Vitamin B12 Deficiency and New Recommendations by the National Institute for Health and Care Excellence: A Challenging Clinical and Laboratory Topic

The reliable identification of vitamin B12 (B12) depletion, both severe and mild to severe, is an important issue for health outcomes at any age (1, 2). B12 deficiency has been linked to cognitive impairment, and even levels at the lower end of the normal range have been associated with Alzheimer disease, vascular dementia, and Parkinson disease (2). B12 supplementation (1 mg/day) is reported to correct the biochemical deficiency and to improve cognition in patients with severe B12 deficiency at baseline (2). However, considering the methodological problems affecting the diagnostic specificity of current B12 assays, the need for supplementation may not be correctly evaluated if the identification of baseline depletion is unreliable. From an examination of the literature, the assessment of thresholds of risk for identifying severe B12 deficiency is a challenging issue, reinforced by the wide array of thresholds reported by different authors and clinical practice guidelines. The UK National Institute for Health and Care Excellence (NICE) has released new recommendations on the diagnosis and management of B12 deficiency in subjects 16 years of age and older, updating the thresholds for identifying severe and mild to severe deficiency (3). NICE states that B12 testing should be performed in subjects at risk for B12 deficiency as listed in Table 1 (3). Pregnant women and newborns with altered levels of biomarkers of cobalamin metabolism detected by a newborn screening program should be added to this (Table 1) (1, 4). NICE recommends using either total B12 or holotranscobalamin (active B12) as the initial test for suspected B12 deficiency and only the latter for testing pregnant women. This is less prone to interferences in pregnancy and in breastfed newborns (4). In other populations, due to the absence of high-quality evidence, NICE clinical practice guidelines agree that total and active B12 may be interchangeable as the initial diagnostic test. Holotranscobalamin is reported to have a higher diagnostic sensitivity and accuracy for early detection of deficiency, both in mixed patient populations and hospitalized and older patients, and to be more useful in monitoring supplementation. However, few laboratories offer measurement of holotranscobalamin, most likely because of the test’s cost and the limited literature evidence replacing measurement of total B12 with active B12. Recommending holotranscobalamin over total B12 testing would lead to a notable change in clinical practice and cost that would be difficult to justify without evidence of cost-effectiveness. Furthermore, holotranscobalamin testing does not eliminate the need for measuring methylmalonic acid levels if results of holotranscobalamin fall in the range 25 to 70 pmol/L in subjects with symptoms or signs of B12 deficiency (3). The assignment of a consensus value to the World Health Organization (WHO) International Standard (IS) code 03/178 for holotranscobalamin may allow the comparison of population data and has offered the opportunity to boost the development of assay methodologies. An increase in laboratory measurements of holotranscobalamin has been recently recorded across northern Europe, the UK, Canada, and Australia.

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