The British Committee for Standards in Haematology (BCSH) published a review entitled “Guidelines on the investigation and diagnosis of cobalamin and folate deficiencies” in 1994(1) and an updated version was published in 2014.¬†¬†This publication can be accessed here.

This review does highlight that at one time deficiency was synonymous with macrocytic anaemia but that many patients with pernicious anaemia may present without either anaemia or macrocytosis.

However, there is currently no consensus. In short, simple guidelines, or a “gold-standard” for estimating cobalamin deficiency and indeed cobalamin status, do not exist, especially in cases with borderline cobalamin values or the elderly.

In fact this absence of a gold standard method hampers the ability to compare the various markers of B12 deficiency with each other. One area of research for Axis-Shield, in collaboration with our academic partners, is to attempt to establish a suitable standard.

Of course measurement of total serum B12 has been, and is, widely used as the standard screening test but there are problems of sensitivity and specificity.

As discussed elsewhere the promise of estimating and using the levels of the two metabolites that can accumulate during cobalamin deficiency (homocysteine andmethylmalonic acid) to improve diagnosis, does not seem to have been fulfilled.

Three thoughtful editorials discuss the pitfalls of this approach (2,3,4).

Given the difficulties faced it is not surprising therefore that a definitive set of guidelines cannot be given. It is to be hoped that measurement of the biologically relevant fraction of cobalamin (that bound by transcobalamin) may provide a better index of cobalaminstatus and allow a resolution of the apparent discrepancies between currently used tests.

A general review on vitamin B12 deficiency diagnosis, that includes discussion of holotranscobalamin (Active B12) measurement, was published a few years ago (5). We expect that newer guidelines will appear in time as newer evidence concerning the various biological and haematological markers is generated.


1. British Committee for Standards in Haematology. Guidelines on the investigation and diagnosis of cobalamin and folate deficiencies. Clin Lab Haematol 1994; 16: 101-105.

2. Green R. Screening for Vitamin B12 Deficiency: Caveat Emptor. Ann Intern Med 1996; 124: 509-511.

3.Schilling RF. Who has Vitamin B12 Deficiency? Proc Assoc Am Phys 1996; 108: 68-70

4. Chanarin I and Metz J. Diagnosis of Cobalamin Deficiency: The Old and the New. Br JHaematol 1997; 97: 695-700.

5. Hvas A-M and Nexo E. Diagnosis and Treatment of Vitamin B12 Deficiency- an update. Haematologica 2006; 91: 1508-1514.