Loomba, Rohit

Background and Aims: Magnetic resonance elastography (MRE) is an accurate, continuous biomarker of liver fibrosis; however, the optimal combination with clinical factors to predict the risk of incident hepatic decompensation is unknown. Therefore, we aimed to develop and validate an MRE-based prediction model for hepatic decompensation for patients with NAFLD. Approach and Results: This international multicenter cohort study included participants with NAFLD undergoing MRE from 6 hospitals. A total of 1254 participants were randomly assigned as training (n = 627) and validation (n = 627) cohorts. The primary end point was hepatic decompensation, defined as the first occurrence of variceal hemorrhage, ascites, or HE. Covariates associated with hepatic decompensation on Cox-regression were combined with MRE to construct a risk prediction model in the training cohort and then tested in the validation cohort. The median (IQR) age and MRE values were 61 (18) years and 3.5 (2.5) kPa in the training cohort and 60 (20) years and 3.4 (2.5) kPa in the validation cohort, respectively. The MRE-based multivariable model that included age, MRE, albumin, aspartate aminotransferase, and platelets had excellent discrimination for the 3- and 5-year risk of hepatic decompensation (c-statistic 0.912 and 0.891, respectively) in the training cohort. The diagnostic accuracy remained consistent in the validation cohort with a c-statistic of 0.871 and 0.876 for hepatic decompensation at 3 and 5 years, respectively, and was superior to Fibrosis-4 in both cohorts (p < 0.05). Conclusions: An MRE-based prediction model allows for accurate prediction of hepatic decompensation and assists in the risk stratification of patients with NAFLD.

Background and Aims: With distinct mechanisms of action, the combination of tropifexor (TXR) and cenicriviroc (CVC) may provide an effective treatment for NASH. This randomized, multicenter, double-blind, phase 2b study assessed the safety and efficacy of TXR and CVC combination, compared with respective monotherapies. Approach and Results: Patients (N = 193) were randomized 1:1:1:1 to once-daily TXR 140 μg (TXR140), CVC 150 mg (CVC), TXR 140 μg + CVC 150 mg (TXR140 + CVC), or TXR 90 μg + CVC 150 mg (TXR90 + CVC) for 48 weeks. The primary and secondary end points were safety and histological improvement, respectively. Rates of adverse events (AEs) were similar across treatment groups. Pruritus was the most frequently experienced AE, with highest incidence in the TXR140 group (40.0%). In TXR and combination groups, alanine aminotransferase (ALT) decreased from baseline to 48 weeks (geometric mean change: −21%, TXR140; −16%, TXR140 + CVC; −13%, TXR90 + CVC; and +17%, CVC). Reductions in body weight observed at week 24 (mean changes from baseline: TXR140, −2.5 kg; TXR140 + CVC, −1.7 kg; TXR90 + CVC, −1.0 kg; and CVC, −0.1 kg) were sustained to week 48. At least 1-point improvement in fibrosis stage/steatohepatitis resolution without worsening of fibrosis was observed in 32.3%/25.8%, 31.6%/15.8%, 29.7%/13.5%, and 32.5%/22.5% of patients in the TXR140, CVC, TXR140 + CVC, and TXR90 + CVC groups, respectively. Conclusions: The safety profile of TXR + CVC combination was similar to respective monotherapies, with no new signals. TXR monotherapy showed sustained ALT and body weight decreases. No substantial incremental efficacy was observed with TXR + CVC combination on ALT, body weight, or in histological end points compared with monotherapy.

Background and Aim: The etiology of liver diseases has changed in recent years, but its impact on the comparative burden of liver cancer between males and females is unclear. We estimated sex differences in the burden of liver cancer across 204 countries and territories from 2010 to 2019. Approach and Result: We analyzed temporal trends in the burden of liver cancer using the methodology framework of the 2019 Global Burden of Disease study. We estimated annual frequencies and age‐standardized rates (ASRs) of liver cancer incidence, death, and disability‐adjusted life‐years (DALYs) by sex, country, region, and etiology of liver disease. Globally in 2019, the frequency of incident cases, deaths, and DALYs due to liver cancer were 376,483, 333,672, and 9,048,723 in males, versus 157,881, 150,904, and 3,479,699 in females. From 2010 to 2019, the incidence ASRs in males increased while death and DALY ASRs remained stable; incidence, death, and DALY ASRs in females decreased. Death ASRs for both sexes increased only in the Americas and remained stable or declined in remaining regions. In 2019, hepatitis B was the leading cause of liver cancer death in males, and hepatitis C in females. From 2010 to 2019, NASH had the fastest growing death ASRs in males and females. The ratio of female‐to‐male death ASRs in 2019 was lowest in hepatitis B (0.2) and highest in NASH (0.9). Conclusions: The overall burden of liver cancer is higher in males, although incidence and death ASRs from NASH‐associated liver cancer in females approach that of males.

Abstract 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.

SummaryBackgroundNonalcoholic steatohepatitis (NASH) is a common cause of chronic liver disease. There is a major need to understand the efficacy of different pharmacological agents for the treatment of NASH.AimTo assess the relative rank‐order of different pharmacological interventions in fibrosis improvement and NASH resolution.MethodsA comprehensive search of several databases was conducted by an experienced librarian. We included randomised controlled‐trials (RCTs) comparing pharmacological interventions in patients with biopsy‐proven NASH. The primary outcome was ≥1 stage improvement in fibrosis. The secondary outcome was NASH resolution.ResultsA total of 26 RCTs with 23 interventions met the eligibility criteria. Lanifibranor and obeticholic acid had the highest probability of being ranked the most effective intervention for achieving ≥1 stage of fibrosis improvement (SUCRA 0.78) and (SUCRA 0.77), respectively. For NASH resolution, semaglutide, liraglutide and vitamin E plus pioglitazone had the highest probability of being ranked the most effective intervention for achieving NASH resolution (SUCRA 0.89), (SUCRA 0.84) and (SUCRA 0.83), respectively. Lanifibranor, obeticholic acid, pioglitazone and vitamin E were significantly better than placebo in achieving ≥1 stage of fibrosis improvement. Conversely, semaglutide, liraglutide, vitamine E plus pioglitazone, pioglitazone, lanifibranor and obeticholic acid were significantly better than placebo in achieving NASH resolution.ConclusionThese data provide relative rank‐order efficacy of various NASH therapies in terms of their improvements in liver fibrosis and NASH resolution. Therapies that have been shown to improve NASH resolution may be combined with therapies that have an antifibrotic effect to further boost treatment response rate in future.

LINKED CONTENTThis article is linked to Pai et al and Rowe papers. To view these articles, visit https://doi.org/10.1111/apt.15503 and https://doi.org/10.1111/apt.15537.

Liver fibrosis is the most important predictor of mortality in nonalcoholic fatty liver disease (NAFLD). Quantitative risk of mortality by fibrosis stage has not been systematically evaluated. We aimed to quantify the fibrosis stage–specific risk of all‐cause and liver‐related mortality in NAFLD. Through a systematic review and meta‐analysis, we identified five adult NAFLD cohort studies reporting fibrosis stage–specific mortality (0‐4). Using fibrosis stage 0 as a reference population, fibrosis stage–specific mortality rate ratios (MRRs) with 95% confidence intervals (CIs) for all‐cause and liver‐related mortality were estimated. The study is reported according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses statement. Included were 1,495 NAFLD patients with 17,452 patient years of follow‐up. Compared to NAFLD patients with no fibrosis (stage 0), NAFLD patients with fibrosis were at an increased risk for all‐cause mortality, and this risk increased with increases in the stage of fibrosis: stage 1, MRR = 1.58 (95% CI 1.19‐2.11); stage 2, MRR = 2.52 (95% CI 1.85‐3.42); stage 3, MRR = 3.48 (95% CI 2.51‐4.83); and stage 4, MRR = 6.40 (95% CI 4.11‐9.95). The results were more pronounced as the risk of liver‐related mortality increased exponentially with each increase in the stage of fibrosis: stage 1, MRR = 1.41 (95% CI 0.17‐11.95); stage 2, MRR = 9.57 (95% CI 1.67‐54.93); stage 3, MRR = 16.69 (95% CI 2.92‐95.36); and stage 4, MRR = 42.30 (95% CI 3.51‐510.34). Limitations of the study include an inability to adjust for comorbid conditions or demographics known to impact fibrosis progression in NAFLD and the inclusion of patients with simple steatosis and nonalcoholic steatohepatitis without fibrosis in the reference comparison group. Conclusion: The risk of liver‐related mortality increases exponentially with increase in fibrosis stage; these data have important implications in assessing the utility of each stage and benefits of regression of fibrosis from one stage to another. (H epatology 2017;65:1557‐1565).