THIAMIN

Thiamin (vitamin B-1) is a water-soluble substance, consisting of thiazole and pyrimidine rings joined by a methylene bridge. Thiamin is found in high concentrations in skeletal muscle, the heart, liver, kidneys and brain. The total amount in an adult is about 30 mg and the biologic half-life in the body is about 15 days. It is not surprising that a state of severe depletion can be seen in patients on a strict thiamin-deficient diet in 18 days. Similarly, the rate of flux of thiamin across the blood-brain barrier in rats is equivalent to the turnover in brain, indicating no spare thiamin capacity for the brain.

Thiamin diphosphate (ThDP) is the active form of thiamin. ThDP serves as a cofactor for several enzymes involved in carbohydrate catabolism, including pyruvate dehydrogenase, transketolase, and a-ketoglutarate, and for the branched-chain a-keto acid dehydrogenase complex that is involved in amino acid catabolism. The former enzymes play crucial roles in the tricarboxylic acid cycle and the pentose phosphate pathway. They are important in the biosynthesis of a number of cell constituents, including the neurotransmitters acetylcholine and gamma-aminobutyric acid (GABA), and in the production of reducing equivalents (NADPH) for biosyntheses and pentoses for nucleic acid synthesis. Because of its involvement in the synthesis of precursors of DNA, thiamin utilization is increased in tumors. Limiting thiamin can inhibit tumor cell proliferation. A neurochemical role for thiamin triphosphate (ThTP) has been postulated; ThTP is localized to neuronal cells and is implicated in neuronal conduction.

Thiamin uptake by the small intestines and by cells within various organs is mediated at physiological concentrations by a saturable, high affinity transport system. The requirement for cellular energy (ATP) for thiamin uptake is a secondary event and results from the rapid diphosphorylation of imported thiamin by thiamin diphosphokinase. Alcohol affects various aspects of thiamin transport/uptake, and these effects may contribute to the prevalence of thiamin deficiency in alcoholics. Alcohol also reduces cellular thiamin diphosphokinase activity.

Deficiencies: The major manifestations of thiamin deficiency in humans involve the cardiovascular (wet beriberi) and nervous (dry beriberi, or neuropathy and/or Wernicke-Korsakoff syndrome) systems. Common findings in beriberi heart disease include peripheral vasodilation, biventricular myocardial failure, and sodium and water retention resulting in high-output state, edema, and potentially acute fulminant cardiovascular collapse (soshin beriberi). Administration of thiamin rapidly restores peripheral vascular resistance, but improvement in myocardial function may be delayed. The predominant features of cerebral beriberi are confusion, disordered ocular motility, ataxia of gait, and neuropathy. Treatment with thiamin can rapidly reverse some of these acute signs while leaving significant clinical sequelae including memory and other cognitive deficits and residual neurologic signs (called Korsakoff's syndrome, or the chronic phase of Wernicke-Korsakoff syndrome) with characteristic neuropathologic findings. Recently, amyloid-precursor protein-like immunoreactivity, similar to findings in Alzheimer's patients, have been demonstrated in the brains of thiamin deficient rats consistent with earlier suggestions of a relationship between thiamin deficiency and Alzheimer's disease.

Additionally, a number of inborn errors of metabolism have been described in which clinical improvements can be documented following administration of pharmacological doses of thiamin, including thiamin-responsive megaloblastic anemia (TRMA), lactic acidosis, branched chain ketoaciduria, and intermittent cerebellar ataxia. TRMA results from a lack of the saturable, high affinity thiamin transport system, and ketoaciduria results from defects in the branch-chain a-keto acid dehydrogenase.

Diet recommendations: The Recommended Dietary Allowance is as follows: 0-5 month infants, 0.2 mg/day; 6 to 11 months, 0.3 mg/day; 1-3 years of age, 0.5 mg/day; 4-8 years, 0.6 mg/day; 9-13 years, 0.9 mg/day; males 14 years old and older, 1.2 mg/day; females 14-18 years of age, 1.0 mg/day; and females 19 years and older, 1.1 mg/day. During pregnancy, the RDA is increased to 1.4 mg/day, and during lactation, 1.5 mg/day. The RDAs are based on the Dietary Reference Intakes of the National Academy of Sciences.

Food sources: Thiamin is present in many dietary products, but is found in large amounts in lean pork, legumes and yeast. Whole grain products, breads and cereals are the major dietary contributors.

Clinical uses: Therapy in deficiency consists of parenteral administration of thiamin (intramuscular or intravenous) as 50-100 mg/day for 7-14 days, followed by oral therapy. In clinical disorders related to thiamin deficiency, therapy is urgent and should bypass the intestinal tract. More moderate doses may be prudent for cancer patients in need of nourishment.

Toxicity: There is no toxicity with oral thiamin. There are only a few reports of toxic reactions to intravenous thiamin, resulting mainly in an anaphylactic reaction.

Recent Research: Investigations using protein crystallography and site-directed mutagenesis have defined how ThDP-utilizing enzymes bind and interact with ThDP and have also shed light on the catalytic mechanism of thiamin. Substantial efforts are being made to understand the genetic and biochemical determinants of inter individual differences in susceptibility to development of thiamin deficiency-related disorders and of the differential vulnerabilities of tissues and cell types to thiamin deficiency.

For further information:

Tanphaichitr, V. (1999) Thiamin. In: Modern Nutrition in Health and Disease (Shils, M. E., Olson, J. A., Shike, M. & Ross, C. A., eds.), 9th ed., pp. 381 - 390. Williams & Wilkins, Baltimore, MD.

Butterworth, R. F., Kril, J. J. & Harper, C. G. (1993) Thiamine-dependent enzyme changes in the brains of alcoholics: relationship to the Wernicke-Korsakoff syndrome. Alcohol. Clin. Exp. Res. 17: 1084-1088.

Prepared By:

David W. McCandless, Ph.D.
Professor and Chairman
Department of Cell Biology & Anatomy
Chicago Medical School
3333 Green Bay Road
North Chicago, IL 60064
Phone: 847-578-3210
FAX: 847-578-3253
Email: mccandld@mis.finchcms.edu

Charles K. Singleton, Ph.D.
Associate Professor of Molecular Biology
Department of Molecular Biology
U5201 Medical Center North
Vanderbilt University
Nashville TN 37235
Phone: 615-322-6516
FAX: 615-343-6707
Email: charles.k.singleton@vanderbilt.edu