What are the causes of a mean corpuscular volume (MCV) greater than 100?

Causes of MCV >100 (Macrocytosis)

Macrocytosis (MCV >100 fL) is most commonly caused by vitamin B12 or folate deficiency, alcohol abuse, certain medications, liver disease, myelodysplastic syndrome (MDS), and reticulocytosis. 1, 2

Common Causes of Macrocytosis

Megaloblastic Causes

• Vitamin B12 deficiency

  • Due to insufficient intake, malabsorption, or lack of intrinsic factor (pernicious anemia)
  • Often presents with neurological symptoms when severe
  • MCV values >120 fL are usually caused by B12 deficiency 3

• Folate deficiency

  • Due to poor dietary intake, increased requirements, or malabsorption
  • Common in alcoholism, pregnancy, and malabsorptive disorders

Non-Megaloblastic Causes

• Alcohol abuse

  • One of the most common causes of macrocytosis 4
  • Can occur without anemia (80.2% of men and 34.1% of women with macrocytosis were alcohol abusers) 4
  • Typically presents with MCV values up to 120 fL 4

• Medications

  • Chemotherapeutic agents
  • Anticonvulsants (e.g., phenytoin, valproate)
  • Hydroxyurea
  • Zidovudine (AZT)
  • Methotrexate

• Liver disease

  • Chronic liver disease
  • Hepatitis
  • Cirrhosis

• Hematologic disorders

  • Myelodysplastic syndromes (MDS)
  • Aplastic anemia
  • Leukemia
  • Hemolytic anemia with reticulocytosis

• Endocrine disorders

  • Hypothyroidism

• Other causes

  • Smoking
  • Reticulocytosis (due to hemolysis or blood loss)
  • Pregnancy
  • Anorexia nervosa 5

Distinguishing Features

Laboratory Findings

• Vitamin B12 deficiency:

  • Low red cell count (<4.0 × 10¹²/L)
  • High red cell distribution width (RDW >15.0%)
  • Normal platelet count
  • Normal platelet mean cell volume 6
  • May have neurological symptoms
  • Megaloblastic changes in bone marrow

• Alcohol abuse:

  • Often has elevated gamma-glutamyltransferase (GGT) 4
  • May have concurrent liver function abnormalities
  • Vacuoles in granulocyte or erythrocyte precursors in bone marrow 4

• Liver disease:

  • Abnormal liver function tests
  • May have other signs of liver dysfunction

• Reticulocytosis:

  • Elevated reticulocyte count
  • Often associated with hemolysis or recent blood loss

Diagnostic Approach

1. Initial laboratory assessment:

   • Complete blood count with indices
   • Peripheral blood smear
   • Reticulocyte count
   • Liver function tests
   • Serum vitamin B12 and folate levels 2

2. Additional testing based on clinical suspicion:

   • Methylmalonic acid and homocysteine levels (more sensitive for B12 deficiency) 3
   • Thyroid function tests
   • Alcohol use assessment
   • Medication review
   • Bone marrow examination if myelodysplastic syndrome is suspected

Clinical Significance

Macrocytosis should not be ignored even when not associated with anemia, as it may be the only indicator of serious underlying pathology 4, 7. In a study of patients with macrocytosis, underlying causes were identified in more than 90% of cases 7.

Common Pitfalls

1. Ignoring macrocytosis in non-anemic patients - Macrocytosis without anemia is often the earliest sign of vitamin B12 or folate deficiency, or may indicate alcohol abuse 4

2. Failing to consider medication effects - Always review the patient's medication list for drugs that can cause macrocytosis

3. Missing concurrent iron deficiency - Iron deficiency can mask macrocytosis by lowering MCV; always check iron studies when evaluating abnormal red cell indices 1

4. Not investigating alcohol use - Alcohol is one of the most common causes of macrocytosis, particularly in men under 60 years (89.3%) 4

5. Overlooking subtle B12 deficiency - Consider measuring methylmalonic acid and homocysteine levels when B12 deficiency is suspected but serum B12 levels are borderline 3