Authors' objectives: The objective of this health technology assessment (HTA) short report was to evaluate the benefits and harms associated with vitamin B12 tests (i.e. serum B12, holotranscobalamin [holoTC] and methylmalonic acid [MMA]) in patients with a clinical suspicion of, or at high risk for, vitamin B12 deficiency. In addition, legal, social, ethical and organisational issues associated with vitamin B12 testing were considered. The applicability of such findings has been discussed within the Swiss context.

Authors' results and conclusions: Direct evidence No direct evidence evaluating the impact of B12 testing on patient-relevant outcomes was identified. Linked evidence: test accuracy One existing SR evaluating the diagnostic accuracy of serum B12 testing (searches up to November 2009) was identified (k = 36). No existing reviews of holoTC or MMA were identified. In addition, six primary studies published since November 2009 were included. Of these, six evaluated vitamin B12 (n = 15,608), five evaluated holoTC (n = 15,531), and two evaluated MMA (n = 11,910). All primary studies were considered to be at risk of bias. Sensitivity of the vitamin B12 test against MMA as a reference standard ranged from 52% to 72%, reported by one SR and three primary diagnostic accuracy studies. Specificity ranged from 41% to 81%. A primary study conducted in Switzerland with a large sample size and novel reference standard (4cB12 method) reported sensitivity of 86% and specificity of 78% in identifying patients with subclinical vitamin B12 deficiency. The quality of evidence was very low. Two paired single-gate diagnostic accuracy studies (n = 2,638) and one paired two-gate diagnostic accuracy study (n = 360) that investigated holoTC as an index test and used MMA as a reference standard reported sensitivity ranging from 56% to 83%, and specificity from 51% to 60%. The paired two-gate diagnostic accuracy study that employed the 4cB12 model as a reference standard reported sensitivity and specificity of 86% and 81%, respectively, in possibly deficient cases (n = 51). The quality of evidence was low. One paired single-gate diagnostic accuracy study used MMA as an index test, one used holoTC as a reference standard (n = 77), and one used a 4cB12 model (n = 11,833). The holoTC study reported sensitivity and specificity of 40% and 94%, respectively (low quality). The 4cB12 study reported sensitivity and specificity of 82% and 83%, respectively (low quality). Serum B12 measured with holoTC as the reference standard typically yielded lower sensitivity and specificity compared to studies that used 4cB12 as the reference standard. The quality of evidence was low. Linked evidence: change in management Three cross-sectional studies evaluated the impact of MMA and B12 testing on clinical management decisions (n = 608). No studies regarding holoTC testing were identified. Two of these studies concluded that hospital patients who received test results indicating low levels of vitamin B12 or MMA were not managed according to recommendations. One study reported that MMA was followed up appropriately in Danish GP clinics, however, it was often used as a screening test in asymptomatic patients. The studies were at a high risk of bias. Linked evidence: effectiveness of change in management Eight SRs reviewed vitamin B12 supplementation in patients with a B12 deficiency. The studies reviewed populations with vitamin B12 deficiency related to a gastrointestinal disorder, pernicious anaemia, before and/or after bariatric surgery, neurodegenerative disorder and/or cognitive impairment, or of unknown aetiology. These studies investigated differences between the dosage and route of vitamin B12 supplementation. In participants with deficient vitamin B12 levels, high doses (i.e. 1,000 µg) of orally administered vitamin B12 was found to be as effective as intramuscular administration in correcting vitamin B12 deficiency and achieving clinical responses. The reviews did not evaluate the safety of supplementation. The risk of bias in the included reviews ranged from low to high. Five SRs and 30 primary research studies investigated the natural course of vitamin B12 deficiency. These studies reported that insufficient vitamin B12 levels, when left untreated, can lead to conditions ranging from mild to severe (e.g., neurological abnormalities, cognitive impairment, haematological abnormalities, complications during pregnancy). Social, legal, ethical and organisational issues Systematic and non-systematic searches identified 22 relevant studies of primary and secondary research. Social and organisational issues related to B12 testing included the medicalisation of vitamins and the subsequent rise in unnecessary testing. Physicians recommended several way to reduce unnecessary vitamin B12 testing in practice: additional educational resources and contemporary guidelines, longer consultation times, and removal of vitamin B12 tests from testing kits. A key ethical concern was related to false positives and false negatives; however, the potential harm caused by these erroneous outcomes is minimised because it takes several years for vitamin B12 levels to become depleted, vitamin deficiency is treatable through supplementation, and physicians are likely to prescribe supplementation for borderline cases of vitamin B12 deficiency. No legal issues were identified. Conclusion There is currently no evidence directly measuring the impact of B12 tests on patient reported outcomes. Similarly, there do not appear to be widely accepted clinical standards for the indications, number and order of tests, and diagnostic thresholds for B12 testing in Swiss practice. Evaluating the diagnostic accuracy of B12 tests is complicated by the absence of an established reference standard, the presence of confounding factors (e.g. renal insufficiency, age), and variable reference thresholds for diagnosis. The current evidence does not inform the most appropriate test, or combination of tests to investigate a patient with suspected, or at high risk of, B12 deficiency, nor the utility of such tests on impacting patient-relevant outcomes.

Authors' methods: Systematic literature searches were conducted to identify existing systematic review (SR) evidence addressing the research questions. In addition, primary literature was sought to fill gaps in existing SR evidence, and to update existing SRs where appropriate. Direct evidence evaluating the impact of B12 testing on patient-relevant outcomes from randomised or nonrandomised trials was sought with priority. In the absence of direct evidence, a linked evidence approach was undertaken. De novo meta-analysis was outside the scope of this evaluation.

Project Status: Completed

URL for project: https://www.bag.admin.ch/bag/en/home/versicherungen/krankenversicherung/krankenversicherung-leistungen-tarife/hta/hta-projekte/vitaminb12tests.html

Year Published: 2021

URL for published report: https://www.bag.admin.ch/dam/bag/en/dokumente/kuv-leistungen/leistungen-und-tarife/hta/berichte/h0037vb12-hta-shortreport.pdf.download.pdf/h0037-hta-shortreport.pdf

URL for additional information: https://www.bag.admin.ch/bag/en/home/versicherungen/krankenversicherung/krankenversicherung-leistungen-tarife/hta/hta-programm.html

English language abstract: An English language summary is available

Publication Type: Rapid Review

Country: Switzerland

Organisation Name: Swiss Federal Office of Public Health (FOPH)

Contact Address: Federal Office of Public Health, Schwarzenburgstrasse 157, CH-3003 Berne, Switzerland

Contact Name: Stephanie Vollenweider

Contact Email: hta@bag.admin.ch

Copyright: Swiss Federal Office of Public Health