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Thiamin(e), also known as vitamin B1, is now known to play a fundamental role in energy metabolism. Its discovery followed from the original early research on the 'anti-beriberi factor' found in rice polishings. After its synthesis in 1936, it led to many years of research to find its action in treating beriberi, a lethal scourge known for thousands of years, particularly in cultures dependent on rice as a staple. This paper refers to the previously described symptomatology of beriberi, emphasizing that it differs from that in pure, experimentally induced thiamine deficiency in human subjects. Emphasis is placed on some of the more unusual manifestations of thiamine deficiency and its potential role in modern nutrition. Its biochemistry and pathophysiology are discussed and some of the less common conditions associated with thiamine deficiency are reviewed. An understanding of the role of thiamine in modern nutrition is crucial in the rapidly advancing knowledge applicable to Complementary Alternative Medicine. References are given that provide insight into the use of this vitamin in clinical conditions that are not usually associated with nutritional deficiency. The role of allithiamine and its synthetic derivatives is discussed. Thiamine plays a vital role in metabolism of glucose. Thus, emphasis is placed on the fact that ingestion of excessive simple carbohydrates automatically increases the need for this vitamin. This is referred to as high calorie malnutrition.
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THIAMIN(E): THE SPARK OF LIFE
ABSTRACT
One of the earliest vitamins to be discovered and synthesized, thiamin was originally spelled with
an “e”. The terminal “e” was dropped when it was found that it was not an amine. It is still spelled with
and without the “e” depending on the text. This chapter provides a brief historical review of the
association of thiamin with the ancient scourge of beriberi. It emphasizes that beriberi is the model for
high calorie malnutrition because of its occurrence in predominantly white rice consuming cultures. Some
of the symptomatology of this ancient scourge is described, emphasizing the difference from that seen in
starvation. High calorie malnutrition, due to excessive ingestion of simple carbohydrates, is widely
encountered in the U.S.A. today. Thiamin deficiency is commonly associated with this, largely because of
its cofactor status in the metabolism of glucose.
The biochemistry of the three phosphorylated esters of thiamin and the transporters are discussed
and the pathophysiology of thiamin deficiency reviewed. The role of thiamin, and particularly its
synthetic derivatives as therapeutic agents, is not fully appreciated in Western civilization and a clinical
section describes some of the unusual cases described in the scientific literature and some experienced by
the author. The possible role of high calorie malnutrition and related thiamin deficiency in juvenile crime
is hypothesized.
History
It is now well known that thiamin deficiency is the major cause of beriberi, a disease that had
affected humans for centuries. The name “Kakke” was the term used for the disease in Japan and this
word can be found in documents as early as 808 (Inouye K, Katsura E. 1965). Until the 17th century the
majority of the population in Japan took unpolished rice as the staple food. Polished rice was associated
with relative affluence, since it looked better on the table when served. Epidemics of beriberi have been
known to occur in association with increased affluence simply because it was expensive to take the rice to
the mill. When white rice was served to friends, it became a signature of the newly acquired affluence. As
the ingestion of well-milled white rice became nation wide, so the incidence of the disease increased.
This is because the B group vitamins are in the discarded husks. The first national statistics on mortality
appeared in 1899 and showed a death rate of 20 per 100,000. This dropped to 0.5 in 1959 after its
nutritional association was discovered. Of considerable interest to us today, for reasons that will appear
later in the chapter, the peak incidence of the disease occurred in August and September every year.
Factory workers would take their lunch between factory buildings. If the sun came round so that it shone
into the corridor, some workers would get the first symptoms of the disease. It was evident that the sun’s
rays would stress them sufficiently to initiate these symptoms. It was therefore hardly surprising that the
etiology in the early 1900s, before its nutritional association became common knowledge, was considered
to be from infection.
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The discovery of the relationship of thiamin with malnutrition came in the late decades of the 19 th
century, but it was many years before scientific knowledge caught up. A Japanese naval surgeon by the
name of Takaki studied in England from 1875 to 1880. He noted that beriberi was less common in the
British Royal Navy than in navy personnel in Japan where the diet on ships was very different. In 1882 a
Japanese naval vessel sailed on a 272 day voyage. On its return, 61% of the crew had succumbed to
beriberi. Two years later, another ship completed the same voyage, but was provided with an ample
supply of dried milk and meat, giving a carbon to nitrogen ration of 16:1. Only 14 crew members had
developed beriberi. Takaki concluded that a lack of nitrogenous food was the cause of the disease, a
notable contribution before vitamins were known.
In 1890, Eijkman found that polished rice, given to pigeons, caused polyneuritis and the
histopathology was similar to that seen in humans in beriberi. Funk and Cooper isolated an “antiberiberi
factor” from rice polishing in 1910 and this was crystallized in 1926 and called Vitamine (Jansen B C T,
Donath W F. 1926). It was not until 1936 that thiamin was synthesized (Williams R R, 1938) leading to
an explosion of basic science and clinical experimentation. The work of Sir Rudolph Peters (Peters R A,
1936) exposed the vitally important association of thiamin with what was later to become the science of
oxidative metabolism.
Clinical facts about beriberi and thiamin deficiency
Although a great many symptoms of beriberi have been described, none of them is considered to
be pathognomonic (Inouye K, Katsura E, 1965). Generally it is classified into the “wet” or edematous
type and “dry”, both being chronic in their course. The peracute and extremely lethal form is known in
Japan as “Shoshin”. Infantile beriberi is associated with sudden death and the clinical picture is startlingly
similar to that of Sudden Infant Death Syndrome that is familiar to us today (Lonsdale D.2001). Wernicke
encephalopathy, usually associated with alcoholism, is at least one form of the disease that affects brain
function in adults. A complete review of the clinical aspects of beriberi was published (Lonsdale D, 1975)
and interested readers are encouraged to look in this publication or a similar one since the complete
information is readily available. It is not necessary to provide the details again here, but there are some
aspects that need to be emphasized because it focuses on some of our modern day clinical problems that
are being sadly overlooked.
Many readers might be of the opinion that the classical forms of nutritional deficiency diseases
have faded into the background of interesting history. This has caused their diverse symptoms to be
neglected by most modern physicians since vitamin enrichment of many foods automatically erases them
from their thinking about differential diagnosis. It must be emphasized that beriberi is a disease where the
caloric intake is high, particularly in the form of simple carbohydrate foods such as starch. Indeed, it can
be superficially compared to a car engine that is being fuelled by a rich mixture of gasoline with
insufficient air and/or inefficient spark plugs. It is the lack of vitamin content, particularly thiamin, that
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results in inefficient oxidative metabolism. Since the brain and heart have a high requirement for oxygen,
it is easy to understand why the brain, nervous system and heart are the organs that are affected
primarily..
Early investigators (Inouye K, Katsura E. 1965) found that the arterial oxygen concentration in
beriberi patients was relatively low while venous oxygen concentration was relatively high. This means,
of course, that tissue oxygen exchange by cells is defective in the disease. Edema, a common clinical
problem today, is one of the important, but not exclusive, signs of beriberi and is always present in the
early stages of the disease. A classical sign is tenderness of the calf muscles when gripped with the hand.
Anasarca is, however, rare even though there may be profound edema. It should enter into differential
diagnosis when cardiovascular and neurological symptoms, especially if there is edema, are present
together. Exertion or mental stress results often in cardiac palpitations and disproportionate dyspnea. The
typical cardiac enlargement that is easily found by chest roentgenography can easily be mistaken for a
viral myocardiopathy and might even lead to consideration of heart transplant if the correct diagnosis is
missed. Cardiac beriberi was reported in England in 1971, (McIntyre N, and Stanley N N, 1971) The
authors emphasized the need for it to be considered in the differential diagnosis of heart failure, even
when the cardiac output is low. Pang et al. (Pang J A, et al. 1986) considered that the Shoshin form of
beriberi was.probably underdiagnosed in the West.
Perhaps the most important thing to emphasize is the effect of beriberi on the autonomic nervous
system (Inouye K, and Katsura E 1965). This is altered early in the disease and produces changes in
vasomotor function. The diastolic blood pressure falls and may even reach zero. The systolic pressure
may rise or remain normal. In classic beriberi the passage of blood through the femoral artery could be
heard, even by an observer standing near the patient. Beriberi victims could be divided into certain
categories by their chemistry. Platt (Platt B S. 1967), an early investigator, reported that many victims
had normoglycemia and were easily treated with thiamin. More severe cases had hyperglycemia and
responded to thiamin with greater difficulty, while others had hypoglycemia and some did not respond at
all to the vitamin. Presumably this would reflect the severity and chronicity of the biochemical changes
incurred and this should be noted since hyperglycemia would automatically be considered evidence of
diabetes in the modern world. Some patients had achlorhydria and others had hyperchlorhydria.
Curiously, under treatment with thiamin, those with achlorhydria became hyperchlorhydric before normal
acid content was established. The exact opposite effect was seen in the hyperchlorhydric patients.
Although the mechanism is unknown, it has suggested that such phenomena might be related to
instability and imbalance of autonomic nervous system signaling. At any rate, it certainly introduces the
fact that beriberi symptomatology is extremely complex and not a matter of simply giving a few
milligrams of thiamin. In fact, it took huge doses of the vitamin for months to abolish the symptoms. We
have found many of these facts to be relevant today, bearing them in mind when confronted with
symptoms and signs that can be confusing in a differential diagnosis, as will be discussed later in the
clinical section.
3
In assessing the role of thiamin deficiency in the modern world, it was thought that a description
of the basic distribution of the autonomic nervous system was a necessary addition to a book devoted to
thiamin metabolism (Lonsdale 1987). It would seem that an example of clinical blindness to the
importance of vitamin supplementation and therapy is that an extremely detailed and erudite book entitled
“Diseases of the Autonomic Nervous System” was edited and published by Sir Roger Bannister
(Bannister R. 1984)). Not one word on malnutrition appeared in that book, in our opinion a very
important oversight.
After the discovery of thiamin in its application to treatment of a scourge that had existed for
thousands of years and still occurs where rice is a staple food, it was natural that a vast amount of
research was initiated. In 1962 a symposium was published to commemorate the synthesis of the vitamin.
Zbinden (Zbinden G. 1962) reported 696 published papers reporting attempted thiamin therapy in more
than 230 different diseases with varying degrees of success. It is probably pertinent to suggest why such
information, important to the health of millions, was more or less abandoned until relatively recently
when vitamins have reemerged for their true nutrient value. Because so many different diagnosed
conditions sometimes responded to the administration of thiamin as a single entity, it offended the
emerging model for disease. Each disease is researched to find a cure that is specific for a given
condition, sometimes referred to as the “silver bullet”. Thiamin provided symptomatic responses in many
different disease entities, indicating that it was addressing the underlying biochemical lesion. Perhaps,
with the relatively new explosion in nutritional therapy, it is possible to start thinking that our disease
model is catastrophically wrong. Since healing is a function of the body itself, all it requires is energy in
order to carry out this role and it seems that a new model for disease is required (Lonsdale D 2006).
Vitamins fell into relative disrepute and even today they are often spurned by physicians who
regard their pharmaceutical use as absurd. This is because even current teaching often provides the
concept that vitamins, as cofactors, only work up to their minute physiological concentration.
Pharmaceutical doses are conceived as being discarded and excreted without considering the necessary
repair to damage that occurs in the enzyme/cofactor bonding as a result of prolonged deficiency.
Biochemistry
Thiamin consists of a pyrimidine ring (2,5- dimethyl-6-aminopyrimidine) and a thiazolium ring
(4-methyl-5-hydroxy ethyl thiazole) joined by a methylene bridge. The naturally occurring vitamin is
found in lean pork and other meats, wheat germ, liver and other organ meats, poultry, eggs, fish, beans
and peas, nuts and whole grains. Dairy products, fruit and vegetables are not good sources. The RDA is
0.5 mg per 1000 kcal. Although this may be adequate for a healthy individual consuming a healthy diet, it
may only be a marginal consumption. Considerable losses occur during cooking or other heat-processing
of food. Polyphenolic compounds in coffee and tea can inactivate thiamin so that heavy use of these
beverages could compromise thiamin nutrition.
4
Thiamin monophosphate
Whether thiamin monophophate (TMP) has a specific function in any cells is still unknown. It is
formed from free thiamin to synthesize the monophosphate which is then phosphorylated again by a
kinase to form thiamin diphosphate, known as the pyrophosphate (TPP). It may be purely analogous to
the stepwise phosphorylation of adenosine, since a third phosphorylation of TPP forms thiamin
triphosphate (TTP).
Thiamin pyrophosphate (TPP)
Also known as cocarboxylase, this is the form of thiamin that is best known. Its biochemical roles
in energy metabolism are multiple. It is a cofactor for enzymatic reactions that cleave alpha-keto acids
and it has long been known that it activates decarboxylation of pyruvate in the pyruvate dehydrogenase
complex. The complex is a group of enzymes and cofactors that form acetyl CoA. This condenses with
oxaloacetate to form citrate, the first component of the citric acid cycle. Since pyruvate is derived from
glucose via the Embden-Meyerhof pathway, it should be emphasized that the energy drive from oxidation
of glucose is dependent upon TPP. It has the same role in the decarboxylating component of alpha-
ketoglutarate dehydrogenase, a link in the sequential metabolism of pyruvate through the citric acid cycle.
A third enzyme complex, similar in structure to pyruvate dehydrogenase is that which decarboxylates the
three branched chain amino acids, leucine, isoleucine and valine From a clinical standpoint, enzymatic
failure and thiamin dependency has been described in both of these enzyme complexes and will be
discussed in the clinical section.
A fourth enzyme that requires TPP is transketolase that is present twice in the pentose shunt. The
functions of this pathway are to provide pentose phosphate for nucleotide synthesis and to supply reduced
NADP for various synthetic pathways. Since the pentose shunt is found in erythrocytes, an easily
obtained tissue, measurement of the activity of this enzyme has become used as an important laboratory
test for thiamin deficiency. It is to be emphasized that it gives information only on TPP deficiency. It
does not indicate deficiency of TTP. The reaction is highly dependent upon the presence of magnesium,
an important point in the study of patients in the clinical setting.
Thiamin triphosphate (TTP)
Although this component is still poorly understood, there is no doubt that it plays a significant part
in thiamin metabolism. In 1938 Minz (Minz B. 1938) first suggested a relationship between thiamin and
nervous excitation when he observed that thiamin was released into the bathing medium when the
pneumoagastric nerve from an ox was stimulated. In 1979 Cooper and Pincus (Cooper J R and Pincus J
H. 1979) reviewed the evidence that there was a possibility that thiamin has a function in the nervous
system distinct from its activity as a cofactor to enzymes. Like Minz, they found that nerve stimulation in
experimental animal systems resulted in decline of the level of TPP and TTP from the stimulated nerve.
The released metabolites were in the form of TMP and free thiamin, making it difficult to interpret the
5
function of the vitamin in nerve conduction. They found that thiamin appeared to be uniformly distributed
in nervous tissue and was highly localized in membrane structures. After intracerebroventricular injection
of radioactive thiamin into rats, the distribution of the esters was found to be: thiamin 8-12%, TMP 12-
14%, TPP 72-74% and TTP 2-3% (Iwata H, Yabushita Y, et al. 1985).
Bettendorff and associates ( Bettendorff L et al. 1987, 1993. 1994) reported their research on
TTP, using the electric organ of the eel Electrophorus electricus, rat brain vesicles and neuroblastoma
cells. They found that 87% of the total thiamin content of the electric organ in the eel was in the form of
TTP, suggesting the great importance of this ester in nerve physiology since this organ is an adaptation of
a synapse to create a condenser. They indicated that the real substrate of TTP phosphatase is probably a
1:1 complex of Mg2+ and TTP. Incubation of rat brain homogenates with thiamin and TPP led to
synthesis of TTP that appeared to be an activator of chloride channels having a large unit conductance. In
mammalian tissues TTP concentrations are regulated by a specific thiamin triphosphatase (Makarchikov
A E, et al.2003). It must be stated, however, that the role of TTP is still incompletely understood.
Thiamin Transporter
The SLC gene family of solute carriers is a family of three transporter proteins with significant
structural similarity, transporting substrates with different structure and ionic charge. SLC19A1 mediates
the transport of reduced folate and its analogs and SLC19A2 mediates the transport of thiamin. SLC19A3
is also capable of transporting thiamin (Ganapthy V, et al.2004. Nabokina S M, et al 2004)
Pathophysiology of thiamin deficiency
The clinical results seen in proven thiamin deficiency are now well known. Its etiological
association with beriberi and Wernicke Korsakoff encephalopathy is accepted by all. Largely because of
our remaining ignorance of the role of TMP and TTP, however, the pathophysiology is still incompletely
understood. There is no doubt that thiamin, in all its forms, has a vital role in many different aspects of
energy metabolism since it catalyzes the normal use of oxygen. This is very well illustrated by the fact,
discussed in relation to the symptoms of beriberi, that arterial oxygen concentration is relatively low
while that of venous oxygen is relatively high. It is also pretty clear that TPP is possibly the rate limiting
factor in entry of pyruvate to the citric acid cycle. Thus, besides being compared with a spark plug in an
engine. it can also be compared to a throttle or accelerator.
A conference was sponsored by the New York Academy of Sciences in 1982 to discuss the
pathophysiology of thiamin deficiency and existing knowledge of the vitamin at that time (Sable H Z, and
Gubler C J, eds. 1982). In pyrithiamine-induced thiamin deficiency in animals the net levels of
phosphocreatine in the lateral vestibular nucleus and other nuclei of brain were increased selectively,
suggesting to the author that this represented under utilization of this source of ATP synthesis
(McCandless D W.1982). Gibson and associates reported evidence of deterioration in the cholinergic
system with thiamin deficiency (Gibson G, et al. 1982) and Meador and associates found evidence for a
6
central cholinergic effect from administration of large doses of thiamin (Meador K J, et al. 1993).
Lonsdale (Lonsdale D. 1982) found that intraperitoneal injection of thiamin tetrahydrofurfuryl disulfide, a
biologically active derivative of thiamin, prolonged the period of sound stimulated seizures in DBA/J2
mice weanlings. Audiogenic seizures in rodents are known to be cholinergic in origin and this type of
seizure undergoes spontaneous remission after only a few days of sensitivity in this strain of mouse. The
increase in severity of the seizures and the prolongation beyond the normal period of audiogenic seizure
initiation supported the role of thiamin in its stimulation of cholinergic CNS activity.
Two publications have indicated that thiamin supplementation has a mild clinical effect in
Alzheimer’s disease (AD) where the abnormality of the cholinergic system is part of the pathophysiology
(Blass J P et al. 1988, Meador K J, et al. 1993). Mastrogiacoma and associates studied thiamin, its
phosphate esters and its metabolizing enzymes in autopsied specimens of brain in AD and controls
(Mastrogiacoma F.et al. 1996). In the AD group the mean levels of free thiamin and TMP were normal.
Concentrations of TPP were reduced by 18-21% although the TPP metabolizing enzymes were normal.
The authors hypothesized ATP deficiency since that is required for increased phosphorylation in thiamin
esters. Thiamine deficiency in rats caused encephalopathy and DNA synthesis decreased significantly in
cortex, brain stem, cerebellum and subcortical structures. This was reversible by the administration of
thiamine (Henderson G I, and Schenker S. 1975).
Creatinuria has been noted in beriberi as well as in experimentally induced thiamin deficiency. An
observation in rats showed that creatinuria occurred as a result of protein calorie deficiency caused by
experimental starvation. Where anorexia was caused by thiamin deprivation the creatinuria occurred
much sooner and was statistically greater in concentration (Lonsdale D 1987). This was mindful of the
greater degree of creatinuria observed in calorically starved T3 injected rats than in calorically sufficient
animals injected with T3, suggesting that membrane physiology was involved in these two differently
stimulated mechanisms. As will be indicated in the clinical section of this chapter, TTP remains as the
outstanding mystery of thiamin metabolism, particularly in brain.
Laboratory methodology
As in the case of other vitamins, blood and urine measurements of thiamin are unreliable. By far
the best test for thiamin deficiency is measurement of transketolase (Boni L, et al. 1980, Jeyasingham M
D, et al 1987)). As already indicated, this enzyme occurs twice in the pentose shunt, a biochemical
pathway that exists in erythrocytes. In the first part of the test, the product of the enzymatic reaction,
sedoheptulose-7-phosphate is measured per unit of blood per minute by spectrophotometry A baseline
activity is then calculated. The reaction is then repeated after the addition of TPP. The test is then
reported in two sections, the first being the baseline activity. This is referred to as transketolase activity
(TKA). The normal range of this in our laboratory is 42-82 mU/L/min, originally derived from apparently
healthy asymptomatic subjects. In the second part of the test, if it is found that TKA increases as a result
of the addition of cofactor, it is reported as a percentage increase over that detected at baseline. This is
7
referred to as the thiamin pyrophosphate effect (TPPE). In our laboratory, this is considered to be
acceptable up to 17% acceleration. In theory, there should be no acceleration and the TPPE should be
zero if the enzyme is saturated with its cofactor. It is possible that the “normal subjects” had not reached a
stage of deficiency that caused symptoms. It should be regarded as a continuum, progressing from ideal
thiamin cofactor status, through marginal deficiency to increasingly severe deficiency generating
symptoms in the affected subject. This test should be readily available in clinical laboratories, but is often
neglected because vitamin deficiencies are generally considered to be rare or even non-existent. It has a
number of important relationships. Sometimes the TKA is low while the TPPE is normal and this would
suggest that there is some abnormality in the enzyme (Blass J P, et al. 1977). In most cases of thiamin
deficiency in our experience the TPPE is increased, sometimes remarkably so. In a more severe
deficiency state the TKA is low and the TPPE is high. Correlating the patient’s symptoms with a fall in
the TPPE is an excellent way of proving the clinical effect of thiamin supplementation. This can be
complicated since the enzyme complex is also dependent on magnesium and other non caloric nutrients
(Eisinger J, et al. 1994). Magnesium depletion aggravates the clinical effects of thiamin deficiency
(Dyckner T, et al. 1985). Magnesium and calcium deficiency affects the distribution of thiamin in rat
brain (Kimura M, et al. 1977). We have recently found several patients whose TPPE could not be
corrected until they had received an adequate supplementation with magnesium (Lonsdale D. 2006,. In
press ). There is still much to learn about the inter-relationships between vitamins and minerals in the
overall management of oxidative metabolism. An increase in TKA was found in B12 deficient patients
but not in those where the anemia was due to folate deficiency (Markannen T, and Kalliomaki J L, 1966.
Wells D G, Et al ,1968).
In 1969 Cooper and associates (Cooper J R, et al. 1969) published their finding of TTP deficiency
in Leigh’s disease, also known as subacute necrotizing encephalomyelopathy. The pathophysiology of
this disease is similar, but not identical, to that of Wernicke’s disease. Diagnosis depended upon their
finding of a substance in urine that reportedly inhibited the formation of TTP (Cooper J R, et al. 1970).
The substance was never identified and this important research was eventually discontinued for lack of
funding,. Urine from several patients suspected of thiamin deficiency symptoms were sent to Cooper’s
laboratory, were reported positive for this test and responded to thiamin supplementation. None of these
patients could be considered to be examples of Leigh’s disease (Lonsdale D. Unpublished observations).
It was the only laboratory study ever reported to indicate TTP deficiency and there is presently no known
clinically available method of depicting this vitally important link in our knowledge of thiamin
metabolism in brain.
Clinical application of thiamin in modern nutrition
It is important to emphasize once again that vitamin supplementation fell into disrepute after the
studies reported in the middle decades of the last century. Very little clinical research has been done since
8
then and major medical journals have consistently rejected what clinical research has been reported. This
book indicates that may be changing, so it is apt to refer back to some of the excellent studies that were
published 50 or more years ago. One of the most important ones in the study of pure thiamin deficiency
(as distinct from the nutritional aspects of beriberi) was performed in 1943 (Williams R D, et al 1943) and
I shall refer to this in some detail since it has great relevance to modern nutritional deficiencies. Severe
thiamin deprivation resulted in depressed mental states, generalized weakness, giddiness, backache,
soreness of muscles, insomnia, anorexia, nausea, vomiting, weight loss, poor muscular tone, low blood
pressure and bradycardia with the subjects at rest. On exertion, heart palpitation and precordial distress
(pseudoangina) occurred. Tachycardia and sinus arrhythmia were observed. The investigators reported
electrocardiographic changes and impairment of gastro intestinal motility.
Moderate, prolonged restriction of thiamin, but not of calories, resulted in emotional instability,
reflected by irritability, moodiness, quarrelsome behavior, lack of cooperation, vague fears and agitation,
mental depression, variable restriction of activity and numerous somatic complaints. The effects on one
subject, a 48 year old woman, were described in detail after 120 days of this deprivation. Blood pressure
was between 90 and 98 and the diastolic between 50 and 60 mm Hg. Heart rate 50-60 bpm and there was
marked sinus arrhythmia. Pallor and giddiness were observed when standing from the sitting position and
rising from the squatting position could be accomplished only with assistance. The patellar tendon
reflexes were hypoactive but could be increased through reinforcement and the Achilles tendon reflex
was absent. The comments of the authors included the statement that symptoms suggestive of dysfunction
of the central and peripheral nervous pathways preceded by months the gross signs of neurologic
dysfunction.
This is an old study and it would not be possible to perform a dangerous experiment of this nature
now. But we should look seriously at the symptomatology since a discerning practitioner will find clinical
effects of this nature today. A simple diet history often will produce clues that make the diagnosis
surprisingly clear. Because of the widespread nature of marginal malnutrition in the U.S. where there is a
heavy emphasis on sweet foods containing the simple carbohydrates, particularly sucrose and fructose,
findings of this nature are often relevant. Limited data are available on the relation between thiamin
requirements and the intake of simple carbohydrate in human physiology, but a study was reported that
investigated the influence of stepwise increases of carbohydrate intake on the status of thiamin in healthy
volunteers under isocaloric conditions (Elmadfa I, et al. 2001). An increase of dietary carbohydrate intake
caused a decrease of plasma and urine levels of thiamin without affecting enzyme activities. A
publication in 1962 (Bhuvaneswaran C, and Sreenivaran A. 1962) discussed problems of thiamine
deficiency states and their treatment. Quoted in this paper is a reference to Yudkin who “showed that,
despite the absence of thiamine, rats can survive for many months if carbohydrate is excluded from the
diet. Polyneuritis and death followed the addition to the diet of as little as 5% carbohydrate”.
The major point to make is that a patient with complaints of the nature described by Williams and
associates is so often regarded today as having psychosomatic disease and is either referred to a
9
psychiatrist or treated empirically with a drug. Some simple clinical observations and laboratory studies
remove the stigma that is usually associated with this diagnosis, at least by the patient. As already
mentioned above, diet history is frequently revealing to the point of wonder at the excesses involving
sugar, soft drinks and alcohol, to name a few of the myriad temptations surrounding the public.
There are several publications that support the contention that high calorie malnutrition of this
nature is responsible for a huge amount of so-called psychosomatic disease (Lonsdale D. 1975, 1990,
Lonsdale D and Shamberger R J. 1980). It is interesting to note that I received a call from the editor of the
Journal for the 1990 paper. She was nervous about its publication and suggested that the word “possible”
should be introduced into the title. A subsequent letter to the editor castigated the Journal for publishing it
at all. This is just a reflection of the incredible resistance that has accompanied evidence of vitamin
deficiency disease for years in contemporary society. Lonsdale and Shamberger (1980) described 20
adolescents with proven evidence of metabolic disturbance associated with the symptoms that are so
common in this age group today. Transketolase abnormalities occurred in all of them and were corrected
by the use of supplementary thiamin. Many of them had abnormalities in serum folate and vitamin B12
that were just as important as the transketolase in interpreting the biochemical effects of malnutrition in
these individuals. The editor would only publish this article if it was reviewed by two acknowledged
experts in the field who criticized it heavily in two editorials that appeared in the issue.
A revealing note should be added to the question of the concentration of thiamin relative to the
intake of glucose. A woman was receiving intravenous hyperalimentation in a hospital setting. The
injected fluid contained 24 mg of thiamin a day, together with a total intake of 5% dextrose water,
yielding a calculated 1036 calories from this source alone. She died and the autopsy revealed Wernicke
encephalopathy (Lonsdale D. 1978). This letter to the editor included the statement that there were no less
than six cases of Wernicke’s encephalopathy found in the same hospital some two years previously. All
of them had been receiving supplementary vitamins.
Autonomic dysfunction, as already discussed, is an important expression of symptomatology in
beriberi and has been associated with modern high calorie malnutrition (Lonsdale D. 1981). This was
noted to be asymmetric in some cases (Lonsdale D. 1990). One of them was a girl whose main complaint
came from her mother. She had violent temper tantrums, but each one was accompanied by a set of
unusual symptoms and signs. She would complain of a migraine-like headache. One pupil would dilate,
the other one did not. She would become white on one half of her body and pink on the other, mindful of
a harlequin. Sweat could be obtained by electrophoresis on one side, but not the other. Sleep spindles
were observed on one side of the brain by electroencephalogram, but not on the other. When stressed by
an intravenous injection of epinephrine the pulse pressures were widely different in the two arms when it
was measured at the same time by two people (Lonsdale D. 1987). By abolishing her appalling diet and
providing her with vitamin supplementation, that included thiamin, she was retested a year later and the
asymmetric functional changes had disappeared.
10
Any pediatrician knows only too well that there are huge numbers of children seen in the U.S.
today with symptoms that are considered to be psychological in nature. Relatively few of them are seen
as examples of limbic system biochemical abnormalities that have ravaged them from their awful diet
(Lonsdale D. 2001). The limbic system is really the primitive brain and is responsible for our emotional
reactions. It can certainly be regarded as a computer that presides over our ability to adapt to the
environment. Inefficient metabolism in this part of the brain would be expected to cause untoward
emotional reactions and autonomic/endocrine signals that might justifiably be defined as “maladaptive”.
Though efforts are often made by parents now to provide a nutritious diet, the devastation usually comes
from the ad lib ingestion of “junk” (empty calories) that the children get between meals. Thiamin
deficiency is relative to the increased calorie content from simple carbohydrates and the reason for
referring to this disastrous menace as “high calorie malnutrition”. The peer pressure is enormous and the
temptations provided by a greedy food industry are all too obvious in the shape of advertising and
promotion. Many citizens in the U.S. are deeply concerned with some of the mysteries of behavior that
beset the generation of children and adolescents. Vandalism is irrational and is extraordinarily common.
Destructive juvenile behavior is written off without considering the underlying mechanisms of anger.
Much has been published in regard to the connection between ingestion of “junk” food and juvenile crime
(Schauss A. 1981, Lonsdale D, 1992,1994) It is an unacceptable societal factor at present because it
offends the concept that crime is always a cold blooded voluntary act.
A case report (Lonsdale D. 1992) dealt in detail with a crime in a young African American who
had a crime-free background. The Public Defender felt that the incident was brought about by
biochemical changes in the brain of this young man. His diet was appalling, involving a huge amount of
carbohydrate and alcohol. Biochemical studies revealed profound changes that included an increase in
urinary catecholamines. In thiamin deficient rats, catecholamine contents in the cerebral cortex, in the
atria and ventricles of the heart and in the spleen were significantly increased compared with those of
control animals. There was a significant reduction of noradrenaline metabolism in these tissues.
Monoamine oxidase activities were depressed in tissues in which the catecholamine content had been
found raised during thiamin deficiency . A close relationship exists between possible changes in enzyme
mechanisms for destroying catecholamines and thiamin deficiency (Iwata H, et al. 1969).
The possibility of thiamine deficiency secondary to diuretic therapy has received only scant
attention. A study showing furosemide induced thiamine deficiency in rats (Yui Y, et al.1978) prompted a
clinical study (Seligman H, et al. 1991) to ascertain whether this commonly used diuretic would induce
thiamine deficiency in 23 furosemide treated patients with congestive heart failure. The authors reported a
high TPPE indicating deficient thiamine status in 21 of the patients as compared with only two control
patients. Thiamine excretion in urine was higher than in controls. Clinical improvement and
normalization of TPPE occurred with thiamine supplementation. The metabolic and hemodynamic
features of the failing heart can be further aggravated by thiamine deficiency and the authors noted that it
11
was thus possible that in patients with advanced congestive heart failure, particularly those receiving
long-term furosemide therapy, thiamine deficiency is one determinant of their poor clinical status
Thiamin dependency
When a cofactor such as thiamin is required in huge doses in order to produce enzymatic function
it is termed dependency. It is clinically deceptive because, even if the symptoms are regarded as related to
vitamin cofactor action, a physiologic dose of the “missing” vitamin might be prescribed on the basic
understanding that it would be curative. When no clinical response is observed, the therapist might
conclude that the concept was wrong and the vitamin discontinued.
A six year old child with intermittent episodes of cerebellar ataxia proved to be the first case of
thiamin dependent defective pyruvic dehydrogenase activity (Lonsdale et al. 1969, Blass J, 1972).
Although thiamin responsiveness could not be demonstrated in vitro, the child’s episodes were prevented
by the ingestion of 600 mg of thiamin a day. If he should succumb to a simple infection the daily dose of
thiamin would have to be doubled. At least one intermittent metabolic disorder has been reported where a
“stress factor” such as infection could initiate the disease (Dancis J, et al.1967) and thiamin plays a role in
the decarboxylation of branched chain amino acids (Elsas L J, et al. 1982).
Some important facts need to be mentioned in regard to this thiamin dependent child who actually
imitated a classic example of childhood beriberi. Episodes of ataxia were almost always initiated by a
simple infection. Other “stress factors” included head injury and inoculation. Even an acute ambient
temperature change could trigger symptoms. On one occasion he entered an air conditioned store from a
90 degree ambient temperature and succumbed to asthma, something that he had never experienced
before. On yet another occasion the air conditioning in the car was turned on and he succumbed again.
The inevitable conclusion was that some form of “stress” would initiate a response where metabolic
efficiency was lacking. This is a concept that might apply to many different conditions where metabolic
efficiency is marginal, as for example, with excess empty calories in the diet.
One of these ataxic episodes was studied in detail. Without any treatment, it resolved
spontaneously over about a 10 day period, reaching a clinical climax at about the 6 th day. Daytime urinary
concentrations of alanine and pyruvate were much higher by day than night throughout the episode and
were inversely proportional to urinary concentrations of aspartate and glutamate. This led to two
conclusions: first that the mechanism was related to circadian rhythm and secondly that this represented
an abnormal redox where pyruvate was being reversely transaminated to the corresponding keto acids,
siphoning off glutamate and aspartate from brain function. With thiamin treatment his optic atrophy and
learning disability gradually improved. Although his younger brother had the same defect, he did not
experience ataxia. As an adolescent, however, he had a relatively mild head injury that rendered him
unconscious. He was taken to an emergency room where it was virtually impossible to get the physician
to understand the nature of the underlying risk and his requirement for an injection of thiamin.
12
Thiamin transporter disease
The SLC19 gene family of solute carriers have been described (Ganapthy V, et al. 2004, Nabokina
S M, et al. 2004), opening up a new aspect of thiamin metabolism. It had long been noted that
megaloblastic anemia could occur that was treatable by the use of supplementary thiamin (Rogers L E, et
al. 1964). the discovery of the transporters made the etiology much clearer. Thiamin responsive
megaloblastic anemia (TRMA) syndrome is now known to be an autosomal recessive disorder with
features that include this form of anemia, mild thrombocytopenia, leucopenia, sensorineural deafness and
diabetes mellitus (Ozdemir M A et al. 2002). Mutations in the SLC19A2 gene encoding a high-affinity
thiamin transporter protein THTR-1 are responsible for the clinical features of this syndrome (Lagarde W
H, et al. 2004).
Three TRMA patients have been reported with heart rhythm abnormalities and structural cardiac
anomalies (Lorber A, et al. 2003). This suggested to the authors that knowledge of the TRMA syndrome
might shed light on more commonly observed cardiac disease where an etiology is unclear. These authors
also agreed that the harmless nature of thiamin administration might even suggest that the vitamin could
be used empirically for routine supplementation in cardiac failure where etiology is unknown.
A mouse model has been generated lacking functional SLC19A2. The mouse was unexpectedly
found to have a male-specific sterility phenotype. Spermatogenic failure was reversed by injections of
large doses of thiamin, giving a new insight into the possible association of thiamin responsive human
infertility (Oishi K, et al. 2004).
Thiaminase
In 1941 Fujita (Fujita A, 1941) was engaged in determining the vitamin content of Japanese
foodstuffs. The thiamin content of some shellfish and crustacea was zero. When thiamin was added, it
could not be recovered because it was being destroyed by an enzyme that occurred in the tissues. He
named the enzyme aneurinase. Subsequently he was able to identify two enzymes that destroyed thiamin
and might be relevant to human disease. Thiaminase I (EC2.5.1.2) is produced by Clostridium
thiaminolyticum, an anerobic organism found in human small intestine and by Bacillus thiaminolyticus,
an aerobic organism that occurs in the colon. This enzyme splits the pyrimidine ring of thiamin from the
thiazolium ring at the methylene bridge and adds a base compound to the pyridinium to create an
analogue inhibitor of thiamin in its metabolic role. Bacillus aneurinolyticus is aerobic and is found in
human colon. It produces thiaminase II (EC 3.5.99.2) that functions in the same way as thiaminase I but
does not add a base compound to the pyrimidine ring.
A chapter on thiaminase (Murata K. 1965) can be found in a book that was written by the Vitamin
B Research Committee of Japan. After the discovery of the two enzymes it was to be expected that there
would be studies performed to ascertain whether they were relevant in human disease. A case of
“thiaminase disease” was reported. The patient had beriberi and potent thiaminase activity was found in
the feces. In another patient with “thiaminase disease” a bacterium was found subsequently to be
13
responsible. Mentioned by Murata in this chapter, an anaerobic organism was found in human feces and
named Clostridium thiaminolyticum. It was also reported that a strain of Candida isolated from the oral
cavity of a human subject produced thiaminase II.
Thiaminase I was found in the ruminal contents of animals affected by cerebrocortical necrosis
(CCN) (Edwin E E, and Jackman R. 1970). When this enzyme is purified it does not have thiamin
splitting activity without the presence of a cofactor. When these investigators dialysed CCN rumen liquor
against phosphate buffer, all thiaminase activity was lost. It could be restored by the addition of various
cofactors, the most potent being nicotinic acid. The subsequent metabolite, pyrimidinyl-nicotinic acid,
was isolated. They concluded that this might have antithiamin properties since it has elements of
similarity to pyrithiamine and amprolium, both known to be thiamin antagonists (McCandless D W,
1982, Brin M, 1964)). The disease could be produced experimentally in calves by administration of
amprolium (Markson L M et al 1974) All 60 strains of Cl sporogenes subsequently examined (Shreeve J
E and Edwin E E. 1974) produced thiaminase. This organism has been recognized under various names
since it was first described by Metchnikoff in 1908 and is commonly found in soil and in intestinal
contents of man and animals. Shreve and Edwin noted in their paper that Clostridium thiaminolyticum,
isolated from human feces was later considered to be a member of the Cl sporogenes species.
An epidemic of seasonal ataxia was reported in Western Nigeria (Adamolekum B, and Ndububa D
A 1994). This disease was later found to be due to activity of thiaminase I extracted from the pupae of an
African silkworm that is consumed as a source of protein (Nishimune T, et al 2000). The significance of
these enzymes in human disease is unclear and little or no research has been performed on the subject
since this early work was reported. A letter to the editor (Loew F M. 1974) suggested that CCN might be
a model for the experimental study of human disease, in particular Wernicke’s encephalopathy and
Leigh’s subacute necrotizing encephalomyelopathy, both of which are etiologically associated with
aspects of thiamin metabolism.
Thiamin derivatives
A notable advance in research of thiamin metabolism in Japan was the discovery of allithiamine
(Fujiwara M. 1965). Allicin, the compound that gives garlic its characteristic odor, is produced from alliin
by the action of alliinase during the grinding of fresh garlic bulbs and conjugates with thiamin in an
alkaline medium to form allithiamine (2’-methyl-4’amino-pyrimidyl-(5’)methylformamino-5-hydroxy-2-
pentenyl-(S) allyl disulfide). It had been found that the aqueous solution thus formed lost the
characteristic thiochrome reaction given by thiamin but exerted full thiamin activity when administered to
animals. The addition of cysteine restored the thiachrome reaction, thus demonstrating that the molecule
was reduced to thiamin. These disulfide derivatives were tested extensively for their chemical and
biological properties by the Vitamin B Research Committee of Japan. Their then unknown characteristics
were found to be quite different from thiamine. Propyl-allithiamine (TPD) was said to have the most
satisfactory actions. This compound, however, produced a profound garlic odor from both animals and
14
human subjects. This later led to synthesis of the tetrahydrofurfuryl disulfide (TTFD) (Figure 1) which
did not produce the garlic odor. It is now marketed in Japan as a prescription item named Alinamin F
(odorless). The biololgical properties of TPD and TTFD are otherwise the same.
When allithiamine is administered by mouth, urinary excretion occurs exclusively in the form of
free thiamine, not in the form of allithiamine. This is because it is easily reduced to thiamine by cysteine
or glutathione.
Allithiamine + L-cysteine thiamine + S-allymercapto-L- cysteine
The concentration of excreted urinary thiamine is much greater than occurs with an equivalent
dose of a water soluble thiamine salt such as thiamine hydrochloride. This is because its absorption from
the intestine is far superior to that of the thiamine salt. After parenteral injection of TPD into healthy male
subjects, blood samples showed much greater concentration of thiamine than an equivalent dose of a
thiamine salt By the use of 35S-labled TPD, it was shown that the mercaptan fragment remained in the
plasma whereas the thiamine segment entered the blood cells. Thus, the open thiazolium ring in
allithiamine derivatives closes to form an intact molecule of intracellular thiamine where its vitamin
activity is required. When mice were pretreated with TPD in a dose of 1 mg. they found that they were
partially protected from potassium cyanide poisoning, given in a dose of 150 micrograms per 10g body
weight. The death rate in pretreated mice occurred in only 11.7% as compared with 70.6% in those that
were not pretreated. It was also found that TPD was effective in prevention of trichloroethylene or lead
intoxication in rabbits. It also resulted in striking reduction in liver damage after administration of carbon
tetrachloride.
An important experiment was reported in dogs. A segment of jejunum was disconnected from its
mesenteric innervation. When TPD was applied topically or given intravenously a marked stimulatory
effect on peristalsis was observed. This effect did not occur at all with a thiamine salt. Body weight
curves of albino rats were far superior when given TPD than with thiamine hydrochloride. A poorly
known therapeutic use of TTFD may well be in its anti-inflammatory effect. Intraperitoneally injected
TTFD and TPD showed a strong inhibitory effect in carrageenin induced rat paw edema (Kitzushima Y,
1967). This effect was supported by finding that TTFD reversed the gradual increase in coronary blood
flow in the heart-lung preparation of a dog by inhibiting the arachidonic acid cascade activation (Matsui
K, et al 1985).
Remove
15
Figure 1. Synthetic allithiamin homologs
All the allithiamine homologues are disulfide derivatives and their easy reduction and consequent
absorption of intracellular thiamine is dependent on this. A large number of S-acyl derivatives were
synthesized and the Vitamin B Research Committee selected three of them for detailed study (Figure 2).
Figure 2 S-acyl-thiamin derivatives
16
Figures 1 and 2 reproduced with permission from Lonsdale D. A review of the biochemistry
and clinical benefits of thiamin(e) and its derivatives. eCAM 2006;3(1):49-59.
All of the disulfide (S-S) and S-acyl (S-ac) derivatives were shown to be absorbed from the
intestine, at a rate comparable to TPD, far more readily than a thiamine salt . It was found, however, that
the S-ac forms were not absorbed into blood cells any better than thiamine hydrochloride. Neither did
they have the preventive effect against the various toxins that TPD pretreated animals experienced. They
ascribed this major difference to the absence of the S-S bond in S-ac thiamines. These, unlike the
disulfide compounds, require enzymatic action in liver or kidney to be reduced to thiamine. An important
aspect of the metabolism of these derivatives is what happens to the fragment left outside the cell on
hydrolysis. The mercaptan from TTFD has been well studied (Kikuchi S, et al, 1970. Fujita T, et al.
1973). Its pharmaceutical effect, if any, is unknown. It was shown to be non toxic and it breaks down
through a series of enzymatic actions to sulfates and sulfones when it is excreted in urine. The fragment
from the S-ac derivatives has not been studied to my knowledge.
Clinical studies
Over the years we have found some unusual aspects of thiamin metabolism in disease. To
illustrate the fallacy of relying on a repetitive symptomatology in alerting a physician to the possibility of
thiamin deficiency/dependency, studies on two children with recurrent febrile lymphadenopathy were
published (Lonsdale D, 1980). One child had a normal transketolase but was found to have the TTP
inhibitor substance in urine (Cooper J R. et al. 1969). His recurrent episodes of high fever and massively
enlarged cervical glands had been treated for two years with antibiotics on the assumption that they were
due to recurrent infection. They ceased with thiamin supplementation and without antibiotic use. To
complicate the involved biochemistry, serum folate and B12 were both markedly increased, but fell into
the normal range after thiamin was started. The folate and B12 increased and symptoms returned when
thiamin was temporarily discontinued. Restoration of thiamin again abolished symptoms: serum folate
and B12 concentrations returned again to normal. Approximately a year later his symptoms returned but
vanished again when a multivitamin was added as a supplement. The other child had an uncomplicated
abnormal transketolase and responded to thiamin supplementation.
Some form of thiamin dependency was depicted in an infant that had the potential clinical
hallmarks of a chromosomal abnormality, studied at the age of 6 weeks. Chromosomal testing was
normal but the infant had an abnormal transketolase. For this reason, thiamin supplementation was
commenced and she began to flourish. Her mother, who has subsequently been found to have symptoms
associated with abnormal transketolase, found that her daughter needed more and more thiamin to treat
recurrent symptoms as she grew. The dose, given without medical advice by the mother, gradually rose to
as high as 7 grams a day. Though she was never completely normal in behavior and learning capacity, she
17
was able to graduate from high school where she played an instrument in the marching band. She died at
the age of 27 years from what was reported as toxic shock syndrome after an infection.
Another remarkable experience was with a child with recurrent life-threatening croup. His three
siblings had had a similar history for the first 4 years of their lives. An abnormal transketolase suggested
thiamin treatment and the recurrent croup ceased. One year later, the mother asked whether thiamin
supplementation should be continued. It was discontinued on the assumption that he had “outgrown” the
problem. Within 3 weeks he required admission to hospital with another attack of croup and thiamin was
restored. It could only be assumed that the pathology might have involved the recurrent laryngeal nerve
(Lonsdale D. Unpublished observations)
A family was reported where sleep apnea occurred in three of six siblings between the ages of 18
and 26 months. Twin females first had irregular respiration and episodes of apnea. One twin succumbed
to an apneic episode while asleep and the diagnosis of sleep apnea was made in the other twin at a sleep
clinic. She also died in an apneic episode 3 months later. A male sibling also died in a similar fashion.
The investigators also reported a child with sleep apnea at the age of 7 weeks who died at 31 months.
Lesions were confined to the respiratory centers of the lower brain stem. The connection with thiamin
was underlined by the discovery of the TTP inhibitor substance (Cooper J R, et al. 1969) in one of these
children and other family members (Adickes E D, et al. 1986). Although this cannot be stated as proven,
it raises the very important question of the association of thiamin metabolism in Sudden Infant Death
Syndrome (SIDS). As long ago as 1944, it was pointed out that sudden death, with a peak incidence at
about 4 months of age, the same time frame as is usual in modern SIDS, occurred as a result of thiamin
deficiency in breast fed infants of Chinese mothers in Hong Kong (Fehily L. 1944). Although the etiology
in modern SIDS is still argued, it should be possible to see it in terms of the combination of genetics (or
epigenetics), poor nutrition and an incidental stress factor (Lonsdale D 2001). Certainly thiamin
metabolism has been very much underlined but largely ignored as a simple and effective therapeutic
intervention in this tragic and preventable event (Jeffrey H E, et al. 1985. Lonsdale D, and Mercer R
D.1972. Lonsdale D. 1977. 1990, Lonsdale D, et al. 1979, 1982). The association of TTP with SIDS was
supported by the finding of its deficiency in the phrenic nerve of autopsied SIDS victims (Barker J N, et
al. 1982). Magnesium deficiency has been reported (Caddell J L,1972)) in SIDS and the strong
association with thiamin metabolism already mentioned would make this a logical relationship that
should be emphasized strongly.
Four case reports of encephalopathy were published where thiamine metabolism appeared to be
involved in the etiology (Lonsdale D, and Price J W, 1973). All of them had elevation of lactic and
pyruvic acids in blood or urine and three of them had TPP inhibitor substance in urine as described by
Cooper and Pincus. None of the three had Leigh’s disease. One of the children described in this
publication was of more than passing interest since it implies that an adequate knowledge of glucose
metabolism is often required in perceiving this kind of biochemical lesion. This girl had severe
psychomotor retardation and failure to thrive. This followed from a low Apgar score at birth, failure of
18
the suck reflex, cyanosis and vomiting in the neonatal and infancy era. At the age of 9 months she began
self mutilation of the lower lip that produced severe damage requiring removal of the upper incisors and
transplant of the parotid duct because of excessive drooling. Although she had increased urinary
excretion of uric acid and at least one episode of uric acidemia, the genetic defect in Lesch Nyhan
syndrome, where compulsive lip biting is characteristic (Lesch M, and Nyhan W L. 1964), is sex-linked
recessive and the defective enzyme, hypoxanthine-guanine phosphoribosyltransferase responsible for this
disease was found to be normal in the child’s erythrocytes. The fact that she had an increase in pyruvic
acid in blood and urine suggested obstruction of pyruvate into the citric acid cycle, perhaps with an
overflow of glucose through the pentose pathway, resulting in increased production of purines and uric
acid. She was treated empirically with thiamine for this reason. Five months later, the urinary pyruvic
acid concentration had decreased significantly and there was definite clinical improvement evidenced by
increased activity, interest in her surroundings and alertness. Granted that this did not constitute a solid
proof, but it must be regarded as a challenge to others to explore the biochemical etiology of such a
disaster as our knowledge increases. Since the body is a biochemical “machine”, it is the “biochemical
lesion” rather than the symptomatology that must be plumbed for real progress in the treatment of
disease.
Branched chain ketoaciduria (Maple syrup urine disease) has been reported due to thiamine
dependency, as already mentioned above. The biochemical abnormalities were reversed by administration
of pharmacological doses of thiamine (Scriver C R, et al. 1971. Duran M, et al 1978). This disease has
been reported to occur intermittently (Dancis J, et al. 1967). Clinical episodes occurred in association
with infections in the same way as the intermittent cerebellar ataxia occurred in the case reported by
Lonsdale and associates (Lonsdale D, et al 1969). The infection is deemed to be an attack that results in
mobilization of the metabolic response and is regarded as a form of “stress”. This results in an exposure
of the underlying defect that is adequate when the subject is not under attack. The concept of “stress”
would apply to other forms of attack and is considered to include head injury and even inoculation as
described in the episodes of cerebellar ataxia reported by Lonsdale et al. This concept was introduced
earlier in the chapter when the first symptoms of beriberi occurred in Chinese workers when they were
suddenly exposed to sunlight. As already mentioned, it also strongly suggests that the disaster of SIDS is
brought about by the combination of a “stress” event (e.g. a cold), immature brainstem control of vital
function and a deficiency of an equally important nutrient such as thiamine or magnesium (Lonsdale D
2001). It has been hypothesized that this concept might be studied further by the use of Boolean algebra
that involves the interlocking of circles and published as the Three Circles of Health (Lonsdale D 1994).
The three circles are entitled Stress, Genetics and Nutrition.
Clinical use of thiamine tetrahydrofurfuryl disulfide (TTFD)
I have had an Independent Investigator License for the clinical use of TTFD since 1973.
Consequently, I have been able to treat hundreds of patients with it and have reported these activities in a
19
number of reviews and case reports, summarized recently (Lonsdale D. 2006). Its therapeutic benefits are
not well known, at least in the U.S.A. where it is not approved by the FDA. Details of an unusual case of
cardiac beriberi were published in a book that is now out of print but available on line (Lonsdale D. 1987,
2006) The boy in question had not been normal since birth and was mildly mentally retarded. The reason
for recurrent episodes of gastro enteritis was never solved, but had always been treated as infections.
After one of these episodes the parents of the then 13-year old boy took him up into mountainous terrain
for a picnic. While sitting in the sun he developed hemiparesis that recovered spontaneously as he was
being driven to the nearest hospital. It is to be noted that this onset of symptoms was similar to the onset
of first symptoms of beriberi in Chinese factory workers when exposed to sunshine, as discussed
previously. The major discovery on arrival at the hospital was a grossly enlarged heart and he was
transferred to our institution where his condition was recognized as beriberi heart disease. He responded
dramatically to TTFD for a while but gradually became resistant to its effects and died. Unfortunately,
the parents were adamant in denying autopsy studies and the basic lesion was never defined, for it was
clear that this was not due to simple dietary thiamin deficiency. In the light of more modern knowledge it
would be possible to postulate an abnormality in thiamin metabolism such as transporter disease.
Some years ago, there were almost annual epidemics of Reye’s syndrome, eventually recognized
as severe repercussions from the use of aspirin given to children with one of the many different viral
diseases. One child that came in to our institution was an 18-month old girl easily recognized as an
example of this syndrome. The treatment given at that time failed and she was comatose and surviving
with the application of life sustaining machinery. It was agreed by all that she had little hope of survival.
Very large doses of TTFD were given both by mouth and intravenously. The first sign of recovery was
reappearance of lip vermilion and pink cheeks. As treatment continued she passed through the stage of
the peculiar state of partial consciousness known as coma vigilum. In this state she accepted food and
followed the faces of attending personnel with her eyes. Consciousness gradually returned and she was
able to walk out of the hospital. There was unfortunately not enough factual evidence for publication of
this case (Lonsdale D. Unpublished observations). Since Reye’s syndrome produced its lethal effects by
attacking brainstem controls, it can be easily suggested that the recovery in this child was due to
restoration of oxidative metabolism in this crucial part of the brain on which depends the survival of each
one of us.
It was consideration of the role of thiamin in the brainstem and limbic system that led to its
experimental use in the treatment of threatened SIDS (Lonsdale D. 1977). My colleagues and I were able
to show that brainstem auditory evoked potentials (BAEP) were abnormal in many children who
presented with symptoms of threatened SIDS (Lonsdale D et al. 1979). The concept of “threatened” in
this syndrome was, for a long time, unaccepted, since the symptomatology is vague and non specific and
the syndrome was regarded as being impossible to forecast. Nevertheless, we encountered a number of
infants whose history of life threatening apnea described by the parents had been sometimes regarded in
emergency rooms as parental over-reaction when the infant was found to be normal on examination. We
20
described the cases of four infants whose history of near-death episodes ceased and clinical recovery
occurred after the administration of TTFD (Lonsdale D et al. 1982). In one patient the BAEP was found
to be extremely abnormal but partially corrected after administration of intravenous TTFD and went on to
a more complete recovery with orally administered TTFD. Although her subsequent life was associated
with mild mental problems, she is now a married woman. Of particular interest in this discussion, her
mother had consumed a great deal of cola drinks during her pregnancy.
The chromosomal etiology in Down’s syndrome is well known as trisomy 21. The biochemical
effects are less well known but are brought about by the over-expression of genes occurring on
chromosome 21. A clinical study in a group of randomly chosen children with Down’s syndrome showed
modest improvement in the measured IQ of some of them (Lonsdale D, and Kissling C D. 1987). A
current epidemic of infantile autism is being encountered and our own experience has shown that about
10-20% of these children have an abnormal TPPE, thought to be a significant marker for oxidative stress
(Gibson G E, and Zhang H. 2002). It prompted a pilot study in the treatment of 10 of these children with
TTFD (Lonsdale D, et al. 2002). Because the enteric coated tablets made by Takeda Chemical Industries
were not available, the powdered form of TTFD was found to be completely unpalatable and rejected by
anyone who tried tasting it, no matter what kind of taste disguise was used. It was therefore administered
in the form of rectal suppositories. Using computer-read special symptom forms prepared and tested by
the Autism Research Institute in San Diego the symptom scores improved in 8 of the 10 children. This
would certainly be a good reason to perform a well designed complete study.
It has now been possible to create a TTFD containing cream that can be applied to the skin,
obviating the oral route completely. A by-product of its use is that the patient often will produce a body
odor that is constantly likened to the characteristic odor of skunk secretion. The secretion of skunks is
known to be due to a mixture of organic mercaptans and the prosthetic group derived from the reduction
of TTFD is a mercaptan. By simple trial it has been found that the administration of 10 mg of biotin given
each day by mouth will often reduce or remove the odor. Another agent that reduces this odor frequently,
discovered by the mother of an autistic child, is the application of fresh lemon juice to the skin. Although
scientific study of the mechanism of action has not been performed, it has become clear that this body
odor from the patient gradually decreases and may disappear altogether as clinical improvement is
observed and the biotin/lemon juice combination is no longer necessary, even though treatment with
TTFD may continue. It has been known for some time that thiamin removes lead from experimentally
induced lead toxicity in animal studies (Olkowski A A,et al. 1991). Our study of TTFD in autistic
children revealed that treatment was associated with increases in urinary lead, arsenic, cadmium and
mercury, the SH-reactive heavy metals. This strongly suggests that it is the thiol nature of TTFD that
gives it its chelating action of these metals.
An open trial with TTFD was performed on 44 patients with polyneuropathy. Thirty-four patients
showed improvement of motor function and some restoration of sensory function. Of 18 patients re-
examined electrophysiologically 3 months later, 6 showed remarkable improvement. There were no side
21
effects noted (Djoenaidi W, et al 1990) The same authors reported three patients with beriberi who
presented with different clinical manifestations. The cardiac symptoms responded dramatically to TTFD
and there were some improvements in their polyneuropathy (Djoenaidi W, et al, 1992). In view of the
harmless nature of the treatment, these authors also suggested the routine administration of TTFD should
be given to all patients in whom heart failure is present without clear evidence of cause. In a 12 week
open trial in Alzheimer’s disease TTFD at an oral dose of 100 mg/day resulted in a mild beneficial effect
on emotional symptoms and intellectual function (Mimori Y et al 1996)
A test known as the intravenous olfaction test with TPD is a simple procedure widely used in
Japan (Harada H, et al. 2002). An olfactory stimulus is provided by intravenous injection of TPD. The
subject smells n-propyl mercaptan , the prosthetic group derived from hydrolysis. This is discharged from
blood into the alveoli and expired. By electroencephalography the authors found alpha-2 and beta-2
waves to be activated over the frontal and temporal regions during the olfactory stimulation. The EEGs
returned to pre-stimulus levels after disappearance of the olfactory sensation.
The S acyl derivative known as benzoyl thiamine monophosphate (BTMP), also known as
Benfotiamine has recently received attention and is reported to have clinical benefit in the complications
of diabetes (Bitsch R, et al,1991, Thornalley P J, 2003, Beltramo E, et al. 2004, Haupt E, et al. 2005).
Alteration of thiamine pharmakoinetics by end stage renal disease improved with administration of
BTMP, suggesting that this derivative might be beneficial in end stage renal disease (Frank T, et al.1999).
It was reported that an open thiazole ring thiol form of thiamine (unspecified) released nitric oxide from
S-nitrosoglutathione (Stepuro A L, et al,2005). This might explain the reported benefit of thiamine
derivatives in the microangiopathy of diabetes and certainly deserves further research and clinical trials.
Conclusion and Hypothesis
The use of thiamin, and its disulfide derivatives in particular, is much neglected in Western
medicine. It was one of the earliest vitamins to be discovered and synthesized and it is surprising that it
has not been featured more in clinical reports and reviews involving nutritional therapy. The nutritional
diseases have been long associated with poverty and starvation. Starvation, however, represents loss of
both calorie yielding food components as well as the non-caloric nutrients, usually a slow attrition to
death. If calories are maintained without appropriate vitamin and mineral content (empty calories), the
outcome is quite different. Beriberi is the classic form of empty calorie disease since it is strongly
associated with white rice in Eastern cultures. Modern Western diets, particularly in children and
adolescents are loaded with simple carbohydrates, placing a metabolic strain on the mechanisms of
oxidative metabolism. The disease outcome is therefore often seen as marginal beriberi.
My experience of more than 30 years of nutritional therapy in the U.S.A. has clearly shown that
malnutrition is extremely widespread. Thiamin figures high on the list of nutrient deficiencies, although it
can also be said that is more an excess of simple carbohydrates that overwhelms the oxidative system
22
rather than a strictly defined vitamin deficiency. Because of vitamin fortification of processed foods and
the relative affluence of our present culture, we are not ready to consider that obscure symptoms,
particularly those that are generally termed functional, are of dietary origin. They are frequently the direct
result of years of dietary abuse and the subsequent deterioration in enzyme action is not easily repaired.
Physiological doses have no effect since the enzyme/cofactor bonding appears to be damaged or partially
atrophied. Thus, physicians often become disenchanted when they suspect vitamin deficiency, treat a
patient with low-dose supplementation and see no benefit. The RDA of thiamin is 1-1.5 mg per 1000 kilo
calories but only in a biochemically healthy individual. Like the RDA of vitamin C is the minimal
amount to prevent scurvy, so is the RDA of thiamin the minimal to prevent beriberi. As was pointed out
in discussion of beriberi, occurring in epidemic form, it took months of high dose thiamin to reverse the
symptoms and sometimes it was irreversible.
One important aspect of this kind of malnutrition is the effect that it has on the emotional
characteristics of behavior. Anger is easily invoked and temper tantrums may be much more violent and
persistent in children. The hypothesis is that the limbic system of the brain becomes much more
responsive to incoming stimuli when its oxidative metabolism becomes inefficient. Primitive reflex
activity in this system might then occur under stress when the supervisory action of the cognitive brain is
overwhelmed. Juvenile crime has been linked with high calorie malnutrition (Schauss A,1981,Gray G E
1987), and the role of thiamin deficiency accentuated (Lonsdale D, 1992,1994) in view of the nature of
dietary excesses as considered earlier in this chapter.
Legal circles have addressed this association in only a very limited manner because our concept of
criminal behavior is that it is purely volitional and performed in cold blood. It is entirely possible,
however, that a perceived anger might give rise to irrational behavior that might explain the presently
inexplicable problem of school shootings, for example. To my knowledge no newspaper account has ever
included any discussion on diet in any one of these insane incidents since it never enters the
consciousness of anyone to make the enquiries. Temporary insanity, at least in the State of Ohio, can be
used in court if it can be shown that a criminal “knew what he was doing but was unable to stop himself
doing it”. The human body is a fuel burning “machine” with the incredible ability to heal itself. Assuming
a genetically, or epigenetically, determined cellular “blueprint”, all it requires is the appropriate fuel and
the catalysts that enable it to go through the complex mechanisms of oxidative metabolism, particularly in
the brain. As we move further and further from our biologic origins, so our risks incurred by appalling
planet earth stewardship increase accordingly. The aim of the food industry is profit and it appeals to our
modern urge to avoid kitchen duty as much as possible by processed convenience foods that provide taste
pleasure irrespective of their nutritional quality.
23
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... Thiamine, in the form of thiamine diphosphate (TDP), is required for aerobic metabolism [7]. It is an essential cofactor for pyruvate dehydrogenase (PDH), the enzyme responsible for the conversion of pyruvate to acetyl coenzyme A, which subsequently enters the citric acid cycle ( Fig. 1) [7]. ...
... Thiamine, in the form of thiamine diphosphate (TDP), is required for aerobic metabolism [7]. It is an essential cofactor for pyruvate dehydrogenase (PDH), the enzyme responsible for the conversion of pyruvate to acetyl coenzyme A, which subsequently enters the citric acid cycle ( Fig. 1) [7]. Hence, thiamine depletion will redirect pyruvate to increase lactate production [8]. ...
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Objective Cardiothoracic surgery is a large field in Australia, and evidence suggests post-cardiopulmonary bypass (CPB) hyperlactataemia is associated with higher morbidity and mortality. Low thiamine levels are a potentially common yet treatable cause of hyperlactataemia and may occur in the setting of exposure to CPB non-biological material. We hypothesized that cardiopulmonary bypass would result in decreased whole-blood thiamine levels, which may therefore result in increased whole-blood lactate levels in the post-operative period. Methods Adult patients undergoing non-emergent CPB were recruited in a single centre, prospective, analytic observational study at Townsville University Hospital, Australia. The primary outcome was a comparison of pre- and post-CPB thiamine diphosphate level, secondarily aiming to assess any relationship between lactate and thiamine levels. Prospective pre- and post-CPB blood samples were taken and analysed at a central reference laboratory. Results Data was available for analysis on 78 patients. There was a statistically significant increase in thiamine diphosphate level from pre-CPB: 1.36 nmol/g Hb, standard deviation (SD) 0.31, 95% confidence intervals (CI) 1.29–1.43, to post-CPB: 1.77 nmol/g Hb, SD 0.53, 95% CI 1.43–1.88, p value < 0.001. There was a non-statistically significant (p > 0.05) trend in rising whole-blood lactate levels with increasing time. Analysis of lactate levels at varying time periods found a significant difference between baseline measurements and increased levels at 13–16 h (p < 0.05). There was no significant relationship observed between whole-blood thiamine levels and post-operative lactate levels. Conclusion Whole-blood thiamine levels were found to increase immediately post-CPB in those undergoing elective cardiac surgery. There was no correlation between whole-blood thiamine levels and post-operative arterial lactate levels.
... Glutathione generation is critical to protect from oxidative stress and free radical production, which is a significant contributing factor to the overall sequela of septic shock. [9] Thiamine deficiency occurs in about one-third of septic patients. [10] Elevated lactate, acidosis, and hypotension occur in septic shock and thiamine deficiency. ...
... Furthermore, chronic alcohol intake causes a decrease in thiamine absorption in the gastrointestinal tract [44]. Tannin, a polyphenol present in coffee and tea, has been reported to inactivate thiamine [45,46]. Therefore, dietary patterns such as high intake of thiamine and low intake of alcohol and preferred beverages (such as coffee and tea) during pregnancy may be important in preventing SGA from the perspective of efficient glucose (carbohydrate) utilization. ...
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Background Although small for gestational age (SGA) is a serious problem worldwide, the association of dietary patterns before and during pregnancy with SGA risk is unclear. We evaluated this association among Japanese pregnant women using three methods: reduced rank regression (RRR) and partial least squares (PLS), methods for extracting dietary patterns that can explain the variation of response variables, and principal component analysis (PCA), a method for extracting dietary patterns of the population. Methods Between July 2013 and March 2017, 22,493 pregnant women were recruited to the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study, a population-based prospective birth cohort study in Japan. Information on dietary intake was obtained using food frequency questionnaires, and dietary patterns were extracted using RRR, PLS, and PCA. Information on birth weight was obtained from obstetric records, and the birth weight SD score and SGA were defined by the method of the Japan Pediatric Society. The associations of dietary patterns with birth weight SD score and SGA risk were investigated using multiple linear regression and multiple logistic regression, respectively. Results A total of 17,728 mother-child pairs were included. The birth weight SD score was 0.15 ± 0.96, and the prevalence of SGA was 6.3%. The dietary patterns extracted by RRR and PLS were similar and characterized by a high intake of cereals and fruits and a low intake of alcoholic and non-alcoholic beverages in both pre- to early pregnancy and from early to mid-pregnancy. Higher adoption of the RRR and PLS patterns in both periods was associated with an increased birth weight SD score and lower risk of SGA. In contrast, the PCA1 pattern was not associated with birth weight SD score or SGA risk in either period. Although the PCA2 pattern was associated with increased birth weight SD score from early to mid-pregnancy, no other associations with birth weight SD score or SGA risk were observed. Conclusions The dietary pattern with a high intake of cereals and fruits and a low intake of alcoholic and non-alcoholic beverages before and during pregnancy was associated with a decreased SGA risk in Japan.
... In fact, a variety of organic phosphate anions were reported to be such coupled substrates of SLC19A1, including TPP, ATP (adenosine triphosphate), ADP (adenosine diphosphate), AMP (adenosine monophosphate), G6P (glucose 6-phosphate), and NAD + (nicotinamide adenine dinucleotide) 23,37,38 . It thus came to our attention that the majority of thiamine would be metabolized in cells to its active form, the organic-phosphate derivative TPP (Fig. 4a), which is the coenzyme involved in biochemical reactions of decarboxylation 39 . ...
Preprint
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Thesis
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