JHEP Reports最新文献

{"title":"Phase II study with sorafenib plus radiotherapy for advanced HCC with portal and/or hepatic vein tumor thrombosis","authors":"Yirui Zhai ,&nbsp;Liming Wang ,&nbsp;Hong Zhao ,&nbsp;Fan Wu ,&nbsp;Lingxia Xin ,&nbsp;Feng Ye ,&nbsp;Wei Sun ,&nbsp;Yan Song ,&nbsp;Lijuan Niu ,&nbsp;Huiying Zeng ,&nbsp;Jingbo Wang ,&nbsp;Yuan Tang ,&nbsp;Yongwen Song ,&nbsp;Yueping Liu ,&nbsp;Hui Fang ,&nbsp;Ningning Lu ,&nbsp;Hao Jing ,&nbsp;Shunan Qi ,&nbsp;Wenwen Zhang ,&nbsp;Shulian Wang ,&nbsp;Bo Chen","doi":"10.1016/j.jhepr.2024.101287","DOIUrl":"10.1016/j.jhepr.2024.101287","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Portal and hepatic vein tumor thrombosis is associated with inferior outcomes in patients with hepatocellular carcinoma (HCC), and systemic treatment alone is often insufficient. This phase II trial evaluated the efficacy and safety of combining sorafenib with radiotherapy in advanced HCC with thrombosis.</div></div><div><h3>Methods</h3><div>Registered at <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> (NCT03535259), this phase II single-arm prospective trial targeted patients with HCC with portal or hepatic vein tumor thrombosis, liver minus gross tumor volume &gt;700 ml, and Eastern Cooperative Oncology Group Performance Status scores of 0 or 1. Participants underwent 40–66 Gy radiotherapy for the hepatic primary tumor and vein tumor thrombosis, with concurrent oral sorafenib (400 mg twice daily) until disease progression or unacceptable adverse events. The primary endpoint was median overall survival (mOS) and the secondary endpoints included overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and Modified Response Evaluation Criteria in Solid Tumors (mRECIST), median progression-free survival (mPFS), time to tumor progression (TTP), tumor thrombosis control, and grade ≥3 adverse events.</div></div><div><h3>Results</h3><div>Between May 2018 and January 2020, 86 patients were enrolled with a median radiotherapy dose of 54 Gy (40–65 Gy). At a median follow-up of 17.2 months, mOS, mPFS, and TTP stood at 16.5, 6.1, and 6.8 months, respectively. ORR reached 47.7% and 52.3% per RECIST and mRECIST, respectively. For the tumor thrombosis, 2-year control rates per mRECIST were 93.1%. No grade 5 adverse events were noted, whereas thrombocytopenia (22.1%) and leukopenia (14.0%) were the main grade 3 adverse events.</div></div><div><h3>Conclusions</h3><div>Concurrent sorafenib and radiotherapy is an effective and well-tolerated treatment for patients with HCC with portal or hepatic vein tumor thrombosis.</div></div><div><h3>Impact and implications:</h3><div>Treatment options for patients with hepatocellular carcinoma (HCC) and vascular tumor thrombus are limited. The efficacy and safety of concurrent sorafenib and radiation for HCC with portal or hepatic vein tumor thrombosis has not been elucidated. This phase II trial shows that concurrent sorafenib and radiotherapy is effective and well-tolerated in the treatment of advanced HCC with portal vein or hepatic vein tumor thrombosis.</div></div><div><h3>Clinical trials registration</h3><div>This study is registered at <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> (NCT03535259).</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 3","pages":"Article 101287"},"PeriodicalIF":9.5,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143182321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Validation of the Chronic Liver Disease Questionnaire for MASH (CLDQ-MASH)","authors":"Zobair M. Younossi,&nbsp;Maria Stepanova,&nbsp;Issah Younossi,&nbsp;Andrei Racila","doi":"10.1016/j.jhepr.2024.101276","DOIUrl":"10.1016/j.jhepr.2024.101276","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;The new nomenclature for metabolic dysfunction-associated steatohepatitis (MASH) requires presence of steatohepatitis in the context of at least one cardiometabolic risk. Having a health-related quality of life (HRQL) instrument validated specifically in patients with MASH is important for clinical research and clinical trials.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;From our non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH) database, patients who met the definition of MASH according to the new criteria were selected. Subjects had completed the Chronic Liver Disease Questionnaire for NAFLD/NASH (CLDQ-NAFLD/NASH) and other HRQL instruments (Functional Assessment of Chronic Illness Therapy – Fatigue [FACIT-F], Short-Form 36 [SF-36]), and had available clinico-laboratory data including fibrosis non-invasive tests (NITs). The CLDQ-MASH was developed following a standard pipeline and subsequently validated in a non-overlapping sample.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;There were 4,213 MASH patients included: age 56 ± 11 years, 44% male, 65% type 2 diabetes, 69% advanced fibrosis (F3–F4). The patients with MASH were split 1:2 into a training set used for development of CLDQ-MASH and a testing set used for validation using standard pipeline. After item reduction and exploratory factor analysis with the training set (&gt;90% variance), the CLDQ-MASH contained 35 items and seven domains. With the non-overlapping testing set, CLDQ-MASH demonstrated excellent face validity, internal consistency (all Cronbach’s alpha &gt;0.78), and high correlations with relevant domains of SF-36, FACIT-F (&lt;em&gt;p&lt;/em&gt; &lt;0.01). Known-groups validity assessment confirmed that CLDQ-MASH can discriminate patients based on liver disease severity (histology- and NIT-based) and the presence of non-hepatic comorbidities (obesity, type 2 diabetes, depression, clinically overt fatigue, insomnia). In a subsample of subjects with 1-year follow-up, the instrument was responsive to changes in Enhanced Liver Fibrosis® scores and liver stiffness measurements (&lt;em&gt;p&lt;/em&gt; &lt;0.05 for four to six domains).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;The CLDQ-MASH can be used as a valid disease-specific HRQL instrument for patients with MASH.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications:&lt;/h3&gt;&lt;div&gt;The new criteria for metabolic dysfunction-associated steatohepatitis (MASH) are different from those previously used for non-alcoholic steatohepatitis so the evidence collected for the previous criteria need to be revisited, including disease-specific instruments for assessment of health-related quality of life. In patients with MASH, Chronic Liver Disease Questionnaire-MASH (CLDQ-MASH; 35 items, seven domains) has excellent psychometric properties including its internal consistency and various aspects of validity, and is responsive to changes in liver disease severity indicators. The CLDQ-MASH can be used as a valid disease-specific hea","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 3","pages":"Article 101276"},"PeriodicalIF":9.5,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143180627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PreS1 deletions in genotype C HBV leads to severe hepatic inflammation and hepatocarcinogenesis via the IRE1-JNK axis","authors":"Yu-Min Choi ,&nbsp;Junghwa Jang ,&nbsp;Dong Hyun Kim ,&nbsp;Ziyun Kim ,&nbsp;Eunseo Kim ,&nbsp;Won Hyeok Choe ,&nbsp;Bum-Joon Kim","doi":"10.1016/j.jhepr.2024.101274","DOIUrl":"10.1016/j.jhepr.2024.101274","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Deletion of 15–21 nucleotides covering the preS1 start codon frequently occurs in patients with chronic HBV (CHB) with HBV genotype C and has been reported to be related to progression to hepatocellular carcinoma (HCC). However, the underlying mechanism causing the distinct phenotype of this HBV variant remains largely unknown. We investigated the mechanism by which preS1Del is related to liver disease progression and enhanced HBV replication, focusing on endoplasmic reticulum (ER) stress.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;The effects of HBV replicative capacity, ER stress signaling, inflammation, cell death, and tumorigenesis resulting from PreS1 deletions were investigated through &lt;em&gt;in vitro&lt;/em&gt; and &lt;em&gt;in vivo&lt;/em&gt; experiments. Inhibitors of the IRE1-JNK pathway and IL6 blockade were used to examine HCC tumor load induced by preS1 deletions.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;The PreS1Del variant selectively activates the IRE1 pathway, mainly via enhanced colocalization between the ER and HBsAg in infected hepatocytes. This leads to enhanced HBV replication and production of tumor-promoting inflammatory cytokines and IL6 and &lt;em&gt;COX2&lt;/em&gt; via the IRE1-JNK signaling pathway. Furthermore, &lt;em&gt;in vivo&lt;/em&gt; data showed that the activation of IRE1-JNK signaling consequently leads to lipid accumulation and apoptosis within 21Del-HBV-infected hepatocytes, collectively driving severe tumorigenesis in the liver. Notably, several inhibitors of the IRE1-JNK pathway dramatically inhibited HBV replication and inflammation induced by 21Del-HBV but not by the wild-type HBV in infected hepatocytes. Furthermore, IL6 blockade significantly reduced HCC tumor load induced by 21Del-HBV.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;PreS1Del leads to enhanced HBV replication and HCC development through IRE1-JNK-IL6/COX2-mediated hepatocyte proliferation and liver inflammation. Inhibitors interfering with the IRE1-JNK-IL6 pathway could selectively inhibit HBV replication and inflammation in preS1Dels, suggesting their potential for the treatment of patients with CHB with preS1-deleted HBV variants.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications:&lt;/h3&gt;&lt;div&gt;Deletion of 15–21 nucleotides at the preS1 start codon is common in patients with CHB with HBV genotype C and is linked to HCC progression. However, the mechanisms underlying the distinct phenotype of this variant remain largely unknown. We found that the preS1Del variant selectively activates the IRE1 pathway, primarily through enhanced IRE1-JNK-IL6 signaling. Inhibition of either the IRE1-JNK pathway or IL6 reduced HBV replication and tumor load in &lt;em&gt;in vivo&lt;/em&gt; HCC models. This study enhances our understanding of the mechanisms of liver disease progression caused by 5ʹ preS1Del variants and provides new insights into treatment strategies for patients with these variants. We believe our findings will resonate with a diverse audience, including patients and their physician","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 3","pages":"Article 101274"},"PeriodicalIF":9.5,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143180626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatitis D virus infection triggers CXCL9-11 upregulation in hepatocytes and liver infiltration of CXCR3+ CD4 T cells","authors":"Jan-Hendrik Bockmann ,&nbsp;Lena Allweiss ,&nbsp;Annika Volmari ,&nbsp;David da Fonseca Araújo ,&nbsp;Matin Kohsar ,&nbsp;Anastasia Hyrina ,&nbsp;Janine Kah ,&nbsp;Zhijuan Song ,&nbsp;Josolyn Chan ,&nbsp;Katja Giersch ,&nbsp;Tassilo Volz ,&nbsp;Marc Lütgehetmann ,&nbsp;Jeffrey J. Wallin ,&nbsp;Dmitry Manuilov ,&nbsp;Meghan M. Holdorf ,&nbsp;Simon P. Fletcher ,&nbsp;Ansgar W. Lohse ,&nbsp;Antonio Bertoletti ,&nbsp;Julian Schulze zur Wiesch ,&nbsp;Maura Dandri","doi":"10.1016/j.jhepr.2024.101273","DOIUrl":"10.1016/j.jhepr.2024.101273","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The role of hepatocytes in producing chemokines and triggering liver inflammation and damage in chronic hepatitis D (CHD) is not fully understood. Herein, we investigated the contribution of primary human hepatocytes (PHHs) infected with HDV in triggering inflammation by producing the chemokines CXCL9–11.</div></div><div><h3>Methods</h3><div>We performed quantitative PCR, RNA <em>in situ</em> hybridisation, activation-induced marker (AIM) assays, and FACS analysis to investigate the CXCR3/CXCL9–11 receptor/ligand axis of T cells in peripheral blood and livers from patients with chronic hepatitis B (n = 27 and 18, respectively) and CHD (n = 20 and 18, respectively). Chemokine expression was investigated in cultured HDV-infected PHHs and in livers of HBV- or HBV/HDV-infected humanised mice in the presence or absence of adoptively transferred human immune cells (n = 35 in total).</div></div><div><h3>Results</h3><div>In patient and chimeric mouse livers, higher expression levels of CXCL9–11 were found in an HBV/HDV-coinfected <em>vs</em>. HBV-mono-infected setting. Similarly, high levels of CXCL9–11 were observed in HDV-infected PHHs <em>in vitro</em>. Analysis by RNA <em>in situ</em> hybridisation on patient livers revealed that HDV-infected hepatocytes were a significant contributor to the chemokine expression. The corresponding chemokine receptor CXCR3 was found upregulated specifically on peripheral bulk CD4 T cells of patients with CHD. CXCR3 upregulation was unspecific and was not detected on HDAg- or HBsAg-specific CD4 T cells by activation-induced marker assay. Lastly, adoptive transfer of human T cells in humanised mice led to recruitment of non-HBV/HDV-specific CD4+ T cells only in the setting of HBV/HDV coinfection, but not in HBV-mono-infected mice.</div></div><div><h3>Conclusions</h3><div>HDV infection upregulated the intrahepatic expression of the CXCL9–11/CXCR3 receptor/ligand axis. Higher amounts of HBV/HDV-unspecific CD4 T cells expressing CXCR3 may contribute to the aggravated liver inflammation frequently observed in patients with CHD.</div></div><div><h3>Impact and implications</h3><div>Chronic hepatitis D (CHD) causes the most severe form of viral hepatitis, and treatment options are still limited; therefore, a more precise understanding of CHD immunopathology is needed. In this study, we demonstrated that HDV infection triggers CXCL9–11 expression in hepatocytes and liver infiltration of CXCR3-expressing CD4 T cells in preclinical models as well as patient biopsies. Because recruitment of Th1-polarised CD4 T cells to the liver has been also described for other severe liver diseases, such as autoimmune hepatitis, it may represent an important mechanism of aggravating liver diseases. The data of this study set hereby the basis for future studies analysing phenotype and function of intrahepatic T cells in CHD.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 3","pages":"Article 101273"},"PeriodicalIF":9.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143182322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Global burden of metabolic dysfunction-associated steatotic liver disease, 2010 to 2021","authors":"Gong Feng ,&nbsp;Giovanni Targher ,&nbsp;Christopher D. Byrne ,&nbsp;Yusuf Yilmaz ,&nbsp;Vincent Wai-Sun Wong ,&nbsp;Cosmas Rinaldi Adithya Lesmana ,&nbsp;Leon A. Adams ,&nbsp;Jerome Boursier ,&nbsp;George Papatheodoridis ,&nbsp;Mohamed El-Kassas ,&nbsp;Nahum Méndez-Sánchez ,&nbsp;Silvia Sookoian ,&nbsp;Laurent Castera ,&nbsp;Wah-Kheong Chan ,&nbsp;Feng Ye ,&nbsp;Sombat Treeprasertsuk ,&nbsp;Helena Cortez-Pinto ,&nbsp;Hon Ho Yu ,&nbsp;Won Kim ,&nbsp;Manuel Romero-Gómez ,&nbsp;Ming-Hua Zheng","doi":"10.1016/j.jhepr.2024.101271","DOIUrl":"10.1016/j.jhepr.2024.101271","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>This study used the Global Burden of Disease data (2010–2021) to analyze the rates and trends of point prevalence, annual incidence, and years lived with disability (YLDs) for metabolic dysfunction-associated steatotic liver disease (MASLD) in 204 countries.</div></div><div><h3>Methods</h3><div>Total numbers and age-standardized rates per 100,000 population for MASLD prevalence, annual incidence, and YLDs were compared across regions and countries by age, sex, and sociodemographic index (SDI). Smoothing spline models were used to evaluate the relationship between the burden of MASLD and SDI. Estimates were reported with uncertainty intervals (UI).</div></div><div><h3>Results</h3><div>Globally, in 2021, the age-standardized rates per 100,000 population of point prevalence of MASLD were 15,018.1 cases (95% UI 13,756.5–16,361.4), annual incidence rates were 608.5 cases (598.8–617.7), and YLDs were 0.5 (0.3–0.8) years. MASLD point prevalence was higher in men than women (15,731.4 <em>vs.</em> 14,310.6 cases per 100,000 population). Prevalence peaked at ages 45–49 for men and 50–54 for women. Kuwait (32,312.2 cases per 100,000 people; 95% UI: 29,947.1–34,839.0), Egypt (31,668.8 cases per 100,000 people; 95% UI: 29,272.5–34,224.7), and Qatar (31,327.5 cases per 100,000 people; 95% UI: 29,078.5–33,790.9) had the highest prevalence rates in 2021. The largest increases in age-standardized point prevalence estimates from 2010 to 2021 were in China (16.9%, 95% UI 14.7%–18.9%), Sudan (13.3%, 95% UI 9.8%–16.7%) and India (13.2%, 95% UI 12.0%–14.4%). MASLD incidence varied with SDI, peaking at moderate SDI levels.</div></div><div><h3>Conclusions</h3><div>MASLD is a global health concern, with the highest prevalence reported in Kuwait, Egypt, and Qatar. Raising awareness about risk factors and prevention is essential in every country, especially in China, Sudan and India, where disease incidence and prevalence are rapidly increasing.</div></div><div><h3>Impact and implications</h3><div>This research provides a comprehensive analysis of the global burden of MASLD, highlighting its rising prevalence and incidence, particularly in countries with varying sociodemographic indices. The findings are significant for both clinicians and policymakers, as they offer critical insights into the regional disparities in MASLD burden, which can inform targeted prevention and intervention strategies. However, the study’s reliance on modeling and available data suggests cautious interpretation, and further research is needed to validate these findings in clinical and real-world settings.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 3","pages":"Article 101271"},"PeriodicalIF":9.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143180810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Copyright and information","authors":"","doi":"10.1016/S2589-5559(24)00264-7","DOIUrl":"10.1016/S2589-5559(24)00264-7","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"6 11","pages":"Article 101260"},"PeriodicalIF":9.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142587218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial Board page","authors":"","doi":"10.1016/S2589-5559(24)00261-1","DOIUrl":"10.1016/S2589-5559(24)00261-1","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"6 11","pages":"Article 101257"},"PeriodicalIF":9.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142587216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep metabolic phenotyping of humans with protein-altering variants in TM6SF2 using a genome-first approach","authors":"Helen Ye Rim Huang ,&nbsp;Cecilia Vitali ,&nbsp;David Zhang ,&nbsp;Nicholas J. Hand ,&nbsp;Michael C. Phillips ,&nbsp;Kate Townsend Creasy ,&nbsp;Eleonora Scorletti ,&nbsp;Joseph Park ,&nbsp;Regeneron Centre ,&nbsp;Kai Markus Schneider ,&nbsp;Daniel J. Rader ,&nbsp;Carolin Victoria Schneider","doi":"10.1016/j.jhepr.2024.101243","DOIUrl":"10.1016/j.jhepr.2024.101243","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aim&lt;/h3&gt;&lt;div&gt;An unbiased genome-first approach can expand the molecular understanding of specific genes in disease-agnostic biobanks for deeper phenotyping. &lt;em&gt;TM6SF2&lt;/em&gt; represents a good candidate for this approach due to its known association with steatotic liver disease (SLD).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;We screened participants with whole-exome sequences in the Penn Medicine Biobank (PMBB, n &gt;40,000) and the UK Biobank (UKB, n &gt;200,000) for protein-altering variants in &lt;em&gt;TM6SF2&lt;/em&gt; and evaluated their association with liver phenotypes and clinical outcomes.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Missense variants in &lt;em&gt;TM6SF2&lt;/em&gt; (E167K, L156P, P216L) were associated with an increased risk of clinically diagnosed and imaging-proven steatosis, independent of the &lt;em&gt;PNPLA3&lt;/em&gt; I48M risk allele and hepatitis B/C (&lt;em&gt;p&lt;/em&gt; &lt;0.001). E167K homozygotes had significantly increased risk of SLD (odds ratio [OR] 5.38, &lt;em&gt;p&lt;/em&gt; &lt;0.001), steatohepatitis (OR 5.76, &lt;em&gt;p&lt;/em&gt; &lt;0.05) and hepatocellular carcinoma (OR 11.22, &lt;em&gt;p&lt;/em&gt; &lt;0.0001), while heterozygous carriers of L156P and P216L were also at an increased risk of steatohepatitis. In addition, carriers of E167K are at a 3-fold increased risk of at-risk MASH (OR 2.75, &lt;em&gt;p&lt;/em&gt; &lt;0.001). CT-derived liver fat scores were higher in E167K and L156P in an allele-dose manner (&lt;em&gt;p&lt;/em&gt; &lt;0.05). This corresponded with the UKB nuclear magnetic resonance-derived lipidomic analyses (n = 105,348), revealing all carriers to exhibit lower total cholesterol, triglycerides and total choline. In silico predictions suggested that these missense variants cause structural disruptions in the EXPERA domain, leading to reduced protein function. This hypothesis was supported by the association of rare loss-of-function variants in &lt;em&gt;TM6SF2&lt;/em&gt; with an increased risk of SLD (OR 4.9, &lt;em&gt;p&lt;/em&gt; &lt;0.05), primarily driven by a novel rare stop-gain variant (W35X) with the same directionality.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;The functional genetic study of protein-altering variants provides insights on the association between loss of &lt;em&gt;TM6SF2&lt;/em&gt; function and SLD and provides the basis for future mechanistic studies.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications:&lt;/h3&gt;&lt;div&gt;The genome-first approach expands insights into genetic risk factors for steatotic liver disease with &lt;em&gt;TM6SF2&lt;/em&gt; being a focal point due to its known association with plasma lipid traits. Our findings validated the association of two missense variants (E167K and L156P) with increased risk of hepatic steatosis on CT and MRI scans, as well as the risk of clinically diagnosed hepatocellular carcinoma independent of the common &lt;em&gt;PNPLA3&lt;/em&gt; I48M risk variant. Notably, we also identified a predicted deleterious missense variant (P216L) linked to steatotic risk and demonstrated that an aggregated gene burden of rare putative loss-of-function variants was associated with the ri","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 1","pages":"Article 101243"},"PeriodicalIF":9.5,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142756824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms and implications of recompensation in cirrhosis","authors":"Salvatore Piano ,&nbsp;Thomas Reiberger ,&nbsp;Jaime Bosch","doi":"10.1016/j.jhepr.2024.101233","DOIUrl":"10.1016/j.jhepr.2024.101233","url":null,"abstract":"<div><div>Decompensated cirrhosis has long been considered the irreversible end stage of liver disease, characterised by further decompensating events until death or liver transplantation. However, the observed clinical improvements after effective antiviral treatments for HBV and HCV and after sustained alcohol abstinence have changed this paradigm, leading to the concept of “recompensation” of cirrhosis. Recompensation of cirrhosis was recently defined by Baveno VII as (i) cure of the primary liver disease aetiology; (ii) disappearance of signs of decompensation (ascites, encephalopathy and portal hypertensive bleeding) off therapy; and (iii) stable improvement of liver function tests (bilirubin, international normalised ratio and albumin). Achieving these recompensation criteria is linked to a significant survival benefit. However, apart from aetiological therapies, no interventions/treatments that facilitate recompensation are available, the molecular mechanisms underlying recompensation remain incompletely understood, and early predictors of recompensation are lacking. Moreover, current recompensation criteria are based on expert opinion and may be refined in the future. Herein, we review the available evidence on cirrhosis recompensation, provide guidance on the clinical management of recompensated patients and discuss future challenges related to cirrhosis recompensation.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"6 12","pages":"Article 101233"},"PeriodicalIF":9.5,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142705062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatocellular carcinoma risk scores for non-viral liver disease: A systematic review and meta-analysis","authors":"Laura Burke ,&nbsp;Alexander Hinkson ,&nbsp;Vincent Haghnejad ,&nbsp;Rebecca Jones ,&nbsp;Richard Parker ,&nbsp;Ian A. Rowe","doi":"10.1016/j.jhepr.2024.101227","DOIUrl":"10.1016/j.jhepr.2024.101227","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Hepatocellular carcinoma (HCC) risk prediction models may provide a more personalised approach to surveillance for HCC among patients with cirrhosis. This systematic review aims to summarise the performance of HCC prediction models in patients with non-viral chronic liver disease.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Method&lt;/h3&gt;&lt;div&gt;The study was prospectively registered with PROSPERO (ID: CRD42022370078) and reported in accordance with PRISMA guidelines. MEDLINE and Embase databases were searched using a validated search filter for prediction model studies. Two reviewers independently assessed studies for inclusion and risk of bias. Measures of model performance (discrimination and calibration) to assess the risk of HCC at specified time points were identified. A random effects meta-analysis was performed on a subset of studies that reported performance of the same model.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;A total of 7,854 studies were identified. After review, 14 studies with a total of 94,014 participants were included; 45% of patients had viral hepatitis, 27% ALD (alcohol-related liver disease) and 19% MASLD (metabolic dysfunction-associated steatotic liver disease). Follow-up ranged from 15.1–138 months. Only one model was developed using a competing risk approach. Age (7 models) and sex (6 models) were the most frequently included predictors. Model discrimination (AUROC or c-statistic) ranged from 0.61–0.947. Only the ‘aMAP’ score (age, male sex, albumin, bilirubin, and platelets) had sufficient external validation for quantitative analysis, with a pooled c-statistic of 0.81 (95% CI 0.80–0.83). Calibration was reported in only 9 of 14 studies. All studies were rated at high risk of bias.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;Studies describing risk prediction of HCC in non-viral chronic liver disease are poorly reported, have a high risk of bias and do not account for competing risk events. Patients with ALD and MASLD are underrepresented in development and validation cohorts. These factors remain barriers to the clinical utility and uptake of HCC risk models for those with the most common liver diseases.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications:&lt;/h3&gt;&lt;div&gt;The recent EASL policy statement emphasises the potential of risk-based surveillance to reduce both hepatocellular carcinoma (HCC)-related deaths and surveillance costs. This study addresses the gap in understanding the performance of current HCC risk models in patients with non-viral liver diseases, reflecting the epidemiological landscape of liver disease in Western countries. In our review of these models we identified several key concerns regarding reporting standards and risk of bias and confirmed that patients with alcohol-related liver disease and metabolic dysfunction-associated steatotic liver disease are underrepresented in model development and validation cohorts. Additionally, most models fail to account for the significant risk of competing events","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 1","pages":"Article 101227"},"PeriodicalIF":9.5,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142698355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}