What are the causes of iron deficiency anemia?

Causes of Iron Deficiency Anemia

Blood Loss (Most Common Pathological Cause)

In men and postmenopausal women, gastrointestinal blood loss is the predominant mechanism and requires urgent investigation to exclude malignancy, even without GI symptoms. 1, 2, 3

Gastrointestinal Sources

• Colorectal and gastric cancer represent approximately one-third of pathological findings in men with iron deficiency anemia 2, 3
• Peptic ulcer disease and NSAID-induced mucosal damage are common causes, with NSAIDs causing occult blood loss even without overt symptoms 1, 2, 4
• Inflammatory bowel disease (Crohn's disease, ulcerative colitis) accounts for 13-90% of cases in affected populations 5
• Angiodysplasia and vascular malformations should be considered when bidirectional endoscopy is negative 4
• Hookworm infections cause gastrointestinal blood loss and iron depletion, though uncommon in developed countries 1

Menstrual Blood Loss

• Menstruation is the most common cause of iron deficiency anemia in premenopausal women, with an average loss of 0.3-0.5 mg iron daily during childbearing years 1, 6, 5
• Heavy menstrual bleeding affects approximately 38% of nonpregnant reproductive-age women with iron deficiency without anemia, and 13% with iron-deficiency anemia 5

Other Bleeding Sources

• Urinary tract bleeding from renal cell carcinoma or other pathology must be excluded with urinalysis in all cases 1, 2, 3
• Epistaxis and frequent blood donation deplete iron stores over time 1, 4, 3

Malabsorption (Critical to Screen)

Celiac disease accounts for 3-5% of all iron deficiency anemia cases and must be screened for in every patient with unexplained anemia, regardless of age or sex. 1, 2, 4, 3

Specific Malabsorption Causes

• Celiac disease requires screening with tissue transglutaminase antibody and duodenal biopsies during upper endoscopy even if serology is negative 2, 4, 3
• Chronic proton pump inhibitor (PPI) therapy impairs iron absorption through hypochlorhydria 1
• Previous gastrectomy, gastric bypass, or bariatric surgery causes malabsorption through multiple mechanisms 1, 4
• Atrophic gastritis reduces gastric acid necessary for iron absorption 1, 5
• Bacterial overgrowth, gut resection, and small bowel tumors contribute to iron malabsorption 1, 2

Inadequate Dietary Intake

• Poor dietary iron intake occurs particularly in individuals of lower socioeconomic status with limited access to iron-rich foods 4, 3, 5
• Vegetarian diets are inherently low in heme iron (the most bioavailable form), though this can be partially compensated by consuming iron with vitamin C 3
• Inadequate dietary intake is a recognized cause but should not deter full GI investigation in men and postmenopausal women 1, 3

Increased Iron Demand

• Pregnancy requires an average of 3 mg iron daily over 280 days' gestation to compensate for tissue growth and blood loss at delivery 1
• During the third trimester, iron deficiency affects up to 84% of pregnant women in high-income countries 5
• Infants and children require iron for growth, with preterm or low-birthweight infants at particular risk due to low iron stores 1

Chronic Inflammatory Conditions (Functional Iron Deficiency)

• Chronic kidney disease causes iron deficiency in 24-85% of patients through impaired erythropoietin production and iron utilization 5
• Heart failure is associated with iron deficiency in 37-61% of patients 5
• Cancer causes iron deficiency in 18-82% of patients 5
• Inflammatory bowel disease causes recurrent iron deficiency through ongoing inflammatory activity even with clinical remission 4

Medication-Related Causes

• Chronic NSAID use causes occult gastrointestinal blood loss even without ulceration or overt bleeding symptoms 1, 4, 3
• Anticoagulants and antiplatelet agents can unmask underlying vascular lesions like angiodysplasia 4
• Androgen deprivation therapy in prostate cancer survivors suppresses erythropoiesis 4, 3

Critical Diagnostic Pitfalls to Avoid

• Do not stop investigating after finding one cause—multiple etiologies coexist in 10-15% of patients, and dual pathology occurs in 1-10% of cases 1, 2, 4
• Do not accept minor endoscopic findings (such as small hiatal hernia) as the sole explanation without completing lower GI investigation 4, 3
• Do not assume dietary deficiency is the sole cause even with a positive dietary history—full GI investigation is still required in adult males 3
• Explicitly ask about all NSAID use, including over-the-counter medications, as patients frequently fail to report these 4, 3
• Do not fail to screen for celiac disease—this results in missed diagnoses in 3-5% of cases 4, 3

Physiological Context

• Men normally lose approximately 1 mg of iron daily through feces and desquamated mucosal and skin cells 1, 3
• Men store approximately 1.0-1.4 g of body iron, significantly more than women (0.2-0.4 g), making iron deficiency in men particularly concerning for pathological blood loss 1, 3
• Approximately 95% of iron required for red blood cell production is recycled from breakdown of old red blood cells, with only 5% from dietary sources 3