Thiamin diphosphate deficiency

Thiamin deficiency can result in three distinct syndromes a chronic peripheral neuritis, beriberi, which may or may not be associated with heart ilure and edema acute pernicious (fulminating) beriberi (shoshin beriberi), in which heart failure and metabolic abnormalities predominate, without peripheral neuritis and Wernicke s encephalopathy with KorsakofPs psychosis, which is associated especially with alcohol and dmg abuse. The central role of thiamin diphosphate in... 

In the 1930s, Peters and co-workers showed that thiamine deficiency in pigeons resulted in the accumulation of lactate in the brainstem [ 15]. Furthermore, they showed that the addition of small quantities of crystalline thiamine to the isolated brainstem tissue from thiamine-deficient birds in vitro resulted in normalization of lactate levels. These findings led to the formulation of the concept of the biochemical lesion in thiamine deficiency. Subsequent studies showed that the enzyme defect responsible for the biochemical lesion was a-KGDH rather than pyruvate dehydrogenase (PHDC), as had previously been presumed. a-KGDH and PHDC are major thiamine diphosphate (TDP)-dependent enzymes involved in brain glucose oxidation (Fig. 34-4). 

Thiamine (vitamin Bi), in the form of thiamine diphosphate (TPP), is a coenzyme of some considerable importance in carbohydrate metabolism. Dietary deficiency leads to the condition beriberi, characterized by neurological disorders, loss of appetite, fatigue, and muscular weakness. We shall study a number of... 

Thiamin-Responsive Pyruvate Dehydrogenase Deficiency Genetic deficiency of pyruvate dehydrogenase Ela (which is on the X chromosome) leads to potentially fatal lactic acidosis, with psychomotor retardation, central nervous system damage, atrophy of muscle fibers and ataxia, and developmental delay. At least some cases respond to the administration of high doses (20 to 3,000 mg per day) of thiamin. In those cases where the enzyme has been studied, there is a considerable increase in the of the enzyme for thiamin diphosphate. Female carriers of this X-linked disease are affected to a variable extent, depending on the X-chromosome inactivation pattern in different tissues (Robinson et al., 1996). 

In vitro, thiamin diphosphate inhibits the kinase that phosphorylates and inactivates branched-chain oxo-acid dehydrogenase, and might be expected to increase the activity of the enzyme in tissues, thus offering an alternative mechanism for thiamin-responsive maple syrup urine disease. However, this seems not to be relevant in vivo, possibly because tissue concentrations of thiamin diphosphate do not rise high enough to affect the activity of the kinase. In thiamin-deficient animals, there is an increase in the total liver content... 

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

Patients with congestive heart failure taking high doses of furosemide can develop thiamine deficiency, which is improved by thiamine supplementation. There is whole-blood thiamine phosphate deficiency, but no reduction in the storage form of thiamine, thiamine diphosphate. These observations suggest that thiamine supplementation may not be necessary in elderly patients taking furosemide for congestive heart failure (5). 

Thiamin potentiates CNS effects of acetylcholine. improved cognitive functioning in patients with Alzheimer s or age-related memory loss taking 3-8g/day. chronic thiamin diphosphate deficiency may contribute to cognitive impairment in Alzheimer"s Diseas. 

Thiamin-related diseases are the result of either insulficient thiamin intake (thiamin deficiency), poisoning by antithiamins, or of mutations in thiamin transporters or thiamin diphosphate-dependent enzymes. 

ETK AC = Erythrocyte Transketolase Activity Coefficient TDP = thiamine diphosphate N.S. = not specified MTD = moderate thiamine deficiency TD = thiamine... 

Erythrocyte transketolase activity was the classic method to assess thiamine status. Two samples of blood are incubated with excess substrate for the pentose phosphate pathway to one is also added excess thiamine diphosphate while the other serves as the control. The amount of substrate remaining and product formed are quantified, and any enhancement in activity resulting from the added thiamine diphosphate indicates that the sample was originally deficient in thiamine to some extent. 

Sources of Neuronal Susceptibility to Thiamine Diphosphate Deficiency... 

Table 33.2 Laboratory markers of thiamine diphosphate deficiency in different groups at risk.

The decarboxylation and oxidation of pyruvate to form acetyl CoA requires the coenzyme thiamin diphosphate, which is formed from vitamin (section 11.6.2). In thiamin deficiency, this reaction is impaired, and deficient subjects are unable to metabolize glucose normally. Especially after a test dose of glucose or moderate exercise they develop high blood concentrations of pyruvate and lactate. In some cases this may be severe enough to result in life-threatening acidosis. 

The activation of apo-transketolase in erythrocyte lysate by thiamin diphosphate added in vitro has become the most widely used and accepted index of thiamin nutritional status. An activation coefficient > 1.25 is indicative of deficiency, and < 1.15 is considered to reflect adequate thiamin nutrition. 

Thiamin or Bj has been recognized historically as the main cause of beriberi. Thiamin exists in free and bound forms (thiamin diphosphate and the protein-phosphate-thiamin complex). The bound forms are split in the gastrointestinal tract. The absorbed thiamin acts as a coenzyme in energy metabolism, mainly in the conversion of glncose to fats. In addition, it has high implications in the functioning of peripheral nerves (nerve impulses), brain, and muscles. Thiamin deficiency causes... 

Beriberi is caused by a deficiency of thiamin (also called thiamine, aneurin(e), and vitamin Bj). Classic overt thiamin deficiency causes cardiovascular, cerebral, and peripheral neurological impairment and lactic acidosis. The disease emerged in epidemic proportions at the end of the nineteenth century in Asian and Southeast Asian countries. Its appearance coincided with the introduction of the roller mills that enabled white rice to be produced at a price that poor people could afford. Unfortunately, milled rice is particularly poor in thiamin thus, for people for whom food was almost entirely rice, there was a high risk of deficiency and mortality from beriberi. Outbreaks of acute cardiac beriberi still occur, but usually among people who live under restricted conditions. The major concern today is subclinical deficiencies in patients with trauma or among the elderly. There is also a particular form of clinical beriberi that occurs in patients who abuse alcohol, known as the Wer-nicke-Korsakoff syndrome. Subclinical deficiency may be revealed by reduced blood and urinary thiamin levels, elevated blood pyruvate/lactate concentrations and a-ketoglutarate activity, and decreased erythrocyte transketolase (ETKL) activity. Currently, the in vitro stimulation of ETKL activity by thiamin diphosphate (TDP) is the most useful functional test of thiamin status where an acute deficiency state may have occurred. The stimulation is measured as the TDP effect. 

Vitamin Bj Vitamin Bj was discovered in 1926 by Jansen and Do-NATH, who synthesized it in its crystalline form from rice bran. It was initially called aneurine due to its antipolyneuropathic effect. Because it contains sulphur, Windaus correctly renamed it thiamine in 1932, a term by which it is still known today. The stixicture of this vitamin was described by Williams and Grewe in 1936. It is made up of pyrimidine and thiazole. Thiamine occurs in nature as free thiamine and in the form of thiamine monophosphate, diphosphate and triphosphate. A maximum amount of 8 — 15 mg is absorbed daily in the proximal portion of the small intestine. In the case of oversupply, thiamine is neither stored nor intestinally absorbed. A regular intake, with a daily requirement of about 1 mg, is necessary. The major coenzyme is thiamine pyrophosphate (TPP). Thiamine deficiency may be caused by malnutrition, impaired absorption, alcoholism, antithiamines or a lack of magnesium. Magnesium is an important cofactor for the coenzyme thiamine pyrophosphate. 

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