What is the likely diagnosis and recommended work‑up and treatment for a patient with low red blood cell count, low hemoglobin, low hematocrit, elevated mean corpuscular volume and elevated mean corpuscular hemoglobin?

Macrocytic Anemia: Likely Vitamin B12 or Folate Deficiency

This patient has macrocytic anemia (MCV 96.8–104.9 fL, with several values >100 fL) with low hemoglobin, low hematocrit, and elevated MCH, most consistent with megaloblastic anemia from vitamin B12 or folate deficiency. 1

Diagnostic Reasoning

Morphologic Classification

• The MCV values ranging from 96.8 to 104.9 fL, with multiple readings exceeding 100 fL, definitively classify this as macrocytic anemia. 1
• Macrocytic anemia (MCV >100 fL) is most commonly megaloblastic, indicating vitamin B12 or folate deficiency caused by insufficient uptake or inadequate absorption through lack of intrinsic factor. 1
• The elevated MCH (31.2–34.6 pg, with several values >33 pg) reflects increased hemoglobin content per red cell, consistent with larger-than-normal erythrocytes. 2

Key Distinguishing Features

• The trend shows MCV values that were initially elevated (100.3–104.9 fL) and have since decreased slightly but remain in the high-normal to macrocytic range (96.4–98.6 fL most recently), suggesting either partial treatment response or evolving deficiency. 2, 3
• Non-megaloblastic causes such as alcoholism, myelodysplastic syndrome (MDS), or drugs like hydroxyurea can also cause macrocytosis but are less common. 1

Essential Diagnostic Workup

First-Line Laboratory Tests (Order Immediately)

• Measure serum vitamin B12 and red blood cell folate levels to confirm or exclude megaloblastic anemia—these are the most common causes of macrocytic anemia. 2, 3
• Obtain a reticulocyte count (or reticulocyte index) to distinguish decreased RBC production from increased destruction or loss. 1, 2
  • A low or normal reticulocyte index (1.0–2.0) indicates impaired erythropoiesis, strongly supporting vitamin B12/folate deficiency, aplastic anemia, or bone marrow dysfunction. 1
  • An elevated reticulocyte index suggests hemolysis or recent blood loss, which is less likely given the macrocytosis pattern. 1
• Review a peripheral blood smear for hypersegmented neutrophils (≥5 lobes), oval macrocytes, and pancytopenia—hallmarks of megaloblastic anemia. 2, 3

Critical Additional Studies

• Check serum ferritin and transferrin saturation to exclude concurrent iron deficiency, which can mask macrocytosis and normalize the MCV, creating a mixed picture. 2, 4, 3
  • Ferritin <30 µg/L (or <100 µg/L with inflammation) indicates iron deficiency. 2, 4
  • Transferrin saturation <15–16% supports iron deficiency. 2, 4
• Obtain thyroid-stimulating hormone (TSH) and liver function tests, as hypothyroidism and liver disease are common non-megaloblastic causes of macrocytosis. 2, 3
• If the reticulocyte count is elevated, measure haptoglobin, lactate dehydrogenase (LDH), and indirect bilirubin to evaluate for hemolysis. 1, 2

Medication and History Review

• Conduct a thorough medication review focusing on thiopurines (azathioprine, 6-mercaptopurine), chemotherapy agents (hydroxyurea), anticonvulsants (phenytoin), and methotrexate—all can induce macrocytosis. 1, 2
• Assess for alcohol use (>2 weeks of heavy intake), gastrointestinal symptoms (diarrhea, malabsorption), prior gastric surgery, or strict vegetarian diet (no animal products), which increase risk of vitamin B12 deficiency. 2, 3, 5

Treatment Approach Based on Etiology

If Vitamin B12 Deficiency Is Confirmed

• Initiate intramuscular cyanocobalamin 1000 mcg daily for 1 week, then weekly for 4 weeks, then monthly for life if pernicious anemia is diagnosed. 5
• Patients with pernicious anemia require lifelong monthly vitamin B12 injections; failure to continue treatment will result in recurrence of anemia and irreversible neurologic damage (subacute combined degeneration of the spinal cord). 5
• Monitor serum potassium closely during the first 48 hours of treatment, as rapid hematopoiesis can precipitate hypokalemia. 5
• Obtain hematocrit and reticulocyte counts daily from days 5–7 of therapy, then frequently until hematocrit normalizes. 5
• If reticulocytes do not increase after treatment or fail to remain at least twice normal while hematocrit is <35%, reevaluate the diagnosis and consider complicating conditions (e.g., concurrent iron or folate deficiency). 5

If Folate Deficiency Is Confirmed

• Treat with oral folic acid supplementation (typically 1 mg daily). 1
• Never administer folic acid alone without first excluding vitamin B12 deficiency, as folic acid >0.1 mg/day can produce hematologic remission in B12 deficiency while allowing irreversible neurologic damage to progress. 5

If Initial Workup Is Nondiagnostic

• If pancytopenia is present, refer to hematology for bone marrow aspirate and biopsy to evaluate for myelodysplastic syndrome or aplastic anemia. 2, 3
• Consider hemoglobin electrophoresis if thalassemia is suspected (though thalassemia typically causes microcytosis, not macrocytosis). 2

Common Pitfalls and Caveats

• Mixed deficiencies (iron plus B12/folate) can normalize the MCV while MCH and MCHC remain abnormal; always check iron studies even when MCV is elevated. 2, 4
• Ferritin is an acute-phase reactant and can be falsely elevated in inflammation, infection, malignancy, or liver disease despite true iron deficiency; ferritin >150 µg/L essentially excludes absolute iron deficiency even with inflammation. 2, 4
• Patients with pernicious anemia have approximately three times the incidence of gastric carcinoma compared to the general population; perform appropriate screening when indicated. 5
• A vegetarian diet containing no animal products (including milk or eggs) provides no vitamin B12; advise such patients to take oral B12 supplementation regularly. 5
• Pregnancy and lactation increase vitamin B12 requirements; deficiency has been recognized in breastfed infants of vegetarian mothers even when the mothers were asymptomatic. 5