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Norberg B. Homocysteine Metabolism VIII – reconsideration and renewal
[editorial]. Rondel 2011; 31. URL: http://www.rondellen.net
Homocysteine Metabolism VIII
Reconsideration and renewal
Summary
The 8th
international conference on homocysteine metabolism was held in 2011 in Lisboa,
June 19-22. The meeting was distinguished by reconsideration and renewal. The
collapse of the homocysteine model, the hypothesis that homocysteine provides a
modifiable risk factor for vascular disease, has had a profound impact on
scientific thinking. In the work-through phase after the crisis, the perspective
is widening and deepening. The remaining fields of interest for clinical
practice are the inborn errors of metabolism resulting in huge
hyperhomocystinuria, the congenital malformations due to deficiency of folate
and/or vitamin B12, and deficiency states of adults and elderly concerning
folate and vitamin B12.
Contents
Homocysteine and vascular disease
Laboratory diagnosis of B12
deficiency
B vitamins and brain atrophy
B vitamins and cancer
Oral B vitamins in therapy
Homocysteine and vascular disease
The role
of homocysteine in vascular disease is in the meta-analysis stage of the
prospective, randomised and placebo-controlled trials. However, it should be
mentioned that Torbjörn K Nilsson from Örebro, Sweden, reported evidence for an
association between haemorrhagic stroke, homocysteine and two polymorphism in
the genetic regulation of homocysteine metabolism (1).
Laboratory diagnosis of B12
deficiency
A team
around Anne Malloy in Dublin tried to sharpen the laboratory diagnosis of
vitamin B12 deficiency (2). Their point of departure was the distribution of
vitamin B12 in erythrocytes from a reference population, 120 healthy probands
aged 18-62 years. The red blood c ells were thought to reflect tissue levels of
vitamin B12.
The
reference range established, the investigators went on to a study group
comprising 700 elderly persons, age range 63-97 years.
The
results suggested that holotranscobalamin was
a better laboratory test of vitamin B12 deficiency than total serum
cobalamin and methylmalonic acid. Particularly, holotranscobalamin accuray was
not compromised by impaired renal function (2).
David
Smith reported that baseline homocysteine values above 13 micromol/L, treated by
B vitamins, slowed brain atrophy of elderly subjects with mild cognitive
impairment (3). The study has previously been analysed in detail in The Rondel
(4). The result is compatible with a controlled study from Japan, previously
also analysed in The Rondel (5).
There
was an old fear from about 1950 that folic acid – and potentially also vitamin
B12 – would fuel the development of tumour diseases. Such suspicions were
supported by long-term follow-up of the controlled studies NORVIT and WENBIT in
homocysteine lowering by B vitamins (6). However, the increases of relative
risks were small, in the range 18-38%. Thus, the increases of absolute risks
were negligible.
The
observations in NORVIT and WENBIT were not confirmed in a controlled British
study of larger size but shorter follow-up (7). However, my working hypothesis
is that future studies will confirm the results of the Norweigian follow-up (6).
It is
reasonable to assume that deficiency
of B vitamins will provide the main link between basic research on homocysteine
metabolism and clinical practice in future years; it is desirable that
indications and doses are adjusted to provide optimal treatment for most
patients without consequent overtreatment,
overdosage, or neglect.
The two
B vitamins of crucial therapeutic significance are vitamin B12 and folic acid.
Vitamin B12 deficiency is fairly common, folate deficiency more rare (8).
It is
generally acknowledged, that oral treatment is feasible in most dificiency
patients (8, 9). In Sweden, three out of four patients with vitamin B12
deficiency were treated with tablets, 1 mg daily, in 2005. The Swedish
experience with oral vitamin B12 therapy then comprised approximately three
million patient years (8).
The
optimal oral dose of folic acid in deficiency patients is 0.5 -1.0 mg daily.The
optimal dose of oral vitamin B12 in deficiency patients is 1 mg daily (8).
Overfilling of body stores carries at least no advantage for the patients (10).
Since
folate and vitamin B12 are joined in a series coupling in metabolism, my working
hypothesis is that in the future most patients with either deficienciy or both
will be treated with a combination tablet, TwoBe, containing 0.5 mg folic acid
and 1 mg cyanocobalamin, one tablet daily (8).
Bo Norberg
E-mail: norberg.bo@gmail.com
References
Nilsson TK.
Prospective study of first stroke in relation to plasma
homocysteine and MTHFR677C>T and 1298A>C genotypes and
haplotypes – evidence for an association with haemorrhagic
stroke. Oral Communication 18, page 55, Abstract Book.
Molloy A,
Scott J, Ueland P, Cunningham C, Casey M. Holotranscobalamin
predicts tissue vitamin B12 status (red cell cobalamin) in
elderly subjects with significantly greater accuracy than either
total serum cobalamin or methylmalonic acid. Oral Communication
12, page 48 in Abstract Book.
Smith D.
Baseline homocysteine is crucially important in trials with B
vitamin: The VITACOG trial. Plenary Lecture, page 27 in Abstract
Book.
Lökk J. Hope
for homocysteine – brain atrophy slowed by B vitamins
[evaluation]. Rondel 2010; 30. URL:
http://www.rondellen.net/evaluation30_eng.htm
Norberg B.
Oral high-dose vitamin B12 and folate – breakthrough by broken
hips [editorial]. Rondel 2005; 24. URL:
http://www.rondellen.net/publisher24_eng.htm
Norberg B.
Focus on folate – folic acid, vitamin B12, and cancer
[editorial]. Rondel 2010; 30. URL:
http://www.rondellen.net/publisher30_eng.htm
The SEARCH
study (Study of the Effectiveness of Additional Reductions in
Cholesterol and Homocysteine (SEARCH) Colloborative Group.
Effects of homocysteine lowering with folic acid plus vitamin
B12 vs. placebo on
mortality and major morbidity in myocardial infarction survirors.
A randomized trial. JAMA 2010; 303(24):2486-2494
(doi:10.1001/jama.2010.840)
Norberg B. Deficiency of vitamin B12 and folate – the branded generic for optimal oral therapy [editorial]. Rondel 2008; 28. URL: http://www.rondellen.net/publisher28_eng.htm
Drugs and Therapeutics Bulletin. Oral or intramuscular vitamin B12? DTB 2009; 47(2):19-21
Liedholm H.
Clinical effects of overfilling – vitamin B12 and folate
repletion in non-deficient elderly [debate]. Rondel 2007; 27.
URL:
http://www.rondellen.net/debate27_eng.htm
Published August 20, 2011