Causes of Elevated Mean Corpuscular Volume (MCV)
The most common causes of elevated MCV (macrocytosis) include vitamin B12 or folate deficiency, alcohol use, medication effects, liver disease, and hematological disorders, with vitamin B12 deficiency being the most frequent cause of megaloblastic macrocytosis. 1
Common Etiologies of Macrocytosis
Nutritional Deficiencies
- Vitamin B12 deficiency - characterized by severe macrocytosis (often MCV >120 fL) with megaloblastic erythropoiesis 1, 2
- Folate deficiency - presents similarly to B12 deficiency with megaloblastic changes 1, 3
- Combined deficiency states may occur, particularly in patients with malabsorption 1
Substance-Related Causes
- Alcohol abuse - one of the most common causes of macrocytosis in hospitalized patients (36.5% in some studies) 2, 4
- Alcoholic liver disease - associated with macrocytosis in 70.3% of cases, with MCV values >100 fL seen in nearly half of alcoholic patients 4
- Female alcoholics have higher rates of macrocytosis (86.3%) compared to males (63%) 4
Medication-Induced Macrocytosis
- Chemotherapeutic agents (hydroxyurea, azathioprine, 6-mercaptopurine) 1
- Anticonvulsants 2
- Antiretroviral medications 1
- These medications can cause macrocytosis that resembles megaloblastic anemia but is not related to vitamin deficiency 1
Other Medical Conditions
- Liver disease (independent of alcohol use) 5, 2
- Hematological disorders and malignancies (myelodysplastic syndrome, leukemia) 5, 3
- Reticulocytosis and hemolytic conditions 2, 3
- Hypothyroidism 5
- Chronic renal failure 3
- Aplastic anemia 3
Diagnostic Approach to Elevated MCV
Initial Evaluation
- Complete blood count with indices and peripheral blood smear examination 1
- Reticulocyte count to differentiate between increased red cell production and megaloblastic processes 1
- Vitamin B12 and folate levels, particularly when MCV exceeds 100 fL 1, 2
Additional Testing Based on Clinical Suspicion
- Liver function tests to evaluate for liver disease 2, 4
- Thyroid function tests if hypothyroidism is suspected 5
- Methylmalonic acid and total homocysteine levels (more sensitive for B12 deficiency) 2
- Detailed medication history to identify drug-induced causes 1, 2
- Alcohol use assessment (MCV >100 fL strongly suggests alcohol-related disease in patients with liver disease) 4
Clinical Significance and Patterns
Morphological Clues
- Megaloblastic anemia: anisocytosis, macro-ovalocytes, and hypersegmented neutrophils (present in 86% of megaloblastic cases) 2, 3
- Higher red cell distribution width (RDW) in megaloblastic conditions compared to other causes 3
- MCV values >120 fL are usually caused by vitamin B12 deficiency 2
Important Considerations
- Macrocytosis may be the only indicator of vitamin deficiency, preleukemia, or alcoholism 5
- Anemia is not always present - 20.9% of vitamin B12 deficiency cases can present with isolated macrocytosis without anemia 3
- In patients with inflammatory bowel disease or small bowel resection, regular monitoring for B12 and folate deficiency is recommended 1
- Macrocytosis needs evaluation even without anemia, as it may be the first clue to underlying pathology 3
Treatment Approach
Treatment should be directed at the underlying cause:
- For nutritional deficiencies: vitamin B12 or folate supplementation 1
- For alcohol-related macrocytosis: alcohol cessation (MCV may normalize within 3 months) 4
- For medication-induced macrocytosis: consider medication adjustment if possible 1
- For underlying conditions: treat the primary disorder (liver disease, hypothyroidism, etc.) 1, 3