Clinical profiles and mortality rates are similar for metabolic dysfunction-associated steatotic liver disease and non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Recently, the term metabolic dysfunction-associated steatotic liver disease (MASLD) has replaced non-alcoholic fatty liver disease (NAFLD). Concern remains regarding whether the evidence generated under the NAFLD definition can be used for MASLD. We compared the clinical profile and outcomes of NAFLD to MASLD using tertiary care- and population-based data. METHODS: Comparison data were obtained from our NAFLD database and the National Health and Nutrition Examination Survey (NHANES III). Clinical profiles and non-invasive tests (enhanced liver fibrosis [ELF] score, fibrosis-4 index [FIB-4] and vibration-controlled transient elastography) were compared. Mortality data were obtained from NHANES-National Death Index. All-cause mortality was assessed by Cox proportional hazards regression models and cause-specific mortality by competing risk analysis. RESULTS: There were 6,429 patients in the NAFLD database (age: 54 ± 12 years, 42% male, BMI 35.4 ± 8.3, waist circumference 112 ± 17 cm, 52% type 2 diabetes). Average scores for ELF, FIB-4 and liver stiffness were 9.6 ± 1.2, 1.69 ± 1.24,14.0 ± 11.8 kPa, respectively; 99% met MASLD criteria; 95% met MASLD on BMI only. Predictive accuracy of ELF and FIB-4 were identical between MASLD and NAFLD. We included 12,519 eligible participants from NHANES (age 43.00 years, 47.38% male, 22.70% obese, 7.28% type 2 diabetes, 82.51% ≥1 cardiometabolic criteria). Among the NHANES study population, there was excellent concordance between MASLD and NAFLD diagnoses: Cohen's kappa coefficient: 0.968 (95% CI 0.962-0.973) with 5.29% of NAFLD cases not meeting MASLD criteria. After a median follow-up of 22.83 years, there were no mortality differences between MASLD and NAFLD diagnoses (p values ≥0.05). CONCLUSIONS: NAFLD and MASLD are similar except individuals with MASLD seem to be older with slightly higher mortality risk, likely owing to cardiometabolic risk factors. Clinical profiles and non-invasive test thresholds were also identical. These data provide evidence that NAFLD and MASLD terminologies can be used interchangeably. For the small proportion of patients with NAFLD who do not meet MASLD criteria, further consideration is needed. IMPACT AND IMPLICATIONS: In June 2023, new terminology (MASLD) was adopted to replace the term NAFLD as a means to better describe what the liver disease is rather than what it is not, as well as to potentially reduce stigma. Given that MASLD requires at least one cardiometabolic risk factor, questions were raised as to whether this change in the definition would nullify the similarities between NAFLD and MASLD and require new evidence to be generated for MASLD. We used our NAFLD database and a US population-based database to show that the vast majority of patients with NAFLD fulfill criteria for MASLD. Non-invasive tests performed similarly in both groups. Mortality risk was slightly higher in those with MASLD, which is attributed to the presence of cardiometabolic risks. These results provide evidence that data generated in the past three decades for NAFLD can be used interchangeably for MASLD.

Assessment of fatigue and its impact in chronic liver disease.

Patient-reported outcomes (PROs), such as health-related quality of life (HRQL), are important outcome measures for patients with chronic liver diseases (CLDs). Presence of cirrhosis and advanced liver disease have been associated with worsened HRQL and fatigue. On the other hand, some patients with earlier stages of CLD also experience fatigue, causing PRO impairment. Treatment for some CLDs may improve HRQL and, sometimes, levels of fatigue. We aimed to provide an in-depth expert review of concepts related to fatigue and HRQL in patients with primary biliary cholangitis, hepatitis C virus and MASLD (metabolic dysfunction-associated steatotic liver disease). A panel of experts in fatigue and CLD reviewed and discussed the literature and collaborated to provide this expert review of fatigue in CLD. Herein, we review and report on the complexity of fatigue, highlighting that it is comprised of peripheral (neuromuscular failure, often in conjunction with submaximal cardiorespiratory function) and central (central nervous system dysfunction) causes. Fatigue and HRQL are measured using validated self-report instruments. Additionally, fatigue can be measured through objective tests (e.g. grip strength). Fatigue has deleterious effects on HRQL and one's ability to be physically active and socially engaged but does not always correlate with CLD severity. Treatments for hepatitis C virus and MASLD can improve levels of fatigue and HRQL, but current treatments for primary biliary cholangitis do not seem to affect levels of fatigue. We conclude that obtaining PRO data, including on HRQL and fatigue, is essential for determining the comprehensive burden of CLD and its potential treatments.

Global survey of stigma among physicians and patients with nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Patients with fatty liver disease may experience stigma from the disease or comorbidities. In this cross-sectional study, we aimed to understand stigma among patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) and healthcare providers. METHODS: Members of the Global NASH Council created two surveys about experiences/attitudes toward NAFLD and related diagnostic terms: a 68-item patient and a 41-item provider survey. RESULTS: Surveys were completed by 1,976 patients with NAFLD across 23 countries (51% Middle East/North Africa [MENA], 19% Europe, 17% USA, 8% Southeast Asia, 5% South Asia) and 825 healthcare providers (67% gastroenterologists/hepatologists) across 25 countries (39% MENA, 28% Southeast Asia, 22% USA, 6% South Asia, 3% Europe). Of all patients, 48% ever disclosed having NAFLD/NASH to family/friends; the most commonly used term was "fatty liver" (88% at least sometimes); "metabolic disease" or "MAFLD" were rarely used (never by >84%). Regarding various perceptions of diagnostic terms by patients, there were no substantial differences between "NAFLD", "fatty liver disease (FLD)", "NASH", or "MAFLD". The most popular response was being neither comfortable nor uncomfortable with either term (56%-71%), with slightly greater discomfort with "FLD" among the US and South Asian patients (47-52% uncomfortable). Although 26% of patients reported stigma related to overweight/obesity, only 8% reported a history of stigmatization or discrimination due to NAFLD. Among providers, 38% believed that the term "fatty" was stigmatizing, while 34% believed that "nonalcoholic" was stigmatizing, more commonly in MENA (43%); 42% providers (gastroenterologists/hepatologists 45% vs. 37% other specialties, p = 0.03) believed that the name change to metabolic dysfunction-associated steatotic liver disease (or MASLD) might reduce stigma. Regarding the new nomenclature, the percentage of providers reporting "steatotic liver disease" as stigmatizing was low (14%). CONCLUSIONS: The perception of NAFLD stigma varies among patients, providers, geographic locations and sub-specialties. IMPACT AND IMPLICATIONS: Over the past decades, efforts have been made to change the nomenclature of nonalcoholic fatty liver disease (NAFLD) to better align with its underlying pathogenetic pathways and remove any potential stigma associated with the name. Given the paucity of data related to stigma in NAFLD, we undertook this global comprehensive survey to assess stigma in NAFLD among patients and providers from around the world. We found there is a disconnect between physicians and patients related to stigma and related nomenclature. With this knowledge, educational programs can be developed to better target stigma in NAFLD among all stakeholders and to provide a better opportunity for the new nomenclature to address the issues of stigma.

Food Insecurity, Low Household Income, and Low Education Level Increase the Risk of Having Metabolic Dysfunction-Associated Fatty Liver Disease Among Adolescents in the United States.

INTRODUCTION: In the United States, 10.2% households (HH) report child food insecurity. We assessed associations between metabolic dysfunction-associated fatty liver disease (MASLD) and food insecurity among the adolescents in the United States. METHODS: This cross-sectional study was performed using data from the National Health and Nutrition Examination Survey 2017-2018. Food insecurity was assessed by the US Department of Agriculture Child Food Security Survey Module. MASLD was defined by transient elastography. RESULTS: Among 771 adolescents (aged 12-18 years) (mean age 14.7 years; 52.5% male; 50.9% White, 12.7% Black, 24.4% Hispanic, and 12.1% other), 9.8% reported food insecurity; MASLD prevalence of 10.12% (95% confidence interval [CI] 7.13%-13.20%) affecting 4.27 million adolescents; and nonalcoholic fatty liver disease prevalence of 10.77% (95% CI 7.76-13.78) affecting 4.52 million adolescents. There was near-perfect concordance between MASLD and nonalcoholic fatty liver disease (Cohen's κ coefficient of 0.971, 95% CI 0.946-0.996). The prevalence of MASLD was greater among food-insecure adolescents vs food-secure ones (17.4% vs 9.4%) and adolescents living with a low HH income vs those with a higher HH income (15.0% vs 7.2%) and living with a head of HH with a lower education level vs one with a higher education level (18.0% vs 8.2%) ( P < 0.05). The fully adjusted model showed that compared with adolescents living in a higher HH income, food-insecure adolescents living in low income HH had a 3-fold greater risk (odds ratio [OR] 3.25, 1.31-8.08) of having MASLD, while food-secure adolescents living in low-income HH had no increased risk (OR 1.58, 0.85-2.93, P = 0.139). The fully adjusted odds of having MASLD was elevated by +163% with the presence of HTN (OR 2.63, 1.02-6.78), +241% with being Hispanic (OR 3.41, 1.36-8.56), and +138% with being male (OR 2.38, 1.20-4.75). In addition, a 1-unit increase in BMI was associated with 25% increase in the odds of having MASLD (OR 1.25, 1.17-1.33) among US adolescents. DISCUSSION: Food insecurity is associated with MASLD among US low-income adolescents especially Hispanic male individuals with obesity and hypertension. Policies addressing inequities are needed.

The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review.

BACKGROUND AND AIMS: NAFLD is a leading cause of liver-related morbidity and mortality. We assessed the global and regional prevalence, incidence, and mortality of NAFLD using an in-depth meta-analytic approach. APPROACH AND RESULTS: PubMed and Ovid MEDLINE were searched for NAFLD population-based studies from 1990 to 2019 survey year (last published 2022) per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Meta-analysis was conducted using random-effects models. Bias risk assessment was per Joanna Briggs Institute. Of 2585 studies reviewed, 92 studies (N=9,361,716) met eligibility criteria. Across the study period (1990-2019), meta-analytic pooling of NAFLD prevalence estimates and ultrasound-defined NAFLD yielded an overall global prevalence of 30.05% (95% CI: 27.88%-32.32%) and 30.69% (28.4-33.09), respectively. Global NAFLD prevalence increased by +50.4% from 25.26% (21.59-29.33) in 1990-2006 to 38.00% (33.71-42.49) in 2016-2019 ( p <0.001); ultrasound-defined NAFLD prevalence increased by +38.7% from 25.16% (19.46-31.87) in 1990-2006 to 34.59% (29.05-40.57) ( p =0.029). The highest NAFLD prevalence was in Latin America 44.37% (30.66%-59.00%), then Middle East and North Africa (MENA) (36.53%, 28.63%-45.22%), South Asia (33.83%, 22.91%-46.79%), South-East Asia (33.07%, 18.99%-51.03%), North America (31.20%, 25.86%-37.08%), East Asia (29.71%, 25.96%-33.76%), Asia Pacific 28.02% (24.69%-31.60%), Western Europe 25.10% (20.55%-30.28%). Among the NAFLD cohort diagnosed without a liver biopsy, pooled mortality rate per 1000 PY was 12.60 (6.68-23.67) for all-cause mortality; 4.20 (1.34-7.05) for cardiac-specific mortality; 2.83 (0.78-4.88) for extrahepatic cancer-specific mortality; and 0.92 (0.00-2.21) for liver-specific mortality. CONCLUSIONS: NAFLD global prevalence is 30% and increasing which requires urgent and comprehensive strategies to raise awareness and address all aspects of NAFLD on local, regional, and global levels.

Impact of Income-to-Poverty Ratio on Long-Term Mortality of Persons with Chronic Liver Disease in the USA, 1999-2018.

INTRODUCTION: Chronic liver disease (CLD) is associated with increased morbidity and mortality. Understanding health disparities can inform appropriate interventions. We aimed to study mortality outcomes of those with CLD by the income level (income-to-poverty ratio <5 as lower income and ≥5 as higher income). METHODS: In this retrospective cohort study, we analyzed data of adults from the National Health and Nutrition Examination Survey, 1999-2018. CLD included viral hepatitis, nonalcoholic fatty liver disease (NAFLD), and alcohol-associated liver disease (ALD). RESULTS: We analyzed 59,204 adults: 47,224 without CLD and 11,980 with CLD. The CLD group was older, more likely male, racial/ethnic minority groups or foreign-born, and had lower educational and income levels (p < 0.001). Most (80.02%) CLD participants did not have college degrees and had lower income (79.18%). Among CLD participants, similar differences were observed between lower and higher income groups. Lower income participants with CLD had significantly higher 10-year cumulative mortality compared to higher income CLD participants (15.26 vs. 8.00%, p < 0.001), with consistent findings in viral hepatitis and NAFLD subgroups (p < 0.001) but not ALD (p = 0.71). Adjusting for age, sex, race, birthplace, lower income CLD participants were 2.01 (hazard ratio [HR]: 2.01; 95% CI: 1.79-2.26) times more likely to die overall and in viral hepatitis (HR: 2.05; 95% CI: 1.31-3.24) and NAFLD subgroups (HR: 2.32; 95% CI: 1.69-3.18) but not ALD (HR: 1.17; 95% CI: 0.55-2.51). CONCLUSION: Lower income, foreign-born, and racial/ethnic minority groups were disproportionately represented among those with CLD, with lower income and CLD individuals having double the mortality risk compared to their higher income counterparts. Interventions should be culturally appropriate and address socioeconomic barriers.

Understanding the Burden of Nonalcoholic Fatty Liver Disease: Time for Action.

The prevalence of nonalcoholic fatty liver disease (NAFLD) in the United States is 38%, having increased by 50% within the past 3 decades. The estimated NAFLD prevalence among people with type 2 diabetes is 55-70%. The presence of type 2 diabetes is associated with a higher likelihood of progression of NAFLD to fibrosis development, liver transplant, and death. Cardiovascular disease is the main cause of mortality among people with NAFLD, and the risk of death is significantly higher in people with both NAFLD and type 2 diabetes. NAFLD carries high patient and economic burdens but low awareness among both the general public and health care providers. This article reviews the epidemiology of NAFLD and discusses the need for appropriate risk stratification, referral for specialty care, management of cardiometabolic risk factors, and treatment of the disease. The authors present a call to action to raise awareness of NAFLD and address its increasing burden in a systematic and efficient manner.

Impact of the COVID-19 pandemic on liver disease-related mortality rates in the United States.

BACKGROUND & AIMS: The pandemic has resulted in an increase of deaths not directly related to COVID-19 infection. We aimed to use a national death dataset to determine the impact of the pandemic on people with liver disease in the USA, focusing on alcohol-associated liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). METHODS: Using data from the National Vital Statistic System from the Center for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) platform and ICD-10 codes, we identified deaths associated with liver disease. We evaluated observed vs. predicted mortality for 2020-2021 based on trends from 2010-2019 with joinpoint and prediction modelling analysis. RESULTS: Among 626,090 chronic liver disease-related deaths between 2010 and 2021, Age-standardised mortality rates (ASMRs) for ALD dramatically increased between 2010-2019 and 2020-2021 (annual percentage change [APC] 3.5% to 17.6%, p <0.01), leading to a higher observed ASMR (per 100,000 persons) than predicted for 2020 (15.67 vs. 13.04) and 2021 (17.42 vs. 13.41). ASMR for NAFLD also increased during the pandemic (APC: 14.5%), whereas the rates for hepatitis B and C decreased. Notably, the ASMR rise for ALD was most pronounced in non-Hispanic Whites, Blacks, and Alaska Indians/Native Americans (APC: 11.7%, 10.8%, 18.0%, all p <0.05), with similar but less critical findings for NAFLD, whereas rates were steady for non-Hispanic Asians throughout 2010-2021 (APC: 4.9%). The ASMR rise for ALD was particularly severe for the 25-44 age group (APC: 34.6%, vs. 13.7% and 12.6% for 45-64 and ≥65, all p <0.01), which were also all higher than pre-COVID-19 rates (all p <0.01). CONCLUSIONS: ASMRs for ALD and NAFLD increased at an alarming rate during the COVID-19 pandemic with the largest disparities among the young, non-Hispanic White, and Alaska Indian/Native American populations. IMPACT AND IMPLICATIONS: The pandemic has led to an increase of deaths directly and indirectly related to SARS-CoV-2 infection. As shown in this study, age-standardised mortality rates for alcohol-associated liver disease and non-alcoholic fatty liver disease substantially increased during the COVID-19 pandemic in the USA and far exceeded expected levels predicted from past trends, especially among the young, non-Hispanic White, and Alaska Indian/Native American populations. However, much of this increase was not directly related to COVID-19. Therefore, for the ongoing pandemic as well as its recovery phase, adherence to regular monitoring and care for people with chronic liver disease should be prioritised and awareness should be raised among patients, care providers, healthcare systems, and public health policy makers.

Global incidence of non-alcoholic fatty liver disease: A systematic review and meta-analysis of 63 studies and 1,201,807 persons.

BACKGROUND & AIMS: The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. We aimed to estimate the pooled global NAFLD incidence. METHODS: We performed a systematic review and meta-analysis of cohort studies of adults without NAFLD at baseline to evaluate the global incidence of ultrasound-diagnosed NAFLD. RESULTS: A total of 63 eligible studies (1,201,807 persons) were analyzed. Studies were from Mainland China/Hong Kong (n = 26), South Korea (n = 22), Japan (n = 14), other (n = 2, Sri Lanka, Israel); 63.8% were clinical center studies; median study year 2000 to 2016; 87% were good quality. Among the 1,201,807 persons at risk, 242,568 persons developed NAFLD, with an incidence rate of 4,612.8 (95% CI 3,931.5-5,294.2) per 100,000 person-years and no statistically significant differences by study sample size (p = 0.90) or study setting (p = 0.055). Males had higher incidence vs. females (5,943.8 vs. 3,671.7, p = 0.0013). Both the obese (vs. non-obese) and the overweight/obese groups (vs. normal weight) were about threefold more likely to develop NAFLD (8,669.6 vs. 2,963.9 and 8,416.6 vs. 3,358.2, respectively) (both p <0.0001). Smokers had higher incidence than non-smokers (8,043.2 vs. 4,689.7, p = 0.046). By meta-regression, adjusting for study year, study setting, and study location, study period of 2010 or after and study setting were associated with increased incidence (p = 0.010 and p = 0.055, respectively). By country, China had a higher NAFLD incidence compared to non-China regions (p = 0.012) and Japan a lower incidence compared to non-Japan regions (p = 0.005). CONCLUSIONS: NAFLD incidence is increasing with a current estimate of 4,613 new cases per 100,000 person-years. Males and overweight/obese individuals had significantly higher incidence rates compared to females and those of normal weight. Public health interventions for prevention of NAFLD are needed with a special emphasis on males, overweight/obese individuals, and higher risk regions. IMPACT AND IMPLICATIONS: Non-alcoholic fatty liver disease (NAFLD) affects approximately 30% of people worldwide and appears to be increasing, but data to estimate the incidence rate are limited. In this meta-analytic study of over 1.2 million people, we estimated an incidence rate of NAFLD of 46.13 per 1,000 person-years with significant differences by sex, BMI, geography, and time-period. As treatment options for NAFLD remain limited, prevention of NAFLD should remain the focus of public health strategies. Studies such as these can help policy makers in determining which and whether their interventions are impactful.

The Potential Role of Fatigue in Identifying Patients With NASH and Advanced Fibrosis Who Experience Disease Progression.

BACKGROUND AND AIMS: Fatigue is common in patients with advanced liver disease. We investigated fatigue and clinical outcomes among patients with advanced nonalcoholic steatohepatitis (NASH). METHODS: In this study, patients with biopsy confirmed NASH and bridging fibrosis (F3) or compensated cirrhosis (F4) were followed for up to 2 years. The Chronic Liver Disease Questionnaire for Nonalcoholic Steatohepatitis (CLDQ-NASH) fatigue domain at baseline (range, 1-7; lower score indicating worse fatigue) quantified fatigue. The Cox proportional hazards model was used to study time to liver-related clinical events (progression to histologic cirrhosis or hepatic decompensation in F3, hepatic decompensation in F4). RESULTS: Of the 1679 NASH patients with fibrosis, 802 had F3 and 877 had F4 (58 ± 9 years of age, 40% male, 74% type 2 diabetes). During median follow-up of 16 months (interquartile range, 14-18), 15% (n = 123) of NASH F3 patients experienced liver-related events and 3.5% (n = 31) of NASH F4 patients experienced hepatic decompensation. Mean baseline CLDQ-NASH fatigue score in F3 patients was 4.77 ± 1.36; NASH F3 patients who experienced liver-related events had lower baseline scores: 4.47 ± 1.36 vs 4.83 ± 1.35 (P = .0091). The mean fatigue score in F4 was 4.56 ± 1.44; these scores were lower in patients who decompensated in follow-up: 3.74 ± 1.31 vs 4.59 ± 1.43 (P = .0011). The association of lower fatigue scores and risk of liver-related or decompensation events was significant after adjustment for confounders (adjusted hazard ratio per 1 point in fatigue score in F3, 0.85; 95% confidence interval, 0.74-0.97; P = .02; adjusted hazard ratio in F4, 0.62; 95% confidence interval, 0.48-0.81; P = .0004). CONCLUSION: Worse fatigue at baseline is associated with a higher risk of adverse clinical events in patients with NASH-related advanced fibrosis and cirrhosis.

The Global Burden of Liver Disease.

Chronic liver disease (CLD) and its associated complications (cirrhosis and liver cancer) cause significant mortality, morbidity, and economic burden. Published data from the World Health Organization and/or the Global Burden of Disease show that the burden of CLD is large and increasing, primarily owing to the increasing burden of nonalcoholic fatty liver disease and alcohol-related liver disease (ALD). Middle Eastern, Northern African, and Asian regions of the globe are most affected by hepatitis B and hepatitis C virus. Furthermore, Middle Eastern and North African regions also are affected by nonalcoholic fatty liver disease, and Eastern European, West African, and Central Asian regions are affected by ALD. In this context, the rate of increase for cirrhosis is highest in the Middle East, as well as in middle high and high sociodemographic index (SDI) regions. On the other hand, the highest SDI countries are experiencing increasing rates of hepatocellular carcinoma (HCC). Assessing HCC burden based on country and etiology shows that China, Korea, India, Japan, and Thailand have the highest hepatitis B virus-related HCC cases, while China, Japan, and the United States have the highest hepatitis C virus-related HCC cases. Additionally, the United States has the highest ALD-related HCC cases, while India, the United States, and Thailand have the highest nonalcoholic steatohepatitis-related HCC cases. Although the burden of CLD is increasing globally, regions of the world are impacted differently as a result of a number of sociodemographic factors.

Racial and Ethnic Disparities in Characteristics and Care Patterns of Chronic Hepatitis B Patients in the United States.

BACKGROUND & AIMS: Chronic hepatitis B (CHB) disproportionately impacts foreign-born patients and those of Asian or Black race. Given the paucity of data, we aimed to study the impact of race and ethnicity on CHB patient characteristics and management. METHODS: A retrospective analysis of adult CHB patients using data recorded in the deidentified Optum Clinformatics Data Mart Database (January 2003‒March 2021) was performed. We characterized and examined the rates of receiving adequate treatment evaluation (measuring hepatitis B virus DNA and alanine transaminase) and hepatitis B virus treatment among the racial and ethnic groups. RESULTS: The study cohort included 42,140 patients: age, 51.9 ± 15.1 years; 56.1% male; 47% Asian; 26% White; 11% Black; and 7% Hispanic. Thirty-three percent of White and 48% of Asian patients had an annual household income greater than $100,000 US compared with 16% for Black and 25% for Hispanic patients (P < .001), with similar disparities in educational levels. Approximately one third of White (29.3%), Black (35.1%), and Hispanic (35.4%), and half of Asian (49.9%) patients received adequate evaluation (P < .001). Among patients who met American Association for the Study of Liver Diseases treatment criteria, treatment rates were similar among White (60.8%; P = .09) and Black (62.8%; P = .48), but lower among Hispanic (54.7%; P = .03), as compared with Asian patients (65.4%). On multivariable logistic regression adjusted for age, sex, provider type, viral co-infection, and fatty liver disease, Hispanic patients were less likely to receive treatment (adjusted hazard ratio, 0.69; 95% CI, 0.53‒0.91; P = .01) compared with Asian patients. CONCLUSIONS: Compared with Asian CHB patients, non-Asian patients were less likely to undergo adequate evaluation and Hispanic patients were less likely to receive treatment for CHB. Additional efforts are needed to improve CHB management, especially for non-Asian patients.

Nonalcoholic Fatty Liver Disease Is Independently Associated With Higher All-Cause and Cause-Specific Mortality.

BACKGROUND & AIMS: The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing globally. We assessed independent associations of NAFLD with all-cause and cause-specific mortality in older community-dwelling adults in the United States. METHODS: Data from the Rancho Bernardo Study cohort, who participated in the research from 1992 to 1996 with mortality data (followed up to July 2019), were analyzed. NAFLD was determined by the improved Fatty Liver Index for the multiethnic US population in the absence of secondary causes of liver disease. Hazard ratios (HRs), 95% CIs, and population-attributable fractions of risk factors on mortality were calculated. Competing-risk analyses of cause-specific mortality were performed. RESULTS: Of the 1523 eligible participants (mean age, 71.8 y; 39.9% male; 99.3% non-Hispanic White; and 10.7% obese), 404 (26.4%) had NAFLD. During 23,311 person-years of follow-up evaluation (mean, 15.22 y; SD, 8.41 y), among NAFLD and non-NAFLD, there were 296 and 717 deaths from all causes, 113 and 263 cardiac deaths, 62 and 112 cancer deaths, and 6 and 2 liver deaths, respectively. NAFLD had a 26% higher all-cause mortality (HR, 1.26; 95% CI, 1.08-1.47) and a 33% (HR, 1.33; 95% CI, 1.04-1.70) and 55% (HR, 1.55; 95% CI, 1.11-2.15) higher cardiac and cancer mortality, respectively, than non-NAFLD. Population-attributable fractions showed 13.9% of deaths, 6.2% of cardiac deaths, and 12.1% of cancer deaths were attributable to NAFLD after adjustments of risk factors (sedentary lifestyle, obesity, hypertension, hyperlipidemia, diabetes). CONCLUSIONS: NAFLD is associated independently with all-cause, cardiac, and cancer mortality. Efforts must continue to raise awareness about NAFLD and develop care pathways and public health efforts to reduce NAFLD burden and associated mortality.

Poor Diagnostic Efficacy of Noninvasive Tests for Advanced Fibrosis in Obese or Younger Than 60 Diabetic NAFLD patients.

BACKGROUND & AIMS: Serum-based noninvasive tests (NITs) have been widely used to assess liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). However, the diagnostic efficacy of NITs across ranges of age, body mass index (BMI), and presence of type 2 diabetes (T2DM) may vary and have not been well-characterized. METHODS: We analyzed 1489 patients with biopsy-proven NAFLD from 6 centers in Japan, Taiwan, and Korea. Using histology as the gold standard, we compared the areas under the receiver operating characteristic (AUROCs) of Fibrosis-4 index (FIB-4), NAFLD fibrosis score (NFS), and the new Hepamet fibrosis score (HFS), with a focus on performance in subgroups as stratified by age, BMI, and the presence of T2DM. RESULTS: By histology, 44.0% of the overall cohort (655/1489) had F2-4, and 20.6% (307/1489) had F3-4 fibrosis. FIB-4 had the highest AUROCs for both F2-4 (0.701 vs NFS 0.676 and HFS 0.682, P = .001) and F3-4 (0.767 vs NFS 0.736 and HFS 0.752, P = .002). However, for F3-4 fibrosis, the AUROCs of all 3 NITs were generally higher in older (>60 years), nonobese (BMI <25 kg/m2), and non-diabetic patients, although overall the best performance was observed with FIB-4 among nonobese (BMI<25) diabetic patients (AUROC, 0.92). The worst performance was observed in younger patients with T2DM for all NITs including FIB-4 (AUROC, 0.63-0.66). CONCLUSIONS: FIB-4 had higher diagnostic efficacy for F3-4 than NFS or HFS, but this varied greatly by age, BMI, and T2DM, with better performance in older, nonobese, and nondiabetic patients. However, all NITs including FIB-4 had unacceptably poor performance in young or obese diabetic patients.

Are there outcome differences between NAFLD and metabolic-associated fatty liver disease?

BACKGROUND: Given the association of NAFLD with metabolic risks, a name change to MAFLD is proposed. We compared the long-term outcomes of NAFLD and MAFLD. METHODS: We included patients with fatty liver disease (FLD) from NHANES III and NHANES 2017-2018 (FLD defined as moderate to severe hepatic steatosis by ultrasound for NHANES III and as having a controlled attenuation parameter ≥285 dB/m for NHANES 2017-2018). NAFLD was defined as FLD without other liver diseases and excess alcohol use. Metabolic-associated fatty liver disease (MAFLD) was defined as FLD and metabolic dysfunction per criteria. All NHANES III participants had linked mortality data through December 31, 2015. RESULTS: NHANES III participants (n = 12,878): mean age 43.1 years old; 49.5% male; 20.3% with FLD, 16.5% with NAFLD, and 18.1% with MAFLD. NHANES 2017-2018 participants (n = 4328): mean age 48.0 years old; 49.1% male; 36.8% with FLD, 34.2% with NAFLD, and 36.3% with MAFLD. Excellent concordance was noted between MAFLD and NAFLD diagnosis in both data sets (kappa coefficient = 0.83-0.94). Except for components of each definition (e.g., alcohol use for MAFLD), no other major differences in clinical characteristics were noted. During up to 27 years of follow-up (median of 22.8 years), no differences in cumulative all-cause and cause-specific mortality were noted. In addition to the stage of fibrosis, insulin resistance was a predictor of liver mortality in NAFLD, and alcohol-associated liver disease (ALD) was a predictor of mortality in MAFLD. CONCLUSIONS: MAFLD and NAFLD have similar clinical profiles and long-term outcomes. The increased liver-related mortality among NAFLD is driven by insulin resistance, and among MAFLD is primarily driven by ALD.

Global burden of NAFLD and chronic liver disease among adolescents and young adults.

BACKGROUND AND AIM: The causes of chronic liver disease (CLD) among adults have changed. Data are lacking on trends among youth. We determined the trends and changes in the global burden of CLD among adolescents and young adults using Global Burden of Disease (GBD) data (2009-2019). APPROACH AND RESULTS: The GBD study estimation methods were used to assess CLD prevalence, incidence, and deaths (21 GBD regions). Annual percent change (APC) calculation by joinpoint regression modeling. Age groups were 15-19, 20-24, and 25-29 years old. Globally in 2019, the 15-29 group accounted for 17.2% (0.29 billion) of CLD prevalent cases, 11.2% (n = 232,072) CLD incident cases, and 3.8% (n = 55,515) CLD deaths. Between 2009 and 2019, CLD prevalence rate increased annually among 25-29 (APC = +0.41%, p < 0.001); remained stable among 20-24 (APC = +0.02%, p = 0.582); and decreased among 15-19 (APC = -2.13%, p < 0.001). CLD prevalence increases were driven by the proportion with NAFLD (15-19: 40.8% to 52.9%, p < 0.001); 20-24: 57.6% to 62.7%, p < 0.001); and 25-29: 66.9% to 70.1%, p < 0.001); the proportion with HBV decreased across all age groups. NAFLD prevalence worsening trend (APC ≥ 0%) was global. Overall CLD death rate decreased annually in all age groups, driven by the decrease in the proportion with HBV [aged 15-19 (from 5.90% to 5.20%, p < 0.001); aged 20-24 (from 18.62% to 16.37%, p < 0.001); and aged 25-29 (from 28.69% to 25.28%, p < 0.001)]; from 2015 to 2019, CLD death rate for HCV (APC = +1.46%) and NAFLD (APC = +2.26%) increased. CONCLUSIONS: Over the past decade, the causes of CLD among 15-29-year-olds have shifted: viral hepatitis remains the most common cause of CLD deaths, but the global burden of HBV incidence is decreasing, whereas NAFLD is the main driver for increased CLD incidence.

Machine learning algorithms for predicting direct-acting antiviral treatment failure in chronic hepatitis C: An HCV-TARGET analysis.

BACKGROUND AND AIMS: We aimed to develop and validate machine learning algorithms to predict direct-acting antiviral (DAA) treatment failure among patients with HCV infection. APPROACH AND RESULTS: We used HCV-TARGET registry data to identify HCV-infected adults receiving all-oral DAA treatment and having virologic outcome. Potential pretreatment predictors (n = 179) included sociodemographic, clinical characteristics, and virologic data. We applied multivariable logistic regression as well as elastic net, random forest, gradient boosting machine (GBM), and feedforward neural network machine learning algorithms to predict DAA treatment failure. Training (n = 4894) and validation (n = 1631) patient samples had similar sociodemographic and clinical characteristics (mean age, 57 years; 60% male; 66% White; 36% with cirrhosis). Of 6525 HCV-infected adults, 95.3% achieved sustained virologic response, whereas 4.7% experienced DAA treatment failure. In the validation sample, machine learning approaches performed similarly in predicting DAA treatment failure (C statistic [95% CI]: GBM, 0.69 [0.64-0.74]; random forest, 0.68 [0.63-0.73]; feedforward neural network, 0.66 [0.60-0.71]; elastic net, 0.64 [0.59-0.70]), and all four outperformed multivariable logistic regression (0.51 [0.46-0.57]). Using the Youden index to identify the balanced risk score threshold, GBM had 66.2% sensitivity and 65.1% specificity, and 12 individuals were needed to evaluate to identify 1 DAA treatment failure. Over 55% of patients with treatment failure were classified by the GBM in the top three risk decile subgroups (positive predictive value: 6%-14%). The top 10 GBM-identified predictors included albumin, liver enzymes (aspartate aminotransferase, alkaline phosphatase), total bilirubin levels, sex, HCV viral loads, sodium level, HCC, platelet levels, and tobacco use. CONCLUSIONS: Machine learning algorithms performed effectively for risk prediction and stratification of DAA treatment failure.

Global treatment rate and barriers to direct-acting antiviral therapy: A systematic review and meta-analysis of 146 studies and 1 760 352 hepatitis C virus patients.

BACKGROUND: Global data on the treatment rate with direct-acting antivirals (DAAs) for chronic hepatitis C (CHC) are sparse. We aimed to evaluate the CHC treatment rate and barriers to treatment in the DAA era. METHODS: We searched PubMed, EMBASE and Cochrane from inception to 5 August 2021, for relevant articles. Patients treated with DAAs without interferon (IFN) therapy were categorized as IFN-free DAAs. Patients receiving DAA with IFN or unclear IFN status were categorized as DAA/IFN. RESULTS: We identified and analysed data from 146 studies (1 760 352 CHC patients). DAA/IFN treatment rate was 16.0% (95% CI: 9.9-23.3, 49 studies, 886 535 patients). IFN-free DAA treatment rate was 52.3% (95% CI: 46.2-58.4, 123 studies, 1 276 754 patients): 45.4% in North America, 64.2% in South America (1 study), 90.4% in Africa (most data from Egypt), 54.4% in Europe, 60.7% in Australia and 60.5% in Asia, (p < .0001); 49% with hepatitis B co-infection and 32.3% with hepatocellular carcinoma (HCC). Treatment was not a priority in 22.8% of patients in Europe and 16.7% in Australia, compared to only 4.8% in North America and 2.1% in Asia (p < .0001). Poor adherence to clinical follow-up was the cause of no treatment in 74.7% of patients in Australia, 37.0% in North America, 7.9% in Europe and 14.3% in Asia (p < .0001). CONCLUSION: Though a marked improvement from IFN/DAA, the treatment rate with IFN-free DAA remains suboptimal (52.3% overall, 32.3% in HCC patients). Non-adherence to clinical follow-up and lack of disease awareness were treatment barriers.

Transient Elastography and Serum-Based Tests for Diagnosis of Fatty Liver and Advanced Fibrosis in a Community Cohort: A Cross-Sectional Analysis.

BACKGROUND: Noninvasive tests (NITs) are necessary for knowing the true prevalence of fatty liver (FL) and advanced fibrosis. NITs for diagnosis of FL and fibrosis were compared. METHODS: Data were obtained from the National Health and Examination Survey (2017-2018). Participants were excluded with other liver diseases, missing data for NIT calculation, and/or excessive alcohol use. Area under the receiver operating characteristic (AUROC) compared the accuracy of 4 FL NITs (CAP, HSI, FLI, USFLI) among themselves and to CAP value of 285 dB/m and 5 fibrosis NITs (transient elastography, APRI, NFS, FIB-4, HEPAmet) among themselves and to LSM ≥8.7 kPa. RESULTS: Among 2,051 participants (average age 47 (±17.7), 48% males, 62% white, 73% overweight/obese, 39% metabolic syndrome), demographics were similar among NIT groups (CAP = 812; HSI = 1,234; FLI = 935; USFLI-824). FL prevalence by NIT: 39% CAP, 58% HSI, 47% FLI, 37% USFLI. Advanced fibrosis prevalence by test: LSM (≥8.7 kPa) 10-14%; FIB-4 (≥2.67) and APRI (≥0.7) 1.3-2.7%; HEPAmet (>0.47) 14-21%. Compared to CAP ≥285, FLI (AUROC = 0.823) and USFLI (AUROC = 0.833) performed better than HSI (AUROC: 0.798). Compared to LSM ≥8.7 kPa, only NFS (AUROC = 0.722) performed well (FIB-4 AUROC = 0.606; APRI = 0.647; HEPAmet = 0.629). Among the CAP cohort, the strongest FL predictor was obesity (OR: 15.2, 95% CI: 7.97-28.9, p < 0.001); the only fibrosis predictor was elevated AST (OR: 1.06, 95% CI: 1.00-1.12, p = 0.04). The addition of CAP or LSM as a second NIT reduced the number of indeterminate patients especially for FL. CONCLUSIONS: Regardless of diagnostic method in 2017-2018, the prevalence of NAFLD was >35%. NITs for FL performed well but not for advanced fibrosis. CAP and LSM as a second NIT reduced those considered indeterminate.

Identification of High-Risk Patients With Nonalcoholic Fatty Liver Disease in Endocrinology Clinics.

The twin epidemics of obesity and type 2 diabetes continue to increase worldwide, so does the associated chronic liver disease, nonalcoholic fatty liver disease (NAFLD). Although NAFLD has been thought of as a benign liver disease, current evidence suggests that it is a complex liver disease that, for approximately 20% of patients, can progress to fibrosis, cirrhosis, hepatocellular carcinoma, liver transplant, and death. It is important to note that, given NAFLD's association with metabolic syndrome, the number one cause of death among those with NAFLD is related to cardiovascular diseases. In addition, NAFLD is associated with impaired patient-reported outcomes and a significant economic burden. As such, efforts are now aimed at using noninvasive tests (NITs) to identify patients with NAFLD and those who are at risk of liver disease progression and adverse outcomes in endocrinology practices whereby appropriate risk stratification and referrals can be undertaken. In this review, we discuss the most common NITs used and provide a simple clinically relevant algorithm using these NITs to identify patients with NAFLD who are at risk of adverse outcomes and subsequent clinical management and referral.