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Alcohol‐associated liver disease (ALD) is a spectrum of liver disorders ranging from steatosis to steatohepatitis, fibrosis, and cirrhosis. Alcohol‐associated hepatitis (AH) is an acute and often severe form of ALD with substantial morbidity and mortality. The mechanisms and mediators of ALD progression and severity are not well understood, and effective therapeutic options are limited. Various bioactive lipid mediators have recently emerged as important factors in ALD pathogenesis. The current study aimed to examine alterations in linoleic acid (LA)‐derived lipid metabolites in the plasma of individuals who are heavy drinkers and to evaluate associations between these molecules and markers of liver injury and systemic inflammation. Analysis of plasma LA‐derived metabolites was performed on 66 individuals who were heavy drinkers and 29 socially drinking but otherwise healthy volunteers. Based on plasma alanine aminotransferase (ALT) levels, 15 patients had no liver injury (ALT ≤ 40 U/L), 33 patients had mild liver injury (ALT > 40 U/L), and 18 were diagnosed with moderate AH (mAH) (Model for End‐Stage Liver Disease score

Bile acids (BAs) play important functions in the development of alcohol‐associated liver disease (ALD). In the current study, urine BA concentrations in 38 patients with well‐described alcohol‐associated hepatitis (AH) as characterized by Model for End‐Stage Liver Disease (MELD), 8 patients with alcohol‐use disorder (AUD), and 19 healthy controls (HCs) were analyzed using liquid chromatography–mass spectrometry. Forty‐three BAs were identified, and 22 BAs had significant changes in their abundance levels in patients with AH. The potential associations of clinical data were compared to candidate BAs in this pilot proof‐of‐concept study. MELD score showed positive correlations with several conjugated BAs and negative correlations with certain unconjugated BAs; taurine‐conjugated chenodeoxycholic acid (CDCA) and MELD score showed the highest association. Cholic acid, CDCA, and apocholic acid had nonsignificant abundance changes in patients with nonsevere ALD compared to HCs but were significantly increased in those with severe AH. Receiver operating characteristic analysis showed that the differences in these three compounds were sufficiently large to distinguish severe AH from nonsevere ALD. Notably, the abundance levels of primary BAs were significantly increased while most of the secondary BAs were markedly decreased in AH compared to AUD. Most importantly, the amount of total BAs and the ratio of primary to secondary BAs increased while the ratio of unconjugated to conjugated BAs decreased as disease severity increased. Conclusion: Abundance changes of specific BAs are closely correlated with the severity of AH in this pilot study. Urine BAs (individually or as a group) could be potential noninvasive laboratory biomarkers for detecting early stage ALD and may have prognostic value in AH morbidity., The abundance changes of bile acids (BAs) in urine are closely correlated with the severity of alcohol‐associated hepatitis (AH). BAs (individually or as a group) could be potential noninvasive laboratory biomarkers for detecting early stage of alcohol‐associated liver disease and may have prognostic value in AH morbidity.

Background & Aims Acute alcoholic hepatitis (AAH) is a major cause of liver-related morbidity and mortality; there are no good blood biomarkers for diagnosis or determining magnitude of cell death. Keratin 18 (KRT18, also called K18), found in epithelial cells, is released from hepatocytes upon death. We investigated whether level of K18 is a better marker of hepatocyte death than standard biomarkers and might be used to identify patients with AAH at risk for death within 90 days. Methods We analyzed data from 173 participants in a large trial performed at 4 medical centers. Participants with AAH were classified as severe (n = 57, model for end-stage liver disease [MELD] scores above 20) or moderate (n = 27, MELD scores from 12 to 19); 38 participants had alcohol use disorder with mild (n = 28) or no liver injury (n = 10); 34 participants had nonalcoholic steatohepatitis; and 17 participants were healthy (controls). We quantified serum levels of K18 using ELISAs and APOPTOSENSE kits. Results Serum level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and the ratio of AST:ALT did not correlate with MELD scores. Patients with alcohol use disorder had higher serum levels of ALT than patients with severe AAH. Levels of K18M65 and K18M30 had statistically significant increases as liver disease worsened, as did the degree of necrosis (ratio of K18 M65:M30). The ratio of K18M65:ALT was increased in serum from patients with AAH compared with controls. Serum levels of K18 identified patients who died within 90 days with greater accuracy than commonly used static biomarkers. Conclusions There is a stronger association between serum level of keratin 18 and amount of hepatocyte death and liver disease severity than for other biomarkers (AST, ALT, and the AST:ALT ratio). The ratio of K18M65:M30 might be used as marker of mechanism of hepatocyte death, and the ratio of K18M65:ALT might be used to distinguish patients with AAH from patients with nonalcoholic steatohepatitis. Serum levels of K18 might be used to identify patients with severe AAH at risk for death. ClinicalTrials.gov identifier # NCT01922895 and NCT01809132 .

Heavy alcohol consumption can cause hyperhomocysteinemia, which could be consequential in the proinflammatory response and worsening of the neurobehavioral domains of alcohol use disorder (AUD), such as alcohol withdrawal. We examined the role of heavy drinking, hyperhomocysteinemia, gut dysfunction and inflammation in early-stage alcoholic liver disease (ALD) in AUD patients. A total of 110 AUD patients without clinical manifestations of liver injury were grouped by the serum homocysteine levels (SHL): normal &le, 13 &micro, mol/L (Group 1 (Gr.1), n = 80), and elevated &gt, mol/L (Group 2 (Gr.2), n = 30). A comprehensive metabolic panel, SHL, a nutritional assessment, and drinking history assessed by the timeline followback questionnaire were evaluated. A subset analysis was performed on 47 subjects (Gr.1 n = 27, Gr.2 n = 20) for additional measures: Clinical Institute Withdrawal Assessment for Alcohol (CIWA) score, plasma cytokines (interleukin-1&beta, (IL-1&beta, )), gut dysfunction markers (lipopolysaccharide (LPS), and LPS-binding protein (LBP)), 27% of the AUD patients exhibited hyperhomocysteinemia. SHL was significantly associated (p = 0.034) with heavy drinking days (HDD90). Subset analyses showed that the withdrawal ratings were both clinically and statistically (p = 0.033) elevated and significantly associated with hyperhomocysteinemia (p = 0.016) in Gr.2. LBP, IL1-&beta, SHL, and HDD90 showed significant cumulative effects (adjusted R2 = 0.627) on withdrawal ratings in Gr.2 subset. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly higher in all Gr.2 patients, AUROC showed a fair level of true positivity for ALT (0.676), and AST (0.686). Il1-&beta, LBP, SHL, and HDD90 showed significant cumulative effects (adjusted R2 = 0.554) on the elevated ALT in Gr.2 subset as well. The gut-brain derived proinflammatory response, patterns of heavy drinking, and hyperhomocysteinemia were closely associated with clinically elevated alcohol withdrawal and elevated liver injury. Hyperhomocysteinemia could have a potential phenotypic marker response indicative of early-stage ALD along with AUD.

Bacterial infection is frequently observed in patients with alcoholic liver disease (ALD). We examined a possible role of Porphyromonas gingivalis in the development/progression and severity of disease in patients with acute alcoholic hepatitis (AAH). Plasma specimens from 47 patients with AAH (16 moderate, Model for End‐Stage Liver Disease [MELD] score 20) and 22 healthy controls (HCs) were collected. Clinical, drinking history (lifetime drinking history [LTDH]), and demographic data were collected. Antibody tests for immunoglobulin (Ig) G, IgM, and IgA against two P. gingivalis strains were performed. Between‐group comparisons and within‐group association analyses were carried out. Patients with severe AAH showed significantly higher plasma levels of IgG, IgA, and IgM against two P. gingivalis strains (W83 and 33277) compared to HCs. Patients with moderate AAH also had significantly elevated anti‐P. gingivalis IgA concentrations for both strains compared to HCs. Male patients with moderate AAH showed a significant inverse association in LTDH and anti‐P. gingivalis IgM. The aspartate aminotransferase:alanine aminotransferase ratio was positively associated with IgM of both strains in male patients with moderate AAH. Female patients with severe AAH showed a significant association between MELD scores and W83 IgM. Conclusion: Antibody response to P. gingivalis in AAH is elevated. Significantly elevated plasma anti‐P. gingivalis IgG, IgA, and IgM in severe AAH provide preliminary data that P. gingivalis could be a novel risk factor in the development/severity of AAH.

Post-stroke psychosis is prevalent and disabling with increased mortality risk. Treatment for post-stroke psychosis is limited in this staggering medical concern. The most commonly used medications are antipsychotics, however, the risk for stroke increases further with the use of antipsychotics. Furthermore, interventional clinical studies have not been carried out to test the efficacy and safety of antipsychotics in the management of post-stroke psychosis. We present a case of post-stroke psychosis to highlight the risks faced by these patients in terms of daily function and safety concerns and the challenges encountered in treatment due to poor response to the conventional antipsychotics; and so calling attention to early diagnosis and improved treatment options. More clinical investigations are needed to address the pathology associated with the clinical presentation and exploring the pharmacotherapies to improve efficacy and safety of treatment for post-stroke psychosis.

Up to 40% of patients with severe alcoholic hepatitis (AH) die within 6 months of presentation, making prompt diagnosis and appropriate treatment essential. We determined the associations between serum keratin-18 (K18) and histological features, prognosis, and differential response to prednisolone in patients with severe AH.Total (K18-M65) and caspase-cleaved K18 (K18-M30) were quantified in pretreatment sera from 824 patients enrolled in the Steroids or Pentoxifylline for Alcoholic Hepatitis trial (87 with suitable histological samples) and disease controls.K18 fragments were markedly elevated in severe AH and strongly predicted steatohepatitis (alcoholic steatohepatitis) on biopsy (area under receiver operating characteristics: 0.787 and 0.807). Application of published thresholds to predict alcoholic steatohepatitis would have rendered biopsy unnecessary in 84% of all AH cases. K18-M30 and M65 were associated with 90-day mortality, independent of age and Model for End-stage Liver Disease score in untreated patients. The association for K18-M65 was independent of both age and Model for End-stage Liver Disease in prednisolone-treated patients. Modelling of the effect of prednisolone on 90-day mortality as a function of pretreatment serum K18 levels indicated benefit in those with high serum levels of K18-M30. At low pretreatment serum K18 levels, prednisolone was potentially harmful. A threshold of K18-M30 5 kIU/L predicted therapeutic benefit from prednisolone above this level (odds ratio: 0.433, 95% confidence interval: 0.19-0.95, P = 0.0398), but not below (odds ratio: 1.271, 95% confidence interval: 0.88-1.84, P = 0.199). Restricting prednisolone usage to the former group would have reduced exposure by 87%.In a large cohort of patients with severe AH, serum K18 strongly correlated with histological severity, independently associated with 90-day mortality, and predicted response to prednisolone therapy. Quantification of serum K18 levels could assist in clinical decision-making.

BackgroundShared etiological pathways of dopamine and serotonin neurotransmission play a central role in heavy alcohol intake and exacerbation in the symptoms of depression.We investigated the role of depression ratings and patterns of heavy drinking on the treatment efficacy of Quetiapine fumarate XR in lowering alcohol intake in alcohol use disorder (AUD) patients.MethodsOne hundred and eight male and female heavy drinking AUD patients in the age range of 18–64 yrs. received 12 weeks of active treatment. Participants were grouped by the severity grading of depression using Montgomery-Asberg Depression Rating Scale (MADRS) (clinically relevant≥8 [CR], clinically non-relevant≤7 [CNR]) at baseline. Drinking history and depression ratings were assessed at the patients visits.ResultsHeavy drinking days (HDD) and total drinks (TD) were significantly fewer in CR patients at the treatment end. A true positive response in AUROC analysis supported the lowering of TD in CR patients. The number of drinking days (NDD) and average drinks per drinking day (AvgD) were lower in the CNR patients at treatment-end. Significant associations with increasing effect sizes were observed for all the heavy drinking measures (HDD, TD, NDD and AvgD) and MADRS scores by the end of the treatment course.ConclusionsBaseline elevated depressive symptoms could likely predict the course of heavy alcohol drinking during the treatment, and efficacy outcome of a treatment. AUD patients with baseline clinically significant depression had a progressive lowering in heavy drinking markers significantly corresponding to the lowering of depression symptoms by the end of treatment with Quetiapine fumarate XR.ClinicalTrials.govNCT#0049862 (https://clinicaltrials.gov/ct2/show/NCT00498628?term=litten&draw=2&rank=3)

Alcohol use disorder (AUD) patients comorbid with hepatitis C virus (HCV) infection (HCV + AUD) could have progressively severe clinical sequels of liver injury and inflammation. Serum zinc and several polyunsaturated fatty acids (PUFAs) get dysregulated in AUD as well as HCV. However, the extent of dysregulation of PUFAs and zinc deficiency and their interaction in HCV + AUD as a comorbid pathology has not been studied. We examined the role of dysregulation of FAs and low zinc in HCV + AUD patients. 138 male and female participants aged 21–67 years were grouped as HCV-only (Gr. 1; n = 13), HCV + AUD (Gr. 2; n = 25), AUD without liver injury (Gr. 3; n = 37), AUD with liver injury (Gr. 4; n = 51), and healthy volunteers (Gr. 5 or HV; n = 12). Drinking history, individual demographic measures, fasting fatty acids, liver function, and zinc were measured and analyzed. HCV + AUD patients showed the highest ALT level compared to the rest of the groups. Serum zinc concentrations were the lowest, and the proinflammatory shift was the highest (characterized by ω6 : ω3 ratio) in the HCV + AUD patients. Total ω3, eicosapentaenoic acid (EPA), and docosapentaenoic acid (DPA5,3) were the lowest in HCV + AUD patients. Total ω3, α-linoleic acid (α-LA) along with covariable number of drinking days past 90 days (NDD90), eicosapentaenoic acid (EPA), and docosapentaenoic acid (DPA5,3) independently showed significant association with low zinc in the HCV + AUD patients. Heavy drinking pattern showed that NDD90 has a significant mediating role in the representation of the relationship between candidate ω3 PUFAs and zinc uniquely in the HCV + AUD patients. Low serum zinc showed a distinctively stronger association with total and candidate ω3s in the HCV + AUD patients compared to the patients with HCV or AUD alone, supporting dual mechanism involved in the exacerbation of the proinflammatory response in this comorbid cohort. This trial is registered with NCT#00001673.

Although several risk factors have been identified for alcohol use disorder, many individuals with these factors do not go on to develop the disorder. Identifying early phenotypic differences between vulnerable individuals and healthy control subjects could help identify those at higher risk. Binge drinking, defined as reaching a blood alcohol level of 80 mg%, carries a risk of negative legal and health outcomes and may be an early marker of vulnerability. Using a carefully controlled experimental paradigm, the authors tested the hypothesis that risk factors for alcohol use disorder, including family history of alcoholism, male sex, impulsivity, and low level of response to alcohol, would predict rate of binging during an individual alcohol consumption session.This cross-sectional study included 159 young social drinkers who completed a laboratory session in which they self-administered alcohol intravenously. Cox proportional hazards models were used to determine whether risk factors for alcohol use disorder were associated with the rate of achieving a binge-level exposure.A greater percentage of relatives with alcoholism (hazard ratio: 1.04, 95% CI=1.02-1.07), male sex (hazard ratio: 1.74, 95% CI=1.03-2.93), and higher impulsivity (hazard ratio: 1.17, 95% CI=1.00 to 1.37) were associated with a higher rate of binging throughout the session. Participants with all three risk factors had the highest rate of binging throughout the session compared with the lowest risk group (hazard ratio: 5.27, 95% CI=1.81-15.30).Binge drinking may be an early indicator of vulnerability to alcohol use disorder and should be carefully assessed as part of a thorough clinical evaluation.

Hazardous consequences of alcohol consumption adversely influence overall health, specifically physical and mental health. Differences in alcohol consumption and manifestations in pathology have been observed between males and females, however research on understanding these differences is limited. Negative consequences of alcohol consumption have now been studied including sex as a significant factor. Some studies have shown differences in the severity of consequences of alcohol consumption between the sexes, both in the mental consequences and changes/ injury in various organ systems. Over time, reports in females on both the dynamics of drinking and on the hazardous consequences of alcohol consumption have grown, primarily because of more awareness, better observation, and the inclusion of sex as a factor in scientific investigations. This paper reviews role of sex differences in pathophysiological and behavioral consequences of alcohol drinking.

Hangover refers to the cluster of physiological and behavioral symptoms that occur following the end of a drinking episode. While hangover has been studied after the typical oral consumption of alcohol, the occurrence of hangover following intravenous (IV) alcohol administration in human laboratory studies has not been previously reported. This study characterizes hangover symptoms and post-infusion drinking behavior following acute IV alcohol administration in social drinkers. Twenty-one to thirty-year-old healthy social drinkers (n = 24) underwent an alcohol clamp session at breath alcohol concentration of 0.06 percent. Hangover symptoms as well as any post-infusion drinking that occurred between the end of the session and the following morning were assessed using the Acute Hangover Scale, and examined for influences of recent drinking history, family history of alcoholism and Sex. Results indicated a 79 percent prevalence of hangover symptoms, with the most common symptoms being 'tired', 'thirsty' and 'headache'. Recent drinking measures showed significant effects on Average Hangover Scale scores, with heavier drinkers showing greater hangover symptoms. There was a significant sex difference in average hangover scores, with females reporting higher scores than males. Subjective measures of stimulation and intoxication were also associated with Average Hangover Scale scores. The probability of post-infusion drinking was not predicted by hangover scores, but was related to recent drinking history; subjective response to alcohol was a significant mediator of this relationship. These findings demonstrate that hangover symptoms are experienced following IV alcohol administration, and extend previous studies of influences of risk factors for alcohol use disorders including recent drinking on hangover.

Aim Chronic heavy alcohol intake frequently causes liver inflammation/injury, and altered mineral metabolism may be involved in this liver pathology. In this study, we evaluated the association of heavy drinking, changes in serum magnesium levels and biochemical evidence of liver injury in alcohol-use-disorder (AUD) patients who had no clinical signs or symptoms of liver injury. We also aimed to identify any sex-based differences in patients with mild or no biochemical evidence of liver injury induced by heavy drinking. Methods 114 heavy drinking alcohol-dependent (AD) female and male patients aged 21–65 years without clinical manifestations of liver injury, who were admitted to an alcohol treatment program, were grouped by alanine aminotransaminase (ALT) levels: ≤ 40 IU/L, as no liver injury (GR.1), and ALT>40 IU/L as mild liver injury (GR.2). Patients were actively drinking until the day of admission. Comprehensive metabolic biochemistry results, fatty acid panel, serum magnesium and drinking history data were collected at admission; and study-specific measures were evaluated. Results In all AD patients, lower magnesium was significantly associated with the heavy drinking marker and heavy drinking days past 90 days (HDD90). A lower serum magnesium concentration was observed in AD patients with mild liver injury. Females of both groups had mean levels of magnesium in the deficient range. A clinically significant drop in magnesium levels was observed only in the GR.2 (mild liver injury) male AD patients. Females showed a significant association between low magnesium levels and the ω6:ω3 polyunsaturated fatty acids (PUFAs) ratio. Conclusions Specific heavy drinking markers showed an association with lower magnesium levels. Low serum magnesium levels are common in subjects with AUD and appear to be associated with the onset of liver injury.

Alcohol use disorder is associated with a wide array of hepatic pathologies ranging from steatosis to alcoholic-related cirrhosis (AC), alcoholic hepatitis (AH), or hepatocellular carcinoma (HCC). Biomarkers are categorized into two main categories: biomarkers associated with alcohol consumption and biomarkers of alcoholic liver disease (ALD). No ideal biomarker has been identified to quantify the degree of hepatocyte death or severity of AH, even though numerous biomarkers have been associated with AH. This review provides information of some of the novel and latest biomarkers that are being investigated and have shown a substantial association with the degree and severity of liver injury and inflammation. Importantly, they can be measured noninvasively. In this manuscript, we consolidate the present understanding and prospects of these biomarkers; and their application in assessing the severity and progression of the alcoholic liver disease (ALD). We also review current and upcoming management options for AH.

Heavy alcohol drinking causes alterations in the metabolism of fatty acids and zinc that participate in inflammation and liver injury. HIV infection has been reported to cause dysregulated polyunsaturated fatty acid (PUFA) and zinc metabolism. In this pilot study, we examined the role of dysregulated PUFA metabolism and zinc deficiency in the liver injury occurring in heavy drinkers with early-stage HIV diagnosis. Fourteen heavy drinking alcohol-dependent (AD) patients [seven with treatment-naive HIV diagnosis (AD+HIV) and seven without HIV infection (AD)] participated in this study. Liver injury, serum zinc, PUFAs, viral load, CD4(+) count, and drinking measures using lifetime drinking history (LTDH), and timeline follow-back past 90 days (TLFB90) were evaluated. Liver injury was also assessed in seven age- and gender-matched socially drinking HIV treatment-naive patients who served as disease controls. HIV viral load by itself did not show any correlation with liver injury. Liver enzymes were significantly elevated in both AD+HIV and AD patients, and AD+HIV patients had significantly higher alanine aminotransferase (ALT) levels than did AD patients, even with lower drinking. Serum zinc was significantly lower in AD+HIV patients. Only AD+HIV patients showed a significant elevation in linoleic acid (LA) and alpha-linoleic acid (ALA) levels. Serum zinc and ALT, LA and ALT, and ALA and ALT were significantly associated only in AD+HIV patients. The association between LA and ALT showed a higher effect than did the ALA and ALT association in the AD+HIV patients. Interestingly, AD+HIV subjects (who drank less), nevertheless, showed more liver injury compared with AD patients, who reported heavier drinking. We speculate that the underlying proinflammatory response resulting from zinc deficiency and an elevation in serum LA likely contributed to liver injury in AD+HIV patients, even with a comparatively lower degree of heavy drinking.

Alcohol-associated liver disease (ALD) remains a major health concern worldwide. Alcohol consumption gives rise to reactive/toxic acrolein, a pathogenic mediator of liver injury in experimental ALD. Elevated acrolein adducts and metabolites are detectable in blood and urine. This study evaluates the major urinary acrolein metabolite, 3-hydroxypropylmercapturic acid (HPMA), in patients with acute alcoholic hepatitis (AAH) and examines its association with disease severity and markers of hepatic inflammation and injury. Urine HPMA was significantly higher in patients with severe [model for end-stage liver disease (MELD) ≥ 20] AAH compared with nonsevere AAH (MELD ≤ 19) or non-alcohol-consuming controls, suggesting that urine HPMA is a novel noninvasive biomarker in severe AAH. The association between HPMA and MELD in patients with AAH was nonlinear. In patients with nonsevere AAH, there was a positive trend, although not significant, whereas in severe AAH the association was negative, indicative of extensive injury and glutathione depletion. Consistent with the multifactorial etiology of ALD, our data identified strong combined effects of HPMA and proinflammatory cytokines on hepatocyte cell death, thereby supporting the pathogenic role of acrolein in liver injury. HPMA, together with IL-1β, showed robust associations with cytokeratin 18 caspase-cleaved fragment (CK18-M30; adjusted R2 = 0.812, P = 0.016) and cytokeratin 18 full-length protein (CK18-M65; adjusted R2 = 0.670, P = 0.048); similarly, HPMA, with IL-8, correlated with CK18-M30 (adjusted R2 = 0.875, P = 0.007) and CK18-M65 (adjusted R2 = 0.831, P = 0.013). The apoptosis index (CK18-M30:CK18-M65 ratio) strongly correlated with HPMA, together with IL-1β (adjusted R2 = 0.777, P = 0.022) or tumor necrosis factor-α (TNFα; adjusted R2 = 0.677, P = 0.046). In patients with severe AAH, IL-1β, IL-8, and TNFα are the predominant proinflammatory cytokines that interact with HPMA and play important mediating roles in influencing the extent/pattern of liver cell death. NEW & NOTEWORTHY This is the first study to examine the urinary acrolein metabolite 3-hydroxypropylmercapturic acid (HPMA) in alcoholic liver disease. HPMA was higher in patients with severe acute alcoholic hepatitis (AAH) compared with controls or nonsevere AAH and may be a novel selective, noninvasive biomarker for severe AAH. Consistent with the multifactorial etiology of alcohol-associated liver disease, we identified strong combined effects of HPMA and proinflammatory cytokines (IL-1β, IL-8, and TNFα) on the extent/pattern of liver cell death, thereby supporting the pathogenic role of acrolein.

Alcohol hangover is a combination of mental, sympathetic, and physical symptoms experienced the day after a single period of heavy drinking, starting when blood alcohol concentration approaches zero. How individual measures/domains of hangover symptomology might differ with moderate to heavy alcohol consumption and how these symptoms correlate with the drinking markers is unclear. We investigated the amount/patterns of drinking and hangover symptomology by the categories of alcohol drinking. We studied males and females in three groups: 12 heavy drinkers (HD, &gt, 15 drinks/week, 34&ndash, 63 years old (y.o.)), 17 moderate drinkers (MD, 5&ndash, 14 drinks/week, 21&ndash, 30 y.o.), and 12 healthy controls (social/light drinkers, SD, &lt, 5 drinks/week, 25&ndash, 54 y.o.). Demographics, drinking measures (Timeline followback past 90 days (TLFB90), Alcohol Use Disorders Identification Test (AUDIT)), and alcohol hangover scale (AHS) were analyzed. Average drinks/day was 5.1-times greater in HD compared to MD. Average AHS score showed moderate incapacity, and individual measures and domains of the AHS were significantly elevated in HD compared to MD. Symptoms of three domains of the AHS (mental, gastrointestinal, and sympathetic) showed domain-specific significant increase in HD. A domain-specific relation was present between AUDIT and specific measures of AHS scores in HD, specifically with the dependence symptoms. Exacerbation in hangover symptomology could be a marker of more severe alcohol use disorder.

Many variables, aside from the amount and duration of alcohol consumption, play a role in the development and progression of alcoholic liver disease (ALD). One critical factor that can be modified is diet/nutrition. We have made major recent advances in our understanding of the interactions of nutrition and ALD. In this article, we review advances made in zinc metabolism/therapy for ALD. There is major zinc dyshomeostasis with ALD which is mediated, in part, by poor intake and absorption, increased excretion, and altered zinc transporters, especially ZIP14. Zinc deficiency plays an etiologic role in multiple mechanisms of ALD, ranging from intestinal barrier dysfunction to hepatocyte apoptosis. Zinc supplementation is highly effective at correcting these ALD mechanisms and preventing/treating experimental ALD. There is no Food and Drug Administration (FDA) approved therapy for any stage of ALD. Because animal and human data suggest that zinc deficiency occurs early in the course of ALD, we treat most ALD patients with daily oral zinc supplementation (220 mg zinc sulfate which contains 50 mg elemental zinc).

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 two 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 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 (LPS) 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 two weeks of abstinence, in a subset of individuals admitted to an alcohol detoxification program. This article is protected by copyright. All rights reserved.

Studies have reported liver injury as a consequence of antipsychotic treatment. Very heavy alcohol drinking (ten or more drinks/day for men and eight for women) also causes liver injury. This study aims to evaluate liver injury with quetiapine extended release (XR) in very heavy drinking alcohol-dependent (AD) patients.Two hundred and eighteen AD patients, 18-65 years of age, received 12 weeks of quetiapine XR or placebo treatment in a dose-escalated manner reaching the full dose of 400 mg/day during week 4. Blood chemistry and hematology were assessed at baseline (W0), post-titration at the end of week 3 (W4), week 8 (W8), and end of week 12 (W13). Patients were further grouped as GR.1 (no liver injury, ALT ≤40) and GR.2 (pre-existing liver injury, ALT40) within each treatment. Drinking history, fasting blood glucose concentration (FBG), and lipid panel were used as covariates in the analyses.Liver injury and total drinks and average drinking measures from the Timeline follow-back questionnaire (TLFB) were highly associated. No significant exacerbation in liver injury was observed in patients treated with quetiapine XR in GR.2. Liver injury as determined by elevated alanine aminotransaminase (ALT) was reported in a few patients in GR.1 who received quetiapine XR; however, the occurrence was low, and the level of liver injury was not significant. FBG and lipid measures showed some elevation, but did not show any significant association with liver injury.Quetiapine XR did not show any significant exacerbation of liver injury in very heavy drinking alcohol-dependent patients with pre-existing liver injury. Frequency and severity of new liver injury cases in quetiapine XR-treated patients without any pre-existing liver injury was also low. Study findings support medical management of AD patients with heavy drinking profile using quetiapine XR formulation.

HIV and HCV co-infection is a unique disease condition, and medical management of such condition is difficult due to severity and systemic complications. Added with heavy alcohol drinking, risk of liver injury increases due to several pro-inflammatory responses that subsequently get involved with alcohol metabolism. Elevated levels of fatty acids have been reported both in viral infections as well as alcoholic liver disease though such investigations have not addressed the adverse events with dual viral infection of HIV and HCV along with heavy drinking. This case report is of a patient with excessive alcohol drinking and first time diagnosis of HIV and HCV dual infection, elaborating concurrent alteration in Linoleic Acid (LA) levels and pro-inflammatory shift in ω-6/ω-3 ratio along with the elevations in liver injury markers. Elevated LA has been recently studied extensively for its role in alcoholic liver disease; and in the present case, we also found it to be clinically relevant to liver injury.

Liver injury is estimated by serum alanine aminotransferases (ALT) levels in experimental animal models. Laboratories use various techniques to measure ALT levels including assay reagents and chemistry analyzers. VetScan VS2 (VS2) is widely used in veterinary clinics and research laboratories for highly reproducible, convenient and effective testing. Alternatively, ALT liquid reagent is used by laboratories to estimate liver injury in animal studies. The aim of this study was to perform comparative analyses of data obtained from these two assays in two different animal models.In this study, we used two different mouse models and compared the ALT levels measured using VetScan VS2 chemistry analyzer and ALT liquid reagent. Immunohistochemical analysis of hepatic tissue was also performed to document liver pathology. The first model is a high fat diet feeding model that results in a mild hepatic steatosis (fat accumulation in the liver) without elevation of ALT levels. For a severe liver injury model, we employed a hepatotoxin-induced liver injury model (carbon tetrachloride, CCl4), which leads to the development of hepatic fibrosis and very high ALT levels.VetScan VS2 and ALT reagent gave different values of ALT for all animal groups. However, linear regression analysis showed a significantly high association between ALT levels obtained by VS2 and ALT liquid reagent in a high-fat feeding model with no liver injury. For the CClThis study demonstrates that both methods give similar results when evaluating liver injury in animal studies. However, the serum dilution factor is critical for severe liver injury assessment when using ALT reagent and requires some optimization. In this regard, VetScan VS2 is easier to use and gives comparable results.

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.

Alcohol hangover is one of the most commonly experienced consequences of alcohol consumption. An alcohol hangover develops as the blood alcohol concentrations (BAC) approaches zero, and is characterized by a general feeling of misery. More insight into the pathology of an alcohol hangover needs to be gained, in order to enhance the understanding of the area, and as a potential contribution to the innovation of a preventative or hangover curing treatment. The Alcohol Hangover Research Group (AHRG) was founded to support the area of alcohol hangover. This proceeding describes the latest findings in the area of alcohol hangovers, and future research plans, discussed at the 8th Alcohol Hangover Research Group meeting, held on June 25, 2016, New Orleans, USA. Novel insight in potential causes, consequences, and treatment of alcohol hangover were revealed during the meeting, as well as further research plans to examine biomarkers of recent alcohol consumption, immune functioning, alcohol metabolism, and potential treatments.

Alcoholic liver disease (ALD) is a major cause of morbidity and mortality worldwide. The clinical spectrum of ALD includes fatty liver, steatohepatitis with or without fibrosis, and cirrhosis. The diagnosis of ALD is made in patients with evidence of liver injury based on clinical history, physical findings, and laboratory abnormalities, when there is evidence of significant alcohol consumption and after other causes of chronic liver disease have been excluded. Signs and symptoms may be essentially nonexistent in steatosis or possibly mild fatigue and abdominal discomfort. On the other hand, those with decompensated disease may present with massive ascites, muscle wasting, gastrointestinal bleeding, and encephalopathy. Many people drink heavily, yet only a limited number (~35 %) develop more advanced liver diseases (alcoholic hepatitis or cirrhosis). Thus, there must be modifying factors that either prevent or facilitate disease activity/progression. These modifiers can either be fixed (e.g., genetic) or can undergo intervention (e.g., continued drinking, smoking, diet). We review ten disease modifiers of particular importance to ALD. Patients with steatosis only may “normalize” with cessation of drinking; however, outcomes are highly variable once the patient has progressed to cirrhosis. Some subjects die quickly with acute-on-chronic liver disease; other patients who abstain from alcohol and correct other disease modifiers may live a relatively normal life; others may do well for long periods of time only to expire from hepatocellular carcinoma. The biggest variable is continued drinking, and cessation of this and modification of other disease modifiers such as smoking should be aggressively pursued.

Heavy drinking contributes to involuntary body movements such as akathisia. Quetiapine has been shown to alleviate symptoms of akathisia; however, its efficacy in the alcohol dependent population is not well established. Thus, we aimed to identify efficacy of Quetiapine in treating akathisia in very heavy drinking alcohol dependent patients. 108 male and female heavy alcohol consuming study participants received 13 weeks of Quetiapine XR. Drinking history (Timeline Followback, TLFB), depression (Montgomery-Asberg Depression Rating Scale, MADRS), and movement (Barnes Akathisia Scale, BARS) measures were collected at baseline (0 W), week 6 (6 W), and week 12 (12 W). The role of drinking, symptoms of depression, and efficacy of Quetiapine for treating akathisia were assessed. In patients with no symptoms of depression (low MADRS), Quetiapine treatment decreased symptoms of akathisia. Patients with clinically significant depression (high MADRS) reported a significant increase in akathisia measures at 6 W which eventually decreased at 12 W to below baseline levels. The increase in akathisia at 6 W corresponded with a significant increase in the patients’ total drinks and heavy drinking pattern. Treatment with Quetiapine progressively lowered the occurrence of akathisia in alcohol dependent patients who do not show symptoms of depression. Quetiapine treatment lowered akathisia over time in heavy drinkers who had clinically significant symptoms of depression.

Suicidal attempts have a very significant effect on the society, and they also reflect on the efforts of the supporting health care and counseling facilities; and the mental health professionals involved. The impact of suicide is further magnified by the needs of persons who attempt suicide multiple times, requiring emergency health care and rehabilitation. Preventing such activities becomes a major task for the support providing agencies as soon as patient with such tendencies are identified. There are repetitive traits that can be observed during the entire therapeutic program among the high-risk group individuals, who are susceptible to this kind of activity and such traits indicate for specific profiling. The aim of the instrument is to prevent the occurrence of the repetitive suicidal attempts of the patients in various world regions, which may have significantly higher and concerning suicide rates. This profile has been constructed on the various parameters recognized in the statistical analysis of the patient population, which have been identified or can be under treat-ment for their suicidal behavior. This instrument is developed to predict the probability of population segments who may attempt suicide and repetitively, by matching the parameters of the profile with that of the patient pool. Building a profile for the purpose of predicting behavior of this kind can strengthen the intervention strategies more comprehensively and reduce such incidents and health care requirements and expenses.

OBJECTIVES/SPECIFIC AIMS: The current study examined hangover following IV alcohol self-administration (IV-ASA) using the Computer-Assisted Infusion System. The goal of the study was to identify predictors of hangover, including drinking history, alcohol sensitivity, family history, expectancies, and sex differences in nondependent drinkers. METHODS/STUDY POPULATION: The study sample included 89 healthy, nondependent drinkers aged 21–45 years. After a screening to exclude any medical illness or psychiatric disorders, participants completed an IV-ASA session. Each session consisted of a 25-minute priming phase, during which participants were prompted to press a button to receive individually standardized alcohol infusions, followed by a 2-hour “open bar” phase, during which they were instructed to recreate a typical drinking experience. Results from the IV-ASA included peak and average BrAC. Drinking patterns were assessed using the Alcohol Use Disorders Identification Test, which provided 3 subscales: consumption (AUDIT-C), dependence (AUDIT-D), and harmful drinking (AUDIT-H). Subjective response to alcohol was measured using the Drug Effects Questionnaire (DEQ). The Alcohol Hangover Scale (AHS) was used to assess hangover for the period between participants’ departure from the study unit and 10 am the next morning. The Alcohol Effects Questionnaire (AEFQ) is a measure which includes 40 true/false statements about how alcohol typically makes respondents feel, and was used to measure alcohol expectancies. RESULTS/ANTICIPATED RESULTS: Results showed that 78% of participants endorsed having at least 1 hangover symptom following IV-ASA. The most commonly reported items were tired, thirsty, headache, and hangover. There was no association between hangover scores and the AUDIT-C or IV-ASA. Because alcohol consumption was not related to hangover symptoms, risky drinking behavior was examined. Results indicated that participants endorsing 4 or more items on the AUDIT-D plus AUDIT-H subscales showed significantly higher average hangover scores. Linear regression analyses indicated that alcohol hangover scores were associated with DEQ items feel, high, and intoxicated. Ongoing analyses are examining additional predictors of hangover including family history, alcohol expectancies, sex differences, and other alcohol sensitivity measures. DISCUSSION/SIGNIFICANCE OF IMPACT: The results indicated that risky drinking patterns and alcohol response measures were positively associated with hangover symptoms in non-dependent drinks, while no correlation between consumption and hangover symptoms were found. Since previous research has shown than greater subjective response is associated with heavy drinking and predictive of alcohol use disorder, it is possible that hangover symptoms is a marker of this relationship. Since the role of hangover in the transition from heavy drinking to disorder still remains unclear, it will be important to characterize this relationship between alcohol sensitivity and hangover as a function of drinking patterns. This understanding may help to prevent this transition from at-risk drinking to alcohol dependent drinking.

Diarrhoea is one of the leading causes of morbidity and mortality in developing countries in Africa and South Asia such as India. Prevalence of diarrheal diseases in those countries is higher than developed western world and largely has been associated with socio-economic and sanitary conditions. However, present available data has not been sufficiently evaluated to study the role of other factors like healthcare development, population density, sex and regional influence on diarrheal prevalence pattern. Study was performed to understand the relationship of diarrheal prevalence with specific measures namely; healthcare services development, demographics, population density, socio-economic conditions, sex, and regional prevalence patterns in India. Data from Annual national health reports and other epidemiological studies were included and statistically analyzed. Our results demonstrate significant correlation of the disease prevalence pattern with certain measures like healthcare centers, population growth rate, sex and region-specific morbidity. Available information on sanitation like water supply and toilet availability and socioeconomic conditions like poverty and literacy measures could only be associated as trends of significance. This study can be valuable for improvisation of appropriate strategies focused on important measures like healthcare resources, population growth and regional significances to evaluate prevalence patterns and management of the diarrhoea locally and globally.

BACKGROUND: Self-administration is a hallmark of all addictive drugs, including alcohol. Human laboratory models of alcohol self-administration have characterized alcohol-seeking behavior, and served as surrogate measures of the effectiveness of pharmacotherapies for alcohol use disorders. Intravenous alcohol self-administration (IV-ASA) is a novel method that assess alcohol exposure driven primarily by the pharmacological response to alcohol, and may have utility in characterizing unique behavioral and personality correlates of alcohol-seeking and consumption. METHODS: This study examined exposure-response relationships for IV-ASA, and the influence of impulsivity and alcohol expectancy, in healthy non-dependent drinkers (n=112). Participants underwent a 2.5 hour free-access IV-ASA session using the Computerized Alcohol Infusion System (CAIS). Serial subjective response measures included the Drug Effects Questionnaire (DEQ) and Alcohol Urge Questionnaire (AUQ). To characterize the motivational aspects of alcohol consumption prior to potential acute adaptation, the number of self-infusions in the first 30-min of the free-access session was used to classify participants as low- and high-responders. RESULTS: High responders showed greater subjective responses during IV-ASA compared to low responders, reflecting robust exposure-driven hedonic responses to alcohol. High responders also reported heavier drinking patterns and lower scores for negative alcohol expectancies on the Alcohol Effects Questionnaire. High responders also showed higher measures of impulsivity on a delayed discounting task, supporting previous work associating impulsivity with greater alcohol use and problems. CONCLUSIONS: These findings indicate that early phase measures of free-access IV-ASA are particularly sensitive to the rewarding and motivational properties of alcohol, and may provide a unique phenotypic marker of alcohol-seeking behavior.Published by Oxford University Press on behalf of CINP 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US. Language: en

The Japanese quail is very a valuable animal model for research in a variety of biologica l disciplines. The purpose of this study was to characterize and interrelate age-dependent testicular parameters with various blood constituents: blood glucose, plasma proteins and packed cell volume that are developing concurrently in the growing bird. Another objective of the study was to identify selective physio- anatomical markers for predicting the testicular growth and the onset of sexual maturity. Male Japanese quail hatchlings were raised in temperature controlled brooders for up to 3 weeks of age under a constant light and then shifted to hanging cages in an air conditioned room set at ~73° F under a 14L: 10D lighting system and ad libitum access to feed and water. Starting d8, a group of 8-10 birds of uniform size and weight were selected randomly at 4-day intervals up to d52 of age for the project. The birds were weighed and blood sampled using the brachial vein and Blood Glucose (BGL), Total Plasma Proteins (PP) and Packed Cell Volume (PCV) levels were measured prior to euthanization . The testes were removed and measured for weight, length, width and Volume (VOL). All the testicular measurements were then correlated with age and body weight. The left testes were larger than the right testes and their differences were evident at d36 of age. Testicular measurements also reflected two distinct growth surges at d28, d32 and d36 of age. Combined Testes Weight (CTW) and Combined Testes Volume (CTV) revealed a strong positive correlation with PCV and PP and a negative correlation with Blood Glucose Level (BGL). Accordingly, these measurements could serve as reliable markers of growth rate and sexual maturation in male Japanese quail.