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• W2155015902 abstract "EDITORIAL FOCUSUnraveling the pathophysiology of alcohol-induced thiamin deficiencyPawel R. KielaPawel R. KielaDepartments of Pediatrics and Immunobiology, University of Arizona Health Sciences Center, Tucson, ArizonaPublished Online:01 Jul 2010https://doi.org/10.1152/ajprenal.00266.2010This is the final version - click for previous versionMoreSectionsPDF (52 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat it took over 4,500 years from the first written description of beriberi in the Chinese medical book Neiching in 2687 B.C. until the first description of the causative “vitamine” deficiency by Polish scientist Casimir Funk in 1911 (1), and the biochemical description of thiamin pyrophosphate structure and its synthesis by Robert Williams in 1936 (11). Humans cannot synthesize thiamin, and it must therefore be obtained through dietary absorption in the intestine and reclaimed in the kidneys. Healthy adults require 1.4 mg of thiamin daily, a requirement further increased in children, during pregnancy, in critically ill patients, and in alcoholic subjects. While dietary deficiency remains the main contributing factor in Asia, chronic alcoholism is the primary cause of thiamin deficiency in Western countries and one of the leading causes of cognitive deficits, Wernicke's encephalopathy, and Korsakoff psychosis (Wernicke-Korsakoff syndrome; WKS) associated with alcohol abuse. While chronic alcohol misuse does not result in encephalopathy if the dietary intake of thiamin is adequate, self-neglect, reduced intake of vitamins and minerals, low capacity of the liver to store thiamin, impaired conversion of thiamin to thiamin pyrophosphate, as well as decreased transport of thiamin across intestinal and/or renal epithelia are all believed to contribute the development of cognitive and neurological deficits (8).The cellular transport of thiamin is mediated by two specific carriers, thiamin transporter-1 (THTR1) and thiamin transporter-2 (THTR2), the products of the SLC19A2 and SLC19A3 genes, respectively. Interestingly, genetic studies with a group of alcoholic subjects affected by WKS and in supernormal controls identified several genetic variants in the SLC19A2 gene (2, 3), with two of the changes in the 3'-untranslated region of SLC19A2 region, potentially affecting gene expression. Deletion of the Slc19a2 gene (THTR1) in mice kept on a low-thiamin diet leads to diabetes, megaloblastic anemia, and sensorineural deafness (5, 6). The lack of significant changes in intestinal thiamin absorption reported by Reidling et al. (7) was attributed to a compensatory increase in THTR2 expression. On the other hand, deletion of Slc19a3 (THTR2) was reported by the same group to result in impaired intestinal thiamin absorption and decreased serum thiamin levels despite elevated THTR1 expression (7). Although THTR2-deficient mice displayed histological symptoms of hepatitis and renal interstitial inflammation and nephrosclerosis, they did not show overt histological changes in the brain (7). This could be explained by species specificity, or by a concerted functional interaction of the two thiamin transporters in maintaining adequate epithelial thiamin transport and cellular utilization of the vitamin. While mice deficient in both transporters (double knockout) have not yet been described, it is conceivable that a pathological processes in which both transporters are negatively affected would translate into more exacerbated phenotype.In an issue of the American Journal of Physiology-Renal Physiology, Subramanian et al. (9) provide a novel and informative report that chronic alcohol consumption in rats fed a Lieber-DeCarli diet results in decreased carrier-mediated thiamin transport across the renal brush-border and basolateral membranes and in transcriptionally-mediated inhibition of the THTR1 and THTR2 expression. Moreover, the expression of thiamin pyrophosphokinase (TPKase), the rate-limiting enzyme in the synthesis of the coenzyme form of thiamin was modestly, albeit significantly reduced. This observation is consistent with the previously reported 27% decrease in the enzymatic activity of TPKase in the kidneys and other organs of rats chronically fed ethanol (4). The authors did not observe changes in the expression of the mitochondrial thiamin pyrophosphate carrier Slc25a19. In an article published in parallel in the American Journal of Physiology-Gastrointestinal and Liver Physiology, the same group provides additional evidence for detrimental effects of chronic alcohol administration on intestinal thiamin absorption, also accompanied by decreased transcription and expression of the Slc19a2 and Slc19a3 genes (10). While the transcriptional mechanisms at the level of Slc19a2 and Slc19a3 gene promoters remains to be determined, these two reports provide a significant advance in our understanding of alcohol-induced thiamin deficiency. In this case, the “two-hit” model is related not only to a simultaneous reduction of expression and activity of the two key thiamin carriers but also to the two affected sites of thiamin absorption. In alcoholic subjects, changes in thiamin supply combined with impaired epithelial thiamin transport and increased metabolic demand are likely the major factors contributing to alcohol-related brain damage.GRANTSThe author is supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants 5R01DK-067286, R01 DK-41274, and R37DK-033209.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the author.REFERENCES1. Funk C. On the chemical nature of the substance which cures polyneuritis in birds induced by a diet of polished rice. J Physiol 43: 395–400, 1911.Crossref | PubMed | Google Scholar2. Guerrini I , Thomson AD , Cook CC , McQuillin A , Sharma V , Kopelman M , Reynolds G , Jauhar P , Harper C , Gurling HM. Direct genomic PCR sequencing of the high affinity thiamine transporter (SLC19A2) gene identifies three genetic variants in Wernicke Korsakoff syndrome (WKS). Am J Med Genet B Neuropsychiatr Genet 137: 17–19, 2005.Crossref | ISI | Google Scholar3. Guerrini I , Thomson AD , Gurling HM. Molecular genetics of alcohol-related brain damage. Alcohol Alcohol 44: 166–170, 2009.Crossref | PubMed | ISI | Google Scholar4. Laforenza U , Patrini C , Gastaldi G , Rindi G. Effects of acute and chronic ethanol administration on thiamine metabolizing enzymes in some brain areas and in other organs of the rat. Alcohol Alcohol 25: 591–603, 1990.Crossref | PubMed | ISI | Google Scholar5. Liberman MC , Tartaglini E , Fleming JC , Neufeld EJ. Deletion of SLC19A2, the high affinity thiamine transporter, causes selective inner hair cell loss and an auditory neuropathy phenotype. J Assoc Res Otolaryngol 7: 211–217, 2006.Crossref | PubMed | ISI | Google Scholar6. Oishi K , Hofmann S , Diaz GA , Brown T , Manwani D , Ng L , Young R , Vlassara H , Ioannou YA , Forrest D , Gelb BD. Targeted disruption of Slc19a2, the gene encoding the high-affinity thiamin transporter Thtr-1, causes diabetes mellitus, sensorineural deafness and megaloblastosis in mice. Hum Mol Genet 11: 2951–2960, 2002.Crossref | PubMed | ISI | Google Scholar7. Reidling JC , Lambrecht N , Kassir M , Said HM. Impaired intestinal vitamin B1 (thiamin) uptake in thiamin transporter-2-deficient mice. Gastroenterology 138: 1802–1809, 2010.Crossref | PubMed | ISI | Google Scholar8. Sechi G , Serra A. Wernicke's encephalopathy: new clinical settings and recent advances in diagnosis and management. Lancet Neurol 6: 442–455, 2007.Crossref | PubMed | ISI | Google Scholar9. Subramanian VS , Subramanya SB , Tsukamoto H , Said HM. Effect of chronic alcohol feeding on physiological and molecular parameters of renal thiamin transport. Am J Physiol Renal Physiol (doi:10.1152/ajprenal.00140.2010).ISI | Google Scholar10. Subramanya SB , Subramanian VS , Said HM. Chronic alcohol consumption and intestinal thiamin absorption: effects on physiological and molecular parameters of the uptake process. Am J Physiol Gastrointest Liver Physiol (doi:10.1152/ajpgi.00132.2010).ISI | Google Scholar11. Williams RR , Cline JK. Synthesis of vitamin B1. J Am Chem Soc 58: 1504–1505, 1936.Crossref | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: P. R. Kiela, Dept. of Pediatrics, Steele Children's Research Center, Univ. of Arizona Health Sciences Center; 1501 N. Campbell Ave., Tucson, Arizona 85724 (e-mail: [email protected]arizona.edu). Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationCited ByThiamine deficiency and cardiovascular disordersNutrition, Metabolism and Cardiovascular Diseases, Vol. 28, No. 10The importance of nutrition in aiding recovery from substance use disorders: A reviewDrug and Alcohol Dependence, Vol. 179Wernicke–Korsakoff Syndrome and DementiaAlcoholWernicke-Korsakoff-Syndrome: Under-Recognized and Under-TreatedPsychosomatics, Vol. 53, No. 6Prenatal exposure of a girl with autism spectrum disorder to 'horsetail' (Equisetum arvense) herbal remedy and alcohol: a case report31 March 2011 | Journal of Medical Case Reports, Vol. 5, No. 1 More from this issue > Volume 299Issue 1July 2010Pages F26-F27 Copyright & PermissionsCopyright © 2010 the American Physiological Societyhttps://doi.org/10.1152/ajprenal.00266.2010PubMed20484298History Received 11 May 2010 Accepted 13 May 2010 Published online 1 July 2010 Published in print 1 July 2010 Metrics" @default.
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