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Mechanisms of Vitamin Deficiency in Chronic Alcohol Misusers and the Development of the Wernicke-Korsakoff Syndrome


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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 B1) 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.
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& Alcoholism
35, Suppl. 1, pp. 2-7, 2000
Department of Gastroenterology, Greenwich District Hospital, London SE10 9HE, UK
September 1999)
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
(1986) clearly
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
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
WE and
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
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
transfer of
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
clinical practice.
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).
40 6080 100 120 140 160 180
B 50
S 10
Before Ethanol
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
12 24
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
(Fig. 3).
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
of thiamine.
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
O'Conner, 1998).
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
impaired appetite,
economic factors
inadequate diet
reduced absorption
Impaired utilization
+ = enzyme
y hepatic storage
v release from
•^necrotic cells
Reduced absorption
folic acid
Urinary excretion
Mg t thiamine
need DNA/RNA
synthesis and
liver regeneration
Y ethanol
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).
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
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
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).
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
with WE.
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
1> 60
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.
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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... Nystagmus and ophthalmoplegia are common signs. Ataxia is characterized by an uncoordinated gait (102)(103). Clinical diagnosis may not be simple: as early as 1986, Harper and colleagues reported that 80% of patients with Wernicke-Korsakoff syndrome, found during autopsy exams, had not been diagnosed as such during life. ...
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... The Royal College of Physicians also produced guidelines recommending 250 mg IV once daily when used prophylactically and 500 mg three times daily for presumptive diagnosis of WKS including acute WE, both for between 3 and 5 days (Thomson et al., 2002). Oral thiamine supplementation is inadequate as no more than 4.5 mg is absorbed from oral doses exceeding 30 mg (Thomson, 2000). In Australia, like the rest of the world, there is no established consensus for thiamine dosing regimens, with many hospitals implementing their own protocols (Pruckner et al., 2019). ...
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Background: The primary cause of Wernicke-Korsakoff syndrome (WKS) is thiamine deficiency, and more than 90% of cases are reported in alcohol-dependent patients. While observational studies show parenteral thiamine administration drastically reduced WKS-related mortality, relevant treatment trials have never been conducted to determine the optimum thiamine dose. Methods: Two double-blind, parallel groups, randomized controlled trials (RCTs) were conducted to determine the optimal thiamine dose required for (1) the prevention of Wernicke's encephalopathy (WE), the acute phase of WKS, in asymptomatic but "at-risk" alcohol misuse patients (Study 1) and (2) the treatment of WE in symptomatic alcohol misuse patients (Study 2). Each study had a dosage regimen comprising three parenteral thiamine doses that were allocated at a ratio of 1:1:1. Study 1: Asymptomatic At-Risk patients (N = 393) received either 100 mg daily, 100 mg thrice daily, or 300 mg thrice daily, for 3 days. Study 2: Symptomatic patients (N = 127) received either 100 mg thrice daily, 300 mg thrice daily, or 500 mg thrice daily, for 5 days. Cognitive function was the primary outcome, assessed using the Rowland Universal Dementia Assessment Scale, two Cogstate subtests, and an adapted Story Memory Recall test. Secondary analyses examined differences in neurological function (ataxia, oculomotor abnormalities, and confusion) at follow-up. Results: No significant differences were observed between any of the dosage conditions for either Study 1 or Study 2 on cognition or neurological functioning. This real-world study found that having a clinically unwell target population with high comorbidity and multiple presentations, coupled with challenges in cross-cultural assessment is likely to complicate RCT findings. Conclusions: The results of this study showed no clear benefit of high dose thiamine over intermediate or lower doses of thiamine, over the time intervals examined, for the treatment and prevention of cognitive and neurological abnormalities related to WKS. Several study limitations temper the interpretation of these findings. Nevertheless, the absence of conclusive evidence for the superiority of high-dose thiamine supports a recommendation for patient-specific treatment, while ensuring that the potential impact of other biochemical factors (e.g., magnesium and other B vitamin deficiencies) are considered and corrected if necessary.
... It is possible that it does not directly cause thiamine deficiency, but rather induces it as a result of its well-known association with malnutrition. More precisely, the poor rate of thiamine absorption at the mucosal level, the impaired hepatic function, and the increased thiamine metabolism associated with alcohol Case Report consumption may all contribute to the development of chronic thiamine deficiency [3,2]. ...
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Wernicke Encephalopathy (WE) is a reversible, acute neuropsychiatric consequence of thiamine deficiency. Alcohol is the most prevalent cause of thiamine deficiency, which results in WE. WE is traditionally manifested by a triad of ophthalmoplegia, gait ataxia and altered mental state. WE is a curable condition, especially in its early stages, but because it is primarily a clinical diagnosis, the variable presentation might result in delayed diagnosis, which can prevent early treatment, thus; resulting in catastrophic outcomes. While the literature has reported secondary causes of WE such as malabsorption, nutritional insufficiency, and chronic wasting, we present a case of Wernicke encephalopathy related to pyloric stenosis in a young non-alcoholic male adult.
... If a diet is thiamine-deficient, the body will deplete its store in 2-3 weeks. 1 Thiamine deficiency is common in patients with heart failure (HF), occurring in 33% of patients. 2 The failing heart exhibits decreased adenosine triphosphate levels when examined using magnetic resonance spectroscopy. ...
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Background Thiamine supplementation may improve cardiac function in older adults with heart failure (HF). Our objectives were to determine (i) the feasibility of conducting a large trial of thiamine supplementation in HF and (ii) the effects of thiamine on clinical outcomes. Methods We conducted a double-blinded randomized placebo-controlled two-period crossover feasibility study from June 2018 to April 2021. Adults aged ≥60 years with symptomatic HF and reduced ejection fraction (≤45%) were included. Participants were randomized to thiamine mononitrate 500mg or placebo for 90 days and switched to the opposite treatment for 90 days after a 6-week washout period. The primary feasibility outcome was recruitment of 24 participants in 11 months. Results We screened 330 patients over 21 months to recruit 24 patients. Participants’ mean age was 73.4 years. The targets for refusal rate, retention rate and adherence rate were met. There were non-significant improvements in left ventricular ejection fraction and NT-proBNP with thiamine. There were 13 serious adverse events in seven patients; none related to the study drug. Conclusions Although we did not reach our recruitment target, we found high-dose thiamine supplementation to be well tolerated with potential improvements in biomarker outcomes. A larger trial of thiamine supplementation is warranted.
... Trente à 80% des patients TUAL présentent une carence en vitamine B1, la thiamine . En effet, ces patients ont tendance à négliger leur alimentation et à présenter des dysfonctionnements gastro-intestinaux et hépatiques qui ont pour conséquence de compromettre l'absorption, le stockage et la phosphorylation de la thiamine (Thomson, 2000;Coulbault et al., 2019). Cette déficience thiaminique peut provoquer une encéphalopathie de Gayet-Wernicke (EGW), qui a été initialement caractérisée par une triade de symptômes cliniques : une confusion (désorientation spatio-temporelle), une ataxie (troubles de l'équilibre), et des anomalies oculomotrices (nystagmus, paralysie du mouvement des yeux) (Wernicke, 1881). ...
Le trouble de l’usage d’alcool (TUAL) est associé à des atteintes cérébrales et cognitives. Ces altérations empêchent les patients de bénéficier des prises en charges psychosociales et augmentent le risque de rechute. Une réversibilité de ces atteintes est possible avec l’abstinence et a été mise en évidence dans le TUAL. En revanche, les patients présentant un syndrome de Korsakoff (SK) ont une amnésie antérograde sévère qui est considérée comme irréversible, même si l’évolution cognitive et cérébrale de ces patients est peu documentée. L’objectif de cette thèse est donc d’étudier la valeur pronostique, l’évolution ainsi que la prise en charge des atteintes cognitives et cérébrales dans le TUAL et le SK. Nos résultats montrent que l’alexithymie et les altérations des systèmes limbique et fronto-cérébelleux observés post-sevrage sont des facteurs de mauvais pronostic du statut addictologique au cours de l’année post-sevrage. Nous montrons qu’après le sevrage, un court séjour en soins de suite et de réadaptation permet une amélioration, voire même une normalisation des fonctions cognitives. Une prise en charge intensive, incluant des ateliers de stimulation cognitive pendant ce séjour, semble favoriser la récupération. Nos résultats ont mis en évidence que chez les patients SK, les déficits sévères de mémoire épisodique sous-tendus par des altérations du circuit de Papez, persistent avec le temps. Les atteintes des fonctions exécutives et du circuit fronto-cérébelleux peuvent récupérer de manière limitée. Ces résultats soulignent la nécessité d’évaluer les atteintes cognitives et cérébrales ayant une valeur pronostique pour la rechute. Ils indiquent également l’importance d’adapter la prise en charge afin de favoriser la récupération cognitive dans le TUAL ou de compenser les troubles mnésiques persistants et invalidants dans le SK.
... Thiamine, also known as Vitamin B 1, is an essential cofactor that is critical for nerve function. It is required for the functioning of several enzymes responsible for carbohydrate and lipid metabolism and the generation of several essential molecules including nucleic acids and neurotransmitters [61,62]. The human body is incapable of producing thiamine itself and therefore it must be derived solely from diet. ...
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Alcohol works on the brain to produce its desired effects, e.g., sociability and intoxication, and hence the brain is an important organ for exploring subsequent harms. These come in many different forms such as the consequences of damage during intoxication, e.g., from falls and fights, damage from withdrawal, damage from the toxicity of alcohol and its metabolites and altered brain structure and function with implications for behavioral processes such as craving and addiction. On top of that are peripheral factors that compound brain damage such as poor diet, vitamin deficiencies leading to Wernicke-Korsakoff syndrome. Prenatal alcohol exposure can also have a profound impact on brain development and lead to irremediable changes of fetal alcohol syndrome. This chapter briefly reviews aspects of these with a particular focus on recent brain imaging results. Cardiovascular effects of alcohol that lead to brain pathology are not covered as they are dealt with elsewhere in the volume.
... All study patients received daily doses of open label thiamine (100 mg twice daily) after the completion of the consenting process. All patients received standard clinical inpatient care for alcohol detoxification and medical management, including counseling according to the "Human Subjects Protection" guideline of NIH [20]. ...
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Background: Hyperuricemia has been reported in liver injury; however its role in the early stage of Alcohol-associated Liver Disease (ALD) has not been examined yet. This study investigated the role of Serum Uric Acid (SUA) in alcohol-related liver disease, gut barrier dysfunction, and inflammation activity. This study also evaluated the efficacy of abstinence, treatment with thiamine and medical management to alleviate hyperuricemia. Methods: 48 heavy drinking Alcohol Use Disorder (AUD) patients (34 males [M]/14 females [F]) participated in this study. Patients were grouped by serum Alanine Aminotransferase (ALT) levels as group 1 (ALT ≤ 40 U/L, 7M/8F) and group 2 (ALT>41U/L, 27M/6F). All patients received open label thiamine 200 mg daily dose. Demographics, drinking history (using Lifetime Drinking History [LTDH], and Timeline Follow Back [TLFB] for the past 90 days) reports were collected at baseline. Baseline and three-week assessments for SUA, biomarkers of liver injury, endotoxemia and inflammation were evaluated. Results: 22 out of 48 AUD patients reported hyperuricemia, primarily in males. SUA was significantly associated with ALT in each group (in group 2, when covaried with HDD90). SUA was also significantly associated with gut barrier dysfunction markers, LBP and LPS, in group 2, SUA and LBP predicted IL-1β significantly in group 2. Uric acid along with IL-1β and HDD90 significantly predicted necrotic type of hepatocyte cell death in group 2. Post-treatment SUA dropped across both the groups, significantly in females; adverse effects of drinking, cytokine and uric acid interaction on liver cell death also decreased in group 2. In vitro experiments validated the efficacy of thiamine on hepatocytic uric acid production in alcohol sensitization. Conclusion: Uric acid, a metabolic risk signal, was likely involved in the interaction of proinflammatory activity with heavy drinking markers at early-stage ALD. Three-week inpatient medical management, along with treatment with thiamine, seems to alleviate baseline hyperuricemia and necrotic type of hepatocytic cell death in AUD patients with liver injury.
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Neurološke bolesti uzrokovane alkoholizmom.
Alcohol is a highly toxic substance and has teratogenic properties that can lead to a wide range of developmental disorders. Excessive use of alcohol can change the structural and functional aspects of a developed brain and other organs. Which can further lead to significant health, social and economic implications in many countries of the world. Convincing evidence support the involvement of microRNAs (miRNAs) as important post-transcriptional regulators of gene expression in neurodevelopment and maintenance. They also show differential expression following an injury. MiRNAs are the special class of small non coding RNAs that can modify the gene by targeting the mRNA and fine tune the development of cells to organs. Numerous pieces of evidences have shown the relationship between miRNA, alcohol and brain damage. These studies also show how miRNA controls different cellular mechanisms involved in the development of alcohol use disorder. With the increasing number of research studies, the roles of miRNAs following alcohol-induced injury could help researchers to recognize alternative therapeutic methods to treat/cure alcohol-induced brain damage. The present review summarizes the available data and brings together the important miRNAs, that play a crucial role in alcohol-induced brain damage, which will help in better understanding complex mechanisms. Identifying these miRNAs will not only expand the current knowledge but can lead to the identification of better targets for the development of novel therapeutic interventions.
• Acetaldehyde has been implicated in the pathogenesis of alcohol-related liver damage by two mechanisms. Adduct formation with many tissue constituents, especially proteins, makes them immunologically foreign or reduces enzyme activity and formation of cytotoxic free radicals from acetaldehyde metabolism. Adduct formation damage to microtubule associated proteins and to hepatocyte membranes impedes protein movement into, out of and around the cell. • Evidence that these mechanisms also have a role in alcoholic brain damage includes raised blood acetaldehyde in alcoholics, especially in those chemically dependent, or in other abnormal states; effects of extra-hepatic free radical toxicity, including induction of superoxide dismutase activity and damaged, abnormal variants of the thiamin-dependent enzyme transketolase and extrahepatic acetaldehyde-adduct formation with haemoglobin. That acetaldehyde-mediated impairment of microtubule systems also damages the brain is suggested by its importance for the maintenance by protein transport of often greatly extended brain cell processes. • Oxygen-derived free radicals can damage brain tissue, the effects including cerebral oedema, neuronal loss and damage to the blood-brain barrier, all changes also reported in the brains from alcoholic patients. Alcohol-related pathology in the brain differing from that in the liver, shows sharper regional variations in vulnerability and adverse effects due to nutritional deficiencies, especially of B-group vitamins. Even though some such deficits are capable of causing encephalopathy in the non-alcoholic, the strong association between them and chronic alcoholism points to possible aggravation by metabolic interactions at various levels between acetaldehyde and thiamin or other B-vitamins. Selective regional vulnerability may reflect differences in ease of acetaldehyde access or to important metabolic differences. Alteration of animal behaviour by acetaldehyde points to a need to correlate clinical evidence of acetaldehyde central nervous cytotoxicity with the incidence of different types of cognitive defect.
In this paper an attempt has been made to identify important factors governing the supply of thiamine and to examine the relative roles of thiamine and ethanol in the pathogenesis of alcoholic brain damage. Thiamine depletion occurs in alcoholics principally through decreased intake, impaired absorp tion and reduced hepatic storage. The kinetics of thiamine uptake and turnover in brain are such that any fall in circulating levels of the vitamin may significantly impair the supply to the brain. The brain depends on an adequate supply of glucose both as an energy source and as a donor of carbon fragments for protein and lipid biosynthesis. Glucose utilisation is, however, thiamine dependent and it is likely that this is a major factor in the production of thiamine deficient brain damage. Ethanol alone can cause a number of structural alterations in brain tissue and these lesions may be found in alcoholics either in association with or in the absence of thiamine deficient lesions. It is also probable that ethanol and thiamine deficiency act synergistically to produce structural damage. Recurrent deficiences of many different kinds also play a part in the production of cumulative brain damage in the alcoholic.
This prospective study compared the effects of tube-fed nutrition with those of a regular diet in alcoholic liver disease. The high prevalence of malnutrition in patients with alcoholic liver disease requires clarification of the benefits of aggressive nutritional support. Patients were randomly assigned a regular diet without or with tube-fed supplementation, delivering 1.5 g/kg protein and 167 kJ/kg daily. Comparisons of encephalopathy, antipyrine clearance, metabolic rate, and biochemical parameters were performed weekly for 4 weeks. Sixteen patients receiving enteral supplementation had antipyrine half-life (50% vs. 3% reduction), serum bilirubin (25% vs. 0% reduction), and median encephalopathy scores that improved more rapidly than those of controls. Initially, 15 controls did not consume adequate calories to meet measured resting energy expenditure. Aggressive nutritional intervention accelerated improvement in alcoholic liver disease. Adverse effects did not offset the demonstrated benefits of a 2-cal/mL, casein-based tube-fed supplement. These findings support the use of standard, casein-based solutions in the treatment of alcoholic liver disease and as the control condition for future studies.
An assessment has been made of metabolic factors possibly causing or contributing to the brain damage associated with chronic alcoholism, especially thiamin lack or disturbance of amino acid metabolism. Abnormalities in the thiamin-dependent enzyme, transketolase, provide evidence of a high incidence of thiamin deficiency as well as of disturbed thiamin metabolism in chronic alcoholics, which are likely to be caused by reduced vitamin intake as well as impaired absorption. A grossly disturbed pattern of amino acids in the blood of patients undergoing treatment for alcohol withdrawal syndromes is likely to be caused by loss of hepatic function and may well aggravate brain damage caused by B group vitamin deficiency. A hypothesis is proposed of how chronic thiamin lack can lead to brain damage.
A recent necropsy study has shown that 80% of patients with the Wernicke-Korsakoff syndrome were not diagnosed as such during life. Review of the clinical signs of these cases revealed that only 16% had the classical clinical triad and 19% had no documented clinical signs. The incidence of clinical signs in this and other retrospective pathological studies is very different from that of prospective clinical studies. This discrepancy may relate to "missed" clinical signs but the magnitude of the difference suggests that at least some cases of the Wernicke-Korsakoff syndrome may be the end result of repeated subclinical episodes of vitamin B1 deficiency. In order to make the diagnosis, clinicians must maintain a high index of suspicion in the "at risk" group of patients, particularly alcoholics. Investigations of thiamine status may be helpful and if the diagnosis is suspected, parenteral thiamine should be given.
Chronic thiamine deprivation in the rat leads to selective neuropathological damage to pontine structures. Onset of neurological symptoms of thiamine deprivation (ataxia, loss of righting reflex) was accompanied by selective decreases (of the order of 30%) in the activity of alpha-ketoglutarate dehydrogenase (alpha KGDH) in lateral vestibular nucleus and hypothalamus. Enzyme activities were decreased to a lesser extent in medulla oblongata, striatum and hippocampus and were unchanged in other brain structures. No changes in alpha KGDH occurred prior to the onset of neurological signs of thiamine deprivation. Administration of the central thiamine antagonist, pyrithiamine, results within 3 weeks in loss of righting reflex and convulsions and in more widespread neuropathological changes than those observed following thiamine deprivation. alpha KGDH activities were found to be substantially diminished in all brain regions studied following pyrithiamine treatment with most severe changes occurring in brain regions found to be vulnerable to pyrithiamine (lateral vestibular nucleus, hypothalamus, midbrain, medulla-pons). In some cases, alpha KGDH changes preceded the appearance of neurological symptoms of pyrithiamine treatment. Such decreases in alpha KGDH may explain previous findings of region-selective changes in energy metabolism and of decreased synthesis of glucose-derived neurotransmitters (acetylcholine, GABA, glutamate) in pyrithiamine-treated rat brain. Thiamine administration to symptomatic pyrithiamine treated rats resulted in reversal of neurological signs of encephalopathy and in normalisation of defective alpha KGDH activity in all brain regions. These findings suggest that the reversible neurological symptoms associated with Wernicke's Encephalopathy in man likely result from region-selective impairment of alpha KGDH.