What is the first differential diagnosis for an elderly male with anemia, normal vitamin B12 levels, iron overload pattern, and mild thrombocytopenia, with a transferrin saturation greater than 40%?

Myelodysplastic Syndrome (MDS)

The first differential diagnosis for this elderly male with anemia, normal B12, iron overload pattern (transferrin saturation >40%), and mild thrombocytopenia is myelodysplastic syndrome (MDS).

Why MDS is the Primary Consideration

This clinical constellation—anemia with cytopenias, iron overload despite anemia, and elderly age—is pathognomonic for MDS. 1 The paradoxical iron overload in the setting of anemia occurs because MDS causes ineffective erythropoiesis, where blood cells die prematurely in the bone marrow rather than maturing properly, leading to both cytopenia and secondary iron accumulation 2, 3.

Key Diagnostic Features Present

• Elderly male: MDS is primarily a disease of the elderly, with median age around 70-80 years 1, 2, 4, 5
• Anemia with thrombocytopenia: Almost all MDS patients have blood cytopenias, most commonly anemia (usually macrocytic) with or without other cytopenias 1
• Iron overload pattern: Elevated transferrin saturation and ferritin are characteristic of MDS due to ineffective erythropoiesis and transfusion burden 1
• Normal B12: This excludes megaloblastic anemia, a key differential 1, 4

Critical Distinguishing Laboratory Pattern

The iron studies showing iron overload rather than iron deficiency are crucial here 1. In MDS, laboratory values typically show elevated ferritin and transferrin saturation because the bone marrow cannot effectively utilize iron for red cell production despite having adequate or excessive iron stores 1. This contrasts sharply with iron deficiency anemia, where transferrin saturation would be low 6.

Immediate Next Steps for Diagnosis

Proceed directly to bone marrow examination with cytomorphology, cytogenetics, and histology of bone marrow trephine biopsy [I, A]. 1 This is the definitive diagnostic approach and should not be delayed.

Essential Diagnostic Workup

1. Peripheral blood smear examination: Look for dysplastic features including:

   • Pseudo-Pelger-Huët anomaly (hyposegmented neutrophils) 1, 3
   • Hypogranular neutrophils 1, 3
   • Giant platelets 1, 3
   • Oval macrocytes or dacryocytes 3

2. Bone marrow aspiration and biopsy: Essential findings include 1:

   • Dysplastic features in ≥10% of cells in one or more lineages
   • Hypercellular marrow (though can be hypocellular)
   • Ring sideroblasts (perform Prussian blue stain) 1, 4
   • Blast percentage (crucial for prognosis)

3. Cytogenetic analysis of bone marrow cells [I, A]: Chromosomal abnormalities are present in many MDS cases and provide prognostic information 1

4. Molecular analysis by next-generation sequencing [I, A]: Particularly useful in cases with unspecific morphological changes and no cytogenetic abnormalities 1. SF3B1 mutations are common and associated with ring sideroblasts and better prognosis 4

Alternative Differentials to Exclude

While MDS is the primary consideration, these must be systematically excluded:

Secondary Causes of Cytopenia with Iron Overload

• Chronic liver disease with portal hypertension: Can cause thrombocytopenia and anemia, but the iron overload pattern and absence of other liver disease stigmata make this less likely 1
• Autoimmune disorders: Should be excluded through appropriate serologic testing 1
• Chronic infections: Less likely given the chronic stable course with ulcer healing 1

Genetic Iron Overload Disorders (Less Likely)

• Hereditary hemochromatosis: Would not typically present with anemia and thrombocytopenia; these patients have normal or elevated hemoglobin 1, 6
• Ferroportin disease: Causes iron overload but rarely presents with anemia (<10% of cases), and when present, anemia is mild and normocytic 1

Critical Clinical Pitfalls to Avoid

Do not initiate empiric iron supplementation. 7 The elevated transferrin saturation indicates iron overload, not deficiency. Adding iron would worsen the iron burden and potentially accelerate organ damage 1, 7.

Do not dismiss this as "anemia of chronic disease" from the ulcer alone. 1 While the healing ulcer may have contributed to anemia initially, the persistent cytopenia with iron overload pattern after ulcer healing points to a primary bone marrow disorder 1, 4.

Do not delay bone marrow examination. 1 Early diagnosis of MDS is critical for risk stratification using IPSS-R scoring and determining appropriate management, which ranges from supportive care to allogeneic stem cell transplantation depending on risk category 1.

Prognostic Considerations

If MDS is confirmed, prognosis depends on 1:

• Bone marrow blast percentage
• Number and severity of cytopenias
• Cytogenetic abnormalities (IPSS-R scoring)
• Molecular mutations (particularly SF3B1, which confers better prognosis) 4

The presence of only mild thrombocytopenia with anemia suggests potentially lower-risk disease, which is common in elderly patients presenting with isolated or dual cytopenias 4.