What is the appropriate management for a patient with severe anemia, macrocytosis, high serum iron, high serum ferritin, and high transferrin saturation, with normal vitamin B12 and folic acid levels?

Severe Macrocytic Anemia with Iron Overload: Myelodysplastic Syndrome Until Proven Otherwise

This patient requires urgent bone marrow examination to evaluate for myelodysplastic syndrome (MDS), as the combination of severe macrocytic anemia (Hb 6.8 g/dL, MCV 102 fL) with elevated iron parameters (high serum iron, ferritin, and transferrin saturation) despite normal B12 and folate strongly suggests a primary bone marrow disorder rather than nutritional deficiency. 1

Diagnostic Reasoning

Why This Is Likely MDS

• Macrocytic anemia with normal B12/folate is a hallmark of MDS, which typically presents as normochromic or macrocytic anemia with cytopenias 1
• The iron overload pattern (elevated ferritin, iron, and transferrin saturation) indicates ineffective erythropoiesis, where the bone marrow cannot properly utilize available iron—a characteristic feature of MDS 1
• The severity of anemia (Hb 6.8 g/dL) with this laboratory pattern makes nutritional causes highly unlikely 2, 3

Critical Next Steps

Immediate bone marrow evaluation is mandatory and should include: 1

• Bone marrow aspirate and trephine biopsy to assess cellularity and dysplasia
• Cytomorphology examining at least 500 cells to identify dysplastic features in ≥10% of cells 1
• Cytogenetics (karyotype analysis) for prognostic stratification 1
• Flow cytometry to demonstrate clonality in difficult cases 1
• Prussian blue (Perls) stain to evaluate for ring sideroblasts 1

Differential Diagnosis to Exclude

Other Causes to Rule Out

Before confirming MDS, systematically exclude: 1, 2

• Medication-induced macrocytosis: Review for hydroxyurea, methotrexate, azathioprine, or other immunosuppressants 2, 3
• Hypothyroidism: Order TSH and free T4, as thyroid dysfunction can cause macrocytic anemia with elevated ferritin 4, 5
• Hemolysis: Check reticulocyte count, haptoglobin, LDH, and indirect bilirubin 4
  • If reticulocyte count is elevated, consider hemolysis or recent hemorrhage 2, 4
  • If reticulocyte count is low/normal with macrocytosis, this supports MDS or other production defects 2
• Chronic kidney disease: Evaluate creatinine and GFR, though CKD typically causes normocytic anemia 1
• Alcohol use: Obtain detailed history, as chronic alcohol can cause macrocytosis with elevated ferritin 2

Why B12/Folate Deficiency Is Unlikely Here

• Normal B12 and folate levels effectively exclude megaloblastic anemia as the primary cause 2, 3
• The iron overload pattern contradicts nutritional deficiency, which typically shows low or normal iron stores 6
• However, if clinical suspicion remains high despite normal B12, consider methylmalonic acid and homocysteine levels to exclude functional B12 deficiency 4

Management Algorithm

Immediate Management (While Awaiting Bone Marrow Results)

Transfusion support: 3

• RBC transfusion is indicated for Hb 6.8 g/dL with symptomatic anemia 3
• Use leukoreduced blood products (standard of care for suspected MDS) 3
• If patient is CMV-negative and potentially a transplant candidate, use CMV-negative and irradiated products 3

Iron chelation consideration: 1

• With elevated iron parameters and anticipated transfusion dependence, monitor for iron overload
• Ferritin and LDH have prognostic value in MDS 1

Post-Diagnosis Management

If MDS is confirmed: 1, 3

For higher-risk MDS (based on IPSS-R scoring): 1, 3

• Azacitidine is the preferred treatment (Category 1 recommendation) or decitabine for patients not candidates for intensive therapy 3
• Consider allogeneic stem cell transplantation for eligible patients 1

For lower-risk MDS with symptomatic anemia: 3

• Erythropoiesis-stimulating agents (ESAs) may be considered based on EPO levels 1
• Continue RBC transfusion support as needed 3

Prognostic stratification: 1

• Classify according to WHO criteria 1
• Apply IPSS-R scoring (based on blast percentage, cytogenetics, and cytopenias) 1

Critical Pitfalls to Avoid

Do not delay bone marrow examination while pursuing additional nutritional workup—the clinical picture strongly suggests MDS 1

Do not assume normal B12/folate excludes all nutritional causes without considering coexisting deficiencies, but in this case, the iron overload pattern makes nutritional deficiency the primary cause extremely unlikely 4

Do not miss medication-induced causes, which are potentially reversible—thoroughly review all medications 2, 3

Do not overlook the possibility of multiple concurrent pathologies (e.g., MDS with coexisting hypothyroidism or medication effects) 4

Monitor for progression: Even if initial bone marrow shows ICUS (idiopathic cytopenias of uncertain significance) or IDUS (idiopathic dysplasia of unknown significance), close follow-up is essential as these can progress to overt MDS 1