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) This publication can be accessed from www.bcshguidelines.com  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, emphasis on haematological indices and blood film examination is strong and the authors did not provide comment on the relative merits of various laboratory and test procedures nor on appropriate testing algorithms. Diagnostic strategies and comparisons of available tests were discussed by Nexø et al (2) who favoured the use of plasma cobalamin and plasma MMA over the Schilling test and various absorption tests. A useful critique and review of available tests was provided by Markle (3) who included some discussion on the use of holotranscobalamin.

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. A recent review was succinctly titled "Diagnosis of cobalamin deficiency: only apparently child's play". (4) 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 and methylmalonic acid) to improve diagnosis, does not seem to have been fulfilled. Three thoughtful editorials discuss the pitfalls of this approach (5,6,7) and more recent publications have cast doubt on the specificity of MMA in particular, especially when elevated levels are encountered in the face of apparently normal total plasma cobalamin levels. (8,9,10)

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 cobalamin status and allow a resolution of the apparent discrepancies between currently used tests. Some recent general reviews on vitamin B12 deficiency, that include discussion of holotranscobalamin measurement, have now been published (11,12,13,14).

REFERENCES

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.      Nexø E, Hansen M, Rasmussen K et al. How to diagnose cobalamin deficiency. Scand J Clin Lab Invest 1994;54 (Suppl 219): 61-76.

3.      Markle HV. Cobalamin. Crit Rev Clin Lab Sci 1996;33: 247-356.

4.      Bächli E and Fehr J. Diagnosis of cobalamin deficiency: only apparently child's play. Schweiz Med Wochenschr 1999; 129: 861-872.

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

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

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

8.      Hvas A-M, Ellegard J and Nexø E. Increase plasma methylmalonic acid level does not predict clinical manifestations of vitamin B12 deficiency. Arch Intern Med 2001; 161: 1534-1541.

9.      Hvas A-M, Ellegard J and Nexø E. Vitamin B12 treatment normalises metabolic markers but has limited clinical effect: A randomised placebo-controlled study. Clin Chem 2001; 47: 1396-1404.

10.  Lindgren A. Elevated serum methylmalonic acid. How much comes from cobalamin deficiency and how much comes from the kidneys? Scand J Clin Lab Invest 2002; 62: 15-20.

11.  Herrmann W, Obeid R, Schorr H and Giesel J. Functional Vitamin B12 Deficiency and Determination of Holotrabscobalamin in Populations at Risk. Clin. Chem. Lab. Med. 2003; 41: 1478-1488.

12.  Schneede J. Prerequisites for establishing general recommendations for diagnosis and treatment of vitamin B12 deficiency and cost utility evaluation of these guidelines. Scand J Clin Invest. 2003; 63: 369-376.

13.  Schneede J and Ueland P-M Novel and Established Markers of Coabalamin Deficiency: Complementary or Exclusive Diagnostic Strategies. Sem. Vasc. Med. 2005; 5: 140-154

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

News

Coming Soon !  The full video recording of the Euromedlab 2007 Active B12 workshop will be available in the next few weeks, register for your copy.

Live CME Web Conference on vitamin B12 deficiency, Prof. Ralph Green, Dec 13th 2007, register now.

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Meetings

8-11 December, 2007
American Society of Hematology, Atlanta, booth 544
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