Definition: hemoglobin <13.5 or hematocrit <41 in men, or 12 and 36 in women. MCV must be greater than 100.

Differential Diagnosis

Depends on whether the anemia is megaloblastic or non-megaloblastic.

• Megaloblastic anemia (MCV > 100): caused by impaired DNA synthesis, and refers to hypersegmented neutrophils (>5% of neutrophils with 5 lobes or any with 6 lobes) seen on the blood smear. The MCV is often greater than 110 and an MCV >120 is almost pathognomonic for megaloblastic anemia. Hyperchromic macro-ovalocytes are relatively specific but insensitive for the diagnosis. On physical exam, look for an atrophic tongue. Causes include:
  • B12 deficiency: check serum B12 level. May be falsely decreased secondary to folate deficiency or type 1 cryoglobulinemia (e.g. multiple myeloma or Waldenstrom’s macroglobulinemia), but a normal level does not rule out deficiency. Differentiate from folate deficiency with homocysteine and methylmalonic acid (both elevated in B12 deficiency, though MMA may be falsely elevated in patients with underlying renal dysfunction) as well as presence of neurologic symptoms (paresthesia and ataxia, with impaired position sense).
    • Etiology: B12 absorption requires both a gastric component (production of intrinsic factor by gastric parietal cells in the stomach) and ileal component (intact cubilin receptor for intrinsic factor-B12 complex in the terminal ileum).
      • Gastric causes of impaired absorption include pernicious anemia (anti-intrinsic factor 1 antibodies), H. pylori infection, gastrectomy, hyperchlorhydria due to Zollinger-Ellison syndrome.
      • Ileal causes include ileitis (radiation, IBD), ileal resection, tropical sprue, lymphoma of the ileus. Intrinsic factor levels and anti-parietal cell antibodies can help in the diagnosis of pernicious anemia.
      • Consider poor intake with special diets.
    • Treatment: high dose oral therapy (1000 micrograms of B12 daily, 2000 daily in adults with impaired absorption) and parenteral therapy (1000 micrograms of B12 weekly until deficiency corrected then spaced out to monthly) are equally effective.
  • Folate deficiency: should be diagnosed with RBC-folate level, as serum folate level fluctuates and is a poor proxy for body folate stores. May be falsely low due to B12 deficiency. Differentiate from B12 deficiency with homocysteine and methylmalonic acid levels (only homocysteine is elevated in folate deficiency). While the prevalence of folate deficiency is now very low in the US, it remains common in people with alcohol use disorder.
    • Etiology: folate absorption occurs in the proximal small intestine, and can be affected by inflammation from celiac disease, tropical sprue, and Whipple's disease, as well as rheumatologic conditions affecting the GI tract. Also consider increased folate requirement in pregnancy, and poor intake.
    • Treatment: folic acid supplementation with 1-5 mg/d orally (sufficient even when malabsorption is present).
  • Drug-induced: common offenders include methotrexate, hydroxyurea, zidovudine, azathioprine, 5-FU, acyclovir, and capecitabine.
• Non-megaloblastic anemia: MCV <110 in most cases. Causes include:
  • Excess alcohol use: can occur even in individuals who are B12 and folate replete.
  • Liver disease.
  • Hypothyroidism.
  • Reticulocytosis: look for polychromasia on peripheral blood smear.
  • Spurious: on older blood counters, may result from hyperglycemia and hypernatremia secondary to osmotic swelling.
  • Aplastic anemia.
  • Myelodysplastic syndromes: look for giant platelets, hypogranulated neutrophils, and bi-lobed nuclei in neutrophils (Pseudo-Pelger-Huet anomaly) on peripheral blood smear.
  • Drugs: anticonvulsants, AZT.

Key Points

• B12 and folate deficiency are the most common causes of megaloblastic anemia. Identify the underlying cause when possible.
• Reticulocytosis usually begins 4-5 days after B12 or folate replenishment is started; if this fails to occur look for additional causes of anemia.
• Folate may partially correct the megaloblastic anemia of B12 deficiency but the neurologic deficits of B12 deficiency will continue to progress.

Aslinia F, Mazza JJ, Yale SH. Megaloblastic anemia and other causes of macrocytosis. Clin Med Res 2006;4:236- 241.

Galloway M, Hamilton M.  Macrocytosis: pitfalls in testing and summary of guidance. BMJ 2007;335:884-886

Green, Ralph, and Ananya Datta Mitra. “Megaloblastic Anemias.” Medical Clinics of North America, vol. 101, no. 2, Mar. 2017, pp. 297–317., doi:10.1016/j.mcna.2016.09.013.