35, Suppl. 1, pp. 2-7, 2000
MECHANISMS OF VITAMIN DEFICIENCY IN CHRONIC ALCOHOL MISUSERS
AND THE DEVELOPMENT OF THE WERNICKE-KORSAKOFF SYNDROME
ALLAN D. THOMSON
Department of Gastroenterology, Greenwich District Hospital, London SE10 9HE, UK
Abstract — The classic signs of vitamin deficiency only occur in states of extreme depletion and are unreliable indicators for early
treatment or prophylaxis of alcoholic patients at risk. Post-mortem findings demonstrate that thiamine (vitamin Bj) deficiency sufficient
to cause irreversible brain damage is not diagnosed ante mortem in 80-90% of these patients. The causes of vitamin deficiency are
reviewed with special attention to the inhibition of oral thiamine hydrochloride absorption in man caused by malnutrition present in
alcoholic patients or by the direct effects of ethanol on intestinal transport. As the condition of the patient misusing alcohol progresses,
damage to brain, liver, gastrointestinal tract, and pancreas continue (with other factors discussed) to further compromise the patient.
Decreased intake, malabsorption, reduced storage, and impaired utilization further reduce the chances of unaided recovery. Failure of
large oral doses of thiamine hydrochloride to provide an effective treatment for Wernicke's encephalopathy emphasizes the need for
adequate and rapid replacement of depleted brain thiamine levels by repeated parenteral therapy in adequate doses.
Occasionally, patients with the classic signs of vitamin de-
ficiency are seen. These patients are, however, grossly
deprived and are at the end of a long road of increasing vitamin
Although there is much evidence to the contrary, vitamin
deficiency is often wrongly perceived as being uncommon
among alcohol misusers, perhaps because the physical signs
are not specific and few laboratory tests are readily available
which accurately reflect their supply and utilization at the cel-
lular level. Indeed, the findings of Harper et
show that thiamine (vitamin B,) deficiency, sufficient to cause
irreversible brain damage, was usually not suspected ante
mortem. Equally, there is no consensus among psychiatrists
and accident and emergency physicians in the UK, who are
frequently responsible for treating alcohol misusers, as to
which vitamins might be beneficial nor for the best method of
administering vitamin B replacement (Hope et ah, 1999).
This paper concentrates mainly on thiamine deficiency, but
many of the contributory factors creating this state are com-
mon to other vitamins. The problems of absorption of thia-
mine hydrochloride are reviewed and the best way to provide
the brain with an adequate continuous supply of thiamine is
THE DEVELOPMENT OF THIAMINE DEFICIENCY
Thiamine (vitamin B;) deficiency classically leads to
beriberi, which was first recognized as long ago as 2600 BC,
although the cause was not identified until the twentieth cen-
tury. Thiamine was one of the first vitamins to be identified,
its structure having been published by Williams (1936).
Early symptoms of thiamine depletion include fatigue,
weakness, and emotional disturbance, which occur before
other physical features. Prolonged gradual deficiency leads to
beriberi with neuropathy, cardiac failure or peripheral oedema.
If thiamine deficiency is more acute and severe, the individual
develops instead a picture of Wernicke's encephalopathy (WE).
This most frequently occurs when overwhelming demands are
made on thiamine reserves which are already critically low.
WE is classically described as having an acute onset with
nystagmus, abducens and conjugate gaze palsies, ataxia of
gait, and global confusion. It has become clear in recent years,
however, that these classic signs are only present together in
approximately 10% of patients and the diagnosis is frequently
Evidence now supports the view that Korsakoff 's psychosis
characterized by amnesic defects, results from inadequate
treatment of WE. The fact, however, that one rarely sees the
full blown syndrome in thiamine deficiency alone suggests that
the neurotoxic effects of alcohol may also play a part, although
the response to prolonged thiamine therapy has been shown to
be beneficial. For further discussion of the relationship between
WE, KP, and beriberi, the reader is referred to the discussion by
Lishman (1998). Because of the close relationship between
reference is often made to the Wernicke-Korsakoff
syndrome (WKS) as though it were a single condition.
Whereas inadequate intake is the main cause of thiamine
deficiency in underdeveloped countries, in most developed
countries of the world there is a close relationship between
alcoholism and WKS, alcoholism accounting for more than
of the cases. There are, however, other causes of thiamine
deficiency seen in areas of poverty and disease such as the
inner cities. Here, for example, teenage mothers who are still
themselves growing are sometimes further depleted by poor
nutrition and drug abuse. Occasionally, there are problems
with patients receiving long-term parenteral therapy, people
on starvation diets, following gastrectomy and stapling, neglect
in old age or in association with AIDS. WKS has been described
in association with carcinoma of the stomach, toxaemia of
pregnancy, pernicious anaemia, and anorexia nervosa. Other
causes have included renal dialysis and it has occurred follow-
ing severe malnutrition in a schizophrenic patient. Frequently,
malnutrition will follow the outbreak of war when food supplies
are disrupted or prisoners have had imposed malnutrition.
Thiamine depletion occurs within 2 to 3 weeks and may give
rise to WKS which may occur without the individual present-
ing for medical care. Studies by Baker et al. in the 1960s
© 2000 Medical Council on Alcoholism
VITAMIN DEFICIENCY IN ALCOHOLISM
showed that, in animals and in man, blood levels of thiamine
fell dramatically after 2 weeks of deprivation. There was an
accompanying reduction in liver and muscle stores and
enzymes that required thiamine diphosphate as a coenzyme
showed impaired function. For example, the activity of trans-
ketolase, an enzyme in the pentose phosphate pathway for
carbohydrate metabolism, dropped significantly after 2 weeks,
thereby demonstrating progression of the malnourished state
from low circulating thiamine levels to a biochemical lesion.
After one or more such episodes of WE, the patient may go
on to the chronic syndrome which may or may not have the
amnestic features of
It has also been suggested that either
chronic WE or KP may result from subclinical episodes of
thiamine deficiency (Lishman, 1981).
Studies in 4684 prisoners of war in the Far East during
the Second World War found that vitamin deficiencies were
usually multiple and that 679 prisoners showed evidence of
thiamine deficiency. WE appeared in this group when acute
and severe thiamine depletion was superimposed on partial
depletion, for example the stress of intercurrent illness,
such as typhoid fever, developing in an already compromised
prisoner or if they were given a large glucose/carbohydrate
load which requires thiamine for its metabolism (Gibberd and
Simmonds, 1980). In industrialized countries, alcoholism has
been associated with reduced thiamine circulating levels in
of patients. Similarly to the prisoners of war, these
patients frequently had multiple vitamin deficiencies. Low
levels of folic acid have been shown in 60-80%, pyridoxine
(vitamin B6) in 50% (Thomson et ah, 1987), and riboflavin
(vitamin B9) in 17% (Thomson et ah, 1996); nicotinic acid
deficiency being less common.
Baker and Frank (1968) and Leevy et al. (1965) in their
pioneering work on vitamin deficiencies in alcoholic patients
developed many assays to measure circulating vitamin levels
in man, including one for thiamine using a highly sensitive
and specific protozoan called Ochromonas danica, which has
mammalian like requirements for
More recently, solid
phase chromatography, electrophoresis, and high-performance
liquid chromatography have been used to measure the very low
levels of thiamine in the blood and other tissues. Similarly,
measuring the activity of transketolase, the enzyme previously
mentioned involved in carbohydrate metabolism, catalysing the
two-carbon fragment from a ketose to the aldehydic
carbon of the aldose in the pentose monophosphate shunt. The
interpretation of the results, however, is more complex than
was initially thought. These tests are not routinely available in
The daily requirement for thiamine is approximately 1.5 mg,
but the whole body stores are only between 30 and 50 mg with
2-4 mg being present in the liver. Thiamine requirements are
related to energy metabolism and energy intake. These obser-
vations are consistent with Baker's findings and explain why a
deficient diet will, therefore, deplete the stores in approxi-
mately 20-25 days. Thiamine is available in meat products,
especially pork and liver, vegetables, milk, legumes, fruits,
and to a lesser extent eggs. Thiamine hydrochloride has been
added to flour in the USA since the 1930s. In the UK, it has
been added since the 1940s but in Australia, in the form of
thiamine mononitrate, only since 1991. As discussed below,
these may not be the best molecular forms of thiamine to over-
come the malabsorption seen in alcoholic patients.
Patients who misuse alcohol frequently choose to drink
alcoholic beverages which contain little thiamine instead of
eating a good mixed diet. As their condition deteriorates,
alcohol may virtually replace any other source of nutrition for
long periods of time. This problem is compounded by the fact
that beer and wine contain carbohydrate which will require
additional thiamine for its metabolism.
Vomiting due to gastritis and diarrhoea often further reduce
the thiamine available for absorption from the intestine.
A test has been developed using [35S]-thiamine hydrochloride
to measure absorption of this vitamin in man. The basis of the
test is that radioactive thiamine is given by mouth together
with a simultaneously administered non-radioactive i.v. flush-
ing dose. After many experiments, the test conditions have
been established, so that the amount of radioactivity appearing
in the urine is a fairly accurate measurement of the amount
of thiamine originally absorbed (Thomson, 1969). In normal
subjects, it has been found that as the size of the oral dose is
increased, a plateau is reached such that giving more thiamine
does not produce any greater absorption than approximately
4.5 mg, however large the oral dose has been (Fig.
absorption depends on an active energy-dependent transport
mechanism, which obeys Michaelis-Menton kinetics, and there
is no evidence in man of the absorption by simple diffusion
which has been observed in rats.
Further experiments showed that giving ethanol by mouth
or i.v. significantly reduced thiamine hydrochloride absorption
(Fig. 2). It caused a 70% reduction in expected serum
radioactivity and a 52% reduction in total absorption in 30%
of the subjects. Experiments during hepatic vein catheter-
ization showed that the route of thiamine absorption remained
24 6 810 1520 25 30
Oral dose (mg)4050
Fig. 1. Relationship between the dose of radioactive thiamine given
orally and the cumulative 72-h urine radioactivity.
A 200-mg dose of non-radioactive thiamine hydrochloride was given
i.v. with each oral dose. Values are means ± SD (bars).
A. D. THOMSON
40 6080 100 120 140 160 180
i=] After Ethanol
Fig. 2. Radioactivity in serum and urine after administration of 5.0 rag
of radioactive thiamine orally to three healthy subjects with and without
prior administration of ethanol.
A 200-mg dose of non-radioactive thiamine was given i.v. along with
the oral dose. When administered, ethanol was given at a dose of 1.5 g/kg.
Values are means ± SD (bars).
40 60 80 100 120 140 160 180
Fig. 3. Radioactivity in serum and urine after administration of 5.0 mg of
radioactive thiamine orally to 12 malnourished alcoholic patients before
and after treatment.
A 200-mg dose of non-radioactive thiamine was given i.v. along with
the radioactive thiamine dose. Values are means ± SD (bars).
unchanged. The inhibitory effects of ethanol on thiamine
hydrochloride absorption have subsequently been confirmed
in animal experiments and in man (Thomson and Pratt, 1992;
Thomson et al, 1996).
In another group of malnourished alcoholic patients, there
was marked inhibition of thiamine absorption even in the
absence of alcohol (Fig. 3). The serum levels of radioactivity
were from 30-98% less than the lower level established for
normal subjects. Portal and hepatic vein levels were reduced
to the same extent. Total absorption was reduced to 13.9 ± 3%
of the 5-mg orally administered dose, compared to 35.3 ± 2.2%
in the control subjects. Additional flushing doses con-
firmed that this reduction was due to reduced absorption,
which was verified by portal and hepatic vein measurements.
There was a wide variation in the degree of malabsorption
with some patients absorbing virtually no thiamine. Absorp-
tion did not return to normal until the patients had been given
a high protein-high vitamin diet for approximately 6 weeks
The effects of malnutrition and alcohol seem to be additive
and explain why some subjects become so thiamine depleted.
As seen in Fig. 4, there are multiple causes for thiamine
deficiency starting with inadequate intake, increased loss from
vomiting, diarrhoea or increased urinary excretion in subjects
with an increased need for this vitamin. Alcohol or mal-
nutrition may reduce the absorption of
Storage in the
liver is impaired by liver damage. In addition, damage to the
protein part of the enzymes may interfere with the utilization
CHANGED NUTRITIONAL REQUIREMENTS
WITH INCREASING LIVER DAMAGE
Progressive alcoholic liver damage is primarily dependent
upon the quantity of alcohol consumed, perhaps with a thres-
hold of 60-80 g of alcohol taken daily for 10 to 12 years
for injury to be initiated. Other factors are also important,
such as gender, genetics, dietary habits, and nutritional status
(McCullough and O'Conner, 1998). For example, the incidence
of cirrhosis is lower than expected in countries with a high
saturated fat intake and obesity is an independent risk factor.
However, hepatitis C infection, which is increased in alcohol
misusers, combines to predispose the patient to more advanced
liver injury than is caused by alcohol alone (McCullough and
Increasing liver damage not only reduces the capacity to
store vitamins, but brings about marked metabolic changes
which impose more demands on the already depleted nutrient
supply (Thomson and Pratt, 1992). Contrary to previous
recent studies of patients with cirrhosis due to ethanol or other
causes have demonstrated that their protein requirements are
increased (Seymour and Whelan, 1999) and that aggressive
enteral nutrition accelerates improvement often without
VITAMIN DEFICIENCY IN ALCOHOLISM
+ = enzyme
y hepatic storage
v release from
Mg t thiamine
• metabolic demands
Fig. 4. Mechanisms of nutritional deficiency in alcoholism.
Reproduced here from Thomson et
(1980), with kind permission of the publishers Ellis Horwood.
causing deterioration in the hepatic encephalopathy (Kearns
1992). Protein-energy malnutrition may occur in 20-60%
of patients with cirrhosis and is dependent upon the degree of
liver damage (Italian Multicentre Cooperative Project, 1994).
Other positive factors in protein-calorie malnutrition include
nausea, anorexia, and the development of a hypermetabolic
state (Seymour and Whelan, 1999). Other studies suggest that
there is increased lipid utilization and insulin resistance causing
diabetes. These metabolic defects exacerbate the degree of
malnutrition and emphasize the need for adequate replace-
ment, including vitamins and minerals (Greco et al., 1998).
In 1997, the European Society for Parenteral and Enteral
Nutrition published guidelines recommending protein intakes
of 1-1.5 g/kg (Plauth et al, 1997) with 30-40 kcal/kg/day, and
similar guidelines have been suggested in the USA (McCullough
and Bugianesi, 1997). Micronutrients should be supplemented
routinely, since deficiency may occur in 10-50% of patients
(Kondrup and Miiller, 1997). Improved nutrition has been shown
to increase survival, surgical outcome, and liver function
(McCullough and Bugianesi, 1997).
SUPPLEMENTATION AND PREVENTION OF WKS
As previously mentioned, bread was not supplemented with
thiamine mononitrate in Australia until 1991. This measure
was taken as part of a concerted effort to deal with the high
incidence of WKS in Australia. Since then, there has been
evidence of a significant fall in the incidence of this disease.
This suggests that some alcohol misusers may be able to bene-
fit from this supplementation to a limited extent, but, during a
similar period, there has been a reported increase in the inci-
dence of KP in Glasgow where the bread has been supple-
mented for many years. In Australia, where there have been
fewer acute cases of WE, there has also been an improvement
in management and education programmes as well as an over-
all reduction in alcohol consumption which may be equally
important in preventing WKS.
There has been an interest for some time in adding thiamine
to beer. This would have the advantage of increasing thiamine
intake as more beer is drunk. However, there remains the un-
answered question of how common and to what degree
A. D. THOMSON
inhibition of thiamine absorption by alcohol is in the 'at risk'
and malnourished population. This requires more study. In
addition, vitamin deficiencies are usually multiple, including
vitamin B6 and niacin which are also required for brain
function, not to mention the importance of protein intake and
THIAMINE DEPLETION IN THE
DEVELOPMENT OF WE
The most serious consequence of thiamine deficiency is
damage to the central nervous system (CNS) causing WKS.
This is characterized by periventricular lesions including the
mamillary bodies, other hypothalamic structures, periventricular
thalamic nuclei, and the structures from the floor of the fourth
ventricle (Thomson and Pratt, 1992).
Thiamine diphosphate (TDP) acts as a coenzyme to a num-
ber of intra-mitochondrial enzymes involved in carbohydrate
and lipid metabolism. TDP, as previously stated, is a cofactor
of the enzyme transketolase, which catalyses an important
step in the pentose phosphate pathway of carbohydrate metab-
olism, being a major source of pentoses for nucleic acid
synthesis and of NADPH for fatty acid synthesis (lipogenesis).
There is also evidence that thiamine triphosphate acts on ion
channels in the brain and nerve cell transmission.
The brain of a 70-kg man weighs approximately 1.5 kg, but
will use 20% of total body oxygen to meet its enormous energy
In fact, one-fifth of all food consumed will probably be
used to provide energy for the brain. The brain depends almost
exclusively on a continuous supply of glucose and 50% of
the cerebral thiamine is involved in pyruvate oxidation, there-
fore directly with energy production. The loss of neurones in
the thiamine-deficient brain probably has multiple causes, which
include impaired energy metabolism, focal acidosis, loss of
transketolase activity, and damage from a regional increase in
glutamate (Butterworth et al, 1986; Pratt et al, 1990).
IMPLICATIONS FOR TREATMENT
The clinician treating a patient with WE has a window of
opportunity when an adequate supply of thiamine to the brain
can reverse the 'biochemical lesion' and limit the permanent
damage which will otherwise result. This depends on making
the correct diagnosis as soon as possible as has been discussed
by Cook elsewhere in this issue (Cook, 2000). It also depends
upon bypassing the intestinal block to absorption, since little
thiamine will be absorbed even from recurrent large oral doses
of thiamine hydrochloride or thiamine mononitrate. It is im-
portant in this respect to recognize that parenteral doses of
1-500 mg of thiamine are generally well tolerated and toxic
effects have been ascribed to rare allergic reactions.
Thiamine transport across the blood-brain barrier is by an
active rate-limited process, which occurs at a maximum rate
of 0.3 p.g/h/g of brain tissue. This is equivalent to the level of
brain thiamine turnover, suggesting that thiamine transport
is only just sufficient to meet cerebral needs under normal
circumstances. At higher blood concentrations thiamine is
transported by passive diffusion, and therefore a high plasma:
CNS concentration gradient, which is achieved by parenteral
therapy, will ensure rapid correction of brain thiamine levels.
There have been a number of published studies comparing
parenteral vs oral thiamine therapy in chronic alcoholics (Cook
et al, 1998). Thomson (1969) and Thomson et al. (1983)
demonstrated that giving 50 mg of thiamine hydrochloride
orally had little effect on the CNS or blood vitamin levels
and did not cause any clinical improvement in patients
Experiments using [35S]-thiamine hydrochloride have
shown that thiamine serum levels fall to 20% of their peak
value within 2 h of parenteral administration (Thomson, 1969)
(see Fig. 5). The accumulated evidence suggests that large
parenteral doses are required which far exceed the total body
stores of thiamine. This may reflect the need of damaged
enzymes for increased supplies of thiamine, or be due to other
Fig. 5. Radioactivity in serum and urine after (a) i.v. administration, (b) i.m. administration of a 200-mg dose of [35S] thiamine hydrochloride.
factors which require further study. It
however, explain why
oral treatment in 'alcohol misusers' is frequently inadequate.
In order to ensure that the CNS vitamin levels in WE patients are
restored, parenteral vitamins should be given three times daily.
GENERAL CONCLUSIONS AND COMMENTS
Vitamin deficiencies, especially thiamine, are frequently
present and often unrecognized especially in alcoholic patients.
While waiting for the classic signs of vitamin deficiency to
develop, these patients will have been nutritionally depleted
for a long period of time. The absorption of thiamine hydro-
chloride is limited in normal subjects, because of the nature of
the absorption process in man, and although the pattern of
absorption remains the same in patients who are either drink-
ing or malnourished, the actual amount that can be absorbed is
markedly reduced. Ethanol or malnutrition can independently
interfere with the absorption and the combination of both is
probably often additive. If patients are going to be treated
adequately, then they need to have their brain thiamine deficit
replaced as soon as possible, in adequate amounts by the most
appropriate route, if irreversible brain damage is to be avoided.
In patients with impaired absorption, this means parenteral
therapy in repeated doses to maintain a high blood:CNS ratio.
Guidelines are discussed elsewhere in this issue but therapy
should continue as long as there is evidence of continuing
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