Iron Deficiency Anemia - Robbins

Overview

Iron Metabolism

Fig. 14.20 - Iron absorbed from the gut binds to plasma transferrin, travels to bone marrow erythroid precursors, enters mature RBCs, and after 120 days is recycled from macrophages back to transferrin.

• ~80% of body iron is functional (hemoglobin, myoglobin, iron-containing enzymes like catalase and cytochromes)
• ~15-20% is storage iron as ferritin and hemosiderin, found in macrophages of the liver, spleen, and bone marrow
• Iron is transported in plasma bound to transferrin (normally ~33% saturated); serum iron averages 120 μg/dL in males, 100 μg/dL in females; total iron-binding capacity (TIBC) is normally 300-350 μg/dL

• Ferritin - protein-iron complex in hepatocytes and macrophages; serum ferritin correlates with body iron stores. In iron deficiency: serum ferritin <12 μg/L; in iron overload: up to 5000 μg/L
• Hemosiderin - aggregated, partially degraded ferritin; turns blue-black with potassium ferrocyanide (Prussian blue stain)

• Dietary iron is absorbed in the proximal duodenum
• Nonheme iron (Fe³⁺) is reduced to Fe²⁺ by ferrireductases (duodenal cytochrome B), then transported across the apical membrane by DMT1 (divalent metal transporter-1)
• Heme iron crosses via separate transporters with much higher bioavailability (~20% vs 1-2% for nonheme)
• Fe²⁺ exits enterocytes across the basolateral membrane via ferroportin, then is oxidized to Fe³⁺ by hephaestin and ceruloplasmin to bind transferrin
• Hepcidin (synthesized by the liver) is the master regulator - it binds ferroportin, causing its degradation, thereby trapping iron in enterocytes and macrophages. High iron stores → high hepcidin → decreased absorption. Low iron stores → low hepcidin → increased absorption
• Inflammatory mediators (e.g., IL-6) upregulate hepcidin; erythroferrone (from erythroblasts) suppresses hepcidin to enhance iron supply during erythropoiesis

Etiology and Pathogenesis

1. Dietary Lack

• Rare in high-resource countries (two-thirds of dietary iron is heme iron from meat)
• Common in low-resource countries where most dietary iron is nonheme (vegetables)
• At-risk groups: infants (breast milk has only ~0.3 mg/L iron; cow's milk iron is poorly bioavailable), vegans, the elderly (restricted diets), and the impoverished
• In the US: seen in infants fed exclusively milk, those with food insecurity, and the elderly
• Bioavailability is enhanced by: ascorbic acid, citric acid, amino acids, sugars
• Bioavailability is reduced by: tannins (tea), carbonates, oxalates, phosphates

2. Impaired Absorption

• Celiac disease, other causes of fat malabsorption (steatorrhea), chronic diarrhea
• Gastrectomy (reduces duodenal acidity and transit time)
• Various forms of gastritis

3. Increased Demand

• Infancy, childhood, adolescence (rapid growth)
• Pregnancy - a major cause worldwide
• Premenopausal females; females in low-resource countries with multiple closely spaced pregnancies are at exceptionally high risk

4. Chronic Blood Loss (Most Important in High-Resource Countries)

• GI tract: peptic ulcers, colon cancer, hemorrhoids, angiodysplasia
• Female genital tract: menorrhagia, metrorrhagia, endometrial cancer
• Key clinical rule: Iron deficiency in adult males or postmenopausal females in high-income countries must be attributed to gastrointestinal blood loss until proven otherwise - to do otherwise risks missing a GI cancer or other bleeding lesion

Sequence of Depletion (Insidious Progression)

1. Iron stores depleted first - serum ferritin falls; no stainable iron in bone marrow macrophages (no anemia yet)
2. Serum iron falls, transferrin (TIBC) rises - increased erythroid activity in bone marrow but still compensated
3. Frank anemia appears - when stores are completely depleted; low serum iron and ferritin, low transferrin saturation, microcytic hypochromic anemia, impaired work capacity, cognitive performance, and immunocompetence

Morphology

• Mild to moderate increase in erythroid progenitors
• Absence of stainable iron in macrophages - the most diagnostically significant finding, best assessed with Prussian blue stain on aspirated marrow

Fig. 14.22 (Robbins Cotran) - Hypochromic microcytic red cells with a narrow rim of peripheral hemoglobin. A transfused, fully hemoglobinized cell is visible in contrast.

• Microcytic red cells (small)
• Hypochromic red cells (pale) - the zone of central pallor normally occupies ~1/3 of cell diameter; in iron deficiency, this is enlarged and hemoglobin may be seen only as a narrow peripheral rim
• Poikilocytosis: characteristic "pencil cells" (small, elongated cells)
• Thrombocytosis (elevated platelet count) is often seen for unclear reasons

Clinical Features

• Most cases are mild and asymptomatic
• Weakness, listlessness, pallor in moderate-to-severe cases
• Dominating signs/symptoms often relate to the underlying cause (GI disease, gynecologic disorder, malnutrition)

• Koilonychia (spoon nails) - thinning, flattening, "spooning" of fingernails
• Alopecia
• Atrophic changes in the tongue (atrophic glossitis) and gastric mucosa
• Intestinal malabsorption
• Pica - compulsion to eat non-foodstuffs (dirt, clay) or specific food ingredients like ice (pagophagia) or flour; due to iron depletion from the CNS
• Plummer-Vinson syndrome (rare triad): microcytic hypochromic anemia + atrophic glossitis + esophageal webs

Laboratory Findings

Key Clinical Maxim (Robbins)

"Persons often die with iron deficiency anemia but virtually never of it. An important point to remember is that in well-nourished persons, microcytic hypochromic anemia is not a disease but rather a symptom of another underlying disorder (e.g., colon cancer leading to chronic blood loss)."

• Robbins & Kumar Basic Pathology, p. 393

Differentiating IDA from Anemia of Chronic Inflammation