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Thiamin addition to alcohol

Note: This report represents information on this subject as of December 1996.

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Resolution 515, "Thiamin Addition to Alcohol," introduced by the Medical Student Section and adopted at the 1995 Annual Meeting, asked the American Medical Association (AMA) to review the scientific basis for adding thiamin or allithiamin to alcoholic beverages for the prevention of Wernicke-Korsakoff syndrome.

Wernicke-Korsakoff Syndrome

Neurologic disorders are common among chronic alcohol abusers. Wernicke in 1881 described the behavioral and pathologic signs of an acute superior hemorrhagic polioencephalitis (Wernicke's encephalopathy) afflicting alcoholics.1 The most common symptoms of Wernicke's encephalopathy include lethargy, fatigue, apathy, impaired awareness, loss of equilibrium, disorientation, difficulty concentrating, retrograde amnesia (loss of previous memories), ophthalmoplegia of varying types and degrees, anorexia, muscular weakness, peripheral numbness, paresthesia, and ataxia.2-5 Six years later, Korsakoff identified a syndrome characterized by disorientation, hallucinations, confabulation, and memory loss6; Korsakoff's psychosis has since been recognized to include perceptual impairments, impaired linguistic processing, anterograde amnesia (inability to form new memories), and global intellectual impairment similar to pre-senile dementia or the dementia of Alzheimer's disease.7-10 It is now recognized that Wernicke-Korsakoff syndrome (WKS) represents a continuum from mild to severe brain damage. Most cases of WKS (80 percent to 90 percent) occur among chronic alcohol abusers,8 with an estimated incidence of up to 12 percent among these individuals (total number of cases in U.S.: approximately 1.5 to 2 million).4,11,12 No estimates of the costs of treatment of these individuals are available. In its most severe form, WKS with ophthalmoplegia, ataxia, and disordered consciousness progresses to death in up to 20 percent of severely affected individuals.2,3

Wernicke described pathological changes in the grey matter, including numerous punctate lesions of the third and fourth ventricles and the aqueduct of Sylvius, and others have noted decreased Purkinje cell density in the folia of the superior cerebellar vermis with increased numbers of Bergmann glia; thinning of the vermis with concomitant astrocytic proliferation; increased pericerebral space; cell death and hemorrhages in the hypothalamic nucleus, mammillary bodies, and other diencephalic nuclei; axonal demyelination and degeneration; and eosinophilic cerebellar neurons.2,8,11,13-15 The hippocampus and the surrounding mesial temporal lobe (limbic structures involved in learning and memory) also may be damaged.16,17 Cerebral glucose utilization (demonstrated via positron emission tomography with 2-fluoro-2-deoxyglucose) is decreased in the cingulate and precuneate areas.18 Computed tomography has revealed evidence of shrinkage of frontal brain regions (enlarged third and lateral ventricles, wider interhemispheric fissures).19 There may be diffuse slowing of the EEG.3

Possible nutritional etiologies of WKS

WKS often occurs as part of the triad of polyneuropathy, chronic malnutrition, and alcoholism.2,3 Interestingly, the incidence of WKS decreased by 70 percent to 80 percent during the Prohibition era.20 The clinical and pathologic manifestations shared by WKS and chronic thiamin deficiency (beri-beri) have led many neurologists and nutritionists (although not all21) to conclude that the anterograde amnesia, diencephalic lesions, and cortical lesions of WKS result primarily from chronic thiamin deficiency, possibly in concert with direct toxic effects of chronic alcohol abuse.10,22-25

Thiamin and thiamin deficiency

Thiamin (vitamin B1) is a required nutrient. Following gastrointestinal absorption, thiamin is polyphosphorylated by thiamin pyrophosphokinase in the liver, kidneys, and leukocytes to thiamin pyrophosphate (TPP), an essential cofactor in several classes of enzymatic reactions. Two such reactions (conversions of pyruvate to acetyl-CoA by pyruvate dehydrogenase and of

±-ketoglutarate to succinyl CoA by ±-ketoglutarate dehydrogenase) are essential to energy production and neuronal function in the brain.8 In addition, cleavage of ±-keto-sugars by transketolase of the hexose monophosphate (pentose phosphate) shunt is required for the production of myelin.8 Furthermore, thiamin may directly participate in the maintenance of the excitability of neurons and in the conduction of nerve impulses.26-29

Thiamin deficiency uncomplicated by alcohol abuse is characterized in humans by increased plasma concentrations of pyruvate and lactate, decreased transketolase activity, and clinical manifestations of beri-beri (lethargy, fatigue, apathy, impaired awareness, loss of equilibrium, disorientation, difficulty concentrating, memory loss, ophthalmoplegia of varying types and degrees, anorexia, muscular weakness, peripheral numbness, paresthesia and ataxia).30,31 Pathologic findings in chronic thiamin deficiency among nonalcoholics are similar (but not identical) to those of WKS, and include necrosis of neurons; distal degeneration of myelin sheaths; axonal deterioration in periventricular areas, mammillary bodies, the superior cerebellar vermis, and various hypothalamic and vestibular nuclei; and cerebellar lactic acidosis.32,33

Primary thiamin deficiency can result from a number of causes, including inadequate thiamin intake and general malnutrition. Secondary thiamin deficiency can be caused by ethanol-induced destruction of intestinal mucosa with inhibition of thiamin absorption34 (gastrointestinal absorption of ingested thiamin is reduced by up to 90 percent by chronic alcohol abuse35), chronic diarrhea, persistent vomiting,36 and hyperemesis gravidarum.37,38 In addition, thiamin availability can become inadequate in the presence of hepatic disease (which interferes with thiamin metabolism and reduces thiamin storage capacity), ethanol-induced acceleration of cerebellar metabolism of thiamin,39 ethanol-induced inhibition of thiamin pyrophosphokinase and of renal tubular reabsorption of filtered thiamin,5,40 and furosemide therapy.41 Because folic acid facilitates thiamin absorption, dietary folate deficiency can reduce the efficiency of thiamin absorption.42 Concurrent magnesium deficiency also may induce clinical signs of thiamin deficiency; magnesium also is a required cofactor in several thiamin-dependent transphosphorylations. A number of other disorders that may affect thiamin bioavailability or metabolism, including gastrointestinal carcinoma, AIDS, anorexia, multiple organ failure syndrome, and rapid parenteral carbohydrate loading, also may trigger polyneuropathy indistinguishable from WKS.2,10,22,43-45

Animal models of thiamin deficiency and WKS

Consistent with the hypothesis that WKS represents a form of thiamin deficiency, thiamin deficiency can result in demyelination and lesions in the cerebellum, thalamus, mammillary body, and basal ganglia in rhesus monkeys.8 These lesions often are accompanied by anorexia, uncoordinated gait, abnormal eye movement, confusion, and memory loss. In addition, daily administration of pyrithiamin (a competitive inhibitor of thiamin pyrophosphokinase) to rats results in diminished central stores of both thiamin and TPP; decreased cerebellar ±-ketoglutarate dehydrogenase activity (and therefore decreased aerobic glycolysis); increased cerebellar concentrations of lactate, alanine, and glutamate; lesions in the mammillary bodies, hypothalamus, lateral vestibular nucleus, intralaminar thalamic nuclei, inferior olivary nucleus, and cerebellum similar to those in human WKS; and impaired learning.32,44,46-51

Thiamin-based therapy for WKS

In humans, either thiamin deficiency alone or alcoholism alone cause only mild encephalopathy; in combination they cause permanent neuronal damage that can progress to psychosis and that is refractory to simple thiamin therapy. Nonetheless, there have been reports that administration of thiamin to humans with mild WKS improves symptoms within one week and results in apparently complete recovery in most patients within one year of the initiation of continued treatment (unless alcohol abuse is resumed).10 Effective daily doses of thiamin range from 100 to 250 mg IV or IM2,10,41 and up to 500 mg/day orally.3 These minimum therapeutic doses are equivalent to 100 to 500 times the adult Recommended Dietary Allowance (RDA) for thiamin (1 to 1.5 mg, depending on age and gender52) and are consistent with the pretreatment presence of prolonged chronic thiamin deficiency sufficient to produce frank beri-beri and potentiate the destructive effects of chronic alcohol abuse.24

Fortification of alcoholic beverages with thiamin

The similarities between WKS and beri-beri, and the thiamin-responsive nature of most cases of WKS, have been taken by some public health officials to suggest that prevention of WKS among chronic alcohol abusers may be achieved simply by assuring the daily intake of 1 to 2 mg of thiamin.53 However, because chronic malnutrition and thiamin malabsorption are endemic among chronic alcohol abusers,53 reliance on adequate dietary intakes of thiamin, thiamin supplementation, or fortification of foods with thiamin may be of very limited success. Alcoholic beverages themselves provide virtually no thiamin; even if the bioavailability of thiamin in such beverages was very high, daily intakes of more than 8 L of whiskey or bourbon, 35 L of beer, or 100 L of port wine or vodka would be needed to satisfy the average adult RDA of about 1.2 mg/day.54,55 Because the bioavailability of thiamin is at most only 4 percent to 5 percent among chronic alcohol abusers,35,56,57 unfortified alcoholic beverages cannot be considered dietary sources of thiamin for these individuals.

An alternative would be to provide supplementary thiamin via the main caloric source of these individuals (alcoholic beverages). Consequently, there have been several proposals to fortify such beverages with prophylactic amounts of thiamin.20,24,25,58,59 The National Health and Medical Research Council of Australia recommended fortification of alcoholic beverages with thiamin in 198724; restoration of the amount of thiamin lost during fermentation or other processing (less than 0.15 mg/L60) was considered to be of insignificant potential benefit. Thiamin fortification of beer has been recommended at a level of 1.35 mg/L, which was estimated to provide an average of 4 to 8 mg of thiamin daily to heavy drinkers.60 Fortification of other alcoholic beverages was recommended at levels estimated to result in similar supplemental intakes of thiamin. However, it has been estimated that these levels of fortification fail to account for ethanol-associated reduction in thiamin bioavailability and were too low.20 In an attempt to account for reduced bioavailability, it has been recommended that thiamin be added to beer at 7.5 mg/L, wine at 15 mg/L, and liquors at 60 mg/L.20

The fortification of alcoholic beverages with thiamin is technically feasible. The solubility of thiamin is greatest at the pH range of most alcoholic beverages (3 to 4), and the stability of thiamin in alcoholic mixtures is acceptable.61 Stored at room temperature, thiamin added to beer, wine, or whiskey is 100 percent recoverable after 6 months62 and is 90 percent recoverable after 1 year.63 The impact of these data on required levels of fortification is minimal. In addition, it has been reported that the presence of thiamin does not cause changes in the taste of alcoholic beverages, even at concentrations well above those under consideration.24

Regulatory issues concerning the fortification and labeling of alcoholic beverages fall under the authority of the Bureau of Alcohol, Tobacco, and Firearms (ATF; Federal Alcohol Administration Act of 1986, Section 5). The Food and Drug Administration has agreed that this responsibility resides within the ATF in a Memorandum of Understanding dated November, 1987 (CPG 7155g.04). Current ATF policy does not permit the fortification of alcoholic beverages with vitamins; however, reversal of this policy position would be consistent with the Fortification Policy of the FDA (21 CFR 104.20(b)), which states that nutrients, including thiamin, "...may appropriately be added to a food to correct a dietary insufficiency recognized by the scientific community to exist and known to result in nutritional deficiency disease if: (1) Sufficient information is available to identify the nutritional problem and the affected population groups, and the food is suitable to act as a vehicle for the added nutrients...."

An objection to proposals to fortify alcoholic beverages with thiamin is based on the poor bioavailability of naturally occurring, water-soluble forms of thiamin in the chronic alcohol abuser.56 In contrast, it has been reported that the partially lipid soluble forms of thiamin (the allithiamins, thiamin propyl disulfide and thiamin tetrahydrofurfuryl disulfide) taken orally are efficiently absorbed by both alcoholics and nonalcoholics (with bioavailabilities of around 50 percent35 and nearly 100 percent,64 respectively) and are as able to improve indices of thiamin status as are parenteral injections of water-soluble thiamin HCl.64,65 It has been recommended that allithiamins be added to liquors at 6 mg/L, wine at 1.5 mg/L, and beers at 0.75 mg/L.20

Other objections to the fortification of alcoholic beverages with nutrients include concern that the marketing of vitamin-enriched beverages could result in the inference that such beverages either are being recommended for health reasons or are safer or healthier than unenriched beverages; this may result in failure to realize the goals of the fortification program if alcoholic beverage intake rises markedly among the target population. AMA Policy 150.992 (AMA Policy Compendium) "Nutritive Quality of Processed Foods", suggests that fortification requires a clear scientific rationale with a high degree of likelihood that the result of the fortification program will be the prevention of the condition associated with a lack of such fortification. Unfortunately, despite the recommendation of the National Health and Medical Research Council of Australia,24 the potential benefits of thiamin fortification of alcoholic beverages on the reduction of the incidence of beri-beri or WKS among chronic alcohol abusers have never been examined in a large-scale clinical trial or on a population-wide basis. In addition, the relative cost-effectiveness of a harm reduction approach to the prevention of WKS is unknown.

These issues do not appear to be fully resolved at this time. However, fortification of alcoholic beverages should not be dismissed summarily, particularly in view of the potential to prevent behavioral abnormalities that accompany alcohol abuse and that impede successful adoption of alcohol-avoidance behaviors. However, such a program would do virtually nothing to address the broader issues of chronic malnutrition and compromised health among chronic alcohol abusers.

Recommendations

The following statements, recommended by the Council on Scientific Affairs, were adopted by the AMA House of Delegates as AMA policy at the 1996 AMA Interim Meeting.

The AMA:

  1. Encourages appropriate local, state and federal agencies to increase their efforts to: (a) improve the overall nutritional and health status of individuals with alcohol dependency; and (b) reduce alcohol dependency; and
  2. Encourages appropriate well-designed studies to evaluate the effectiveness and cost-effectiveness of adding thiamin to alcoholic beverages to prevent Wernicke-Korsokoff syndrome.

References

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