Incidence of Etiology-specific Hepatocellular Carcinoma: Diverging Trends and Significant Heterogeneity by Race and Ethnicity.

BACKGROUND & AIMS: The main causes of hepatocellular carcinoma (HCC) include chronic hepatitis C and B viral infections (HCV, HBV), nonalcoholic fatty liver disease (NAFLD), and alcohol-related disease (ALD). Etiology-specific HCC incidence rates and temporal trends on a population-basis are needed to improve HCC control and prevention. METHODS: All 14,420 HCC cases from the Florida statewide cancer registry were individually linked to data from the hospital discharge agency and the viral hepatitis department to determine the predominant etiology of each case diagnosed during 2010 to 2018. Age-adjusted incidence rates (AAIRs) were used to assess the intersection between etiology and detailed race-ethnicity. Etiology-specific temporal trends based on diagnosis year were assessed using Joinpoint regression. RESULTS: HCV remains the leading cause of HCC among men, but since 2017 NAFLD-HCC is the leading cause among women. HCV-HCC AAIRs are particularly high among U.S.-born minority men, including Puerto Rican (10.9 per 100,000), African American (8.0 per 100,000), and U.S.-born Mexican American men (7.6 per 100,000). NAFLD is more common among all Hispanics and Filipinos and HBV-HCC among Asian and Haitian black men. HCV-HCC surpasses HBV-HCC in Asian women. ALD-HCC is high among specific Hispanic male groups. Population-based HCV-HCC rates experienced a rapid decline since 2015 (-9.6% annually), whereas ALD-HCC (+6.0%) and NAFLD-HCC (+4.3%) are rising (P < .05). CONCLUSIONS: New direct acting anti-viral drugs have impacted rates of HCV-HCC, offsetting important increases in both ALD- and NAFLD-HCC. Hispanics may be a group of concern because of higher rates for ALD- and NAFLD-HCC. HCC etiology varies remarkably and may warrant specific interventions by detailed race-ethnicity.

Multiple Barriers Impede Screening for Hepatitis Delta: An Internet-Based Survey of Healthcare Providers.

INTRODUCTION: Hepatitis delta virus (HDV) increases risk of cirrhosis and hepatocellular carcinoma in patients with hepatitis B; however, HDV screening rates are low. We assessed providers' perceived barriers to HDV screening and management. METHODS: We distributed an Internet-based survey to members of 3 gastroenterology/hepatology organizations. RESULTS: Most respondents, 69.3%, correctly identified the appropriate HDV screening test. Several reported barriers to HDV care, including uncertainty of screening criteria, 55.5%, and lack of treatment knowledge, 66.7%. DISCUSSION: Our findings highlight the need for increased education regarding HDV care. Education should be combined with standardized approaches that increase ease of HDV screening.

The Liver Cirrhosis Network Cohort Study: Cirrhosis Definition, Study Population, and Endpoints.

BACKGROUND: One of the primary goals of the Liver Cirrhosis Network (LCN) is to develop a cohort study to better understand and predict the risk of hepatic decompensation and other clinical and patient-reported outcomes among patients with Child A cirrhosis. METHODS: The LCN consists of a Scientific Data Coordinating Center (SDCC) and 10 clinical centers whose investigators populate multiple committees. The LCN Definitions and Measurements Committee developed preliminary definitions of cirrhosis and its complications by literature review, expert opinion, and reviewing definition documents developed by other organizations. The Cohort Committee developed the study protocol with the input of the steering committee. RESULTS: The LCN developed a prospective cohort study to describe and predict the rates of incident clinical events pertaining to first decompensation and patient reported outcomes. The LCN developed a pragmatic definition of compensated cirrhosis incorporating clinical, laboratory, imaging, and histological criteria. Definitions of incident and recompensated ascites, overt hepatic encephalopathy, variceal hemorrhage, bleeding due to portal gastropathy, and hepatocellular carcinoma were also codified. CONCLUSION: The LCN Cohort Study design will inform the natural history of cirrhosis in contemporary patients with compensated cirrhosis. The LCN Definitions and Measures Committee developed criteria for the definition of cirrhosis to standardize entry into this multi-center cohort study and standardized criteria for liver-related outcome measures. This effort has produced definitions intended to be both sensitive and specific as well as easily operationalized by study staff such that outcomes critical to the LCN cohort are identified and reported in an accurate and generalizable fashion.

Low Health Literacy, Lack of Knowledge, and Self-Control Hinder Healthy Lifestyles in Diverse Patients with Steatotic Liver Disease.

INTRODUCTION: In parallel with the obesity and diabetes epidemics, steatotic liver disease (SLD) has emerged as a major global public health concern. The mainstay of therapy is counseling on weight loss and increased exercise. However, such lifestyle modifications infrequently lead to success. We aimed to identify barriers to diet and lifestyle modification in patients with SLD. METHODS: Patients with SLD completed a 14-item questionnaire that assigned barriers to healthy eating to three categories: lack of knowledge, lack of self-control, and lack of time, with a higher summary score indicating more perceived barriers. We administered assessments of health literacy and physical activity. We analyzed the data using descriptive statistics and ordinal regression analysis. RESULTS: We included 151 participants with a median age of 64; 54% were female and 68.2% were Hispanic. Median BMI was 31.9 kg/m2. Most respondents, 68.2%, had low health literacy and were either underactive, 29.1% or sedentary, 23.2%. Lack of self-control was the strongest barrier to achieving a healthy lifestyle, followed by lack of knowledge. Lack of time was not significant barrier. Patients with the most significant barriers were more likely to have obesity, low health literacy, and be sedentary. DISCUSSION: Lack of self-control and knowledge are the greatest barriers to adopting a healthy lifestyle in patients with SLD. Future clinical interventions should integrate education that targets various health literacy levels with behavioral approaches to improve a sense of agency.

Actionable Solutions to Achieve Health Equity in Chronic Liver Disease.

There are well-described racial and ethnic disparities in the burden of chronic liver diseases. Hispanic persons are at highest risk for developing nonalcoholic fatty liver disease, the fastest growing cause of liver disease. Hepatitis B disproportionately affects persons of Asian or African descent. The highest rates of hepatitis C occur in American Indian and Alaskan Native populations. In addition to disparities in disease burden, there are also marked racial and ethnic disparities in access to treatments, including liver transplantation. Disparities also exist by gender and geography, especially in alcohol-related liver disease. To achieve health equity, we must address the root causes that drive these inequities. Understanding the role that social determinants of health play in the disparate health outcomes that are currently observed is critically important. We must forge and/or strengthen collaborations between patients, community members, other key stakeholders, health care providers, health care institutions, professional societies, and legislative bodies. Herein, we provide a high-level review of current disparities in chronic liver disease and describe actionable strategies that have potential to bridge gaps, improve quality, and promote equity in liver care.

Clinical, histological and molecular profiling of different stages of alcohol-related liver disease.

OBJECTIVE: Alcohol-related liver disease (ALD) ranges from never-decompensated ALD (ndALD) to the life-threatening decompensated phenotype, known as alcohol-related hepatitis (AH). A multidimensional study of the clinical, histological and molecular features of these subtypes is lacking. DESIGN: Two large cohorts of patients were recruited in an international, observational multicentre study: a retrospective cohort of patients with ndALD (n=110) and a prospective cohort of patients with AH (n=225). Clinical, analytical, immunohistochemistry and hepatic RNA microarray analysis of both disease phenotypes were performed. RESULTS: Age and mean alcohol intake were similar in both groups. AH patients had greater aspartate amino transferase/alanine amino transferase ratio and lower gamma-glutamyl transferase levels than in ndALD patients. Patients with AH demonstrated profound liver failure and increased mortality. One-year mortality was 10% in ndALD and 50% in AH. Histologically, steatosis grade, ballooning and pericellular fibrosis were similar in both groups, while advanced fibrosis, Mallory-Denk bodies, bilirubinostasis, severe neutrophil infiltration and ductular reaction were more frequent among AH patients. Transcriptome analysis revealed a profound gene dysregulation within both phenotypes when compare to controls. While ndALD was characterised by deregulated expression of genes involved in matrisome and immune response, the development of AH resulted in a marked deregulation of genes involved in hepatocyte reprogramming and bile acid metabolism. CONCLUSIONS: Despite comparable alcohol intake, AH patients presented with worse liver function compared with ndALD patients. Bilirubinostasis, severe fibrosis and ductular reaction were prominent features of AH. AH patients exhibited a more profound deregulation of gene expression compared with ndALD patients.

Emerging drugs for the treatment of hepatocellular carcinoma.

INTRODUCTION: Hepatocellular carcinoma (HCC) remains a leading cause of liver-related mortality. Cirrhosis of any etiology is the major risk factor although HCC can develop in its absence in patients with hepatitis B and increasingly in those with nonalcoholic fatty liver disease. When detected at an early stage, curative options include surgical resection, liver transplantation, and/or ablative therapies. Unfortunately, most cases of HCC are recognized at an advanced stage when options are limited and noncurative. However, new systemic therapies with tyrosine kinase inhibitors and immunotherapy have expanded therapeutic options in advanced HCC. Advances in systemic therapy have given patients with advanced HCC hope and prolonged their survival. AREAS COVERED: We discuss recent data and ongoing research efforts to improve the treatment of hepatocellular carcinoma with discussion of current and upcoming systemic therapies combining agents of different classes. EXPERT OPINION: Systemic therapy for HCC is in evolution. The inclusion of immunotherapy to systemic therapy has revolutionized the field of HCC treatment. Identification of the appropriate combination and sequence of systemic therapy coupled with discovery of reliable HCC biomarkers will lead to improved survival and individualized HCC therapy.

Outcomes following SARS-CoV-2 infection in patients with chronic liver disease: An international registry study.

BACKGROUND & AIMS: Chronic liver disease (CLD) and cirrhosis are associated with immune dysregulation, leading to concerns that affected patients may be at risk of adverse outcomes following SARS-CoV-2 infection. We aimed to determine the impact of COVID-19 on patients with pre-existing liver disease, which currently remains ill-defined. METHODS: Between 25th March and 8th July 2020, data on 745 patients with CLD and SARS-CoV-2 (including 386 with and 359 without cirrhosis) were collected by 2 international registries and compared to data on non-CLD patients with SARS-CoV-2 from a UK hospital network. RESULTS: Mortality was 32% in patients with cirrhosis compared to 8% in those without (p <0.001). Mortality in patients with cirrhosis increased according to Child-Pugh class (A [19%], B [35%], C [51%]) and the main cause of death was from respiratory failure (71%). After adjusting for baseline characteristics, factors associated with death in the total CLD cohort were age (odds ratio [OR] 1.02; 1.01-1.04), Child-Pugh A (OR 1.90; 1.03-3.52), B (OR 4.14; 2.4-7.65), or C (OR 9.32; 4.80-18.08) cirrhosis and alcohol-related liver disease (OR 1.79; 1.03-3.13). Compared to patients without CLD (n = 620), propensity-score-matched analysis revealed significant increases in mortality in those with Child-Pugh B (+20.0% [8.8%-31.3%]) and C (+38.1% [27.1%-49.2%]) cirrhosis. Acute hepatic decompensation occurred in 46% of patients with cirrhosis, of whom 21% had no respiratory symptoms. Half of those with hepatic decompensation had acute-on-chronic liver failure. CONCLUSIONS: In the largest such cohort to date, we demonstrate that baseline liver disease stage and alcohol-related liver disease are independent risk factors for death from COVID-19. These data have important implications for the risk stratification of patients with CLD across the globe during the COVID-19 pandemic. LAY SUMMARY: This international registry study demonstrates that patients with cirrhosis are at increased risk of death from COVID-19. Mortality from COVID-19 was particularly high among patients with more advanced cirrhosis and those with alcohol-related liver disease.

HCV testing: Order and completion rates among baby boomers obtaining care from seven health systems in Florida, 2015-2017.

Many U.S. residents infected with hepatitis C virus (HCV) are baby boomers (born 1945-1965), who remain undiagnosed. Past CDC and USPSTF guidelines recommended one-time HCV testing for all baby boomers, with newer guidelines recommending universal screening for all adults. This retrospective cohort study examined electronic medical records for patient visits from 2015 to 2017 within the OneFlorida Data Trust and University of South Florida Health system. We assessed percentages of HCV tests ordered and completed across four age groups (those born before 1945, 1945-1965, 1966-1985, and after 1985). In 2019, we used logistic regression to examine factors associated with HCV test ordering and completion among baby boomers, including age, race, sex, number of primary care visits, HIV status, hepatitis diagnosis, and liver cancer history. All age groups had low rates of HCV test orders. 4.4% of baby boomers had a test ordered in 2015, and 6.7% in 2016. Of those, 94.5% and 89.7% completed testing, respectively. All other races/ethnicities had lower likelihood of testing completion than Whites (Blacks (aOR 0.82, 95%, CI 0.75-0.91); Asians (0.69, 0.52-0.92); Hispanics (0.29, 0.26-0.32)), although test orders were higher for Asians (1.48, 1.37-1.61) and Blacks (1.78, 1.73-1.82). Tests ordered (11.42, 10.94-11.92) and completed (2.25, 1.94-2.60) were more likely among those with hepatitis history. Test orders were more likely for HIV-positive patients (3.68, 3.45-3.93), but completion was less likely (0.67, 0.57-0.78). Interventions are needed to increase testing rates so that HCV infections are treated early, mitigating HCV-related morbidity and mortality, especially related to liver cancer.

The association between etiology of hepatocellular carcinoma and race-ethnicity in Florida.

BACKGROUND AND AIM: The incidence of hepatocellular carcinoma (HCC) has risen considerably in the US since 1980. The main causes include metabolic disorders (NAFLD, diabetes, obesity, metabolic syndrome), alcohol-related disease (ALD) and hepatitis C and B virus infections (HCV, HBV). Etiology-specific HCC incidence rates by detailed race-ethnicity are needed to improve HCC control and prevention efforts. METHODS: All HCC cases diagnosed in Florida during 2014-2015 were linked to statewide hospital discharge data to determine etiology. Age-specific and age-adjusted rates were used to assess the intersection between etiology and detailed racial-ethnicities, including White, African American, Afro-Caribbean, Asian, Cuban, Puerto Rican and Continental Hispanic (Mexican, South and Central American). RESULTS: Of 3666 HCC cases, 2594 matched with discharge data. HCV was the leading cause of HCC among men and women (50% and 43% respectively), followed by metabolic disorders (25% and 37%) and ALD (16% and 9%). Puerto Rican and African American men had the highest HCV-HCC rates, 7.9 and 6.3 per 100 000 respectively. Age-specific rates for HCV-HCC peaked among baby boomers (those born in 1945-1965). Metabolic-HCC rates were highest among populations above age 70 and among Continental Hispanics. Afro-Caribbean men had high rates of HBV-HCC, whereas Puerto Rican men had high ALD-HCC. CONCLUSIONS: HCC etiology is associated with specific race/ethnicity. While HCV-related HCC rates are projected to decrease soon, HCC will continue to affect Hispanics disproportionately, based on higher rates of metabolic-HCC (and ALD-HCC) among Continental Hispanics, who demographically represent 80% of all US Hispanics. Multifaceted approaches for HCC control and prevention are needed.

Knowledge and Perceptions of Hepatitis B and Hepatocellular Carcinoma Screening Guidelines Among Trainees: A Tale of Three Centers.

BACKGROUND: Hepatitis B (HBV), the leading cause of hepatocellular carcinoma (HCC) worldwide, disproportionately affects minorities in the USA. Undiagnosed HBV precludes HCC screening and contributes to late-stage cancer presentation and decreased survival. Barriers to HBV and HCC screening include lack of insurance and limited diffusion of guidelines. We aimed to assess knowledge about HBV and HCC screening indications and explore barriers to screening. METHODS: We surveyed trainees from the University of Miami/Jackson Memorial Hospitals, Palmetto General Hospital, and Mount Sinai Medical Center. We assessed knowledge using clinical vignettes. We performed bivariate and Chi-squared analyses. RESULTS: There were 183 respondents; median age was 31 and 52% were male. The sample was 35% Hispanic, 29% White, 18% Asian, and 9% Black. Training department was Internal Medicine, 71%; Family Medicine, 11%; Infectious Diseases, 6%; or Gastroenterology, 7%. Only 59% correctly estimated national HBV prevalence; 25% correctly estimated global prevalence. In vignettes with behavioral risk factors, trainees correctly advised screening, 63-96%. However, when the risk factor was the birthplace, correct responses ranged from 33 to 53%. Overall, 45% chose an incorrect combination of HBV screening tests. Perceived barriers to screening included limited expertise in screening of immigrants and limited patient education. Respondents were more likely to recommend HCC screening in cirrhotic patients versus non-cirrhotic HBV patients. Key barriers to HCC screening included uncertainty about HCC guidelines and patient financial barriers. CONCLUSIONS: Knowledge of HBV and HCC screening recommendations is suboptimal among trainees. Efforts to broadly disseminate HBV and HCC guidelines through targeted educational interventions are needed.

Phase 2 study of pembrolizumab and circulating biomarkers to predict anticancer response in advanced, unresectable hepatocellular carcinoma.

BACKGROUND: Checkpoint inhibitors have shown modest activity in patients with advanced hepatocellular carcinoma (HCC). Herein, the authors report a prospective single-institution clinical/translational phase 2 study of pembrolizumab in patients with advanced HCC and circulating biomarkers closely related to response. METHODS: Pembrolizumab was administered at a dose of 200 mg intravenously every 3 weeks among patients who may have developed disease progression while receiving, were intolerant of, or refused sorafenib. The circulating levels of cytokines, chemokines, programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and PD-L2 were correlated with response, tumor PD-L1 expression, and other clinicopathological features. RESULTS: A total of 29 patients were treated and 28 patients were evaluable for response. The most common laboratory grade 3/4 adverse events were increases in aspartate aminotransferase and/or alanine aminotransferase and serum bilirubin, which for the most part were reversible. In terms of efficacy, one patient achieved a complete response and 8 patients achieved partial responses for an overall response rate of 32%. Four other patients had stable disease. The median progression-free survival was 4.5 months and the median overall survival was 13 months. Response did not correlate with prior sorafenib therapy, PD-L1 tumor staining, or a prior history of hepatitis. Correlative studies revealed that high baseline plasma TGF-ß levels (≥200 pg/mL) significantly correlated with poor treatment outcomes after pembrolizumab. Tumor PD-L1 and plasma PD-L1/PD-1 levels were associated with plasma IFN-γ or IL-10. CONCLUSIONS: Pembrolizumab was found to demonstrate activity in patients with advanced HCC. Toxicity generally was tolerable and reversible. A set of immunological markers in blood plasma as well as PD-L1 staining indicated that baseline TGF-ß could be a predictive biomarker for response to pembrolizumab.

Alcohol abstinence in patients surviving an episode of alcoholic hepatitis: Prediction and impact on long-term survival.

Alcoholic hepatitis (AH) is the most severe form of alcoholic liver disease. Most studies have focused on short-term prognosis, whereas factors associated with long-term survival are largely unknown. The aims of our study were to (1) determine the impact of complete abstinence from alcohol on long-term survival and (2) identify prognostic factors at admission capable of predicting abstinence during long-term follow-up in patients with AH. One hundred forty-two patients with biopsy-proven AH that survived the first episode were included. Demographic, psychiatric, and biochemical variables at admission and drinking status during follow-up were obtained. Cox regression, logistic regression, and classification and regression trees (CART) analyses were used for statistical analysis. Overall mortality was 38% with a median follow-up of 55 months. During follow-up, complete abstinence was reported in 39% and was associated with better long-term survival (hazard ratio, 0.53; P = 0.03). After adjustment for baseline prognostic scoring systems (Model for End-Stage Liver Disease and age, bilirubin, international normalized ratio, creatinine scores), complete abstinence was independently associated with survival (P < 0.05). Age and lack of past alcoholism treatments were independently associated with complete abstinence (P < 0.001 and P = 0.02, respectively) during follow-up. CART analysis generated a simple and practical algorithm based on the combination of past alcoholism treatments and age. Using CART analysis, we stratified 2 subgroups of patients with high (65%) and low (26%-29%) rates of complete abstinence after an episode of AH. CONCLUSION: Complete abstinence after an episode of AH positively impacts long-term survival. The combination of 2 variables easily obtained at admission might be useful to predict long-term abstinence after an episode of AH. Strategies aimed at promoting alcohol abstinence in these patients are necessary. (Hepatology 2017;66:1842-1853).

The Impact of Race on Survival After Hepatocellular Carcinoma in a Diverse American Population.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) incidence is increasing at differential rates depending on race. We aimed to identify associations between race and survival after HCC diagnosis in a diverse American population. METHODS: Using the cancer registry from Sylvester Comprehensive Cancer Center, University of Miami and Jackson Memorial Hospitals, we performed retrospective analysis of 999 patients diagnosed with HCC between 9/24/2004 and 12/19/2014. We identified clinical characteristics by reviewing available electronic medical records. The association between race and survival was analyzed using Cox proportional hazards regression. RESULTS: Median survival in days was 425 in Blacks, 904.5 in non-Hispanic Whites, 652 in Hispanics, 570 in Asians, and 928 in others, p < 0.01. Blacks and Asians presented at more advanced stages with larger tumors. Although Whites had increased severity of liver disease at diagnosis compared to other races, they had 36% reduced rate of death compared to Blacks, [hazard ratio (HR) 0.64, 95% confidence interval (CI) 0.51-0.8, p < 0.01]. After adjusting for significant covariates, Whites had 22% (HR 0.78, 95% CI 0.61-0.99, p 0.04) reduced risk of death, compared to Blacks. Transplant significantly reduced rate of death; however, only 13.3% of Blacks had liver transplant, compared to 40.1% of Whites, p < 0.01. CONCLUSIONS: In this diverse sample of patients, survival among Blacks is the shortest after HCC diagnosis. Survival differences reflect a more advanced tumor stage at presentation rather than severity of underlying liver disease precluding treatment. Improving survival in minority populations, in whom HCC incidence is rapidly increasing, requires identification and modification of factors contributing to late-stage presentation.

Lack of Knowledge and Low Readiness for Health Care Transition in Eosinophilic Esophagitis and Eosinophilic Gastroenteritis.

OBJECTIVES: A growing population of adolescents/young adults with eosinophilic esophagitis (EoE) and eosinophilic gastroenteritis (EGE) will need to transition from pediatric to adult health providers. Measuring health care transition (HCT) readiness is critical, but no studies have evaluated this process in EoE/EGE. We determined the scope and predictors of HCT knowledge in patients and parents with EoE/EGE and measured HCT readiness in adolescents/young adults. METHODS: We conducted an online survey of patients 13 years or older and parents of patients with EoE/EGE who were diagnosed when 25 years or younger. Parents answered questions regarding their children and their own knowledge of HCT. HCT readiness was assessed in adolescents/young adults aged 13 to 25 years with the Self-Management and Transition to Adulthood with Rx Questionnaire (a 6-domain self-report tool) with a score range of 0 to 90. RESULTS: Four hundred fifty participants completed the survey: 205 patients and 245 parents. Included in the analysis (those diagnosed with EoE/EGE at age 25 years or younger) were 75 of 205 patients and children of 245 parent respondents. Overall, 78% (n = 52) of the patients and 76% (n = 187) of parents had no HCT knowledge. Mean HCT readiness score in adolescents/young adults (n = 50) was 30.4 ±â€Š11.3 with higher scores in domains of provider communication and engagement during appointments. Mean parent-reported (n = 123) score was 35.6 ±â€Š9.7 with higher scores in medication management and disease knowledge. CONCLUSIONS: There was a significant deficit in HCT knowledge, and HCT readiness scores were lower than other chronic health conditions. HCT preparation and readiness assessments should become a priority for adolescents/young adults with EoE/EGE and their parents.

A histologic scoring system for prognosis of patients with alcoholic hepatitis.

BACKGROUND & AIMS: There is no histologic classification system to determine prognoses of patients with alcoholic hepatitis (AH). We identified histologic features associated with disease severity and created a histologic scoring system to predict short-term (90-day) mortality. METHODS: We analyzed data from 121 patients admitted to the Liver Unit (Hospital Clinic, Barcelona, Spain) from January 2000 to January 2008 with features of AH and developed a histologic scoring system to determine the risk of death using logistic regression. The system was tested and updated in a test set of 96 patients from 5 academic centers in the United States and Europe, and a semiquantitative scoring system called the Alcoholic Hepatitis Histologic Score (AHHS) was developed. The system was validated in an independent set of 109 patients. Interobserver agreement was evaluated by weighted κ statistical analysis. RESULTS: The degree of fibrosis, degree of neutrophil infiltration, type of bilirubinostasis, and presence of megamitochondria were independently associated with 90-day mortality. We used these 4 parameters to develop the AHHS to identify patients with a low (0-3 points), moderate (4-5 points), or high (6-9 points) risk of death within 90 days (3%, 19%, and 51%, respectively; P < .0001). The AHHS estimated 90-day mortality in the training and test sets with an area under the receiver operating characteristic value of 0.77 (95% confidence interval, 0.71-0.83). Interrater agreement values were 0.65 for fibrosis, 0.86 for bilirubinostasis, 0.60 for neutrophil infiltration, and 0.46 for megamitochondria. Interestingly, the type of bilirubinostasis predicted the development of bacterial infections. CONCLUSIONS: We identified histologic features associated with the severity of AH and developed a patient classification system that might be used in clinical decision making.