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Background: Nonalcoholic fatty liver disease (NAFLD) with resulting nonalcoholic steatohepatitis (NASH) are increasingly a cause of cirrhosis and hepatocellular carcinoma (HCC) globally. This burden is expected to increase as epidemics of obesity, diabetes and metabolic syndrome continue to grow. The goal of this analysis was to use a Markov model to forecast NAFLD disease burden using currently available data. Methods:A model was used to estimate NAFLD and NASH disease progression in 8 countries based on data for adult prevalence of obesity and type 2 diabetes mellitus (DM). Published estimates and expert consensus were used to build and validate the model projections. Results:If obesity and DM level off in the future, we project a modest growth in total NAFLD cases (0-30%), between 2016-2030, with the highest growth in China as result of urbanization and the lowest growth in Japan as result of a shrinking population.However, at the same time, NASH prevalence will increase 15-56%, while liver mortality and advanced liver disease will more than double as result of an aging/increasing population.Conclusions: NAFLD and NASH represent a large and growing public health problem and efforts to understand this epidemic and to mitigate the disease burden are needed.If obesity and DM continue to increase at current and historical rates, both NAFLD and 4 NASH prevalence are expected to increase. Since both are reversible, public health campaigns to increase awareness and diagnosis, and to promote diet and exercise can help manage the growth in future disease burden.Lay summary: Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) can lead to advanced liver disease, and are occurring in increasing numbers in tandem with epidemics of obesity and diabetes. A mathematical model was built to understand how the disease burden associated with NAFLD and NASH will change over time. Results suggest increasing numbers of cases of advanced liver disease and liver-related mortality in the coming years. 5 BACKGROUNDNonalcoholic fatty liver disease (NAFLD) is a leading cause of liver disease globally [1][2][3]. This condition is characterized by excess liver fat in the absence of other causes such as alcohol consumption [4,5]. Obesity, type 2 diabetes mellitus (DM) and metabolic syndrome (MetS) are consistently identified as the most important risk factors for NAFLD [4,6].In order to classify the population, NAFLD may be divided into two groups: NAFL (steatosis only) or NASH (nonalcoholic steatohepatitis), where steatosis is accompanied by inflammation and ballooning. NASH frequently progresses to liver fibrosis [7] that is the main risk factor for liver-related mortality [8]. Odds of progression to advanced liver disease, including hepatic decompensation and hepatocellular carcinoma (HCC), are higher among those with NASH compared to those with NAFL [7]. Increasing age, obesity, DM and the presence of NASH have been consistently identified as risk factors for progression to cirrhosis [6,9].There is a...

Hepatocellular carcinoma (HCC) can have viral or non-viral causes1–5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH–HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH–HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH–HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.

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Genome-wide association study Histologically confirmed NAFLD Replication cohort of 559 NAFLD cases and 945 controls genotyped for top SNPs Highlights Genome-wide association study involved 1,483 biopsied NAFLD cases and 17,781 controls. Main analysis shows genome-wide significance for PNPLA3, TM6SF2, HSD17B13 and GCKR. Sub-analyses show significance near LEPR for NASH and near PYGO1 for steatosis. Except for GCKR, the genome-wide significant signals were replicated.