Review
Malnutrition is common in chronic alcoholics. Hypocalcemia, hyponatremia, hypokalemia and, hypophosphatemia have all been associated with chronic alcoholism. Alcohol intake is also associated with low serum magnesium, selenium and zinc levels. Water-soluble vitamins, such as vitamin B1, B2, B3, B6, B9 and C, and fat-soluble vitamins, such as vitamin A, D, E and K have also been reported to be deficient in alcoholics. General causes of malnutrition in alcoholics are inadequate nutrient, particularly lack of water-soluble vitamins in their diet, reduced uptake, impaired utilization, increased requirements of nutrients and genetic predisposition to nutrient deficiency. Nutrient deficiencies are, therefore, a virtually inevitable consequence of alcohol abuse, not only because alcohol displaces food, but also because alcohol directly interferes with the body's use of nutrients, making them ineffective even if they are present. Chronic alcoholics exhibit a number of neurological disorders which are related to nutritional deficiencies, in particular vitamin deficiencies that are essential for normal cerebral functioning. Specific vitamin and nutrient deficiencies arising in chronic alcoholics may result in severe functional impairment and tissue damage, mainly neuronal and vascular, in the brain. Nutritional deficiency in alcoholics also causes neurotransmitter dysfunction, ion channel dysfunction, oxidative stress and metabolic dysfunction in the brain. Nutritional deficiency in chronic alcoholics frequently leads to a mild to moderate cognitive impairment, including impairment in perceptual-motor skills, visual-spatial functions, learning/memory, and abstraction and problem solving. There are a number of nutritional deficiencies which need to be cared for but magnesium, thiamine, and other B vitamins need to be administered immediately. Nutritional therapy can aid in the recovery from alcoholism. Patients who have received nutritional therapy reported significantly less alcohol craving as well as significantly greater nutrient intakes, and a greater number abstained from alcohol. Although abstinence and proper nutrition remain the cornerstones of treatment, pharmacological modification of neurotransmitter function and/or enhancement of cerebral metabolism combined with behavioral methods may also be beneficial.
Correspondence: Ihn-Geun Choi, MD, PhD, Department of Neuropsychiatry, Hallym University, Han-Gang Sacred Heart Hospital, 94-200 Youngdungpo-dong, Youngdungpo-gu, Seoul 150-719, Korea
Tel: +82-2-2639-5461, Fax: +82-2677-9095, E-mail: ihngeun@hallym.or.kr
Malnutrition is common in chronic alcoholics, although its severity may depend on the social characteristics of the patient group under study and their severity of alcohol dependence1. Alcoholics represent the largest group of patients with treatable nutritional disorders in Western countries2.
Approximately 20-50% of individuals admitted to the hospital for alcohol withdrawal or Laennec's cirrhosis have been found to be hypocalcemic, and severe, symptomatic hypocalcemia is often seen in seriously ill alcoholics3. As many as 40% of decompensated cirrhotics may also manifest significant hyponatremia at the time of hospitalization4. Hypokalemia is also common in patients with alcoholic liver disease5. Hypokalemia is seen in approximately 50% of chronic alcoholics who are hospitalized for acute alcohol with-drawal and usually develops after their hospitalization. However, hypokalemia common in alcoholics does not always represent true potassium depletion. Although most cirrhotics have a diminished total body potassium content, intracellular potassium concentration is usually normal4. A number of studies have recorded low inorganic phosphorus concentrations in chronic alcoholics6,7. On admission, 30% of patients with chronic alcoholism had hypophosphatemia8.
Alcoholism is the most commonly recognized cause of disturbed magnesium balance. Alcohol intake per drinking day correlated negatively with serum magnesium9.
Approximately 25-50% of the patients hospitalized for alcohol related problems are hypomagnesemic3. Low serum magnesium concentrations are frequently encountered especially during acute alcohol withdrawal10. Alcohol intake is also associated with low serum selenium levels. Among alcoholics admitted for detoxification, selenium was diminished despite the absence of severe malnutrition, as depressed blood selenium levels occur frequently in patients with chronic heavy ethanol ingestion even in the absence of severe liver disease or overt malnutrition11,12. Among males, alcohol intake per drinking day correlated negatively with serum selenium. Among females, serum selenium concentration had a significant negative correlation with average daily alcohol intake, but not with alcohol intake per drinking day9.
Chronic alcoholism is also associated with low serum zinc level13. Low plasma, erythrocyte and hepatic zinc concentrations also follow chronic ingestion of alcohol22. Zinc values were also low in patients suffering from alcoholic cirrhosis23. The depression of zinc levels was related to the severity of the hepatic lesions, the lowest levels being observed among cirrhotics. Female alcoholics were more severely affected than males with respect to their zinc levels, although they consumed lesser amounts of alcohol and had a shorter duration of alcohol intake24. However, there is no indication for zinc supplementation in well-nourished alcoholics25, because the nutritional state of the alcoholics alone may not be an adequate explanation for their low serum zinc level26. A reduction in zinc concentration occurs in the central nervous system of chronic alcoholics27. It was shown that involuntary intoxication
of rats with 10% ethanol solution for 8 months caused a reduction in zinc
content in the brain28.
Thiamin deficiency, either overt or subclinical, has been reported in 30-80% of alcoholics14. Erythrocyte transketolase determination can be used to indicate a functional deficiency of thiamin18. Thirty-eight percent of alcoholics showed significant erythrocyte transketolase activation deficits indicative of severe thiamine deficiency29. Riboflavin deficiency is recognized as a common complication of chronic alcoholism15. Furthermore, pyridoxine deficiency, as measured by low plasma pyridoxal-5'-phosphate (PLP), was observed in more than 50% of alcoholics without abnormal hematologic indices of abnormal liver function17. Vitamin
B12 deficiency was rarely seen in chronic alcoholics30. Folic acid deficiency, either overt or subclinical, has been reported in 6-80% of alcoholics14. Folate deficiency is common in "derelict" chronic alcoholics with inadequate diet16,30. Evidence of niacin deficiency is difficult to detect in alcoholics5. However, low circulating levels of nicotinic acid have been reported in 35% of chronic alcoholics16. Vitamin C is deficient in alcoholics with and without liver disease31. It was found that acute ethanol intoxication was accompanied by a decrease in the ascorbic acid content in the brain, liver and kidneys32.
Deficiencies of the fat-soluble vitamins A, D and E are not frequently reported in alcoholics without significant liver and/or pancreatic disease14. Alcoholics had significantly lower serum concentrations of vitamin A compared to a control group of healthy subjects. The depression of vitamin A levels was related to the severity of the hepatic lesions, the lowest levels being observed among cirrhotics. Female alcoholics were more severely affected than males with respect to their vitamin A levels, although they consumed lesser amounts of alcohol and had a shorter duration of alcohol intake24. Marrakchi et al33. suggest that attention should be paid to the vitamin A deficiency in erythrodermic or pustular psoriasis and to the vitamin E deficiency when these inflammatory diseases are associated with chronic alcoholism.
Alcoholics have low circulating levels of 25-hydroxyvitamin D5. Fifty-eight percent of the heavy alcohol consumers had a concentration of 25-hydroxyvitamin
D3 below lower limit of reference (20 ng/ml)19. Alcoholics were found to be deficient in vitamin E relative to controls34. Before abstinence, vitamin E levels were significantly depressed in alcoholics compared with the controls, in both plasma and erythrocytes35. Vitamin K deficiency is rare in alcoholics5. However, the production of abnormal prothrombin is frequently present in alcoholics and this may represent a subclinical vitamin K deficiency21.
Hypoglycemia occurs in patients drinking heavily and not eating36, but it seems that there is no significant caloric and protein undernutrition in alcoholic subjects37.
Circulating levels of vitamins can be a valuable guide to nutritional status, although care is needed when interpreting the results of such tests in alcoholics. Sensitive microbiological and biochemical tests for assessing vitamin status have been available for some years, and in addition, new biochemical methods are constantly being developed38.
Pathophysiology of nutritional deficiencies in alcoholism
Chronic alcoholics are likely to develop multifactorial malnutrition. General causes of malnutrition in alcoholics are inadequate nutrient, particularly lack of water-soluble vitamins in their diet, reduced uptake and impaired utilization of nutrients18,38. Alcohol not only depresses food intake by virtue of food displacement and suppressed appetite, but also by interfering with the absorption, storage, mobilization, activation, and metabolism of nutrients39. Hypomagnesemia and hypophosphatemia, which are very common in hospitalized alcoholics, result from deficient intake, malabsorption, excessive renal losses, and cellular uptake of both ions3. Alcohol causes urinary magnesium waste, but other mechanisms related to alcoholism contribute to the magnesium deficiency including malnutrition, gastrointestinal losses, phosphate deficiency, acidosis and/or alkalosis, vitamin D deficiency and free fatty acidemia associated with alcohol withdrawal40.
Most dramatic is alcohol's effect on folate. When alcohol is present, it is as though the body were actively trying to expel folate from all its sites of action and storage. The liver, which normally contains enough folate to meet all needs, leaks folate into the blood. As blood folate concentrations rise, the kidneys are deceived into excreting folate, as though it were excess. The intestine normally releases and retrieves folate continuously, but it becomes damaged by folate deficiency and alcohol toxicity, as a result it fails to retrieve its own folate and misses out on any that may trickle in from food as well. Alcohol also interferes with the action of what little folate is left, and this inhibits the production of new cells, especially the rapidly dividing cells of the intestine and the blood. Alcohol abuse causes a folate deficiency that devastates the digestive function41.
Nutrient deficiencies are thus a virtually inevitable consequence of alcohol abuse, not only because alcohol displaces food but also because alcohol directly interferes with the body's use of nutrients, making them ineffective even if they are present41.
a. Dietary intake
Alcohol remains a prevailing cause of malnutrition resulting in a variety of deficient states secondary to decreased intake of nutrients42. General malnutrition is often reflected in body weight loss, mainly of adipose and muscle tissue. This loss of nutritional reserves is partly due to inadequate protein intake in the face of continued alcohol ingestion. Reduced dietary intake of vitamins and minerals in alcoholics contributes to specific nutrient deficiencies1.
Hypocalcemia in alcoholics can result from deficient intake3. Chronic alcoholism also results in thiamine deficiency as a result of inadequate dietary intake and of impaired absorption of the vitamin43,44. Chronic alcohol feeding can induce riboflavin deficiency when intake of the vitamin is marginal44. Inadequate diet was often seen in alcoholics with reduced folate concentrations30. Vitamin C levels, deficient in alcoholics with and without liver disease, correlate with dietary intake31. Plasma beta-carotene levels reduced to some extent among heavy alcohol drinkers below levels are due to differences in the carotene intake45. The causes of 25 (OH) D deficiency in alcoholics include inadequate dietary intake3. Intake of vitamin E was reduced by 62% among the alcoholics compared to the controls19. During periods of hard-drinking alcoholics had a markedly reduced intake of alpha-tocopherol compared to periods of moderate-drinking and abstinence20.
b. Maldigestion and malabsorption
In addition to various well-described primary malnutrition syndromes, secondary malnutrition may result from the interference of ethanol with nutrient digestion, absorption or utilization42. Alcohol inhibits absorption of vitamins and nutrients by active transport processes, an effect that may be crucial in precipitating specific nutrient deficiencies (e.g. thiamine) in alcoholics1.
Hypocalcemia in alcoholics can result from malabsorption3. Chronic alcohol abuse decreases the absorption of zinc46. Intestinal cells fail to absorb B vitamins, notably thiamine, folate, and vitamin
B1241. Impaired absorption occurs only in the presence of ethanol and is not observed after chronic administration or withdrawal47. Pyridoxine absorption is primarily passive and is affected only by very high concentrations of ethanol. Although all mechanisms (absorption, hepatic uptake or storage, urinary excretion) may contribute to folate deficiency, decreased absorption appears to be the most important quantitatively47. Chronic alcohol consumption impairs folate coenzymes, and causes possible malabsorption of enterohepatically circulated folates in folate deficiency even when other essential nutrients are provided48. Althausen et al49. reported that alcohol inhibited vitamin A absorption in humans. One of the causes of 25 (OH) D deficiency in alcoholics is malabsorption3.
c. Impaired nutrient metabolism
Alcohol abuse not only displaces nutrients from the diet but also affects every tissue's metabolism of nutrients41. Low vitamin D activity may contribute significantly to calcium and phosphate deficiencies3. Ethanol (10%) ingestion enhanced the hepatic lipid peroxidation and decreased the calcium and magnesium contents in the blood and liver, thus chronic alcohol ingestion results in calcium and magnesium loss50. When alcohol is withdrawn, free fatty acids rise sharply and plasma magnesium falls51.
Alcohol has been reported to have a direct effect on zinc metabolism, and alcoholics are known to have reduced serum zinc levels13,52. Abnormalities of zinc metabolism in chronic alcoholics are possibly secondary to homeostatic alterations associated with hepatic failure27. Alcohol-induced hepatitis may have caused a predisposition to altered zinc metabolism and possible zinc deficiency which was exacerbated by subsequent zinc deprivation53. Low plasma zinc concentrations may also be due to increased hepatic production of interleukin by Kupffer cells stimulated by ethanol or its metabolites54.
Alcohol may interfere with the conversion of thiamine to its active form, the coenzyme thiamine pyrophosphate, or impair utilization of the active form14. There is evidence to suggest that alcohol
reduces thiamine phosphorylation to thiamine pyrophosphate (TPP) in the brain43. Impairment of thiamin metabolism in patients with alcohol dependence syndrome is possibly due to altered protein binding55. Similarly, ethanol interferes with the conversion of pyridoxine to its active form, the coenzyme PLP56. PLP is destroyed more rapidly in erythrocytes in the presence of acetaldehyde, the first product of ethanol oxidation, perhaps by displacement of PLP from its protective binding protein and its exposure to phosphatase17,41,57.
A common complication of chronic alcohol abuse is folic acid deficiency which can result from a direct effect of ethanol on folate metabolism, such as the acute decrease in serum folate levels58. In vivo hydrolysis of polyglutamyl folate was reduced by 35% in one ethanol-fed minipig. Decreased hydrolysis of polyglutamyl folate may represent an early step in the development of folate deficiency in chronic alcoholics59. Ethanol also interferes with the formation and release of 5-methyltetrahydrofolic acid, the principal circulating form of folate, which is also the folate coenzyme
necessary for DNA synthesis60,61.
Enhancement of hepatic vitamin A degradation due to alcohol consumption is a likely explanation for vitamin A depletion14. Vitamin A deficiency may be secondary to zinc deficiency in alcoholics18. Low levels of vitamin A in cirrhotics may have arisen as a result of impaired mobilization from the liver due to zinc deficiency, or to non-availability of hepatic zinc. The depression of zinc and vitamin A levels was related to the severity of the hepatic lesions, the lowest levels being observed among cirrhotics24. World MJ, Ryle PR, Thomson
AD: Alcoholic malnutrition and the small intestine. Alcohol Alcohol 1985; 20: 89-124.
Auerhahn
C: Recognition and management of alcohol-related nutritional deficiencies. Nurse Pract 1992; 17: 40-49.
Pitts
TO, van Thiel DH: Disorders of Divalent Ions and Vitamin D Metabolism in Chronic Alcoholism. In: Galanter M, editor. Recent Development in Alcoholism. New York, NY, Plenum Press, 1986, pp 357-369.
Pitts TO, van Thiel
DH: Disorders of the Serum Electrolytes, Acid-Base Balance, and Renal Function in Alcoholism. Recent Developments in Alcoholism. Edited by Galanter M. New York, NY, Plenum Press, 1986, pp 311-320.
Sherlock
S: Nutrition and the alcoholic. Lancet 1984; 1: 436-439.
McCollister RJ, Flink EB, Doe
RP: Magnesium balance studies in chronic alcoholism. J Lab Clin Med 1960; 55: 98-104.
Stein JH, Smith WO, Ginn
HE: Hypophosphatemia in acute alcoholism. Am J Med Sci 1966; 252: 112-117.
De Marchi S, Cecchin E. Basile A, Bertotti A, Nardini R, Bartoli
E: Renal tubular dysfunction in chronic alcohol abuse-effects of abstinence. N Engl J Med 1993; 329: 1927-1934.
Karkkainen P, Mussalo-Rauhamaa H, Poikolainen K, Lehto
J: Alcohol intake correlated with serum trace elements. Alcohol Alcohol 1988; 23: 278-282.
Touitou Y, Godard JP, Ferment O, Chastang C, Proust J, Bogdan A, Auzeby A, Touitou
C: Prevalence of magnesium and potassium deficiencies in the elderly. Clin Chem 1987; 33: 518-523.
Dworkin BM, Rosenthal WS, Gordon GG, Jankowski
RH: Diminished blood selenium levels in alcoholics. Alcohol Clin Exp Res 1984; 8: 535-538.
Dworkin B, Rosenthal WS, Jankowski RH, Gordon GG, Haldea
D: Low blood selenium levels in alcoholics with and without advanced liver disease. Correlations with clinical and nutritional status. Dig Dis Sci 1985; 30: 838-844.
Valle BL, Wacker WE, Bartholomay AF, Hoch
FL: Zinc metabolism in hepatic dysfunction II, Correction of metabolic patterns with biochemical findings. N Engl J Med 1957; 257: 1055-1065.
Morgan
MY: Alcohol and Nutrition. Br Med Bull 1982; 38: 21-29.
Rosenthal WS, Adham NF, Lopez R, Cooperman
JM: Riboflavin deficiency in complicated chronic alcoholism. Am J Clin Nutr 1973; 26: 858-860.
Leevy CM, Baker H, Tenhove W, Frank O, Cherrick
GR: B-complex vitamins in liver disease of the alcoholic. Am J Clin Nutr 1965; 16: 339-346.
Lumeng L, Li
TK: Vitamin B6 metabolism in chronic alcohol abuse. Pyridoxal phosphate levels in plasma and the effects of acetaldehyde on pyridoxal phosphate synthesis and degradation in human erythrocytes. J Clin Invest 1974; 53: 693-704.
Roe
DA: Nutritional Assessment of Alcoholics. Alcohol and the Diet. Edited by Roe DA. Westport, CT, AVI Publishing Company, Inc., 1979, pp 149-182.
Bjorneboe GA, Johnsen J, Bjorneboe A, Morland J, Drevon
CA: Effect of heavy alcohol consumption on serum concentrations of fat-soluble vitamins and selenium. Alcohol Alcohol 1987; 1 (Suppl): 533-537.
Bjorneboe GA, Johnsen J, Bjorneboe A, Bache-Wiig JE, Morland J, Drevon
CA: Diminished serum concentration of vitamin E in alcoholics. Ann Nutr Metab 1988; 32: 56-61.
Iber FL, Shamszad M, Miller PA, Jacob
R: Vitamin K deficiency in chronic alcoholic males. Alcohol Clin Exp Res 1986; 10: 679-681.
Sullivan
JF: Effects of alcohol on urinary zinc excretion. Q J Stud Alcohol 1962; 23: 216-220.
Aaseth J, Smith-Kielland A, Thomassen
Y: Selenium, alcohol and liver diseases. Ann Clin Res 1986; 18: 43-47.
Atukorala TM, Herath CA, Ramachandran
S: Zinc and vitamin A status of alcoholics in a medical unit in Sri Lanka. Alcohol Alcohol 1986; 21: 269-275.
Dechavanne M, Barbier Y, Prost G, Pehlivanian E, Tolot
E: Calcium 47 absorption in alcoholic cirrhosis. Effect of 25 hydroxylcholecalciferol. Nouv Presse Med 1974; 3: 2549-2551.
Dinsmore WW, McMaster D, Callender ME, Buchanan KD, Love
AH: Trace elements and alcohol. Sci Total Environ 1985; 42: 109-119.
Kasarskis EJ, Manton WI, Devenport LD, Kirkpatrick JB, Howell GA, Klitenick MA, Frederickson
CJ: Effects of alcohol ingestion on zinc content of human and rat central nervous systems. Exp Neurol 1985; 90: 81-95.
Skal'nyi AV, Kukhtina EN, Ol'khovskaia IP, Glushchenko
NN: Reduction of voluntary alcohol consumption under the effects of prolonged-action zinc. Biull Eksp Biol Med 1992; 113: 383-385.
D'Amour ML, Bruneau J, Butterworth
RF: Abnormalities of peripheral nerve conduction in relation to thiamine status in alcoholic patients. Can J Neurol Sci 1991; 18: 126-128.
Airoldi M, Fantasia R, Aloigi-Luzzi D, Stefanetti C, Desero D, Chiodini E, Gobbi
A: Macrocytosis, megaloblastosis and folate status in chronic alcoholics. Minerva Med 1987;78:739-743.
O'keane M, Russell RI, Goldberg
A: Ascorbic acid status of alcoholics. J Alcohol 1972; 7: 6-11.
Shugalei I, Degtiar VV, Butvin IN, Grivenko
GP: Effect of alcohol intoxication on ascorbic and dehydroascorbic acid levels in rat tissue and human blood. Ukr Biokhim Zh 1986; 58: 81-83.
Marrakchi S, Kim I, Delaporte E, Briand G, Degand P, Maibach HI, Thomas
P: Vitamin A and E blood levels in erythrodermic and pustular psoriasis associated with chronic alcoholism. Acta Derm Venereol 1994; 74: 298-301.
Cook CC, Walden RJ, Graham BR, Gillham C, Davies S, Prichard
BN: Trace element and vitamin deficiency in alcoholic and control subjects. Alcohol Alcohol 1992; 27: 207-207.
Girre C, Hispard E, Therond P, Guedj S, Bourdon R, Dally
S: Effect of abstinence from alcohol on the depression of glutathione peroxidase activity and selenium and vitamin E levels in chronic alcoholic patients. Alcohol Clin Exp Res 1990; 14: 909-912.
Freinkel N, Singer DL, Arky R, Bleicher SJ, Anderson JB, Silbert
CK: Alcohol hypoglycemia. I. Carbohydrate metabolism of patients with clinical alcohol hypoglycemia and the experimental reproduction of the syndrome with pure alcohol. J Clin Invest 1963; 42: 1112-1133.
Lopez DG, Pumarino H, Bustamante E, Oviedo S, Rios
M: Nutritional study of alcoholics with specific reference to calcium and phosphorus. Rev Med Chil 1991; 119: 652-658.
Ryle PR, Thomson
AD: Nutrition and vitamins in Alcoholism. Contemp Issues Clin Biochem 1984; 1: 188-224.
Roe
DA: Diet-Drug Interactions and Incompatibilities. Edited by Hathcock JM, Coon J. Nutrition and Drug Interrelations. New York, NY, Academic Press, 1978, pp 319-345.
Shane SR, Flink
EB: Magnesium deficiency in alcohol addiction and withdrawal. Magnes Trace Elem 1991; 10: 263-268.
Whitney EN. Catalgo CB, Rolfes
SR: Alcohol and Nutrition. Understanding Normal and Clinical Nutrtion. 4ed. Edited by Whitney EN, Catalgo CB, Rolfes SR. Minneapolis, MN, West Publishing Company, 1994, pp 233-241.
Lieber
CS: Alcohol-nutrition interaction (1983). ASDC J Dent Child 1984; 51: 137-140.
Butterworth
RF: Effects of thiamine deficiency on brain metabolism: implication for the pathogenesis of the Wernicke-Korsakoff syndrome. Alcohol Alcohol 1989; 24: 271-279.
Thomson AD, Jeyasingham MD, Pratt OE, Shaw
GK: Nutrition and alcoholic encephalopathies. Acta Med Scand 1987; 717 (Suppl): 55-65.
Heseker H, Schneider
R: Requirement and supply of vitamin C, E and beta-carotene for elderly men and women. Eur J Clin Nutr 1994; 48: 118-127.
Dinsmore W, Callender ME, McMaster D, Todd SJ, Love
AH: Zinc absorption in alcoholics using zinc-65. Digestion 1985; 32: 238-242.
Mitchell
MC: Alcohol. Present Knowledge in Nutrition. 6ed. Edited by Brown ML. Washington, DC, International Life Sciences Institute Nutrition Foundation, 1990, pp 457-462.
Blocker
DE, Thenen SW: Intestinal absorption, liver uptake, and excretion of 3H-folic acid in folic
acid-deficient, alcohol-consuming nonhuman primates. Am J Clin Nutr 1987; 46: 503-510.
Althausen TL, Uyeyama K, Loran
MR: Effects of alcohol on absorption of vitamin A in normal and in gastrectomized subjects. Gasroenterology 1960; 38: 942-945.
Flora SJ, Kumar D, Sachan SR, Das Gupta
S: Combined exposure to lead and ethanol on tissue concentration of essential metals and some biochemical indices in rat. Biol Trace Elem Res 1991; 28: 157-164.
Flink
EB: Magnesium deficiency in alcoholism. Alcohol Clin Exp Res 1986; 10 (6): 590-594.
Wu CT, Lee JN, Shen WW, Lee
SL: Serum zinc, copper, and ceruloplasmin levels in male alcoholics. Biol Psychiatry 1984; 19: 1333-1338.
Taylor CM, Goode HF, Aggett PJ, Bremner I, Walker BE, Kelleher
J: Symptomatic zinc deficiency in experimental zinc deprivation. J Clin Pathol 1992; 45: 83-84.
Veitch RL, Lumeng L, Li
TK: Vitamin B6 metabolism in chronic alcohol abuse. The effect of ethanol oxidation on hepatic pyridoxal-5-phosphate metabolism. J Clin Invest 1975; 55: 1026-1032.
Tallaksen CM, Bohmer T, Bell
H: Blood and serum thiamin and thiamin phosphate esters concentrations in patients with alcohol dependence syndrome before and after thiamin treatment. Alcohol Clin Exp Res 1992; 16: 320-325.
Hines
JD: Reversible megaloblastic and sideroblastic marrow abnormalities in alcoholic patients. Br J Haematol 1969; 16: 87-101.
Lumeng
L: The role of acetaldehyde in mediateing the deleterious effect of ethanol on pyridoxal 5'-phosphate metabolism. J Clin Invest 1978; 62: 286-293.
McMartin KE, Collins TD, Bairnsfather
L: Cumulative excess urinary excretion of folate in rats after repeated ethanol treatment. J Nutr 1986; 116: 1316-1325.
Reisenauer AM, Buffington CA, Villanueva JA, Halsted
CH: Folate absorption in alcoholic pigs: in vivo intestinal perfusion studies. Am J Clin Nutr 1989; 50: 1429-1435.
Paine CJ, Eichner ER, Dickson
V: Concordance of radioassay and microbiological assay inthe study of the ethanolinduced fall in serum folate level. Am J Med Sci 1973; 266: 134-138.
Hillman RS, McGuffin R, Campbell
C: Alcohol interference with the folate enterohepatic cycle. Trans Assoc Am Physicians 1977; 90: 145-156.
Bjorneboe A, Bjorneboe GE, Drevon
CA: Absorption, transport and distribution of vitamin E. J Nutr 1990; 120: 233-242.
Drevon
CA: Absorption, transport and metabolism of vitamin E. Free Radic Res Commun 1991; 14: 229-246.
Frank O, Luisada-Opper A, Sorrell MF, Thomson AD, Baker
H: Vitamin deficits in severe alcoholic fatty liver of man calculated from multiple reference units. Exp Mol Pathol 1971; 15: 191-197.
Leo MA, Lieber
CS: Hepatic vitamin A depletion in alcoholic liver injury. N Engl J Med 1982; 37: 597-601.
Lieber
CS: Alcohol, liver, and nutrition. J Am Coll Nutr 1991; 10:602-632.
Ragland
G: Electrolyte abnormalities in the alcoholic patient. Emerg Med Clin North Am 1990; 8: 761-773.
Karayalcin S, Arcasoy A, Uzualimoglu
O: Zinc plasma levels after oral zinc tolerance test in non-alcoholic cirrhosis. Dig Dis Sci 1988; 33: 1096-1102.
Cavdar
AO: Fetal alcohol syndrome, malignancies, and zinc deficiency [letter]. J Pediatr 1984; 105: 335-335.
Nasolodin VV, Rusin VI, Vorob'ev
VA: Effect of alcohol on iron, aluminum and zinc balance. Vopr Pitan 1987; 1: 23-26.
McMartin
KE: Increased urinary folate excretion and decreased plasma folate levels in the rat after acute ethanol treatment. Alcohol Clin Exp Res 1984; 8: 172-178.
Faizallah
R, Morris AI, Krasner N, Walker RJ: Alcohol enhances vitamin C excretion in the urine. Alcohol Alcohol 1986; 21: 81-84.
Martin PR, Adinoff B, Weingartner H, Mukherjee AB, Eckardt
MJ: Alcoholic organic brain disease: nosology and pathophysiologic mechanisms. Prog Neuropsychopharmacol Biol Psychiatry 1986; 10: 147-164.
Blass JP, Gibson
GE: Abnormality of a thiamine-requiring enzyme in patients with Wernicke-Korsakoff syndrome. N Engl J Med 1977; 297: 1367-1370.
Mukherjee
AB, Svoronos S, Ghazanfari A, Martin PR, Fisher A, Roecklein B, Rodbard D,
Staton R, Behar D, Berg CJ, and Ramanethapuram Manjunath: Transketolase abnormality in cultured fibroblasts from familial chronic alcoholic men and their male offspring. J Clin Invest 1987; 78: 1039-1043.
Martin PR, McCool BA, Singleton
CK: Genetic sensitivity to thiamine deficiency and development of alcoholic organic brain disease. Alcohol Clin Exp Res 1993; 17: 31-37.
Singleton CK, Pekovich SR, McCool BA, Martin
PR: The thiamine-dependent hysteretic behavior of human transke-tolase: implications for thiamine deficiency. J Nutr 1995; 125: 189-194.
Freund G, Ballinger WE,
Jr: Loss of cholinergic muscarinic receptors in the frontal cortex of alcohol abusers. Alcohol Clin Exp Res 1988; 12: 630-638.
Victor M, Adams
RD: On the etiology of the alcoholic neurologic diseases with special reference to the role of nutri-tion. Am J Clin Nutr 1961; 9: 348-397.
Joyce
EM: Aetiology of alcoholic brain damage: alcoholic neurotoxicity or thiamine malnutrition? Br Med Bull 1994; 50: 99-114.
Willenbring
ML: Organic mental disorders associated with heavy drinking and alcohol dependence. Clin Geriatr Med 1988; 4: 869-887.
Victor M, Adams RD, Collins
GH: The Wernicke-Korsakoff Syndrome. Philadelphia, PA, F.A. Davis Company, 1971.
Lishman
W: Cerebral disorder in alcoholism: syndromes of impairment. Brain 1981; 104: 1-20.
Serdaru M, Hausser-Hauw C, Laplane D, Buge A, Castaigne P, Goulon M, Lhermitte F, Hauw
JJ: The clinical spectrum of alcoholic pellagra encephalopathy. A retro-spective analysis of 22 cases studied pathologically. Brain 1988; 111: 829-842.
Parry
TE: Folate responsive neuropathy. Presse Med 1994; 23: 131-137.
Gimsing P, Melgaard B, Andersen K, Vilstrup H, Hippe
E: Vitamin B-12 and folate function in chronic alcoholic men with peripheral neuropathy and encephalopathy. J Nutr 1989; 119: 416-424.
Lambie
DG: Alcoholic brain damage and neurologcal symptoms of alcohol withdrawal--manifestations of over-hydration. Med Hypotheses 1985; 16: 377-388.
Bahr M, Sommer N, Peterson D, Wietholter H, Dichgans
J: Central pontine myelosis associated with low potassium levels in alcoholism. J Neurol 1990; 237: 275-276.
Phillips SC, Cragg
BG: Blood-brain barrier dysfunction in thiamine-deficient, alcohol- treated rats. Acta Neuropathol (Berl) 1984; 62: 235-241.
Halliday G, Ellis J, Harper
C: The locus coeruleus and memory: a study of chronic alcoholics with and without the memory impairement of Korsakoff's psychosis. Brain Res 1992; 598: 33-37.
Kril JJ, Homewood
J: Neuronal changes in the cerebral cortex of the rat following alcohol treatment and thiamin deficiency. J Neuropathol Exp Neurol 1993; 52: 586-593.
Jacobson RR, Lishman
WA: Cortical and diencephalic lesions in Korsakoff's syndrome: a clinical and CT scan study. Psychol Med 1990; 20: 63-75.
Phillips
SC: Neuro-toxic interaction in alcohol-treated, thiamine-deficient mice. Acta Neuropathol (Berl) 1987; 73: 171-176.
Hauw JJ, De Baecque C, Hausser-Hauw C, Serdaru
M: Chromatolysis in alcoholic encephalopathies. Pellagra-like changes in 22 cases. Brain 1988; 111: 843-857.
Hata T, Meyer JS, Tanahashi N, Ishikawa Y, Imai A, Shinohara T, Velez M, Fann WE, Kandula P, Sakai
F: Three-dimensional mapping of local cerebral perfusion in alcoholic encephalopathy with and without Wenicke-Korsakoff syndrome. J Cereb Blood Flow Metab 1987; 7: 35-44.
Charness
ME: Brain Lesions in Alcoholics. Alcohol Clin Exp Res 1993; 17: 2-11.
Kopelman
MD: The Korsakoff Syndrome. Br J Psychiatry 1995; 166: 154-173.
Mann K, Schroth G, Stetter F, Schied HW, Bartels M, Batra A, Heimann
H: Thiamine deficiency and brain atrophy in alcoholic patients. Nervenarzt 1991; 62: 177-181.
Wang Y, Watson
RR: Ethanol, immune responses, and murine AIDS: the role of vitamin E as an immunostimulant and antioxidant. Alcohol 1994; 11: 75-84.
Lovinger
DM: Excitotoxicity and alcohol-related brain damage. Alcohol Clin Exp Res 1993;17:19-27.
Menzano E, Carlen
PL: Zinc deficiency and corticosteroids in the pathogenesis of alcoholic brain dysfunction--a review. Alcohol Clin Exp Res 1994;18:895-901.
Altura BM, Altura BT, Gupta
RK: Alcohol intoxication results in rapid loss in free magnesium in brain and disturbances in brain bioenergetics: relation to cerebrovasospasm, alcohol-induced strokes, and barbiturate anesthesia-induced deaths. Magnes Trace Elem 1991; 10: 122-135.
Topinka J, Binkova B, Sram RJ, Fojtikova
I: DNA-repair capacity and lipid peroxidation in chronic alcoholics. Mutat Res 1991; 263: 133-136.
Seyoum GG, Persaud
TV: Can methionine and zinc prevent the embryopathic effects of alcohol? Med Hypotheses 1991; 34 (2): 153-156.
Thomson AD, Pratt OE, Jeyasingham M, Shaw
GK: Alcohol and brain damage. Hum Toxicol 1988; 7: 455-463.
Rindi G, Imarisio L, Patrini
C: Effects of acute and chronic ethanol administration on regional thiamin pyrophosphokinase activity of the rat brain. Biochem Pharmacol 1986; 36: 3903-3908.
Rindi
G: Alcohol and thiamine of the brain. Alcohol Alcohol 1989; 24: 493-495.
Lambie DG, Johnson
RH: Drugs and folate metabolism. Drugs 1985; 30: 145-155.
Crellin R, Bottiglieri T, Reynolds
EH: Folates and psychiatric disorders. Drugs 1993; 45: 623-636.
Molina JA, Bermejo F, del Ser T, Jimenez-Jimenez FJ, Herranz A, Fernandez-Calle P, Ortuno B, Villanueva C, Sainz
MJ: Alcoholic cognitive deterioration and nutritional deficiencies. Acta Neurol Scand 1994; 89: 384-390.
Vischer A, Hell
D: Cognitive deficits, vitamin status and controlled thiamine substitution in alcohol dependent patients in withdrawal treatment. Nervenarzt 1989; 60: 633-640.
Parsons OA, Nixon
SJ: Neurobehavioral sequelae of alcoholism. Neurol Clin 1993; 11: 205-218.
Gullestad L, Dolva LO, Soyland E, Manger AT, Falch D, Kjekshus
J: Oral magnesium supplementation improves metabolic variables and muscle strength in alcoholics. Alcohol Clin Exp Res 1992; 16: 986-990.
Ema M, Gebrewold A, Altura BT, Altura
BM: Magnesium sulfate prevents alcohol-induced spasms of cerebral blood vessels: an in situ study on the brain micro-circulation from male versus female rats. Magnes Trace Elem 1991; 10: 269-280.
Spittle B, Parker
J: Wernicke's encephalopathy complicating schizophrenia. Aust N Z J Psychiatry 1993; 27: 638-352.
van der Westhuyzen J, Davis RE, Icke GC, Metz
J: Thiamine deficiency in black male hosteldwellers. The need for thiamine supplementation of sorghum beer. S Afr Med J 1987; 71: 231-234.
Zarazaga A, Garcia de Lorenzo A, Montanes P, Culebras
JM: Folates in human nutrition, Different clinical situations in which folate deficiencies exist. Nutr Hosp 1991; 6: 207-226.
Hornig D, Strolz
F: Recommended dietary allowance: support from recent research. J Nutr Sci Vitaminol 1992; Spec No1: 73-176.
Biery JR, Williford JH,
Jr., McMullen EA: Alcohol craving in rehabilitation: assessment of nutrition therapy. J Am Diet Assoc 1991; 91: 463-466.
Martin PR, Eckardt MJ, Linnoila
M: Treatment of chronic organic mental disorders associated with alcoholism. Recent Dev Alcohol 1989; 7: 329-350.
Ariaev
VL: Comparative evaluation of the suppressive effects of lithium preparations in the treatment of experimental chronic habituation to alcohol. Zh Nervopatol Psikhiatr Im S S Korsakova 1984; 84: 756-762.
The causes of 25(OH)D deficiency in alcoholics include reduced hepatic 25-hydroxylase activity and lack of exposure to the sun.
Those with Laennec's cirrhosis also have low levels of vitamin D binding protein due to impaired hepatic protein synthesis and as a result, have low serum concentrations of total, but not free, 1,25-dihydroxyvitamin D3. New clinical evidence from heavy drinkers and from experimental work in rats suggests that alcohol may increase oxidation of alpha-tocopherol, causing reduced tissue concentrations of alpha-tocopherol62,63.
d. Decreased hepatic storage of nutrients
Alcoholics with fatty infiltration of the liver have reduced hepatic concentrations of folate, riboflavin, nicotinamide, pantothenic acid, pyridoxine, vitamin
B12, thiamine and vitamin A14,64. Hepatic uptake of folate appears to be decreased by acute ethanol administration and hepatic accumulation of PLP is decreased significantly by ethanol47. Hepatic storage of vitamin A is reduced by ethanol65. Ethanol administration in animals was found to depress hepatic levels of vitamin A, even when administered diets containing large amounts of the vitamin, reflecting, in part, accelerated microsomal degradation through newly discovered microsomal pathways of retinol metabolism, inducible by either ethanol or drug administration66.
e. Increased nutrient requirements
Alcoholics have increased nutrient requirements due to greater metabolic demands and the need for tissue repair38. Vitamins particularly required for tissue repair are folic acid, pyridoxine and vitamin
B1214.
f. Increased urinary and fecal losses
Increase in urination is associated with alcohol consumption41. The acute effect of ethyl alcohol ingestion is to induce diuresis with excretion of free water and the preservation of electrolytes. Excess water and electrolytes are acutely excreted in response to additional alcohol ingestion. With the cessation of alcohol intake, this excess will be excreted over several days67. The water takes with it important minerals such as magnesium, potassium, calcium, and zinc, depleting the body's reserves41.
Hyponatremia, common in decompensated cirrhotics, is caused by an impairment of renal free water clearance and concomitant water ingestion. Excessive proximal renal tubular sodium reabsorption and nonosmotic vasopressin release underlie the defect in renal water excretion in cirrhosis. In some alcoholics gastrointestinal and renal potassium losses and nutritional potassium deficiency may cause potassium depletion4. Hypocalcemia in alcoholics can result from renal calcium waste3. Induction of magnesium excretion by alcohol ingestion (167-260% of control values) occurs in chronic alcoholics51.
Overconsumption of alcohol may lead to severe zinc deficiency, probably via hyperzincuria52,68,69, because the decreased serum albumin levels may limit the availability of albumin for the transport of zinc in the plasma24. An increased loss of iron, aluminum and zinc through the intestine and kidneys, causing the preconditions for the development of deficiency of these metals in the body, was observed in males and females, engaged in sports, after a single intake of moderate doses of alcohol70.
Urinary loss of pyridoxine is accelerated by ethanol and results in very low levels of both pyridoxine and PLP in plasma of alcoholics, particularly those with liver disease47. Acute ethanol administration in rats produces a marked increase in the urinary excretion of folate compounds, which leads to a decrease in plasma folate levels. The concentration of folate in the rat urine, as well as the amount of urinary folate excretion were markedly increased 4 hours after ethanol administration. After 14 hours, total plasma folate levels were significantly depressed to 50% of control levels71. Excess urinary folate excretion accumulated so that the longer the rats were exposed to ethanol, the greater the urinary loss58. Faizallah et al72. reported that alcohol produced a 47% increase in urinary ascorbic acid excretion in normal male volunteers. A similar ascorbiuresis in chronic alcoholics would be an additional factor in the causation of vitamin C deficiency in these patients.
g. Genetics
Another cause of the development of alcoholism may be a genetic predisposition to thiamine deficiency73. Blass and Gibson74 propose that an inborn abnormality of the enzyme transketolase may be necessary before thiamin deficiency can lead to Wernicke-Korsakoff syndrome. An inborn error (i.e., high Km of transketolase for thiamine pyrophosphate) predisposing to thiamine deficiency diseases similar to those reported in Wernicke-Korsakoff syndrome may occur in the general population. However, this variant seems to occur more frequently among familial chronic alcoholic men and their male offspring without any history of alcoholism. The inheritance pattern of this enzyme variant as revealed from an Amish pedigree study may be autosomal recessive75. Polymorphisms of any of the enzymes that require TPP as a cofactor may account for genetic heterogeneity in the susceptibility to thiamine deficiency76. The substantial lag in formation of active holoenzyme and the findings of interindividual variation and cell type variation in the lag period suggest mechanisms for the loss of transketolase activity during thiamine deficiency and may explain, at least in part, the differential sensitivity to deficiency demonstrated by tissues and individuals77.
Neuropsychiatric syndromes related with nutritional deficiencies in alcoholism
Alcohol abuse causes impairment of cognitive functions ranging from mild forms to end-stage dementia78. Chronic alcoholics also exhibit a number of neurological disorders which are related to nutritional deficiencies79. Of particular importance are vitamin deficiencies such as thiamine, nicotinic acid, pyridoxine and vitamin B12 that are essential for normal cerebral functioning14.
The clinical presentation of brain damaged alcoholics is heterogenous and includes minimal cognitive impairment, amnesia and dementia. Thiamine malnutrition, affecting the diencephalon, can account for all clinical forms. Therefore, most organic brain syndromes in alcoholics can be considered as variants of the Wernicke-Korsakoff syndrome and rigorous attention should be paid to the nutritional status of all alcoholics80. Alcohol amnestic disorder seems to result from the combination of drinking, malnutrition, and genetic vulnerability to thiamine deficiency. Dementia associated with alcoholism is most likely a combination of intermediate brain syndrome and alcohol amnestic disorder81. Victor et al82. describes an over attack of Wernicke's encephalopathy as a prelude to the amnestic syndrome in well over 80% of cases. Clinical experience suggests that many cases of Korsakoff's psychosis develop their amnesic difficulties without any identifiable history of a Wernicke episode83. Thiamine deficiency seems to play a contributory (but not exclusive) role in the pathogenesis of alcoholic peripheral neuropathy. Deficiencies of other vitamins as well as direct neurotoxic effects of alcohol could also be involved in this phenomenon29.
Marchiafava-Bignami disease, resulting from vitamin B deficiency, is a special form of alcoholic thiamin deficiency, only to be distinguished from the Wernicke-Korsakoff syndrome by the peculiar distribution of cerebral lesions (i.e., symmetrical degeneration of the central portion of the corpus callosum)18. Neurological pellagra was associated with Marchiafava-Bignami disease and/or Wernicke-Korsakoff disease in 13 of 22 cases of heavy alcohol drinkers. The possibility of pellagra occurring during thiamine and pyridoxine therapy and 'nicotinic acid deficiency' should be considered in alcoholic encephalopathies84. Ten of twenty folate deficient patients presented with a peripheral neuropathy, eight with subacute combined degeneration of the cord and two with myelopathy85. Folate deficiency may also contribute to the development of alcoholic polyneuropathy86.
Neuropathology of nutritional deficiencies in alcoholism
The end result of malnutrition may be severe functional impairment and tissue damage in organs, mainly the liver and the brain, as a consequence of specific vitamin and nutrient deficiencies arising in chronic alcoholics1.
a. Neuronal damage
Central nervous system damage is a major complication of alcohol abuse87. Chronic alcohol-related brain damage can often be a direct result of nutrient depletion, particularly of the vitamins thiamine,
B12, nicotinamide, and pyridoxine38. Disturbances in serum potassium levels (hypokalemia) as well as rapid correction of hyponatraemia may be associated with pontine swelling and dysfunction which, if undetected, leads to central pontine myelinolysis88.
Vitamin deficiency, particularly thiamine deficiency, plays a role in producing pathological and psychological changes of alcoholic brain damage87. Rats maintained on a thiamine-deficient diet for 38 days lost weight and displayed neurological symptoms. The PA value, representing the permeability of the blood-brain barrier to 14C-sucrose, significantly increased. Axonal degeneration was present in the olfactory glomeruli89. The loss of noradrenergic locus coeruleus neurons has been identified as the possible critical lesion inducing amnesia in alcoholic patients with Wernicke-Korsakoff syndrome. However, thiamine deficiency does not result in a reduction in the number of pigmented cells in the locus coeruleus, and refutes the hypothesis that locus coeruleus cell loss is critical for amnesia in Wernicke-Korsakoff syndrome90. A significant loss of Niss1-stained neurons and a loss of parvalbumin-immunoreactive GABA-containing neurons was seen in the cerebral cortex of rats following alcohol treatment and thiamin deficiency. The results imply that thiamin deficiency is integrally involved in the pathogenesis of alcohol-related cortical neuronal loss91. In addition to their well-established diencephalic lesions, many Korsakoff patients have sustained widespread cerebral damage. Shrinkage in the frontal brain regions appear to be especially pronounced92. Axon terminal degeneration was seen in the olfactory bulbs and deep cerebellar nuclei in mice given the combined treatment of alcohol and thiamine deficiency93.
In some patients with alcoholic encephalopathies, chromatolysis similar to that reported in endemic pellagra was discovered on postmortem examination. The changes consisted of central chromatolysis, seen predominantly in the brainstem, especially in the pontine nuclei, where they were constant, and in the cerebellar dentate nuclei. Nuclei of cranial nerves (mainly the third, sixth, seventh and eighth), the reticular nuclei, arcuate nuclei and posterior horn cells, were also markedly affected. Changes were sometimes seen in the cerebral cortex, the interpeduncular nuclei, the central mesencephalic grey matter, the colliculi, the tenth and twelfth cranial nerves and perihypoglossal nuclei, the gracile and cuneate nuclei and anterior horn cells. This distribution was different from that reported in endemic and endogenous pellagra or in isoniazid-induced pellagra encephalopathy. The chromatolysis of alcoholic pellagra did not appear to be a retrograde change related to axonal degeneration. Microscopic examination of the pons is essential in alcoholic encephalopathies94.
b. Vascular damage
In Wernicke-Korsakoff syndrome, most prominent reductions of local cerebral blood flow were also seen in the hypothalamus and basal forebrain nuclei, but the thalamus, basal ganglia, and limbic systems were severely reduced. Chronic alcohol abuse, in the absence of thiamine deficiency, reduces cerebral blood flow by direct neurotoxic effects. If thiamine deficiency is also present, more severe and localized hemodynamic reductions are superimposed95.
c. Neuroimaging studies
Distinguishing ethanol neurotoxicity from nutritional deficiency can be facilitated by magnetic resonance imaging, which can visualize some of the specific macroscopic lesions of Wernicke's encephalopathy, central pontine myelinolysis, cerebellar degeneration, and Marchiafava-Bignami syndrome. Computerized morphometric studies of alcoholic brains have revealed ventricular enlargement, selective loss of subcortical white matter, and alterations in neuronal size, number, architecture, and synaptic complexity. These lesions tend to be more severe when there is coexisting nutritional deficiency or liver disease, suggesting that ethanol neurotoxicity may not be the sole cause96. Neuro-imaging studies have confirmed autopsy findings of more widespread structural and metabolic abnormalities in Korsakoff patients, particularly involving the frontal lobes97. However, CT findings on thiamine-deficient patients did not differ from those on patients without thiamine deficiency, and correlations between thiamine deficiency and subcortical atrophy before treatment were not significant. It is believed that there is a reversible brain shrinkage in chronic alcoholics98.
Neurophysiology of nutritional deficiencies in alcoholism
Brain dysfunction sustained with cumulative subclinical episodes of thiamin deficiency during periods of alcohol abuse may facilitate the development of tolerance and physical dependence that may cause progressive increases in alcohol consumption and further brain damage76. Prolonged consumption of alcohol results in alterations of immune responses, ultimately manifested by increasing susceptibility to infectious agents. Such changes can be due to nutritional deficiency, as well as to the direct effects of alcohol or its metabolites on immune cells, oxidative stress, and neutrophil dysfunctions99.
a. Neurotransmitter dysfunction
Hyperexcitability following chronic alcohol exposure appears to result in enhanced activation of glutamatergic synapses in the brain. This enhanced glutamatergic transmission probably results from a combination of increased NMDA receptor activation, decreased GABAA receptor activation and increased function of voltage-activated calcium channels100. It has been hypothesized that low brain zinc, noted in chronic alcoholics, enhances N-methyl-D-aspartate (NMDA) exci-totoxicity101. Studies suggest that NMDA receptor-initiated excitotoxicity may result from alcohol-related thiamine deficiency. Therefore, excitotoxic damage due to neural compensation for sustained alcohol levels and nutritional deficits may underlie aspects of alcohol-related brain damage100.
b. Ion channel dysfunction
Alcohol produces rapid brain intracellular acidosis due to the loss in brain [Mg++]. Binge or heavy drinking of alcohol may result in stroke-like events and sudden death via rapid alterations in brain cellular bioenergetics102.
c. Oxidative stress
The reduced plasma levels of alpha-tocopherol and selenium after heavy consumption of ethanol may be of particular interest in view of the protective effect exerted by antioxidants towards cell damage19. The reduced alpha-tocopherol and selenium may influence the maintenance of normal cell structure and functions, and contribute to development of diseases frequently observed in alcoholics20. Prior to abstinence, glutathione peroxidase activity and selenium and vitamin E levels were significantly depressed in the alcoholics. There is a deficiency in the antioxidant defense system of chronic alcoholics before the occurrence of severe liver disease35. Also, zinc deficiency in alcoholics can produce neuronal damage through increased free radical formation101. The DNA excision-repair capacity of lymphocytes measured as unscheduled DNA synthesis induced by N-methyl-N-nitrosourea in lymphocytes was decreased in alcoholics, and lipid peroxidation in plasma was significantly higher as a consequence of alcohol overconsumption. A negative correlation was found between lipid peroxidation and vitamin C levels and between unscheduled DNA synthesis and lipid peroxidation values. These results support the hypothesis of a connection between cell membrane status and DNA damage and repair and the possible role of active oxygen species in cell damage caused by ethanol103.
d. Metabolic dysfunction
Zinc deficiency decreases alcohol dehydrogenase activity and thus slows down the elimination of ethanol104. A grossly disturbed pattern of amino acids in the blood of patients undergoing treatment for alcohol withdrawal syndromes is likely to be caused by loss of hepatic function and brain damage caused by B group vitamin deficiency44. Damage to the protein moeity of some of the thiamin-using enzymes has possible mechanisms of brain cell necrosis105. There is evidence to suggest that alcohol reduces thiamine phosphorylation to TPP in the brain. TPP is a cofactor for the pyruvate dehydrogenase complex, alpha-ketoglutarate dehydrogenase and transketolase, three enzymes involved in cerebral glucose and energy metabolism39. Decreased activity of the transketolase enzyme is an essential abnormality of Wernicke-Korsakoff syndrome18. Transketolase may serve a role as an intracellular thiamine "sink" that would provide for the unidirectional, active transport of thiamine across neuronal membranes. Transketolase could not only provide TPP to replace released thiamine, it also provide a means for the uptake of thiamine in conjunction with released neurotransmitters following neural firing. A transketolase with reduced affinity for TPP could lead to impaired ion channel and/or excitatory amino acid inactivation, especially during extreme thiamine deficiency and periods of neural hyperexcitability
following chronic alcohol consumption76.
Chronic ethanol ingestion also significantly reduces regional brain thiamine pyrophosphokinase activity106, which is essential for the phosphorylation and intracellular accumulation of thiamine. In this way, the availability of TPP can be decreased, contributing to the depression of the tricarboxylic acid cycle, in which TPP plays an important role. In other words, the depression of thiamine cerebral metabolism may be both a cause and an effect of the depressed energy metabolism which is observed in chronic alcoholism. It is noteworthy that chronic ethanol intake depresses cerebral thiamine metabolism when dietary thiamine intake is adequate or even abundant107.
Folates are a group of compounds which are required in the diet and are important in DNA, amino acids and possibly also amine metabolism108. The folic acid and vitamin
B12 metabolism are intimately related. Folate and vitamin B12 are required for the synthesis of purines and pyrimidines, and therefore, are important for nucleic acid and nucleoprotein synthesis