How is pernicious anemia diagnosed?

Diagnosis of Pernicious Anemia

Diagnose pernicious anemia through a stepwise approach: first confirm macrocytic anemia with low hemoglobin and elevated MCV, then measure serum vitamin B12 (which will be low, typically <150 pg/mL), and finally confirm the autoimmune etiology by testing for intrinsic factor blocking antibodies (73% sensitive, 100% specific) and anti-parietal cell antibodies. 1, 2, 3

Initial Screening: Confirm Anemia

• Obtain a complete blood count to identify anemia, defined as hemoglobin <130 g/L in adult men or <120 g/L in non-pregnant adult women 4
• Pernicious anemia classically presents as macrocytic anemia with elevated mean corpuscular volume (MCV), though hematologic variables may be normal in early cobalamin deficiency 1, 5
• Check reticulocyte count, which will be normal or low (not elevated), indicating inadequate bone marrow response rather than hemolysis 1

Classify the Anemia Pattern

The diagnostic algorithm depends on MCV and reticulocyte findings 1:

• Macrocytic anemia with normal/low reticulocytes suggests vitamin B12 deficiency, folate deficiency, myelodysplastic syndrome, hypothyroidism, or medication effects 1
• A high red cell distribution width (RDW) may indicate combined deficiencies (e.g., concurrent B12 and iron deficiency) that can mask macrocytosis 1

Confirm Vitamin B12 Deficiency

• Measure serum vitamin B12 level—pernicious anemia typically shows severe deficiency (<150 pg/mL) 2, 6
• Urinary methylmalonic acid is a more sensitive alternative when B12 levels are equivocal, as it remains elevated in true B12 deficiency 5
• Consider measuring homocysteine, lactate dehydrogenase (often elevated), and haptoglobin (may be low due to ineffective erythropoiesis) 1

Critical pitfall: Hematologic parameters may be entirely normal in early cobalamin deficiency, so maintain high clinical suspicion based on neurologic symptoms (paresthesias, ataxia, weakness, cognitive changes) even with normal blood counts 2, 5, 7

Establish Autoimmune Etiology

Once B12 deficiency is confirmed, prove pernicious anemia specifically:

• Intrinsic factor blocking antibodies: 73% sensitivity, 100% specificity—the most specific test for pernicious anemia 1, 3
• Anti-parietal cell antibodies: More sensitive but less specific; present in up to 90% of pernicious anemia cases 3, 7, 6
• Elevated fasting gastrin and decreased pepsinogen I suggest oxyntic mucosa damage from atrophic body gastritis 3

Additional Diagnostic Considerations

• Esophagogastroduodenoscopy with gastric body biopsy can confirm atrophic body gastritis, the histologic hallmark of pernicious anemia 3, 6
• The Schilling test (historically used to assess B12 absorption) is rarely performed now and results should be interpreted cautiously 5
• Screen for associated autoimmune conditions: thyroid disease (40% of cases), type 1 diabetes (10%), vitiligo, and other components of autoimmune polyendocrine syndrome 3, 7

When to Suspect Pernicious Anemia

Look for these clinical clues 2, 3, 7:

• Neurologic symptoms: bilateral lower extremity weakness, paresthesias, ataxia, loss of proprioception, urinary incontinence, cognitive changes, or psychiatric symptoms
• Gastrointestinal symptoms: dyspepsia, nausea, vomiting, diarrhea (though many patients are asymptomatic)
• Fatigue, weakness, pallor out of proportion to anemia severity
• Personal or family history of autoimmune disease
• Age >60 years (though 15% of cases occur in younger patients) 3

Critical pitfall: Neurologic sequelae may become irreversible despite B12 replacement if diagnosis is delayed, so maintain high suspicion and test liberally when clinical features suggest B12 deficiency 2, 7

Avoid These Common Diagnostic Errors

• Do not assume normal hemoglobin excludes pernicious anemia—neurologic symptoms may precede hematologic abnormalities 2, 5
• Do not attribute macrocytosis solely to medications (azathioprine, methotrexate) or alcohol without excluding B12 deficiency 1
• Do not miss concurrent iron deficiency, which can mask macrocytosis and create a falsely normal MCV 1
• Do not overlook pernicious anemia in younger patients—while predominantly a disease of the elderly, approximately 15% occur in younger individuals 3