What are the causes of macrocytosis?

Causes of Macrocytosis

The main causes of macrocytosis include vitamin B12 deficiency, folate deficiency, medications (particularly thiopurines, methotrexate, anticonvulsants, and zidovudine), alcohol abuse, liver disease, hypothyroidism, reticulocytosis, and primary bone marrow disorders.

Definition and Classification

Macrocytosis is defined as an elevated mean corpuscular volume (MCV) greater than 100 fL. It can be classified into two main categories based on peripheral blood smear findings:

Megaloblastic Macrocytosis

• Characterized by macro-ovalocytes and hypersegmented neutrophils
• Primary causes:
  • Vitamin B12 deficiency
  • Folate deficiency

Non-megaloblastic Macrocytosis

• Normal neutrophil morphology
• Primary causes:
  • Medications
  • Alcohol abuse
  • Liver disease
  • Hypothyroidism
  • Reticulocytosis
  • Myelodysplastic syndromes

Detailed Causes

1. Vitamin B12 Deficiency

• Causes:
  • Ileal disease or resection (particularly in Crohn's disease)
  • Pernicious anemia
  • Strict vegan diet
  • H. pylori gastritis
  • Antacid use

In inflammatory bowel disease (IBD), particularly Crohn's disease with ileal involvement, vitamin B12 deficiency is common with prevalence ranging from 5.6% to 38% 1. Resection of more than 30 cm of distal ileum puts patients at high risk for B12 deficiency 1.

2. Folate Deficiency

• Causes:
  • Malnutrition
  • Malabsorption
  • Increased utilization (hemolysis, pregnancy)
  • Medications (particularly sulfasalazine and methotrexate)

Medications are a significant cause of folate deficiency through:

• Inhibition of dihydrofolate reductase (methotrexate) 1
• Folate malabsorption (sulfasalazine) 1

3. Medication-Induced Macrocytosis

• Thiopurines (azathioprine, 6-mercaptopurine) - cause macrocytosis through myelosuppressive activity 1
• Anticonvulsants (particularly valproate)
• Zidovudine (AZT) - has become a common cause in certain populations 2
• Methotrexate
• Hydroxyurea
• Immunosuppressants

4. Alcohol Abuse

• Direct toxic effect on bone marrow
• Often associated with folate deficiency
• May be accompanied by liver disease

5. Liver Disease

• Altered membrane lipid composition of erythrocytes
• Often coexists with alcohol abuse

6. Hypothyroidism

• Reduced bone marrow activity
• Decreased erythropoiesis

7. Reticulocytosis

• Increased young red blood cells (larger than mature RBCs)
• Seen in hemolysis or post-hemorrhage states

8. Primary Bone Marrow Disorders

• Myelodysplastic syndromes
• Myeloproliferative disorders
• Aplastic anemia
• Leukemias
• Lymphomas

Diagnostic Approach

When evaluating macrocytosis, the following approach is recommended:

1. Initial Assessment:

   • Complete blood count with MCV
   • Reticulocyte count
   • Peripheral blood smear examination
   • Vitamin B12 and folate levels
   • Liver function tests
   • Thyroid function tests
   • Medication review

2. If megaloblastic features are present:

   • Focus on vitamin B12 and folate deficiency
   • Check methylmalonic acid and homocysteine levels if B12 deficiency is suspected but B12 levels are borderline

3. If non-megaloblastic features are present:

   • With high reticulocyte count: Consider hemolysis or hemorrhage
   • With normal/low reticulocyte count: Consider medications, alcohol, liver disease, or bone marrow disorders

Special Considerations

Unexplained Macrocytosis

Approximately 10% of patients will have unexplained macrocytosis after initial evaluation 3. These patients require close follow-up as:

• 11.6% may develop a primary bone marrow disorder
• 16.3% may develop worsening cytopenias
• 69.7% may have stable disease
• 2.3% may resolve spontaneously

Pediatric Macrocytosis

In children, the most common causes differ from adults:

• Drug ingestion (35%), particularly anticonvulsants, zidovudine, and immunosuppressants 4
• Congenital heart disease
• Down syndrome
• Reticulocytosis
• Bone marrow failure/myelodysplasia

Pitfalls and Caveats

1. Coexisting conditions: Microcytosis and macrocytosis can coexist, resulting in a normal MCV. Look for elevated red cell distribution width (RDW) as a clue 1.

2. Reticulocytosis: Epoetin therapy and iron overload can cause macrocytosis due to increased reticulocytes, which may be misinterpreted as vitamin deficiency 1.

3. Normal upper limit: Slight elevations of MCV (91-92 fL) may represent the upper limit of normal rather than pathology 4.

4. Changing epidemiology: The relative frequency of causes has changed over time, with medications becoming increasingly common and vitamin deficiencies becoming proportionally less common in some populations 2.