JHEP Reports最新文献

{"title":"Carvedilol decreases hepatic vascular resistance by reducing fibrogenesis and reversing endothelial dysfunction in cirrhotic rats","authors":"Yeldos Nulan , Eric Felli , Sonia-Emilia Selicean , Manuel Prampolini , Annalisa Berzigotti , Jordi Gracia-Sancho , Jaume Bosch","doi":"10.1016/j.jhepr.2025.101681","DOIUrl":"10.1016/j.jhepr.2025.101681","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Cirrhosis increases hepatic vascular resistance (IHVR) by disrupting liver architecture due to fibrosis, and by elevating hepatic vascular tone due to hepatic endothelial dysfunction. IHVR increases portal pressure (PP), later aggravated by increased portal blood inflow. Carvedilol, a third-generation non-selective β-blocker with anti-α1-adrenergic activity, reduces PP more than propranolol, likely decreasing IHVR. However, its intrahepatic effects remain largely unexplored. This study aimed to address these issues.</div></div><div><h3>Methods</h3><div>Human cell lines (LX2 and HUVECs) and primary liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs) isolated from cirrhotic rats (12-week thioacetamide [TAA] model) were treated with vehicle, carvedilol (10 μM), or propranolol (10 μM). Nitric oxide release, oxidative stress, and cell contraction were assessed. Cirrhotic rats were treated with vehicle, carvedilol (10 mg/kg/day for 2 weeks), or propranolol (30 mg/kg/day for 2 weeks) at early and advanced stages of cirrhosis (9 and 12 weeks of TAA). Hepatic hemodynamics, liver fibrosis, antioxidant activity, and inflammatory biomarkers were evaluated.</div></div><div><h3>Results</h3><div>Carvedilol increased nitric oxide release in LSECs and HUVECs and significantly reduced contraction of HSCs and LX2 cells in cirrhotic conditions. <em>In vivo</em>, carvedilol significantly reduced PP in both early and advanced cirrhosis (12-week TAA: −22%, <em>p =</em> 0.0008; 9-week TAA: −17%, <em>p =</em> 0.0038), decreased liver fibrosis area (−26.8%, <em>p =</em> 0.0013 <em>vs.</em> −23.1%, <em>p =</em> 0.0047), and reduced α-SMA expression (−22.7%, <em>p =</em> 0.0018 <em>vs.</em> −17.4%, <em>p =</em> 0.0455). Additionally, carvedilol improved endothelial dysfunction and reduced oxidative stress and inflammation. Propranolol did not exert these beneficial effects and produced a smaller, non-significant reduction in PP (−7%, <em>p =</em> 0.4029).</div></div><div><h3>Conclusions</h3><div>The greater reduction in PP achieved with carvedilol is mediated not only by its non-selective β-blocker effects but, more importantly, by its ability to reverse hepatic endothelial dysfunction, reduce fibrosis, enhance antioxidant activity, and exert moderate anti-inflammatory effects. These findings support extending the use of carvedilol even to patients without overt signs of portal hypertension.</div></div><div><h3>Impact and implications</h3><div>Carvedilol is considered the best β-blocker for treating portal hypertension. In this study we show that carvedilol, unlike traditional β-blockers such as propranolol, downregulates the factors that lead to increased portal pressure in cirrhosis: it lowers the hepatic vascular tone by counteracting hepatic sinusoidal endothelial dysfunction, and decreases liver fibrosis by deactivating hepatic stellate cells and inhibiting their proliferation. On top of decreasing portal","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 3","pages":"Article 101681"},"PeriodicalIF":7.5,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146077000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma exchange as potential treatment of severe immune checkpoint inhibitor-induced hepatitis","authors":"Lucy Meunier ,&nbsp;Clement Monet ,&nbsp;Antonio Saviano ,&nbsp;Marwin Farrugia ,&nbsp;François Villeret ,&nbsp;Fanny Lebossé ,&nbsp;Marion Khaldi ,&nbsp;Olivier Moranne ,&nbsp;Christine Chambon ,&nbsp;Philippe Ichai ,&nbsp;Astrid Laurent-Bellue ,&nbsp;Ariane Laparra ,&nbsp;Rodolphe Anty ,&nbsp;Simona Tripon ,&nbsp;Mialy Randrianarisoa ,&nbsp;Alexandre Maria ,&nbsp;Lina Hountondji ,&nbsp;Eleonora De Martin","doi":"10.1016/j.jhepr.2025.101684","DOIUrl":"10.1016/j.jhepr.2025.101684","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Immune checkpoint inhibitors (ICIs) improve cancer survival but can cause severe immune-related hepatitis. Standard therapy with corticosteroids and second-line agents such as mycophenolate mofetil fails in some cases. Therapeutic plasma exchange (TPE) has been suggested as rescue therapy, but supporting evidence is limited.</div></div><div><h3>Methods</h3><div>We retrospectively analyzed French multicenter data (March 2021–April 2025) on patients with grade 4 ICI-induced hepatitis refractory to corticosteroids ± other immunosuppressants who underwent TPE.</div></div><div><h3>Results</h3><div>Thirteen patients (median age 63 years; 54% male) were included. Eleven had acute hepatitis, including seven with acute liver injury, and two had steroid-refractory cholestatic hepatitis. TPE was initiated a median of 28 days after hepatitis onset (median MELD score 21) and administered in 2–8 sessions. Liver function improved in eight patients (61.5%), allowing resumption of anticancer therapy without ICI rechallenge in five. Three patients with cirrhosis and hepatocellular carcinoma died of liver failure, and three died from other causes. TPE-related adverse events were mild to moderate.</div></div><div><h3>Conclusion</h3><div>TPE is feasible, safe, and may be effective for severe steroid- and immunosuppressant-refractory ICI-induced hepatitis. Early initiation could improve outcomes; prospective studies are needed to clarify optimal timing and patient selection.</div></div><div><h3>Impact and implications</h3><div>Severe immune checkpoint inhibitor-induced hepatitis represents a rare but life-threatening complication for which therapeutic options are limited once corticosteroids and immunosuppressants fail. Our study provides the first multicenter evidence suggesting that therapeutic plasma exchange (TPE) is a feasible and safe approach that may improve hepatic outcomes in this setting. These findings are particularly relevant for oncologists, hepatologists, and intensivists facing refractory immune checkpoint inhibitor-induced liver injury, as TPE could offer a bridge to recovery when liver transplantation is not feasible. Early consideration of TPE, alongside careful patient selection, could optimize outcomes, although larger prospective studies are required to confirm efficacy and define the best timing and indications.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 3","pages":"Article 101684"},"PeriodicalIF":7.5,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146057557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of estrogen receptor alpha stabilizes regulatory T cell function in autoimmune hepatitis","authors":"Lina Zhang ,&nbsp;Barbora Gromova ,&nbsp;Du Hanh Nguyen ,&nbsp;Cortney Cagle ,&nbsp;Graziela S. Gomes ,&nbsp;William Li ,&nbsp;Li Gao ,&nbsp;Wei Zhang ,&nbsp;Jonathon J. Graham ,&nbsp;Na Wang ,&nbsp;Ahmadreza Kalbasi ,&nbsp;Eva Csizmadia ,&nbsp;Angelina Wei ,&nbsp;Jessica Cassavaugh ,&nbsp;Alan Bonder ,&nbsp;Vilas Patwardhan ,&nbsp;Sizun Jiang ,&nbsp;Satya K. Kota ,&nbsp;Maria Serena Longhi","doi":"10.1016/j.jhepr.2025.101678","DOIUrl":"10.1016/j.jhepr.2025.101678","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Regulatory T cell (Treg) dysfunction is a hallmark of autoimmune hepatitis (AIH), a serious hepatopathy often progressing to end-stage liver disease despite immunosuppression. Treg impairment in AIH has been linked to defective signaling through the aryl hydrocarbon receptor (AhR), a modulator of adaptive immunity. Herein, we investigated whether increased estrogen receptor alpha (ERα), an AhR non-canonical binding partner, impacts Treg immunity and contributes to the sex bias observed in AIH.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Tregs were isolated from the peripheral blood of pre-menopausal, post-menopausal and male patients with AIH, as well as controls. Their function, stability, transcriptome and response to AhR were assessed in the absence or presence of methylpiperidinopyrazole (MPP), an ERα-selective antagonist. Therapeutic effects of MPP were tested in a model of Concanavalin-A-induced liver injury in humanized mice.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;ERα was upregulated in Tregs from pre-menopausal females with AIH (1.1 ± 0.3) compared with healthy pre-menopausal females (0.4 ± 0.1; &lt;em&gt;p&lt;/em&gt; = 0.038), and in pre-menopausal compared with post-menopausal females with AIH (0.3 ± 0.1; &lt;em&gt;p&lt;/em&gt; = 0.04). In pre-menopausal females with AIH, MPP enhanced Treg suppressive capacity (2.5-fold increase; &lt;em&gt;p&lt;/em&gt; = 0.001), restored response to AhR activation (2-fold increase; &lt;em&gt;p&lt;/em&gt; = 0.03), and reduced functional plasticity, evidenced by decreased IL-17A and RORC expression under pro-inflammatory conditions. MPP also ameliorated Concanavalin-A-induced hepatitis in &lt;em&gt;NOD/scid/gamma&lt;/em&gt; mice reconstituted with human CD4+ ERα+ cells, as shown by reduced ALT levels (101 ± 24 &lt;em&gt;vs&lt;/em&gt;. 25 ± 8; &lt;em&gt;p&lt;/em&gt; = 0.024), diminished hepatic inflammation on histology, and increased intrahepatic CD4+FOXP3+ and CD4+CD39+ T-cell frequencies. Bioinformatic and inhibition analyses identified hypoxia-inducible factor-1α as a key inducer of ERα in AIH Tregs.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;ERα upregulation drives Treg dysfunction in pre-menopausal females with AIH and likely contributes to the sex bias in the disease. ERα blockade stabilizes Tregs and limits inflammation &lt;em&gt;in vivo&lt;/em&gt;, representing a promising therapeutic strategy to enhance and sustain immune tolerance in AIH.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;Regulatory T cell (Treg) dysfunction plays a key role in the breakdown of immune tolerance in autoimmune hepatitis (AIH), a severe hepatopathy that often progresses to end-stage liver disease despite immunosuppression. Here we report that upregulation of estrogen receptor-alpha (ERα) alters Treg function and stability in pre-menopausal females with AIH, and that blockade of ERα using a specific antagonist stabilizes Tregs and curbs inflammation in humanized mice with liver injury. These findings implicate aberrant ERα signaling in the sex bias of AIH and support ERα inhibiti","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101678"},"PeriodicalIF":7.5,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145882439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cumulative lipid exposure in young adulthood and risk of midlife MASLD","authors":"Yun Chen ,&nbsp;Yinan Zheng ,&nbsp;Longgang Zhao ,&nbsp;Tao Gao ,&nbsp;Yishu Qu ,&nbsp;John Jeffrey Carr ,&nbsp;James G. Terry ,&nbsp;Hongyan Ning ,&nbsp;Kyeezu Kim ,&nbsp;Michelle T. Long ,&nbsp;Xinyuan Zhang ,&nbsp;John T. Wilkins ,&nbsp;Aimin Chen ,&nbsp;Kai Zhang ,&nbsp;Norrina Bai Allen ,&nbsp;Donald M. Lloyd-Jones ,&nbsp;Lifang Hou ,&nbsp;Xuehong Zhang","doi":"10.1016/j.jhepr.2025.101679","DOIUrl":"10.1016/j.jhepr.2025.101679","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;The importance of maintaining optimal lipid levels across young adulthood in preventing metabolic dysfunction-associated steatotic liver disease (MASLD) is unclear. This study aimed to evaluate associations of lipid profiles through young adulthood with midlife MASLD risk and assess the mediating effect of epigenomic biomarkers.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;This study included 2,577 participants from the Coronary Artery Risk Development in Young Adults study using data from baseline (Year 0 [Y0], 1985-1986) to Y25 (2010-2011). Time-weighted average (TWA) lipid exposures during young adulthood (ages 18-39 years) were estimated using up to seven measurements (Y0–Y20). Non-contrast abdominal CT scans were performed to measure steatosis at Y25 (mean age, 50 years). Blood DNA methylation (DNAm) was measured at &gt;840,000 methylation sites at Y20. A total of 492 MASLD cases were identified.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Compared with optimal TWA lipid levels, multivariable-adjusted odds ratios of developing MASLD were 3.26 (95% CI 2.51-4.25) for abnormal triglycerides (≥100 &lt;em&gt;vs.&lt;/em&gt; &lt;75 mg/dl), 2.39 (95% CI 1.73-3.31) for high-density lipoprotein cholesterol (&lt;40 [men]/50 [women] &lt;em&gt;vs.&lt;/em&gt; ≥60 mg/dl), 1.77 (95% CI 1.37-2.30) for non-high-density lipoprotein cholesterol (≥150 &lt;em&gt;vs.&lt;/em&gt; &lt;130 mg/dl), 1.74 (95% CI 1.19-2.51) for apolipoprotein B (≥110 &lt;em&gt;vs.&lt;/em&gt; &lt;90 mg/dl), 1.43 (95% CI 1.08-1.90) for low-density lipoprotein cholesterol (≥130 &lt;em&gt;vs.&lt;/em&gt; &lt;100 mg/dl), and 1.39 (95% CI 1.07-1.81) for total cholesterol (≥200 &lt;em&gt;vs.&lt;/em&gt; &lt;180 mg/dl). These associations were consistent across sex, race, alcohol intake, and genetic susceptibility. DNAm markers located in &lt;em&gt;CPT1A, ABCG1&lt;/em&gt;, and &lt;em&gt;DHCR24&lt;/em&gt; genes mediated 2.9%-15.4% of observed associations.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Cumulative exposure to abnormal lipids through young adulthood contributes to MASLD development in midlife, with these associations partially mediated by lipid-associated DNAm.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;Dyslipidemia is a major modifiable risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD). Evidence largely focuses on mid-to-late-life lipid levels, while the impact of cumulative lipid exposure through young adulthood on midlife MASLD risk remains unclear. Using seven repeated lipid measures in a longitudinal observational study, we found that cumulative abnormal lipid exposure during young adulthood (ages 18-39 years) strongly predicted MASLD risk over a 25-year follow-up, outperforming single-visit measures. DNA methylation markers in &lt;em&gt;CPT1A, ABCG1,&lt;/em&gt; and &lt;em&gt;DHCR24&lt;/em&gt; mediated 2.9%-15.4% of observed associations. Our findings underscore the value of assessing cumulative lipid exposure for midlife MASLD risk stratification and highlight epigenomic mediators as potential targets to strengthen MASLD prevention stra","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 3","pages":"Article 101679"},"PeriodicalIF":7.5,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146077001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Shunt magnitude is a key determinant of overt hepatic encephalopathy in patients undergoing TIPS","authors":"Davide Roccarina ,&nbsp;Dario Saltini ,&nbsp;Marco Senzolo ,&nbsp;Silvia Nardelli ,&nbsp;Martina Rosi ,&nbsp;Valentina Adotti ,&nbsp;Marcello Bianchini ,&nbsp;Lara Biribin ,&nbsp;Stefania Gioia ,&nbsp;Cristian Caporali ,&nbsp;Lucia Ragozzino ,&nbsp;Tomas Guasconi ,&nbsp;Margherita Falcini ,&nbsp;Federico Casari ,&nbsp;Antonio Piscopo ,&nbsp;Francesco Pindozzi ,&nbsp;Stefano Gitto ,&nbsp;Silvia Aspite ,&nbsp;Gianmarco Falcone ,&nbsp;Angelica Ingravallo ,&nbsp;Francesco Vizzutti","doi":"10.1016/j.jhepr.2025.101676","DOIUrl":"10.1016/j.jhepr.2025.101676","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Under-dilated transjugular intrahepatic portosystemic shunts (U-TIPS) has been proposed to reduce the risk of overt hepatic encephalopathy (OHE) while effectively treating portal hypertension (PH) complications. In this study we assessed how end-procedural porto-caval pressure gradient (PCPG), obtained in sedated patients, and endoprosthesis dilation affect the risk of OHE after TIPS.</div></div><div><h3>Methods</h3><div>Consecutive patients with cirrhosis receiving TIPS for refractory ascites or recurrent PH-related bleeding were enrolled. OHE within 1-year was analyzed using a competing risk model, accounting for death and liver transplantation. Adequate hemodynamic response (AHR) was defined as post-TIPS PCPG &lt;12 mmHg or reduction ≥60% in refractory ascites, and &lt;12 mmHg or reduction ≥50% in PH-related bleeding. PCPG values outside of the above criteria were considered as inadequate response. U-TIPS was defined as endoprosthesis dilation ≤7 mm, as opposed to standard TIPS (S-TIPS).</div></div><div><h3>Results</h3><div>Among 408 patients enrolled, 50% received U-TIPS, 63% achieved AHR, and 46% had a PCPG &lt;10 mmHg. One-year cumulative incidence of OHE was 33% and 50% in U-TIPS and S-TIPS, respectively (<em>p</em> &lt;0.001). In the univariable analysis, both AHR and PCPG &lt;10 mmHg, and S-TIPS were associated with higher cumulative incidence of OHE. In a model comprising age, previous history of OHE, TIPS indication, liver disease severity and endoprosthesis dilation, only S-TIPS along with older age, previous history of OHE and Child-Pugh class B and C, were statistically significantly associated with OHE.</div><div>Subgroup analysis stratified by U-TIPS <em>vs.</em> S-TIPS confirmed that AHR and PCPG &lt;10 mmHg were not associated with OHE within either TIPS group.</div></div><div><h3>Conclusions</h3><div>The magnitude of the shunt emerges as an independent key determinant of post-TIPS OHE.</div></div><div><h3>Impact and implications</h3><div>TIPS carries a significant risk of overt hepatic encephalopathy. Low portosystemic pressure gradient and larger shunt diameter have been reported to increase the risk of overt hepatic encephalopathy. The TIPS dilation diameter represents an independent key determinant of post-TIPS overt hepatic encephalopathy. Thus, TIPS under-dilation reduces overt hepatic encephalopathy occurrence while effectively controlling portal hypertension complications even without meeting established hemodynamic targets.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101676"},"PeriodicalIF":7.5,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-wide association study identifies three PNPLA3/SAMM50 SNPs associated with HCC development in non-viral liver disease","authors":"Xia-Rong Liu ,&nbsp;Tsai-Hsuan Yang ,&nbsp;Tung-Hung Su ,&nbsp;Szu-Ching Yin ,&nbsp;Yi-Ting Chen ,&nbsp;Fen-Fang Chen ,&nbsp;See-Tong Pang ,&nbsp;Ming-Chih Hou ,&nbsp;Yen-Chun Peng ,&nbsp;Shun-Fa Yang ,&nbsp;Peng-Ju Huang ,&nbsp;Sing-Lian Lee ,&nbsp;Ming Chen ,&nbsp;Chih-Yang Huang ,&nbsp;Ya-Hsuan Chang ,&nbsp;Hsuan-Yu Chen ,&nbsp;Hwai-I Yang ,&nbsp;Ming-Lung Yu ,&nbsp;Chien-Jen Chen ,&nbsp;Jia-Horng Kao ,&nbsp;Mei-Hsuan Lee","doi":"10.1016/j.jhepr.2025.101673","DOIUrl":"10.1016/j.jhepr.2025.101673","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Few genome-wide association studies have examined genetic variants associated with hepatocellular carcinoma (HCC) risk in individuals seronegative for HBsAg and anti-HCV, and the long-term impact of these variants remains uncertain.</div></div><div><h3>Methods</h3><div>This multi-stage study analyzed adults &gt;30 years old who were seronegative for HBsAg and anti-HCV. In the genome-wide association study discovery phase, 765 HCC cases and 9,949 controls were analyzed for 308,693 SNPs, with significant SNPs confirmed in community-based (171 HCC cases, 684 controls) and hospital-based (470 HCC cases, 5,460 controls) validation sets. A cohort of 67,909 participants, followed from 2012 to 2021, was used to evaluate the long-term HCC risk associated with these variants.</div></div><div><h3>Results</h3><div>Ten SNPs in <em>PNPLA3/SAMM50</em> were significantly associated with HCC risk (<em>p</em> &lt;1.62 × 10^-7) and were in high linkage disequilibrium. Three SNPs (rs738409, rs2281135, rs2235776) were replicated and demonstrated strong associations with HCC, independent of steatosis. Over 267,238 person-years of follow-up, 32 new HCC cases occurred, with elevated risks observed in individuals homozygous for the risk genotypes: GG (rs738409), AA (rs2281135), and TT (rs2235776). The adjusted hazard ratios (95% CI) were 3.37 (1.32–8.63), 2.80 (1.06–7.37), and 2.64 (0.91–7.66), respectively. In allelic models, carriers of the risk allele had higher HCC risk, with adjusted hazard ratios (95% CI) of 1.88 (1.14–3.10) for rs738409, 1.68 (1.02–2.78) for rs2281135, and 1.61 (0.98–2.67) for rs2235776.</div></div><div><h3>Conclusions</h3><div>This study identified <em>PNPLA3/SAMM50</em> variants significantly associated with long-term HCC risk in individuals without viral hepatitis. These findings highlight their potential utility as biomarkers for HCC risk stratification and underscore the need for further research into underlying mechanisms.</div></div><div><h3>Impact and implications</h3><div>Variants in the <em>PNPLA3/SAMM50</em> locus were significantly associated with hepatocellular carcinoma (HCC) risk in individuals seronegative for HBsAg and anti-HCV. The stepwise increase in HCC risk with higher numbers of risk alleles suggests their potential utility as biomarkers to identify high-risk individuals without a history of chronic hepatitis B or C virus infection. These findings provide a foundation for genetic risk stratification and precision prevention strategies in populations where non-viral etiologies of HCC are becoming increasingly important.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101673"},"PeriodicalIF":7.5,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Self-supervised learning to predict intrahepatic cholangiocarcinoma transcriptomic classes on routine histology","authors":"Aurélie Beaufrère ,&nbsp;Tristan Lazard ,&nbsp;Rémy Nicolle ,&nbsp;Gwladys Lubuela ,&nbsp;Jérémy Augustin ,&nbsp;Miguel Albuquerque ,&nbsp;Baptiste Pichon ,&nbsp;Camille Pignolet ,&nbsp;Victoria Priori ,&nbsp;Nathalie Théou-Anton ,&nbsp;Mickael Lesurtel ,&nbsp;Mohamed Bouattour ,&nbsp;Kévin Mondet ,&nbsp;Jérôme Cros ,&nbsp;Julien Calderaro ,&nbsp;Thomas Walter ,&nbsp;Valérie Paradis","doi":"10.1016/j.jhepr.2025.101675","DOIUrl":"10.1016/j.jhepr.2025.101675","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The transcriptomic classification of intrahepatic cholangiocarcinoma (iCCA) has recently been refined from two to five classes, each associated with pathological features, targetable genetic alterations, and survival outcomes. Despite its potential prognostic and therapeutic value, the transcriptomic classification is not routinely used in practice because of technical limitations, including insufficient tissue material and the high cost of molecular analyses. Here, we assessed a self-supervised learning (SSL) model for predicting iCCA transcriptomic classes on digitised whole-slide images (WSIs)</div></div><div><h3>Methods</h3><div>Transcriptomic classes defined from RNA sequencing data were available for all samples. The SSL method (Giga-SSL) was used to train our model on a discovery set of 766 WSIs from 137 biopsies and 109 surgical specimens obtained from 246 patients, using a five-fold cross-validation scheme. The model was validated in The Cancer Genome Atlas (TCGA) cohort (n = 29) and a French external validation set (n = 32), both using WSIs from surgical samples.</div></div><div><h3>Results</h3><div>The most frequent transcriptomic class was the hepatic stem-like class (37% [90/246] in the discovery set). Our model showed good to very good performance in predicting the four most frequent transcriptomic classes in the discovery set (AUC 0.63-0.84), especially for the hepatic stem-like class (AUC 0.84). The model performed equally well in predicting these transcriptomic classes in the two validation sets, with AUCs ranging from 0.76 to 0.80 in the TCGA set and 0.62 to 0.92 in the French external set.</div></div><div><h3>Conclusions</h3><div>We developed and validated an SSL-based model capable of predicting iCCA transcriptomic classes from routine histological slides of both biopsy and surgical samples. This approach may facilitate the clinical implementation of transcriptomic classification, improve prognostic assessment, and guide therapeutic decision-making in iCCA.</div></div><div><h3>Impact and implications</h3><div>Predicting transcriptomic classes directly from routine histological slides has the potential to enhance the clinical management of intrahepatic cholangiocarcinoma, enabling more accurate prognostication and supporting therapeutic decision-making. By eliminating the need for manual slide annotation, large tissue samples, or resource-intensive molecular analyses, our self-supervised learning-based model offers a practical and scalable solution that can be applied to both biopsy and surgical specimens. This approach could accelerate the adoption of transcriptomic classification in everyday practice and help guide more personalized treatment strategies for patients with intrahepatic cholangiocarcinoma.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101675"},"PeriodicalIF":7.5,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145814291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell analysis of heterogeneity in reverted hiPSC-derived human hepatic stellate cells","authors":"Xinjia Wang ,&nbsp;Eun Hee Ha ,&nbsp;Lu Bian ,&nbsp;Zhuoying Feng ,&nbsp;Fan Zhang ,&nbsp;Kyle O’Shaughnessy ,&nbsp;Lei Wang ,&nbsp;Andrea Hochwald ,&nbsp;Yifei Zheng ,&nbsp;Weibo Chen ,&nbsp;Yujie Zhang ,&nbsp;Xianfang Wu","doi":"10.1016/j.jhepr.2025.101669","DOIUrl":"10.1016/j.jhepr.2025.101669","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Activated HSCs are known to drive fibrogenesis, but their fate following injury resolution remains unclear. We aimed to investigate whether human activated HSCs revert to a less activated state, and to characterize features of such reversion using a human induced pluripotent stem cell (hiPSC)-derived multicellular liver model.</div></div><div><h3>Methods</h3><div>We used a hiPSC-derived liver culture containing hepatocytes, HSCs, and macrophages. HSCs were activated by HCV infection or a lipotoxic milieu modeling metabolic dysfunction-associated steatotic liver disease (MASLD) and subjected to injury resolution through antiviral treatment or replacement with a healthy medium. Reverted HSCs were characterized via gene expression profiling, functional assays, and single-cell RNA sequencing (scRNA-seq). The role of macrophage-derived IL-10 in HSC reversion was investigated through receptor knockdown and cytokine treatment experiments.</div></div><div><h3>Results</h3><div>Following either HCV clearance or withdrawal of lipotoxic stress, activated HSCs reverted to a less activated state, regaining lipid droplets and vitamin A storage while re-expressing quiescent HSC markers. scRNA-seq revealed heterogeneity among reverted HSCs, identifying subpopulations expressing apoptotic, senescent, or quiescent-like signatures. A distinct lipid-high, PTK2-low population closely resembled naïve quiescent HSCs. Functional assays demonstrated that rHSCs retained partial quiescence but exhibited heightened sensitivity to fibrogenic re-stimulation (n = 4, <em>p</em> &lt;0.05). Mechanistically, macrophage-derived IL-10 promoted HSC reversion by inducing vitamin A metabolism-related genes, including <em>LRAT</em> and <em>RBP1</em> (n = 4, <em>p</em> &lt;0.01).</div></div><div><h3>Conclusions</h3><div>Activated human HSCs demonstrate plasticity, reverting to a quiescent-like state following resolution of viral or metabolic injury, although they remain primed for reactivation. Macrophage-derived IL-10 plays a critical role in driving this reversion by regulating vitamin A metabolism. These findings provide insights into HSC dynamics and suggest potential therapeutic avenues for liver fibrosis by targeting HSC reversion.</div></div><div><h3>Impact and implications</h3><div>Removing the cause of liver injury—curing hepatitis C or withdrawing lipotoxic stress—allows scar-forming liver cells (hepatic stellate cells) to partly revert to a healthier, vitamin-A-storing state; single-cell profiling reveals its heterogeneity and identify a subset nearing true quiescence. This rebound depends on intercellular interaction, in part on the immune signal IL-10 from macrophages, yet reverted cells remain easier to re-activate. These findings provide insights into dynamics of hepatic stellate cells and suggest potential therapeutic avenues for liver fibrosis by targeting stellate cell reversion.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101669"},"PeriodicalIF":7.5,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145882438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liver biopsy quality criteria to exclude cirrhosis in case of suspicion of porto-sinusoidal vascular disorder","authors":"Chloé de Broucker ,&nbsp;Valérie Paradis ,&nbsp;Maria Luisa Botero ,&nbsp;Miguel Albuquerque ,&nbsp;Audrey Payancé ,&nbsp;Aurélie Plessier ,&nbsp;Laure Elkrief ,&nbsp;François Durand ,&nbsp;Sophie Hillaire ,&nbsp;Paul-Emile Zafar ,&nbsp;Juan Carlos Garcia Pagan ,&nbsp;Pierre-Emmanuel Rautou","doi":"10.1016/j.jhepr.2025.101670","DOIUrl":"10.1016/j.jhepr.2025.101670","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Baveno VII guidelines based porto-sinusoidal vascular disorder (PSVD) diagnosis on a liver biopsy excluding cirrhosis. However, evidence-based quality criteria for liver biopsy are lacking. This study aimed to determine biopsy length and staining appropriate to rule out cirrhosis.</div></div><div><h3>Methods</h3><div>Liver explants from 12 patients with cirrhosis and 12 with PSVD were selected. Slides were stained with Picrosirius red or Masson’s trichrome. A total of 36,000 virtual liver biopsies were randomly generated, including different biopsy widths (572 and 1,000 μm corresponding to transjugular and percutaneous biopsies, respectively) and lengths (5 mm, 10 mm, 15 mm, 20 mm, 25 mm; fragmented 5 + 10 mm and 5 + 5 + 5 mm). Biopsies were assessed by an expert pathologist for the presence or absence of cirrhosis.</div></div><div><h3>Results</h3><div>Overall sensitivity of percutaneous biopsies for the diagnosis of cirrhosis was 85%, higher with Picrosirius red (86%) than with Masson’s trichrome (83%) (<em>p</em> &lt;0.001). Sensitivity increased with the length of percutaneous biopsies, reaching a plateau from 15 mm (88%). Sensitivity was significantly higher for percutaneous (89%) than for transjugular biopsies (84%) (<em>p</em> &lt;0.001). A plateau was also observed from 15 mm for transjugular biopsies. Fragmented biopsies with at least one 10-mm-long fragment (5 + 10 mm) had similar sensitivity as 15-mm-long biopsies. Diagnostic accuracy was lower in case of Laennec A cirrhosis, HBV-associated disease, or incomplete septal fibrosis. Validation by a second pathologist gave similar results.</div></div><div><h3>Conclusions</h3><div>For the diagnosis of PSVD, the minimum length of liver biopsy to exclude cirrhosis was 15 mm with at least one fragment of 10 mm. Picrosirius red had a better performance than Masson's trichrome staining. The transjugular route showed lower sensitivity, but provides additional information.</div></div><div><h3>Impact and implications</h3><div>This study shows that, for the diagnosis of porto-sinusoidal vascular disorder, the minimum length of liver biopsy to exclude cirrhosis is 15 mm, with a minimum fragment of 10 mm. Picrosirius red had a slightly better performance than Masson's trichrome staining. Future guidelines might consider that a ≥15-mm-long biopsy, with a fragment ≥10 mm, is sufficient to rule out cirrhosis in case of suspicion of porto-sinusoidal vascular disorder with signs of portal hypertension.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101670"},"PeriodicalIF":7.5,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating HBV RNA and hepatitis B core-related antigen as determinants of HBsAg loss in persons with HIV in Europe","authors":"Lorin Begré ,&nbsp;Anders Boyd ,&nbsp;Marie-Laure Plissonnier ,&nbsp;Barbara Testoni ,&nbsp;Charles Béguelin ,&nbsp;Franziska Suter-Riniker ,&nbsp;Caroline Scholtès ,&nbsp;Jürgen K. Rockstroh ,&nbsp;Karine Lacombe ,&nbsp;Lars Peters ,&nbsp;Marintha Heil ,&nbsp;Massimo Levrero ,&nbsp;Andri Rauch ,&nbsp;Fabien Zoulim ,&nbsp;Gilles Wandeler","doi":"10.1016/j.jhepr.2025.101671","DOIUrl":"10.1016/j.jhepr.2025.101671","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>HBsAg loss improves clinical outcomes in persons with HIV and HBV coinfection. We aimed to evaluate if hepatitis B core-related antigen and circulating HBV RNA levels were associated with HBsAg loss in Euro-B, a multi-cohort collaboration including data from the Swiss HIV Cohort Study, EuroSIDA, and the French HIV/HBV cohort.</div></div><div><h3>Methods</h3><div>We included persons with HIV, a positive HBsAg, and ≥6 months of follow-up on tenofovir-containing antiretroviral therapy. We evaluated quantitative HBsAg, HBV DNA, hepatitis B core-related antigen, and HBV RNA levels over time and assessed HBsAg loss (<em>i.e.</em> quantitative HBsAg &lt;0.05 IU/ml) during tenofovir therapy.</div></div><div><h3>Results</h3><div>Among 599 participants median age was 41 years (IQR 35–47), 18.4% were female and 47.3% HBeAg-positive. We observed HBsAg loss in 12.9% of participants after 2 years and in 18.2% during a median follow-up of 8.2 years (IQR 3.6–13.1). Individuals who were HBeAg-negative were more likely to have a negative hepatitis B core-related antigen and HBV RNA below the detection limit than participants who were HBeAg-positive. Quantitative HBsAg ≤1,000 IU/ml at baseline was the strongest predictor of HBsAg loss regardless of HBeAg status. Additionally, HBsAg loss was associated with lower baseline HBV RNA levels (odds ratio 0.66, 95% CI 0.49–0.88) and higher baseline HBV DNA levels in participants who were HBeAg-positive.</div></div><div><h3>Conclusions</h3><div>In this European cohort of persons with HIV/HBV, 18% experienced HBsAg loss during tenofovir-containing antiretroviral therapy. In addition to low baseline quantitative HBsAg levels, HBV RNA may predict HBsAg loss in individuals who are HBeAg-positive.</div></div><div><h3>Impact and implications</h3><div>The present study builds on a multi-cohort collaboration including persons with HIV/HBV from Europe. It provides estimates on the probability of HBsAg loss during long-term tenofovir-containing antiretroviral therapy and describes the potential of the novel biomarkers HBV RNA and hepatitis B core-related antigen as its predictors. The discrepancies regarding HBV RNA and HBcrAg levels before and during therapy observed between persons who were HBeAg-negative and HBeAg-positive with HIV/HBV may influence treatment decisions and the development of new treatment strategies.</div></div><div><h3>Clinical Trials Registration</h3><div>The study is registered at ClinicalTrials.gov (NCT04984772).</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101671"},"PeriodicalIF":7.5,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145882437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}