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Background and Aims: The American Gastroenterological Association (AGA) recently launched the Clinical Care Pathway for the Risk Stratification and Management of Patients with NAFLD to identify adults with significant fibrosis. We aimed to examine this pathway's performance in the US population., Approach and Results: Using the 2017-2018 National Health and Nutrition Examination Survey data, we identified participants aged ≥18 with available Fibrosis-4 (FIB-4) score and liver stiffness measurement (LSM) in the absence of other liver diseases. Based on the AGA clinical pathway, FIB-4 < 1.3 and LSM < 8 kilopascals (kPa) by vibration-controlled transient elastography (VCTE) are associated with low risk of significant fibrosis. Using these cutoffs, we examined the pathway performance using negative predictive value (NPV) and positive predictive value (PPV) and explored alternative risk-stratification strategies. There were 2322 participants with available data (projected to 94.2 million US adults). The NPV of LSM ≥ 8 kPa among those with FIB-4 < 1.3 was 90%, whereas the PPV among those with FIB-4 1.3-2.67 was 13%. As diabetes was a strong predictor of fibrosis, we propose a simple, alternative strategy to eliminate the indeterminate FIB-4 range and perform VCTE in those with FIB-4 ≥ 1.3 and diabetes. This strategy would decrease the number of VCTEs from 14.5 to 4.9 million and increase PPV from 13% to 33% without compromising the NPV among those who did not undergo VCTE., Conclusion: The implementation of the current AGA clinical pathway would lead to overutilization of VCTE. An alternative strategy using FIB-4 ≥ 1.3 and diabetes to select adults undergoing second-line testing will improve this pathway's performance and minimize unnecessary VCTEs., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background and Aims: We assessed the burden of nonalcoholic fatty liver disease (NAFLD)-related acute on chronic liver failure (ACLF) among transplant candidates in the United States, along with waitlist outcomes for this population., Approach and Results: We analyzed the United Network for Organ Sharing registry from 2005 to 2017. Patients with ACLF were identified using the European Association for the Study of the Liver/Chronic Liver Failure criteria and categorized into NAFLD, alcohol-associated liver disease (ALD), and hepatitis C virus (HCV) infection. We used linear regression and Chow's test to determine significance in trends and evaluated waitlist outcomes using Fine and Gray's competing risks regression and Cox proportional hazards regression. Between 2005 and 2017, waitlist registrants for NAFLD-ACLF rose by 331.6% from 134 to 574 candidates (P < 0.001), representing the largest percentage increase in the study population. ALD-ACLF also increased by 206.3% (348-1,066 registrants; P < 0.001), whereas HCV-ACLF declined by 45.2% (P < 0.001). As of 2017, the NAFLD-ACLF population consisted primarily of persons aged ≥60 years (54.1%), and linear regression demonstrated a significant rise in the proportion of patients aged ≥65 in this group (β = 0.90; P = 0.011). Since 2014, NAFLD-ACLF grade 1 was associated with a greater risk of waitlist mortality relative to ALD-ACLF (subhazard ratio [SHR] = 1.24; 95% confidence interval [CI], 1.05-1.44) and HCV-ACLF (SHR = 1.35; 95% CI, 1.08-1.71), among patients aged ≥60 years. Mortality was similar among the three groups for patients with ACLF grade 2 or 3., Conclusions: NAFLD is the fastest rising etiology of cirrhosis associated with ACLF among patients listed in the United States. As the NAFLD population continues to grow and age, patients with NAFLD-ACLF will likely have the highest risk of waitlist mortality., (© 2020 by the American Association for the Study of Liver Diseases.)

Nonalcoholic fatty liver disease (NAFLD) is a global public health concern. Its natural history, the development of nonalcoholic steatohepatitis (NASH) and fibrosis, is highly variable, prone to endogenous (e.g., genetics, microbiota) and exogenous (e.g., nutrition, alcohol, physical activity) disease modifiers, and can fluctuate over time. The complexity of its pathophysiology is reflected by the multitude of pharmacological targets in development. NASH clinical trials have provided valuable insight that is applicable to future trial design. Endpoints for NASH have evolved over the past decade and will continue to be refined. Currently accepted endpoints for conditional approval include resolution of NASH without worsening of fibrosis and/or improvement in fibrosis without worsening of NASH by standardized evaluation of paired liver histology. In pediatric NASH, practical obstacles, pubertal hormonal changes, and stringent safety requirements mandate adaptations in trial design. In adult patients with NASH-related cirrhosis, clinical events (e.g. decompensation, hepatocellular carcinoma, transplantation, death) are more prevalent and thereby are viable primary endpoints. Consideration of the natural fluctuation of disease, the clinical implication of the chosen primary endpoint, and factors that may affect placebo response will facilitate an accurate determination of efficacy of emerging therapeutics for NASH. Conclusion: The June 2018 American Association for the Study of Liver Diseases and European Association for the Study of the Liver joint workshop on NAFLD endpoints summarized important findings from ongoing and completed trials, defined the scientific evidence supporting distinct endpoints, and provided guidance for future trial design., (© 2019 by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver.)

Background and Aims: Epidemiological data on dietary risk factors for nonalcoholic fatty liver disease (NAFLD) from population-based studies, particularly in an ethnically diverse population, are scarce. We examined dietary factors in relation to NAFLD risk in African Americans, Japanese Americans, Latinos, native Hawaiians, and whites in the Multiethnic Cohort (MEC)., Approach and Results: A nested case-control analysis was conducted within the MEC, a large prospective study with >215,000 older adult participants in Hawaii and California. NAFLD was identified using Medicare claims data, and controls were selected among participants without liver disease and individually matched to cases by birth year, sex, ethnicity, and length of Medicare enrollment. Diet was assessed at baseline through a validated quantitative food frequency questionnaire. Diet-NAFLD associations were quantified by odds ratios and 95% confidence intervals using multivariable conditional logistic regression. The study consisted of 2,974 NAFLD cases (518 with cirrhosis, 2,456 without cirrhosis) and 29,474 matched controls. Red meat (P trend = 0.010), processed red meat (P trend = 0.004), poultry (P trend = 0.005), and cholesterol (P trend = 0.005) intakes were positively associated with NAFLD, while dietary fiber intake (P trend = 0.003) was inversely associated with risk. Stronger associations were observed between red meat and cholesterol and NAFLD with cirrhosis than without cirrhosis (P heterogeneity ≤0.014)., Conclusions: Dietary factors are independently associated with NAFLD and NAFLD-related cirrhosis in a multiethnic population. Decreasing the consumption of cholesterol, red and processed meat, and poultry and increasing consumption of fiber may reduce the risk for NAFLD and related advanced liver disease., (© 2019 by the American Association for the Study of Liver Diseases.)

Nonalcoholic steatohepatitis (NASH) cirrhosis is the fastest growing indication for liver transplantation (LT) in the United States. We aimed to determine the temporal trend behind the rise in obesity and NASH-related additions to the LT waitlist in the United States and make projections for future NASH burden on the LT waitlist. We used data from the Organ Procurement and Transplantation Network database from 2000 to 2014 to obtain the number of NASH-related LT waitlist additions. The obese population in the United States from 2000 to 2014 was estimated using data from the U.S. Census Bureau and the National Health and Nutrition Examination Survey. Based on obesity trends, we established a time lag between obesity prevalence and NASH-related waitlist additions. We used data from the U.S. Census Bureau on population projections from 2016 to 2030 to forecast obesity estimates and NASH-related LT waitlist additions. From 2000 to 2014, the proportion of obese individuals significantly increased 44.9% and the number of NASH-related annual waitlist additions increased from 391 to 1,605. Increase in obesity prevalence was strongly associated with LT waitlist additions 9 years later in derivation and validation cohorts (R 2 = 0.9). Based on these data, annual NASH-related waitlist additions are anticipated to increase by 55.4% (1,354-2,104) between 2016 and 2030. There is significant regional variation in obesity rates and in the anticipated increase in NASH-related waitlist additions (P < 0.01). Conclusion: We project a marked increase in demand for LT for NASH given population obesity trends. Continued public health efforts to curb obesity prevalence are needed to reduce the projected future burden of NASH. (Hepatology 2017)., (Copyright © 2017 by the American Association for the Study of Liver Diseases.)

Unlabelled: Nonalcoholic fatty liver disease (NAFLD) contributes to premature death along with obesity, diabetes, and cardiovascular disease (CVD). We examined whether hepatic steatosis (HS) on ultrasound and liver enzyme activities were associated with increased liver disease mortality in the U.S. National Health and Nutrition Examination Survey (NHANES), 1988-1994, with up to 23 years of linked-mortality data. Survey-linked National Death Index records were analyzed among 14,527 adult participants who were negative for viral hepatitis B and C and iron overload. HS on ultrasound was categorized as normal, mild, moderate, or severe. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase (GGT) elevation was defined as the highest sex-specific decile. Cumulative mortality was 36.2% from all causes, including 16.3% from CVD, 10.8% from cancer, 5.4% from diabetes, and 1.1% from liver disease. Severe HS was associated with increased liver disease mortality in both age-adjusted (hazard ratio [HR]: 3.92; 95% confidence interval [CI]: 1.49-10.27; P for trend: 0.011) and multivariate-adjusted analyses (HR, 2.68; 95% CI: 1.02-7.03; P for trend: 0.072). HS was not independently associated with mortality from all causes, CVD, cancer, or diabetes. Higher liver disease mortality was found with elevated ALT (HR, 4.08; 95% CI: 1.99-8.33), AST (HR, 4.33; 95% CI: 2.18-8.59), and GGT (HR, 7.91; 95% CI: 3.06-20.46). GGT elevation was associated with increased overall mortality (HR, 1.45; 95% CI: 1.21-1.74). Liver enzymes were otherwise unrelated to overall or cause-specific mortality., Conclusions: In the U.S. population, severe hepatic steatosis on ultrasound and liver enzyme elevation were associated with increased liver disease mortality, but were not independently associated with mortality from all causes (except for GGT), CVD, cancer, or diabetes., (© 2015 by the American Association for the Study of Liver Diseases.)

Chronic liver disease (CLD) and cirrhosis are major sources of morbidity and mortality in the United States. Little is known about the epidemiology of these two diseases in ethnic minority populations in the United States. We examined the prevalence of CLD and cirrhosis by underlying etiologies among African Americans, Native Hawaiians, Japanese Americans, Latinos, and whites in the Multiethnic Cohort. CLD and cirrhosis cases were identified using Medicare claims between 1999 and 2012 among the fee-for-service participants (n = 106,458). We used International Classification of Diseases Ninth Revision codes, body mass index, history of diabetes mellitus, and alcohol consumption from questionnaires to identify underlying etiologies. A total of 5,783 CLD (3,575 CLD without cirrhosis and 2,208 cirrhosis) cases were identified. The prevalence of CLD ranged from 3.9% in African Americans and Native Hawaiians to 4.1% in whites, 6.7% in Latinos, and 6.9% in Japanese. Nonalcoholic fatty liver disease (NAFLD) was the most common cause of CLD in all ethnic groups combined (52%), followed by alcoholic liver disease (21%). NAFLD was the most common cause of cirrhosis in the entire cohort. By ethnicity, NAFLD was the most common cause of cirrhosis in Japanese Americans, Native Hawaiians, and Latinos, accounting for 32% of cases. Alcoholic liver disease was the most common cause of cirrhosis in whites (38.2%), while hepatitis C virus was the most common cause in African Americans (29.8%)., Conclusions: We showed racial/ethnic variations in the prevalence of CLD and cirrhosis by underlying etiology; NAFLD was the most common cause of CLD and cirrhosis in the entire cohort, and the high prevalence of NAFLD among Japanese Americans and Native Hawaiians is a novel finding, warranting further studies to elucidate the causes. (Hepatology 2016;64:1969-1977)., Competing Interests: the authors disclose no conflicts, (© 2016 by the American Association for the Study of Liver Diseases.)

Background and Aims: The surge in unhealthy alcohol use during the COVID-19 pandemic may have detrimental effects on the rising burden of alcohol-associated liver disease (ALD) on liver transplantation (LT) in the USA. We evaluated the effect of the pandemic on temporal trends for LT including ALD., Approach and Results: Using data from United Network for Organ Sharing, we analyzed wait-list outcomes in the USA through March 1, 2021. In a short-period analysis, patients listed or transplanted between June 1, 2019, and February 29, 2020, were defined as the "pre-COVID" era, and after April 1, 2020, were defined as the "COVID" era. Interrupted time-series analyses using monthly count data from 2016-2020 were constructed to evaluate the rate change for listing and LT before and during the COVID-19 pandemic. Rates for listings (P = 0.19) and LT (P = 0.14) were unchanged during the pandemic despite a significant reduction in the monthly listing rates for HCV (-21.69%, P < 0.001) and NASH (-13.18%; P < 0.001). There was a significant increase in ALD listing (+7.26%; P < 0.001) and LT (10.67%; P < 0.001) during the pandemic. In the COVID era, ALD (40.1%) accounted for more listings than those due to HCV (12.4%) and NASH (23.4%) combined. The greatest increase in ALD occurred in young adults (+33%) and patients with severe alcohol-associated hepatitis (+50%). Patients with ALD presented with a higher acuity of illness, with 30.8% of listings and 44.8% of LT having a Model for End-Stage Liver Disease-Sodium score ≥30., Conclusions: Since the start of COVID-19 pandemic, ALD has become the most common indication for listing and the fastest increasing cause for LT. Collective efforts are urgently needed to stem the rising tide of ALD on health care resources., (© 2021 by the American Association for the Study of Liver Diseases.)

Background and Aims: Nonalcoholic fatty liver disease (NAFLD) encompasses a range of conditions, from simple steatosis to nonalcoholic steatohepatitis. Studies in the United States have reported an increased mortality risk among individuals with NAFLD; therefore, the population attributable fractions (PAFs) for mortality were examined., Approach and Results: A total of 12,253 adult individuals with ultrasound assessment of NAFLD from the Third National Health and Nutrition Examination Survey and mortality follow-up through 2015 were included in the analysis. Cox proportional hazard regression was used to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for NAFLD in association with all-cause and cause-specific mortality. Overall, sex- and race/ethnicity-specific PAFs and 95% CIs were estimated. In the current study, presence of NAFLD was associated with a 20% increased risk of all-cause mortality (HR, 1.20; 95% CI, 1.08, 1.34). The overall PAF for all-cause mortality associated with NAFLD was 7.5% (95% CI, 3.0, 12.0). The PAF for diabetes-specific mortality was 38.0% (95% CI, 13.1, 63.0) overall, 40.8% (95% CI, 2.1, 79.6) in men, and 36.8% (95% CI, 6.6, 67.0) in women. The PAF for liver disease (LD)-specific mortality was notably higher in men (68.3%; 95% CI, 36.3, 100.0) than women (3.5%; 95% CI, -39.7, 46.8). In the race-specific analysis, the PAFs of NAFLD for all-cause mortality (9.3%; 95% CI, 4.0, 14.6) and diabetes-specific mortality (44.4%; 95% CI, 10.8, 78.0) were significantly greater than zero only for whites., Conclusions: In the United States, approximately 8% of all-cause mortality and more than one-third of LD- and diabetes-specific deaths are associated with NAFLD. With these high percentages, efforts are needed to reduce the burden of NAFLD in the United States., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA.)

Nonalcoholic fatty liver disease (NAFLD) comprises more than two thirds of patients with chronic liver disease in the United States. The effect of alcohol consumption on survival in patients with NAFLD is not clear. We gathered data on National Health and Nutrition Examination Survey participants from 1988 to 2010, and linked them to the National Death Index for follow-up of their survival. We diagnosed NAFLD based on a previously validated biochemical model (Hepatic Steatosis Index). We built multivariate Cox proportional hazards models to evaluate the effect of alcohol consumption on survival of patients with NAFLD. After excluding participants with significant alcohol use, viral hepatitis, or increased transferrin saturation, 4,568 participants with NAFLD were included in the analysis. In a Cox model adjusted for age, sex, and smoking history, drinking 0.5-1.5 drinks per day decreased the risk of overall mortality by 41% (hazard ratio [HR] = 0.59, 95% confidence interval [CI] 0.40-0.85, P = 0.005) compared with not drinking. Drinking ≥1.5 drinks per day showed a trend toward harm (HR = 1.16, 95% CI 0.99-1.36, P = 0.119). After further adjustment for race, physical activity, education level, diabetes, and fiber and polyunsaturated fatty acid intake, drinking 0.5-1.5 drinks per day continued to show a significant protective effect (HR = 0.64, 95% CI 0.42-0.97, P = 0.035), and drinking ≥1.5 drinks per day showed a significant harmful effect on mortality (HR = 1.45, 95% CI 1.01-2.10, P = 0.047). Among patients with NAFLD, modest alcohol consumption is associated with a significant decrease in all-cause mortality, whereas drinking ≥1.5 drinks per day is associated with an increase in mortality. These results help to inform the discussion of potential risks and benefits of alcohol use in patients with NAFLD., (© 2018 by the American Association for the Study of Liver Diseases.)

Nonalcoholic fatty liver disease (NAFLD) is a significant health burden in adolescents and young adults (AYAs) which has substantially risen in prevalence over the last decades. The occurrence of NAFLD parallels high rates of obesity and metabolic syndrome in this age group, with unhealthy lifestyle also playing an independent role. Genetic factors, sex, and ethnicity should be considered in a risk stratification model. NAFLD and nonalcoholic steatohepatitis (NASH) in AYAs often go unrecognized and, if untreated, can progress eventually to cirrhosis requiring liver transplantation (LT) before the age of 40. Recently, NASH has increased as an indication for LT in this age group. Important knowledge gaps include the feasibility of noninvasive diagnostic tests and imaging modalities as well as uncertainty about unique histological features and their predictive value. Future clinical trials focused on AYAs are needed to determine effectiveness of therapies. Tools for increasing awareness and prevention of NAFLD in AYAs are greatly needed. (Hepatology 2017;65:2100-2109)., (© 2017 by the American Association for the Study of Liver Diseases.)

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing. The health care burden resulting from the multidisciplinary management of this complex disease is unknown. We assessed the total health care cost and resource utilization associated with a new NAFLD diagnosis, compared with controls with similar comorbidities. We used OptumLabs Data Warehouse, a large national administrative claims database with longitudinal health data of over 100 million individuals enrolled in private and Medicare Advantage health plans. We identified 152,064 adults with a first claim for NAFLD between 2010 and 2014, of which 108,420 were matched 1:1 by age, sex, metabolic comorbidities, length of follow-up, year of diagnosis, race, geographic region, and insurance type to non-NAFLD contemporary controls from the OptumLabs Data Warehouse database. Median follow-up time was 2.6 (range 1-6.5) years. The final study cohort consisted of 216,840 people with median age 55 (range 18-86) years, 53% female, 78% white. The total annual cost of care per NAFLD patient with private insurance was $7,804 (interquartile range [IQR] $3,068-$18,688) for a new diagnosis and $3,789 (IQR $1,176-$10,539) for long-term management. These costs are significantly higher than the total annual costs of $2,298 (IQR $681-$6,580) per matched control with similar metabolic comorbidities but without NAFLD. The largest increases in health care utilization that may account for the increased costs in NAFLD compared with controls are represented by liver biopsies (relative risk [RR] = 55.00, 95% confidence interval [CI] 24.48-123.59), imaging (RR = 3.95, 95% CI 3.77-4.15), and hospitalizations (RR = 1.87, 95% CI 1.73-2.02). Conclusion: The costs associated with the care for NAFLD independent of its metabolic comorbidities are very high, especially at first diagnosis. Research efforts shouldfocus on identification of underlying determinants of use, sources of excess cost, and development of cost-effective diagnostic tests., (© 2018 by the American Association for the Study of Liver Diseases.)

Unlabelled: Hepatocellular carcinoma (HCC) is increasingly reported in patients with nonalcoholic fatty liver disease (NAFLD). Our aim was to assess the prevalence and mortality of patients with NAFLD-HCC. We examined Surveillance, Epidemiology and End Results (SEER) registries (2004-2009) with Medicare-linkage files for HCC, which was identified by the International Classification of Diseases for Oncology, third edition codes using topography and morphology codes 8170-8175. Medicare-linked data was used to identify NAFLD, hepatitis C virus (HCV), hepatitis B virus (HBV), alcoholic liver disease (ALD), and other liver disease using International Classification of Diseases, Ninth Revision, Clinical Modification codes. NAFLD was also defined by clinical diagnosis (cryptogenic cirrhosis, obese-diabetics with cryptogenic liver disease). A logistic regression model was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for risk of HCC. In addition, adjusted hazard ratios for 1-year mortality were estimated by Cox's proportional hazard regression. A total of 4,929 HCC cases and 14,937 controls without HCC were included. Of the HCC cases, 54.9% were related to HCV, 16.4% to ALD, 14.1% to NAFLD, and 9.5% to HBV. Across the 6-year period (2004 to 2009), the number of NAFLD-HCC showed a 9% annual increase. NAFLD-HCC were older, had shorter survival time, more heart disease, and were more likely to die from their primary liver cancer (all P < 0.0001). Of those who received a transplant after HCC (n = 488), only 5% were related to NAFLD-HCC. In multivariate analysis, NAFLD increased the risk of 1-year mortality (OR, 1.21; 95% CI: 1.01-1.45). Additionally, older age, lower income, unstaged HCC increased risk of 1-year mortality while receiving a liver transplant (LT), and having localized tumor stage were protective (all P < 0.05)., Conclusions: NAFLD is becoming a major cause of HCC in the United States. NAFLD HCC is associated with shorter survival time, more advanced tumor stage, and lower possibility of receiving a LT., (© 2015 by the American Association for the Study of Liver Diseases.)

Unlabelled: Nonalcoholic steatohepatitis (NASH) is currently the third leading indication for liver transplantation (LT) in the U.S. and is predicted to become the leading indication for LT in the near future. The trends in NASH-related hepatocellular carcinoma (HCC) among LT recipients in the U.S. remain undefined. We performed a retrospective cohort study to evaluate trends in the etiology of HCC among adult LT recipients in the U.S. from 2002 to 2012, using national data from the United Network for Organ Sharing registry. From 2002-2012, there were 61,868 adults who underwent LT in the U.S., including 10,061 patients with HCC. The total number and proportion of HCC LT recipients demonstrated a significant increase following the implementation of the Model for Endstage Liver Disease (MELD) scoring system in 2002 (3.3%, n=143 in 2000 versus 12.2%, n=714 in 2005 versus 23.3%, n=1336 in 2012). The proportion of hepatitis C virus (HCV)-related HCC increased steadily from 2002 to 2012, and HCV remained the leading etiology of HCC throughout the MELD era (43.4% in 2002 versus 46.3% in 2007 versus 49.9% in 2012). NASH-related HCC also increased significantly, and NASH is the second leading etiology of HCC-related LT (8.3% in 2002 versus 10.3% in 2007 versus 13.5% in 2012). From 2002 to 2012, the number of patients undergoing LT for HCC secondary to NASH increased by nearly 4-fold, and the number of LT patients with HCC secondary to HCV increased by 2-fold., Conclusion: NASH is the second leading etiology of HCC leading to LT in the U.S. More important, NASH is currently the most rapidly growing indication for LT in patients with HCC in the U.S., (© 2014 by the American Association for the Study of Liver Diseases.)

Unlabelled: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder in the United States; however, few data are available about racial and ethnic variation. We investigated relationships between ethnicity, NAFLD severity, metabolic derangements, and sociodemographic characteristics in a well-characterized cohort of adults with biopsy-proven NAFLD. Data were analyzed from 1,026 adults (≥18 years) in the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) from 2004 to 2008, for whom liver histology data were available within 6 months of enrollment. Associations between ethnicity (i.e., Latino versus non-Latino white) and NAFLD severity (i.e., NASH versus non-NASH histology and mild versus advanced fibrosis) were explored with multiple logistic regression analysis. We also investigated effect modification of ethnicity on metabolic derangements for NAFLD severity. Within the NASH CRN, 77% (N = 785) were non-Latino white and 12% (N = 118) were Latino. Sixty-one percent (N = 628) had NASH histology and 28% (N = 291) had advanced fibrosis. Latinos with NASH were younger, performed less physical activity, and had higher carbohydrate intake, compared to non-Latino whites with NASH. Gender, diabetes, hypertension, hypertriglyceridemia, aspartate aminotransferase (AST), platelets, and the homeostasis model assessment of insulin resistance (HOMA-IR) were significantly associated with NASH. Age, gender, AST, alanine aminotransferase, alkaline phosphatase, platelets, total cholesterol, hypertension, and HOMA-IR, but not ethnicity, were significantly associated with advanced fibrosis. The effect of HOMA-IR on the risk of NASH was modified by ethnicity: HOMA-IR was not a significant risk factor for NASH among Latinos (odds ratio [OR] = 0.93; 95% confidence interval [CI]: 0.85-1.02), but was significant among non-Latino whites (OR, 1.06; 95% CI: 1.01-1.11)., Conclusion: Metabolic risk factors and sociodemographic characteristics associated with NASH differ by ethnicity. Additional insights into NASH pathogenesis may come from further studies focused on understanding ethnic differences in this disease., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Unlabelled: Information on the long-term prognosis of nonalcoholic fatty liver disease (NAFLD) is limited. We sought to describe the long-term morbidity and mortality of patients with NAFLD with advanced fibrosis or cirrhosis by prospectively studying 247 such patients from four international centers (in Australia, USA, UK and Italy). Their natural history was then compared with 264 patients with HCV infection who were either naïve or non-responders to treatment. Both cohorts were Child-Pugh class A and had advanced fibrosis (stage 3) or cirrhosis (stage 4) confirmed by liver biopsy at enrollment. In the NAFLD cohort, followed up for a mean of 85.6 months (range, 6-297), there were 48 (19.4%) liver-related complications and 33 (13.4%) deaths or liver transplants. In the HCV cohort, followed up for 74.9 months (mean; range, 6-238), there were 47 (16.7%) liver-related complications and 25 (9.4%) deaths or liver transplants. When adjusting for baseline differences in age and gender, the cumulative incidence of liver-related complications was lower in the NAFLD than the HCV cohort (P = 0.03), including incident hepatocellular cancer (6 versus 18; P = 0.03), but that of cardiovascular events (P = 0.17) and overall mortality (P = 0.6) were similar in both groups. In the NAFLD cohort, platelet count, stage 4 fibrosis, lowered platelet count, and lowered serum cholesterol and alanine aminotransferase (ALT) levels were associated with liver-related complications; an aspartate aminotransferase/ALT ratio >1 and older age were associated with overall mortality, and higher serum bilirubin levels and stage 4 fibrosis were associated with liver-related mortality., Conclusions: Patients with NAFLD with advanced fibrosis or cirrhosis have lower rates of liver-related complications and hepatocellular cancer than corresponding patients with HCV infection, but similar overall mortality. Some clinical and laboratory features predict liver-related complications and other outcomes in patients with NAFLD., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Unlabelled: Nonalcoholic fatty liver disease is a common cause of chronic liver disease in the general population. Nonalcoholic steatohepatitis (NASH), the aggressive form of nonalcoholic fatty liver disease, is associated with an increased risk of liver-related mortality and cardiovascular disease. At present, a liver biopsy is the only generally acceptable method for the diagnosis of NASH and assessment of its progression toward cirrhosis. Although several treatments have shown evidence of efficacy in clinical trials of varying design, there are no approved treatments for NASH, and published trials are often too divergent to allow meaningful comparisons. There is thus a lack of established noninvasive, point-of-care diagnostics and approved treatment on one hand and a substantial population burden of disease on the other. These provide the rationale for developing consensus on key endpoints and clinical trial design for NASH., Conclusion: This article summarizes the consensus arrived at a meeting of the American Association for the Study of Liver Diseases on the key endpoints and specific trial design issues that are germane for development of diagnostic biomarkers and treatment trials for NASH., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Unlabelled: Previous studies examining the relationship between hepatic iron deposition and histological severity in nonalcoholic fatty liver disease (NAFLD) have been inconclusive. The goal of this study was to examine the relationship between hepatic iron deposition and liver histology in 849 patients enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network. Hepatic iron staining was performed in a central laboratory, and the stains were scored for grade and cellular and parenchymal localization by a central pathology committee; the relationship between the grade and pattern of iron deposition and the clinical, laboratory, and histological variables was examined with univariate and multivariate analyses. Stainable hepatic iron was present in 293 of 849 patients (34.5%) in one of three histological patterns: a hepatocellular (HC) pattern [63/849 (7.4%)], a reticuloendothelial system (RES) cell pattern [91/849 (10.7%)], or a mixed RES/HC pattern [139/849 (16.4%)]. Patients with the RES iron-staining pattern were more likely to have advanced fibrosis compared to those with those with HC iron (P = 0.01). Patients with RES iron were also more likely to have advanced histological features such as fibrosis (P = 0.049), portal inflammation (P = 0.002), HC ballooning (P = 0.006), and definite nonalcoholic steatohepatitis (P = 0.007) compared to those with patients with HC or mixed iron patterns. The presence of RES iron (odds ratio = 1.60, 95% confidence interval = 1.10-2.33, P = 0.015) was independently associated with advanced hepatic fibrosis on multiple regression analysis after adjustments for age, gender, diabetes status, and body mass index., Conclusion: The presence and pattern of hepatic iron deposition are associated with distinct histological features in patients with NAFLD and may have implications for pathophysiology and therapy., (Copyright © 2010 American Association for the Study of Liver Diseases.)

Background and Aims: A new term, metabolic dysfunction-associated steatotic liver disease (MASLD), has been proposed by a multi-society expert panel. However, it remains unclear whether hepatic steatosis per se in MASLD contributes to an increased risk of mortality in individuals with any cardio-metabolic risk factor (CMRF), which is also a significant risk factor for increased mortality. This study aimed to compare all-cause and cause-specific mortality between the "MASLD/MetALD" and "no steatotic liver disease (SLD)" groups in individuals with any CMRF., Approach and Results: A population-based cohort study was conducted using 10,750 participants of the Third National Health and Nutrition Examination Survey. All-cause and cause-specific (cardiovascular, cancer, diabetes, and liver) mortality risks were compared between the "MASLD," "MetALD," and "no SLD" groups using the Cox proportional hazards model with complex survey design weights, adjusted for confounders. Over 26 years, the "MASLD" group did not show significantly increased all-cause (adjusted HR 1.04[95% CI: 0.95-1.14], p = 0.413), cardiovascular (0.88 [0.75-1.04], p = 0.139), or cancer (1.06[0.84-1.33], p = 0.635) mortality risk compared to the "no SLD" group in individuals with any CMRF. The MetALD group was associated with increased all-cause (1.41 [1.05-1.89], p = 0.022), cancer (2.35 [1.33-4.16], p = 0.004), and liver (15.04 [2.96-76.35], p = 0.002) mortality risk compared with the no SLD group. This trend was more pronounced in the MetALD group with advanced fibrosis assessed by Fibrosis-4 (FIB-4)., Conclusions: In individuals with CMRF, the presence of steatotic liver disease (MASLD) alone did not increase the risk of mortality, except in cases with more alcohol consumption (MetALD). Therefore controlling metabolic risk factors and reducing alcohol consumption in people with MASLD or MetALD will be crucial steps to improve long-term health outcomes., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Chronic liver disease (CLD) is a progressive illness with high symptom burden and functional and cognitive impairment, often with comorbid mental and substance use disorders. These factors lead to significant deterioration in quality of life, with immense burden on patients, caregivers, and healthcare. The current healthcare system in the United States does not adequately meet the needs of patients with CLD or control costs given the episodic, reactive, and fee-for-service structure. There is also a need for clinical and financial accountability for CLD care. In this context, we describe the key elements required to shift the CLD care paradigm to a patient-centered and value-based system built upon the Porter model of value-based health care. The key elements include (1) organization into integrated practice units, (2) measuring and incorporating meaningful patient-reported outcomes, (3) enabling technology to allow innovation, (4) bundled care payments, (5) integrating palliative care within routine care, and (6) formalizing centers of excellence. These elements have been shown to improve outcomes, reduce costs, and improve overall patient experience for other chronic illnesses and should have similar benefits for CLD. Payers need to partner with providers and systems to build upon these elements and help align reimbursements with patients' values and outcomes. The national organizations such as the American Association for Study of Liver Diseases need to guide key stakeholders in standardizing these elements to optimize patient-centered care for CLD., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background and Aims: Existing tools for perioperative risk stratification in patients with cirrhosis do not incorporate measures of comorbidity. The Hospital Frailty Risk Score (HFRS) is a widely used measure of comorbidity burden in administrative dataset analyses. However, it is not specific to patients with cirrhosis, and application of this index is limited by its complexity., Approach and Results: Adult patients with cirrhosis who underwent nontransplant abdominal operations were identified from the National Inpatient Sample, 2016-2018. Adjusted associations between HFRS and in-hospital mortality and length of stay were computed with logistic and Poisson regression. Lasso regularization was used to identify the components of the HFRS most predictive of mortality and develop a simplified index, the cirrhosis-HFRS. Of 10,714 patients with cirrhosis, the majority were male, the median age was 62 years, and 32% of operations were performed electively. HFRS was associated with an increased risk of both in-hospital mortality (OR=6.42; 95% CI: 4.93, 8.36) and length of stay (incidence rate ratio [IRR]=1.79; 95% CI: 1.72, 1.88), with adjustment. Using lasso, we found that a subset of 12 of the 109 ICD-10 codes within the HFRS resulted in superior prediction of mortality in this patient population (AUC = 0.89 vs. 0.79, p < 0.001)., Conclusions: While the 109-component HFRS was associated with adverse surgical outcomes, 12 components accounted for much of the association between the HFRS and mortality. We developed the cirrhosis-HFRS, a tool that demonstrates superior predictive accuracy for in-hospital mortality and more precisely reflects the specific comorbidity pattern of hospitalized patients with cirrhosis undergoing general surgery procedures., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background and Aims: The incidence of HCC has recently been consistently reported to decline in the United States. However, decreased overall mortality of HCC has just been suggested and needs further examination., Approach and Results: Using data from the Surveillance, Epidemiology, and End Results databases, we assessed HCC incidence, incidence-based mortality (IBM), and 1-year survival rates from 1992 through 2017 in the United States. These secular trends were analyzed using the National Cancer Institute's Joinpoint Regression Program. Age-period-cohort analyses were performed to address underlying reasons for the observed temporal trends. The incidence and mortality of liver cancer in the United States by different etiologies were acquired from the Global Burden of Disease study (1990-2019) as a likely validation set. Joinpoint and age-period-cohort analyses were performed by etiologies. The incidence rates of HCC increased during 1992-2011 and sharply decreased thereafter by -2.3% annually (95% CI: -3.5% to -1.1%). IBM peaked in 2013 (age-standardized mortality rate: 6.98 per 100,000 person-years) in the US population. IBM started to decrease significantly in 2013 by -3.2%/year (95% CI: -5.4% to -1.1% per year) after a continuous increase of 3.5% annually during 1993-2013. Overall, the 1-year survival of HCC improved from 21.4% to 56.6% over the study period. However, the highest HCC incidence and mortality risk for patients aged 60-69 and born between 1952-1957 were found., Conclusions: We found significantly decreased overall HCC-specific mortality since 2013 in the US population, along with decreased incidence and continuously improved survival. The changing etiologies, advances in screening and diagnosis, and improved treatment modality and allocation might all contribute to the downward trends of the disease burden of HCC in the United States., (© 2022 American Association for the Study of Liver Diseases.)

Background and Aims: The risk for hepatocellular carcinoma (HCC) is increased in acute hepatic porphyrias (AHP). The aim of this study was to explore the clinicopathologic characteristics, outcomes, and frequency of HCC in patients with AHP in the United States., Approach and Results: This cross-sectional analysis evaluated patients with HCC in a multicenter, longitudinal study of AHP. Among 327 patients with AHP, 5 (1.5%) were diagnosed with HCC. Of the 5 HCC cases, 4 had acute intermittent porphyria and 1 had variegate porphyria, confirmed by biochemical and/or genetic testing. All patients were white females, with a median age of 27 years (range 21-75) at diagnosis. The median age at HCC diagnosis was 69 years (range 61-74). AHP was asymptomatic in 2 patients; 2 reported sporadic attacks; and 1 reported recurrent attacks (>4 attacks/year). All patients had a single HCC lesion on liver imaging that was 1.8-6.5 centimeters in diameter. Serum alpha fetoprotein levels were below 10 ng/mL in all 4 patients with available results. Four patients underwent liver resection, and 1 was treated with radioembolization. No significant inflammation or fibrosis was found in adjacent liver tissues of 3 patients who underwent liver resection. Two patients developed recurrence of HCC at 22 and 26 months following liver resection. All patients are alive with survival times from HCC diagnosis ranging from 26-153 months., Conclusion: In this U.S. study, 1.5% of patients with AHP had HCC. HCC in AHP occurred in the absence of cirrhosis, which contrasts with other chronic liver diseases. Patients with AHP, regardless of clinical attacks, should be screened for HCC, beginning at age 50. The pathogenesis of hepatocarcinogenesis in AHP is unknown and needs further investigation., (© 2020 by the American Association for the Study of Liver Diseases.)

Background and Aims: Little is known about the role of low-carbohydrate diets (LCDs) in the development of hepatocellular carcinoma (HCC). We prospectively evaluated the associations between plant-based and animal-based LCDs and risk of HCC in the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS)., Approach and Results: Dietary intake was assessed every 4 years using validated food frequency questionnaires. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). HRs are shown for a 1-standard deviation (SD) increment with variables modeled as continuous. During 3,664,769 person-years of follow-up, there were 156 incident HCC cases. Although there were no associations between overall or animal-based LCD score and risk of HCC, plant-based LCD score was inversely associated with HCC risk (HR, 0.83; 95% CI, 0.70-0.98; P trend  = 0.03). Carbohydrate intake, especially from refined grains (HR, 1.18; 95% CI, 1.00-1.39; P trend  = 0.04), was positively, while plant fat (HR, 0.78; 95% CI, 0.65-0.95; P trend  = 0.01) was inversely associated with HCC risk. Substituting 5% of energy from plant fat and protein for carbohydrate (HR, 0.74; 95% CI, 0.58-0.93; P trend  = 0.01) or refined grains (HR, 0.70; 95% CI, 0.55-0.90; P trend  = 0.006) was associated with lower HCC risk. In conclusion, a plant-based LCD and dietary restriction of carbohydrate from refined grains were associated with a lower risk of HCC. Substituting plant fat and protein for carbohydrate, particularly refined grains, may decrease HCC incidence., Conclusions: Our findings support a potential benefit in emphasizing plant sources of fat and protein in the diet for HCC primary prevention; additional studies that carefully consider hepatitis B and C virus infections and chronic liver diseases are needed to confirm our findings., (© 2020 by the American Association for the Study of Liver Diseases.)