History and exam

Key diagnostic factors

common

fatigue

The relation between fatigue and anemia is unclear.[4] Fatigue does not appear to be increased in patients with mild to moderate anemia (hemoglobin from 8 to 12 g/dL) and treatment of this range of anemia does not necessarily lead to improvements in fatigue. However, patients with hemoglobin below 8 g/dL may have a component of fatigue that will correct with correction of their anemia.

dyspnea on exertion

Dyspnea may occur due to impaired red blood cell production and decreased oxygen-carrying capacity.

pica

Pica is the abnormal craving or appetite for nonfood substances, such as soil, ice, paint, or clay. It has been reported in up to 55% of patients with IDA.[88] Ingestion of some materials, such as clay, has chelating effects, which can impair the absorption of iron. These cravings correct within 2 weeks of iron replacement.

restless legs syndrome

Iron deficiency and IDA are known causes of restless legs syndrome, and treatment of the iron deficiency often leads to alleviation of these symptoms.[89]

nail changes

Typical nail changes occur in a stepwise fashion of thinning, flattening, and then spooning of the nails (koilonychia); however, spooning is rare. Approximately 28% of patients have some nail changes.[4]

Chronic exposure to hot soap suds or caustic chemicals may also give rise to these nail changes.[Figure caption and citation for the preceding image starts]: KoilonychiaReproduced with permission from Bickle Ian. Clinical exam skills: Hand signs BMJ 2004;329:0411402 [Citation ends].com.bmj.content.model.Caption@305d3668

uncommon

dysphagia

Approximately 7% of patients may complain of a gradual onset of swallowing difficulties with discomfort sharply located in the area of the cricoid cartilage consistent with Plummer-Vinson syndrome.[4] This triad of dysphagia, IDA, and esophageal webs or strictures predominantly affects middle-aged women.[90]

Other diagnostic factors

common

impaired muscular performance

Many measures of muscular performance, such as total exercise time, maximal workload, heart rate, and serum lactate levels after exercise, are impaired by IDA and correct with iron replacement.[4]

glossitis and angular stomatitis

Glossitis with soreness or burning of the tongue with loss or atrophy of papillae can occur. Approximately 50% of patients may have some changes. These resolve after 1 to 2 weeks of iron replacement therapy.[4] Patients can also have angular stomatitis with sores in the corners of the mouth.

dyspepsia

Gastric biopsies in patients with iron deficiency are much more likely to show gastritis (75%) than in patients without iron deficiency (29%). Patients can also have absent or reduced acid secretion in the stomach (achlorhydria).[4]

Helicobacter pylori infection is associated with IDA refractory to oral iron.[91]

pallor

Nonspecific sign of anemia. May be assessed by observation of the patient’s conjunctivae.[92]

hair loss

Associated with iron deficiency, mostly in women.[93][94] However, this association is controversial because the evidence is unclear.

uncommon

rectal lesion on examination

Blood loss from the lower gastrointestinal tract may be caused by a rectal lesion, such as hemorrhoids or a neoplasm.

growth impairment

Iron deficiency in infancy can lead to growth impairment, which is corrected with iron replacement.[4]

cognitive and behavioral impairment

Cognitive and behavioral impairment, especially attention deficits, have been noted in children with IDA.[4][12] These appear to correct with iron replacement. However, debate remains in this area.[95][96][97]

heart failure

High-output heart failure can be seen in patients with severe anemia, especially with a hemoglobin less than 5 g/dL. This can be reversed with iron replacement, may not require specific treatment. Caution should be used in giving transfusions in this setting, because of the risk of fluid overload.[98]

recurrent infections

Iron is necessary for proper neutrophil functioning and there are some studies to suggest that infection-fighting capacity is decreased in patients with iron deficiency. However, further study is required before a definite connection can be made.[99]

Risk factors

strong

pregnancy

Pregnancy increases iron requirements due to expansion of maternal red blood cell mass and growth of the fetus and placenta.[15][16] This results in a net loss of approximately 580 mg of iron during the gestation period, with the highest loss occurring in the third trimester.[15][16]

In the US, the prevalence of IDA in pregnant women ages 12 to 49 years is reported to be 2.6% (based on National Health and Nutrition Examination Survey data from 1999 to 2010).[9] Prevalence of iron deficiency is reported to be 5.3%, 12.7%, and 27.5% in the first, second, and third trimesters, respectively.[9]

vegetarian and vegan diet

In one German study, approximately 40% of vegans ages 19 to 50 years were iron deficient.[20]

One systematic review reported lower serum iron levels in adult vegetarians compared with adult nonvegetarians (-2.97 microgram/dL).[21]

Dietary iron exists in two forms: heme iron and nonheme iron. Vegetarian and vegan diets contain nonheme iron, which is not as easily absorbed as heme iron found in meat.[22]

menorrhagia

Menstrual iron loss (approximately 2 mg daily during menstruation) is inversely related to iron status as measured by ferritin.[14][23] Therefore, any bleeding disorder (e.g., von Willebrand disease) or disease (e.g., fibroids) that can lead to menorrhagia can be considered a risk factor for IDA.

hookworm infestation

Can be a frequent cause of blood loss in sub-Saharan Africa, Asia, Latin America, and the Caribbean, and has been linked to iron deficiency.[24]

chronic kidney disease

Patients with chronic kidney disease develop IDA through multiple mechanisms including reduced intestinal absorption, decreased release of iron from body stores, bleeding caused by gastritis and platelet dysfunction, blood loss during dialysis, and malnutrition.[19] Iron deficiency may render patients unresponsive to erythropoiesis stimulating agents.

celiac disease

IDA is reported in up to 46% of cases of subclinical celiac disease and may be the presenting feature.[25]

gastrectomy/achlorhydria

Gastric acid facilitates iron absorption. Patients with achlorhydria and those who have had a gastrectomy (including sleeve gastrectomy) are at increased risk for IDA due to low or absent gastric acid production.[26]

Long-term follow-up of patients after gastrectomy showed a high rate of iron deficiency (up to 90%), which appears to correct with iron supplementation.[27][28] Roux-en-Y gastric bypass leads to achlorhydria and reduced iron absorption in the duodenum and proximal jejunum.[29]

nonsteroidal anti-inflammatory drugs (NSAID) use

NSAID use has been shown to cause stomach and duodenal ulcers (22% vs. 12% in nonusers), and small intestinal ulcers (8.4% vs. 0.6% in nonusers), which can lead to chronic gastrointestinal bleeds and IDA.[28]

chronic heart failure

Multiple mechanisms contribute to the development of anemia in patients with heart failure, and iron deficiency is common. One prospective study identified iron deficiency in over 72% of anemic patients admitted to hospital with an acute decompensation of chronic heart failure.[30]

weak

preterm or low birth weight

Preterm and low birth weight infants have low total body iron. This deficiency may be exacerbated by rapid postnatal growth.[31][32]

infant feeding with cows' milk

A prospective longitudinal cohort study conducted in Europe found that infant feeding with cows' milk was significantly associated with IDA at 12 months (odds ratio 1.39, 95% confidence interval 1.14-1.69).[33]

black women and Mexican women

In the US, the prevalence of IDA among nonpregnant females ages 15 to 49 years is reported to be: 11.8% in non-Hispanic black women; 8.5% in Mexican women; and 3% in non-Hispanic white women (based on National Health and Nutrition Examination Survey data collected between 2007 and 2010).[9]

low socioeconomic status

IDA is significantly more common in infants with low socioeconomic status.[33]

Postpartum IDA has been reported among women from low-income populations in the US.[34][35]

obesity

Risk of iron deficiency is higher in overweight and obese children and adolescents, likely due to chronic inflammation rather than dietary factors.[36] Childhood and adolescent obesity (body mass index above 85th percentile) carries an odds ratio of 2.0 to 2.3 for IDA.[37]

Helicobacter pylori infection

Studies have found an association between H pylori and IDA.[38][39] US data indicate that H pylori infection is associated with a 40% increased prevalence of iron deficiency.[39]

It is unclear how H pylori infection leads to IDA, but possible mechanisms include poor iron absorption subsequent to acid suppression, and blood loss related to gastritis or ulcer disease.[40] IDA appears to decrease after eradication of H pylori infection.[41]

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