Global epidemiology of alcohol-associated cirrhosis and HCC: trends, projections and risk factors.

Heavy alcohol consumption is a major cause of morbidity and mortality. Globally, alcohol per-capita consumption rose from 5.5 litres in 2005 to 6.4 litres in 2016 and is projected to increase further to 7.6 litres in 2030. In 2019, an estimated 25% of global cirrhosis deaths were associated with alcohol. The global estimated age-standardized death rate (ASDR) of alcohol-associated cirrhosis was 4.5 per 100,000 population, with the highest and lowest ASDR in Africa and the Western Pacific, respectively. The annual incidence of hepatocellular carcinoma (HCC) among patients with alcohol-associated cirrhosis ranged from 0.9% to 5.6%. Alcohol was associated with approximately one-fifth of global HCC-related deaths in 2019. Between 2012 and 2017, the global estimated ASDR for alcohol-associated cirrhosis declined, but the ASDR for alcohol-associated liver cancer increased. Measures are required to curb heavy alcohol consumption to reduce the burden of alcohol-associated cirrhosis and HCC. Degree of alcohol intake, sex, older age, obesity, type 2 diabetes mellitus, gut microbial dysbiosis and genetic variants are key factors in the development of alcohol-associated cirrhosis and HCC. In this Review, we discuss the global epidemiology, projections and risk factors for alcohol-associated cirrhosis and HCC.

Management of alcohol use disorder in patients with cirrhosis in the setting of liver transplantation.

The prevalence of alcohol use disorder (AUD) has been steadily increasing over the past decade. In parallel, alcohol-associated liver disease (ALD) has been increasing at an alarming rate, especially among young patients. Data suggest that most patients with ALD do not receive AUD therapy. Although liver transplantation is the only curative therapy for end-stage ALD, transplant candidacy is often a matter of debate given concerns about patients being under-treated for AUD and fears of post-transplantation relapse affecting the allograft. In this Review, we discuss diagnosis, predictors and effects of relapse, behavioural therapies and pharmacotherapies, and we also propose an integrative, multidisciplinary and multimodality approach for treating AUD in patients with cirrhosis, especially in the setting of liver transplantation. Notably, this approach takes into account the utility of AUD pharmacotherapy in patients on immunosuppressive medications and those with renal impairment after liver transplantation. We also propose a comprehensive and objective definition of relapse utilizing contemporary biomarkers to guide future clinical trials. Future research using the proposed approach and definition is warranted with the goal of optimizing AUD treatment in patients with cirrhosis, the transplant selection process and post-transplantation care of patients with AUD.

A genetic risk score and diabetes predict development of alcohol-related cirrhosis in drinkers.

BACKGROUND & AIMS: Only a minority of excess alcohol drinkers develop cirrhosis. We developed and evaluated risk stratification scores to identify those at highest risk. METHODS: Three cohorts (GenomALC-1: n = 1,690, GenomALC-2: n = 3,037, UK Biobank: relevant n = 6,898) with a history of heavy alcohol consumption (≥80 g/day (men), ≥50 g/day (women), for ≥10 years) were included. Cases were participants with alcohol-related cirrhosis. Controls had a history of similar alcohol consumption but no evidence of liver disease. Risk scores were computed from up to 8 genetic loci identified previously as associated with alcohol-related cirrhosis and 3 clinical risk factors. Score performance for the stratification of alcohol-related cirrhosis risk was assessed and compared across the alcohol-related liver disease spectrum, including hepatocellular carcinoma (HCC). RESULTS: A combination of 3 single nucleotide polymorphisms (SNPs) (PNPLA3:rs738409, SUGP1-TM6SF2:rs10401969, HSD17B13:rs6834314) and diabetes status best discriminated cirrhosis risk. The odds ratios (ORs) and (95% CIs) between the lowest (Q1) and highest (Q5) score quintiles of the 3-SNP score, based on independent allelic effect size estimates, were 5.99 (4.18-8.60) (GenomALC-1), 2.81 (2.03-3.89) (GenomALC-2), and 3.10 (2.32-4.14) (UK Biobank). Patients with diabetes and high risk scores had ORs of 14.7 (7.69-28.1) (GenomALC-1) and 17.1 (11.3-25.7) (UK Biobank) compared to those without diabetes and with low risk scores. Patients with cirrhosis and HCC had significantly higher mean risk scores than patients with cirrhosis alone (0.76 ± 0.06 vs. 0.61 ± 0.02, p = 0.007). Score performance was not significantly enhanced by information on additional genetic risk variants, body mass index or coffee consumption. CONCLUSIONS: A risk score based on 3 genetic risk variants and diabetes status enables the stratification of heavy drinkers based on their risk of cirrhosis, allowing for the provision of earlier preventative interventions. LAY SUMMARY: Excessive chronic drinking leads to cirrhosis in some people, but so far there is no way to identify those at high risk of developing this debilitating disease. We developed a genetic risk score that can identify patients at high risk. The risk of cirrhosis is increased >10-fold with just two risk factors - diabetes and a high genetic risk score. Risk assessment using this test could enable the early and personalised management of this disease in high-risk patients.

Oxidative stress-induced growth inhibitor 1 in alcohol-induced liver cirrhosis.

INTRODUCTION AND OBJECTIVE: Human oxidative stress-induced growth inhibitor 1 (OSGIN1) is a protein identified in 2001 which belongs to the OKL38 protein family. The aim of the study was to investigate the levels of this protein depending on the severity of alcohol-induced liver cirrhosis. MATERIAL AND METHODS: The study group consisted of 60 patients: 30 patients with cirrhosis in the P-Ch A and B stage and 30 in the P-Ch C stage. The control group consisted of 18 healthy individuals without liver diseases, who did not abuse alcohol. Oxidative stress induced growth inhibitor 1 (OSGIN1), fibroblast growth factor 1 (FGF1) and fibroblast growth factor 21 (FGF21) were determined in blood serum using enzyme-linked immunosorbent assay (ELISA) kits. All absorbance readings were conducted using an Epoch Microplate Spectrophotometer (BioTek Instrumentals, Inc., Winooski, VT, USA). OSGIN1, FGF1 and FGF21 concentrations were determined using Sandwich enzyme immunoassay kits (by Cloud Clone Corp., Katy, TX, USA). Statistica 13.3 (TIBCO Software, Inc.) was used for data analysis. RESULTS: The concentration of OSGIN1 was 0.028 ± 0.017 in the control group which increased with the advancement of liver cirrhosis (stage of Pugh-Child): 0.075 ± 0.098 in the P-Ch A + B group and 0.121 ± 0.134 in the P-Ch C stage. Multiple comparison tests confirmed statistically significant differences in OSGIN1 concentration between the control group and P-Ch C (p <0.02). Significant correlations were noted between OSGIN1 and FGF1 (r = 0.39; p = 0.004) and between OSGIN1 and FGF21 (r = 0.53; p <0.0001). CONCLUSIONS: The study revealed that the level of OSGIN1 increased significantly in the P-Ch C stage of liver cirrhosis. It is possible that OSGIN1 may be used for the non-invasive diagnosis of ALD, but its possible diagnostic value is still very uncertain.

Results of Early Transplantation for Alcohol-Related Cirrhosis: Integrated Addiction Treatment With Low Rate of Relapse.

BACKGROUND & AIMS: In 2018, our team initiated a prospective pilot program to challenge the paradigm of the "6-month rule" of abstinence for patients with alcohol-related liver disease (ALD) requiring transplant. Our pilot involved an in-depth examination of patients' alcohol use, social support, and psychiatric comorbidity, as well as the provision of pre- and post-transplantation addiction treatment. METHODS: Patients with ALD were assessed for inclusion in the pilot by a multidisciplinary team. Relapse prevention therapy was provided directly to all patients deemed to meet the program's inclusion criteria. Random biomarker testing for alcohol was used pre and post transplantation. RESULTS: We received 703 referrals from May 1, 2018 to October 31, 2020. After fulfilling the program's criteria, 101 patients (14%) were listed for transplantation and 44 (6.2%) received transplants. There were no significant differences in survival rates between those receiving transplants through the pilot program compared with a control group with more than 6 months of abstinence (P = .07). Three patients returned to alcohol use during an average post-transplantation follow-up period of 339 days. In a multivariate analysis, younger age and lower Model for End-Stage Liver Disease scores at listing were associated with an increased likelihood of a return to alcohol use (P < .05); length of abstinence was not a predictor. CONCLUSIONS: Our prospective program provided direct monitoring and relapse prevention treatment for patients with ALD and with less than 6 months of abstinence and resulted in a reduction of post-transplantation return to drinking. This pilot study provides a framework for the future of more equitable transplant care.

Incidence and management patterns of alcohol-related liver disease in Korea: a nationwide standard cohort study.

The recent incidence and management patterns of alcohol-related liver disease (ARLD) are not well defined in Korea. We sought to evaluate the epidemiology of ARLD with regard to disease severity and alcohol cessation management after diagnosis. We performed an observational cohort study of standardized Common Data Model data from the Health Insurance Review and Assessment-National Patient Samples database between 2012 and 2016. The incidence and demographic properties of ARLD were extracted and divided into non-cirrhotic alcoholic liver disease (ALD) and alcoholic liver cirrhosis (ALC). ALC was compared with non-alcoholic cirrhosis by severity at diagnosis. The management patterns were captured by the initiation of pharmaco- and behavioral therapy for alcohol cessation. We analyzed data from 72,556 ALD to 7295 ALC patients. The ALD incidence was stable from 990 to 1025 per 100,000 people. In ALD, the proportion of patients who were ≥ 65 years old, the proportion of female patients, and the comorbidity index increased significantly during the study period (all P values < 0.001). ALC accounted for > 20% of all cirrhosis, with decompensation occurring twice as often as in non-alcoholic cirrhosis. The initiation of alcoholism management was stationary in ARLD, remaining at < 10% for both pharmacotherapy and behavioral therapy, regardless of severity or the site of diagnosis. The incidence of ARLD did not decrease during the study period. Moreover, an increasing trend in the proportion of people vulnerable to drinking was observed. Unfortunately, management for the cessation of alcohol use remains very low. The best way to manage ARLD should be evaluated in further study.

Alcohol Recidivism Following Transjugular Intrahepatic Portosystemic Shunt Placement: Frequency and Predictive Factors.

PURPOSE: To determine the frequency and predictive factors for alcohol recidivism following transjugular intrahepatic portosystemic shunts (TIPS) placed in patients with alcoholic cirrhosis. METHODS: One hundred ninety-nine patients who had a TIPS placed at a single institution for different indications in the setting of alcoholic cirrhosis were reviewed. Length of sobriety prior to TIPS placement and maintained sobriety at 1, 3 and 6-12 months after TIPS placement were recorded. Smoking history, substance abuse and psychiatric comorbidities were also recorded as was ascitic response to TIPS at 1, 3 and 6-12 months. RESULTS: At 1 month 11/199 (5.5%) patients had experienced a relapse while, 20/199 (10.1%) had at 3 months, and 44/199 (22.1%) had at 12 months. There was no difference in ascitic response in those who did and did not relapse at 1 month (p = 0.57), 3 months (p = 1.00) or 1 year (p = 0.44). The mean time of sobriety at the time of TIPS placement for those who relapsed by 12 months was significantly less than those who did not relapse (5.11 (1.10-7.90) months vs 18.32 (8.63-48.12) months, p < 0.001). Concurrent psychiatric comorbidity (p < 0.001), substance abuse (p < 0.001), age less than 40 (p = 0.004) and smoking history at the time of procedure (p < 0.001) were also associated with alcohol relapse. CONCLUSION: Recidivism is a frequent issue for patients following TIPS placement; those who have concurrent psychiatric comorbidity, substance abuse, smoking history are younger than 40 and shorter sobriety duration prior to TIPS may be at increased risk.

Second hits exacerbate alcohol-related organ damage: an update.

Chronic and excessive alcohol abuse cause direct and indirect detrimental effects on a wide range of body organs and systems and accounts for ~4% of deaths worldwide. Many factors influence the harmful effects of alcohol. This concise review presents newer insights into the role of select second hits in influencing the progression of alcohol-induced organ damage by synergistically acting to generate a more dramatic downstream biological defect. This review specifically addresses on how a lifestyle factor of high fat intake exacerbates alcoholic liver injury and its progression. This review also provides the mechanistic insights into how increasing matrix stiffness during liver injury promotes alcohol-induced fibrogenesis. It also discusses how hepatotropic viral (HCV, HBV) infections as well as HIV (which is traditionally not known to be hepatotropic), are potentiated by alcohol exposure to promote hepatotoxicity and fibrosis progression. Finally, this review highlights the impact of reactive aldehydes generated during alcohol and cigarette smoke coexposure impair innate antimicrobial defense and increased susceptibility to infections. This review was inspired by the symposium held at the 17th Congress of the European Society for Biomedical research on Alcoholism in Lille, France entitled 'Second hits in alcohol-related organ damage'.

Long-term outcomes in patients with decompensated alcohol-related liver disease, steatohepatitis and Maddrey's discriminant function <32.

BACKGROUND & AIMS: Patients with alcoholic hepatitis and a modified Maddrey's discriminant function (mDF) <32 have a low risk of short-term mortality. However, few data exist concerning long-term outcomes. The aims of this study were to evaluate 5-year survival rates and to identify predictive factors for long-term prognosis in this patient population. METHODS: We studied patients from 2 centers who were admitted for hepatic decompensation (ascites, hepatic encephalopathy, or jaundice) and who had histological findings of steatohepatitis and an mDF <32. Clinical and biological parameters were recorded at the time of liver biopsy and alcohol consumption was recorded during follow-up. We performed Cox proportional hazard survival analysis to identify factors associated with 5-year survival. RESULTS: One hundred and twenty-one patients were included (male: 64%, mean age: 51.5 ± 10.3 years, presence of cirrhosis: 84%). The median model for end-stage liver disease and mDF scores were 14 (IQR 11.7-16.1) and 19 (IQR 11.1-24), respectively. During follow-up, 30% of the patients remained abstinent. Survival rates at 1, 6, 12, 24, and 60 months were 96.7 ± 1.6%, 90.1 ± 2.7%, 80.8 ± 3.6%, 69.9 ± 4.3%, and 50.7 ± 4.9%, respectively. The majority of deaths (80%) were liver related. In multivariable analysis, encephalopathy at baseline and alcohol abstinence were predictive of 5-year survival. The 5-year survival rates of patients without and with encephalopathy at baseline were 60.5 ± 5.8% and 29.7 ± 8.0%, respectively, and the 5-year survival rates of abstinent and non-abstinent patients were 74.0 ± 8.0% and 40.9 ± 5.8%, respectively. CONCLUSIONS: The mortality rate of patients with alcoholic hepatitis and an mDF <32 is around 50% at 5 years. Hepatic encephalopathy at baseline and lack of alcohol abstinence impair long-term prognosis. New treatment strategies, including measures to ensure abstinence, are required. LAY SUMMARY: Patients with alcoholic hepatitis that is of intermediate severity have a low risk of short-term mortality but not much is known regarding long-term outcomes for these patients. This study clearly indicates that patients with intermediate disease characteristics have poor long-term outcomes. The presence of hepatic encephalopathy at the time of diagnosis and the absence of alcohol abstinence during follow-up are factors that predict poor long-term mortality.

Addition of trans fat and alcohol has divergent effects on atherogenic diet-induced liver injury in rodent models of steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are common causes of chronic liver disease. The overlap between ALD and NAFLD suggests the existence of metabolic steatohepatitis. Development of in vivo models that reflect various aspects of human steatohepatitis is essential for drug discovery. We aimed to characterize several models of steatohepatitis (SH) and to investigate whether the pathology could be modulated. Sprague-Dawley rats were fed a high-fat diet (HFD) for 9 wk, followed by either a high-fat, high-cholesterol and cholate diet (HFC) or a HFC diet containing 13% trans fat (HFC-TF). A subset received 15% ethanol-water twice a week for 12 wk. Serum triglycerides, cholesterol, LDL, HDL, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and rodent NH2-terminal propeptide of type III collagen (rPRO-C3) were assessed. The liver was weighed and evaluated using modified Nonalcoholic Steatohepatitis Clinical Research Network histological score system criteria. All diets induced hepatomegaly, but only HFC-TF increased the size of visceral adipose tissue. Trans fat augmented HFC-induced dyslipidemia, and cholesterol was higher and HDL was lower in the HFC-TF groups. Alcohol lowered triglycerides in both dietary groups. HFC elevated ALT and AST, which were lowered by trans fat. All diets induced histological SH, addition of trans fat induced more steatosis but less inflammation. Inclusion of alcohol augmented the HFC-induced inflammation. All diets induced mild fibrosis. Inclusion of trans fat and alcohol significantly increased rPRO-C3. The addition of trans fat reduced the HFC-induced inflammation but augmented steatosis and dyslipidemia. Inclusion of alcohol induced a more inflammatory and fibrogenic phenotype.NEW & NOTEWORTHY Alcoholic liver disease and nonalcoholic liver disease share significant overlap, which suggests the existence of metabolic steatohepatitis. Trans fat has been implicated in steatohepatitis development. Here, we show that the addition of trans fat to an atherogenic diet results in a more steatotic but less inflammatory phenotype, whereas the addition of alcohol to an atherogenic diet augments the inflammatory and fibrogenic properties of the diet.

Genetic Variation in HSD17B13 Reduces the Risk of Developing Cirrhosis and Hepatocellular Carcinoma in Alcohol Misusers.

BACKGROUND AND AIMS: Carriage of rs738409:G in patatin-like phospholipase domain containing 3 (PNPLA3) is associated with an increased risk for developing alcohol-related cirrhosis and hepatocellular carcinoma (HCC). Recently, rs72613567:TA in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) was shown to be associated with a reduced risk for developing alcohol-related liver disease and to attenuate the risk associated with carriage of PNPLA3 rs738409:G. This study explores the risk associations between these two genetic variants and the development of alcohol-related cirrhosis and HCC. APPROACH AND RESULTS: Variants in HSD17B13 and PNPLA3 were genotyped in 6,171 participants, including 1,031 with alcohol-related cirrhosis and HCC, 1,653 with alcohol-related cirrhosis without HCC, 2,588 alcohol misusers with no liver disease, and 899 healthy controls. Genetic associations with the risks for developing alcohol-related cirrhosis and HCC were determined using logistic regression analysis. Carriage of HSD17B13 rs72613567:TA was associated with a lower risk for developing both cirrhosis (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.72-0.88; P = 8.13 × 10-6 ) and HCC (OR, 0.77; 95% CI, 0.68-0.89; P = 2.27 × 10-4 ), whereas carriage of PNPLA3 rs738409:G was associated with an increased risk for developing cirrhosis (OR, 1.70; 95% CI, 1.54-1.88; P = 1.52 × 10-26 ) and HCC (OR, 1.77; 95% CI, 1.58-1.98; P = 2.31 × 10-23 ). These associations remained significant after adjusting for age, sex, body mass index, type 2 diabetes, and country. Carriage of HSD17B13 rs72613567:TA attenuated the risk for developing cirrhosis associated with PNPLA3 rs738409:G in both men and women, but the protective effect against the subsequent development of HCC was only observed in men (ORallelic , 0.75; 95% CI, 0.64-0.87; P = 1.72 × 10-4 ). CONCLUSIONS: Carriage of variants in PNPLA3 and HSD17B13 differentially affect the risk for developing advanced alcohol-related liver disease. A genotypic/phenotypic risk score might facilitate earlier diagnosis of HCC in this population.

Management of end-stage alcohol-related liver disease and severe acute alcohol-related hepatitis: position paper of the Italian Society on Alcohol (SIA).

Worldwide, the prevalence of alcohol use disorder (AUD) is 20-30% in men and 10-15% in women, and cirrhosis due to alcohol-related liver disease (ALD) is responsible for 0.9% of global deaths and 47.9% of cirrhosis-related deaths. End-stage ALD (ESALD) is the final condition of alcohol-related cirrhosis, and severe acute alcohol-related hepatitis (SAAH) is a distinct clinical syndrome associated with the consumption of large amounts of alcohol. In some cases, ESALD, and SAAH may need liver transplantation (LT). Thus, the management of ESALD and SAAH in patients affected by AUD may be an essential part of the clinical skills for hepatologists. For these reasons, the national board of the Italian Society on Alcohol have reviewed the most recent data on the management of ESALD, SAAH and LT for ALD in patients with AUD, formulating a position paper with related recommendations regarding four issues of specific clinical interest in this field: (a) the management of hepatic encephalopathy in patients with AUD, and LT in patients with ESALD; (b) the management of SAAH; (c) the management of AUD in patients with ESALD and SAAH; (d) special populations: polydrug addicts.

Tissue-based miRNA mapping in alcoholic liver cirrhosis: different profiles in cirrhosis with or without hepatocellular carcinoma.

Context: Alcoholic liver cirrhosis is a significant risk factor for the development of hepatocellular carcinoma (HCC). The importance of tumour-associated cirrhosis in the development or progression of HCC is not understood. MiRNAs are important regulators for HCC development, but their role in HCC due to alcoholic liver cirrhosis is unclear.Objective: The aim of this study is the detection of miRNA expression in alcoholic liver cirrhosis, tumour-associated cirrhosis, and HCC.Materials and methods: We analysed the differences in the miRNA profiles of HCC, tumour-associated cirrhosis, and cirrhosis without HCC samples from 30 patients who underwent liver transplantation because of alcoholic liver disease.Results: Microarray analyses revealed 40 significantly differentially expressed miRNAs between HCC tissue and tumour-associated cirrhosis tissue. Furthermore, the microarray analysis discovered 56 differentially expressed miRNAs in tumour-associated cirrhosis and cirrhosis without HCC.Discussion: The differences of miRNA profile in alcoholic liver cirrhosis with and without HCC could improve understanding of HCC development, as well as lead to a new diagnostic tool in HCC screening.Conclusion: We were able to show for the first time, the differences of miRNA profile as promising biomarker in HCC, tumour-associated cirrhosis, and cirrhosis without HCC in context of alcoholic liver disease.

Zinc deficiency and advanced liver fibrosis among HIV and hepatitis C co-infected anti-retroviral naïve persons with alcohol use in Russia.

BACKGROUND AND AIMS: Liver disease in people living with HIV co-infected with hepatitis C virus is a source of morbidity and mortality in Russia. HIV accelerates liver fibrosis in the setting of HCV co-infection and alcohol use. Zinc deficiency is common among people living with HIV and may be a factor that facilitates the underlying mechanisms of liver fibrosis. We investigated the association between zinc deficiency and advanced liver fibrosis in a cohort of HIV/HCV co-infected persons reporting heavy drinking in Russia. METHODS: This is a secondary data analysis of baseline data from 204 anti-retroviral treatment naïve HIV/HCV co-infected Russians with heavy drinking that were recruited into a clinical trial of zinc supplementation. The primary outcome of interest in this cross-sectional study was advanced liver fibrosis. Zinc deficiency, the main independent variable, was defined as plasma zinc <0.75 mg/L. Exploratory analyses were performed examining continuous zinc levels and fibrosis scores. Analyses were conducted using multivariable regression models adjusted for potential confounders. RESULTS: The prevalence of advanced liver fibrosis was similar for those with zinc deficiency compared to those with normal zinc levels, (27.7% vs. 23.0%, respectively). We did not detect an association between zinc deficiency and advanced liver fibrosis in the adjusted regression model (aOR: 1.28, 95% CI: 0.62-2.61, p = 0.51) nor in exploratory analyses. CONCLUSIONS: In this cohort of Russians with HIV/HCV co-infection, who are anti-retroviral treatment naïve and have heavy alcohol use, we did not detect an association between zinc deficiency or zinc levels and advanced liver fibrosis.

Prediction of Alcohol Relapse Among Liver Transplant Candidates With Less Than 6 Months of Abstinence Using the High-Risk Alcoholism Relapse Score.

The selection of liver transplantation (LT) candidates with alcohol-use disorder (AUD) is influenced by the risk of alcohol relapse (AR) after LT. We aimed to investigate the risk factors of AR after LT and its impact on graft and recipient outcomes. A retrospective study was conducted that included all consecutive patients with AUD undergoing LT from January 2004 to April 2016 (n = 309), excluding patients with alcoholic hepatitis. Odds ratios (ORs) and 95% confidence intervals (CIs) for AR were analyzed by multinomial logistic regression. Cox regression with time-dependent covariates was used to analyze patient survival and graft cirrhosis. There were 70 (23%) patients who presented AR (median follow-up, 68 months), most of them (n = 44, 63%) presenting heavy AR. The probability of heavy AR was 2.3%, 7.5%, 12%, and 29% at 1, 3, 5, and 10 years after LT, respectively. The independent risk factors for heavy AR included a High-Risk Alcoholism Relapse (HRAR) score ≥3 (OR, 2.39; 95% CI, 1.02-5.56; P = 0.04) and the duration of abstinence (months) before LT (OR, 0.81; 95% CI, 0.66-0.98; P = 0.03). In recipients with <6 months of abstinence before LT, the probability of heavy AR after LT was higher in patients with an HRAR score ≥3 than in those with an HRAR score <3 (20%, 36.7%, and 47% versus 6.8%, 12.4%, and 27% at 1, 3, and 5 years, respectively; log-rank 0.013). The risk of graft cirrhosis was increased in patients with heavy AR (hazard ratio, 3.44; 95% CI, 1.58-7.57; P = 0.002) compared with nonrelapsers, with no differences in patient survival. In conclusion, the HRAR score is helpful in identifying the risk of harmful AR after LT in candidates with <6 months of alcohol abstinence without alcoholic hepatitis. These patients could benefit from a longterm integrative patient-centered approach after LT until lifestyle changes are implemented.

Free triiodothyronine is associated with the occurrence and remission of nonalcoholic fatty liver disease in euthyroid women.

BACKGROUND: The association between nonalcoholic fatty liver disease (NAFLD) and free triiodothyronine (FT3) in euthyroid subjects was in dispute. We aimed to investigate this issue in a population-based cohort study. MATERIALS AND METHODS: A total of 3144 euthyroid subjects at baseline from the Shanghai Nicheng Atherosclerosis Study were selected for the cross-sectional analysis, and 2089 subjects being followed up after 2.2 years were selected for the longitudinal analysis. NAFLD was diagnosed by ultrasound. The cut-off point of elevated alanine aminotransferase (ALT) level was 40 U/L. The FIB-4 index was used to assess the risk of advanced liver fibrosis. RESULTS: Age-adjusted mean levels of FT3 and FT3/free thyroxine (FT4) ratio were higher in subjects with NAFLD than those without NAFLD and linearly increased with a higher risk of NAFLD progression (assessed by levels of ALT and FIB-4 index) in euthyroid women but not in men. After adjustment for confounding variables, FT3 levels significantly increased with the presence of NAFLD (ß = 0.1, P < 0.001) and linearly increased with a higher risk of NAFLD progression in euthyroid women. After a 2.2-year follow-up, FT3 levels increased with the occurrence of NAFLD (mean change percentage: 1.4%) and decreased with the remission of NAFLD (mean change percentage: -2.7%) in euthyroid women. CONCLUSIONS: There are positive associations of FT3 levels with NAFLD and the risk of NAFLD progression in euthyroid women. The changes in FT3 levels with the alteration of NAFLD status may be an adaptive response to maintain energy and metabolic homeostasis.

Fibrosis and alcohol-related liver disease.

Histological fibrosis stage is one of the most important prognostic factors in compensated and decompensated alcohol-related liver disease (ALD). Morphological assessment of fibrosis is useful for patient stratification, enabling individualised management, and for evaluation of treatment effects in clinical studies. In contrast to most chronic liver diseases where fibrosis is portal-based, fatty liver disease (FLD) of alcoholic or non-alcoholic aetiology (NAFLD) is associated with a centrilobular pattern of injury which leads to perivenular fibrosis and/or pericellular fibrosis. Progression of FLD drives expansive pericellular fibrosis, linking vascular structures and paving the way for the development of cirrhosis. At the cirrhotic stage, ongoing tissue damage leads to increasing fibrosis severity due to parenchymal loss and proliferation of fibrous scars. Histologic fibrosis staging systems have been devised, based on topography and the extent of fibrosis, for most chronic liver diseases. The utility of histological staging is reflected in different risks associated with individual fibrosis stages which cannot be reliably distinguished by non-invasive fibrosis assessment. In contrast to NAFLD, ALD-specific staging systems that enable the standardised prognostication required for clinical management and trials are lacking. Although morphological similarities between NAFLD and ALD exist, differences in clinical and histological features may substantially limit the utility of established NAFLD-specific staging systems for prognostication in ALD. This review summarises morphological features of fibrosis in ALD and compares them to other chronic liver diseases, particularly NAFLD. ALD-related fibrosis is examined in the context of pathogenetic mechanisms of fibrosis progression, regression and clinical settings that need to be considered in future prognostically relevant ALD staging approaches.

Effects of Alcohol Consumption and Metabolic Syndrome on Mortality in Patients With Nonalcoholic and Alcohol-Related Fatty Liver Disease.

BACKGROUND & AIMS: Non-alcoholic and alcohol-related fatty liver disease are overlapping diseases in which metabolic syndrome and alcohol consumption each contribute to progressive liver disease. We aimed to assess the effects of alcohol consumption and metabolic syndrome on mortality in individuals with fatty liver. METHODS: We searched the National Health and Nutrition and Examination Survey III for adults (20-74 years old) with hepatic steatosis, detected by ultrasound, for whom mortality and follow-up data were available. We collected data from the alcohol use questionnaire (self-reported number of days a participant drank alcohol; the number of drinks [10 g alcohol] per day on a drinking day; the number of days the participant had 5 or more drinks) and calculated the average amount of alcohol consumption in drinks/day for each participant during the year preceding enrollment. Excessive alcohol consumption for men was >3 drinks/day and for women was >1.5 drinks/day. We also collected clinical data, and mortality data were obtained from the National Death Index. Demographic and clinical parameters were compared among consumption groups using the χ2 test for independence or survey regression models. We used Cox proportional hazard models to identify independent predictors of all-cause and cause-specific mortality. RESULTS: The study cohort included 4264 individuals with hepatic steatosis (mean age, 45.9 years; 51% male; 76% white; 46% with metabolic syndrome; 6.2% with excessive alcohol use). There was no significant difference in mean age between individuals with vs without excessive alcohol consumption (P=.65). However, overall mortality was significantly higher among participants with excessive alcohol consumption (32.2%) vs participants with non-excessive alcohol use (22.2%) after mean 20 years of follow up (P=.003), as well as after 5 years of follow up. In multivariate analysis, the presence of metabolic syndrome (adjusted hazard ratio [aHR], 1.43; 95% CI, 1.12-1.83) and excessive alcohol consumption (aHR, 1.79; 95% CI, 1.21-2.66) were independently associated with an increased risk of death in individuals with hepatic steatosis; any lower average amount of alcohol consumption was not associated with mortality (all P>.60). In a subgroup analysis, the association of excessive alcohol use with mortality was significant in individuals with metabolic syndrome (aHR, 2.46; 95% CI, 1.40-4.32) but not without it (P=.74). CONCLUSION: In review of data from the National Health and Nutrition and Examination Survey III, we associated alcohol consumption with increased mortality in participants with fatty liver and metabolic syndrome. These findings indicate an overlap between non-alcoholic and alcohol-related fatty liver disease.