worst): Papillary>Follicular>Medullary

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*PARATHYROID GLAND (PTH)

Pt can have tetany with a normal total Ca. Ca is bound and free
metabolically active (which is true for ANY hormone the part that is bound is totally metabolically
inactive). So, who does Ca interact with? Parathyroid Hormone

-Ca is low = PTH is high

-Ca is high = PTH is low.

Roughly 1/3 of the binding sites in albumin are occupied by Ca. So, in other words, roughly 40%
of the total Ca is bound to albumin. 47% is ionized Ca floating around and the rest is phosphate
and sulfates. The ionized Ca is the metabollicaly active form.

Most Common Cause overall of hypocalcemia = hypoalbuminemia.

Have low albumin level, therefore decreased level, and less of albumin binds Ca. So, before you
look at PTH levels, look at albumin levels if that is low, this is the cause of hypocalcemia. This is
not affecting the free hormone level, just that albumin is decreased. This is same as Thyroid
Binding Globuline being decreased, leading to decreased T4.

Alkalosis (respiratory or metabolic): have decreased H ions, and pH is increased. What are
the acidic amino acids? Glutamate, Aspartate. Why are they acidic? Have COOH groups (as
opposed to basic amino acids , which have more basic NH groups).

The reason why albumin is such a great binder of Ca is because it has the most negative charges
in the body, because it has the most acidic amino acids in it. So, if you have an alkalotic state
with less H ions then COOH groups become COO negative groups. Because if you have less H
ions, its COO negative and albumin has MORE of a negative charge in an
alkalotic state, which means it can bind more Ca.

So, where does it get it from? Ionized free Ca (so a bunch of ionized free Ca binds to the the
albumin). However,
DOES decrease the ionized Ca level, leading to TETANY.

So, total is the same, but the ionized level has decreased. What is the mech of tetany? Have
threshold for the Action Potencial before the nerve is stimulated. Then you have a resting
membrane potential. So, a decreased ionized Ca level will lower the threshold for activating the
nerve and muscle. If it s -60 for normal threshold.

is the mechanism of tetany) so you are lowering the threshold. In hypercalcemia, the opposite
occurs and you are increasing the threshold, so it takes more ionized Ca to activate the nerve.

Parathyroid Hormone on Y axis and Ca in X axis height of square = PTH and width = Ca

*Low serum Ca, low PTH = primary hypoparathyroidism

Most Common Cause of hypoparathyroidism= previous thyroid surgery

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 Example: pt goes in to remove thyroid cancer (these days they autotranplant it to the arm)

Example: newborn with cyanosis, irritable and xray of chest shows not
anteriormediastinum shadow diagnosis? DiGeorge hypoparathyroidism and no thymus.

Example: low Ca, high PTH = secondary hypoparathyrodism so whatever is causing the
hypocalcemia is causing a compensatory increase in PTH (called secondary hypoparathyrodism
the Most Common Cause of hypoparathyroidism is renal failure because these pts have
hypovitaminosis D, which decreases Ca and increases PTH). So, any decreases in Ca with
cause a compensatory increase in PTH.

Example: high Ca, high PTH = primary hyperparathyroidism = gland is not obeying negative
feedback. This is most common Cause of hyperparathyroidism is hypercalcemia in a
community;

If pt is in a hospital, Most Common Cause hypercalcemia = metastasis to bone (malignancy

induced). Most hypercalcemia pts are asmptomatic; if they ARE symptomatic, they have stones.
Most Common symptomatic presentation for hypercalcemia = Calcium Stones.

Labs: increased Ca increased PTH, low phosphate (normally PTH increases Ca reabsorption and
decreased phophorus reabsorption). Almost always over 50 years.

Example: high Ca, low PTH = all other causes except primary hyperparathyroidism. Most
Common due to malignancy. Can PTH like peptide cause hypercalcemia? Yes (so if you
measure PTH it will be normal). Squamous cell of the lung, renal adenocacinoma, or
metastasis to bone (breaking bone down), sarcoidsis (leading to hypercalcemia), multiple
myeloma (leading to hypercalcemia) all will have LOW PTH.

So, what is the simples and easiest way to determine hypercalcemina in a pt? PTH level

PTH is high = primary hyperparathyroidism

PTH low = it s all the causes Ex. malignancy).

*ADRENAL GLAND

Cushing Syndrome

PURPLE striae, obesity, thin extremities.

Most Common Cause of Cushing disease is pt on long term steroid therapy (Ex. pts with
renal transplants, pt on immunosuppressant, Lupus)

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 If this is excluded, need to think of 3 sources: pituitary Cushings, adrenal Cushings, ectopic
Cushings.

Which of the three will have the highest ACTH levels? Ectopic (small cell carcinoma).

Which would have the lowest ACTH levels? Adrenal. Why? Because it s making cortisol,
which would suppress the ACTH. Pit Cushings is usually a b9 tumor making ACTH.

There are 2 good screening tests for Cushings (when you have excluded the fact that they are
not on steroids).

1. 24 hr urine test for free cortisol. This is looking for cortisol in the urine, not attached to
It must mean that you have a lot of excess of it to have that much of
it in your urine. This is the BEST screening test for Cushings. This test distinguishes

Example: see obese pt moon face

Cushings; however, get a 24 hours urine cortisol test and
truly have Cushings in other words, they have 99% sensitivity and specificity.

2. Board going to ask about: Dexamethasone suppression test (low vs high dose). What
cortisol analog. If you give dexamethasone to a normal person, it
will suppress ACTH. If you suppress ACTH, the cortisol levels with be low, indicating the
cortisol levels are suppressible. So, what happens when you give a LOW dose of
dexamethasone in a pt with Cushings? you see a lack of suppression. Therefore pt has
.
However the LOW dose just tells you pt has Cushings, not what kind they have, so it just a
screening test (if you did a 24 hr cortisol urine level, it would be positive).

Remember that there are two endocrine diseases that you CAN suppress

1. PITUITARY Cushings
2. Prolactinoma.

So, if you give high dose of dexamethasone, you are able to suppress the ACTH release
by the pituitary and cortisol goes down. It will not be suppressed in adrenal and ectopic
Cushings (small cell).

IN THE BOARD [Read last sentence if you get a long question]

Example: for one of these, they will describe Cushings, and ask about dexmeth suppression
first thing to do is look at high dose suppression if its suppressed, its automatically pituitary
cushings (not a hard question!)

So, why do the pts look like this? Pt has hypercortisolism, which is gluconeogenic. So, need
substrates for gluconeogenesis main substrate is amino acids from muscles. Where are the
muscles located? Arms and legs so pt will get a break down of muscle in the extremities, which
is why they have thin arms and thin legs. Then will get alanine transaminated and get pyruvate.
So, will always have thin arms and extremities. Because it is gluconeogenic, what will the glucose
be? High. What does that do to insulin release? Increases it. What does insulin do to fat?
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 Increases fat storage. What part of the body has the most adipose? Face and trunk. So, you are
getting an increase in deposition of Tryglicerides in the face and trunk and back. So, the thin
extremities are due to breaking down muscle for amino acids in gluconeogenesis. The moon
facies, buffalo hump and truncal obesity is due to increase in insulin and fat deposition. The
stretch marks are due to obesity, and they are purple because cortisol decreases collagen
synthesis. Will get structurally weaker collagen. It s like purpura within the stretch mark (like
senile purpura). Break down the vessels because increase in cortisol.

Example: sign of tetany; this pt has HTN,

hypernatremia, hypokalemia, and metabolic alkalosis dx? Primary aldosteronism. (have tetany
bc alkalosis neg charges on albumin are increased, and ioninzed Ca level decreases). Like:

*Adrenal Medulla tumors

Most Common in adults = pheochromocytoma (benign

b9, HTN) (Adult, Hypertension, tumor in adrenal medulla = pheo).

Pt that has unstable Hypertension anxiety, sweat a lot; get a 24 hours urine test for
Vanillymandelic Acid (VMA) and metenephrine (these are metabolic endproducts of
Norepinephrine (NE) an Epinephirne (Epi).

Are there associated with pheochromocytoma? Yes MEN IIa and MEN IIb, neurofibromatosis
(Ex. pt with neurofibromatosis with Hypertension what test you get? VMA and metanephrine 24
hours urine, because high associated with pheo).

Most Common of adrenal tumor in kids = neuroblastoma (MALIGNANT).

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Both of these are from renal medulla, both are neural crest origin, both produce
Hypertension.

Example:: 12 y
- started to get
petechial lesions all over the body, no cortisol, no mineralocorticoids, hypovolemic shock, died, on
autopsy both adrenal glands are hemorrhaged Diagnosis? Waterhouse Freidrickson
Organism? Neisseria Menengitidis.

Most Common Cause of meningitis from 1 month to 18 yrs of age = Neisseria meningitidis.
It is the ONLY meningitis with petechial lesions (and they always mention this).

Cause of hypocortisolism that i

Most Common Cause of Addisons = autoimmune destruction of the gland (used to be

Tuberculosis due to autoimmune destruction).

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The entire adrenal cortex is destroyed, therefore the mineralocorticoids and glucocorticoids are
low. So, there is low cortisol with HIGH ACTH. What does that do to melanocytes? Increases

them, leading to hypigmentation in the mouth

and elsewhere.

There is NO aldosterone. There are 2 pumps (Na/K pump and proton/K pump). Are you gonna
lose Na? Yes which will lead to hyponatremia and HYPERkalemia (peaked T waves). Will
you be able to get rid of the protons in the urine? No therefore will have metabolic acidosis.
So, you have hyponatremia, hyperkalemia, metabolic acidosis, hyperpigmentation.

Example: ambiguous genetalia what is first step in management? Chromosome analysis

have to find out what the genetic sex is.
phenotypically cannot tell, (play odds) adrenogenital
syndrome due to 21 hydroxylase deficiency.

17 hydroxylase is responsible for 17 ketosteriods (include DHEA, androstenedione, and are weak
androgens). Androstenedione can be converted into testosterone and testosterone into
dihydrotestosterone.

17 hydroxycorticoids are 11 deoxycortisol and cortisol

So, if you have an increase in 17 hydroxycorticoids = increase in 11 deoxycortisol and

cortisol

If you have an increase in 17 ketosteroids = increase in DHEA and androstenedione.

When you have an enzyme deficiency, things proximal to the block increase and things
distal to the block decrease

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 With 21 hydroxylase deficiency = decrease mineralcorticoids and glucocortiocoids and
increase androgens, lead to ambiguous genetalia (excess androgens), lose salt, high ACTH,
therefore hyperpigmented.

With 11 hydroxylase deficiency decreased cortisol, decreased aldosterone, but increased

11 deoxycorticosterone (weak mineralcoricoid), increased 17 hydroxylase and 17
ketosteroid little girl will have ambiguous genitalia, little boy will have precocious puberty
(excess androgens), Hypertension due Na retention.

17 hydroxylase deficiency no androgens, increased in mineralocorticoids (Hypertension),

ecause no development (no
external genitalia because no 17 ketosteroid, testestoterone, or dihydrotestosterone). In a little girl
she will be underdevoped.

*Islet cell tumors

Only 2 to know:

1. Insulinomas: is pt injecting or do they really have insulinoma?

When you break proinsulin down into insulin, you release C peptide, so for every insulin
molecule that is released; there is C peptide that is released with it. So, if you inject human
insulin into yourself, and produce a low glucose level and C peptide will be SUPPRESSED.
If you have an islet cell tumor, glucose will be low, insulin will be high and C peptide will be
INCREASED.

Example: pts that have access to insulin get this (Drs., nurses, pharmacists)

2. ZE syndrome: making too much gastrin, leads to peptic ulcers.

Audio File: Day5 5Musculoskeletal

*DIABETES MELLITUS

Type 1-
Absolute insulin deficiency

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Antibodies against islet cells
DKA (Diabetic Ketoacidotic)
HLA (Human Leucocyte Antigen) relationship
Insulin used (always)

Type 2
Family history of diabetes
Obesity
Amyloid in islet cells (chronic disease)
Hyperosmolar non-ketotic coma
Insulin used when eventually pt get resistant to Sulfolynureas.

PATHOGENESIS: 2 mechanisms:

1) Osmotic Damage

Tissue has to have aldose reductase: only 2 have them:

i) Lens, glucose sorbitol, osmotic reactive, absorbs water into the lens.

Parasite in a Retinal vessels in lens get weak, microaneurysm can rupture and lead to
blindness.

ii) Scwann Cells: Most Common Cause cause of peripheral neuropathy is Diabetes:

2) Non-enzymatic Glycosylation

Renders the Bone Marrow permeable to proteins producing: Hyaline arteriolosclorosis,

diabetic nephrophathy

HbA1c: long term control of Diabetes Mellitus.

Slide: Retina in diabetic-microaneurysms (red dots)

Due: osmotic pressure in pericytes.

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 Slide: Retina in a diabetic-neovascularization

Example: 50 years old, blurry vision; gets a prescription from a optometrist, new
glasses, one month later, blurry vision again. Gets new prescription, one month
later, blurry vision again. Diagnostic: Diabetes.

Glucose is being converted to sorbitol-water is going in and changing the refractive index of
the lens. Classic question. HAVE to get a FASTING BLOOD GLUCOSE.

Lab: Fasting glucose >126 mg/dl on two separate occasions.

Example: Beh Sc link: The FBS level has been decreased from 140 mg/dl to 126 mg/dl. Is
this increasing the specificity or the sensitivity of the test?

A: HIGH Sensitivity. By bringing it lower. Ex. closer to the normal range, you are going to
be able to pick up more people with diabetes. When it was 140, it was high sp: to eliminate
false positives. So it was unequivocally a diabetic if it was > 140.

*Gestational Diabetes

Deficiency: Woman who did not have diabetes, but after becoming pregnant develops
diabetes.

Risk factors for baby: Respiratory Distress Syndrome, premature delivery.

Women with Gestational Diabetes, are at a higher risk for developing diabetes later on.

Amyloid in Beta islets: Type 2

Antibodies against islets; inflammation: Type1

(Coxackie virus implicated)

HLA correlation: HLA DR3 and DR4=Type 1; propensity for developing Type 1, if certain
environmental factor comes in such as infection: Coxsackie, mumps, Ebstain Barr Virus.

HLAB27: Ankylosing Spondylitis

Enviromental factors: Chlamydeal Infection, Ulcerative Colitis, Shigellosis, Psoriasis

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 MUSCULO SKELETAL SYSTEM

1. GOUT: you need to identify the crystals:

Pseudogout: Two type of crystal

Rhomboid crystals in synovial fluid = pseudogout

But Pseudogout could also have a needle-shaped crystal

(like those of mono-sodium urate in Gout) which makes Diagnosis difficult. So you use a
special filter to make the whole slide red and then the crystals are made to look yellow or blue.

When the color of the crystals is yellow when the plane of filter is parallel to the analyzer=
Negatively birefringent =GOUT

East west direction: color is blue and parallel to analyzer=Positively birefringent =

PSEUDOGOUT (calcium pyrophosphate)

2. ARTHRYTIS

Most common of arthritis is Osteoarthritis (Progressive wearing down of articular cartilage)

Sometimes leads to reaction to injury: production of osteophytes or bony SPUR formation at

the margin of the joint=

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 Note the enlargement of the distal interphalangeal
(DIP) (Heberden's nodes) and Proximal Interphalangeal (PIP) joints (Bouchard's nodes),
enlargements represent osteophytes.

3. Rheumatoid Arthritis

Inflammatory joint disease; enlarged Metacarpophalangeal (MCP) joints

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Rh factor sets up the inflammation: IgM Antibody against IgG. IgG is in synovial fluid. IgM-
IgG form complexes, activate the complement system, damage the joint, synovial fluid gets
inflamed, starts growing and growing, starts growing over the articular cartilage= PANNUS;
hyperplastic synovial fluid. Joints can get fixed, and ankylosed and cannot move.

joints, and if it is not controlled using anti-inflammatory

drugs then eventually they cannot move it at all.

Slide: Rheumatoid nodules.

Can be seen in Rheumatic fever as well.

Example: older pt having trouble eating and swallowing crackers, feels like there is sand in my eye
all the time. On examination: eyes and mouth are dry. Diagnosis?

The Pt with Rheumatic Arthritis and auto-immune destruction of lacrimal glands, salivary glands.
Keratoconjunctivitis sicca..

What is the name of the patient who have Rheumatoid nodules in lung + pneumoconiosis?
= Caplan Syndrome
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 Treatment of Rheumatic Arthritis= Methotrexate

Example: Pt with Rheumatic Arthritis, develops a macrocytic anemia with hypersegmented

neutrophils, neurological exam is normal, interstitial fibrosis in lung. What is the drug?
Methotrexate

4. Gout = podagra

Big toe, usually first one to be involved; usually at night.

Monosodium urate crystals are precipitated in synovial fluid and taken up by the neutrophils that
phagocytose it and release chemicals inflammatory reaction.

About 25% of people might have elevated uric acid.

Diagnostic: HAS to be by presence of uric acid crystals in the joint.

Treatment: Indomethacin to control inflammation.

Cause: over production (Treatment=allopurinol: blocks Xanthine oxidase) or under excretion

of uric acid (>90% of cases) Treatment=uricosuric drugs like probenecid and Sulfinpyrazone.

5. Chronic Gout = tophus: deposition of monosodium urate in

soft tissue Giant malleolus. Very disabling as it erodes the joint. Treatment = allopurinol

Slide: Tophus that was polarized showing Monosodium Ureate crystals

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 Slide: X-ray of digit showing erosion by tophus

6. GENETIC GOUT:

*Multifactorial inheritance

AVOID red meats (full of purines)

AVOID Alcohol. Mechanism:

Metabolic acidosis: uric acid has to compete with other acids for excretion in proximal tubule.
Alcohol increases all the lactic acid, and beta hydroxyl butyric acids. So all these acids compete
and win against uric acid, and get excreted. Uric acid keeps waiting and waiting; and builds up
and causes gout.

*Ankylosing spondylitis (AS)

HLAB27 association

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Slide: Note anterior flexion which often results in
restrictive lung disease. Hunched over, restricts movement of chest cavity, blood gas
abnormalities,

20 years old, morning when he woke up, sudden

pain in sacro-lumbar region. Inflammatory reaction seen on X-ray, as the day progresses
pain decreases. Eventually, the inflammation spreads to the vertebral column, and it fuses
= . (Left=normal---Right=bamboo spine)

Also develop: Uveitis, Aortitis, iridocyclitis, blurry vision, eventually go blind.

Example: Genetic disease where degenerative arthritis in vertical column, on autopsy, black
cartilage; urine on exposure to air turns black. Alkoptonuria: Autosomal recesive,
homogentisic acid oxidase enzyme deficiency.

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Slide: 20 years old, dysuria, increased freq, urinalysis=
leucocyte esterase positive, sterile pyuria--sexually active, had non-specific urethritis,
conjunctivitis, was treated. It was Chlamydia trachomatis conjunctivitis, but one week later, got
sterile conjunctivitis and tendonitis in Achilles tendon.

So patient with non-infectious conjunctivitis, previously had Chlamydia trachomatis infection

and then developed conjunctivitis and arthritis (HLA B27 positive): Reiter's syndrome

Another Env trigger in HLAB27 positive pt: Ulcerative Colitis

Septic arthritis due to disseminated gonococcemia

Note the hot knee and the pustule on the wrist, on aspirating: gram negative diplococci
Have: S=Synovitis=joints; T= Tenosynovitis= joints in hands and feet; D= Dermatitis=pustules

Most Common Cause of septic arthritis in US= Gonorrhoea

For it to become disseminated, need to be deficient in the final pathway of Complement system:
C5-C9 (some say C6-C9)

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 Slide: Note the Ixodes tick (vector of Borrelia
burgdorferi and Babesia microti), note the erythematous rash in the bottom screen - the tick
bite is in the center of the rash and the rash extends out in concentric circles from that point, the
rash is called erythema chronicum migrans (pebble thrown in water) Pathognomonic of Lyme's
disease

Early form Treatment: tetracycline

Apart from disabling joint disease: myocarditis plus

palsy: CN VII involved + pt will have Babesiosis

Above Pt develops Hemolytic anemia, what did he see in his peripheral blood smear? Babesia
microti (ring form similar to Plasmodium falciparum)

Remember: the Ixodes tick has the reservoir for Borrelia burgdorferi (white tailed deer that
has Babesia microti) AND Babesia microti intra-erythrocytic parasite

Treatment: Ceftriaxone

7. BONE DISORDERS

*Osteogenesis imperfecta

*Slide: Kid with an eyeball, blue sclera: Autosomal

Dominant disorder with defect in synthesis of type I collagen, note the blue sclera- loss of
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collagen in sclera allows bluish color of choroidal vessels to shine through: Osteogenesis
imperfecta .

Board Question: Defective synthesis of type 1 collagen

velopment of blue sclera?

Collagen in sclera, type 1 is defective, so it is so thin, so you can see the underlying
choroidal veins that give the blue color.

*
Defect in too much bone: defect in osteoclasts.

*Osteomalacia: Decreased mineralization of bone: organic part of bone is normal. Cartilage is

ok, osteoid is ok; its not getting mineralized.

*Osteoporosis

Slide: Decreased width of intervertebral cartilage. Note the

collapse of the vertebra due to loss of bone mass: patients lose more bone than is
replaced.

Slide:
Mechanism: In woman Postmenopausal osteoporosis is due to the loss of the inhibitory
effect of estrogen on the release of interleukin 1 from osteoblasts; not enough estrogen to
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stop the activity of Interleukin-1 (osteoclast activating factor) from breaking your bone
down. Both mineral AND organic component. WHOLE mass of bone is reduced.

Diagnosis of osteoporosis: Dual photom Absorptiometry: density of the bone in whole

body is measured. Non invasive, very easy.

Most Common fracture in osteoporosis: compression fracture of the vertebras bodies:

make lose stature,

2nd Most Common fracture in osteoporosis: .

Board Question: Is swimming a good exercise for preventing osteoporosis? NO, Because
swimmin no make stress on bones. It is great exercise for aerobics. But it does not prevent
osteoporosis.

Make stress help to build up the bone: Walking is good. Weight bearing is even better than
walking! Walk with Dumbells! Get aerobics and increase in bone mass!

Example: In space, lack of gravity and astronauts are given bisphosphonates, Vit D and calcium to
get bone density back: because serious problem of osteoporosis in space.

Tip: reproductive women need to: Every Day

1) Exercise
2) 1500 mg of Ca
3) 400-800 units of Vit D
4) Vitamin pill that contains Iron

8. BONE TUMORS

Exostosis (osteochondroma)

Note the cartilaginous cap on the surface of the bone. This causes a protuberance of the bone.
Most common benign bone tumor.

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*Chondrosarcoma of the hip Most Common malignant one.

*Osteogenic sarcoma

Slide: Note metaphyseal origin of the cancer and

extension into the muscle, note the splinter of periosteum that is elevated which would
correspond to Codman's triangle.

Slide: X-ray of proximal humerus showing the "sunburst"

appearance of osteogenic sarcoma that is extending into the muscle, osteogenic
implies that the cancer is making bone.

Adolescent, sun burst appearance, codmans triangle, knee area = Osteogenic Sarcome

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 Suppressor Gene relationship: Rb suppressor Chromosome 13

MUSCULAR DISORDERS

Duchennes muscular dystrophy

Elevated Serum CK, Absence of dystrophin protein

Sex linked recessive, missing Dystrophin gene

Variant: Bec : make dystrophin but is defective dystrophin.

Analogy: alfa 1 antitrypsin deficiency:

Most Common Cause of Hepatocellular Carcinoma in children: alfa 1 antitripsin

deficiency. Alfa 1 anti-trypsin is present but it cannot get OUT of the hepatocytes: so get
Hepatocellular Carcinoma.

Most common cause of panacinar emphysema in adult: alfa 1 antitripsin deficiency.

Absent alfa 1 anti-trypsin: get pan acinar emphysema.

Audio File: Day 5 6Musculoskeletal

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1. Myotonic dystrophy Most Common adult dystrophy,
Autosomal Dominant
Triplet repeat disease repetition of trinucleotides (there are 4 diseases with this abnormality
Huntington Disease, Fragile X have mental retardation and macrorchidism (big testes in
adolescents), Friedr

In future generations, disease gets worse anticipation. Therefore, can anticipate that in
future diseases it will get worse. For each generation, there are more triplet repeats added on,
leading to a more defective protein and the disease gets worse and worse.

Board Question: genetic counselor telling couple that they have a disease, where if are to
have children, the disease
counseler, had a child and the child died only after 1 month. What was it? triplet repeats
disorder (anticipation) Muscle weakness in face (so mouth is drooped open).

Example: pt with failure to release grip on golf stick (or when shaking hand) they cannot relax
their muscle grip and have diabetes, cardiac abnormality.

2. Myasthenia Gravis
AutoAntibody against Acetilcholine (Ach) receptor ntibody.

Example: of type II Hypersensitivity ntibody against the receptor

(by definition, this makes it type II). Whether you destroy the receptor or just block it is irrelevant.
Acetilcholine cannot hook into it and therefore there is muscle weekness. The first muscles
affected are the lids (parpados), which leads to lid lag. They also get double vision because
muscles of the eye are messed up, leading to diplopia. Eventually, they get dysphagia for
solids and liquids (gets stuck in upper esophagus, because this is where there is STRIATED
muscle). Eventually muscle disease prevails throughout. Feel energized in the morning and
feel tired at night. Tensilon test positive. Can die.

Treatment: acetylcholinestrase inhibitors. By giving an inhibitor, block the breakdown of Ach

and build up Ach. With few receptors you have in there, there is a larger chance of hooking up to

much Ach is there, so pt is screwed. Then, her only option is a thymectomy.

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 The thymus is in the anterior mediastimun.

Trick Board Question: What is the pathology? They can describe Myastenias Gravis and
ask, what do you expect to see in the mediastinum? B Cell Hyperplasia germinal follicles
in the thymus (remember, this T cell country, so its abnormal to have B cell germinal
follicles in the thymus) they are the ones making the Antibody causing the Myastenia
Gravis. So, by doing a thymectomy for Treatment, you are removing the Antibody producing
tissue. 1/3 pts get a complete cure. 1/3 gets a partial cure, and 1/3 die because they waited too
long for thymectomy and Treatment So, B cell hyperplasia
is the Most Common thing you see, not thymoma. This where the Antibodies is being
made.

3. Lupus

Butterfly distribution on the face (malar rash)

Of all the autoimmune diseases this one is the most likely one to have a
sensitivity). The Antibody you want to order to prove that its lupus is anti-Smith Antibody
(which has 100% specificity, therefore no false positive therefore 100% Postive Predicted
Value ntibody, you have Lupus. The other
Antibody is anti dsDNA this not only indicates that you have lupus, but also that you
have KIDNEY disease. That has 98% specificity, too. So, these are two good Antibodies to
confirm lupus. Morning stiffness is present in lupus (simulates Rh arthritis/photophobia),
rash, pericarditis; Lupus Erithematosus cell preparation Anti DNA Antibody are
phagocytosed by neutrophils, and they have altered DNA. Not specific for lupus (waste of
time).

Anti-ro can also be in lupus pts, and

conduction system (leads to complete heart block).

4. Progressive Systemic Sclerosis/CREST

Tight face, telangiectasia ,

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Raynauds Phenomenon , dysphagia (solids and liquids),

Dystrophic calcification (calcinosis),

Sclerodactly ; if kidneys involved, it is progressive systemic sclerosis,

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5. Dermatomyositis Racoon eyes, elevated serum CK, rash over the
proximal interphalangeal joint (PIP) highest associated with underlying
cancer.

6. Sjogrens syndrome

Associated with rh arthritis, autoimmune Immune destruction: Antibodies destroy salivary

glands leading to dry mouth: Xerostomia , lacrimal glands leading to dry eyes:
Keratoconjuntivitis.

Example: biopsy of lower lip which is a confirmatory test its looking to see if there is destruction
of the minor salivary glands see lymphocytes (which is confirmatory diagnosis).

Antibody are anti-SSa (like anti-Ro) and anti-SSb (like anti-

Skin
Basal cell carcinoma (upper lip)

Squamous cell carcinoma (lower lip)

Psoriasis silvery lesion that is red and raised. Can

involve the hands, scalp pts think they have dandruff (like seborreic dermatitis from malasezia
furfura), but they really have psoriasis. On .
Rash at pressure points especially in the elbow.

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 Atopic dermatitis child with allergic diathesis starts disease; have eczema
(like atopic dermatitis); type I Hypersensitivity.

Contact dermatitis Ex. to metal (nickel); type IV

Hypersensitivity reaction.

Board Example: About the pathophysiology of this lesion is equalant to the physiopathology of
which the followings what? Positive D, because both are type IV Hypersensitivity reaction.

Seborrheic Dermatitis Due to Malassezia furfur (a fungus)

Immunocompromise pt (Ex. AIDs). This is a preAIDs lesion.

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Tinea capitis

Example: pt with bald spot on head, fluouresces and seen with black light blacklight (UV-A light).
Trichophyton tonsurans is Most Common Cause of tinea capitis. Because the fungus
involves the inner portion of the shaft, there are no fluorescent metabolites, and is Wood light
negative.

All the other superficial dermatophyte infections including:

Tinea corporis (ring worm)

Example: red outer edge and clear center, what is first step in workup? Scrape outside and do

KOH preparation, and see hyphae and yeast forms . All

other superficial dermatophyte infections (except Tinea capitis) are due to trychophyton
rubra. What is the color around Tinea capitis? Red (= rubra) (how to remember it).

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Molluscum contagiosum Sandy like material in crater,
children, self inoculate, Poxvirus makes these (DNA virus), Volcano crater look, with sandy stuff in
it.

Pityriasis Rosea (COMMON IN BOARDS) is NOT a fungus!!!!

Example: pt came to your office with a rash on butt non pruritic rash, NON INFECTIOUS

Herald Patch (first sign of pityriasis rosea; oblong looking

with red on outside and pale in middle. You think this is Tinea corporis, but it s oblong (and not
circular). Do a KOH preparation, find nothing; then put topi
days later comes back with rash in the line of langer in Christmas tree like distribution.

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Dysplastic Nevus syndrome
Example: precursor lesion for malignant melanoma; if you have over 100 nevi all over body,
you have dysplastic nevus syndrome, Very common. Must go to dermatologist once a year
because need to look at dysplastic nevi.

4 different types of malignant melanoma

What is first step in management? Excision
1. Superficial spreading malignant melanoma (Most Common)

2. On face of older pt Lentigo maligna melanoma ; irregular border,

corn colored, LEAST likely to met of all malignant melanomas.

Example: black population does not get malignant melanomas because the black pigment in the skin
prevents UV light damage and propensity for cancer. However, there is one type of cancer they
malignant melanoma they CAN get: Acrolentiginous malignant melanoma
of/tip of)

BOARD QUESTION: black pt with dyspnea, on xray finds multiple metastases all over body. Biopsy
is done and pt has malignant melanoma, which part of the body would you examine to find the
primary disease? Under the nails, palms or sole of the feet this is Acrolentiginous malignant
melanoma

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 Acral Lentiginous Malignant Melanoma
This is the MOST AGGRESSIVE of all the melanomas. This has nothing to do with
radiation.

Example: Nodular malignant melanoma also very aggressive.

The most important thing affecting prognosis is depth of invasion (key to prognosis
magic # is more than .76 mm). If it s less than .76, its not gonna metastasis.

Toxins 2 poisonous spiders

*Black widow
Has a neurotoxin causes spasm of the muscles in the upper thighs and abdomen so strong
it s almost like tetanus; pain muscle contractions, especially in the abdomen. There is an
antivenom, painful bite.

Example: person went down into their cellar, lifted boxes, felt sharp prick on finger, and
developed contractures over a period of hrs due to black widow bite.

*Brown recluse spider (like violin spider) Painless

bite, has a necrotoxin, leading to ulcer.

Where are receptors to androgens? Sebaceous glands (this is why men get more zits than
woman testosterone will release lipid rich material which gets into the hair follicle. Then, if
you have proprionum acnei (anaerobe) it has lipases that breakdown fat from the sebaceous
gland and produces Fatty Acid that irritate the follicle and end up with acne.

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 So, men more likely to get it because they have acne. It all
occurs in the erector pili muscle of the skin. So, there are androgen receptors sebaceous
glands and erector pili muscle.

Drug used to prevent hirsutism? Spironolactone (same drug used to block aldosterone);
this drug is good because it blocks androgen receptors and therefore prevents hirsutism. Can
also lead to gynecomastia in men.

CNS
Spinal fluid derives from choroid plexus laterally in the 3rd and 4th ventricles. Its an ultrafiltrate of
plasma.

What is the difference in serum and spinal fluid? Way more protein in spinal fluid because

fluid about 60% of what it is in serum (if the spinal fluid glucose level have 20 were low, and
then something is in there utilizing it for energy such as bacteria or fungus or cancer cells). Is
there anything MORE in spinal fluid than serum? Chloride (way higher in spinal fluid than
serum) - around 120. These are important because there are injuries to the head.

Example: baseball that hits the eye in an orbital blowout fracture can potentially break cribriform
plate, leading to dripping fluid out, which could be snot, serum, or spinal fluid. So, its importan to
know differenss between the two.

Example: wacked in the head fluid out of ear (otorrhea), hemorrhage leads to battle sign. This is
a fracture of the basilar plate and there is spinal fluid there.
Most of the fluid comes out the aqueduct of sylvius which is the Most Common Cause of

hydrocephalus in children because it gets blocked off until you get a build
up of spinal fluid in the 3rd vent and lateral ventricular, which is a narrow area and leads to
hydrocephalus. Then, it comes to the fourth ventricule and needs to get out because it needs to

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 get into the subarachnoid space. So, it goes through the foramen of Luschka and Magendie, so
fluid goes out.

Dura matter = means strong

hematoma (blood clot between bone and dura). The only pressure that can split the periosteum away
from dura is arterial pressure. So, this is the one when the middle mengial artery ruptures, and
can be done with arterial pressure (not venous).

It gets into the subarachnoid space (to protect us a cushion against damage). Get rid of spinal fliud
in arachonoid granulation. [A tumor can arise from the arachnoid granulations meningioma.] It
goes through the arachnoid granulations, (there are NO LYMPHATICS IN BRAIN) and the dural
sinuses and conglomerate into the jugular vein, which is emptied into the right side of the heart.

So, when you do a valsalva and the neck veins distend, that pressure transmits all the way back to
the dural sinuses, to the arachnoid granulations through the spinal fluid , and right down the the
needle in the subarachnoid space at L4 and the pressure goes up. This is called quakens step
maneuver. It is a great test for when you are doing a spinal tap to see if the entire subarachnoid
ee that manometer go up, there is something blocking the spinal fluid
more proximally.

Example: ecause the pressure are huge and and

lead to a herniated disk.

Tentorium Cerebelli
70% of brain tumors in adults are supratentorial (involve cerebral cortex)
70% of brain tumors in kids are infratentorial (cerebellar, cystic astrocytoma, medulloblastoma)

Hydrocephalus: Communicating vs Noncommunicating

Communication of spinal fluid in ventricles with subarchnoid space.

1. Noncommunicating = Most Common Cause = stenosis of the Aqueduct of Sylvius

Something is preventing communication between spinal fluids in the ventricles from getting into
the subarachnoid space. Another cause to block communication something going in the 4th
ventricle, ependymoma in kids will block it off, or meningitis in base of brain (TB), leads to scar
tissue because blocks foramen of magendie and luschka.

Get hydrocephalus because the sutures have not fused. If you miss hydrocephalus in adult
and sutures have fused, will lead to dilatation of the ventricles and eventually over years, the
pressure will turn back to normal because the increased pressures keep the choroid plexus
from making so much but the damage are done, leading to: Dementia, ataxia, urinary
incontinence. Like normal pressure hydrocephalus (because pressures normalize).

2. Communicating
Still communicating, but still a build up of pressure. One cause could be tumor of choroid
plexus (papillary looking). So, if you have a tumor there, you have a greater ultrafiltrate of
plasma and would be making more plasma. Also, would be making more spinal fluid. There
would still be a communication with here, but the pressure would build up because making
more than you commonly do.
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 More commonly, what if you have a subarachnoid bleed or meningitis? Then pt has scarred off
arachnoid granulations and has no way of draining it out. So, still have a communication, but
cannot get rid of it (Most Common to happend).

Arnold Chiari Malformation

Example: pull down spinal cord. This would bring the medulla into the cervical region and maybe
a lil part of the cerebellum. Leads to hydrocephalus and platybasia (flattening of the base of the
skull)

Dandy walker syndrome

Cerebellar vermis is not developed

Herniation
Why would we herniate in the brain? Because there is cerebral edema and no other place to go.

The famous ones are tonsillar herniation through the

foramen magnum. (from the cerebellum) cerebellar herniation has been squeezed into the
foramen magnum, and has constriction. Can cause immediate death.

Uncal herniation medial portion of the temporal lobe

herniates through the tentorium cerebelli and pressing against midbrain, leads to hemorrhage
ge). Also an oculomotor nerve that is gonna be compressed. So, this will lead
to opthalomoplegia (LR6SO4, 3), so everything innervated by CN III is paralyzed. With
oculomotor nerve palsy, it is down and out. (Down and in is CN 4 palsy if CN 6 is
paralyzed, will look cross eyed). Look at pupil.

Example: MRI of oribit, name muscles, Parasympathetic constrict the pupil (normally),
sympathetics dilate (normally). So, if you mess up the parasympathetics, which normally
constrict, it will lead to mydriasis.

The first sign of uncal herniation is mydriasis of pupil on side of herniation (so it dilates on
that side). Also, posterior cerebral artery can get blocked with uncal herniation, leading to post
lobe infarction.
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 Board Advice: You have to Know brainstem and Craneal Nerves and how it related to herniation.

Papilledema
Any cause of increased incranial pressure: Vitamin A toxicity.
Lead poisoning delta-aminolevulinic acid leads to increased permeability.

Audio file Day5 7CNS (Hydrocephalous information before this page)

Tuberous Sclerosis
Autosomal Dominants
Hamartomas (noneoplastic proliferation of things)
Ventricles have bumps called tubercles which are hamartomas which have proliferation of
astrocytes. They produce hamartomas that bulge into the ventricle, called candle stick dripping.
Hemartomas of the kidney called angiomyolipomas, Mental Retardation, cardiac tumors
(rhabdomyomas), shagreen patches, areas of hypopigmentation, woods light shine out

Anencephaly- Worst of neural tube defects, Absent brain

Vertebral arch defects

*Spina bifida occulta tufts of hair come out, vertebral arches do not touch, and no meninges
come out.

*Meningoceole meninges come out.

*Meningomylocele both meninges and spinal cord come out.

-High alpha feto protein levels in blood of mother; Alpha feto protein levels in blood of
mother decreased in downs syndrome.
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 -Have to be on folate to prevent neural tube defects (neural tube finished forming by 30 days,
so make sure she is on folate if she is trying to get pregnant).

*Neurofibromatosis
Albright syndrome (precocious puberty, café au lait, bone zits), Café au lait (coffee colored non
raised lesions) spot,

plexiform neurofibromas,

hyperpigmentation in the axilla (axillary freckling),

neurofibromas, Autosomal Dominant Diseases, therefore late manifestations (especially for
neurofibromatosis), penetrance, variable expressivity (you are expressing the disease, but
different levels of how severe the disease is)

Board Question: pt with Hypertension and this picture, what test would you get? Relationship of
neurofibroma with pheochromocytoma, therefore get a 24 hours urine for Vanillilmandelic Acid
(VMA) and metanephrine.

*Acoustic schwannoma
Example: pt with sensorinerual hearining loss b9 tumor of Schwann cells around CN 8.
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*Meningiomas
Optic nerve gliomas

*Syringomyelia
Example
notice this, on exam loss of musculature (loss of Lower Motor Neuron) in intrinsic muscles of the
hand, loss of pain and temperature in cape like distribution across back.

Amyotrophic Lateral Sclerosis (ALS) in ALS, first place of

is Upper Mottor Neuron
and Lower Motor Neuron loss, PURE MOTOR, (if pt has pain,this is sensory and not ALS)

Big cystic cavity knocking off spinothalamic knocking off pain and temperature. Can knock off the
corticospinal tract and anterior horn cells, so it will be a COMBO of sensory AND motor loss for
syringiomyelia.

Infections

Meningitis inflammation of meninges and nuchal rigidity,

Photophobia, headache and if you move your head or extend your knee, you will stretch the
meniges, leading to pain (stretching inflamed meninges).

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 (Positive Brudzinski (flexion of the hips and knees in response to passive flexion of the neck

and hurts) signals meningeal irritation and Kernig's test

s hip 90 degrees then )

Encephalitis sleeping sickness they are always sleeping and drowsy; they have mental status
abnormalities.

Pus at the base of the brain can possibly block lushka and majendie, leading to obstructive
hydrocephaly and noncommunicating.

Treatment for meningitis: use steroids and Antibiotics. why? Steroids prevent scar tissue
foration and complications that arise with it (ie hydrocephalus).

This is standard Tuberculous meningitis Treatment (Tuberculosis in brain causes vasculitis and
scarring).

Complication of meningitis: DEAFNESS.

Rabies
Example:: meningitis, cerebral abcess, Rabies (Most Common Cause in States = skunks

, dogs in 3rd world)

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 Negri bodies (perkinje cell inclusion) see in rabies.

CMV (Cytomegalovirus)

Example: section of kid (brain) - see white stuff going around ventricles due Periventricular
calicifications.

Most Common congenital infection = Cytomegalovirus.

BOARD QUESTION: What body fluid is the most productive to culture to diagnosed
cytomegalovirus? Urine

Meningitis

What is Most Common meningitis/sepis in first month of life? Group B streptococco

agalactae because many women have this organism in their vagina, so they are carriers. A
premature ruptured membrane lets the organism get up, get a chorioamnionitis and into the
bloodstream.

2nd Most Common Cause of meningitis is E coli

3rd Most Common Cause of meningitis is listeria monocytogenes (gram + rod with tumbling
motility as does Trichomonas vaginalis)

What food should pregnant women avoid? Soft cheeses (Ex. feta cheese, but listeria is
present).

Most Common in 1 month 18 years = Neisseira meningitides

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 (not Haemofilus influenza because vaccination)
Most Common in 18+ = Streptococco pnemoniae

Example: 52 years man, nuchal rigidity, taps shows increased protein, increased neutrophils and
decreased glucose diagnosis? Streptococco pneumoniae. What is the gram stain? Gram +
diploccus

Cryptococcus

India ink see narrow based bud for Cryptococcus

Who do you think this is in? Immunocompromised pts

What is Most Common immunodeficiency in USA? AIDs

Most Common Cause meningitis in AIDs pts? Cryptococcus

Mucormycosis
In frontal lobe, therefore from a diabetic in ketoacidosis

Example: special stain on AIDs pt with CD 4 ct of 50, CT showed space occupying lesion

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 Diagnosis? Toxoplasmosis

Example: pig herder, and long time problem with focal

epileptic seizures (dilating therapy) multiple calcified and cystic lesions in brain dx?
Cysticercosis

Example: Jacob Cruetzfeltds from prions (mad cow) who is most likely to get?
Neuropathologists, neurosurgeons, beef, lettuce from Arizona (cow manure on it)

Traumatic lesions

Epidural hematoma (above dura) hit in head middle

meningeal have to fracture bone (under arterial pressures, can separate dura from periosteum).
When you get 50 mls of blood, you get uncal herniation and die. Ie get him, say they are ok, 6 hrs
later epidural hematoma and death.

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Subdural hematoma rupture of bridging veins between dura
and arachonoid membrane. If you have cerebral atrophy, then the space bewteen the dura and
arachnoid membranes is bigger. Bridging veins dangling break and get a hematoma. Fluctuating
levels of consciousness. Left untreated lead to dementia. Do CT to r/o epi and subdural hematoma
(also for strokes if it s a hemorrhagic stroke).

Strokes
Slide: Brain: one side is bigger. Atherosclerotic stroke:

pale infarct of brain. At bifurcation, there is an

atherosclerotic plaque and thrombus. No blood flow to brain and it infracted, starts breaking
down, no reperfusion, so it remains a pale infarct. If the thrombus did break apart, and reperfusse
the brain, the blood in the goes into the area of infarction and is called a hemorrhagic infarct.
However, pale infarcts more common. If no blood, and there is
infarction, pt is a candidate for heparin therapy. Over time, if pt survives, ends up with cystic
space where there was infarction and this is called liquefactive necrosis--pale infarct, liquefactive
necrosis.

Slide: hemorrhagic infarct blood is to edge of brain this is an embolic Stroke.

Usually from left side of the heart. The vessel it always

goes to is middle cerebral artery. It gets into the Circle of Willis and into the middle cerebral. If
you embolize down, will go into the superior mesenteric.

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 The reason it is hemorrhagic is because pt will get breakdown of fibrinolytic system of the embolus

atherosclerotic stroke and hemorrhagic stroke are both infarcts one is pale and the other is
hemorrhagic.

Slide: Hypertension (intercerebral bleeding) pressures cause

lenticulostriate vessels to come up and supply this area of the brain. Derive from the middle
cerebral aneurysms, called Charcot Bouchard aneurysm and it ruptures, leading to giant
hematoma and blood clot. Horrible prognosis.

So, embolic stroke goes to surface of the brain

intracerebral bleed from Hypertension.

Example: subarachnoid hemorrhage mostly due to

rupture congenital berry aneurysm. Most common at the junction anterior commucating
branch of anterior cerebral artery.

Less common cause of Subaracnoid Hemorrage (SAH):

Arterio Venous (AV) malformation

There is an Arterio Venous malformation of middle cerebral artery producing:

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 Sturge Weber syndrome (on same side as skin lesion of the
face).

Lacunar infarcts small areas on the brain; unusual because

they hit areas of the brain. Depending on where in the internal capsule, can have a pure motor stroke
or pure sensory. Most Common due to Hypertension.

Multiple Sclerosis (MS)

Most Common demyelinating Disease (autoimmune): Multiple Sclerosis

*Slide: demylinated: white matter has myelin it, grey

Plaques of Multiple
Sclerosis.

There is 2 ways to demylinate:

1) Knock off cell that makes myelin in the brain (oligodendrocytes in brain, schwann cell in
Periferal Nervous System) viruses do this subacute sclerosis, progressive multifocal
leukoencephalopathy, Human Papiloma Virus they affect the oligodendrocyte;

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 2) Can also have Antibodies against myelin and not the oligodendrocyte, which is Multiple
Sclerosis paresthesias,

Nystagmus, ataxia, optic neuritis with blurry vision (Most Common Cause of Optic Neuritis =
Multiple Sclerosis because demylination of optic nerve)

Internuclear opthalmaplegia (demylination of Medial Longitudinal Fasciculus) - pathognomonic

Spinal tap will show increased protein, normal glucose, and increase lymphs.

Classic lesion: senile plaque, neurits, amyloid Beta protein so beta amyloid protein is toxic to
neurons and the more you have the more toxic pathognomonic of alzheimers, on chromosome
neurofibrillary tangles (in any dementia and Huntingston Disease)
Alzheimer problems in higer levels dementia
Only way to diagnosis is autopsy (confirmation) see senile plaques

Hydrocephalus Ex Vacuo in a Alzheimer Patient.

Severe atrophy of brain and ventricles look bigger than they should be Dementia.

Resting tremor

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