Lay Summaries - Volume 75 Issue 6

Lay Summary:  Regulatory T-cells (Tregs) can promote tumor development by suppressing cancer immunosurveillance, but their role in carcinogenesis during non-alcoholic steatohepatitis (NASH) progression is unknown. Herein, we discovered that selectively increased intrahepatic Tregs can promote an immunosuppressive environment in NASH livers. Neutrophil extracellular traps (NETs) link innate and adaptive immunity by promoting Treg differentiation via metabolic reprogramming of naïve CD4+ T-cells. This mechanism could be targeted to prevent liver cancer in patients with NASH.
Lay Summary:  Our findings provide further support for the idea that non-alcoholic fatty liver disease (NAFLD) is a part of a broader multi-system disease that also includes obesity, diabetes, high blood pressure, and high cholesterol. Therefore, re-defining NAFLD as metabolic dysfunction-associated fatty liver disease (MAFLD) may help improve our understanding of predictors that increase the risk of death.
Lay Summary:  PRO-C3 is a serological biomarker associated with liver disease activity and fibrosis. Its performance for the detection of disease activity and fibrosis is improved when it is incorporated into the ADAPT score. Herein, we showed that ADAPT was better at selecting patients with non-alcoholic steatohepatitis for inclusion in clinical trials than other non-invasive scores.
Lay Summary:  Direct-acting antivirals lead to virological cure in the majority of patients with chronic hepatitis C virus infection. However, the risk of liver disease progression or complications in patients with fibrosis and cirrhosis remains in some patients even after virological cure. Herein, we show that extracellular vesicle modifications could be linked to long-term liver disease progression in patients who have achieved virological cure; these modifications could potentially be used as biomarkers or treatment targets in such patients.
Lay Summary:  Cases of liver injury have been reported among patients treated with protease inhibitor-based direct-acting antivirals for hepatitis C infection, but it is not clear if the risk of liver injury among people starting these drugs is increased compared to those starting non-protease inhibitor-based therapy. In this study, patients receiving protease inhibitor-based treatment had a higher risk of liver inflammation than those receiving a non-protease inhibitor-based treatment, regardless of the presence of pre-treatment advanced liver fibrosis/cirrhosis. However, the risk of severe liver dysfunction and decompensation were not higher for patients treated with protease inhibitor-based regimens.
Lay Summary:  Hepatitis A virus is a leading cause of acute viral hepatitis worldwide. T cells were thought to contribute to liver injury during acute infection. We now show that virus-specific T cells protect against infection and limit liver injury.
Lay Summary:  Stable cell lines producing high-titer cell culture-generated hepatitis B virus (HBV) of various genotypes were established. HBV genotypes showed stable infectivity in both in vitro and in vivo models, which are valuable tools for antiviral development.
Lay Summary:  Granulocyte-colony stimulating factor was considered as a novel treatment for acute-on-chronic liver failure (ACLF). We performed the first randomized, multicenter, controlled phase II trial, which showed that G-CSF did not improve survival or other clinical endpoints in patients with ACLF. Therefore, G-CSF should not be used to treat liver disease outside clinical studies.
    Cirrhosis and Liver Failure
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    Gennaro D’Amico, Luigi Maruzzelli, Aldo Airoldi, Ioannis Petridis, Giulia Tosetti, Antonio Rampoldi, Mario D’Amico, Roberto Miraglia, Stella De Nicola, Vincenzo La Mura, Marco Solcia, Riccardo Volpes, Giovanni Perricone, Cristiano Sgrazzutti, Angelo Vanzulli, Massimo Primignani, Angelo Luca, Giuseppe Malizia, Alessandro Federico, Marcello Dallio, Angelo Andriulli, Angelo Iacobellis, Luigi Addario, Matteo Garcovich, Antonio Gasbarrini, Luchino Chessa, Francesco Salerno, Giulia Gobbo, Manuela Merli, Lorenzo Ridola, Gianluca Svegliati Baroni, Giuseppe Tarantino, Nicola Caporaso, Filomena Morisco, Pietro Pozzoni, Agostino Colli, Luca Saverio Belli
    Journal of Hepatology, Vol. 75, Issue 6, p1355–1366
Lay Summary:  While the discriminative performance of the model for end-stage liver disease (MELD) score is credited to be fair to good, its calibration, the correspondence of observed to predicted mortality, is still unsettled. We found that application of 3 different versions of the MELD in 2 independent cirrhosis cohorts yielded largely imprecise mortality predictions particularly in non-viral cirrhosis. Thus, we propose a recalibration and suggest candidate variables for an update to the model.
Lay Summary:  Patients with cirrhosis and more severe portal hypertension are at higher risk of non-tumoral portal vein thrombosis development. Acquired or inherited hemostatic disorders, as well as inflammatory status, do not seem to predict the development of portal vein thrombosis in patients with cirrhosis.
Lay Summary:  Intrahepatic cholangiocarcinoma is a highly aggressive cancer arising from epithelial cells lining the biliary tree, characterized by dissemination into the liver parenchyma via lymphatic vessels. Herein, we show that the proteins THBS1, THBS2 and PEDF, once released in the tumor microenvironment, inhibit vascular growth, while promoting cancer-associated lymphangiogenesis. Therefore, targeting THBS1, THBS2 and PEDF may be a promising strategy to reduce cancer-associated lymphangiogenesis and counteract the invasiveness of intrahepatic cholangiocarcinoma.
Lay Summary:  This study of treatments in patients with hepatocellular carcinoma found that selective internal radiation therapy (SIRT) has an adverse effect on liver function that may affect patient outcomes. Patients should be carefully selected before they undergo SIRT and the treatment technique should be optimised for maximum protection of non-target liver parenchyma.
Lay Summary:  Intratumor molecular heterogeneity is a key feature of tumorigenesis that is linked to treatment failure and patient prognosis. In this study, we present a single-cell atlas of liver tumors from patients treated with immunotherapy and describe intratumoral cell states and their hierarchical relationship. We suggest osteopontin, encoded by the gene SPP1, as a candidate regulator of tumor evolution in response to treatment.
    Liver Transplantation
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    Julien Vionnet, Rosa Miquel, Juan G. Abraldes, Jurate Wall, Elisavet Kodela, Juan-Jose Lozano, Pablo Ruiz, Miguel Navasa, Aileen Marshall, Frederik Nevens, Will Gelson, Joanna Leithead, Steven Masson, Elmar Jaeckel, Richard Taubert, Phaedra Tachtatzis, Dennis Eurich, Kenneth J. Simpson, Eliano Bonaccorsi-Riani, Sandy Feng, John Bucuvalas, James Ferguson, Alberto Quaglia, Julia Sidorova, Maria Elstad, Abdel Douiri, Alberto Sánchez-Fueyo
    Journal of Hepatology, Vol. 75, Issue 6, p1409–1419
Lay Summary:  A large proportion of liver transplant patients with normal liver tests have inflammatory liver lesions, which in 17% of cases are molecularly indistinguishable from those seen at the time of rejection. ALT, class II donor-specific antibodies and liver stiffness are useful in identifying patients with this form of subclinical rejection. We propose these markers as a useful tool to help clinicians determine if the immunosuppression administered is adequate.
    Experimental and Translational Hepatology
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    Taihua Yang, Marion Poenisch, Rajendra Khanal, Qingluan Hu, Zhen Dai, Ruomeng Li, Guangqi Song, Qinggong Yuan, Qunyan Yao, Xizhong Shen, Richard Taubert, Bastian Engel, Elmar Jaeckel, Arndt Vogel, Christine S. Falk, Axel Schambach, Daniela Gerovska, Marcos J. Araúzo-Bravo, Florian W.R. Vondran, Tobias Cantz, Nigel Horscroft, Asha Balakrishnan, Frédéric Chevessier, Michael Ott, Amar Deep Sharma
    Journal of Hepatology, Vol. 75, Issue 6, p1420–1433
    Open Access
Lay Summary:  Liver fibrosis and cirrhosis remain unmet medical needs and contribute to high mortality worldwide. Herein, we take advantage of a promising therapeutic approach to treat liver fibrosis and cirrhosis. We demonstrate that restoration of a key gene, HNF4A, via mRNA encapsulated in lipid nanoparticles decreased injury in multiple mouse models of fibrosis and cirrhosis. Our study provides proof-of-concept that mRNA therapy is a promising strategy for reversing liver fibrosis and cirrhosis.
Lay Summary:  The clinical efficacy of COVID-19 vaccines in immunocompromised patients is unknown. We performed a prospective study to evaluate immune responses to COVID-19 vaccines (Moderna, Pfizer or Johnson & Johnson) in 62 liver transplant recipients, 79 patients with cirrhosis and 92 with chronic liver diseases without cirrhosis. We found that 17.8% of liver transplant recipients, 3.8% of those with cirrhosis and 4.3% of those with chronic liver diseases without cirrhosis had undetectable antibody levels. In total, 61.3% of liver transplant recipients and 24% of those with chronic liver diseases (with or without cirrhosis) had poor antibody responses (undetectable or suboptimal). Liver transplantation, use of immunosuppressive medications and vaccination with a single dose of Johnson & Johnson vaccine were associated with poor antibody responses when adjusted for other factors.