What are the differential diagnoses and recommended work‑up for a patient with low hemoglobin, markedly increased mean corpuscular volume, elevated red‑cell distribution width, and an inappropriately low absolute reticulocyte count?

Macrocytic Anemia with Low Reticulocyte Count: Diagnostic Approach

This presentation of low hemoglobin with high MCV, elevated RDW, and inappropriately low absolute reticulocyte count most strongly suggests vitamin B12 or folate deficiency as the primary diagnosis, and your immediate workup must include serum B12, folate (both serum and RBC), and methylmalonic acid levels. 1

Key Differential Diagnoses

The combination of macrocytosis with a low/normal reticulocyte count indicates a hypoproliferative bone marrow disorder rather than hemolysis or hemorrhage (which would elevate reticulocytes). 1, 2 The elevated RDW suggests heterogeneous red cell populations, which can indicate:

Primary Considerations:

• Vitamin B12 deficiency (defined as <150 pmol/L or <203 ng/L) - the most common megaloblastic cause 1
• Folate deficiency (serum folate <10 nmol/L or RBC folate <305 nmol/L) - another common megaloblastic cause 1
• Myelodysplastic syndrome (MDS) - particularly if other cell lines are affected 1, 3
• Medication-induced macrocytosis - hydroxyurea, methotrexate, azathioprine, antiretrovirals 1, 4
• Hypothyroidism - check TSH and free T4 1
• Chronic alcohol use - impairs B12 absorption and directly causes macrocytosis 1, 4

Less Common Causes:

• Aplastic anemia - though typically presents with normocytic anemia in severe cases, NSAA can show macrocytosis in 58% of patients 3
• Pure red cell aplasia 1
• Bone marrow infiltration by malignancy 1

Immediate Diagnostic Workup

Order these tests immediately to establish the diagnosis:

• Serum vitamin B12 level - if borderline (150-200 pmol/L), add methylmalonic acid (>271 nmol/L confirms deficiency) 1
• Serum folate AND RBC folate - both are necessary as serum folate alone can be misleading 1
• Complete blood count with differential - assess for pancytopenia suggesting MDS or aplastic anemia 5
• Peripheral blood smear - look for hypersegmented neutrophils (megaloblastic), dysplastic features (MDS), or other abnormalities 1
• TSH and free T4 - exclude hypothyroidism 1
• Liver function tests - assess for liver disease contributing to macrocytosis 2
• Creatinine and inflammatory markers (CRP) - CKD and inflammation can cause anemia 5, 1

Critical Caveat About Iron Status:

The elevated RDW is particularly important because it can indicate coexisting iron deficiency even when MCV is elevated - microcytosis and macrocytosis can mask each other, resulting in a falsely normal or only slightly elevated MCV. 1 Therefore:

• Check ferritin and transferrin saturation - but remember that ferritin is an acute-phase reactant and can be falsely elevated in inflammation (up to 100 μg/L may still indicate iron deficiency when inflammation is present) 1
• In inflammatory conditions, transferrin saturation <20% is more reliable than ferritin alone 5

Treatment Algorithm

CRITICAL: Always treat vitamin B12 deficiency BEFORE initiating folate supplementation to prevent precipitating or worsening subacute combined degeneration of the spinal cord. 1, 6 This is a non-negotiable principle.

If Vitamin B12 Deficiency Confirmed:

• Without neurological symptoms: Cyanocobalamin 1 mg IM three times weekly for 2 weeks, then 1 mg every 2-3 months for life 1
• With neurological symptoms: Hydroxocobalamin 1 mg IM on alternate days until no further improvement, then 1 mg every 2 months 1
• Monitor response: Expect reticulocyte count to increase within 5-7 days; if not, reassess diagnosis 6

If Folate Deficiency Confirmed (after excluding B12 deficiency):

• Oral folic acid 5 mg daily for minimum 4 months 1
• Note: Doses >0.1 mg/day can produce hematologic remission in B12 deficiency while allowing irreversible neurologic damage to progress 6

If No Vitamin Deficiency Found:

• Consider bone marrow biopsy with cytogenetics to evaluate for MDS, especially if pancytopenia or other cytopenias are present 1
• Refer to hematology if diagnosis remains unclear after initial workup or if MDS is suspected 1

Monitoring Response to Treatment

• Hemoglobin should increase by ≥2 g/dL within 4 weeks of appropriate treatment 1
• Reticulocyte count should increase (at least twice normal) within 5-7 days and remain elevated until hematocrit normalizes 6
• If reticulocytes fail to increase appropriately, reassess the diagnosis and consider complicating factors (concurrent iron deficiency, inflammation, unrecognized MDS) 6

Common Pitfalls to Avoid

• Do not assume CKD-related anemia is the cause - while CKD causes anemia, it typically produces normocytic-normochromic anemia, not macrocytic 5
• Do not miss coexisting iron deficiency - the elevated RDW is your clue that mixed deficiency may be present 1
• Do not give folate before excluding B12 deficiency - this can mask anemia while allowing irreversible spinal cord damage 1, 6
• Do not overlook medication review - many common drugs cause macrocytosis 1, 2
• Do not forget to screen for gastric cancer in confirmed pernicious anemia - 3-fold increased risk 6