How
we wish to be cited:
Norberg B. Provocative proposal – global guidelines for oral vitamin B12
therapy [editorial]. Rondel 2006; 26. URL:
http://www.rondellen.net
Summary
Analysis of past and present literature suggests that the optimal dose for oral
treatment with vitamin B12 is cyanocobalamin, 1 mg daily. Vitamin B12 should
always be combined with oral folic acid, 0.4-1 mg daily, since these vitamins
provide a functional entity in methionine metabolism. A possible need of
pyridoxine is subject to debate. The main risk groups for deficiency are aged
people and women planning and performing pregnancy and breast-feeding.
Homocysteine is a sensitive marker of early stages of B12-folate deficiency but
not a modifiable risk factor for any particular disease of old age. It is
proposed that all countries allow the registration of adequate preparations of
vitamin B12 and folic acid, free of prescriptions and subventions from the
health care system. Such a reform would allow citizens to make their own
cost-benefit analysis of B12-folate supplementation.
Illustration
Serum concentrations of vitamin B12 after oral long-term treatment with
cyanocobalamin, 0.5 mg daily (red) or 1 mg daily (green). Original data
re-constructed from Berlin et al 1965 and 1968 (see 1-4). The clinical trial
started 1961 with 0.5 mg B12 daily (n=64). During 1962-63, patients began to be
switched from 0.5 to 1 mg B12 daily (right tail of red distribution). Less than
20 patients left the study before switching to 1 mg daily (left tail of green
distribution).
Introduction
Oral
treatment of vitamin B12 deficiency was subject to comprehensive documentation
by the
It is
suggested that oral vitamin B12 should always be combined with oral folic acid,
0.4 – 1 mg daily, for homocysteine lowering and deficiency treatment (cf
11-13). The need of other B vitamins in this context is not documented.The aim
of the present editorial is to propose guidelines for oral treatment of vitamin
B12 and folate deficiency for countries still lacking such traditions in
clinical routine.
Role of vitamin B12 and
folate
Vitamin
B12 (cobalamin) and folate (in therapy folic acid) are linked together in a
series coupling in the methionine cycle (13). Thus, deficiency of one vitamin
produces the same symptoms as deficiency of the other vitamin; it is reasonable
to suggest that vitamin B12 and folic acid as one functional entity are
consequently combined in therapy.
In the
first step of methionine metabolism, methyltetrahydrofolate is the substrate (methyl
donor), vitamin B12 in the shape of methylcobalamin coenzyme in the re-cycling
of homocysteine to methionine. Demethylated tetrahydrofolate goes to DNA synthesis, essential for the growth and
maturation of new cells. Methylated homocysteine is methionine, precursor of S-adenosylmethionine (SAM), the main methyl
donor of the body. Deficiency of SAM is thought to result in the neurological
signs, symptoms and lesions of deficiency of vitamin B12 and/or folate.
In
summary, lack of tetrahydrofoalte results in few and large cells, macrocytes
(14). The advanced clinical state is pernicious anaemia, thin mucous membranes,
and disturbances of fertility (15). The lack of SAM results in neurological
disturbances of different degrees due to impaired synthesis of myelin sheaths
and transmittors (16).
Causes
of deficiency and persons at risk
Deficiency
of vitamin B12 and folate are due to the same main causes – poor feeding, poor
uptake from stomach and bowel, increased losses, increased need (5,6,17). Thus,
the risk groups for deficiency are fertile women (due to menstruation, pregnancy,
breast-feeding), anorectics, alcoholics, persons with inflammatory conditions or
previous surgical procedures in stomach or bowel (atrophic gastritis, coeliac
disease, Crohn´s disease, rheumatoid arthritis). The greatest risk is, however,
old age. Approximately every second citizen develops at least biochemical signs
of deficiency during his last ten years of life (cf 5,6,11).
Stores,
kinetics, refilling, and maintenance
Normal
body stores of vitamin B12 are estimated to amount to 3000-5000 microgram. The
daily losses are assessed to lie in the range 1-3 microgram per day. A
deficiency develops often insidiously during 2-3 years or longer. The appearance
of deficiency may be much faster in case the maintenance is completely deleted
or body stores are low at the start. On the other hand, the appearance of
symptoms may be extremely slow, over a decade, when some refilling, although
insufficient, occurs (4,7,12).
Symptoms
are thought to appear when body stores of vitamin B12 have sunk to 100-700
micrograms (12). Exhausted body stores may be refilled to approximately 50% by
intramuscular injection, 1 mg weekly for five weeks, or oral cyanocobalamin, 1
mg daily, for 200 days (7,12).
It
should be emphasised that the B12 carrier proteins of the blood, now usually
called haptocorrin and transcobalamin, provide the rate limiting link in
therapeutical refilling of body stores. In some persons, the carriers are
overloaded by 25 microgram of parenteral cyanocobalamin (12, 18); out of 1000
microgram, only 15% are retained within 48 hours.
Hydroxocobalamin
produces approximately three times higher serum values than cyanocobalamin one
month after injection. The usual regimen with hydroxocobalamin is 1 mg every
third month. However, those who listen to their patients will find that a
considerable number of them are tired and gloomy at that point; the subjective
symptoms are swiftly cured by another injection (cf 7,12).
The
B12 carriers of the blood may be overloaded by oral cyanocobalamin over 0.5 mg
(4). This is the probable rationale for the choice of 0.5 mg as the dose in
extended pharmaco-kinetic studies of the
In a
modern study (19), the doubling of oral cyanocobalamin from 0.5 mg to 1 mg
produced a 50% rise of B12 levels in serum. It is reasonable to assume that this
observation reflected urinary excretion of vitamin B12 in some persons treated
with oral cobalamin, 1 mg daily.
From
the above-mentioned considerations, it is suggested that oral treatment with
cyanocobalamin should be performed with 1 mg daily in order to provide safety
margins for food interference with B12 uptake and individual variability of B12
uptake (1-4). This regimen will be convenient for 80-90% of all patients, reduce
health care costs, and reduce fluctuations of patient mood to ordinary
individual level (1-10). For those persons dependant upon injections, it is
suggested that hydroxocobalamin is given subcutaneously, 1000 microgram each
month.
In
contrast to vitamin B12 deficiency, nearly all deficiency states of folate are
treated with oral preparations. Therapy is dominated by folic acid (folacin,
pteroylmonoglutamic acid). Body stores of folate are estimated to lie in the
range 5-10 mg, daily turnover 0.1-0.2 mg, duration of body stores in the absence
of maintenance 2-4 months (12). Monotherapy with folic acid provides a potential
peril by masking an incipient B12 deficiency (12,20).
It
should be emphasised that at the time of a deficiency diagnosis (B12, folate,
iron), the dominating deficiency will block the usage of the other
micronutrients, dam up their serum levels, and create a false impression that
the patient is well nourished except the overt deficiency (cf 9). The optimal
dose of folic acid is 0.4-1 mg daily (12).
Clincal
picture and management of deficiency
A
negative balance of vitamin B12 and/or folate eventually depletes body stores.
The first clinical symptoms are non-specific and varied – fatigue, melancholy,
loss of vitality in body and soul, assessable decrease in productivity and
prestations, more hair in the comb or at the floor of the shower, impaired
memory, a feeling of frozenness.
The
classical neuropathy of B12-folate deficiency involves the distal parts of the
extremities, numbness in fingers, hands, toes, feet, fornications – “glove
on hand, sock on foot”. Impaired balance might be the first sign – inability
to ride the bicycle or climb a stair. The gait may become atactic. However, the
neurological symptoms and signs of B12-folate deficiency are just as
non-specific as the corresponding haematological symptoms and signs.
During
physical examination of a case of suspected deficiency of vitamin B12 and/or
folate, the testing of plantar sensibility, vibratory sense in the distal joint
of the big toe, and balance are particularly swift and useful (2,7,12,22).
Decreased function often heals in 1-3 months. Advanced cases are rare and may
heal in 2-3 years, often with considerable pain during some months.
Sound
evidence for irreversible neuropathy due to B12-folate deficiency is evasive.
The best evidence for the possibility of irreversible deficiency lesions is
provided by the growing foetus - neuronal tube defects, other congenital
malformations, miscarriages.
About
one third of the patients with B12/folate deficiency will appear with
neurological symptoms, others with mucosal or haematological symptoms (7).
Advanced stages of vitamin B12 and/or folate deficiency are now rare, such as
pernicious anaemia, aspermia, advanced neuropathy (2,5,6,15,21,22); most
patients are diagnosed and treated in early stages of deficiency.
Contemporary
patients with B12-folate deficiency are usually detected in the preclinical
“metabolic” phase of deficiency, often without anaemia or with only slight
anaemia, haemoglobin value over 100 g/L (cf 9,23). Thus, the diagnosis has to be
supported by biochemical markers of deficiency or malabsorption. The level of
serum cobalamins has the virtue that low levels usually may be trusted to
reflect deficiency. Normal levels do not exclude deficiency, especially not in
alcoholics and patients with hepatopathy or inflammatory diseases (cf 17).
In the
investigation of a case of suspected B12-folate deficiency, the role of
antibodies against parietal cells and intrinsic factor is subject to debate.
Most Swedish physicians follow the analysis and advice of Anders Lindgren (17)
– diagnosis of atrophic gastritis
by serum gastrin, serum pepsinogen A, and if necessary gastroscopy. Likewise,
the diagnosis of coeliac disease is based on gliadine antibodies and gastroscopy.
The idea is that atrophic gastritis and coeliac disease are strongly associated
with negative B12-folate balance. Thus, full substitution is warranted.
The
main weakness of the gastro-duodenal approach is the focus on one essential
feature of B12-folate uptake with risks of overdiagnosing and overtreating. In
contrast, homocysteine provides a rapid and sensitive marker for deficiency of
vitamin B12 and/or folate. Unfortunately, it is non-specific. In the clinical
routine of primary health care, the rules of thumb are (13):
1.
A homocysteine
value below 15 micromol/L excludes present deficiency at cell level but says
nothing about B12-folate stores. The wallet contains the appropriate cash for
the day, but the bank account may be empty or overloaded.
2.
Homocysteine
values between 15-25 micromol/L are suggestive of deficiency.
3.
Homocysteine
values between 25-200 micromol/L indicate vitamin B12 and/or folate deficiency.
Homocysteine
provides an ideal screening test for early stages of vitamin B12 and/or folate
deficiency (24). It may also be used in order to confirm early response 3-4
weeks after start of therapy. In contrast, homocysteine should not be used in
the monitoring of patient compliance during long-term treatment. It is
reasonable to assume that homocysteine is a swift marker analogous to iron
variables and reticulocytosis, which reflect the availability of vitamin B12 and
folate for the cells at the moment of blood sampling during the first weeks of
deficiency treatment in anaemia.
In
some countries, homocysteine has been marketed as an independent and causal risk
factor for vascular disease. The result of three randomised and controlled
intervention studies – VISP, NORVIT, HOPE-2 – provided no support for this
hypothesis (26-29). Present evidence suggests that the effect of vitamin B12 and
folic acid is explained by the classical concept of rectifying deficiency
(2,30). In future trials of homocysteine lowering, the oral doses should be
vitamin B12 1 mg, folic acid 0.4-1 mg, and pryridoxine 3 mg or less (4,12,31).
Serum
levels of vitamin B12 and folate are thought to reflect the filling and
maintenance of body stores during oral deficiency treatment (cf
4,5,7,8,13,24,25). Thus, it is reasonable to suggest that these methods are
preferred in long-term monitoring of patient compliance. In contrast, serum
levels of vitamin B12 in parenteral therapy is a more complex parameter,
reflecting interchange of vitamin B12 between injection site and body stores,
with a considerable B12 loss into urine (12,18). However, skilled clinicians may
obtain acceptable clinical results without optimal laboratory tools (5,6,23).
It
should be emphasised that there is always a cause of B12 and/or folate
deficiency. This cause should be identified and considered in future management.
There are also some differential diagnoses to be minded. Usually, B12-folate
therapy is life-lasting. Attempts to stop therapy must be monitored quarterly
during the first two years and then at least one follow-up examination each year
for the rest of the patient´s life (cf 4,7,12). Treatment with vitamin B12
should always be supported by folic acid, 0.4-1 mg daily and folic acid should
never be given without adequate B12 protection (cf 9,12).
In the
period 1950-1970, vitamin B12 deficiency was often treated with low doses of
oral vitamin B12, sometimes combined with intrinsic factor (4,12,18). Although
such regimens could produce spectacular initial responses in anaemia in terms of
iron consumption and reticulocytosis (cf 32,33), the body stores were not
replenished and relapses were numerous.
Vitamin
B12 doses below 1 mg daily are thought to be responsible for the bad
international reputation of oral B12 regimens; such doses should stay with the
past. It is not necessary to re-invent the fire, the wheel, and the chiffer of
null.
In
contrast to deficiency patients, healthy people do not need pill supplementation
of vitamins and minerals. In addition to micronutrient content in ordinary food,
cereals are generously fortified in most countries (e.g. Special K ClassicTM,
All Bran RegularTM).
Side
effects of B vitamins
There
is some fear that B vitamin therapy might be associated with side effects
concerning vascular disease (26-29), cognition (34,35), cancer (36). However,
the evidence for substantial side effects is based on shaky pillars and provides
no contra-indication for the treatment of diagnosed deficiency. In any case, the
serum vitamin levels of oral treatment tend to lie below those seen in
parenteral treatment (4,7,8,12,18).
The
regimens suggested in the present essay are also sufficient for neurological
symptoms and dementia (4,7,22,37). Direct comparisons between oral and
parenteral B12 therapy are of limited size (38). Although extended studies with
modern scientific methods are desirable, past research and the clinical
experience in
Current
paradigm shift
About
1960, the therapy of vitamin B12 deficiency became parenteral, because
crystalline cyanocobalamin and crystalline hydroxocobalamin were introduced on
the market. From about 1970, the Swedish physicians gradually turned from
parenteral therapy to oral cyanocobalamin, 1 mg daily (5,6). Thus, the Swedish
tradition provided an alternative paradigm within a dominating global paradigm
of parenteral B12 treatment (cf 39).
From
about 1990, there was an anticipation that homocysteine would turn out as a
causal risk factor for vascular disease. Such diseases were expected to improve
from homocysteine lowering by B vitamins (29).
The
collapse of the risk factor model of homocysteine (26-29) produces a creative
chaos in accordance with the structure of scientific revolutions (39). It is
reasonable to assume that the scientific society will return to treatment of
vitamin B12 and folate deficiency in early stages. The detection of such stages
may be aided by chemical markers such as homocysteine. Thus, the deficiency
marker model of homocysteine persists.
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