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Background: Studies attempted to estimate MASLD-related advanced fibrosis (AF) and cirrhosis (MC) prevalence utilized tests with low positive predictive value (PPV) which overestimates prevalence. AGILE3 + and 4 scores were developed to increase the PPV of both; respectively. In this study, we used these scores to assess the prevalence of AF and MC. Methods: Participants aged ≥ 18 years with VCTE exam in the NHANES 2017–2018 cycle were included. We excluded pregnant women, patients with excessive alcohol intake, hepatitis B/C, and ALT or AST > 500 IU/L. MASLD was defined with CAP score > 248 dB/m. MASLD subjects with AGILE 3 + score of ≥ 0.68 and AGILE 4 score of ≥ 0.57 were considered to have advanced fibrosis and cirrhosis; respectively. AGILE 3 + of 0.45–0.67 and AGILE 4 of 0.25–0.57 were grey zone, whereas AGILE 3 + < 0.45 and AGILE 4 < 0.25 were considered a rule-out. Results: 1244 subjects were included in the final analysis. The Median age was 53 (51.4–54.6) years, 55.6% were male, median BMI was 33.8 kg/m2 and 41.1% had T2DM. Based on AGILE 3+, 80.3% of the MASLD population were at low risk for AF and 11.5% were in grey zone. The prevalence of AF due to MASLD was 8.1% corresponding to 4.5 million Americans. Based on AGILE 4 score, 96.5% of the MASLD population were at low risk for cirrhosis and 2.4% were in the grey zone. The prevalence of MASLD-cirrhosis was 1.1% corresponding to 610,000 Americans. Conclusion: Our results suggest that approximately 4.5 million people in the U.S. have AF and 0.6 million have cirrhosis due to MASLD. [ABSTRACT FROM AUTHOR]

Background: Curative surgical treatments afford the best prognosis for patients with intrahepatic cholangiocarcinoma (iCCA); however, the comparative effectiveness of treatment options and factors associated with curative treatment receipt for early stage iCCA remain unknown.Methods: The authors identified patients who were diagnosed with early stage iCCA, defined as a unifocal tumor <3 cm, during 2004-2018 from the National Cancer Database. Multivariable logistic and Cox regression analyses were used to identify the factors associated with curative treatment and overall survival (OS), respectively.Results: The proportion of patients with early stage iCCA increased from 4.5% in 2004 to 7.3% in 2018, with the odds of early stage detection increasing by 3.1% per year (odds ratio [OR], 1.031; 95% CI, 1.015-1.049). Of 1093 patients who had early stage iCCA, 464 (42.5%) underwent resection, 113 (10.3%) underwent ablation, 62 (5.7%) underwent liver transplantation, and 454 (41.5%) received noncurative treatments. Hispanic patients (adjusted OR [aOR], 0.57; 95% CI, 0.33-0.97) and Black patients (aOR, 0.47; 95% CI, 0.28-0.77) were less likely to receive curative treatments than White patients. Compared with patients who underwent surgical resection, those who underwent liver transplantation had a trend toward improved OS (adjusted hazard ratio [aHR], 0.63; 95% CI, 0.37-1.08), whereas those who underwent local ablation (aHR, 1.39; 95% CI, 1.01-1.92) and noncurative treatments (aHR, 3.97; 95% CI, 3.24-4.88) experienced worse OS.Conclusions: More than one third of patients with early stage iCCA did not receive curative treatment, with Hispanic and Black patients being less likely to receive curative treatments than White patients. Surgical resection and liver transplantation were associated with improved survival compared with local ablation. Future studies should investigate disparities in curative treatment receipt and outcomes for early stage iCCA. [ABSTRACT FROM AUTHOR]

Background: The prevalence of fatty liver disease is potentially increasing in adolescents and young adults (AYAs) due to the obesity and alcohol pandemics. The aim of this study was to assess the prevalence of alcohol-associated fatty liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) in a representative U.S. cohort utilizing transient elastography to directly measure hepatic steatosis and suspected fibrosis.Methods: AYAs (age 15-39 years) with valid FibroScan® measurements in the National Health and Nutrition Examination Survey (NHANES) database (2017-2018) were included in the analyses. Those with viral hepatitis, pregnancy, or ALT/AST > 500 U/L were excluded. The population was divided into those with excessive alcohol consumption (ALQ130) and those without. Controlled attenuation parameter (CAP) score ≥ 248 dB/m was used to identify suspected ALD and NAFLD. In those with evidence of ALD, the following cutoffs of liver stiffness measurement (LSM) were used for suspected fibrosis: F ≥ F2 at LSM ≥ 7.5 kPa and F ≥ F3 at ≥ 9.5 kPa, respectively. In those with suspected NAFLD, the following LSM cutoffs were used: F ≥ F2 at 6.1 and F ≥ F3 at ≥ 7.1, respectively. Cutoffs were chosen based on published literature to maximize sensitivity.Results: Comparing to those without, subjects with excessive alcohol consumption tended to be older (29.8 vs 28.5 years), have a higher BMI (29.3 vs 28.9 kg/m2), and be from a White ethnicity (65.3% vs. 55.4%). In subjects with excessive alcohol consumption, suspected ALD was present in 56.59% (95% CI 41.57-70.49). In those with suspected ALD, suspected significant fibrosis (F ≥ F2) was present in 12.3% (95% CI 4.74-28.34) and advanced fibrosis (F ≥ F3) was present in 6.31% (95% CI 0.69-39.55). Similarly, in subjects without excessive alcohol consumption, suspected NAFLD was present in 40.04% (36.64-43.54). In those with suspected NAFLD, suspected significant fibrosis (F ≥ F2) was present in 31.07% (27.25-35.16) and suspected advanced fibrosis (F ≥ F3) was present in 20.15% (16.05-24.99).Conclusion: A significant percentage of AYAs are at risk for ALD and NAFLD and a subset of these subjects is at risk for significant fibrosis. Efforts should focus on increasing awareness of the prevalence of ALD and NAFLD in this population and to mitigate modifiable risk factors. [ABSTRACT FROM AUTHOR]

This cohort analysis investigated the prevalence of nonalcoholic fatty liver disease (NAFLD) and NAFLD with fibrosis at different stages, associated clinical characteristics, and comorbidities in the general United States population and a subpopulation with type 2 diabetes mellitus (T2DM), using the National Health and Nutrition Examination Survey (NHANES) database (2017–2018). Machine learning was explored to predict NAFLD identified by transient elastography (FibroScan®). Adults ≥20 years of age with valid transient elastography measurements were included; those with high alcohol consumption, viral hepatitis, or human immunodeficiency virus were excluded. Controlled attenuation parameter ≥302 dB/m using Youden's index defined NAFLD; vibration‐controlled transient elastography liver stiffness cutoffs were ≤8.2, ≤9.7, ≤13.6, and >13.6 kPa for F0–F1, F2, F3, and F4, respectively. Predictive modeling, using six different machine‐learning approaches with demographic and clinical data from NHANES, was applied. Age‐adjusted prevalence of NAFLD and of NAFLD with F0–F1 and F2–F4 fibrosis was 25.3%, 18.9%, and 4.4%, respectively, in the overall population and 54.6%, 32.6%, and 18.3% in those with T2DM. The highest prevalence was among Mexican American participants. Test performance for all six machine‐learning models was similar (area under the receiver operating characteristic curve, 0.79–0.84). Machine learning using logistic regression identified male sex, hemoglobin A1c, age, and body mass index among significant predictors of NAFLD (P ≤ 0.01). Conclusion: Data show a high prevalence of NAFLD with significant fibrosis (≥F2) in the general United States population, with greater prevalence in participants with T2DM. Using readily available, standard demographic and clinical data, machine‐learning models could identify subjects with NAFLD across large data sets. [ABSTRACT FROM AUTHOR]

Background: Recent trends of hepatocellular carcinoma (HCC) mortality and outcome remain unknown in the United States. We investigated the recent trends of primary liver cancer (excluding intrahepatic cholangiocarcinoma) mortality and HCC stage, treatment, and overall survival (OS) in the United States.Methods: The National Center for Health Statistics Database was analyzed to investigate the trend of primary liver cancer mortality. We analyzed the Surveillance, Epidemiology, and End Results 18 Database to assess the temporal trend of tumor size, stage, treatment, and OS of HCC. We investigated the association between HCC diagnosis year and OS using Cox regression analysis. All statistical tests were 2-sided.Results: During 2000-2018, liver cancer mortality rates increased until 2013, plateaued during 2013-2016 (annual percent change = 0.1%/y, 95% confidence interval [CI] = -2.1%/y to 2.4%/y, P = .92), and started to decline during 2016-2018 (annual percent change = -1.5%/y, 95% CI = -3.2%/y to 0.2%/y, P = .08). However, mortality continues to increase in American Indian and Alaska Native, individuals aged 65 years or older, and in 33 states. There was a 0.61% (95% CI = 0.53% to 0.69%, P < .001) increase in localized stage HCC and a 0.86-mm (95% CI = -1.10 to -0.62 mm, P < .001) decrease in median tumor size per year. The 1-year OS rate increased from 36.3% (95% CI = 34.3% to 38.3%) to 58.1% (95% CI = 56.9% to 59.4%) during 2000-2015, and the 5-year OS rate almost doubled from 11.7% (95% CI = 10.4% to 13.1%) to 21.3% (95% CI = 20.2% to 22.4%) during 2000-2011. Diagnosis year (per year) (adjusted hazard ratio = 0.96, 95% CI = 0.96 to 0.97) was independently associated with OS in multivariable analysis.Conclusions: Primary liver cancer mortality rates have started to decline in the United States with demographic and state-level variation. With an increasing detection of localized HCC, the OS of HCC has improved over the past decades. [ABSTRACT FROM AUTHOR]

Background: Nonalcoholic fatty liver disease (NAFLD) has become the most common form of chronic liver disease in the USA. Interestingly, most patients with NAFLD are unaware of having any liver disease (LD). We aimed to assess the awareness of suspected NAFLD and factors associated with being aware of LD.Methods: Adult subjects with suspected NAFLD (BMI > 25) with elevated ALT in the absence of secondary causes of LD who participated in the continuous national health and nutrition examination survey (NHANES) during 2001-2016 were identified and analyzed. Trends of NAFLD awareness were then assessed in periods of 4 years each. Multivariable logistic regression analysis was performed to assess factors associated with LD awareness.Results: A total of 7033 subjects were included in the final analysis (1731, 1757, 1711, and 1834 subjects for the periods of 2001-2004, 2005-2008, 2009-2012, and 2013-2016, respectively). Over the study duration, an increase in BMI, waist circumference, diabetes, and HbA1c; and a decrease in the number of smokers, platelets count, bilirubin, total cholesterol, and LDL level were noticed (p < 0.001). Awareness of having LD across study periods has increased over time from 1.5% in the 2001-2004 periods to 3.1% in the 2013-2016 periods. Multivariable logistic regression analysis showed that older age, ethnicity (non-black), having fewer drinks/week, metabolic syndrome, higher ALT, ALP, and GGT were associated with being aware of having LD.Conclusions: Awareness of having LD among subjects with suspected NAFLD has increased over the last two decades, but more than 95% of these patients are still unaware of having LD. Educational programs to increase awareness of LD and risk factors for NAFLD should be implemented on a large scale.Clinical Trial Registration Number: Not required, as we used de-identified NHANES data. [ABSTRACT FROM AUTHOR]

Introduction: Nonalcoholic fatty liver disease (NAFLD) affects between 25% and 33% of the population, is more common in obese individuals, and is the most common cause of chronic liver disease in the United States. However, despite rising prevalence, effective treatments remain limited. Areas covered: We performed a literature search across multiple databases (Pubmed, Medline, etc.) to identify significant original research and review articles to provide an up-to-date and concise overview of disease pathogenesis and diagnostic evaluation and to expand on available treatment options with a specific focus on the potential role of bariatric surgery. Here we provide the most comprehensive review of bariatric surgery for the management of NAFLD, noting benefits from different procedures and multiple reports showing improvements in steatosis, inflammation and fibrosis over the duration of follow-up. Expert commentary: The morbidity of NAFLD is significant as it may become the most common indication for liver transplantation within the next 5 years. In addition to known benefits of weight loss and diabetes resolution, bariatric surgery has the potential to halt and reverse disease progression and future controlled trials should be performed to further define its benefit in the treatment of NAFLD in morbidly obese patients. [ABSTRACT FROM PUBLISHER]

Background and Aims: Non-invasive tests (NITs) are underutilized for diagnosis and risk stratification in metabolic dysfunction-associated steatotic liver disease (MASLD), despite good accuracy. This study aimed to identify challenges and barriers to the use of NITs in clinical practice., Methods: We conducted a qualitative exploratory study in Germany, Italy, United Kingdom and United States. Phase 1 participants (primary care physicians, hepatologists, diabetologists, researchers, healthcare administrators, payers and patient advocates; n = 29) were interviewed. Phase 2 participants (experts in MASLD; n = 8) took part in a group discussion to validate and expand on Phase 1 findings. Finally, we triangulated perspectives in a hybrid deductive/inductive thematic analysis., Results: Four themes hindering the use of NITs emerged: (1) limited knowledge and awareness; (2) unclear referral pathways for patients affected by liver conditions; (3) uncertainty over the value of NITs in monitoring and managing liver diseases; and (4) challenges justifying system-level reimbursement. Through these themes, participants perceived a stigma associated with liver diseases, and primary care physicians generally lacked awareness, adequate knowledge and skills to use recommended NITs. We identified uncertainties over the results of NITs, specifically to guide lifestyle intervention or to identify patients that should be referred to a specialist. Participants indicated an ongoing need for research and development to improve the prognostic value of NITs and communicating their cost-effectiveness to payers., Conclusions: This qualitative study suggests that use of NITs for MASLD is limited due to several individual and system-level barriers. Multi-level interventions are likely required to address these barriers., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: In the American Gastroenterological Association/American Association for the Study of Liver Diseases (AGA/AASLD) Clinical Care Pathway, Fibrosis-4 index (FIB-4) is used to stratify patients at risk for metabolic dysfunction-associated steatotic liver disease (MASLD) as low-, indeterminate-, or high-risk for developing advanced liver fibrosis. We assessed the performance of FIB-4 in a general population., Methods: Using the 2017 to 2020 National Health and Nutrition Examination Surveys dataset, we selected subjects ≥18 years who had FibroScan data. We followed AGA/AASLD guidelines to identify subjects with characteristics that place them at risk for MASLD-associated liver fibrosis. Other causes of liver disease were excluded. Our final cohort had 3741 subjects. We then categorized these subjects based on recommended FIB-4 cutoffs. FibroScan liver stiffness measurement (LSM) served as the outcome measurement., Results: Among the 2776 subjects (74.2%) classified as low risk by FIB-4, 277 subjects (10%) were not classified at low risk by LSM, and 75 subjects (2.7%) were classified as high risk by LSM. Among the 86 subjects classified as high risk by FIB-4, 68 subjects (79.1%) were not at high risk by LSM, and 54 subjects (62.8%) were at low risk by LSM. Subjects misclassified by FIB-4 as low risk were older; had a higher body mass index, waist circumference, glycohemoglobin A1c level, alanine transaminase, aspartate transaminase, diastolic blood pressure, controlled attenuation parameter score, white blood cell count, alkaline phosphatase, and fasting glucose level; but had lower high-density lipoprotein, and albumin level (all P < .05). Misclassified subjects were also more likely to have prediabetes/diabetes., Conclusion: Using FIB-4 in the AGA/AASLD guidelines to risk-stratify subjects at risk for MASLD-associated fibrosis results in many subjects being misclassified into the low- and high-risk categories. Therefore, it may be worthwhile considering caution in interpretation and/or alternative strategies., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Following the Delphi consensus process, the term steatotic liver disease (SLD) was introduced to replace fatty liver disease, while the term metabolic dysfunction-associated steatotic liver disease (MASLD) emerged as the successor to the term nonalcoholic fatty liver disease (NAFLD). 1 This revised nomenclature aims to enhance precision and mitigate negative connotations and potential stigmatization, while refining comprehension and disease categorization. Concurrently, a novel category was introduced to capture individuals whose alcohol consumption exceeded the previously defined thresholds of NAFLD but remained unclassified within the existing system. This category, termed MetALD, now delineates a spectrum of conditions and is defined as a daily intake of 20 to 50 g of alcohol (or weekly 140-350 g) for females and 30 to 60 g daily for males (or weekly 210-420 g). 1 Within the MetALD spectrum, some individuals might predominantly exhibit MASLD characteristics, whereas others might be more inclined toward alcoholic liver disease (ALD). 1 In the present study, we used a US nationally representative data set to calculate the prevalence of SLD and its subcategories in the United States., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

NASH is the fastest-growing cause of liver cirrhosis and is the leading indication for liver transplantation (LT). However, significant racial and ethnic disparities in waitlist outcomes and LT allocation may unfairly disadvantage minorities. Our aim was to characterize racial and ethnic disparities in waitlist mortality and transplantation probability among patients with NASH. This is a retrospective analysis of the United Network for Organ Sharing registry data of LT candidates from January 1, 2000 to December 31, 2021. Outcomes analysis was performed using competing risk analysis with the Fine and Gray model. The multivariable adjustment was conducted, and mixed-effect regression was used to compare the model for end-stage liver disease scores at listing and removal. Of 18,562 patients with NASH cirrhosis, there were 14,834 non-Hispanic Whites, 349 African Americans, 2798 Hispanics, 312 Asians, and 269 of other races/ethnicities; African American (effect size: 2.307, 95% CI: 1.561-3.053, and p < 0.001) and Hispanic (effect size: 0.332, 95% CI: 0.028-0.637, p = 0.032) patients were found to have a significantly higher model for end-stage liver disease scores at the time of listing than non-Hispanic Whites. African Americans had a higher probability of receiving LT relative to non-Hispanic Whites (subdistribution HR: 1.211, 95% CI: 1.051-1.396, and p = 0.008). However, Hispanic race/ethnicity was associated with a lower transplantation probability (subdistribution HR: 0.793, 95% CI: 0.747-0.842, and p < 0.001) and increased waitlist mortality (subdistribution HR: 1.173, CI: 1.052-1.308, and p = 0.004) compared with non-Hispanic Whites. There are significant racial and ethnic disparities in waitlist outcomes of patients with NASH in the US. Hispanic patients are less likely to receive LT and more likely to die while on the waitlist compared with non-Hispanic Whites despite being listed with a lower model for end-stage liver disease scores., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Ultrasound-based surveillance has suboptimal sensitivity for early hepatocellular carcinoma (HCC) detection, generating interest in alternative surveillance modalities. We aim to investigate the association between prediagnostic CT or MRI and overall survival in a contemporary cohort of patients with HCC. Using the Surveillance Epidemiology and End Results (SEER)-Medicare database, we analyzed Medicare beneficiaries diagnosed with HCC between 2011 and 2015. Proportion of time covered (PTC) was defined as the proportion of the 36-month period prior to HCC diagnosis in which patients had received abdominal imaging (ultrasound, CT, MRI). Cox proportional hazards regression was used to investigate the association between PTC and overall survival. Among 5,098 patients with HCC, 3,293 (65%) patients had abdominal imaging prior to HCC diagnosis, of whom 67% had CT/MRI. Median PTC by any abdominal imaging was 5.6% [interquartile range (IQR): 0%-36%], with few patients having PTC >50%. Compared with no abdominal images, ultrasound [adjusted HR (aHR): 0.87, 95% confidence interval (CI): 0.79-0.95] and CT/MRI group (aHR: 0.68, 95% CI: 0.63-0.74) were associated with improved survival. Lead-time adjusted analysis showed improved survival continued to be observed with CT/MRI (aHR: 0.80, 95% CI: 0.74-0.87) but not ultrasound (aHR: 1.00, 95% CI: 0.91-1.10). Increased PTC was associated with improved survival, with a larger effect size observed with CT/MRI (aHR per 10%: 0.93, 95% CI: 0.91-0.95) than ultrasound (aHR per 10%: 0.96, 95% CI: 0.95-0.98). In conclusion, PTC by abdominal images was associated with improved survival in patients with HCC, with potential greater benefit using CT/MRI. Regular utilization of CT/MRI before cancer diagnosis may have potential survival benefit compared to ultrasound in patients with HCC., Significance: Our population-based study using SEER-Medicare database demonstrated that proportion of time covered by abdominal imaging was associated with improved survival in patients with HCC, with potential greater benefit using CT/MRI. The results suggest that CT/MRI surveillance may have potential survival benefit compared with ultrasound surveillance in high-risk patients for HCC. A larger prospective study should be conducted for external validation., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Background & Aims: The extent to which nonalcoholic fatty liver disease (NAFLD) contributes to hepatocellular carcinoma (HCC) prevalence in contemporary practices and whether there are any etiologic differences in surveillance receipt, tumor stage, and overall survival (OS) remain unclear. We aimed to estimate the burden of NAFLD-related HCC and magnitude of associations with surveillance receipt, clinical presentation, and outcomes in a contemporary HCC cohort., Methods: In a cohort of HCC patients from the Surveillance, Epidemiology and End Results-Medicare database between 2011 and 2015, we used multivariable logistic regression to identify factors associated with surveillance receipt, early-stage tumor detection, and curative treatment. Cox regression was used to identify factors associated with OS., Results: Among 5098 HCC patients, NAFLD was the leading etiology, accounting for 1813 cases (35.6%). Compared with those with hepatitis C-related HCC, NAFLD was associated with lower HCC surveillance receipt (adjusted odds ratio, 0.22; 95% confidence interval [CI], 0.17-0.28), lower early-stage HCC detection (adjusted odds ratio, 0.49; 95% CI, 0.40-0.60), and modestly worse OS (adjusted hazard ratio, 1.20; 95% CI, 1.09-1.32). NAFLD subgroup analysis showed that early-stage HCC, absence of ascites/hepatic encephalopathy, surveillance, and curative treatment receipt were associated with improved OS. NAFLD patients with coexisting liver disease were more likely to have surveillance, early-stage detection, curative treatment, and improved OS than NAFLD patients without coexisting liver diseases., Conclusions: NAFLD is the leading etiology of HCC among Medicare beneficiaries. Compared with other etiologies, NAFLD was associated with lower HCC surveillance receipt, early-stage detection, and modestly poorer survival. Multifaceted interventions for improving surveillance uptake are needed to improve prognosis of patients with NAFLD-related HCC., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Immunotherapy has emerged as an effective treatment for patients with advanced-stage HCC. We aimed to investigate the efficacy of immunotherapy for advanced HCC in a nationwide cohort and racial and ethnic disparities in access to immunotherapy., Approach and Results: We used the US National Cancer Database to identify patients with tumor-node-metastasis stage 3 or 4 HCC between 2017 and 2018. We performed multivariable Cox regression to identify factors associated with overall survival (OS) and logistic regression to identify factors associated with receipt of immunotherapy. Of the 3,990 patients treated for advanced HCC, 3,248 (81.4%) patients received chemotherapy and 742 (18.6%) patients received immunotherapy as a first-line treatment. Immunotherapy was associated with improved OS compared with chemotherapy (adjusted HR: 0.76, 95% CI: 0.65-0.88) after adjusting for covariates. There were racial and ethnic disparities in access to immunotherapy, with Hispanic (adjusted OR [aOR]: 0.63, 95% CI: 0.46-0.83) and Black patients (aOR: 0.71, 95% CI: 0.54-0.89) less likely to receive immunotherapy compared with White patients. There was a significant interaction between race-ethnicity and facility type, with higher disparity observed in nonacademic centers (interaction p = 0.004)., Conclusions: Immunotherapy was associated with improved OS compared with chemotherapy in advanced HCC. There are significant disparities in early access to immunotherapy, likely due to differential access to clinical trials and experimental therapies. A comprehensive approach to monitoring and eliminating racial-ethnic disparities in the management of advanced HCC is urgently needed., (© 2022 American Association for the Study of Liver Diseases.)

Studies have examined nonalcoholic fatty liver disease (NAFLD) prevalence and severity in Asians; however, this is not well understood in Asian Americans (both East and South Asian Americans) as few studies have analyzed this population. We aimed to describe characteristics, prevalence of NAFLD, and its severity in Asian Americans in the National Health and Nutrition Examination Surveys (NHANES) from 2017 to 2018. Respondents 18 years and older with interview, laboratory testing, and transient elastography data were included. Other causes of liver disease were excluded. Controlled attenuation parameter (CAP) cutoff ≥ 274 dB/m, as published in the literature, defined NAFLD. Sensitivity analysis for CAP cutoffs ≥ 248 and ≥302 dB/m were performed. We found that 450 out of 3639 respondents were Asian Americans, and prevalence using CAP ≥ 274 dB/m was 43.23%. Using sensitivity analysis cutoffs of CAP ≥ 248 dB/m and CAP ≥ 302 dB/m, the prevalence was 57.38% and 28.03%, respectively. Compared with non-Asian Americans with NAFLD, Asian Americans with NAFLD had significantly lower body mass index (BMI) and less prevalent smoking history. Comorbidities, such as prediabetes, diabetes, and hypertension, were not significantly different between Asian and non-Asian Americans with NAFLD. Compared to non-Asian Americans with NAFLD, Asian Americans with NAFLD exhibited higher aminotransferases and triglycerides. Fibrosis assessed by transient elastography was not significantly different between Asian and non-Asian Americans with NAFLD. Despite decreased prevalence of BMI ≥ 30 kg/m 2 , Asian Americans experienced similar NAFLD prevalence with increased hepatocellular injury and triglyceridemia compared to non-Asian Americans. Fibrosis stages were similar to non-Asian Americans., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease in the United States and worldwide. The progressive form of NAFLD, nonalcoholic steatohepatitis (NASH), is a leading indication for liver transplant. Comorbidities associated with NAFLD development and NASH include type 2 diabetes, obesity, metabolic syndrome, and dyslipidemia. Extrahepatic morbidity and mortality are considerable as NAFLD is associated with an increased risk of cardiovascular disease and chronic kidney disease. Once NAFLD is diagnosed, the presence of liver fibrosis is the central determinant of hepatic prognosis. Severe liver fibrosis requires aggressive clinical management. No pharmacologic agents have regulatory approval in the United States for the treatment of NAFLD or NASH. Management is centered on efforts to reduce underlying obesity (lifestyle, medications, surgical or endoscopic interventions) and metabolic derangements (prediabetes, type 2 diabetes, hypertension, hyperlipidemia, and others). Current pharmacologic therapy for NAFLD is limited mainly to the use of vitamin E and pioglitazone, although other agents are being investigated in clinical trials. Cardiovascular and metabolic risk factors must also be assessed and managed. Here, NAFLD evaluation, diagnosis, and management are considered in the primary care setting and endocrinology clinics., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Recent trends of hepatocellular carcinoma (HCC) mortality and outcome remain unknown in the United States. We investigated the recent trends of primary liver cancer (excluding intrahepatic cholangiocarcinoma) mortality and HCC stage, treatment, and overall survival (OS) in the United States., Methods: The National Center for Health Statistics Database was analyzed to investigate the trend of primary liver cancer mortality. We analyzed the Surveillance, Epidemiology, and End Results 18 Database to assess the temporal trend of tumor size, stage, treatment, and OS of HCC. We investigated the association between HCC diagnosis year and OS using Cox regression analysis. All statistical tests were 2-sided., Results: During 2000-2018, liver cancer mortality rates increased until 2013, plateaued during 2013-2016 (annual percent change = 0.1%/y, 95% confidence interval [CI] = -2.1%/y to 2.4%/y, P = .92), and started to decline during 2016-2018 (annual percent change = -1.5%/y, 95% CI = -3.2%/y to 0.2%/y, P = .08). However, mortality continues to increase in American Indian and Alaska Native, individuals aged 65 years or older, and in 33 states. There was a 0.61% (95% CI = 0.53% to 0.69%, P < .001) increase in localized stage HCC and a 0.86-mm (95% CI = -1.10 to -0.62 mm, P < .001) decrease in median tumor size per year. The 1-year OS rate increased from 36.3% (95% CI = 34.3% to 38.3%) to 58.1% (95% CI = 56.9% to 59.4%) during 2000-2015, and the 5-year OS rate almost doubled from 11.7% (95% CI = 10.4% to 13.1%) to 21.3% (95% CI = 20.2% to 22.4%) during 2000-2011. Diagnosis year (per year) (adjusted hazard ratio = 0.96, 95% CI = 0.96 to 0.97) was independently associated with OS in multivariable analysis., Conclusions: Primary liver cancer mortality rates have started to decline in the United States with demographic and state-level variation. With an increasing detection of localized HCC, the OS of HCC has improved over the past decades., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: Intrahepatic cholangiocarcinoma (iCCA) and hepatocellular carcinoma (HCC) are the most common primary liver cancers (PLCs). Differences in their clinical features and outcomes are open for investigation in a large-scale study. We aim to investigate the differences in clinical features and outcomes between iCCA and HCC., Approach and Results: The Surveillance, Epidemiology, and End Results Program 18 Database (2000-2017) was used to extract demographic and clinical features of HCC and iCCA patients. Logistic regression analysis was performed to identify factors associated with iCCA diagnosis versus HCC. Cox regression analysis was used to assess factors affecting overall survival (OS). There were 13,611 iCCA and 96,151 HCC patients. Half of iCCA (50.7%) and three quarters of HCC (76.3%) patients were male. Diagnosis in recent year, age (<50 or ≥65), female sex, non-Hispanic White race, higher income, rural area, and higher tumor burden were independently associated with iCCA diagnosis versus HCC. Patients with iCCA had worse OS than those with HCC (9 vs. 13 months; P < 0.001). However, OS was comparable between iCCA and HCC in multivariable analysis (adjusted hazard ratio [aHR] = 1.02; 95% CI = 0.99-1.05). In subgroup analyses, iCCA was associated with better OS than HCC in patients with tumor ≥5 cm (aHR = 0.83; 95% CI = 0.80-0.86), lymph node involvement (aHR = 0.76; 95% CI = 0.72-0.81), distant metastasis (aHR = 0.76; 95% CI = 0.73-0.79), poorly/undifferentiated tumors (aHR = 0.88; 95% CI = 0.83-0.94), and those receiving noncurative treatment (aHR = 0.96; 95% CI = 0.93-0.98)., Conclusions: We identified the demographic, socioeconomic, and clinical features associated with iCCA diagnosis over HCC among patients with PLC. Although iCCA patients presented at an advanced stage, OS was similar between iCCA and HCC in multivariable analysis. iCCA was associated with longer OS for subgroups with poor prognostic features., (© 2021 by the American Association for the Study of Liver Diseases.)

Objectives: To evaluate the cost savings outcomes, from the payer's perspective, of deploying vibration-controlled transient elastography/controlled attenuation parameter (VCTE/CAP) machines for detecting and monitoring fatty liver disease (FLD)., Study Design: We modeled disease transitions and costs under the current observed pathway and under an alternative pathway in which VCTE/CAP devices are adopted. Marginal savings (or costs) due to implementing the device are derived by comparing the aggregate costs between the 2 pathways. Sources of potential savings are 2-fold. First, VCTE/CAP tests result in early identification of patients with FLD (the majority are currently undiagnosed), allowing for proactive intervention and behavior change to slow the progression of disease in these patients. Second, VCTE/CAP tests can reduce the aggregate volume of some current diagnosis methods, such as liver biopsy, imaging, and laboratory work., Methods: Our model relied on administrative claims data consisting of 5 million commercial members and 3 million Medicare members to inform baseline statistics on disease prevalence, health care cost and utilization, and disease progression associated with different severities of liver disease. We consulted expert clinical opinion and medical literature to inform our assumptions related to device adoption and use., Results: Scenario testing demonstrated positive net savings within 2 to 3 years after device deployment. Across a 5-year time span, we estimate net savings up to $2.64 per member per month (PMPM) for Medicare payers and up to $1.91 PMPM for commercial payers., Conclusions: We conclude that deploying VCTE/CAP devices is a financially advantageous solution to address the epidemic of FLD.

Background and Aims: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with a disproportionate impact on racial/ethnic minority groups. However, state-level variation in racial/ethnic disparities and temporal trends of HCC incidence remain unknown. Therefore, we aimed to characterize (1) state-level racial/ethnic disparity in HCC incidence, (2) state-level temporal changes in HCC incidence, and (3) the ecological correlation between HCC incidence and obesity/physical activity levels in the USA., Approach and Results: Trends in HCC incidence between 2001 and 2017 were calculated using data from the Centers for Disease Control and Prevention's National Program of Cancer Registries and the National Cancer Institute's Surveillance, Epidemiology and End Results, and annual percent change in rates were calculated. State-level percent of obesity and level of physical activity were obtained from the Centers for Disease Control and Prevention, and the correlation among obesity, physical activity, and state-specific average annual percent change was tested by Pearson correlation coefficient. There were striking state-level racial/ethnic disparities in HCC incidence; incidence rate ratios ranged between 6.3 and 0.9 in Blacks, 6.1 and 1.7 in Asians/Pacific Islanders, 3.8 and 0.9 in Hispanics, and 6.0 and 0.9 in American Indians/Alaska Natives (compared with Whites as reference). Despite overall decreasing HCC incidence rates after 2015, HCC incidence continued increasing in 26 states over recent years. HCC incidence trends had a moderate correlation with state-level obesity (r = 0.45, P < 0.001) and a moderate inverse correlation with state-level physical activity (r = -0.40, P = 0.004)., Conclusions: There is wide state-level variation in racial/ethnic disparity of HCC incidence. There are also disparate incidence trends across states, with HCC incidence continuing to increase in over half of the states. Regional obesity and lack of physical activity have moderate correlations with HCC incidence trends, suggesting that interventions targeting these factors may help curb rising HCC incidence., (© 2021 by the American Association for the Study of Liver Diseases.)

Competing Interests: MN has been on the advisory board for 89BIO, Gilead, Intercept, Pfizer, Novartis, Novo Nordisk, Allergan, Blade, EchoSens, Fractyl, Terns, OWL, Siemens, Roche Diagnostic, and Abbott; has received research support from Allergan, Bristol Myers Squibb, Gilead, Galmed, Galectin, Genfit, Conatus, Enanta, Pfizer, Madrigal, Novartis, Shire, Viking’ and Zydus; and is a minor shareholder or has stocks in Anaetos, Rivus Pharma, and Viking. FK reports grants from Merck and Gilead. AGS has been on advisory boards and served as a consultant for Wako Diagnostics, Roche, Exact Sciences, Glycotest, Bayer, Eisai, Exelixis, Bristol Myers Squibb, AstraZeneca, Genentech, and TARGET-RWE. NER declared no competing interests.

Background & Aims: Despite apparent differences between men and women in the prevalence and incidence of nonalcoholic fatty liver disease (NAFLD), there are limited epidemiologic data regarding the associations of reproductive and hormone-related factors with NAFLD. We examined the associations of these factors and exogenous hormone use with NAFLD risk in African American, Japanese American, Latino, Native Hawaiian, and white women., Methods: We conducted a nested case-control study (1861 cases and 17,664 controls) in the Multiethnic Cohort Study. NAFLD cases were identified using Medicare claims data; controls were selected among participants without liver disease and individually matched to cases by birth year, ethnicity, and length of Medicare enrollment. Reproductive and hormone-related factors and covariates were obtained from the baseline questionnaire. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% CIs., Results: Later age at menarche was associated inversely with NAFLD (P trend  = .01). Parity, regardless of number of children or age at first birth, was associated with increased risk of NAFLD (OR, 1.25; 95% CI, 1.05-1.48). Oral contraceptive use also was linked to increased risk of NAFLD (OR, 1.14; 95% CI, 1.01-1.29; duration of use P trend  = .04). Compared with women with natural menopause, those with oophorectomy (OR, 1.41; 95% CI, 1.18-1.68) or hysterectomy (OR, 1.33; 95% CI, 1.11-1.60) had an increased risk of NAFLD. A longer duration of menopause hormone therapy (only estrogen therapy) was linked with an increasing risk of NAFLD (OR per 5 years of use, 1.08, 95% CI, 1.01-1.15)., Conclusions: Findings from a large multiethnic study support the concept that menstrual and reproductive factors, as well as the use of exogenous hormones, are associated with the risk of NAFLD., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

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.)

Importance: Millions of Americans gained insurance through the state expansion of Medicaid, but several states with large populations of racial/ethnic minorities did not expand their programs., Objective: To investigate the implications of Medicaid expansion for liver transplant (LT) wait-listing trends for racial/ethnic minorities., Design, Setting, and Participants: A cohort study was performed of adults wait-listed for LT using the United Network of Organ Sharing database between January 1, 2010, and December 31, 2017. Poisson regression and a controlled, interrupted time series analysis were used to model trends in wait-listing rates by race/ethnicity. The setting was LT centers in the United States., Main Outcomes and Measures: (1) Wait-listing rates by race/ethnicity in states that expanded Medicaid (expansion states) compared with those that did not (nonexpansion states) and (2) actual vs predicted rates of LT wait-listing by race/ethnicity after Medicaid expansion., Results: There were 75 748 patients (median age, 57.0 [interquartile range, 50.0-62.0] years; 48 566 [64.1%] male) wait-listed for LT during the study period. The cohort was 8.9% Black and 16.4% Hispanic. Black patients and Hispanic patients were statistically significantly more likely to be wait-listed in expansion states than in nonexpansion states (incidence rate ratio [IRR], 1.54 [95% CI, 1.44-1.64] for Black patients and 1.21 [95% CI, 1.15-1.28] for Hispanic patients). After Medicaid expansion, there was a decrease in the wait-listing rate of Black patients in expansion states (annual percentage change [APC], -4.4%; 95% CI, -8.2% to -0.6%) but not in nonexpansion states (APC, 0.5%; 95% CI, -4.0% to 5.2%). This decrease was not seen when Black patients with hepatitis C virus (HCV) were excluded from the analysis (APC, 3.1%; 95% CI, -2.4% to 8.9%), suggesting that they may be responsible for this expansion state trend. Hispanic Medicaid patients without HCV were statistically significantly more likely to be wait-listed in the post-Medicaid expansion era than would have been predicted without Medicaid expansion (APC, 13.2%; 95% CI, 4.0%-23.2%)., Conclusions and Relevance: This cohort study found that LT wait-listing rates have decreased for Black patients with HCV in states that expanded Medicaid. Conversely, wait-listing rates have increased for Hispanic patients without HCV. Black patients and Hispanic patients may have benefited differently from Medicaid expansion.

Background: It remains unknown to what extent hepatocellular carcinomas (HCCs) are detected very early (T1 stage; ie, unifocal <2 cm) in the United States. The aim of this study was to investigate the trends and factors associated with very early detection of HCC and resultant outcomes., Methods: Patients with HCC diagnosed from 2004 through 2014 were identified from the National Cancer Database. Logistic regression was used to identify factors associated with T1 HCC detection, and Cox proportional hazard analyses identified factors associated with overall survival among patients with T1 HCC., Results: Of 110,182 eligible patients, the proportion with T1 HCC increased from 2.6% in 2004 to 6.8% in 2014 (P<.01). The strongest correlate of T1 HCC detection was receipt of care at an academic institution (odds ratio, 3.51; 95% CI, 2.31-5.34). Older age, lack of insurance, high Model for End-Stage Liver Disease (MELD) score, high alpha-fetoprotein, increased Charlson-Deyo comorbidity score, and nonsurgical treatment were associated with increased mortality, and care at an academic center (hazard ratio [HR], 0.27; 95% CI, 0.15-0.48) was associated with reduced mortality in patients with T1 HCC. Liver transplantation (HR, 0.27; 95% CI, 0.20-0.37) and surgical resection (HR, 0.67; 95% CI, 0.48-0.93) were independently associated with improved survival compared with ablation. This is the first study to examine the trend of T1 HCC using the National Cancer Database, which covers approximately 70% of all cancer diagnoses in the United States, using robust statistical analyses. Limitations of the study include a retrospective study design using administrative data and some pertinent data that were not available., Conclusions: Despite increases over time, <10% of HCCs are detected at T1 stage. The strongest correlates of survival among patients with T1 HCC are receiving care at an academic institution and surgical treatment.

Non-alcoholic steatohepatitis (NASH) is the most common chronic liver disease worldwide, and the fastest growing indication for liver transplantation in the United States. NASH is now the leading etiology for liver transplantation in women, the second leading indication for men, and the most common cause amongst recipients aged 65 years and older. Patients with end-stage liver disease related to NASH represent a unique and challenging patient population due the high incidence of associated comorbid diseases, including obesity, type 2 diabetes (T2D), and hypertension. These challenges manifest in the pre-liver transplantation period with increased waitlist times and waitlist mortality. Furthermore, these patients carry considerable risk of morbidity and mortality both before after liver transplantation, with high rates of T2D, cardiovascular disease, chronic kidney disease, poor nutrition, and disease recurrence. Successful transplantation for these patients requires identification and management of their comorbidities in the face of liver failure. Multidisciplinary evaluations include a thorough pre-transplant workup with a complete cardiac evaluation, control of diabetes, nutritional support, and even, potentially, consultation with a bariatric surgeon. This article provides a comprehensive review of the conditions and challenges facing patients with NASH cirrhosis undergoing liver transplantation and provides recommendations for evaluation and management to optimize them before liver transplantation to produce successful outcomes., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflict of interest., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

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.)

Background: Historically, liver allografts with >30% macrosteatosis (MaS) on donor biopsy have been associated with early allograft dysfunction and worse graft survival; however, successful outcomes have been reported in small cohorts. This study proposes an elevated MaS threshold for organ utilization without detriment to graft survival., Methods: The UNOS Standard Transplant Analysis and Research database was evaluated for transplants between 2006-2015. Graft survival up to 1-year was evaluated by Kaplan-Meier (KM) survival analyses, and by univariate and multivariable logistic regression analyses, including donor and recipient characteristics. Odds ratios (OR) with 95% confidence intervals (CI) for risk of graft loss are reported., Results: Thirty-day risk of graft loss was increased with MaS as low as 10-19% (OR [95% CI] 1.301 [1.055-1.605], p<0.0001) and peaked with MaS 50-59% (2.921 [1.672-5.103]). At 1-year, risk of graft loss remained elevated with MaS 40-49% (1.465 [1.002-2.142]) and MaS 50-59% (1.978 [1.281-3.056], p = 0.0224). Multivariable models were created for Lower and Higher MELD recipients and MaS cutoffs were established. In Lower MELD recipients, organs with ≥50% MaS had increased risk of graft loss at 30 days (2.451 [1.541-3.897], p = 0.0008) and 1-year post-transplant (1.720 [1.224-2.418], p = 0.0125). Higher MELD recipients had increased risk of graft loss at 30 days with allografts showing MaS ≥40% (4.204 [1.440-5.076], p = 0.0016). At 1-year the risk remained increased, but MaS was not significant predictor of graft loss.048 [1.131-3.710], p = 0.0616). In both MELD cohorts, organs with MaS levels below threshold had similar survival to those transplanted without a donor biopsy., Conclusions: In conjunction with recipient selection, organs with MaS up to 50% may be safely used without detriment to outcomes., Competing Interests: Mazen Noureddin (MN) has been on the advisory board or a speaker for Allergan, Gilead, Intercept, Pfizer, Novartis, Blade, EchoSens North America, OWL, Simply Speaking, and Abbott; MN has received research support from Allergan, BMS, Gilead, Galmed, Galectin, Genfit, Conatus, Enanta, Novartis, Shire and Zydus; MN is a minor shareholder or has stocks in Anaetos and Viking. This does not alter our adherence to PLOS ONE policies on sharing data and/or materials.

Objectives: Chronic infection with hepatitis C virus (HCV) was previously the leading indication for liver transplant (LT) in the United States. However, since 2014 the use of direct-acting antivirals (DAAs) has decreased the chronic HCV burden, while the prevalence of nonalcoholic steatohepatitis (NASH) has risen substantially through the last decade. Both gender and ethnic disparities in indications for LT have been shown in the past but no data on this have been reported since the implementation of DAAs., Methods: We assessed changes in etiologies for LT listing and in gender and ethnic differences in those listed for LT. Adult patients registered for LT in the United Network for Organ Sharing/Organ Procurement and Transplantation Network database between January 1, 2004 and December 31, 2016 were included. Multinomial logistic regression modeling was used to test for changes in waitlist or liver transplant rates., Results: The study included 127,164 adult patients registered for LT. By 2016, alcoholic liver disease (ALD) was the leading etiology for waitlisting and LT; NASH was second; hepatocellular carcinoma (HCC) due to chronic HCV and chronic HCV alone were 3rd and 4th. NASH was the leading cause for LT for women and the 2nd leading cause for men (following ALD). NASH increased as the cause in all ethnic subgroups and was the leading cause in 2016 among Asian, Hispanic, and non-Hispanic white females. We also found that although the indication for liver transplant for hepatocellular carcinoma (HCC) due to HCV has increased over the years, this indication decreased for the first time between 2015 and 2016 in both males and females., Conclusions: NASH is currently the second leading cause for LT waitlist registration/liver transplantation overall, and in females, the leading cause. Given the rate of increase, NASH will likely rise to become the leading indication for LT in males as well.

Background & Aims: Acute-on-chronic liver failure (ACLF) is a syndrome of systemic inflammation and organ failures. Obesity, also characterized by chronic inflammation, is a risk factor among patients with cirrhosis for decompensation, infection, and mortality. Our aim was to test the hypothesis that obesity predisposes patients with decompensated cirrhosis to the development of ACLF., Methods: We examined the United Network for Organ Sharing (UNOS) database, from 2005-2016, characterizing patients at wait-listing as non-obese (body mass index [BMI] <30), obese class I-II (BMI 30-39.9) and obese class III (BMI ≥40). ACLF was determined based on the CANONIC study definition. We used Cox proportional hazards regression to assess the association between obesity and ACLF development at liver transplantation (LT). We confirmed our findings using the Nationwide Inpatient Sample (NIS), years 2009-2013, using validated diagnostic coding algorithms to identify obesity, hepatic decompensation and ACLF. Logistic regression evaluated the association between obesity and ACLF occurrence., Results: Among 387,884 patient records of decompensated cirrhosis, 116,704 (30.1%) were identified as having ACLF in both databases. Multivariable modeling from the UNOS database revealed class III obesity to be an independent risk factor for ACLF at LT (hazard ratio 1.24; 95% CI 1.09-1.41; p <0.001). This finding was confirmed using the NIS (odds ratio 1.30; 95% CI 1.25-1.35; p <0.001). Regarding specific organ failures, analysis of both registries demonstrated patients with class I-II and class III obesity had a greater prevalence of renal failure., Conclusion: Class III obesity is a newly identified risk factor for ACLF development in patients with decompensated cirrhosis. Obese patients have a particularly high prevalence of renal failure as a component of ACLF. These findings have important implications regarding stratifying risk and preventing the occurrence of ACLF., Lay Summary: In this study, we identify that among patients with decompensated cirrhosis, class III obesity (severe/morbid obesity) is a modifiable risk factor for the development of acute-on-chronic liver failure (ACLF). We further demonstrate that regarding the specific organ failures associated with ACLF, renal failure is significantly more prevalent in obese patients, particularly those with class III obesity. These findings underscore the importance of weight management in cirrhosis, to reduce the risk of ACLF. Patients with class III obesity should be monitored closely for the development of renal failure., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

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.)

Nonalcoholic fatty liver disease (NAFLD) is currently the most common liver disease worldwide affecting over one-third of the population in the U.S. It has been associated with obesity, type 2 diabetes, hyperlipidemia, and insulin resistance and is initiated by the accumulation of triglycerides in hepatocytes. Isolated hepatic steatosis (IHS) remains a benign process, while a subset develops superimposed inflammatory activity and progression to nonalcoholic steatohepatitis (NASH) with or without fibrosis. However, the molecular mechanisms underlying NAFLD progression are not completely understood. Liver biopsy is still required to differentiate IHS from NASH as easily accessible noninvasive biomarkers are lacking. In terms of treatments for NASH, pioglitazone, vitamin E, and obeticholic acid have shown some benefit. All of these agents have potential complications associated with long-term use. Nowadays, a complex hypothesis suggests that multiple parallel hits are involved in NASH development. However, the 'key switch' between IHS and NASH remains to be discovered. We have recently shown that knocking out enzymes involved in S-adenosylmethionine (SAMe) metabolism, the main biological methyl donor in humans that is abundant in the liver, will lead to NASH development in mice. This could be due to the fact that a normal SAMe level is required to establish the proper ratio of phosphatidylethanolamine to phosphatidylcholine that has been found to be important in NAFLD progression. New data from humans have also suggested that these enzymes play a role in the pathogenesis of NAFLD and that some of SAMe cycle metabolites may serve as noninvasive biomarkers of NASH. In this review, we discuss the evidence of the role of SAMe in animal models and humans with NAFLD and how studying this area may lead to the discovery of new noninvasive biomarkers and possibly personalized treatment for NASH., (© 2015 by the Society for Experimental Biology and Medicine.)