ALCOHOL, NUTRITION AND ALCOHOL HUSTIC DAMAGE

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Alcohol and nutrition 1 ALCOHOL, NUTRITION AND ALCOHOLIC HEALTH DAMAGE Daniel Bunout Approximately 30% of alcoholics develop liver damage as a result of excessive alcohol intake and the reasons for the increased susceptibility of some individuals to this complication are not known. The search for possible risk factors for alcoholic liver damage has yielded variable results. It has been thought that the frequency of damage should be proportional to the total dose of alcohol ingested by an individual. This hypothesis was apparently confirmed by Lelbach, who published curves demonstrating an almost perfect correlation between the frequency of liver damage and the cumulative dose of alcohol that an individual ingests during his life. Unfortunately, these have not been reproduced by other authors. Many have suggested that sex is important, since apparently women are more susceptible to harm, however there are no well-controlled studies that prove that women, with the same amount of alcohol ingested, actually have more damage. Genetic factors could influence and HLA markers that could be related to the damage have been sought. Again, the results have been negative or doubtful. Likewise, a relationship between genetic polymorphism for alcohol gastric dehydrogenase and predisposition to liver damage has been sought, when alcohol is metabolized in the first passage through the stomach. There is evidence to suggest that those who have isoforms of gastric ADH with a low Km for alcohol may metabolize more alcohol in the stomach with a consequent lower arrival of ethanol to the liver. The genetic regulation of hepatic aldehyde dehydrogenase (ALDH) is also important. Orientals present, with a high frequency, a polymorphic variant of ALDH2 that makes them metabolize less acetaldehyde and have facial ruddiness reactions similar to those observed as a consequence of the use of disulfirane. Since acetaldehyde has been attributed an important role in the pathogenesis of alcoholic liver damage, the higher concentration of this compound that these subjects should have could give them some protection against the generation of liver damage by limiting alcohol intake. Finally, the nutritional status of excessive drinkers or the nutritional effects of alcohol have been considered an important risk factor in the genesis of liver damage. In fact, For a long time there was talk of alcoholic liver cirrhosis – nutrition almost automatically implicating nutrition in the pathogenesis of alcohol damage. To know more about the association between nutrition and liver damage by alcohol, the nutritional effects of alcohol will be reviewed, relevant aspects of the pathogenesis of alcoholic liver damage and the possible association between both aspects. NUTRITIONAL EFFECTS OF ALCOHOL: One of the main causes of malnutrition in adults in developed countries is excessive alcohol intake. An alcoholic can replace up to 60% of caloric intake by alcohol. This compound contributes calories but, apparently, the use of calories derived from alcohol is less efficient. This phenomenon was demonstrated many years ago,

twoAlcohol and nutrition 2 replaced part of their dietary calories with alcohol. Subsequently, experiments in animals and humans showed that alcohol increased thermogenesis. In addition, the displacement and malabsorption of nutrients can lead to specific deficiencies whose clinical importance can be variable. Among these, deficiency of vitamin B complex can lead to altered sensorium, peripheral neuropathy and cardiac abnormalities. Vitamin A deficiency can cause visual and gonadal alterations. and zinc deficiency cause immune problems. In addition, alcohol metabolism distorts virtually all the nutrients and the consequences of these alterations may be important in the genesis of liver damage. Carbohydrates: For years, The only alteration in carbohydrate metabolism induced by alcohol that was considered important was the inhibition of neoglucogenesis that could lead to catastrophic hiopoglicemias. However, the phenomenon that most worries is the intolerance to carbohydrates that alcoholic patients develop. It has been observed that alcoholics have altered intravenous glucose tolerance curves whose cause is not well known. The existence of peripheral insulin resistance in these individuals, measured using the glucose clamp technique, has been demonstrated by some authors and not by others. More consistent has been the finding of an inhibition of insulin secretion stimulated by glucose, caused by alcohol. Simultaneously, alcohol decreases hepatic glucose production, both in alcoholics and in normal individuals. In conclusion, excessive consumption of alcohol has a diabetogenic effect, caused by an inhibition of insulin secretion and less likely by an increase in peripheral resistance to this hormone. Proteins: The overall effect of chronic alcohol consumption is to cause a loss of proteins. The absorption of proteins is inhibited at the intestinal level by alcohol and the urinary excretion of nitrogen increases. Studies in experimental animals and humans have shown that the consumption of ethanol leads to negative nitrogen balance, which even persists during the period of recent abstinence. Alcoholics have an increased leucine flow when compared to normal subjects. These findings suggest that in addition to the lower absorption, chronic alcohol consumption leads to greater protein catabolism. The cause of this greater catabolism is not exactly known. It is possible that alcohol acts as a direct toxic on muscular proteins damaging them and producing a myopathy that is observed in almost 50% of alcoholics when it is looked for directly. It is also possible that part of the catabolic effect of alcoholism is due to the effects of cytokines on the muscle. Alcoholism in humans and animals induces the expression of mrna and the secretion of these peptides (vide infra). Lipids: It is possible that alcohol acts as a direct toxic on muscular proteins damaging them and producing a myopathy that is observed in almost 50% of alcoholics when it is looked for directly. It is also possible that part of the catabolic effect of alcoholism is due to the effects of cytokines on the muscle. Alcoholism in humans and animals induces the expression of mrna and the secretion of these peptides (vide infra). Lipids: It is possible that alcohol acts as a direct toxic on muscular proteins damaging them and producing a myopathy that is observed in almost 50% of alcoholics when it is looked for directly. It is also possible that part of the catabolic effect of alcoholism is due to the effects of cytokines on the muscle. Alcoholism in humans and animals induces the expression of mrna and the secretion of these peptides (vide infra). Lipids:

3Alcohol and nutrition 3 Alcohol inhibits lipolysis by markedly reducing levels of circulating free fatty acids. This metabolic effect was described more than 30 years ago and was recently confirmed by our group carrying out studies of marked palmitate replacement. This reduction of lipid mobilization has been associated with the genesis of alcoholic fatty liver, however there is no concrete evidence to make this type of approach. Along with the inhibition of lipolysis, alcohol increases the circulating levels of ketone bodies, an effect that seems paradoxical but that may be due to the conversion of the acetate generated during the metabolization of alcohol into acetoacetate and β hydroxybutyrate. The increase of ketone bodies is difficult to detect in clinic since it occurs at the expense of β hydroxybutyrate, because the ratio NADH: NAD increases and tend to accumulate reduced metabolites. The latter compound is not detected by the reactive tapes for ketones. Alcoholic ketosis can be a cause of metabolic acidosis in alcoholics in recent abstinence, which should be kept in mind. The consumption of alcohol also affects serum lipid levels, with an increase in triglyceride levels that quickly return to normal with abstinence. The mechanism of increased triglycerides is not known, but it is known that clearance by lipoprotein lipase is not altered by alcohol. Possibly, this effect is due to an increase in the secretion of very low density lipoproteins by the liver. In addition, we must remember that moderate alcohol consumption increases HDL cholesterol levels. The metabolism of fatty acids is also altered with alcohol. In experimental animals as well as in humans, alcohol changes the lipid fatty acid composition of various tissues in a relatively constant manner, with an increase in saturated fatty acids and a decrease in polyunsaturates (vide infra). ALCOHOL HEPATIC DAMAGE: There is consensus that one of the central mechanisms that leads to the genesis of liver damage by alcohol is the induction of the microsomal drug metabolizing system, specifically the cytochrome P 450 IIE1 (CYP2E1). A classic observation is that both animals and humans who consume alcohol for prolonged periods increase the clearance rate of this substance. Initially it was postulated that the increase in clearance could be due to a greater reoxidation of NADH, derived from an activation of the NA: K hepatocyte membrane ATPase. Subsequent studies have not been able to verify this hypothesis and it is currently thought that the most important mechanism to explain the increase in alcohol metabolism is the induction of CYP2E1. There are numerous experimental and clinical evidences that this cytochrome is specifically induced by the chronic consumption of alcohol. The consequences of this induction that can lead to liver damage are multiple: 1. Centrilobulillar hypoxia: The necrosis of hepatocytes that occurs with the liver consumption of alcohol is predominantly centrilobular, an area where oxygen availability is limited. It is in this same area where CYP2E1 is expressed with greater intensity, so it is metabolized more Subsequent studies have not been able to verify this hypothesis and it is currently thought that the most important mechanism to explain the increase in alcohol metabolism is the induction of CYP2E1. There are numerous experimental and clinical evidences that this cytochrome is specifically induced by the chronic consumption of alcohol. The consequences of this induction that can lead to liver damage are multiple: 1. Centrilobulillar hypoxia: The necrosis of hepatocytes that occurs with the liver consumption of alcohol is predominantly centrilobular, an area where oxygen availability is limited. It is in this same area where CYP2E1 is expressed with greater intensity, so it is metabolized more Subsequent studies have not been able to verify this hypothesis and it is currently thought that the most important mechanism to explain the increase in alcohol metabolism is the induction of CYP2E1. There are numerous experimental and clinical evidences that this cytochrome is specifically induced by the chronic consumption of alcohol. The consequences of this induction that can lead to liver damage are multiple: 1. Centrilobulillar hypoxia: The necrosis of hepatocytes that occurs with the liver consumption of alcohol is predominantly centrilobular, an area where oxygen availability is limited. It is in this same area where CYP2E1 is expressed with greater intensity, so it is metabolized more There are numerous experimental and clinical evidences that this cytochrome is specifically induced by the chronic consumption of alcohol. The consequences of this induction that can lead to liver damage are multiple: 1. Centrilobulillar hypoxia: The necrosis of hepatocytes that occurs with the liver consumption of alcohol is predominantly centrilobular, an area where oxygen availability is limited. It is in this same area where CYP2E1 is expressed with greater intensity, so it is metabolized more There are numerous experimental and clinical evidences that this cytochrome is specifically induced by the chronic consumption of alcohol. The consequences of this induction that can lead to liver damage are multiple: 1. Centrilobulillar hypoxia: The necrosis of hepatocytes that occurs with the liver consumption of alcohol is predominantly centrilobular, an area where oxygen availability is limited. It is in this same area where CYP2E1 is expressed with greater intensity, so it is metabolized more zone where oxygen availability is limited. It is in this same area where CYP2E1 is expressed with greater intensity, so it is metabolized more zone where oxygen availability is limited. It is in this same area where CYP2E1 is expressed with greater intensity, so it is metabolized more

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