Cortisol dysregulation and cognitive impairment in abstinent male alcoholics

BACKGROUND: Alcoholics have impaired cortisol response to stress, indicating dysregulation in the extrahypothalamic systems responsible for activating cortisol secretion in response to stressor exposure. There is a growing literature indicating a relationship between hypothalamic-pituitary-adrenocortical axis activity and neurocognitive functioning. This study examined the hypothesis that dysregulation of the hypothalamic-pituitary-adrenocortical axis may be associated with some neuropsychological impairments in alcoholics. METHODS: Serum cortisol was obtained during cognitive testing and after exposure to cold pressor and mental arithmetic stress in 48 male alcoholics abstinent for 32 +/- 6.7 days and in 30 controls; cortisol was also obtained from 18 of the alcoholic patients during withdrawal. Neurocognitive tasks included the Wechsler Memory Scale and Wisconsin Card Sorting Test. Relationships among alcoholics' cognitive test scores, cortisol levels, and drinking practices were examined by correlation and regression analyses. RESULTS: Verbal memory deficits were more severe in alcoholics who had more withdrawals and ingested a higher typical quantity of alcohol during the prior year ( p< 0.05). Higher levels of cortisol during withdrawal, an index of withdrawal severity, were associated with more errors on the Wisconsin Card Sorting Test ( p< 0.005). As previously reported, the alcoholics had lower cortisol levels after stress compared with controls. Lower poststress cortisol levels were associated with poorer logical memory on the Wechsler Memory Scale and more errors on the Wisconsin Card Sorting Test ( p< 0.05). Among controls, memory deficits occurred only in relation to higher poststress cortisol levels. CONCLUSIONS: Poorer cognitive performance in alcoholics was related to more withdrawals, heavier alcohol consumption, and higher cortisol levels during a recent withdrawal. Alcoholics' cognitive impairment was also related to attenuated stress cortisol responses. Altered stress regulation of the hypothalamic-pituitary-adrenal axis should be studied further as a potential factor related to impaired cognitive function in recovering alcoholics.     

Influence of liver disease on hepatic alcohol and aldehyde dehydrogenases

The hepatic activities and the isoenzyme patterns of both alcohol dehydrogenase and aldehyde dehydrogenase have been studied in 60 alcoholics with varying degrees of liver damage (from normal tissue or minimal changes to cirrhosis with alcoholic hepatitis) and in 24 nonalcoholics with chronic hepatitis or cirrhosis in order to ascertain their association with liver damage. In alcoholics both alcohol dehydrogenase and low-Km aldehyde dehydrogenase activities decreased proportionally with the severity of liver disease. In contrast, in nonalcoholics, there was a reduction of low-Km aldehyde dehydrogenase activity related to the severity of liver injury, but alcohol dehydrogenase was similar in patients with chronic hepatitis and nonalcoholic cirrhosis. There were no significant changes in total and high-Km aldehyde dehydrogenase activities among the different histologic groups studied, although the lowest activities were observed in patients with more severe liver injury. The prevalence of atypical alcohol dehydrogenase was similar in alcoholic (6.6%) and in nonalcoholic (8.3%) liver disease. All patients exhibited isoenzyme aldehyde dehydrogenase II, whereas isoenzyme I was not detected in 39.5% of the alcoholic patients and in 9.5% of those with nonalcoholic liver disease. The lack of aldehyde dehydrogenase I was observed in cases with the lowest enzymatic activities. These results suggest that the decrease of alcohol and aldehyde dehydrogenase activities in alcoholics is not a primary defect and, therefore, their decrease is secondary to liver damage. It is speculated that the diminution of alcohol dehydrogenase, found particularly in alcoholics, could be due to centrilobular cell necrosis.     

Alcohol and hepatitis C

BACKGROUND/AIMS: Alcohol use and hepatitis C are prominent risk factors for liver injury and this review offers the current understanding of each factor's effects on liver disease. METHODS: A Medline database search was preformed for English articles with a focus on alcohol, hepatitis C and liver disease. Article citations were also considered for further applicable articles, and the strongest studies were included in our review. RESULTS: Up to 60% of patients with hepatitis C have a past history of alcohol use. In patients with hepatitis C, chronic alcohol consumption of more than 5 drinks/day increases the rate of liver fibrosis, risk for cirrhosis, hepatocellular carcinoma, and, possibly, death from liver disease. Numerous studies have further found that even moderate amounts of alcohol can be detrimental to hepatitis C patients. The prevalence of hepatitis C is higher in alcoholics with advanced liver disease than in alcoholics without liver disease. Also, recent alcohol use decreases the response rate to interferon treatment. CONCLUSIONS: Hepatitis C and alcohol use are often co-occurring risk factors for liver disease, and though their interaction is not clear, it is known that heavy drinking significantly promotes liver disease progression.     

Qualitative differences in the visual retention test performance of older non-insulin dependent diabetic patients

To evaluate the qualitative and quantitative differences in the performance of older diabetic patients on Benton’s Visual Retention Test (BVRT), a cross sectional study of 46 non-insulin dependent diabetic men and 59 nondiabetic men over the age of 55 years was carried out. The recent memory was assessed with the Benton’s Visual Retention Test. Diabetic patients had a significantly higher error score (10.96 ± 4.07) compared to nondiabetic subjects (9.08 ± 4.45), F (1,103) = 4.923, p<0.029. Diabetic patients were more likely to make the following types of errors: omissions, distortions, size errors and left errors. Older diabetic patients appear to have mild impairment in recent memory compared to nondiabetic subjects. The qualitative pattern of the test results is suggestive of cerebrovascular etiology of the cognitive changes.     

Impaired Lymphocyte Proliferative Response to Mitogen in Alcoholic Patients. Absence of a Relation to Liver Disease Activity

Concanavalin A-induced lymphocyte proliferation was studied in 25 patients with alcoholic hepatitis or compensated alcoholic cirrhosis. Nine alcoholics without evidence of liver disease were also evaluated. A nonlinear correlation equation, which was natural logarithmic, was applied to individual dose-response proliferation curves and permitted comparisons between patient groups and controls. The proliferative response in all patient groups was significantly lower when compared to healthy controls and was independent of the presence or absence of liver disease. This suggests that some changes in immune function observed in alcoholics may be linked to the direct effects of alcohol on the immune system rather than to the associated liver disease.     

Effect of hepatitis C virus infection and abstinence from alcohol on survival in patients with alcoholic cirrhosis

GOALS: We assessed the effect of HCV infection and abstinence from alcohol on survival in a cohort of patients with alcoholic cirrhosis. BACKGROUND: Hepatitis C virus (HCV) infection may be an important cofactor for liver disease in chronic alcoholics. STUDY: The study population consisted of 213 patients with the diagnosis of alcoholic cirrhosis, 72 of these patients were infected by HCV. Complete alcohol abstinence after diagnosis of alcoholic cirrhosis was recorded in 86 patients. The reference group consisted of 89 patients with anti-HCV positivity who had never consumed alcohol. Survival was analyzed by the Kaplan and Meier method and predictors of survival by the Cox's multiple regression model. RESULTS: HCV infection was not a determinant factor for survival in alcoholic cirrhosis. Age and Child-Pugh grade at the time of diagnosis of cirrhosis and persistence of alcohol consumption after diagnosis were independent predictors of poor outcome. The cumulative survival curve in abstinent alcoholics was significantly different from that of alcoholics who maintained the same pattern of alcohol consumption (log-rank = 4.30, p = 0.0381). Moreover, the cumulative survival in patients with anti-HCV-positive cirrhosis who stopped drinking after diagnosis was similar to that in patients with HCV-positive cirrhosis who had never consumed alcohol (log-rank 0.26, p = 0.61). CONCLUSIONS: Cumulative survival in alcoholic cirrhosis does not seem to be influenced by the presence or absence of markers of HCV infection. Once liver cirrhosis has been diagnosed in the alcoholic patient, complete alcohol abstinence should be strongly recommended.     

Liver disease in alcohol and hepatitis C

The prevalence of hepatitis C is 7-10-fold higher in alcoholics than it is in the general population. Among alcoholics, the prevalence of hepatitis C is higher in alcoholics with advanced liver disease. Serum ALT and hepatitis C viral load may improve if alcoholic patients with hepatitis C stop drinking for more than 4 months.Up to 60% of patients with hepatitis C have a past history of alcohol use. In patients with hepatitis C, chronic alcohol consumption of more than 5 drinks per day increases the rate of liver fibrosis. Hepatitis C patients who ingest more than 5 alcoholic drinks per day are at increased risk for cirrhosis, hepatocellular carcinoma and, possibly, death from liver disease. Recent alcohol use decreases the response rate to interferon treatment. The detrimental effects of small amounts (3 or fewer drinks per day) of alcohol consumption in patients with hepatitis C are not known.     

Albumin and collagen gene regulation in alcohol- and virus-induced human liver disease

Common features of chronic alcoholic liver disease are progressive hypoalbuminemia and a spectrum of liver fibrosis. The molecular mechanisms that account for these effects are still the subject of controversy. Therefore, in the present study we evaluated albumin and collagen gene expression in livers of alcohol abusers and patients with virus-induced liver disease. Albumin and pro alpha 1(I) collagen messenger RNA levels were determined in 30 patients who underwent diagnostic liver biopsy. Of 14 alcoholics, 7 had alcoholic hepatitis alone and the other 7 had cirrhosis plus alcoholic hepatitis. Of 16 nonalcoholic patients with chronic viral infection, 6 had chronic active hepatitis and 10 had cirrhosis plus chronic active hepatitis. Total RNA was extracted from a portion of each biopsy specimen, hybridized with a human albumin or collagen complementary DNA clone, and compared with 2 normal surgical specimens, which served as controls. The Northern hybridization studies showed that (a) despite the presence of inflammation and fibrosis, the albumin messenger RNA levels of alcoholics were similar to those of the controls; (b) these alcoholics had significantly higher levels of albumin messenger RNA than did patients with similar histological levels of disease due to viral infection; and (c) all the categories of patients had markedly increased procollagen messenger RNA levels compared with controls. Given these results it is tempting to speculate that alcohol may actually increase albumin messenger RNA content in humans as it does in animals. Furthermore, the increased procollagen messenger RNA levels in fibrotic livers suggest that an increase in collagen syntheses may be a significant factor in the pathogenesis of hepatic fibrosis.     

Effect of ethanol on human polynuclear neutrophils. In vitro and in vivo study

Human polynuclear neutrophilic function was studied to determine the role of alcohol in the increased susceptibility to infection of chronic alcoholics: in vitro studies investigated the effects of different concentrations of ethanol; in vivo studies included comparison with healthy subjects after alcohol intake, with excessive drinkers without liver disease and with chronic alcoholics with confirmed cirrhosis. In vitro depression of polynuclear neutrophilic function was observed only with significantly higher concentrations of ethanol than encountered clinically. In social and excessive drinkers, phagocytosis was decreased but there was no change in bactericidal activity. On the other hand, in cirrhotic alcoholics chemotaxis, phagocytosis and bactericidal activity were all significantly reduced. A direct action of alcohol alone on polynuclear function would not seem to be the cause of the increased risk of bacterial infection of chronic alcoholics.     

Improvement in Cognitive Functioning of Alcoholics Following Orthotopic Liver Transplantation

Cognitive functioning in alcoholic cirrhotics before and 1 year following orthotopic liver transplantation was compared with age- and sex-matched normal subjects. The alcoholic group improved significantly following transplantation on tests measuring psychomotor, visuopractic and abstracting abilities whereas the performance of normal controls remained virtually unchanged. In contrast, memory capacity in alcoholics with cirrhosis did not statistically improve following successful transplantation. Further investigation, using more sophisticated measures of memory function, are required to determine whether memory deficits are either associated with alcohol neurotoxicity or an irreversible component of hepatic encephalopathy. These findings suggest that a reversible hepatic encephalopathy underlies many of the neuropsychologic deficits observed in cirrhotic alcoholics and can be ameliorated following successful liver transplantation.     

Polymorphism in the interleukin-1 receptor antagonist gene is associated with alcoholism in Spanish men

BACKGROUND: A polymorphism located in intron 2 of the interleukin-1 receptor antagonist (IL1RN) gene recently has been associated with the development of hepatic fibrosis in Japanese alcoholics. In the present study, we analyzed whether there is an association between this polymorphism, alcoholism, and alcoholic liver disease in a Spanish male population of alcoholics. METHODS: The IL1RN genotype was assessed by polymerase chain reaction by using oligonucleotides that flank a variable nucleotide tandem repeat polymorphism located in intron 2 of this gene in 90 male alcoholic patients from Spain: 30 alcohol-dependent men, 30 alcohol abusers, and 30 alcoholics with liver cirrhosis. We also studied 40 healthy subjects. RESULTS: The distribution of the IL1RN allelic frequencies in Spanish healthy subjects is similar to that previously reported in White subjects. However, the A1 allele is overrepresented in Spanish alcoholics when compared with healthy subjects. No significant differences in allelic frequencies were observed between alcoholics with liver cirrhosis and alcoholics without liver disease or between alcohol-dependent subjects and alcohol abusers. CONCLUSION: The presence of the A1 allele of the IL1RN gene is associated with a higher risk of alcoholism in Spanish men.     

Pattern of Alcohol-related Liver Disease in Dependant Alcoholics: the Indian dimension

To study the incidence and profile of alcoholic liver disease in dependant alcoholics, 56 patients, 31 with moderate and 25 with severe dependence on alcohol, were assessed by a severity of alcohol dependence questionnaire. All the patients were males. Forty-five (80.4%) dependant alcoholics were found to have alcoholic liver disease, diagnosed either by abnormal biochemical tests (78.6%) or when available, specific histological lesions (87.8%). Of the 49 (87.5%) patients in whom liver biopsy could be obtained, fatty liver was seen in 17 (34.7%), hepatitis in 22 (44.9%) and cirrhosis in four (8.2%) patients. Liver biopsy was normal in the remaining six (12.2%) patients. Symptoms suggestive of alcoholic liver disease were however, observed in only 18.6% patients. No significant difference was seen in the nature and severity of biochemical and histological liver injury between patients with moderate or severe dependence on alcohol. It can be concluded that significant hepatic abnormalities exist in a high percentage of dependant alcoholics in India. Increased awareness and institution of measures for early screening of these patients for the presence of underlying liver disease are warranted.     

The influence of HLA antigens on progression of alcoholic liver disease

The aim of our study was to elucidate further possible genetic influences on the incidence and progression of alcoholic liver disease. We determined HLA A, B and DR antigens in a well-controlled group of chronic alcoholics with and without liver disease, in repeated liver biopsies over period of 8.1 years (+/- 0.4 SEM). Patients with the antigen B 35 had an increased incidence of alcoholic liver cirrhosis, and especially a more rapid progression to cirrhosis (p less than 0.01). Increased susceptibility of these patients was shown by a more rapid progression of liver disease, despite the consumation of less alcohol over a shorter period. Results of this long-term study suggest that there is a sub-group of alcoholics genetically predisposed to higher susceptibility with more rapid deterioration of alcohol-induced liver disease.     

Alcohol-induced liver disease

Hepatic changes resulting from the regular ingestion of alcohol are many and include fat infiltration, alcoholic hepatitis, and cirrhosis. Only 10% to 15% of chronic alcoholics develop liver disease. Women are more susceptible. An area of considerable importance is the high prevalence of concomitant infection with hepatitis C virus in chronic alcoholics. Patients who have hepatitis C and alcohol-induced liver injury are much more likely to develop progressive liver disease and cirrhosis. Corticosteroid therapy has proven useful in the treatment of patients with severe acute alcoholic hepatitis.     

Independent effects of liver disease and chronic alcoholism on thyroid function and size: the possibility of a toxic effect of alcohol on the thyroid gland

In an autopsy study we found thyroid volume significantly decreased in alcoholics with liver cirrhosis as compared to matched controls: 15 mL (range, 7 to 37 mL) v 25 mL (range, 13 to 90 mL) (P less than .01). At the same time the amount of fibrosis of the thyroid glands was higher in the alcoholics as compared to the matched controls: 20% (range, 6% to 40%) v 12% (range, 6% to 23%) (P less than .01). In order to evaluate the relative importance of alcohol consumption and liver disease on thyroid function and ultrasonically determined size, three groups of patients and matched controls (sex, age, weight, and smoking habits) were investigated: group 1, 18 patients with nonalcoholic liver cirrhosis; group 2, 21 consecutive chronic alcoholics (greater than 100 g of alcohol daily for greater than 5 years) without liver cirrhosis (all had biopsy proven fatty change or normal liver); group 3, 31 nonalcoholic patients with chronic nonhepatic, nonrenal disease. In group 1 median thyroid volume and serum FT4I, FT3I, and TSH levels were unchanged compared with the controls. In group 2 median thyroid volume was 13 mL (range, 9 to 32 mL) compared with 27 mL (range, 12 to 44 mL) in the controls (P less than .005). Serum T3 and FT3I levels were reduced, while T4, FT4I, and TSH levels were unaltered. In group 3 serum T3 and FT3I levels were reduced while serum FT4I and TSH levels and thyroid volume were unaltered compared with the controls. It is suggested that alcohol may have a toxic effect on the thyroid gland independent of the degree of liver damage.     

Cognitive impairment in alcoholic and nonalcoholic cirrhotic patients

Cognitive impairment is common in patients with advanced liver disease. It has been suggested that patients with alcoholic liver disease (ALD) have more impaired cognition than nonalcoholics. The objective of this study was to characterize any differences in cognitive functions between alcoholic cirrhotic patients and non-alcoholic cirrhotic patients of similar age, education, and severity of liver disease. We assessed cognitive functions in 117 patients with alcoholic cirrhosis and 163 patients with nonalcoholic cirrhosis using a brief battery of neuropsychological tests. In addition, all patients had standard psychiatric examinations to assess the effect of the disease severity, alcoholism, anxiety, and depression on the test scores. The study showed a higher proportion of patients with cognitive impairment in the alcoholic group. Alcoholics performed poorly in tests of memory and motor speed compared with nonalcoholics, despite similar premorbid IQ and education. Because patients with alcoholic cirrhosis had more severe liver disease (Child-Pugh score 8.5 +/- 2.2 vs. 7.6 +/- 2.2, P =.03) than nonalcoholics, the results were reanalyzed after adjusting for the linear effects of Child-Pugh score on cognitive test scores. We also used two-way analysis of variance to examine the interaction between Child class and alcoholism. Finally, the test scores were compared within each Child class. These analyses revealed no primary or interaction effect of alcoholism and confirmed that the differences in the test scores observed in alcoholics reflect the greater severity of their liver disease. The severity of cognitive impairment is similar in both alcoholic and non-alcoholic cirrhotic patients when adjusted for the severity of liver disease.     

-238 G>A polymorphism of tumor necrosis factor alpha gene (TNFA) is associated with alcoholic liver cirrhosis in alcoholic Spanish men

BACKGROUND: The tumor necrosis factor alpha gene (TNFA) has been recently associated to alcoholic steatohepatitis. We have analyzed the distribution of genotypes and alleles of two polymorphisms at positions -238 and -308 in the promoter region of the TNFA gene in a Spanish male population of alcoholics with and without alcoholic liver cirrhosis. METHODS: 149 male alcoholics (84 without alcoholic liver disease, and 65 with alcoholic liver cirrhosis) and 90 control subjects were included. Genotyping was done by polymerase chain reaction and digestion with restriction enzymes. RESULTS: No significant differences in the distribution of genotypes and alleles of the -308 TNFA gene polymorphism were observed between alcoholics and non-alcoholics, or between alcoholics with liver cirrhosis and those without liver disease. However, we found an association between the -238 TNFA polymorphism and alcoholic liver cirrhosis; the frequency of the heterozygous genotype being significantly higher in alcoholics with cirrhosis than in those without liver damage. CONCLUSION: The -238 TNFA-A allele is associated with a higher risk to develop alcoholic liver cirrhosis. This polymorphism could be considered as a genetic factors that confer predisposition to suffer liver cirrhosis in the alcoholic population of Castile and León.     

Ethanol metabolism in liver cirrhosis and chronic alcoholism.

Ethanol metabolism and its influence on serum lactate/pyruvate ratio was studied after intravenous infusion of ethanol in 17 patients: 4 controls, 5 alcoholics with cirrhosis, 4 non-alcoholic cirrhotics and 4 alcoholics without liver disease. All refrained from the use of alcohol and drugs 4 weeks prior to the experiment. After maximal ethanol blood levels were achieved at the end of the infusion, ethanol removal occurred at two different rates. This was probably due to the fact that different volumes of ethanol were distributed with time: a fast period (30 to 60 min) and a slow period (60 to 180 min). The rates of disappearence in the two periods were similar in all groups which suggests that liver cirrhosis, independent of clinical severity and/or chronic alcoholism with previous abstinence from alcohol, does not modify ethanol metabolic rates in the liver. The relation lactate/pyruvate doubled in all cases but it occurred within 30 minutes in the groups without liver disease and within 60 minutes in the cirrhotics. This could account for the decreased liability of cirrhotic patients to alcohol hypoglycemia.     

Nutritional aspects of alcoholic liver disease

Development of ethanol-induced fatty liver, alcoholic hepatitis, and cirrhosis has been attributed in part to nutritional deficiencies for many years. Special attention must be focused on treating alcohol-induced liver disease while providing replacement of deficient amino acids, vitamins, minerals, and other nutrients. Avoidance of alcohol intake is required to eliminate progressive liver disease in alcoholics. This is best achieved by using educational and social programs to convince patients and their caretakers of the great necessity to eliminate alcohol intake.