Thiamine (vitamin B1) is the water-soluble vitamin that is the essential cofactor for the pyruvate dehydrogenase complex (PDH) — the gateway enzyme that links the glycolysis to the TCA cycle by converting the pyruvate (the end product of the glycolysis) to the acetyl-CoA (the substrate for the TCA cycle and for the fatty acid synthesis). The pyruvate dehydrogenase complex is a large, multi-subunit enzyme complex that is located in the mitochondrial matrix, and it requires five cofactors for its function — the thiamine pyrophosphate (TPP, which is the active coenzyme form of thiamine and which is the cofactor for the E1 subunit of the PDH complex), the lipoic acid (which is the cofactor for the E2 subunit), the CoA (which is the substrate for the acetyl transfer), the FAD (which is the cofactor for the E3 subunit), and the NAD (which is the cofactor for the E3 subunit). The thiamine is unique among these cofactors in that it is the one that is most commonly deficient in the diet — the thiamine deficiency produces the beriberi (which is characterised by the peripheral neuropathy, the muscle weakness, the heart failure, and the Wernicke-Korsakoff syndrome), and it is one of the most important nutritional deficiencies in the world, affecting approximately 1-2 billion people, particularly in the developing world, in the alcoholism, and in the elderly. The typical dietary thiamine intake is 1-1.5mg daily (from the whole grains, the pork, the legumes, and the seeds), and the RDA is 1.2mg daily for men and 1.1mg daily for women — but the thiamine requirement is dramatically increased in people with the alcoholism (who have both the reduced dietary intake and the impaired thiamine absorption), with the diabetes (who have the increased urinary thiamine loss), and with the hyperthyroidism (who have the increased thiamine turnover).
Pyruvate Dehydrogenase and the Metabolic Gate
The pyruvate dehydrogenase complex is the metabolic gate between the glycolysis and the TCA cycle — it is the enzyme that determines whether the pyruvate is shunted into the acetyl-CoA pool (for the TCA cycle oxidation and for the fatty acid synthesis) or into the lactate pool (for the anaerobic glycolysis). The regulation of the PDH is therefore critical for the metabolic health — the PDH is regulated by the covalent modification (phosphorylation/inactivation by the PDH kinase, which is activated by the NADH and the acetyl-CoA; dephosphorylation/activation by the PDH phosphatase, which is activated by the calcium and by the insulin), by the allosteric regulation (by the substrate availability and by the product inhibition), and by the transcriptional regulation (by the nutritional and hormonal signals). Without adequate thiamine and functional PDH, the pyruvate cannot be converted to the acetyl-CoA, the acetyl-CoA pool in the mitochondria is depleted, the TCA cycle cannot proceed, the ATP synthesis is impaired, and the pyruvate is shunted to the lactate (producing the lactic acidosis) — this metabolic block is the primary mechanism of the thiamine deficiency and it explains why the thiamine deficiency produces the lactic acidosis, the neurological dysfunction, and the cardiac dysfunction that are the hallmark of the beriberi.
The clinical importance of the thiamine for the PDH function is underscored by the observation that the thiamine deficiency produces the lactic acidosis — because without the functional PDH, the pyruvate cannot enter the TCA cycle and is instead reduced to the lactate by the lactate dehydrogenase. The thiamine deficiency should always be suspected in patients with the unexplained lactic acidosis, particularly in the alcoholism, in the malnutrition, and in the parenteral nutrition without the thiamine supplementation.
Thiamine and the Beriberi
The beriberi is the classic clinical syndrome of the thiamine deficiency — it is characterised by the peripheral neuropathy (dry beriberi), by the heart failure with the high-output state (wet beriberi), and by the Wernicke-Korsakoff syndrome (the thiamine deficiency encephalopathy). The dry beriberi is characterised by the peripheral neuropathy (symmetric sensory-motor polyneuropathy that affects the distal extremities first), by the muscle weakness, by the loss of sensation, and by the areflexia — which are the result of the impaired energy metabolism in the peripheral nerves. The wet beriberi is characterised by the high-output cardiac failure (with the peripheral vasodilation, the tachycardia, the cardiomegaly, and the peripheral oedema), by the pulmonary congestion, and by the pericardial effusion — which are the result of the impaired ATP synthesis in the cardiac muscle and of the peripheral vasodilation that is caused by the thiamine deficiency. The Wernicke-Korsakoff syndrome is characterised by the acute encephalopathy (with the confusion, the ataxia, the ophthalmoplegia, and the nystagmus — the classic triad of the Wernicke encephalopathy) and by the chronic memory disorder (with the anterograde and retrograde amnesia and the confabulation — the Korsakoff psychosis) — which are the result of the selective vulnerability of the thalamus and the mammillary bodies to the thiamine deficiency.
Practical Application
For general thiamine supplementation, the evidence-based approach is to supplement with 50-100mg of thiamine daily (as thiamine hydrochloride or as thiamine pyrophosphate, the active coenzyme form). For the treatment of the thiamine deficiency (beriberi, Wernicke-Korsakoff), the high-dose thiamine (500mg IV or IM daily for 3-5 days, followed by 250mg daily for 5 days, followed by 100mg daily orally) is required to ensure the adequate brain thiamine levels. The RDA of thiamine is 1.2mg daily for men and 1.1mg daily for women, and the tolerable upper intake level has not been established (because the thiamine is water-soluble and excess amounts are excreted in the urine). For comprehensive neurological and cardiovascular support, thiamine pairs well with the alpha-lipoic acid (which is the other cofactor of the PDH complex and which has complementary effects on the glucose metabolism and on the mitochondrial function), with the CoQ10 (which is required for the electron transport chain and which is regenerating vitamin E), with the magnesium (which is a cofactor for many of the enzymes of the energy metabolism and which is often deficient in people with the thiamine deficiency), and with the B-complex vitamins (which are required for the function of all B-vitamin-dependent enzymes in the energy metabolism).
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