What are the etiologies of iron deficiency anemia?

Etiologies of Iron Deficiency Anemia

Iron deficiency anemia results from three primary mechanisms: blood loss, inadequate intake/absorption, and increased physiological demand, with gastrointestinal blood loss being the leading cause in men and postmenopausal women. 1

Blood Loss

Gastrointestinal Sources

• Malignancy: Colorectal cancer and gastric cancer are major causes requiring investigation in men and postmenopausal women 1
• Peptic ulcer disease: Including NSAID-induced mucosal damage and anastomotic ulcers (particularly post-bariatric surgery) 2, 1
• Inflammatory bowel disease: Occurs in up to 90% of IBD patients through ulceration, chronic blood loss, and occult bleeding 2
• Portal hypertensive gastropathy: Results from increased portal pressure in cirrhosis patients 2
• Hookworm infections: Associated with gastrointestinal blood loss, though uncommon in the United States 2

Gynecological Sources

• Menstrual blood loss: The most common cause in premenopausal women 1, 3
• Pregnancy: Contributes to iron deficiency through increased demand and blood loss 3

Other Bleeding Sources

• Urinary tract bleeding: Including renal cell carcinoma causing chronic blood loss 2, 1
• Epistaxis: Particularly in hereditary hemorrhagic telangiectasia 2
• Blood donation: Repeated donations deplete iron stores 2, 1

Malabsorption

Gastrointestinal Disorders

• Celiac disease: Found in 3-5% of iron deficiency anemia cases and should be routinely excluded in all age groups 2, 1, 4
• Atrophic gastritis: Both autoimmune and Helicobacter pylori-related forms impair iron absorption 2, 5, 4
• Post-surgical states: Previous gastrectomy, gastric bypass, or intestinal resection disrupts duodenal/proximal jejunal absorption 2, 4

Medication-Induced

• Chronic proton pump inhibitor therapy: Long-term use (≥1-2 years) causes dose-dependent iron deficiency through hypochlorhydria, with adjusted odds ratio of 2.49 for high-dose use 2, 6

Other Malabsorptive Conditions

• Bacterial overgrowth: Impairs iron uptake 2
• Small bowel tumors: Rare cause of malabsorption 2

Inadequate Intake

• Dietary insufficiency: Inadequate iron intake from diet, particularly in developing countries 2, 7
• Malnutrition: Generalized undernutrition affecting iron availability 2

Increased Demand

• Pregnancy: Increased physiological requirements for fetal development 2, 3
• Infancy and childhood: Rapid growth phases require increased iron, particularly in preterm or low-birthweight infants 2
• Endurance athletes: High hepcidin levels may contribute to iron deficiency 2

Chronic Disease States

Inflammatory Conditions

• Chronic kidney disease: Multifactorial causes including reduced intake, reduced absorption, dialysis losses, and functional iron deficiency from elevated hepcidin 2, 5
• Chronic heart failure: Found in 40-70% of cases due to malabsorption, malnutrition, GI blood loss, and hepcidin-mediated reduced iron mobilization 2, 5
• Chronic inflammatory disorders: Inflammation increases hepcidin, reducing iron absorption and mobilization 2, 5

Rare Genetic Causes

• Iron-refractory iron deficiency anemia (IRIDA): Caused by TMPRSS6 gene mutations, unresponsive to oral iron and only partially responsive to parenteral iron 5, 8

Critical Clinical Considerations

• Multiple etiologies frequently coexist: Finding one cause should not deter further investigation, particularly in older adults 2, 1
• Age and sex determine investigation approach: Approximately one-third of men and postmenopausal women have underlying pathological GI abnormalities requiring bidirectional endoscopy 1
• Functional iron deficiency: Occurs when inflammation prevents iron mobilization despite adequate stores, common in CKD, CHF, and IBD 2