Editorial orientation about the debate

Since 1968 (4), there has been an international consensus that 1 mg daily of oral cyanocobalamin is a safe and reliable treatment for B12 deficiency. The figure below (4, Fig 8) is reproduced with the permission of Journal of Internal Medicine. It suggests that a lower dose, 0,5 mg, is associated with treatment failure (serum B12 below 300 pmol/L, corresponding to 400 pg/ml). The failure rate might be as high as 50-80%. Herman Nilsson-Ehle is the first to challenge this 40-year-old consensus. He recommends 0.5 mg cyanocobalamin daily for deficiency treatment. His documentation consists of a trial for four months on healthy probands withouout follow-up (2). His arguments follow below. BN

At the annual meeting of the Swedish Society of Medicine in Göteborg, the symposium "Homocysteine from the cradle to the grave" was held. This is a summary and some background data relating to the presentation by associate professor Herman Nilsson-Ehle, Section of Hematology and Coagulation, Sahlgrenska University Hospital, Göteborg

High plasma homocysteine (Hcy) is associated with a number of clinical situations, but the common denominators are in practice vitamin deficiency (folic acid, vitamin B₁₂, and to some extent vitamin B₆) and impaired renal function. Hcy in adults increases with age, but the significance of vitamin deficiency and renal function for this increase is not entirely settled. The definition of a "high" Hcy relates to traditional reference intervals, which however not should be confused with clinically determined decision limits for diagnosis, investigation or therapy. Methodology is crucial, and the imprecision should be less than 10% [1], not least for intraindividual control purpose. We found, in a double blind placebo-controlled study of 209 free-living elderly subjects, "high" (>16 micromol/l) Hcy in 64 and 45 % the men and women, respectively. Using a traditional upper reference limit as computed on a "healthy" subsample of the same material, the fraction of "high" Hcy was 8 and 7%, respectively. Treatment with an oral B vitamin combination (0.8mg folic acid, 0.5mg vitamin B₁₂ and 3mg B₆ per day for four months) produced a decline in Hcy by 32%, (p <0.001 compared with placebo), and the distributions of Hcy became in accordance with the reference of our laboratory, upper limit approximately 16 micromol/l. Using Hcy, methylmalonic acid (MMA) and different vitamin concentrations, we calculated the fraction of subjects with initial B₁₂ and folic acid deficiency to maximum 7.2% and 11% [2]. There were no other hematological signs of deficiency, either at study start or revealed by therapy. At present, data regarding other clinical correlates to "high" Hcy and MMA are being analysed (motor & cognitive function), in addition to the possible significance of glomerular filtration and atrophic gastritis in this population.

The relations between vitamin deficiency, causes thereof and "high" Hcy or MMA are over-lapping and can schematically be illustrated (Fig1). The central filled circle is clinical vitamin deficiency, the open left circle are causes and the right circle "high" Hcy or MMA. The over-lapping is extensive but not total. Generally accepted criteria for clinical vitamin deficiency are "low" vitamin concentrations in combination with "high" Hcy/MMA and clinical symptoms/findings (hematopoiesis, nervous system, mucosae, reproductive organs). Clinical deficiency is verified by a clinical response. Normalisation of vitamin- or Hcy/MMA concentrations is not sufficient for diagnosing deficiency. In subjects with malabsorption and malnutrition, the development of vitamin deficiency is slow, and not all such subjects (e.g. ventricular or intestinal resection, drug interaction, veganism diet, atrophic gastritis) have clinical vitamin deficiency. For clinical aspects in Swedish, see [3].

Treatment of clinical B₁₂ deficiency (remission therapy) can be both oral and parenteral. The latter route is recommended in case of neuropathy, and consists of 1mg hydroxocobalamin s.c. or i.m. once every 1- 2 days for 1-2 weeks or until remission. Initially, serum folates and iron (transferrin saturation) should be monitored, additional therapy with folate and iron may be warranted. Parenteral maintenance treatment consists of 1 mg hydroxocobalamin every 1 – 3 months. Oral remission therapy is feasible, 1mg cyanocobalamin 2 x 2.

Oral vitamin B₁₂ therapy is unusual internationally, but is a part of the Swedish tradition after pioneering research in the 1960´s by Berlin et al. [4]. This group showed, that vitamin B₁₂ absorption is both mediated by intrinsic factor (IF), but also takes place in a dose-dependent manner by passive intestinal diffusion. IF is most important in healthy subjects at low doses of the vitamin, and an uptake of 2 microg was considered sufficient for normal turnover. The epoch-making finding was an IF-independent B₁₂ absorption comprising 1.2% of an oral dose within a broad interval (0.1 – 1000mg), also in subjects with ventricular or intestinal resection. A dose of 0.5mg vitamin B₁₂ gave a mean uptake of 9.7(range 3.5-26.3) mcrg in healthy subjects, 7.9(range 1.8-29.4) mcrg in 64 patients with pernicious anemia (n=46), malabsorption (n=13), total gastrectomy (n=3), jejunectomy (n=1), ileitis (n=1). In a clinical therapeutic trial of these 64 patients, oral vitamin B₁₂ (0.5 or 1mg per day) was given, median follow up > 55 (range 10-70) months. During the last three years of the study, 1mg per day was given throughout; six of the patients were recruited during this period. The exact number of patients given 0.5 or 1 mg was not given. In exceptional cases, repeated low (<150 pg/ml equivalent to 112 pmol/l) serum B₁₂ concentrations (microbiological method, Euglena gracilis) were found, these patients were switched to 1mg per day, with successful improvements of the concentrations. At the end of study, no patient had a low serum B₁₂, there were no signs of B₁₂ anemia or neuropathy during the study. There were no negative side effects.

Berlin et al thereby proved that oral maintenance treatment is feasible also in patients with severe B₁₂ malabsorption. The doses employed correspond to 250-500 times recommended daily allowance (RDA), and 0.5mg per day was sufficient in all but exceptional cases. For security reasons, mainly compliance, 1mg per day was recommended. In Sweden, there is nowadays a combination preparation containing 0.5mg cyanocobalamin, 0.8 mg folic acid and 3mg vitamin B₆, with the indication "prophylaxis against symptomatic deficiency in malnutrition or malabsorption, particularly in the elderly". According to the Berlin data the cobalamin dose in this preparation is sufficient for maintenance treatment, but in exceptional cases, 1 mg is needed. The patients are also nowadays subject to regular controls for the underlying gastrointestinal disease, compliance to oral medication (serum B₁₂ and Hcy) and other deficiency states (i.e. iron and folic acid), in addition to clinical status. In the 1960´s, vitamin B₁₂ concentrations were analysed with a microbiological method (Euglena gracilis), which gave a good measure of biologically active vitamin B₁₂. It’s not possible to translate the Berlins´ criteria for "low" B₁₂ concentrations to present methods. This is, however not necessary; a low Hcy precludes inadequate vitamin supply to intracellular metabolism, unlike "grey-zone" values of vitamin concentrations.

Folic acid is readily absorbed in the proximal intestine; large oral doses (5mg 2 x2-3) can be given. Severe isolated folic acid deficiency with megaloblastic anemia is uncommon; often there is a concomitant B₁₂ – or iron deficiency. B₁₂ deficiency should be verified or excluded; large doses of folic acid may cure a megaloblastic B₁₂ anemia, but not other types of B₁₂ deficiency, e.g. neuropathy. Intestinal malabsorption, i.e. celiac disease, should be suspected. Deficiency of folic acid without megaloblastic anemia is more common than previously appreciated, and genetic abnormalities in certain enzymes of folate metabolism may contribute to this. Maintenance treatment with folic acid can be reduced to 5-10 mg per day, and the underlying cause determines the length of treatment, and lower doses may be tested [5]. These patients should also be monitored clinically and with laboratory tests including Hcy.

Such treatment should be restricted to certain risk groups for malabsorption or malnutrition, the left circle of Fig 1. Prophylactic treatment includes regular controls, the intensity of which is decided by the clinical situation, a minimum requirement is monitoring of Hcy. Important risk groups are patients with atrophic gastritis, resection of stomach or intestine, veganism or other malnutrition. Subjects with probable B₁₂ malabsorption (e.g. atrophic gastritis) should be given 0.5 mg B₁₂ or more per day [4], a healthy person (e.g. vegan) needs doses corresponding to RDA. In Sweden, there are at present five oral preparations containing 3-10 mcrg B₁₂. N b vegans may also have B₁₂ malabsorption, furthermore inadequate folate status! If larger doses of folic acid than 0.4mg is needed, there are two medications with higher doses, the above mentioned combination with 0.8mg folic acid (plus 0.5mg B₁₂ and 3mg B₆) and one preparation with 5 mg. Regarding B vitamin prophylaxis to other risk groups (enzyme defects, drugs interfering with vitamin metabolism, increased cellular turnover, severe renal insufficiency), no specific recommendations are given here. These patients are mostly treated according to recommendations within the fields of rheumatology, nephrology, neurology and hematology.

Fertile women are recommended a daily intake of at least 0.4 mg folic acid to reduce the risk of foetal neural tube defect if pregnant. This is difficult to accomplish by eating fruit and vegetables, and there are prescription free supplements. Some countries (e.g. USA and Canada) have adopted folic acid fortification of food for this purpose. In practice, Hcy is often tested on persons without a typical clinical picture or a defined risk for deficiency, sometimes on the request of the patient. Some centres in e.g. Germany, Austria and Switzerland (D.A.CH.-liga) have a more active strategy for patients with risk for or manifest vascular disease [6]. Prophylactic pharmacological treatment for lowering moderately high Hcy and MMA without vitamin deficiency or risk thereof (Fig 1, right circle) is at present not warranted outside studies. This may change when a casual relationship between a "high" Hcy and e.g. cardiovascular disorders or dementia is proven.

Herman Nilsson-Ehle, MD, associate professor
Department of Internal Medicine
Sektion of Haematology
Sahlgrenska University Hospital
SE-413 45 Göteborg, Sweden
E-mail: herman.nilsson-ehle@medic.gu.se

[1]. Refsum H, Smith AD, Ueland PM, Nexo E, Clarke R, McPartlin J, Johnston C, Engbaek F, Schneede J, McPartlin C, Scott JM. Facts and recommendations about total homocysteine determinations: an expert opinion. Clin Chem 2004;50:3-32.

[2]. Lewerin C, Nilsson-Ehle H, Matousek M, Lindstedt G, Steen B. Reduction of plasma homocysteine and serum methylmalonate concentrations in apparently healthy elderly subjects after treatment with folic acid, vitamin B(12) and vitamin B(6): a randomised trial. Eur J Clin Nutr 2003;57:1426-36.

[3]. Nilsson-Ehle H. B12-folatbrist utan anemi. Internetmedicin (URL: http://www.internetmedicin.se) 2002;.

[4]. Berlin H, Berlin R, Brante G. Oral treatment of pernicious anemia with high doses of vitamin B12 without intrinsic factor. Acta Med Scand 1968;184:247-58.

[5]. Clarke R. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists´ Collaboration. Br Med J 1998;316:894-8.

[6]. Stanger O, Herrmann W, Pietrzik K, Fowler B, Geisel J, Dierkes J, Weger M. Clinical use and rational management of homocysteine, folic acid, and B vitamins in cardiovascular and thrombotic diseases. Z Kardiol 2004;93:439-53.

Figure 1

Published December 31, 2004