Background and Aims Sustained virologic response (SVR) to interferon (IFN)‐free therapies ameliorates portal hypertension (PH); however, it remains unclear whether a decrease in hepatic venous pressure gradient (HVPG) after cure of hepatitis C translates into a clinical benefit. We assessed the impact of pretreatment HVPG, changes in HVPG, and posttreatment HVPG on the development of hepatic decompensation in patients with PH who achieved SVR to IFN‐free therapy. Moreover, we evaluated transient elastography (TE) and von Willebrand factor to platelet count ratio (VITRO) as noninvasive methods for monitoring the evolution of PH. Approach and Results The study comprised 90 patients with HVPG ≥ 6 mm Hg who underwent paired HVPG, TE, and VITRO assessments before (baseline [BL]) and after (follow‐up [FU]) IFN‐free therapy. FU HVPG but not BL HVPG predicted hepatic decompensation (per mm Hg, hazard ratio, 1.18; 95% confidence interval, 1.08‐1.28; P < 0.001). Patients with BL HVPG ≤ 9 mm Hg or patients who resolved clinically significant PH (CSPH) were protected from hepatic decompensation. In patients with CSPH, an HVPG decrease ≥ 10% was similarly protective (36 months, 2.5% vs. 40.5%; P < 0.001) but was observed in a substantially higher proportion of patients (60% vs. 24%; P < 0.001). Importantly, the performance of noninvasive methods such as TE/VITRO for diagnosing an HVPG reduction ≥ 10% was inadequate for clinical use (area under the receiver operating characteristic curve [AUROC],  < 0.8), emphasizing the need for HVPG measurements. However, TE/VITRO were able to rule in or rule out FU CSPH (AUROC, 0.86‐0.92) in most patients, especially if assessed in a sequential manner. Conclusions Reassessment of HVPG after SVR improved prognostication in patients with pretreatment CSPH. An “immediate” HVPG decrease ≥ 10% was observed in the majority of these patients and was associated with a clinical benefit, as it prevented hepatic decompensation. These results support the use of HVPG as a surrogate endpoint for interventions that lower portal pressure by decreasing intrahepatic resistance.

Objectives: We aimed to explore the prevalence of portal hypertension in the most common etiologies of patients with compensated advanced chronic liver disease (cACLD) and develop classification rules, based on liver stiffness measurement (LSM), that could be readily used to diagnose or exclude clinically significant portal hypertension (CSPH) in clinical practice. Methods: International cohort study including patients with paired LSM/hepatic venous pressure gradient (HVPG), LSM ≥10kPa and no prior decompensation. Portal hypertension was defined by an HVPG>5 mmHg. A positive predictive value (PPV) ≥90% was considered to validate LSM cut-offs for CSPH (HVPG≥10 mmHg), while a negative predictive value ≥90% ruled out CSPH. Results: 836 patients were evaluated: hepatitis C (HCV, n=358), non-alcoholic steatohepatitis (NASH, n=248), alcohol (ALD, n=203) and hepatitis B (HBV, n=27). Portal hypertension prevalence was >90% in all cACLD etiologies, except for NASH patients (60.9%), being even lower in NASH obese patients (53.3%); these lower prevalences of portal hypertension in NASH patients were maintained across different strata of LSM values. LSM≥25 kPa was the best cut-off to rule in CSPH in ALD, HBV, HCV and non-obese NASH patients, while in obese NASH patients the PPV was only 62.8%. A new model for NASH patients (ANTICIPATE-NASH model) to predict CSPH considering BMI, LSM and platelet count was developed and a nomogram constructed. LSM≤15 kPa plus platelets ≥150x10 9 /L ruled out CSPH in most etiologies. Conclusions: Patients with cACLD of NASH etiology, especially obese NASH patients, present lower prevalences of portal hypertension compared to other cACLD etiologies. LSM≥25 kPa is sufficient to rule in CSPH in most etiologies, including non-obese NASH patients, but not in obese NASH patients. Response to Reviewers:Point-by-point answers to reviewers' comments: Editor/Editorial Board Comments: Editors: After reviewing the manuscript and the comments from the peer reviewers, we would like to ask the authors to address the following issues raised by the editors:1. Was there any correlation of their findings with EGD, and specifically with the absence/presence of high-risk esophageal varices warranting prophylaxis with betablockers or endoscopic band ligation? This a very good point, but information regarding endoscopy was not requested to the participating centers (only LSM and HVPG were available) and it was not an objective of this study. Only the "ANTICIPATE" cohort had endoscopy data and this has been published in the "Anticipate" paper (Hepatology 2016; 64:2173-84) and the Expanded Baveno paper (Hepatology 2017; 66:1980-8).2. Can the authors please convert lab values in table 1 from SI to conventional units? Done.3. We request the authors provide clearer instructions on how to use the nomogram from figure 3. Maybe they can provide an example or improve the instructions, something similar to what was described for the nomogram in figure 4 of the Hepatology 2016 paper on the "Anticipate" study. Thank you for the...

Lifestyle represents the most relevant factor for non‐alcoholic fatty liver disease (NAFLD) as the hepatic manifestation of the metabolic syndrome. Although a tremendous body of clinical and preclinical data on the effectiveness of dietary and lifestyle interventions exist, the complexity of this topic makes firm and evidence‐based clinical recommendations for nutrition and exercise in NAFLD difficult. The aim of this review is to guide readers through the labyrinth of recent scientific findings on diet and exercise in NAFLD and non‐alcoholic steatohepatitis (NASH), summarizing “obvious” findings in a holistic manner and simultaneously highlighting stimulating aspects of clinical and translational research “beyond the obvious”. Specifically, the importance of calorie restriction regardless of dietary composition and evidence from low‐carbohydrate diets to target the incidence and severity of NAFLD are discussed. The aspect of ketogenesis—potentially achieved via intermittent calorie restriction—seems to be a central aspect of these diets warranting further investigation. Interactions of diet and exercise with the gut microbiota and the individual genetic background need to be comprehensively understood in order to develop personalized dietary concepts and exercise strategies for patients with NAFLD/NASH.

Background and Aims Cholestasis is associated with disease severity and worse outcome in COVID‐19. Cases of secondary sclerosing cholangitis (SSC) after severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection have been described. Approach and Results Hospitalized patients with COVID‐19 between 03/2020 and 07/2021 were included. Patients were stratified as having (i) no chronic liver disease (CLD), (ii) non‐advanced CLD (non‐ACLD), or (iii) advanced CLD (ACLD). Patients with CLD and non–COVID‐19 pneumonia were matched to patients with CLD and COVID‐19 as a control cohort. Liver chemistries before (Pre) and at first, second, and third blood withdrawal after SARS‐CoV‐2 infection (T1–T3) and at last available time point (last) were recorded. A total of 496 patients were included. In total, 13.1% ( n = 65) had CLD (non‐ACLD: 70.8%; ACLD: 29.2%); the predominant etiology was NAFLD/NASH (60.0%). COVID‐19–related liver injury was more common among patients with CLD (24.6% vs. 10.6%; p = 0.001). After SARS‐CoV‐2 infection, patients with CLD exhibited progressive cholestasis with persistently increasing levels of alkaline phosphatase (Pre: 91.0 vs. T1: 121.0 vs. last: 175.0 U/L; p < 0.001) and gamma‐glutamyl transferase (Pre: 95.0 vs. T1: 135.0 vs. last: 202.0 U/L; p = 0.001). A total of 23.1% of patients with CLD ( n = 15/65) developed cholestatic liver failure (cholestasis plus bilirubin ≥6 mg/dl) during COVID‐19, and 15.4% of patients ( n = 10/65) developed SSC. SSC was significantly more frequent among patients with CLD and COVID‐19 than in patients with CLD and non–COVID‐19 pneumonia ( p = 0.040). COVID‐19–associated SSC occurred predominantly in patients with NAFLD/NASH and metabolic risk factors. A total of 26.3% ( n = 5/19) of patients with ACLD experienced hepatic decompensation after SARS‐CoV‐2 infection. Conclusions About 20% of patients with CLD develop progressive cholestasis after SARS‐CoV‐2 infection. Patients with NAFLD/NASH and metabolic risk factors are at particular risk for developing cholestatic liver failure and/or SSC after COVID‐19.

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