EVIDENCE-BASED ANSWER
Start with a detailed history, paying particular attention to medications and alcohol use (strength of recommendation [SOR]: B, prospective cohort studies). Blood testing can include a peripheral smear, evaluation for vitamin deficiencies (especially B12 deficiency), and liver function tests (SOR: B, inconsistent prospective cohort studies). Thyroid testing may be useful for older patients (SOR: B, prospective study). Reticulocyte count and bone marrow evaluation, although important to rule out hemolysis and myelodysplastic changes, may not be necessary for patients with isolated macrocytosis without anemia (SOR: B, prospective cohort studies). In unexplained macrocytosis, bone marrow evaluation may show early marrow changes, particularly in the elderly (SOR: B, prospective cohort study).
Evidence summary
Significant macrocytosis is usually defined as a mean corpuscular volume greater than 99 femtoliters (fL). The prevalence of macrocytosis (with or without anemia) ranges from 1.7% to 5.0%.1-4 As many as 60% to 80% of primary care patients may not have anemia.3,4
Because no study has looked specifically at evaluating macrocytosis without anemia, extrapolation from studies of all presentations of macrocytosis (with and without anemia) must help guide evaluation.1,3,5-7 The causes of macrocytosis vary depending on the population studied (TABLE). In primary care, alcohol use and vitamin deficiency are common causes. Even after evaluation, approximately 10% of cases remain unexplained.3
TABLE
Causes of macrocytosis: What prospective studies show
| CAUSE | PERCENT OF PATIENTS BY STUDY | ||||
|---|---|---|---|---|---|
| DAVIDSON 6 (N=200) | BREEDVELD 1 (N=70) | KEENAN 5 (N=80) | SAVAGE 7 (N=300) | MAHMOUD 10 (N=124) | |
| Alcohol | 18 | 27 | 36 | 26 | 14 |
| Vitamin deficiency | 13 | 39 (6% had both deficiencies) | 16 | 6 | 24 |
| B12 | 8 | 23 | 10 | 5 | 12 |
| Folate | 5 | 10 | 6 | 1 | 12 |
| Medications | 30 | 1 | —* | 37 | 2 |
| Liver disease | 16 | 3 | 9 | 6 | 2 |
| Hematologic disease | 15 | 19 | 14 | 14 | 20 |
| Malignancy/premalignancy | 15 | 13 | 11 | 6 | 20 |
| Reticulocytosis | 0 | 6 | 3 | 8 | —† |
| Hypothyroidism | —† | 3 | 6 | 1 | 12 |
| Unexplained | 23 | 9 | 28 | 7 | 19 |
| * Excluded patients on cytotoxic and chemotherapeutic medications | |||||
| † Not evaluated. | |||||
Clues in the history, physical exam, and lab results
A history focusing specifically on alcohol use and medications—especially chemotherapeutics, antiretroviral drugs, and antiseizure medications—can provide important clues to the cause of macrocytosis. During the physical examination, look for signs consistent with chronic liver disease.
Laboratory studies can help identify vitamin deficiencies, liver disease, and thyroid disease. A normal serum B12 level may not rule out a true B12 deficiency, but normal levels of the metabolites methylmalonic acid and homocysteine do essentially rule it out.8 In this era of folic acid fortification, the utility of the serum folate level is uncertain. Several studies suggest empiric treatment with folic acid instead of testing for a deficiency when B12 deficiency has been ruled out.7,9