What is the most likely diagnosis and appropriate work‑up for a patient with microcytic anemia (low MCV), marked thrombocytosis (platelet count 935 × 10⁹/L), and elevated alanine aminotransferase (ALT 220 U/L)?

Diagnostic Approach to Microcytic Anemia with Thrombocytosis and Elevated Transaminases

This patient most likely has iron-deficiency anemia causing reactive thrombocytosis, with the elevated ALT suggesting either concurrent liver pathology or a systemic inflammatory process that requires urgent investigation for gastrointestinal blood loss.

Most Likely Diagnosis

Iron-deficiency anemia is the primary diagnosis, supported by the combination of:

• Microcytosis (low MCV) with marked thrombocytosis (935 × 10⁹/L) strongly indicates iron deficiency, as thrombocytosis peaks in the third week of iron deficiency and serves as a reactive marker that favors iron deficiency over anemia of chronic disease 1
• Platelet counts between 450–1000 × 10⁹/L are characteristic of secondary (reactive) thrombocytosis, most commonly caused by iron deficiency, active malignancy, chronic inflammatory disease, or recent splenectomy 2
• The elevated ALT (220 U/L) requires investigation but does not exclude iron deficiency; it may represent concurrent hepatic pathology, NSAID-induced liver injury, or systemic inflammation 3

Immediate Laboratory Work-Up

Order these tests immediately to confirm iron deficiency and assess for inflammation:

• Serum ferritin is the single most powerful test for iron deficiency: ferritin <30 μg/L confirms iron deficiency in the absence of inflammation, while ferritin <45 μg/L provides optimal sensitivity and specificity in clinical practice 1, 4
• Transferrin saturation (TSAT) should be calculated (serum iron ÷ total iron-binding capacity × 100), as TSAT <16–20% confirms iron-deficient erythropoiesis even when ferritin appears falsely normal due to inflammation 1, 4
• C-reactive protein (CRP) must be measured concurrently because ferritin is an acute-phase reactant that can be falsely elevated by inflammation, infection, malignancy, or hepatic disease; in inflammatory states, ferritin up to 100 μg/L may still indicate iron deficiency 1, 4
• Red cell distribution width (RDW) should be reviewed: RDW >14% with low MCV has 91.4% accuracy for iron-deficiency anemia, whereas RDW ≤14% suggests thalassemia minor 1, 4
• Complete hepatic panel including AST, alkaline phosphatase, bilirubin, albumin, and prothrombin time to characterize the liver enzyme elevation 3
• Reticulocyte count is typically low in iron deficiency, reflecting inadequate bone marrow response 1

Investigation of Underlying Cause

Once iron deficiency is confirmed, mandatory investigation for the source of blood loss must proceed immediately:

Gastrointestinal Evaluation

• Adult men 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, 4
• Upper endoscopy with duodenal biopsies screens for celiac disease (present in 2–3% of iron-deficiency cases), gastric cancer, peptic ulcer disease, and NSAID-induced gastropathy 1, 4
• Colonoscopy detects colonic carcinoma, adenomatous polyps, angiodysplasia, and inflammatory bowel disease as potential bleeding sources 1, 4
• The probability of serious gastrointestinal pathology rises with greater anemia severity, supporting endoscopic evaluation at any anemia grade when iron deficiency is confirmed 1

Hepatic Investigation

• The elevated ALT (220 U/L) requires evaluation for alcoholic liver disease, non-alcoholic fatty liver disease, viral hepatitis, drug-induced liver injury (particularly NSAIDs), or hemochromatosis 3
• In alcoholic hepatitis, AST is typically elevated 2–6 times the upper limit of normal, with AST/ALT ratio >2 in 70% of cases; however, ALT >200 U/L is uncommon in alcoholic hepatitis alone and suggests another etiology 3
• Right upper quadrant ultrasound should be performed to assess liver parenchyma, exclude biliary obstruction, and evaluate for hepatic masses 3

Additional Considerations

• Document NSAID and aspirin use, as these medications cause occult gastrointestinal bleeding and can elevate transaminases 4
• In premenopausal women, assess menstrual blood loss, but do not exclude gastrointestinal pathology without endoscopic evaluation 4
• Screen for celiac disease serologically (tissue transglutaminase IgA with total IgA) before endoscopy, as celiac disease accounts for 2–3% of iron-deficiency cases 1

Immediate Treatment Protocol

Begin oral iron supplementation immediately while diagnostic work-up proceeds:

• Ferrous sulfate 325 mg (65 mg elemental iron) three times daily for at least 3 months after hemoglobin normalizes to replenish iron stores 1, 4
• Add ascorbic acid (vitamin C) 250 mg with each iron dose to enhance absorption 1, 5
• Hemoglobin should rise ≥10 g/L (≥1 g/dL) within 2 weeks, confirming iron deficiency even when initial iron studies are equivocal 1, 4
• If no response within 2–4 weeks, consider non-compliance, ongoing blood loss (most common), malabsorption, or rare genetic disorders 1, 4
• Switch to intravenous iron (iron sucrose or ferric carboxymaltose) if malabsorption is documented or oral iron fails, with expected hemoglobin increase of ≥2 g/dL within 4 weeks 1, 5

Differential Diagnosis to Exclude

Do not assume all microcytic anemia with thrombocytosis is iron deficiency:

• Anemia of chronic disease presents with ferritin >100 μg/L, TSAT <20%, and elevated inflammatory markers; thrombocytosis is uncommon 1, 6
• Thalassemia trait shows RDW ≤14%, normal or elevated ferritin, and MCV disproportionately low relative to hemoglobin; order hemoglobin electrophoresis if iron studies are normal 1, 6
• Sideroblastic anemia presents with high ferritin, high transferrin saturation, and failure to respond to oral iron; bone marrow examination for ring sideroblasts confirms diagnosis 1
• Essential thrombocythemia is unlikely given the microcytosis, but molecular testing (JAK2, CALR, MPL mutations) should be considered if thrombocytosis persists after iron repletion 2

Critical Pitfalls to Avoid

• Do not attribute iron-deficiency anemia in adults solely to dietary insufficiency; occult gastrointestinal blood loss, especially from malignancy, must be excluded 1
• Do not rely on ferritin alone when inflammation or liver disease is present; calculate TSAT and measure CRP to identify functional iron deficiency 1, 4
• Do not postpone gastrointestinal investigation to "optimize" the patient with iron therapy alone; the bleeding source must be identified promptly 1
• Do not overlook combined micronutrient deficiencies; iron deficiency may coexist with vitamin B12 or folate deficiency, suggested by elevated RDW 1
• Do not assume thrombocytosis is primary (essential thrombocythemia) without first excluding and treating iron deficiency, as reactive thrombocytosis resolves with iron repletion 2