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Geriatr Gerontol Int 2017

REVIEW ARTICLE

Iron deficiency anemia in older adults: A review

Etienne Joosten

Department of Internal Medicine, Division of Geriatric Medicine, University Hospitals Leuven, Leuven, Belgium

Anemia in older adults is a risk factor for numerous negative outcomes. There is no standard definition, but in most
studies, anemia is defined as a hemoglobin value <12 g/dL for women and <13 g/dL for men. Absolute iron defi-
ciency anemia is defined as the combination of anemia and the absence of total body iron. Serum ferritin is the most
frequently used diagnostic parameter, but its concentration increases with age and in the presence of inflammatory
diseases. Other laboratory tests, such as transferrin saturation, soluble transferrin receptor and the soluble transferrin
receptor/ferritin index might provide useful information, but there is a wide variety in the cut-off values and interpre-
tation of the results. Recent research regarding hepcidin as a central regulator of iron homeostasis is promising, but
it has not been used yet for the routine diagnosis of iron deficiency anemia. In older iron deficiency anemia patients,
an esophagogastroduodenoscopy and colonoscopy should be initiated in order to identify the underlying bleeding
cause. CT colonography can replace a colonoscopy, and in specific cases, a video capsule is recommended. It
remains crucial to keep in mind which potential benefits might be expected from these investigations in this vulnera-
ble population, taking into account the comorbidity and life expectancy, and one should discuss in advance the pos-
sible therapeutic options and complications with the patient, a family member or a proxy. Oral iron administration is
the standard treatment, but parenteral iron is a convenient and safe way to provide the total iron dose in one or a
few sessions. Geriatr Gerontol Int 2017; ••: ••–••.

Keywords: anemia, iron deficiency anemia, older adults, review.

Introduction iron stores, anemia of inflammation [AI]) and func-

tional iron deficiency (treatment with erythropoiesis
Anemia is a common clinical problem in older adults. stimulating agents).16 The differential diagnosis
It is mostly defined according to the World Health between IDA and AI is sometimes difficult because of
Organization criteria as a hemoglobin value <12 g/dL the aspecific symptomatology, multimorbidity and diffi-
in women and <13 g/dL in men, although others have culties in the interpretation of the biochemical iron
proposed lower age-adjusted values for hemoglobin to parameters. During the past decades, a great deal of
define anemia.1,2 Using these World Health Organiza- research has been carried out in the field of the patho-
tion criteria, the anemia prevalence ranges from 8.1% physiology of iron homeostasis, more specifically the
to 24.7% in community-dwelling older persons, 31% role of hepcidin, resulting in novel diagnostic labora-
to 60% in nursing home patients and 40% to 72% in tory analyses.17,18 IDA is an important disease in older
hospitalized older patients.3–7 Anemia in older patients adults because of the potential underlying disorders,
is recognized as a risk factor for negative outcomes, such as gastrointestinal ulcers and tumors, arteriove-
such as reduced physical performance and muscle nous malformations, and malabsorption disorders. The
strength, falls and fractures, hospitalization, cognitive aim of the present article was to provide an overview of
impairment, depression, and mortality.3,5,8–15 the optimal diagnostic strategy, investigation and treat-
Anemia related to iron deficiency (iron restricted ment of absolute IDA in older adults.
erythropoiesis, independent of the iron stores) can be
associated with iron deficiency anemia (IDA; absent
iron stores), iron sequestration (normal or increased Pathophysiology of iron metabolism
The human body contains 3–4 g of iron, of which 70%
Accepted for publication 31 August 2017. is incorporated into the hemoglobin of the red blood
Correspondence: Dr Etienne Joosten MD PhD, Division of cells. The average daily iron uptake, 1–2 mg, is bal-
Geriatric Medicine, University Hospitals Leuven, Herestraat anced out by iron loss as the result of sweating, loss of
49, B-3000 Leuven, Belgium. Email: etienne.joosten@uzleuven.be epithelial cells of the skin, and mucosal cells of the

© 2017 Japan Geriatrics Society doi: 10.1111/ggi.13194 | 1

 E Joosten

gastrointestinal and genitourinary tract. Plasma con- Table 1 Laboratory criteria for the differential
tains 2–4 mg of iron, bound to serum transferrin. For diagnosis between iron deficiency anemia and anemia
the production of red blood cells and body metabolism, of inflammation in older patients
20–25 mg of iron is required on a daily basis and there-
fore, iron recycling from aging red blood cells is neces- IDA AI
sary. Dietary iron is available in the heme (Fe2+ or Serum iron # #
ferrous iron) and the non-heme form (Fe3+ or ferric Serum transferrin nl or " # or nl
iron). A review about intestinal iron absorption can be Transferrin saturation <25% <25%
found elsewhere.19–21 Hepcidin plays a central role in Serum ferritin <50 μg/L >100 μg/L
iron homeostasis by inhibiting both the iron transport Serum transferrin receptor " #
from the enterocytes into the plasma in the proximal Serum hepcidin ## "
duodenum, as well as the release of iron from the body
AI, anemia of inflammation; IDA, iron deficiency anemia; nl,
iron stores. The serum hepcidin levels are low in normal. For most laboratory tests, there are no generally
patients with IDA, and this results in elevated intestinal accepted decision limits (the values presented in the table are
iron absorption and release of iron from the macro- from Joosten28).
phages. In inflammatory disorders, hepcidin production
is stimulated by an increased interleukin-6 production Serum ferritin as an indicator for the assessment of iron
in the liver, and this blocks the intestinal iron absorp- stores is also widely available, well standardized and
tion and the release of iron from the body currently the most used parameter to diagnose IDA.
stores.17,18,20,22 However, it is an acute phase reactant, and its serum
level increases with age.30–32 A broad range of ferritin
Symptoms and clinical presentation thresholds up to 100 μg/L and even higher have been
proposed in many older and recent studies depending
Older patients with IDA are often asymptomatic and on age, sex, patient selection and specific disease cate-
the diagnosis is made during a routine blood analysis. gories (i.e. absolute IDA, chronic kidney disease, can-
Symptoms and signs can be aspecific as a result of ane- cer, chronic heart failure and other inflammatory
mia, such as fatigue, paleness, dyspnea, angina pectoris disorders) and treatment options (i.e. erythropoietin
and edema, or more specifically related to IDA, such as stimulating agents in combination with iron therapy).
koilonychia, pica and atrophic glossitis.23,24 There is As a consequence, it remains unclear in older patients
also some evidence that IDA is associated with restless which cut-off point is the most appropriate for the
legs syndrome in geriatric patients.25 Chronic blood diagnosis of IDA and the differential diagnosis with
loss, such as hematuria, and hemorrhoidal and gyneco- other causes, especially AI (Table 1). In older patients, a
logical blood loss, are mostly obvious causes associated serum ferritin <50 μg/L is highly suggestive of iron defi-
with IDA. In specific cases, the combination of symp- ciency.33,34 To what extent the association of a low
toms and clinical signs, such as melena and abdominal transferrin saturation to the serum ferritin level might
pain or malabsorption and diarrhea, are suggestive for a increase the diagnostic accuracy for iron deficiency is
specific underlying cause, such as colonic cancer or unclear. A low transferrin saturation suggests an inade-
celiac disease, respectively.26 quate iron supply for red blood cell production, and is
also often found in patients with AI.28 A combination
Diagnosis and epidemiology of IDA of non-iron related parameters, such as C-reactive pro-
tein and the erythrocytic sedimentation rate, as markers
The diagnosis of IDA remains a challenge for the clini- of inflammation can be useful to estimate the effect of
cian. Neither a standardized test or set of tests, nor gen- inflammation in IDA patients, but it is not exactly
erally accepted decision limits and reference intervals known which cut-off points should be used.30,31,35
for each specific test exist.19,22,23 Furthermore, the Indeed, many older patients with IDA and a serum fer-
underlying cause for the IDA is often multifactorial in ritin level <20 μg/L have an elevated C-reactive protein
older patients.27 Several non-invasive laboratory tests level or erythrocytic sedimentation rate.27 In recent
are available, and each test requires a thorough knowl- years, a better understanding of the pathophysiology of
edge of its pros and cons before a proper interpretation the iron homeostasis has led to the introduction of
of its contribution to the diagnosis of IDA is possible. newer laboratory analyses, such as serum transferrin
The red blood cell indices have limited information, receptor (sTfR), reticulocyte hemoglobin content or
and the mean corpuscular volume can be microcytic or reticulocyte hemoglobin equivalent and serum hepci-
normocytic in IDA patients, while microcytic anemia din.36 The sTfR has the potential advantage over serum
can also occur in patients with AI.23,28 Serum iron, ferritin that it lacks an acute phase component.36 How-
transferrin and the calculated transferrin saturation are ever, the sTfR and sTfR over serum ferritin ratio are
widely used, but are not diagnostic for IDA.23,28,29 not widely available, and the assay is not standardized.

2 | © 2017 Japan Geriatrics Society

 Iron deficiency anemia in older adults

In a recent meta-analysis, the sTfR assay had a sensitiv- Table 2 Common diseases associated with iron
ity of 86% and a specificity of 75%, and our previously deficiency anemia in elderly patients
published research found serum ferritin superior to
sTfR for the diagnosis of IDA in older patients.37,38 Chronic blood loss
Reticulocyte hemoglobin content and reticulocyte Esophagitis and gastritis
hemoglobin equivalent, as an early sign of functional Gastric and duodenal ulcer
iron deficiency, can easily be generated by automated Esophageal and gastric cancer
cell counters, but its diagnostic usefulness in older Large hiatal hernia
patients with IDA is limited.29,39–41 Hepcidin levels are Angiodysplasia
elevated in patients with acute or chronic inflammatory Colonic cancer
anemia, and are low in patients with IDA.17,18 This bio- Colonic polyps
marker is not yet routinely available, and variability in Hematuria
measurements between different laboratories has ham- Uterine bleeding
pered the identification of uniform cut-offs for serum Drugs (non-steroidal inflammatory drugs, salicylates,
hepcidin. The results of a few studies in older patients anticoagulants)
are conflicting, but it is a promising laboratory test for Malabsorption
the diagnosis of iron disorders.42–45 Helicobacter pylori
When iron malabsorption is suspected (celiac dis- Autoimmune gastritis
ease, gastritis, Helicobacter pylori), an oral iron absorp- Celiac disease
tion test can be carried out after an oral iron load. Proton pump inhibitors
This test is not validated, multiple oral iron doses are Adapted from Lopez et al.23, Goddard et al.26, Rockey and
used and the interpretation of the results is not stan- Cello51, Joosten et al.52 and Hershko and Camaschella53 with
dardized. However, it is a non-invasive test that can permission.
provide some limited additional information.46,47 A
bone marrow smear with Prussian blue is generally and colonoscopy had a likely cause for IDA, and
considered as the gold standard investigation for the non-bleeding (atrophic gastritis, celiac disease, H. pylori
diagnosis of iron deficiency, but it is invasive and gastritis) was more frequent than bleeding-associated
uncomfortable for the patient, the interpretation can diseases (peptic ulcer, cancer, hiatal hernia, vascular
vary significantly between investigators, and it is in ectasia).56 Urogenital blood loss, as in renal cancer or
general not a part of the diagnostic work-up of the bladder cancer, can cause IDA. In most cases, this is
anemic older patient.48 clinically evident or can be found by testing the urine
Given the lack of consensus on the diagnosis of for blood. Gastrointestinal bleeding is the predominant
IDA, one should not be surprised that the prevalence cause to explain IDA.26,51 Given the strong association
of IDA in an older population varies widely within vari- between gastrointestinal disorders and IDA, endo-
ous subgroups. IDA was diagnosed in 16.6–25% of scopic examination of the upper and lower gastroin-
non-hospitalized older adults, 22–40% of institutional- testinal tract should be considered in older patients
ized older adults and 15–65% of hospitalized older with IDA unless there is an overt non-gastrointestinal
adults.5–7,49,50 Even more problematic is the diagnosis explanation for the blood loss. The preparation and
of the combination of IDA and AI for which no clear the investigation by means of a colonoscopy is often
laboratory diagnostic criteria for older adults are burdensome in older patients, without a clear thera-
available.27 peutic benefit in a significant number of patients
because of poor general condition as a result of frailty,
Additional investigations and etiology Alzheimer’s dementia, terminal heart failure, lack of
cooperation, palliative setting and refusal by the
History (hematemesis, melena, hematuria, uterine patient or their proxy. A computed tomography
blood loss, weight loss, previous gastrointestinal sur- (CT) colonography (virtual colonoscopy) does not
gery), drug use (non-steroidal anti-inflammatory drugs, involve an endoscope, but requires bowel preparation.
aspirin, anticoagulans, corticosteroids, proton pump It can be useful in selected patients, but its diagnostic
inhibitors) and clinical examination remain the corner- accuracy in older patients with IDA is unclear.26 Older
stone of the initial approach to the older patient with patients with unexplained IDA after a routine upper
IDA.23,24,26 The main causes for IDA in older patients and lower gastrointestinal endoscopy have a favorable
are chronic blood loss and iron malabsorption, outcome.57 In a retrospective study, a mixed group of
whereas the role of a reduced dietary iron intake is still 471 ambulant and hospitalized adults aged ≥80 years
unclear (Table 2).54,55 However, 85% of patients with with IDA was investigated, of which 276 patients
IDA (mean age 59 years), but without gastrointestinal (59%) did not undergo any diagnostic investigation of
symptoms, that were investigated with a gastroscopy the gastrointestinal tract.58 The authors stated that

© 2017 Japan Geriatrics Society | 3

 E Joosten

omission of additional diagnostic procedures did not Criteria for iron deficiency anemia
appear to be associated with comorbidity, and not hemoglobin<12 g/dL (female)
investigating patients with IDA seems appropriate hemoglobin<13 g/dL (male)
depending on the therapeutic consequences, life and
expectancy and relevant comorbidity. It remains some- serum ferritin<50 µg/L
times difficult to prove that a potential lesion found
during an endoscopic investigation also effectively
causes IDA, and there is also some uncertainty as to Serology for celiac disease
which benign lesions, such as erosive gastritis, small esophagogastroduodenoscopy ± biospsy
polyps and ulcers, might effectively be the cause of colonoscopy (or CT colography)
IDA. In a previously published study, we investigated (small bowel capsule endoscopy in specific indications)
151 older patients with iron deficiency with and with-
out anemia.52 A potential lesion was found in 47 out
of the 96 patients with IDA, of which 32 were benign
lesions and 15 were cancers (2 gastric cancers,
13 colonic cancers), whereas 31 out of the 55 non- Oral iron absorption test before iron replacement if no clear
diagnosis
anemic patients with iron deficiency had a potential
gastrointestinal lesion; 23 benign and eight cancers
(1 esophageal, 2 gastric and 5 colonic cancers). As a
consequence, endoscopic investigation can also be
considered in older iron-deficient patients without
anemia.52 Start with oral iron replacement
The approach to a gastrointestinal investigation is parenteral iron if intolerance or response oral iron inadequate
population-specific, and one has to consider first to
what extent that investigation will change the therapeu-
tic and prognostic options, taking into account the Figure 1 Flow chart for the gastrointestinal investigation of
increased risk of complications in this vulnerable older patients with iron deficiency anemia. CT, computed
patient group. Small bowel capsule endoscopy can be tomography.
considered as the next step in the investigation of
patients with IDA with a negative esophagogastroduo-
denoscopy and colonoscopy. Common small bowel celiac disease, are important, but their detailed contri-
lesions seen on capsule endoscopy in older patients are bution to IDA in an elderly population is not well
angiodysplasia and ulcerations, whereas cancer, inflam- known.53
matory bowel disease and celiac disease are less com-
mon. However, most of the studies on capsule Treatment
endoscopy were carried out in highly selected patient
groups. A substantial number of patients found the The treatment primarily consists of iron replacement,
capsule endoscopy study very tiresome and difficult; either orally or parenterally. The total iron dose supple-
the diagnostic yield in older patients with IDA varies mentation can be calculated according to specific for-
between 53% and 72%, but the related therapeutic mulas, such as the Ganzoni formula (target hemoglobin
options are mostly limited.59–62 Hence, a capsule [g/dL] − actual hemoglobin [g/dL] × 2.4 × bodyweight
endoscopy should only be carried out in selected cases [kg] + 500 mg) or specific guidelines as proposed by
of older patients. The figure shows the flow chart for the manufacturer, but there is no standard iron calcula-
gastrointestinal investigation of older patients with IDA tion for the most appropriate iron deficit dose.64 A large
in University Hospitals Leuven, Leuven, Bel- number of oral iron formulations are widely available,
gium (Fig. 1). and the most commonly prescribed preparations are
Most patients with IDA and a negative upper and ferrous sulphate, gluconate and fumarate. It is still
lower gastrointestinal endoscopy have a favorable out- unclear whether there is a difference between the differ-
come without further investigation, especially when the ent preparations in terms of hematological efficacy and
anemia resolves after treatment.63 Other investigations, adverse events.19,23,24,26,65–67 The recommended daily
such as an abdominal CT scan, are less invasive and iron dose for adults varies, and is usually between
can be carried out as an alternative when endoscopic 60 and 200 mg elementary iron, with or without vita-
investigations are not indicated, but this investigation min C to improve the iron absorption, in one to three
has a low sensitivity for IDA-associated lesions. Gastro- daily doses. However, recent research has shown that
intestinal causes of IDA that are associated with iron oral iron supplement at doses of ≥60 mg increases
malabsorption, such as atrophic gastritis, H. pylori and serum hepcidin for up to 24 h, and is associated with

4 | © 2017 Japan Geriatrics Society

 Iron deficiency anemia in older adults

lower iron absorption the next day.68 An analog phe- an esophagogastroduodenoscopy and colonoscopy
nomenon of “mucosal block” was already shown in should be initiated in order to identify the underlying
1987 with the small-dose iron tolerance test.69 These cause of bleeding. CT colonography can replace a colo-
findings might support the administration of lower oral noscopy, and in specific cases, a video capsule is
iron dosages and alternate day supplementation. Evi- recommended. It remains crucial to keep in mind
dence for this was found in a previous study where the which potential benefits might be expected from these
oral administration of 15 mg and 50 mg of elemental investigations in this vulnerable patient population, and
iron on a daily basis was shown to be as effective as a one should discuss the pros and cons with the patient,
dose of 150 mg in older IDA patients, but with fewer a family member or a proxy. Oral iron administration is
adverse events.70 A treatment duration of 3–6 months the standard treatment, but parenteral iron is a conve-
is usually required for the repletion of the iron stores, nient and relatively safe way to provide the total iron
but an increase in serum ferritin level up to 100 μg/L or dose in one or a few sessions. In the case of negative
more is a good alternative end-point. The side-effects findings, we propose an oral iron absorption test and
are well-known, and include nausea, constipation, diar- await the outcome of a trial with iron supplementation.
rhea, abdominal discomfort and black stools.23 The
absence of a significant response to oral iron supple- Acknowledgements
mentation can be attributed to a IDA misdiagnosis,
malabsorption or persistent chronic blood loss that The author is grateful to Martin Hiele MD PhD,
exceeds the amount of iron that can be absorbed from Department of Gastroenterology of the University Hos-
an oral supplement.53 Patients with intolerance to oral pitals Leuven, Belgium, for reviewing the manuscript.
iron, malabsorption or chronic blood loss might benefit
from parenteral iron.23,24,26,53,71 Several parenteral iron Disclosure statement
preparations are available, and the most commonly pre-
scribed preparations are iron sucrose, ferric carboxy- The author declares no conflict of interest.
maltose and iron dextran.24 The total iron dose to
replete the iron stores can be provided in one or a few
more sessions depending on the formula used, it is safe
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