What are the mechanisms of iron deficiency?

Mechanisms of Iron Deficiency

Iron deficiency develops through three primary mechanisms: inadequate dietary intake/absorption, increased physiological demands exceeding supply, and pathological blood loss—with hepcidin-mediated iron sequestration representing a distinct fourth mechanism in inflammatory states. 1

Primary Mechanisms

1. Inadequate Iron Supply (Absolute Iron Deficiency)

Insufficient dietary intake is the most common cause globally, particularly affecting:

• Infants aged 4-18 months when maternal iron stores are depleted and dietary iron is inadequate 1
• Premenopausal women due to menstrual losses (the leading cause worldwide) 1
• Populations with limited access to iron-rich foods 2

Malabsorption occurs through:

• Gastrointestinal disorders reducing iron uptake at the duodenal enterocyte level 3, 4
• Reduced expression of iron transport proteins (DMT1, ferroportin) on enterocyte surfaces 1

2. Increased Physiological Demands

Rapid growth periods create iron deficiency when stores cannot meet erythropoietic needs:

• Infancy (ages 9-18 months): Full-term infants deplete maternal iron stores by 4-6 months; preterm/low-birthweight infants deplete stores by 2-3 months due to lower initial stores and faster growth 1
• Adolescence: Rapid body growth increases total iron requirements 5
• Pregnancy: Increased maternal blood volume and fetal iron demands (30 mg/day requirement vs. 10 mg/day baseline) 1

3. Pathological Blood Loss

Chronic blood loss depletes iron stores progressively:

• Gastrointestinal bleeding (most common in men and postmenopausal women, including occult colon cancer) 4
• Menstrual blood loss exceeding dietary replacement 1
• Hemodialysis-related losses: 165 mL/year (conventional 3x/week) to 385 mL/year (daily dialysis) from residual blood in tubing and dialyzer 1
• Uremic enteropathy causing occult intestinal bleeding 1

4. Functional Iron Deficiency (Inflammation-Mediated)

Hepcidin overproduction blocks iron mobilization despite adequate stores 1, 6:

• Inflammatory cytokines (IL-6, IL-1, TNF) stimulate hepatic hepcidin synthesis 1
• Hepcidin binds ferroportin on enterocytes and reticuloendothelial macrophages, causing internalization and degradation of this iron export protein 1
• Result: Iron becomes sequestered in macrophages and hepatocytes, unavailable for erythropoiesis despite normal/elevated ferritin levels 1, 6

Clinical contexts where this occurs:

• Cancer-related anemia (cytokine-driven hepcidin elevation) 1
• Chronic kidney disease (decreased hepcidin excretion plus inflammation) 1
• Chronic heart failure (affects 40-70% of patients due to systemic inflammation) 6
• ESA therapy creating "kinetic iron deficiency" where erythropoietic demand exceeds iron mobilization capacity 6, 7

Pathophysiological Spectrum

Iron deficiency progresses through three stages 1:

1. Iron depletion: Reduced storage iron (low ferritin) without functional impairment
2. Iron-deficient erythropoiesis: Depleted stores plus reduced transport iron (low transferrin saturation), with increased erythrocyte protoporphyrin as iron becomes rate-limiting for heme synthesis 1
3. Iron-deficiency anemia: Severe shortage causing underproduction of hemoglobin, resulting in microcytic, hypochromic red blood cells 1

Regulatory Failure Mechanisms

Hepcidin dysregulation underlies several iron disorders 1:

• Genetic hemochromatosis: Deficient hepcidin synthesis causes iron overload
• IRIDA (iron refractory iron deficiency anemia): TMPRSS6 gene mutation causes unregulated hepcidin synthesis, creating refractory iron deficiency 1

The body cannot excrete iron in a regulated manner, making prevention of deficiency entirely dependent on adequate absorption matching losses 1. This physiological constraint makes iron balance particularly vulnerable during high-demand states or when absorption is impaired.

Critical Clinical Pitfall

Ferritin is an acute-phase reactant, making it unreliable in inflammatory conditions 1, 6. A patient with ferritin 60 ng/mL and active inflammation may actually have absolute iron deficiency, as the inflammatory state artificially elevates ferritin levels 1. In obesity-related inflammation, ferritin up to 100 μg/L may still represent true iron deficiency 8.