What are the common causes and pathophysiology of iron-deficiency anemia?

Development of Iron Deficiency Anemia

Iron deficiency anemia develops through three primary mechanisms: chronic blood loss (most common), inadequate dietary intake/malabsorption, and increased physiological demands, with chronic blood loss from gastrointestinal or menstrual sources being the dominant pathway in adults. 1

Core Pathophysiologic Mechanisms

Chronic Blood Loss

• Gastrointestinal bleeding is the most common cause in men and postmenopausal women, with approximately one-third having an underlying pathological abnormality in the GI tract 1
• Menstrual blood loss is the predominant mechanism in reproductive-age women, affecting 38% with iron deficiency without anemia and 13% with iron-deficiency anemia 2
• Blood is iron-rich, and even occult chronic bleeding gradually depletes iron stores over time, eventually progressing to anemia 1
• Critical clinical point: In men and postmenopausal women with unexplained IDA, about one-third of those with GI pathology will have cancer, mandating urgent bidirectional endoscopy 1

Malabsorption

• Iron is absorbed most efficiently in the duodenum and proximal jejunum, making this anatomic region critical 3
• Celiac disease is found in 3-5% of IDA cases and should be routinely screened serologically or via small bowel biopsy 1
• Atrophic gastritis impairs iron absorption because gastric acid (pH <3) is required to release iron from dietary nutrients and solubilize Fe²⁺ and Fe³⁺ 3, 2
• Post-bariatric surgery patients develop IDA multifactorially, primarily from bypassing the duodenum/proximal jejunum and reduced acid secretion 3

Inadequate Dietary Intake

• Poor dietary iron intake is a common cause globally, particularly in populations of low socioeconomic status 2, 4
• Decreased dietary iron contributes significantly alongside malabsorption in many cases 4

Increased Physiological Demands

• Pregnancy: Iron deficiency affects up to 84% of pregnant women during the third trimester in high-income countries 2
• Increased iron requirements during pregnancy, growth periods in children, and lactation can outpace intake 2

Progression of Iron Deficiency

Iron deficiency progresses through distinct stages: initial depletion of iron stores → iron-deficient erythropoiesis → frank iron-deficiency anemia 2

• Early stage shows low ferritin (depleted stores) without anemia
• Intermediate stage demonstrates reduced transferrin saturation (<20%) as functional iron becomes limited 2
• Final stage manifests as microcytic anemia with low hemoglobin 5

Special Populations and Mechanisms

Chronic Inflammatory Conditions

• Inflammatory bowel disease (IBD): IDA occurs in up to 90% of patients through multiple mechanisms: GI blood loss (both overt and occult), poor iron absorption, and inadequate intake 3
• Chronic kidney disease: 24-85% affected due to decreased erythropoietin production, chronic inflammation elevating hepcidin, and uremic bleeding 2
• Heart failure: 37-61% affected, with iron deficiency worsening outcomes independent of anemia 2
• Cancer: 18-82% affected due to chronic inflammation, bleeding, and nutritional factors 2

Hepcidin-Mediated Mechanisms

• In chronic inflammatory conditions, interleukin-6 stimulates hepcidin production, which blocks enteric iron uptake and traps iron in macrophages 6
• This creates functional iron deficiency (anemia of chronic disease) where total body iron may be normal but unavailable for erythropoiesis 6
• Iron-refractory iron deficiency anemia (IRIDA) is a rare congenital disorder with pathologically elevated hepcidin from TMPRSS6 gene mutations, causing resistance to oral iron 6, 7

Drug-Related Mechanisms

• NSAIDs cause gastric erosions and increase GI bleeding risk 2
• Anticoagulants unmask or exacerbate occult GI bleeding 1

Key Diagnostic Considerations

• Serum ferritin is the single most useful marker, with <30 ng/mL indicating iron deficiency in non-inflammatory states 1, 2
• In inflammatory conditions, higher ferritin thresholds must be used, and transferrin saturation <20% becomes more reliable 2, 8
• A hemoglobin rise ≥10 g/L within 2 weeks of iron therapy strongly suggests absolute iron deficiency even with equivocal iron studies 1

Common Pitfalls

• Failing to investigate the underlying cause: IDA is not a diagnosis but a manifestation requiring identification of the source 1
• Missing GI malignancy: Unexplained IDA in at-risk individuals (men, postmenopausal women) requires urgent GI investigation even without GI symptoms 1
• Overlooking celiac disease: Routine screening is essential as it affects 3-5% of IDA cases 1
• Misinterpreting ferritin in inflammation: Normal or elevated ferritin does not exclude iron deficiency in patients with chronic inflammatory conditions 8