Thiamin Deficiency

Thiamin deficiency can result in three distinct syndromes: a chronic peripheral neuritis, beriberi, which may or may not be associated with heart failure and edema; acute pernicious (fulminating) beriberi (shoshin beriberi), in which heart failure and metabolic abnormalities predominate, with little evidence of peripheral neuritis; and Wernicke's encephalopathy with Korsakoff's psychosis, a thiamin-responsive condition associated especially with alcoholism and narcotic abuse.

In general, a relatively acute deficiency is involved in the central nervous system lesions of the Wernicke-Korsakoff syndrome, and a high-energy intake, as in alcoholics, is also a predisposing factor. Dry beriberi is associated with a more prolonged, and presumably less severe, deficiency, with a generally low food intake, whereas higher carbohydrate intake and physical activity predispose to wet beriberi.

In experimental animals, thiamin deficiency is associated with severe anorexia. One of the problems in interpreting the literature on thiamin deficiency is distinguishing between effects of thiamin deficiency per se and effects of general lack of food and inanition. Even more than with other vitamins, studies of thiamin deficiency require strictpair-feeding of control animals with those receiving the deficient diet. The mechanism of anorexia is unclear. Its development shows a clear correlation with the loss of transketolase activity in the intestinal mucosa, but not the loss of pyruvate or 2-oxoglutarate dehydrogenase activity. Animals treated with oxythiamin, which does not cross the blood-brain barrier, and therefore has little effect on central nervous system metabolism, show anorexia. This suggests that the effect is on the intestinal mucosa rather than the central nervous system. In addition, it is possible that the changes in GABA and 5-hydroxytryptamine turnover in thiamin deficiency (Section 6.4.6) may be involved in the etiology of anorexia, because potentiation of GABA and 5-hydroxytryptamine activity is part of the action of a number of clinically used appetite suppressants.

6.4.1 Dry Beriberi

Chronic deficiency of thiamin, especially associated with a high carbohydrate diet, results in beriberi, which is a symmetrical ascending peripheral neuritis. Initially, the patient complains of weakness, stiffness, and cramps in the legs, and is unable to walk for more than a short distance. There may be numbness of the dorsum of the feet and ankles, and vibration sense may be diminished.

As the disease progresses, the ankle jerk reflex is lost, and the muscular weakness spreads upward, involving first the extensor muscles of the foot, then the muscles of the calf, and finally the extensors and flexors of the thigh. At this stage, there is pronounced toe and foot drop - the patient is unable to keep either the toe or the whole foot extended off the ground. When the arms are affected, there is a similar inability to keep the hand extended - wrist drop.

The affected muscles become tender, numb, and hyperesthetic. The hyperesthesia extends in the form of a band around the limb, the so-called stocking and glove distribution, and is followed by anesthesia. There is deep muscle pain and, in the terminal stages, when the patient is bedridden, even slight pressure (as from bed clothes), causes considerable pain.

In thiamin-deficient rats, electron microscopy of the sciatic and plantar nerves shows distally pronounced axonal degeneration, with an increase in the number of mitochondria and proliferation of vesicular elements of the endoplasmic reticulum. This is followed by disintegration of neurotubules and neurofilaments, and finally axonal shrinkage and myelin disruption (Pawlik etal., 1977).

6.4.2 Wet Beriberi

The heart may also be affected in beriberi, with dilatation of arterioles, rapid blood flow, and increased pulse rate and pressure, and increased jugular venous pressure leading to right-sided heart failure and edema (so-called wet beriberi).

The signs of chronic heart failure may be seen without peripheral neuritis. The arteriolar dilatation, and possibly also the edema, probably results from high circulating concentrations of lactate and pyruvate, a result of impaired activity of pyruvate dehydrogenase.

Together with the fall in pyruvate dehydrogenase, there is a fall in the concentration of ATP in the heart, although the ATP:ADP ratio in most tissues is not affected by thiamin deficiency (McCandless et al., 1970).

6.4.3 Acute Pernicious (Fulminating) Beriberi - Shoshin Beriberi

Heart failure without increased cardiac output, and no peripheral edema, may also occur acutely, associated with severe lactic acidosis. This was a common presentation of deficiency in Japan, where it was called shoshin (= acute) beriberi; in the 1920s, nearly 26,000 deaths a year were recorded.

With improved knowledge of the cause, and improved nutritional status, the disease has become more-or-less unknown, although it occurs among alcoholics, when the lactic acidosis may be life-threatening, without clear signs of heart failure. There have been a number of case reports among patients receiving total parenteral nutrition, when it may occur as early as 4 days after the start of parenteral nutrition in patients with initially low thiamin status (Campbell, 1984; Kitamura et al., 1996).

Acute infantile beriberi in infants breast-fed by deficient mothers may involve high-output cardiac failure, as in shoshin beriberi, as well as signs of central nervous system involvement similar to those seen in Wernicke's encephalopathy (Section 6.4.4).

6.4.4 The Wernicke-Korsakoff Syndrome

Although the classical signs of beriberi are of peripheral neuritis, most of the biochemical studies (Peters, 1963) were performed on the central nervous system of pigeons, because they show central nervous system abnormalities in thiamin deficiency and signs of peripheral neuritis. Although peripheral neuritis and acute cardiac beriberi and lactic acidosis occur in thiamin deficiency associated with alcohol abuse, the more usual presentation is as the Wernicke-Korsakoff syndrome caused by central nervous system lesions. There is some evidence that thiamin deficiency alone is not sufficient to cause the Wernicke-Korsakoff syndrome, but that alcohol is also a necessary factor (Homewood and Bond, 1999). However, although alcohol is neurotoxic and causes neuronal damage in the cerebral cortex, there is little evidence to support a separate classification of alcoholic dementia; most, if not all, of the organic brain damage associated with alcohol abuse can be considered to be from thiamin deficiency (Joyce, 1994).

Initially, there is a confused state, Korsakoff's psychosis, that is characterized by confabulation and loss of recent memory, although memory for past events maybe unimpaired. Later, clear neurological signs develop - Wernicke's encephalopathy. This is characterized by nystagmus and extraocular palsy. Postmortem examination shows hemorrhagic lesions in the thalamus, pon-tine tegmentum, and mammillary body, with severe damage to astrocytes, neuronal dendrites, and myelin sheaths.

Wernicke's encephalopathy may be more common than is believed on clinical grounds. Harper (1979) reported that 1.7% of all postmortem examinations in Western Australia over a 4-year period showed clear anatomical evidence of the disease, yet only 13% of the patients had been diagnosed as suffering from the condition. Other studies have similarly shown that only 10% to 20% of cases confirmed by postmortem examination had been diagnosed on clinical grounds (Zubaran et al., 1997). There appears to have been a reduction in the prevalence of the Wernicke-Korsakoff syndrome in Australia after mandatory enrichment of flour with thiamin (Ma and Truswell, 1995).

The irreversible brain lesions are associated with decreased activity of 2-oxoglutarate dehydrogenase and increased activity of the GABA shunt (Section 6.3.1.3), leading to localized lactic acidosis and excitotoxic levels of glutamate, as well as localized increased permeability of the blood-brain barrier, evidence of radical activity, and inflammatory responses to radical action. In addition, the activity of kynurenine aminotransferase (Section 9.5.4) in glial cells is regulated by the availability of its oxo-acid substrates, pyruvate and2-oxoglutarate, so that increased accumulation of these two metabolites will result in increased synthesis and release into synapses of kynurenic acid, which is an antagonist of both the N-methyl-D-aspartate glutamate receptor and acetylcholine receptors (Heroux and Butterworth, 1995; Langlais, 1995; Leong and Butterworth, 1996; McEntee, 1997; Hazell et al., 1998; Calingasan and Gibson, 2000).

A number of studies have suggested that there may be genetic polymor-phismoftransketolase(Section6.3.2) and that some variants maybe associated with increased susceptibility to the Wernicke-Korsakoff syndrome. Blass and Gibson (1977) showed that transketolase in cultured fibroblasts from patients with Wernicke-Korsakoff syndrome had a Km for thiamin diphosphate 12-fold higher than that from control subjects. This difference persisted through serial passage in culture, suggesting it was a genetic rather than environmental effect. Nixon and coworkers (1984) demonstrated different patterns of multiple bands of transketolase on isoelectric focusing; 39 or their 42 patients with Wernicke-Korsakoff syndrome showed the same unusualpattern that was only seen in 8 of 36 control subjects. Wang and coworkers (1997) expressed human transketolase in Escherichia coli and showed that formation of the normal enzyme required a cytosolic factor derived from human cells that was absent in cultured cells from a patient with Wernicke-Korsakoff syndrome, in which the enzyme showed enhanced sensitivity to thiamin deficiency. However, from reviews of a number of studies, there is little evidence to support the hypothesis that susceptibility to the Wernicke-Korsakoff syndrome is a genetic defect (Blansjaar et al., 1991; Schenketal., 1998).

6.4.5 Effects of Thiamin Deficiency on Carbohydrate Metabolism

The role of thiamin diphosphate in pyruvate dehydrogenase means that, in deficiency, there is impaired conversion of pyruvate to acetyl CoA, and hence impaired entry of pyruvate into the citric acid cycle. Especially in subjects on a relatively high carbohydrate diet, this results in increased plasma concentrations of lactate and pyruvate, which may lead to life-threatening lactic acidosis.

The increase in plasma lactate and pyruvate after a test dose of glucose was used historically as a means of assessing thiamin nutritional status (Section 6.5).

In addition to the potential to maintain citric acid cycle activity by way of the GABA shunt (Section 6.3.1.3), the activity of 2-oxoglutarate dehydrogenase is less impaired in thiamin deficiency than the activities of pyruvate dehydrogenase and transketolase. Synthesis of the apoenzymes of pyruvate dehydrogenase and transketolase is reduced, whereas there is no change in the expression of 2-oxoglutarate dehydrogenase, suggesting a potential role for thiamin or a metabolite in regulation of the expression of genes for thiamin dependent enzymes (Pekovich et al., 1996,1998).

6.4.6 Effects of Thiamin Deficiency on Neurotransmitters

As noted in Section 6.3.1.3, brain GABA falls in thiamin deficiency, but there is increased flux through the GABA shunt. The changes in the cerebellum occur early, and asymptomatic animals are more sensitive than normal to the GABA antagonist picrotoxin. Brain concentrations of glutamate and aspartate are also reduced in thiamin deficiency, as are several other neurotransmitters.

6.4.6.1 Acetylcholine One effect of the impaired activity of pyruvate dehydrogenase in thiamin deficiency is a reduction in the brain content of acetyl CoA, and a reduction in both the pool size and turnover of acetylcholine. This is reflected in functional impairment; within 1 day of the initiation of treatment with pyrithiamin, animals show impaired performance in a tightrope test. Repletion with thiamin, or the administration of either the directly acting muscarinic cholinergic agonist arecoline or the centrally acting acetyl cholinesterase inhibitor physostigmine, rapidly restores normal performance (Barclay et al., 1981).

6.4.6.2 5-Hydroxytryptamine There is no change in the concentration of 5-hydroxytryptamine (serotonin) in the brains of thiamin-deficient rats, but there is an increase in its metabolite, 5-hydroxy-indoleacetic acid, and an increase in the accumulation of 5-hydroxytryptamine alter the administration of monoamine oxidase inhibitors, suggesting an increased rate of 5-hydroxytryptamine turnover. Pyrithiamintreatmentleads to signs of increased serotoninergic activity, especially changes in sleep patterns, which are normalized by the administration of thiamin (Plaitakis et al., 1981; Crespi and Jouvet, 1982). There is no obvious metabolic role of thiamin in the synthesis or catabolism of 5-hydroxytryptamine, and it is likely that the changes are secondary to changes in GABA turnover, and hence the activity of GABA neurons that are organizationally superior to some serotoninergic tracts.

6.4.7 Thiaminases and Thiamin Antagonists

Thiaminolytic enzymes are found in a variety of microorganisms and foods, and a number of thermostable compounds present in foods (especially polyphenols) cause oxidative cleavage of thiamin, as does sulfite, which is widely used in food processing. The products of thiamin cleavage by sulfite and thiaminases are shown in Figure 6.1.

In people whose thiamin intake is marginal, colonization of the gastrointestinal tract with thiaminolytic microorganisms may be a factor in the development of beriberi. The thiaminases present in raw fish can result in so-called Chastek paralysis of foxes and mink, as a result of destruction of thiamin, and may be important in parts of the world where much of the apparent thiamin intake is from fish that is eaten raw or fermented. The polyphenols and thiami-nase in bracken fern can cause thiamin deficiency (blind staggers) in horses, and tannic acid in tea and betel nut have been associated with human thiamin deficiency.

There are two classes of thiaminase. Thiaminase I catalyzes abase exchange reaction between the thiazole moiety of thiamin and a variety of bases, commonly primary, secondary, or tertiary amines, but also nicotinamide and other pyridine derivatives, and sometimes proline and sulfhydryl compounds. Thiaminase I is relatively widespread in a variety of microorganisms, plants, and fish. In addition to depleting thiamin, the products ofbase exchange catalyzed by thiaminase I are structural analogs of the vitamin and may have antagonistic effects (Edwin and Jackman, 1970). Similarly, the neurotoxic effects of the antibiotic metronidazole, which is a thiazole, may be from its activity as a substrate for thiaminase I, forming thiamin antimetabolites (Alston and Abeles, 1987).

Thiaminase II catalyzes a simple hydrolysis, releasing thiazole and meth-oxypyrimidine, which has some antivitamin B6 antimetabolic activity. It is relatively rare and is restricted to a small number of microorganisms.

The destruction of thiamin by polyphenols is not a stoichiometric reaction, and reducing compounds such as ascorbate and cysteine inhibit the reaction. In alkaline conditions, the thiazole ring of thiamin undergoes a reversible cleavage to the thiol. Thiamin thiol can react with a variety of thiol or disulfide compounds to form alkyl thiamin derivatives (allithiamins), some of which have biological activity. However, the thiol can also undergo oxidation catalyzed by polyphenols, resulting in the formation of thiamin disulfide, which has no biological activity.

Experimentally, two analogs of thiamin, pyrithiamin and oxythiamin (see Figure 6.1), are used to induce thiamin deficiency. Both are inhibitors of, and substrates for, thiamin pyrophosphokinase. Pyrithiamin also competes with thiamin for the blood-brain barrier uptake mechanism and is accumulated in the central nervous system by metabolic trapping. Oxythiamin does not cross the blood-brain barrier and has little or no effect on the central nervous system. Oxythiamin diphosphate is a potent inhibitor of thiamin diphosphate-dependent enzymes, whereas pyrithiamin diphosphate is a poor inhibitor. In general, oxythiamin acts as a peripheral thiamin antagonist, while pyrithiamin depletes the vitamin.

6.5 ASSESSMENT OF THIAMIN NUTRITIONAL STATUS

The impairment of pyruvate dehydrogenase in thiamin deficiency (Section 6.4.5) results in a considerable increase in the plasma concentrations of lac-tate and pyruvate. This has been exploited as a means of assessing thiamin nutritional status by measuring changes in the plasma concentrations of lactate, pyruvate, and glucose after an oral dose of glucose and mild exercise. This is not specific for thiamin deficiency; a variety of other conditions can also result in metabolic acidosis. Although it may be useful in depletion/repletion studies, it is used little nowadays in screening or assessment of nutritional status, and a number of more sensitive and specific tests of thiamin status are available (as shown in Table 6.1).

6.5.1 Urinary Excretion of Thiamin and Thiochrome

Although there are a number of urinary metabolites of thiamin, a significant amount of the vitamin is excreted unchanged or as thiochrome, especially if intake is adequate, and therefore the urinary excretion can provide useful information on nutritional status. Excretion decreases proportionally with intake in adequately nourished subjects; but, at low intakes, there is a threshold below which further reduction in intake has little effect on excretion.

The excretion of a test dose of thiamin has also been used as an index of status; after a parenteral dose of 5 mg (19 ^mol) of thiamin, adequately nourished subjects excrete more than 300 nmol of the vitamin over 4 hours, whereas deficient subjects excrete less than 75 nmol.

6.5.2 Blood Concentration of Thiamin

In experimental animals and in depletion studies, measurement of the concentration of thiamin in plasma or whole blood provides an indication of the progression of deficiency. The normal method is by the formation of thiochrome, which is fluorescent; only free thiamin, and not the phosphates, undergoes

Table 6.1 Indices of Thiamin Nutritional Status

Adequate Marginal Deficient

Intake

Table 6.1 Indices of Thiamin Nutritional Status

Adequate Marginal Deficient

Intake

mmol/1,000 kcal

>1.1

0.75-1.1

<0.75

mmol/MJ

>0.27

0.18-0.27

<0.18

mg/1,000 kcal

>0.3

0.2-0.29

< 0.2

|xg/MJ

>72

48-72

<48

Urinary excretion

mmol/mol creatinine

>28

11-27

<11

mg/g creatinine

>66

27-65

<27

nmol/24 h

>375

150-375

<150

lg/24 h

>100

40-99

<40

Urinary excretion over 4 h after a 19 nmol (5 mg) parenteral dose

nmol

>300

75-300

<75

|g

>80

20-79

<20

Transketolase activation coefficient

<1.15

1.15-1.24

>1.25

Erythrocyte thiamin diphosphate

nmol/L

>150

120-150

<120

|g/L

>64

50-64

<50

Sources: From data reported by Brin, 1964; Sauberlich et al., 1974; Finglass, 1993.

Sources: From data reported by Brin, 1964; Sauberlich et al., 1974; Finglass, 1993.

oxidation to thiochrome, so measurement before and alter reaction of the sample with alkaline phosphatase permits determination of free and total thiamin.

Erythrocytes and leukocytes contain mainly thiamin diphosphate, whereas plasma contains free thiamin and thiamin monophosphate. The concentration of thiamin diphosphate in erythrocytes is normally between 110 and 330 nmol per L of packed cells. The total thiamin concentration in erythrocytes is about 4- to 5-fold higher than in plasma and that in leukocytes is 10-fold higher again.

Whole blood total thiamin below 150 nmol per L is considered to indicate deficiency. However, the changes observed in depletion studies are small. Even in patients with frank beriberi, the total thiamin concentration in erythrocytes is only 20% lower than normal; whole blood thiamin is not a sensitive index of status.

6.5.3 Erythrocyte Transketolase Activation

Activation of apotransketolase in erythrocyte lysate by thiamin diphosphate added in vitro has become the most widely used and accepted index of thiamin nutritional status. Apotransketolase is unstable both in vivo and in vitro; therefore, problems may arise in the interpretation of results, especially if samples have been stored for any appreciable time. An activation coefficient >1. 25 is indicative of deficiency, and <1.15 is considered to reflect adequate thiamin nutrition.

6.6 THIAMIN REQUIREMENTS AND REFERENCE INTAKES

It is apparent from the central role of thiamin in carbohydrate metabolism that the requirement will depend on carbohydrate intake to a considerable extent. In practice, requirements are calculated on the basis of total energy intake, assuming that the average diet provides 40% of energy from fat. For diets that are lower in fat, and hence higher in carbohydrate and protein, thiamin requirements will be somewhat higher.

On thebasis of depletion/repletion studies, an intake of0.2 mgper 1,000 kcal is required to maintain normal urinary excretion, but an intake of 0.3 mg per 1,000 kcal is required for a normal transketolase activation coefficient. At low levels of energy intake, there will be a requirement for metabolism of endogenous substrates and to maintain nervous system thiamin triphosphate.

Reference intakes (see Table 6.2) are based on 0.5 mgper 1,000 kcal (0.12 mg per MJ) for adults consuming more than 2,000 kcal per day, with the proviso that even in fasting there is a requirement for 0.8 mg of thiamin per day to permit the metabolism of endogenous energy-yielding substrates.

6.6.1 Upper Levels of Thiamin Intake

There is no evidence of any toxic effect of high intakes of thiamin, although high parenteral doses have been reported to cause respiratory depression in animals and anaphylactic shock in human beings. Hypersensitivity and contact dermatitis have been reported in pharmaceutical workers handling thiamin. As noted in Section 6.2, absorption of dietary thiamin is limited, and no more than about 2.5 mg (10 ^mol) can be absorbed from a single dose; free thiamin is rapidly filtered by the kidneys and excreted.

6.6.2 Pharmacological Uses of Thiamin

Apart from children with thiamin-responsive maple syrup urine disease (Section 6.3.1.4) and thiamin-responsive megaloblastic anemia (Section 6.2), there are no established pharmacological uses of thiamin other than the treatment of deficiency. Because of the neurological involvement in thiamin deficiency, the vitamin has been used in nerve tonics, although there is no evidence that it has any effect except in cases of deficiency.

Studies in thiamin-deficient animals revealed the presence of Alzheimerlike amyloid plaques in the brain. Although there is no evidence of similar plaque formation in the brains of patients with the Wernicke-Korsakoff syndrome, this has led to trials of thiamin for treatment of Alzheimer's disease

Table 6.2 Reference Intakes of Thiamin (mg/day)

U.K.

EU

U.S./Canada

FAO

Age

1991

1993

1998

2001

0-6 m

0.2

0.2

0.2

7-9 m

0.2

0.3

0.3

0.3

10-12 m

0.3

0.3

0.3

0.3

1-3 y

0.5

0.5

0.5

0.5

4-6 y

0.7

0.7

0.5

0.6

7-8 y

0.7

0.8

0.5

0.9

Males

9-10 y

0.7

0.8

0.9

0.9

11-13 y

0.9

1.0

0.9

1.2

14-15 y

0.9

1.0

1.2

1.2

16-18 y

1.1

1.2

1.2

1.2

19-30 y

1.0

1.1

1.2

1.2

31-50 y

1.0

1.1

1.2

1.2

>50 y

0.9

1.1

1.2

1.2

Females

9-10 y

0.7

0.8

0.9

0.9

11-13 y

0.7

0.9

0.9

1.1

14-15 y

0.7

0.9

1.0

1.1

16-18 y

0.8

0.9

1.1

1.1

19-30 y

0.8

0.9

1.1

1.1

31-50 y

0.8

0.9

1.1

1.1

>50 y

0.8

0.9

1.1

1.1

Pregnant

0.9

1.0

1.4

1.4

Lactating

0.9

1.1

1.4

1.5

EU, European Union; FAO, Food and Agriculture Organization; WHO, World Health

Organization.

Sources: Department of Health, 1991; Scientific Committee for Food, 1993; Institute

of Medicine, 1998; FAO/WHO, 2001

(Calingasan et al., 1996). Whereas some studies have shown beneficial effects, a systematic review has concluded that there is no evidence of beneficial effects of thiamin supplementation in Alzheimer's disease (Rodriguez-Martin etal., 2001).

FURTHER READING

Bettendorff L (1996) A non-cofactor role of thiamine derivatives in excitable cells?

Archives of Physiology and Biochemistry 104, 745-51. Butterworth RF (1982) Neurotransmitter function in thiamine deficiency. Neurochem-

istry International 4, 449-65. KopelmanMD (1995) The Korsakoff syndrome. British Journal of Psychiatry 166,154-73. Kril JJ (1996) Neuropathology of thiamine deficiency disorders. Metabolic Brain Diseases 11, 9-17.

Peters R (1963) Biochemical Lesions and Lethal Synthesis. Oxford: Pergamon Press. Reuker JB, Girard DE, and Cooney TG (1985) Wernicke's encephalopathy. New England

Journal of Medicine 312, 1035-8. Schellenberger A (1998) Sixty years of thiamin diphosphate biochemistry. Biochimica et

Biophysica Acta 1385, 177-86. Zubaran C, Fernandes JG, and Rodnight R (1997) Wernicke-Korsakoff syndrome. Postgraduate Medical Journal 73, 27-31.

References cited in the text are listed in the Bibliography.

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