What are the causes of iron deficiency?

Causes of Iron Deficiency

Blood Loss

Gastrointestinal blood loss is the leading cause of iron deficiency in men and postmenopausal women, and must be investigated urgently as it may represent malignancy. 1, 2

• Malignancy: Colorectal cancer, gastric cancer, oesophageal cancer, and small bowel tumors (lymphoma, leiomyoma) are critical causes requiring urgent investigation 1, 2
• Benign GI lesions: Peptic ulcer disease, angiodysplasia, colonic polyps, inflammatory bowel disease (Crohn's disease, ulcerative colitis), and Meckel's diverticulum 1, 3
• Medication-induced: NSAID use causing mucosal damage and occult bleeding 1, 2
• Other GI causes: Portal hypertensive gastropathy, gastric antral vascular ectasia (watermelon stomach), duodenal polyps, and carcinoma of the ampulla of Vater 1, 3

Menstrual blood loss is the most common cause in premenopausal women, particularly heavy menstrual bleeding (≥80 mL/month) affecting approximately 10% of women. 1, 4

• Intrauterine device use increases menstrual blood loss and iron deficiency risk 1
• Oral contraceptive use decreases iron deficiency risk 1

Other bleeding sources include:

• Urinary tract bleeding (renal cell carcinoma) 2, 3
• Epistaxis, especially in hereditary hemorrhagic telangiectasia 2, 3
• Blood donation, particularly repeated donations 1, 2, 3

Malabsorption

Celiac disease is found in 3-5% of iron deficiency cases and should be routinely excluded in all age groups. 2, 3, 4

• Gastric causes: Atrophic gastritis (autoimmune or Helicobacter pylori-related), previous gastrectomy (partial or total), and gastric bypass surgery impair iron absorption 1, 3
• Chronic PPI therapy: Causes dose-dependent iron deficiency through hypochlorhydria, with an adjusted odds ratio of 2.49 for high-dose use 3
• Small bowel disorders: Bacterial overgrowth, Whipple's disease, lymphangiectasia, and intestinal resection or bypass 1, 2, 3
• Bariatric surgery: Common following resection or bypass surgery involving the stomach and/or small bowel 1

Inadequate Dietary Intake

Inadequate dietary iron intake is the major cause of iron deficiency in developing countries and certain populations in developed countries. 1, 4, 5

• Limited access to food due to low family income, migrant or refugee status 1
• Low-iron or specialized diets 1
• Borderline deficient diets, though a positive dietary history should not preclude full GI investigation 1

Increased Physiological Demands

Pregnancy increases iron requirements threefold in the second and third trimesters to approximately 5.0 mg iron/day, and most pregnant women cannot maintain adequate iron stores without supplementation. 1, 3, 4

• Blood volume expansion by approximately 35% and fetal/placental growth 1
• Iron deficiency affects up to 84% of pregnant women during the third trimester in high-income countries 4

Infancy and childhood, particularly in preterm or low-birthweight infants who have reduced iron stores at birth 1, 3

• Early introduction of whole cow's milk (before age 1 year) and consumption >24 oz daily after the first year are risk factors, as cow's milk has little iron and may cause occult GI bleeding 1
• Goat's milk carries the same risk as cow's milk 1

Adolescence (ages 12-18 years) due to rapid growth, with risk subsiding after peak pubertal growth in boys but persisting in girls due to menstruation 1

Chronic Disease States (Functional Iron Deficiency)

Chronic inflammatory conditions increase hepcidin, reducing iron absorption and mobilization despite adequate stores. 3, 4

• Chronic kidney disease: Iron deficiency in 24-85% of cases due to reduced intake, reduced absorption, dialysis losses, and hepcidin-mediated reduced iron mobilization 3, 4
• Chronic heart failure: Iron deficiency in 40-70% of cases due to malabsorption, malnutrition, GI blood loss, and hepcidin effects 3, 4
• Inflammatory bowel disease: Iron deficiency in 13-90% of cases 3, 4
• Cancer: Iron deficiency in 18-82% of cases 4

Critical Clinical Considerations

Multiple etiologies frequently coexist, and finding one cause should not deter further investigation, particularly in older adults where dual pathology (significant disease in both upper and lower GI tract) occurs in 1-10% of cases. 1, 2, 3

Approximately one-third of men and postmenopausal women with iron deficiency have an underlying pathological GI abnormality requiring bidirectional endoscopy. 2, 3