Liver cancer international最新文献

{"title":"Initial Clinical Experience With the Oral Cholate Challenge Test: Results From the 2023–2024 Early Access Program","authors":"Stuart C. Gordon,&nbsp;James Burton,&nbsp;Bhaktasharan Patel,&nbsp;EAP Participants","doi":"10.1002/lci2.70027","DOIUrl":"https://doi.org/10.1002/lci2.70027","url":null,"abstract":"<p>The oral cholate challenge test of liver health, intended for use in compensated advanced chronic liver disease, was launched through an Early Access Program (EAP) in 2023–2024. Tests were provided to 16 clinicians at five liver centres across the US. The tested patients (<i>n</i> = 129) represented a range of etiologies and stages of disease. Top clinical uses were: (1) informing the decision for endoscopy to test for varices (<i>n</i> = 56, 43%), (2) defining risk for large oesophageal varices (LEV) (<i>n</i> = 92, 71%), and (3) baseline for monitoring disease progression or treatment effects (<i>n</i> = 33, 26%). The test's disease severity index (DSI) stratified patients according to risk for portal hypertension and LEV: 49 (38%) low risk, 31 (24%) moderate risk and 49 (38%) high risk. The potential impact of DSI ≤ 18.3 on EGD avoidance (38%) in clinical practice replicated that which was observed in prior validation studies (41%).</p>","PeriodicalId":93331,"journal":{"name":"Liver cancer international","volume":"6 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/lci2.70027","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145284736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Proof-of-Concept Phase 2a Partly Randomised Study Evaluating Leronlimab in Patients With Presumed Non-Cirrhotic Metabolic Dysfunction–Associated Steatohepatitis","authors":"Melissa Palmer,&nbsp;A. Cyrus Arman,&nbsp;Eric J. Lawitz,&nbsp;William E. Sanchez,&nbsp;Shilpi Mittal,&nbsp;Tarek Hassanein,&nbsp;Scott G. Hansen,&nbsp;Joseph Meidling,&nbsp;Bernie Cunningham,&nbsp;Neil E. Buss,&nbsp;Jacob P. Lalezari","doi":"10.1002/lci2.70028","DOIUrl":"https://doi.org/10.1002/lci2.70028","url":null,"abstract":"<p>Chemokine receptor type 5 (CCR5) is upregulated in the livers of patients with metabolic dysfunction–associated steatohepatitis (MASH). Leronlimab, a humanised IgG4κ monoclonal antibody, directly binds the extracellular domains of CCR5, modulates downstream signalling and potentially can slow, reverse or prevent fibrosis. The aim of this study was to evaluate the safety and efficacy of leronlimab in participants with MASH. Phase 2a, multicentre, two-part study evaluated two doses of once-weekly subcutaneous leronlimab for 13 weeks in participants with non-cirrhotic MASH diagnosed either histologically, by FibroScan, or by Shearwave ultrasound. 87 participants were enrolled: 60 were randomised to leronlimab 700 mg (<i>n</i> = 30) or to placebo (<i>n</i> = 30) (Part 1) and <i>n</i> = 27 allocated to the leronlimab 350 mg arm (Part 2 open-label). Baseline demographics and clinical characteristics were generally similar between Parts 1 and 2. The primary efficacy endpoint, absolute change from baseline in liver fat content assessed by MRI-PDFF at week 14, was not met for Part 1 (absolute increase of 0.42% leronlimab 700 mg versus 1.15% placebo) but was met for Part 2 (1.09% absolute reduction in the leronlimab 350 mg arm versus 1.12% increase placebo). The secondary efficacy endpoint, absolute change from baseline in MRI-cT1 at week 14, was not met for Part 1 but was met for Part 2. All drug-related adverse events were mild or moderate. This proof-of-concept study demonstrated that leronlimab has a favourable safety profile and was well tolerated. While in the open-label 350 mg arm of the study, leronlimab was associated with numerically mild antisteatotic and antifibrotic activity in patients with non-cirrhotic MASH, further evaluation in a randomised controlled trial is necessary to substantiate these results.</p><p><b>Trial Registration:</b> ClinicalTrials.gov identifier: NCT04521114; https://clinicaltrials.gov/study/NCT04521114. The trial was first posted on 20 August 2020.</p>","PeriodicalId":93331,"journal":{"name":"Liver cancer international","volume":"6 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/lci2.70028","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145284662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neonatal Liver-Specific UBA3 Deficiency Leads to TNF-α-Dependent Necroptosis of Liver Sinusoidal Endothelial Cells During Cyst Formation","authors":"Jiaqin Wang,&nbsp;Hang Song,&nbsp;Xueying Zhang,&nbsp;Guanglei Xu,&nbsp;Shulian Li,&nbsp;Jiyan Zhang","doi":"10.1002/lci2.70024","DOIUrl":"https://doi.org/10.1002/lci2.70024","url":null,"abstract":"<p>It has been revealed that cystic fibrosis liver disease, a rare disease, leads to endothelial aberrance with a pro-inflammatory phenotype. The mechanisms underlying endothelial aberrance remain to be explored. Furthermore, it was reported that mice with liver-specific deficiency of NAE1, a component of neddylation E1, show premature death and progressive development of multiple bloody fluid-filled cysts with up-regulated TNF signalling. Therefore, we investigated how neddylation and TNF signalling get involved in cyst formation, focusing on endothelial cells. Liver-specific deficiency of UBA3, the catalytic subunit of neddylation E1 and <i>Tnf</i> knockout (<i>Tnf</i>^−/−) mouse models were used. Histology was examined with haematoxylin and eosin staining. Serum levels of total bilirubin and direct bilirubin were measured to reflect duct injury. Fluorescent multiplex immunohistochemistry was performed to detect the number and necroptosis of endothelial cells. Neonatal liver-specific UBA3 deficiency leads to the formation of bloody cysts with signs of duct injury. CRISPR/Cas-mediated <i>Tnf</i> knockout fails to affect cyst formation and duct injury in <i>Uba3</i>^ΔLiver livers but abrogates bleeding. Liver-specific UBA3 deficiency results in a dramatic reduction of Lyve-1⁺ liver sinusoidal endothelial cells (LSECs) and a simultaneous tendency of increased CD34⁺ endothelial cells. The effects diminish in the absence of TNF-α. The reduction of LSECs upon liver-specific UBA3 deficiency is associated with enhanced necroptosis, which also diminishes in the absence of TNF-α. Neonatal liver-specific UBA3 deficiency leads to TNF-α-dependent bleeding during cyst formation through, at least partially, necroptosis-mediated damage of LSECs.</p>","PeriodicalId":93331,"journal":{"name":"Liver cancer international","volume":"6 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/lci2.70024","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"rs55959738 is Associated with Hepcidin in Metabolic Dysfunction-Associated Steatotic Liver Disease","authors":"Niharika Samala,&nbsp;Tae-Hwi L.Schwantes-An,&nbsp;Amber Burt,&nbsp;James E. Nelson,&nbsp;Gail Jarvick,&nbsp;Naga P. Chalasani,&nbsp;Kris V. Kowdley","doi":"10.1002/lci2.70023","DOIUrl":"https://doi.org/10.1002/lci2.70023","url":null,"abstract":"<p>In individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) increased hepatic hepcidin gene expression, is associated with hepatic iron deposition, which is in turn associated with more severe steatohepatitis and fibrosis. We investigated single nucleotide polymorphisms (SNPs) associated with serum hepcidin level in MASLD. A targeted Genome Wide Association Studies (GWAS) was performed in individuals with biopsy-proven MASLD of European ancestry in the nonalcoholic steatohepatitis-clinical research network (NASH CRN) database I and PIVENS. Association between SNPs and serum hepcidin level was tested using PLINK2. Linear regression was performed to determine association with SNPs and serum hepcidin level in individuals with MASLD. MASLD cohort included 563 individuals, (65% female, 29% had diabetes-2, mean age = 49.7 ± 10.8 years, mean BMI = 34.8 ± 6.5 kg/m²). Mean hepcidin level was 71.6 ± 48.2 ng/ml, and mean ferritin level was 239.3 ± 270.1 ng/dl. After adjusting for age, sex, BMI, diabetes-2, and presence of hepatic iron staining, the SNP rs55959738 (T) on chromosome 6 was associated with lower serum hepcidin level (<i>β</i> = −0.48, se = 0.09, <i>p</i> = 3.29E-08) in the cohort. The association even after adjusting for <i>PNPLA3</i> G allele or common pathogenic <i>HFE</i> variants (C282Y and H63D). The SNP rs55959738 is intergenic in location and is in linkage disequilibrium with SNORD genes. In MASLD, a novel SNP rs55959738 on chromosome 6 is associated with lower serum hepcidin level, independent of common <i>HFE</i> and <i>PNPLA3</i> variants. Additional studies to explore the role of SNP rs55959738 on hepcidin mediated inflammation in MASLD.</p>","PeriodicalId":93331,"journal":{"name":"Liver cancer international","volume":"6 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/lci2.70023","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145101902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatitis C Virus Clearance Is Associated With the Improvement of the Branched-Chain Amino Acid to Tyrosine Ratio (BTR) of Patients With Mild-To-Advanced Fibrosis","authors":"Masaaki Mino,&nbsp;Eiji Kakazu,&nbsp;Akitoshi Sano,&nbsp;Mio Tsuruoka,&nbsp;Katsunori Sekine,&nbsp;Yoshihiko Aoki,&nbsp;Masatoshi Imamura,&nbsp;Michitaka Matsuda,&nbsp;Taiji Yamazoe,&nbsp;Taizo Mori,&nbsp;Sachiyo Yoshio,&nbsp;Jun Inoue,&nbsp;Masataka Tsuge,&nbsp;Shiro Oka,&nbsp;Tatsuya Kanto","doi":"10.1002/lci2.70025","DOIUrl":"https://doi.org/10.1002/lci2.70025","url":null,"abstract":"<p>The progression of chronic hepatitis caused by hepatitis C virus (HCV) is associated with abnormalities in amino acid metabolism. We aimed to characterise the changes in free amino acid (FAA) in the peripheral blood of HCV patients undergoing direct antiviral agents (DAAs). We retrospectively enrolled 183 HCV patients: 116 without hepatocellular carcinoma (HCC) treated with DAAs, and 67 with HCC (19 were treated with DAAs and 48 were not). Biochemical parameters, including 20 FAAs, were measured at four time points (before treatment, at SVR12, at SVR24, and at last follow-up) between 2006 and 2022. The mean observation period was 54 ± 25 months for patients without HCC and 42 ± 26 months for those with HCC. We examined the relationships among the branched-chain amino acid to tyrosine ratio (BTR) and clinical factors. Propensity score matching (PSM) was performed to compare outcomes in HCC patients who achieved sustained virological response (SVR) with those who did not. This was a retrospective study with no dietary intervention, and subgroup analyses were limited by sample size. In non-HCC patients, BTR significantly increased 12 weeks post-SVR and continued to increase throughout follow-up. This improvement was more marked in patients with advanced fibrosis. The changes in tyrosine were inversely correlated with those of M2BPGi, whereas those in BCAA were not. In HCC patients, those achieving SVR maintained their BTR, whereas untreated patients showed significant deterioration. After PSM, similar improvements in FAA imbalances occurred in post-SVR HCC patients. Clearance of HCV is associated with improvement of the BTR across patients with mild to advanced fibrosis or successfully treated HCC, suggesting that gradual recovery of amino acid imbalance reflects improved nutritional status.</p>","PeriodicalId":93331,"journal":{"name":"Liver cancer international","volume":"6 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/lci2.70025","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145101141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alpha-1 Antitrypsin–Mediated Liver Disease: A Role for the NRF1–Proteasome Axis?","authors":"Alexandra Lehmann,&nbsp;Esra Karatas,&nbsp;Céline Leon,&nbsp;Sylvaine di-Tomasso,&nbsp;Cyril Dourthe,&nbsp;Jean-William Dupuy,&nbsp;Anne-Aurélie Raymond,&nbsp;Sophie Collardeau-Frachon,&nbsp;Marion Bouchecareilh","doi":"10.1002/lci2.70026","DOIUrl":"https://doi.org/10.1002/lci2.70026","url":null,"abstract":"<p>The ubiquitin–proteasome system (UPS) and autophagy are the two primary cellular pathways for degrading the Z mutant in Alpha 1-Antitrypsin Deficiency (AATD). These degradation pathways maintain hepatic cellular proteostasis in the context of AATD-mediated liver disease. Although alterations in proteasomal degradation have been demonstrated in AATD mouse models, the role of the UPS pathway in AATD-mediated liver disease remains poorly understood. Here, we show that the master regulator of proteostasis, nuclear factor erythroid 2-like 1 (NFE2L1 or NRF1), is activated in response to proteasome impairment caused by the Z variant, mediating proteasome recovery. Under basal conditions, this proteasome bounce-back response is sufficient to compensate for the impairment caused by Z variant expression. However, the NRF1–proteasome axis is downregulated in cirrhotic livers from AATD patients, suggesting that reduced NRF1 activity may contribute to the progression of AATD-associated liver disease. Our findings supported the involvement of the NRF1–proteasome axis in the hepatic proteotoxic response to Z-AAT and highlighted it as a potential therapeutic target to mitigate or prevent AATD-related liver injury.</p>","PeriodicalId":93331,"journal":{"name":"Liver cancer international","volume":"6 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/lci2.70026","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Validation of Biomarkers Z-AAT Polymers and Fibrinopeptide Aα-Val541 in Peripheral Blood of Patients With pi*ZZ Alpha-1 Antitrypsin Deficiency","authors":"Naomi N. Kappe,&nbsp;Jan Stolk,&nbsp;Emily F. A. van ’t Wout,&nbsp;Sabina M. Janciauskiene,&nbsp;Pieter S. Hiemstra,&nbsp;Bart van Hoek","doi":"10.1002/lci2.70022","DOIUrl":"https://doi.org/10.1002/lci2.70022","url":null,"abstract":"<p>Alpha-1 antitrypsin (AAT) deficiency is a monogenetic condition caused by various single mutations in the SERPINA1 gene. Homozygous carriage of the Z allele (Pi*ZZ) increases the risk of pulmonary emphysema and liver cirrhosis. Z-AAT polymerises and accumulates in hepatocytes, causing liver damage. Secretion of Z-AAT polymers into the circulation is thought to contribute to lung inflammation. Fibrinopeptide Aα-Val⁵⁴¹ is a biomarker of neutrophil-derived proteinase 3 (PR3) enzyme activity, which is inhibited by AAT. We hypothesised that liver transplantation (LT), which results in normal levels of circulating wild-type AAT, reduces circulating polymers and Aα-Val⁵⁴¹ in Pi*ZZ individuals. Plasma was obtained from five Pi*ZZ individuals before and after LT. Z-AAT polymers were measured using a mouse monoclonal antibody (LG96), and fibrinopeptide Aα-Val⁵⁴¹ levels were assessed using a Europium-based immunoassay. After transplantation, polymers were absent or nearly absent, and Aα-Val⁵⁴¹ levels were substantially reduced. Circulating polymers and Aα-Val⁵⁴¹ levels were markedly reduced in Pi*ZZ individuals receiving a LT.</p>","PeriodicalId":93331,"journal":{"name":"Liver cancer international","volume":"6 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/lci2.70022","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144881261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"External Validation of the Hepatic Steatosis Index for the Detection of Steatotic Liver Disease in Zambia","authors":"Carlotta Mondoka,&nbsp;Guy Muula,&nbsp;Edford Sinkala,&nbsp;Aretha Mumba,&nbsp;Kenan Simumba,&nbsp;Samuel Bosomprah,&nbsp;Carolyn Bolton-Moore,&nbsp;Annalisa Berzigotti,&nbsp;Bernard Surial,&nbsp;Gilles Wandeler,&nbsp;Belinda Varaidzo Chihota,&nbsp;IeDEA-Southern Africa","doi":"10.1002/lci2.70021","DOIUrl":"https://doi.org/10.1002/lci2.70021","url":null,"abstract":"<p>The hepatic steatosis index (HSI) is used to detect steatotic liver disease (SLD), but its diagnostic performance in African populations is unknown. We performed an external validation of HSI among adults in Zambia. We consecutively screened treatment-naïve people with HIV and individuals without HIV in Zambia using the controlled attenuation parameter (CAP) by vibration controlled transient elastography (VCTE). Model discrimination and calibration were assessed using the c-index and calibration plots. Among 401 participants, 161 (40.1%) were people with HIV. Median age was 37 years (interquartile range 32–43), 244 (60.9%) were female, and 131 (32.7%) were overweight or obese. VCTE-confirmed SLD was present in 41 (10.2%) participants, whereas 92 (22.9%) had an HSI ≥ 36. The c-index to diagnose SLD was 0.67 (95% confidence interval 0.56–0.77). The calibration plot indicated that HSI overestimated the risk for SLD. HSI showed a poor diagnostic performance for the detection of SLD among adults in Zambia.</p>","PeriodicalId":93331,"journal":{"name":"Liver cancer international","volume":"6 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/lci2.70021","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144725531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Socioeconomic Status, Clinical Characteristics and Mortality in Two Subtypes of ALD According to the New SLD Classifications","authors":"Qi Feng,&nbsp;Pinelopi Manousou,&nbsp;Chioma N. Izzi-Engbeaya,&nbsp;Mark Woodward","doi":"10.1002/lci2.70019","DOIUrl":"https://doi.org/10.1002/lci2.70019","url":null,"abstract":"<p>Under the new steatotic liver disease (SLD) framework, alcohol-related liver disease (ALD) is defined including two subtypes: (1) people with cardiometabolic risk factors (CMRFs) and with alcohol consumption &gt; 50/60 g/day (for female/male), noted as ALD-1, and (2) people with daily alcohol consumption &gt; 20/30 g/day but without CMRF, noted as ALD-2. However, little is known about the difference between these subtypes. Using UK biobank data, we identified individuals with ALD-1 and ALD-2 using the standard definition. We compared the two groups on their socioeconomic status, clinical characteristics, and mortality. Among 11 583 participants with ALD, only 17 (0.15%) had ALD-2. Compared to ALD-1, those with ALD-2 were more likely to be non-White, socioeconomically deprived, and smokers, with higher levels of ALT, AST, GGT, and FIB4 scores. The mortality rate was significantly higher in ALD-2 than ALD-1 (31.9 vs. 11.3 per 1000 person-years, HR 2.45 (95% CI 1.09, 5.50)). ALD-1 and ALD-2 exhibit substantial heterogeneity in socioeconomic status, lifestyle factors, clinical characteristics, and prognoses, suggesting distinct underlying mechanisms. These findings highlight the need for tailored management strategies that address the unique characteristics of each subtype.</p>","PeriodicalId":93331,"journal":{"name":"Liver cancer international","volume":"6 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/lci2.70019","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144171595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preascitic Sodium Retention in Cirrhosis: A Role for Disregulated Proteolysis by Proprotein Convertases?","authors":"Giovanni Sansoè,&nbsp;Manuela Aragno,&nbsp;Florence Wong","doi":"10.1002/lci2.70020","DOIUrl":"https://doi.org/10.1002/lci2.70020","url":null,"abstract":"<p>Loss of effective arterial blood volume, secondary hyperaldosteronism, adrenergic activation and nonosmotic hypersecretion of vasopressin induce sodium and water retention in cirrhotic patients with ascites. The mechanisms of sodium retention that precede ascites formation remain elusive. In patients who are at the preascites stage of cirrhosis, no sign of reduced effective volaemia is found; nonetheless, tubular sodium retention is already present. Maturation and full functionality of epithelial sodium channels (ENaC) in distal segments of the nephron and, therefore, final control of sodium excretion are dependent on regulated proteolysis by proprotein convertases. Evidence of abnormal or incomplete maturation of ENaCs in preascitic cirrhosis exists, but the complex mechanisms of regulated proteolysis leading to ENaC maturation through sequential action of serine endopeptidases (i.e., furin, site-1 protease, prostasin, plasmin) have never been studied in liver cirrhosis. Also, the mechanisms of cirrhosis-associated immune dysfunction, which are characterised by systemic sterile inflammation and release of proinflammatory cytokines that profoundly influence renal function, remain largely unknown. Release of proinflammatory cytokines and functions of respective receptors are controlled through regulated proteolysis by cell membrane metallopeptidases (mainly ADAM-10 and -17). Once again, little is known in preascitic cirrhosis about potential disregulated proteolysis of proinflammatory cytokines that may trigger systemic inflammation and renal dysfunction. We advance a new hypothesis that (a) may link proprotein convertases to disregulated proteolysis of tubular sodium channels, renin-angiotensin system receptors and inflammatory mediators, and that (b) may shed light on the mechanisms of sodium retention before any systemic neurohormonal activation in liver cirrhosis.</p>","PeriodicalId":93331,"journal":{"name":"Liver cancer international","volume":"6 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/lci2.70020","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143904962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}