Hepatology Communications最新文献

{"title":"Blocking interleukin-1 receptor type 1 (IL-1R1) signaling in hepatocytes slows down diethylnitrosamine-induced liver tumor growth in obese mice.","authors":"Nadine Gehrke, Lea J Hofmann, Beate K Straub, Dirk A Ridder, Ari Waisman, Leonard Kaps, Peter R Galle, Jörn M Schattenberg","doi":"10.1097/HC9.0000000000000568","DOIUrl":"https://doi.org/10.1097/HC9.0000000000000568","url":null,"abstract":"<p><strong>Background: </strong>An increasing number of HCC develops in the context of metabolic dysfunction-associated steatotic liver disease and its inflammatory form, metabolic dysfunction-associated steatohepatitis, even in the absence of cirrhosis. Chronic metabolic inflammation is the driving force of metabolic dysfunction-associated steatotic liver disease progression and a key factor in hepatocarcinogenesis. Given the prominent role of IL-1 signaling in inflammation and metabolic diseases, we investigated the relevance of the hepatocyte-specific IL-1 receptor type 1 knockout in metabolic dysfunction-associated steatohepatitis-related noncirrhotic HCC.</p><p><strong>Methods: </strong>For HCC induction, Il1r1Hep-/- mice received a single i.p. injection of diethylnitrosamine at 2 weeks and were fed with high-fat plus high-carbohydrate diet, starting from 4 weeks. After 18 weeks of diet intervention, mice were sacrificed, and macroscopic and microscopic tumor loads were assessed.</p><p><strong>Results: </strong>Knockout of the hepatic IL-1 receptor type 1 pathway significantly reduced liver tumor growth. Il1r1Hep-/- mice were also less susceptible to hepatic steatosis, insulin resistance, and associated hepatic c-Jun N-terminal kinase activation than their wild-type (WT) littermates. Reduced Ki-67 and cyclin D1 levels, as well as decreased phosphorylation of signal transducer and activator of transcription 3, occur in Il1r1Hep-/- livers, lowering cancer cell proliferation and growth. Additionally, in Il1r1Hep-/- livers, the chemokine (C-X-C motif) ligand 1/2-driven accumulation of myeloid-derived suppressor cells and CD8+ T-cell infiltration were reduced compared to the wild type.</p><p><strong>Conclusions: </strong>Metabolic inflammation mediated by the hepatocytic IL-1 receptor type 1 is a cofactor in mutagenic hepatocarcinogenesis. Targeting IL-1 signaling could be an adjunct strategy to the current immunomodulatory HCC treatments.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11608749/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142768545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Missense variants in the TRPM7 α-kinase domain are associated with recurrent pediatric acute liver failure.","authors":"Lea D Schlieben, Melanie T Achleitner, Billy Bourke, Max Diesner, René G Feichtinger, Alexander Fichtner, Christa Flechtenmacher, Nedim Hadzic, Robert Hegarty, Andreas Heilos, Andreas Janecke, Vassiliki Konstantopoulou, Dominic Lenz, Johannes A Mayr, Thomas Müller, Holger Prokisch, Georg F Vogel","doi":"10.1097/HC9.0000000000000598","DOIUrl":"10.1097/HC9.0000000000000598","url":null,"abstract":"<p><strong>Background: </strong>Pediatric acute liver failure (PALF) is a rare and life-threatening condition. In up to 50% of PALF cases, the underlying etiology remains unknown during routine clinical testing. This lack of knowledge complicates clinical management and liver transplantation decisions. Recently, whole-exome sequencing has identified genetic disorders in a large number of cases without specific laboratory biomarkers or metabolic fingerprints.</p><p><strong>Methods: </strong>We describe how further analysis of whole-exome sequencing data combined with proteomic analyses in 5 previously unsolved PALF patients, where no pathogenic variants in genes previously associated with acute liver failure were identified, revealed rare biallelic variants in transient receptor potential cation channel subfamily M member 7 (TRPM7).</p><p><strong>Results: </strong>We establishe TRPM7 as a novel disease gene for PALF. Yet, the cation channel kinase TRPM7 has not been associated with any Mendelian disorder. No homozygous loss-of-function variants were found in in-house exomes or publicly available databases. Rare biallelic TRPM7-variants were significantly enriched in the PALF cohort compared with a pediatric control cohort. Viral infections preceded the majority of PALF episodes. Recurrent PALF episodes characterized the disease course with rapid progression, leading to early death in 3 cases. Proteomic analyses of patient fibroblasts unveiled significantly reduced TRPM7 protein levels, indicative of functional impairment. Severely reduced Mg2+ levels in one individual with a mutation in the channel domain suggests a potential interaction between disturbed Mg2+ homeostasis and PALF. The consistent presence of mutations in the TRPM7 protein-kinase-domain across all patients suggests its specific relevance in PALF.</p><p><strong>Conclusions: </strong>Our data extend the genetic spectrum of recurrent PALF and prompt consideration of TRPM7 in children with unexplained liver failure.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11608757/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142768546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling metabolic-associated steatohepatitis with human pluripotent stem cell-derived liver organoids.","authors":"Xiaoshan Wu, Dacheng Jiang, Yuchen Wang, Xin Li, Chenyu Liu, Yanhao Chen, Wei Sun, Ruikun He, Yi Yang, Xiaosong Gu, Chunping Jiang, Qiurong Ding","doi":"10.1097/HC9.0000000000000585","DOIUrl":"https://doi.org/10.1097/HC9.0000000000000585","url":null,"abstract":"<p><strong>Background: </strong>Metabolic-associated steatohepatitis (MASH) is one of the most prevalent liver diseases worldwide, with a global prevalence estimated between 3% and 5%, posing a significant health burden. Human liver organoids (HLOs) have previously been generated to model steatohepatitis, offering a potential cellular disease model for studying MASH. However, the current HLO model lacks detailed molecular characterizations and requires further improvement.</p><p><strong>Methods: </strong>HLOs derived from human pluripotent stem cells were treated with oleic acid and TGFβ to mimic the MASH progression. Treated HLOs were then analyzed using both bulk and single-cell RNA sequencing. Functional characterization was performed through staining with BODIPY, TMRM, CellROX, and Collagen I, as well as terminal deoxynucleotidyl transferase dUTP nick end labeling and ELISA assays. In addition, a test using the MASH HLO model to validate the hepatoprotective effects of several herb extracts was also conducted.</p><p><strong>Results: </strong>Both RNA-seq and single-cell RNA sequencing demonstrated a close resemblance of multiple molecular signatures and key intercellular communications in and between hepatocyte-like cells and stellate-like cells in the MASH HLO model, compared to human MASH. Furthermore, functional characterizations revealed progressive features of human MASH in the MASH HLO model, including severe steatosis, oxidative stress, mitochondrial dysfunction, inflammation, and fibrosis. In addition, the Schisandra extracts have been demonstrated to have significant antioxidative, anti-inflammatory, and antifibrotic properties in the context of MASH.</p><p><strong>Conclusions: </strong>This study offers an improved HLO disease model of human MASH, which can be potentially applied to facilitate the understanding of the MASH pathogenesis and the discovery of effective treatments.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11608672/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142768547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The pyruvate dehydrogenase kinase inhibitor dichloroacetate mitigates alcohol-induced hepatic inflammation and metabolic disturbances in mice.","authors":"Jianguo Wu, Emily Huang, Megan R McMullen, Vaibhav Singh, Marko Mrdjen, Annette Bellar, Li Wang, Nicole Welch, Jaividhya Dasarathy, Srinivasan Dasarathy, David Streem, J Mark Brown, Laura E Nagy","doi":"10.1097/HC9.0000000000000547","DOIUrl":"10.1097/HC9.0000000000000547","url":null,"abstract":"<p><strong>Background: </strong>Dichloroacetate (DCA), a pan-pyruvate dehydrogenase kinase inhibitor, ameliorates multiple pathological conditions and tissue injury and shows strong potential for clinical applications. Here, we investigated the preventive effects of DCA in a murine model of alcohol-associated liver disease.</p><p><strong>Methods: </strong>C57BL/6J mice were subjected to the acute-on-chronic model of alcohol-associated liver disease and treated with DCA. Livers were assessed in liver histology, biochemistry, and gene expression. Mass spectrometry was used to compare protein expression and metabolite levels.</p><p><strong>Results: </strong>DCA inhibited hepatic expression of inflammatory genes but did not prevent steatosis and hepatocellular injury in ethanol-fed mice. Consistently, DCA repressed the expression of mRNAs for inflammatory genes in LPS-stimulated murine bone-marrow-derived macrophages and human monocytic THP-1 cells and inhibited both gene expression and protein release of interleukin-1 beta. DCA prevented hepatic accumulation of isovaleric acid in ethanol-fed mice, a short-chain fatty acid primarily produced by gut microbiota. In vitro, isovaleric acid potentiated LPS's effects, while DCA prevented this proinflammatory action. Ethanol feeding increased the expression of proteins involved in diverse metabolic pathways, including branched-chain amino acid (BCAA) degradation. In ethanol-fed mice, hepatic Fischer's ratio (the molar ratio of BCAAs to aromatic amino acids Phe and Tyr) and BTR (the molar ratio of BCAAs to Tyr) showed a decrease compared to pair-fed mice; however, this decrease was not observed in DCA-treated ethanol-fed mice. DCA blunted the ethanol-induced increase of BCKDHA, the rate-limiting enzyme in BCAA catabolism, and cytochrome P450 2E1.</p><p><strong>Conclusions: </strong>Ethanol-induced hepatic inflammatory responses and metabolic disturbances were prevented by DCA in mice, indicating the potential to develop pyruvate dehydrogenase kinase inhibitors as an effective therapy to treat alcohol-associated liver disease.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11608733/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142768550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biological and clinical role of TREM2 in liver diseases.","authors":"Ke Ma, Shouliang Guo, Jin Li, Tao Wei, Tingbo Liang","doi":"10.1097/HC9.0000000000000578","DOIUrl":"https://doi.org/10.1097/HC9.0000000000000578","url":null,"abstract":"<p><p>Liver diseases constitute a major health burden worldwide, accounting for more than 4% of all disease-related mortalities. While the incidence of viral hepatitis is expected to decrease, metabolic liver disorders are increasingly diagnosed. Liver pathology is diverse, with functional and molecular alterations in both parenchymal and mesenchymal cells, including immune cells. Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor of the immunoglobulin superfamily and mainly expressed on myeloid cells. Several studies have demonstrated that TREM2 plays a critical role in tissue physiology and various pathological conditions. TREM2 is recognized as being associated with the development of liver diseases by regulating tissue homeostasis and the immune microenvironment. The biological and clinical impact of TREM2 is complex, given its diverse context-dependent functions. This review aims to summarize recent progress in understanding the association between TREM2 and different liver disorders and shed light on the clinical significance of targeting TREM2.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11567705/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical predictors and noninvasive imaging in Fontan-associated liver disease: A systematic review and meta-analysis.","authors":"Jae Hee Seol, Jinyoung Song, Soo Jin Kim, Hoon Ko, Jae Yoon Na, Min Jung Cho, Hee Joung Choi, Jue Seong Lee, Kyung Jin Oh, Jo Won Jung, Se Yong Jung","doi":"10.1097/HC9.0000000000000580","DOIUrl":"10.1097/HC9.0000000000000580","url":null,"abstract":"<p><strong>Background: </strong>Despite the development of several imaging modalities for diagnosing Fontan-associated liver disease (FALD), there is no optimal protocol for the follow-up of FALD. We conducted a systematic review and meta-analysis to identify factors related to liver fibrosis using biopsy reports and to identify alternative noninvasive modalities that could better reflect liver histological changes in FALD.</p><p><strong>Methods: </strong>A systematic review and meta-analysis were conducted following the PRISMA guidelines Table S2. We searched Embase, PubMed, and Cochrane databases for studies on FALD, focusing on those assessing clinical factors associated with liver fibrosis severity through liver biopsy and noninvasive imaging techniques.</p><p><strong>Results: </strong>A total of 42 studies were identified, of which 12 conducted meta-analyses and subgroup analyses of the severity of liver fibrosis using liver biopsies. Liver biopsy results showed a weak positive correlation between Fontan duration and fibrosis severity (R = 0.36). Subgroup analyses revealed significant differences in hemodynamic parameters, such as Fontan pressure, between patients with mild and severe fibrosis. Platelet count, aspartate aminotransferase to platelet ratio index, and fibrosis-4 index were significantly associated with fibrosis severity, with severe fibrosis showing lower platelet counts and higher aspartate aminotransferase to platelet ratio index and fibrosis-4 index levels. Noninvasive imaging modalities, particularly magnetic resonance elastography and shear wave elastography, demonstrated strong correlations with biopsy-confirmed fibrosis severity.</p><p><strong>Conclusions: </strong>This study identifies key clinical factors, and noninvasive modalities accurately reflect liver fibrosis severity in patients with FALD. Clinical factors such as platelet count, aspartate aminotransferase to platelet ratio index, and fibrosis-4 index may aid in identifying patients at risk for severe fibrosis. In addition, magnetic resonance elastography and shear wave elastography are promising tools for noninvasive assessment in our study. Further research is needed to refine these diagnostic approaches and improve patient management.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11567714/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine-learning methodologies to predict disease progression in chronic hepatitis B in Africa.","authors":"Hailemichael Desalegn, Xianchen Yang, Yi-Syuan Yen, Nega Berhe, Brooke Kenney, Geoffrey H Siwo, Weijing Tang, Ji Zhu, Akbar K Waljee, Asgeir Johannessen","doi":"10.1097/HC9.0000000000000584","DOIUrl":"https://doi.org/10.1097/HC9.0000000000000584","url":null,"abstract":"<p><strong>Background: </strong>Little is known about the determinants of disease progression among African patients with chronic HBV infection.</p><p><strong>Methods: </strong>We used machine-learning models with longitudinal data to establish predictive algorithms in a well-characterized cohort of Ethiopian HBV-infected patients without baseline liver fibrosis. Disease progression was defined as an increase in liver stiffness to >7.9 kPa or initiation of treatment based on meeting the eligibility criteria.</p><p><strong>Results: </strong>Twenty-four of 551 patients (4.4%) experienced disease progression after a median follow-up time of 69 months. A random forest model based on a combination of available laboratory tests (standard hematology and biochemistry) demonstrated the best predictive properties with the AUROC ranging from 0.82 to 0.88.</p><p><strong>Conclusion: </strong>We conclude that combined metrics based on simple and available laboratory tests had good predictive properties and should be explored further in larger HBV cohorts.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11567701/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Validation of the Hospital Anxiety and Depression Scale in patients with decompensated cirrhosis.","authors":"Chengbo Zeng, John Donlan, Teresa Indriolo, Lucinda Li, Enya Zhu, Joyce C Zhou, Malia E Armstrong, Kedie Pintro, Nora Horick, Raymond T Chung, Areej Ei-Jawahri, Maria O Edelen, Nneka N Ufere","doi":"10.1097/HC9.0000000000000588","DOIUrl":"10.1097/HC9.0000000000000588","url":null,"abstract":"","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11567708/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sphingosine kinase 2 (SphK2) depletion alters redox metabolism and enhances inflammation in a diet-induced MASH mouse model.","authors":"Kaitlyn G Jackson, Derrick Zhao, Lianyong Su, Marissa K Lipp, Cameron Toler, Michael Idowu, Qianhua Yan, Xuan Wang, Emily Gurley, Nan Wu, Puneet Puri, Qun Chen, Edward J Lesnefsky, Jeffrey L Dupree, Phillip B Hylemon, Huiping Zhou","doi":"10.1097/HC9.0000000000000570","DOIUrl":"10.1097/HC9.0000000000000570","url":null,"abstract":"<p><strong>Background: </strong>Sphingosine-1 phosphate (S1P) is a bioactive lipid molecule that modulates inflammation and hepatic lipid metabolism in MASLD, which affects 1 in 3 people and increases the risk of liver fibrosis and hepatic cancer. S1P can be generated by 2 isoforms of sphingosine kinase (SphK). SphK1 is well-studied in metabolic diseases. In contrast, SphK2 function is not well characterized. Both sphingolipid and redox metabolism dysregulation contribute to MASLD pathologic progression. While SphK2 localizes to both the nucleus and mitochondria, its specific role in early MASH is not well defined.</p><p><strong>Methods: </strong>This study examined SphK2 depletion effects on hepatic redox metabolism, mitochondrial function, and inflammation in a 16-week western diet plus sugar water (WDSW)-induced mouse model of early MASH.</p><p><strong>Results: </strong>WDSW-SphK2-/- mice exhibit increased hepatic lipid accumulation and hepatic redox dysregulation. In addition, mitochondria-localized cholesterol and S1P precursors were increased. We traced SphK2-/--mediated mitochondrial electron transport chain impairment to respiratory complex-IV and found that decreased mitochondrial redox metabolism coincided with increased oxidase gene expression and oxylipin production. Consistent with this relationship, we observed pronounced increases in hepatic inflammatory gene expression, prostaglandin accumulation, and innate immune homing in WDSW-SphK2-/- mice compared to WDSW-wild-type mice.</p><p><strong>Conclusions: </strong>These studies suggest SphK2-derived S1P maintains hepatic redox metabolism and describe the potential consequences of SphK2 depletion on proinflammatory gene expression, lipid mediator production, and immune infiltration in MASH progression.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11567706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of the kynurenine pathway identified in individuals with covert hepatic encephalopathy.","authors":"Georgia Zeng, Shivani Krishnamurthy, Ananda Staats Pires, Anna Guller, Joga Chaganti, Nway Tun, Ian Lockart, Sara Montagnese, Bruce Brew, Gilles J Guillemin, Mark Danta, Benjamin Heng","doi":"10.1097/HC9.0000000000000559","DOIUrl":"https://doi.org/10.1097/HC9.0000000000000559","url":null,"abstract":"<p><strong>Background: </strong>HE is a neuropsychiatric complication of liver disease characterized by systemic elevation in ammonia and proinflammatory cytokines. These neurotoxins cross the blood-brain barrier and cause neuroinflammation, which can activate the kynurenine pathway (KP). This results in dysregulated production of neuroactive KP metabolites, such as quinolinic acid, which is known to cause astrocyte and neuronal death. Our aim was to compare KP activity between patients with covert HE (CHE), patients without encephalopathic cirrhosis (NHE), and healthy controls (HCs).</p><p><strong>Methods: </strong>This was a single-center prospective cohort study conducted between 2018 and 2021 at St Vincent's Hospital, Sydney. Overall, 13 patients with CHE, 10 patients with NHE, and 12 with HC were recruited. Patients with cirrhosis were diagnosed with CHE if they scored ≤-4 on the Psychometric Hepatic Encephalopathy Score. KP metabolite levels were quantified on plasma samples via HPLC and gas chromatography/mass spectrometry. One-way Kruskal-Wallis test was used to compare the expression levels of KP enzymes.</p><p><strong>Results: </strong>KP was highly activated in patients with cirrhosis, demonstrated by higher levels of activity in the rate-limiting enzymes, indoleamine 2,3-dioxygenase, and tryptophan-2,3-dioxygenase in both CHE (65.04±20.72, p=0.003) and patients with NHE (64.85±22.10, p=0.015) compared to HC (40.95±7.301). Higher quinolinic acid concentrations were demonstrated in CHE (3726 nM±3385, p<0.001) and patients with NHE (1788 nM±632.3, p=0.032) compared to HC (624 nM±457). KP activation was positively correlated with inflammatory marker C-reactive protein in patients with CHE (Rs=0.721, p≤0.01).</p><p><strong>Conclusions: </strong>KP is highly activated in patients with CHE, resulting in heightened production of neurotoxic metabolites. Dysregulation of the pathway is demonstrable in patients who do not yet show clinical signs of neurocognitive impairment. Therapeutic agents that modulate KP activity may be able to alleviate symptoms of patients with CHE.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11567712/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}