How to diagnose pernicious anemia

How to Diagnose Pernicious Anemia

Diagnose pernicious anemia by demonstrating vitamin B12 deficiency (serum B12 <200 pg/mL) combined with positive anti-intrinsic factor antibodies, which are highly specific for this autoimmune condition. 1

Initial Laboratory Testing

Start with a complete blood count (CBC) to identify macrocytic anemia, though recognize that hematologic variables may be entirely normal in early pernicious anemia 2. The classic findings include:

• **Hemoglobin <12 g/dL (women) or <13 g/dL (men)** with elevated MCV >100 fL 3
• Low reticulocyte count indicating impaired red blood cell production 3, 4
• Elevated red cell distribution width (RDW) 3

However, approximately 50% of patients with subclinical B12 deficiency have normal serum B12 levels, making additional testing essential when clinical suspicion is high 5.

Confirming B12 Deficiency

Measure serum vitamin B12 levels as the initial screening test, but be aware of critical limitations 1, 5:

• Serum B12 <200 pg/mL confirms deficiency 5
• False-normal B12 results can occur in pernicious anemia due to interfering anti-intrinsic factor antibodies in competitive-binding assays 6

When B12 levels are borderline (200-400 pg/mL) or normal despite high clinical suspicion (macrocytic anemia, neurological symptoms, megaloblastic bone marrow), measure functional markers of B12 deficiency 6:

• Methylmalonic acid (MMA) - elevated early in B12 deficiency and more sensitive than serum B12 7, 2, 5
• Homocysteine - also elevated in B12 deficiency 7, 5

Establishing Pernicious Anemia as the Cause

Once B12 deficiency is confirmed, test for anti-intrinsic factor antibodies, which are highly specific for pernicious anemia 1, 5:

• Anti-intrinsic factor antibodies are the diagnostic hallmark 1
• Anti-parietal cell antibodies can also be measured but are less specific 8, 5

The Schilling test, historically used to assess B12 absorption, has been largely supplanted by serologic testing for these antibodies 2, 5.

Clinical Presentation Clues

Suspect pernicious anemia when patients present with 1, 8:

• Neurological symptoms: paresthesias, ataxia, weakness, decreased sensation, hyperreflexia, urinary incontinence 8
• Psychiatric manifestations: depression, psychotic episodes 8
• Hematologic findings: fatigue, pallor 8
• Associated autoimmune conditions: vitiligo, thyroid disease 8

Neurological symptoms may precede or occur without anemia, making a high index of suspicion critical 8.

Diagnostic Algorithm

1. Order CBC with indices - look for macrocytic anemia (MCV >100 fL), though it may be normal 3, 2
2. Measure serum B12 - if <200 pg/mL, deficiency is confirmed 5
3. If B12 is normal but clinical suspicion remains high, measure MMA and homocysteine - both will be elevated in true B12 deficiency 6, 5
4. Once B12 deficiency is established, test for anti-intrinsic factor antibodies - positive result confirms pernicious anemia 1, 5
5. Consider anti-parietal cell antibodies as supportive evidence 8, 5

Critical Pitfalls to Avoid

• Never rely solely on serum B12 levels - false-normal results occur in up to 50% of subclinical cases and can be caused by assay interference from anti-intrinsic factor antibodies 6, 5
• Do not dismiss pernicious anemia based on normal hemoglobin - neurological manifestations can occur without anemia 2, 8
• Always check functional markers (MMA, homocysteine) when clinical suspicion is high despite normal B12 - this prevents delayed diagnosis and permanent neurological damage 6, 8
• Inflammatory conditions do not significantly affect B12 testing interpretation, unlike iron studies 9