Thiamine Deficiency and Alcoholic Brain Disease : Part 2

by National Institute of Health

(Page 2 of 5)

The role of thiamine in the development of WKS is supported by findings that giving this nutrient to patients with WKS reverses many of the acute symptoms of the disease, although in some people certain chronic neuropsychiatric consequences of previous thiamine deficiency may persist even with appropriate treatment. In the most severe cases, these persistent symptoms meet the criteria of full-blown Korsakoff's psychosis. Other people may exhibit more subtle neurological signs and symptoms, such as abnormalities in a brain region called the cerebellum and an inflammation or degeneration of peripheral nerves (neuropathy) as well as changes in behavior and problems with learning, memory, and decisionmaking.

In affluent countries such as the United States, where other forms of malnutrition are uncommon, thiamine deficiency and the resulting WKS occur most commonly among alcoholics. To date there are only a few estimates of how common WKS is among alcoholics. In autopsy studies, brain abnormalities characteristic of WKS were present in approximately 13 percent of alcoholics. These abnormalities include lesions in brain areas called the mamillary bodies, thalamus, hypothalamus, brain stem, and cerebellum. Other studies have found that only about 20 percent of alcoholics in whom the presence of WKS was confirmed at autopsy had been diagnosed with the disorder before death. Thus, the clinical presentation is not always easily recognized by physicians; often examination of the brain at autopsy is required for definitive diagnosis.

Although WKS in developed countries occurs most commonly among alcoholics, other groups of patients are also at risk of developing the disease. For example, all people who are malnourished (because they are HIV infected or are undergoing cancer chemotherapy) or who have a metabolic disease leading to impaired thiamine absorption (uptake) or utilization can develop thiamine deficiency. Patients with severe kidney disease who are undergoing regular dialysis are also prone to encephalopathy, and a substantial portion of them have been found to suffer from thiamine deficiency. Finally, patients who receive intravenous infusions of carbohydrates (the sugar dextrose) may experience episodes of thiamine deficiency, particularly if they are already at risk of receiving inadequate levels of this nutrient because they are alcoholics, as thiamine is used in the metabolism of those carbohydrates.

Cerebellar Degeneration

Considerably more common than WKS among alcoholics is a condition called cerebellar degeneration, which typically develops after 10 or more years of heavy drinking. In autopsy studies, 40 percent or more of alcoholics showed signs of this condition, which is characterized by shrinkage of certain regions of the cerebellum. This brain area is involved primarily in muscle coordination. It also is increasingly recognized for its role in various aspects of cognitive and sensory functioning. Accordingly, cerebellar degeneration is associated with difficulties in movement coordination and involuntary eye movements, such as nystagmus. Cerebellar degeneration is found both in alcoholics with WKS and in those without it, but because WKS patients typically have a higher degree of cerebellar atrophy, it appears likely that thiamine deficiency also is the predominant cause of cerebellar degeneration.

The frequent occurrence of cerebellar degeneration in alcoholics is consistent with studies demonstrating that the cerebellum is particularly sensitive to the effects of thiamine deficiency. As a result of this particular susceptibility, the effects of thiamine deficiency would be expected to appear first in the cerebellum, manifesting as cerebellar degeneration and its associated symptoms. In a smaller number of patients, the consequences of insufficient thiamine then would progress to other brain regions and lead to more widespread brain dysfunction, including alcohol amnestic disorder or alcohol-induced persisting dementia.

Thiamine's Actions in the Cell

To understand the mechanisms through which thiamine deficiency, whether induced by alcoholism or other causes, leads to brain damage, one first must understand the normal role of thiamine in the cell. Investigations of this issue have focused on three enzymes that require thiamine as a cofactor. These enzymes are called transketolase, pyruvate dehydrogenase (PDH) and alpha-ketoglutarate dehydrogenase (α-KGDH); they all participate in the catabolism of sugar molecules (carbohydrates) in the body, as described in the following paragraphs. Each of these enzymes consists of several components that must be assembled to yield the functional enzyme, and the addition of thiamine is a critical step in this assembly process. As a result, thiamine deficiency causes suboptimal levels of functional enzymes in the cell, in addition to interfering with the activity of those enzymes.

Transketolase is an important enzyme in a biochemical pathway called the pentose phosphate pathway. In this set of biochemical reactions, a molecule called glucose-6-phosphate, which is derived from the sugar glucose, is modified by transketolase, yielding two products - a sugar called ribose-5-phosphate and a molecule called reduced nicotinamide adenine dinucleotide phosphate (NADPH). Both of these molecules are essential for the production of numerous other important molecules in the cell. Ribose-5-phosphate is needed for the synthesis of nucleic acids, complex sugar molecules, and other compounds. NADPH provides hydrogen atoms for chemical reactions that result in the production of steroids, fatty acids, amino acids, certain neurotransmitters, and other molecules. In addition, NADPH plays an important role in the synthesis of glutathione, a compound that is essential in the body's defense against oxidative stress. To function properly, all cells require certain levels of NADPH and ribose-5-phosphate, and the biochemical reaction mediated by transketolase is crucial for maintaining the appropriate levels of both molecules.

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