Duodenal gamma-glutamyltransferase activity in human biopsies: effect of chronic ethanol consumption and duodenal morphology

Gamma-glutamyltransferase activity was determined in duodenal biopsies, and in the sera of forty-six non-alcoholic and eighteen alcoholic patients with a daily alcohol consumption of more than 80 g. Additionally, duodenal morphology was examined in biopsy material obtained at the same time. In both alcoholics (P less than 0.05) and in non-alcoholics (P less than 0.001) the duodenal gamma-glutamyltransferase activity revealed a significant positive correlation with duodenal villus length. In addition, alcoholics exhibited a significant decrease in duodenal villus length (338 +/- 13 vs. 363 +/- 13 microns, P less than 0.01), and a significant increase in duodenal gamma-glutamyltransferase activity (13.0 +/- 1.4 vs. 8.4 +/- 0.6 mU mg-1 protein, P less than 0.01) when compared to controls. No significant correlation was found between duodenal and serum gamma-glutamyltransferase activity in alcoholics and non-alcoholics. During follow up of two patients, duodenal gamma-glutamyltransferase activity decreased and duodenal villus length increased after withdrawing alcohol. These data underline the damaging effect of alcohol on the duodenal mucosa and demonstrate that chronic alcohol intake reversibly effects duodenal gamma-glutamyltransferase. In addition, the small intestine appears of minor importance as an origin for the elevated serum gamma-glutamyltransferase activities seen in the alcoholic.     

Gamma-glutamyltransferase, aspartate aminotransferase and alkaline phosphatase as markers of alcohol consumption in out-patient alcoholics

Serum activity of gamma-glutamyltransferase, aspartate aminotransferase and alkaline phosphatase were determined in 316 patients attending an out-patients clinic for treatment of alcoholism. The activity of gamma-glutamyltransferase was raised in 34% and that of aspartate aminotransferase and alkaline phosphatase in 18% and 7%. Neither the activity of gamma-glutamyltransferase, aspartate aminotransferase nor alkaline phosphatase showed any significant (P greater than 0.05) correlation with the history of alcohol consumption. The activities of gamma-glutamyltransferase and aspartate aminotransferase were raised significantly more often in patients with recent alcohol consumption than in patients who had abstained for more than 9 days. The concentration of alkaline phosphatase was not significantly (P greater than 0.05) different in these groups. The predictive value of raised and normal activities of gamma-glutamyltransferase, in deciding whether a patient had had recent alcohol consumption or not, was not superior to the predictive value of raised and normal activities of aspartate aminotransferase.     

Improved diagnostic classification of alcohol abusers by combining carbohydrate-deficient transferrin and gamma-glutamyltransferase

BACKGROUND: Biochemical markers can provide objective evidence of high alcohol consumption. However, currently available markers have limitations in their diagnostic performance. METHODS: The diagnostic values of the most frequently used markers [carbohydrate-deficient transferrin (CDT), gamma-glutamyltransferase (GGT), aspartate aminotransferase, alanine aminotransferase, and mean corpuscular volume] were studied in an analysis of six different clinical studies (n = 1412) on alcohol abusers and social drinkers. The purpose of the analyses was to determine whether a combination of markers would improve the diagnosis of subjects. RESULTS: Discrimination between alcohol abusers and social drinkers, as measured by the areas under nonparametric ROC plots, was significantly better (P<0.001) for the new combined marker [gamma-CDT = 0.8. ln(GGT) + 1.3. ln(CDT)] than for any of the separate markers or combination of CDT or GGT with other markers. The cutoff values for gamma-CDT (6.5) can be taken to be the same among males and females. CONCLUSIONS: The combined variable gamma-CDT is a powerful tool to discriminate alcohol abusers from social drinkers and is recommended for clinical use.     

Disturbances of electrolytes and blood chemistry in acute alcohol intoxication

Prevalence of electrolyte disturbances and biochemical changes were determined in patients admitted to the emergency room of the Department of Internal Medicine in Innsbruck, Austria during a six-month period. The value of biochemical parameters for the detection of chronic alcohol abuse was also investigated. The most frequent electrolyte disturbances found were hypernatremia (41%), hyperchloremia (21%), hypermagnesemia (17%) and hypocalcemia (15%), whereas hypokalemia and hypophosphatemia were observed quite rarely (5% and 3.4%, respectively). The most frequent biochemical changes observed were consistent with signs of cellular toxicity i.e. increased liver enzymes (elevated gamma-glutamyltransferase (GGT), aspartate aminotransferase, alanine aminotransferase and lactic dehydrogenase) as well as signs of pancreatitis (elevated serum lipase and amylase) and muscle damage (elevated creatine kinase). The most frequent changes in blood counts were leucocytosis (23%), thrombocytopenia (14%), and anemia (12%). C-reactive protein showed only minimal elevation. Male sex and level of blood alcohol were detected as major risk factors for the diagnosis of chronic alcohol abuse in the patient sample investigated. When testing the value of routinely measured parameters for predicting the presence of chronic alcohol abuse, GGT and mean corpuscular volume of red blood cells (MCV) appeared to be of equal value. A combination of elevated blood alcohol with an increase in either of these markers may be interpreted as high risk for chronic alcohol abuse in this particular group of patients.     

Intercurrent complications in chronic alcoholic men admitted to the intensive care unit following trauma

Objective A chronic alcoholic group following trauma was investigated to determine whether their ICU stay was longer than that of a non-alcoholic group and whether their intercurrent complication rate was increasedDesign Prospective study.Setting An intensive care unit.Patients A total of 102 polytraumatized patients were transferred to the ICU after admission to the emergency room and after surgical treatment. Of these patients 69 were chronic alcoholics and 33 were allocated to the non-alcoholic group. The chronic-alcoholic group met the DSM-III-R and ICD-10 criteria for alcohol dependence or chronic alcohol abuse/harmful use. The daily ethanol intake in these patients was 60 g. Diagnostic indicators included an alcoholismrelated questionnaire (CAGE), conventional laboratory markers and carbohydrate-deficient transferrin.Measurement and results Major intercurrent complications such as alcohol withdrawal syndrome (AWS), pneumonia, cardiac complications and bleeding disorders were documented and defined according to internationally accepted criteria. Patients did not differ significantly between groups regarding age, TRISS and APACHE score on admission. The rate of major intercurrent complications was 196% in the chronic alcoholic vs 70% in the non-alcoholic group (P=0.0001). Because of the increased intercurrent complication rate, the ICU stay was significantly prolonged in the chronic-alcoholic group by a median period of 9 days.Conclusions Chronic alcoholics are reported to have an increased risk of morbidity and mortality. However, to our knowledge, nothing is known about the morbidity and mortality of chronic alcoholics in intensive care units following trauma. Since chronic alcoholics in the ICU develop mor major complications with a significantly prolonged ICU stay following trauma than non-alcoholics, it seems reasonable to intensify research to identify chronic alcoholics and to prevent alcohol-related complications.     

Beverage-specific effects of ethanol consumption on its biological markers

BACKGROUND: Serum gamma-glutamyltransferase (GGT) and erythrocyte mean corpuscular volume (MCV) are well-known biological markers of excessive ethanol consumption. METHODS: The beverage-specific effects of ethanol consumption on GGT level and MCV value were analyzed cross-sectionally and retrospectively among middle-aged Japanese men who underwent a retirement health checkup (n = 974). RESULTS: Both the consumption of distilled alcohol and that of fermented alcohol positively correlated with the logarithm of GGT [standard regression coefficient (beta) 0.261 and 0.174, respectively]. The prevalence rate of elevated GGT levels > or = 70 IU/L) was higher among heavy drinkers of distilled alcohol than among heavy drinkers of fermented alcohol (38.8% vs. 27.6%, p = 0.013). The MCV value correlated with distilled alcohol consumption (beta: 0.212, p < 0.0001) but not with fermented alcohol consumption (beta: 0.043, not significant). The prevalence rate of an elevated MCV (> or = 97 fL) was higher among heavy drinkers of distilled alcohol than among heavy drinkers of fermented alcohol (35.3% vs. 16.8%, p < 0.001). CONCLUSIONS: These results suggest that MCV is less sensitive for detecting heavy consumption of fermented alcohol than for detecting that of distilled alcohol in apparently healthy middle-aged men.     

缺糖基转铁蛋白对酒精性肝病的诊断

目的 检测酒精性肝病(ALD)患者血清中的缺糖基转铁蛋白(CDT)与总TI的比值％CDT,并与GGT、MCV、ALT、AST等指标比较,评价其对ALD的诊断价值。方法 选择健康不饮酒对照组、非酒精性肝病的其他肝病组(NALD组)、ALD组(3组均为男性),分别检测％CDT、GGT、MCV、ALT、AST等指标,各指标在不同组间的比较用F检验;各项目之间的关系研究用直线相关,计算相关系数;同时绘制各指标的ROC曲线。结果 ALD组中的％CDT显著高于对照组、NAID组。％CDT诊断ALD的ROC曲线下面积为0．857,敏感度0．75,特异度0．88,而GGT这三者分别为0．751、0．75、0．76,MCV分别为0．669、0．30、0．78,ALT分别为0．512、0．25、0．72,AST分别为0．426、0．25、0．68。％CDT、与GGT不相关,但两者联合检测敏感度提高到90％。结论 对于ALD的诊断,％CDT、GGT、MCV均具有一定的诊断价值,尤其％CDT是一个很好的辅助诊断指标。％CDT与GGT联用可提高敏感度。     

Long-term ethanol consumption and macrocytosis: diagnostic and pathogenic implications

Although excessive alcohol consumption is known to elevate the mean cell volume (MCV) of erythrocytes, the relationships among the intensity of ethanol exposure, the generation of abnormal red blood cell indices, and the underlying pathogenic mechanisms have remained unclear. The authors examined 105 alcoholics with a wide range of ethanol consumption (40-500 g of ethanol/day), 62 moderate drinkers (mean consumption 1-40 g/day), and 24 abstainers, who underwent detailed interviews, measurements of blood cell counts, markers of liver status, and circulating antibodies against ethanol-derived protein modifications. Follow-up information was collected from healthy volunteers with detailed records on drinking habits. Data from the NORIP project for laboratory parameters in apparently healthy moderate drinkers or abstainers (n = 845) were used for reference interval comparisons. The highest MCV (P < 0.001) and mean cell hemoglobin (MCH) (P < 0.01) occurred in the alcoholics. However, the values in the moderate drinkers also responded to ethanol intake such that the upper normal limit for MCV based on the data from moderate drinkers was 98 fl, as compared with 96 fl from abstainers. Follow-up cases with carefully registered drinking habits showed parallel changes in MCV and ethanol intake. Anti-adduct IgA and IgM against acetaldehyde-induced protein modifications were elevated in 94% and 64% of patients with high MCV, respectively, the former being significantly less frequent in the alcoholics with normal MCV (63%) (P < 0.05). The data indicate dose-related responses in red blood indices upon chronic ethanol consumption, which may also be reflected in reference intervals for hematological parameters in health care. Generation of immune responses against acetaldehyde-modified erythrocyte proteins may be associated with the appearance of such abnormalities.     

Haemolysis as an interference factor in clinical chemistry

Using fully mechanized analytical equipment, interference by haemolysis in the determination of 26 clinical chemical parameters was determined quantitatively by adding haemolysate to serum. Haemoglobin concentrations up to 6.6 g/l caused essentially no interference in the following determinations: albumin (immuno-nephelometric), alpha-amylase, calcium, chloride, cholesterol, cholinesterase, creatinine, iron, glucose, glutamate dehydrogenase, uric acid, urea, sodium, inorganic phosphate, total protein, transferrin and triglycerides. In the presence of haemoglobin, erroneously high values were found for: lactate dehydrogenase (haemoglobin higher than 0.2 g/l), aspartate aminotransferase, potassium and acid phosphate (haemoglobin higher than 1.5 g/l), creatine kinase (haemoglobin higher than 2.5 g/l) and alanine aminotransferase (haemoglobin higher than 3.4 g/l). Erroneously low values were found for bilirubin (haemoglobin higher than 0.8 g/l), alkaline phosphatase and albumin (by electrophoresis) (haemoglobin higher than 1.5 g/l) and gamma-glutamyltransferase (haemoglobin higher than 3.0 g/l).     

Effect of alcohol on delta-aminolevulinic acid dehydratase and porphyrin metabolism in man.

The influence of alcohol on porphyrin metabolism was investigated in 6 healthy non-alcoholics and 19 patients with chronic alcohol abuse. In the healthy subjects, blood and urine samples were obtained before and after acute alcohol exposure, whereas in the chronic alcoholics only one examination was performed. In both groups a significant inhibition of delta-aminolevulinic acid dehydratase was demonstrated. The activity was partially restored in vitro by addition of zinc ions or dithiothreitol. A combination of both activators produced reactivation to normal levels. Coproporphyrinuria was more prominent in chronic alcoholics (373 nmol/24 h on average, upper norm 119 nmol/24 h) compared to non-alcoholics (140 nmol/24 h). Urinary porphobilinogen and delta-amino-levulinic acid were normal except for a moderately increased delta-aminolevulinic acid in four healthy individuals. In conclusion, alcohol causes reversible inhibition of delta-aminolevulinic acid dehydratase. The metabolic changes reflect both an inhibition of delta-aminolevulinic acid dehydratase and coproporphyrinogen oxidase; a simultaneous, moderate induction of hepatic delta-aminolevulinic acid synthase is suggested. Erythrocyte delta-aminolevulinic acid dehydratase activity could serve as a sensitive indicator for both acute and chronic alcohol consumption even better than coproporphyrinuria.     

Body mass index and liver enzyme activity in serum.

The association between body mass index (BMI) and serum liver enzyme activity [gamma-glutamyltransferase (GGT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST)] was studied in 3167 subjects, 2373 men and 794 women. The subjects were managers and employees, ages 18-64 years, who were examined during a program of preventive medicine. Analysis of covariance was used to compare the serum liver enzyme activities (expressed as natural logarithms) of the subjects, who were subdivided according to BMI, while also considering age, alcohol and cigarette consumption, and physical activity. In men, the percentage increase in the geometric mean of liver enzyme activity of the obese subjects (BMI greater than 30 kg/m2) compared with that of the normal subjects (BMI less than or equal to 25 kg/m2) was 47.7% (P less than 0.001) for GGT, 55.3% (P less than 0.001) for ALT, and 19.7% (P less than 0.001) for AST; in women, the increase was 63.2% (P less than 0.01) for GGT, 58.4% (P less than 0.001) for ALT, and 7.3% (P greater than 0.05) for AST. Thus, our observations demonstrate a relation between BMI and serum liver enzyme activity.     

Combining markers of nephrotoxicity and hepatotoxicity for improved monitoring and detection of chronic alcohol abuse.

BACKGROUND: Most of the commonly used markers of chronic alcohol abuse reflect alcohol hepatotoxicity; however, such abuse is deleterious to the kidneys as well. Combined use of serum markers of liver origin and urinary markers of kidney origin may be of diagnostic advantage. METHODS: The study was performed in 73 male alcoholics undergoing detoxification and 36 male alcoholics who had maintained abstinence for > or =6 weeks. Factor analysis, discriminant analysis and receiver operating characteristic (ROC) analysis were used to assess the discriminative power of two urinary markers of alcohol nephrotoxicity, namely beta-N-acetylhexosaminidase (Hex, EC 3.2.1.52) and alanine aminopeptidase (EC 3.4.11.2), and of three serum markers of alcohol hepatotoxicity, namely aspartate aminotransferase (EC 2.6.1.1), alanine aminotransferase (EC 2.6.1.2) and gamma-glutamyltransferase (GGT, EC 2.3.2.2), and of their quantitative combinations. RESULTS: The discriminative power of the urinary markers matched that of the serum markers. Hex and GGT appeared to be the best for discriminating the study groups. Their combination given by the equation G&H=0.62 x ln(GGT)+0.72 x ln(Hex) showed excellent discriminative ability (ROC area under the curve 0.92) that was significantly higher than that of any single marker in this report, indicating superior diagnostic accuracy of the compound marker. CONCLUSIONS: Kidney-derived urinary markers, particularly Hex, can complement or replace, if necessary, serum markers of chronic alcohol abuse that relate to alcohol hepatotoxicity. The compound marker proposed seems a promising tool for the monitoring and perhaps detection of chronic alcohol abuse and warrants further studies.     

Biomarkers in alcoholism

Alcoholism ranks as one of the main current threats to the health and safety of people in most Western countries. Therefore, a high priority should be given to aims at reducing its prevalence through more effective diagnosis and early intervention. The need for objective methods for revealing alcohol abuse in its early phase has also been widely acknowledged. It is postulated here that the diagnosis of alcohol use disorders could be markedly improved by a more systematic use of specific questionnaires and laboratory tests, including blood ethanol, serum gamma-glutamyltransferase (GGT), carbohydrate-deficient transferrin (CDT), and mean corpuscular volume of erythrocytes (MCV). Recent research has provided new insights into the relationships between ethanol intake, biomarkers, and factors affecting their diagnostic validation, including gender, age, and the effects of moderate drinking and obesity. It appears that the concept of reference intervals for several ethanol-sensitive parameters in laboratory medicine needs to be revisited. CDT is currently the most specific marker of alcohol abuse, and when combined with GGT using a mathematically formulated equation a high sensitivity is reached without loss of assay specificity. Possible new biomarkers include minor ethanol metabolites (protein-acetaldehyde condensates and associated autoimmune responses, ethylglucuronide, and phosphatidylethanolamine), 5-hydroxytryptophol, and genetic markers although so far their routine applications have been limited.     

Matrix metalloproteinase-9 is elevated in serum of alcohol abusers

BACKGROUND: Moderate alcohol consumption has been shown to protect against coronary heart disease. However, excessive alcohol use has been suggested to have detrimental effects on the cardiovascular system. We examined whether there is an association between alcohol abuse and circulating levels of matrix metalloproteinase-9 (MMP-9), which has been linked to unstable coronary heart disease and arterial inflammation. DESIGN: Serum MMP-9 concentrations were compared between 40 male alcoholics (mean age 42 years) with ethanol consumption > 1000 g week(-1) and 40 social drinker males with an ethanol consumption of < 200 g week(-1) (mean age 45 years). RESULTS: The mean serum MMP-9 concentration was significantly higher in sera of alcoholics compared to control subjects (70.9 +/- 47.7 g L(-1) and 43.1 +/- 19.2 g L(-1), respectively; P = 0.001). Within the alcoholic group, MMP-9 concentration did not correlate with age, gamma glutamyl transferase, carbohydrate-deficient transferrin, aspartate aminotransferase, alanine aminotransferase or alkaline phosphatase. CONCLUSION: Our finding of elevated MMP-9 concentrations in sera of chronic alcohol abusers helps understand the mechanisms of cardiovascular risk among these subjects.     

Gastroduodenal morphology and related symptoms in chronic alcoholics

Twenty-four chronic alcoholics admitted to hospital for detoxification after a drinking spree were examined by upper gastrointestinal endoscopy. Biopsy specimens were taken from corpus/fundus, antrum and duodenum for tissue histology (eosin stain). From the duodenum villus index and ultrastructure (scanning electron microscopy, SEM) were also performed. As a control group 12 subjectively healthy non-alcoholics referred to upper gastrointestinal endoscopy mainly for dyspepsia were chosen.Gastrointestinal symptoms were common in alcoholics (88%). Endoscopic and histological gastroduodenitis were not more common in the alcohol group. There was no correlation between gastrointestinal symptoms and endoscopic or histological gastroduodenitis in both groups. In the duodenum, 50% of the alcoholics and 82% in the control group had alterations by scanning electron microscopy. Ten of the 11 alcoholics with an abnormal ultrastructure had diarrhoea. In the control group dyspepsia (ulcus suspect) was correlated to a pathological SEM.     

Graphical analysis of laboratory data in the differential diagnosis of cholestasis: a computer-assisted prospective study

Data on 15 laboratory analytes obtained in 145 prospectively investigated cholestatic patients with viral hepatitis, chronic intrahepatic cholestasis and extrahepatic biliary obstruction were submitted to a computer-based graphical evaluation using probabilistic test analysis. This revealed a marginal utility for alkaline phosphatase, gamma-glutamyltransferase and the direct/total bilirubin ratio at specific cut-off points for the exclusion of extrahepatic cholestasis (PVneg 90%-100%). Aspartate aminotransferase and alanine aminotransferase values with cut-off points at 200 U/l and 300 U/l, respectively, were powerful discriminators between acute viral hepatitis and the other disease categories, while lactate dehydrogenase, erythrocyte sedimentation rate and the ratios gamma-glutamyltransferase/alanine aminotransferase as well as total bilirubin/gamma-glutamyltransferase were useful at specific cut-off points indicating the absence of this diagnosis (PVneg 92%-100%). An aspartate aminotransferase/alanine aminotransferase ratio above 1.5 and serum gamma-globulin concentrations above 20 g/l strongly suggested cholestasis due to chronic parenchymal liver disease (PVpos 92% and 90%, respectively). This graphical approach to laboratory data analysis enhances the understanding of the interrelations between cut-off points and sensitivity, specificity and predictive values and also of the influence of disease prevalence on disease prediction. It also adds to present knowledge by demonstrating the clinical relevance of several readily available, albeit rarely utilized diagnostic analytes.     

Biomarkers of alcoholism: an updated review

Alcoholic beverages, and the problems they engender, have been familiar in human societies since the beginning of recorded history. Among a variety of blood tests used to aid the diagnosis of alcohol consumption and related disorders, laboratory tests are particularly useful in settings where cooperativeness is suspected or when a history is not available. Biochemical and haematological tests, such as gamma-glutamyltransferase activity, aspartate aminotransferase activity and erythrocyte mean corpuscular volume, are established markers of alcohol intake. Carbohydrate-deficient transferrin is the only test approved by the FDA for the identification of heavy alcohol use. Total serum sialic acid and sialic acid index of Apolipoprotein J have the potential to be included in a combination of measurements providing an accurate, more exact, assessment of alcohol consumption in a variety of clinical and research settings. Several other markers with considerable potential for measuring recent alcohol intake include beta-hexosaminidase, acetaldehyde adducts and the urinary ratio of serotonin metabolites, 5-hydroxytryptophol and 5-hydroxyindoleacetic acid. These markers provide hope for more sensitive and specific aids to diagnosis and improved monitoring of alcohol intake.     

Biomarkers of alcohol consumption in patients classified according to the degree of liver disease severity

OBJECTIVE: In the search for optimal biomarkers of excessive drinking, only a few studies have been conducted to compare the relationships between ethanol consumption, liver status, and various laboratory markers of ethanol-induced diseases. MATERIAL AND METHODS: Concentrations of carbohydrate-deficient transferrin (%CDT and CDTect methods), serum sialic acid (SA), gamma-glutamyl transferase (gamma-GT), aspartate aminotransferase (ASAT), mean corpuscular volume (MCV), and a marker of fibrogenesis (PIIINP) were studied in 102 alcoholics with (n=59) or without (n=43) alcoholic liver disease. Controls were 34 healthy volunteers who were either social drinkers or abstainers. RESULTS: Although concentrations of all markers were significantly higher in the alcoholic patients than in the healthy controls, their diagnostic characteristics showed a considerable degree of variation. The %CDT, SA, and MCV showed the strongest correlations with the amount of recent alcohol intake. The presence of liver pathology notably influenced the results of CDTect, GT, ASAT, and PIIINP. In ROC analyses, the highest rates of diagnostic accuracy for detecting hazardous drinking were reached with GT (0.94), CDT (0.86), and SA (0.85), followed by MCV (0.79) and ASAT (0.77). Upon abstinence, the estimated times for normalization varied between 10 days (CDTect) and 25 days (GT). CONCLUSIONS: Our data suggest distinct differences in the clinical characteristics of biological markers of ethanol consumption. While the overall accuracy of CDT and GT appear to be highest in the detection of problem drinking, serum SA and PIIINP measurements are of further value when the effects of liver pathology and ethanol drinking need to be differentiated.     

Immunological aspects of circulating immune complexes in kidney diseases in patients with chronic alcoholism

AIM: Characterization of the content and features of circulating immune complexes (CIC) in chronic alcoholics with renal diseases. MATERIALS AND METHODS: Quantitative and qualitative characteristics of CIC, RNA and DNA levels in CIC were studied in 58 patients suffering from chronic alcoholism stage II. The patients had the history of 10 and more years of alcohol abuse, exhibited symptoms of chronic renal affection with clinical picture of chronic glomerulonephritis. RESULTS: Glomerulonephritis in chronic alcoholics was accompanied with higher CIC, CIC IgM and IgA levels compared to healthy subjects and non-alcoholics with glomerulonephritis. Alcoholics had also higher DNA and CIC DNA. CONCLUSION: Quantitative and qualitative assessment of CIC in chronic alcoholics with renal disease provide information valuable for the disease diagnosis and prognosis.     

Chronic alcohol neuroadaptation and stress contribute to susceptibility for alcohol craving and relapse

Alcoholism is a chronic relapsing disorder. Major characteristics observed in alcoholics during an initial period of alcohol abstinence are altered physiological functions and a negative emotional state. Evidence suggests that a persistent, cumulative adaptation involving a kindling/allostasis-like process occurs during the course of repeated chronic alcohol exposures that is critical for the negative symptoms observed during alcohol withdrawal. Basic studies have provided evidence for specific neurotransmitters within identified brain sites being responsible for the negative emotion induced by the persistent cumulative adaptation following intermittent-alcohol exposures. After an extended period of abstinence, the cumulative alcohol adaptation increases susceptibility to stress- and alcohol cue-induced negative symptoms and alcohol seeking, both of which can facilitate excessive ingestion of alcohol. In the alcoholic, stressful imagery and alcohol cues alter physiological responses, enhance negative emotion, and induce craving. Brain fMRI imaging following stress and alcohol cues has documented neural changes in specific brain regions of alcoholics not observed in social drinkers. Such altered activity in brain of abstinent alcoholics to stress and alcohol cues is consistent with a continuing ethanol adaptation being responsible. Therapies in alcoholics found to block responses to stress and alcohol cues would presumably be potential treatments by which susceptibility for continued alcohol abuse can be reduced. By continuing to define the neurobiological basis of the sustained alcohol adaptation critical for the increased susceptibility of alcoholics to stress and alcohol cues that facilitate craving, a new era is expected to evolve in which the high rate of relapse in alcoholism is minimized.