Ovid: Modern Nutrition in Health and Disease Page 1 of 15

Editors: Shils, Maurice E.; Shike, Moshe; Ross, A. Catharine; Caballero, Benjamin;
Cousins, Robert J.
Title: Modern Nutrition in Health and Disease, 10th Edition
Copyright ©2006 Lippincott Williams & Wilkins

> Table of Contents > Part II - Specific Dietary Components > C - Vitamins > 23 - Thiamin

23
Thiamin 1

Roger F. Butterworth

HISTORICAL LANDMARKS
Chinese medical texts referred to beriberi as early as 2700 bc, but it was not until AD 1884
that Takaki, a surgeon general in the Japanese navy, showed that the disease was the
consequence of dietary inadequacy. Some years later, Eijkman, a military doctor in the
Dutch Indies, discovered that fowl fed on a diet of cooked, polished rice developed paralysis
that he attributed to a nerve poison in the endosperm of rice. An associate, Grijns, later
correctly interpreted the connection between excessive consumption of polished rice and
beriberi; he concluded that rice contained an essential nutrient in the outer layers of the
grain that was removed in polishing (1). In 1911, Funk isolated an antineuritic substance
from rice bran that he called a “vitamine†on account of its containing an amino group.
Dutch chemists, again working in Java, went on to isolate and crystallize the active agent
whose structure (Fig. 23.1) was later determined by Williams, a US chemist, in 1934.
Thiamin was finally synthesized in 1936.

CHEMISTRY AND BIOCHEMISTRY

Chemically, thiamin (also known as vitamin B or aneurin) is 3-(4-amino-2-methylpyrimid-5-
ylmethyl)-5(2-hydroxyethyl)-4-methylthiazonium (see Fig. 23.1) and has a molecular weight
(as the hydrochloride salt) of 337.3 (2). Thiamin is a water-soluble vitamin. Aqueous
solutions of thiamin are stable at acid pH but are unstable in alkaline solutions or when
exposed to ultraviolet light. Both the pyrimidine and thiazole moities (see Fig. 23.1) are
necessary for biologic activity (3). Thiamin is readily cleaved at the methylene bridge by
sulfite treatment of pH 6.0.

DIETARY SOURCES AND REQUIREMENTS

Thiamin concentrations are highest in yeast and in the pericarp and germ of cereals (3,4).
Major dietary sources of thiamin are shown in Table 23.1. An extensive list of food sources
and contents of this vitamin is given in Appendix Table A-23.

Most cereals and breads are nowadays fortified with thiamin. Conversely, milk and dairy
products, seafood, and most fruits are poor sources of thiamin, and thiamin is absent from
refined sugars. Thiamin is sensitive to high temperatures, and prolonged cooking of foods
may result in a loss of thiamin content. Baking of bread, for example, leads to a 20 to 30%
reduction in thiamin, and pasteurization of milk may also result in thiamin losses of up to
20%. In contrast, freezing of foods does not result in significant reductions of thiamin
content. Because thiamin is a water-soluble vitamin, significant amounts are lost in
discarded cooking water. Thiamin is also destroyed by x-rays and by ultraviolet irradiation
of food stuffs (3,4). Dietary reference intake values for thiamin by life stage group (4) are
shown in Table 23.2.

Thiamin deficiency may result from inadequate dietary intake of the vitamin as well as from

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decreased absorption,
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defective transport, increased requirements (as discussed earlier), and enhanced losses (4).
Populations at particularly high risk for the development of thiamin deficiency include
patients with alcoholism, human immunodeficiency virus–acquired immunodeficiency
syndrome (HIV-AIDS) (5), gastrointestinal and liver diseases, and persistent vomiting
(hyperemesis gravidarum) (6), as well as those receiving parenteral nutrition (7) when
thiamin is omitted from the formula in error or when the thiamin is destroyed by prolonged
contact with the amino acid solution. Certain drugs such as the antihyperglycemic agent
tolazamide may also cause thiamin deficiency (8). Thiamin deficiency is also seen in hunger
strikers and in patients with anorexia nervosa.

Figure 23.1. The thiamin molecule consists of a pyrimidine ring and a thiazole moiety,
which are linked by a methylene (CH 2 ) bridge. Thiamin is a water-soluble white
crystalline solid.

TABLE 23.1. THIAMIN CONTENT OF COMMON FOODS

FOOD TYPE THIAMIN CONTENT (mg/100 g)

Wheat flour (wholemeal) 0.4–0.5

Rice

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Whole rice 0.5

Polished rice 0.03

Rice bran 2.3

Vegetables

Peas 0.36

Other legumes 0.4–0.6

Potatoes 0.1

Cow's milk 0.04

Meats

Beef 0.3

Lamb 0.2

Pork ≤1.0

Poultry 0.1

Refined sugars Nil

TABLE 23.2. CRITERIA AND DIETARY REFERENCE INTAKE

VALUES FOR THIAMIN BY LIFE STAGE GROUP

EAR (mg/d) a RDA (mg/d) b

LIFE STAGE AI c
GROUP CRITERION MALE FEMALE MALE FEMALE (mg/d)

0–6 mo Average thiamin intake from human milk 0.2

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7–12 mo Extrapolation from adult requirements 0.3

1–3 y Extrapolation from 0.4 0.4 0.5 0.5

adult EAR

4–8 y Extrapolation from 0.5 0.5 0.6 0.6

adult EAR

9–13 y Extrapolation from 0.7 0.7 0.9 0.9

adult EAR

14–18 y Extrapolation from 1.0 0.9 1.2 1.0

adult EAR

18–>70 y Depletion/repletion 1.0 0.8 1.2 1.1

studies; erthrocyte
transketolase
activity

Pregnancy

14–50 Adult female EAR 1.2 1.4

y plus estimated
daily thiamin
accumulation by
fetus

Lactation

14–50 Adolescent female 1.2 1.4

y EAR plus average
amount of thiamin
secreted in human
milk

a
EAR, estimated average requirement, the intake that meets the estimated nutrient
needs of half of the individuals in a group.
b
RDA, recommended dietary allowance, the intake that meets the nutrient need of
almost all (97–98%) of individuals in a group.
c
AI, adequate intake, the observed average of experimentally determined intake by
a defined population or subgroup that appears to sustain a defined nutritional
status, such as growth rate, normal circulating nutrient values, or other functional
indicators of health. The AI is used if sufficient scientific evidence is not available
to derive an EAR. For healthy infants receiving human milk, the AI is the mean

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intake. The AI is not equivalent to an RDA.

From Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for
Thiamin, Riboflavin, Niacin, Vitamin B 6 , Folate, Vitamin B 1 2 , Biotin, and Choline.
Washington, DC: National Academy Press, 1998:58–86, with permission.

THIAMINASES AND ANTITHIAMIN COMPOUNDS IN FOODS

Certain foods contain thiaminases, which rapidly degrade thiamin (3). Thiaminase I is also
encountered in some raw fish, shellfish, and ferns, as well as in microorganisms such as
Clostridium thiaminolyticus. Thiaminase II, which has an action distinct from that of
thiaminase I, is found in other organisms such as Candida aneurinolytica. Thiaminases act
during food storage or during passage through the gastrointestinal tract. Consequently,
regular consumption of raw fish (with or without fermentation), raw shellfish, and ferns
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are risk factors for the development of thiamin deficiency. Thiaminases are thermolabile.

Antithiamin compounds, conversely, are thermostable and have been identified in some
ferns, teas, and betel nut, in which the toxic agents were found to be analogs of
polyphenolic compounds such as tannic acid (tannin).

ABSORPTION AND EXCRETION

Thiamin is absorbed by the small intestine by two distinct mechanisms, namely, active
transport (at concentrations <2 µmol/L) and passive diffusion (at higher concentrations)
(3). Active thiamin transport is greatest in jejunum and ileum. Intestinal transport of
thiamin is rate limiting in humans. Following uptake from the gastrointestinal tract, thiamin
is transported by the portal blood to the liver.

Total thiamin concentrations in the normal adult human body have been estimated to be of
the order of 25 to 30 mg. Relatively high concentrations are found in skeletal muscle, heart,
liver, kidney, and brain. Thiamin turnover rates in brain are region dependent (Table 23.3),
with highest turnover rates evident in more caudal brain structures and cerebellum
compared with rostrally situated structures such as striatum and cerebral cortex (9). Given
these relatively fast turnover rates and because thiamin is not stored to any large extent in
any tissue, a continuous dietary supply is necessary. Thiamin and its acid metabolites (2-
methyl-4-amino-5-pyrimidine carboxylic acid, 4-methyl-thiazole-5-acetic acid and thiamin
acetic acid) are excreted principally in the urine (3).

ROLE OF THIAMIN IN CELL FUNCTION

Enzyme Cofactor
Following uptake into the cell, thiamin is rapidly phosphorylated to its diphosphate ester
(thiamin diphosphate [TDP]), previously referred to as thiamin pyrophospate. TDP is an
essential cofactor for important enzymes involved in glucose and amino acid metabolism by

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the cell (10,11,12). Such enzymes include transketolase, a key enzyme component of the
pentose shunt pathway, pyruvate dehydrogenase complex, an enzyme complex situated at
the point of entry of pyruvate carbon into the tricarboxylic acid cycle, α-ketoglutarate
dehydrogenase (αKGDH), a rate-limiting enzyme and constituent of the tricarboxylic acid
cycle, and branched-chain keto acid dehydrogenases. The first three of these TDP-dependent
enzymes are implicated in glucose and energy metabolism by the cell, as shown in simplified
schematic form in Figure 23.2.

Figure 23.2. Thiamin diphosphate–dependent enzymes. αKGDH, α-ketoglutarate

dehydrogenase; PDHC, pyruvate dehydrogenase complex; TK, transketolase.

TABLE 23.3. THIAMIN TURNOVER RATES IN PERIPHERAL

NERVE, SPINAL CORD, AND BRAIN REGIONS

THIAMIN TURNOVER RATE (µg/g tissue/h)

Peripheral nerve 0.58

Spinal cord 0.39

Brain

Cerebellum 0.55

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Medulla oblongata 0.54

Pons 0.45

Hypothalamus 0.36

Midbrain 0.29

Striatum 0.27

Cerebral cortex 0.16

Adapted from Rindi G, Patrini C, Comincioli V et al. Thiamine content and turnover
rates of some rat nervous regions, using labeled thiamine as a tracer. Brain Res
1980;181:369–80, with permission.

Not surprisingly, given the mitochondrial localization of the dehydrogenase and the
importance of the pentose shunt pathway in cellular glucose metabolism, thiamin deficiency
results in a plethora of metabolic consequences including the accumulation of lactate (13)
and alanine (12), a reduction of tricarboxylic acid cycle intermediates, and reduced
synthesis of high-energy phosphates (14). In the brain, where the tricarboxylic acid cycle is
essential for
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the synthesis of neurotransmitters such as acetylcholine and γ-aminobutyric acid, thiamin
deficiency also results in decreases in their synthesis (7,11,12) (see Fig. 23.2). Addition of
thiamin to thiamin-deprived cellular preparations in vitro (15) or to intact thiamin-deficient
animals (12) results in a rapid normalization in activities of TDP-dependent enzymes and
their associated metabolites and neurotransmitters (12). This reversible metabolic
phenomenon has been referred to as “the biochemical lesion†in thiamin deficiency.

Component of Neuronal Membranes

Electrical stimulation of nerve preparations results in the release of thiamin, a finding that
led to the proposal that thiamin has a cellular function distinct from its role in the form of
TDP as enzyme cofactor (discussed earlier). TDP may be further phosphorylated to thiamin
triphosphate (TTP) by the enzyme TDP phosphoryltransferase, which is expressed in brain,
liver, kidney, and heart. The precise role of TTP has yet to be determined, but investigators
have suggested that it activates high-conductance chloride channels (16). TTP also has
regulatory properties on certain proteins involved in the clustering of acetycholine receptors
suggestive of a direct role in the regulation of cholinergic neurotransmission (17).

TTP is rapidly hydrolyzed to TDP (by the action of TTPase) then to thiamin monophosphate
by the action of TDPase and finally to free thiamin by the action of thiamin
monophosphatase). Recent studies suggest that thiamin phosphorylation-dephosphorylation
reactions represent a compartmentalized series of processes in brain involving both neurons
and surrounding glial cells (18). Genes coding for the enzymes involved in thiamin
phosphorylation and dephosphorylation are currently being cloned and characterized, and
this information is expected to assist greatly in our understanding of the role of these

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processes in cellular function.

SELECTIVE NEURONAL CELL DEATH RESULTING FROM

THIAMIN DEFICIENCY
Investigators have proposed that thiamin deficiency leads to two distinct types of
neuropathologic lesions. The first type comprises neuronal disintegration, mild endothelial
swelling, and sparing of the neuropil, generally confined to the thalamus and inferior olives.
Conversely, destruction of the neuropil, endothelial swelling, and neuronal sparing occur in
mammillary bodies and periventricular brainstem nuclei (19). Several mechanisms have
been proposed to explain the phenomenon of selective neuronal cell damage and death
resulting from thiamin deficiency.

Cellular Energy Failure

As discussed earlier, thiamin deficiency is characterized by decreases in brain concentrations
of TDP and a reduction in activities of TDP-dependent enzymes (12). Attention has been
focused particularly on the role of decreased αKGDH in the pathogenesis of neuronal cell
death resulting from thiamin deficiency because it is well established that αKGDH is a rate-
limiting enzyme in the tricarboxylic acid cycle responsible for cellular energy production.

Prolonged reductions in activity of αKGDH resulting from thiamin deficiency lead to

decreased glucose (pyruvate) oxidation and increased brain concentrations of alanine and
lactate. Studies of oxidative metabolism in mitochondria isolated from the brains of thiamin-
deficient animals reveal decreased respiration using α-ketoglutarate as substrate but no
such changes in respiration using succinate (20), a finding consistent with decreased
activities of αKGDH (see Fig. 23.2). Measurement of high-energy phosphates in brain in
thiamin deficiency reveals decreased levels of adenosine triphosphate in brainstem (14).
Decreased activity of αKGDH resulting from thiamin deficiency also results in decreased
synthesis of amino acid neurotransmitters such as glutamate and γ-aminobutyric acid (12).
Focal accumulation of lactate leading to reduced pH has also been described (13), and
disintegration of mitochondria has also been reported in degenerating diencephalic neurons
of thiamin-deficient animals (11).

Oxidative Stress
Increased production of reactive oxygen species has been reported in brain in thiamin
deficiency (21). Other markers of oxidative stress in experimental thiamin deficiency include
microglial activation (22) and increased expression and activity of inducible nitric oxide
synthase leading to increased nitrotyrosine immunoreactivity in vulnerable regions of the
brain (23). Vascular factors also contribute to oxidative damage to neurons in thiamin
deficiency. Such factors include increased endothelial nitric oxide synthase, and targeted
disruption (knockout) of the endothelial nitric oxide synthase (eNOS) gene has been shown
to attenuate the neuronal cell death resulting from thiamin deficiency significantly (11).
Antioxidants are neuroprotective in experimental thiamin deficiency (24).

The nature of the neuropathologic damage resulting from thiamin deficiency is similar to
some degree to that encountered in excitotoxic brain injury (i.e., brain injury resulting from
excessive stimulation of N-methyl-D-aspartate receptors by glutamate, a process known as
excitotoxicity and shown to result in excessive accumulation of intracellular calcium leading
to the activation of cell death mechanisms). Evidence consistent with a role for
excitotoxicity in relation to neuronal cell loss resulting from thiamin deficiency includes the
finding of increased extracellular concentrations of glutamate in vulnerable brain regions
(25), and pretreatment of thiamin-deficient animals with the competitive N-methyl-D-
aspartate receptor antagonist MK801 leads to significant neuroprotection (26). One
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explanation for the increases of extracellular brain glutamate in thiamin deficiency may
relate to the finding of a selective downregulation of astrocytic glutamate transporters in
brain structures vulnerable to thiamin deficiency (27).

MEASUREMENT OF THIAMIN STATUS

Measurements of blood thiamin levels and urinary thiamin excretion are not reliable indices
of thiamin status. Consequently, these measurements have been replaced by indirect assays
of thiamin status based on measurement and activation of the TDP-dependent enzyme
transketolase in red blood cell hemolysates (28) or direct measurement of TDP in these
hemolysates using high-performance liquid chromatography (HPLC) (29).

Erythrocyte Transketolase Activation Assay

This widely used assay is based on measurement of transketolase activity in hemolysates of
red blood cells in the absence of (and in the presence of) added excess cofactor (TDP). The
enzymatic reaction catalyzed by transketolase is as follows:

Samples of hemolyzed whole blood are incubated with the enzyme substrate (ribose-5-
phosphate) in a buffer at pH 7.4, 37°C with or without added TDP (10 mM). The product,
sedoheptulose-7-phosphate produced per milliliter of blood per hour, is a measure of
transketolase activity. The difference in enzymatic activity between the sample to which
excess TDP has been added compared with that without added excess cofactor is then
defined as the TDP effect.

In physiologically normal human volunteers, hemolysate transketolase activities are in the

range of 90 to 160 µg sedoheptulose formed/mL/hour, and the TDP effect values range
from 0 to 15% depending on the levels of circulating TDP in physiologically normal subjects.
Patients with marginal thiamin deficiency manifest TDP effect values in the 15 to 25% range,
and those with values in excess of 25% are generally considered to be thiamin deficient.
Following parenteral thiamin administration to deficient persons, TDP effect values generally
return to within normal ranges within 24 hours (28).

High-Performance Liquid Chromotography

The advent of HPLC led to the publication of several procedures to measure thiamin and its
phosphate esters in blood directly. One of the most reliable of these methods makes use of
HPLC and precolumn derivatization. Blood samples are hemolyzed and deproteinized with
perchloric acid, and supernatants are then oxidized to their thiochrome derivatives following
the addition of potassium ferricyanide and sodium hydroxide and subsequent neutralization.
Analysis times are short using this technique, and recovery is excellent. Reference values
for TDP in healthy volunteers are 120±17.5 nmol/L (20).

HUMAN THIAMIN DEFICIENCY DISORDERS

Human disorders resulting directly from thiamin deficiency include several forms of beriberi
and Wernicke encephalopathy (WE; Wernicke-Korsakoff syndrome). In addition,
abnormalities of TDP-dependent enzymes have been reported in a wide range of
neurodegenerative and inherited metabolic diseases.

Beriberi
Clinical manifestations of beriberi vary with age. The three major forms of the disorder are
dry beriberi, wet beriberi, and infantile beriberi (3). Dry beriberi is characterized principally
by peripheral neuropathy consisting of symmetric impairment of sensory, motor, and reflex

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functions affecting distal more than proximal limb segments and causing calf muscle
tenderness. Wet beriberi is associated with edema, tachycardia, cardiomegaly, and
congestive heart failure in addition to peripheral neuropathy. Hemodynamic changes in wet
beriberi include high cardiac output and low peripheral resistance. Rarely, patients manifest
fulminant or “shoshin†beriberi, the major features of which are tachycardia and
circulatory collapse.

Developing brain is more sensitive than adult brain to the deleterious effects of thiamin
deficiency (30,31); for example, it is well established that infantile beriberi occurs in infants
breast-fed by mothers who themselves may be asymptomatic. Reports from many world
populations continue to describe a high prevalence of thiamin deficiency and its
complications in pregnant and lactating women, a population known to have increased
thiamin requirements. Populations at particular high risk for the development of maternal
thiamin deficiency include victims of trade embargoes as well as displaced persons in
refugee camps (32).

Increased thiamin requirements during the third semester of pregnancy are thought to result
from increased sequestration by the fetus and placenta. Thiamin concentrations are higher
in umbilical cord blood compared with maternal blood, a finding consistent with preferential
delivery of thiamin to the developing infant.

The major cause of maternal thiamin deficiency in many parts of the world continues to be
the eating of a staple diet of polished rice together with ingestion of foods containing
thiaminases or antithiamine compounds. Other causes of maternal thiamin deficiency include
alcohol abuse, gastrointestinal disease, hyperemesis gravidarum, and HIV-AIDS.
Investigators have shown that maternal thiamin deficiency contributes to intrauterine
growth retardation (30), a condition that results in delayed myelination of the brain caused
by reduced activity of TDP-dependent
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enzymes. Maternal thiamin deficiency may also contribute to the pathogenesis of the fetal
alcohol syndrome.

Infantile beriberi commonly presents between the ages of 2 and 6 months. Infants may
manifest cardiac, aphonic, or pseudomeningitic forms of the disorder. Infants with cardiac
beriberi frequently exhibit a loud piercing cry, vomiting, and tachycardia (3). Convulsions
are not uncommon, and death may ensue if thiamin is not administered promptly.

Wernicke Encephalopathy (Wernicke-Korsakoff Syndrome)

WE is a common neuropsychiatric complication of chronic alcoholism (10). It is also
encountered in patients with severe gastrointestinal disease, those with HIV-AIDS (5), and
with the injudicious administration of parenteral glucose or hyperalimentation without
adequate B-vitamin supplementation (5). Activities of all three TDP-dependent enzymes are
reduced in brain tissue obtained at autopsy from patients with WE (33).

In patients with alcoholism, thiamin deficiency results from inadequate dietary intake of the
vitamin, reduced absorption from gastrointestinal disease, and reduced liver thiamin stores
caused by hepatic steatosis or fibrosis (10). In addition, ethanol per se inhibits thiamin
transport in the gastrointestinal system and blocks phosphorylation of thiamin to its cofactor
form (TDP) (34).

The diagnosis of WE is based generally on the acute appearance of ocular palsies,

nystagmus, and ataxia of gait, as well as disorders of mentation (1). In addition, more than
80% of patients with WE show signs of peripheral neuropathy. However, these diagnostic
criteria are nonspecific, and the diagnosis of WE is missed in a large percentage of both
patients with alcoholism (35) and those with HIV-AIDS (5). The reason for the high degree
of underdiagnosis rests with the overzealous use of the classic triad of symptoms

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(ophthalmoplegia, ataxia, confusion) espoused by many textbooks. In practice, many cases

of WE confirmed at autopsy do not manifest this triad of symptoms, and patients may show
only psychomotor slowing or apathy (5). A rewriting of this textbook definition of WE is long
overdue. In the meantime, thiamin deficiency should be suspected in all patients with
grossly impaired nutritional status associated with chronic diseases, with particular attention
being paid to patients with alcoholism, gastrointestinal diseases, HIV-AIDS, and persistent
vomiting. Thiamin should be administered parenterally in a timely manner. It is essential to
administer thiamin to all such patients before infusions of glucose or parenteral nutrition are
given.

Korsakoff psychosis (KP) is generally considered to occur with deterioration of brain function
in patients initially diagnosed with WE (1). However, KP may be present at the time of
diagnosis of WE or even, in a small number of cases, present without WE symptoms. KP is
an amnestic-confabulatory syndrome characterized by retrograde and anterograde amnesia,
impairment of conceptual functions, and decreased spontaneity and initiative.

Neuropathology
In the acute stages of WE, hemorrhagic lesions of mammillary bodies and periventricular
regions of the thalamus are observed (36). Multiple acute insults eventually give rise to a
chronic lesion, characterized by loosening of the neuropil and cell loss, that manifests as
mammillary body atrophy and ventricular dilatation. One also sees a significant loss of
neurons in the superior cerebellar vermis in WE, a phenomenon also referred to as alcoholic
cerebellar degeneration.

Magnetic resonance imaging permits the diagnosis and assessment of the extent of brain
lesions. Mammillary body atrophy and loss of thalamic tissue leading to ventricular
enlargement as well as cerebellar atrophy are clearly discernible (37).

Genetics
Although thiamin deficiency is very common in patients with alcoholism, only relatively small
numbers (10–12%) go on to develop WE, an observation that led to the proposal of a
genetic predisposition to the disorder. A great deal of attention in this regard has been paid
to the TDP-dependent enzyme transketolase. Initially, investigators proposed that a
reduction in affinity of transketolase for its cofactor (TDP) could represent one such genetic
abnormality. Reports of both biochemical and chromatographic variants of transketolase in
cells from patients with WE have appeared in the literature (38,39). However, more recently
the coding sequences of the transketolase gene were compared between cells from
physiologically normal individuals and from patients with WE, and no significant differences
were observed (40), a finding suggesting that, if alterations of transketolase do exist in
these patients, these alterations are posttranslational. Further studies are required to clarify
this issue.

Thiamin Diphosphate–Dependent Enzymes in Brain in

Neurodegenerative Diseases
Brain tissue obtained at autopsy from patients with Alzheimer disease contains reduced
activities of TDP-dependent enzymes (41,42). Activities of αKGDH in particular are
significantly reduced in both genetic and sporadic forms of Alzheimer disease. Decreased
activities of αKGDH have also been described in the brains of patients with other
neurodegenerative diseases including Parkinson disease and progressive subnuclear palsy
(11). The most plausible explanation for the selective loss of αKGDH activity in these
diseases may relate to the deleterious
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effects of oxidative stress resulting from the cell death cascade mechanisms in these

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disorders (11).

Other Thiamin-Related Disorders

Other disorders in which a putative role for thiamin has been implicated include subacute
necrotizing encephalomyelopathy, opsoclonic cerebellopathy (a paraneoplastic syndrome),
and Nigerian seasonal ataxia. In addition, several inherited disorders of TDP-dependent
enzymes have been reported (43). Some of these latter disorders may respond to thiamin
treatment.

Clinical Response to Thiamin Administration

Parenteral thiamin should be administered promptly to patients suspected of having beriberi
or WE. Doses in the 50- to 100-mg range are initially administered intravenously or
intramuscularly to replenish cellular thiamin stores (particularly liver) (3). Parenteral rather
than oral thiamin administration is particularly important in patients with gastrointestinal
disease and/or alcoholism, in whom thiamin absorption is likely to be impaired.

In wet beriberi, rapid improvement consisting of reduction in heart rate, respiratory rate,
and clearing of pulmonary congestion occurs generally within 24 hours (3). Rapid
improvements are also seen in infants with dry beriberi; recovery of impaired sensation and
motor weakness, in contrast, may take several weeks or months.

Response to thiamin administration in patients with WE is variable, depending on the

symptoms and the degree of neuronal cell loss. Ophthalmoplegia (nystagmus, ptosis)
generally improves rapidly (within 24 hours), a finding suggesting that these symptoms are
the result of biochemical (metabolic) lesions in ocular-motor and vestibular nuclei. Gait
ataxia, convsersely, responds more sluggishly to thiamin administration because, in most
cases, loss of cerebellar neurons has occurred (44). Similarly, the amnestic deficit that is
generally thought to result from lesions in the medial-dorsal nucleus of the thalamus shows
variable response to thiamin administration; most patients show some residual memory
deficit. Improvements of peripheral neuropathy in both beriberi and WE syndrome may
require several months of thiamin treatment (44).

1
Abbreviations
HIV-AIDS
human immunodeficiency virus–acquired immunodeficiency syndrome

HPLC
high-performance liquid chromatography

αKGDH
α-ketoglutarate dehydrogenase

KP
Korsakoff psychosis

TDP
thiamin diphosphate

TTP
thiamin triphosphate

WE
Wernicke encephalopathy

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References
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2. International Union of Nutritional Sciences Committee on Nomenclature. J Nutr

1990;120:7–14.

3. Tanphaichitr V. Thiamin. In: Shils ME, Olsen JA, Shike M et al., eds Modern Nutrition
in Health and Disease. 9 t h ed. Baltimore: Lippincott Williams & Wilkins, 1999.

4. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for
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Selected Readings
Butterworth RF. Thiamin deficiency and brain disorders. Nutr Res Rev
2004;16:277–83.

Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Thiamin,
Riboflavin, Niacin, Vitamin B 6 , Folate, Vitamin B 1 2 , Biotin, and Choline. Washington, DC:
National Academy Press, 1998:58–86.

Jordan F, Patel MS. Thiamin. In: Jordan F, Patel MS, eds. Catalytic Mechanisms in
Normal and Disease States. New York: Marcel Dekker, 2004.

Maurice V, Adams RD, Collins GH. The Wernicke-Korsakoff Syndrome and Related
Neurologic Disorders Due to Alcoholism and Malnutrition. 2 n d ed. Philadelphia: FA Davis,
1989.

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