Thiamine Deficiency and Alcoholic Brain Disease : Part 3

by National Institute of Health

(Page 3 of 5)

The other two enzymes requiring thiamine, PDH and α-KGDH, also participate in different steps of the breakdown and conversion of glucose-6-phosphate through two consecutive chains of biochemical reactions called glycolysis and the citric acid cycle. The main function of these pathways is the generation of a molecule called adenosine triphosphate (ATP), which provides energy for numerous cellular processes and reactions. Decreases in the activities of PDH and α-KGDH can result in reduced ATP synthesis, which in turn can contribute to cell damage and even cell death. In addition, proper functioning of PDH is essential for the production of the neurotransmitter acetylcholine as well as for the synthesis of a compound called myelin, which forms a sheath around the extensions (axons) of many neurons, thereby ensuring the ability of these neurons to conduct signals. The citric acid cycle and α-KGDH play a role in maintaining the levels of the neurotransmitters glutamate, gamma-aminobutyric acid (GABA), and aspartate, as well as in protein synthesis. Thus, the thiamine-using enzymes play numerous vital roles in the functioning of cells, and particularly of neurons.

When thiamine levels decrease, the activity levels of all three enzymes are reduced to some extent. The specific reductions depend both on the enzyme and on the cell type studied. Overall, transketolase activity may be the most sensitive measure of thiamine deficiency. Studies using rats found that transketolase activity may be reduced as much as 90 percent in the brain regions that are most sensitive to thiamine deficiency. Substantial decline in transketolase activity resulting from thiamine deficiency has even been found in various brain areas of alcoholics who do not exhibit the clinical and neuropathological signs of WE, suggesting that thiamine deficiency can cause adverse effects even before severe brain damage becomes obvious.

Thiamine Uptake Into the Cell

Thiamine is ingested with the diet, and to exert its effects in the cells it must be transported from the gastrointestinal tract to the tissues and cells. This transport involves at least four steps: uptake from the intestine into the cells that line the intestine, transport out of those cells into the bloodstream, uptake from the blood into the tissues and cells; for thiamine transported to the brain this also includes crossing the blood-brain barrier. Transport within the cells to the areas where the thiamine is needed (to the cell's energy factories, the mitochondria, where PDH and α-KGDH act, or to the nucleus, where thiamine regulates gene activity).

These transport steps are accomplished by one or more thiamine transporter molecules. Researchers recently have identified and cloned the gene for a human thiamine transporter. However, the characteristics of the thiamine transport process differ among different tissues and cell types, suggesting that variants of one transporter type or even different types of transporters may exist. Indeed, a second thiamine transporter gene recently has been cloned. As will be described in more detail in the section "Differential Sensitivity to Thiamine Deficiency," subtle variations in the transporter molecule among cells or among people, resulting in a reduced capacity to transport thiamine, may contribute to the differential sensitivity to thiamine deficiency.

Once taken up into the cells, thiamine first is modified by the addition of one or more phosphate groups. The compound containing two phosphate groups (thiamine diphosphate is the actual active molecule that serves as a cofactor for the various thiamine-requiring enzymes. The levels of phosphate-free thiamine in the cell are relatively low and are tightly regulated by rapid conversion to the phosphorylated forms.

Mechanisms of Thiamine Deficiency-Induced Cell Damage

Thiamine deficiency can lead to cell damage in the central nervous system through several mechanisms. First, the changes in carbohydrate metabolism, particularly the reduction in α-KGDH activity, can lead to damage to the mitochondria. Because the mitochondria produce by far the most energy required for cellular function, mitochondrial damage can result in cell death through a mechanism called necrosis. Second, disturbances associated with thiamine deficiency in some cell types lead to apoptosis - a form of programmed cell death that serves to remove damaged cells from the organism. Third, altered carbohydrate metabolism can lead to a cellular state called oxidative stress, characterized by excess levels of highly reactive molecules called free radicals and/or the presence of insufficient levels of compounds to eliminate those free radicals. Oxidative stress can lead to various types of cell damage and even cell death.

Alcohol's Effects on Thiamine Uptake and Function

As noted earlier, thiamine deficiency in affluent countries clearly is linked to alcoholism, occurring in up to 80 percent of alcoholics. However, only a subset of these alcoholics develop brain disorders such as WKS. Moreover, identical twins (who share all of their genetic information) show greater similarity with respect to alcohol-induced brain disease than do fraternal twins (who share on average 50 percent of their genetic information). These two observations have led to the conclusion that a genetic predisposition to thiamine deficiency and its effects may exist, as will be discussed in more detail in the section "Differential Sensitivity to Thiamine Deficiency."

Research over the past 30 years has identified several mechanisms through which alcoholism may contribute to thiamine deficiency. The most important of these mechanisms include: inadequate nutritional intake, decreased absorption of thiamine from the gastrointestinal tract and reduced uptake into cells, impaired utilization of thiamine in the cells.

About the Author

NIH is the nation's medical research agency - making important medical discoveries that improve health and save lives. The National Institutes of Health (NIH), a part of the U.S. Department of Health and Human Services, is the primary Federal agency for conducting and supporting medical research.