The virtue of test treatment
Discriminating deficiency from myelodysplasia

Editorial background
Under the heading "Practice", Dr Vinod Devalia, consultant haematologist in Bridgeend, Wales, depicted two stumbling-blocks in the diagnosis of vitamin B12 deficiency in the 19 August issue of BMJ (1). Especially, the confusion of vitamin B12 deficiency with myelodysplasia might lead to an unnecessary bone marrow transplantation instead of deficiency treatment. In a commentary, BN suggests that test treatment at an early stage of diagnosing should include at least cobalamin and folate, since these vitamins are coupled in a series linkage in cell metabolism. (Figure legend: The "blood bush", an illustration of blood cell differentiation. Myelodysplasia (MDS) is a maturation block at the level of the stem cell.)

Introduction
The case report of Dr Devalia sent shock waves through the primary health care of the world. Until 9 September, the paper had provoked seven rapid responses with one reply from the author (1). The risk of an unnecessary bone marrow transplantation is gruesome to all physicians.

Refractory anaemia and myelodysplasia
The question is why it is easy to confuse myelodysplasias with some shapes of vitamin B12 - and by analogy also folate - deficiency. The answer appears to be that cells accumulate in the late stages of the interphase of the cell cycle, predominantly just before nuclear division, under the influence of vitamin deficiency, intoxications, and neoplastic transformation (cf 2). Thus, the bone marrow picture becomes more or less "megaloblastic".

In the period 1950-1980, the anemias were called "refractory", which did not respond to treatment with vitamin B12, folic acid, or (rarely) pyridoxine (3). About 1970, it was recognised that a main part of the refractory anaemias were in fact due to neoplastic transformation. The name of the states was then changed to myelodysplasia or MDS (myelodysplastic syndromes).

Changing scene from 1970
The concept of "refractory anaemia" implies that

1. iron stores are satisfactory - in fact usually in excess as a token of maturation arrest,
2. test treatment with vitamin B12 and folic acid has failed. Before about 1970, only blood transfusions then remained, when needed.

During the last 30 years, the treatment of deficiency of vitamin B12 and folate has moved from hospitals to primary health care. Aggressive chemotherapy and bone marrow transplantations have become generally available in postindustrial societies. Thus, the risk of confusing myelodysplasia and vitamin deficiency may have increased, in case deficiency is excluded by biochemical tests only (1).

Comments by rapid responders
Among the rapid responders, Dr Malcolm S Hamilton and co-workers present an interesting analysis of false normal B12 assays (1). They suggest that a high titre of antibodies against intrinsic factor interfered with the B12 assay and caused false normal values in one of the present cases.

From a clinical point of view, Dr Emmanuel Andrès and co-workers from Strasbourg suggest test treatment with oral cyanocobalamin, 1 mg daily, for at least 7 days. The UK physicians generally prefer exclusion treatment by parenteral route.

Concluding remarks
All laboratory methods are reported to be uncertain in some circumstances (4). Exclusion therapy with vitamin B12 and folic acid appears to be the decisive method for sorting deficiency from myelodysplasia. In case oral therapy is used, I suggest that cyanocobalamin, 2 mg twice daily, is used for at least a week; the B12 treatment should be combined with folic acid, at least 1 mg daily during the same time period (cf 5).

Bo Norberg

References

1.  Devalia V. Diagnosing vitamin B-12 deficiency on the basis of serum B-12 assay. BMJ 2006;333:385-6
2. Nilsson-Ehle H. The Macrocyte Secrets[evaluation] Rondellen 2001; 8. URL: http://www.rondellen.net/evaluation08_eng.htm
3. Lee GR, Bitchell TC, Forster J, Athens JW, Lukens JN (eds). Wintrobe´s Clinical Hematology, Ed 9, p 1949-1958. Philadelphia: Lea & Febiger; 1993
4. Solomon LR. Cobalamin-responsive disorders in the ambulatory care setting: unreliability of cobalamin, methylmalonic acid, and homocysteine testing. Blood 2005; 105:978-85
5. Norberg B. Provocative proposal - global guidelines for oral vitamin B12 therapy [editorial]. Rondel 2006; 26. URL: http://www.rondellen.net/publisher26_eng.htm

Published November 20, 2006