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Vitamin B1: 205 Research Abstracts

1. Ann Neurol. 2003 Jul;54(1):19-29.

Alcoholic neuropathy is clinicopathologically distinct from thiamine-deficiency neuropathy.

Koike H, Iijima M, Sugiura M, Mori K, Hattori N, Ito H, Hirayama M, Sobue G.

Department of Neurology, Nagoya University, Graduate School of Medicine, Nagoya, Japan.

Characteristics of alcoholic neuropathy have been obscured by difficulty in isolating them from features of thiamine-deficiency neuropathy. We assessed 64 patients with alcoholic neuropathy including subgroups without (ALN) and with (ALN-TD) coexisting thiamine deficiency. Thirty-two patients with nonalcoholic thiamine-deficiency neuropathy (TDN) also were investigated for comparison. In ALN, clinical symptoms were sensory-dominant and slowly progressive, predominantly impairing superficial sensation (especially nociception) with pain or painful burning sensation. In TDN, most cases manifested a motor-dominant and acutely progressive pattern, with impairment of both superficial and deep sensation. Small-fiber-predominant axonal loss in sural nerve specimens was characteristic of ALN, especially with a short history of neuropathy; long history was associated with regenerating small fibers. Large-fiber-predominant axonal loss predominated in TDN. Subperineurial edema was more prominent in TDN, whereas segmental de/remyelination resulting from widening of consecutive nodes of Ranvier was more frequent in ALN. Myelin irregularity was greater in ALN. ALN-TD showed a variable mixture of these features in ALN and TDN. We concluded that pure-form of alcoholic neuropathy (ALN) was distinct from pure-form of thiamine-deficiency neuropathy (TDN), supporting the view that alcoholic neuropathy can be caused by direct toxic effect of ethanol or its metabolites. However, features of alcoholic neuropathy is influenced by concomitant thiamine-deficiency state, having so far caused the obscure clinicopathological entity of alcoholic neuropathy.

2. Nippon Jinzo Gakkai Shi. 2003;45(4):393-7.

[Acute encephalopathy due to thiamine deficiency with hyperammonemia in a chronic hemodialysis patient: a case report]

[Article in Japanese]

Ookawara S, Suzuki M, Saitou M.

Department of Internal Medicine, Nishikawa Town Hospital, Japan.

Hemodialysis(HD) patients are at risk for thiamine deficiency because of low intake and accelerated loss of thiamine during HD. We report here an HD patient, an 82-year-old woman, who developed acute encephalopathy due to thiamine deficiency with hyperammonemia. She was admitted to Nishikawa Town Hospital due to pneumonia and was treated with ABPC/SBT for one week. While she was cured of pneumonia, she had a persistently poor appetite. On the twenty-fourth day after admission, HD with intradialytic parenteral nutrition(IDPN), which consisted of 10% glucose 500 ml, in order to correct her malnutrition, was started. She suddenly presented confusion, speech disturbance and ophthalmoplegia. HD with IDPN was stopped after two hours because of her symptoms. Laboratory studies disclosed plasma glucose of 186 mg/dl and serum ammonium of 155 micrograms/dl. Arterial blood gas analysis(inhaling 3 l/min O2) showed severe metabolic acidosis and respiratory acidosis (pH 7.138, pCO2 44.8 mmHg, pO2 108.9 mmHg, HCO3- 15.1 mmol/l). Her malnutrition, unexplained metabolic acidosis and neurological presentation raised the suspicion of acute encephalopathy due to thiamine deficiency. Fursultiamine 100 mg was administered intravenously. After two hours, metabolic acidosis disappeared (pH 7.437, pCO2 33.9 mmHg, pO2 161.0 mmHg, HCO3- 22.9 mmol/l), and she regained her clear consciousness and serum ammonium decreased at 16 micrograms/dl on the next morning. Serum lactate and thiamine level were shown later to be 57.5 mg/dl and 27 nmol/l, respectively. Her clinical course suggests that the glucose load including IDPN may have caused deterioration of the neurological disorder under the condition of thiamine deficiency. Furthermore, it is possible that a relationship exists between thiamine deficiency and hyperammonemia.

3. Harefuah. 2003 May;142(5):329-31, 400, 399.

[Thiamine deficiency among Chinese workers in Israel]

[Article in Hebrew]

Kleiner-Baumgarten A, Sidi A, Abu-Shakra M, Klain M, Bilenko N, Sela BA.

Internal Medicine Day-Hospital Unit, Soroka University Medical Center, Faculty of Health Sciences, Ben Gurion University, Beer Sheva.

The death of a 23-year-old Chinese construction worker in southern Israel from refractory metabolic acidosis after presenting symptoms of edema and loss of sensation in his legs raised the suspicion of Beriberi disease. As thiamine deficiency was suspected, two other Chinese workers from the same construction site, who also complained of pain and swelling in their legs were tested and found to have a significant deficiency. In addition 56.5% of 46 Chinese workers at the site were found to have a thiamine deficiency without any significant clinical symptoms. A nutritional evaluation demonstrated a lack of thiamine in the workers diet due to a limited variety of food, their dietary preferences, and cooking style. There was also a lack of attention given to providing essential nutrients including thiamine by their employees. Clinicians must be aware that thiamine deficiency and beriberi disease may be common in this apparently healthy population.

4. J Neurol Neurosurg Psychiatry. 2003 May;74(5):674-6.

Reversible acute axonal polyneuropathy associated with Wernicke-Korsakoff syndrome: impaired physiological nerve conduction due to thiamine deficiency?

Ishibashi S, Yokota T, Shiojiri T, Matunaga T, Tanaka H, Nishina K, Hirota H, Inaba A, Yamada M, Kanda T, Mizusawa H.

Department of Neurology and Neurological Sciences, Graduate School, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.

Acute axonal polyneuropathy and Wernicke-Korsakoff encephalopathy developed simultaneously in three patients. Nerve conduction studies (NCS) detected markedly decreased compound muscle action potentials (CMAPs) and sensory nerve action potentials (SNAPs) with minimal conduction slowing; sympathetic skin responses (SSRs) were also notably decreased. Sural nerve biopsies showed only mild axonal degeneration with scattered myelin ovoid formation. The symptoms of neuropathy lessened within two weeks after an intravenous thiamine infusion. CMAPs, SNAPs, and SSRs also increased considerably. We suggest that this is a new type of peripheral nerve impairment: physiological conduction failure with minimal conduction delay due to thiamine deficiency.

5. J Clin Pharm Ther. 2003 Feb;28(1):47-51.

Effect of intravenous infusions of thiamine on the disposition kinetics of thiamine and its pyrophosphate.

Drewe J, Delco F, Kissel T, Beglinger C.

Division of Clinical Pharmacology and Toxicology, University Clinic, Kantonsspital Basel and Institute for Clinical Pharmacy, University of Basel, Basel, Switzerland. juergen.drewe@unibas.ch

BACKGROUND: Thiamine supplementation is necessary in patients with thiamine deficiency syndromes. Experimental evidence suggests that tissue uptake and the elimination of thiamine are dose-dependent. AIM: The aim of the present study was to investigate the effect of different i.v. infusion rates of thiamine on blood concentrations of thiamine and its active metabolite thiamine pyrophosphate (TPP) and on renal excretion of thiamine. METHODS: Twelve healthy subjects received in a two-period block randomized study 150 mg thiamine intravenously over either 1 or 24 h. RESULTS: The maximum blood concentrations (Cmax) of thiamine were significantly higher after the more rapid infusion (RI; 2300 ng/mL) than after the slower infusion (SI; 177 ng/mL). The AUC of thiamine was identical after both infusion protocols. There was a slightly (10%) increased AUC of TPP (P < 0.08) after SI, whereas C(max) values were comparable. Urinary excretion of thiamine was significantly decreased from 83.6% of the applied dose after RI to 57.6% after the SI. CONCLUSIONS: Our data suggest an increased tissue uptake of thiamine when it is given as an SI compared with a RI of the same dose. It is concluded, therefore, that an SI of thiamine may be superior to RI or bolus injections to treat severe deficiency syndromes.

6. Ann Cardiol Angeiol (Paris). 2001 Apr;50(3):160-8.

[Is thiamine supplementation necessary in patient with cardiac insufficiency?]

[Article in French]

Blanc P, Boussuges A.

Service de reanimation polyvalente, service de cardiologie, CHD Felix Guyon, 97405 Saint-Denis, La Reunion, France. ph-blanc@chd-fguyon.fr

Interest has recently risen regarding thiamine deficiency in patients with cardiac deficiency who are receiving long-term diuretic therapy. Thiamine deficiency can lead biventricular myocardial failure (cardiac beriberi), and treatment consists of thiamine administration. Studies have shown that long-term furosemide use may be associated with thiamine deficiency through urinary loss, contributing to cardiac insufficiency in patients with congestive heart failure. Thiamine supplementation could improved left ventricular function. However, the results of those studies are controversial, and none study have till proved the clinical impact of a systematic administration of thiamine in a cohort of patients with cardiac insufficiency. To date, and waiting for available literature, thiamine administration should be consider in patients at risk for thiamine deficiency (elderly, malnourished, alcoholic), and in patients receiving very large doses of diuretics.

7. Psychiatr Genet. 2002 Dec;12(4):217-24.

Individual susceptibility to Wernicke-Korsakoff syndrome and alcoholism-induced cognitive deficit: impaired thiamine utilization found in alcoholics and alcohol abusers.

Heap LC, Pratt OE, Ward RJ, Waller S, Thomson AD, Shaw GK, Peters TJ.

Department of Clinical Biochemistry, Kings College School of Medicine and Dentistry, London, UK.

To investigate mechanisms predisposing to alcoholic brain damage, thiamine (vitamin B1 ), riboflavin (vitamin B2 ) and pyridoxine (vitamin B6 ) status was compared in persistent alcohol misusers (PAM) admitted for detoxification without evidence of significant brain damage, in alcoholics known to have severe chronic brain damage (BDAM), and in age, gender and ethnicity matched controls. Thus, activities of thiamine-dependent transketolase (ETK), riboflavin-dependent glutathione reductase, and pyridoxine-dependent aspartate amino transferase were assayed, together with the enzyme activities following addition of the appropriate co-factor. Twenty per cent of the PAM group had an abnormally low ETK activity and an abnormally high activation ratio, while 45% were abnormal in either one or both parameters. An additional 10% of the PAM group had an abnormally high activation ratio but normal ETK activity, as did 30% of the BDAM group. These subgroups of alcohol misusers may have increased requirements for thiamine secondary to an abnormality of the transketolase protein that may predispose such patients to alcoholic brain damage. There was no evidence of riboflavin or pyridoxine deficiency in either of the patient groups. We conclude that thiamine deficiency was commonly present in the alcoholic patients, and that a subgroup of patients may be predisposed to more severe brain damage as a consequence of abnormalities in the transketolase protein.

8. Panminerva Med. 2002 Dec;44(4):295-300.

Mitochondrial diabetes, diabetes and the thiamine-responsive megaloblastic anaemia syndrome and MODY-2. Diseases with common pathophysiology?

Maassen JA.

Department of Molecular Cell Biology, Leiden University Medical Centre, Leiden and EVM Institute, Medisch Centrum, Vrije Universiteit, Amsterdam, the Netherlands. J.A.Maassen@lumc.nl

Diabetes represents a conglomerate of diseases with chronic hyperglycaemia as hallmark. The present review discusses those diabetic cases that associate with variants in genes that affect the magnitude of the glycolytic flux and oxidative disposal of glucose by mitochondria in pancreatic beta-cells. These genetic variants result in an attenuated secretion of insulin in response to glucose stimulation. The diabetic states that associate with these genetic variants are MODY 2, thiamine responsive anaemia syndrome (TRAS) and mitochondrial diabetes. These disease states highlight the critical contribution of the carbohydrate flux through glycolysis and mitochondria and its coupling to ATP production in determining insulin secretion.

9. Biochim Biophys Acta. 2002 Oct 9;1588(1):79-84.

Thiamine-responsive pyruvate dehydrogenase deficiency in two patients caused by a point mutation (F205L and L216F) within the thiamine pyrophosphate binding region.

Naito E, Ito M, Yokota I, Saijo T, Matsuda J, Ogawa Y, Kitamura S, Takada E, Horii Y, Kuroda Y.

Department of Pediatrics, School of Medicine, University of Tokushima, Kuramoto Cho 3, Tokushima, Japan. enaito@clin.med.tokushima-u.ac.jp

The human pyruvate dehydrogenase complex (PDHC) catalyzes the thiamine-dependent decarboxylation of pyruvate. Thiamine treatment is very effective for some patients with PDHC deficiency. Among these patients, five mutations of the pyruvate dehydrogenase (E1)alpha subunit have been reported previously: H44R, R88S, G89S, R263G, and V389fs. All five mutations are in a region outside the thiamine pyrophosphate (TPP)-binding region of the E1alpha subunit.We report the biochemical and molecular analysis of two patients with clinically thiamine-responsive lactic acidemia. The PDHC activity was assayed using two different concentrations of TPP. These two patients displayed very low PDHC activity in the presence of a low (1 x 10(-4) mM) TPP concentration, but their PDHC activity significantly increased at a high (0.4 mM) TPP concentration. Therefore, the PDHC deficiency in these two patients was due to a decreased affinity of PDHC for TPP. Treatment of both patients with thiamine resulted in a reduction in the serum lactate concentration and clinical improvement, suggesting that these two patients have a thiamine-responsive PDHC deficiency. The DNA sequence of these two male patients' X-linked E1alpha subunit revealed a point mutation (F205L and L216F) within the TPP-binding region in exon 7.

10. Neuroendocrinol Lett. 2002 Aug;23(4):303-8.

Treatment of autism spectrum children with thiamine tetrahydrofurfuryl disulfide: a pilot study.

Lonsdale D, Shamberger RJ, Audhya T.

Preventive Medicine Group, 24700 Center Ridge Road, Westlake, OH 44145, USA. dlonsdale@pol.net

OBJECTIVES: In a Pilot Study, the clinical and biochemical effects of thiamine tetrahydrofurfuryl disulfide (TTFD) on autistic spectrum children were investigated. SUBJECTS AND METHODS: Ten children were studied. Diagnosis was confirmed through the use of form E2, a computer assessed symptom score. For practical reasons, TTFD was administered twice daily for two months in the form of rectal suppositories, each containing 50 mg of TTFD. Symptomatic responses were determined through the use of the computer assessed Autism Treatment Evaluation Checklist (ATEC) forms. The erythrocyte transketolase (TKA) and thiamine pyrophosphate effect (TPPE), were measured at outset and on completion of the study to document intracellular thiamine deficiency. Urines from patients were examined at outset, after 30 days and after 60 days of treatment and the concentrations of SH-reactive metals, total protein, sulfate, sulfite, thiosulfate and thiocyanate were determined. The concentrations of metals in hair were also determined. RESULTS: At the beginning of the study thiamine deficiency was observed in 3 out of the 10 patients. Out of 10 patients, 6 had initial urine samples containing arsenic in greater concentration than healthy controls. Traces of mercury were seen in urines from all of these autistic children. Following administration of TTFD an increase in cadmium was seen in 2 children and in lead in one child. Nickel was increased in the urine of one patient during treatment. Sulfur metabolites in urine did not differ from those measured in healthy children. CONCLUSIONS: Thiamine tetrahydrofurfuryl disulfide appears to have a beneficial clinical effect on some autistic children, since 8 of the 10 children improved clinically. We obtained evidence of an association of this increasingly occurring disease with presence of urinary SH-reactive metals, arsenic in particular.

11. Klin Med (Mosk). 2002;80(7):39-42.

[Urine levels of thiamine and riboflavine in diuretic therapy of patients with cardiovascular diseases]

[Article in Russian]

Shikh EV.

Diuretic therapy entails decreased plasma concentrations of thiamine and riboflavine. Vitamins eliminated with urine more rapidly when diuresis accelerates. This process is not related to diuresis cause. A linear relationship exists between diuresis intensity and amount of eliminated thiamine and riboflavine. Thus it is shown that diuretic therapy provokes thiamine and riboflavine elimination from the body.

12. J Neurol Sci. 2002 Sep 15;201(1-2):33-7.

Diagnosis and molecular analysis of three male patients with thiamine-responsive pyruvate dehydrogenase complex deficiency.

Naito E, Ito M, Yokota I, Saijo T, Ogawa Y, Kuroda Y.

Department of Pediatrics, School of Medicine, University of Tokushima, Kuramoto Cho 3, 770-8503, Tokushima, Japan. enaito@clin.med.tokushima-u.ac.jp

Pyruvate dehydrogenase complex (PDHC) deficiency is a major cause of congenital lactic acidemia in children. PDHC catalyzes the thiamine-dependent decarboxylation of pyruvate. Thiamine treatment was effective for some patients with PDHC deficiency. We reexamined 30 patients with congenital lactic acidemia of unknown origin who had normal PDHC activity in their cultured fibroblasts using a routine assay with a high (0.4 mM) thiamine pyrophosphate (TPP) concentration. We measured the activity of PDHC in the presence of a low (1x10(-4) mM) TPP concentration, and analyzed for mutations in the E1alpha subunit gene. Three males had low PDHC activity in the presence of 1x10(-4) mM TPP. The DNA sequence of these three patients' X-linked E1alpha subunit revealed a substitution of alanine for valine at position 71 (V71A) in exon 3, phenylalanine for cysteine at position 101 (C101F) in exon 4, and glycine for arginine at position 263 (R263G) in exon 8, respectively. Thiamine treatment was effective in these three patients. Therefore, they had a thiamine-responsive PDHC deficiency due to a point mutation in the E1alpha subunit gene. PDHC activity should be measured at a low TPP concentration to detect thiamine-responsive PDHC deficiency so that thiamine treatment can be initiated as soon as possible.

13. Gastric Cancer. 2002;5(2):77-82.

Reduced thiamine (vitamin B1) levels following gastrectomy for gastric cancer.

Iwase K, Higaki J, Yoon HE, Mikata S, Miyazaki M, Kamiike W.

Department of Surgery, Rinku General Medical Center, Izumisano Municipal Hospital, 2-23 Rinku-Orai-Kita, Izumisano, Osaka 598-8577, Japan.

BACKGROUND: Vitamin B1 deficiency is well known as a possible complication following gastric restrictive surgery for morbid obesity; however, reduced vitamin B1 levels in patients who have undergone gastrectomy for gastric cancer have not been discussed previously.METHODS: Serum vitamin B1 levels were determined after the return to normal daily activity in 54 patients with distal gastrectomy for gastric cancer, 32 patients with total gastrectomy for gastric cancer, and 30 patients with radical surgery for colorectal cancer. Changes from serum vitamin B1 levels before operation to those after return to normal daily activity, without nutritional support, were investigated in 25 patients with gastrectomy for gastric cancer and 26 patients with radical surgery for colorectal cancer.RESULTS: Decreased serum vitamin B1 levels, below the normal range, were recognized in 7 of the 54 distally gastrectomized patients and in 5 of the 32 totally gastrectomized patients, whereas no such decrease was recognized in any patient after colorectal surgery. Decreased serum vitamin B1 level was recognized within 6 months after the operation in 6 of the 7 distally gastrectomized patients showing a decreased vitamin B1 level and in 3 of the 5 totally gastrectomized patients showing a decreased vitamin B1 level. Postoperative serum vitamin B1 levels were significantly lower than those before operation in patients with gastrectomies, whereas there was no significant difference in serum vitamin B1 levels before and after the surgeries in patients with surgery for colorectal cancer.CONCLUSION: Vitamin B1 levels may be reduced in gastrectomized patients, especially within 6 months after operation, even after their return to normal daily activity without nutritional support.

14. J Neural Transm. 2002 Jul;109(7-8):1035-44.

Cerebrospinal fluid levels of thiamine in patients with Alzheimer's disease.

Molina JA, Jimenez-Jimenez FJ, Hernanz A, Fernandez-Vivancos E, Medina S, de Bustos F, Gomez-Escalonilla C, Sayed Y.

Department of Neurology, Hospital Universitario Doce de Octubre, E-28030 Madrid, Spain.

Thiamine is an essential cofactor for several important enzymes involved in brain oxidative metabolism, such as the alpha-ketoglutarate dehydrogenase complex (KGDHC), pyruvate-dehydrogenase complex (PDHC), and transketolase. Some investigators reported decreased thiamine-diphosphate levels and decreased activities of KGDHC, pyruvate-dehydrogenase complex and transketolase in the brain tissue of Alzheimer's disease (AD) patients. We measured cerebrospinal (CSF) levels of thiamine-diphosphate, thiamine-monophosphate, free thiamine, and total thiamine, using ion-pair reversed phase high performance liquid chromatography, in 33 patients with sporadic AD and 32 matched controls.The mean CSF levels of thiamine-derivatives did not differ significantly from those of controls, while the mean plasma levels of thiamine-diphosphate, free and total thiamine were significantly lower in the AD-patient group. CSF and plasma thiamine levels were not correlated with age, age at onset, duration of the disease, and scores of the MiniMental State Examination, with the exception of plasma thiamine-diphosphate with MiniMental State Examination (r = 0.41, p < 0.05) in the AD-patients group. CSF and plasma values did not predict dementia progression, assessed with the MiniMental State Examination scores. These results suggest that CSF thiamine levels are not related with the risk for and the progression of AD.

15. AIDS Read. 2002 May;12(5):222-4.

High doses of riboflavin and thiamine may help in secondary prevention of hyperlactatemia.

McComsey GA, Lederman MM.

Pediatric Infectious Diseases Division, Rainbow Babies and Children's Hospital, Western Reserve University, Cleveland, USA.

Lactic acidosis is the most dramatic manifestation of nucleoside reverse transcriptase inhibitor (NRTI)-associated mitochondrial dysfunction. The optimal management of subjects who recover from an episode of lactic acidosis--or its milder form, symptomatic hyperlactatemia--remains unclear. Most physicians opt to restart NRTI-sparing regimens, but such an option may not be available for heavily antiretroviral-experienced patients. Therefore, there is a need to investigate ways to prevent the recurrence of hyperlactatemia in patients who require NRTI-based therapy.

16. BMC Biochem. 2002 Apr 25;3(1):8.

Mitochondria from cultured cells derived from normal and thiamine-responsive megaloblastic anemia individuals efficiently import thiamine diphosphate.

Song Q, Singleton CK.

Department of Biological Sciences, Vanderbilt University, VU Station B 351634, Nashville TN 37235-1634, USA. tony.song@vanderbilt.edu

BACKGROUND: Thiamine diphosphate (ThDP) is the active form of thiamine, and it serves as a cofactor for several enzymes, both cytosolic and mitochondrial. Isolated mitochondria have been shown to take up thiamine yet thiamine diphosphokinase is cytosolic and not present in mitochondria. Previous reports indicate that ThDP can also be taken up by rat mitochondria, but the kinetic constants associated with such uptake seemed not to be physiologically relevant. RESULTS: Here we examine ThDP uptake by mitochondria from several human cell types, including cells from patients with thiamine-responsive megaloblastic anemia (TRMA) that lack a functional thiamine transporter of the plasma membrane. Although mitochondria from normal lymphoblasts took up thiamine in the low micromolar range, surprisingly mitochondria from TRMA lymphoblasts lacked this uptake component. ThDP was taken up efficiently by mitochondria isolated from either normal or TRMA lymphoblasts. Uptake was saturable and biphasic with a high affinity component characterized by a Km of 0.4 to 0.6 microM. Mitochondria from other cell types possessed a similar high affinity uptake component with variation seen in uptake capacity as revealed by differences in Vmax values. CONCLUSIONS: The results suggest a shared thiamine transporter for mitochondria and the plasma membrane. Additionally, a high affinity component of ThDP uptake by mitochondria was identified with the apparent affinity constant less than the estimates of the cytosolic concentration of free ThDP. This finding indicates that the high affinity uptake is physiologically significant and may represent the main mechanism for supplying phosphorylated thiamine for mitochondrial enzymes.

17. Dig Dis Sci. 2002 Mar;47(3):543-8.

Thiamine deficiency in hepatitis C virus and alcohol-related liver diseases.

Levy S, Herve C, Delacoux E, Erlinger S.

Department of Hepatology and INSERM U-481 and Hopital Beaujon, Clichy, France.

Thiamine deficiency is a common feature in chronic alcoholic patients, and its pathophysiology remains poorly understood. Until now, thiamine deficiency has been considered to be mainly the result of alcoholism irrespective of the underlying liver disease. The aims of the study were to compare the prevalence of thiamine deficiency in alcohol- and hepatitis C virus-(HCV-) related cirrhosis and in patients with chronic hepatitis C without cirrhosis. Forty patients with alcoholic cirrhosis (group A), 48 patients with HCV-related cirrhosis (group B), and 59 patients with chronic hepatitis C without cirrhosis (group C) were included prospectively. Thiamine status was evaluated by concomitant determination of erythrocyte transketolase activity, thiamine diphosphate (TDP) effect, and direct measurement of erythrocyte thiamine and its phosphate esters by HPLC. Thiamine was mainly present in erythrocytes in its diphosphorylated form. Prevalence of thiamine deficiency and levels of TDP in thiamine-deficient patients were similar in patients of group A (alcoholic cirrhosis) and of group B (viral C cirrhosis). None of the patients with chronic hepatitis (group C) was deficient. Thiamine deficiency was not correlated with the severity of the liver disease or disease activity. No impairment of thiamine phosphorylation was found in the three groups. conclusion, alcoholic or HCV-related cirrhotics have the same range of thiamine deficiency, while no patient without cirrhosis has thiamine deficiency, and impaired phosphorylation does not account for the deficiency observed in cirrhotics. We suggest that thiamine should be given to patients with cirrhosis irrespective of its cause.

18. Curr Mol Med. 2001 May;1(2):197-207.

Molecular mechanisms of thiamine utilization.

Singleton CK, Martin PR.

Department of Biological Science, Vanderbilt University, Nashville, TN 37235, USA. Charles.K.Singleton@Vanderbilt.edu

Thiamine is required for all tissues and is found in high concentrations in skeletal muscle, heart, liver, kidneys and brain. A state of severe depletion is seen in patients on a strict thiamine-deficient diet in 18 days, but the most common cause of thiamine deficiency in affluent countries is alcoholism. Thiamine diphosphate is the active form of thiamine, and it serves as a cofactor for several enzymes involved primarily in carbohydrate catabolism. The enzymes are important in the biosynthesis of a number of cell constituents, including neurotransmitters, and for the production of reducing equivalents used in oxidant stress defenses and in biosyntheses and for synthesis of pentoses used as nucleic acid precursors. Because of the latter fact, thiamine utilization is increased in tumor cells. Thiamine uptake by the small intestines and by cells within various organs is mediated by a saturable, high affinity transport system. Alcohol affects thiamine uptake and other aspects of thiamine utilization, and these effects may contribute to the prevalence of thiamine deficiency in alcoholics. The major manifestations of thiamine deficiency in humans involve the cardiovascular (wet beriberi) and nervous (dry beriberi, or neuropathy and/or Wernicke-Korsakoff syndrome) systems. A number of inborn errors of metabolism have been described in which clinical improvements can be documented following administration of pharmacological doses of thiamine, such as thiamine-responsive megaloblastic anemia. Substantial efforts are being made to understand the genetic and biochemical determinants of inter-individual differences in susceptibility to development of thiamine deficiency-related disorders and of the differential vulnerabilities of tissues and cell types to thiamine deficiency.

19. Neurochem Int. 2002 May;40(6):493-504.

Interactions of oxidative stress with thiamine homeostasis promote neurodegeneration.

Gibson GE, Zhang H.

Burke Medical Research Institute, Weil Medical College, Cornell University, 785 Mamaroneck Avenue, White Plains, NY 10605, USA. ggibson@med.cornell.edu

Thiamine-dependent processes are diminished in brains of patients with several neurodegenerative diseases. The decline in thiamine-dependent enzymes can be readily linked to the symptoms and pathology of the disorders. Why the reductions in thiamine linked processes occur is an important experimental and clinical question. Oxidative stress (i.e. abnormal metabolism of free radicals) accompanies neurodegeneration and causes abnormalities in thiamine-dependent processes. The vulnerability of thiamine homeostasis to oxidative stress may explain deficits in thiamine homeostasis in numerous neurological disorders. The interactions of thiamine with oxidative processes may be part of a spiral of events that lead to neurodegeneration, because reductions in thiamine and thiamine-dependent processes promote neurodegeneration and cause oxidative stress. The reversal of the effects of thiamine deficiency by antioxidants, and amelioration of other forms of oxidative stress by thiamine, suggest that thiamine may act as a site-directed antioxidant. The data indicate that the interactions of thiamine-dependent processes with oxidative stress are critical in neurodegenerative processes.

20. Acta Diabetol. 2001;38(3):135-8.

Benfotiamine is similar to thiamine in correcting endothelial cell defects induced by high glucose.

Pomero F, Molinar Min A, La Selva M, Allione A, Molinatti GM, Porta M.

WHO Collaborating Centre for Diabetes-Related Blindness, Department of Internal Medicine, University of Turin, Italy.

We investigated the hypothesis that benfotiamine, a lipophilic derivative of thiamine, affects replication delay and generation of advanced glycosylation end-products (AGE) in human umbilical vein endothelial cells cultured in the presence of high glucose. Cells were grown in physiological (5.6 mM) and high (28.0 mM) concentrations of D-glucose, with and without 150 microM thiamine or benfotiamine. Cell proliferation was measured by mitochondrial dehydrogenase activity. AGE generation after 20 days was assessed fluorimetrically. Cell replication was impaired by high glucose (72.3%+/-5.1% of that in physiological glucose, p=0.001). This was corrected by the addition of either thiamine (80.6%+/-2.4%, p=0.005) or benfotiamine (87.5%+/-8.9%, p=0.006), although it not was completely normalized (p=0.001 and p=0.008, respectively) to that in physiological glucose. Increased AGE production in high glucose (159.7%+/-38.9% of fluorescence in physiological glucose, p=0.003) was reduced by thiamine (113.2%+/-16.3%, p=0.008 vs. high glucose alone) or benfotiamine (135.6%+/-49.8%, p=0.03 vs. high glucose alone) to levels similar to those observed in physiological glucose. Benfotiamine, a derivative of thiamine with better bioavailability, corrects defective replication and increased AGE generation in endothelial cells cultured in high glucose, to a similar extent as thiamine. These effects may result from normalization of accelerated glycolysis and the consequent decrease in metabolites that are extremely active in generating nonenzymatic protein glycation. The potential role of thiamine administration in the prevention or treatment of vascular complications of diabetes deserves further investigation.

21. Int J Geriatr Psychiatry. 2002 Feb;17(2):189-92.

Using thiamine to reduce post-ECT confusion.

Linton CR, Reynolds MT, Warner NJ.

Cognitive side-effects are commonly seen following electroconvulsive therapy which convey no therapeutic benefit but are troublesome to both patient and clinician. Various efforts have been made in the past to minimize these symptoms. Although modification of technical parameters related to ECT administration has led to some limited improvement in this regard, attention is now being increasingly focussed on pharmacological approaches. A number of agents have been explored in this context, however, as far as we are aware, the use of thiamine has not yet been investigated. We present three cases of elderly patients undergoing ECT for major depression in whom thiamine administration was associated with beneficial effects on post-ECT confusion. We review the evidence suggesting that thiamine deficiency may be implicated in the confusional state following ECT and recommend that consideration be given to its use in preventing and treating this problematic side-effect, especially in elderly patients. Copyright 2002 John Wiley & Sons, Ltd.

22. J Nutr Health Aging. 2002;6(1):75-7.

Reduced serum concentrations of riboflavine and ascorbic acid, and blood thiamine pyrophosphate and pyridoxal-5-phosphate in geriatric patients with and without pressure sores.

Selvaag E, Bohmer T, Benkestock K.

Department of medicine, Aker University Hospital, Oslo, Norway.

BACKGROUND: Patients with pressure sores have as part of their treatment been reefed with energy and proteins with varying result. It has been uncertain, however, to what an extent these patients also were depleted of micronutrients which might be critical for ulcer healing. OBJECTIVE: To study the nutritional intake and nutritional status of a number of micronutrients in geriatric pressure sore patients and in matched controls. DESIGN: The nutritional intake and nutritional status as anthropometric measures, serum conc. of albumin, zinc, and of vitamins (ascorbic acid, riboflavin, calcidiol), were measured. Thiamin pyrophosphate and pyridoxal-5-phosphate were determined in whole blood from 11 geriatric in-patients with pressure sores and 11 matched controls. RESULTS: The serum conc. of ascorbic acid was significantly (p< 0.05) more reduced in pressure sore patients (mean+/-S.D.) 4.2+/-3.4 (ug/ml) than in control patients 7.4+/-5.4 (ug/ml) which still was lower than in a reference group (10.9+/-1.9) (ug/ml). In all the geriatric patients compared to the reference group, the conc. of serum-riboflavin was reduced to about 15 %, thiamine-pyrophosphate and pyridoxine-5-phosphate in whole blood and serum calcidiol to about 50 %, without any differences between the pressure sore patients and the matched controls. CONCLUSION: Refeeding of pressure sore patients who often are catabolic and have increased needs for protein and energy, should include micronutrients not only to cover recommended dietary allowances, but sufficient to reach normal nutritional status for the individual micronutrient.

23. Am J Kidney Dis. 2001 Nov;38(5):941-7.

Thiamine deficiency and unexplained encephalopathy in hemodialysis and peritoneal dialysis patients.

Hung SC, Hung SH, Tarng DC, Yang WC, Chen TW, Huang TP.

Department of Medicine, Division of Nephrology, TaipeiVeterans General Hospital, Taiwan.

Patients with end-stage renal disease undergoing regular dialysis are prone to encephalopathy, but the cause is often unclear. Dialysis patients are at risk for thiamine deficiency, which may mimic many uremic complications, including encephalopathy. To determine whether unexplained encephalopathy in regular dialysis patients is associated with thiamine deficiency, we conducted a prospective study that enrolled 30 consecutive dialysis patients with altered mental status admitted to a referred hospital during a 1-year period. A complete history, physical and neurological examinations, laboratory investigations, and computed tomographic scans or magnetic resonance imaging of the brain were obtained for each subject. In 10 of the 30 patients, diagnoses remained obscure after the initial workup. Manifestations included confusion, chorea, acute visual loss, rapidly progressive dementia, myoclonus, convulsions, and coma. Intravenous thiamine was administered to these 10 patients. All 10 patients had thiamine deficiency confirmed by a marked response to thiamine supplementation and/or a low serum thiamine concentration (35.3 +/- 6.0 nmol/L; normal, >50 nmol/L). Nine patients recovered, but one patient failed to respond because of delayed treatment. We conclude that in regular dialysis patients, unexplained encephalopathy can be mainly attributed to thiamine deficiency. This condition is fatal if unrecognized and can be successfully treated with prompt thiamine replacement.

24. Int J Vitam Nutr Res. 2001 Jul;71(4):217-21.

The thiamine status of adult humans depends on carbohydrate intake.

Elmadfa I, Majchrzak D, Rust P, Genser D.

Institute of Nutritional Sciences, University of Vienna.

Thiamine requirements for humans are generally expressed as absolute values per day (mg/d) or in relation to total caloric intake. Limited data are available on the relation between thiamine requirements and the intake of carbohydrates. This study was performed to investigate the influence of stepwise increases of carbohydrate intake on the status of thiamine in healthy volunteers under isocaloric conditions. During an adaptation phase of four days, the carbohydrate intake of twelve healthy volunteers (6 male, 6 female) was 55% of total energy intake. During the subsequent intervention periods, carbohydrate intake was increased to 65% of total energy for four days and to 75% for another four days. Thiamine intake, total energy intake, and physical activity were kept constant throughout the study. HPLC analysis was used to measure thiamine in plasma, urine and feces. Erythrocyte transketolase activity (ETK) was determined enzymatically. During the intervention periods thiamine decreased significantly (p < 0.05) in plasma (from 19.3 +/- 3.3 to 16.4 +/- 4.0 nmol/l) as well as in urine (from 72 +/- 56 to 58 +/- 21 mumol/mol creatinine). ETK and feces content of thiamine remained unchanged. An increase of dietary carbohydrate intake from 55% to 65% and 75%, respectively, of total caloric intake for four days per period at isocaloric conditions causes a decrease of plasma and urine levels of thiamine without affecting enzyme activities.

25. Postgrad Med J. 2001 Sep;77(911):582-5.

Thiamine deficiency in patients with B-chronic lymphocytic leukaemia: a pilot study.

Seligmann H, Levi R, Konijn AM, Prokocimer M.

Clinical Pharmacology Unit, Bnai Zion Medical Center, Technion Faculty of Medicine, Haifa, Israel. konijn@md2.huji.ac.il

Malignancy associated primary thiamine deficiency has been documented in several experimental tumours, sporadic clinical case reports, and in a number of patients with fast growing haematological malignancies. Thiamine status was assessed prospectively in 14 untreated B-chronic lymphocytic leukaemia (CLL) patients, and in 14 age matched control patients with non-malignant disease. Patients with any known cause of absolute, relative, or functional thiamine deficiency were excluded. High (>15%) thiamine pyrophosphate effect (TPPE), indicating thiamine deficiency, was found in five out of 14 CLL patients (35.7%) and in none of the controls (p=0.057). Mean (SD) TPPE in the thiamine deficient patients group was 21.6 (3.4)%. In all the patients, thiamine deficiency was subclinical. No correlates for the thiamine deficiency have been found save for an increment of more than 20% in the total leucocyte count over the preceding three months, which was found in all five thiamine deficient patients compared with only one of the nine non-thiamine deficient CLL patients. Thus, CLL patients may be prone to develop primary thiamine deficiency possibly promoted by the increased leucocytes span, which may increase thiamine consumption. Since even subclinical thiamine deficiency may be detrimental to the patient's clinical course, and in view of the theoretical danger of thiamine promoted tumour cell proliferation, further large scale studies are warranted to confirm this observation, and to elucidate the issue of thiamine supplementation to CLL patients.

26. J Neurol Neurosurg Psychiatry. 2001 Sep;71(3):357-62.

Postgastrectomy polyneuropathy with thiamine deficiency.

Koike H, Misu K, Hattori N, Ito S, Ichimura M, Ito H, Hirayama M, Nagamatsu M, Sasaki I, Sobue G.

Department of Neurology, Nagoya University School of Medicine, Nagoya 466-8550, Japan.

OBJECTIVE: Polyneuropathy has been reported after gastrectomy performed to treat various lesions. Although thiamine deficiency is a possible cause of this neuropathy, the pathogenesis still remains to be clarified. Seventeen patients with peripheral neuropathy with thiamine deficiency after gastrectomy are described. METHODS: Seventeen patients with polyneuropathy after gastrectomy accompanied by thiamine deficiency were selected. Patients were restricted to those with total or subtotal gastric resection to treat ulcer or neoplasm. Patients who had undergone operations to treat morbid obesity were excluded. RESULTS: Intervals between the operation and onset of neuropathy varied from 2 months to 39 years. Most patients did not seem malnourished. Serum concentrations of B vitamins other than thiamine were nearly normal. Symmetric motor-sensory polyneuropathy, predominantly involving the lower limbs, had progressed over intervals varying from 3 days to 8 years. Relative degrees of motor and sensory impairment also varied extensively. Some cases that progressed rapidly mimicked Guillain-Barre syndrome. Electrophysiological and pathological findings were those of axonal neuropathy. Substantial functional recovery from polyneuropathy was seen in most patients by 3 to 6 months after initiating thiamine supplementation. Motor recovery was better than sensory recovery. CONCLUSIONS: Various symptoms were seen in patients with postgastrectomy neuropathy. Thiamine deficiency should be considered in the differential diagnosis of motor-sensory polyneuropathy after gastrectomy.

27. Am J Physiol Cell Physiol. 2001 Sep;281(3):C786-92.

Mechanism of thiamine uptake by human jejunal brush-border membrane vesicles.

Dudeja PK, Tyagi S, Kavilaveettil RJ, Gill R, Said HM.

Department of Medicine, West Side Veterans Affairs Medical Center and University of Illinois at Chicago, 60612, USA. pkdudeja@uic.edu

Thiamine, a water-soluble vitamin, is essential for normal cellular functions, growth and development. Thiamine deficiency leads to significant clinical problems and occurs under a variety of conditions. To date, however, little is known about the mechanism of thiamine absorption in the native human small intestine. The objective of this study was, therefore, to characterize the mechanism of thiamine transport across the brush-border membrane (BBM) of human small intestine. With the use of purified BBM vesicles (BBMV) isolated from the jejunum of organ donors, thiamine uptake was found to be 1) independent of Na(+) but markedly stimulated by an outwardly directed H(+) gradient (pH 5.5(in)/pH 7.5(out)); 2) competitively inhibited by the cation transport inhibitor amiloride (inhibitor constant of 0.12 mM); 3) sensitive to temperature and osmolarity of the incubation medium; 4) significantly inhibited by thiamine structural analogs (amprolium, oxythiamine, and pyrithiamine), but not by unrelated organic cations (tetraethylammonium, N-methylnicotinamide, or choline); 5) not affected by the addition of ATP to the inside and outside of the BBMV; 6) potential insensitive; and 7) saturable as a function of thiamine concentration with an apparent Michaelis-Menten constant of 0.61 +/- 0.08 microM and a maximal velocity of 1.00 +/- 0.47 pmol. mg protein(-1). 10 s(-1). Carrier-mediated thiamine uptake was also found in BBMV of human ileum. These data demonstrate the existence of a Na(+)-independent, pH-dependent, amiloride-sensitive, electroneutral carrier-mediated mechanism for thiamine absorption in native human small intestinal BBMV.

28. J Biol Chem. 2001 Oct 5;276(40):37186-93. Epub 2001 Jul 31.

Identification of a mouse thiamine transporter gene as a direct transcriptional target for p53.

Lo PK, Chen JY, Tang PP, Lin J, Lin CH, Su LT, Wu CH, Chen TL, Yang Y, Wang FF.

Institute of Biochemistry, National Yang Ming University, Shih-Pai, Taipei 112, Taiwan.

p53 tumor suppressor is a transcription factor that functions, in part, through many of its downstream target genes. We have identified a p53-inducible gene by performing mRNA differential display on IW32 murine erythroleukemia cells containing a temperature-sensitive p53 mutant allele, tsp53(Val-135). Sequence analysis of the full-length cDNA revealed its identity as the mouse homologue of the human thiamine transporter 1 (THTR-1). Induction of the mouse THTR-1 (mTHTR-1) mRNA was detectable as early as 1 h at 32.5 degrees C; upon shifting back to 38.5 degrees C, mTHTR-1 transcript was rapidly degraded with a half-life of less than 2 h. Elevation of mTHTR-1 expression was found in DNA damage-induced normal mouse embryonic fibroblast cells, but not in p53(-/-) mouse embryonic fibroblast cells, suggesting that mTHTR-1 induction was p53-dependent. A region within the first intron of the mTHTR-1 gene bound to p53 and conferred the p53-mediated transactivation. Furthermore, increased thiamine transporter activities were found in cells overexpressing mTHTR-1 and under conditions of DNA damage or p53 activation. Our findings indicate that p53 may be involved in maintaining thiamine homeostasis through transactivation of THTR-1.

29. J Pediatr Gastroenterol Nutr. 2001 Jul;33(1):64-9.

Thiamine, riboflavin, pyridoxine, and vitamin C status in premature infants receiving parenteral and enteral nutrition.

Friel JK, Bessie JC, Belkhode SL, Edgecombe C, Steele-Rodway M, Downton G, Kwa PG, Aziz K.

Department of Biochemistry, Memorial University of Newfoundland, St. John's, Newfoundland A1B 3X9, Canada. jfriel@morgan.ucs.mun.ca

BACKGROUND: There is a paucity of data about water soluble vitamin status in low birthweight infants. Therefore, the authors' objective was to assess current feeding protocols. METHODS: The authors measured serum concentrations for riboflavin, pyridoxine, and vitamin C and functional assays for thiamine and riboflavin longitudinally in 16 premature infants (birthweight, 1,336 +/- 351 g; gestational age, 30 +/- 2.5 weeks) before receiving nutrition (time 1, 2 +/- 1 days), during supplemental or parenteral nutrition (time 2, 16 +/- 10 days) and while receiving full oral feedings (time 3, 32 +/- 15 days). In plasma, vitamin C was measured colorimetrically, and riboflavin and pyridoxine were measured using high-performance liquid chromatography. The erythrocyte transketolase test as a functional evaluation of thiamine and the erythrocyte glutathione reductase test for riboflavin were measured colorimetrically. RESULTS: At time 1, nutrient intake of vitamins were negligible because infants were receiving intravenous glucose and electrolytes only. Intakes differed between time 2 and time 3 for thiamine (510 +/- 280 and 254 +/- 115 microg. kg-1. d-1, respectively), riboflavin (624 +/- 305 and 371 +/- 193 microg. kg-1. d-1, respectively), and pyridoxine (394 +/- 243 and 173 +/- 85 microg/100 kcal, respectively), but not for vitamin C (32 +/- 17 and 28 +/- 12 mg. kg-1. d-1, respectively). Blood levels at times 1, 2, and 3 were for thiamine (4.9 +/- 2.7%, 3.3 +/- 6.6%, and 4.1 +/- 9% erythrocyte transketolase test, respectively), riboflavin (0.91 +/- 0.31, 0.7 +/- 0.3, 0.91 +/- 0.18 erythrocyte glutathione reductase test, respectively), riboflavin (19.5 +/- 17, 23.3 +/- 8.6, 17.6 +/- 10 ng/mL, respectively), pyridoxine (32 +/- 25, 40 +/- 16, 37 +/- 26 ng/mL, respectively), and vitamin C (5.2 +/- 3, 5 +/- 2.2, 10 +/- 5 microg/mL, respectively) and did not differ at those times. CONCLUSIONS: Current intakes of these vitamins, except for possibly vitamin C, during parenteral and enteral nutrition seem to result in adequate plasma concentrations and normal functional indices.

30. Neurology. 2001 Jun 26;56(12):1727-32.

Painful alcoholic polyneuropathy with predominant small-fiber loss and normal thiamine status.

Koike H, Mori K, Misu K, Hattori N, Ito H, Hirayama M, Sobue G.

Department of Neurology, Nagoya University School of Medicine, Japan.

BACKGROUND: Although polyneuropathy related to chronic alcoholism has been reported frequently, its clinical features and pathogenesis remain to be clarified. OBJECTIVE: To determine the clinicopathologic features and pathogenesis of alcoholic polyneuropathy associated with pain in patients with normal thiamine status, particularly in comparison to beriberi neuropathy. PATIENTS AND METHODS: Clinical, electrophysiologic, and histopathologic findings were assessed in 18 patients with painful alcoholic polyneuropathy and normal thiamine status. RESULTS: Symmetric sensory-dominant polyneuropathy predominantly involving the lower limbs was the major clinical pattern. Painful sensations with or without burning quality represented the initial and major symptom. Progression of symptoms usually was gradual, continuing over months or years. Electrophysiologic and pathologic findings mainly indicated an axonal neuropathy. Densities of small myelinated fibers and unmyelinated fibers were more severely reduced than the density of large myelinated fibers, except in patients with a long history of neuropathic symptoms and marked axonal sprouting. CONCLUSIONS: The clinicopathologic features of painful symptoms and small axon loss are distinct from those of beriberi neuropathy. Sensory-dominant involvement with prominent neuropathic pain is characteristic of alcoholic neuropathy when thiamine deficiency is not involved, supporting the view of direct neurotoxic effect by alcohol or its metabolites.

31. Cochrane Database Syst Rev. 2001;(2):CD001498.

Update of: Cochrane Database Syst Rev. 2000;(2):CD001498.

Thiamine for Alzheimer's disease.

Rodriguez-Martin JL, Qizilbash N, Lopez-Arrieta JM.

Iberoamerican Cochrane Centre, Department of Epidemiology, Hospital de la Santa Creu i Sant Pau, Sant Antoni M feminine Claret, 171, Barcelona, Catalunya, Spain, 08041. jrodriguezma@hsp.santpau.es

BACKGROUND: Vitamin B1 (thiamine) plays an important role in Wernicke-Korsakoff syndrome (a form of amnesia caused by brain damage occurring in long-term alcoholics who rely mainly on alcohol for nutrition). The acute syndrome is normally reversible but may proceed to profound dementia, although its progress can be stopped by a timely injection of a large dose of thiamine. There have been suggestions that thiamine may have a beneficial effect in Alzheimer's disease. OBJECTIVES: The objective of this systematic review is to evaluate the efficacy of thiamine for people with Alzheimer's disease. SEARCH STRATEGY: The Cochrane Controlled Trials Register (Issue 3:2000), the CDCIG Trials Register and other sources were searched for this update in July 2000 using the terms 'alzheimer*', thiamin* and vitamin B1'. In addition bibliographies of published reviews, and conference proceedings were searched and pharmaceutical companies and trials investigators were contacted. SELECTION CRITERIA: All unconfounded, double-blind, randomized trials in which treatment with thiamine was administered for more than a day and compared with placebo in patients with dementia of the Alzheimer's type. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two reviewers and the odds ratios (95% CI) or the average differences (95% CI) were estimated. MAIN RESULTS: There are three included studies, but few results were reported that could be included. The cross-over studies did not report results from the first phase. It was not possible to pool any results for a meta-analysis. Nolan 1991 reports results that show no evidence of an effect on MMSE at 3, 6, 9 and 12 months for thiamine compared with placebo for those who completed the trial. Meador 1993a noted that 3/8 on thiamine compared with 6/9 on placebo were worse as measured on the ADAS-Cog at 3 months compared with baseline, but the difference is not statistically significant. Blass 1988 and Nolan 1991 reported that no significant side-effects were noted during the study, and Meador 1993a did not mention side-effects. Blass 1988 noted that 5/16 and Nolan 1991 that 5/15 did not complete the study, but neither mentioned the groups to which these people belonged. REVIEWER'S CONCLUSIONS: It is not possible to draw any conclusions from this review. The number of people included in the studies if less than 50 and the reported results are inadequate.

32. Am J Physiol Gastrointest Liver Physiol. 2001 Jul;281(1):G144-50.

Mechanism of thiamine uptake by human colonocytes: studies with cultured colonic epithelial cell line NCM460.

Said HM, Ortiz A, Subramanian VS, Neufeld EJ, Moyer MP, Dudeja PK.

Department of Veterans Affairs Medical Center, Long Beach, California 90822, USA. hmsaid@uci.edu

Thiamine (vitamin B(1)) is essential for normal cellular functions and growth. Mammals cannot synthesize thiamine and thus must obtain the vitamin via intestinal absorption. The intestine is exposed to a dietary thiamine source and a bacterial source in which the vitamin is synthesized by the normal microflora of the large intestine. Very little is known about thiamine uptake in the large intestine. The aim of this study was, therefore, to address this issue. Our results with human-derived colonic epithelial NCM460 cells as a model system showed thiamine uptake to be 1) temperature- and energy dependent, 2) Na(+) independent, 3) increased with increasing buffer pH from 5 to 8 and after cell acidification but inhibited by amiloride, 4) saturable as a function of concentration, 5) inhibited by thiamine structural analogs but not by unrelated organic cations, and 6) inhibited by modulators of a Ca(2+)/calmodulin-mediated pathway. NCM460 cells and native human colonic mucosa expressed the recently cloned human thiamine transporter THTR-1 (product of the SLC19A2 gene) at both mRNA and protein levels. These results demonstrate for the first time that human NCM460 colonocytes possess a specific carrier-mediated system for thiamine uptake that appears to be under the regulation of an intracellular Ca(2+)/calmodulin-mediated pathway. It is suggested that bacterially synthesized thiamine in the large intestine may contribute to thiamine nutrition of the host, especially toward cellular nutrition of the local colonocytes.

33. Can J Neurol Sci. 2001 May;28(2):134-40.

Biogenic amine metabolites and thiamine in cerebrospinal fluid in heredo-degenerative ataxias.

Botez MI, Young SN.

Department of Medicine, Hotel Dieu Hospital and University of Montreal.

BACKGROUND: The aims of the present study were: i) to measure levels of the dopamine metabolite homovanillic acid (HVA), the serotonin metabolite 5-hydroxindoleacetic acid (5HIAA) and precursor tryptophan, as well as the noradrenaline metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and thiamine in the cerebrospinal fluid (CSF) of patients with Friedreich's ataxia (FA), olivopontocerebellar atrophy (OPCA), and the autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSAC), as compared with sex- and age-matched control subjects. PATIENTS AND METHODS: CSF amine related compound levels and thiamine results were compared in 40 FA, 44 OPCA and nine ARSAC patients with those of 94 sex- and age-matched subjects. Neuroimaging (CT scans and single photon emission computed tomographies i.e. SPECT) were carried out in all patients and controls. Genetic studies were conducted on OPCA patients. CSF amine related compounds were measured by high performance liquid chromatography, whereas CSF thiamine levels were measured by a microbiological method. RESULTS: FA patients had significantly lower CSF HVA, 5HIAA and thiamine values than control patients and a trend for lower MHPG levels. In OPCA patients, CSF HVA, MHPG and thiamine values were markedly lower whereas CSF 5HIAA values showed only a trend towards lower levels; in ARSAC patients only thiamine and HVA CSF values were lower than those in control subjects. CONCLUSION: After presenting the relationships between neurochemical findings on one side, the degree of ataxia, the degree of cerebellar atrophy and the SPECT findings on the other, the authors concluded that replacement and neuroprotective clinical trials in these patients would have to include two or three drugs because the neurotransmitter deficiencies are multiple.

34. Nutrition. 2001 Apr;17(4):351-2.

Comment in: Nutrition. 2002 Jan;18(1):118.

Severe metabolic acidosis and heart failure due to thiamine deficiency.

Ozawa H, Homma Y, Arisawa H, Fukuuchi F, Handa S.

Department of Internal Medicine, Tokai University Oiso Hospital, Oiso, Japan.

We report the case of a male patient with severe metabolic acidosis and heart failure caused by thiamine deficiency. He was admitted in August 1998 to the Tokai University Oiso Hospital because of severe dyspnea. The patient was diagnosed with heart failure and metabolic acidosis of unknown causes based on arterial blood gas analysis, chest x ray, and ultrasonic echocardiographic examinations. Our previous experience in treating a patient with thiamine deficiency caused by total parenteral nutrition without thiamine supplementation suggested that this patient was deficient in thiamine. The serum thiamine level was low and the lactate level was high. After intravenous administration of thiamine, the acidosis and heart failure disappeared. Dietary analysis showed that thiamine intake was low (0.32 mg/1000 kcal/d). Thiamine deficiency should be included in the differential diagnosis when encountering cases of heart failure with severe metabolic acidosis, even in developed countries.

35. Int J STD AIDS. 2001 Jun;12(6):407-9.

Severe lactic acidosis and thiamine administration in an HIV-infected patient on HAART.

Arici C, Tebaldi A, Quinzan GP, Maggiolo F, Ripamonti D, Suter F.

Unita Operativa Perativa di Malattie Infettive, Ospedali Riuniti di Bergamo, Italy. aricirm@tin.it

Severe lactic acidosis has been increasingly reported as a potentially fatal complication of HIV treatment. We report on an asymptomatic HIV-infected woman treated with stavudine, lamivudine and indinavir for one year. She was hospitalized because of progressive dispnoea, oedema, cyanosis and severe lactic acidosis. Arterial blood pH was 6.98, bicarbonate 4.4 mmol/l (normal value 22-26), blood lactate: 29.7 mmol/l (normal value <2.2). Hepatic function was normal. She had an impressively rapid response (within a few hours) to empirical treatment with thiamine (100 mg i.v.). No evidence of sepsis or malabsorption were identified and vitamin B1 level was not tested before thiamine infusion. Three months later she was re-started successfully on nelfinavir plus nevirapine. The rapid response to thiamine infusion deserves a careful attention and such an approach should be considered in similar cases as a support treatment of this potentially life-threatening complication of HIV therapy.

36. Blood Cells Mol Dis. 2001 Jan-Feb;27(1):135-8.

Thiamine-responsive megaloblastic anemia syndrome: a disorder of high-affinity thiamine transport.

Neufeld EJ, Fleming JC, Tartaglini E, Steinkamp MP.

Division of Hematology, Children's Hospital, Boston, Massachusetts 02115, USA. ellis.neufeld@tch.harard.edu

Thiamine-responsive megaloblastic anemia (TRMA) syndrome (OMIM No. 249270) comprises a distinctive triad of clinical features: megaloblastic anemia with ringed sideroblasts, diabetes mellitus, and progressive sensorineural deafness. The TRMA gene has been mapped and cloned. Designated "SLC19A2" as a member of the solute carrier gene superfamily, this gene is mutated in all TRMA kindreds studied to date. The product of the SLC19A2 gene is a membrane protein which transports thiamine (vitamin B1) with sub-micromolar affinity. Cells from TRMA patients are uniquely sensitive to thiamine depletion to the nanomolar range, while pharmacologic doses of vitamin B1 ameliorate the anemia and diabetes. Here we review the current status of studies aimed at understanding the pathophysiology of this unique transport defect. Copyright 2001 Academic Press.

37. Clin Nephrol. 2000 May;53(5):400-3.

Efficacy of hemodiafiltration in a child with severe lactic acidosis due to thiamine deficiency.

Pela I, Seracini D, Lavoratti GC, Sarti A.

Paediatric Clinic 1, Paediatrics Department, University of Florence, Italy.

We report the case of a child in whom severe lactic acidosis (LA) and hyperammonemia developed after twenty days of total parenteral nutrition (TPN) for diffuse esophageal damage due to caustic ingestion. The revision of TPN preparation revealed that thiamine was never included and the hypothesis of thiamine deficiency was later confirmed measuring the serum thiamine level. Because severe metabolic acidosis the dialytic treatment with hemodiafiltration (HDF) and bicarbonate infusion were performed: the patient very quickly recovered with dramatic reestablishment of the acid-basic balance. Thiamine administration restored lactate metabolism. We emphasize that HDF is a useful and prompt treatment for LA to get over the critical phase of neurological and cardiological damage.

38. Am J Gastroenterol. 2001 Mar;96(3):864-8.

Thiamine treatment of chronic hepatitis B infection.

Wallace AE, Weeks WB.

Department of Psychiatry and Community and Family Medicine, Dartmouth Medical School, Hanover, New Hampshire, USA.

OBJECTIVE: Chronic hepatitis B is an international health concern that causes cirrhosis, hepatocellular carcinoma, liver failure, and death. Current treatment options are expensive and associated with side effects; however, indirect evidence suggests a relationship between relative thiamine deficiency and chronic hepatitis B infection. METHODS: The authors present three case studies wherein multiple crossovers of daily thiamine administration were used to evaluate a hypothesized association between thiamine treatment and aminotransferase levels. RESULTS: In each case study, thiamine administration was associated with reduction in aminotransferase levels and the fall of HBV DNA to undetectable levels. Analyses by t test demonstrated a statistically significant reduction in aminotransferase levels in all three cases. CONCLUSIONS: The relationship between thiamine administration and chronic hepatitis B infection warrants further study. If proven effective in reducing liver damage or inducing remission of the hepatitis B virus in larger trials, thiamine will offer obvious advantages over the current treatments for chronic viral hepatitis B infection.

39. J Biochem (Tokyo). 2001 Apr;129(4):543-9.

Suppression of the accumulation of triosephosphates and increased formation of methylglyoxal in human red blood cells during hyperglycaemia by thiamine in vitro.

Thornalley PJ, Jahan I, Ng R.

Department of Biological Sciences, University of Essex, Central Campus, Wivenhoe Park, Colchester CO4 3SQ, Essex, UK. thorp@essex.ac.uk

The accumulation of triosephosphates and the increased formation of the potent glycating agent methylglyoxal in intracellular hyperglycaemia are implicated in the development of diabetic complications. A strategy to counter this is to stimulate the anaerobic pentosephosphate pathway of glycolysis by maximizing transketolase activity by thiamine supplementation, with the consequent consumption of glyceraldehyde-3-phosphate and increased formation of ribose-5-phosphate. To assess the effect of thiamine supplementation on the accumulation of triosephosphates and methylglyoxal formation in cellular hyperglycaemia, we incubated human red blood cell suspensions (50% v/v) in short-term culture with 5 mM glucose and 50 mM glucose in Krebs-Ringer phosphate buffer at 37 degrees C as models of cellular metabolism under normoglycaemic and hyperglycaemic conditions. In hyperglycaemia, there is a characteristic increase in the concentration of the triosephosphate pool of glycolytic intermediates and a consequent increase in the concentration and metabolic flux of the formation of methylglyoxal. The addition of thiamine (50-500 microM) increased the activity of transketolase, decreased the concentration of the triosephosphate pool, decreased the concentration and metabolic flux of the formation of methylglyoxal, and increased the concentration of total sedoheptulose-7-phosphate and ribose-5-phosphate. Biochemical changes implicated in the development of diabetic complications were thereby prevented. This provides a biochemical basis for high dose thiamine therapy for the prevention of diabetic complications.

40. Ann Fr Anesth Reanim. 2001 Jan;20(1):40-3.

[Postoperative encephalopathies: thiamine deficiency, an unrecognized etiology]

[Article in French]

Vidal S, Andrianjatovo JJ, Dubau B, Winnock S, Maurette P.

Departement d'anesthesie-reanimation III, CHU Pellegrin, 33076 Bordeaux, France.

We report the case of a patient who experienced a postoperative Wernicke encephalopathy 8 days after a left hepatectomy performed for metastasis related to a rectal cancer. During the six months before surgery the patient lost 10 kg of weight (15%). Moreover, in the postoperative period the patient received exclusively 5% dextrose solution intravenously. On the 8th postoperative day, an alteration of consciousness, a vertical nystagmus and an ataxia led to consider the diagnosis of thiamine deficiency that was then established by the decrease in the transcetolase activity of the red blood cells. Vitamin B1 supply improved the clinical status rapidly and completely. This observation allows to review aetiologies and clinical forms of thiamine shortage. In addition, it stresses the detection of exposed patients and the prevention methods.

41. Am J Kidney Dis. 2001 Feb;37(2):427-30.

Chorea induced by thiamine deficiency in hemodialysis patients.

Hung SC, Hung SH, Tarng DC, Yang WC, Huang TP.

Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.

Thiamine deficiency is mainly encountered in alcoholics or food faddists, but it may complicate chronic dialysis because of low intake and accelerated loss of thiamine in dialysis patients. We report here 2 hemodialysis (HD) patients who developed chorea induced by thiamine deficiency. We propose that thiamine deficiency, with a consequent dysfunction of the basal ganglia, may induce chorea in HD patients.

42. Eur Neurol. 2001;45(1):34-7.

Thiamine-responsive acute neurological disorders in nonalcoholic patients.

Merkin-Zaborsky H, Ifergane G, Frisher S, Valdman S, Herishanu Y, Wirguin I.

Department of Neurology, Soroka University Medical Center, Goldman Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.

Wernicke's encephalopathy (WE) is most commonly associated with alcoholism, although other causes have also been implicated. In the years 1994-1997, 9 patients with no history of alcohol abuse presented with acute signs of ophthalmoplegia or nystagmus and ataxia which resolved within 48 h after intravenous thiamine. There were 7 women and 2 men aged 17-57 (7 below the age of 30). Precipitating events included vomiting 2, drastic weight-reducing diet 2, renal colic in a postpartum woman 1, colonic surgery 2 and chronic hemodialysis 1. In 2 patients there was no obvious precipitating event but their history was suggestive of a genetic predisposition. Mental changes were slight or absent in all patients and all of them made good functional recovery. These cases suggest that the diagnosis of WE should be considered more often in nonalcoholics in various clinical settings. Copyright 2001 S. Karger AG, Basel

43. Ophthalmic Genet. 2000 Dec;21(4):243-50.

Thiamine-responsive megaloblastic anemia syndrome (TRMA) with cone-rod dystrophy.

Meire FM, Van Genderen MM, Lemmens K, Ens-Dokkum MH.

Department of Pediatric Ophthalmology, Ghent University Hospital, Ghent, Belgium.

Thiamine-responsive megaloblastic anemia (TRMA) is an autosomal recessive disease in which the active thiamine uptake into cells is disturbed. The molecular basis underlying the disorder has been related to mutations in the gene SLC19A2 on chromosome 1q23.3 that encodes a functional thiamine transporter. The protein is predicted to have 12 transmembrane domains. TRMA is characterized by sensorineural deafness, diabetes mellitus, megaloblastic anemia, and cardiomyopathy. Optic nerve atrophy and retinal dystrophy have been reported in a small number of patients. We report a 15-year-old girl with TRMA and cone-rod dystrophy and confirm that retinal dystrophy may form part of the syndrome. Differential diagnosis of syndromes with deafness, diabetes mellitus, and optic nerve atrophy or retinal dystrophy are discussed. The authors suggest that ERG be performed in all patients with TRMA.

44. Rev Med Interne. 2000 Nov;21(11):993-7.

[Pericardial extravasation as an indicator of congestive heart failure due to thiamine deficiency in a young adult]

[Article in French]

Hurreesing C, Babuty D, Fauchier L, d'Alteroche L, Montout M, Poret P, Cosnay P.

Service de cardiologie B, hopital Trousseau, Tours, France.

INTRODUCTION: Thiamine (B1) deficiency is one of the classical causes of congestive heart failure. Although in the western world and in other developed regions this disorder is generally associated with chronic alcoholism, it may also only occur as a result of a deficient diet. EXEGESIS: A young patient was admitted for electrocardiographic examination, and pericardial extravasation was recorded. The etiological assessment showed a case of congestive heart failure due to thiamine (B1) deficiency. A hemodynamic examination and investigation of thiamine blood levels confirmed this diagnosis. The patient's health status improved following thiamine administration, with complete and rapid regression of symptoms of congestive heart failure. CONCLUSION: Although cardiomyopathic beriberi is infrequent, it should systematically be taken into account in the etiology of congestive heart failure. The present study also notes that a dietary thiamine deficiency is uncommon, but should nevertheless be considered when other symptoms of denutrition are present.

45. Przegl Lek. 2000;57(7-8):369-73.

[The effect of cocarboxylase treatment on erythrocyte transketolase and blood thiamine in patients with end stage renal disease undergoing maintenance hemodialysis]

[Article in Polish]

Pietrzak I, Czarnecki R, Baczyk K, Mlynarczyk M, Kaczmarek M.

Klinika Nefrologii, Instytutu Chorob Wewnetrznych, Akademii Medycznej im. K. Marcinkowskiego w Poznaniu.

The depressed ETKA in ESRD patients is supposed to be caused and/or aggravated by several factors among which the diminished content of thiamine in blood and/or disturbances of thiamine utilization seem to play the major role. This role stems from the fact that thiamine acts as the cofactor of transketolase. In order to check the therapeutic significance of this relationship we introduced the thiamine pyrophosphoric acid ester chloride (Cocarboxylasum-CC) administration in 25 patients (mHD + CC). Immediately after each HD performance CC was given i.v. during 12 weeks in a doses of 5 mg/kg b.w., 3 times a week. The blood for ETKA value, free and total thiamine in plasma and erythrocytes, as well as, the total protein and albumins/globulins index investigation was drawn before, after 6 and 12 weeks of CC administration, and 3 months after cessation of this therapy. In 10 patients, on maintenance HD nontreated by CC (mHD), the blood was drawn at the same time intervals. Normal values we obtained from 15 healthy volunteers. For ETKA evaluation photocolorimetric method was used, thiamine content in blood was estimated by fluorimetric method. At the beginning of the study the mean value of ETKA, in two examined groups, was found statistically decreased (p < 0.01) when compared with normals. Mean values of thiamine in plasma and erythrocytes were lower but did not differ significantly from those in normals. After 6 weeks of CC administration ETKA value increased, but only after 12 weeks it increased significantly (p < 0.01), reaching normal value. On the other hand, striking increase in plasma thiamine and erythrocyte thiamine levels was observed after 6 weeks of CC administration already (p < 0.01). Three months after cessation of CC administration significant decrease in ETKA value and thiamine level in blood was observed (p < 0.01). ETKA returned to lower value than in normals even in the presence of still high thiamine levels in blood. In mHD patients nontreated by CC the ETKA value and thiamine levels in blood did not change significantly during all periods of study. The nutritional status assessed by total protein and albumins/globulins index did not change in both groups through the study. We conclude, the administration of high doses of CC to ESRD patients on maintenance hemodialysis HD was successful in terms of increasing ETKA value and thiamine levels in blood without any side effects. Thus, supplementation with large doses of CC deserves further study because it promises to be another adjunct in the treatment of potential thiamine deficiency and metabolic disturbances in the course of dialysotherapy.

46. Am J Med Sci. 2000 Oct;320(4):278-80.

Unilateral internuclear ophthalmoplegia and recovery with thiamine in Wernicke syndrome.

Kumar PD, Nartsupha C, West BC.

Department of Medicine, Huron Hospital/Cleveland Clinic Health System, Ohio 44112, USA. ponondileep@hotmail.com

Internuclear ophthalmoplegia is usually caused by multiple sclerosis, tumors, or vascular lesions of the brain stem. We report a patient with Wernicke syndrome who presented with a right-sided internuclear ophthalmoplegia. He recovered completely with intravenous thiamine (vitamin B1). There were no lesions in the magnetic resonance image (MRI) of the brain, suggesting a derangement at the cellular level as the cause.

47. Med Hypotheses. 2000 Jul;55(1):88-90.

Thiamine supplementation to prevent induction of low birth weight by conventional therapy for gestational diabetes mellitus.

Bakker SJ, ter Maaten JC, Gans RO.

Department of Internal Medicine, University Hospital Groningen, The Netherlands. s.j.i.bakker@int.azg.nl

Conventional treatment for gestational diabetes mellitus increases the proportion of infants born with a low birth weight, a risk factor for cardiovascular disease and diabetes mellitus in later life. Thiamine supplementation during pregnancy may be shown to be a safe preventive measure. During pregnancy, approximately 50% of the women develop a biochemical thiamine deficiency, whereas the thiamine status falls, but remains within normal limits, in most other women. Thiamine is essential for glucose oxidation, insulin production by pancreatic beta-cells and cell growth. It is therefore likely that thiamine supplementation in pregnant women not only improves their glucose tolerance but also stimulates the intra-uterine growth, thereby preventing a low birth weight to ensue from conventional therapy which only improves glucose tolerance.

48. Acad Emerg Med. 2000 Oct;7(10):1156-9.

Low plasma thiamine levels in elder patients admitted through the emergency department.

Lee DC, Chu J, Satz W, Silbergleit R.

Department of Emergency Medicine, North Shore University Hospital, Manhasset, NY 11030, USA. dlee@nshs.edu

OBJECTIVES: To determine the prevalence of thiamine deficiency in a high-risk group of elder emergency department (ED) patients who reside in nursing homes and need admission to the hospital, and to determine the effect of patients' diets on this prevalence. METHODS: This was an observational pilot study of 75 consecutive ED patients aged 65 years or older who lived in a nursing home and were admitted to the hospital. Plasma thiamine levels were measured by high-pressure liquid chromatography on serum samples collected within 24 hours of hospital admission. Nursing home records were reviewed to determine whether patients received nutritional supplementation or enteral tube feedings. RESULTS: Seventy patients participated and had a mean plasma thiamine level of 27.3 microg/dL (95% CI = 20.2 to 34.4). Fourteen percent (n = 10, 95% CI = 8% to 24%) were thiamine-deficient (<10 microg/dL). Patients not receiving dietary supplements or tube feedings (n = 26) had lower mean thiamine levels (20.3 microg/dL, 95% CI = 12.7 to 27.9) and were thiamine-deficient more often (27%) than patients receiving dietary support (n = 44, 31.5 microg/dL, 95% CI = 24.7 to 38.3, 7% thiamine-deficient). CONCLUSIONS: Elder nursing home patients seen in the ED and admitted to the hospital are frequently thiamine-deficient. Empiric thiamine supplementation is often used in the ED for other high-risk patients, such as alcoholic individuals, and may be appropriate for high-risk elder patients. Further research is needed to determine whether thiamine supplementation in these patients can improve their clinical outcomes.

49. J Med Genet. 2000 Sep;37(9):669-73.

A novel mutation in the thiamine responsive megaloblastic anaemia gene SLC19A2 in a patient with deficiency of respiratory chain complex I.

Scharfe C, Hauschild M, Klopstock T, Janssen AJ, Heidemann PH, Meitinger T, Jaksch M.

Department of Medical Genetics, Klinikum Innenstadt, Ludwig-Maximilians- University, Munich, Germany.

The thiamine transporter gene SLC19A2 was recently found to be mutated in thiamine responsive megaloblastic anaemia with diabetes and deafness (TRMA, Rogers syndrome), an early onset autosomal recessive disorder. We now report a novel G1074A transition mutation in exon 4 of the SLC19A2 gene, predicting a Trp358 to ter change, in a girl with consanguineous parents. In addition to the typical triad of Rogers syndrome, the girl presented with short stature, hepatosplenomegaly, retinal degeneration, and a brain MRI lesion. Both muscle and skin biopsies were obtained before high dose thiamine supplementation. While no mitochondrial abnormalities were seen on morphological examination of muscle, biochemical analysis showed a severe deficiency of pyruvate dehydrogenase and complex I of the respiratory chain. In the patient's fibroblasts, the supplementation with high doses of thiamine resulted in restoration of complex I activity. In conclusion, we provide evidence that thiamine deficiency affects complex I activity. The clinical features of TRMA, resembling in part those found in typical mitochondrial disorders with complex I deficiency, may be caused by a secondary defect in mitochondrial energy production.

50. Proc Soc Exp Biol Med. 2000 Sep;224(4):246-55.

Thiamine intestinal transport and related issues: recent aspects.

Rindi G, Laforenza U.

Institute of Human Physiology, University of Pavia, Pavia, Italy.

In the intestinal lumen thiamine is in free form and very low concentrations. Absorption takes place primarily in the proximal part of the small intestine by means of a dual mechanism, which is saturable at low (physiological) concentrations and diffusive at higher. Thiamine undergoes intracellular phosphorylation mainly to thiamine pyrophosphate, while at the serosal side only free thiamine is present. Thiamine uptake is enhanced by thiamine deficiency, and reduced by thyroid hormone and diabetes. The entry of thiamine into the enterocyte, as evaluated in brush border membrane vesicles of rat small intestine in the absence of H+ gradient, is Na+- and biotransformation-independent, completely inhibited by thiamine analogs and reduced by ethanol administration and aging. The transport involves a saturable mechanism at low concentrations of vitamin and simple diffusion at higher. Outwardly oriented H+ gradients enhance thiamine transport, whose saturable component is a Na+-independent electroneutral uphill process utilizing energy supplied by the H+ gradient, and involving a thiamine/ H+ 1:1 stoichiometric exchange. The exit of thiamine from the enterocyte, as evaluated in basolateral membrane vesicles, is Na+-dependent, directly coupled to ATP hydrolysis by Na+-K+-ATPase, and inhibited by thiamine analogs. Transport of thiamine by renal brush border membrane vesicles is similar to the intestinal as far as both H+ gradient influence and specificity are concerned. In the erythrocyte thiamine transport is a Na+-independent, electroneutral process yet with two components: saturable, prevailing at low thiamine concentrations, and diffusive at higher. The saturable (specific) component is missing in patients of the rare disease known as thiamine-responsive megaloblastic anaemia (TRMA), producing a general disturbance of thiamine transport up to thiamine deficiency. The TRMA gene is located in chromosome 1q23.3. Recently, the thiamine transporter has been cloned: it is a protein of 497 amino acid residues with high homology with the reduced-folate transporter.

51. Eur J Clin Pharmacol. 2000 Jun;56(3):251-7.

High thiamine diphosphate concentrations in erythrocytes can be achieved in dialysis patients by oral administration of benfontiamine.

Frank T, Bitsch R, Maiwald J, Stein G.

Institute of Nutrition, Department of Human Nutrition, Friedrich-Schiller-University, Jena, Germany. Thomas.Frank@uni-jena.de

OBJECTIVE: The influence of either orally administered S-benzoylthiamine-O-monophosphate (benfotiamine) or thiamine nitrate on the thiamine status was tested in a randomised, two-group comparison study in 20 end-stage renal disease (ESRD) patients. Main outcome measures were the pharmacokinetics of thiamine diphosphate (TDP) in blood, the in vitro erythrocyte transketolase activity, its activation coefficient (alpha-ETK) and the TDP concentration in erythrocytes. METHODS: After ingestion of a single dose of either 100 mg thiamine nitrate (corresponding to 305 micromol thiamine) or 100 mg benfotiamine (corresponding to 214 micromol thiamine), the blood levels of thiamine phosphate esters were analysed by means of high-performance liquid chromatography for a 24-h period. The TDP concentration in erythrocytes was calculated using the haematocrit and TDP concentration in blood. Erythrocyte transketolase activity and alpha-ETK were measured before and 10 h after administration. The pharmacokinetics of TDP in blood were compared with healthy subjects of other studies retrieved from database query. RESULTS: Regarding the blood concentrations of TDP, the patients with ESRD had a 4.3 times higher area under the concentration time curve after benfotiamine administration than after thiamine nitrate. After benfotiamine administration, the peak plasma concentration of TDP exceeded that in healthy subjects by 51%. In the ESRD patients, after 24 h, the mean TDP concentration in erythrocytes increased from 158.7+/-30.9 ng/ml initially to 325.8+/-50.9 ng/ml after administration of benfotiamine and from 166.2+/-51.9 ng/ml to 200.5+/-50.0 ng/ml after thiamine nitrate administration. The ratio between the maximum erythrocyte TDP concentration and basal concentration was 2.66+/-0.6 in the benfotiamine group and 1.44+/-0.2 in the group receiving thiamine nitrate (P < 0.001). After 24 h, it was 2.11+/-0.4 and 1.23+/-0.2, respectively. The transketolase activity increased from 3.54+/-0.7 microkat/l initially to 3.84+/-0.6 microkat/l after benfotiamine intake (P = 0.02) and from 3.71+/-0.8 microkat/l to 4.02+/-0.7 microkat/l after thiamine nitrate intake (P = 0.08). Likewise, alpha-ETK decreased from initially 1.10+/-0.07 to 1.04+/-0.04 (P = 0.04) and from 1.12+/-0.05 to 1.08+/-0.06 (P = 0.09). After 24 h, the phosphorylation ratio in whole blood decreased from 12.9+/-6.9 initially to 5.6+/-3.2 after benfotiamine administration (P = 0.02) and from 13.5+/-7.3 to 9.0+/-4.8 (P = 0.03) after administration of thiamine nitrate. No correlation between erythrocyte TDP concentration and transketolase activity and/or alpha-ETK was observed in ESRD patients, either before or 10 h after administration. CONCLUSION: Compared with thiamine nitrate, the oral administration of benfotiamine leads to higher TDP concentrations in erythrocytes accompanied with a significant improvement of the erythrocyte transketolase activity in ESRD patients.

52. Vet Hum Toxicol. 2000 Aug;42(4):236-7.

Effect of thiamine hydrochloride on lead induced lipid peroxidation in rat liver and kidney.

Senapati SK, Dey S, Dwivedi SK, Patra RC, Swarup D.

Division of Medicine, Indian Veterinary Research Institute, Izatnagar.

Thiamine hydrochloride was studied on lead-induced endogenous lipid peroxidation in rat hepatic and renal tissues following po doses of 2.73 mg lead/kg bw for 6 w. Simultaneous use of 25 mg thiamine hydrochloride/kg bw po reduced lead accumulation in liver and kidneys. There were significant decreases in endogenous lipid peroxide in liver and kidney from thiamine hydrochloride-treated rats. Histopathological lesions in thiamine-treated livers and kidneys were milder in comparison to lesions in untreated Pb-exposed animals. This indicates the prophylactic potential of thiamine for lead-induced lipid peroxidation.

53. Anticancer Res. 2000 May-Jun;20(3B):2245-8.

Population thiamine status and varying cancer rates between western, Asian and African countries.

Boros LG.

UCLA School of Medicine, Harbor-UCLA Research and Education Institute, Torrance 90502, USA. boros@gcrc.humc.edu

The role of food supplements in the form of vitamins has not been extensively investigated in relation to varying cancer rates between populations of different geographical regions. New data indicate that thiamine (vitamin B1), a common food supplement in Western food products, is directly involved in nucleic acid ribose synthesis of tumor cells in its biologically activated form through the non-oxidative transketolase catalyzed pentose cycle reaction. Whether thiamine plays a role in increased cancer rates in the Western World by enhancing tumor cell proliferation, while increased consumption of thiaminase rich food limiting thiamine availability protects against common malignancies in Asia and Africa has not been evaluated. In the Western World, thiamine is a popular vitamin supplement in the form of tablets and it is also added to basic food items such as milled flour, cereals, peanut butter, refreshment drinks and pastas. On the contrary, thiaminase, the natural thiamine-degrading enzyme, is abundantly present in raw and fermented fish, certain vegetables and roasted insects consumed primarily in Africa and Asia. Excess thiamine supplementation in common food products may contribute to the increased cancer rates of the Western World.

54. Am J Clin Nutr. 2000 Aug;72(2 Suppl):598S-606S.

Effect of physical activity on thiamine, riboflavin, and vitamin B-6 requirements.

Manore MM.

Food and Nutrition Laboratory, the Department of Family Resources and Human Development, Arizona State University, Tempe, AZ 85212, USA. melinda.manore@asu.edu

Because exercise stresses metabolic pathways that depend on thiamine, riboflavin, and vitamin B-6, the requirements for these vitamins may be increased in athletes and active individuals. Theoretically, exercise could increase the need for these micronutrients in several ways: through decreased absorption of the nutrients; by increased turnover, metabolism, or loss of the nutrients; through biochemical adaptation as a result of training that increases nutrient needs; by an increase in mitochondrial enzymes that require the nutrients; or through an increased need for the nutrients for tissue maintenance and repair. Biochemical evidence of deficiencies in some of these vitamins in active individuals has been reported, but studies examining these issues are limited and equivocal. On the basis of metabolic studies, the riboflavin status of young and older women who exercise moderately (2.5-5 h/wk) appears to be poorer in periods of exercise, dieting, and dieting plus exercise than during control periods. Exercise also increases the loss of vitamin B-6 as 4-pyridoxic acid. These losses are small and concomitant decreases in blood vitamin B-6 measures have not been documented. There are no metabolic studies that have compared thiamine status in active and sedentary persons. Exercise appears to decrease nutrient status even further in active individuals with preexisting marginal vitamin intakes or marginal body stores. Thus, active individuals who restrict their energy intake or make poor dietary choices are at greatest risk for poor thiamine, riboflavin, and vitamin B-6 status.

55. Muscle Nerve. 2000 Jul;23(7):1069-75.

Mitochondrial myopathy and familial thiamine deficiency.

Sato Y, Nakagawa M, Higuchi I, Osame M, Naito E, Oizumi K.

First Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan. y-sato@ktarn.or.jp

We studied two siblings with a mitochondrial myopathy, familial thiamine deficiency, and an A3243G mutation of the mitochondrial DNA (mtDNA). The elder brother (patient 1, now 36 years old) developed myopathy and beriberi heart at 20 years of age. Thiamine therapy resolved the cardiac symptoms and hyperpyruvicemia and improved the myopathy. The younger brother presented aged 19 years with a myopathy (patient 2, now 35 years old). Thiamine deficiency was present in the siblings and parents, and ragged-red fibers (RRFs) were noted in muscle biopsies from the siblings. Analysis 17 years later demonstrated thiamine malabsorption and an A3243G mutation of the mtDNA in both siblings and their mother, progressive myopathy, and an increased number of RRFs and elevated serum CKMB activity in patient 1. Thiamine treatment decreased the serum concentrations of lactate and pyruvate in patient 2, but not patient 1. The role of thiamine in mitochondrial dysfunction caused by an electron transfer disorder in the setting of A3243G mtDNA mutation is discussed. Copyright 2000 John Wiley & Sons, Inc.

56. Hum Mutat. 2000;16(1):37-42.

The spectrum of mutations, including four novel ones, in the thiamine-responsive megaloblastic anemia gene SLC19A2 of eight families.

Raz T, Labay V, Baron D, Szargel R, Anbinder Y, Barrett T, Rabl W, Viana MB, Mandel H, Baruchel A, Cayuela JM, Cohen N.

Department of Genetics, Tamkin Human Molecular Genetics Research Facility, Technion-Israel Institute of Technology, Bruce Rappaport Faculty of Medicine, Haifa, Israel.

Thiamine responsive megaloblastic anemia (TRMA) is an autosomal recessive disorder with a triad of symptoms: megaloblastic anemia, deafness, and non-type 1 diabetes mellitus. Occasionally, cardiac abnormalities and abnormalities of the optic nerve and retina occur as well. Patients with TRMA often respond to treatment with pharmacological doses of thiamine. Recently, mutations were found in patients with TRMA in a thiamine transporter gene (SLC19A2). We here describe the mutations found in eight additional families. We found four novel mutations and three that were previously described. Of the novel ones, one is a nonsense mutation in exon 1 (E65X), two are missense mutations in exon 2 (S142F, D93H), and another is a mutation in the splicing donor site at the 5' end of intron 4 (C1223+1G>A). We also summarize the state of knowledge on all mutations found to date in TRMA patients. SLC19A2 is the first thiamine transporter gene to be described in humans. Reviewing the location and effect of the disease causing mutations can shed light on the way the protein functions and suggest ways to continue its investigation. Copyright 2000 Wiley-Liss, Inc.

57. Eur J Paediatr Neurol. 2000;4(3):115-7.

Outcome of thiamine treatment in a child with Leigh disease due to thiamine-responsive pyruvate dehydrogenase deficiency.

Di Rocco M, Lamba LD, Minniti G, Caruso U, Naito E.

II Paediatric Division, Gaslini Institute, Genoa, Italy.

We describe a child with severe psychomotor retardation, peripheral neuropathy and bilateral abnormal signal in basal ganglia on magnetic resonance imaging, consistent with Leigh disease. Fibroblast pyruvate dehydrogenase assayed with routine method was normal. However, because of neurological improvement after treatment with thiamine, pyruvate dehydrogenase activity was studied again with thiamine pyrophosphate concentration adjusted to the normal human tissue level and found to be deficient. We report here on diagnostic difficulties and clinical follow-up of this patient.

58. JPEN J Parenter Enteral Nutr. 2000 May-Jun;24(3):154-8.

Thiamine deficiency in children with congenital heart disease before and after corrective surgery.

Shamir R, Dagan O, Abramovitch D, Abramovitch T, Vidne BA, Dinari G.

Division of Pediatric Gastroenterology and Nutrition, Schneider Children's Medical Center of Israel. shamirr@netvision.net.il

BACKGROUND: Malnutrition is common in children with congenital heart disease, while thiamine deficiency (TD) is common in malnutrition, in critically ill children, and in adults with congestive heart failure treated with loop diuretics. Our goal was to determine whether children with congenital heart disease had TD and whether treatment with loop diuretics is related to TD in these patients. METHODS: Twelve children with ventricular septal defect (VSD) treated with furosemide, and 10 children with tetralogy of Fallot (TOF) referred for corrective surgery were consecutively enrolled into a prospective study. Data were collected 24 hours before surgery and 5 days after surgery for nutrition evaluation, medications used, anthropometric measurements, and laboratory markers of malnutrition. Thiamine and pyridoxine deficiencies were evaluated using activated enzyme assays. RESULTS: Seven children (32% of patients) did not meet the recommended daily allowance (RDA) for calories and 18% of patients did not meet the RDA for thiamine intake. Anthropometric measurements were low in both groups, more so in those with VSD, although the difference did not reach statistical significance. Overall, 18% (1/12 with VSD and 3/10 with TOF) of children with congenital heart disease had thiamine deficiency before surgery. Three of the four children with TD had adequate intake of thiamine. Six children (27%) had TD 5 days postsurgery (3 children with VSD and 3 children with TOF). CONCLUSIONS: TD is common in children with congenital heart disease (CHD) referred for corrective surgery both before and after surgery. Our results suggest that neither diuretic treatment nor malnutrition can fully explain the development of TD in these children.

59. J Nutr Health Aging. 2000;4(2):69-71.

Diuretic use: a risk for subclinical thiamine deficiency in elderly patients.

Suter PM, Haller J, Hany A, Vetter W.

Medical Policlinic, Division of Hypertension, University Hospital, Ramistrasse 100, CH 8091 Zurich, Switzerland. polpms@usz. unizh.ch

Long term diuretic therapy represents one central pharmacologic therapy of heart insufficiency and hypertension. Diuretics lead not only to an increased urinary excretion of electrolytes but also of water soluble vitamins. In this prospective study we evaluated the effect of hospitalization on the overall biochemical vitamin status in subjects older than 50 years (n=149, mean +/- SD age 70 +/- 10 years). Vitamin nutriture and other parameters were assessed at admission and discharge (duration of the hospitalization 19 +/- 1 day). Only vitamin B1 nutriture worsened during the hospitalization and in a multivariate procedure the only significant predictor of the change in the vitamin B1 nutriture was the use of diuretics during the hospitalization (F=4.06, p < 0.001). The changes in the ETK (erythrocyte transketolase activity in whole blood) and a-ETK (ETK activity coefficient) during the hospital stay correlated with the cumulative dosage of furosemide adjusted for the duration of the therapy (r = 0.36, p < 0.001 and r = - 0.28, p > 0.03). Our data suggest that hospitalized elderly are at increased risk for vitamin B1 deficiency especially when on a diuretic treatment. It is possible that a low dose thiamine supplementation my help to prevent the development of a subclinical wet-beriberi in older subjects on diuretics.

60. Ann N Y Acad Sci. 2000 Apr;903:353-6.

Vascular endothelium is a site of free radical production and inflammation in areas of neuronal loss in thiamine-deficient brain.

Calingasan NY, Gibson GE.

Weill Medical College of Cornell University, Burke Medical Research Institute, White Plains, New York 10605, USA.

Free radical production in vascular endothelial cells and inflammatory responses in perivascular microglia accompany the selective neuronal death induced by TD. Lipid peroxidation and tyrosine nitration occur in neurons within susceptible areas. Thus, region- and cell-specific oxidative stress contributes to selective neurodegeneration during TD. These data are consistent with the hypothesis that in TD, vascular factors constitute a critical part of a cascade of events leading to increases in blood-brain barrier permeability to nonneuronal proteins and iron, leading to inflammation and oxidative stress. Inflammatory cells may release deleterious compounds or cytokines that exacerbate the oxidative damage to metabolically compromised neurons. Similar mechanisms may operate in the pathophysiology of neurodegenerative diseases in which vascular factors, inflammation and oxidative stress are implicated including AD.

61. J Intern Med. 2000 May;247(5):597-600.

Reduced thiamine phosphate, but not thiamine diphosphate, in erythrocytes in elderly patients with congestive heart failure treated with furosemide.

Hardig L, Daae C, Dellborg M, Kontny F, Bohmer T.

Department of Medicine, Section of Cardiology, Sahlgrenska University Hospital/Ostra, Goteborg, Sweden.

OBJECTIVES: To measure the concentrations of thiamine and thiamine esters by high-pressure liquid chromatography (HPLC) in elderly patients treated with furosemide for heart failure and in a control group. DESIGN: A cross-sectional study of blood thiamine and thiamine ester concentrations. SUBJECTS: Forty-one patients admitted to hospital for heart failure and 34 elderly living at home. No vitamin supplementation was allowed. RESULTS: Compared with the healthy controls, furosemide-treated patients had significantly reduced whole blood thiamine phosphate (TP; 4.4 +/- 2.2 vs. 7.6 +/- 2.0 nmol L-1) and thiamine diphosphate (TPP; 76 +/- 21.5 vs. 91 +/- 19.8 nmol L-1) (mean +/- SD). When the thiamine concentrations were related to the haemoglobin concentrations, which were reduced in the heart failure patients, the levels of TP (nmol g-1 Hb) were 0.38 +/- 0.26 vs. 0.54 +/- 0.17 (P < 0.0001), and of TPP were 6.35 +/- 1.76 vs. 6.37 +/- 1.29 (P = 0.95). There were no differences in T and TP concentrations in plasma between the two groups. CONCLUSIONS: The elderly patients with heart failure treated with furosemide have not reduced the storage form of thiamine, TPP, but only TP. This change is most likely not an expression of a thiamine deficiency, but rather of an altered metabolism of thiamine, which is not understood at present.

62. Cochrane Database Syst Rev. 2000;(2):CD001498.

Update in: Cochrane Database Syst Rev. 2001;(2):CD001498.

Thiamine for Alzheimer's disease.

Rodriguez-Martin JL, Lopez-Arrieta JM, Qizilbash N.

Departamento de Psicobiologia, Universidad Nacional de Educacion a Distancia, Ciudad Universitaria s/n, PO Box 60148, Madrid, Spain, 28040. jrodriguez@meridian.es

BACKGROUND: Vitamin B1 (thiamine) plays an important role in Wernicke-Korsakoff syndrome (a form of amnesia caused by brain damage occurring in long-term alcoholics who rely mainly on alcohol for nutrition). The acute syndrome is normally reversible but may proceed to profound dementia, although its progress can be stopped by a timely injection of a large dose of thiamine. There have been suggestions that thiamine may have a beneficial effect in Alzheimer's disease. OBJECTIVES: The objective of this systematic review is to evaluate evidence of the effect of thiamine for Alzheimer's disease. SEARCH STRATEGY: The Cochrane Controlled Trials Register and the CDCIG Register were searched using the terms 'thiamine*, alzheimer* and vitamin* B1'. Other sources were also searched. SELECTION CRITERIA: All unconfounded, double-blind, randomized trials in which treatment with thiamine was administered for more than a day and compared to placebo in patients with dementia of the Alzheimer's type. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two reviewers, pooled if appropriate and possible, and the pooled odds ratios (95% CI) or the average differences (95% CI) were estimated. No intention-to-treat data were available to be used. MAIN RESULTS: Few data were available for review. The data were compatible with thiamine producing harm, no change or improvement. For measures of cognition, the effect of thiamine was non-significantly worse than placebo on the Mini Mental State Examination score (0-30; high=good) at 12 months: WMD -4.3 (95% CI: -14.4 - +5.8) and at time points 3, 6 and 9 months. Change from baseline analyses showed placebo to be significantly better than thiamine at all time points beyond three months; WMD -4.8 (95% CI: -6.0 to -3.6) at 12 months. There was no statistically significant difference in the test of Verbal Fluency and the Boston Naming Test. These analyses were based only on those who completed the study and not on intention-to-treat analyses. There were no results presented for withdrawal by treatment group. Data on measures of functional autonomy, behaviour, quality of life, dependency, or effect on carer were not available. REVIEWER'S CONCLUSIONS: This review finds no evidence that thiamine is a useful treatment for the symptoms of Alzheimer's disease. The data are so poor and sparse that it is difficult to state almost anything of its effect in Alzheimer's disease. Thiamine cannot be recommended for patients with Alzheimer's disease.

63. Age Ageing. 2000 Mar;29(2):111-6.

Comment in: Age Ageing. 2000 Mar;29(2):99-101.

Is thiamine deficiency in elderly people related to age or co-morbidity?

Wilkinson TJ, Hanger HC, George PM, Sainsbury R.

Department of Health Care of the Elderly, The Princess Margaret Hospital, Christchurch, New Zealand. tim.wilkinson@chmeds.ac.nz

OBJECTIVES: to compare erythrocyte thiamine pyrophosphate concentrations in elderly people with those in healthy younger people; to determine if any differences can be attributed to age or to co-morbidities. DESIGN: cross-sectional and 3-year longitudinal surveys. SETTING: primary care. PATIENTS: 100 volunteer blood donors and 222 elderly people from a general practice register. MEASUREMENTS: thiamine pyrophosphate concentrations using high performance liquid chromatography; physical examination, medical and medication history; grip strength, body mass index and plasma albumin. RESULTS: the mean [95% confidence interval (CI)] thiamine pyrophosphate concentration was 152 nmol/l (147-158) in the elderly group and 224 (213-235) nmol/l in the younger group (P < 0.001). Ninety-six (43.4%) of the elderly subjects had thiamine pyrophosphate concentrations below the fifth percentile of the younger subjects (140 nmol/l). Over 3 years thiamine pyrophosphate concentrations fell in the elderly cohort by 20% (95% CI: 14.5-24.5%; P < 0.01). Thiamine pyrophosphate concentrations in 39 healthy older people were no different from those in elderly people with co-morbidity but were significantly lower than those in the younger people. Elderly people with absent vibration sense in their feet had a lower thiamine pyrophosphate concentration than the rest of the group [129 (117-142)nmol/l compared with 156 (150-162)nmol/l; P < 0.01)]. Thiamine pyrophosphate concentrations were not related to prevalent diseases, common medications, body mass index, grip strength or plasma albumin. CONCLUSION: lower thiamine pyrophosphate concentrations in elderly people appear to be related more to age itself than to co-existent illnesses.

64. Fortschr Neurol Psychiatr. 2000 Mar;68(3):113-20.

[Thiamine treatment in psychiatry and neurology]

[Article in German]

Hinze-Selch D, Weber MM, Zimmermann U, Pollmacher T.

Max-Planck-Institut fur Psychiatrie, Munchen.

Every physician knows that alcohol dependence, alcohol withdrawal and Wernicke-Korsakow-syndrome require substitution with thiamine, in acute stages even parenterally. This would be trivial if there was not the widespread fear of anaphylactic, even lethal reactions to parenteral thiamine application. The present article reviews the literature published on thiamine since 1936, when the first synthetic, parenteral thiamine preparation became available, and, on this basis, tries to give practical advice and therapeutic regimens for the treatment of thiamine deficiency states. Controlled clinical studies on indications and differential thiamine therapy have not been published. From the data that are available, the following conclusions can be drawn: 1) Acute mortality of Wernicke-Korsakow-syndrome is about 20%. 2) Oral thiamine is safe. 3) The risk for an anaphylactic shock due to parenteral thiamine administration is below 1 to 100,000. 4) Not only alcohol but any condition with either increased metabolic need (pregnancy, consuming diseases) or deficient nutrition (including eating disorders) can lead to thiamine deficiency. Therefore, we suggest: 1) Oral thiamine substitution with at least 50 mg per day and supply of a sufficient and complete diet should be given to any person that might be at risk for thiamine deficiency. 2) Any patient suspicious for acute thiamine deficiency needs to be treated under inpatient conditions and there needs to receive 50 to 100 mg thiamine intravenously 3 to 4 times a day. 3) General practitioners, psychiatrists and neurologists should take care of the oral supplementation of thiamine, sufficient nutrition, and they are the physicians to diagnose early stages of thiamine deficiency.

65. Presse Med. 2000 Feb 12;29(5):240-1.

Comment in: Presse Med. 2000 Jun 24;29(22):1231.

[Right heart failure caused by thiamine deficiency (cardiac beriberi)]

[Article in French]

Akpan T, Peschard S, Brinkane AH, Bergheul S, Leroy-Terquem E, Levy R.

Service de Medecine interne, CHI Meulan, Les Mureaux.

BACKGROUND: Vitamin B1 deficiency (beriberi) is very uncommon in France. It leads to high output cardiac failure totally different from the situation observed in alcoholic patients. We report a typical case of cardiac beriberi. CASE REPORT: The patient was referred for dyspnea with high output cardiac failure. Echocardiography evidenced severe pulmonary hypertension and high cardiac output. The more common causes of heart failure were ruled out. The dietary habits of the patient (suggested beriberi which was confirmed by the low serum thiamin and therapeutic test with vitamin B1. DISCUSSION: High output cardiac failure should suggest possible Shoshin beriberi, particularly in subjects with imported dietary habits living in a precarious socioeconomic situation.

66. No To Shinkei. 2000 Jan;52(1):59-63.

[A case of Wernicke-Korsakoff syndrome with dramatic improvement in consciousness immediately after intravenous infusion of thiamine]

[Article in Japanese]

Kikuchi A, Chida K, Misu T, Okita N, Nomura H, Konno H, Takase S, Takeda A, Itoyama Y.

Department of Neurology, Kohnan Hospital, Sendai, Japan.

A 68-year-old man was hospitalized on March 4, 1998 for disturbances in consciousness. In 1995, he had received proximal subtotal gastrectomy and reconstructive surgery of the jejunal interposition for gastric cancer. Thereafter he had been taking enough food without the habit of taking liquor. In October 1997, his short term memory was becoming gradually worse. On February 12, 1998, he suffered from numbness in the feet, and then dysphagia, unsteady gait, and diplopia developed gradually. On February 26, brain MRI showed no abnormalities. On March 3, he had a fever of 38.5 degrees C and his consciousness became unclear. Neurological examination revealed semi-coma, total ophthalmoplegia, and absence of doll's eye movement. Deep tendon reflexes were absent. The serum thiamine level was 9 ng/ml (normal range: 20-50). Brain MRI demonstrated symmetrical high intensity lesions in the periaqueductal area of the midbrain, dorsomedial nuclei of bilateral thalami, and vestibular nuclei. About 30 seconds after intravenous infusion of thiamine, his consciousness improved dramatically, but returned to semi-coma after about two minutes. Wernicke-Korsakoff syndrome usually occurs acutely. In the present case, however, the disease showed slow onset, chronic progression, and then rapid worsening after fever. Reconstructive surgery of the jejunal interposition might have caused the slow onset of Wernicke-Korsakoff syndrome, and fever might have facilitated the rapid progression of the disease. An immediate high concentration of thiamine modifies the kinetics of acetylcholine receptor ion channels, thereby maintaining wakefulness, and the level of consciousness may change dramatically.

67. Hunan Yi Ke Da Xue Xue Bao. 1998;23(1):27-30.

[Thiamine status of university teacher families in Changsha]

[Article in Chinese]

Huang S, Ren G.

Department of Nutrition and Food Hygiene, Hunan Medical University, Changsha.

To evaluate the thiamine status of the population consuming the refined cereals and its products, we studied thiamine concentration in 23 food samples and human urine, and three-day dietary survey was conducted. The results showed that the thiamine content in the staple food was much lower than that in the raw material. The thiamine intake from diet was below to 80% RDA in 42.8% investigated families and the thiamine energy ratio was lower than 0.5 mg/4186.8 kJ in 71.5% of them. For the ratio of urinary tiamine (mg)/urinary inosine (g), 51.3% subjects exhibited decreased excretion, especially in the school-age children. We conclude that those people who take the refined cereals and its products as a staple food, is in the risk of thiamine deficiency.

68. Ann N Y Acad Sci. 1999;893:404-11.

Mechanisms of selective neuronal cell death due to thiamine deficiency.

Todd K, Butterworth RF.

Neuroscience Research Unit, Centre Hospitalier de l'Universite de Montreal, Quebec, Canada. kgtodd@ualberta.ca

Multiple mechanisms contribute to the selective brain lesions observed in WKS and experimental thiamine deficiency. Recent evidence of early microglial activation and increased free radical production suggest that oxidative stress processes play an important early role in the brain damage associated with thiamine deficiency.

69. Ann Vasc Surg. 2000 Jan;14(1):37-43.

Thiamine (Vitamin B1) protects against glucose- and insulin-mediated proliferation of human infragenicular arterial smooth muscle cells.

Avena R, Arora S, Carmody BJ, Cosby K, Sidawy AN.

Department of Surgery, Veterans Affairs Medical Center, George Washington and Georgetown University Medical Centers, Washington, DC, USA.

Accelerated proliferation of arterial smooth muscle cells (ASMC) plays an important role in the development of atherosclerosis, which preferentially affects the infragenicular vasculature in patients with diabetes mellitus. High insulin and glucose levels, which are present in patients with type II diabetes, have an additive effect in infragenicular ASMC proliferation in vitro. Thiamine is a coenzyme important in intracellular glucose metabolism. The objective of this study is to determine the effect of thiamine on human infragenicular ASMC proliferation induced by high glucose and insulin levels in vitro. Human infragenicular ASMC isolated from diabetic patients undergoing lower extremity amputation were used. Cells were cultured at 37 degrees C in 5% CO(2). Cells were identified as ASMC by immunohistochemical analysis. Cells from passages 3-5 were exposed to glucose concentrations of 0.1 and 0.2% with and without insulin concentrations of 100 ng/mL and 1000 ng/mL, in the presence or absence of 200 microM of thiamine. Standard hemocytometry and (3)H-thymidine incorporation quantified cell proliferation after incubation for 6 days and 24 hr, respectively. The data suggest that thiamine inhibits human infragenicular ASMC proliferation induced by high glucose and insulin. Vitamin B1 intake may prove important in delaying the atherosclerotic complications of diabetes.

70. Eur J Anaesthesiol. 1999 Oct;16(10):733-5.

Thiamine for the treatment of nucleoside analogue-induced severe lactic acidosis.

Schramm C, Wanitschke R, Galle PR.

Department of Medicine, Johannes Gutenberg-University, Mainz, Germany.

Nucleoside analogue-induced lactic acidosis is an often fatal condition in patients with HIV. There is only one report of successful treatment with riboflavin. We describe a 30-year-old female with AIDS and nucleoside analogue-induced lactic acidosis that exacerbated shortly after introducing total parenteral nutrition and reversed within hours after the addition of thiamine. Successful treatment of nucleoside analogue-induced lactic acidosis with a high dose of thiamine supports the hypothesis that vitamin deficiency is an important cofactor in the development of this rare and unpredictable condition in patients with HIV. We suggest that high dose B-vitamins should be given to any patient presenting with lactic acidosis under nucleoside analogue treatment.

71. J Neurol Sci. 1999 Dec 1;171(1):56-9.

Concomitant administration of sodium dichloroacetate and thiamine in west syndrome caused by thiamine-responsive pyruvate dehydrogenase complex deficiency.

Naito E, Ito M, Yokota I, Saijo T, Chen S, Maehara M, Kuroda Y.

Department of Pediatrics, School of Medicine, University of Tokushima, Tokushima, Japan.

We treated a female patient with West syndrome caused by thiamine-responsive pyruvate dehydrogenase complex (PDHC) deficiency. Infantile spasms occurred in association with elevated blood and CSF lactate concentrations; these symptoms disappeared when lactate concentrations had been lowered by treatment with concomitant sodium dichloroacetate (DCA) and high dose thiamine. Sequencing the patient's PDHC E(1)alpha subunit revealed a substitution of serine for glycine at position 89 in exon 3 (G89S). This mutation must be a de novo mutation because it was not found in either parents' genome DNA. To our knowledge, five previously described patients with PDHC deficiency have displayed the West syndrome. All six known patients, including our own, were female, even though an approximately equal number of males and females have been identified with PDHC deficiency and overall West syndrome occurs somewhat more frequently in males. These results indicated that West syndrome occurred more frequently in female patients with PDHC deficiency. It is suggested that lactate concentration should be measured in patients with West syndrome for potential PDHC deficiency, especially in females.

72. Am J Physiol. 1999 Oct;277(4 Pt 1):C645-51.

Transport of thiamine in human intestine: mechanism and regulation in intestinal epithelial cell model Caco-2.

Said HM, Ortiz A, Kumar CK, Chatterjee N, Dudeja PK, Rubin S.

Veterans Affairs Medical Center, Long Beach, California, 90822, USA. hmsaid@uc.edu

The present study examined the intestinal uptake of thiamine (vitamin B(1)) using the human-derived intestinal epithelial cells Caco-2 as an in vitro model system. Thiamine uptake was found to be 1) temperature and energy dependent and occurred with minimal metabolic alteration; 2) pH sensitive; 3) Na(+) independent; 4) saturable as a function of concentration with an apparent Michaelis-Menten constant of 3.18 +/- 0.56 microM and maximal velocity of 13.37 +/- 0.94 pmol. mg protein(-1). 3 min(-1); 5) inhibited by the thiamine structural analogs amprolium and oxythiamine, but not by unrelated organic cations tetraethylammonium, N-methylnicotinamide, and choline; and 6) inhibited in a competitive manner by amiloride with an inhibition constant of 0.2 mM. The role of specific protein kinase-mediated pathways in the regulation of thiamine uptake by Caco-2 cells was also examined using specific modulators of these pathways. The results showed possible involvement of a Ca(2+)/calmodulin (CaM)-mediated pathway in the regulation of thiamine uptake. No role for protein kinase C- and protein tyrosine kinase-mediated pathways in the regulation of thiamine uptake was evident. These results demonstrate the involvement of a carrier-mediated system for thiamine uptake by Caco-2 intestinal epithelial cells. This system is Na(+) independent and is different from the transport systems of organic cations. Furthermore, a CaM-mediated pathway appears to play a role in regulating thiamine uptake in these cells.

73. Int J Clin Pharmacol Ther. 1999 Sep;37(9):449-55.

Alteration of thiamine pharmacokinetics by end-stage renal disease (ESRD).

Frank T, Bitsch R, Maiwald J, Stein G.

Department of Human Nutrition, Institute of Nutrition, Friedrich Schiller University of Jena, Germany.

OBJECTIVE: In a comparative study with 20 end-stage renal disease (ESRD) patients the pharmacokinetics of two therapeutically used thiamine (vitamin B1) preparations were assessed. SUBJECTS, MATERIAL AND METHODS: After a single oral dose of either 100 mg benfotiamin (S-benzoylthiamine-o-monophosphate, BTMP) or 100 mg thiamine mononitrate (TN), blood levels of thiamine phosphate esters were analyzed by HPLC after precolumn derivatization to thiochrome phosphate esters for a 24-hour period. RESULTS: The pharmacokinetic parameters AUC0-24h, Cmax and tmax of the benfotiamin group in whole blood and plasma exceeded significantly those in the TN group. Only 1.0 vs. 0.6% of the administered dose were excreted in urine in the BTMP group and TN group, respectively. A high cellular efficacy, as was concluded from the short-term stimulation of the thiamine-dependent transketolase activity in erythrocytes (ETKA), was assessed for BTMP as well as TN. The activation coefficient (ETK-AC) decreased significantly from 1.10 to 1.04 vs. 1.12 to 1.07 in both the BTMP as well as TN groups, respectively. In addition, a high transfer rate to thiamine diphosphate (TDP) was observed in the patients after ingestion of BTMP. The TDP concentration in whole blood increased by 2.6 and 1.4 times from baseline levels to Cmax in the BTMP and TN groups, respectively. The AUC0-24h of TDP in whole blood after BTMP ingestion exceeded those after TN ingestion by 420%. CONCLUSION: These findings justify the therapeutic application of BTMP in ESRD, because a high intracellular concentration of TDP may protect against numerous adverse effects of uremia in the long run.

74. J Lab Clin Med. 1999 Sep;134(3):238-43.

Urinary loss of thiamine is increased by low doses of furosemide in healthy volunteers.

Rieck J, Halkin H, Almog S, Seligman H, Lubetsky A, Olchovsky D, Ezra D.

Department of Medicine, Sheba Medical Center, Tel Hashomer, Israel.

Prolonged furosemide treatment is associated with urinary loss of thiamine and thiamine deficiency in some patients with congestive heart failure and low dietary thiamine intake. In the rat, diuretic-induced thiamine urinary loss is solely dependent on increased diuresis and is unrelated to the type of diuretic used. We studied the effects of single intravenous doses of furosemide (1, 3, and 10 mg) and of normal saline infusion (750 mL) on urinary thiamine excretion in 6 volunteers. Over a 6-hour period, furosemide induced dose-dependent increases in urine flow and sodium excretion rates (mean +/- SD), from 51 +/- 17 mL/h at baseline to 89 +/- 29 mL/h, 110 +/- 38 mL/h, and 183 +/- 58 mL/h (F = 10.4, P < .002) and from 5.1 +/- 2.3 mmol/h to 9.4 +/- 6.8 mmol/h, 12.1 +/- 2.6 mmol/h, and 20.9 +/- 10.6 mmol/h (F = 6.3, P < .005) for the three doses, respectively (104 +/- 35 mL/h and 13.0 +/- 6.2 mmol/h for the saline infusion). During this period the thiamine excretion rate doubled from baseline levels (mean of four 24-hour periods before the diuretic interventions) of 6.4 +/- 5.1 nmol/h to 11.6 +/- 8.2 nmol/h (F = 5.03, P < .01, for all four interventions, no difference being found between them), then returning over the following 18 hours to 6.1 +/- 3.9 nmol/h. The thiamine excretion rate was correlated with the urine flow rate (r = 0.54, P < .001), with no further effect of the type of intervention or sodium excretion rate. These findings complement our previous results in animals and indicate that sustained diuresis of >100 mL/h induces a nonspecific but significant increase in urinary loss of thiamine in human subjects. Thiamine supplements should be considered in patients undergoing sustained diuresis, when dietary deficiency may be present.

75. J Lab Clin Med. 1999 Sep;134(3):232-7.

Comment in: J Lab Clin Med. 1999 Sep;134(3):192-3.

Urinary thiamine excretion in the rat: effects of furosemide, other diuretics, and volume load.

Lubetsky A, Winaver J, Seligmann H, Olchovsky D, Almog S, Halkin H, Ezra D.

Department of Medicine, Sheba Medical Center, Tel-Hashomer, Israel.

Long-term furosemide therapy is associated with increased urinary loss of thiamine. To examine the mechanism of furosemide-induced urinary thiamine loss, we measured urinary excretion of thiamine in rats in response to increasing doses of furosemide, acetazolamide, chlorothiazide, amiloride, mannitol, and extracellular fluid (ECF) volume loading by saline infusion. All animals were in normal thiamine balance as reflected by a thiamine pyrophosphate effect (TPPE) of 2.25% +/- 0.60% (mean +/- SEM), and all had normal renal function. Urinary flow increased in response to diuretic administration in a dose-dependent manner, reaching (mean) peak urinary flow rates of 283 to 402 microL/min. Fractional excretion of sodium (FE(Na)) exhibited the same pattern, reaching peak values of 12.3% to 23.2%. Urinary thiamine excretion increased in proportion to the incremental doses of diuretic agents, reaching (mean) maximal values of 7.44 to 9.34 pmol/min, with no significant difference (P = .11) between the various diuretics tested nor in response to saline loading. None of the diuretics tested differed in the effect on thiamine excretion, which was clearly flow dependent and only partially related to fractional sodium excretion. Urinary flow rate, being the single significant predictor, explained 78% (R2 = 0.78) of the variability in thiamine excretion rates. These findings indicate that urinary thiamine loss is caused by a nonspecific, flow-dependent mechanism common to all of the diuretics tested.

76. Neurosci Lett. 1999 Aug 13;271(1):33-6.

Cerebrospinal fluid levels of thiamine in patients with Parkinson's disease.

Jimenez-Jimenez FJ, Molina JA, Hernanz A, Fernandez-Vivancos E, de Bustos F, Barcenilla B, Gomez-Escalonilla C, Zurdo M, Berbel A, Villanueva C.

Department of Neurology, Hospital Universitario 'Principe de Asturias', Madrid, Spain. fjimenezj@meditex.es

Thiamine is an essential cofactor for several important enzymes involved in brain oxidative metabolism, such as the alpha-ketoglutarate dehydrogenase complex (KGDHC), pyruvate-dehydrogenase complex, and transketolase. The activity of KGDHC is decreased in the substantia nigra or patients with Parkinson's disease (PD). We measured cerebrospinal (CSF) levels of thiamine-diphosphate, thiamine-monophosphate, free thiamine, and total thiamine, using ion-pair reversed phase high performance liquid chromatography, in 24 PD patients and 40 matched controls. The mean CSF levels of thiamine-derivatives did not differ significantly from those of controls, with the exception of lower CSF free thiamine levels in the PD-patient group. PD patients under levodopa therapy had significantly higher CSF thiaminediphosphate and total thiamine than those not treated with this drug. CSF thiamine levels were not correlated with age, age at onset, duration of the disease, scores of the Unified Parkinson Disease Rating Scale of the Hoehn and Yahr staging in the PD group. These results suggest that low CSF free thiamine levels could be related with the risk for PD.

77. Acta Diabetol. 1999 Jun;36(1-2):73-6.

Comment in: Acta Diabetol. 2000;37(2):103.

Lipophilic thiamine treatment in long-standing insulin-dependent diabetes mellitus.

Valerio G, Franzese A, Poggi V, Patrini C, Laforenza U, Tenore A.

Department of Pediatrics, P.le S. Maria della Misericordia, I-33100 Udine, Italy.

Thiamine plays an important role in the regulation of glucose metabolism and pancreatic beta-cell functioning. A role for this vitamin in cellular glucose transport has been indicated in the literature. The aim of this study was to determine whether a lipophilic form of thiamine (benzoyloxymethyl-thiamine, BOM) was able to improve metabolic control in patients with long-standing insulin-dependent diabetes mellitus (type 1). A total of 10 children with type 1 diabetes of long duration (age 11.4 +/- 1.2 years, duration of the disease 4.5 +/- 0.7 years, means +/- SEM) were studied before and after treatment with BOM in a randomized double-blind and placebo-controlled study. Five patients were assigned to the BOM-treated group and five to the placebo-group. In all patients basal and glucagon-stimulated C-peptide secretion was undetectable. Thiamine status was assayed by measuring the plasma content of thiamine and its monophosphate form at entry and after 3 months of treatment. The blood HbA(1C) levels and the daily dose of insulin per kg body weight were assessed in both groups before treatment, after 1 month and 3 months of treatment, then 3 months following its suspension. The plasma content of thiamine + thiamine monophosphate in type 1 diabetic patients (35.3 +/- 3.6 pmol/mL) was significantly lower when compared with that measured in six age-matched normal subjects (53.2 +/- 2.3 pmol/mL, P < 0.05).

78. Nat Genet. 1999 Jul;22(3):305-8.

The gene mutated in thiamine-responsive anaemia with diabetes and deafness (TRMA) encodes a functional thiamine transporter.

Fleming JC, Tartaglini E, Steinkamp MP, Schorderet DF, Cohen N, Neufeld EJ.

Division of Hematology, Children's Hospital, Dana Farber Cancer Institute, and Harvard Medical School, Boston, Massachusetts 02115, USA.

Thiamine-responsive megaloblastic anaemia with diabetes and deafness (TRMA; MIM 249270) is an autosomal recessive disease thought to be due to a defect in thiamine (vitamin B1) transport. Pharmacological doses of thiamine correct the anaemia, and in some cases improve the diabetes, although progressive sensorineural deafness is irreversible. Previous studies localized the TRMA gene to a 4-cM region on chromosome 1q23.3 (ref. 5), and fine-mapping has recently narrowed that region further. We have previously demonstrated that fibroblasts from people with TRMA lack high-affinity thiamine transport. Expression of a gene encoding a known yeast thiamine transporter, THI10 (refs 8-10), in TRMA mutant cells prevents apoptotic cell death in thiamine-depleted medium. On the basis of these studies, we hypothesized that a defective thiamine transporter causes TRMA. We undertook a candidate gene approach to identify putative thiamine transporters in the 1q23.3 critical region. Here we present evidence that the gene SLC19A2 (for solute carrier family 19 (thiamine transporter), member 2) encodes the first known mammalian thiamine transporter, which we designate thiamine transporter-1 (THTR-1).

79. Ann Fr Anesth Reanim. 1999 Apr;18(4):445-50.

[Severe lactic acidosis and thiamine deficiency during parenteral nutrition in a child]

[Article in French]

Remond C, Viard L, Paut O, Giraud P, Camboulives J.

Departement d'anesthesie et reanimation pediatrique, Hopital d'Enfants de la Timone, Marseille, France.

We report the case of a leukemic child treated with chemotherapy and parenteral nutrition for three weeks, who developed a severe lactic acidosis. Clinical features included both digestive and neurological disorders associated with a moderate cardiovascular collapse. After elimination of a toxic, a neoplastic or a septic cause, a thiamin (or vitamin B1) deficiency was suspected because of the lack of vitamin supply to parenteral nutrition. Intravenous administration of thiamin rapidly controlled lactic and clinical features. The diagnosis was confirmed by a low plasmatic concentration of thiamin. Thiamin deficiency must be suspected in case of severe lactic acidosis during parenteral nutrition and systematically prevented by supply of vitamins.

80. Am J Med Sci. 1999 Apr;317(4):261-2.

Lactic acidosis caused by thiamine deficiency in a pregnant alcoholic patient.

Mukunda BN.

Department of Medicine, Meridia Huron Hospital, Cleveland, Ohio 44112, USA.

BACKGROUND: Metabolic acidosis from accumulation of lactic acid is a relatively common condition, whereas its causation by thiamine deficiency is not. METHODS: We studied a pregnant alcoholic patient who presented with hyperemesis and a high anion gap acidosis. RESULTS: Lactic acidosis and thiamine deficiency were confirmed. The patient's symptoms and acidosis resolved with thiamine administration. CONCLUSIONS: Lactic acidosis caused by thiamine deficiency must be suspected when pregnant patients at risk for thiamine deficiency present with a high anion gap acidosis. A large dose of thiamine must be administered immediately.

81. Mayo Clin Proc. 1999 Mar;74(3):259-63.

Metabolic acidosis and thiamine deficiency.

Romanski SA, McMahon MM.

Division of Endocrinology, Metabolism, and Nutrition, Mayo Clinic Rochester, MN 55905, USA.

We describe a 19-year-old patient who was receiving home parenteral nutrition in whom lactic acidosis developed. A review of her home parenteral nutrition formula revealed the absence of multivitamins, most significantly thiamine. After thiamine administration, the acidosis resolved, and the patient experienced pronounced clinical improvement. Clinicians must be aware that thiamine is essential for normal glucose metabolism and that thiamine deficiency can lead to lactic acidosis. Thiamine deficiency should be included in the differential diagnosis of lactic acidosis. The recent shortage of intravenous multivitamin preparations has led to documented cases of lactic acidosis as a result of thiamine deficiency, and a previous shortage led to several deaths due to lactic acidosis as a consequence of thiamine deficiency. All patients receiving parenteral nutrition must also receive adequate vitamin supplementation.

82. Ann Hematol. 1999 Feb;78(2):105-7.

Downbeat nystagmus caused by thiamine deficiency: an unusual presentation of CNS localization of large cell anaplastic CD 30-positive non-Hodgkin's lymphoma.

Mulder AH, Raemaekers JM, Boerman RH, Mattijssen V.

Department of Medicine, St. Joseph Hospital, Veldhoven, The Netherlands.

A 24-year-old woman with a large cell anaplastic CD 30-positive T-cell non-Hodgkin's lymphoma (NHL) developed downbeat nystagmus, anisocoria, and oscillopsia. Prior to overt cerebral invasion by NHL, she had a thiamine deficiency with very low thiamine concentrations in the CSF, probably caused by protracted vomiting and increased vitamin B1 consumption by intrathecal tumor cells. We believe that her neurologic symptoms were caused -- at least partly -- by thiamine deficiency, as she reacted well to thiamine supplementation at the beginning of treatment.

83. J Clin Invest. 1999 Mar;103(5):723-9.

Defective high-affinity thiamine transporter leads to cell death in thiamine-responsive megaloblastic anemia syndrome fibroblasts.

Stagg AR, Fleming JC, Baker MA, Sakamoto M, Cohen N, Neufeld EJ.

Division of Hematology/Oncology, Children's Hospital, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.

We have investigated the cellular pathology of the syndrome called thiamine-responsive megaloblastic anemia (TRMA) with diabetes and deafness. Cultured diploid fibroblasts were grown in thiamine-free medium and dialyzed serum. Normal fibroblasts survived indefinitely without supplemental thiamine, whereas patient cells died in 5-14 days (mean 9.5 days), and heterozygous cells survived for more than 30 days. TRMA fibroblasts were rescued from death with 10-30 nM thiamine (in the range of normal plasma thiamine concentrations). Positive terminal deoxynucleotide transferase-mediated dUTP nick end-labeling (TUNEL) staining suggested that cell death was due to apoptosis. We assessed cellular uptake of [3H]thiamine at submicromolar concentrations. Normal fibroblasts exhibited saturable, high-affinity thiamine uptake (Km 400-550 nM; Vmax 11 pmol/min/10(6) cells) in addition to a low-affinity unsaturable component. Mutant cells lacked detectable high-affinity uptake. At 30 nM thiamine, the rate of uptake of thiamine by TRMA fibroblasts was 10-fold less than that of wild-type, and cells from obligate heterozygotes had an intermediate phenotype. Transfection of TRMA fibroblasts with the yeast thiamine transporter gene THI10 prevented cell death when cells were grown in the absence of supplemental thiamine. We therefore propose that the primary abnormality in TRMA is absence of a high-affinity thiamine transporter and that low intracellular thiamine concentrations in the mutant cells cause biochemical abnormalities that lead to apoptotic cell death.

84. Mol Genet Metab. 1999 Mar;66(3):193-8.

Localization of the thiamine-responsive megaloblastic anemia syndrome locus to a 1.4-cM region of 1q23.

Banikazemi M, Diaz GA, Vossough P, Jalali M, Desnick RJ, Gelb BD.

Department of Human Genetics, Mount Sinai School of Medicine, New York, New York 10029, USA.

Thiamine-responsive megaloblastic anemia (TRMA) is a rare autosomal recessive syndrome characterized by megaloblastic anemia, deafness, and diabetes mellitus. A genome scan previously established linkage of this disorder to 1q23 and haplotype analysis defined a 16-cM critical region. Molecular genetic analyses of four unrelated multiplex Iranian families inheriting TRMA confirmed linkage to the same region and identified recombinant chromosomes which permitted refinement of the critical region to a narrow 1.4-cM interval. The haplotypes of the families differed, consistent with at least two independent mutational events. This refinement of the TRMA locus to less than 10% of that previously published should markedly facilitate the identification and evaluation of positional candidate and novel genes which may cause this disorder. Copyright 1999 Academic Press.

85. Lancet. 1999 Feb 13;353(9152):546-9.

Thiamine deficiency and malaria in adults from southeast Asia.

Krishna S, Taylor AM, Supanaranond W, Pukrittayakamee S, ter Kuile F, Tawfiq KM, Holloway PA, White NJ.

Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

BACKGROUND: Thiamine deficiency (beriberi) is common in some parts of southeast Asia. Acute thiamine deficiency can mimic many complications of malaria, such as encephalopathy and lactic acidosis. We examined the incidence of thiamine deficiency in adults admitted to hospital with malaria in Thailand. METHODS: For this prospective study, we recruited consecutive patients with malaria or other febrile illness who presented to Paholpolpayuhasena Hospital, Kanchanaburi, Thailand, between May and July, 1992. We used the activation coefficient (alpha) for transketolase activity in erythrocytes to measure thiamine deficiency (defined as alpha>1.31) in patients with severe and uncomplicated malaria and in controls (patients' relatives and healthy volunteers). To exclude the possibility of interference in the assays, transketolase activity was also measured in erythrocytes used to culture parasites. FINDINGS: 12 (52%) of 23 patients with severe malaria and ten (19%) of 54 patients with uncomplicated malaria had alpha values above the normal range (p<0.0001 and p=0.0014, respectively, compared with controls), which indicated severe thiamine deficiency. Thiamine deficiency was more severe in patients with cerebral malaria than in those with uncomplicated malaria and the controls (p=0.008). INTERPRETATION: In adults admitted to hospital in Thailand, thiamine deficiency commonly complicates acute falciparum malaria, particularly in severe infections, and could contribute to dysfunction of the central nervous system.

PIP: Beriberi or thiamine deficiency is common in countries where malaria is endemic. The hypotheses that subclinical thiamine deficiency complicates malaria and may be associated with lactic acidosis and coma were investigated in a prospective study conducted in Kanchanaburi, Thailand. 77 consecutive patients who presented to Paholpolpayuhasena Hospital between May and July 1992 with malaria or other febrile illnesses and 50 healthy relatives and volunteers were enrolled. The activation coefficient for transketolase activity in erythrocytes was used to measure thiamine deficiency. The mean Box-Cox transformed coefficients were 0.166 among cases with severe malaria (n = 23), 0.145 in cases with uncomplicated malaria (n = 54), 0.138 in healthy volunteers (n = 27), 0.137 in febrile controls (n = 10), and 0.122 in healthy relatives of patients (n = 13). 12 patients (52%) with severe malaria and 10 (19%) of those with uncomplicated malaria had coefficients above the normal range. Thiamine deficiency occurred in significantly more patients with cerebral malaria than in those with uncomplicated malaria (odds ratio, 4.8; 95% confidence interval, 1.68-13.8). The 12 patients who died from severe malaria had higher coefficient values than the 115 patients and controls who survived. Finally, the 15 patients with lactic acidosis had significantly higher coefficient values than those without this complication. A study of thiamine administration to patients with cerebral malaria is recommended to allow distinctions between the findings recorded in this study and the possibility of a causal link.

86. J Nutr. 1999 Feb;129(2):366-71.

Thiamine deficiency is prevalent in a selected group of urban Indonesian elderly people.

Andrade Juguan J, Lukito W, Schultink W.

SEAMEO-TROPMED Regional Center for Community Nutrition, University of Indonesia, Jakarta 10430, Indonesia.

This cross-sectional study involved 204 elderly individuals (93 males and 111 females). Subjects were randomly recruited using a list on which all 60-75 y-old-people living in seven sub-villages in Jakarta were included. The usual food intake was estimated using semiquantitative food frequency questionnaires. Hemoglobin, plasma retinol, vitamin B-12, red blood cell folate and the percentage stimulation of erythrocyte transketolase (ETK), as an indicator of thiamine status, were analyzed. Median energy intake was below the assessed requirement. More than 75% of the subjects had iron and thiamine intakes of approximately 2/3 of the recommended daily intake, and 20.2% of the study population had folate intake of approximately 2/3 of the recommended daily intake. Intakes of vitamins A and B-12 were adequate. Biochemical assessments demonstrated that 36.6% of the subjects had low thiamine levels (ETK stimulation > 25%). The elderly men tended to have lower thiamine levels than the elderly women. The overall prevalence of anemia was 28.9%, and the elderly women were affected more than the elderly men. Low biochemical status of vitamins A, B-12 and RBC folate was found in 5.4%, 8.8 % and 2.9% of the subjects, respectively. Dietary intakes of thiamine and folate were associated with ETK stimulation and plasma vitamin B-12 concentration (r = 0.176, P = 0.012 and r = 0.77, P = 0.001), respectively. Results of this study suggest that anemia, thiamine and possibly vitamin B-12 deficiency are prevalent in the elderly living in Indonesia. Clearly, micronutrient supplementation may be beneficial for the Indonesian elderly population living in underprivileged areas.

87. Gerontology. 1999;45(2):96-101.

Comment in: Gerontology. 2000 Sep-Oct;46(5):293.

Clinical relevance of thiamine status amongst hospitalized elderly patients.

Pepersack T, Garbusinski J, Robberecht J, Beyer I, Willems D, Fuss M.

Division of Geriatric Medicine, Brugmann University Hospital, Free University of Brussels, Belgium.

BACKGROUND: The prevalence and the consequences of thiamine deficiency among elderly patients admitted to acute geriatric wards are not known. OBJECTIVES: (1) To assess the prevalence of thiamine deficiency in patients admitted to a geriatric ward compared to age-matched ambulatory outpatients; (2) to identify their diseases and problems associated with thiamine deficiency, and (3) to determine the relationship between the thiamine status and the cognitive and functional status of these patients. MATERIALS AND METHODS: 118 aged hospitalized patients (83 +/- 7 years; mean age +/- SD) were prospectively enrolled on admission to the geriatric ward. Their cognitive status was assessed using the Mini-Mental State Examination (MMSE) and their ability to perform their activities of daily living (ADL) using ADL scales. The effect of exogenous thiamine pyrophosphate (TPP) addition on the blood transketolase (TK) activity (TPP TK effect) served to estimate thiamine deficiency. Socioeconomic data, diseases and treatment were identified as potential associated risk factors. This group of hospitalized patients was divided according to their thiamine status to characterize the conditions associated with thiamine deficiency. Thirty-five outpatients without any functional or cognitive impairment served as a control group. RESULTS: Of 118 inpatients, 46 (39%) presented with a TPP TK effect of >15%, and 6 with values of >22%, indicating moderate and severe thiamine deficiency, respectively. Only 6 of 30 outpatients (20%) exhibited a TPP TK effect of >15% and none of them reached values of >18%. Although it tended to be lower in outpatients, the mean TPP TK effect did not statistically differ from the mean of inpatients. Thiamine-deficient inpatients comprised a larger proportion of institutionalized subjects than nondeficient inpatients (87 versus 47%, p < 0.001). Functional status, cognitive functions and the occurrence of delirium did not differ according to their thiamine status. By contrast, thiamine-deficient inpatients exhibited a higher proportion of Alzheimer's disease, depression, cardiac failure and falls. Furosemide was more frequently taken by thiamine-deficient patients. CONCLUSIONS: Severe thiamine deficiency remained quite low among the hospitalized elderly. The prevalence of moderate thiamine deficiency approached 40%. Institutionalized subjects were at particular risk of developing thiamine deficiency. Its clinical relevance on functional status and on cognitive function remained not significant. By contrast, a high proportion of falls, Alzheimer's disease, depression, cardiac failure and furosemide use could have been related to thiamine deficiency.

88. Schweiz Med Wochenschr. 1998 Oct 31;128(44):1743-4.

Anaphylaxis to parenteral thiamine (vitamin B1).

Morinville V, Jeannet-Peter N, Hauser C.

Unite d'allergologie, Hopital cantonal universitaire, Geneve.

Anaphylaxis as an adverse systemic reaction to thiamine (vitamin B1) has been described in the literature since 1938. Although its precise mechanism is still uncertain, the reaction appears to involve immediate type hypersensitivity and to be exclusively related to parenteral administration. The following case report is a reminder of this reaction to thiamine which may be administered by general practitioners, emergency physicians and internists.

89. J Neurosurg. 1998 Dec;89(6):1025-8.

Thiamine-deficient lactic acidosis with brain tumor treatment. Report of three cases.

Kuba H, Inamura T, Ikezaki K, Kawashima M, Fukui M.

Department of Neurosurgery, Neurological Institute, Faculty of Medicine, Kyushu University, Fukuoka, Japan.

Lactic acidosis due to thiamine deficiency is known to complicate chemotherapy and radiotherapy treatment of malignant extracranial tumors, but to the authors' knowledge, this complication has not been reported in patients treated for malignant brain tumors. They report three such cases, demonstrating that this complication can occur during treatment of brain tumors. In all patients, consciousness levels deteriorated within 1 to 2 days. Serum lactic acid levels increased to concentrations between 62 and 96.7 mg/dl, resulting in severe metabolic acidosis. A low blood thiamine level (9 ng/ml) was demonstrated at the onset in one case, and high-dose thiamine infusions dramatically improved lactic acidemia as well as impairment of consciousness in two cases. In the other case, hydrocephalus was suspected initially, resulting in a delay in thiamine supplementation. Clinical differentiation of this form of lactic acidosis from hydrocephalus or tumor progression can be very difficult in a patient undergoing treatment for a malignant brain tumor. Demand for thiamine is thought to be increased in patients with malignant brain tumors, and supplemental thiamine during treatment is necessary to prevent lactic acidosis. When this complication occurs, immediate treatment with sufficient thiamine is essential, together with normalization of pH by using sodium bicarbonate. With timely intervention, the level of consciousness can recover to the preacidotic state with no new neurological deficits.

90. Tidsskr Nor Laegeforen. 1998 Oct 20;118(25):3946-9.

[Thiamine treatment today]

[Article in Norwegian]

Tallaksen CM, Bovim G.

Nevrologisk avdeling, Rikshospitalet, Oslo.

This article reviews some of the established data on thiamin and the most common symptoms of deficiency. Guidelines for appropriate therapy are offered. Thiamin or vitamin B1 was among the first vitamins to be discovered. Beriberi was the first disease to be associated with thiamin deficiency, and Wernicke's encephalopathy was shown to respond to thiamin treatment a few years later. However, thiamin treatment remains inadequate or delayed. Treatment is efficient in the early stages, but delays often causes permanent damage. It is important that all physicians are aware of what patients are susceptible to develop thiamin deficiency and that they recognize the symptoms as early as possible.

91. Am J Clin Nutr. 1998 Nov;68(5):1075-80.

Folic acid, riboflavin, thiamine, and vitamin B-6 status of a group of first-time blood donors.

Booth CK, Clark T, Fenn A.

School of Public Health, Queensland University of Technology, Red Hill, Australia. christine.booth@dsto.defence.gov.au

Reference intervals for long-term status measures of folate, riboflavin, thiamine, and vitamin B-6 were determined in a select group of adults. Reference subjects had no adverse medical history and did not use tobacco, alcohol, or nutritional supplements, and their diets met > or =70% of the Australian recommended dietary intake for nutrients. Red blood cell concentrations of thiamine and folate were measured by microbiological methods. Vitamin B-6 and riboflavin status were measured on the basis of the erythrocyte aspartate transaminase activity coefficient and erythrocyte glutathione reductase activity coefficient, respectively. A survey of first-time blood donors, which was conducted in Australia in 1995, revealed a significant prevalence of low red blood cell thiamine concentrations (13%) when compared with the calculated normal reference intervals. However, the most important finding in the survey was that the group of healthy, nonanemic adults (first-time blood donors) was found to have a median red blood cell folate concentration 24% below the median concentration of the carefully selected (nonsupplemented) reference group. Plasma total homocysteine concentrations indicated folate deficiency in the reference group. Therefore, the 2.5th percentile cutoff for reference group red blood cell folate concentrations may have underestimated the prevalence of folate deficiency in the survey group. These data, coupled with the lack of Australian food-composition data for folate in particular, reinforce the need for monitoring nutritional status by both dietary and biochemical means. We recommend consideration of mandatory fortification of the Australian food supply with folic acid.

92. Diabetologia. 1998 Oct;41(10):1168-75.

The association of dietary fibres with glucose tolerance is partly explained by concomitant intake of thiamine: the Hoorn Study.

Bakker SJ, Hoogeveen EK, Nijpels G, Kostense PJ, Dekker JM, Gans RO, Heine RJ.

Institute for Endocrinology, Reproduction and Metabolism, University Hospital Vrije Universiteit, Amsterdam, The Netherlands.

Epidemiologic studies have shown an association between the intake of dietary fibres and 2-h glucose values. Food rich in dietary fibres is often also rich in thiamine. Animal studies have shown that thiamine deficiency can induce glucose intolerance. Our aim was to investigate the association between fibre consumption and thiamine intake on the one hand and glucose tolerance on the other hand. We used data from the Hoorn Study, a study of glucose tolerance among 1008 men and 1188 women, aged 50-75 years, without diabetes. In linear regression analyses, fibre intake was inversely associated with fasting glucose. There was also an inverse association between fibre intake and 2-h glucose but it disappeared for the greater part after adjustment for fasting glucose. Fibre intake appeared to be strongly correlated with thiamine intake, and this correlation explained the remaining part of the association between fibre intake and 2-h glucose. Thiamine intake appeared to have a strong and relevant association with 2-h glucose, which was independent of fibre intake and fasting glucose. This association was borderline after adjustment for potential confounders. In women, but not in men, the effect of thiamine intake, independent of potential confounders. In conclusion, part of the association between fibre intake and glucose tolerance is possibly attributable to concomitant thiamine intake.

93. Br J Haematol. 1998 Sep;102(4):1098-100.

Thiamine-responsive myelodysplasia.

Bazarbachi A, Muakkit S, Ayas M, Taher A, Salem Z, Solh H, Haidar JH.

Department of Internal Medicine, American University of Beirut, Lebanon.

The triad of thiamine-responsive anaemia, diabetes mellitus and deafness has been reported in 15 patients with macrocytic anaemia, sometimes associated with moderate thrombocytopenia. The bone marrow aspirate usually shows megaloblastic changes and ringed sideroblasts. However, tri-lineage myelodysplasia has never been reported. We describe two patients who presented with diabetes, deafness and thiamine-responsive pancytopenia. Bone marrow aspirate and biopsy were typical of tri-lineage myelodysplasia. These findings suggest that thiamine may have a role in the regulation of haemopoiesis at the stem cell level. We propose the term 'thiamine-responsive myelodysplasia' rather than that of thiamine-responsive anaemia.

94. Biochem Biophys Res Commun. 1998 Aug 28;249(3):745-53.

An allosteric drug, o,o'-bismyristoyl thiamine disulfide, suppresses HIV-1 replication through prevention of nuclear translocation of both HIV-1 Tat and NF-kappa B.

Shoji S, Furuishi K, Ogata A, Yamataka K, Tachibana K, Mukai R, Uda A, Harano K, Matsushita S, Misumi S.

Department of Biochemistry, Faculty of Pharmaceutical Sciences, Kumamoto University, Japan. shoji@gpo.kumamoto-u.ac.jp

The efficacy of o,o'-bismyristoyl thiamine disulfide (BMT) was examined in detail against HIV-1 laboratory isolates (HTLV-IIIB, JRFL, and MN), primary isolates (KMT and KMO), and simian immunodeficiency virus (SIVmac251) in vitro. BMT inhibited the replication of HIV-1 in both laboratory and primary isolates in vitro. In addition, BMT exhibited antiviral activity against SIVmac251. Minimizing energy studies of BMT structure reveal that a trans-disulfide of thiamine (holo drug) disulfide (TDS, protodrug) is allosterically transited to the reactive twisted disulfide of BMT (allo drug) by o,o'-bismyristoyl esterification of TDS. BMT inhibits nuclear translocation of both HIV-1 transactivator (TAT) and the cellular transcriptional nuclear factor-KB (NF-kappa B), resulting in the suppression of HIV-1 replication.

95. Eur J Pediatr. 1998 Aug;157(8):648-52.

Thiamine-responsive lactic acidaemia: role of pyruvate dehydrogenase complex.

Naito E, Ito M, Yokota I, Saijo T, Matsuda J, Kuroda Y.

Department of Paediatrics, School of Medicine, University of Tokushima, Japan.

Lactic acidaemia is sometimes associated with a defect of the pyruvate dehydrogenase complex (PDHC), catalysing the thiamine-dependent decarboxylation of pyruvate. The activity of PDHC for different thiamine pyrophosphate (TPP) concentrations was determined in 13 patients with lactic acidaemia, clinically responsive to thiamine treatment in order to assess the role of PDHC in the aetiology of thiamine-responsive lactic acidaemia. Culture of lymphoblastoid cells and skin fibroblasts and muscle biopsies were performed in these 13 patients. The activity of PDHC to sodium dichloroacetate (DCA), known as the activator of PDHC, was also examined. Three groups were identified according to PDHC activity. Group 1 (two patients) displayed very low PDHC activity, which was not increased by DCA. This PDHC activity increased at high TPP concentrations. Group 2 (five patients) displayed below normal PDHC activity at low TPP concentrations, increased by DCA. This PDHC activity became normal at high TPP concentrations. PDHC deficiency in these patients of groups 1 and 2 was due to a decreased affinity of PDHC for TPP. Group 3 included six patients with normal PDHC activity at low as well as high TPP concentrations. This PDHC activity was increased by DCA. CONCLUSION: High concentrations of TPP may be required for maximal activity of PDHC in some patients with lactic acidaemia. The assay of PDHC activity, performed at a low concentration of TPP (1 x 10(-4)mM) allows selection of patients with thiamine-responsive lactic acidaemia.

96. Cardiol Young. 1998 Jan;8(1):113-5.

Thiamine deficiency mimicking acute rejection following cardiac transplantation.

Gennery AR, Bartlett K, Hasan A.

Department of Paediatric Cardiology, Freeman Hospital, High Heaton, UK.

We describe a recipient of an orthotopic cardiac transplant who developed severe ventricular dysfunction following an episode of sepsis. He had normal cardiac biopsies and responded to treatment with thiamine. Causes other than rejection should be considered in patients who have received a cardiac transplant and who present in cardiac failure.

97. Rev Mal Respir. 1998 Jun;15(3):303-4.

[Thiamine deficiency. A cause of cardiac insufficiency not to be ignored]

[Article in French]

Beaud C, Fuhrman C, Perchet H, Monnet I, Chouaid C, Housset B.

Service de Pneumologie, Hospitalier Intercommunal de Creteil.

Thiamine deficiency is one of the classical causes of high out put for heart failure. Deficiency of this vitamin may be nutritional or secondary to alcoholic intoxication. We felt it would be interesting to describe a typical case of cardiac beriberi in order to recall the clinical presentation and the pathophysiology.

98. Med J Aust. 1998 Jun 1;168(11):542-5.

Comment in: Med J Aust. 1998 Jun 1;168(11):534-5.

Prevalence of Wernicke-Korsakoff syndrome in Australia: has thiamine fortification made a difference?

Harper CG, Sheedy DL, Lara AI, Garrick TM, Hilton JM, Raisanen J.

Department of Pathology, University of Sydney, NSW. cliveh@pathology.su.oz.au

OBJECTIVE: To determine the prevalence of the Wernicke-Korsakoff syndrome (WKS) in Australia and compare this with previous studies. DESIGN AND SETTING: Prospective autopsy study at the New South Wales Institute of Forensic Medicine, 1996-1997. METHODS: Brains of deceased people (aged over 15 years) derived from 2212 sequential autopsies performed between 1 January 1996 and 31 December 1997 were studied macroscopically and microscopically to identify cases of WKS. MAIN OUTCOME MEASURES: Standard histological criteria for WKS and any available clinical data. RESULTS: Twenty-five cases of WKS were identified (prevalence, 1.1%), mostly among the 5.9% of the 2212 people who had a history suggestive of alcohol abuse. Only four cases (16%) had been diagnosed during life. CONCLUSIONS: There has been a significant reduction in the prevalence of WKS in Australia since the introduction of thiamine enrichment of bread flour. While the prevalence is still higher than in most other Western countries, further research is needed before adding thiamine to alcoholic beverages can be recommended.

99. Int J Clin Pharmacol Ther. 1998 Apr;36(4):216-21.

Comparative bioavailability of various thiamine derivatives after oral administration.

Greb A, Bitsch R.

Department of Human Nutrition, Institute of Nutrition and Environment, Friedrich Schiller University, Jena, Germany.

In a multiple change-over study the bioequivalence of 3 thiamine preparations, used therapeutically as neurotropic agents for the treatment of polyneuropathies, was tested in a collective of 7 volunteers. After ingestion of a single dose of either 100 mg benfotiamin CS-benzoylthiamine-o-monophosphate), fursultiamin (thiamintetrahydrofurfuryldisulfide) or thiaminedisulfide, thiamine blood levels were analyzed for a 10-hour period. Thiamine was measured by HPLC after precolumn derivatization to thiochrome. The maximal thiamine concentration Cmax and its time (tmax) in plasma and hemolysate, the area under concentration time curve (AUC), and thiamine excretion in 24-hour urine were assessed as criteria of bioavailability. Additionally the erythrocytic transketolase activity (ETK) and alphaETK were determined as indicators of the cellular thiamine availability. After benfotiamin ingestion a more rapid and earlier increase of thiamine in plasma and hemolysate was observed in contrast to fursultiamin and the disulfide. All biokinetic data demonstrated a significantly improved thiamine bioavailability from benfotiamin compared with the other preparations. The lowest bioavailability was detected with thiamindisulfide. From our results it can be concluded that oral administration of benfotiamin is best suitable for therapeutical purposes owing to its excellent absorption characteristics.

100. J Nutr. 1998 Apr;128(4):683-7.

Erratum in: J Nutr 1998 Jul;128(7):1247.

Thiamine deficiency decreases steady-state transketolase and pyruvate dehydrogenase but not alpha-ketoglutarate dehydrogenase mRNA levels in three human cell types.

Pekovich SR, Martin PR, Singleton CK.

Department of Molecular Biology, Vanderbilt University, Nashville, TN 37235, USA.

Reductions in the levels and activities of enzymes that utilize thiamine diphosphate (ThDP) as a cofactor are thought to be responsible for the tissue damage suffered during thiamine deficiency. Although loss of cofactor can account in part for loss of enzyme activity, thiamine and its phosphorylated derivatives may also regulate the expression of the genes encoding these proteins. To examine this possibility, steady-state mRNA levels for three ThDP-dependent enzymes were measured in human fibroblasts, lymphoblasts and neuroblastoma cells cultured under conditions of thiamine sufficiency and deficiency. In all three cell types, the mRNA levels of transketolase and the E1beta subunit of pyruvate dehydrogenase complex were lower in thiamine-deficient cultures. In contrast, mRNA levels for a ThDP-binding subunit of alpha-ketoglutarate dehydrogenase, the E1 subunit did not differ. These results indicate that thiamine or a thiamine metabolite regulates the expression in humans of some, but not all, genes encoding ThDP-utilizing enzymes.