Iron Deficiency Anemia - Exam Essay

1. Definition

2. Iron Metabolism (Background Essential for Pathogenesis)

• Total body iron: ~3,450 mg in males; ~2,450 mg in females
• Functional pool (most of body iron): Hemoglobin (~2,100 mg males), myoglobin (~300 mg), iron-containing enzymes (cytochromes, catalase)
• Storage pool: Ferritin and hemosiderin, found in hepatocytes and macrophages of spleen, liver, and bone marrow
• Transport: Iron circulates bound to transferrin (normally ~33% saturated; serum iron ~120 µg/dL males, ~100 µg/dL females; total iron-binding capacity 300-350 µg/dL)
• Daily balance: Iron is lost at 1-2 mg/day through shed epithelial cells. The average Western diet provides 10-20 mg/day; only ~20% of heme iron and 1-2% of non-heme iron is absorbed

• Non-heme iron is reduced (Fe³⁺ → Fe²⁺) by ferrireductases, then transported across the apical enterocyte membrane by divalent metal transporter-1 (DMT1)
• Iron exits the enterocyte basolaterally via ferroportin, is oxidized back to Fe³⁺ by hephaestin/ceruloplasmin, and binds transferrin in plasma
• When body iron is high: hepcidin rises → binds ferroportin → ferroportin is degraded → iron is trapped in enterocytes as ferritin and lost with cell shedding
• When body iron is low: hepcidin falls → ferroportin is active → more iron is absorbed
• In iron deficiency: hepcidin levels fall, maximizing absorption

3. Causes and Pathogenesis

A. Dietary Lack

• Rare in high-resource countries where ~2/3 of dietary iron is heme (from meat)
• Common in low-resource countries where most dietary iron is poorly absorbable inorganic (plant) form
• At risk even in high-resource settings: infants (high growth demand), vegans, the elderly (restricted diets), and the impoverished
• Dietary absorption enhanced by: ascorbic acid, citric acid, amino acids, sugars
• Dietary absorption inhibited by: tannins (tea), carbonates, oxalates, phosphates

B. Impaired Absorption

• Celiac disease (sprue) and other malabsorptive states
• Gastrectomy (reduces duodenal acidity needed for iron uptake; speeds transit)
• Chronic diarrhea

C. Increased Requirement

• Pregnancy and infancy - most important worldwide
• Growing children and adolescents
• Premenopausal females (especially with multiple pregnancies)

D. Chronic Blood Loss (most important cause in developed countries)

• Gastrointestinal: peptic ulcers, colon cancer, hemorrhoids, hookworm infection
• Gynecologic: menorrhagia, metrorrhagia, endometrial cancer
• Critical clinical point: Iron deficiency in adult males or postmenopausal females in high-income countries must be attributed to GI blood loss until proven otherwise - an alert clinician investigating unexplained IDA may discover an occult GI cancer and save a life

Sequential Stages of Iron Depletion

4. Morphology (Microscopic)

Peripheral Blood Smear

1. Microcytosis - red cells are smaller than normal (MCV < 82 fL)
2. Hypochromia - cells are pale due to reduced hemoglobin content
   • Normal central pallor = ~1/3 of cell diameter
   • In IDA: central pallor is enlarged; hemoglobin is seen only as a narrow peripheral rim
3. Poikilocytosis - especially "pencil cells" (small, elongated red cells) - characteristic of IDA
4. Anisocytosis - variation in red cell size (elevated RDW)
5. Target cells may occasionally appear

Bone Marrow

• Mild to moderate erythroid hyperplasia (increased erythroid progenitors)
• Absent stainable iron in macrophages - diagnostically significant finding
  • Confirmed by Prussian blue stain (potassium ferrocyanide) - no blue-black granules in marrow macrophages
  • This is the most reliable morphologic sign of iron deficiency

Summary of Lab Findings

5. Clinical Features (Brief)

• Often mild and asymptomatic
• Nonspecific: weakness, listlessness, pallor, dyspnea on exertion
• Long-standing severe IDA causes koilonychia (spoon nails), alopecia, atrophic glossitis, gastric atrophy, intestinal malabsorption
• Pica - craving for non-foodstuffs (dirt, clay, ice/pagophagia) - characteristic neurobehavioral complication
• Plummer-Vinson syndrome (rare triad): hypochromic microcytic anemia + atrophic glossitis + esophageal webs

Key Exam Points to Remember

• IDA is the most common nutritional disorder worldwide and the most common cause of microcytic hypochromic anemia
• Hepcidin is the master regulator of iron absorption; it falls in IDA to maximize iron uptake
• Chronic blood loss is the most important cause in developed countries; always rule out GI malignancy in adult males/postmenopausal females
• Pencil cells + absent bone marrow iron (Prussian blue) are the hallmark morphologic findings
• IDA is a symptom of an underlying disorder, not a primary disease - identifying the cause is clinically essential
• Serum ferritin is the most sensitive early marker of iron depletion
• Responds to oral iron with reticulocytosis in 5-7 days