What are the possible causes and recommended evaluation for isolated macrocytosis (mean corpuscular volume 103.9 fL) with normal hemoglobin (13.7 g/dL) and low mean corpuscular hemoglobin concentration in this patient?

Evaluation of Isolated Macrocytosis with Normal Hemoglobin

This patient has isolated macrocytosis (MCV 103.9 fL) with normal hemoglobin and low MCHC, which most commonly indicates alcohol use, medication effect, or early vitamin B12 deficiency—even though frank anemia has not yet developed. 1

Immediate Diagnostic Workup

Order the following tests to identify the underlying cause:

• Reticulocyte count to distinguish between impaired red cell production (low/normal count) versus increased turnover from hemolysis or recent blood loss (elevated count) 1, 2
• Vitamin B12 and folate levels to exclude megaloblastic causes, as 20.9% of B12-deficient patients present with isolated macrocytosis without anemia 1, 3
• Thyroid-stimulating hormone (TSH) to screen for hypothyroidism, a common non-megaloblastic cause 1, 4
• Liver function tests to assess for chronic liver disease or alcohol-related hepatotoxicity 1, 3
• Peripheral blood smear to look for hypersegmented neutrophils (present in 86% of megaloblastic cases) and macro-ovalocytes (present in 72% of megaloblastic cases) 3

Interpretation Based on Reticulocyte Count

If Reticulocyte Count is Low or Normal (RI ≤ 2)

This pattern indicates impaired erythropoiesis and directs evaluation toward:

• Vitamin B12 or folate deficiency (24.1% of macrocytosis cases), which characteristically presents with macrocytosis and low reticulocyte count 1, 3
• Medication effects (12.9% of cases), particularly thiopurines, methotrexate, anticonvulsants, or chemotherapy agents 1, 3
• Hypothyroidism or chronic liver disease, both of which produce homogeneous macrocytosis 1, 4
• Bone marrow failure syndromes or myelodysplastic syndrome, especially if MCV exceeds 114 fL or if pancytopenia develops 5

If Reticulocyte Count is Elevated (RI > 2-3)

This pattern suggests increased red cell production and requires evaluation for:

• Hemolysis, confirmed by low haptoglobin, elevated LDH, elevated indirect bilirubin, and peripheral smear examination for schistocytes 1, 2
• Recent or occult blood loss, which stimulates reticulocyte release (reticulocytes are larger cells that elevate MCV) 4, 6

Clinical History Priorities

Obtain a focused history addressing:

• Alcohol consumption, as alcoholism accounts for 36.5% of macrocytosis cases and can produce MCV values up to 114 fL 3, 5
• Current medications, focusing on thiopurines, chemotherapy, anticonvulsants, and methotrexate 1, 3
• Gastrointestinal symptoms (diarrhea, malabsorption, prior gastric surgery) that increase risk for B12 deficiency 1
• Symptoms of hypothyroidism (fatigue, cold intolerance, weight gain) 1

Significance of Low MCHC (30.2 g/dL)

The low MCHC in this patient suggests:

• Possible coexisting iron deficiency, which can mask the degree of macrocytosis by producing a mixed population of microcytic and macrocytic cells 1
• Order iron studies (serum ferritin, transferrin saturation) to exclude concurrent iron deficiency, as mixed deficiencies can neutralize the MCV but produce an elevated RDW 1, 2

MCV-Based Risk Stratification

The degree of MCV elevation helps narrow the differential diagnosis:

• MCV 100-114 fL (this patient): Most commonly caused by alcohol/liver disease, early B12 deficiency, medications, hypothyroidism, or chronic renal failure 5
• MCV 114-130 fL: Suggests bone marrow failure, myeloid malignancy, or hemolytic anemia 5
• MCV >130 fL: Highly specific for megaloblastic anemia (B12/folate deficiency) or certain medications 5

Common Pitfalls to Avoid

• Do not dismiss macrocytosis because hemoglobin is normal—isolated macrocytosis may be the first clue to vitamin deficiency, preleukemia, or alcoholism, and 20.9% of B12-deficient patients present without anemia 3, 6
• Do not assume normal B12 levels exclude functional B12 deficiency—if clinical suspicion remains high, measure methylmalonic acid and homocysteine, as 63.3% of macrocytosis patients have elevated homocysteine 1, 7
• Do not overlook medication review—drug-induced macrocytosis accounts for 12.9% of cases and is often reversible 3
• Do not interpret a "normal" reticulocyte count as reassuring—it may represent an inappropriately low marrow response in the setting of macrocytosis 2

When to Refer to Hematology

Refer for bone marrow examination if:

• Pancytopenia develops alongside macrocytosis 1
• MCV exceeds 114 fL without an obvious cause 5
• Initial workup (B12, folate, TSH, liver function, alcohol history, medication review) is nondiagnostic 1
• Peripheral smear shows dysplastic features suggestive of myelodysplastic syndrome 5