Re: B12 Expert Group on Vitamins and Minerals 2003
Это, наверное , старовато. Вот напр и доказательная медицина Кохрейн (для нас
- неврачей - падочка-выручалочка):
http://summaries.cochrane.org/CD004655/oral-vitamin-b12-versus-intramuscular-vitamin-b12-for-vitamin-b12-deficiency
С уважением Ольга
From: Stas AV <exst***@o*****.ru>
To: science.news.bessmertie <privatmemb***@y*****.com>
Sent: Monday, March 26, 2012 7:16 PM
Subject: B12 Expert Group on Vitamins and Minerals 2003
General Information
Chemistry
Vitamin B12 (cobalamin, Cbl) is a water-soluble vitamin and a member of a
family of related molecules
known as corrinoids which contain a corrin nucleus made up of a
tetrapyrrolic ring structure. The centre
of the tetrapyrrolic ring nucleus contains a cobalt ion that can be attached
to methyl, deoxyadenosyl-,
hydroxo- or cyano- groups.
Natural occurrence
Vitamin B12 originates from bacteria, fungi and algae, and is present in
virtually all animal tissues. Plants
contain no vitamin B12 beyond that derived from microbial contamination.
Occurrence in food, food supplements and medicines
Major dietary sources of vitamin B12, mainly in the forms of methyl,
deoxyadenosyl- and
hydroxocobalamin, include meat (e.g. 0.1 mg/kg in lamb), particularly liver
( 0.1 mg/kg) and fish (e.g.
0.03-0.1 mg/kg in salmon, 0.01-0.03 mg/kg in tuna). Hydroxocobalamin and, in
particular, cyanocobalamin
are synthetic forms used in vitamin supplements, pharmaceuticals and in the
fortification of food. Methyl
cobalamin has been used therapeutically outside the UK, for example, in
Japan.
Recommended amounts
The RNI for vitamin B12 in adults in the UK is 0.0015 mg/day (COMA, 1991).
There is no increment
required during pregnancy but there is a recommended increment of 0.0005
mg/day for breast
feeding mothers.
Analysis of tissue levels and vitamin B12 status
Measurement of vitamin B12 in plasma is routinely used to determine
deficiency, but may not be a reliable
indication in all cases. In pregnancy, for example, tissue levels are normal
but serum levels are low.
Various other plasma markers have been identified (including methylmalonic
acid, homocysteine,
holotranscobalamin, anti-intrinsic factor antibodies) and methods devised
(Schilling test, cobalamin
absorbance test, serum gastrin deoxyuridine suppression test) to distinguish
different causes of deficiency.
Brief overview of non-nutritional beneficial effects
Results of studies in humans have suggested that large doses of vitamin B12
(particularly methyl
cobalamin) may influence biological rhythms and thus may be beneficial in
the treatment of sleep
disorders. Vitamin B12 has also been reported to increase light sensitivity
by affecting melatonin
secretion. Vitamin B12, in combination with folic acid, has been suggested
to be beneficial in certain
disorders, such as idiopathic osteoarthritis and vitiligo.
Expert Group on Vitamins and Minerals 2003
93
Risk Assessment Vitamin B12 1
Function
Vitamin B12 serves as a cofactor to at least two enzymes, methionine
synthase and methylmalonyl
CoA mutase. Methionine synthase is pivotal in one-carbon metabolism, being
crucial in the synthesis
of the universal methyl donor S-adenosyl methionine and in the cellular
import and metabolism of
folate. Methylmalonyl CoA mutase converts L-methylmalonyl CoA to succinyl
CoA and is important
in even-chained fatty acid synthesis.
Deficiency
Dietary deficiency is rare in younger people living in the community but
occurs more frequently in older
people, particularly those living in institutional environments. Individuals
adhering to vegan diets may
also be at risk. Deficiency is mostly attributable to inherited or acquired
defects resulting in
malabsorption or the impairment of transport of the vitamin within the body.
Deficiency impacts on
the haematopoietic and nervous systems. Associated diseases include
megaloblastic anaemia and
neuropathies typically sub-acute combined degeneration of the spinal cord.
Vitamin B12 deficiency can
lead to moderate hyperhomocysteinaemia, a possible risk factor for occlusive
vascular disease.
Oral supplements are indicated prophylactically where there is a likelihood
of deficiency in those
whose gastrointestinal function is normal e.g. in individuals who are strict
vegetarians. Inherited and
acquired disorders relating to vitamin B12 malabsorption are usually treated
by repeated injection.
However, oral administration of very high doses of vitamin B12 has been
shown to be effective in the
treatment of pernicious anaemia.
Interactions
Steroid drugs, such as prednisone, have been reported to increase the
absorption of vitamin B12 in
patients with pernicious anaemia. Excessive alcohol consumption and some
drugs may decrease
absorption of vitamin B12. Oral co-administration with ascorbic acid may
result in destruction of vitamin
B12. Concurrent administration of chloramphenicol may lead to antagonism of
the haematopoietic
response to vitamin B12.
Absorption and bioavailability
Vitamin B12 requires intrinsic factor (IF), secreted mainly from the gastric
parietal cells, to ensure
adequate absorption at normal dietary intake levels. Thus the absorption of
physiological doses of
vitamin B12 is limited to approximately 0.0015 - 0.002 mg/dose or meal, due
to saturation of the uptake
system. Regardless of dose, approximately 1.2% of vitamin B12 is absorbed by
passive diffusion and
consequently this process becomes quantitatively important at
pharmacological levels of exposure.
Protein binding in certain foods may reduce the bioavailability of the
vitamin, particularly in individuals
with impaired gastric acid and/or digestive enzyme secretion. The different
forms of crystalline
cobalamin appear to be absorbed or retained to different extents, depending
on the dose. Differences
are most apparent at low doses.
Ingested vitamin B12 is released from the food matrix by the action of
digestive enzymes and gastric acid
and becomes bound to salivary haptocorrin-binding proteins. As the pH rises
further along the gut, and
under the influence of pancreatic enzymes, vitamin B12 is released from the
salivary haptocorrin and
becomes complexed with intrinsic factor (IF). The cobalamin-IF complex binds
to a specific cell wall
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Expert Group on Vitamins and Minerals 2003
95
receptor of the ileal enterocyte and is internalised by endocytosis. Once
inside the cell, the IF is
degraded and the liberated vitamin is converted to the methyl or the
deoxyadenosyl form, is bound to
transcobalamin II (TC II) binding protein and then exported into the portal
blood. In the general
circulation, most cobalamin is bound to transcobalamin I (TC I) but the
majority of cobalamin available
for uptake into the tissues is that bound to TC II.
Distribution and metabolism
Vitamin B12 is distributed into the liver, bone marrow and virtually all
other tissues, including the
placenta and breast milk of nursing mothers. The liver is the predominant
storage site for vitamin B12.
Uptake into cells occurs through receptor mediated endocytosis involving
specific TC II cell wall
receptors. Once inside the tissues/cells, the complex is degraded by the
lysosomes, and the
released cobalamin is metabolised either to methyl-cobalamin in the cytosol,
where it binds to
methionine synthase, or to deoxyadenosyl-cobalamin in the mitochondria,
where it binds to
methylmalonyl CoA mutase.
Excretion
Excretion occurs mainly via the faeces and urine, but also through the
shedding of skin cells. Excretion is
very slow, with significant enterohepatic cycling.
Toxicity
Human data
There are a few case reports of adverse effects associated with ingestion of
vitamin B12, either as a
supplement, or following the consumption of yeast extract products, which
also contain
cyanocobalamin. Five cases of allergic reactions were reported, three of
which were recurrences of
symptoms in individuals who had been previously exposed to cobalamin by the
parenteral route. One
further case reported the occurrence of a skin eruption that resembled acne
rosacea. Vitamin B12
exposures were generally not specified.
No adverse effects were reported in an experiment designed to determine the
uptake of single oral
doses of cyanocobalamin (up to 100 mg). However, only three participants
were administered the very
high doses.
Oral studies have been conducted to investigate the effects of vitamin B12
on pernicious anaemia.
However, although no adverse effects are apparent, these studies are not
relevant to the general
population since absorption of vitamin B12 is reduced in this condition. The
effect of high oral-dose
cyanocobalamin on plasma homocysteine levels in healthy females of
child-bearing age and the
benefits of cyanocobalamin in patients with seasonal affective disorder have
been investigated. No
adverse affects related to treatment were reported in any study including
those in which individuals
received up to 4.5 mg/day cyanocobalamin for 14 days, 2.0 mg/day
cyanocobalamin for up to one year
or 1.0 mg/day cyanocobalamin for several years. Less information is
available following the oral
administration of the hydroxocobalamin form of vitamin B12. However, no
adverse effects were reported
1
in individuals administered 0.3 mg/day for up to 12 months. No adverse
effects were reported in a
controlled study in which 125 individuals received 6.0 mg/day
methylcobalamin for up to 12 weeks.
Adverse reactions (not specified) were reported in one of 16 and in one of
23 oligozoospermia patients
given 6 or 12 mg/day methyl cobalamin, respectively, for 16 weeks,
presumably via the oral route.
However, this study was not controlled.
Animal data
The data-base on the oral toxicity of vitamin B12 in laboratory animals is
limited. Doses of 1.5 to 3.0
mg/kg bw by intraperitoneal and subcutaneous administration were found to be
acutely toxic in mice
(CNS effects; convulsions, cardiac and respiratory failure and ultimately
death). However, much higher
doses ( 5 g/kg bw) cyanocobalamin appeared to be tolerated by mice
following oral administration.
There is no evidence relating to vitamin B12 and teratogenicity or adverse
effects on fertility or postnatal
development.
Carcinogenicity and genotoxicity
There is no evidence suggesting that vitamin B12 is carcinogenic or
genotoxic in vitro or in vivo. How ever,
although data are not consistent, there is some limited evidence to suggest
that high doses of vitamin
B12 may have tumour promoting activity.
Mechanisms of toxicity
No data have been identified.
Dose-response characterisation
No relevant data have been identified.
Vulnerable groups
No vulnerable groups have been identified.
Genetic variations
No genetic variations have been identified.
Part 1 Water Soluble Vitamins
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Studies of particular importance in the risk assessment
(For full review see
http://www.food.gov.uk/science/ouradvisors/vitandmin/evmpapers or the
enclosed CD).
Waife et al., 1963
As part of a non-controlled supplementation trial in patients with
pernicious anaemia (n=27) no adverse
reactions were reported in individuals receiving 0.3 mg hydroxocobalamin/day
for up to one year.
Berlin et al., 1968
No adverse effects attributable to vitamin B12 (cyanocobalamin) were
recorded in a long-term clinical
trial of 64 patients with pernicious anaemia, and other types of vitamin B12
deficiency given a daily oral
dose of 0.5 mg rising to 1.0 mg of cyanocobalamin (without intrinsic factor)
for 10 to 70 months
(42 patients received treatment for over 4 years). However, as noted
previously, systemic absorption in
these patients is limited.
Juhlin and Olsson, 1997
One hundred patients with vitiligo were treated with oral folic acid (5 mg)
and vitamin
B12 (1.0 mg cyanocobalamin) twice daily, for up to 12 months. There were no
reports of adverse effects.
However, 27/100 and 48/100 participants had stopped taking the supplements
after 1 - 2 months and
3 - 6 months, respectively but reasons for withdrawal were not stated
Takahashi et al., 1999
As part of a double-blind study to assess the therapeutic effect of methyl
cobalamin on sleep-wake
disorder, patients were administered either 6.0 (n=21) or 0.03 mg/day (n=27)
methylcobalamin for 8
weeks. The lower dose group was considered as a control group because
ethical permission was not
granted for the inclusion of a placebo control group. There was no report of
any adverse effects. The
route of administration was not clear from the information given. Data were
not available for all
patients at the end of 8 weeks (two of the 6.0 mg/day dose group and three
of the 0.03 mg/day group)
Exposure assessment
Total exposure/intake18:
Food Mean: 0.0062 mg/day
97.5th percentile: 0.020 mg/day (1986/7 NDNS)
Supplements up to 3.0 mg/day (Annex 4)
Estimated maximum intake: 0.020 + 3.0 = 3.0 mg/day
No potential high intake groups have been identified.
Expert Group on Vitamins and Minerals 2003
18 The survey data do not distinguish the different forms of vitamin B12.
Dietary vitamin B12 is mainly in the methyl, deoxyadenosyl and
hydroxocobalamin forms.
Hydroxo- and particularly cyanocobalamin are the forms usually present in
dietary supplements.
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Part 1 Water Soluble Vitamins
1
Risk assessment
Vitamin B12 is a water-soluble vitamin. At physiological doses, as occurs in
food, the amount absorbed is
largely limited (approximately 0.002 mg/meal) by the capacity of the
intrinsic factor-wall receptor
uptake system. At pharmacological levels of dosing, diffusion becomes more
important as the route of
absorption. Vitamin B12 present in excess of the binding capacity of the
liver, plasma and other tissues is
excreted by glomerular filtration.
It is generally accepted that ingested vitamin B12 (cobalamin) has a very
low toxicity in humans. Most
available documented data are either in the form of case reports of possible
vitamin B12-associated
adverse effects or from clinical trials or supplementation studies designed
primarily to investigate
potential beneficial effects. The latter generally involve the use of the
cyanocobalamin or
methylcobalamin forms of vitamin B12 and do not always specifically report
an absence of adverse
effects.
The animal toxicity database for vitamin B12 is very limited. Doses of 1.5
to 3.0 mg/kg bw by
intraperitoneal and subcutaneous administration were found to be acutely
toxic in mice (CNS effects;
convulsions, cardiac and respiratory failure and ultimately death). However,
much higher doses ( 5
g/kg bw) cyanocobalamin appeared to be tolerated by mice following oral
administration.
ESTABLISHMENT OF GUIDANCE LEVEL
There are insufficient data from studies in humans and animals to set a Safe
Upper Level for vitamin B12.
Clinical studies have reported no adverse effects following administration
of up to 6.0 mg/day of
methylcobalamin for several weeks and up to 1.0 mg/day cyanocobalamin for
several years. Clinical
trials and supplementation studies involving up to 100 individuals to
investigate the beneficial effects of
oral cyanocobalamin have not reported any treatment-related adverse
reactions following doses of 0.3
to 4.5 mg for periods ranging from 14 days to several years. Cyanocobalamin
is the type of vitamin B12
most frequently included in supplements in the UK. The study by Juhlin and
Olsson (1997), supported by
the absence of an identified hazard and widespread clinical experience with
oral and parenteral
treatment, suggests that supplemental intakes of 2.0 mg cyanocobalamin/day
should not produce any
adverse effects and this intake can be used for guidance purposes. This is
equivalent to 0.034 mg/kg
bw/day in a 60 kg adult. No uncertainty factor is needed because human data
from large numbers of
individuals are available. However, it should be noted that this figure has
been established in particular
subgroups of the population, i.e. vitiligo suffers and those treated for
pernicious anaemia, and may not
be completely applicable to the general population.
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References
Berlin, H., Berlin, R., Brante, G. (1968). Oral treatment of pernicious
anemia with high doses of vitamin B12
without intrinsic factor. Acta Medica Scandinavica 184, 274-258.
COMA (1991). Dietary Reference Values for Food Energy and Nutrients for the
United Kingdom. Report
of the Panel on Dietary Reference Values, Committee on Medical Aspects of
Food and Nutrition Policy.
HMSO, London.
Juhlin, L., Olsson, M.J. (1997). Improvement of vitiligo after oral
treatment with vitamin B12 and folic acid
and the importance of sun exposure. Acta Dermatol-venereologica 77, 460-462.
Takahashi, K., Okawa, M., Matsumoto, M., Mishima, K., Yamadera, H., Sasaki,
M., Ishizuka, Y., Yamada, K.,
Higuchi, T., Okamoto, N., Furuta, H., Nakagawa ,H., Ohta, T., Kuroda, K.,
Sugita, Y., Inoue, Y., Uchimura, N.,
Nagayama, H., Miike, T., Kamei, K. (1999). Double-blind test on the efficacy
of methylcobalamin on sleepwake
rhythm disorders. Psychiatry and Clinical Neurosciences 53, 211-213.
Waife, S.O., Jansen, C.J., Crabtree, R.E., Grinnan, E.L., Fouts, P.J.
(1963). Oral vitamin B12 without intrinsic
factor in the treatment of pernicious anemia. Annals of Internal Medicine
58, 810-817.
