Pub Date : 2024-08-22DOI: 10.1016/j.jhepr.2024.101187
Ingrid Wei Zhang , María Belén Sánchez-Rodríguez , Cristina López-Vicario , Mireia Casulleras , Marta Duran-Güell , Roger Flores-Costa , Ferran Aguilar , Michael Rothe , Paula Segalés , Carmen García-Ruiz , José C. Fernández-Checa , Jonel Trebicka , Vicente Arroyo , Joan Clària
<div><h3>Background & Aims</h3><div>In patients with cirrhosis, acute decompensation (AD) correlates with a hyperinflammatory state driven by mitochondrial dysfunction, which is a significant factor in the progression toward acute-on-chronic liver failure (ACLF). Elevated circulating levels of acylcarnitine, indicative of mitochondrial dysfunction, are predictors of mortality in ACLF patients. Our hypothesis posits that acylcarnitines not only act as biomarkers, but also actively exert detrimental effects on circulating immune cells.</div></div><div><h3>Methods</h3><div>Plasma acylcarnitine levels were measured in 20 patients with AD cirrhosis and 10 healthy individuals. The effects of selected medium- and long-chain acylcarnitines on mitochondrial function were investigated in peripheral leucocytes from healthy donors by determining mitochondrial membrane potential (Δψm) and mitochondrial respiration using the JC-1 dye and Agilent Seahorse XF technology. Changes regarding mitochondrial ultrastructure and redox systems were assessed by transmission electron microscopy and gene and protein expression analysis.</div></div><div><h3>Results</h3><div>Plasma levels of several acylcarnitine species were significantly elevated in patients with AD cirrhosis compared with healthy individuals, alongside increased levels of inflammatory mediators (cytokines and chemokines). Notably, the long-chain acylcarnitine palmitoylcarnitine (C16:0-carnitine, 1.51-fold higher, <em>p =</em> 0.0059) impaired Δψm and reduced the spare respiratory capacity of peripheral mononuclear leucocytes. Additionally, C16:0-carnitine induced mitochondrial oxidative stress, suppressed the expression of the antioxidant gene <em>HMOX1</em>, and increased <em>CXCL8</em> expression and IL-8 release. Etomoxir, which blocks acylcarnitine entry into the mitochondria, reversed the suppression of <em>HMOX1</em>. Similarly, trimetazidine, a fatty acid beta-oxidation inhibitor, prevented C16:0-carnitine-induced <em>CXCL8</em> expression. Importantly, oxidative stress and Δψm impairment caused by C16:0-carnitine were less severe in the presence of albumin, a standard therapy for AD cirrhosis.</div></div><div><h3>Conclusions</h3><div>Our findings suggest that long-chain acylcarnitines induce mitochondrial injury in immune cells, thereby contributing to the development of immune dysfunction associated with cirrhosis.</div></div><div><h3>Impact and implications</h3><div>Patients with acute decompensation of cirrhosis and acute-on-chronic liver failure (ACLF) display a systemic hyperinflammatory state and leukocyte mitochondrial dysfunction. We discovered that apart from being increased in the circulation of these patients, the long-chain palmitoylcarnitine is able to elicit cytokine secretion paired with mitochondrial dysfunction in leukocytes from healthy donors. In particular, we show that inhibiting the metabolism of palmitoylcarnitine could reverse these detrimental effects. Our findings unde
{"title":"Palmitoylcarnitine impairs immunity in decompensated cirrhosis","authors":"Ingrid Wei Zhang , María Belén Sánchez-Rodríguez , Cristina López-Vicario , Mireia Casulleras , Marta Duran-Güell , Roger Flores-Costa , Ferran Aguilar , Michael Rothe , Paula Segalés , Carmen García-Ruiz , José C. Fernández-Checa , Jonel Trebicka , Vicente Arroyo , Joan Clària","doi":"10.1016/j.jhepr.2024.101187","DOIUrl":"10.1016/j.jhepr.2024.101187","url":null,"abstract":"<div><h3>Background & Aims</h3><div>In patients with cirrhosis, acute decompensation (AD) correlates with a hyperinflammatory state driven by mitochondrial dysfunction, which is a significant factor in the progression toward acute-on-chronic liver failure (ACLF). Elevated circulating levels of acylcarnitine, indicative of mitochondrial dysfunction, are predictors of mortality in ACLF patients. Our hypothesis posits that acylcarnitines not only act as biomarkers, but also actively exert detrimental effects on circulating immune cells.</div></div><div><h3>Methods</h3><div>Plasma acylcarnitine levels were measured in 20 patients with AD cirrhosis and 10 healthy individuals. The effects of selected medium- and long-chain acylcarnitines on mitochondrial function were investigated in peripheral leucocytes from healthy donors by determining mitochondrial membrane potential (Δψm) and mitochondrial respiration using the JC-1 dye and Agilent Seahorse XF technology. Changes regarding mitochondrial ultrastructure and redox systems were assessed by transmission electron microscopy and gene and protein expression analysis.</div></div><div><h3>Results</h3><div>Plasma levels of several acylcarnitine species were significantly elevated in patients with AD cirrhosis compared with healthy individuals, alongside increased levels of inflammatory mediators (cytokines and chemokines). Notably, the long-chain acylcarnitine palmitoylcarnitine (C16:0-carnitine, 1.51-fold higher, <em>p =</em> 0.0059) impaired Δψm and reduced the spare respiratory capacity of peripheral mononuclear leucocytes. Additionally, C16:0-carnitine induced mitochondrial oxidative stress, suppressed the expression of the antioxidant gene <em>HMOX1</em>, and increased <em>CXCL8</em> expression and IL-8 release. Etomoxir, which blocks acylcarnitine entry into the mitochondria, reversed the suppression of <em>HMOX1</em>. Similarly, trimetazidine, a fatty acid beta-oxidation inhibitor, prevented C16:0-carnitine-induced <em>CXCL8</em> expression. Importantly, oxidative stress and Δψm impairment caused by C16:0-carnitine were less severe in the presence of albumin, a standard therapy for AD cirrhosis.</div></div><div><h3>Conclusions</h3><div>Our findings suggest that long-chain acylcarnitines induce mitochondrial injury in immune cells, thereby contributing to the development of immune dysfunction associated with cirrhosis.</div></div><div><h3>Impact and implications</h3><div>Patients with acute decompensation of cirrhosis and acute-on-chronic liver failure (ACLF) display a systemic hyperinflammatory state and leukocyte mitochondrial dysfunction. We discovered that apart from being increased in the circulation of these patients, the long-chain palmitoylcarnitine is able to elicit cytokine secretion paired with mitochondrial dysfunction in leukocytes from healthy donors. In particular, we show that inhibiting the metabolism of palmitoylcarnitine could reverse these detrimental effects. Our findings unde","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"6 11","pages":"Article 101187"},"PeriodicalIF":9.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142533173","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}
Safety data for patients with hepatocellular carcinoma (HCC) treated with atezolizumab-bevacizumab in the real-world setting remain uncertain. Thus, the aim of this study was to evaluate the incidence of adverse events (AEs) in patients with HCC treated with atezolizumab-bevacizumab in the literature.
Methods
In this systematic review and meta-analysis, we searched PubMed for original studies reporting percentages of AEs in patients with HCC receiving atezolizumab-bevacizumab between 2020 to 2023, using the search terms “Atezolizumab/Bevacizumab”, “HCC” and “Adverse events”. We summarized the incidence of AEs and performed a meta-analysis in order to evaluate the incidence of AEs reported in the literature.
Results
A total of 30 studies (3,867 patients) were included. The analysis revealed heterogeneity in AE reporting, with arterial hypertension, proteinuria, and fatigue being the most frequently reported AEs whereas incidence of bleeding was reported in 66.7% of the studies and rare immune-related AEs were reported in 26.7% of the studies. The meta-analysis revealed pooled incidence rates of 79% for any grade AEs: 56% for grade 1/2 and 30% for grade ≥3. While the pooled rates of hypertension, anorexia, bleeding, pruritus, rash, and thyroid dysfunction were similar to those reported in the IMbrave150 trial, higher rates were observed in the literature for proteinuria, fatigue, ALT and AST elevations and gastrointestinal perforation. For grade ≥3 AEs, the percentages were consistent with the IMbrave150 trial, except for lower incidences of arterial hypertension and thrombosis in the literature. The exposure-adjusted incidence rates for proteinuria (55.7%), hypertension (45.3%) and fatigue (33.6%) were high. Heterogeneity was observed in the analysis of AEs across articles within the same cohorts of patients.
Conclusion
We observed a significant variability in AE reporting for atezolizumab-bevacizumab treatment in HCC in the literature, underscoring the need for standardized reporting practices.
Impact and implications
Considering the demonstrated safety of atezolizumab-bevacizumab in randomized-controlled trials, this meta-analysis offers valuable insights into reported occurrences of adverse events. Our study highlights significant heterogeneity among studies, underscoring the need to improve adverse event recording. Understanding the incidence and severity of treatment-related adverse events beyond clinical trials is essential for prompt intervention and may help in preventing treatment discontinuation and complications, potentially leading to better outcomes without significantly compromising quality of life due to adverse events.
{"title":"Heterogeneity in adverse events related to atezolizumab-bevacizumab for hepatocellular carcinoma reported in real-world studies","authors":"Claudia Campani , Dimitrios Pallas , Sabrina Sidali , Olga Giouleme , Lorraine Blaise , Véronique Grando , Gisele Nkontchou , Alix Demory , Pierre Nahon , Nathalie Ganne-Carrié , Jean-Charles Nault","doi":"10.1016/j.jhepr.2024.101190","DOIUrl":"10.1016/j.jhepr.2024.101190","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Safety data for patients with hepatocellular carcinoma (HCC) treated with atezolizumab-bevacizumab in the real-world setting remain uncertain. Thus, the aim of this study was to evaluate the incidence of adverse events (AEs) in patients with HCC treated with atezolizumab-bevacizumab in the literature.</div></div><div><h3>Methods</h3><div>In this systematic review and meta-analysis, we searched PubMed for original studies reporting percentages of AEs in patients with HCC receiving atezolizumab-bevacizumab between 2020 to 2023, using the search terms “Atezolizumab/Bevacizumab”, “HCC” and “Adverse events”. We summarized the incidence of AEs and performed a meta-analysis in order to evaluate the incidence of AEs reported in the literature.</div></div><div><h3>Results</h3><div>A total of 30 studies (3,867 patients) were included. The analysis revealed heterogeneity in AE reporting, with arterial hypertension, proteinuria, and fatigue being the most frequently reported AEs whereas incidence of bleeding was reported in 66.7% of the studies and rare immune-related AEs were reported in 26.7% of the studies. The meta-analysis revealed pooled incidence rates of 79% for any grade AEs: 56% for grade 1/2 and 30% for grade ≥3. While the pooled rates of hypertension, anorexia, bleeding, pruritus, rash, and thyroid dysfunction were similar to those reported in the IMbrave150 trial, higher rates were observed in the literature for proteinuria, fatigue, ALT and AST elevations and gastrointestinal perforation. For grade ≥3 AEs, the percentages were consistent with the IMbrave150 trial, except for lower incidences of arterial hypertension and thrombosis in the literature. The exposure-adjusted incidence rates for proteinuria (55.7%), hypertension (45.3%) and fatigue (33.6%) were high. Heterogeneity was observed in the analysis of AEs across articles within the same cohorts of patients.</div></div><div><h3>Conclusion</h3><div>We observed a significant variability in AE reporting for atezolizumab-bevacizumab treatment in HCC in the literature, underscoring the need for standardized reporting practices.</div></div><div><h3>Impact and implications</h3><div>Considering the demonstrated safety of atezolizumab-bevacizumab in randomized-controlled trials, this meta-analysis offers valuable insights into reported occurrences of adverse events. Our study highlights significant heterogeneity among studies, underscoring the need to improve adverse event recording. Understanding the incidence and severity of treatment-related adverse events beyond clinical trials is essential for prompt intervention and may help in preventing treatment discontinuation and complications, potentially leading to better outcomes without significantly compromising quality of life due to adverse events.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"6 11","pages":"Article 101190"},"PeriodicalIF":9.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142539623","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 : 2024-08-22DOI: 10.1016/j.jhepr.2024.101189
Nataliia Petriv , Huizhen Suo , Inga Hochnadel , Kai Timrott , Nina Bondarenko , Lavinia Neubert , Elena Reinhard , Nils Jedicke , Patrick Kaufhold , Carlos Alberto Guzmán , Ralf Lichtinghagen , Michael P. Manns , Heike Bantel , Tetyana Yevsa
<div><h3>Background & Aims</h3><div>Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death. Metabolic dysfunction-associated steatotic liver disease (MASLD) is a significant cause of HCC. Current treatment options for HCC are very limited. Recent evidence highlights B cells as key drivers in MASLD progression toward HCC. However, it remains unclear whether multiple B cell populations or a distinct B cell subset regulates inflammatory responses during liver disease progression. The scope of this study was to define protumorigenic B cell subsets in MASLD and HCC.</div></div><div><h3>Methods</h3><div>Multicolor flow cytometry, immunohistochemistry, and immunofluorescence analyses were performed to investigate B cell populations locally (in liver tissue) and systemically (in the blood) in mice with MASLD (n = 6) and HCC (n = 5–6). The results obtained in mice were also verified in patients with MASLD (n = 19) and HCC (n = 16).</div></div><div><h3>Results</h3><div>Our study revealed an increase of two regulatory B cell (Breg) subsets, CD19<sup>+</sup>B220<sup>+</sup>CD5<sup>+</sup>CD1d<sup>+</sup> (<em>p</em> <0.0001) and CD19<sup>-</sup>B220<sup>+</sup>CD5<sup>+</sup>CD1d<sup>-</sup> (<em>p</em> <0.0001), both of which highly overexpress IgM/IgD, PD-L1, and IL-10, in the livers of mice with MASLD and HCC. Furthermore, we showed that B-cell depletion therapy in combination with a <em>Listeria-</em>based vaccine decreased CD19<sup>-</sup>B220<sup>+</sup>CD5<sup>+</sup>CD1d<sup>-</sup> Bregs (<em>p</em> = 0.0103), and improved survival of mice with HCC. We also found CD19<sup>+</sup>CD5<sup>+</sup>IL-10<sup>+</sup> (<em>p</em> = 0.0167), CD19<sup>+</sup>CD5<sup>+</sup>PD-L1<sup>+</sup> (<em>p</em> = 0.0333) and CD19<sup>+</sup>CD5<sup>+</sup>IgM<sup>+</sup>IgD<sup>+</sup> (<em>p</em> = 0.0317) B cells in human HCCs. In addition, strong overexpression of IgM/IgD, PD-L1, IL-10, were detected on non-switched memory B cells (<em>p</em> = 0.0049) and plasmablasts (<em>p</em> = 0.0020). The examination of blood samples obtained from patients with MASLD showed an increase of total B cells expressing IL-10 (<em>p</em> <0.0001) and IgM/IgD (<em>p</em> = 0.3361), CD19<sup>+</sup>CD20<sup>+</sup>CD5<sup>+</sup>CD1d<sup>+</sup> Bregs (<em>p</em> = 0.6424) and CD19<sup>+</sup>CD20<sup>+</sup>CD27<sup>+</sup> non-switched memory B cells (<em>p</em> = 0.0003).</div></div><div><h3>Conclusions</h3><div>Our results provide novel insights into the protumorigenic roles of several B cell subsets, the specific targeting of which could abrogate the progression of liver disease.</div></div><div><h3>Impact and implications</h3><div>Hepatocellular carcinoma (HCC) is the primary liver cancer with a constantly rising mortality rate. Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging important cause of HCC. Current treatment options for HCC are limited and there is a high risk of recurrence. The study aims to iden
背景& 目的肝细胞癌（HCC）是癌症相关死亡的第三大原因。代谢功能障碍相关性脂肪性肝病（MASLD）是导致 HCC 的重要原因。目前治疗 HCC 的方法非常有限。最近的证据表明，B 细胞是 MASLD 向 HCC 发展的关键驱动因素。然而，在肝病进展过程中，是否有多个 B 细胞群或一个独特的 B 细胞亚群调节炎症反应，目前仍不清楚。本研究的目的是确定 MASLD 和 HCC 中的原发肿瘤性 B 细胞亚群。方法采用多色流式细胞术、免疫组织化学和免疫荧光分析方法，研究 MASLD 小鼠（n = 6）和 HCC 小鼠（n = 5-6）局部（肝组织）和全身（血液）的 B 细胞群。结果我们的研究发现，在患有 MASLD 和 HCC 的小鼠肝脏中，CD19+B220+CD5+CD1d+ (p <0.0001)和 CD19-B220+CD5+CD1d- (p <0.0001)这两种调节性 B 细胞 (Breg) 亚群有所增加，它们都高度过表达 IgM/IgD、PD-L1 和 IL-10。此外，我们还发现，结合李斯特菌疫苗的 B 细胞耗竭疗法可减少 CD19-B220+CD5+CD1d- Bregs（p = 0.0103），并提高 HCC 小鼠的存活率。我们还在人类 HCC 中发现了 CD19+CD5+IL-10+ (p = 0.0167)、CD19+CD5+PD-L1+ (p = 0.0333) 和 CD19+CD5+IgM+IgD+ (p = 0.0317) B 细胞。此外，在非转换记忆 B 细胞（p = 0.0049）和浆细胞（p = 0.0020）中检测到 IgM/IgD、PD-L1、IL-10 的强过量表达。对 MASLD 患者血液样本的检查显示，表达 IL-10 (p <0.0001)和 IgM/IgD (p = 0.3361)、CD19+CD20+CD5+CD1d+ Bregs (p = 0.6424) 和 CD19+CD20+CD27+ 非转换记忆 B 细胞 (p = 0.0003) 的 B 细胞总数增加。影响和意义肝细胞癌（HCC）是死亡率持续上升的原发性肝癌。代谢功能障碍相关性脂肪性肝病（MASLD）是新出现的导致 HCC 的重要原因。目前治疗 HCC 的方法有限，而且复发风险很高。本研究旨在通过探索 MASLD 和 HCC 的免疫学方面来确定新的治疗策略。我们的研究结果扩展了目前关于 B 细胞在 MASLD 和 HCC 进展中的作用的知识。这项研究强调了IgM+IgD+调节性B细胞（Bregs）在恶性肝病进展中的参与。这些 Bregs 的特征是高表达 PD-L1、IL-10、IgM 和 IgD。在对小鼠肝病的研究中还发现了另外两种具有免疫抑制表型的 B 细胞亚群--浆细胞和非转换记忆 B 细胞。以这些B细胞为靶点，可以更有效地治疗HCC。
{"title":"Essential roles of B cell subsets in the progression of MASLD and HCC","authors":"Nataliia Petriv , Huizhen Suo , Inga Hochnadel , Kai Timrott , Nina Bondarenko , Lavinia Neubert , Elena Reinhard , Nils Jedicke , Patrick Kaufhold , Carlos Alberto Guzmán , Ralf Lichtinghagen , Michael P. Manns , Heike Bantel , Tetyana Yevsa","doi":"10.1016/j.jhepr.2024.101189","DOIUrl":"10.1016/j.jhepr.2024.101189","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death. Metabolic dysfunction-associated steatotic liver disease (MASLD) is a significant cause of HCC. Current treatment options for HCC are very limited. Recent evidence highlights B cells as key drivers in MASLD progression toward HCC. However, it remains unclear whether multiple B cell populations or a distinct B cell subset regulates inflammatory responses during liver disease progression. The scope of this study was to define protumorigenic B cell subsets in MASLD and HCC.</div></div><div><h3>Methods</h3><div>Multicolor flow cytometry, immunohistochemistry, and immunofluorescence analyses were performed to investigate B cell populations locally (in liver tissue) and systemically (in the blood) in mice with MASLD (n = 6) and HCC (n = 5–6). The results obtained in mice were also verified in patients with MASLD (n = 19) and HCC (n = 16).</div></div><div><h3>Results</h3><div>Our study revealed an increase of two regulatory B cell (Breg) subsets, CD19<sup>+</sup>B220<sup>+</sup>CD5<sup>+</sup>CD1d<sup>+</sup> (<em>p</em> <0.0001) and CD19<sup>-</sup>B220<sup>+</sup>CD5<sup>+</sup>CD1d<sup>-</sup> (<em>p</em> <0.0001), both of which highly overexpress IgM/IgD, PD-L1, and IL-10, in the livers of mice with MASLD and HCC. Furthermore, we showed that B-cell depletion therapy in combination with a <em>Listeria-</em>based vaccine decreased CD19<sup>-</sup>B220<sup>+</sup>CD5<sup>+</sup>CD1d<sup>-</sup> Bregs (<em>p</em> = 0.0103), and improved survival of mice with HCC. We also found CD19<sup>+</sup>CD5<sup>+</sup>IL-10<sup>+</sup> (<em>p</em> = 0.0167), CD19<sup>+</sup>CD5<sup>+</sup>PD-L1<sup>+</sup> (<em>p</em> = 0.0333) and CD19<sup>+</sup>CD5<sup>+</sup>IgM<sup>+</sup>IgD<sup>+</sup> (<em>p</em> = 0.0317) B cells in human HCCs. In addition, strong overexpression of IgM/IgD, PD-L1, IL-10, were detected on non-switched memory B cells (<em>p</em> = 0.0049) and plasmablasts (<em>p</em> = 0.0020). The examination of blood samples obtained from patients with MASLD showed an increase of total B cells expressing IL-10 (<em>p</em> <0.0001) and IgM/IgD (<em>p</em> = 0.3361), CD19<sup>+</sup>CD20<sup>+</sup>CD5<sup>+</sup>CD1d<sup>+</sup> Bregs (<em>p</em> = 0.6424) and CD19<sup>+</sup>CD20<sup>+</sup>CD27<sup>+</sup> non-switched memory B cells (<em>p</em> = 0.0003).</div></div><div><h3>Conclusions</h3><div>Our results provide novel insights into the protumorigenic roles of several B cell subsets, the specific targeting of which could abrogate the progression of liver disease.</div></div><div><h3>Impact and implications</h3><div>Hepatocellular carcinoma (HCC) is the primary liver cancer with a constantly rising mortality rate. Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging important cause of HCC. Current treatment options for HCC are limited and there is a high risk of recurrence. The study aims to iden","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"6 12","pages":"Article 101189"},"PeriodicalIF":9.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142657238","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 : 2024-08-22DOI: 10.1016/j.jhepr.2024.101194
Oren Tirosh , Michal Verman , Dana Ivancovsky-Wajcman , Laura Sol Grinshpan , Naomi Fliss-Isakov , Muriel Webb , Oren Shibolet , Revital Kariv , Shira Zelber-Sagi
<div><h3>Background & Aims</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly related to nutrition. However, only a few human and animal studies have tested the association between MASLD and dairy consumption and the effect of milk fat on liver damage. Therefore, we aimed at testing the association between consumption of dairy product and the incidence of MASLD and fibrosis markers in humans, and the effect of milk fat <em>vs.</em> other fats on MASLD in animal studies.</div></div><div><h3>Methods</h3><div>A prospective 7-year follow-up cohort study was performed including baseline and follow-up fasting blood tests, liver evaluation and a face-to-face interview on health status and behaviour using structured questionnaires. MASLD was determined by ultrasonography or by controlled attenuation parameter (CAP), and liver fibrosis by FibroTest™ or FibroScan®. An animal study was performed in which 6-week-old C57BL/6j male mice were fed a high-fat diet (HFD) consisting of lard, soybean oil, and milk fat for 12 weeks. Metabolic impairment was assessed during the animal experiment, and serum advanced glycation end-products (AGEs) and liver damage were evaluated.</div></div><div><h3>Results</h3><div>A total of 316 patients were included in the prospective cohort. In multivariable analysis, high consumption of low-medium fat low-sugar dairy products (g/day above the baseline sex-specific median) was associated with a lower risk for MASLD incidence (OR 0.42, 95% CI 0.18–0.95, <em>p =</em> 0.037) or incidence/persistence at follow-up (OR 0.58, 0.34–0.97, <em>p =</em> 0.039). Constantly high consumption of high-fat low-sugar dairy products was associated with greater odds for new onset/persistence of MASLD. Neither low-medium nor high-fat dairy consumption was related to fibrosis markers. In mice, all HFDs induced similar weight gain and steatosis and did not affect liver enzymes. Milk fat increases serum cholesterol and AGEs levels more than lard or soybean oil.</div></div><div><h3>Conclusions</h3><div>Low-medium fat low-sugar dairy products may be protective and should be preferred over high-fat dairy to prevent MASLD. HFDs from different fat sources with a wide spectrum of fatty acid saturation content are equally deleterious.</div></div><div><h3>Impact and implications</h3><div>MASLD is related to nutrition, but evidence of an association between high-fat and low-fat dairy products is lacking, therefore, we evaluated this association by performing experimental studies in mice and an observational human study. For MASLD prevention, a differential effect based on the type of dairy products should be considered: low-medium fat low-sugar dairy products were found to be protective, in contrast high-fat dairy and generally high-fat diets may be harmful. It would be advisable to prefer low-fat low-sugar dairy products and minimise intake of high-fat dairy products; however, additional evidence is needed to allow generalisa
{"title":"Differential effects of low or high-fat dairy and fat derived from dairy products on MASLD","authors":"Oren Tirosh , Michal Verman , Dana Ivancovsky-Wajcman , Laura Sol Grinshpan , Naomi Fliss-Isakov , Muriel Webb , Oren Shibolet , Revital Kariv , Shira Zelber-Sagi","doi":"10.1016/j.jhepr.2024.101194","DOIUrl":"10.1016/j.jhepr.2024.101194","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly related to nutrition. However, only a few human and animal studies have tested the association between MASLD and dairy consumption and the effect of milk fat on liver damage. Therefore, we aimed at testing the association between consumption of dairy product and the incidence of MASLD and fibrosis markers in humans, and the effect of milk fat <em>vs.</em> other fats on MASLD in animal studies.</div></div><div><h3>Methods</h3><div>A prospective 7-year follow-up cohort study was performed including baseline and follow-up fasting blood tests, liver evaluation and a face-to-face interview on health status and behaviour using structured questionnaires. MASLD was determined by ultrasonography or by controlled attenuation parameter (CAP), and liver fibrosis by FibroTest™ or FibroScan®. An animal study was performed in which 6-week-old C57BL/6j male mice were fed a high-fat diet (HFD) consisting of lard, soybean oil, and milk fat for 12 weeks. Metabolic impairment was assessed during the animal experiment, and serum advanced glycation end-products (AGEs) and liver damage were evaluated.</div></div><div><h3>Results</h3><div>A total of 316 patients were included in the prospective cohort. In multivariable analysis, high consumption of low-medium fat low-sugar dairy products (g/day above the baseline sex-specific median) was associated with a lower risk for MASLD incidence (OR 0.42, 95% CI 0.18–0.95, <em>p =</em> 0.037) or incidence/persistence at follow-up (OR 0.58, 0.34–0.97, <em>p =</em> 0.039). Constantly high consumption of high-fat low-sugar dairy products was associated with greater odds for new onset/persistence of MASLD. Neither low-medium nor high-fat dairy consumption was related to fibrosis markers. In mice, all HFDs induced similar weight gain and steatosis and did not affect liver enzymes. Milk fat increases serum cholesterol and AGEs levels more than lard or soybean oil.</div></div><div><h3>Conclusions</h3><div>Low-medium fat low-sugar dairy products may be protective and should be preferred over high-fat dairy to prevent MASLD. HFDs from different fat sources with a wide spectrum of fatty acid saturation content are equally deleterious.</div></div><div><h3>Impact and implications</h3><div>MASLD is related to nutrition, but evidence of an association between high-fat and low-fat dairy products is lacking, therefore, we evaluated this association by performing experimental studies in mice and an observational human study. For MASLD prevention, a differential effect based on the type of dairy products should be considered: low-medium fat low-sugar dairy products were found to be protective, in contrast high-fat dairy and generally high-fat diets may be harmful. It would be advisable to prefer low-fat low-sugar dairy products and minimise intake of high-fat dairy products; however, additional evidence is needed to allow generalisa","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"6 11","pages":"Article 101194"},"PeriodicalIF":9.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142441926","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 : 2024-08-22DOI: 10.1016/j.jhepr.2024.101188
Connie Chan , Mateus Lemos , Peter Finnegan , William Gagnon , Richard Dean , Maryam Yazdanafar , Joseph Zepeda , Marie-Claude Vohl , Michael Trauner , Joshua R. Korzenik , Olivier Barbier , Maria L. Marco , Christopher L. Bowlus
Background & Aims
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease with a strong association with inflammatory bowel disease and variable disease progression. We aimed to gain insights into the role of fecal bile acids (BA) on disease progression by determining the relationships between fecal BA, diet, and gut microbes, with markers of disease progression, BA synthesis, and farnesoid X receptor (FXR) activity.
Methods
BA levels in serum and stool, dietary intake, and markers of BA synthesis, and FXR activity were measured in 26 patients with early stage, large duct PSC. Fecal microbiota were quantified by 16S rRNA gene sequencing.
Results
Compared with controls, fecal unconjugated deoxycholic acid (DCA) levels were lower in patients with PSC (padj = 0.04). Alcohol intake and the abundance of Blautia and Lachnoclostridium were associated with greater fecal DCA levels in patients with PSC after adjusting for inflammatory bowel disease and treatment with ursodeoxycholic acid. Fecal DCA levels were negatively associated with total bilirubin levels in patients with PSC (p = 0.006) suggesting a protective role. However, fecal DCA was associated with greater serum levels of 7α-hydroxy-4-cholesten-3-one, a marker of BA synthesis, and was not associated with fibroblast growth factor 19, a marker of intestinal FXR activity.
Conclusions
Alcohol intake, Blautia and Lachnoclostridium abundance was associated with increased fecal DCA levels, which in turn seemed to have had a protective effect in patients with early-stage PSC. However, this effect was not mediated by BA synthesis or FXR activation.
Impact and implications
Primary sclerosing cholangitis (PSC) is a cholestatic liver disease with a direct interaction between the gut and the liver. In this study of patients with early-stage PSC, levels of fecal deoxycholic acid correlated with serum total bilirubin, a marker of clinical outcomes. In addition, Blautia and Lachnoclostridium were associated with fecal deoxycholic acid suggesting an interaction between these gut bacteria, fecal bile acids, and disease progression. Future research to determine the underlying mechanisms of these associations may lead to novel targets to prevent PSC disease progression.
{"title":"Fecal deoxycholic acid associates with diet, intestinal microbes, and total bilirubin in primary sclerosing cholangitis","authors":"Connie Chan , Mateus Lemos , Peter Finnegan , William Gagnon , Richard Dean , Maryam Yazdanafar , Joseph Zepeda , Marie-Claude Vohl , Michael Trauner , Joshua R. Korzenik , Olivier Barbier , Maria L. Marco , Christopher L. Bowlus","doi":"10.1016/j.jhepr.2024.101188","DOIUrl":"10.1016/j.jhepr.2024.101188","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease with a strong association with inflammatory bowel disease and variable disease progression. We aimed to gain insights into the role of fecal bile acids (BA) on disease progression by determining the relationships between fecal BA, diet, and gut microbes, with markers of disease progression, BA synthesis, and farnesoid X receptor (FXR) activity.</div></div><div><h3>Methods</h3><div>BA levels in serum and stool, dietary intake, and markers of BA synthesis, and FXR activity were measured in 26 patients with early stage, large duct PSC. Fecal microbiota were quantified by 16S rRNA gene sequencing.</div></div><div><h3>Results</h3><div>Compared with controls, fecal unconjugated deoxycholic acid (DCA) levels were lower in patients with PSC (<em>p</em><sub>adj</sub> = 0.04). Alcohol intake and the abundance of <em>Blautia</em> and <em>Lachnoclostridium</em> were associated with greater fecal DCA levels in patients with PSC after adjusting for inflammatory bowel disease and treatment with ursodeoxycholic acid. Fecal DCA levels were negatively associated with total bilirubin levels in patients with PSC (<em>p</em> = 0.006) suggesting a protective role. However, fecal DCA was associated with greater serum levels of 7α-hydroxy-4-cholesten-3-one, a marker of BA synthesis, and was not associated with fibroblast growth factor 19, a marker of intestinal FXR activity.</div></div><div><h3>Conclusions</h3><div>Alcohol intake, <em>Blautia</em> and <em>Lachnoclostridium</em> abundance was associated with increased fecal DCA levels, which in turn seemed to have had a protective effect in patients with early-stage PSC. However, this effect was not mediated by BA synthesis or FXR activation.</div></div><div><h3>Impact and implications</h3><div>Primary sclerosing cholangitis (PSC) is a cholestatic liver disease with a direct interaction between the gut and the liver. In this study of patients with early-stage PSC, levels of fecal deoxycholic acid correlated with serum total bilirubin, a marker of clinical outcomes. In addition, <em>Blautia</em> and <em>Lachnoclostridium</em> were associated with fecal deoxycholic acid suggesting an interaction between these gut bacteria, fecal bile acids, and disease progression. Future research to determine the underlying mechanisms of these associations may lead to novel targets to prevent PSC disease progression.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"6 12","pages":"Article 101188"},"PeriodicalIF":9.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142657169","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 : 2024-08-20DOI: 10.1016/j.jhepr.2024.101186
Brandon M. Lehrich , Junyan Tao , Silvia Liu , Theo Z. Hirsch , Tyler M. Yasaka , Catherine Cao , Evan R. Delgado , Xiangnan Guan , Shan Lu , Long Pan , Yuqing Liu , Sucha Singh , Minakshi Poddar , Aaron Bell , Aatur D. Singhi , Jessica Zucman-Rossi , Yulei Wang , Satdarshan P. Monga
<div><h3>Background & Aims</h3><div>Patients with β-catenin (encoded by <em>CTNNB1</em>)-mutated hepatocellular carcinoma (HCC) demonstrate heterogenous responses to first-line immune checkpoint inhibitors (ICIs). Precision-medicine based treatments for this subclass are currently in clinical development. Here, we report derivation of the Mutated β-catenin Gene Signature (MBGS) to predict <em>CTNNB1</em>-mutational status in patients with HCC for future application in personalized medicine treatment regimens.</div></div><div><h3>Methods</h3><div>Co-expression of mutant-Nrf2 and hMet ± mutant-β-catenin in murine livers in mice led to HCC development. The MBGS was derived using bulk RNA-seq and intersectional transcriptomic analysis of β-catenin-mutated and non-mutated HCC models. Integrated RNA/whole-exome-sequencing and spatial transcriptomic data from multiple cohorts of patients with HCC was assessed to address the ability of MBGS to detect <em>CTNNB1</em> mutation, the tumor immune microenvironment, and/or predict therapeutic responses.</div></div><div><h3>Results</h3><div>Bulk RNA-seq comparing HCC specimens in mutant β-catenin-Nrf2, β-catenin-Met and β-catenin-Nrf2-Met to Nrf2-Met HCC model yielded 95 common upregulated genes. In The Cancer Genome Atlas (TCGA)-LIHC dataset, differential gene expression analysis with false discovery rate (FDR) = 0.05 and log<sub>2</sub>(fold change) >1.5 on the 95 common genes comparing <em>CTNNB1</em>-mutated <em>vs.</em> wild-type patients narrowed the gene panel to a 13-gene MBGS. MBGS predicted <em>CTNNB1</em>-mutations in TCGA (n = 374) and French (n = 398) patient cohorts with AUCs of 0.90 and 0.94, respectively. Additionally, a higher MBGS expression score was associated with lack of significant improvement in overall survival or progression-free survival in the atezolizumab-bevacizumab arm <em>vs.</em> the sorafenib arm in the IMbrave150 cohort. MBGS performed comparable or superior to other <em>CTNNB1</em>-mutant classifiers. MBGS overlapped with Hoshida S3, Boyault G5/G6, and Chiang CTNNB1 subclass tumors in TCGA and in HCC spatial transcriptomic datasets visually depicting these tumors to be situated in an immune excluded tumor microenvironment.</div></div><div><h3>Conclusions</h3><div>MBGS will aid in patient stratification to guide precision medicine therapeutics for <em>CTNNB1</em>-mutated HCC subclass as a companion diagnostic, as anti-β-catenin therapies become available.</div></div><div><h3>Impact and implications:</h3><div>As precision medicine for liver cancer treatment becomes a reality, diagnostic tools are needed to help classify patients into groups for the best treatment choices. We have developed a molecular signature that could serve as a companion diagnostic and uses bulk or spatial transcriptomic data to identify a unique subclass of liver tumors. This subgroup of liver cancer patients derive limited benefit from the current standard of care and are expected to benefit from
{"title":"Development of mutated β-catenin gene signature to identify CTNNB1 mutations from whole and spatial transcriptomic data in patients with HCC","authors":"Brandon M. Lehrich , Junyan Tao , Silvia Liu , Theo Z. Hirsch , Tyler M. Yasaka , Catherine Cao , Evan R. Delgado , Xiangnan Guan , Shan Lu , Long Pan , Yuqing Liu , Sucha Singh , Minakshi Poddar , Aaron Bell , Aatur D. Singhi , Jessica Zucman-Rossi , Yulei Wang , Satdarshan P. Monga","doi":"10.1016/j.jhepr.2024.101186","DOIUrl":"10.1016/j.jhepr.2024.101186","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Patients with β-catenin (encoded by <em>CTNNB1</em>)-mutated hepatocellular carcinoma (HCC) demonstrate heterogenous responses to first-line immune checkpoint inhibitors (ICIs). Precision-medicine based treatments for this subclass are currently in clinical development. Here, we report derivation of the Mutated β-catenin Gene Signature (MBGS) to predict <em>CTNNB1</em>-mutational status in patients with HCC for future application in personalized medicine treatment regimens.</div></div><div><h3>Methods</h3><div>Co-expression of mutant-Nrf2 and hMet ± mutant-β-catenin in murine livers in mice led to HCC development. The MBGS was derived using bulk RNA-seq and intersectional transcriptomic analysis of β-catenin-mutated and non-mutated HCC models. Integrated RNA/whole-exome-sequencing and spatial transcriptomic data from multiple cohorts of patients with HCC was assessed to address the ability of MBGS to detect <em>CTNNB1</em> mutation, the tumor immune microenvironment, and/or predict therapeutic responses.</div></div><div><h3>Results</h3><div>Bulk RNA-seq comparing HCC specimens in mutant β-catenin-Nrf2, β-catenin-Met and β-catenin-Nrf2-Met to Nrf2-Met HCC model yielded 95 common upregulated genes. In The Cancer Genome Atlas (TCGA)-LIHC dataset, differential gene expression analysis with false discovery rate (FDR) = 0.05 and log<sub>2</sub>(fold change) >1.5 on the 95 common genes comparing <em>CTNNB1</em>-mutated <em>vs.</em> wild-type patients narrowed the gene panel to a 13-gene MBGS. MBGS predicted <em>CTNNB1</em>-mutations in TCGA (n = 374) and French (n = 398) patient cohorts with AUCs of 0.90 and 0.94, respectively. Additionally, a higher MBGS expression score was associated with lack of significant improvement in overall survival or progression-free survival in the atezolizumab-bevacizumab arm <em>vs.</em> the sorafenib arm in the IMbrave150 cohort. MBGS performed comparable or superior to other <em>CTNNB1</em>-mutant classifiers. MBGS overlapped with Hoshida S3, Boyault G5/G6, and Chiang CTNNB1 subclass tumors in TCGA and in HCC spatial transcriptomic datasets visually depicting these tumors to be situated in an immune excluded tumor microenvironment.</div></div><div><h3>Conclusions</h3><div>MBGS will aid in patient stratification to guide precision medicine therapeutics for <em>CTNNB1</em>-mutated HCC subclass as a companion diagnostic, as anti-β-catenin therapies become available.</div></div><div><h3>Impact and implications:</h3><div>As precision medicine for liver cancer treatment becomes a reality, diagnostic tools are needed to help classify patients into groups for the best treatment choices. We have developed a molecular signature that could serve as a companion diagnostic and uses bulk or spatial transcriptomic data to identify a unique subclass of liver tumors. This subgroup of liver cancer patients derive limited benefit from the current standard of care and are expected to benefit from ","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"6 12","pages":"Article 101186"},"PeriodicalIF":9.5,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142657239","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 : 2024-08-12DOI: 10.1016/j.jhepr.2024.101183
Adele Mourad , Rona McGeer , Emma Gray , Anna-Marie Bibby-Jones , Heather Gage , Lidia Salvaggio , Vikki Charles , Natasha Sanderson , Margaret O’Sullivan , Thomas Bird , Sumita Verma
Background & Aims
Only a handful of countries are on target to achieve elimination of HCV by 2030. People experiencing homelessness (PEH) remain an important HCV reservoir. The END C study evaluated clinical, patient reported, and health economic outcomes of a decentralised integrated model.
Methods
This prospective study assessed a decentralised regional service based at multiple homeless sites in southeast England. Novel linkage-care strategies were used. We assessed generic and liver specific health-related quality of life (HRQoL) (SF-12v2; EQ-5D-5L, and SFLDQol) pre-/post-HCV treatment, and cost per HCV case detected and cured. The primary outcome was sustained virological response (SVR12) in the intention-to-treat (ITT) population.
Results
We recruited 418 individuals with mean age 44.45 ± 10.6 years, 78% were male, 74% were currently homeless, current injecting drug use or alcohol use was 25% and 65%, respectively. Prevalence of cirrhosis (liver stiffness measurement ≥12 kPa) was 12%. A total of 28% (n = 116) were HCV PCR-positive of whom 105 individuals received direct acting antiviral treatment. The ITT SVR12 rates were 81% (95% CI 72%–88%), the only predictor of SVR12 was >80% treatment adherence (OR 20.69, 95% CI 6.227–68.772, p <0.001). HRQoL improved significantly after SVR12: SF-12v2 (General Health, Mental Health, Social Functioning, Mental Health Composite Score p <0.049); SFLDQoL (Symptoms/Effects of Liver Disease, Distress, Loneliness p <0.004) and EQ-5D-5L (Index Score, Visual Analog Scale p <0.001). Costs (British pound 2022) per HCV case detected and per case cured were £359 and £257, respectively. Reinfection rates were 6.82/100 person years.
Conclusion
The END C study endorses a multisite decentralised service for PEH enabling excellent linkage to care, high SVR12 rates, and significant improvements in generic and liver specific HRQoL, all being achieved at modest costs. Such services are paramount to help achieve HCV elimination.
Impact and implications:
In people experiencing homeless, we found a high prevalence of HCV, alcohol, and substance misuse including overdoses and mental health issues. Despite this, an integrated and decentralised service resulted in excellent linkage to care with high SVR12 rates. Even in this complex cohort with multiple comorbidities, SVR12 was associated with significant improvements in both generic and liver specific HRQoL. This was all achieved at modest costs in a community setting. Such models of care are feasible, easy to replicate, and essential if we are to achieve HCV elimination.
{"title":"A novel multisite model to facilitate hepatitis C virus elimination in people experiencing homelessness","authors":"Adele Mourad , Rona McGeer , Emma Gray , Anna-Marie Bibby-Jones , Heather Gage , Lidia Salvaggio , Vikki Charles , Natasha Sanderson , Margaret O’Sullivan , Thomas Bird , Sumita Verma","doi":"10.1016/j.jhepr.2024.101183","DOIUrl":"10.1016/j.jhepr.2024.101183","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Only a handful of countries are on target to achieve elimination of HCV by 2030. People experiencing homelessness (PEH) remain an important HCV reservoir. The END C study evaluated clinical, patient reported, and health economic outcomes of a decentralised integrated model.</div></div><div><h3>Methods</h3><div>This prospective study assessed a decentralised regional service based at multiple homeless sites in southeast England. Novel linkage-care strategies were used. We assessed generic and liver specific health-related quality of life (HRQoL) (SF-12v2; EQ-5D-5L, and SFLDQol) pre-/post-HCV treatment, and cost per HCV case detected and cured. The primary outcome was sustained virological response (SVR12) in the intention-to-treat (ITT) population.</div></div><div><h3>Results</h3><div>We recruited 418 individuals with mean age 44.45 ± 10.6 years, 78% were male, 74% were currently homeless, current injecting drug use or alcohol use was 25% and 65%, respectively. Prevalence of cirrhosis (liver stiffness measurement ≥12 kPa) was 12%. A total of 28% (n = 116) were HCV PCR-positive of whom 105 individuals received direct acting antiviral treatment. The ITT SVR12 rates were 81% (95% CI 72%–88%), the only predictor of SVR12 was >80% treatment adherence (OR 20.69, 95% CI 6.227–68.772, <em>p <</em>0.001). HRQoL improved significantly after SVR12: SF-12v2 (General Health, Mental Health, Social Functioning, Mental Health Composite Score <em>p <</em>0.049); SFLDQoL (Symptoms/Effects of Liver Disease, Distress, Loneliness <em>p <</em>0.004) and EQ-5D-5L (Index Score, Visual Analog Scale <em>p <</em>0.001). Costs (British pound 2022) per HCV case detected and per case cured were £359 and £257, respectively. Reinfection rates were 6.82/100 person years.</div></div><div><h3>Conclusion</h3><div>The END C study endorses a multisite decentralised service for PEH enabling excellent linkage to care, high SVR12 rates, and significant improvements in generic and liver specific HRQoL, all being achieved at modest costs. Such services are paramount to help achieve HCV elimination.</div></div><div><h3>Impact and implications:</h3><div>In people experiencing homeless, we found a high prevalence of HCV, alcohol, and substance misuse including overdoses and mental health issues. Despite this, an integrated and decentralised service resulted in excellent linkage to care with high SVR12 rates. Even in this complex cohort with multiple comorbidities, SVR12 was associated with significant improvements in both generic and liver specific HRQoL. This was all achieved at modest costs in a community setting. Such models of care are feasible, easy to replicate, and essential if we are to achieve HCV elimination.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"6 11","pages":"Article 101183"},"PeriodicalIF":9.5,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142533172","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 : 2024-08-09DOI: 10.1016/j.jhepr.2024.101185
Fabrizia Carli , Giuseppe Della Pepa , Silvia Sabatini , Antonio Vidal Puig , Amalia Gastaldelli
Metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH) is recognised as a metabolic disease characterised by excess intrahepatic lipid accumulation due to lipid overflow and synthesis, alongside impaired oxidation and/or export of these lipids. But where do these lipids come from? The main pathways related to hepatic lipid accumulation are de novo lipogenesis and excess fatty acid transport to the liver (due to increased lipolysis, adipose tissue insulin resistance, as well as excess dietary fatty acid intake, in particular of saturated fatty acids). Not only triglycerides but also other lipids are secreted by the liver and are associated with a worse histological profile in MASH, as shown by lipidomics. Herein, we review the role of lipid metabolism in MASLD/MASH and discuss the impact of weight loss (diet, bariatric surgery, GLP-1RAs) or other pharmacological treatments (PPAR or THRβ agonists) on hepatic lipid metabolism, lipidomics, and the resolution of MASH.
{"title":"Lipid metabolism in MASLD and MASH: From mechanism to the clinic","authors":"Fabrizia Carli , Giuseppe Della Pepa , Silvia Sabatini , Antonio Vidal Puig , Amalia Gastaldelli","doi":"10.1016/j.jhepr.2024.101185","DOIUrl":"10.1016/j.jhepr.2024.101185","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH) is recognised as a metabolic disease characterised by excess intrahepatic lipid accumulation due to lipid overflow and synthesis, alongside impaired oxidation and/or export of these lipids. But where do these lipids come from? The main pathways related to hepatic lipid accumulation are <em>de novo</em> lipogenesis and excess fatty acid transport to the liver (due to increased lipolysis, adipose tissue insulin resistance, as well as excess dietary fatty acid intake, in particular of saturated fatty acids). Not only triglycerides but also other lipids are secreted by the liver and are associated with a worse histological profile in MASH, as shown by lipidomics. Herein, we review the role of lipid metabolism in MASLD/MASH and discuss the impact of weight loss (diet, bariatric surgery, GLP-1RAs) or other pharmacological treatments (PPAR or THRβ agonists) on hepatic lipid metabolism, lipidomics, and the resolution of MASH.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"6 12","pages":"Article 101185"},"PeriodicalIF":9.5,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142593365","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 : 2024-08-08DOI: 10.1016/j.jhepr.2024.101184
Joan Clària , Ferran Aguilar , Juan-José Lozano , Laura Jiménez-Gracia , Juan C. Nieto , Berta Romero-Grimaldo , Xavi Marcos-Fa , Emma Giarracco , Emmanuel Weiss , Jonel Trebicka , Inmaculada Hernàndez , Javier Fernandez , Mireia Casulleras , Cristina López-Vicario , Sinan Muldur , Alex Hopke , Alexandru Vlagea , Ana M. Aransay , Domenica Marchese , Mauro Bernardi , Richard Moreau
Background & Aims
Patients with acutely decompensated (AD) cirrhosis are immunocompromised and particularly susceptible to infections. This study investigated the immunomodulatory actions of albumin by which this protein may lower the incidence of infections.
Methods
Blood immunophenotyping was performed in 11 patients with AD cirrhosis and 10 healthy volunteers (HV). Bulk and single-cell RNA sequencing (scRNA-seq) and flow cytometry were performed in peripheral blood mononuclear cells (PBMCs) from 20 patients with AD cirrhosis and 34 HV exposed to albumin. Albumin’s effects on degranulation, phagocytosis, chemotaxis, and swarming of neutrophils from six patients with AD cirrhosis and nine HV were assessed by measuring myeloperoxidase enzymatic activity, the engulfment of fluorescent-labeled Escherichia coli and zymosan, and interactions of neutrophils with Candida albicans at single-cell resolution in microfluidic chambers, respectively. Whole blood RNA sequencing (RNA-seq) analyses were performed in 49 patients admitted for severe AD cirrhosis, of whom 30 received albumin during hospitalization.
Results
Compared with HV, patients with AD cirrhosis showed severe lymphopenia and defective neutrophil antimicrobial function. Bulk and scRNA-seq analyses revealed significantly (false discovery rate [FDR] <0.05) increased signatures related to B cells, myeloid cells, and CD4+ T cells in PBMCs incubated with albumin. Changes in the B cell population were confirmed by flow cytometry. Neutrophils exposed to albumin also exhibited augmented chemotactic and degranulation responses, enhanced phagocytosis, and increased pathogen-restrictive swarming. RNA-seq data analysis in patients who had received albumin revealed specific upregulation of signatures related to B cells and neutrophils together with transcriptional changes in CD4+ T cells (FDR <0.05).
Conclusions
The finding that albumin promotes the transcriptional reprogramming and expansion of the B cell compartment and improves neutrophil antimicrobial functions indicates mechanisms that may lower the incidence of infections in patients with severe AD cirrhosis receiving albumin therapy.
Impact and implications:
Patients with acutely decompensated cirrhosis receiving albumin as treatment have a lower incidence of infections. The reason for this protection is currently unknown, but the present study provides data that support the ability of albumin to boost the antimicrobial functions of immune cells in these patients. Moreover, these findings encourage the design of controlled clinical studies specifically aimed at investigating the effects of albumin administration on the immune system.
背景& 目的急性失代偿期（AD）肝硬化患者免疫力低下，特别容易受到感染。本研究调查了白蛋白的免疫调节作用，这种蛋白质可降低感染的发生率。方法对 11 名急性失代偿期肝硬化患者和 10 名健康志愿者（HV）进行了血液免疫分型。对暴露于白蛋白的 20 名 AD 肝硬化患者和 34 名健康志愿者的外周血单核细胞（PBMC）进行了大量和单细胞 RNA 测序（scRNA-seq）以及流式细胞术。通过在微流控室内以单细胞分辨率测量髓过氧化物酶的酶活性、荧光标记的大肠杆菌和齐莫散的吞噬作用以及中性粒细胞与白色念珠菌的相互作用，分别评估了白蛋白对 6 名 AD 型肝硬化患者和 9 名 HV 患者的中性粒细胞的脱颗粒、吞噬、趋化和成群作用的影响。结果与HV相比，AD肝硬化患者表现出严重的淋巴细胞减少和中性粒细胞抗菌功能缺陷。大量和scRNA-seq分析显示，与白蛋白培养的PBMCs中B细胞、骨髓细胞和CD4+ T细胞相关的特征显著增加（假发现率[FDR] <0.05）。流式细胞术证实了 B 细胞群的变化。暴露于白蛋白的中性粒细胞也表现出趋化和脱颗粒反应增强、吞噬能力增强以及病原体限制性蜂拥增加。对接受过白蛋白治疗的患者进行的 RNA-seq 数据分析显示，与 B 细胞和中性粒细胞相关的特征发生了特异性上调，CD4+ T 细胞的转录也发生了变化（FDR <0.05）。影响和意义：接受白蛋白治疗的急性失代偿期肝硬化患者的感染率较低。这种保护作用的原因目前尚不清楚，但本研究提供的数据支持了白蛋白增强这些患者免疫细胞抗菌功能的能力。此外，这些研究结果还鼓励设计临床对照研究，专门研究白蛋白对免疫系统的影响。
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Pub Date : 2024-08-06DOI: 10.1016/j.jhepr.2024.101181
Parissa Tabrizian , Rebecca Marino , Pierce K.H. Chow
Immune checkpoint inhibitors (ICIs) have revolutionised the treatment landscape for advanced hepatocellular carcinoma (HCC). The combination of atezolizumab and bevacizumab has demonstrated efficacy, establishing a new standard of care for advanced HCC. Neoadjuvant studies have shown promising results with high response rates, increasing research into ICIs’ role. In the peri-operative setting, in addition to adjuvant and neo-adjuvant therapies, strategies for "downstaging" and "bridging" patients to liver transplantation (LT) are being investigated, broadening the eligible candidate pool. Furthermore, therapeutic advances have reshaped conversion strategies for hepatic resection, with emerging evidence indicating a role for adjuvant immunotherapy in patients at high risk of postoperative recurrence. In LT, concerns have arisen over the potential conflict between immunosuppression needs and the immune-enhancing effects of ICIs, with reports of severe rejection. However, liver-specific factors may lessen rejection risks, prompting exploration into the safety of pre-transplant ICI administration. Moreover, ongoing trials must prioritise patient selection and vigilant management protocols. Despite the remarkable progress in immunotherapy, the intricate molecular interactions within the tumour microenvironment and their implications on oncogenic pathways remain incompletely understood. This highlights the need for specialised expertise to effectively integrate immunotherapy into the surgical management of HCC. Key challenges include ensuring safety, optimising oncological outcomes, managing the risk of graft rejection in transplant recipients, and refining patient selection criteria. In this review, we aim to provide a comprehensive overview of the evolving role of immunotherapy in the surgical management of HCC, discussing the rationale for its application in both pre- and post-surgical contexts, leveraging current clinical experience, identifying potential limitations, and envisioning future applications. By integrating existing knowledge and highlighting areas for further investigation, this review seeks to inform clinical practice and guide future research endeavours.
{"title":"Liver resection and transplantation in the era of checkpoint inhibitors","authors":"Parissa Tabrizian , Rebecca Marino , Pierce K.H. Chow","doi":"10.1016/j.jhepr.2024.101181","DOIUrl":"10.1016/j.jhepr.2024.101181","url":null,"abstract":"<div><div>Immune checkpoint inhibitors (ICIs) have revolutionised the treatment landscape for advanced hepatocellular carcinoma (HCC). The combination of atezolizumab and bevacizumab has demonstrated efficacy, establishing a new standard of care for advanced HCC. Neoadjuvant studies have shown promising results with high response rates, increasing research into ICIs’ role. In the peri-operative setting, in addition to adjuvant and neo-adjuvant therapies, strategies for \"downstaging\" and \"bridging\" patients to liver transplantation (LT) are being investigated, broadening the eligible candidate pool. Furthermore, therapeutic advances have reshaped conversion strategies for hepatic resection, with emerging evidence indicating a role for adjuvant immunotherapy in patients at high risk of postoperative recurrence. In LT, concerns have arisen over the potential conflict between immunosuppression needs and the immune-enhancing effects of ICIs, with reports of severe rejection. However, liver-specific factors may lessen rejection risks, prompting exploration into the safety of pre-transplant ICI administration. Moreover, ongoing trials must prioritise patient selection and vigilant management protocols. Despite the remarkable progress in immunotherapy, the intricate molecular interactions within the tumour microenvironment and their implications on oncogenic pathways remain incompletely understood. This highlights the need for specialised expertise to effectively integrate immunotherapy into the surgical management of HCC. Key challenges include ensuring safety, optimising oncological outcomes, managing the risk of graft rejection in transplant recipients, and refining patient selection criteria. In this review, we aim to provide a comprehensive overview of the evolving role of immunotherapy in the surgical management of HCC, discussing the rationale for its application in both pre- and post-surgical contexts, leveraging current clinical experience, identifying potential limitations, and envisioning future applications. By integrating existing knowledge and highlighting areas for further investigation, this review seeks to inform clinical practice and guide future research endeavours.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"6 11","pages":"Article 101181"},"PeriodicalIF":9.5,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142427463","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}
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