Alcohol-associated liver disease: Epidemiology and management.

Alcohol is the leading cause of preventable liver morbidity and mortality worldwide, as it is also the most frequent cause of advanced liver disease. Alcohol-associated liver disease (ALD) covers different phenotypes ranging from steatosis to the development of inflammation (steatohepatitis), fibrosis and ultimately, in a proportion of patients, the development of liver cirrhosis and its associated complications. ALD has a complex pathogenesis that includes the interplay of both genetic and environmental factors, yet the precise mechanisms are largely unknown. Alcohol-associated hepatitis (AH) is a severe clinical presentation of ALD, which is characterized by abrupt jaundice and clinical decompensations of liver disease. AH occurs in a percentage of patients with underlying ALD and active alcohol consumption. Currently, there are no approved targeted therapies able to interfere in the pathogenesis of ALD and halt the progression of the disease, therefore alcohol abstinence is the most effective measure to improve prognosis in this patient population. In this regard, alcohol cessation remains the first-line treatment in all stages of alcohol disease. In patients with advanced ALD nonresponding to medical therapy, liver transplantation is the only approach that improves prognosis, and it should be considered in patients with decompensated cirrhosis. In the last years, AH has emerged as a new indication of early liver transplantation in non-responders to medical therapy, with promising results in highly selected patients. In this review, we provide an update on the epidemiology, risk factors, natural history, diagnosis, pathogenesis, and current treatments for ALD, taking into account the importance of assessing and managing alcohol consumption as the etiological factor and the main driver of prognosis in patients with ALD.

Applying an equity lens to liver health and research in Europe.

Liver disease is a major cause of premature death and disability in Europe. However, morbidity and mortality are not equally distributed in the population. In spite of this, there are few studies addressing the issue of health inequalities in Europe. In this Public Health Corner article, we compare the research conducted on health inequalities in Europe to other settings and highlight the main differences based upon an extensive review of the literature. We report that only 10.2% of studies were led by European institutions or conducted in European populations and that certain topics such as alcohol-related liver disease are largely overlooked. In addition, we discuss the relevance of including a health equity lens when conducting clinical, epidemiological and health systems' research in liver disease and set out the basic requirements to tackle health inequalities in liver disease in Europe.

Racial and Health Disparities among Cirrhosis-related Hospitalizations in the USA.

Background and Aims: Alcohol-associated liver disease (ALD) is the most common cause of advanced liver disease worldwide, including in the USA. Alcohol use and cirrhosis mortality is higher in American Indian/Alaska Native (AI/AN) compared to Whites. Data are scanty on ALD as a liver disease etiology in AI/AN compared to other races and ethnicities. Methods: The National Inpatient Sample on 199,748 cirrhosis-related hospitalizations, 14,241 (2,893 AI/AN, 2,893 Whites, 2,882 Blacks, 2,879 Hispanics, and 2,694 Asians or other races) matched 1:1 for race/ethnicity on demographics, insurance, and income quartile of the residence zip code analyzed. Results: After controlling for geographic location and hospital type, odds ratio (OR) and 95% confidence interval (CI) for ALD as cirrhosis etiology was higher among admissions in AI/AN vs. Whites [1.55 (1.37-1.75)], vs. Blacks [1.87 (1.65-2.11)], vs. Hispanic [1.89 (1.68-2.13)] and Asians/other races [2.24 (1.98-2.53)]. OR was also higher for AI/AN vs. all other races for alcohol-associated hepatitis (AH) as one of the discharge diagnoses. The findings were similar in a subgroup of 4,649 admissions with decompensated cirrhosis and in a cohort of 350 admissions with acute-on-chronic liver failure as defined by EASL-CLIF criteria. Alcohol use disorder diagnosis was present in 38% of admissions in AI/AN vs. 24-30% in other races, p<0.001. A total of 838 (5.9%) admissions were associated with in-hospital mortality. OR (95% CI) for in-hospital mortality in AI/AN individuals was 34% reduced vs. Blacks [0.66 (0.51-0.84)], but no difference was observed on comparison with other races. Conclusions: ALD, including AH, is the most common etiology among cirrhosis-related hospitalizations in the USA among AI/AN individuals. In-hospital mortality was observed in about 6% of admissions, which was higher for Blacks and similar in other races compared to admissions for AI/AN. Public health policies should be implemented to reduce the burden of advanced ALD among AI/AN individuals.

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.

Charges for Alcoholic Cirrhosis Exceed All Other Etiologies of Cirrhosis Combined: A National and State Inpatient Survey Analysis.

BACKGROUND: Inpatient charges for patients with cirrhosis are substantial. We aimed to examine trends in inpatient charges among patients with cirrhosis to determine the drivers of healthcare expenditures. We hypothesized that alcoholic cirrhosis (AC) was a significant contributor to overall expense. METHODS: We performed a retrospective analysis of the Health Care Utilization Project Nationwide Inpatient Sample Database 2002-2014 (annual cross-sectional data) and New York and Florida State Inpatient Databases 2010-2012 (longitudinal data). Adult patients with cirrhosis of the liver were categorized as AC versus all other etiologies of cirrhosis combined. Patient characteristics were analyzed using ordinary least squares regression modeling. A random effects model was used to evaluate 30-day readmissions. RESULTS: In total, 1,240,152 patients with cirrhosis were admitted between 2002 and 2014. Of these, 567,510 (45.8%) had a diagnosis of AC. Total charges for AC increased by 95.7% over the time period, accounting for 59.9% of all inpatient cirrhosis-related charges in 2014. Total aggregate charges for AC admissions were $28 billion and increased from $1.4B in 2002 to $2.8B by 2014. In the NIS and SID, patients with AC were younger, white and male. Readmission rates at 30, 60, and 90 days were all higher among AC patients. CONCLUSIONS: Inpatient charges for cirrhosis care are high and increasing. Alcohol-related liver disease accounts for more than half of these charges and is driven by sheer volume of admissions and readmissions of the same patients. Effective alcohol addictions therapy may be the most cost-effective way to substantially reduce inpatient cirrhosis care expenditures.

Alcoholic liver disease.

Alcoholic liver disease (ALD) is the most prevalent type of chronic liver disease worldwide. ALD can progress from alcoholic fatty liver (AFL) to alcoholic steatohepatitis (ASH), which is characterized by hepatic inflammation. Chronic ASH can eventually lead to fibrosis and cirrhosis and in some cases hepatocellular cancer (HCC). In addition, severe ASH (with or without cirrhosis) can lead to alcoholic hepatitis, which is an acute clinical presentation of ALD that is associated with liver failure and high mortality. Most individuals consuming >40 g of alcohol per day develop AFL; however, only a subset of individuals will develop more advanced disease. Genetic, epigenetic and non-genetic factors might explain the considerable interindividual variation in ALD phenotype. The pathogenesis of ALD includes hepatic steatosis, oxidative stress, acetaldehyde-mediated toxicity and cytokine and chemokine-induced inflammation. Diagnosis of ALD involves assessing patients for alcohol use disorder and signs of advanced liver disease. The degree of AFL and liver fibrosis can be determined by ultrasonography, transient elastography, MRI, measurement of serum biomarkers and liver biopsy histology. Alcohol abstinence achieved by psychosomatic intervention is the best treatment for all stages of ALD. In the case of advanced disease such as cirrhosis or HCC, liver transplantation may be required. Thus, new therapies are urgently needed.

Disparities between research attention and burden in liver diseases: implications on uneven advances in pharmacological therapies in Europe and the USA.

OBJECTIVES: Effective oral therapies for hepatitis B and C have recently been developed, while there are no approved pharmacological therapies for alcoholic and non-alcoholic fatty liver diseases (ALD and NAFLD). We hypothesise that fewer advances in fatty liver diseases could be related to disparities in research attention. METHODS: We developed the Attention-to-Burden Index (ABI) that compares the research activities during 2010-2014, and an estimate of disease burden of these 4 major liver diseases. The resulting ratio reflects either overattention (positive value) or inadequate attention (negative value) compared with disease burden. The mean research attention and disease burden were calculated from 5 and 6 different parameters, respectively. The efficacy rate of current pharmacological therapies was assessed from published clinical trials. FINDINGS: The mean research attention for hepatitis B and C was 31% and 47%, respectively, while NAFLD and ALD received 17% and 5%. The overall burden was 5% and 28% for hepatitis B and C, and 17% and 50% for NAFLD and ALD. The calculated ABI for hepatitis B and C revealed a +6.7-fold and +1.7-fold overattention, respectively. NAFLD received an appropriate attention compared with its burden, while ALD received marked inadequate attention of -9.7-fold. The efficacy rate of current pharmacological agents was 72% for hepatitis B, 89% for hepatitis C, 25% for non-alcoholic steatohepatitis and 13% for alcoholic hepatitis. Importantly, we found a positive correlation between the mean attention and the efficacy rate of current therapies in these 4 major liver diseases. INTERPRETATION: There are important disparities between research attention and disease burden among the major liver diseases. While viral hepatitis has received considerable attention, there is a marked inadequate attention to ALD. There is a critical need to increase awareness of ALD in the liver research community.

Alcoholic hepatitis: Translational approaches to develop targeted therapies.

UNLABELLED: Alcoholic liver disease is a leading cause of liver-related mortality worldwide. In contrast to recent advances in therapeutic strategies for patients with viral hepatitis, there is a significant lack of novel therapeutic options for patients with alcoholic liver disease. In particular, there is an urgent need to focus our efforts on effective therapeutic interventions for alcoholic hepatitis (AH), the most severe form of alcoholic liver disease. AH is characterized by an abrupt development of jaundice and complications related to liver insufficiency and portal hypertension in patients with heavy alcohol intake. The mortality of patients with AH is very high (20%-50% at 3 months). Available therapies are not effective in many patients, and targeted approaches are imminently needed. The development of such therapies requires translational studies in human samples and suitable animal models that reproduce the clinical and histological features of AH. In recent years, new animal models that simulate some of the features of human AH have been developed, and translational studies using human samples have identified potential pathogenic factors and histological parameters that predict survival. CONCLUSION: This review summarizes the unmet needs for translational studies on the pathogenesis of AH, preclinical translational tools, and emerging drug targets to benefit the AH patient. (Hepatology 2016;64:1343-1355).

Trends in the management and burden of alcoholic liver disease.

Alcoholic liver disease (ALD) is the most prevalent cause of advanced liver disease in Europe and is the leading cause of death among adults with excessive alcohol consumption. There is a dose-response relationship between the amount of alcohol consumed and the risk of ALD. The relative risk of cirrhosis increases in subjects who consume more than 25 g/day. The burden of alcohol-attributable liver cirrhosis and liver cancer is high and is entirely preventable. Health agencies should develop population-based policies to reduce the prevalence of harmful and/or hazardous alcohol consumption and foster research in this field to provide new diagnostic and therapeutic tools. Disease progression of patients with ALD is heavily influenced by both genetic and environmental factors. Non-invasive methods for the diagnosis of fibrosis have opened new perspectives in the early detection of advanced ALD in asymptomatic patients. Alcoholic hepatitis, the most severe form of ALD, carries a high short-term mortality (around 30-50% at 3 months). Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis but duration of therapy should be adapted to early response. Liver transplantation is the best option for patients with severe liver dysfunction. However, alcohol relapse after transplantation remains a critical issue and drinking habits of transplanted patients need to be routinely screened.