In an adult patient with red blood cell (RBC) morphology showing anisocytosis, poikilocytosis, and hypochromia, what is the most likely diagnosis and what work‑up and treatment should be pursued?

Diagnostic Approach to Anisocytosis, Poikilocytosis, and Hypochromia

Iron deficiency anemia is the most likely diagnosis in an adult patient presenting with RBC morphology showing anisocytosis, poikilocytosis, and hypochromia, and immediate workup should include serum ferritin, transferrin saturation, and investigation for the source of iron loss. 1

Initial Laboratory Confirmation

The diagnostic priority is to confirm iron deficiency with specific laboratory tests:

• Serum ferritin is the single most powerful test for confirming iron deficiency, with levels <15 μg/L indicating absent iron stores (99% specificity), <30 μg/L indicating low stores, and a cutoff of 45 μg/L providing optimal sensitivity and specificity in routine practice. 1, 2

• Transferrin saturation <16-20% confirms iron deficiency, particularly when ferritin may be falsely elevated by inflammation, malignancy, or hepatic disease. 1

• C-reactive protein should be measured concurrently because ferritin is an acute-phase reactant that can be falsely elevated in inflammatory conditions; in the presence of inflammation, ferritin up to 100 μg/L may still represent iron deficiency. 1

• Mean corpuscular hemoglobin (MCH) is more reliable than MCV for detecting iron deficiency because it is less affected by specimen storage conditions and is reduced in both absolute and functional iron deficiency. 1, 2

• The combination of low MCV with elevated RDW (>14.0%) strongly suggests iron deficiency, while low MCV with RDW ≤14.0% suggests thalassemia minor. 1

Differential Diagnosis Considerations

While iron deficiency is most common, other causes must be excluded:

• Anemia of chronic disease presents with ferritin >100 μg/L, transferrin saturation <20%, and elevated inflammatory markers. 1

• Thalassemia trait should be considered if iron studies are normal or near-normal, particularly with extreme microcytosis (MCV <70 fL) or appropriate ethnic background; hemoglobin electrophoresis is diagnostic. 1

• Pyruvate kinase deficiency typically shows unremarkable RBC morphology with only mild anisocytosis and poikilocytosis, making it less likely when hypochromia is prominent. 3

• Sideroblastic anemia may present with microcytic hypochromic cells but is much rarer; X-linked sideroblastic anemia (ALAS2 defects) may respond to pyridoxine 50-200 mg daily. 1

Mandatory Investigation for Source of Iron Loss

Once iron deficiency is confirmed, investigating the source of blood loss takes priority over simply treating with iron supplementation:

• Adult males with hemoglobin <110 g/L and non-menstruating women with hemoglobin <100 g/L warrant fast-track gastrointestinal referral for both upper endoscopy with duodenal biopsies and colonoscopy. 1

• Upper endoscopy with duodenal biopsies is mandatory to exclude celiac disease (present in 2-3% of iron deficiency cases), gastric malignancy, NSAID-induced gastropathy, and peptic ulcer disease. 1

• Colonoscopy is high-yield in adults for detecting colonic carcinoma, adenomatous polyps, angiodysplasia, and inflammatory bowel disease. 1

• In premenopausal women, heavy menstrual bleeding is the most common cause, but gastrointestinal evaluation should still be considered if menstrual loss does not fully account for the severity of anemia. 1

Treatment Algorithm

First-line treatment is oral iron supplementation with ferrous sulfate 200 mg three times daily:

• Oral ferrous sulfate 200 mg three times daily should be administered for at least 2-4 weeks initially, with continuation for 3 months total after correction of anemia to replenish iron stores. 1, 2

• A hemoglobin rise ≥10 g/L within 2 weeks confirms iron deficiency, even when iron studies are equivocal, and justifies continuing therapy. 1, 2

• Alternative oral formulations (ferrous gluconate or ferrous fumarate) can be tried if ferrous sulfate is not tolerated; ascorbic acid can be added to enhance absorption. 1

• Intravenous iron (iron sucrose or iron gluconate) should be considered if there is malabsorption, ongoing losses exceeding oral replacement capacity, or true intolerance to oral iron, with expected hemoglobin increase of at least 2 g/dL within 4 weeks. 1, 4

Monitoring and Follow-Up

• Hemoglobin, MCV, and MCH should be checked after 2-4 weeks to assess response to therapy. 2

• Monitor hemoglobin and red cell indices at three-monthly intervals for one year, then after a further year, providing additional oral iron if hemoglobin or MCV falls below normal. 1

• Serum ferritin and transferrin saturation should be monitored to assess iron store repletion and detect potential iron overload in patients receiving multiple transfusions or long-term therapy. 1

Critical Pitfalls to Avoid

• Do not attribute iron deficiency in adults solely to dietary inadequacy—occult gastrointestinal blood loss, especially from malignancy, must be excluded. 1

• Do not rely on ferritin alone in inflammatory states—add transferrin saturation to accurately diagnose iron deficiency when inflammation is present. 1

• Do not accept upper GI findings (esophagitis, erosions, peptic ulcer) as the sole cause without also examining the lower GI tract, because dual pathology is present in approximately 10-15% of patients. 1

• Do not overlook combined deficiencies—iron deficiency may coexist with vitamin B12 or folate deficiency, suggested by an elevated RDW. 1

• Do not assume all microcytic anemia is iron deficiency—anemia of chronic disease, thalassemia, and sideroblastic anemia require different management. 1