Global perspective on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis - prevalence, clinical impact, economic implications and management strategies.

BACKGROUND: The metabolically-based liver disease, nonalcoholic fatty liver disease (NAFLD), is the most common cause of chronic liver disease currently affecting 38% of the world's adult population. NAFLD can be progressive leading to nonalcoholic steatohepatitis (NASH), liver transplantation, liver cancer, liver-related mortality and is associated with decreased quality of life from impaired physical functioning and increased healthcare resource utilisation. However, screening for NAFLD is cost-prohibitive but screening for high risk NAFLD (NAFLD with F2 fibrosis or greater) is imperative. AIM: To review the global perspective on NAFLD and NASH METHODS: We retrieved articles from PubMed using search terms NAFLD, prevalence, clinical burden, economic burden and management strategies. RESULTS: NAFLD/NASH shows geographical variation across the globe. Highest prevalence rates are in South America and the Middle East and North Africa; lowest prevalence is in Africa. NAFLD's economic impact is from direct and indirect medical costs and loss in worker productivity. It is projected that, over the next two decades, the total cost of NAFLD and diabetes will exceed $1.5 trillion (USD). Risk stratification algorithms identifying "high risk NAFLD" were made following non-invasive tests for NAFLD identification and fibrosis development. These algorithms should be used in primary care and endocrinology settings so timely and appropriate interventions (lifestyle and cardiometabolic risk factor management) can be initiated. CONCLUSIONS: To reduce the burgeoning burden of NAFLD/NASH, management should include risk stratification algorithms for accurate identification of patients, linkage to appropriate settings, and initiation of effective treatment regimens.

The Global Epidemiology of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis Among Patients With Type 2 Diabetes.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD), now known as metabolic dysfunction associated steatotic liver disease (MASLD), is closely associated with type 2 diabetes (T2D). Our aim was to estimate the most recent global prevalence of NAFLD/MASLD, nonalcoholic steatohepatitis (NASH), now known as metabolic dysfunction associated steatohepatitis (MASH), advanced fibrosis, and mortality among patients with T2D. METHODS: We systematically searched PubMed and Ovid MEDLINE for terms including NAFLD, NASH, and T2D published in 1990-2023 according to PRISMA. The meta-analysis was conducted using a random-effects model. Assessment of bias risk used the Joanna Briggs Institute appraisal tool. RESULTS: From 3134 studies included in the initial search, 123 studies (N = 2,224,144 patients with T2D) were eligible. Another 12 studies (N = 2733 T2D patients with liver biopsy) were eligible for histologic assessments. The global pooled prevalence of NAFLD/MASLD among patients with T2D was 65.33% (95% confidence interval, 62.35%-68.18%). This prevalence increased from 55.86% (42.38%-68.53%) in 1990-2004 to 68.81% (63.41%-73.74%) in 2016-2021 (P = .073). The highest NAFLD/MASLD prevalence among T2D patients was observed in Eastern Europe (80.62%, 75.72%-84.73%), followed by the Middle East (71.24%, 62.22%-78.84%), and was lowest in Africa (53.10%, 26.05%-78.44%). Among patients with liver biopsy data, the global pooled prevalence of NASH/MASH, significant fibrosis, and advanced fibrosis was 66.44% (56.61%-75.02%), 40.78% (24.24%-59.70%), and 15.49% (6.99%-30.99%), respectively. The pooled all-cause mortality was 16.79 per 1000 person-years (PY) (10.64-26.40), 4.19 per 1000 PY (1.34-7.05) for cardiac-specific mortality; 6.10 per 1000 PY (0.78-4.88) for extrahepatic cancer-specific mortality; and 2.15 per 1000 PY (0.00-2.21) for liver-specific mortality. CONCLUSIONS: The prevalence of NAFLD/MASLD among T2D is high and growing. The majority of NAFLD/MASLD patients with T2D have NASH/MASH, and a significant proportion have advanced fibrosis.

How to Identify Advanced Nonalcoholic Fatty Liver Disease in the Primary Care Setting.

Nonalcoholic fatty liver disease (NAFLD) affects 30 to 40% of the population globally and is increasingly considered the most common liver disease. Patients with type 2 diabetes, obesity, and cardiovascular diseases are at especially increased risk for NAFLD. Although most patients with NAFLD do not have progressive liver disease, some patients progress to cirrhosis, liver cancer, and liver mortality. Given the sheer number of patients with NAFLD, the burden of disease is enormous. Despite this large and increasing burden, identification of NAFLD patients at risk for progressive liver disease in the primary care and diabetology practice settings remains highly suboptimal. In this review, our aim is to summarize a stepwise approach to risk stratify patients with NAFLD which should help practitioners in their management of patients with NAFLD.

Nonalcoholic fatty liver disease (NAFLD) and associated mortality in individuals with type 2 diabetes, pre-diabetes, metabolically unhealthy, and metabolically healthy individuals in the United States.

BACKGROUND: The prevalence of nonalcoholic fatty liver disease (NAFLD) is high among subjects with type 2 diabetes (T2D). However, the prevalence and outcomes of NAFLD among individuals with pre-diabetes (PreD) and metabolically healthy and metabolically unhealthy individuals without T2D are not known. Our aim was to assess prevalence and mortality of NAFLD among these four groups. METHODS: The Third National Health and Nutrition Examination Survey (NHANES) III (1988-1994) with mortality data (follow up to 2019) via linkage to the National Death Index was utilized. NAFLD was defined by ultrasound and absence of other liver diseases and excess alcohol use. Pre-D was defined as fasting plasma glucose values of 100-125 mg/dL and/or HbA1c level between 5.7 %-6.4 % in the absence of established diagnosis of T2D. Metabolically healthy (MH) was defined if all of the following criteria were absent: waist circumference of ≥102 cm (men) or ≥ 88 cm (women) or BMI of ≥30; blood pressure (BP) ≥ 130/85 mmHg or using BP-lowering medication; triglyceride level ≥ 150 mg/dL or using lipid-lowering medication; lipoprotein cholesterol level of <40 mg/dL (men) or < 50 mg/dL (women); homeostasis model assessment of insulin resistance (HOMA-IR) score ≥ 2.5; C-reactive protein (CRP) level of >2 mg/L; Pre-D and T2D. Metabolically unhealthy (MU) individuals were defined as the presence of any component of metabolic syndrome but not having Pre-D and T2D. Competing risk analyses of cause-specific mortality were performed. FINDINGS: 11,231 adults (20-74y) were included: mean age 43.4 years; 43.9 % male; 75.4 % white, 10.8 % Black, and 5.4 % Mexican American, 18.9 % NAFLD, 7.8 % T2D; 24.7 % PreD; 44.3 % MU; and 23.3 % in MH individuals. In multivariable adjusted logistic model, as compared to MH individuals, the highest risk of having NAFLD were in T2D individuals (Odd Ratio [OR] = 10.88 [95 % confidence interval: 7.33-16.16]), followed by Pre-D (OR = 4.19 [3.02-5.81]), and MU (OR = 3.36 [2.39-4.71]). During a median follow up of 26.7 years (21.2-28.7 years), 3982 died. NAFLD subjects had significantly higher age-adjusted mortality than non-NAFLD (32.7 % vs. 28.7 %, p < .001). Among subjects with NAFLD, the highest age-standardized cumulative mortality was observed among those with T2D (41.3 %), followed by with Pre-D (35.1 %), MU subjects (30.0 %), and MH subjects (21.9 %) (pairwise p-values<.04 vs. MH). Multivariable adjusted cox models showed that NAFLD with T2D had a higher risk of all-causes and cardiac-specific deaths (Hazard Ratio [HR] = 4.71 [2.23-9.96] and HR = 20.01 [3.00-133.61]), followed by NAFLD with Pre-D (HR = 2.91 [1.41-6.02] and HR = 10.35 [1.57-68.08]) and metabolically unhealthy NAFLD (HR = 2.59 [1.26-5.33] and HR = 6.74 [0.99-46.03]) compared to metabolically healthy NAFLD. In addition to older age, independent predictors of mortality among NAFLD with T2D included high CRP, CVD, CKD, high FIB-4, and active smoking. Similarly, among NAFLD with PreD, high CRP, CKD, CVD, hypertension, and active smoking were associated with mortality. Finally, CVD and active smoking were predictors of mortality among metabolically unhealthy NAFLD, and active smoking was the only mortality risk among metabolically healthy NAFLD subjects. INTERPRETATION: Metabolic abnormality impacts both prevalence and outcomes of subjects with NAFLD.

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.

Vigorous physical activity provides protection against all-cause deaths among adults patients with nonalcoholic fatty liver disease (NAFLD).

BACKGROUND: Mortality benefits of vigorous leisure time physical activity (LTPA) among adults with NAFLD is not known. AIM: To investigate association between LTPA and reduction in all-cause mortality among adults with NAFLD. METHODS: We used NHANES (1999-2006) self-reported PA data for adults (≥40 years) with mortality follow-up through December 31, 2015. US-Fatty Liver Index in absence of secondary causes identified NAFLD. Moderate and vigorous LTPA were calculated by the 2018 PA Guidelines for Americans. RESULTS: NAFLD prevalence among 5211 adults (46.2% male; 75.8% white; mean age 53.2 years) was 32.7%. Adults with NAFLD were less likely to report the recommended minimal PA (≥ 150 min/week, 55.5% vs 64.8%) or highly active PA (≥300 min/week, 39.2% vs 48.5%) compared to adults without NAFLD. Over a median follow-up of 12.3 years, 355 deaths among adults with NAFLD and 510 deaths among adults without NAFLD were registered. In the metabolic comorbidities-adjusted model, adults with NAFLD who reported ≥50% of their total PA as vigorous activity had a 56% reduction in all-cause mortality risk (HR:0.44, 95%CI: 0.25-0.76) and cancer-specific mortality risk (HR: 0.21, 0.06-0.66) but not cardiac-specific mortality (p > 0.05) compared to adults with NAFLD who did not report any LTPA. This association remained significant even among adults with NAFLD who met the recommended minimal PA, among adults with NAFLD who reported any LTPA, and among adults with NAFLD who had metabolic abnormalities and in sensitivity analysis. CONCLUSIONS: Engaging in vigorous activity is beneficial for adults with NAFLD - especially those with metabolic abnormalities.

Sarcopenia, healthy living, and mortality in patients with chronic liver diseases.

Chronic liver diseases (CLDs) are associated with increased morbidity and mortality. Sarcopenia is an important complication of CLD that can be impacted by several modifiable risk factors. Our aim was to assess the associations between healthy living, sarcopenia, and long-term outcomes among patients with CLD. We used the Third National Health and Nutrition Examination Survey data with National Death Index-linked mortality files. We used the American Heart Association's Life's Simple 7 (LS7) metrics as surrogates of healthy living. The study included 12,032 subjects (34.9% CLDs [0.5% hepatitis B virus (HBV), 1.8% hepatitis C virus (HCV), 5.7% alcohol-associated liver disease (ALD), 26.9% nonalcoholic fatty liver disease (NAFLD)] and 65.1% controls). Prevalence of sarcopenia was higher among NAFLD than other CLDs and the controls (40.7% in NAFLD, 27.2% in ALD, 22.4% in HCV, 16.8% in HBV, and 18.5% in controls; p < 0.001). Among NAFLD and ALD, patients with sarcopenia were less likely to meet ideal LS7 metrics than those without sarcopenia. During 27 years of follow-up, among 4 patients with CLDs and the controls, all-cause cumulative mortality was highest among patients with HCV (35.2%), followed by ALD (34.7%) and NAFLD (29.6%). The presence of sarcopenia was associated with higher risk of all-cause mortality only among subjects with NAFLD (hazard ratio [HR] 1.24; 95% confidence interval [CI] 1.01-1.54; p = 0.04). Among subjects with NAFLD, presence of sarcopenia was associated with higher risk of cardiovascular-specific (HR 2.28 [1.71-3.05; p < 0.01]), cancer-specific (HR 1.90 [1.37-2.65]; p < 0.01), diabetes-specific (HR 6.42 [2.87-14.36]; p < 0.01), and liver-specific mortality (HR 2.49 [1.08-5.76]; p = 0.04). The multivariable model showed that component of LS7 metrics that provided the strongest protection against sarcopenia were ideal body mass index, ideal blood pressure, ideal physical activity, and ideal glycemic control among subjects with NAFLD subjects. Conclusions: Among subjects with NAFLD, sarcopenia is associated with a higher risk of all-cause mortality and liver mortality. Attainment of ideal LS7 metrics provides protection against sarcopenia in NAFLD.

Health-Related Quality of Life and Health Care Resource Utilization in Patients With Chronic Liver Disease and Primary Liver Cancer in the United States: Analysis of Medical Expenditure Panel Survey.

Background: Worldwide, liver cancer (LC) is the fifth and third most common type of cancer and cancer-related mortality, respectively. Our aim was to assess health-related quality of life (HRQL) and resource utilization in chronic liver disease (CLD) patients with LC. Methods: We used the Medical Expenditure Panel Survey 2004-2013. All patients had HRQL (Short Form-12, Patient Health Questionnaire-2, Kessler Psychological Distress Scale) and resource utilization data. We used patients with CLD without LC and colon cancer (CC) as controls. Results: A total of 1882 CLD patients (53 ± 14 years, 45% male, 53% white, 15% black, 23% Hispanic, 6% Asian, 42% employed, 48% private insurance, and 11% uninsured) were included. Of the cohort, 102 (5.4%) patients had LC. LC patients were older, more likely to be male and white, less employed but less likely uninsured than CLD patients without LC (all P < 0.05). In comparison to both non-LC CLD and CC controls, LC had worse health: 40% vs. 27% vs. 25% reported fair health and 29% vs. 20% vs. 16% poor health status (P < 0.05). Furthermore, LC patients more frequently reported physical limitations: 51% vs. 35% vs. 35%, respectively (P = 0.01). Physical HRQL scores were lower in LC patients compared with both CLD and CC controls. Although mental health scores in LC were similar to non-LC CLD controls, they were lower than in CC. In addition, most aspects of healthcare resource utilization were higher for LC patients compared with both non-LC CLD and CC controls. Conclusion: While having CLD causes impairment of patients' HRQL, LC further adds to this impairment and also contributes to a substantial resource utilization.

Independent Predictors of Mortality Among Patients With NAFLD Hospitalized With COVID-19 Infection.

The impact of the coronavirus disease 2019 (COVID-19) pandemic among patients with chronic liver disease is unknown. Given the high prevalence of nonalcoholic fatty liver disease (NAFLD), we determined the predictors of mortality and hospital resource use among patients with NAFLD admitted with COVID-19 by using electronic medical records data for adult patients with COVID-19 hospitalized in a multihospital health system who were discharged between March and December 2020. NAFLD was diagnosed by imaging or liver biopsy without other liver diseases. Charlson's comorbidity index (CCI) and Elixhauser comorbidity index (ECI) scores were calculated. In the study sample, among the 4,835 patients hospitalized for COVID-19, 553 had NAFLD (age: 55 ± 16 years, 51% male, 17% White, 11% Black, 58% Hispanic, 8% Asian, 5% from congregated living, 58% obese, 15% morbid obesity [body mass index ≥ 40], 51% type 2 diabetes, 63% hypertension, mean [SD] baseline CCI of 3.9 [3.2], and baseline ECI of 13.4 [11.3]). On admission, patients with NAFLD had more respiratory symptoms, higher body temperature and heart rate, higher alanine aminotransferase and aspartate aminotransferase than non-NAFLD controls (n = 2,736; P < 0.05). Of the patients with NAFLD infected with COVID-19, 3.9% experienced acute liver injury. The NAFLD group had significantly longer length of stay, intensive care unit use, and mechanical ventilation, with a crude inpatient mortality rate of 11%. In multivariate analysis, independent predictors of inpatient mortality among patients with NAFLD infected with COVID-19 were older age, morbid obesity, ECI score ≥ 11, higher Fibrosis-4 Index (FIB-4) score, and oxygen saturation <90% (all P < 0.05), but not sex, race/ethnicity, or any individual comorbidity (all P > 0.05). Conclusion: Patients with NAFLD infected with COVID-19 tend to be sicker on admission and require more hospital resource use. Independent predictors of mortality included higher FIB-4 and multimorbidity scores, morbid obesity, older age, and hypoxemia on admission.

Causes of death in patients with Non-alcoholic Fatty Liver Disease (NAFLD), alcoholic liver disease and chronic viral Hepatitis B and C.

INTRODUCTION AND OBJECTIVES: Cause of mortality in patients with chronic liver diseases (CLDs) may differ based on underlying etiology of liver disease. Our aim was to assess different causes of death in patients with the most common types of CLD using a national database from the United States. MATERIALS AND METHODS: Death data from 2008 and 2018 from the National Vital Statistics System (NVSS) by the National Center for Health Statistics (NCHS) were used. The rank of cause-of-death for each etiology of CLDs was assessed. Causes of death were classified by the ICD-10 codes. Liver-related deaths included liver cancer, cirrhosis and CLDs. RESULTS: Among a total of 2,826,531 deaths in 2018, there were 85,807 (3.04%) with underlying CLD (mean age at death 63.0 years, 63.8% male, 70.8% white). Liver-related mortality was the leading cause of death for all types of CLD [45.8% in non-alcoholic fatty liver disease (NAFLD), 53.0% in chronic hepatitis C (CHC), 57.8% in chronic hepatitis B (CHB), 81.8% in alcoholic liver disease (ALD)]. This was followed by death from cardiac causes (NAFLD 10.3%, CHC 9.1%, CHB 4.6%, ALD 4.2%) and extrahepatic cancer (NAFLD 7.0%, CHC 11.9%, CHB 14.9%, ALD 2.1%). Although liver cancer was the leading cause of cancer death, lung, colorectal and pancreatic cancer were also common causes of cancer death. CONCLUSIONS: Among deceased patients with CLD, underlying liver disease was the leading cause of death. Among solid cancers, liver cancer was the leading cause of cancer-related mortality.

Performance of the Enhanced Liver Fibrosis Test to Estimate Advanced Fibrosis Among Patients With Nonalcoholic Fatty Liver Disease.

Importance: The most important surrogate for increased risk of adverse clinical outcomes among patients with nonalcoholic fatty liver disease (NAFLD) is the patient's stage of liver fibrosis. There is a significant barrier to risk-stratifying patients in clinical practice owing to the need for liver biopsy. Objective: To determine the performance of the enhanced liver fibrosis (ELF) test as a noninvasive test for assessment of liver fibrosis among patients with NAFLD. Design, Setting, and Participants: This retrospective cross-sectional study was conducted among patients recruited from a large, community-based hospital system's outpatient liver clinic from 2001 to 2020. Patients with NAFLD defined as steatosis greater than 5% without evidence of other liver disease or excessive alcohol use were included. Data were analyzed from August 2020 through February 2021. Intervention: Enhanced liver fibrosis score was calculated. Main Outcomes and Measures: Advanced fibrosis was identified by liver biopsy or transient elastography. Results: Among 829 patients with NAFLD, the mean (SD) age was 53.1 (14.0) years, there were 363 (43.8%) men, 294 patients (35.5%) had type 2 diabetes, and the mean (SD) fibrosis-4 (fib-4) score was 1.34 (0.97). There were 463 patients with liver biopsy, among whom 113 individuals (24.4%) had bridging fibrosis or cirrhosis; among 462 patients with transient elastography data, 79 individuals (17.1%) had liver stiffness results of 9.6 kPa or more (ie, advanced fibrosis). Patients with advanced fibrosis had statistically significantly increased mean (SD) ELF scores compared with patients without advanced fibrosis as determined by biopsy (10.1 [1.3] vs 8.6 [1.0]; P < .001) or transient elastography (10.0 [1.1] vs 9.0 [0.8]; P < .001). Among all patients with NAFLD, the area under the receiver operating characteristic curve (AUROC) for ELF in identifying patients with advanced fibrosis was 0.81 (95% CI, 0.77-0.85) for patients diagnosed by biopsy and 0.79 (95% CI, 0.75-0.82) for those diagnosed by transient elastography. Performance of the ELF score was similar among patients with NAFLD who were aged 65 years or older (AUROC, 0.74; 95% CI, 0.58-0.87) or had type 2 diabetes (AUROC, 0.78; 95% CI, 0.71-0.84). The combination of an ELF score of 7.2 or greater with a fib-4 score of 0.74 or greater was associated with a negative predictive value of 95.1% (95% CI, 91.8%-98.4%) and a sensitivity of 92.5% (95% CI, 87.4%-97.5%), which can reliably rule out advanced fibrosis. An ELF score of 9.8 or greater with a fib-4 score of 2.9 or greater was associated with a positive predictive value of 95.0% (95% CI, 85.5%-100%) and a specificity of 99.7% (95% CI, 99.1%-100%), which can be used to rule in advanced fibrosis. Conclusions and Relevance: These findings suggest that the ELF test performs well in identifying patients with NAFLD who are at increased risk of advanced fibrosis and that this test combined with fib-4 score may be reliably used in clinical practice to assess the presence or absence of advanced fibrosis among patients with NAFLD.

Burden of non-alcoholic fatty liver disease in Asia, the Middle East and North Africa: Data from Global Burden of Disease 2009-2019.

BACKGROUND & AIM: Non-alcoholic fatty liver disease (NAFLD) has become a major cause of chronic liver disease (CLD) worldwide. Our aim was to assess the burden of liver complications (LC, cirrhosis and liver cancer) related to NAFLD (LC-NAFLD) between 2009-2019 in Asia and the Middle East and North Africa (MENA) region. METHODS: We used Global Burden of Disease data to assess incidence, mortality, and disability-adjusted life years (DALYs) for LC-NAFLD from Asia and the MENA region. Annual % change (APC) in rates were computed using a joinpoint regression model. Associations of LC-NAFLD with low physical activity, diet and metabolic risks were determined by partial Spearman correlation coefficients (ρ). RESULTS: Globally in 2019, there were 170,000 incident cases of LC-NAFLD, accounting for 6.6% of LC incident cases from all CLDs. There were 168,969 deaths related to LC-NAFLD, accounting for 8.6% of LC deaths from all CLDs. Asia accounted for 48.3% of the global incidence of LC-NAFLD and for 46.2% of deaths attributable to LC-NAFLD, while MENA accounted for 8.9% and 8.6%, respectively. There were 2.08 million DALYs in Asia and 340,000 DALYs in MENA. From 2009 to 2019, regions in Asia and MENA experienced a rise in DALYs attributable to LC-NAFLD (compared to LC from other CLDs), ranging from South Asia (APC = +2.12% vs. -0.94%) to high-income Asia Pacific (APC = -0.07%, p = 0.646 vs. -0.97%). In Asia, NAFLD-related DALYs were significantly correlated with dietary risks (95% CI 0.280-0.763, p = 0.004), metabolic risks (0.341-0.790, p <0.001) and tobacco use (0.134-0.691, p = 0.007). In MENA, low physical activity (0.557-0.918, p <0.001), metabolic risks (0.432-0.888, p = 0.001), and dietary risks (0.315-0.855, p = 0.001) correlated with DALYs. CONCLUSIONS: NAFLD is posing a substantial burden in Asia and MENA. About half of the global burden of LC-NAFLD is accounted for by these regions. LAY SUMMARY: Non-alcoholic fatty liver disease (NAFLD) has emerged as one of the most common causes of chronic liver disease worldwide. We used Global Burden of Disease data to assess the incidence, mortality, and disability-adjusted life years attributable to NAFLD-related liver complications in Asia, the Middle East and North Africa. NAFLD is poised to contribute to a substantial liver disease burden in these regions. Regional and global policies are needed to address the increasing burden of complications of NAFLD.

The Growing Burden of Disability Related to Chronic Liver Disease in the United States: Data From the Global Burden of Disease Study 2007-2017.

Chronic liver disease (CLD) causes significant morbidity and mortality in the United States with regional variations. Comparable and consistent state-level measures of CLD-related morbidity and disability among U.S. states have not been well studied. Our aim was to assess the CLD burden within the United States between 2007 and 2017 based on the most common causes of CLD: hepatitis B virus, hepatitis C virus (HCV), alcoholic liver disease (ALD), and nonalcoholic fatty liver disease (NAFLD). The Global Burden of Disease database was used for the years 2007-2017. International Classification of Diseases, Tenth Revision, codes were used to identify liver cancer (LC) and cirrhosis. Disability-adjusted life years (DALYs) were computed by the summation of years of life lost and years lived with disability. All rates reported here were age-standardized rates per 100,000 population. In 2017, there were 167,324 incident CLDs, 21% from LC and 79% from cirrhosis; this number was 30% higher than in 2007. The highest rate increases were seen in Kentucky, New York, and Pennsylvania. In 2017, there were 90,046 CLD-related deaths, which was 34% higher than in 2007. Highest rank increases were seen in Kentucky, Montana, and Washington. The rate of CLD incidence and death due to NAFLD was higher than other causes of CLD. In 2017, CLD caused 2.33 million DALYs, which was 27% higher than in 2007 and was mainly driven by HCV (37.2%), ALD (27.7%), and NAFLD (10.6%). California, Texas, and Florida had the highest DALYs; however, the highest CLD-DALY rates per 100,000 population were seen in New Mexico, District of Columbia, and Oklahoma. Conclusion: The CLD-related burden is increasing in the majority of U.S. states at an unprecedented rate. The impact of this burden on individual states is heterogeneous, and there are important disparities among states that merit further investigation.

Performance of Noninvasive Liver Fibrosis Tests in Morbidly Obese Patients with Nonalcoholic Fatty Liver Disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is highly prevalent in morbidly obese patients, and fibrosis is an independent predictor of mortality. Noninvasive tests (NITs) are being developed for the detection of advanced fibrosis (AF). PURPOSE: To assess the performance of three NITs (NAFLD fibrosis score, NFS, fibrosis-4 index, FIB-4, and aspartate aminotransferase-to-platelet ratio, APRI), in the identification of AF among morbidly obese patients. MATERIALS AND METHODS: Patients, who underwent bariatric surgery between 2004 and 2009 and had liver biopsy, were included. Fibrosis stages ≥ F2 and ≥ F3 were defined as significant and AF, respectively. Published and optimal thresholds (Youden index) for NFS, FIB-4 and APRI, sensitivity, specificity, positive and negative predictive values (PPV-NPV), and area under the receiver operator curves (AUROC) were evaluated. RESULTS: Among 584 patients (mean age 43.3 ± 11.3 years, 21.2% male, 75% white, mean BMI 45.5 ± 8.80), 31.7% had NASH. Stages distributions were F1 = 68.1%, F2 = 16.4%, F3 = 8%, and F4 = 3.2%. At published thresholds, all 3 NITs performed poorly for detection of AF, with AUROC < 0.62. Overall performance at optimal thresholds improved to 0.68, 0.72, and 0.74 for NFS, FIB-4, and APRI, respectively. At optimal thresholds, all tests had good NPV (94.4-95.9%) but low PPV (24.2-32.5%). Combinations of the tests did not improve their performance. CONCLUSIONS: NFS, FIB-4, and APRI fall short to detect advanced fibrosis but valuable for excluding advanced fibrosis. More research is needed to develop new NITs with high positive predictive value.

The Growing Burden of Disability Related to Nonalcoholic Fatty Liver Disease: Data From the Global Burden of Disease 2007-2017.

Chronic liver disease (CLD) is a growing cause of morbidity and mortality worldwide. The burden of CLD varies according to etiology and geographic location. We assessed the global burden of disability from the most important complications of CLD (cirrhosis and liver cancer [LC]) according to the most common etiologies between 2007 and 2017. We obtained years living with disability (YLD), years of life lost (YLL), and disability-adjusted life-years (DALYs) data from the Global Burden of Disease 2017 study. Between 2007 and 2017, LC DALYs decreased by 4.52% and cirrhosis DALYs decreased by 10.58%. Nevertheless, in 2017, CLD caused 62.16 million DALYs (33.4% LC and 66.5% cirrhosis), of which 96.8% came from YLL (34.1% LC and 65.9% cirrhosis) and 3.2% from YLD (11.6% LC and 88.4% cirrhosis). In 2017, Asia accounted for 66% of all DALYs globally. Central Asia, Africa regions, Southeast Asia, and Eastern Europe had the highest liver-related DALYs (≥1,000 per 100,000), whereas the lowest rates (≤500 per 100,000) were seen in high-income regions, such as Asia Pacific, North America, Western Europe, and Australasia. In 2007, hepatitis B virus caused the majority (47.5%) of liver-related DALYs, followed by hepatitis C virus (23.7%), alcoholic liver disease (14.2%), and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) (6.4%). In 2017, these rates shifted to 45.7%, 24.1%, 4.8%, and 7.1%, respectively. Between 2007 and 2017, cirrhosis-related DALYs due to NAFLD/NASH increased by 23.4%, whereas the increment was 37.5% for LC-related DALYs due to NAFLD/NASH. Conclusion: DALYs due to viral hepatitis still account for the largest proportion of CLD-related DALYs. Although DALYs from all other liver diseases have remained stable in the last decade, DALYs related to NAFLD/NASH are growing. National, regional, and global policies are needed to address the disability burden of NAFLD across the world.

Contribution of sarcopenia and physical inactivity to mortality in people with non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Physical inactivity and sedentary lifestyle have contributed to the epidemic of obesity and non-alcoholic fatty liver disease (NAFLD). We assessed the association between physical activity, NAFLD, and sarcopenia, and their contributions to mortality. METHODS: Data from the National Health and Nutrition Examination Survey (NHANES) 1999-2004 with Linked Mortality file (through 2015) was utilised. NAFLD was determined by the US Fatty Liver Index in the absence of secondary causes of liver disease. Sarcopenia was defined using appendicular lean mass divided by body mass index by the Foundation for the National Institutes of Health criteria. Activity level was determined using standard self-reports. Publicly available imputed dual-energy X-ray absorptiometry data sets were used. RESULTS: Of 4,611 NHANES participants (48.2% males; 72.5% White; mean age 45.9 years), NAFLD was present in 1,351 (29.3%), of whom 17.7% had sarcopenia. Of the NAFLD group, 46.3% was inactive, whilst intermediate and ideal physical activity rates were observed in 14.2% and 39.5%, respectively. Sarcopenia was significantly and inversely related to higher physical activity level, both amongst NAFLD (odds ratio [OR] = 0.45 [95% CI 0.30-0.69]) and non-NAFLD (OR = 0.51 [0.35-0.75]) groups. During a median follow-up of 13.5 years, a total of 586 subjects died, of whom 251 had NAFLD. Amongst those who died with NAFLD, 33.0% had sarcopenia and 54.3% were inactive. Compared with NAFLD without sarcopenia, NAFLD with sarcopenia was associated with a higher risk of all-cause (hazard ratio [HR] = 1.78 [1.16-2.73]), cardiac-specific (HR = 3.19 [1.17-8.74]), and cancer-specific mortality (HR = 2.12 [1.08-4.15]). CONCLUSIONS: Inactivity is associated with presence of sarcopenia, whilst sarcopenia is associated with increased mortality amongst NAFLD patients. Sarcopenia should be a part of clinical assessment of patients with NAFLD. Treatment of NAFLD should include optimal management of sarcopenia. LAY SUMMARY: Nonalcoholic fatty liver disease (NAFLD) and sarcopenia have similar pathophysiological profiles. Our data show that sarcopenia is associated with inactivity in subjects with NAFLD. The presence of sarcopenia in patients with NAFLD poses increased risk for all-cause and cardiac-specific mortality.

Mortality of NAFLD According to the Body Composition and Presence of Metabolic Abnormalities.

Although nonalcoholic fatty liver disease (NAFLD) is associated with obesity, it can also occur in lean and metabolically normal individuals. Our aim was to determine the effect of different combinations of abdominal adiposity and overall adiposity on the mortality of NAFLD. The Third National Health and Nutrition Examination Survey with mortality data from the National Death Index were used. NAFLD was defined as steatosis without other liver diseases. Body composition was categorized according to waist circumference (WC) and body mass index (BMI). Obesity pattern was defined according to BMI (lean, overweight, and obese) and WC (normal and obese) using accepted definitions. The "metabolically abnormal" group had visceral obesity, insulin resistance, type 2 diabetes, hypertension, or hyperlipidemia. Of the 9,341 study individuals (47.9% male; 76.8% white), NAFLD was present in 3,140 (33.6%), of whom 0.6% had lean BMI and normal WC, and 1.7% had lean BMI and obese WC. The prevalence of metabolically normal NAFLD was 3.26% (95% confidence interval [CI]: 2.62%-3.90%), with most of these subjects having lean BMI (79.2%). During an average follow-up of 22.4 years, 24.1% of the subjects died from all causes. Among these deceased individuals, 41.7% had NAFLD at baseline. Causes of death were cardiovascular disease (24.8%), cancer-related (24.3%), type 2 diabetes-related (4.4%), and liver-related (1.7%). Individuals with NAFLD who were lean by BMI but obese by WC had higher risk of all-cause mortality. Individuals with NAFLD with normal BMI but obese WC had a higher risk of cardiovascular mortality (hazard ratio 2.63 [95% CI: 1.15-6.01]) as compared with overweight (by BMI) NAFLD with normal WC. Conclusion: The risk of mortality in NAFLD can be affected by the presence of visceral obesity, especially in the lean BMI group. These data have important management implications for patients with NAFLD.

Nonalcoholic Fatty Liver Disease and Alcoholic Liver Disease are Major Drivers of Liver Mortality in the United States.

In the United States, chronic viral hepatitis B and C (CHB and CHC), nonalcoholic fatty liver disease (NAFLD), and alcohol-related liver disease (ALD) are the main causes of liver deaths attributable to hepatocellular carcinoma (HCC) and cirrhosis. Our aim was to assess the changes in the rates of mortality and years of potential life lost (YLL) for HCC and cirrhosis due to different liver diseases. We used multiple-cause mortality data (2007-2017) from the National Center for Health Statistics. Annual percentage change (APC) in age-standardized death rate per 100,000 (ASDR) and age-standardized years of life lost per 100,000 (ASYLLR) were calculated. In the United States in 2017, there were 2,797,265 deaths with 73,424 liver deaths, contributing to 1,467,742 of YLL. Of the liver deaths, HCC was noted in 12,169 (16.6%) and cirrhosis in 60,111 (82.0%). CHC was responsible for 50.4% of HCC deaths; NAFLD, 35.4%; HBV, 6.0%; ALD, 5.4%; and others, 2.8%. NAFLD was responsible for 48.9% of cirrhosis deaths; ALD, 34.7%; CHC, 12.3%; CHB, 0.9%; and others, 3.2%. Between 2007 and 2017, the increase in ASDR for HCC due to ALD and NAFLD accelerated after 2014 (APC, 11.38% and 6.55%, respectively) whereas CHC stabilized (APC, 0.63%; P = 0.272) after 2011. The increase in ASYLLR of HCC escalated after 2014 for ALD and NAFLD (APC, 12.12% and 6.15%, respectively) and leveled out for CHC after 2012 (APC, -1.05%; P = 0.056). Furthermore, the highest annual increase in ASDR and ASYLLR for cirrhosis was due to ALD (APC, 3.24% and 3.34%, respectively) followed by NAFLD (APC, 1.23% and 0.49%, respectively). Conclusion: Over the past decade, ASDR and ASYLLR due to ALD and NAFLD have been increasing in the United States. The rising burden of HCC and cirrhosis are primarily driven by NAFLD and ALD.

Extrahepatic manifestations and healthcare expenditures of non-alcoholic fatty liver disease in the Medicare population.

BACKGROUND AND AIM: Non-alcoholic fatty liver disease (NAFLD) is a very common liver disease which has been associated with a number of the extrahepatic manifestations (EHMs) and healthcare expenditures. Our aim was to assess the presence and impact of these EHMs of NAFLD on mortality and healthcare expenditures. METHODS: Medicare beneficiaries (2005-2016) were included. ICD-9 and ICD-10 codes were used to identify patients with NAFLD and EHMs which included cardiovascular disease (CVD), hypertension (HTN), diabetes (DM), hyperlipidemia (HL), non-hepatocellular carcinoma (HCC) cancers, and others. Temporal trends among different groups were analyzed by join point regression model. Independent predictors of outcomes were evaluated in multiple generalized linear or logistic regression models. RESULTS: Among 30,908,679 Medicare beneficiaries (5% sample of Medicare data from 2005-2016), 1,980,950 (6.4%) had NAFLD diagnosis. From 2005 to 2016, the prevalence of NAFLD in the Medicare population increased at an average annual increase of 3.1%. The most common diseases associated with NAFLD were DM (86.3%), followed by HTN (85.2%), HL (79.8%), and CVD (35.8%). One-year mortality rate in NAFLD patients increased from 3.55 to 6.33 per 1000 from 2005 to 2016. One-year mortality was independently associated with diagnosis of HCC, cirrhosis, DM (outpatient), depression, dementia, lung disease, renal failure, thyroid disorder (inpatient), neurological disorder as well as non-HCC cancers. CONCLUSION: NAFLD is associated with a number of EHMs that increases its mortality and increased healthcare expenditure.