How Sensitive Is the Total B12 Test for Diagnosis of B12 Deficiency? A Systematic Review

Problem

Vitamin B12 (B12) deficiency is common and eminently treatable. Untreated deficiency can lead to irreversible neurological damage and poor quality of life. Several studies indicate poor sensitivity of the total B12 test (tB12), but a systematic review of diagnostic accuracy has not been done before.

Approach

We aimed to assess the evidence regarding sensitivity, specificity and diagnostic yield of tB12 for the diagnosis of B12 deficiency, with methylmalonic acid (MMA) as the reference test. A systematic search of six online databases and two trial registries was conducted for the terms 'methylmalonic' and 'B12' or synonyms. Eligible studies should be primary studies, reported in English or a Western European language, have studied human, adult participants (over 18 years old), not pregnant or lactating, and not selected for renal failure, have measured tB12 and MMA, and report sensitivity and specificity, or sufficient data for calculation of diagnostic 2x2 tables. Two reviewers screened title and abstract, so far one reviewer did full text screen, quality assessment and data extraction.

Findings

Searches identified 11,369 studies. After removal of duplicates, excluded populations and languages, 7,843 studies were screened by title and abstract by two reviewers, of which 1208 went to full text review. So far full text review was conducted of 498/1208 studies, quality assessment of 22 eligible studies, data extraction of thirteen studies deemed to have low or medium risk of bias by one reviewer. At cut-off levels commonly used in clinical practice (below 200 pmol/L for tB12, and below 400 nmol/L for MMA), the tB12 test had a sensitivity of 8-48.6%, specificity 83.1-98.4%. False negative results occurred in 9.3-36.8% of the five studies which included only older people.

Consequences

The tB12 test has good specificity but low sensitivity at clinically used cut-off levels. High levels of clinical suspicion in at-risk populations and access to more sensitive tests are needed to improve diagnosis. Further work will include full text review of all 1208 screened studies, quality assessment and data extraction by two researchers.