Alcoholic Cirrhotics Research Articles

Compensated Cirrhosis Is Associated With Increased Risk of Complications Following Total Hip Arthroplasty in a Large Medicare Database

BackgroundThe aim of this study is to evaluate medical and surgical complications of liver cirrhosis patients following total hip arthroplasty (THA), with attention to different etiologies of cirrhosis and their financial burden following THA. MethodsIn total, 18,321 cirrhotics and 722,757 non-cirrhotics who underwent primary elective THA between 2006 and 2013 were identified from a retrospective database review. This cohort was further subdivided into 2 major etiologies of cirrhosis (viral and alcoholic cirrhosis) and other cirrhotic etiology. Cirrhotics were compared to non-cirrhotics for hospital length of stay, 90-day mean total charges and reimbursement, hospital readmission, and major medical and arthroplasty-specific complications. ResultsCirrhosis was associated with increased rates of major medical complications (4.3% vs 2.4%; odds ratio [OR] 1.20, P < .001), minor medical complications, transfusion (3.4% vs 2.1%; OR 1.16, P = .001), encephalopathy, disseminated intravascular coagulation, and readmission (13.5% vs 8.6%; OR 1.18, P < .001) within 90 days. Cirrhosis was associated with increased rates of revision, periprosthetic joint infection, hardware failure, and dislocation within 1 year postoperatively (3.1% vs 1.6%; OR 1.37, P < .001). Cirrhosis independently increased hospital length of stay by 0.14 days (P < .001), and it independently increased 90-day charges and reimbursements by $13,791 (P < .001) and $1707 (P < .001), respectively. Viral and alcoholic cirrhotics had higher rates of 90-day and 1-year complications compared to controls—other causes only had higher rates of 90-day medical complications, encephalopathy, readmission, and 1-year revision, hardware failure, and dislocation compared to controls. ConclusionCirrhosis, especially viral and alcoholic etiologies, is associated with higher risk of early postoperative complications and healthcare utilization following elective THA.

Impact of Compensated Cirrhosis Etiology on Postoperative Outcomes Following Total Knee Arthroplasty

BackgroundCirrhotics often demonstrate worse outcomes than their non-cirrhotic counterparts following orthopedic surgery; however, there are limited arthroplasty-focused data on this occurrence. Additionally, variances in postoperative outcomes among the different etiologies of cirrhosis have not been well described. The aim of this study is to evaluate the effect compensated cirrhosis had on postoperative outcomes following elective total knee arthroplasty (TKA). MethodsIn total, 1,734,568 patients who underwent primary TKA from 2006 to 2013 were identified using the Medicare Claims Database. Patients were divided into those with a history of compensated cirrhosis and those with no history of liver disease. Subgroup analysis was performed based on the etiology of cirrhosis. Multivariate logistic regression was used to evaluate postsurgical outcomes of interest. ResultsCirrhotic patients had higher risk of developing disseminated intravascular coagulation (odds ratio [OR] 2.76, P = .003), encephalopathy (OR 3.00, P < .001), and periprosthetic infection (OR 1.79, P < .001) compared to controls. Following subgroup analysis, alcoholic cirrhotics had high risk of periprosthetic infection (OR 2.12, P < .001), fracture (OR 3.28, P < .001), transfusion (OR 2.45, P < .001), and encephalopathy (OR 7.34, P < .001) compared to controls. Viral cirrhosis was associated with an increase in 90-day charges ($14,941, P < .001) compared to controls, while cirrhosis secondary to other causes was associated with few adverse outcomes compared to controls. ConclusionLiver cirrhosis is an independent risk factor for increased perioperative morbidity and financial burden following TKA. Cirrhosis due to etiologies other than viral infections and alcoholism are associated with few adverse outcomes. Surgeons should be aware of these complications to properly optimize postoperative management.

Soluble α-Klotho in Liver Cirrhosis and Alcoholism.

Alpha Klotho is a transmembrane protein that serves as co-receptor for FGF23. Ectodomain of membrane bound α Klotho may be shed by membrane bound proteases (activated, among other factors, by tumor necrosis factor (TNF)-α) generating the soluble form of the protein (sKl) that functions as a hormone by itself. It modulates calcium influx into cells, blunts IGF-1/Insulin signaling, promotes synthesis of antioxidants, generally slows down tumor progression, delays cell senescence, is neuroprotective and promotes oligodendrocyte maturation and myelin synthesis, and muscle rejuvenation. It may be involved in inflammation and exerts antifibrogenic effects. Some of these pathways may become altered in alcoholism or liver cirrhosis, but data are scattered and scarce and an update is required. Literature survey. Alcohol consumption in non-alcoholics is inversely related to sKl, but alcoholic cirrhotics showed higher-than-normal sKl values in association with liver function derangement. In hepatoma cells, the intensity of Klotho staining was related to faster tumor progression and a shortened life span. Among severe alcoholic cirrhotics sKl is directly related to serum TNF-α levels, and, inversely, to brain atrophy. Given the antioxidant, anti-inflammatory, and antifibrogenic effects of Klotho, perhaps the increase in cirrhosis (and in other inflammatory conditions, such as sepsis or cancer) reflects an attempt to regulate increased inflammation, but clinical and experimental research is urgently needed in this field.

Positive familial history for metabolic traits predisposes to early and more severe alcoholic cirrhosis: A cross-sectional study.

Familial aggregation of metabolic traits in NAFLD is well documented. However, relevance of these traits in alcoholic cirrhosis is not well studied. We aimed to explore the association of family history of metabolic traits with age at diagnosis, severity and complications of alcoholic cirrhosis. In a cross-sectional study, all consecutive patients with alcoholic cirrhosis presenting to our tertiary care centre were included. Family and personal history, demographic characteristics, medical history, anthropometric measurements and laboratory data were recorded. The amount and duration of alcohol consumption were also carefully recorded. Out of 1084 alcoholic cirrhotics (age 48.5±10.1years, all males), family history for metabolic traits was documented in 688 (63.5%) patients. These patients had younger age at diagnosis, increased incidence of jaundice, ascites, variceal bleed and hepatic encephalopathy with consequently higher MELD and CTP score. These patients developed cirrhosis despite shorter median duration (13years, IQR 7-20 vs 21, IQR 18-25) and lesser amount of alcohol consumption (74g/d, IQR 24-96 vs 144, IQR 100-148). Patients with both family and personal history of metabolic traits had a higher risk by 3.3 times (95% CI 2.2-4.8) of an early age at diagnosis, 13.2 times (95% CI 8.7-20.1) of progression to cirrhosis with lesser amount of alcohol consumption and 4.6 times (95% CI 3.1-6.9) with lesser duration of alcohol consumption. Positive family and personal history of metabolic traits predispose to alcoholic cirrhosis with an earlier age at onset and more severity despite lesser exposure to alcohol.

From the Editor’s Desk…: October 2018

From the Editor’s Desk…: October 2018

A return to harmful alcohol consumption impacts on portal hemodynamic changes following alcoholic hepatitis.

Increased hepatic venous pressure gradient (HVPG) plays a role in the clinical manifestations of alcoholic hepatitis (AH). The evolution of HVPG and the influence of alcohol use in the intermediate term are unclear. The aim of this study was to explore HVPG modifications following AH taking into consideration alcohol use and clinical manifestations. Patients with AH (n=37; age 52 years; model for end-stage liver disease: 18.5; Maddrey score: 43) and chronic excessive drinkers with compensated cirrhosis (n=19; age: 54 years; model for end-stage liver disease: 9.2) underwent HVPG measurement and liver biopsy. Ten long-standing abstinent alcoholic cirrhotics served as controls. After discharge, patients were monitored for alcohol use and clinical complications, with repeated HVPG after a median duration of 100 days. Inflammation was determined using plasma C-reactive protein. At baseline, compared with chronic excessive drinkers and alcoholic cirrhotics, patients with AH had increased HVPG (18.1±0.6 vs. 13.8±1.4 vs. 15±1.3 mmHg, P<0.05). During follow-up, patients who became abstinent or reported occasional drinking were more likely to achieve a greater than 20% reduction in HVPG compared with those returning to harmful alcohol (45 vs. 0%, P<0.01), and suffered from fewer complications (25 vs. 68%, P<0.03). High baseline C-reactive protein levels correlated to the Maddrey (r=0.38), but no relationship was observed between changes in inflammation and HVPG. Elevated HVPG is a feature of AH, with a clinically significant reduction in values in abstinent or occasional drinkers after weeks of follow-up. A return to harmful alcohol has a negative impact on portal hemodynamics and associated clinical complications.

The study of psychometric test for detection and assessment in subclinical hepatic encephalopathy

Background: During past two decades, psychometric tests have been used extensively for detection of SHE. However, the results have been variables with different tests. In real practice we require the tests, which can be administered quickly by treating physician with simplicity and with simple instrument or only with a simple form. Objective: (1) To apply a battery of psychometric tests in cases of cirrhosis of liver. (2) To correlate findings of psychometric tests with Child`s index of severity for cirrhosis of liver. Methodology: 25 patients of cirrhosis of liver diagnosed by ultrasonography, biochemical and clinical evidence, admitted in the Medicine ward, will constitute the study group. These patients will undergo a battery of psychometric tests and EEG along with other routine hematological and radiological test. 25 control group with confounding factors as age, sex, education and socioeconomic status. Results: We observed that on WAPIS test cirrhotic performed significantly worse than controls. Mean IQSD non-Alcoholic cirrhotic on WAPIS was [67.7811.29] and Mean IQSD of alcoholic cirrhotics was (66.459.71). On analysis of data the difference was not significant (p&gt;0.005). Taken together the performance test was abnormal in 14 (56%) cases. Conclusion: We concluded that for quick assessment of mental status and screening for detecting SHE in cases of cirrhosis of liver with portal hypertension, TMT test is useful and for complete assessment of cerebral function derangement WAPIS is most sensitive and complete test.

Survey of alcohol-related cirrhosis at a tertiary care center in North East India.

Alcohol use is increasing in North East India and is important to estimate the influence of these changes in the epidemiology of alcohol related cirrhosis. Among 1000 consecutive patients of cirrhosis, diagnosed by a combination of clinical, radiological and/or histopathological features, etiology was established by history of significant alcohol abuse, determining viral and autoimmune markers and by metabolic screening. Patients not confirmed to be cirrhotic were excluded from the study. All cases were studied to determine clinical features, complications, disease prognosis, and mortality. Alcoholic cirrhotics were then compared with nonalcohol etiology. 72.2% alcoholic cirrhosis were compared with 27.8% patients of nonalcohol etiology and alcoholic cirrhotics were younger (45 + 9.4years vs. 47.9 + 12.5years), predominantly males (M/F ratio 37:1 vs. 1.8:1) with significantly high incidence of jaundice (38.5% vs. 30.5%), night blindness (14.4% vs. 3.6%), ascites (76.3% vs. 69.1%), upper gastrointestinal bleed (46.4% vs. 34.5%), and hepatic encephalopathy (24.1% vs. 10.4%). Biochemical parameters that were significantly higher in alcoholics were mean bilirubin (4.7 + 8.7 vs. 3.1 + 4.7mg/dL), AST/ALT ratio (2.03 vs. 1.4), gamma-glutaryl transaminase levels (209.7 + 37.9 vs. 93.9 + 14IU/mL), and serum ammonia (75.1 + 55.7 vs. 52.1 + 45.4mg/dL). Mean model for end-stage liver disease, scores, and Child C disease was significantly higher in alcoholics (18.6 + 7.7 vs. 15.6 + 6.4) and (54.1% vs. 37%), respectively, representing advanced disease at presentation. Mortality within 1month was significantly higher among alcoholic cirrhosis (9.8% vs. 3.2%). Thus, alcoholic cirrhosis is of major concern in North East India as majority patients are in most productive age group and presented with advanced disease. Short-term mortality was high among alcoholic cirrhotics. Proper education and legislation are essential to mitigate the consequences of this disease.

Prevalence of occult hepatitis B infection in patients visiting tertiary care hospital

BackgroundTo study the prevalence of occult hepatitis B virus infection (OBI) in a tertiary care hospital. Methods50 HBsAg negative individuals, each amongst blood donors, alcohol dependence syndrome (ADS), alcoholic cirrhotics, hepatitis C virus (HCV)/cryptogenic cirrhotics, end-stage renal disease (ESRD) on maintenance haemodialysis for one year, all malignancies prior to chemotherapy and HIV positive patients were evaluated for anti-HBc total antibody, and blood hepatitis B virus (HBV) DNA amplification in those tested positive. ResultsA total of 60/369 (16.2%) individuals were anti-HBc total positive, 13/50 (26%) of HCV/cryptogenic cirrhotics, 13/52 (25%) of HIV positive, 10/50 (20%) of patients with malignancy, 10/51 (19.6%) and 7/59 (11.9%) of alcoholic cirrhotics and ADS respectively had intermediate prevalence, while, blood donors 5/55 (9.1%), ESRD patients 2/52 (3.8%) had low prevalence. 12 patients (20% of all anti-HBc total positive cases) were HBV DNA positive, 5 HCV cirrhotics (10% of total HCV/cryptogenic), 4 HIV positive (7.69%), 1 each of ADS (1.69%), alcoholic cirrhotics (1.96%) and malignancy group (2%). Blood donors and ESRD patients were negative for HBV DNA. ConclusionHBV DNA amplification may under diagnose OBI and anti-HBc total positivity may be a better surrogate marker. Nucleic acid testing of blood donors, however is preferred, especially in high endemic areas. OBI must be looked for in cirrhotics, HIV infection, and patients with cancers prior to chemotherapy, as they may contribute to morbidity in them.

Malnutrition in cirrhosis increases morbidity and mortality.

Malnutrition is frequent in patients with cirrhosis and is associated with complications like ascites, hepatic encephalopathy, infections, and death. We determined the prevalence of malnutrition by various methods and its clinical importance in patients with cirrhosis. Consecutive patients of cirrhosis from August 2013 to February 2015 were assessed. Nutritional status was assessed by traditional model (mid-arm circumference, triceps skinfold thickness, serum albumin, creatinine height index, total lymphocyte count), handgrip, and body composition analysis measuring skeletal muscle mass and body fat mass. All patients were followed up for 12 months to assess the outcome. 247 patients (age 42.10 ± 10.14 years, 81% male) were included in the study. Etiology of cirrhosis was alcohol in 53% patients. Prevalence of malnutrition was 59.5% according to traditional model, 66.8% by body composition analysis and 71.4% by handgrip. Nutritional status was poor in alcoholic cirrhotics versus nonalcoholics as assessed by triceps skinfold thickness (9.33 ± 2.9 vs 11.64 ± 3.5 mm; P = 0.001), serum albumin (25.1 ± 4 vs 28.1 ± 4 g/L; P = 0.001), and body fat mass (7.6 ± 3.1 vs 8.7 ± 3.3 kg; P = 0.008). Prevalence of malnutrition was 12/27 (44.5%), 96/131 (73.3%) and 84/89 (94.4%) in Child's class A, B, and C respectively. Complications requiring hospitalization (71.3% vs 38.2%; 0.002) and mortality (41.1% vs 18.2%; P = 0.001) were more in malnourished patients compared to well nourished. Nutritional assessment parameters significantly correlated with the liver disease severity (P < 0.05). Prevalence of malnutrition is high in patients with cirrhosis. It is associated with increased complications and mortality.

Genetic polymorphisms of ADH1B, ADH1C and ALDH2 in Turkish alcoholics: lack of association with alcoholism and alcoholic cirrhosis.

No data exists regarding the alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) gene polymorphisms in Turkish alcoholic cirrhotics. We studied the polymorphisms of ADH1B, ADH1C and ALDH2 genes in alcoholic cirrhotics and compared the results with non-cirrhotic alcoholics and healthy volunteers. Overall, 237 subjects were included for the study: 156 alcoholic patients (78 cirrhotics, 78 non-cirrhotic alcoholics) and 81 healthy volunteers. Three different single-nucleotide-polymorphism genotyping methods were used. ADH1C genotyping was performed using a polymerase chain reaction-restriction fragment length polymorphism method. The identified ADH1C genotypes were named according to the presence or absence of the enzyme restriction sites. ADH1B (Arg47Hys) genotyping was performed using the allele specific primer extension method, and ALDH2 (Glu487Lys) genotyping was performed by a multiplex polymerase chain reaction using two allele-specific primer pairs. For ADH1B, the frequency of allele *1 in the cirrhotics, non-cirrhotic alcoholics and healthy volunteers was 97.4%, 94.9% and 99.4%, respectively. For ADH1C, the frequency of allele *1 in the cirrhotics, non-cirrhotic alcoholics and healthy volunteers was 47%, 36.3% and 45%, respectively. There was no statistical difference between the groups for ADH1B and ADH1C (p&gt;0.05). All alcoholic and non-alcoholic subjects (100%) had the allele *1 for ALDH2. The obtained results for ADH1B, ADH1C, and ALDH gene polymorphisms in the present study are similar to the results of Caucasian studies. ADH1B and ADH1C genetic variations are not related to the development of alcoholism or susceptibility to alcoholic cirrhosis. ALDH2 gene has no genetic variation in the Turkish population.

Incidence, risk factors and outcome ofde novotumors in liver transplant recipients focusing on alcoholic cirrhosis

Orthotopic liver transplantation (OLT) is an established life-saving procedure for alcoholic cirrhotic (AC) patients, but the incidence of de novo tumors ranges between 2.6% and 15.7% and is significantly increased in comparison with patients who undergo OLT for other etiologies. Tobacco, a known carcinogen, has been reported to be between 52% and 83.3% in AC patients before OLT. Other risk factors that contribute to the development of malignancies are dose-dependent immunosuppression, advanced age, viral infections, sun exposure, and premalignant lesions (inflammatory bowel disease, Barrett's esophagus). A significantly more frequent incidence of upper aerodigestive (UAD) tract, lung, skin, and kidney-bladder tumors has been found in OLT recipients for AC in comparison with other etiologies. Liver transplant recipients who develop de novo non-skin tumors have a decreased long-term survival rate compared with controls. This significantly lower survival rate is more evident in AC recipients who develop UAD tract or lung tumors after OLT mainly because the diagnosis is usually performed at an advanced stage. All transplant candidates, especially AC patients, should be encouraged to cease smoking and alcohol consumption in the pre- and post-OLT periods, use skin protection, avoid sun exposure and over-immunosuppression, and have a yearly otopharyngolaryngeal exploration and chest computed tomography scan in order to prevent or reduce the incidence of de novo malignancies. Although still under investigation, substitution of calcineurin inhibitors for sirolimus or everolimus may reduce the incidence of de novo tumors after OLT.

Colonic inflammation and secondary bile acids in alcoholic cirrhosis

Alcohol abuse with/without cirrhosis is associated with an impaired gut barrier and inflammation. Gut microbiota can transform primary bile acids (BA) to secondary BAs, which can adversely impact the gut barrier. The purpose of this study was to define the effect of active alcohol intake on fecal BA levels and ileal and colonic inflammation in cirrhosis. Five age-matched groups {two noncirrhotic (control and drinkers) and three cirrhotic [nondrinkers/nonalcoholics (NAlc), abstinent alcoholic for >3 mo (AbsAlc), currently drinking (CurrAlc)]} were included. Fecal and serum BA analysis, serum endotoxin, and stool microbiota using pyrosequencing were performed. A subgroup of controls, NAlc, and CurrAlc underwent ileal and sigmoid colonic biopsies on which mRNA expression of TNF-α, IL-1β, IL-6, and cyclooxygenase-2 (Cox-2) were performed. One hundred three patients (19 healthy, 6 noncirrhotic drinkers, 10 CurrAlc, 38 AbsAlc, and 30 NAlc, age 56 yr, median MELD: 10.5) were included. Five each of healthy, CurrAlc, and NAlc underwent ileal/colonic biopsies. Endotoxin, serum-conjugated DCA and stool total BAs, and secondary-to-primary BA ratios were highest in current drinkers. On biopsies, a significantly higher mRNA expression of TNF-α, IL-1β, IL-6, and Cox-2 in colon but not ileum was seen in CurrAlc compared with NAlc and controls. Active alcohol use in cirrhosis is associated with a significant increase in the secondary BA formation compared with abstinent alcoholic cirrhotics and nonalcoholic cirrhotics. This increase in secondary BAs is associated with a significant increase in expression of inflammatory cytokines in colonic mucosa but not ileal mucosa, which may contribute to alcohol-induced gut barrier injury.

Changes in gut bacterial populations and their translocation into liver and ascites in alcoholic liver cirrhotics

BackgroundThe liver is the first line of defence against continuously occurring influx of microbial-derived products and bacteria from the gut. Intestinal bacteria have been implicated in the pathogenesis of alcoholic liver cirrhosis. Escape of intestinal bacteria into the ascites is involved in the pathogenesis of spontaneous bacterial peritonitis, which is a common complication of liver cirrhosis. The association between faecal bacterial populations and alcoholic liver cirrhosis has not been resolved.MethodsRelative ratios of major commensal bacterial communities (Bacteroides spp., Bifidobacterium spp., Clostridium leptum group, Enterobactericaea and Lactobacillus spp.) were determined in faecal samples from post mortem examinations performed on 42 males, including cirrhotic alcoholics (n = 13), non-cirrhotic alcoholics (n = 15), non-alcoholic controls (n = 14) and in 7 healthy male volunteers using real-time quantitative PCR (RT-qPCR). Translocation of bacteria into liver in the autopsy cases and into the ascites of 12 volunteers with liver cirrhosis was also studied with RT-qPCR. CD14 immunostaining was performed for the autopsy liver samples.ResultsRelative ratios of faecal bacteria in autopsy controls were comparable to those of healthy volunteers. Cirrhotics had in median 27 times more bacterial DNA of Enterobactericaea in faeces compared to the healthy volunteers (p = 0.011). Enterobactericaea were also the most common bacteria translocated into cirrhotic liver, although there were no statistically significant differences between the study groups. Of the ascites samples from the volunteers with liver cirrhosis, 50% contained bacterial DNA from Enterobactericaea, Clostridium leptum group or Lactobacillus spp.. The total bacterial DNA in autopsy liver was associated with the percentage of CD14 expression (p = 0.045). CD14 expression percentage in cirrhotics was significantly higher than in the autopsy controls (p = 0.004).ConclusionsOur results suggest that translocation of intestinal bacteria into liver may be involved as a one factor in the pathogenesis of alcoholic liver cirrhosis.

Evaluation of genome-wide loci of iron metabolism in hereditary hemochromatosis identifies PCSK7 as a host risk factor of liver cirrhosis

Genome-wide association studies (GWAS) have revealed genetic determinants of iron metabolism, but correlation of these with clinical phenotypes is pending. Homozygosity for HFE C282Y is the predominant genetic risk factor for hereditary hemochromatosis (HH) and may cause liver cirrhosis. However, this genotype has a low penetrance. Thus, detection of yet unknown genetic markers that identify patients at risk of developing severe liver disease is necessary for better prevention. Genetic loci associated with iron metabolism (TF, TMPRSS6, PCSK7, TFR2 and Chr2p14) in recent GWAS and liver fibrosis (PNPLA3) in recent meta-analysis were analyzed for association with either liver cirrhosis or advanced fibrosis in 148 German HFE C282Y homozygotes. Replication of associations was sought in additional 499 Austrian/Swiss and 112 HFE C282Y homozygotes from Sweden. Only variant rs236918 in the PCSK7 gene (proprotein convertase subtilisin/kexin type 7) was associated with cirrhosis or advanced fibrosis (P = 1.02 × 10(-5)) in the German cohort with genotypic odds ratios of 3.56 (95% CI 1.29-9.77) for CG heterozygotes and 5.38 (95% CI 2.39-12.10) for C allele carriers. Association between rs236918 and cirrhosis was confirmed in Austrian/Swiss HFE C282Y homozygotes (P = 0.014; ORallelic = 1.82 (95% CI 1.12-2.95) but not in Swedish patients. Post hoc combined analyses of German/Swiss/Austrian patients with available liver histology (N = 244, P = 0.00014, ORallelic = 2.84) and of males only (N = 431, P = 2.17 × 10(-5), ORallelic = 2.54) were consistent with the premier finding. Association between rs236918 and cirrhosis was not confirmed in alcoholic cirrhotics, suggesting specificity of this genetic risk factor for HH. PCSK7 variant rs236918 is a risk factor for cirrhosis in HH patients homozygous for the HFE C282Y mutation.

Alcohol-induced autophagy contributes to loss in skeletal muscle mass

Patients with alcoholic cirrhosis and hepatitis have severe muscle loss. Since ethanol impairs skeletal muscle protein synthesis but does not increase ubiquitin proteasome-mediated proteolysis, we investigated whether alcohol-induced autophagy contributes to muscle loss. Autophagy induction was studied in: A) Human skeletal muscle biopsies from alcoholic cirrhotics and controls, B) Gastrocnemius muscle from ethanol and pair-fed mice, and C) Ethanol-exposed murine C2C12 myotubes, by examining the expression of autophagy markers assessed by immunoblotting and real-time PCR. Expression of autophagy genes and markers were increased in skeletal muscle from humans and ethanol-fed mice, and in myotubes following ethanol exposure. Importantly, pulse-chase experiments showed suppression of myotube proteolysis upon ethanol-treatment with the autophagy inhibitor, 3-methyladenine (3MA) and not by MG132, a proteasome inhibitor. Correspondingly, ethanol-treated C2C12 myotubes stably expressing GFP-LC3B showed increased autophagy flux as measured by accumulation of GFP-LC3B vesicles with confocal microscopy. The ethanol-induced increase in LC3B lipidation was reversed upon knockdown of Atg7, a critical autophagy gene and was associated with reversal of the ethanol-induced decrease in myotube diameter. Consistently, CT image analysis of muscle area in alcoholic cirrhotics was significantly reduced compared with control subjects. In order to determine whether ethanol per se or its metabolic product, acetaldehyde, stimulates autophagy, C2C12 myotubes were treated with ethanol in the presence of the alcohol dehydrogenase inhibitor (4-methylpyrazole) or the acetaldehyde dehydrogenase inhibitor (cyanamide). LC3B lipidation increased with acetaldehyde treatment and increased further with the addition of cyanamide. We conclude that muscle autophagy is increased by ethanol exposure and contributes to sarcopenia.

A Study to assess, the Extent of Autonomic Dysfunction Based on the Standard Cardiovascular Tests in Different Grades of Alcoholics

Aim: Autonomic system is the one which extensively supplies the inner organs. Much attention is not given to it clinically and there are few tests available to assess it. The tests which are available are less used in patients to assess the autonomic function. Alcoholism is a factor which affects most of the system in the human body. Its effect on autonomic nervous system is extensive. As a result of this autonomic failure there would be damage to multiple systems. Study design: In this study the effect of alcoholism in a group of people grading them as social drinkers, chronic alcoholics and alcoholic cirrhotics have been done using the seven standard autonomic function tests. The extent of autonomic damage in all these different groups was done. The results were compared against a group of controls. Results: There was autonomic damage observed in all three groups with a distribution of 50% mild damage and 30% of moderate damage in social drinkers. A 20% of severe damage (combined damage) in chronic alcoholics and 90% of severe damage in alcoholic cirrhotics were obtained. A significant difference was observed between all groups of alcoholics and the controls (p< 0.01) Conclusion: The extent of autonomic damage seems to be underestimated in alcoholics. More care should be given to high social drinkers as they too exhibited autonomic damage. Also these simple tests should be performed as a routine on all alcoholics for an early detection of the situation.

Therapy for alcoholic liver disease

Alcoholism results in about 2.5 million deaths annually worldwide, representing 4% of all mortality. Although alcoholism is associated with more than 60 diseases, most mortality from alcoholism results from alcoholic liver disease (ALD). ALD includes alcoholic steatosis, alcoholic hepatitis, and alcoholic cirrhosis, in order of increasing severity. Important scoring systems of ALD severity include: Child-Pugh, a semi-quantitative scoring system useful to roughly characterize clinical severity; model for end-stage liver disease, a quantitative, objective scoring system used for prognostication and prioritization for liver transplantation; and discriminant function, used to determine whether to administer corticosteroids for alcoholic hepatitis. Abstinence is the cornerstone of ALD therapy. Psychotherapies, including twelve-step facilitation therapy, cognitive-behavioral therapy, and motivational enhancement therapy, help support abstinence. Disulfiram decreases alcohol consumption by causing unpleasant sensations after drinking alcohol from accumulation of acetaldehyde in serum, but disulfiram can be hepatotoxic. Adjunctive pharmacotherapies to reduce alcohol consumption include naltrexone, acamprosate, and baclofen. Nutritional therapy helps reverse muscle wasting, weight loss, vitamin deficiencies, and trace element deficiencies associated with ALD. Although reduced protein intake was previously recommended for advanced ALD to prevent hepatic encephalopathy, a diet containing 1.2-1.5 g of protein/kg per day is currently recommended to prevent muscle wasting. Corticosteroids are first-line therapy for severe alcoholic hepatitis (discriminant function ≥ 32), but proof of their efficacy in decreasing mortality remains elusive. Pentoxifylline is an alternative therapy. Complications of advanced ALD include ascites, spontaneous bacterial peritonitis, esophageal variceal bleeding, hepatic encephalopathy, hepatorenal syndrome, hepatopulmonary syndrome, and portopulmonary hypertension. Alcoholic cirrhotics have increased risk of developing hepatomas. Liver transplantation is the ultimate therapy for severe ALD, but generally requires 6 mo of proven abstinence for eligibility. Alcoholic cirrhotics who maintain abstinence generally have a relatively favorable prognosis after liver transplantation.

Genetic factors affecting susceptibility to alcoholic liver disease in an Indian population

Introduction. Indians are more likely to develop alcoholic cirrhosis compared to Caucasians, though the cause remains obscure. North Indians tend to consume more alcohol than other parts of the country. Genetic factors are likely to play a major role in these observations. This study investigated whether 10 different polymorphisms were associated with alcohol dependence and/or cirrhosis in North Indians. These were in ADH2*2 (rs1229984), ADH3*2 (rs698), CYP2E1*1D, CYP2E1*5 (rs3813867 and rs2031920), TNF-α (rs1800629), TNF-α (rs361525), IL-1ß (rs3087258), CD-14 (rs2569190), IL-10 (rs1800872) and PNPLA3 (rs738409).Material and methods. Hundred healthy controls and 120 chronic alcoholics (60 alcoholic noncirrhotics and 60 alcoholic cirrhotics) attending various departments of PGIMER, Chandigarh were genotyped using PCR-RFLP methods.Results. Alcoholic cirrhotics compared to healthy individuals demonstrated a statistically significant increase in PNPLA3 (10109G) allele (p = 0.037, OR = 2.12, 95% CI 1.29–3.4). Rest of the associations were not significant after correction for multiple testing.Conclusion.PNPLA3 10109G predisposed North Indian subjects to alcoholic cirrhosis.

Cryptogenic cirrhosis is the leading cause for listing for liver transplantation in Sri Lanka

Hepatitis B and C are rare in Sri Lanka. Nonalcoholic fatty liver disease is increasing in the country. Eighty-one patients referred for liver transplantation (LT) over a period of 18 months were prospectively evaluated. Ninety-two percent (n = 74) were males. Cryptogenic cirrhosis was the leading indication for LT (58%, n = 47) followed by alcohol in 27% (n = 33). Hepatitis B and C were not seen in our cases. The liver biochemistry and clinical status of cirrhosis were similar in cryptogenic and alcoholic cirrhotics. Fourteen patients died while waiting for transplant, and nine transplants were performed. Cryptogenic cirrhosis is the leading cause for LT in Sri Lanka.