Pub Date : 2024-09-30DOI: 10.1097/HEP.0000000000001111
Takahiro Kodama
{"title":"Geographical and molecular disparity of HBV integration: Implications for hepatocarcinogenesis and clinical outcomes in HCC.","authors":"Takahiro Kodama","doi":"10.1097/HEP.0000000000001111","DOIUrl":"https://doi.org/10.1097/HEP.0000000000001111","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337937","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}
Pub Date : 2024-09-30DOI: 10.1097/HEP.0000000000001110
Ying Shang, Hannes Hagström
{"title":"Reply: Should NAFLD be automatically be relabeled as MASLD?","authors":"Ying Shang, Hannes Hagström","doi":"10.1097/HEP.0000000000001110","DOIUrl":"https://doi.org/10.1097/HEP.0000000000001110","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337940","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}
Pub Date : 2024-09-30DOI: 10.1097/HEP.0000000000001109
Dilara Turan Gökçe, Yusuf Yilmaz
{"title":"Letter to the Editor: Should NAFLD be automatically relabeled as MASLD?","authors":"Dilara Turan Gökçe, Yusuf Yilmaz","doi":"10.1097/HEP.0000000000001109","DOIUrl":"https://doi.org/10.1097/HEP.0000000000001109","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337939","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}
Pub Date : 2024-09-30DOI: 10.1097/HEP.0000000000001096
Xiao-Tong Lin, Yuan-Deng Luo, Cui Mao, Yi Gong, Yu Hou, Lei-Da Zhang, Yong-Peng Gu, Di Wu, Jie Zhang, Yu-Jun Zhang, De-Hong Tan, Chuan-Ming Xie
Background and aims: Patients with aggressive hepatocellular carcinoma (HCC) have limited therapeutic options. Therefore, a better understanding of HCC pathogenesis is needed to improve treatment. Genomic studies of HCC have improved our understanding of cancer biology. However, the ubiquitomic characteristics of HCC remain poorly understood. We aimed to reveal the ubiquitomic characteristics of HCC and provide clinical feature biomarkers of the aggressive HCC that may be used for diagnosis or therapy in the clinic.
Approach and results: The comprehensive proteomic, phosphoproteomic, and ubiquitomic analyses were performed on tumors and adjacent normal liver tissues from 85 HCC patients. HCCs displayed overexpression of drugable targets CBR1-S151 and CPNE1-S55. COL4A1, LAMC1 and LAMA4 were highly expressed in the DFS poor patients. Phosphoproteomic and ubiquitomic features of HCC revealed crosstalk in metabolism and metastasis. Ubiquitomics predicted diverse prognosis and clarified HCC subtype-specific proteomic signatures. Expression of biomarkers TUBA1A, BHMT2, BHMT, and ACY1 exhibited differential ubiquitination levels and displayed high prognostic risk scores, suggesting that targeting these proteins or their modified forms may be beneficial for future clinical treatment. We validated that TUBA1A K370 deubiquitination drove severe HCC and labeled an aggressive subtype of HCCs. TUBA1A K370 deubiquitination was at least partly attributed to AKT-mediated USP14 activation in HCC. Notably, targeting AKT-USP14-TUBA1A complex promoted TUBA1A degradation and blocked liver tumorigenesis in vivo.
Conclusions: This study expands our knowledge of ubiquitomic signatures, biomarkers, and potential therapeutic targets in HCC.
{"title":"Integrated ubiquitomics characterization of hepatocellular carcinomas.","authors":"Xiao-Tong Lin, Yuan-Deng Luo, Cui Mao, Yi Gong, Yu Hou, Lei-Da Zhang, Yong-Peng Gu, Di Wu, Jie Zhang, Yu-Jun Zhang, De-Hong Tan, Chuan-Ming Xie","doi":"10.1097/HEP.0000000000001096","DOIUrl":"https://doi.org/10.1097/HEP.0000000000001096","url":null,"abstract":"<p><strong>Background and aims: </strong>Patients with aggressive hepatocellular carcinoma (HCC) have limited therapeutic options. Therefore, a better understanding of HCC pathogenesis is needed to improve treatment. Genomic studies of HCC have improved our understanding of cancer biology. However, the ubiquitomic characteristics of HCC remain poorly understood. We aimed to reveal the ubiquitomic characteristics of HCC and provide clinical feature biomarkers of the aggressive HCC that may be used for diagnosis or therapy in the clinic.</p><p><strong>Approach and results: </strong>The comprehensive proteomic, phosphoproteomic, and ubiquitomic analyses were performed on tumors and adjacent normal liver tissues from 85 HCC patients. HCCs displayed overexpression of drugable targets CBR1-S151 and CPNE1-S55. COL4A1, LAMC1 and LAMA4 were highly expressed in the DFS poor patients. Phosphoproteomic and ubiquitomic features of HCC revealed crosstalk in metabolism and metastasis. Ubiquitomics predicted diverse prognosis and clarified HCC subtype-specific proteomic signatures. Expression of biomarkers TUBA1A, BHMT2, BHMT, and ACY1 exhibited differential ubiquitination levels and displayed high prognostic risk scores, suggesting that targeting these proteins or their modified forms may be beneficial for future clinical treatment. We validated that TUBA1A K370 deubiquitination drove severe HCC and labeled an aggressive subtype of HCCs. TUBA1A K370 deubiquitination was at least partly attributed to AKT-mediated USP14 activation in HCC. Notably, targeting AKT-USP14-TUBA1A complex promoted TUBA1A degradation and blocked liver tumorigenesis in vivo.</p><p><strong>Conclusions: </strong>This study expands our knowledge of ubiquitomic signatures, biomarkers, and potential therapeutic targets in HCC.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337938","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}
Pub Date : 2024-09-26DOI: 10.1097/hep.0000000000001104
Miaomiao Song, Han Wang, Xueqin Tian, Jingtao Gao, Chen Song, Yuxin Zhao, Shan Jiang, Wei Lu, Cun Guo, Yang Lv, Peiqing Zhao, Chuang Li, Xiangfeng Song, Tingmin Chang, Yunwei Lou, Hui Wang
Background and Aims: Concanavalin A (ConA) administration induces a rapid and severe liver injury in mice, and invariant natural killer T (iNKT) cells are recognized to be the key effector cells in this process. However, the underlying regulatory mechanisms are not well defined. Approach and Results: We found that iNKT cells constitutively expressed TIPE2 (Tumor necrosis factor-α-induced protein 8-like 2, or TNFAIPL2). Genetic TIPE2 ablation strongly sensitized mice to ConA-induced hepatitis, accompanied with hyperactivation of iNKT cells. Moreover, Tipe2 -/- mice were also more susceptible to α-galactosylceramide (αGalCer)-induced liver injury, with elevated serum ALT level and enhanced proinflammatory cytokine production. CD1d signaling blockade or iNKT cell elimination through antibodies reduced the effect of TIPE2 deficiency on liver injury. Mechanistic studies revealed that TIPE2 in iNKT cells functioned as a negative regulator, limiting iNKT cell activity and cytokine production through PIP3- AKT/mTOR pathway. TIPE2-mediated protection from liver injury was further validated by the administration of adeno-associated viruses expressing TIPE2, which effectively ameliorated ConA-induced hepatic injury. However, TIPE2 was dispensable in two other liver injury models, including D-GalN/LPS and APAP-induced hepatitis. Conclusion: Our findings reveal a new role of TIPE2 in the attenuation of iNKT cell-mediated hepatic injury. We propose that TIPE2 serves as an important regulator of immune homeostasis in the liver, and might be exploited for the therapeutic treatment of autoimmune liver diseases.
{"title":"TIPE2 protein restrains invariant NKT activation and protects against immune-mediated hepatitis in mice","authors":"Miaomiao Song, Han Wang, Xueqin Tian, Jingtao Gao, Chen Song, Yuxin Zhao, Shan Jiang, Wei Lu, Cun Guo, Yang Lv, Peiqing Zhao, Chuang Li, Xiangfeng Song, Tingmin Chang, Yunwei Lou, Hui Wang","doi":"10.1097/hep.0000000000001104","DOIUrl":"https://doi.org/10.1097/hep.0000000000001104","url":null,"abstract":"Background and Aims: Concanavalin A (ConA) administration induces a rapid and severe liver injury in mice, and invariant natural killer T (iNKT) cells are recognized to be the key effector cells in this process. However, the underlying regulatory mechanisms are not well defined. Approach and Results: We found that iNKT cells constitutively expressed TIPE2 (Tumor necrosis factor-α-induced protein 8-like 2, or TNFAIPL2). Genetic TIPE2 ablation strongly sensitized mice to ConA-induced hepatitis, accompanied with hyperactivation of iNKT cells. Moreover, <jats:italic toggle=\"yes\">Tipe2</jats:italic> <jats:sup> -/- </jats:sup> mice were also more susceptible to α-galactosylceramide (αGalCer)-induced liver injury, with elevated serum ALT level and enhanced proinflammatory cytokine production. CD1d signaling blockade or iNKT cell elimination through antibodies reduced the effect of TIPE2 deficiency on liver injury. Mechanistic studies revealed that TIPE2 in iNKT cells functioned as a negative regulator, limiting iNKT cell activity and cytokine production through PIP3- AKT/mTOR pathway. TIPE2-mediated protection from liver injury was further validated by the administration of adeno-associated viruses expressing TIPE2, which effectively ameliorated ConA-induced hepatic injury. However, TIPE2 was dispensable in two other liver injury models, including D-GalN/LPS and APAP-induced hepatitis. Conclusion: Our findings reveal a new role of TIPE2 in the attenuation of iNKT cell-mediated hepatic injury. We propose that TIPE2 serves as an important regulator of immune homeostasis in the liver, and might be exploited for the therapeutic treatment of autoimmune liver diseases.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":13.5,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142325491","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}
Pub Date : 2024-09-26DOI: 10.1097/hep.0000000000001063
Yang Sun, Henan Wei, Wentao Yu, Haoran Gao, Jinhui Li, Xiaoyu Li, Haijiao Zhang, Haoen Zhang, Sen Miao, Lihua Zhao, Ruizeng Yang, Jinjin Xu, Yi Lu, Fang Wei, Hu Zhou, Daming Gao, Yunyun Jin, Lei Zhang
Background and Aims: The Hippo signaling has emerged as a crucial regulator of tissue homeostasis, regeneration, and tumorigenesis, representing a promising therapeutic target. Neurofibromin 2 (NF2), a component of Hippo signaling, is directly linked to human cancers but has been overlooked as a target for cancer therapy. Approach and Results: Through a high-content RNA interference genome-wide screen, the actin-binding protein Drebrin (DBN1) has been identified as a novel modulator of YAP localization. Further investigations have revealed that DBN1 directly interacts with NF2, disrupting the activation of large tumor suppressor kinases (LATS1/2) by competing with LATS kinases for NF2 binding. Consequently, DBN1 knockout considerably promotes YAP nuclear exclusion and repression of target gene expression, thereby preventing cell proliferation and liver tumorigenesis. We identified three lysine residues (K238, K248, and K252) essential for DBN1-NF2 interaction and developed a mutant DBN1 (DBN1-3Kmut) that is defective in NF2 binding and incompetent to trigger NF2-dependent YAP activation and tumorigenesis both in vitro and in vivo. Furthermore, BTP2, a DBN1 inhibitor, successfully restored NF2-LATS kinase binding and elicited potent antitumor activity. The combination of sorafenib and BTP2 exerted synergistic inhibitory effects against HCC. Conclusions: Our study identifies a novel DBN1-NF2-LATS axis, and pharmacological inhibition of DBN1 represents a promising alternative intervention targeting the Hippo pathway in cancer treatment.
{"title":"The actin-binding protein drebrin disrupts NF2-LATS kinases complex assembly to facilitate liver tumorigenesis","authors":"Yang Sun, Henan Wei, Wentao Yu, Haoran Gao, Jinhui Li, Xiaoyu Li, Haijiao Zhang, Haoen Zhang, Sen Miao, Lihua Zhao, Ruizeng Yang, Jinjin Xu, Yi Lu, Fang Wei, Hu Zhou, Daming Gao, Yunyun Jin, Lei Zhang","doi":"10.1097/hep.0000000000001063","DOIUrl":"https://doi.org/10.1097/hep.0000000000001063","url":null,"abstract":"Background and Aims: The Hippo signaling has emerged as a crucial regulator of tissue homeostasis, regeneration, and tumorigenesis, representing a promising therapeutic target. Neurofibromin 2 (NF2), a component of Hippo signaling, is directly linked to human cancers but has been overlooked as a target for cancer therapy. Approach and Results: Through a high-content RNA interference genome-wide screen, the actin-binding protein Drebrin (DBN1) has been identified as a novel modulator of YAP localization. Further investigations have revealed that DBN1 directly interacts with NF2, disrupting the activation of large tumor suppressor kinases (LATS1/2) by competing with LATS kinases for NF2 binding. Consequently, <jats:italic toggle=\"yes\">DBN1</jats:italic> knockout considerably promotes YAP nuclear exclusion and repression of target gene expression, thereby preventing cell proliferation and liver tumorigenesis. We identified three lysine residues (K238, K248, and K252) essential for DBN1-NF2 interaction and developed a mutant DBN1 (DBN1-3K<jats:sup>mut</jats:sup>) that is defective in NF2 binding and incompetent to trigger NF2-dependent YAP activation and tumorigenesis both in vitro and in vivo. Furthermore, BTP2, a DBN1 inhibitor, successfully restored NF2-LATS kinase binding and elicited potent antitumor activity. The combination of sorafenib and BTP2 exerted synergistic inhibitory effects against HCC. Conclusions: Our study identifies a novel DBN1-NF2-LATS axis, and pharmacological inhibition of DBN1 represents a promising alternative intervention targeting the Hippo pathway in cancer treatment.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":13.5,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142325487","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}
Pub Date : 2024-09-26DOI: 10.1097/hep.0000000000001061
Mazen Noureddin, Emily Truong, Rebeca Mayo, Ibon Martínez-Arranz, Itziar Mincholé, Jesus M. Banales, Marco Arrese, Kenneth Cusi, María Teresa Arias-Loste, Radan Bruha, Manuel Romero-Gómez, Paula Iruzubieta, Rocio Aller, Javier Ampuero, José Luis Calleja, Luis Ibañez-Samaniego, Patricia Aspichueta, Antonio Marín-Duce, Tatyana Kushner, Pablo Ortiz, Stephen A. Harrison, Quentin M. Anstee, Javier Crespo, José M. Mato, Arun J. Sanyal
{"title":"Letter to the Editor: Serum identification of At-Risk MASH: The metabolomics-advanced steatohepatitis fibrosis score (MASEF)","authors":"Mazen Noureddin, Emily Truong, Rebeca Mayo, Ibon Martínez-Arranz, Itziar Mincholé, Jesus M. Banales, Marco Arrese, Kenneth Cusi, María Teresa Arias-Loste, Radan Bruha, Manuel Romero-Gómez, Paula Iruzubieta, Rocio Aller, Javier Ampuero, José Luis Calleja, Luis Ibañez-Samaniego, Patricia Aspichueta, Antonio Marín-Duce, Tatyana Kushner, Pablo Ortiz, Stephen A. Harrison, Quentin M. Anstee, Javier Crespo, José M. Mato, Arun J. Sanyal","doi":"10.1097/hep.0000000000001061","DOIUrl":"https://doi.org/10.1097/hep.0000000000001061","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":13.5,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142325490","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}
Pub Date : 2024-09-26DOI: 10.1097/hep.0000000000001046
Cynthia L. Hsu, Limin Wang, Evan Maestri, Aleesha R. Jacob, Whitney L. Do, Susan Mayo, Francisco Bosques-Padilla, Elizabeth C. Verna, Juan G. Abraldes, Robert S. Brown Jr., Victor Vargas, Jose Altamirano, Juan Caballería, Debbie L. Shawcross, Alexandre Louvet, Michael R. Lucey, Philippe Mathurin, Guadalupe Garcia-Tsao, Peter Stärkel, Ramon Bataller, AlcHepNet Investigators, Xin W. Wang, Bernd Schnabl
Background and Aims: Alcohol-associated hepatitis (AH) is associated with very high mortality despite abstinence from alcohol; up to 40% of patients die within 6 months of diagnosis. Patients with AH are especially prone to infections, which can lead to multiorgan dysfunction and poorer prognosis. Approach and Results: We performed comprehensive serological profiling of the viral and bacterial infection history of 36 healthy controls, 48 patients with alcohol use disorder, and 224 patients with AH from 2 multicenter observational studies. We used systematic viral and bacterial epitope scanning by VirScan, a phage-display immunoprecipitation and sequencing technology that detects the peptides recognized by antibodies in patient sera, to comprehensively analyze antiviral and antibacterial antibodies and identify serologic biomarkers to predict patient outcomes. We found significant differences in the serological profiles of the 3 populations. The number of serum antibody epitopes in patients with alcohol use disorder during abstinence was increased compared with during active alcohol use. A decreased number and diversity of viral and bacterial antibody targets were detected in the sera of patients with AH, particularly those with a higher Child-Pugh score. In patients with AH, a decrease in the serum antiviral, but not antibacterial, antibody repertoire was associated with decompensation and mortality. Ninety-day mortality in AH could be predicted using a serum viral epitope signature. Conclusions: Abstinence from alcohol is associated with a significant increase in serum viral and bacterial antibody response. Decreased serum antiviral antibody repertoire is predictive of decompensation of liver disease and mortality in patients with AH.
{"title":"Viral antibody response predicts morbidity and mortality in alcohol-associated hepatitis","authors":"Cynthia L. Hsu, Limin Wang, Evan Maestri, Aleesha R. Jacob, Whitney L. Do, Susan Mayo, Francisco Bosques-Padilla, Elizabeth C. Verna, Juan G. Abraldes, Robert S. Brown Jr., Victor Vargas, Jose Altamirano, Juan Caballería, Debbie L. Shawcross, Alexandre Louvet, Michael R. Lucey, Philippe Mathurin, Guadalupe Garcia-Tsao, Peter Stärkel, Ramon Bataller, AlcHepNet Investigators, Xin W. Wang, Bernd Schnabl","doi":"10.1097/hep.0000000000001046","DOIUrl":"https://doi.org/10.1097/hep.0000000000001046","url":null,"abstract":"Background and Aims: Alcohol-associated hepatitis (AH) is associated with very high mortality despite abstinence from alcohol; up to 40% of patients die within 6 months of diagnosis. Patients with AH are especially prone to infections, which can lead to multiorgan dysfunction and poorer prognosis. Approach and Results: We performed comprehensive serological profiling of the viral and bacterial infection history of 36 healthy controls, 48 patients with alcohol use disorder, and 224 patients with AH from 2 multicenter observational studies. We used systematic viral and bacterial epitope scanning by VirScan, a phage-display immunoprecipitation and sequencing technology that detects the peptides recognized by antibodies in patient sera, to comprehensively analyze antiviral and antibacterial antibodies and identify serologic biomarkers to predict patient outcomes. We found significant differences in the serological profiles of the 3 populations. The number of serum antibody epitopes in patients with alcohol use disorder during abstinence was increased compared with during active alcohol use. A decreased number and diversity of viral and bacterial antibody targets were detected in the sera of patients with AH, particularly those with a higher Child-Pugh score. In patients with AH, a decrease in the serum antiviral, but not antibacterial, antibody repertoire was associated with decompensation and mortality. Ninety-day mortality in AH could be predicted using a serum viral epitope signature. Conclusions: Abstinence from alcohol is associated with a significant increase in serum viral and bacterial antibody response. Decreased serum antiviral antibody repertoire is predictive of decompensation of liver disease and mortality in patients with AH.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":13.5,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142325489","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}
Determining suitable copper parameters for monitoring Wilson disease remains a topic of ongoing discussion. International recommendations currently rely on the combination of urinary copper excretion and non-specific liver markers when considering therapy and time elapsed since diagnosis. The emergence of exchangeable copper (CuEX) as a novel measurement reflecting the “free copper pool” held promise as a valuable target to ensure metabolic stability during follow-up, although validation of target ranges remain unknown. We aimed at evaluating CuEX quantification in repeated samples from 92 real-world WD patients during a 2-year period. Patients were classified as “stable” if diagnosis had been made more than one year before and were compliant to stable anti-copper drug and dose. Otherwise, patients were classified as “non-stable”. Two-hundred and thirteen CuEX samples were obtained per clinical practice. Overall, 57% of CuEX measurements fell below the reference “range of normality”, whereas only 34% were within and 9% were above normal levels. There was no association of CuEX levels with therapy, elapsed time from diagnosis or clinical stability, although most of the samples above normality corresponded to non-stable patients. Only 23.4% of the CuEX samples were aligned with data obtained from concomitant urinary copper excretion. Our findings suggest that CuEX is a suboptimal tool for assessing copper homeostasis when used alone and should be used with caution if no additional information is available. Normal reference intervals for WD-treated patients should be redefined, as most of CuEX quantifications fell in the lower range, with no sign of overtreatment in these patients.
{"title":"Exchangeable copper for patients with Wilson disease at follow-up: rethinking normal ranges or changing methodology","authors":"Zoe Mariño, Clàudia Garcia-Solà, José Ríos, Ariadna Bono, Sonia García, Anna Miralpeix, Rocío Andreu, Cristina Aguado, Xavier Forns, Mercè Torra, Marina Berenguer","doi":"10.1097/hep.0000000000001105","DOIUrl":"https://doi.org/10.1097/hep.0000000000001105","url":null,"abstract":"Determining suitable copper parameters for monitoring Wilson disease remains a topic of ongoing discussion. International recommendations currently rely on the combination of urinary copper excretion and non-specific liver markers when considering therapy and time elapsed since diagnosis. The emergence of exchangeable copper (CuEX) as a novel measurement reflecting the “<jats:italic toggle=\"yes\">free copper pool</jats:italic>” held promise as a valuable target to ensure metabolic stability during follow-up, although validation of target ranges remain unknown. We aimed at evaluating CuEX quantification in repeated samples from 92 real-world WD patients during a 2-year period. Patients were classified as “stable” if diagnosis had been made more than one year before and were compliant to stable anti-copper drug and dose. Otherwise, patients were classified as “non-stable”. Two-hundred and thirteen CuEX samples were obtained per clinical practice. Overall, 57% of CuEX measurements fell below the reference “range of normality”, whereas only 34% were within and 9% were above normal levels. There was no association of CuEX levels with therapy, elapsed time from diagnosis or clinical stability, although most of the samples above normality corresponded to non-stable patients. Only 23.4% of the CuEX samples were aligned with data obtained from concomitant urinary copper excretion. Our findings suggest that CuEX is a suboptimal tool for assessing copper homeostasis when used alone and should be used with caution if no additional information is available. Normal reference intervals for WD-treated patients should be redefined, as most of CuEX quantifications fell in the lower range, with no sign of overtreatment in these patients.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":13.5,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317281","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}
Pub Date : 2024-09-24DOI: 10.1097/hep.0000000000001107
Yun-Fan Liaw, George Papatheodoridis
Long-term nucleos(t)ide analogue (Nuc) therapy in chronic hepatitis B (CHB) may lead to hepatitis B virus (HBV) suppression, alanine aminotransferase (ALT) normalization, improvement of histological lesions, and prevention of liver disease progression, but rarely achieve HBsAg loss, the hallmark of functional cure. HBeAg-negative CHB patients have often been recommended to continue Nuc therapy until HBsAg loss, which usually means indefinitely. However, long-term/life-long Nuc therapy is associated with increasing costs and concerns of adverse outcomes subsequent to poor adherence and/or self-cessation/loss-to-follow-up. Hence, 2012 Asian-Pacific guidelines recommended that HBeAg-negative CHB patients can stop Nuc therapy after ≥12 months of HBV DNA undetectability. Subsequent Asian and few European studies have found the strategy of finite Nuc therapy to be feasible and reasonably safe. In 2016-2017, stopping Nuc was also included as a conditional strategy for HBeAg-negative CHB patients in the American and European guidelines. Furthermore, progressively increasing HBsAg loss rates with prolongation of off-Nuc follow-up were documented, being higher in Caucasians and more apparent beyond years 4-5 in Asian patients. Recently, a large study in patients with HBV cirrhosis showed not only higher 10-year HBsAg loss rate (15.3 vs. 1.6%) but also ~50% lower 10-year hepatocellular carcinoma incidence (16.5 vs. 29.5%) and 60% lower liver-related mortality/transplantation rate (6.1 vs. 15.1%) after Nuc cessation, as compared with well-matched patients continuing Nuc therapy. Since novel drug development aiming for functional cure has not been satisfactory, the strategy of finite Nuc therapy in HBeAg-negative CHB seems to be the best realistic option for functional cure today.
{"title":"Finite nucleos(t)ide-analogue therapy for functional cure in HBeAg-negative chronic hepatitis B: recent development in the paradigm shift","authors":"Yun-Fan Liaw, George Papatheodoridis","doi":"10.1097/hep.0000000000001107","DOIUrl":"https://doi.org/10.1097/hep.0000000000001107","url":null,"abstract":"Long-term nucleos(t)ide analogue (Nuc) therapy in chronic hepatitis B (CHB) may lead to hepatitis B virus (HBV) suppression, alanine aminotransferase (ALT) normalization, improvement of histological lesions, and prevention of liver disease progression, but rarely achieve HBsAg loss, the hallmark of functional cure. HBeAg-negative CHB patients have often been recommended to continue Nuc therapy until HBsAg loss, which usually means indefinitely. However, long-term/life-long Nuc therapy is associated with increasing costs and concerns of adverse outcomes subsequent to poor adherence and/or self-cessation/loss-to-follow-up. Hence, 2012 Asian-Pacific guidelines recommended that HBeAg-negative CHB patients can stop Nuc therapy after ≥12 months of HBV DNA undetectability. Subsequent Asian and few European studies have found the strategy of finite Nuc therapy to be feasible and reasonably safe. In 2016-2017, stopping Nuc was also included as a conditional strategy for HBeAg-negative CHB patients in the American and European guidelines. Furthermore, progressively increasing HBsAg loss rates with prolongation of off-Nuc follow-up were documented, being higher in Caucasians and more apparent beyond years 4-5 in Asian patients. Recently, a large study in patients with HBV cirrhosis showed not only higher 10-year HBsAg loss rate (15.3 vs. 1.6%) but also ~50% lower 10-year hepatocellular carcinoma incidence (16.5 vs. 29.5%) and 60% lower liver-related mortality/transplantation rate (6.1 vs. 15.1%) after Nuc cessation, as compared with well-matched patients continuing Nuc therapy. Since novel drug development aiming for functional cure has not been satisfactory, the strategy of finite Nuc therapy in HBeAg-negative CHB seems to be the best realistic option for functional cure today.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":13.5,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317207","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}
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