JHEP Reports最新文献

{"title":"Protective value of ischemia-free liver transplantation on post-transplant acute kidney injury","authors":"Qiang Zhao ,&nbsp;Jinbo Huang ,&nbsp;Meiting Qin ,&nbsp;Yunhua Tang ,&nbsp;Zhiying Liu ,&nbsp;Yefu Li ,&nbsp;Zhiyong Guo ,&nbsp;Jia Dan ,&nbsp;Yu Nie ,&nbsp;Xiaoshun He","doi":"10.1016/j.jhepr.2025.101339","DOIUrl":"10.1016/j.jhepr.2025.101339","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Ischemia-free liver transplantation (IFLT) completely avoids ischemia–reperfusion injury (IRI), thus potentially reducing acute kidney injury (AKI) after liver transplantation (LT). Therefore, this study investigated whether IFLT has a protective effect against AKI after LT.</div></div><div><h3>Methods</h3><div>In total, 862 patients who had undergone LT between 2017 to 2022 were divided into an ischemia-free liver transplantation group (IFLT group) and conventional liver transplantation group (CLT group) based on the surgical methods used. Propensity score matching (PSM) was used for post hoc randomization in the 1:1 matching between the groups. Post-transplant kidney function, graft function, and patient survival were compared between the groups. Multivariate logistic regression analysis was used to identify the risk factors of AKI after LT.</div></div><div><h3>Results</h3><div>Overall, 745 out of 862 patients were finally enrolled, of whom 98 underwent IFLT. PSM created 94 pairs of patients. IFLT resulted in a significant reduction in Stage-3 AKI (3.2% <em>vs.</em> 16.0%, <em>p</em> = 0.003), severe AKI (SAKI) (13.8% <em>vs.</em> 25.5%, <em>p</em> = 0.044), and renal replacement therapy (RRT) ratio (3.2% <em>vs.</em> 12.8%, <em>p</em> = 0.015) compared with the CLT group. The early allograft dysfunction (EAD) incidence of the IFLT group significantly decreased (8.5% <em>vs.</em> 44.7%, <em>p</em> &lt;0.001). Livers from the extended criteria donation (ECD) were received in 49 patients who underwent IFLT and 46 patients who underwent CLT. Compared with the ECD-CLT group, the Stage-3 AKI and SAKI incidence in the ECD-IFLT group were both decreased (<em>p &lt;</em>0.05). Multivariate logistic regression analysis further confirmed that both using IFLT and avoiding ECD were protective factors for post-transplant Stage-3 AKI.</div></div><div><h3>Conclusions</h3><div>IFLT significantly reduces the incidence of post-transplant SCKI, Stage-3 AKI, and RRT. Importantly, this protective effect is also present in patients receiving ECD livers.</div></div><div><h3>Impact and implications</h3><div>Ischemia-free liver transplantation significantly reduces the incidence of severe acute kidney injury, Stage-3 acute kidney injury and renal replacement therapy after liver transplantation. Importantly, this protective effect is also present in patients receiving extended criteria donation livers.</div></div><div><h3>Clinical trial number</h3><div><span><span>ChiCTR2400081755</span><svg><path></path></svg></span>.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 4","pages":"Article 101339"},"PeriodicalIF":9.5,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143696635","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":"Trans-splenic anterograde coil assisted transvenous obliteration vs. retrograde transvenous obliteration: Are we heading the right way?","authors":"Sagnik Biswas ,&nbsp;Sanchita Gupta ,&nbsp;Shivanand Gamanagatti ,&nbsp;Shalimar","doi":"10.1016/j.jhepr.2025.101341","DOIUrl":"10.1016/j.jhepr.2025.101341","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 5","pages":"Article 101341"},"PeriodicalIF":9.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143738929","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":"Comment on “Lower incidence of hepatocellular carcinoma with tenofovir alafenamide in chronic hepatitis B: Evidence from a large-scale cohort”","authors":"Ji-Eun Han ,&nbsp;Gi Hyeon Seo ,&nbsp;Soon Sun Kim","doi":"10.1016/j.jhepr.2025.101334","DOIUrl":"10.1016/j.jhepr.2025.101334","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 5","pages":"Article 101334"},"PeriodicalIF":9.5,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143738815","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":"Minimal residual ascites 3 months after TIPS implantation implicates worse clinical outcomes in patients with cirrhosis","authors":"Jim Benjamin Mauz ,&nbsp;Lukas Hartl ,&nbsp;Andrea Kornfehl ,&nbsp;Sarah Lisa Schütte ,&nbsp;Paul Hemetsberger ,&nbsp;Theresa Müllner-Bucsics ,&nbsp;Mathias Jachs ,&nbsp;Anja Tiede ,&nbsp;Hannah Rieland ,&nbsp;Michael Schwarz ,&nbsp;Nina Dominik ,&nbsp;Georg Kramer ,&nbsp;Bernhard Meyer ,&nbsp;Lukas Reider ,&nbsp;Michael Trauner ,&nbsp;Heiner Wedemeyer ,&nbsp;Mattias Mandorfer ,&nbsp;Benjamin Maasoumy ,&nbsp;Thomas Reiberger ,&nbsp;Tammo Lambert Tergast","doi":"10.1016/j.jhepr.2025.101335","DOIUrl":"10.1016/j.jhepr.2025.101335","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Transjugular intrahepatic portosystemic shunt (TIPS) implantation is indicated for recurrent/refractory ascites in patients with cirrhosis. The prognostic impact of residual minimal ascites after TIPS implantation has not yet been investigated.</div></div><div><h3>Methods</h3><div>We included patients with cirrhosis undergoing covered TIPS implantation for refractory ascites in Vienna (2000–2022) and Hannover (2009–2021) with available abdominal ultrasound 3 months after TIPS insertion (3M). The patients were followed up for further decompensation and transplant-free mortality. Two distinct competing risk regression models (Adjusted model I and Adjusted model II) were performed to determine the prognostic impact of no <em>vs.</em> minimal ascites at 3M.</div></div><div><h3>Results</h3><div>Overall, 292 patients with male predominance (71.7%) and mostly alcohol-related liver disease (71.7%) were included. At 3M, n = 105 (36.0%) patients showed no ascites on abdominal ultrasound, whereas n = 82 (28.1%) exhibited minimal and n = 105 (36.0%) moderate/severe ascites. The portal pressure gradient after TIPS implantation was similar in the three groups (median 7 mmHg; <em>p</em> = 0.311). Patients with no or minimal ascites had comparable Model for End-Stage Liver Disease and Freiburg Index of Post-TIPS Survival scores at baseline and 3M. Competing risk regression models showed that minimal ascites (<em>vs.</em> no ascites) was an independent predictor of further decompensation (Adjusted model I: adjusted subdistribution hazard ratio [aSHR], 1.69; 95% CI, 1.03–2.77; <em>p</em> = 0.038; Adjusted model II: aSHR, 1.76; 95% CI, 1.07–2.88; <em>p</em> = 0.026) and transplant-free mortality (Adjusted model I: aSHR, 1.76; 95% CI, 1.08–2.88; <em>p</em> = 0.024; Adjusted model II: aSHR, 1.73; 95% CI, 1.05–2.82; <em>p</em> = 0.030).</div></div><div><h3>Conclusions</h3><div>Patients with residual minimal ascites at 3M remain at higher risk for further decompensation and transplant-free mortality compared with those with no residual ascites.</div></div><div><h3>Impact and implications</h3><div>This study evaluated the prognostic relevance of residual ascites grades in patients with advanced chronic liver disease after TIPS placement. Severe ascites was linked to the worst outcomes, underscoring the need for urgent liver transplantation evaluation. However, even minimal residual ascites significantly increased the risk of further decompensation and transplant-free mortality. These findings suggest that patients with minimal residual ascites will benefit from enhanced post-TIPS clinical monitoring. Further research is warranted to uncover the underlying mechanisms and investigate the potential of targeted interventions to improve outcomes in this vulnerable group.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 7","pages":"Article 101335"},"PeriodicalIF":9.5,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205553","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":"Macrophage ATG16L1 promotes liver regeneration after partial hepatectomy","authors":"Xinyu Zhan ,&nbsp;Yan Bai ,&nbsp;Qing Zhu ,&nbsp;Yiyun Gao ,&nbsp;Fan Li ,&nbsp;Qingfa Bu ,&nbsp;Zeyu Zhu ,&nbsp;Zhuqing Rao ,&nbsp;Haoming Zhou","doi":"10.1016/j.jhepr.2025.101330","DOIUrl":"10.1016/j.jhepr.2025.101330","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Autophagy plays an important role in liver regeneration. However, most studies are limited to hepatocytes, and the function and mechanism of macrophage autophagy in liver regeneration remain unclear. This study investigated the role of the essential autophagy gene encoding autophagy-related 16-like 1 (<em>ATG16L1</em>), which regulates the macrophage phenotype in liver regeneration.</div></div><div><h3>Methods</h3><div>We generated <em>FloxP-Atg16l1</em> (<em>Atg16l1</em>^{<em>FL/FL</em>}), <em>Lyz2-Cre Atg16l1</em> knockout (KO) (<em>Atg16l1</em>^{<em>M-KO</em>}), and myeloid-specific <em>Atg16l1-overexpression</em>-knock-in (<em>Atg16l1</em>^<em>OE</em>) mice. These mice were subjected to 70% partial hepatectomy to demonstrate the role of ATG16L1 in macrophages during liver regeneration.</div></div><div><h3>Results</h3><div>ATG16L1 expression was significantly upregulated in macrophages during the early stages of liver regeneration. ATG16L1 deletion in macrophages substantially delayed liver regeneration in mice and caused a marked imbalance in Ly6C^hi and Ly6C^lo macrophage proportions in the liver. RNA-sequencing analysis revealed that, compared with macrophages isolated from <em>Atg16l1</em>^{<em>FL/FL</em>} mice, those from <em>Atg16l1</em>^{<em>M-KO</em>} mice exhibited significant downregulation of genes associated with oxidative phosphorylation and upregulation of proinflammatory gene expression. Mechanistically, ATG16L1 loss impaired mitophagy in macrophages, leading to the accumulation of mitochondrial damage and a metabolic shift that promoted proinflammatory macrophage polarization. ATG16L1 deficiency not only promoted macrophage mitochondrial (mt)DNA release and cyclic GMP-AMP synthase–stimulator of interferon genes (STING) activation, but also suppressed STING degradation. Sustained STING hyperactivation and subsequent increased release of downstream interferons further contributed to the inhibition of liver regeneration. Notably, pharmacological activation or genetic overexpression of ATG16L1 significantly enhanced liver regeneration in mice.</div></div><div><h3>Conclusions</h3><div>ATG16L1 has a pivotal role in liver regeneration by affecting the phenotype and function of macrophages. Thus, targeting ATG16L1 in macrophages could present a novel strategy for promoting liver regeneration.</div></div><div><h3>Impact and implications</h3><div>The autophagy-related gene <em>ATG16L1</em> mediates mitophagy, facilitating the clearance of damaged mitochondria in macrophages following partial hepatectomy and maintaining a reparative macrophage phenotype. ATG16L1 deficiency triggers excessive STING activation and inhibits its degradation, thereby suppressing liver regeneration. Thus, targeting ATG16L1 in macrophages could represent a novel strategy to promote liver regeneration.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 5","pages":"Article 101330"},"PeriodicalIF":9.5,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143842532","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":"Protective role of physical activity against HCC risk in type 2 diabetes: Evidence and public health perspectives","authors":"Haiquan Shi ,&nbsp;Huan Zou ,&nbsp;Hongchao Zhu ,&nbsp;Zuyin Ge ,&nbsp;Sheng Li","doi":"10.1016/j.jhepr.2025.101331","DOIUrl":"10.1016/j.jhepr.2025.101331","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 5","pages":"Article 101331"},"PeriodicalIF":9.5,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143815578","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":"PLOD1 promotes the malignancy of hepatocellular carcinoma by facilitating the NF-κB/IL-6/STAT3-dependent TCA cycle","authors":"Chengfei Zhang ,&nbsp;Yangchun Zhou ,&nbsp;Minghua Hu ,&nbsp;Yue Pan ,&nbsp;Xin Chen ,&nbsp;Qi Sun ,&nbsp;Zhijie Ma ,&nbsp;Cheng Wang ,&nbsp;Yong Zha ,&nbsp;Feng Zhu ,&nbsp;Hongping Xia","doi":"10.1016/j.jhepr.2025.101329","DOIUrl":"10.1016/j.jhepr.2025.101329","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Procollagen lysyl hydroxylase 1 (PLOD1) is crucial in regulating collagen synthesis and cross-linking. However, its roles and underlying mechanisms in the progression of hepatocellular carcinoma (HCC) remain unclear. Herein, we aimed to investigate the underlying biological functions and mechanisms of PLOD1 in HCC.</div></div><div><h3>Methods</h3><div>The expression levels of PLOD1 in HCC were measured by qPCR, Western blot, and immunohistochemistry. Cell proliferation, apoptosis, and stemness were examined by CCK8, flow cytometry, sphere formation, and aldehyde dehydrogenase activity assays. The subcutaneous tumorigenicity model, orthotopic tumorigenicity model, and hepatotoxin-induced HCC model were used for <em>in vivo</em> experiments. RNA-sequence and untargeted metabolomics analysis were performed to identify underlying mechanisms.</div></div><div><h3>Results</h3><div>PLOD1 is found to be highly expressed in both human (<em>p &lt;</em>0.0001) and mouse HCC (<em>p</em> &lt;0.01) and is associated with a poor prognosis (<em>p</em> = 0.047). <em>In vitro</em> and <em>in vivo</em> experiments reveal that overexpression of PLOD1 promotes the proliferation and stemness of HCC cells. Meanwhile, the depletion of PLOD1 attenuates the occurrence and growth of HCC, leading to cell cycle arrest (<em>p</em> &lt;0.01) and apoptosis (<em>p</em> &lt;0.001) in HCC. Mechanistically, PLOD1 positively regulates the NF-κB/IL-6/STAT3 signaling pathway and accelerates TCA cycle metabolic reprogramming. Blocking the NF-κB/IL-6/STAT3 signaling pathway and TCA cycle can effectively mitigate PLOD1-induced proliferation and stemness of HCC cells.</div></div><div><h3>Conclusions</h3><div>Our study uncovers the PLOD1/NF-κB/IL-6/STAT3 axis as a therapeutic target for inhibiting the progression and stemness of HCC.</div></div><div><h3>Impact and implications</h3><div>The roles and underlying mechanisms of PLOD1 in the progression of HCC remain unclear. In this study, we report that PLOD1 is highly expressed in patients with HCC and promotes the proliferation and stemness of HCC cells by activating the NF-κB/IL-6/STAT3-dependent TCA cycle. Knocking down hepatic PLOD1 using adeno-associated virus results in reduced progression of HCC in mice, suggesting that PLOD1 may serve as a potential therapeutic target for HCC.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 5","pages":"Article 101329"},"PeriodicalIF":9.5,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143842534","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":"Adapted hepatitis C virus clone infects innate immunity-deficient mouse hepatocytes with minimal human HCV entry factors","authors":"Julie Ann Sheldon ,&nbsp;Melina Winkler ,&nbsp;Qinggong Yuan ,&nbsp;Nicola Frericks ,&nbsp;Richard John Phillip Brown ,&nbsp;Csaba Miskey ,&nbsp;Natascha Gödecke ,&nbsp;Sara Behme ,&nbsp;Katharina Rox ,&nbsp;Giorgia Mysegades ,&nbsp;Florian Vondran ,&nbsp;Dagmar Wirth ,&nbsp;Thomas Pietschmann","doi":"10.1016/j.jhepr.2025.101328","DOIUrl":"10.1016/j.jhepr.2025.101328","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Hepatitis C virus (HCV) has a narrow species tropism and cannot infect mice. To understand HCV species tropism and to develop better animal models, we adapted HCV to infect mouse cells deficient in innate immunity and with minimal human HCV host factors.</div></div><div><h3>Methods</h3><div>HCV was adapted via passaging an HCV infectious virus clone several times in human hepatoma cells, mouse liver cells, and eventually primary mouse hepatocytes deficient in innate immunity and ectopically expressing human occludin and human CD81. Using RNAseq the sequence of the adapted virus was analyzed, and several clones were generated to study replication and infection kinetics as well as neutralization assays in several human/mouse cell lines and primary hepatocytes from human, mouse, and macaques.</div></div><div><h3>Results</h3><div>Accumulation of 35 non-synonymous and 66 synonymous mutations correlated with &gt;1,000-fold enhanced production of infectious progeny from primary mouse hepatocytes. These mutations did not confer drug resistance or evasion from innate immunity. They did not enhance fitness in human or macaque hepatocytes. We show that non-synonymous mutations are necessary and sufficient for adaptation, and that changes to the glycoproteins are not essential. Mutations outside of viral envelope proteins enhanced specific infectivity and facilitated viral spread in murine cells.</div></div><div><h3>Conclusions</h3><div>This study reveals key viral factors governing HCV species tropism. The mouse-adapted HCV opens up possibilities for the development of animal models to analyze HCV pathogenesis, immune control, and vaccine development.</div></div><div><h3>Impact and implications</h3><div>This work demonstrates the feasibility in principle of HCV adaptation to replication in and infection of non-human cells. This is made possible by a manageable number of non-synonymous mutations and opens up new ways to elucidate the principles of HCV species tropism and to develop important animal models for HCV research in the long term.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 5","pages":"Article 101328"},"PeriodicalIF":9.5,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143738816","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":"Hemodynamic profile of terlipressin and octreotide in patients with cirrhosis and portal hypertension: a randomized, single-blind clinical trial","authors":"Valeria Perez-Campuzano ,&nbsp;Pol Olivas ,&nbsp;José Ferrusquía-Acosta ,&nbsp;Sonia Torres ,&nbsp;Roger Borras ,&nbsp;Anna Baiges ,&nbsp;Lara Orts ,&nbsp;Pamela Vizcarra ,&nbsp;Maria-Angeles Falga ,&nbsp;Joana Codina ,&nbsp;Sarah Shalaby ,&nbsp;Asunción Ojeda ,&nbsp;Fanny Turon ,&nbsp;Virginia Hernández-Gea ,&nbsp;Andrés Cárdenas ,&nbsp;Juan-Carlos García-Pagán","doi":"10.1016/j.jhepr.2024.101325","DOIUrl":"10.1016/j.jhepr.2024.101325","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Continuous infusion of terlipressin may result in a more sustained reduction in portal pressure with fewer adverse effects than administered as a bolus. This study aimed to compare the hepatic and cardiopulmonary hemodynamic effects and safety profiles of bolus &lt;em&gt;vs&lt;/em&gt;. terlipressin continuous infusion.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;This is a single-center, single-blinded, double-dummy, parallel-group, clinical trial in which 38 patients with cirrhosis and portal hypertension were randomized to receive the following: 1 mg bolus of terlipressin + continuous infusion of placebo (TERLBOL, n = 12), a bolus of placebo + continuous infusion of terlipressin (2 or 4 mg/day if &lt;10% reduction in hepatic venous pressure gradient [HVPG] at 30 min of infusion) (TERLINF, n = 14), or a bolus of octreotide (50 μg) + continuous infusion of octreotide (50 μg/h) (OCTR, n = 12) as an additional control group. HVPG, cardiopulmonary pressures, and cardiac output were measured at baseline and after 30, 60, and 120 min.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Sixty-eight percent of patients were male, with a median age of 59 years. There were no significant differences in baseline characteristics. In the TERLBOL group, there was a nonsignificant reduction in HVPG (at 120 min, -4.9%; &lt;em&gt;p&lt;/em&gt; = 0.14). However, cardiopulmonary and mean arterial pressures significantly increased, whereas cardiac output and heart rate significantly decreased. In the TERLINF group, there were nonsignificant changes in cardiopulmonary hemodynamics or HVPG (NS) despite doubling the infusion dose after 30 min in 13/14 patients. In the OCTR group, there was a nonsignificant reduction in HVPG (at 120 min, -4.9%; &lt;em&gt;p&lt;/em&gt; = 0.08), and pulmonary capillary pressure significantly decreased. All treatments were well tolerated, and no adverse events were observed.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;&lt;em&gt;T&lt;/em&gt;here were nonsignificant reductions in HVPG with the three therapeutic strategies. Further investigations are warranted to determine the optimal dosing strategy for continuous infusion of terlipressin in patients with cirrhosis and portal hypertension.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications:&lt;/h3&gt;&lt;div&gt;The results of our study do not show a significant reduction in portal pressure, at least in the first 2 h after the selected dose. Although the study was not performed in the setting of acute variceal bleeding and terlipressin was used as a standard therapy, these results do not support the treatment strategy of terlipressin infusion alone at the doses studied for the management of acute variceal bleeding, where a quick reduction in portal pressure is thought to play a major role controlling variceal bleeding. It is important to highlight that the continuously infused terlipressin regimen is better tolerated and appears to have a better cardiopulmonary safety profile. Other treatment strategies of continuous terlipressin infusion, such ","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 4","pages":"Article 101325"},"PeriodicalIF":9.5,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143654477","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":"CRISPR/Cas9 gene therapy increases the risk of tumorigenesis in the mouse model of hereditary tyrosinemia type I","authors":"Tong Chen ,&nbsp;Mercedes Barzi ,&nbsp;Nika Furey ,&nbsp;Hyunjae R. Kim ,&nbsp;Francis P. Pankowicz ,&nbsp;Xavier Legras ,&nbsp;Sara H. Elsea ,&nbsp;Ayrea E. Hurley ,&nbsp;Diane Yang ,&nbsp;David A. Wheeler ,&nbsp;Malgorzata Borowiak ,&nbsp;Beatrice Bissig-Choisat ,&nbsp;Pavel Sumazin ,&nbsp;Karl-Dimiter Bissig","doi":"10.1016/j.jhepr.2025.101327","DOIUrl":"10.1016/j.jhepr.2025.101327","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The therapeutic potential of CRISPR gene editing has been demonstrated in various animal models; however, little is known about its long-term consequences. This study seeks to bridge this gap by investigating the lasting consequences of CRISPR gene therapy in an animal model of hereditary tyrosinemia type I (HT-I). We compared the standard of care—nitisinone, a small molecule inhibitor of hydroxyphenylpyruvate dioxygenase (HPD)—with the deletion of the <em>Hpd</em> gene by CRISPR gene therapy. Both treatments block flux through tyrosine catabolism and thereby prevent the accumulation of toxic catabolites in HT-I.</div></div><div><h3>Methods</h3><div>We assessed the efficacy and safety of CRISPR gene editing in fumarylacetoacetate hydrolase-deficient (<em>Fah-/-</em>) mice, the mouse model of HT-I, 12 months post treatment with either nitisinone or CRISPR deletion of <em>Hpd</em>. We deleted the <em>Hpd</em> gene using an adenovirus containing Cas9 and an adeno-associated virus containing two sgRNA against the <em>Hpd</em> gene. Primary endpoints were survival, urine biochemistry, liver (immuno)histochemistry, and genetic analyses.</div></div><div><h3>Results</h3><div>CRISPR deletion and pharmacological inhibition of HPD both demonstrate efficient metabolic correction and rescue of lethality. Surprisingly, we detected a markedly increased incidence of hepatocellular cancer in the CRISPR gene therapy group (71%, 12/17 mice) compared with four control groups (nitisinone [19%, four of 21 mice], sgRNA only [6%, one of 16 mice], Cas9 only [11%, two of 19 mice], and hydrodynamic tail vein injection of both CRISPR constructs [24%, four of 17 mice]). All analyzed tumors in the CRISPR gene therapy group were deleted for <em>Hpd</em> but showed on-and-off target vector integrations.</div></div><div><h3>Conclusions</h3><div>CRISPR gene therapy increases the risk of hepatocellular cancer in the mouse model of HT-I. Because HT-I is characterized by inherent cancer susceptibility, this severe adverse event exposes the potential limitations of CRISPR gene therapy in cancer-prone disorders.</div></div><div><h3>Impact and implications</h3><div>Not much is known about the long-term consequences of somatic gene editing. Our study investigates CRISPR gene therapy in tyrosinemia type I using viral vectors. Although the CRISPR-based therapy effectively treated the metabolic condition, it was associated with a higher incidence of liver cancer than the current standard of care. These findings highlight the potential risks of using CRISPR gene therapy in conditions predisposed to cancer development.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 4","pages":"Article 101327"},"PeriodicalIF":9.5,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143698143","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}