Medication-Induced and Congenital Causes of Macrocytosis in Children

Etiologies and Diagnostic Approach

• Azathioprine and 6-mercaptopurine induce macrocytosis through myelosuppressive activity rather than vitamin deficiency, as noted by Clinical Nutrition 1, 2
• Methotrexate causes macrocytosis by inhibiting dihydrofolate reductase, blocking conversion of dihydrofolic acid to tetrahydrofolic acid, according to Clinical Nutrition 1, 2
• Sulfasalazine induces macrocytosis through folate malabsorption, as reported by Clinical Nutrition 1, 2
• Cyanotic heart disease specifically causes macrocytosis through compensatory erythrocytosis in response to chronic hypoxemia, as found in Circulation 3
• Reticulocytosis causes macrocytosis because immature reticulocytes are larger cells that shift into circulation, as described in the American Journal of Kidney Diseases 4, 5
• In children with inflammatory bowel disease and ileal involvement or resection, vitamin B12 deficiency becomes more prevalent, as noted by Clinical Nutrition 2
• Folate deficiency occurs from low intake, malabsorption, excess utilization from mucosal inflammation, and medications in IBD patients, according to Clinical Nutrition 2
• The American Academy of Pediatrics recommends reticulocyte count to differentiate production versus destruction causes, although the specific guideline is not mentioned, a similar approach is suggested by Praxis Medical Insights 6
• If reticulocyte count is normal or low with macrocytosis, consider vitamin B12 deficiency, folate deficiency, myelodysplastic syndrome, medications, or hypothyroidism, as suggested by Praxis Medical Insights 6
• Macrocytosis is generally defined as MCV >100 fL in adults, but age-appropriate norms must be used in children, as described in the American Journal of Kidney Diseases 4, 5
• Always treat B12 deficiency before folate supplementation to avoid precipitating subacute combined degeneration of the spinal cord, as recommended by Praxis Medical Insights 6