Iron Deficiency Anemia
Microcytic hypochromic anemia from depleted iron stores — most common anemia worldwide.
Also known as: IDA, iron deficiency, microcytic anemia, hypochromic anemia
Overview
Anemia resulting from insufficient body iron to sustain normal erythropoiesis. Defined by reduced hemoglobin with low ferritin (<30 ng/mL in most adults, <15 ng/mL highly specific) and reduced transferrin saturation (<20%).
Epidemiology
Most common cause of anemia globally and in the United States. Highest prevalence in menstruating women, pregnant patients, infants/toddlers, and adults with chronic blood loss. In men and postmenopausal women, GI blood loss must be excluded.
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Risk factors
- Heavy menstrual bleeding, pregnancy, lactation
- GI blood loss: peptic ulcer disease, colorectal neoplasm, hookworm, NSAID use, angiodysplasia
- Malabsorption: celiac disease, atrophic gastritis, H. pylori, post-gastric bypass, PPI use
- Inadequate intake: strict vegetarian/vegan diet, infants on cow's milk before 1 year
- Frequent blood donation, hemodialysis
- Endurance athletes (foot-strike hemolysis, hepcidin elevation)
Pathophysiology
Iron is required for heme synthesis. When demand exceeds supply (loss > absorption), storage iron (ferritin) is mobilized first, then transport iron (transferrin saturation falls), and finally functional iron in erythrocytes. Erythropoiesis becomes iron-restricted, producing small (microcytic), pale (hypochromic) red cells with reduced hemoglobin content.
Clinical presentation
Symptoms
- Fatigue, dyspnea on exertion, exercise intolerance, lightheadedness
- Headache, poor concentration, irritability
- Pica (craving ice/pagophagia, clay, starch) — relatively specific for iron deficiency
- Restless legs syndrome
- Hair loss, brittle nails
Signs / physical exam
- Pallor of conjunctiva, palms, nail beds
- Tachycardia, systolic flow murmur
- Koilonychia (spoon nails) — advanced/chronic
- Angular cheilitis, atrophic glossitis (smooth red tongue)
- Plummer-Vinson syndrome: dysphagia + esophageal web + IDA (rare, premalignant)
Classic findings
Pica with ice craving plus microcytic anemia and low ferritin is highly suggestive of iron deficiency.
Differential diagnosis
- Anemia of chronic disease (ACD) — Ferritin normal or elevated (acute phase reactant), low TIBC, low transferrin saturation; iron sequestered by hepcidin
- Thalassemia trait — Microcytosis disproportionate to mild anemia, normal RDW, Mentzer index <13 (MCV/RBC); hemoglobin electrophoresis abnormal in beta-thal
- Sideroblastic anemia — Microcytic or dimorphic; ringed sideroblasts on marrow iron stain; elevated ferritin and iron
- Lead poisoning — Basophilic stippling, occupational/environmental exposure, elevated blood lead level
- Combined deficiency (B12/folate + iron) — Normocytic MCV with wide RDW; both micro- and macrocytic populations on smear
Diagnostic workup
Diagnostic criteria
Microcytic anemia (Hb low, MCV <80 fL) plus ferritin <30 ng/mL OR transferrin saturation <20% with consistent clinical context.
Labs
- CBC with peripheral smear — microcytic (MCV <80), hypochromic, anisocytosis (elevated RDW), pencil cells, target cells
- Iron studies — low ferritin (<30 ng/mL diagnostic in most adults; <100 ng/mL may indicate deficiency in inflammation/CKD), low serum iron, elevated TIBC, transferrin saturation <20%
- Reticulocyte count — inappropriately low for degree of anemia
- Soluble transferrin receptor — elevated in IDA, normal in ACD (useful when ferritin uninterpretable)
- Stool occult blood; consider tissue transglutaminase IgA (celiac screen) in unexplained IDA
Imaging
- Upper and lower endoscopy in men and postmenopausal women with IDA, and in premenopausal women not responding to iron
- Capsule endoscopy if EGD/colonoscopy nondiagnostic and bleeding persists
Diagnostic algorithm
| Parameter | Iron Deficiency | Anemia of Chronic Disease | Thalassemia Trait |
|---|---|---|---|
| MCV | Low | Normal or low | Low (disproportionate) |
| RDW | High | Normal | Normal |
| Ferritin | Low (<30) | Normal or high | Normal or high |
| Serum iron | Low | Low | Normal or high |
| TIBC | High | Low | Normal |
| Transferrin saturation | Low (<20%) | Low | Normal or high |
| sTfR | High | Normal | Normal or high |
Treatment
First-line
- Identify and correct the underlying cause (most important step)
- Oral iron — ferrous sulfate 325 mg (65 mg elemental), ferrous gluconate, ferrous fumarate; one tablet every other day improves absorption and tolerability versus daily dosing
- Take on empty stomach with vitamin C (orange juice) to enhance absorption; avoid concurrent calcium, antacids, PPIs, coffee, tea
- Continue iron 3-6 months after hemoglobin normalizes to replete stores
Second-line / adjunct
- IV iron — ferric carboxymaltose, iron sucrose, ferumoxytol, low-molecular-weight iron dextran; indicated for intolerance to oral iron, malabsorption (celiac, IBD, post-bypass), CKD on dialysis, ongoing blood loss exceeding oral absorption, or need for rapid replenishment (late pregnancy)
- Transfusion reserved for hemodynamic instability, severe symptomatic anemia, or active hemorrhage
Complications
- High-output heart failure (severe chronic anemia)
- Impaired neurocognitive development in infants and young children
- Adverse pregnancy outcomes: preterm birth, low birth weight, postpartum depression
- Worsened outcomes in HF, CKD, and post-operative recovery
- Plummer-Vinson syndrome with risk of esophageal squamous cell carcinoma
PANCE pearls
- Reticulocytosis should be visible within 7-10 days of starting oral iron; hemoglobin rises ~1 g/dL every 2-3 weeks.
- Failure to respond to oral iron suggests ongoing loss, malabsorption, noncompliance, or wrong diagnosis (think thalassemia, ACD).
- IV iron does NOT require a test dose for newer formulations (ferric carboxymaltose, ferumoxytol); anaphylaxis risk is much lower than with older high-molecular-weight iron dextran.
- Ferritin is an acute phase reactant — can be falsely normal in inflammation, infection, malignancy, CKD. Use transferrin saturation and soluble transferrin receptor in these settings.
- Every-other-day dosing minimizes hepcidin-driven absorption blockade and improves total iron uptake compared to daily dosing.
References
- ASH 2020 — American Society of Hematology 2020 guidelines for management of iron deficiency anemia
- AGA 2020 — AGA Clinical Practice Guidelines on the Gastrointestinal Evaluation of Iron Deficiency Anemia (Ko et al., Gastroenterology 2020)
- WHO 2011 — WHO Hemoglobin concentrations for the diagnosis of anemia and assessment of severity
- Stoffel et al. — Iron absorption from oral iron supplements given on consecutive versus alternate days (Lancet Haematology 2017)
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