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 such as primary biliary cholangitis (PBC), chronic hepatitis C viral infection (HCV) and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), 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 PBC, HCV and MASLD. As such, 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 fatigue is comprised of peripheral (neuromuscular failure, often in conjunction with sub-maximal 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 HCV and MASLD can improve levels of fatigue and HRQL, but current treatments for PBC do not seem to affect levels of fatigue. We conclude that obtaining PRO data to include HRQL and fatigue are essential for determining the comprehensive burden of CLD and its potential treatments. IMPACT AND IMPLICATIONS: Fatigue is a complex phenomenon associated with both a peripheral cause (neuromuscular failure and sub-maximal cardiorespiratory function) and a central cause (central nervous system dysfunction). Although fatigue is common among patients with CLD, it does not always correlate with the severity of the liver disease, but fatigue is related with significant decreases in patients' health related quality of life (HRQL). Appreciating the impact of fatigue using validated self-report measurements is important to better understand the burden of CLD and the effectiveness of treatment.

The burden of nonalcoholic fatty liver disease (NAFLD) is rapidly growing in every region of the world from 1990 to 2019.

BACKGROUND: The latest meta-analyses suggest NAFLD is increasing globally. Its limitations may preclude accurate estimates. We evaluated the global NAFLD burden and its' trends in prevalence and NAFLD liver-related mortality (LRM) by sex, age, region, and country over the past 3 decades using data from the Global Burden of Disease (GBD) 2019 study. METHODS: Crude and age-standardized NAFLD prevalence and NAFLD-LRM rates were obtained for all-age individuals with NAFLD from 204 countries/territories between 1990 and 2019. Joinpoint trend analysis assessed time trends. Weighted average of the annual percent change (APC) over the period 1990-2019 and 2010-2019 were reported. RESULTS: All-age (children and adults) crude global NAFLD prevalence increased:10.5% (561 million)-16.0% (1,236 million); an APC increase: + 1.47% (95% CI, 1.44%, 1.50%). Among adults (+20 y), crude NAFLD prevalence increased (1990: 17.6%, 2019:23.4%; APC: + 1.00%, 95% CI: 0.97%, 1.02%). In all-age groups, the crude NAFLD-LRM rate (per 100,000) increased (1990: 1.75%, 2019: 2.18%; APC: + 0.77% (95% CI, 0.70%, 0.84%). By Joinpoint analysis, from 2010 to 2019, worsening all-age trends in NAFLD prevalence and LRM were observed among 202 and 167 countries, respectively. In 2019, there were 1.24 billion NAFLD prevalent cases and 168,969 associated deaths; Asia regions accounted for 57.2% of all-age prevalent cases and 46.2% of all-age NAFLD-LRM. The highest all-age crude NAFLD prevalence rate was the Middle East and North Africa (LRM 26.5%); the highest all-age crude NAFLD-LRM rate was Central Latin America (5.90 per 100,000). CONCLUSIONS: NAFLD is increasing globally in all-age groups-over 80% of countries experienced an increase in NAFLD and NAFLD-LRM. These data have important policy implications for affected countries and for global health.

Nonalcoholic fatty liver disease mortality may not be decreasing: A need for careful interpretation of GBD 2019 estimates of liver deaths.

The Global Burden of Disease (GBD) data provide information on population health; however, careful understanding of the estimation methods and limitations of these data is critical. Herein, Paik et al. discuss the recent study by Chew and colleagues in the context of these limitations, highlighting how a worsening trend in NAFLD-liver mortality may have been underestimated in the analysis.

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 Growing Economic and Clinical Burden of Nonalcoholic Steatohepatitis (NASH) in the United States.

Background: Nonalcoholic steatohepatitis (NASH) is a cause of chronic liver disease. Aim: Model the burden of NASH in the United States according to obesity. Methods: The discrete-time Markov model comprised adult NASH subjects moving through 9 health states and 3 absorbing death states (liver, cardiac, and other deaths) with 1-year cycles and a 20-year horizon. Given that reliable natural history data for NASH are not available, transition probabilities were estimated from the literature and population-based data. These rates were disaggregated to determine age-obesity group rates by applying estimated age-obesity patterns. The model considers 2019 prevalent NASH cases and new incident NASH cases (2020-2039), assuming that recent trends will continue. Annual per-patient costs by health state were based on published data. Costs were standardized to 2019 US dollars and inflated by 3% annually. Results: NASH cases in the United States are forecasted to increase by +82.6%, from 11.61 million (2020) to 19.53 million (2039). During the same period, cases of advanced liver disease increased +77.9%, from 1.51 million to 2.67 million, while its proportion remained stable (13.46%-13.05%). Similar patterns were observed in both obese and non-obese NASH. Among NASH, 18.71 million overall deaths, 6.72 million cardiac-specific deaths, and 1.71 million liver-specific deaths were observed by 2039. During this period, the projected cumulative direct healthcare costs were $1208.47 billion (obese NASH) and $453.88 billion (non-obese NASH). By 2039, the projected NASH attributable healthcare cost per patient increased from $3636 to $6968. Conclusions: There is a substantial and growing clinical and economic burden of NASH in the United States.

Nonalcoholic Fatty Liver Disease: Disease Burden and Disease Awareness.

Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide and has been implying an unprecedented burden to health care systems. The prevalence of NAFLD has exceeded 30% in developed countries. Considering the asymptomatic nature of undiagnosed NAFLD, high suspicion and noninvasive diagnosis have utmost importance especially in primary care level. At this point, patient and provider awareness should be optimal for early diagnosis and risk stratification for patients at risk of progression.

Economic Burden and Patient-Reported Outcomes of Nonalcoholic Fatty Liver Disease.

In addition to adverse clinical outcomes such as liver-related morbidity and mortality, nonalcoholic fatty liver disease (NAFLD) is associated with a substantial public health and economic burden and could also potentially impair health-related quality of life and other patient-reported outcomes. The disease also affects multiple aspects of patients' quality of life which are the most pronounced in physical health-related and fatigue domains as well as work productivity, and get more severe in patients with advanced liver disease or with non-hepatic comorbidities. The economic burden of NAFLD is substantial and is increasing, with the highest costs in those with advanced disease.

Healthcare and socioeconomic costs of NAFLD: A global framework to navigate the uncertainties.

Left unaddressed, non-alcoholic fatty liver disease (NAFLD) will continue to have substantial health, economic and social implications. To address the challenge, a paradigm shift is needed in the way NAFLD is conceptualised. Concerted, collaborative action across medical specialities, industry sectors and governments will be vital in tackling this public health threat. To drive this change, in this review, we present data on the current global healthcare and socioeconomic costs of NAFLD and highlight priority actions. The estimated healthcare costs of patients with NAFLD are nearly twice as high as their age-matched counterparts without the disease and are highest in those with advanced fibrosis and end-stage liver disease. NAFLD is accountable for the highest increase in DALYs (disability-adjusted life years) among all liver diseases globally. NAFLD and non-alcoholic steatohepatitis (NASH)-specific drug therapies are not yet available and there is considerable uncertainty regarding cost, optimal length of treatment, and their impact on liver-related outcomes and mortality. Among the currently available bariatric procedures, sleeve gastrectomy is reported to be the most cost-effective for NASH resolution. Gastric bypass remains very expensive, while data on bariatric endoscopy are limited. Lastly, we propose a global NAFLD/NASH investment framework to guide the development of achievable yet ambitious country-specific targets and strategic actions to optimise resource allocation and reduce the prevalence of NAFLD and NASH. Its focus on high-level inputs will be critical to enabling a political and financial environment that supports clinical-level implementation of NAFLD prevention, treatment and care efforts, across all settings.

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.

Reliability of histologic assessment for NAFLD and development of an expanded NAFLD activity score.

BACKGROUND AND AIMS: The NASH Clinical Research Network histologic scoring system, the gold-standard NASH histology assessment for clinical trials, has demonstrated intrarater and interrater variability. An expert panel in a previous systematic Research and Development/University of California Los Angeles (RAND/UCLA) study determined that existing histologic scoring systems do not fully capture NASH disease activity and fibrosis, and standardized definitions of histologic features are needed. We evaluated the reliability of existing and alternate histologic measures and their correlations with a disease activity visual analog scale to propose optimal components for an expanded NAFLD activity score (NAS). APPROACH AND RESULTS: Four liver pathologists who were involved in the prior RAND/UCLA study underwent standardized training and multiple discussions with the goal of improving agreement. They were blinded to clinical information and scored histologic measures twice, ≥2 weeks apart, for 40 liver biopsies representing the full spectrum of NAFLD. Index intraclass correlation coefficient (ICC) estimates demonstrated intrarater (0.80-0.85) and interrater (0.60-0.72) reliability. Hepatocyte ballooning items had similar interrater ICCs (0.68-0.79), including those extending scores from 0-2 to 0-4. Steatosis measures (interrater ICCs, 0.72-0.80) correlated poorly with disease activity. Correlations with disease activity were largest for hepatocyte ballooning and Mallory-Denk bodies (MDBs), with both used to develop the expanded NAS (intrarater ICC, 0.90; interrater ICC, 0.80). Fibrosis measures had ICCs of 0.70-0.87. CONCLUSIONS: After extensive preparation among a group of experienced pathologists, we demonstrated improved reliability of multiple existing histologic NAFLD indices and fibrosis staging systems. Hepatocyte ballooning and MDBs most strongly correlated with disease activity and were used for the expanded NAS. Further validation including evaluation of responsiveness is required.

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.

Dietary Risks for Liver Mortality in NAFLD: Global Burden of Disease Data.

Nonalcoholic fatty liver disease (NAFLD) is a common but complex chronic liver disease, driven by environmental and genetic factors. We assessed metabolic and dietary risk factor associations with NAFLD liver mortality using the Global Burden of Disease (GBD) 2017 data. NAFLD liver deaths were calculated (per 100,000) as age-standardized rates (ASRs) from 195 countries and territories (21 GBD regions; 7 GBD superregions). Dietary risks included low intake of fruits, vegetables, legumes, whole grains, nuts/seeds, milk, fiber, calcium, seafood omega-3 fatty acids, and polyunsaturated fatty acids, and high intake of red meat, processed meat, sugar-sweetened beverages, trans fatty acids, and sodium. Metabolic risks included high low-density lipoprotein cholesterol, systolic blood pressure (BP), fasting glucose (FG), body mass index (BMI), as well as low bone mineral density and impaired kidney function (IKF). Socio-demographic index (SDI)-adjusted partial Spearman correlation coefficients and multivariable generalized linear regression models/bidirectional stepwise selection (significance level for entry, 0.2; for stay, 0.05) determined the associations. The ASR for NAFLD liver deaths was 2.3 per 100,000 (2017) and correlated with dietary risk factors (0.131, -0.010-0.267) and metabolic risk factors (SDI-adjusted = 0.225, 95% CI 0.086-0.354). High intake of sugar-sweetened beverages and red meat (0.358, 0.229-0.475; 0.162, 0.022-0.296), and low intake of nuts/seed and milk (0.154, 0.014-0.289; 0.145, 0.004-0.280) was significant for NAFLD liver deaths. Other risk factors for liver death included IKF (0.402, 0.276-0.514), increased BMI (0.353, 0.223-0.407), FG (0.248, 0.111-0.376), and BP (0.163, 0.022-0.297). High intake of trans fatty acids (2.84% increase [1.65%-4.03%]) was the largest associated risk of NAFLD liver deaths. In addition to metabolic risks, dietary risks independently drive the global burden of NAFLD-related liver mortality. Conclusion: These data provide additional support for policies to improve dietary environment for NAFLD burden reduction.

The impact of hepatocellular carcinoma diagnosis on patients' health-related quality of life.

BACKGROUND: Patients with hepatocellular cancer (HCC) are known to have worse health-related quality of life (HRQL) than the general population. However, the change in HRQL from before the diagnosis to after diagnosis remains unknown and is difficult to estimate. We aimed to compare HCC cases with matched controls to evaluate the differences in change in HRQL from before to after HCC diagnosis. METHODS: We performed propensity score-matched analysis using the self-reported HRQL data from the Surveillance, Epidemiology, and End Results registries (SEER) data linked with Medicare Health Outcomes Survey (MHOS) data (1998-2014). Cases were selected as Medicare beneficiaries (aged ≥65 years) who were diagnosed with HCC between their baseline assessment and follow-up assessment. Matched controls were selected from the same data resource and the same time period to include subjects without cancer diagnosis by propensity scores. HRQL was assessed using the Medical Outcomes Study Short Form-36 (SF-36). RESULTS: The study included 62 subjects who developed HCC and 365 matched controls. Compared to their baseline HRQL scores, after diagnosis of HCC, subjects were more likely to report declines in scores related to the mental component of HRQL. When stratified by time since diagnosis, mental component remained significantly lower as the disease advanced. In contrast, only general health aspects of physical health worsened after HCC diagnosis. CONCLUSIONS: Diagnosis of HCC has a profound negative impact on patients' HRQL. Mental health component deteriorated significantly over time. The need of including mental health services within a multidisciplinary HCC care model is clearly evident.

Defining comprehensive models of care for NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is now the leading cause of chronic liver disease globally. Despite the increased demand placed on health-care systems, little attention has been given to the design and implementation of efficient and effective models of care for patients with NAFLD. In many health-care settings, no formal pathways exist and, where pathways are in place, they are often not standardized according to good practices. We systematically searched the peer-reviewed literature with the aim of identifying published examples of comprehensive models of care that answered four key questions: what services are provided? Where are they provided? Who is offering them? How are they coordinated and integrated within health-care systems? We identified seven models of care and synthesized the findings into eight recommendations nested within the 'what, where, who and how' of care models. These recommendations, aimed at policy-makers and practitioners designing and implementing models of care, can help to address the increasing need for the provision of good practice care for 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 global burden of cirrhosis: A review of disability-adjusted life-years lost and unmet needs.

Cirrhosis is a burden on the individual and on public health. The World Health Organization's metric of public health burden is the disability-adjusted life-year (DALY), the sum of years of life lost due to premature death and years of life lived with disability. The more DALYs attributable to a disease, the greater its burden on public health. Cirrhosis was responsible for 26.8% fewer DALYs in 2019 than in 1990, which is positive, but the reduction in DALYs across the spectrum of diseases in and outside the liver was 34.4%. Hepatitis C (26% of DALYs), alcohol (24%), and hepatitis B (23%) contribute almost equally to the global burden of cirrhosis. The contribution from non-alcoholic fatty liver disease (8%) is small but increasing. There is substantial global variation in the burden and causes of cirrhosis. We find that the poorest countries carry the greatest burden of cirrhosis, and that this burden is primarily caused by cirrhosis from hepatitis B infection. Interventions targeting hepatitis B infection are known, but not fully implemented. In more affluent countries, alcohol and hepatitis C are the dominant causes of cirrhosis, but non-alcoholic fatty liver will likely become a dominant cause of cirrhosis in parallel with the increasing prevalence of obesity. We also argue that the World Health Organization underestimates the public health burden associated with cirrhosis because it assigns zero disability to compensated cirrhosis and considers decompensated cirrhosis as only mildly disabling.

Patient-reported outcomes in patients with non-alcoholic fatty liver disease: A narrative review of Chronic Liver Disease Questionnaire-non-alcoholic fatty liver disease/non-alcoholic steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and one of the leading causes of hepatocellular carcinoma and liver transplantation. Moreover, patients with NAFLD frequently complain of non-specific symptoms including fatigue, abdominal discomfort, as well as anxiety, and NAFLD is reported to affect patient-reported outcomes (PROs). Thus, for clarifying the total burden of NAFLD, it is crucial to assess all associated outcomes, including not only clinical and economic outcomes but also PROs. PROs are thought to reflect what is happening in one's daily life and is an important way patients and health-care professionals communicate. There are various instruments for the assessment of PROs. Recently, a NAFLD/non-alcoholic steatohepatitis (NASH)-specific instrument called "Chronic Liver Disease Questionnaire (CLDQ)-NAFLD/NASH" has been developed. CLDQ-NAFLD/NASH comprises six domains: (i) abdominal symptoms, (ii) activity/energy, (iii) emotional health, (iv) fatigue, (v) systemic symptoms, and (vi) worry. CLDQ-NAFLD/NASH has demonstrated excellent internal consistency, face validity, content validity, and test-retest reliability. It has been sufficiently validated in two international phase 3 clinical trials. In this review, we summarize features of various instruments for assessing PROs by focusing on CLDQ-NAFLD/NASH. We also examine the validity of CLDQ-NAFLD/NASH in Japanese patients and alterations in CLDQ-NAFLD/NASH score in Japanese patients with significant hepatic fibrosis. Moreover, we discuss the utility of CLDQ-NAFLD/NASH in phase 3 clinical trials and in a real-world clinical setting.

Nonalcoholic Steatohepatitis Is the Most Rapidly Increasing Indication for Liver Transplantation in the United States.

BACKGROUND & AIMS: The profile of chronic liver disease (CLD) in the United States has changed due to obesity trends and advances in treatment of viral hepatitis. We assessed liver transplant listing trends by CLD etiology. METHODS: Adult candidates for liver transplantation were selected from the Scientific Registry of Transplant Recipients (2002 through 2019). We calculated proportion trends for common CLD etiologies at time of placement on the wait list, including chronic infection with hepatitis B virus, chronic infection with hepatitis C virus (HCV), nonalcoholic steatohepatitis (NASH, including cryptogenic cirrhosis), alcohol-related liver disease (ALD) without or with chronic HCV infection, autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis, in patients with and without hepatocellular carcinoma (HCC). RESULTS: From the 168,441 patients with known etiology and non-acute liver failure on the liver transplant waitlist, 27,799 patients (16.5%) had HCC. In 2002, the most common etiologies in patients without HCC were chronic HCV infection (37%) and ALD (16%), whereas only 5% had NASH. Among patients with HCC, 58% had chronic HCV infection and 10% had ALD and only 1% had NASH. In 2019, among patients without HCC, NASH was the second leading indication for liver transplantation (28% of patients), after ALD (38% of patients). Among patients with HCC, chronic HCV infection remained the leading indication (40% of patients) but NASH (24% of patients) surpassed ALD (16% of patients) to become the second leading indication. NASH was the leading indication in women without HCC (34%), in patients older than 54 years (36%), and in patients on Medicare (41%). In trend analysis, NASH was the most rapidly increasing indication for liver transplantation in patients without HCC (Kendall tau=0.97; P < .001) and in patients with HCC (tau=0.94; P < .0001). CONCLUSIONS: In an analysis of data from the Scientific Registry of Transplant Recipients (2002 through 2019), we found NASH to be the second most common indication for liver transplant in 2019, and the fastest increasing indication. In 2019, NASH was the leading indication for liver transplantation among women without HCC.

Clinical assessment for high-risk patients with non-alcoholic fatty liver disease in primary care and diabetology practices.

BACKGROUND: Primary care practitioners (PCPs) and diabetologists are at the frontline of potentially encountering patients with NASH. Identification of those at high risk for adverse outcomes is important. AIM: To provide practical guidance to providers on how to identify these patients and link them to specialty care. METHODS: US members of the Global Council on NASH evaluated the evidence about NASH and non-invasive tests and developed a simple algorithm to identify high-risk NASH patients for diabetologists and primary care providers. These tools can assist frontline providers in decision-making and referral to gastroenterology/hepatology practices for additional assessments. RESULTS: The presence of NASH-related advanced fibrosis is an independent predictor of adverse outcomes. These patients with NASH are considered high risk and referral to specialists is warranted. Given that staging of fibrosis requires a liver biopsy, non-invasive tests for fibrosis would be preferred. Consensus recommendation from the group is to risk-stratify patients based on metabolic risk factors using the FIB-4 as the initial non-invasive test due to its simplicity and ease of use. A FIB-4 score ≥1.3 can be used for further assessment and linkage to specialty care where additional technology to assess liver stiffness or serum fibrosis test will be available. CONCLUSION: Due to the growing burden of NAFLD and NASH, PCPs and diabetologists are faced with increased patient encounters in their clinical practices necessitating referral decisions. To assist in identifying high-risk NASH patients requiring specialty care, we provide a simple and easy to use algorithm.

Modelling the economic and clinical burden of non-alcoholic steatohepatitis in East Asia: Data from Hong Kong.

AIM: Non-alcoholic steatohepatitis (NASH) is the progressive form of non-alcoholic fatty liver disease (NAFLD) and prevalence is rising in Asia due to increasing rates of urbanization, sedentary lifestyles, and poor nutrition. METHODS: We built a Markov model with 20-year horizon to estimate the burden of NASH in Hong Kong. Cohort size was determined by population size, prevalence of NAFLD, and incidence of NASH in 2017. Health states include hepatic steatosis, fibrosis stages 0-3, compensated and decompensated cirrhosis, hepatocellular carcinoma, post-liver transplant, and liver-related, cardiovascular, and background mortality. Transition probabilities were estimated from published reports and we converted 2017 Gazette price from the Hospital Authority of Hong Kong to US dollars. We discounted costs by 3% annually. Health utilities were assumed to be the same as in the USA. RESULTS: Non-alcoholic steatohepatitis will cost $1.32 billion and 124 liver transplants over 20 years, with average cost per person-year of $257. Sensitivity analyses show our model is robust in predicting costs for the prevalent population but likely overestimates costs for the incident population. CONCLUSIONS: Non-alcoholic steatohepatitis will contribute to a significant clinical and economic burden in Hong Kong over the next two decades. Due to the limited number of donors and small number of liver transplants undertaken annually, patients with advanced liver disease due to NASH in Hong Kong are more likely to die from NASH than their counterparts in North America and Europe. Thus, rising prevalence of metabolic syndrome in elderly adults in Hong Kong make NASH an important consideration for clinicians and policy makers.