Thiamine, deficiency

Beriberi, Thiamine Deficiency. The recognition of vitamins and their importance to the health of human beings came about when Eijkman, a Dutch pathologist, was sent to Java in an attempt to cure an epidemic of beriberi that had appeared in one of the hospitals. Eijkman kept a flock of chickens on the hospital grounds to assist in discovering the disease agent he assumed was involved in the etiology of beriberi. These chickens were fed the scraps from the plates of the hospital patients—primarily poHshed rice, the common food in that part of the world (11). 

In humans, thiamine is both actively and passively absorbed to a limited level in the intestines, is transported as the free vitamin, is then taken up in actively metabolizing tissues, and is converted to the phosphate esters via ubiquitous thiamine kinases. During thiamine deficiency all tissues stores are readily mobilhed. Because depletion of thiamine levels in erythrocytes parallels that of other tissues, erythrocyte thiamine levels ate used to quantitate severity of the deficiency. As deficiency progresses, thiamine becomes indetectable in the urine, the primary excretory route for this vitamin and its metaboHtes. Six major metaboHtes, of more than 20 total, have been characterized from human urine, including thiamine fragments (7,8), and the corresponding carboxyHc acids (1,37,38). 

Beri-beri or clinically manifest thiamin deficiency exists in several subforms infantile beri-beri and adult beri-beri. Infantile beri-beri occurs in exclusively breastfed infants of thiamin-deficient mothers. Adults can develop different forms of the disease, depending on their constitution, environmental conditions, the relative contribution of other nutrients to the diet as well as the duration and severity of deficiency. First of all, there is a so called dry or atrophic (paralytic or nervous) form, including peripheral degenerative polyneuropathy, muscle weakness and paralysis. Second, a wet or exudative (cardiac) form exists. In this form, typical symptoms are lung and peripheral oedema as well as ascites. Finally, there is a cerebral form, that can occur as Wernicke encephalopathy or Korsakoff psychosis. Tli is latter form mostly affects chronic alcoholics with severe thiamin deficiency. 

Cessation of prolonged heavy alcohol abuse may be followed by alcohol withdrawal or life-threatening alcohol withdrawal delirium. Typical withdrawal symptoms are autonomic hyperactivity, increased hand tremor, insomnia and anxiety, and are treated with benzodizepines and thiamine. Alcoholism is the most common cause of thiamine deficiency and can lead in its extreme form to the Wernicke s syndrome that can be effectively treated by high doses of thiamine. 

Thiamin has a very low toxicity (oral LD5o of thiaminchloride hydrochloride in mice 3-15 g/kg body weight). The vitamin is used therapeutically to cure polyneuropathy, beri-beii (clinically manifest thiamin deficiency), and Wernicke-Korsakoff Syndrome ( Wernicke encephalopathy and Korsakoff psychosis). In mild polyneuropathy, 10-20 mg/d water-soluble or 5-10 mg/d lipid-soluble thiamin are given orally. In more severe cases, 20-50 mg/d water-soluble or 10-20 mg/d lipid-soluble thiamin are administered orally. Patients suffering from beri-beri or from early stages of Wernicke-Korsakoff Syndrome receive 50-100 mg of thiamin two times a day for several days subcutaneously or intravenously until symptoms are alleviated. Afterwards, the vitamin is administered orally for several weeks. 

Thiamin Deficiency Affects the Nervous System Heart... 

Thiamin deficiency can result in three distinct syndromes a chronic peripheral neuritis, beriberi, which may or may not be associated with heart ilure and edema acute pernicious (fulminating) beriberi (shoshin beriberi), in which heart failure and metabolic abnormalities predominate, without peripheral neuritis and Wernicke s encephalopathy with KorsakofPs psychosis, which is associated especially with alcohol and dmg abuse. The central role of thiamin diphosphate in... 

Langlais, P. J., McRee, R. C., Nalwalk, J. A. and Hough, L. B. Depletion of brain histamine produces regionally selective protection against thiamine deficiency-induced lesions in the rat. Metab. Brain Dis. 17 199-210, 2002. 

Navaro, D., Zwingmann, C., Hazell, A. S. and Butterworth, R. F. Brain lactate synthesis in thiamine deficiency a re-evaluation using H-13C nuclear magnetic resonance spectroscopy. /. Neurosci. Res. 79 33—41, 2005. 

Thiamine deficiency results in early decreases in activity of the... 

Oxidative stress contributes to selective neuronal cell death in thiamine-deficiency 600... 

Hepatic encephalopathy Hyperbilirubinemia Hypocalcemia Hypercalcemia Hyperparathyroidism Hypoparathyroidism Thiamine deficiency (Wernicke s) encephalopathy Diabetic ketoacidosis Nonketotic hyperosmolar coma Phosphate depletion Hypoglycemia Hypoxemia Hypercapnia... 

Thiamine deficiency results in early decreases in activity of the mitochondrial enzyme a-ketoglutarate dehydrogenase in brain. Wernicke s encephalopathy, also known as the Wernicke-Korsakoff syndrome is a neuropsychiatric disorder characterized by ophthalmoplegia, ataxia and memory loss. Wernicke s encephalopathy is encountered in chronic alcoholism, in patients with HIV-AIDS and in other disorders associated with grossly impaired nutritional status. The condition results from thiamine deficiency. 

In the 1930s, Peters and co-workers showed that thiamine deficiency in pigeons resulted in the accumulation of lactate in the brainstem [ 15]. Furthermore, they showed that the addition of small quantities of crystalline thiamine to the isolated brainstem tissue from thiamine-deficient birds in vitro resulted in normalization of lactate levels. These findings led to the formulation of the concept of the biochemical lesion in thiamine deficiency. Subsequent studies showed that the enzyme defect responsible for the biochemical lesion was a-KGDH rather than pyruvate dehydrogenase (PHDC), as had previously been presumed. a-KGDH and PHDC are major thiamine diphosphate (TDP)-dependent enzymes involved in brain glucose oxidation (Fig. 34-4). 

Neuropathologic studies in animals with experimental thiamine deficiency consistently show early damage to glial cells rather than neurons. Studies in human patients with Wernicke s encephalopathy likewise show changes in astroglia, together with microglial proliferation, which is... 

A recent study showed significant increases of expression of eNOS in the brains of rats treated with pyrithia-mine [20]. Increased eNOS expression was apparent prior to the onset of neurological symptoms and was restricted to vulnerable medial thalamus and inferior colliculus. Expression of inducible (iNOS) and neuronal (nNOS) isoforms were minimally altered in brain in thiamine deficiency and it has also been shown that targeted disruption of the eNOS (but not the iNOS or nNOS) gene results in reduced extent of neuropathological damage in thalamus of thiamine deficient animals [21] (Fig. 34-5). 

FIGURE 34-5 Induction of endothelial nitric oxide synthase (eNOS) in medial thalamus of thiamine-deficient rats. (A) Increased eNOS mRNA. (B) Increased eNOS immunolabeling of vascular endothelial cells (magnification x200). 

The suggestion that eNOS-derived NO is implicated in neuronal cell death mechanisms in thiamine deficiency contrasts with current views in cerebral ischemia in which increased eNOS-derived NO is thought to play a neuro-protective role by virtue of its vasodilatory potential. 

Todd, K. G. and Butterworth, R. F. Early microglial response in experimental thiamine deficiency an immunohisto-chemical analysis. Glia 25,190-198,1999. 

Kruse, M., Desjardins, P. and Butterworth, R. F. Increased brain endothelial nitric synthase expression in thiamine deficiency relationship to selective vulnerability. Neurochem. Int. 43 49-56, 2004. 

As might be predicted from these similarities between PNS and CNS, many disease entities can affect both these tissues. It should be noted, however, that the clinical expression of such diseases is variable and is sometimes restricted to the PNS. For example, patients with thiamine deficiency may display symmetrical distal sensorimotor polyneuropathy without accompanying CNS degeneration. Untreated infection with human immunodeficiency virus (HIV) may cause early polyneuropathy, with dementia appearing months or years later. Similarly, patients with sulfatidase deficiency or adrenoleukodystrophy may present initially with polyneuropathy, while their CNS dysfunction remains clinically undetectable. 

Neuropathy can result from deficiency of vitamins or hormones. Alcoholics often obtain a large proportion of their caloric needs from ethanol, and hence become thiamine-deficient. Alcoholic neuropathy results from a combination of thiamine deficiency, which impairs... 

Koike, H., Iijima, M., Sugiura, M. et al. Alcoholic neuropathy is clinicopathologically distinct from thiamine-deficiency neuropathy. Ann. Neurol. 54 19-29,2003. 

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