Cobalamin Deficiency, Methylation and
G.E. Schuitemaker, M.D. and A.J. Hoogland 1
An article in the New England Jour- ficiency are paleness and fatigue. In general,
nal of Medicine from 1988 drew the deficiency is diagnosed on the observation
attention to a scant discerned problem: of enlarged red blood cells (macrocyto-
neuropsychiatric disorders due to vitamin sis). However this symptom cannot be
B12 (cobalamin) deficiency occured in pa- distiguished from folate deficiency. The
tients, mainly elderly, who didn’t present general opinion is that distinction usually
with hematological deviations.1 After ad- only manifests after several years, when
ministration of vitamin B12, the symptoms neuropsychiatric symptoms come forward:
disappeared in practically all patients. The tingling hands and/or feet (always sym-
research demonstrated that in daily prac- metrical), boredom, fatigue and lethargy,
tice a deficiency of vitamin B12 is often shortness of breath, palpitations, sore
not recognized as the cause of severe and mouth with a thick, often painful tongue.
frequently occuring psychiatric disorders. Frequently a pale complexion with soft yel-
Advanced research confirmed these results.2 low discoloration (because of a deteriorated
Other research points out the danger of liver function) is seen. Irritability, loss of
undiagnosed vitamin B12 deficiency, espe- memory, mild depression and mood swings
cially in pernicious anaemia. can also be observed.
B12 Status and Pernicious Anemia B12 Deficiency and Alzheimer’s Disease
Pernicious anemia is an autoimmune New methods to assess vitamin B12 sta-
disease with the principle characteristic be- tus show that vitamin B12 deficiency occurs
ing that the stomach is not able to produce much more often than was previously as-
intrinsic factor necessary for adequate sumed.4 Assessment of the methylmalonic
resorption of vitamin B12 from food. The acid level is a precise method to determine
disease shows a megaloblastic blood picture possible existence of vitamin B12 deficiency,
as a result of a chronic lack of vitamin B12. if necessary supported by assessment of
Suprisingly, the research shows only a slight homocystein and cystathionin.
connection between low vitamin B12 status When these assessments are performed
and pernicious anaemia.3 Yet vitamin B12 in elderly people, high percentages are
blood levels are important for the diagno- often found, which indicates the existence
sis of pernicious anaemia. For this reason of deficiencies of the vitamins cobalamin,
pernicious anaemia is often missed. Fur- folic acid and pyridoxal phosphate (vitamin
thermore, a correct diagnosis is hindered B6) in the elderly.5
by the rather aspecificity of vitamin B12 de- Ten percent of all people between 65
ficiency, and such a deficiency manifesting and 75 years old, 20% of those between
itself over the long term. Also the general 75 and 85 years old and 30% of all those
opinion that storage of this vitamin in the over 85 years old suffer from some sort
human body is sufficient to supply it for of dementia.6 The literature provides ex-
three to six years does not help in diagnos- tended information on the deteriorated
ing pernicious anemia adequately. vitamin B12 status in patients with senile
The first symptoms of a cobalamin de- dementia of the Alzheimer type (SDAT).
Van Tiggelen described subnormal levels
1. Ortho Institute, P.O. Box 82, 7080 AB Gendringen, The
of vitamin B12 in the cerebrospinal fluid
Cobalamin Deficiency, Methylation and Neurological Disorders
of SDAT patients, in spite of normal se- Methylation is Part of Many Processes
rum levels.5,7 Later others described B12 Methyltransferases take part in a
anomaly in SDAT patients.8,9 To clarify large number of body processes,including
connections mentioned above one should regulation of protein structure, regula-
first gain some insight into the reactions of tion of DNA expression, production of
methylation (Figure 1)10 phos-pholipids, and production of certain
hormones and neurotransmitters.10 There
Methylation are also indications that methylation of
In the body cobalamin is active in two phospholipids is the common mechanism
forms. As adenosylcobalamin, a cofactor of of receptor signalling across cell mem-
the enzyme methylmalonyl-CoA-mutase, brane.13
or as methylcobalamin, a cofactor of the Methyltransferases transfer a methyl
enzyme methionine synthase. group away from S-adenosylmethionine
The first form (adenosylcobalamin) (SAM) forming S-adenosyl-homocystein
is involved in conversion of methylmalo- (SAH). SAH is a strongly competitive
nyl-CoA (MM-CoA) into succinyl-CoA. inhibitor of methyltransferases and ac-
In case of shortage of vitamin B12 this cumulation of SAH in the cell will inhibit
conversion takes place insufficiently methylation reactions. The ratio between
and a different conversion takes place of these two compounds is called the methyla-
MM-CoA, namely in methylmalonic acid tion ratio. A low ratio indicates inhibition
(MMA). A raised MMA-level can serve as of methylation.
an exclusive rate of vitamin B12 deficiency. SAH is broken down by S-adenosyl-
This conversion is particularly important homocysteinhydrolase into homocysteine
in the brain and is known as the propionate and adenosine. Adenosine is rapidly
metabolism.11,12 metabolised into, for example, inosine.
The second form of vitamin B12 (meth- Homocysteine has three elimination path-
ylcobalamin) is co-enzyme of methionine- ways: remethylation to methionine (the
synthase. This is an important enzyme in main elimination route), breakdown to
the reaction which transfers a methyl group cystathionine or excretion from the cell.
from 5-methyl tetrahydrofolate (5-MTHF)
to homocysteine, forming methionine. Remethylation in the Brain
This reaction is the key reaction of the so Remethylation of homocysteine is
called methylation, a series of reactions possible in two ways. The first is by way of
in the body transferring methyl groups. the above mentioned enzyme methionine
In these reactions S-adenosyl methionine synthase, but remethylation can also take
(SAM) is used as methyl donor by methyl- place by way of the enzyme betaine meth-
transferase enzymes. SAM is synthesized from yltransfersase. This enzyme is present in
methionine.11,12 only a few organs, such as liver and kidneys
Figure 1. The Methylation Process
Journal of Orthomolecular Medicine Vol. 11, No. 4, 1996
and is not present in the brains. In this case of SAM to SAH are found after exposure
methylation reactions depend totally on to nitrogen oxides. Adequate supply of
functioning of methionine synthase.10 methionine appears to be able to prevent
When both remethylation pathways neuropathy at least partly.15 The addition of
fail, homocysteine is converted with dif- S-adenosyl methionine itself appears in sev-
ficulty into cystathionine , and cysteine eral studies to have many beneficial effects
because the regulating enzyme is activated on the central nervous system, especially
by high levels of SAM, and these are lack- on the monoamine neurotransmitter me-
ing. Consequently SAH and homocysteine tabolism and receptor systems. Provision
accumulate, the ratio between SAM of these methyl donors is responsible for
and SAH (methylation ratio) is low and the remyelination observed in patients with
methylation is inhibited.10 The brain is inborn disorders of folic acid metabolism
capable of remethylation of homocysteine and methylation.16
exclusively by way of methionine synthase
and in case of disfunctioning methionine Affected Liver is an Extra Risk Factor
synthase enzyme is totally dependent on In patients with affected liver func-
plasma methionine supply, derived from tion, such as in alcoholics, chronic pheny-
food or from organs such as the liver, which toin users and patients exposed to hepato-
has the disposal of an alternative synthesis toxic chemicals with neurotoxic potential,
pathway. If this supply also fails, clinical abnormally low levels of cobalamin are
symptoms manifest. found in cerebrospinal fluid.7,17 This could
be indicative of an abnormal conversion
Neuropathy Caused by B12 Deficiency of neurologically active cobalamin by the
Neuropathy as a complication of co- affected liver, for example by changed ac-
balamin deficiency is characterized by demy- tivity of microsomal liver enzymes.18-20 In
elinisation of the posterolateral nerves of the patients with predominantly neurological
spine. At first it was thought to be due to a symptoms of cobalamin deficiency, higher
disturbance of the enzyme methylmalon- serum levels of cobalamin analogues are
CoA-mutase. Shortage of adenosylcobala- found than in patients with hematological
min may inhibit the enzyme, which may symptoms.21 This finding is supported by
result in production of abnormal fatty data derived from studies of alcoholics.22
acids. Incorporation of these defective
fatty acids in myelin may lead to demy- Interaction with Thiamine Metabolism
elination.14 It is possible that functional vitamin
Recent evidence however points to a B12 deficiency blocks resorption, transport
mechanism by way of the enzyme methio- and biological activity of thiamine. In
nine synthase by methylcobalamin. The particular, methylcobalamin deficiency
most important proof of this is derived could induce reduction of the intestinal
from experiments with nitrogen oxides. alkaline phosphatase level, blocking intes-
Nitrogen oxides are strong inhibitors of tinal resorption and possibly also biological
the enzyme methionine synthase. They activation of thiamin.23,24 Deficiency of
inactivate methylcobalamin by oxidation biological active thiamine in the brains
of monovalent cobalt groups to cobalt is connected with a range of neurological
oxide, which then forms biological inactive diseases, as is known from brain research
cobalamin analogues. Exposure to nitrogen in chronic alcoholics.
oxides (also in anaesthesia) results in neu-
ropathy in humans, primates, fruitbats and Folic Acid
pigs.15 In cerebrospinal fluid and neural Folate deficiency is common in elderly.
tissue of these animals extremely low ratios Research among 1250 randomly selected
Cobalamin Deficiency, Methylation and Neurological Disorders
elderly persons showed that 8% had low syndromes and can occur without reduced
serum folate levels.25 Alcoholics, too, run serum level or hematological deviations.
a higher risk of folate deficiency because Assessment of the methylmalonic acid
alcohol specifically affects the formation level is a specific and reliable method to
of tetrahydrofolate. At first, effects of folate determine vitamin B 12 status. Elderly
deficiency are indistinguishable from vita- people often appear to have abnormal me-
min B12 deficiency. Differentiation between thyl malonic acid levels, which indicates
these deficiencies is possible only after a disturbed methylation. Senile Alzheimer’s
long period, when vitamin B12 deficiency is dementia, too, is often accompanied by an
visible by degeneration of nerve tissue. affected B12 status.
The biologically active form of folic The brain has available, in constrast to
acid in the body is 5-methyltetrafolate organs such as the liver, only one method
(5-MTHF), mentioned before as a methyl to remethylate homocysteine to methio-
donor for the enzyme methionine synthase, nine. However B12 deficiency inhibits the
that converts homocysteine to methionine. enzyme responsible for this conversion,
The body, as mentioned, has at its disposal and the brain, therefore, becomes totally
alternative supply routes for methyl groups dependent on supply of methionine in the
in case of insufficient supply of folic acid. blood. When this supply fails, neuropathy,
But in longstanding folate deficiency these among other things, may develop. Folic
protective mechanisms, too, may fail and acid as methyl donor is an important fac-
result in neurological disorders. Folic acid tor in methylation and also in converting
can act in methylation reactions in other vitamin B12 into a biological active form.
ways. Several interactions are documented A complicating factor when the liver
between vitamin B12 and folic acid, which is affected by alcohol or toxic substances.
suppose that folic acid, or rather 5-MTHF, As a consequence vitamin B12 is probably
plays a part in the conversion of cobala- converted abnormally, through which bio-
min to methylco-balamin.26 This theory logical inactive cobalamin analogues enter
is supported by clinical observations of the bloodstream. Disturbance of vitamin
patients with a neuropsychiatric syndromes B1 metabolism may also contribute to
which are responsive to folate. In research development of neurological symptoms in
in elderly patients with depression as- vitamin B12 deficiency.
sociated with mild dementia, 5-MTHF
supplements remedied symptoms in 45% References
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