Pub Date : 2024-04-26DOI: 10.1016/j.jhepr.2024.101104
Simon Johannes Gairing , Chiara Mangini , Lisa Zarantonello , Elise Jonasson , Henrike Dobbermann , Philippe Sultanik , Peter Robert Galle , Joachim Labenz , Dominique Thabut , Jens Uwe Marquardt , Patricia P. Bloom , Mette Munk Lauridsen , Sara Montagnese , Christian Labenz
Background & Aims
Data on the association between proton pump inhibitor (PPI) use and hepatic encephalopathy (HE) are conflicting, and data from multicentre studies are scarce. The aim of this study was to dissect the potential association between PPI use and minimal (MHE) and overt HE (OHE).
Methods
Data from patients with cirrhosis recruited at seven centres across Europe and the US were analysed. MHE was defined by the psychometric hepatic encephalopathy score (PHES). PPI use was recorded on the day of testing with PHES. Patients were followed for OHE development and death/liver transplantation.
Results
A total of 1,160 patients with a median MELD of 11 were included (Child-Pugh stages: A 49%/B 39%/C 11%). PPI use was noted in 58% of patients. Median follow-up time was 18.1 months, during which 230 (20%) developed an OHE episode, and 224 (19%) reached the composite endpoint of death/liver transplantation. In multivariable analyses, PPI use was neither associated with the presence of MHE at baseline nor OHE development during follow-up. These findings were consistent in subgroup analyses of patients with Child-Pugh A or B cirrhosis and after excluding patients with a history of OHE. PPI use was also not associated with a higher risk of OHE, neither in patients with an indication for treatment nor in patients without an indication.
Conclusions
PPI use is not associated with a higher risk of HE in patients with cirrhosis. Based on these findings, at present, a prescription should not be prohibited in case of a generally accepted indication.
Impact and implications
Data on the association between proton pump inhibitor (PPI) use and hepatic encephalopathy (HE) are conflicting. In this study, PPI use was not associated with a higher risk of minimal HE at baseline or overt HE during follow-up in patients with cirrhosis. Based on these findings, prescription of a PPI for a generally accepted indication should not be prohibited in patients with cirrhosis.
{"title":"Proton pump inhibitor use and risk of hepatic encephalopathy: A multicentre study","authors":"Simon Johannes Gairing , Chiara Mangini , Lisa Zarantonello , Elise Jonasson , Henrike Dobbermann , Philippe Sultanik , Peter Robert Galle , Joachim Labenz , Dominique Thabut , Jens Uwe Marquardt , Patricia P. Bloom , Mette Munk Lauridsen , Sara Montagnese , Christian Labenz","doi":"10.1016/j.jhepr.2024.101104","DOIUrl":"https://doi.org/10.1016/j.jhepr.2024.101104","url":null,"abstract":"<div><h3>Background & Aims</h3><p>Data on the association between proton pump inhibitor (PPI) use and hepatic encephalopathy (HE) are conflicting, and data from multicentre studies are scarce. The aim of this study was to dissect the potential association between PPI use and minimal (MHE) and overt HE (OHE).</p></div><div><h3>Methods</h3><p>Data from patients with cirrhosis recruited at seven centres across Europe and the US were analysed. MHE was defined by the psychometric hepatic encephalopathy score (PHES). PPI use was recorded on the day of testing with PHES. Patients were followed for OHE development and death/liver transplantation.</p></div><div><h3>Results</h3><p>A total of 1,160 patients with a median MELD of 11 were included (Child-Pugh stages: A 49%/B 39%/C 11%). PPI use was noted in 58% of patients. Median follow-up time was 18.1 months, during which 230 (20%) developed an OHE episode, and 224 (19%) reached the composite endpoint of death/liver transplantation. In multivariable analyses, PPI use was neither associated with the presence of MHE at baseline nor OHE development during follow-up. These findings were consistent in subgroup analyses of patients with Child-Pugh A or B cirrhosis and after excluding patients with a history of OHE. PPI use was also not associated with a higher risk of OHE, neither in patients with an indication for treatment nor in patients without an indication.</p></div><div><h3>Conclusions</h3><p>PPI use is not associated with a higher risk of HE in patients with cirrhosis. Based on these findings, at present, a prescription should not be prohibited in case of a generally accepted indication.</p></div><div><h3>Impact and implications</h3><p>Data on the association between proton pump inhibitor (PPI) use and hepatic encephalopathy (HE) are conflicting. In this study, PPI use was not associated with a higher risk of minimal HE at baseline or overt HE during follow-up in patients with cirrhosis. Based on these findings, prescription of a PPI for a generally accepted indication should not be prohibited in patients with cirrhosis.</p></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589555924001083/pdfft?md5=fe9b07957df90163d254a17deba0aece&pid=1-s2.0-S2589555924001083-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141479909","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}
Pub Date : 2024-04-25DOI: 10.1016/j.jhepr.2024.101102
Rongtao Lai , Xinjie Li , Jie Zhang , Jun Chen , Changqing Yang , Wen Xie , Yuecheng Yu , Xiaoyan Guo , Xinrong Zhang , Guoliang Lu , Xi’an Han , Qing Xie , Chengwei Chen , Tao Shen , Yimin Mao , Chinese Drug Induced Liver Disease Study Group
Background & Aims
Currently, there is limited knowledge on the clinical profile of drug-induced liver injury (DILI) in Chinese children. We aimed to assess the clinical characteristics, suspected drugs, and outcomes associated with pediatric DILI in China.
Methods
This nationwide, multicenter, retrospective study, conducted between 2012 and 2014, analyzed 25,927 cases of suspected DILI at 308 medical centers using the inpatient medical register system. Utilizing the Roussel Uclaf causality assessment method score, only patients with scores ≥6 or diagnosed with DILI by three experts after scoring <6 were included in the analysis. Among them, 460 cases met the EASL biochemical criteria. The study categorized children into three age groups: toddlers (≥30 days to <6 years old), school-age children (6 to <12 years old), and adolescents (12 to <18 years old).
Results
Hepatocellular injury was the predominant clinical classification, accounting for 63% of cases, with 34% of these cases meeting Hy's law criteria. Adolescents comprised the majority of children with moderate/severe DILI (65%). Similarly, adolescents faced a significantly higher risk of severe liver injury compared to younger children (adjusted odd ratios 4.75, p = 0.002). The top three most frequently prescribed drug classes across all age groups were antineoplastic agents (25.9%), antimicrobials (21.5%), and traditional Chinese medicine (13.7%). For adolescents, the most commonly suspected drugs were antitubercular drugs (22%) and traditional Chinese medicine (23%).
Conclusion
Adolescents are at a greater risk of severe and potentially fatal liver injury compared to younger children. Recognizing the risk of pediatric DILI is crucial for ensuring safe medical practices.
Impact and implications:
Drug-induced liver injury, a poorly understood yet serious cause of pediatric liver disease, encompasses a spectrum of clinical presentations, ranging from asymptomatic liver enzyme elevation to acute liver failure. This retrospective study, utilizing a large Chinese cohort of pediatric liver injury cases from 308 centers nationwide, characterized the major clinical patterns and suspected drugs in detail, revealing that adolescents are at a greater risk of severe liver injury compared to younger children. Vigilant care and careful surveillance of at-risk pediatric patients are crucial for physicians, researchers, patients, caregivers, and policymakers. Additional multicenter prospective studies are needed to evaluate the risk of hepatotoxicity in outpatients and hospitalized pediatric patients.
{"title":"Drug-induced liver injury in children: A nationwide cohort study from China","authors":"Rongtao Lai , Xinjie Li , Jie Zhang , Jun Chen , Changqing Yang , Wen Xie , Yuecheng Yu , Xiaoyan Guo , Xinrong Zhang , Guoliang Lu , Xi’an Han , Qing Xie , Chengwei Chen , Tao Shen , Yimin Mao , Chinese Drug Induced Liver Disease Study Group","doi":"10.1016/j.jhepr.2024.101102","DOIUrl":"10.1016/j.jhepr.2024.101102","url":null,"abstract":"<div><h3>Background & Aims</h3><p>Currently, there is limited knowledge on the clinical profile of drug-induced liver injury (DILI) in Chinese children. We aimed to assess the clinical characteristics, suspected drugs, and outcomes associated with pediatric DILI in China.</p></div><div><h3>Methods</h3><p>This nationwide, multicenter, retrospective study, conducted between 2012 and 2014, analyzed 25,927 cases of suspected DILI at 308 medical centers using the inpatient medical register system. Utilizing the Roussel Uclaf causality assessment method score, only patients with scores ≥6 or diagnosed with DILI by three experts after scoring <6 were included in the analysis. Among them, 460 cases met the EASL biochemical criteria. The study categorized children into three age groups: toddlers (≥30 days to <6 years old), school-age children (6 to <12 years old), and adolescents (12 to <18 years old).</p></div><div><h3>Results</h3><p>Hepatocellular injury was the predominant clinical classification, accounting for 63% of cases, with 34% of these cases meeting Hy's law criteria. Adolescents comprised the majority of children with moderate/severe DILI (65%). Similarly, adolescents faced a significantly higher risk of severe liver injury compared to younger children (adjusted odd ratios 4.75, <em>p</em> = 0.002). The top three most frequently prescribed drug classes across all age groups were antineoplastic agents (25.9%), antimicrobials (21.5%), and traditional Chinese medicine (13.7%). For adolescents, the most commonly suspected drugs were antitubercular drugs (22%) and traditional Chinese medicine (23%).</p></div><div><h3>Conclusion</h3><p>Adolescents are at a greater risk of severe and potentially fatal liver injury compared to younger children. Recognizing the risk of pediatric DILI is crucial for ensuring safe medical practices.</p></div><div><h3>Impact and implications:</h3><p>Drug-induced liver injury, a poorly understood yet serious cause of pediatric liver disease, encompasses a spectrum of clinical presentations, ranging from asymptomatic liver enzyme elevation to acute liver failure. This retrospective study, utilizing a large Chinese cohort of pediatric liver injury cases from 308 centers nationwide, characterized the major clinical patterns and suspected drugs in detail, revealing that adolescents are at a greater risk of severe liver injury compared to younger children. Vigilant care and careful surveillance of at-risk pediatric patients are crucial for physicians, researchers, patients, caregivers, and policymakers. Additional multicenter prospective studies are needed to evaluate the risk of hepatotoxicity in outpatients and hospitalized pediatric patients.</p></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S258955592400106X/pdfft?md5=5f1eecbe2c859d877fa23e6be36e48be&pid=1-s2.0-S258955592400106X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140793967","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}
Pub Date : 2024-04-25DOI: 10.1016/j.jhepr.2024.101101
Kunpeng Huang , Changyan Wang , Bosheng Mei , Jinglei Li , Tianxing Ren , Hanjing Zhan , Yunwei Zhang , Bowen Zhang , Xinyu Lv , Qi Zhang , Yong Guan , Xiaofei Zhang , Guoliang Wang , Wenming Pan , Peng Xu , Hui Wang , Jinxiang Zhang
Background & Aims
Persistent cholestasis has been associated with poor prognosis after orthotopic liver transplantation. In this study, we aimed to investigate how the accumulation of tauro-beta-muricholic acid (TβMCA), resulting from the reprogramming of bile acid (BA) metabolism during liver ischemia/reperfusion (IR) stress, attenuates liver inflammation.
Methods
Ingenuity Pathway Analysis was performed using transcriptome data from a murine hepatic IR model. Three different models of hepatic IR (liver warm IR, bile duct separation-IR, common bile duct ligation-IR) were employed. We generated adeno-associated virus-transfected mice and CD11b-DTR mice to assess the role of BAs in regulating the myeloid S1PR2-GSDMD axis. Hepatic BA levels were analyzed using targeted metabolomics. Finally, the correlation between the reprogramming of BA metabolism and hepatic S1PR2 levels was validated through RNA-seq of human liver transplant biopsies.
Results
We found that BA metabolism underwent reprogramming in murine hepatocytes under IR stress, leading to increased synthesis of TβMCA, catalyzed by the enzyme CYP2C70. The levels of hepatic TβMCA were negatively correlated with the severity of hepatic inflammation, as indicated by the serum IL-1β levels. Inhibition of hepatic CYP2C70 resulted in reduced TβMCA production, which subsequently increased serum IL-1β levels and exacerbated IR injury. Moreover, our findings suggested that TβMCA could inhibit canonical inflammasome activation in macrophages and attenuate inflammatory responses in a myeloid-specific S1PR2-GSDMD-dependent manner. Additionally, Gly-βMCA, a derivative of TβMCA, could effectively attenuate inflammatory injury in vivo and inhibit human macrophage pyroptosis in vitro.
Conclusions
IR stress orchestrates hepatic BA metabolism to generate TβMCA, which attenuates hepatic inflammatory injury by inhibiting the myeloid S1PR2-GSDMD axis. Bile acids have immunomodulatory functions in liver reperfusion injury that may guide therapeutic strategies.
Impact and implications:
Our research reveals that liver ischemia-reperfusion stress triggers reprogramming of bile acid metabolism. This functions as an adaptive mechanism to mitigate inflammatory injury by regulating the S1PR2-GSDMD axis, thereby controlling the release of IL-1β from macrophages. Our results highlight the crucial role of bile acids in regulating hepatocyte-immune cell crosstalk, which demonstrates an immunomodulatory function in liver reperfusion injury that may guide therapeutic strategies targeting bile acids and their receptors.
{"title":"Bile acids attenuate hepatic inflammation during ischemia/reperfusion injury","authors":"Kunpeng Huang , Changyan Wang , Bosheng Mei , Jinglei Li , Tianxing Ren , Hanjing Zhan , Yunwei Zhang , Bowen Zhang , Xinyu Lv , Qi Zhang , Yong Guan , Xiaofei Zhang , Guoliang Wang , Wenming Pan , Peng Xu , Hui Wang , Jinxiang Zhang","doi":"10.1016/j.jhepr.2024.101101","DOIUrl":"10.1016/j.jhepr.2024.101101","url":null,"abstract":"<div><h3>Background & Aims</h3><p>Persistent cholestasis has been associated with poor prognosis after orthotopic liver transplantation. In this study, we aimed to investigate how the accumulation of tauro-beta-muricholic acid (TβMCA), resulting from the reprogramming of bile acid (BA) metabolism during liver ischemia/reperfusion (IR) stress, attenuates liver inflammation.</p></div><div><h3>Methods</h3><p>Ingenuity Pathway Analysis was performed using transcriptome data from a murine hepatic IR model. Three different models of hepatic IR (liver warm IR, bile duct separation-IR, common bile duct ligation-IR) were employed. We generated adeno-associated virus-transfected mice and CD11b-DTR mice to assess the role of BAs in regulating the myeloid S1PR2-GSDMD axis. Hepatic BA levels were analyzed using targeted metabolomics. Finally, the correlation between the reprogramming of BA metabolism and hepatic S1PR2 levels was validated through RNA-seq of human liver transplant biopsies.</p></div><div><h3>Results</h3><p>We found that BA metabolism underwent reprogramming in murine hepatocytes under IR stress, leading to increased synthesis of TβMCA, catalyzed by the enzyme CYP2C70. The levels of hepatic TβMCA were negatively correlated with the severity of hepatic inflammation, as indicated by the serum IL-1β levels. Inhibition of hepatic CYP2C70 resulted in reduced TβMCA production, which subsequently increased serum IL-1β levels and exacerbated IR injury. Moreover, our findings suggested that TβMCA could inhibit canonical inflammasome activation in macrophages and attenuate inflammatory responses in a myeloid-specific S1PR2-GSDMD-dependent manner. Additionally, Gly-βMCA, a derivative of TβMCA, could effectively attenuate inflammatory injury <em>in vivo</em> and inhibit human macrophage pyroptosis <em>in vitro</em>.</p></div><div><h3>Conclusions</h3><p>IR stress orchestrates hepatic BA metabolism to generate TβMCA, which attenuates hepatic inflammatory injury by inhibiting the myeloid S1PR2-GSDMD axis. Bile acids have immunomodulatory functions in liver reperfusion injury that may guide therapeutic strategies.</p></div><div><h3>Impact and implications:</h3><p>Our research reveals that liver ischemia-reperfusion stress triggers reprogramming of bile acid metabolism. This functions as an adaptive mechanism to mitigate inflammatory injury by regulating the S1PR2-GSDMD axis, thereby controlling the release of IL-1β from macrophages. Our results highlight the crucial role of bile acids in regulating hepatocyte-immune cell crosstalk, which demonstrates an immunomodulatory function in liver reperfusion injury that may guide therapeutic strategies targeting bile acids and their receptors.</p></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589555924001058/pdfft?md5=f024edf2605ecb0532a35f0ea0b6aed0&pid=1-s2.0-S2589555924001058-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140776339","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}
Pub Date : 2024-04-25DOI: 10.1016/j.jhepr.2024.101100
Maria C. van Hooff , Rozanne C. de Veer , Vincent Karam , Rene Adam , Pavel Taimr , Wojciech G. Polak , Hasina Pashtoun , Sarwa Darwish Murad , Christophe Corpechot , Darius Mirza , Michael Heneghan , Peter Lodge , Gabriel C. Oniscu , Douglas Thorburn , Michael Allison , Herold J. Metselaar , Caroline M. den Hoed , Adriaan J. van der Meer
Background & Aims
Tacrolimus has been associated with recurrence of primary biliary cholangitis (PBC) after liver transplantation (LT), which in turn may reduce survival. This study aimed to assess the association between the type of calcineurin inhibitor used and long-term outcomes following LT in patients with PBC.
Methods
Survival analyses were used to assess the association between immunosuppressive drugs and graft or patient survival among adult patients with PBC in the European Liver Transplant Registry. Patients who received a donation after brain death graft between 1990 and 2021 with at least 1 year of event-free follow-up were included.
Results
In total, 3,175 patients with PBC were followed for a median duration of 11.4 years (IQR 5.9–17.9) after LT. Tacrolimus (Tac) was registered in 2,056 (64.8%) and cyclosporin in 819 (25.8%) patients. Following adjustment for recipient age, recipient sex, donor age, and year of LT, Tac was not associated with higher risk of graft loss (adjusted hazard ratio [aHR] 1.07, 95% CI 0.92-1.25, p = 0.402) or death (aHR 1.06, 95% CI 0.90-1.24, p = 0.473) over cyclosporin. In this model, maintenance mycophenolate mofetil (MMF) was associated with a lower risk of graft loss (aHR 0.72, 95% CI 0.60-0.87, p <0.001) or death (aHR 0.72, 95% CI 0.59-0.87, p <0.001), while these risks were higher with use of steroids (aHR 1.31, 95% CI 1.13-1.52, p <0.001, and aHR 1.34, 95% CI 1.15-1.56, p <0.001, respectively).
Conclusions
In this large LT registry, type of calcineurin inhibitor was not associated with long-term graft or recipient survival, providing reassurance regarding the use of Tac post LT in the population with PBC. Patients using MMF had a lower risk of graft loss and death, indicating that the threshold for combination treatment with Tac and MMF should be low.
Impact and implications:
This study investigated the association between immunosuppressive drugs and the long-term survival of patients with primary biliary cholangitis (PBC) following donation after brain death liver transplantation. While tacrolimus has previously been related to a higher risk of PBC recurrence, the type of calcineurin inhibitor was not related to graft or patient survival among patients transplanted for PBC in the European Liver Transplant Registry. Additionally, maintenance use of mycophenolate was linked to lower risks of graft loss and death, while these risks were higher with maintenance use of steroids. Our findings should provide reassurance for physicians regarding the continued use of Tac after liver transplantation in the population with PBC, and suggest potential benefit from combination therapy with mycophenolate.
背景& 目的他克莫司与肝移植(LT)后原发性胆汁性胆管炎(PBC)的复发有关,这反过来可能会降低存活率。本研究旨在评估PBC患者使用的钙神经蛋白抑制剂类型与LT术后长期预后之间的关系。方法使用存活率分析评估欧洲肝移植注册中心的成年PBC患者中免疫抑制剂与移植物或患者存活率之间的关系。结果共对3175名PBC患者进行了随访,LT术后的中位随访时间为11.4年(IQR为5.9-17.9)。2056例(64.8%)患者使用了他克莫司(Tac),819例(25.8%)患者使用了环孢素。在对受者年龄、受者性别、供者年龄和 LT 年份进行调整后,他克比环孢素的移植物丢失风险(调整后危险比 [aHR] 1.07,95% CI 0.92-1.25,p = 0.402)或死亡风险(aHR 1.06,95% CI 0.90-1.24,p = 0.473)更低。在该模型中,维持性霉酚酸酯(MMF)与较低的移植物丢失风险(aHR 0.72,95% CI 0.60-0.87,p <0.001)或死亡风险(aHR 0.72,95% CI 0.59-0.87,p <0.001)相关,而使用类固醇的风险较高(aHR 1.31,95% CI 1.13-1.52,p <0.结论在这一大型LT登记中,钙神经蛋白抑制剂的类型与长期移植物或受体存活率无关,为PBC人群在LT后使用Tac提供了保证。使用MMF的患者发生移植物丢失和死亡的风险较低,这表明Tac和MMF联合治疗的门槛应该较低。影响和意义:本研究调查了免疫抑制剂与脑死亡肝移植后捐献的原发性胆汁性胆管炎(PBC)患者的长期存活率之间的关系。虽然他克莫司与较高的原发性胆汁性胆管炎复发风险有关,但在欧洲肝移植登记处的原发性胆汁性胆管炎移植患者中,钙神经蛋白抑制剂的类型与移植物或患者的存活率无关。此外,维持使用霉酚酸酯与较低的移植物丢失和死亡风险有关,而维持使用类固醇的风险较高。我们的研究结果应能让医生对PBC患者在肝移植后继续使用Tac感到放心,并表明与霉酚酸酯联合治疗可能会带来益处。
{"title":"Type of calcineurin inhibitor and long-term outcomes following liver transplantation in patients with primary biliary cholangitis – an ELTR study","authors":"Maria C. van Hooff , Rozanne C. de Veer , Vincent Karam , Rene Adam , Pavel Taimr , Wojciech G. Polak , Hasina Pashtoun , Sarwa Darwish Murad , Christophe Corpechot , Darius Mirza , Michael Heneghan , Peter Lodge , Gabriel C. Oniscu , Douglas Thorburn , Michael Allison , Herold J. Metselaar , Caroline M. den Hoed , Adriaan J. van der Meer","doi":"10.1016/j.jhepr.2024.101100","DOIUrl":"10.1016/j.jhepr.2024.101100","url":null,"abstract":"<div><h3>Background & Aims</h3><p>Tacrolimus has been associated with recurrence of primary biliary cholangitis (PBC) after liver transplantation (LT), which in turn may reduce survival. This study aimed to assess the association between the type of calcineurin inhibitor used and long-term outcomes following LT in patients with PBC.</p></div><div><h3>Methods</h3><p>Survival analyses were used to assess the association between immunosuppressive drugs and graft or patient survival among adult patients with PBC in the European Liver Transplant Registry. Patients who received a donation after brain death graft between 1990 and 2021 with at least 1 year of event-free follow-up were included.</p></div><div><h3>Results</h3><p>In total, 3,175 patients with PBC were followed for a median duration of 11.4 years (IQR 5.9–17.9) after LT. Tacrolimus (Tac) was registered in 2,056 (64.8%) and cyclosporin in 819 (25.8%) patients. Following adjustment for recipient age, recipient sex, donor age, and year of LT, Tac was not associated with higher risk of graft loss (adjusted hazard ratio [aHR] 1.07, 95% CI 0.92-1.25, <em>p =</em> 0.402) or death (aHR 1.06, 95% CI 0.90-1.24, <em>p =</em> 0.473) over cyclosporin. In this model, maintenance mycophenolate mofetil (MMF) was associated with a lower risk of graft loss (aHR 0.72, 95% CI 0.60-0.87, <em>p <</em>0.001) or death (aHR 0.72, 95% CI 0.59-0.87, <em>p <</em>0.001), while these risks were higher with use of steroids (aHR 1.31, 95% CI 1.13-1.52, <em>p <</em>0.001, and aHR 1.34, 95% CI 1.15-1.56, <em>p <</em>0.001, respectively).</p></div><div><h3>Conclusions</h3><p>In this large LT registry, type of calcineurin inhibitor was not associated with long-term graft or recipient survival, providing reassurance regarding the use of Tac post LT in the population with PBC. Patients using MMF had a lower risk of graft loss and death, indicating that the threshold for combination treatment with Tac and MMF should be low.</p></div><div><h3>Impact and implications:</h3><p>This study investigated the association between immunosuppressive drugs and the long-term survival of patients with primary biliary cholangitis (PBC) following donation after brain death liver transplantation. While tacrolimus has previously been related to a higher risk of PBC recurrence, the type of calcineurin inhibitor was not related to graft or patient survival among patients transplanted for PBC in the European Liver Transplant Registry. Additionally, maintenance use of mycophenolate was linked to lower risks of graft loss and death, while these risks were higher with maintenance use of steroids. Our findings should provide reassurance for physicians regarding the continued use of Tac after liver transplantation in the population with PBC, and suggest potential benefit from combination therapy with mycophenolate.</p></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589555924001046/pdfft?md5=88c34490c373429461b8ab0d15041535&pid=1-s2.0-S2589555924001046-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140776143","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}
Pub Date : 2024-04-25DOI: 10.1016/j.jhepr.2024.101099
Keith Wan Hang Chiu , Chi Leung Chiang , Kenneth Sik Kwan Chan , Yuan Hui , Jingyun Ren , Xiaojuan Wei , Kwok Sing Ng , Ho Fun Victor Lee , Nam Hung Chia , Tan-To Cheung , Stephen Chan , Albert Chi-Yan Chan , Kwok Chai Kelvin Ng , Wai Kay Walter Seto , Pek-Lan Khong , Feng-Ming Kong (Spring)
Background & Aims
Combined 18F-fluorodeoxyglucose (FDG) and 11C-acetate (dual-tracer) positron-emission tomography/computed tomography (PET/CT) is being increasingly performed for the management of hepatocellular carcinoma (HCC), although its role is not well defined. Therefore, we evaluated its effectiveness in (i) staging, (ii) characterization of indeterminate lesions on conventional imaging, and (iii) detection of HCC in patients with unexplained elevations in serum alpha-fetoprotein (AFP) levels.
Methods
We retrospectively assessed 525 consecutive patients from three tertiary centers between 2014 and 2020. For staging, we recorded new lesion detection rates, changes in the Barcelona Clinic Liver Cancer (BCLC) classification, and treatment allocation due to dual-tracer PET/CT. To characterize indeterminate lesions and unexplained elevation of serum AFP levels, the sensitivity and specificity of dual-tracer PET/CT in diagnosing HCC were evaluated. A multidisciplinary external review and a cost-benefit analysis of patients for metastatic screening were also performed.
Results
Dual-tracer PET/CT identified new lesions in 14.3% of 273 staging patients, resulting in BCLC upstaging in 11.7% and treatment modifications in 7.7%. It upstaged 8.1% of 260 patients undergoing metastatic screening, with estimated savings of US$495 per patient. It had a sensitivity and specificity of 80.7% (95% CI 71.2-88.6%) and 94.8% (95% CI 90.4-98.6%), respectively, for diagnosing HCC in 201 indeterminate lesions. It detected HCC in 45.1% of 51 patients with unexplained elevations in serum AFP concentrations. External review revealed substantial agreement between local and external image interpretation and patient assessment (n = 273, κ = 0.822; 95% CI 0.803-0.864).
Conclusions
Dual-tracer PET/CT provides added value beyond conventional imaging in patients with HCC by improving staging, confirming HCC diagnosis with high accuracy in patients with indeterminate lesions, and detecting HCC in patients with unexplained elevation of serum AFP.
Impact and implications
Compared to CT or MRI, dual-tracer positron-emission tomography/computed tomography (PET/CT) led to upstaging in 12% of patients with hepatocellular carcinoma (HCC) undergoing staging, resulting in treatment modification in 8% of cases and a cost saving of US$495 per patient. It also accurately detected HCC in high-risk cases where CT or MRI were equivocal or normal. Dual-tracer PET/CT provides added value beyond conventional imaging in patients with HCC by improving staging, confirming HCC diagnosis with high accuracy in patients with indeterminate lesions, and detecting HCC in patients with unexplained elevation of serum AFP.
{"title":"Dual-tracer PET/CT in the management of hepatocellular carcinoma","authors":"Keith Wan Hang Chiu , Chi Leung Chiang , Kenneth Sik Kwan Chan , Yuan Hui , Jingyun Ren , Xiaojuan Wei , Kwok Sing Ng , Ho Fun Victor Lee , Nam Hung Chia , Tan-To Cheung , Stephen Chan , Albert Chi-Yan Chan , Kwok Chai Kelvin Ng , Wai Kay Walter Seto , Pek-Lan Khong , Feng-Ming Kong (Spring)","doi":"10.1016/j.jhepr.2024.101099","DOIUrl":"10.1016/j.jhepr.2024.101099","url":null,"abstract":"<div><h3>Background & Aims</h3><p>Combined <sup>18</sup>F-fluorodeoxyglucose (FDG) and <sup>11</sup>C-acetate (dual-tracer) positron-emission tomography/computed tomography (PET/CT) is being increasingly performed for the management of hepatocellular carcinoma (HCC), although its role is not well defined. Therefore, we evaluated its effectiveness in (i) staging, (ii) characterization of indeterminate lesions on conventional imaging, and (iii) detection of HCC in patients with unexplained elevations in serum alpha-fetoprotein (AFP) levels.</p></div><div><h3>Methods</h3><p>We retrospectively assessed 525 consecutive patients from three tertiary centers between 2014 and 2020. For staging, we recorded new lesion detection rates, changes in the Barcelona Clinic Liver Cancer (BCLC) classification, and treatment allocation due to dual-tracer PET/CT. To characterize indeterminate lesions and unexplained elevation of serum AFP levels, the sensitivity and specificity of dual-tracer PET/CT in diagnosing HCC were evaluated. A multidisciplinary external review and a cost-benefit analysis of patients for metastatic screening were also performed.</p></div><div><h3>Results</h3><p>Dual-tracer PET/CT identified new lesions in 14.3% of 273 staging patients, resulting in BCLC upstaging in 11.7% and treatment modifications in 7.7%. It upstaged 8.1% of 260 patients undergoing metastatic screening, with estimated savings of US$495 per patient. It had a sensitivity and specificity of 80.7% (95% CI 71.2-88.6%) and 94.8% (95% CI 90.4-98.6%), respectively, for diagnosing HCC in 201 indeterminate lesions. It detected HCC in 45.1% of 51 patients with unexplained elevations in serum AFP concentrations. External review revealed substantial agreement between local and external image interpretation and patient assessment (n = 273, κ = 0.822; 95% CI 0.803-0.864).</p></div><div><h3>Conclusions</h3><p>Dual-tracer PET/CT provides added value beyond conventional imaging in patients with HCC by improving staging, confirming HCC diagnosis with high accuracy in patients with indeterminate lesions, and detecting HCC in patients with unexplained elevation of serum AFP.</p></div><div><h3>Impact and implications</h3><p>Compared to CT or MRI, dual-tracer positron-emission tomography/computed tomography (PET/CT) led to upstaging in 12% of patients with hepatocellular carcinoma (HCC) undergoing staging, resulting in treatment modification in 8% of cases and a cost saving of US$495 per patient. It also accurately detected HCC in high-risk cases where CT or MRI were equivocal or normal. Dual-tracer PET/CT provides added value beyond conventional imaging in patients with HCC by improving staging, confirming HCC diagnosis with high accuracy in patients with indeterminate lesions, and detecting HCC in patients with unexplained elevation of serum AFP.</p></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":8.3,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589555924001034/pdfft?md5=bb52838d4baa2f35a863bf5dd56fb34f&pid=1-s2.0-S2589555924001034-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140778229","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}
Pub Date : 2024-04-24DOI: 10.1016/j.jhepr.2024.101075
Giammauro Berardi , Alessandro Cucchetti , Carlo Sposito , Francesca Ratti , Martina Nebbia , Daniel M. D’Souza , Franco Pascual , Epameinondas Dogeas , Samer Tohme , Alessandro Vitale , Francesco Enrico D’Amico , Remo Alessandris , Valentina Panetta , Ilaria Simonelli , Marco Colasanti , Nadia Russolillo , Amika Moro , Guido Fiorentini , Matteo Serenari , Fernando Rotellar , Vincenzo Mazzaferro
Background & Aims
Metabolic syndrome (MS) is a growing epidemic and a risk factor for the development of hepatocellular carcinoma (HCC). This study investigated the long-term outcomes of liver resection (LR) for HCC in patients with MS. Rates, timing, patterns, and treatment of recurrences were investigated, and cancer-specific survivals were assessed.
Methods
Between 2001 and 2021, data from 24 clinical centers were collected. Overall survival (OS), recurrence-free survival (RFS), and cancer-specific survival were analyzed as well as recurrence patterns and treatment. The analysis was conducted using a competing-risk framework. The trajectory of the risk of recurrence over time was applied to a competing risk analysis. For post-recurrence survival, death resulting from tumor progression was the primary endpoint, whereas deaths with recurrence relating to other causes were considered as competing events.
Results
In total, 813 patients were included in the study. Median OS was 81.4 months (range 28.1–157.0 months), and recurrence occurred in 48.3% of patients, with a median RFS of 39.8 months (range 15.7–174.7 months). Cause-specific hazard of recurrence showed a first peak 6 months (0.027), and a second peak 24 months (0.021) after surgery. The later the recurrence, the higher the chance of receiving curative intent approaches (p = 0.001). Size >5 cm, multiple tumors, microvascular invasion, and cirrhosis were independent predictors of recurrence showing a cause-specific hazard over time. RFS was associated with death for recurrence (hazard ratio: 0.985, 95% CI: 0.977–0.995; p = 0.002).
Conclusions
Patients with MS undergoing LR for HCC have good long-term survival. Recurrence occurs in 48% of patients with a double-peak incidence and time-specific hazards depending on tumor-related factors and underlying disease. The timing of recurrence significantly impacts survival. Surveillance after resection should be adjusted over time depending on risk factors.
Impact and implications
Metabolic syndrome (MS) is a growing epidemic and a significant risk factor for the development of hepatocellular carcinoma (HCC). The present study demonstrated that patients who undergo surgical resection for HCC on MS have a good long-term survival and that recurrence occurs in almost half of the cases with a double peak incidence and time-specific hazards depending on tumor-related factors and underlying liver disease. Also, the timing of recurrence significantly impacts survival. Clinicians should therefore adjust follow-up after surgery accordingly, considering timing of recurrence and specific risk factors. Also, the results of the present study might help design future trials on the use of adjuvant therapy following resection.
{"title":"Recurrence and tumor-related death after resection of hepatocellular carcinoma in patients with metabolic syndrome","authors":"Giammauro Berardi , Alessandro Cucchetti , Carlo Sposito , Francesca Ratti , Martina Nebbia , Daniel M. D’Souza , Franco Pascual , Epameinondas Dogeas , Samer Tohme , Alessandro Vitale , Francesco Enrico D’Amico , Remo Alessandris , Valentina Panetta , Ilaria Simonelli , Marco Colasanti , Nadia Russolillo , Amika Moro , Guido Fiorentini , Matteo Serenari , Fernando Rotellar , Vincenzo Mazzaferro","doi":"10.1016/j.jhepr.2024.101075","DOIUrl":"10.1016/j.jhepr.2024.101075","url":null,"abstract":"<div><h3>Background & Aims</h3><p>Metabolic syndrome (MS) is a growing epidemic and a risk factor for the development of hepatocellular carcinoma (HCC). This study investigated the long-term outcomes of liver resection (LR) for HCC in patients with MS. Rates, timing, patterns, and treatment of recurrences were investigated, and cancer-specific survivals were assessed.</p></div><div><h3>Methods</h3><p>Between 2001 and 2021, data from 24 clinical centers were collected. Overall survival (OS), recurrence-free survival (RFS), and cancer-specific survival were analyzed as well as recurrence patterns and treatment. The analysis was conducted using a competing-risk framework. The trajectory of the risk of recurrence over time was applied to a competing risk analysis. For post-recurrence survival, death resulting from tumor progression was the primary endpoint, whereas deaths with recurrence relating to other causes were considered as competing events.</p></div><div><h3>Results</h3><p>In total, 813 patients were included in the study. Median OS was 81.4 months (range 28.1–157.0 months), and recurrence occurred in 48.3% of patients, with a median RFS of 39.8 months (range 15.7–174.7 months). Cause-specific hazard of recurrence showed a first peak 6 months (0.027), and a second peak 24 months (0.021) after surgery. The later the recurrence, the higher the chance of receiving curative intent approaches (<em>p</em> = 0.001). Size >5 cm, multiple tumors, microvascular invasion, and cirrhosis were independent predictors of recurrence showing a cause-specific hazard over time. RFS was associated with death for recurrence (hazard ratio: 0.985, 95% CI: 0.977–0.995; <em>p</em> = 0.002).</p></div><div><h3>Conclusions</h3><p>Patients with MS undergoing LR for HCC have good long-term survival. Recurrence occurs in 48% of patients with a double-peak incidence and time-specific hazards depending on tumor-related factors and underlying disease. The timing of recurrence significantly impacts survival. Surveillance after resection should be adjusted over time depending on risk factors.</p></div><div><h3>Impact and implications</h3><p>Metabolic syndrome (MS) is a growing epidemic and a significant risk factor for the development of hepatocellular carcinoma (HCC). The present study demonstrated that patients who undergo surgical resection for HCC on MS have a good long-term survival and that recurrence occurs in almost half of the cases with a double peak incidence and time-specific hazards depending on tumor-related factors and underlying liver disease. Also, the timing of recurrence significantly impacts survival. Clinicians should therefore adjust follow-up after surgery accordingly, considering timing of recurrence and specific risk factors. Also, the results of the present study might help design future trials on the use of adjuvant therapy following resection.</p></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":8.3,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S258955592400079X/pdfft?md5=bbd5899b23c2a832f6713b301e8f04a4&pid=1-s2.0-S258955592400079X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140792121","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}
Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are the cornerstone of systemic therapy for patients with hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer. In the various therapeutic studies with CDK4/6 inhibitors, elevations in liver tests were more frequent than in the control groups. The mechanism of CDK4/6 inhibitor-induced liver toxicity is not well understood; moreover, natural history and appropriate management are poorly described.
Methods
We conducted a retrospective study, collecting cases of CDK4/6 hepatitis from the REFHEPS (Réseau Francophone pour l’étude de l’HEpatotoxicité des Produits de Santé) database.
Results
In this study, we report on 22 cases of hepatitis induced by CDK4/6 inhibitors (ribociclib, n = 19 and abemaciclib, n = 3). According to the CTCAE classification, all hepatitis cases were grade 3 or 4. Twelve (54.6%) patients had a liver biopsy showing acute centrilobular hepatitis with foci of necrosis and lymphocytic infiltrate. Nine (40.9%) patients were treated with corticosteroids for resolution of hepatitis. In three cases, another CDK4/6 inhibitor could be resumed after resolution of the hepatitis without recurrence.
Conclusions
CDK4/6 inhibitor-induced hepatitis is poorly described in the literature but there are several arguments pointing out that these drugs should be included in the DI-ALH (drug-induced autoimmune-like hepatitis) category.
Impact and implications
This study highlights the clinical significance and hepatotoxic risks of CDK4/6 inhibitors, like ribociclib and abemaciclib, in HR+/HER2-metastatic breast cancer treatment. It underscores the necessity for enhanced hepatic monitoring and tailored management strategies, including corticosteroid intervention for unresolved hepatitis post-withdrawal. These findings are crucial for oncologists, hepatologists, and patients, guiding therapeutic decisions and indicating careful liver function monitoring during therapy. The utility of corticosteroids in managing drug-induced hepatitis and the feasibility of resuming CDK4/6 inhibitor therapy post-recovery are notable practical outcomes. Nonetheless, the study's retrospective nature and limited case numbers introduce constraints, underscoring the need for further research to refine our understanding of CDK4/6 inhibitor-associated hepatotoxicity.
背景& 目的环素依赖性激酶4/6(CDK4/6)抑制剂是激素受体阳性、HER2-阴性(HR+/HER2-)转移性乳腺癌患者全身治疗的基石。在使用 CDK4/6 抑制剂进行的各种治疗研究中,肝脏检查结果升高的频率高于对照组。CDK4/6抑制剂诱发肝脏毒性的机制尚不十分清楚;此外,对其自然史和适当的处理方法也描述不详。方法我们开展了一项回顾性研究,从 REFHEPS(Réseau Francophone pour l'étude de l'HEpatotoxicité des Produits de Santé)数据库中收集 CDK4/6 肝炎病例。结果在本研究中,我们报告了 22 例 CDK4/6 抑制剂(ribociclib,n = 19;abemaciclib,n = 3)诱发的肝炎病例。根据 CTCAE 分级,所有肝炎病例均为 3 级或 4 级。12例(54.6%)患者的肝活检结果显示为急性中央叶肝炎,伴有坏死灶和淋巴细胞浸润。九名患者(40.9%)接受了皮质类固醇治疗,肝炎得到缓解。结论CDK4/6 抑制剂诱发的肝炎在文献中描述较少,但有一些论点指出,这些药物应被纳入 DI-ALH(药物诱发的自身免疫性肝炎)类别。影响和意义本研究强调了CDK4/6抑制剂(如ribociclib和abemaciclib)在HR+/HER2转移性乳腺癌治疗中的临床意义和肝毒性风险。它强调了加强肝脏监测和定制管理策略的必要性,包括对停药后未缓解的肝炎进行皮质类固醇干预。这些发现对肿瘤学家、肝病学家和患者至关重要,可指导治疗决策,并表明在治疗期间应仔细监测肝功能。皮质类固醇在控制药物性肝炎方面的效用以及恢复 CDK4/6 抑制剂治疗的可行性都是值得注意的实际成果。尽管如此,这项研究的回顾性和有限的病例数还是带来了一些制约因素,突出表明我们需要进一步研究,以完善我们对CDK4/6抑制剂相关肝毒性的认识。
{"title":"CDK4/6 inhibitor-induced liver injury: Clinical phenotypes and role of corticosteroid treatment","authors":"Lucy Meunier , Eleonora De Martin , Bénédicte Delire , Wiliam Jacot , Severine Guiu , Amel Zahhaf , Dominique Larrey , Yves Horsmans","doi":"10.1016/j.jhepr.2024.101098","DOIUrl":"10.1016/j.jhepr.2024.101098","url":null,"abstract":"<div><h3>Background & Aims</h3><p>Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are the cornerstone of systemic therapy for patients with hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer. In the various therapeutic studies with CDK4/6 inhibitors, elevations in liver tests were more frequent than in the control groups. The mechanism of CDK4/6 inhibitor-induced liver toxicity is not well understood; moreover, natural history and appropriate management are poorly described.</p></div><div><h3>Methods</h3><p>We conducted a retrospective study, collecting cases of CDK4/6 hepatitis from the REFHEPS (Réseau Francophone pour l’étude de l’HEpatotoxicité des Produits de Santé) database.</p></div><div><h3>Results</h3><p>In this study, we report on 22 cases of hepatitis induced by CDK4/6 inhibitors (ribociclib, n = 19 and abemaciclib, n = 3). According to the CTCAE classification, all hepatitis cases were grade 3 or 4. Twelve (54.6%) patients had a liver biopsy showing acute centrilobular hepatitis with foci of necrosis and lymphocytic infiltrate. Nine (40.9%) patients were treated with corticosteroids for resolution of hepatitis. In three cases, another CDK4/6 inhibitor could be resumed after resolution of the hepatitis without recurrence.</p></div><div><h3>Conclusions</h3><p>CDK4/6 inhibitor-induced hepatitis is poorly described in the literature but there are several arguments pointing out that these drugs should be included in the DI-ALH (drug-induced autoimmune-like hepatitis) category.</p></div><div><h3>Impact and implications</h3><p>This study highlights the clinical significance and hepatotoxic risks of CDK4/6 inhibitors, like ribociclib and abemaciclib, in HR+/HER2-metastatic breast cancer treatment. It underscores the necessity for enhanced hepatic monitoring and tailored management strategies, including corticosteroid intervention for unresolved hepatitis post-withdrawal. These findings are crucial for oncologists, hepatologists, and patients, guiding therapeutic decisions and indicating careful liver function monitoring during therapy. The utility of corticosteroids in managing drug-induced hepatitis and the feasibility of resuming CDK4/6 inhibitor therapy post-recovery are notable practical outcomes. Nonetheless, the study's retrospective nature and limited case numbers introduce constraints, underscoring the need for further research to refine our understanding of CDK4/6 inhibitor-associated hepatotoxicity.</p></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":8.3,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589555924001022/pdfft?md5=8fab6013f8ad741aba85d1ba0050f8fa&pid=1-s2.0-S2589555924001022-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140770548","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}
Pub Date : 2024-04-15DOI: 10.1016/j.jhepr.2024.101094
Frederik Peeters , Sarah Cappuyns , Marta Piqué-Gili , Gino Phillips , Chris Verslype , Diether Lambrechts , Jeroen Dekervel
Primary liver cancer, more specifically hepatocellular carcinoma (HCC), remains a significant global health problem associated with increasing incidence and mortality. Clinical, biological, and molecular heterogeneity are well-known hallmarks of cancer and HCC is considered one of the most heterogeneous tumour types, displaying substantial inter-patient, intertumoural and intratumoural variability. This heterogeneity plays a pivotal role in hepatocarcinogenesis, metastasis, relapse and drug response or resistance. Unimodal single-cell sequencing techniques have already revolutionised our understanding of the different layers of molecular hierarchy in the tumour microenvironment of HCC. By highlighting the cellular heterogeneity and the intricate interactions among cancer, immune and stromal cells before and during treatment, these techniques have contributed to a deeper comprehension of tumour clonality, hematogenous spreading and the mechanisms of action of immune checkpoint inhibitors. However, major questions remain to be elucidated, with the identification of biomarkers predicting response or resistance to immunotherapy-based regimens representing an important unmet clinical need. Although the application of single-cell multi-omics in liver cancer research has been limited thus far, a revolution of individualised care for patients with HCC will only be possible by integrating various unimodal methods into multi-omics methodologies at the single-cell resolution. In this review, we will highlight the different established single-cell sequencing techniques and explore their biological and clinical impact on liver cancer research, while casting a glance at the future role of multi-omics in this dynamic and rapidly evolving field.
{"title":"Applications of single-cell multi-omics in liver cancer","authors":"Frederik Peeters , Sarah Cappuyns , Marta Piqué-Gili , Gino Phillips , Chris Verslype , Diether Lambrechts , Jeroen Dekervel","doi":"10.1016/j.jhepr.2024.101094","DOIUrl":"10.1016/j.jhepr.2024.101094","url":null,"abstract":"<div><p>Primary liver cancer, more specifically hepatocellular carcinoma (HCC), remains a significant global health problem associated with increasing incidence and mortality. Clinical, biological, and molecular heterogeneity are well-known hallmarks of cancer and HCC is considered one of the most heterogeneous tumour types, displaying substantial inter-patient, intertumoural and intratumoural variability. This heterogeneity plays a pivotal role in hepatocarcinogenesis, metastasis, relapse and drug response or resistance. Unimodal single-cell sequencing techniques have already revolutionised our understanding of the different layers of molecular hierarchy in the tumour microenvironment of HCC. By highlighting the cellular heterogeneity and the intricate interactions among cancer, immune and stromal cells before and during treatment, these techniques have contributed to a deeper comprehension of tumour clonality, hematogenous spreading and the mechanisms of action of immune checkpoint inhibitors. However, major questions remain to be elucidated, with the identification of biomarkers predicting response or resistance to immunotherapy-based regimens representing an important unmet clinical need. Although the application of single-cell multi-omics in liver cancer research has been limited thus far, a revolution of individualised care for patients with HCC will only be possible by integrating various unimodal methods into multi-omics methodologies at the single-cell resolution. In this review, we will highlight the different established single-cell sequencing techniques and explore their biological and clinical impact on liver cancer research, while casting a glance at the future role of multi-omics in this dynamic and rapidly evolving field.</p></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":8.3,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589555924000983/pdfft?md5=a5349a06110e1bd28809a065f3667fc9&pid=1-s2.0-S2589555924000983-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140781822","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}
Treatment of alcohol use disorder (AUD) improves survival in patients with alcohol-related cirrhosis. However, medications for alcohol use disorder (MAUD) are underutilized in this population, partially due to concerns regarding drug-induced liver injury (DILI). Our aim was to evaluate the safety of naltrexone in patients with cirrhosis.
Methods
This was a retrospective study of patients with cirrhosis who were prescribed naltrexone using the VOCAL (Veterans Outcomes and Costs Associated with Liver Disease) database. Patients with new initiation of naltrexone after diagnosis of cirrhosis who had liver enzymes checked within a 3-month time frame were included. A chart review was performed on patients who developed alanine aminotransferase or alkaline phosphatase elevations to more than 2× or 5× the upper limit of normal, respectively. The RUCAM (Roussel Uclaf causality assessment method) was used to determine if DILI occurred.
Results
A total of 3,285 patients with cirrhosis were initiated on naltrexone, of whom 2,940 had laboratory testing during the high-risk DILI period. Only 2% of patients had liver enzyme elevations, and among those, 30 (48%) were classified as “DILI excluded” and 32 (52%) were classified as “DILI unlikely”. No patients were classified as possible, probable, or highly probable DILI. No deaths or new decompensations were attributed to naltrexone.
Conclusions
Naltrexone in patients with cirrhosis was not associated with development of DILI using RUCAM scoring. Naltrexone appears to be safe in patients with compensated and decompensated cirrhosis.
Impact and Implications
Naltrexone is an effective medication for treating alcohol use disorder but is underutilized in patients with underlying liver disease due to historical concerns regarding hepatotoxicity. This retrospective study shows no drug-induced liver injury in a large cohort of patients with cirrhosis with new initiation of naltrexone. This study may encourage providers to prescribe naltrexone to patients with existing liver disease with ongoing alcohol use disorder.
{"title":"Safety of naltrexone in patients with cirrhosis","authors":"Rachel Thompson , Tamar Taddei , David Kaplan , Anahita Rabiee","doi":"10.1016/j.jhepr.2024.101095","DOIUrl":"10.1016/j.jhepr.2024.101095","url":null,"abstract":"<div><h3>Background & Aims</h3><p>Treatment of alcohol use disorder (AUD) improves survival in patients with alcohol-related cirrhosis. However, medications for alcohol use disorder (MAUD) are underutilized in this population, partially due to concerns regarding drug-induced liver injury (DILI). Our aim was to evaluate the safety of naltrexone in patients with cirrhosis.</p></div><div><h3>Methods</h3><p>This was a retrospective study of patients with cirrhosis who were prescribed naltrexone using the VOCAL (Veterans Outcomes and Costs Associated with Liver Disease) database. Patients with new initiation of naltrexone after diagnosis of cirrhosis who had liver enzymes checked within a 3-month time frame were included. A chart review was performed on patients who developed alanine aminotransferase or alkaline phosphatase elevations to more than 2× or 5× the upper limit of normal, respectively. The RUCAM (Roussel Uclaf causality assessment method) was used to determine if DILI occurred.</p></div><div><h3>Results</h3><p>A total of 3,285 patients with cirrhosis were initiated on naltrexone, of whom 2,940 had laboratory testing during the high-risk DILI period. Only 2% of patients had liver enzyme elevations, and among those, 30 (48%) were classified as “DILI excluded” and 32 (52%) were classified as “DILI unlikely”. No patients were classified as possible, probable, or highly probable DILI. No deaths or new decompensations were attributed to naltrexone.</p></div><div><h3>Conclusions</h3><p>Naltrexone in patients with cirrhosis was not associated with development of DILI using RUCAM scoring. Naltrexone appears to be safe in patients with compensated and decompensated cirrhosis.</p></div><div><h3>Impact and Implications</h3><p>Naltrexone is an effective medication for treating alcohol use disorder but is underutilized in patients with underlying liver disease due to historical concerns regarding hepatotoxicity. This retrospective study shows no drug-induced liver injury in a large cohort of patients with cirrhosis with new initiation of naltrexone. This study may encourage providers to prescribe naltrexone to patients with existing liver disease with ongoing alcohol use disorder.</p></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":8.3,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589555924000995/pdfft?md5=6becd2b5a1dce49cddd823ef33f439ea&pid=1-s2.0-S2589555924000995-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140763398","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}
Pub Date : 2024-04-09DOI: 10.1016/j.jhepr.2024.101090
Chee-Seng Lee , Chia-Ray Lin , Huey-Huey Chua , Jia-Feng Wu , Kai-Chi Chang , Yen-Hsuan Ni , Mei-Hwei Chang , Huey-Ling Chen
Background & Aims
The gut microbiome plays an important role in liver diseases, but its specific impact on biliary atresia (BA) remains to be explored. We aimed to investigate the microbial signature in the early life of patients with BA and to analyze its influence on long-term outcomes.
Methods
Fecal samples (n = 42) were collected from infants with BA before and after Kasai portoenterostomy (KPE). The stool microbiota was analyzed using 16S rRNA next-generation sequencing and compared with that of age-matched healthy controls (HCs). Shotgun metagenomic sequencing analysis was employed to confirm the bacterial composition in 10 fecal samples before KPE. The correlation of the microbiome signature with liver function and long-term outcomes was assessed.
Results
In the 16S rRNA next-generation sequencing analysis of fecal microbiota, the alpha and beta diversity analyses revealed significant differences between HCs and patients with BA before and after KPE. The difference in microbial composition analyzed by linear discriminant analysis and random forest classification revealed that the abundance of Bifidobacterium longum (B. longum) was significantly lower in patients before and after KPE than in HCs. The abundance of B. longum was negatively correlated with the gamma-glutamyltransferase level after KPE (p <0.05). Patients with early detectable B. longum had significantly lower total and direct bilirubin 3 months after KPE (p <0.005) and had a significantly lower liver transplantation rate (hazard ratio: 0.16, 95% CI 0.03-0.83, p = 0.029). Shotgun metagenomic sequencing also revealed that patients with BA and detectable B. longum had reduced total and direct bilirubin after KPE.
Conclusion
The gut microbiome of patients with BA differed from that of HCs, with a notable abundance of B. longum in early infancy correlating with better long-term outcomes.
Impact and implications
Bifidobacterium longum (B. longum) is a beneficial bacterium commonly found in the human gut. It has been studied for its potential impacts on various health conditions. In patients with biliary atresia, we found that a greater abundance of B. longum in the fecal microbiome is associated with improved clinical outcomes. This suggests that early colonization and increasing B. longum levels in the gut could be a therapeutic strategy to improve the prognosis of patients with biliary atresia.
{"title":"Gut Bifidobacterium longum is associated with better native liver survival in patients with biliary atresia","authors":"Chee-Seng Lee , Chia-Ray Lin , Huey-Huey Chua , Jia-Feng Wu , Kai-Chi Chang , Yen-Hsuan Ni , Mei-Hwei Chang , Huey-Ling Chen","doi":"10.1016/j.jhepr.2024.101090","DOIUrl":"10.1016/j.jhepr.2024.101090","url":null,"abstract":"<div><h3>Background & Aims</h3><p>The gut microbiome plays an important role in liver diseases, but its specific impact on biliary atresia (BA) remains to be explored. We aimed to investigate the microbial signature in the early life of patients with BA and to analyze its influence on long-term outcomes.</p></div><div><h3>Methods</h3><p>Fecal samples (n = 42) were collected from infants with BA before and after Kasai portoenterostomy (KPE). The stool microbiota was analyzed using 16S rRNA next-generation sequencing and compared with that of age-matched healthy controls (HCs). Shotgun metagenomic sequencing analysis was employed to confirm the bacterial composition in 10 fecal samples before KPE. The correlation of the microbiome signature with liver function and long-term outcomes was assessed.</p></div><div><h3>Results</h3><p>In the 16S rRNA next-generation sequencing analysis of fecal microbiota, the alpha and beta diversity analyses revealed significant differences between HCs and patients with BA before and after KPE. The difference in microbial composition analyzed by linear discriminant analysis and random forest classification revealed that the abundance of <em>Bifidobacterium longum</em> (<em>B. longum</em>) was significantly lower in patients before and after KPE than in HCs. The abundance of <em>B. longum</em> was negatively correlated with the gamma-glutamyltransferase level after KPE (<em>p <</em>0.05). Patients with early detectable <em>B. longum</em> had significantly lower total and direct bilirubin 3 months after KPE (<em>p <</em>0.005) and had a significantly lower liver transplantation rate (hazard ratio: 0.16, 95% CI 0.03-0.83, <em>p =</em> 0.029). Shotgun metagenomic sequencing also revealed that patients with BA and detectable <em>B. longum</em> had reduced total and direct bilirubin after KPE.</p></div><div><h3>Conclusion</h3><p>The gut microbiome of patients with BA differed from that of HCs, with a notable abundance of <em>B. longum</em> in early infancy correlating with better long-term outcomes.</p></div><div><h3>Impact and implications</h3><p><em>Bifidobacterium longum</em> (<em>B. longum</em>) is a beneficial bacterium commonly found in the human gut. It has been studied for its potential impacts on various health conditions. In patients with biliary atresia, we found that a greater abundance of <em>B. longum</em> in the fecal microbiome is associated with improved clinical outcomes. This suggests that early colonization and increasing <em>B. longum</em> levels in the gut could be a therapeutic strategy to improve the prognosis of patients with biliary atresia.</p></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589555924000946/pdfft?md5=d79304e95bb4211ee9327dafd74559e5&pid=1-s2.0-S2589555924000946-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140777209","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}