Differential Diagnosis for Macrocytic Anemia with Normal B12 and Folate

Single Most Likely Diagnosis

• Alcohol-related macrocytosis: This is often the most common cause of macrocytic anemia when B12 and folate levels are normal. Chronic alcohol consumption can lead to macrocytosis due to its direct toxic effect on bone marrow, impaired folate metabolism, and possible poor dietary intake.

Other Likely Diagnoses

• Hypothyroidism: Although less common than alcohol-related causes, hypothyroidism can lead to macrocytic anemia. The mechanism involves decreased production of erythropoietin and possibly altered metabolism of B12 and folate.
• Liver disease: Liver diseases, such as cirrhosis, can cause macrocytosis due to impaired liver function affecting B12 and folate metabolism, and possibly due to alcohol abuse in some cases.
• Medication-induced macrocytosis: Certain medications, including some anticonvulsants (e.g., phenytoin), can interfere with folate metabolism, leading to macrocytic anemia even when folate levels are reported as normal.

Do Not Miss Diagnoses

• Myelodysplastic syndromes (MDS): Although less common, MDS can present with macrocytic anemia. It's crucial to consider this diagnosis due to its potential for progression to acute leukemia and the need for specific management.
• Autoimmune hemolytic anemia: This condition can sometimes present with macrocytosis due to the increased turnover of red blood cells. It's essential to diagnose and treat promptly to avoid severe anemia and other complications.
• Paroxysmal nocturnal hemoglobinuria (PNH): A rare, acquired, life-threatening disease of the blood characterized by the destruction of red blood cells, bone marrow failure, and the potential for thrombotic events. Macrocytosis can be a feature due to the hemolytic process.

Rare Diagnoses

• Ornithine transcarbamylase deficiency: A rare genetic disorder affecting the urea cycle, which can lead to hyperammonemia and, in some cases, macrocytic anemia.
• Copper deficiency: Although more commonly associated with microcytic anemia, copper deficiency can rarely cause macrocytic anemia, likely due to its role in various enzymatic processes.
• Zinc deficiency: Similar to copper, zinc plays a crucial role in numerous biochemical pathways, and its deficiency can lead to macrocytosis, though this is rare and usually seen in the context of severe malnutrition or specific genetic disorders.