CLINICAL CASES OF THIAMINE DEFICIENCY
Case Report #1
ID/CC
A
57-year-old white male was admitted to the hospital. He was disoriented to place and time. He had a severe memory defect, ataxia, and signs of peripheral
neuropathy.
He
had been a heavy drinker for over 25 years. Over the last six years he had been
repeatedly admitted for episodes of acute confusion.
Nerve-conduction
studies confirmed the presence of neuropathy.
Liver function tests gave normal results. His brain scan was normal.
The activity of erythrocyte transketolase in the presence of excess thiamine
pyrophosphate (TPP) was slightly higher than normal.
However, the apparent Km for binding
of thiamine pyrophosphate (TPP) was between 10 and 20 times higher than normal.
Treatment
He
was treated with thiamine tetrahydrofurfuryl disulfide for over 5 months.
His general condition improved, but his memory did not.
Questions
Reference:
Case Discussion
1. Wernicke-Korsakoff syndrome occurs commonly among chronic alcoholics. The poor diet of chronic alcoholics leads to an inadequate thiamine intake. Also, because of their intake of alcohol they may have a higher-than-usual need for vitamins to handle the excess calories from the alcohol. Chronic alcoholics also have a much higher incidence of GI tract disease involving inadequate thiamine absorption. A less common cause of Wernicke-Korsakoff syndrome is an in-born genetic error in an important metabolic enzyme, which may also contribute to encephalopathy. The exact relationship of the encephalopathy to the lack of thiamine (or the loss of activity of thiamine-dependent enzymes) is not known, but several enzymes, important for proper energy production, require thiamine, and the brain is especially sensitive to upsets in energy production.
2. Thiamine tetrahydrofurfuryl disulfide, a derivative of thiamine, is given because it is much more readily absorbed than thiamine itself.
3. Oral multivitamins alone are not sufficient for treating this patient, for two reasons: (1) Chronic consumption of alcohol may impair the GI absorption of thiamine. (2) Furthermore, from the patient’s lab data, the transketolase assay results indicate that the enzyme has an impaired ability to bind TPP. This suggests that a thiamine deficiency due to malnutrition is not the primary etiology. In this case, an in-born genetic error, a mutated enzyme with lower-than-usual affinity for TPP, is the primary cause of the patient's complaints. But the patient's alcohol abuse is a major (but secondary) contributing factor to the patient's condition.
4. Although Wernicke-Korsakoff syndrome usually results from a lack of dietary thiamine, the patient's Km value suggests that a genetic defect in his thiamine-dependent enzymes may the the primary cause of his Wernicke-Korsakoff syndrome. The aberrant Km value here indicates that the transketolase has lower affinity for TPP than usual. In this case, the syndrome is mainly due to defective binding of the thiamine-dependent enzyme with its cofactor, TPP, and the consequent loss of enzymatic activity.
5. Oral thiamine therapy (thiamine tetrahydrofurfuryl disulfide) alone may improve the patient's general condition, but it may not improve the patient's memory. This is probably due to long-term damage to cells in the brain due to impaired energy production in those cells.
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A
20-year-old female patient was admitted to the hospital for persistent vomiting,
diarrhea, and nausea.
She
had Crohn’s disease since age 9 and was on chronic total parenteral nutrition
(TPN). Two months before admission,
multivitamin infusion (MVI) was discontinued in the TPN because of the shortage
of its supply. An oral multivitamin
tablet was substituted instead.
Fat
stores and muscle tissue were decreased.
Her respiratory rate was 24/min.
Her blood pressure, while she was standing, was 105/65 mmHg.
Liver
tests were normal. The serum
lactate concentration was substantially increased.
Magnetic resonance imaging (MRI) showed several areas of abnormally high signal on T2- weighted images (transverse magnetization, which generates a cross-section image via radio-frequency pulse) in the brainstem, thalamus, and mamillary bodies.
50
mg of intravenous thiamine.
Reference:
Hahn, Jin S. et al., (1998) "Wernicke encephalopathy and beriberi during total parenteral nutrition attributable to multivitamin infusion shortage", Pediatr. 101, 100 (Abstract)
Case Discussion
1. Clinical signs and symptoms of thiamine deficiency are primarily manifested by CNS and cardiovascular disorders. Symptoms include mental confusion, muscle wasting, tachycardia, and ataxia. Also, increased microhemorrhages in the breasts, thalamus and brainstem are common in thiamine deficient patients. The physical exam and MRI of this patient is consistent with these clinical signs and symptoms of thiamine deficiency.
2. Thiamine pyrophosphate functions as a coenzyme vital to tissue respiration for generating energy. It is required for oxidative decarboxylation of pyruvate to acetyl CoA, providing entry of oxidizable substrate into the Krebs cycle and eventually to the electron transport chain for the generation of large amounts of energy (ATP). Glucose is indispensable for maintaining the functional integrity of nerve tissue; and, under normal circumstances, glucose is the sole source of energy for the brain. When thiamine is insufficient, less pyruvate can enter the TCA cycle, and energy production is impaired. Consequently, fat stores and muscle tissue will be used for gluconeogenesis in response to the reduced supply of glucose to the brain cells.
3. Pyruvate dehydrogenase is the most commonly affected enzyme in thiamine deficiency, but other thiamine-dependent enzymes (transketolase, alpha-ketoglutarate dehydrogenase, etc.) may also be involved. Pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase are the primary enzymes responsible for converting glucose to energy in high yield. The patient's physical exam indicates that her fat stores and muscle tissues were substantially decreased, as if the patient has trouble producing enough energy from dietary foodstuffs. This further supports the idea that that one or both of these enzymes may be inhibited.
4. Exogenous thiamine rapidly corrects and maintains the proper metabolism in the body. With adequate energy production restored, the body can pump ions and water as needed to maintain proper blood pressure (such pumping is quite energy-intensive). Glucose is rapidly utilized by the nervous tissue, restoring proper functioning of the central nervous system and relieving the diplopia.
5. The patient suffers from Crohn’s disease (a chronic inflammation of GI tract) as a result, her GI absorption of thiamine may be impaired.
6. The T2-weighted image is a useful diagnostic tool to confirm the clinical signs (i.e., CNS symptoms) of thiamine deficiency. Lesions and increased microhemorrhages in the thalamus and brainstem are common in the thiamine deficient patient, and can be detected by the use of a T2 scan.
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