What is the differential diagnosis for a patient with chronic iron‑deficiency anemia, secondary thrombocytosis, and scattered tiny calcified granulomas in the liver and spleen?

Differential Diagnosis: Calcified Hepatosplenic Granulomas with Iron-Deficiency Anemia and Thrombocytosis

The most likely diagnosis is chronic iron-deficiency anemia causing secondary thrombocytosis, with the calcified granulomas representing a separate, likely remote infectious or inflammatory process. 1, 2

Primary Hematologic Differential

1. Iron-Deficiency Anemia with Reactive Thrombocytosis (Most Likely)

This constellation is the most common cause of combined anemia and thrombocytosis. 3, 4, 5

Key diagnostic features:

• Ferritin <30 ng/mL (or <100 ng/mL if inflammation present) confirms absolute iron deficiency 6, 1
• Transferrin saturation <16–20% indicates iron-restricted erythropoiesis 1, 2
• Platelet counts in iron deficiency typically reach 700×10³/µL but can exceed 1000–2500×10³/µL in severe cases 3, 4, 7
• Thrombocytosis resolves completely with iron repletion, distinguishing it from primary myeloproliferative disease 3, 4, 7

Mechanism: Iron deficiency stimulates thrombopoietin production and megakaryocyte proliferation, while simultaneously reducing erythropoiesis 5. The thrombocytosis is reactive, not clonal 3, 4.

Critical pitfall: Extreme thrombocytosis (>1000×10³/µL) can mimic essential thrombocythemia, but bone marrow evaluation will show normal megakaryocyte morphology without JAK2 mutation 3, 7.

2. Essential Thrombocythemia (ET) – Must Be Excluded

Diagnostic criteria require:

• Sustained platelet count ≥450×10⁹/L 6
• Bone marrow showing proliferation of enlarged, mature megakaryocytes with hyperlobulated nuclei 6
• JAK2V617F mutation or other clonal marker 6
• Exclusion of iron deficiency: Failure of iron replacement to normalize hemoglobin excludes PV; presence of iron deficiency does NOT exclude ET if other criteria are met 6

Key distinguishing features:

• In ET, iron deficiency may coexist but thrombocytosis persists after iron correction 6
• Bone marrow shows characteristic large, hyperlobulated megakaryocytes in loose clusters 6
• Splenomegaly is common in ET but also occurs in 80% of chronic hemolytic anemias 6

3. Adult-Onset Still's Disease (AOSD) – Consider if Systemic Symptoms Present

Diagnostic features:

• Anemia of chronic disease with reactive thrombocytosis occurs in virtually all active cases 6
• Ferritin levels are extremely elevated (4,000–250,000 ng/mL) and correlate with disease activity 6
• Hepatomegaly and liver dysfunction occur in 50–75% of patients 6
• Granulomas are NOT a typical feature of AOSD 6

This diagnosis is unlikely unless the patient has:

• Spiking fevers (100% of cases) 6
• Salmon-pink evanescent rash (51–94% of cases) 6
• Sore throat (38–92% of cases) 6
• Polyarthritis, particularly involving wrists with pericapitate narrowing 6

Differential for Calcified Hepatosplenic Granulomas

The granulomas represent a separate pathologic process, most likely remote infection:

Infectious Etiologies (Most Common)

• Histoplasmosis (most common cause of calcified hepatosplenic granulomas in endemic areas)
• Tuberculosis (second most common)
• Brucellosis
• Q fever (Coxiella burnetii)
• Schistosomiasis (if travel history to endemic regions)

Non-Infectious Etiologies

• Sarcoidosis (granulomas typically non-calcified acutely, but can calcify over years)
• Chronic granulomatous disease (primary immunodeficiency)

Key point: Calcified granulomas indicate remote, healed infection rather than active disease [@general medical knowledge]. Active granulomatous disease would present with systemic symptoms and non-calcified lesions.

Diagnostic Algorithm

Step 1: Confirm Iron-Deficiency Anemia

• Measure serum ferritin, transferrin saturation, complete iron panel [@6@, 2]
• Check inflammatory markers (CRP, ESR) to interpret ferritin correctly [@2@, 1]
• If ferritin <15 µg/L: absolute iron deficiency confirmed (99% specificity) [@6@, 2]
• If ferritin 30–100 µg/L with elevated CRP: mixed iron deficiency and anemia of chronic disease [@2@, 1]

Step 2: Investigate Source of Iron Loss

• In men and postmenopausal women: Bidirectional endoscopy is mandatory to exclude GI malignancy [@2@, @7@]
• In premenopausal women: Assess menstrual blood loss; reserve endoscopy for age ≥50, GI symptoms, or treatment failure [@7@]
• Screen for celiac disease (tissue transglutaminase antibodies): present in 3–5% of iron-deficiency cases 2
• Test for Helicobacter pylori (stool antigen or urea-breath test) [@7@]

Step 3: Exclude Primary Myeloproliferative Disease

• If platelets >1000×10³/µL or thrombocytosis persists after iron correction:
  • Bone marrow biopsy with cytogenetics [@3@]
  • JAK2V617F mutation testing 6
  • Exclude BCR-ABL (chronic myeloid leukemia) [@3@]
  • Exclude del(5q), t(3;3), inv(3) (myelodysplastic syndrome) [@3@]

Step 4: Evaluate Calcified Granulomas

• If asymptomatic with calcified lesions: Likely remote healed infection; no acute intervention needed
• Obtain travel and exposure history for endemic fungal infections (histoplasmosis, coccidioidomycosis)
• If systemic symptoms present (fever, weight loss, night sweats):
  • Chest X-ray or CT to assess for active tuberculosis or sarcoidosis
  • Tuberculin skin test or interferon-gamma release assay
  • Serum ACE level if sarcoidosis suspected
  • Fungal serologies (histoplasma, coccidioides) if endemic exposure

Treatment Approach

Immediate Management

• Initiate oral iron supplementation immediately: Ferrous sulfate 65 mg elemental iron daily (or alternate-day dosing to improve absorption) [@7@]
• Expected response: Hemoglobin should rise ≥10 g/L within 2 weeks; platelets normalize within 4–8 weeks after iron correction [@9@, 4, @12@]

Indications for IV Iron

• Oral intolerance, malabsorption (celiac disease, IBD, post-bariatric surgery), ongoing blood loss exceeding oral replacement, or chronic inflammatory conditions [@6@, 2]
• Ferric carboxymaltose 15 mg/kg (max 1000 mg per dose) produces reticulocytosis within 3–5 days 1

Monitoring

• Recheck CBC, ferritin, and platelet count at 8–10 weeks [@7@]
• Target ferritin >100 ng/mL to fully replenish stores [@6@, 2]
• If thrombocytosis persists after iron correction: Proceed to bone marrow biopsy to exclude ET [@3@, @9@]

Critical Pitfalls to Avoid

• Do not assume extreme thrombocytosis (>1000×10³/µL) is always primary myeloproliferative disease: Iron deficiency can cause platelet counts up to 2500×10³/µL [@9@, 4, @12@]
• Do not overlook celiac disease: Present in 3–5% of iron-deficiency cases and causes treatment failure if missed 2
• Do not attribute calcified granulomas to active systemic disease without supporting clinical evidence: Calcification indicates remote, healed infection [@general medical knowledge]
• Do not delay GI investigation in men or postmenopausal women: Iron deficiency may be the sole manifestation of GI malignancy 6, 2
• Do not confuse anemia of chronic disease with iron deficiency: Check CRP/ESR and interpret ferritin thresholds accordingly (ferritin <100 µg/L can still indicate deficiency in inflammation) 6, 1