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Background Interactions between the liver, the gut, and the immune system are critical components of alcoholic liver disease (ALD). The aim of this study was to explore the associations between alcohol-induced liver injury, endotoxemia, and inflammation at admission and over time during abstinence, as well as to examine the sex-related differences in these parameters in alcohol-dependent individuals admitted to an alcohol treatment program. Methods A cohort of 48 otherwise healthy participants with alcohol use disorder, but no clinical signs of alcoholic liver injury (34 males [M]/14 females [F]) admitted to an alcohol detoxification program, was stratified into 2 groups based on baseline plasma alanine aminotransferase (ALT) levels (as a marker of liver injury). Group 1 (ALT < 40 U/l, 7M/8F) and Group 2 (ALT ≥ 40 U/l, 27M/6F) were identified. Plasma biomarkers of liver damage, endotoxemia, and inflammation were examined at baseline, day 8, and day 15 of the admission. The drinking history was also evaluated. Results Sixty-nine percent of patients had elevated ALT and other markers of liver damage, including aspartate aminotransferase and cytokeratin 18 (CK18 M65 and CK M30) at baseline, indicating the presence of mild ALD. Elevated CK18 M65:M30 ratio suggested a greater contribution of necrotic rather than apoptotic hepatocyte cell death in the liver injury observed in these individuals. Females showed greater elevations of liver injury markers compared to males, although they had fewer drinks per day and shorter lifetime duration of heavy drinking. Liver injury was associated with systemic inflammation, specifically, elevated plasma tumor necrosis factor-alpha levels. Compared to patients without liver injury, patients with mild ALD had greater endotoxemia (increased serum lipopolysaccharide levels), which decreased with abstinence and this decrease preceded the drop in CK18 M65 levels. Conclusions The study documented the association of mild alcohol-induced liver injury and endotoxemia, which improved with 2 weeks of abstinence, in a subset of individuals admitted to an alcohol detoxification program. [ABSTRACT FROM AUTHOR]

Background A common single nucleotide polymorphism (C385A) in the human fatty acid amide hydrolase ( FAAH) gene has been associated with decreased distress responses in healthy volunteers, but its role in psychiatric disorders remains unknown. Here, we obtained genotypes and carried out a secondary analysis of subjects from a trial of comorbid posttraumatic stress disorder ( PTSD) and alcohol dependence ( AD). We evaluated the effects of C385A variation on behavioral and biochemical biomarkers of distress responses. Methods Forty-nine patients with PTSD and AD were admitted for 4 weeks to an experimental medicine unit at the National Institutes of Health Clinical Center. Following detoxification, stress reactivity and peripheral endocannabinoid (eCB) levels were assessed in response to a challenge session using personalized auditory guided imagery. Over the course of the study, subjects were also evaluated for changes in PTSD symptom severity. Results FAAH C385A allele carriers showed a marked increase in serum anandamide levels at baseline and throughout the stress challenge procedure compared with C allele homozygotes, while levels of eCBs primarily metabolized through other enzymatic activity, such as 2-arachidonoylglycerol, did not differ between genotype groups. FAAH C385A carriers also had decreased subjective anxiety responses to the stress challenge. Similar effects of FAAH C385A genotype were found at the level of clinical PTSD symptom severity, in particular in the arousal domain. Conclusions This is to our knowledge the first study showing that FAAH C385A variation modulates stress responses in subjects with disorders characterized by increased stress reactivity. These findings point to the eCB pathway as a promising target for future antistress therapeutics. [ABSTRACT FROM AUTHOR]

Background Heavy alcohol consumption frequently causes liver inflammation/injury, and certain fatty acids ( FAs) may be involved in this liver pathology. In this study, we evaluated the association of heavy drinking and the changes in the FA levels involved in the ω-6 (pro-inflammatory) and ω-3 (anti-inflammatory) state in alcohol-dependent ( AD) patients who had no clinical manifestations of liver injury. We aimed to identify sex-based differences in patients with mild or no biochemical evidence of liver injury induced by heavy drinking. Methods A total of 114 heavy drinking AD female and male patients aged 21 to 65 years without clinical manifestations of liver injury, who were admitted to an alcohol dependence treatment program, were grouped by the alanine aminotransferase ( ALT) levels: ≤40 IU/l, as no liver injury ( GR.1), and >40 IU/l, as mild liver injury ( GR.2). Patients were actively drinking until the day of admission. Comprehensive metabolic panel, comprehensive FA panel, and drinking history data were evaluated. Results Elevated ALT and aspartate aminotransferase (AST) showed close association with markers of heavy alcohol intake. In the patients with mild biochemical liver injury ( GR.2), females showed significantly higher AST level than males. Significant association of AST and total drinks in past 90 days ( TD90) in females, and AST and heavy drinking days in past 90 days ( HDD90) in males was observed. The ω-6:ω-3 ratio showed a significant pro-inflammatory response only in females with mild liver injury ( GR.2) when adjusted by drinking history marker, TD90. Docosahexaenoic acid ( DHA) and eicosapentaenoic acid ( EPA) were increased in males with liver injury, while females did not show any comparable rise in EPA; and DHA levels were lower. Conclusions Measures of heavy drinking, TD90 and HDD90, predicted changes in liver injury. Changes in the ω-3 and ω-6 FA levels and the ω-6:ω-3 ratio showed a pro-inflammatory shift in patients with biochemical liver injury with a significant effect in females. Changes in FAs involved in the inflammatory state may represent one mechanism for liver inflammation/injury in response to heavy alcohol drinking. [ABSTRACT FROM AUTHOR]

Background Positively reinforcing properties of alcohol are in part mediated by activation of the ventral striatum ( VS). Alcohol-induced release of endogenous opioids is thought to contribute to this response. Preclinical studies show that the opioid antagonist naltrexone ( NTX) can block this cascade, but its ability to do so in treatment-seeking alcoholics has not been examined. Our objective was to study the effects of NTX on alcohol-induced VS activation and on amygdala response to affective stimuli in treatment-seeking alcohol-dependent inpatients. Methods Sixty-three treatment-seeking alcoholics were randomized to receive NTX (50 mg) or placebo ( PLC) daily. On Day 7, participants underwent an alcohol cue reactivity session, and craving was measured using the Penn Alcohol Craving Scale. On Day 9, participants received a saline infusion followed by an alcohol infusion and also viewed affective stimuli in a magnetic resonance scanner. Results Irrespective of medication treatment condition, the alcohol infusion did not activate the VS in the alcohol-dependent patients. Unexpectedly, VS activation was greater in NTX treated patients than in the PLC group. NTX treated patients also reported increased craving in response to alcohol cue exposure, and increased subjective response to alcohol ('high' and 'intoxicated') compared to PLC subjects. No significant effects of alcohol infusion on brain response to affective stimuli were in the NTX or PLC groups. Conclusions Unlike previous findings in social drinkers, a moderate level of intoxication did not activate the VS in treatment-seeking alcoholics. This is likely to reflect tolerance to the positively reinforcing properties of alcohol in this clinical population. Our findings may help explain the efficacy of NTX to reduce heavy drinking, but not to maintain abstinence. [ABSTRACT FROM AUTHOR]

Background Childhood trauma has been linked with a number of negative outcomes later in life, including alcohol dependence ( AD). Previous studies have suggested a mediating role for neuroticism in the relationship between childhood trauma and psychopathology. In this study, we investigate the prevalence of multiple types of childhood trauma in treatment-seeking alcohol-dependent patients, and the associations between childhood trauma and AD severity using multiple mediation analysis. Methods The prevalence of 5 types of childhood trauma-emotional abuse, sexual abuse, physical abuse, emotional neglect, and physical neglect-was assessed in treatment-seeking alcohol-dependent patients ( n = 280) and healthy controls ( n = 137) using the Childhood Trauma Questionnaire. Multiple mediation analyses were used to model associations between childhood trauma measures and alcohol-related outcomes, primarily the severity of AD in the alcohol-dependent sample. Results Childhood trauma was significantly more prevalent and more severe in the alcohol-dependent subjects. In addition, childhood trauma was found to influence AD severity, an effect that was mediated by neuroticism. When individual trauma types were examined, emotional abuse was found to be the primary predictor of AD severity, both directly and through the mediating effects of the impulsivity subfacet of neuroticism. Physical abuse also had a moderate direct effect on AD severity. Mediation analysis did not reveal any association between childhood trauma and Alcohol Use Disorders Identification Test score in the nondependent control sample. Conclusions Childhood trauma is highly prevalent in treatment-seeking alcoholics and may play a significant role in the development and severity of AD through an internalizing pathway involving negative affect. Our findings suggest that alcoholics with a history of childhood emotional abuse may be particularly vulnerable to severe dependence. [ABSTRACT FROM AUTHOR]

Background This study examined the prevalence of single- and multiple-type childhood trauma exposure ( CTE) among alcoholic patients undergoing inpatient detoxification and treatment. The relationships between various types of CTE and lifetime psychiatric comorbidities and suicide attempts were also explored. Methods A total of 196 alcoholic inpatients were assessed by Structured Clinical Interview for DSM-IV Axis I Disorders and Childhood Trauma Questionnaire ( CTQ) for CTE history. Results The overall prevalence of CTE in the entire sample was high (55.1%). Specifically, the prevalence of emotional abuse was 21.4%, physical abuse 31.1%, sexual abuse 24.0%, emotional neglect 20.4%, and physical neglect 19.9%. Regarding multiple types of CTE, 31.7 and 18.9% reported at least 2 and at least 3 CTE types, respectively. Strikingly, among those with at least 1 positive CTQ category, more than half reported 2 or more CTE types. A history of emotional abuse increased the risk of mood disorder, in particular major depressive disorder, as well as posttraumatic stress disorder ( PTSD). Physical abuse contributed to the prediction of suicide attempts, while sexual abuse was associated with a diagnosis of anxiety disorder, PTSD, and multiple comobidities (e.g., anxiety and mood disorder). The number of reported CTE types or the total score of the CTQ predicted an increased risk of having single or multiple psychiatric comorbidities as well as suicide attempts. Conclusions We observed high rates of a broad range of CTE types and a trend for CTE-specific enhancement of risk for various psychiatric outcomes among alcoholic inpatients. Of note, a dose-response relationship between number of CTE types and risk of psychiatric comorbidities as well as suicide attempts was found. We suggest a wide range of CTE should be included when exploring the effects of CTE or developing prevention and treatment strategies among alcoholic subjects. [ABSTRACT FROM AUTHOR]

Background: Proper ascertainment of the history of alcohol consumption by an individual is an important component of medical diagnosis of disease and influences the implementation of appropriate treatment strategies that include prescription of medication, as well as intervention for the negative physical and social consequences of hazardous/harmful levels of alcohol consumption. Biological (biometric) diagnostic tests that provide information on current and past quantity and frequency of alcohol consumption by an individual, prior to onset of organ damage, continue to be sought. Methods: Platelet monoamine oxidase B (MAO-B) protein was quantitated in 2 populations of subjects who had histories of different levels of alcohol consumption. Levels were assayed by immunoblotting or by ELISA. The development and evaluation of the new ELISA-based measure of platelet MAO-B protein levels is described. Results: One subject population constituted a nontreatment-seeking, cross-sectional subject sample, and the other population was a longitudinally followed, hospitalized group of subjects. An algorithm combining measures of platelet MAO-B protein with the plasma levels of carbohydrate-deficient transferrin (CDT) and with liver enzymes (aspartate aminotransferase or γ-glutamyltransferase [GGT]) can detect hazardous/harmful alcohol use (HHAU) with the highest sensitivity and specificity in the cross-sectional nontreatment-seeking population. In the treatment-seeking population, low MAO-B protein levels at admission are associated with heavy drinking prior to admission, and these protein levels increase over a period of abstinence from alcohol. Conclusions: The platelet MAO-B protein measurement is particularly effective for male alcohol consumers. The combined use of MAO-B protein measures together with measures of CDT and GGT does, however, improve the diagnostic utility of both markers for ascertaining HHAU in women. Furthermore, measurement of changes in platelet MAO-B protein levels during treatment for alcohol dependence may help monitor the success of the treatment program. [ABSTRACT FROM AUTHOR]