What is the most likely cause and appropriate work‑up for a patient with low hemoglobin, elevated mean corpuscular volume, and low red‑cell distribution width?

Macrocytic Anemia with Low RDW: Diagnostic Approach

The combination of low hemoglobin, elevated MCV, and low RDW most strongly suggests a homogeneous macrocytic process, with vitamin B12 or folate deficiency being the primary consideration, though medication effects (particularly thiopurines), hypothyroidism, liver disease, and aplastic anemia must also be evaluated.

Understanding the Laboratory Pattern

The specific combination of findings provides critical diagnostic clues:

• Elevated MCV with LOW RDW indicates a uniform population of large red cells, distinguishing this from iron deficiency (which causes high RDW) or mixed deficiencies (which also elevate RDW) 1, 2
• Low RDW (<14%) suggests all red cells are similarly enlarged, pointing toward a single underlying process rather than multiple concurrent deficiencies 2
• This pattern contrasts sharply with iron deficiency anemia, where elevated RDW (>14%) is characteristic and often appears before MCV changes 1, 3, 4

Most Likely Causes

Primary Considerations

Vitamin B12 or Folate Deficiency:

• Macrocytosis with normal or low reticulocyte count is the hallmark of megaloblastic anemia 1, 5
• However, 31-35% of patients with untreated pernicious anemia can have normal RDW, particularly in early deficiency stages 6
• Some patients with B12 deficiency may even have normal MCV initially, making this diagnosis challenging 6

Medication-Induced Macrocytosis:

• Thiopurine therapy (azathioprine, 6-mercaptopurine) commonly causes macrocytosis with homogeneous red cell populations 1
• This is particularly relevant in inflammatory bowel disease patients 1

Aplastic Anemia:

• Non-severe aplastic anemia presents with macrocytic anemia in 58% of cases, often with elevated RDW (64%), though some patients have normal RDW 7
• Severe aplastic anemia typically shows normocytic anemia (only 8.5% macrocytic) 7

Secondary Considerations

• Hypothyroidism causes non-megaloblastic macrocytosis with homogeneous red cells 5
• Liver disease produces macrocytosis without anisocytosis 5
• Alcohol excess creates uniform macrocytosis 5

Essential Diagnostic Workup

Immediate Laboratory Tests

First-Line Studies:

• Reticulocyte count - Low/normal indicates impaired erythropoiesis (vitamin deficiency, bone marrow failure); elevated suggests hemolysis or blood regeneration 1, 8, 5
• Vitamin B12 and folate levels - Essential to identify megaloblastic anemia 1, 8
• Peripheral blood smear - Look for hypersegmented neutrophils (megaloblastic anemia), oval macrocytes, or pancytopenia patterns 1
• Thyroid-stimulating hormone (TSH) - Screen for hypothyroidism 5
• Liver function tests - Evaluate for chronic liver disease 5

Additional Studies Based on Initial Results:

• If reticulocytes are elevated: Measure haptoglobin, LDH, and indirect bilirubin to evaluate for hemolysis 1, 8
• If pancytopenia is present: Consider bone marrow examination for aplastic anemia or myelodysplastic syndrome 7
• Serum ferritin and transferrin saturation - To exclude coexisting iron deficiency, which can mask macrocytosis and normalize MCV 1, 4

Clinical History Priorities

• Medication review: Document thiopurine use, chemotherapy agents, anticonvulsants, and methotrexate 1
• Alcohol consumption history 5
• Gastrointestinal symptoms: Diarrhea, malabsorption, or history of gastric surgery (B12 deficiency risk) 1
• Neurological symptoms: Paresthesias, ataxia, cognitive changes (B12 deficiency) 8
• Dietary assessment: Strict vegan diet (B12 deficiency risk) 5

Critical Pitfalls to Avoid

Coexisting Deficiencies:

• Microcytosis and macrocytosis can neutralize each other, resulting in normal MCV but elevated RDW 1, 4
• In this scenario with LOW RDW, a mixed picture is less likely, but iron studies should still be obtained 1
• If ferritin is <30 μg/L (or <100 μg/L with inflammation), iron deficiency coexists and may be masking more severe macrocytosis 1, 3

Folate Supplementation Risk:

• High-dose folic acid can mask B12 deficiency symptoms while allowing neurological damage to progress 8
• Always measure both B12 and folate before initiating treatment 8

Normal RDW Does Not Exclude B12 Deficiency:

• Up to one-third of pernicious anemia patients have normal RDW, especially in early stages 6
• Do not rely solely on RDW to exclude vitamin deficiency 6

Algorithmic Approach

1. Obtain reticulocyte count immediately - This determines the next step 1, 8

2. If reticulocyte count is LOW or NORMAL:

   • Measure vitamin B12 and folate levels 1, 8
   • Check TSH and liver function tests 5
   • Review medication list for causative agents 1
   • If pancytopenia present, consider hematology referral for bone marrow evaluation 7

3. If reticulocyte count is ELEVATED:

   • Evaluate for hemolysis: haptoglobin, LDH, indirect bilirubin, peripheral smear 1, 8
   • Consider recent blood loss or regeneration after treatment 5

4. Obtain iron studies regardless of pathway to exclude masked iron deficiency 1, 4

5. If all initial tests are unrevealing, consult hematology for consideration of bone marrow examination or hemoglobin electrophoresis 1, 8