Pathogenesis of Iron Deficiency Anemia (IDA)

Overview

Normal Iron Metabolism (Background)

• Total body iron: ~3-5 g in adults (males > females)
• Distribution: ~70% in hemoglobin, ~25% in storage (ferritin/hemosiderin), ~5% in myoglobin and enzymes, <0.1% in plasma (bound to transferrin)
• Daily requirement: ~1 mg absorbed (men), ~1.5-2 mg (menstruating women), ~3-4 mg (pregnancy)
• Dietary iron: ~10-20 mg/day ingested; only 5-10% absorbed (increases to 20-30% in deficiency)
• Regulation: Hepcidin (liver) - the master iron regulator; it degrades ferroportin, reducing iron export from enterocytes and macrophages

Causes of Negative Iron Balance

Three Stages of IDA Pathogenesis

Stage 1 - Pre-latent (Iron Store Depletion)

• Body iron stores (ferritin and hemosiderin in liver, spleen, bone marrow) are depleted
• Serum ferritin falls (most sensitive early marker; <12 µg/L in adults)
• Hemoglobin, transferrin saturation, and serum iron remain normal
• No anemia yet; patient is asymptomatic
• Bone marrow shows absent stainable iron (Prussian blue stain)

Stage 2 - Latent (Iron-Deficient Erythropoiesis)

• Iron stores exhausted; supply to erythroid precursors begins to fail
• Serum iron falls, TIBC rises (liver upregulates transferrin synthesis)
• Transferrin saturation falls (<16%)
• Erythrocytes still normal in size initially, but erythropoiesis becomes iron-restricted
• Free erythrocyte protoporphyrin (FEP) rises - heme precursor accumulates because iron is unavailable
• Reticulocyte hemoglobin content (CHr) falls - sensitive marker
• Still no overt anemia (Hb near normal), but red cell production is suboptimal

Stage 3 - Overt IDA (Frank Anemia)

• Iron supply is so deficient that hemoglobin synthesis is severely impaired
• Developing erythroblasts in marrow cannot synthesize adequate heme
• Red cells are produced with low hemoglobin content → microcytic, hypochromic red cells (MCV <80 fL, MCH <27 pg, MCHC <32 g/dL)
• Peripheral blood smear: microcytes, hypochromic cells, pencil (cigar) cells (elliptocytes), target cells, anisocytosis, poikilocytosis
• RDW rises (anisocytosis - mixture of normal and small cells)
• Hemoglobin falls below reference range → symptomatic anemia

Key Molecular/Cellular Mechanisms

Hepcidin-Ferroportin Axis

• In IDA: iron deficiency suppresses hepcidin (via HIF-2α, ERFE from erythroblasts)
• Low hepcidin → ferroportin is preserved on duodenal enterocytes and macrophages → increased iron absorption and recycling
• This is a compensatory mechanism trying to restore iron balance

Effect on Erythropoiesis

• Iron is required for heme synthesis (incorporated into protoporphyrin IX by ferrochelatase)
• Deficiency → failure of heme synthesis → hemoglobin tetramers cannot form properly
• Erythroblasts undergo more divisions relative to hemoglobin accumulation → smaller cells (microcytosis)
• Reduced hemoglobin per cell → central pallor of RBCs (hypochromia)

Non-Hematopoietic Effects

• Iron is a cofactor for many enzymes (cytochromes, ribonucleotide reductase, myoglobin)
• Explains non-anemic symptoms: fatigue, impaired cognition, reduced work capacity, Pica, Plummer-Vinson syndrome (esophageal webs), angular cheilitis, koilonychia (spoon nails), glossitis

Summary of Lab Changes in Each Stage

Key Distinguishing Points

• Ferritin is the earliest and most sensitive indicator of iron depletion (but is an acute phase reactant - can be falsely elevated in inflammation)
• Transferrin saturation <16% marks iron-deficient erythropoiesis
• TIBC rises in IDA (unlike ACD where TIBC falls/normal)
• Soluble transferrin receptor (sTfR) rises in IDA but NOT in anemia of chronic disease - useful for distinguishing the two
• sTfR/log ferritin ratio (Thomas plot) helps differentiate IDA from functional iron deficiency in ACD