Antibodies against acetaldehyde-modified epitopes: presence in alcoholic, non-alcoholic liver disease and control subjects.

Several studies have recently shown the presence of antibodies against acetaldehyde-modifications in the sera of alcoholic patients. To assess the specificity of this immune response, plasma immunoreactivity with proteins modified in vitro by acetaldehyde was measured using an enzyme-linked immunosorbent assay in 97 alcoholic patients with varying degrees of alcoholic liver disease, in 35 patients with non-alcoholic liver diseases and in 33 control subjects who were social drinkers. All three groups showed some response against acetaldehyde-modified epitopes. The highest plasma reactivities were found in alcoholics, especially those with steatosis and alcoholic hepatitis. Plasma from patients with non-alcoholic liver disease and control subjects also reacted with the acetaldehyde conjugates, but to a lesser extent than plasma from alcoholics. The reliability of these antibodies as markers of either alcohol abuse or alcoholic liver disease therefore appears to be low. However, further studies using more precisely modified proteins or elucidation of the classes of immunoglobulin involved in the immune response against the modified proteins may give clearer differences between the three groups.     

Selenium status in patients with liver cirrhosis and alcoholism

1. Selenium status and blood levels of other nutrients related to lipid peroxidation were studied in patients with advanced alcoholic liver cirrhosis, in male alcoholics who had been abstinent for at least 1 month and in healthy control subjects. 2. Plasma Se was decreased in alcoholic cirrhosis but not among alcoholics in abstinence. Platelet glutathione peroxidase (EC 1.11.1.9; GSH-Px) activity was decreased in cirrhotic patients, whereas GSH-Px in blood and plasma was the same as in controls for both groups of patients. 3. Plasma retinol and plasma alpha-tocopherol were decreased in alcoholic cirrhosis, whereas plasma ascorbic acid was the same in all groups. 4. The decreases in platelet GSH-Px, plasma Se and alpha-tocopherol indicate a deranged antioxidant defence in patients with advanced alcoholic cirrhosis, but the levels of these and other nutrients were generally not correlated to common clinical chemical indicators of liver disease.     

Rôle des acides gras alimentaires dans la physiopathologie des hépatopathies alcooliques

Many experimental studies in animals suggest that dietary fat plays an important role in the pathogenesis of alcoholic liver disease. Polyunsaturated fatty acids potentiate alcohol-induced liver injury at least in part by inducing cytochrome P450 2E1, cyclooxygenase-2 and lipid peroxydation. On the other hand, dietary saturated fatty acids reduce steatosis, necrosis, inflammation and fibrosis in conjunction with decreased expression of TNF-α and cyclooxygenase-2, and reduce lipid peroxidation. Dilinoleoyl-phosphatidylcholine prevents alcohol-induced fibrosis and cirrhosis in baboons and stimulates collagenase activity in cultured lipocytes. There are few human studies which confirm these experimental results. Epidemiological studies suggest a relationship between daily fat intake, particularly dietary polyunsaturated fatty acids, and the risk of liver cirrhosis in alcoholics. The studies having demonstrated that being overweight is a risk factor of alcoholic cirrhosis and that the apolipoprotein E polymorphism influences the severity of liver injury in alcoholic cirrhotics strongly favor the role of fatty acids in the pathogenesis of human alcoholic liver disease.     

Chemiluminescence and superoxide dismutase in the plasma in patients with alcoholic and non-alcoholic liver injuries

The chemiluminescence level and superoxide dismutase (SOD) activity were determined in the plasma of patients with alcoholic and non-alcoholic liver injuries. Chemiluminescence level was significantly higher in alcoholics than in non-alcoholics. It increased significantly in patients with fatty livers and had a tendency to increase with the progression of alcoholic liver injury from a fatty liver to liver cirrhosis. Mn-SOD activity was elevated in patients with alcoholic liver injuries. Furthermore, there was a positive correlation between the levels of plasma chemiluminescence and plasma Mn-SOD activity. The increases in chemiluminescence and Mn-SOD activity suggests that the generation of a large amount of activated oxygen is associated with the pathogenesis and progression of alcoholic liver injury in humans.     

THE EFFECT OF ALCOHOL ON MALE AND FEMALE SEXUAL FUNCTION

In the chronic male alcoholics several mechanisms are involvedin the pathogenesis of the sexual dysfunction that manifestsitself clinically as testicular atrophy, gynaecomastia, impotenceand sterility. Animal studies have distinctly demonstrated theability of alcohol to impair testosterone production and spermatogenesisboth through its direct toxic effects on the testes and throughinterference in the function of the hypothalamic-pituitary-gonadalaxis. The alcohol-induced enhancement of testosterone catabolismalso contributes to the loss of plasma testosterone. Apart frombeing hypoandrogenized, chronic alcoholic men are also exposedto the excessive oestrogen effect that results from the accumulationof oestrogenic hormones, principally from that of oestrone,and from the changes in oestrogen receptors. The role of hyperprolactinaemiain the alterations of sexual function of chronic male alcoholicsis unknown. The significance of liver damage in the pathogenesisof hormonal disturbances is emphasized by the finding that,apart from impairment of spermatogenesis, the hormonal changesseem to be most marked in alcoholic men with liver cirrhosis. Animal studies have again dearly demonstrated the toxicity ofalcohol to female gonads. Consistent with the animal findings,menstrual abnormalities, decreased female sexual characteristicsand sterility associated with ovarian atrophy have been reportedin chronic alcoholic women. The loss of oestrogens and progesteroneprovides the hormonal basis for these changes. In spite of markedhypo-oestrogenization, plasma gonadotropin levels have not beenelevated in chronic female alcoholics, indicating that disturbedregulation of gonadotropin secretion is an important factorin the genesis of ovarian failure in these patients, even ifovarian function may also be directly impaired. Hyperprolactinaemiais not one of the hormonal hallmarks of sexual dysfunction inchronic alcoholic women.     

Contrasts in interleukin-1 and interleukin-2 activity in alcoholic hepatitis and cirrhosis

To investigate whether disordered immune function, as shown by abnormalities in lymphokine production, is present in alcoholic liver disease, interleukin-1 and interleukin-2 activity were assayed in a group of patients with acute alcoholic hepatitis in the absence of underlying cirrhosis, and a group of patients with inactive alcoholic cirrhosis. Activities of both IL-1 and IL-2 in alcoholic hepatitis were similar to those of normal individuals, although in abstinent patients with alcoholic cirrhosis, IL-1 activity was increased and IL-2 activity decreased. Lymphocyte transformation in response to PHA in patients with alcoholic hepatitis was significantly impaired when compared with normal controls, and addition of exogenous IL-2 did not correct this impaired response over a wide range of concentrations of both PHA and IL-2. These observations suggest the underlying defects in cell mediated immunity in acute alcoholic hepatitis, as assessed by blast transformation, could be fundamentally different from those of alcoholic cirrhosis and could be secondary to the metabolic effects of acetaldehyde or altered redox potentials on the behaviour of proliferating cells.     

Elevated levels of blood lead in alcoholic liver disease

Summary In order to investigate the effect of alcohol intake on the activity of erythrocyte aminolevulinate dehydratase (ALA-D), serum alcohol concentration and ALA-D activity was determined in 4 groups of patients. Group I: 18 chronic alcoholics (active phase). Group II: 14 chronic alcoholics (inactive phase). Group III: 13 chronic alcoholics suffering from a biopsy verified liver cirrhosis. Group IV: 16 non-alcoholic patients with biopsy verified liver cirrhosis. Blood lead concentration was determined in patients from group III and IV.ALA-D values were found to be within the normal range in patients from group I, II and IV. 8 patients from group III had abnormally low ALA-D values and 4 of these had elevated blood lead values. Data from group III and IV yields a significant (P < 0.001) negative correlation between blood lead and ALA-D values. No correlation could be demonstrated between serum alcohol and ALA-D values from group I and III.It is suggested that patients suffering from liver cirrhosis may accumulate lead at an increased rate and that alcohol intake in these patients may cause a release of lead from the liver to the blood and thereby a depression of ALA-D activity.     

Hypertension in early alcohol withdrawal in chronic alcoholics

AIMS: Hypertension is an established risk factor in chronic alcoholics, but little is known about the relationship between blood pressure (BP), severity of their alcohol abuse, and severity of alcohol withdrawal syndrome (AWS). METHOD: BP was assessed daily for 18 days in a series of chronic alcoholics on early alcohol withdrawal (AW), while also assessing the severity of their AWS on the CIWA-Ar scale. RESULTS: A sharp and sustained decrease in BP was observed after AW; at T0, BP had increased in 55% of patients, and at T18 in 21%. The variation of BP is partially explained by years of at-risk drinking and AWS severity, but other factors may play a role in hypertension in alcoholics, as a large amount of BP variation was not explained by the alcohol-abuse-related parameters that we studied. BP values were not correlated with cigarette smoking, anxiety, or depression. Hypertension found in 'detoxified' alcoholics (approximately 20%) may be related to alcohol-independent hypertension or to a long-lasting alcohol-induced derangement of the BP regulating mechanisms. Further research is needed in these patients to elucidate the mechanisms of persistent hypertension and to set up a treatment protocol. At present, careful monitoring is advisable, as well as pharmacological treatment for moderate or severe hypertension; often a modification of life-style is needed which includes physical activity and possibly sodium (Na) restriction, since hypertension in detoxified alcoholics seems to be Na sensitive. CONCLUSION: Complete alcohol abstinence must be recommended to all hypertensive alcoholics, as AW-induced transient hypertension was found to be harmless in all our subjects, and abstinence leads to a complete recovery from hypertension in most cases.     

Serum lipids in alcoholic patients with and without cirrhosis of the liver, with particular reference to endogenous familial hypertriglyceridemia.

The purpose of this study was to determine the frequency of hypertriglyceridemia in alcoholic patients with and without cirrhosis of the liver. It had been observed by others that subjects with endogenous familial hypertriglyceridemia (type IV hyperlipoproteinemia) showed an exaggerated lipidemic response to ingestion of alcohol, and, therefore, might be predisposed to hepatic cirrhosis. Comparison of 40 alcoholic cirrhotics with 40 noncirrhotic alcoholic patients showed no increased incidence of hypertriglyceridemia in either group. The findings suggest that the frequency of cirrhosis in the general population is not materially affected by subjects with this metabolic defect.     

Alcoholic liver disease: to transplant or not to transplant?

Liver transplantation for patients with alcoholic liver disease remains very controversial. We review recent data which suggest that, contrary to earlier reports, many alcoholic patients with end-stage liver disease are able to meet stringent selection criteria and that these selected alcoholics achieve a good result from a liver transplant. Conversely, non-selected alcoholics have a significantly poorer survival. This raises the question as to what is the most appropriate method to select alcoholic patients for liver transplantation. We advocate a selection process which considers the potential recipients' medical, surgical and psychiatric suitability rather than their diagnosis. We outline how we have arrived at this approach in part because of the heterogeneity of patients who carry the diagnosis 'alcoholic liver disease'. We describe how we try to estimate prognosis for future abstinence, which is based on a profile of historical features rather than a fixed period of sobriety. Using this approach, the incidence of recidivism in the first 2 years after transplantation has been low. Prospective longitudinal studies are needed to improve methods of selection for the management of alcoholic patients undergoing liver transplantation.     

Comorbid anxiety and affective disorder in alcohol-dependent patients seeking treatment: the first Multicentre Study in Germany

The goals of this study were to describe demographic variables, drinking history, and the 6-month prevalence of Axis I comorbidity among alcohol-dependent subjects in GERMANY: The variables: amount of alcohol consumption, age at onset of the first alcohol consumed, age at onset of daily alcohol consumption, age at onset of withdrawal symptoms and number of detoxifications were related to the different comorbid disorders and gender. In this study, 556 patients from 25 alcohol treatment centres were enrolled between 1 January 1999 and 30 April 1999. After a minimum of 10 days of sobriety patients who fulfilled ICD-10 and DSM-IV criteria of alcohol dependence were interviewed for data collection using the Mini-DIPS (German version of the Anxiety Disorders Interview Schedule) and a standardized psychosocial interview. The 6-month prevalence of comorbid Axis I disorders was 53.1%. Among the patients with comorbidity, affective and anxiety disorders were most frequent. Comorbid stress disorder was associated with an early start of drinking, an early beginning of withdrawal symptoms, highest number of detoxifications, and the highest amount of alcohol consumed. Female patients with anxiety disorder consumed more alcohol and started earlier than females without this comorbid disorder. The data do not answer the question of the pathogenesis of comorbid disorders and alcoholism, but indicate that stress disorders in alcoholic patients and anxiety disorders in female alcoholics influence the course and severity of alcoholism.     

Biochemical markers of chronic alcoholism

Usefulness of several biochemical markers for the monitoring of chronic alcoholism were studied. Among generally used markers, only gamma-GTP showed a significant difference between alcoholic and non-alcoholic liver diseases. Serum glutamate dehydrogenase (GDH) activity was significantly high in alcoholic liver disease. When the ratios of GDH to ornithine carbamyl transferase (OCT) were calculated, differences between alcoholic and non-alcoholic liver diseases became clearer without overlapping of any value. Serum desialo-transferrin was found in about 60% of the alcoholics, and disappeared by abstinence. Microheterogeneity of serum protein was also found in other glycoproteins. Serum prealbumin level was significantly high in alcoholics without severe liver disease. Acetaldehyde dehydrogenase (ALDH) activity of erythrocytes was significantly low in alcoholics, and gradually increased after abstinence. These results indicate that microheterogeneity of glycoproteins, serum prealbumin level and erythrocyte ALDH activity are good markers of alcohol abuse, and serum GDH/OCT ratio is the most sensitive marker of alcoholic liver injury. Serum gamma-GTP activity is a good marker of both conditions.     

Nutritional status of alcoholic patients: it's possible relationship to alcoholic liver damage

This study was performed to look for a possible relationship between the nutritional status and the presence of liver damage in alcoholic patients. One hundred chronic alcoholics admitted for treatment to the Alcoholism Ward, without clinical signs of liver failure, were studied. In 84, anthropometric nutritional indexes, liver function tests, and a liver biopsy were performed; in 69 patients a dietary survey was obtained. A dietary imbalance was observed in the total group; 65% of ingested calories were derived from ethanol. The intake of proteins, vitamins, and minerals was below the RDA, NAS/USA, and no differences were found between patients with and without liver damage. Neither were significant differences in daily alcohol calories or total ethanol dose found between both groups of patients. Mean anthropometric values were within 80 to 100% of commonly used standards. However, patients with alcoholic hepatitis and/or cirrhosis had a significantly higher percentage of ideal body weight, compared to alcoholics with normal livers or less severe histological alterations (109.7 +/- 20.3 versus 95.6 +/- 12.5, SD, p less than 0.005). A similar difference was observed in arm muscle areas. These findings show that overweight is associated with liver alterations in the alcoholic and should be investigated as a risk factor to develop liver damage.     

Role of the GABAB receptor system in alcoholism and stress: focus on clinical studies and treatment perspectives

Alcoholism and stress share some common neurobiological circuits, including the GABAergic system. In particular, the GABA_B receptor seems to play an important role. The GABA_B receptor agonist baclofen has been studied as a treatment for alcohol-dependent subjects. Baclofen administration in alcohol-dependent patients was able to promote abstinence, inducing the remission of withdrawal symptoms, reducing alcohol craving, and reducing alcohol intake. Baclofen also reduced anxiety in alcohol-dependent subjects, probably acting on brain stress circuitry and/or on other neuroendocrine systems. Baclofen also showed excellent safety and tolerability, even in alcohol-dependent patients with advanced liver disease (i.e., cirrhosis). Future studies should investigate which alcoholic subtype may better benefit of the administration of baclofen in the treatment of alcohol dependence.     

Controlled study on the combined effect of alcohol and tobacco smoking on testosterone in alcohol-dependent men

Aims: The present study examined the association between pre-treatmentdrinking and smoking parameters and plasma testosterone levelsbefore and after alcohol withdrawal. Methods: A total of 51alcohol-dependent men and 43 age-matched healthy men were investigated.In alcoholics, free testosterone in plasma was measured on theday of admission, after detoxification and after 6 weeks ofsobriety. Results: While the testosterone level of alcoholicmen did not differ from healthy controls at the onset of withdrawal,it was significantly higher for the alcoholics after 6 weeksof sobriety than for the healthy controls. Higher alcohol consumptionand higher tobacco use before detoxification led to higher levelsof testosterone concentration before and after withdrawal. Conclusions:The effect of alcohol and tobacco is cumulative, with higherlevels of alcohol and tobacco consumption being associated withhigher levels of testosterone before and after alcohol withdrawal.     

Alcoholic liver disease: roles of alcohol and malnutrition

A toxic effect of alcohol is the principal cause of the development of liver disease in alcoholism. Fatty infiltration of the liver is a consequence of ethanol metabolism due mainly to an increased synthesis and decreased degradation of fatty acids. Mechanisms that have been suggested for ethanol-induced hepatocellular necrosis include centrolobular hypoxia due to an increased oxygen requirement and intracellular accumulation of protein, fat, and water which results in increased cell size. Hepatocellular necrosis, however, may not be a necessary stage in the development of cirrhosis. Chronic ethanol administration increases hepatic collagen deposition, and acute and chronic ethanol administration inhibit liver cell regeneration. Increased humoral and cellular immunological activity to liver tissue and its components may contribute to the persistence of liver disease in the alcoholic. However, only a small proportion of alcoholics and baboons fed alcohol develop cirrhosis, suggesting that other factors, either genetic, environmental, or nutritional, play a role. Malnutrition is common in alcoholics. Liver disease is more common in some malnourished populations, and has been produced by nutrient deficiencies. Decreased dietary intake, as well as malabsorption and alterations in the metabolism of nutrients, are causes of nutrient deficiencies in alcoholism. Some of the effects of alcohol on the liver may be mediated by its actions on nutrient absorption and metabolism.     

Blood cell superoxide dismutase and enolase activities as markers of alcoholic and nonalcoholic liver diseases

Monitoring of chronic alcoholism would be facilitated by using sensitive biochemical markers in blood cells, mainly to detect differences between alcoholic subjects with or without liver injury. We propose two types of markers: the first one is superoxide dismutase (SOD) activity involved in the conversion of superoxide radicals (O2-.) formed during acetaldehyde oxidation by xanthine oxidase after chronic alcohol consumption; the second one is enolase activity with both isoenzyme forms: nonneuronal enolase (NNE) and neuron specific enolase (NSE) which has been shown to be modified in many injuries related to the glycolytic pathways. For SOD activity we found a significant increase in alcoholic patients with liver injury and mainly in cirrhotic patients with ascitis. Both enolase activities were also found to be significantly increased in alcoholic patients with liver injury but NNE activity was also increased in alcoholics without apparent liver disease. Our results suggest that increased activity of SOD and NSE in blood cells may be related to liver injury mainly in alcoholism while increased NNE activity may also be a marker of alcohol abuse without liver injury.     

Interleukin-1 gene cluster polymorphisms and alcoholism in Spanish men

AIMS: In an attempt to explain differences in susceptibility to alcoholism and alcohol liver disease (ALD), different genes have been analysed, among them those encoding inflammatory cytokines. Thus, it has been reported recently that both the interleukin 1 receptor antagonist (IL1RN) and the IL1beta (IL1B) genes may influence the risk of ALD in Japanese alcoholics. We analysed the distribution of single nucleotide polymorphisms (SNPs) located in the IL1A, IL1B, IL1R1 and IL1RN genes in alcoholic and non-alcoholic Spanish subjects. METHODS: DNA samples were obtained from 139 male alcoholics, 78 of whom were diagnosed as alcohol dependent (32 patients with liver cirrhosis and 46 without ALD) and 61 as alcohol abusers (25 with liver cirrhosis and 36 without ALD). As a control, we studied 81 age- and sex-matched healthy volunteers. RESULTS: Alleles -511 IL1B*1 and IL1RN*1 were represented more in alcoholic patients than in the control group. We did not find any association of alcoholism or ALD with polymorphisms in the IL1A and IL1R1 genes. CONCLUSIONS: We conclude that the proteins encoded by the IL1RN and IL1B genes may be involved in susceptibility to alcoholism in Spanish men, probably through a different pathway from that involved in the regulation of the inflammatory response.     

Growth hormone response to the GABA-B agonist baclofen in 3-week abstinent alcoholics.

Gamma-aminobutyric acid (GABA) dysfunction is a known feature of alcoholism. We investigated GABA-B receptor activity in 3-week abstinent alcoholics using the growth hormone (GH) response to baclofen, a GABA-B receptor agonist. The study aimed to investigate the relationship between GABA-B receptor activity and alcohol withdrawal. GH response to baclofen was measured in alcohol-dependent males without depression (n = 22) who were on day 21 of alcohol abstinence and in healthy control male subjects (n = 23). After 20mg baclofen was given orally to the subjects, blood samples for GH assay were obtained every 30 min for the subsequent 150 min. The patients were divided into two subgroups (continuing withdrawal and recovered withdrawal subgroups) according to their withdrawal symptom severity scores on day 21 of alcohol cessation. Baclofen administration significantly altered GH secretion in the controls, but not in the patients. When GH response to baclofen was assessed as DeltaGH, it was lower in the patients with continuing withdrawal symptoms than in the controls and in the recovered withdrawal group. Impaired GH response to baclofen in all patients mainly pertained to the patients whose withdrawal symptoms partly continued. Our results suggest that reduced GABA-B receptor activity might be associated with longer-term alcohol withdrawal symptoms in alcoholic patients.     

Osteopenia assessed by body composition analysis is related to malnutrition in alcoholic patients.

Osteopenia is frequent among alcoholics. Its pathogenesis seems to be multifactorial, including ethanol intake, hormonal changes, liver cirrhosis, and malnutrition. Our objective is to determine the relative role of malnutrition on bone loss. One hundred and eighty-one male alcoholic patients, drinkers of more than 80 g ethanol/day, were included, recording data on the intensity of alcoholism, liver cirrhosis, nutritional assessment based on feeding habits, body mass index (BMI), midarm anthropometrics, subjective nutritional assessment, lean and fat mass by dual energy X-ray absorptiometry (DEXA), serum proteins and insulin growth factor Type I (IGF-I), calcitropic hormones, parathyroid hormone (PTH), osteocalcin 25OHD3, and bone mass assessed by DEXA, which was also performed in 43 healthy controls. Alcoholics showed decreased serum osteocalcin, PTH, 25OHD3, IGF-I, and bone mass. Alcoholics were frequently malnourished with decreased BMI, lean, and fat mass. The loss of bone mass was not related to the alteration of calcitropic hormones, to the intensity of alcoholism, or to the existence of liver cirrhosis, but to malnutrition. For a similar BMI, bone loss was more intense in alcoholics than in controls, especially in those with irregular feeding habits. Although cross-sectional ones, our data suggest that alcoholic osteopenia may be interpreted as a form of nutritional osteoporosis, notwithstanding the influence of other factors.