What does an elevated mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) indicate?

Elevated MCV and MCH: Diagnostic Significance

Elevated MCV (mean corpuscular volume) and MCH (mean corpuscular hemoglobin) together indicate that your red blood cells are larger than normal and contain more hemoglobin than usual, most commonly pointing to vitamin B12 or folate deficiency, though alcoholism, certain medications, and myelodysplastic syndrome must also be considered. 1

Primary Causes to Investigate

The three most common etiologies account for approximately 73% of all macrocytosis cases 2:

• Vitamin B12 deficiency (24% of cases) – the single most important diagnosis to exclude because untreated deficiency causes irreversible neurological damage 1, 2
• Chronic alcohol use (36% of cases) – can elevate MCV independent of nutritional deficiencies 1, 2
• Medications (13% of cases) – including anticonvulsants (diphenytoin), methotrexate, sulfasalazine, azathioprine, hydroxyurea, and chemotherapy agents 1, 3

Other important causes include folate deficiency, hypothyroidism, liver disease, myelodysplastic syndrome, and hemolysis 1, 4.

Critical First-Line Laboratory Tests

Order these tests immediately to identify the underlying cause:

• Vitamin B12 level (deficiency defined as <150 pmol/L or <203 ng/L) – mandatory first-line test 1, 3
• Folate level (serum folate <10 nmol/L or RBC folate <305 nmol/L indicates deficiency) 1, 3
• Reticulocyte count – distinguishes between production failure (low/normal count suggesting B12/folate deficiency or MDS) versus destruction/bleeding (elevated count suggesting hemolysis or hemorrhage) 1, 3, 4
• Serum ferritin and transferrin saturation – essential because coexisting iron deficiency can mask the full expression of macrocytosis, and mixed deficiencies are common 1, 3
• Peripheral blood smear – look for hypersegmented neutrophils (86% sensitive for megaloblastic anemia) and macro-ovalocytes (72% sensitive) 2, 4

Diagnostic Algorithm Based on Reticulocyte Count

If Reticulocyte Count is Low or Normal:

This pattern indicates impaired red blood cell production 1, 3:

• Measure vitamin B12 and folate levels immediately 1, 3
• Check thyroid-stimulating hormone (TSH) to exclude hypothyroidism 3, 4
• Review medication list for causative agents 1, 3
• If pancytopenia is present, refer urgently to hematology for bone marrow evaluation to exclude myelodysplastic syndrome 1, 3

If Reticulocyte Count is Elevated:

This pattern suggests hemolysis or recent hemorrhage 1, 3:

• Measure haptoglobin (low in hemolysis), LDH (elevated in hemolysis), and indirect bilirubin (elevated in hemolysis) 1, 5
• Examine peripheral smear for schistocytes 5
• Consider direct antiglobulin (Coombs) test if autoimmune hemolysis is suspected 5

Critical Pitfall: Mixed Deficiencies

Always check iron studies even when MCV is elevated, because concurrent iron deficiency can neutralize macrocytosis and produce a falsely normal MCV with an elevated red cell distribution width (RDW). 1, 3, 5 In inflammatory conditions, ferritin may be falsely elevated despite true iron deficiency; use transferrin saturation <20% as a more reliable indicator 3, 5.

Treatment Priorities

CRITICAL: Always exclude and treat vitamin B12 deficiency BEFORE initiating folate supplementation, as folate can mask B12 depletion and allow irreversible neurological damage to progress. 1, 3

For B12 deficiency with neurological symptoms:

• Hydroxocobalamin 1 mg intramuscularly on alternate days until no further improvement, then 1 mg every 2 months for life 1, 3

For B12 deficiency without neurological symptoms:

• Hydroxocobalamin 1 mg intramuscularly three times weekly for 2 weeks, then 1 mg every 2-3 months for life 1, 3

For folate deficiency (after excluding B12 deficiency):

• Oral folic acid 5 mg daily for minimum 4 months 1, 3

When to Refer to Hematology Urgently

Immediate hematology consultation is required if: 1, 3

• The cause remains unclear after complete workup
• Suspicion for myelodysplastic syndrome exists (especially with pancytopenia or unexplained macrocytosis in elderly patients)
• Hemolytic anemia is confirmed
• Pancytopenia is present (low white cells, red cells, and platelets)
• No response to appropriate vitamin replacement after 2-3 weeks

Monitoring Treatment Response

• Serial monitoring of MCV, MCH, hemoglobin, and reticulocyte count assesses response to vitamin or iron replacement 1
• An increase in hemoglobin of at least 2 g/dL within 4 weeks indicates acceptable response 3

Special Considerations

Macrocytosis can occur without anemia – approximately 21% of vitamin B12 deficiency cases present with isolated macrocytosis, making it essential to investigate elevated MCV even when hemoglobin is normal 2, 6. This may be the first clue to underlying pathology requiring treatment 2.