Iron Deficiency Anemia - Harrison's Principles of Internal Medicine, 22nd Edition (2025)

Iron Metabolism - Background

• Total body iron: ~3.5 g in adult males, ~2.7 g in adult females
• ~2 g resides in hemoglobin of circulating erythrocytes
• ~1 g stored in liver (hepatocytes), spleen, and bone marrow macrophages as ferritin/hemosiderin
• Only 3-4 mg circulates bound to transferrin (but with fast turnover)
• Erythroid precursors require 20-25 mg/day - mainly supplied by macrophage recycling of old RBCs

• High hepcidin → decreased plasma iron
• Low hepcidin → increased plasma iron (as in iron deficiency)
• Hepcidin is induced by high iron (via BMP-SMAD pathway) and inflammation (via IL-6/STAT3)
• Hepcidin is suppressed by iron deficiency (via TMPRSS6) and by erythroferrone (secreted by erythroblasts after EPO stimulation)

• Only 1-2 mg/day absorbed from diet (matching daily losses)
• Heme iron (meat) is more bioavailable than non-heme iron
• Non-heme iron requires reduction to Fe²⁺ by duodenal cytochrome b (DcytB) before transport via DMT1
• Iron enters portal blood via ferroportin, is oxidized to Fe³⁺ by hephaestin, then binds transferrin
• Absorption is upregulated in iron deficiency, pregnancy, and hypoxia

Definition and Stages of Iron Deficiency

Causes of Iron Deficiency

• Infancy, adolescence (growth spurts)
• Pregnancy (requires ~1,000 mg additional iron total)
• Lactation

• Inadequate dietary intake (vegetarian/vegan diets, poverty)
• Malabsorption: celiac disease, gastric bypass, chronic atrophic gastritis
• Proton pump inhibitor use (reduces gastric acid needed for non-heme iron reduction)
• Helicobacter pylori infection

• Gastrointestinal: peptic ulcer, gastric/colonic cancer, angiodysplasias, NSAID use, aspirin (100 mg/day aspirin raises IDA risk 20% in elderly), inflammatory bowel disease
• Uterine: menorrhagia (most common cause in premenopausal women)
• Urinary: chronic hematuria, intravascular hemolysis with hemoglobinuria
• Iatrogenic: frequent blood draws, frequent blood donation

Clinical Features

• Fatigue, weakness, exertional dyspnea, pallor
• Palpitations, headache, poor concentration

• Pica - craving for non-food items (ice = pagophagia, clay = geophagia, starch = amylophagia)
• Koilonychia - spoon-shaped, brittle nails
• Angular cheilitis - cracking at corners of mouth
• Atrophic glossitis - smooth, red, painful tongue
• Dysphagia - Plummer-Vinson (Patterson-Kelly) syndrome (web in upper esophagus)
• Restless legs syndrome - common association
• Impaired immune function, reduced physical performance

Laboratory Diagnosis

• Microcytic (MCV < 80 fL), hypochromic RBCs
• Anisocytosis, poikilocytosis
• Target cells, pencil cells (elliptocytes)
• Low reticulocyte count (hypoproliferative pattern)

Differential Diagnosis of Microcytic Anemia

Treatment

Oral Iron (First-line)

• Ferrous sulfate 325 mg (65 mg elemental iron) three times daily - standard regimen
• Newer evidence favors alternate-day dosing (e.g., 150 mg elemental iron every other day), which reduces hepcidin upregulation and may improve net absorption vs. daily dosing
• Duration: Continue for 3-6 months after hemoglobin normalizes to replenish stores
• Hemoglobin should rise 1-2 g/dL within 4 weeks - use as therapeutic response check
• Side effects: nausea, constipation, abdominal pain (reduce by taking with food, though absorption decreases)
• Enhance absorption: take on empty stomach, with vitamin C, avoid tea/coffee/antacids/calcium

Intravenous Iron (Second-line)

• Intolerance or non-compliance with oral iron
• Malabsorption (celiac disease, gastric bypass, IBD)
• Severe ongoing blood loss exceeding oral replacement capacity
• Preoperative optimization
• CHF: recommended when ferritin <100 µg/L OR transferrin saturation <20% with ferritin 100-300 µg/L
• Cancer-related anemia when ferritin <100 µg/L (to reduce transfusion need)

• Ferric carboxymaltose (can give 1,000 mg in single dose)
• Low-molecular-weight iron dextran
• Ferric gluconate, iron sucrose (require multiple smaller doses)
• Iron isomaltoside

Blood Transfusion

• Reserved for severe symptomatic anemia (Hb <7-8 g/dL in hemodynamically stable patients, per restrictive transfusion guidelines)
• Does not correct the underlying cause - iron therapy still required

Special Situations

• Daily iron requirement rises to 27 mg/day (vs. 18 mg non-pregnant)
• Oral iron supplementation recommended from first trimester
• IV iron used in second/third trimester when oral iron fails or is not tolerated
• Severe IDA in pregnancy linked to preterm birth, low birth weight, postpartum hemorrhage

• Iron deficiency is common in CHF and associated with worse outcomes independent of hemoglobin level
• IV iron (ferric carboxymaltose) improves symptoms and quality of life in CHF patients with iron deficiency, even without anemia

• Ferritin cutoff for iron deficiency in elderly is higher (45-70 µg/L) than in younger patients
• Always exclude GI malignancy
• 100 mg aspirin for primary prevention raises IDA risk 20% in the elderly

Key Pearls from Harrison's 22E

1. Ferritin is the single best test to detect early iron deficiency, but it is an acute-phase reactant - always interpret in clinical context.
2. Alternate-day oral iron is as effective or superior to daily dosing due to hepcidin pharmacodynamics.
3. In men and postmenopausal women - IDA = GI malignancy until proven otherwise.
4. Pica (especially pagophagia/ice craving) is a specific symptom of iron deficiency and may precede anemia.
5. Plummer-Vinson syndrome = IDA + dysphagia + esophageal web - associated with increased risk of postcricoid carcinoma.
6. IV iron in CHF improves functional capacity and quality of life even without correcting anemia (iron plays a direct role in cardiac and skeletal muscle energy metabolism).
7. Soluble transferrin receptor (sTfR) rises in iron deficiency but NOT in anemia of inflammation - useful to differentiate the two.