Thiamine Deficiency and Alcoholic Brain Disease : Part 4

by National Institute of Health

(Page 4 of 5)

Inadequate Nutritional Intake

Although most people require a minimum of 0.33 mg thiamine for each 1,000 kcal of energy they consume, alcoholics tend to consume less than 0.29 mg/1,000 kcal. In fact, in an early study of 3,000 alcoholics admitted to hospitals because of alcohol withdrawal symptoms or other alcohol-related illnesses, 40 percent exhibited periodic thiamine deficiency during drinking binges, 25 percent exhibited prolonged thiamine deficiency with some periods of normal intake, and 35 percent exhibited continuous thiamine deficiency. A later study found that alcoholic patients had significantly lower average levels of a thiamine compound containing one phosphate group (thiamine monophosphate), but the average levels of free thiamine and ThDP were similar in alcoholics and control subjects. However, some of the alcoholics in that study had extremely high levels of free thiamine, suggesting that they may have had a problem in the steps that lead to the conversion of thiamine into its active, phosphate-containing form.

Decreased Uptake of Thiamine From the Gastrointestinal Tract

Animal studies have helped elucidate the mechanisms of normal and alcohol-impaired thiamine uptake from the gastrointestinal tract into the blood and cells. To be used by the body, thiamine must cross a number of barriers, first transferring across the membranes of the cells lining the gut (enterocytes), then entering those cells, and then crossing the membranes at the other end of the cells to enter the bloodstream. At low thiamine concentrations, such as those normally found in the human body, this transfer is achieved by a specific thiamine transporter molecule that requires energy. This is called an active transport process and seems to be associated with the rapid addition of two phosphate groups by the enzyme thiamine diphosphokinase (TPK) once the thiamine is inside the cell. At high thiamine concentrations, however, such as can be achieved after additional thiamine is administered, thiamine transport occurs through a passive process - that is, a mechanism that requires no energy.

Acute alcohol exposure interferes with the absorption of thiamine from the gastrointestinal tract at low, but not at high, thiamine concentrations. Furthermore, in studies using rats, the activity of the TPK enzyme from various tissues decreased with acute alcohol exposure to about 70 percent of the activity level in control animals, and with chronic alcohol exposure to about 50 percent. Although no studies have addressed whether alcohol directly affects TPK in humans, indirect analyses have found that the ratio of phosphorylated thiamine (primarily ThDP) to thiamine is significantly lower in alcoholics than in nonalcoholics - that is, that less thiamine is converted to ThDP. This finding suggests that TPK is less active in the alcoholics.

Thiamine malabsorption could become clinically significant if combined with the reduced dietary thiamine intake that is typically found in alcoholics, when other aspects of thiamine utilization are compromised by alcohol, or when a person requires increased thiamine amounts because of his or her specific metabolism or condition (in pregnant or lactating women).

Impaired Thiamine Utilization

The cells' utilization of thiamine can be affected in different ways by chronic alcohol use. As mentioned earlier, once thiamine is imported into the cells, it is first converted into ThDP by the addition of two phosphate groups. ThDP then binds to the thiamine-using enzymes, a reaction that requires the presence of magnesium. Chronic alcohol consumption frequently leads to magnesium deficiency, however, which also may contribute to an inadequate functioning of the thiamine-using enzymes and may cause symptoms resembling those of thiamine deficiency. In this case, any thiamine that reaches the cells cannot be used effectively, exacerbating any concurrently existing thiamine deficiency.

Abstinence from alcohol and improved nutrition have been shown to reverse some of the impairments associated with thiamine deficiency, including improving brain functioning. Researchers also administered thiamine to alcoholic patients and laboratory animals and found that this treatment reversed some of the behavioral and metabolic consequences of thiamine deficiency. Most recently, researchers administered different thiamine doses for two days to a group of alcoholics undergoing detoxification, none of whom were diagnosed with WKS, and then tested the participant's working memory. These studies found that participants who received the highest thiamine dose performed best on tests of working memory.

Differential Sensitivity to Thiamine Deficiency

Differences in Sensitivity Among People

Several findings suggest that not all people are equally sensitive to thiamine deficiency and its consequences. For example, although thiamine deficiency may occur in up to 80 percent of alcoholics, only about 13 percent of alcoholics develop WKS. This means that the severest consequences of thiamine deficiency develop only in a subset of people who consume alcohol and have poor nutrition on a chronic basis. A possible explanation for this differential sensitivity is that some people are genetically predisposed to develop brain damage after experiencing repeated episodes of alcohol-related thiamine deficiency. To investigate this hypothesis, researchers have studied the activities of thiamine-using enzymes in patients with and without Korsakoff's psychosis, arguing that variants of these enzymes may exist that could differ in their susceptibility to thiamine deficiency. The results of these investigations, however, have been inconsistent.2 (2 The studies cited in this section mostly used enzymes isolated from skin or blood cells of the participants. Although it is not known whether the effects of thiamine deficiency on these cells are identical to those on brain cells, the thiamine-using enzymes in these cells should be similar to the enzymes in brain cells, which are not accessible to the researchers. Using such model systems to investigate mechanisms of cell function has a long tradition in research.)

One study compared the activity of transketolase, PDH, and α-KGDH derived from skin cells of people with and without Korsakoff's psychosis. These investigators found that transketolase from the Korsakoff's patients bound ThDP less avidly than did the enzyme from the control subjects. Transketolase from the Korsakoff's patients could function normally when sufficient thiamine or ThDP was present; under conditions of thiamine deficiency, however, the transketolase molecules would not be able to bind enough ThDP to maintain normal enzyme activity. As a result, the Korsakoff's patients would be more susceptible to developing complications of thiamine deficiency than would people with a transketolase variant that more readily binds ThDP. The investigators found no differences, however, between Korsakoff's patients and control subjects in the ability of the PDH and α-KGDH enzymes to bind ThDP.

In another study, researchers studied transketolase activity in alcoholic men without Korsakoff's psychosis and their sons who had not yet been exposed to alcohol (who were alcohol naive) and compared it with transketolase activity in nonalcoholic volunteers and their sons. This analysis found that the enzyme from the alcoholic men and their sons also bound ThDP less strongly than did the enzyme from the healthy volunteers and their sons (fathers and sons were similar to each other in both groups). This finding suggests that the genetic makeup of alcoholics or those who are at risk of becoming alcoholic (sons of alcoholics who are still alcohol naive) might cause them to be more affected by thiamine deficiency than nonalcoholics.

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