Alcohol and alcoholism (Oxford, Oxfordshire). Supplement最新文献

Ethanol abuse is a well known association of pancreatitis. Research into the pathogenesis of alcoholic pancreatitis has generally followed two directions. Firstly, factors which may predispose alcoholics to pancreatitis have been examined. To date, these studies have been negative and the predisposing factor(s) remain unknown. The second approach has involved studies on the constant metabolic effects of ethanol on the pancreas which may render the acinar cell susceptible to digestive enzyme induced injury. Recently developed models of experimental pancreatitis have implicated intracellular activation of digestive enzymes by lysosomal enzymes as an early event. Using the Lieber-DeCarli model of ethanol administration to rats, a number of changes have been described in pancreatic acinar cells which may predispose the gland to autodigestion. These changes include: (1) increased glandular content of digestive enzymes as a result of increases in mRNA levels for these enzymes; (2) increased glandular content of the lysosomal enzyme cathepsin B (known to be capable of activating trypsinogen); (3) increased fragility of lysosomes possibly mediated by cholesteryl esters and fatty acid ethyl esters; and (4) increased fragility of zymogen granules. These effects of ethanol constitute a "primed" setting (the "Drinker's Pancreas") for autodigestion. Triggering factors for autodigestion in this setting have not yet been identified.

General etiologic categories related to possible mechanisms of fetal alcohol-induced brain damage are explored. Possible general mechanisms include alterations in protein synthesis, prostaglandins, gangliosides, hypoxia and free radical damage. A multiple systems cascade is presented to illustrate how multiple mechanisms could act together to produce a variety of effects.

Alcohol dependent male outpatients were monitored for a period of six months. Indicators of alcohol consumption were compared using clinical information three times per week, serum levels of carbohydrate deficient transferrin (CDT) weekly and urine samples of 5-hydroxytryptophol daily. Individualized reference values of CDT were calculated by using an increase of three times the lowest coefficient of variation in the group, which meant that an increase of < or = 30% from the lowest value of each individual was considered a significant increase, and therefore an indication of alcohol consumption. By this approach, it was possible to improve the ability to detect relapses in alcohol dependent patients using serum CDT once a week compared to CDT using reference values recommended by the manufacturer.

Intracerebral microdialysis was used to investigate release of amino acid neurotransmitters in response to acute and chronic injection of alcohol in unanaesthetised animals. Increases in taurine levels but not of glutamate or GABA were found after acute injection of alcohol. Chronic injection of alcohol, in increasing doses over six weeks, resulted in substantially greater increases in taurine levels. Basal levels of all three amino acids were increased after chronic injection of alcohol, up to a dose of 2 g/kg body weight, but not at higher doses. Higher doses may overcome the compensatory capacity which induces increases concentrations of these neuromodulators after chronic exposure to alcohol.

To assess the interaction of alcohol and HCV infection in hepatocarcinogenesis, we prospectively studied 447 patients with liver cirrhosis (LC) who presented to our out-patient clinics in a month; 163 patients with habitual drinking (AL-LC) who had taken more than 72 g alcohol per day (HCV positive 79 cases: HCV+AL; HCV negative 84 cases: AL); 176 with HCV infection but without alcohol intake; 39 with HB infection; and 82 with liver disease from other etiologies such as primary biliary cirrhosis (PBC). In the HCV group, HCC developed in 15 patients in the first year and 10 in the second year; the cumulative appearance rate was 11% and 16%, respectively. There was no difference in the HCC appearance rate between the two groups. In the AL group, the cumulative HCC occurrence rate was only 2% in the first year, and 2% in the second year. The appearance rate was significantly lower in the AL group compared with the HCV and the HCV+AL groups. One-hundred and fourteen patients (94 with HCV, 20 with HCV+AL) who had a history of blood transfusion more than 10 years ago were selected. A year-adjusted disease occurrence rate calculated by the Kaplan-Meier method showed that the HCV+AL group had a significantly higher disease occurrence rate than the HCV group. Theses results suggest that although alcohol alone does not become an independent risk factor for HCC from LC, it may accelerate the development of HCC caused by HCV, at least in the group with a history of blood transfusion.

The efficacy of the homotaurine-derivative acamprosate (calcium acetylhomotaurinate) to increase abstinence rates in weaned alcoholics was examined in a placebo-controlled double-blind multicentre study involving 272 subjects. Preliminary results indicate a significantly higher abstinence rate during and at the end of the study (42.8% vs. 20.7%, p < 0.01), a higher number of abstinent days and a lower drop-out rate in the treated than in the placebo group.

The human stomach has both low and high K(m) ADH isozymes, resulting in significant ethanol metabolism in gastric cells in vitro, and decreased bioavailability of ethanol (first pass metabolism: FPM) in vivo. Intraduodenal or intraportal infusion of amounts of ethanol equivalent to those emptied into the duodenum or disappearing from pylorus-ligated stomachs produced significantly higher blood levels than intragastric administration, whereas portal ligation had no effect, documenting the role of gastric ethanol metabolism in vivo. This "protective barrier" against the systemic effects of ethanol disappears after gastrectomy and is partly lost in the alcoholic because of accelerated gastric emptying and decreased gastric ADH activity, respectively. The latter is also lower in women than in men, at least below the age of 50. Some ADH isozymes require a relatively high ethanol concentration for optimal activity; therefore, the concentration of alcoholic beverages affects the amount metabolized. Fasting strikingly decreases FPM, most likely because of accelerated gastric emptying, resulting in shortened exposure of ethanol to gastric ADH and its more rapid intestinal absorption. Commonly used drugs, such as aspirin, acetaminophen and some H2-blockers decrease gastric ADH activity in vitro and produce increased blood alcohol levels in vivo, particularly at a low alcohol dose, equivalent to social drinking. Effects at higher ethanol dosage are still the subject of controversy. However, not all subjects display significant FPM, and published negative reports with H2 blockers do not specify whether first pass metabolism was present to begin with; some of the negative investigations also used dilute concentrations of alcohol, shown to minimize gastric metabolism. Thus, the stomach can metabolize amounts of ethanol of clinical relevance, an effect which is attenuated by various drugs, resulting in increased blood levels.

We review evidence that genetic factors play no less important a role in the etiology of alcoholism in women than in men. Potential mediators of this genetic influence (differences in personality or alcohol sensitivity) exhibit equal heritability in men and women. Genetically determined differences in alcohol preference (or consumption level), a phenotype widely used in animal models of alcoholism, have been neglected as a mechanism of alcoholism inheritance. Using data from the 1992-3 interview survey of the Australian twin panel (N = 5995 twins), we have reexamined the mediating role of personality and alcohol consumption variables. By comparing the non-alcoholic co-twins of alcoholic twins, and twins from concordant unaffected pairs (separately for MZ and DZ pairs), we have avoided the problem of obtaining consumption and personality assessments that are contaminated by history of alcoholism. In MZ pairs, in both genders, co-twin's heavy alcohol exposure (drinking 5+ drinks in one day) and co-twin's Novelty Seeking score, are both predictive of alcoholism in the respondent. The effect of co-twin's heavy alcohol exposure remains significant even when the respondent's personality variables are controlled for, implying that there are genetic effects on alcoholism risk mediated through consumption pattern that are independent of those mediated through personality differences.

The A1 (minor) allele of the D2 dopamine receptor (DRD2) gene has been shown to be associated with alcoholism, particularly the severe form of this disorder. This allele has also been found to be involved in a variety of other substance use disorders including, cocaine and nicotine dependence, polysubstance abuse and obesity. Moreover, reduced dopaminergic function has been found in subjects carrying the DRD2 A1 allele, suggesting that the DRD2 may be a reinforcement or reward gene. Analysis of the available data suggests that the DRD2 variants represent one of the most prominent single-gene determinants of susceptibility to severe alcoholism and other substance use disorders. However, environmental factors and other genes must, in combination, play the larger role.

There is a growing body of evidence to suggest that cytokines may be involved in the aetiology of alcoholic hepatitis. To study the effects of chronic ethanol feeding on cytokine production we have maintained rats on the control and ethanol-containing forms of the Lieber-DeCarli liquid diet for six weeks. The animals were then given an i.v. injection of endotoxin to induce hepatitis. It was found that the ethanol-fed animals had biochemical and histological evidence of mild to severe liver damage whereas control-fed animals had minimal liver damage. When plasma levels of cytokines were measured, it was found that the ethanol-fed rats produced much higher levels of tumour necrosis factor and interleukin 6 bioactivity than the control-fed rats. However, elevated levels of interleukin 1 protein were not seen in the ethanol-fed animals.