From Shadows to Spotlight: Exploring the Escalating Burden of Alcohol-Associated Liver Disease and Alcohol Use Disorder in Young Women.

INTRODUCTION: The burden of alcohol-related complications is considerable, particularly alcohol-associated liver disease and alcohol use disorder (AUD). However, there are deficiencies in comprehensive epidemiological research focusing on these issues, especially among young women who display higher susceptibility to such complications compared with their male counterparts. We thus aimed to determine the global burden of these conditions in this vulnerable group. METHODS: Leveraging data from the Global Burden of Disease Study 2019, we analyzed the prevalence, mortality, and disability-adjusted life years of alcohol-associated cirrhosis (AC), liver cancer from alcohol, and AUD in young women. The findings were categorized by region, nation, and sociodemographic index. RESULTS: The highest age-standardized prevalence rates were observed in AUD (895.96 [95% uncertainty interval (UI) 722.6-1,103.58]), followed by AC (65.33 [95% UI 48.37-86.49]) and liver cancer from alcohol (0.13 [95% UI 0.09-0.19]) per 100,000 people. The highest age-standardized mortality rates were observed in AC (0.75 [95% UI 0.55-0.97]), followed by AUD (0.48 [95% UI 0.43-0.53]) and liver cancer from alcohol (0.06 [95% UI 0.04-0.09]). The highest burdens of AC and AUD were observed in Central Europe, whereas the high-income Asia Pacific had the highest burden of liver cancer from alcohol. DISCUSSION: Throughout the past decade, the trend of AUD varied among regions while the impact of alcohol-associated liver disease has increased, requiring urgent public health strategy to mitigate these complications, particularly in female patients in Europe and the Asia-Pacific region.

Rising alcohol-associated liver disease-related mortality rates in the United States from 1999 to 2022.

We examined trends in alcohol-associated liver disease (ALD)-related mortality in the United States from 1999 to 2022, focusing on sex, racial differences, and specific age groups. We analyzed age-adjusted mortality rates for ALD-related deaths using the CDC WONDER database and assessed differences between sex and racial groups. ALD-related mortality rates increased significantly between 1999 and 2022, with a more pronounced increase in females. White, Asian, Pacific Islander (AAPI), and American Indian or Alaska Native (AI/AN) groups showed significant uptrends in ALD-related mortality, while African Americans (AA) experienced a nonsignificant decline. Age-specific trends revealed substantial increases in crude mortality rates across various age groups, with the largest increase observed in the younger age groups of 25-34 years, with an average percent change of 11.12% from 2006 to 2022 (average annual percent change of 7.1% for the study period), and 35-44 years, which showed an average percent change of 17.2% from 2018 to 2022 (average annual percent change of 3.8% for the study period). This study reveals increased ALD-related mortality rates in the United States from 1999 to 2022, with disparities among sex, racial groups, and younger age groups. Continued monitoring and evidence-based interventions are needed to address the growing burden of ALD-related mortality, particularly in the younger population.

Causes of death in patients with Non-alcoholic Fatty Liver Disease (NAFLD), alcoholic liver disease and chronic viral Hepatitis B and C.

INTRODUCTION AND OBJECTIVES: Cause of mortality in patients with chronic liver diseases (CLDs) may differ based on underlying etiology of liver disease. Our aim was to assess different causes of death in patients with the most common types of CLD using a national database from the United States. MATERIALS AND METHODS: Death data from 2008 and 2018 from the National Vital Statistics System (NVSS) by the National Center for Health Statistics (NCHS) were used. The rank of cause-of-death for each etiology of CLDs was assessed. Causes of death were classified by the ICD-10 codes. Liver-related deaths included liver cancer, cirrhosis and CLDs. RESULTS: Among a total of 2,826,531 deaths in 2018, there were 85,807 (3.04%) with underlying CLD (mean age at death 63.0 years, 63.8% male, 70.8% white). Liver-related mortality was the leading cause of death for all types of CLD [45.8% in non-alcoholic fatty liver disease (NAFLD), 53.0% in chronic hepatitis C (CHC), 57.8% in chronic hepatitis B (CHB), 81.8% in alcoholic liver disease (ALD)]. This was followed by death from cardiac causes (NAFLD 10.3%, CHC 9.1%, CHB 4.6%, ALD 4.2%) and extrahepatic cancer (NAFLD 7.0%, CHC 11.9%, CHB 14.9%, ALD 2.1%). Although liver cancer was the leading cause of cancer death, lung, colorectal and pancreatic cancer were also common causes of cancer death. CONCLUSIONS: Among deceased patients with CLD, underlying liver disease was the leading cause of death. Among solid cancers, liver cancer was the leading cause of cancer-related mortality.

Associations Between Alcohol Use and Liver-Related Outcomes in a Large National Cohort of Patients With Cirrhosis.

Alcohol use can cause hepatic necroinflammation and worsening portal hypertension in patients with cirrhosis. We aimed to evaluate the associations between degree of alcohol use and clinical liver-related outcomes according to etiology of cirrhosis. In this retrospective cohort analysis, 44,349 U.S. veterans with cirrhosis from alcohol-associated liver disease (ALD), chronic hepatitis C virus (HCV) infection, or nonalcoholic fatty liver disease were identified who completed the Alcohol Use Disorders Identification Test Consumption questionnaire in 2012. Based on this score, level of alcohol use was categorized as none, low level, or unhealthy. Multivariable Cox proportional hazards regression was used to assess for associations between alcohol use and mortality, cirrhosis decompensation (new ascites, encephalopathy, or variceal bleeding), and hepatocellular carcinoma (HCC). At baseline, 36.4% of patients endorsed alcohol use and 17.1% had unhealthy alcohol use. During a mean 4.9 years of follow-up, 25,806 (57.9%) patients died, 9,409 (21.4%) developed a new decompensation, and 4,733 (11.1%) developed HCC. In patients with ALD-cirrhosis and HCV-cirrhosis, unhealthy alcohol use, compared with no alcohol use, was associated with higher risks of mortality (adjusted hazard ratio [aHR] = 1.13, 95% confidence interval [CI] = 1.07-1.19 and aHR = 1.14, 95% CI = 1.08-1.20, respectively) and decompensation (aHR = 1.18, 95% CI = 1.07-1.30 and aHR = 1.08, 95% CI = 1.00-1.16, respectively). Alcohol use was not associated with HCC, regardless of cirrhosis etiology. Conclusion: Unhealthy alcohol use was common in patients with cirrhosis and was associated with higher risks of mortality and cirrhosis decompensation in patients with HCV-cirrhosis and ALD-cirrhosis. Therefore, health care providers should make every effort to help patients achieve abstinence. The lack of association between alcohol use and HCC merits further investigation.

Evaluation of Early vs Standard Liver Transplant for Alcohol-Associated Liver Disease.

Importance: Traditionally, liver transplant (LT) for alcohol-associated liver disease (ALD) requires 6 months of abstinence. Although early LT before 6 months of abstinence has been associated with decreased mortality for decompensated ALD, this practice remains controversial and concentrated at a few centers. Objective: To define patient, allograft, and relapse-free survival in early LT for ALD, and to investigate the association between these survival outcomes and early vs standard LT. Design, Setting, and Participants: This cohort study analyzed all patients with ALD who underwent their first LT at a single academic referral center between October 1, 2012, and November 13, 2020. Patients with known pretransplant hepatocellular carcinoma, hepatitis B or C, or an alternative cause of liver failure were excluded. Follow-up period was defined as the time from LT to the most recent encounter with a transplant center or death. Exposures: The exposure of interest was early LT, which was defined as less than 180 days of pre-LT abstinence. Standard LT was defined as 180 days or more of pre-LT abstinence. Patients were separated into early LT and standard LT by time from abstinence to LT. Main Outcomes and Measures: The outcomes were patient, allograft, relapse-free, and hazardous relapse-free survival for patients who underwent early LT or standard LT. These groups were compared by log-rank testing of Kaplan-Meier estimates. Hazardous relapse was defined as binge, at-risk, or frequent drinking. Abstinence was reassessed at the most recent follow-up visit for all patients. Results: Of the 163 patients with ALD included in this study, 88 (54%) underwent early LT and 75 (46%) underwent standard LT. This cohort had a mean (SD) age at transplant of 52 (10) years and was predominantly composed of 108 male patients (66%). Recipients of early LT vs standard LT were younger (median [interquartile range (IQR)] age, 49.7 [39.0-54.2] years vs 54.6 [48.7-60.0] years; P < .001) and had a higher median (IQR) Model for End-stage Liver Disease score at listing (35.0 [29.0-39.0] vs 20.0 [13.0-26.0]; P < .001). Both recipients of early LT and standard LT had similar 1-year patient survival (94.1% [95% CI, 86.3%-97.5%] vs 95.9% [95% CI, 87.8%-98.7%]; P = .60), allograft survival (92.7% [95% CI, 84.4%-96.7%] vs 90.5% [95% CI, 81.0%-95.3%]; P = .42), relapse-free survival (80.4% [95% CI, 69.1%-88.0%] vs 83.5% [95% CI, 72.2%-90.6%]; P = .41), and hazardous relapse-free survival (85.8% [95% CI, 75.1%-92.2%] vs 89.6% [95% CI, 79.5%-94.9%]; P = .41). Conclusions and Relevance: Adherence to the 6-month rule was not associated with superior patient survival, allograft survival, or relapse-free survival among selected patients. This finding suggests that patients with ALD should not be categorically excluded from LT solely on the basis of 6 months of abstinence, but rather alternative selection criteria should be identified that are based on need and posttransplant outcomes.

Daily Dose of Bovine Lactoferrin Prevents Ethanol-Induced Liver Injury and Death in Male Mice by Regulating Hepatic Alcohol Metabolism and Modulating Gut Microbiota.

SCOPE: Lactoferrin (Lf) possess a protective potential to liver, but whether it can prevent alcoholic liver injury (ALI) remains unclear. METHODS AND RESULTS: Four groups of male C57BL/6J mice are fed with different diets, namely, AIN-93G diet for control (CON) and ethanol (EtOH) groups, and AIN-93G diet with 0.4% and 4% casein replaced by Lf for low-dose Lf (LLf) and high-dose Lf (HLf) groups, respectively. ALI is induced by giving 20% ethanol ad libitum combined with four "binges". Lf can remarkably decrease EtOH-induced mortality. Lf promotes aldehyde dehydrogenase-2 (ALDH2) expression and suppressing cytochrome P450 2E1 (CYP2E1) overexpression, resulting in the reduced hepatic superoxide and inflammation levels, which ultimately leads to the hepatic injury alleviation. However, HLf increases acetyl-CoA carboxylase and fatty acid synthase protein levels, which suggests that excessive intake may weaken the beneficial effects of Lf. Moreover, LLf increases the relative abundances of Akkermansia and Lactobacillus. Additionally, the study shows that Lf likely exerts action in its digestive product forms rather than intact Lf molecular in normal condition. CONCLUSION: LLf can ameliorate ALI, which is associated with the regulation of hepatic alcohol metabolism and the modulation of gut microbiota. However, excessive Lf intake may result in a diminished benefit.

Liver-specific Nrf2 deficiency accelerates ethanol-induced lethality and hepatic injury in vivo.

Alcoholic liver disease (ALD) is a major cause of morbidity and mortality from liver disorders. Various mechanisms, including oxidative stress and impaired lipid metabolism, have been implicated in the pathogenesis of ALD. Our previous studies showed that nuclear factor erythroid-derived 2-like 2 (Nrf2) is a master regulator of adaptive antioxidant response and lipid metabolism by using a liver-specific Nrf2 knockout (Nrf2(L)-KO) mouse model. In the current study, an ALD model was developed by a Lieber-DeCarli liquid-based ethanol diet given to this Nrf2(L)-KO mouse strain. We found that Nrf2(L)-KO mice were quite sensitive to lethality from 6.3% ethanol diet. We thus decreased the ethanol concentration to 4.2% to obtain tissues to analyze the role of hepatic Nrf2 in the development of ALD. We found that mild hepatic steatosis occurred with both liquid control and 4.2% ethanol diet feeding, which contain 35% fat. Both the fatty acid ß-oxidation marker peroxisome proliferators-activated receptor α (PPARα), and lipogenesis regulator PPARγ were reduced with ethanol feeding in Nrf2(L)-KO mice, compared to Nrf2 floxed control mice (Nrf2-LoxP). However, Nrf2(L)-KO livers showed more cell injury than the livers of Nrf2-LoxP mice. Consistent with these data, there was increased proportion of apoptotic cells in the liver of ethanol-fed Nrf2(L)-KO mice comparing Nrf2-LoxP controls. Mechanistically, Nrf2 mediated expression of ethanol detoxification enzymes, such as alcohol dehydrogenase 1 and aldehyde dehydrogenase1a1, likely contributed to the sensitivity to ethanol toxicity. In conclusion, hepatic Nrf2 is critical to the development of ALD, particularly the morbidity and liver injury.

Impact of Public Health Policies on Alcohol-Associated Liver Disease in Latin America: An Ecological Multinational Study.

BACKGROUND AND AIMS: Alcohol-associated liver disease (ALD) is the leading cause of liver-related mortality in Latin America, yet the impact of public health policies (PHP) on liver disease is unknown. We aimed to assess the association between alcohol PHP and deaths due to ALD in Latin American countries. APPROACH AND RESULTS: We performed an ecological multinational study including 20 countries in Latin America (628,466,088 inhabitants). We obtained country-level sociodemographic information from the World Bank Open Data source. Alcohol-related PHP data for countries were obtained from the World Health Organization Global Information System of Alcohol and Health. We constructed generalized linear models to assess the association between the number of PHP (in 2010) and health outcomes (in 2016). In Latin America, the prevalence of obesity was 27% and 26.1% among male and female populations, respectively. The estimated alcohol per capita consumption among the population at 15 years old or older was 6.8 L of pure alcohol (5.6 recorded and 1.2 unrecorded). The overall prevalence of alcohol use disorders (AUD) was 4.9%. ALD was the main cause of cirrhosis in 64.7% of male and 40.0% of female populations. A total of 19 (95%) countries have at least one alcohol-related PHP on alcohol. The most frequent PHP were limiting drinking age (95%), tax regulations (90%), drunk-driving policies and countermeasures (90%), and government monitoring systems and community support (90%). A higher number of PHP was associated with a lower ALD mortality (PR, 0.76; 95% CI, 0.61-0.93; P = 0.009), lower AUD prevalence (PR, 0.80; 95% CI, 0.65-0.99; P = 0.045), and lower alcohol-attributable road traffic deaths (PR, 0.81; 95% CI, 0.65-1.00; P = 0.051). CONCLUSIONS: Our study indicates that in Latin America, countries with higher number of PHP have lower mortality due to ALD, lower prevalence of AUD, and lower alcohol-attributable road traffic mortality.

Mortality in biopsy-proven alcohol-related liver disease: a population-based nationwide cohort study of 3453 patients.

OBJECTIVE: Patients with alcohol-related liver disease (ALD) are at increased risk of death, but studies have rarely investigated the significance of histological severity or estimated relative risks compared with a general population. We examined mortality in a nationwide cohort of biopsy-proven ALD. DESIGN: Population-based cohort study in Sweden comparing 3453 individuals with an International Classification of Disease (ICD) code for ALD and a liver biopsy from 1969 to 2017 with 16 535 matched general population individuals. Swedish national registers were used to ascertain overall and disease-specific mortality, starting follow-up at the latest of first ICD diagnosis or liver biopsy plus 3 months. Cox regression adjusted for relevant confounders was used to estimate HRs in ALD and histopathological subgroups. RESULTS: Median age at diagnosis was 58 years, 65% were men and 52% had cirrhosis at baseline. Five-year cumulative mortality was 40.9% in patients with ALD compared with 5.8% in reference individuals. The risk for overall mortality was significantly increased (adjusted HR (aHR)=4.70, 95% CI 4.35 to 5.08). The risk of liver-related death was particularly high (43% of all deaths, aHR=167.6, 95% CI 101.7 to 276.3). Mortality was significantly increased also in patients with ALD without cirrhosis and was highest in the first year after baseline but persisted after ≥10 years of follow-up (aHR=2.74, 95% CI 2.37 to 3.16). CONCLUSION: Individuals with biopsy-proven ALD have a near fivefold increased risk of death compared with the general population. Individuals with ALD without cirrhosis were also at increased risk of death, reaffirming the need to increase vigilance in the management of these individuals.

Alpha-1 antitrypsin governs alcohol-related liver disease in mice and humans.

OBJECTIVE: Alcohol-related liver disease (ALD) is a global healthcare problem with limited treatment options. Alpha-1 antitrypsin (AAT, encoded by SERPINA1) shows potent anti-inflammatory activities in many preclinical and clinical trials. In our study, we aimed to explore the role of AAT in ALD. DESIGN: An unselected cohort of 512 patients with cirrhosis was clinically characterised. Survival, clinical and biochemical parameters including AAT serum concentration were compared between patients with ALD and other aetiologies of liver disease. The role of AAT was evaluated in experimental ALD models. RESULTS: Cirrhotic ALD patients with AAT serum concentrations less than 120 mg/dL had a significantly higher risk for death/liver transplantation as compared with patients with AAT serum concentrations higher than 120 mg/dL. Multivariate Cox regression analysis showed that low AAT serum concentration was a NaMELD-independent predictor of survival/transplantation. Ethanol-fed wild-type (wt) mice displayed a significant decline in hepatic AAT compared with pair-fed mice. Therefore, hAAT-Tg mice were ethanol-fed, and these mice displayed protection from liver injury associated with decreased steatosis, hepatic neutrophil infiltration and abated expression of proinflammatory cytokines. To test the therapeutic capability of AAT, ethanol-fed wt mice were treated with human AAT. Administration of AAT ameliorated hepatic injury, neutrophil infiltration and steatosis. CONCLUSION: Cirrhotic ALD patients with AAT concentrations less than 120 mg/dL displayed an increased risk for death/liver transplantation. Both hAAT-Tg mice and AAT-treated wt animals showed protection from ethanol-induced liver injury. AAT could reflect a treatment option for human ALD, especially for alcoholic hepatitis.

Long-term outcomes after resection of alcohol-related versus hepatitis-related hepatocellular carcinoma: A SEER-Medicare database analysis.

BACKGROUND: The objective of this study was to define the relative impact of alcohol and/or hepatitis-related HCC etiology on the outcomes of patients who underwent resection or transplantation for HCC. METHODS: The SEER-Medicare database was used to identify patients with HCC between 2004 and 2015. Patients with history of alcohol abuse or hepatitis were identified. Overall survival (OS) and cancer-specific survival (CSS) were calculated using the Kaplan-Meier method and multivariable Cox regression analysis. RESULTS: Among 1140 patients, 11.9% (n = 136) of patients had alcohol-related HCC, 30.0% (n = 342) hepatitis-related HCC, and 58.1% (n = 662) had other cause-related HCC. On multivariable analysis, patients with alcohol-related HCC (HR:1.06, 95%CI:0.82-1.35) or hepatitis-related HCC (HR:1.05, 95%CI:0.88-1.26) had similar hazards of death compared with patients who had non-alcohol/non-hepatitis-related HCC. Patients who had tumor size ≤5 cm had lower hazards of death (HR:0.81, 95%CI:0.68-0.97), while individuals who underwent liver resection (vs. transplantation) had almost a two-fold higher hazards of death (HR:1.99, 95%CI:1.47-2.69). CONCLUSION: Tumor specific factors (i.e. tumor size and stage) and operative approach (i.e. resection vs. transplantation) -rather than HCC etiology- dictated both OS and CSS.

Excess Mortality After Liver Transplantation in Young Women With Alcohol-Associated Liver Disease.

INTRODUCTION: Young adults with alcohol-associated liver disease (ALD) are the fastest increasing demographic contributing to liver-related deaths; their outcomes after liver transplantation (LT) are understudied. METHODS: Using the United Network for Organ Sharing registry, we performed sex-specific analyses because of a significant interaction between sex and the explanatory variable, age. Cox regression was used with overall post-LT death as the primary outcome, adjusted for survival characteristics and center clustering. We calculated the absolute difference in adjusted 5-year post-LT survival between patient groups. Causes of death were supplemented by manual review of free-text entries. RESULTS: Among 42,014 LT recipients, 16,190 women (2,782 with ALD and 13,408 without ALD) and 25,824 men (9,502 with ALD and 16,322 without ALD), age of 40-50 years had the lowest risk of death. Women with ALD younger than 40 years had incrementally lower adjusted 5-year survival (95% confidence interval): 74% (63%-88%) for those aged 18-29 years, 82% (78%-87%) for those aged 30-39 years, and 90% (88%-92%) for those aged 40-49 years. Among women without ALD, men with ALD, and men without ALD, adjusted 5-year survival for ages 18-29, 30-39, and 40-49 years was similar. Among women, not men, there were significant interactions between younger age and ALD. Adjusted hazard for mortality for women with ALD vs without ALD was greater for those who aged 18-29 years (2.82 vs 1.09, P = 0.002) and 30-39 years (1.83 vs 1.09, P = 0.007 [reference age 40-49 years]). Among women with ALD, those aged 18-29 and 30-39 years had an absolute 17.7% and 9.5% excess in adjusted 5-year mortality vs similarly aged women without ALD. DISCUSSION: Young women (age < 40) with ALD have excess mortality beyond one-year post-LT. Recurrent disease or explicit mention of alcohol was the most common identified cause of death in this demographic.

[Epidemiology of Alcoholic Liver Disease in Korea].

The harmful use of alcohol is associated with significant medical and socioeconomic burdens responsible for approximately 6% of all deaths worldwide. In Korea, the total alcohol consumption recently decreased slightly from 14.8 L of alcohol per person on average in 2011 to 9.1 L in 2015. On the other hand, over the past 10 years (2007-2017), the rates of monthly alcohol consumption, which is defined as drinking more than once a month, and the rates of high-risk alcohol consumption, defined as drinking more than seven standard drinks twice a week or more, have increased. In particular, the death rate due to alcoholic liver disease was the highest and increasing among those in their 50s who play crucial socioeconomic roles. In addition, the most notable change over the past 10 years has been the increase in alcohol consumption in young women aged between 20 and 39, and the increase in deaths among women due to alcoholic liver disease. In Korea, alcoholic liver disease is ranked 2nd-3rd as the causes of chronic liver disease, liver cirrhosis, and hepatocellular carcinoma, having a significant negative socioeconomic impact.

Disparities in the Deaths of Despair by Occupation, Massachusetts, 2000 to 2015.

OBJECTIVE: To explore mortality rates and trends according to the occupation of workers who died from the deaths of despair (DoD). METHODS: Death certificates for deaths due to poisonings (including opioid-related overdoses), suicides, and alcoholic liver disease occurring in Massachusetts from 2000 to 2015 were collected and coded according to the occupation of the decedent. Mortality rates and trends in mortality were calculated for each occupation. RESULTS: DoDs increased by more than 50% between 2000 to 2004 and 2011 to 2015. There were substantial differences in mortality rates and trends according to occupation. Blue collar workers were at a particularly elevated risk for DoD and had elevated trends for these deaths, notably: construction and farming, fishing, and forestry workers. CONCLUSIONS: Interventions should be targeted to occupations with elevated mortality rates and trends. Occupational risk factors that may contribute to these disparities should be explored.

Mortality After Extrahepatic Gastrointestinal and Abdominal Wall Surgery in Patients With Alcoholic Liver Disease: A Systematic Review and Meta-Analysis.

AIMS: This meta-analysis aimed to define the perioperative risk of mortality in patients with alcoholic liver disease (ALD) undergoing extrahepatic gastrointestinal surgery. METHODS: Systematic searches of Embase, Medline and CENTRAL were undertaken to identify studies reporting about patients with ALD undergoing extrahepatic gastrointestinal surgery published since database inception to January 2019. Studies were only considered if they reported on mortality as an outcome. Pooled analysis of mortality was stratified as benign and malignant surgery and specific operative procedures where feasible. RESULTS: Of the 2899 studies identified, only five studies met inclusion criteria, representing cholecystectomy (one study), umbilical hernia repair surgery (one study) and oesophagectomy (three studies). The total number of patients with ALD in these studies was 172. Therefore, any study on liver disease patients undergoing extrahepatic surgery that crucially included a subset with alcohol aetiology was included as a secondary analysis even though they failed to stratify mortality by underlying aetiology. The total number of studies that met this expanded inclusion criteria was 62, reporting on 37,703 patients with liver disease of which 1735 (4.5%) had a definite diagnosis of ALD. Meta-analysis of proportions of in-hospital mortality in patients with ALD undergoing upper gastrointestinal cancer surgery (oesophagectomy) was 23% [95% confidence interval (CI) 14-35%, I2 = 0%]. In-hospital mortality following oesophagectomy in liver disease patients of all aetiologies was lower, 14% (95% CI 9-21%, I2 = 41.1%). CONCLUSION: Postoperative in-hospital mortality is high in patients with liver disease and ALD in particular. However, the currently available evidence on ALD is limited and precludes definitive conclusions on postoperative mortality risk.

Sex and Gender Disparities in Pretransplant Characteristics and Relationships with Postoperative Outcomes in Liver Transplant Recipients with Alcoholic Liver Disease.

OBJECTIVES: Previous studies of liver transplant recipients have reported discrepancies with regard to gender and/or sex differences but have focused on pretransplant outcomes. Female candidates are less likely to receive liver transplant and more likely to die or be delisted than their male counterparts. Here, we examined differences in men versus women with alcoholic liver disease before liver transplant and the effects of these differences on posttransplant survival. MATERIALS AND METHODS: We analyzed the Scientific Registry of Transplant Recipients records of adult, deceased-donor, whole liver transplant recipients with decompensated alcoholic liver disease from 2002 to 2017 to evaluate the effects of gender on survival in 2 alcoholic liver disease cohorts: (a) including and (b) excluding recipients with additional diagnoses. Pretransplant characteristics were compared using chi-square or t tests. Kaplan-Meier and multivariable proportional hazards regression models were used to evaluate the main and covariable-adjusted effects of gender on survival. RESULTS: Of 13781 transplant recipients with decompensated end-stage liver disease, as defined by Model for End-Stage Liver Disease score ≥ 15, 10924 (79%) were men and 2857 (21%) were women. Women had higher Model for End-Stage Liver Disease scores, higher rates of stage 4 and 5 chronic kidney disease, and were more likely to be on dialysis or ventilator support at time of transplant (all P < .05). Among all recipients, and after adjusting for risk factors, men were approximately 9% more likely than women to experience long-term graft loss (hazard ratio = 1.093; 95% confidence interval, 1.00-1.19; P = .043). However, sex difference was not associated with risk of graft loss among those without additional diagnoses (hazard ratio = 1.09; 95% confidence interval, 0.99-1.21; P = .095). CONCLUSIONS: Although women with alcoholic liver disease who undergo liver transplant have higher severity of illness than their male counterparts, long-term outcomes are comparable.

Projected prevalence and mortality associated with alcohol-related liver disease in the USA, 2019-40: a modelling study.

BACKGROUND: Alcohol-related liver disease is the leading indication for liver transplantation in the USA. After remaining stable for over three decades, the number of deaths due to alcohol-related liver disease has been increasing as a result of increased high-risk drinking. We aimed to project trends in alcohol-related cirrhosis and deaths in the USA up to 2040 and assess the effect of potential changes in alcohol consumption on those trends. METHODS: In this modelling study, we developed a multicohort state-transition (Markov) model of high-risk alcohol drinking patterns and alcohol-related liver disease in high-risk drinking populations born in 1900-2016 in the USA projected up to 2040. We used data from the National Epidemiologic Survey on Alcohol and Related Conditions, National Institute of Alcohol Abuse and Alcoholism, US National Death Index, National Vital Statistics System, and published studies. We modelled trends in alcohol-related liver disease under three projected scenarios: the status quo scenario, in which current trends continued; a moderate intervention scenario, in which trends in high-risk drinking reduced to 2001 levels under some hypothetical moderate intervention; and a strong intervention, in which trends in high-risk drinking decreased by 3·5% per year under some hypothetical strong intervention. The primary outcome was to project deaths associated with alcohol-related liver disease from 2019 to 2040 for each pattern of alcohol consumption under the different scenarios. FINDINGS: Our model closely reproduced the observed trends in deaths due to alcohol-related liver disease from 2005 to 2018. Under the status quo scenario, age-standardised deaths due to alcohol-related liver disease are expected to increase from 8·23 (95% uncertainty interval [UI] 7·92-9·29) per 100 000 person-years in 2019 to 15·20 (13·93-16·19) per 100 000 person-years in 2040, and from 2019 to 2040, 1 003 400 (95% CI 896 800-1 036 200) people are projected to die from alcohol-related liver disease, resulting in 1 128 400 (1 113 200-1 308 400) DALYs by 2040. Under the moderate intervention scenario, age-standardised deaths due to alcohol-related liver disease would increase to 14·49 (95% UI 12·55-14·57) per 100 000 person-years by 2040, with 968 100 (95% UI 845 600-975 900) individuals projected to die between 2019 and 2040-35 300 fewer deaths than under the status quo scenario (a 3·5% decrease). Whereas, under the strong intervention scenario, age-standardised deaths due to alcohol-related liver disease would peak at 8·65 (95% UI 8·12-9·51) per 100 000 person-years in 2024 and decrease to 7·60 (6·96-8·10) per 100 000 person-years in 2040, with 704 300 (95% CI 632 700-731 500) individuals projected to die from alcohol-related liver disease in the USA between 2019 and 2040-299 100 fewer deaths than under the status quo scenario (a 29·8% decrease). INTERPRETATION: Without substantial changes in drinking culture or interventions to address high-risk drinking, the disease burden and deaths due to alcohol-related liver disease will worsen in the USA. Additional interventions are urgently needed to reduce mortality and morbidity associated with alcohol-related liver disease. FUNDING: American Cancer Society and the Robert Wood Johnson Health Policy Research Fellowship.

Clinical Patterns and Outcome of Hepatocellular Carcinoma in Patients with Nonalcoholic Fatty Liver Disease.

Background: Nonalcoholic fatty liver disease (NAFLD) may develop into liver cirrhosis and hepatocellular carcinoma (HCC). The aim of this study was to compare the clinical patterns and survival outcomes of NAFLD-related HCC patients and those of alcoholic liver disease (ALD)-related or hepatitis B virus (HBV)-related HCC patients. Methods: A total of 622 HCC patients with associated NAFLD (n = 56), ALD (n = 173), or HBV infection (n = 393) were enrolled. The clinical characteristics and survival were analyzed according to the underlying liver diseases. Results: NAFLD-related HCC patients were more commonly older women and had more metabolic risk factors but were less likely to have cirrhosis and ascites, compared to ALD-related or HBV-related HCC patients. NAFLD-related HCC more often had an infiltrative pattern (P=0.047), a larger tumor (P=0.001), more macrovascular invasion (P=0.022), and exceeded the Milan criteria (P=0.001), but was less frequently diagnosed during tumor surveillance (P=0.025). Survival analysis did not show any difference among NAFLD-related, ALD-related, and HBV-related HCC patients. Furthermore, propensity score matching analysis did not reveal a significant difference in the median survival between the different groups (NAFLD vs. ALD, 14.0 months [95% confidence interval (CI), 2.0-26.0] vs. 13.0 months [95% CI, 0-26.3]; P=0.667, NAFLD vs. HBV, 14.0 months [95% CI, 2.0-26.0] vs. 12.0 months [95% CI, 4.3-17.8]; P=0.573). Conclusions: NAFLD-related HCCs were more often detected at an advanced stage with infiltrative patterns, although they showed no significant difference in survival compared to ALD-related or HBV-related HCCs. A future prospective research should be focused on identifying NAFLD patients who require strict surveillance in order to early detect and timely treat HCC.

Reducing variation in hospital mortality for alcohol-related liver disease in North West England.

BACKGROUND: Variations in emergency care quality for alcohol-related liver disease (ARLD) have been highlighted. AIM: To determine whether introduction of a regional quality improvement (QI) programme was associated with a reduction in potentially avoidable inpatient mortality. METHOD: Retrospective observational cohort study using hospital administrative data spanning a 1-year period before (2014/2015) and 3 years after a QI initiative at seven acute hospitals in North West England. The intervention included serial audit of a bundle of process metrics. An algorithm was developed to identify index ("first") emergency admissions for ARLD (n = 3887). We created a standardised mortality ratio (SMR) to compare relative mortality and regression models to examine risk-adjusted odds of death. RESULTS: In 2014/2015, three of seven hospitals had an SMR above the upper control limit ("outliers"). Adjusted odds of death for patients admitted to outlier hospitals was higher than non-outliers (OR 2.13, 95% CI 1.32-3.44, P = 0.002). Following the QI programme there was a step-wise reduction in outliers (none in 2017/2018). Odds of death was 67% lower in 2017/2018 compared to 2014/2015 at original outlier hospitals, but unchanged at other hospitals. Process audit performance of outliers was worse than non-outliers at baseline, but improved after intervention. CONCLUSIONS: There was a reduction in unexplained variation in hospital mortality following the QI intervention. This challenges the pessimism that is prevalent for achieving better outcomes for patients with ARLD. Notwithstanding the limitations of an uncontrolled observational study, these data provide hope that co-ordinated efforts to drive adoption of evidence-based practice can save lives.