Lay Summaries - Volume 73 Issue 6

Lay Summary:  Since liver biopsy analysis plays such an important role in clinical studies of non-alcoholic steatohepatitis, it is important to understand the reliability of hepato-pathologist readings. We examined both inter- and intra-reader variability in a large data set of paired liver biopsies from a clinical trial. We found very poor inter-reader and modest intra-reader variability. This result has important implications for entry criteria, fibrosis stratification, and the ability to measure a treatment effect in clinical trials.
Lay Summary:  NFATc4 is activated in the non-alcoholic steatohepatitis of mice and patients. Inhibition of NFATc4 activation alleviates lipid deposition, inflammatory response, and fibrosis progression in the liver.
Lay Summary:  The liver is known for its unique immune functions. Herein, we identify a novel mechanism by which virus-infected hepatocytes can selectively eliminate themselves through reduced mitochondrial resilience to calcium challenge.
Lay Summary:  Over the past few years, the wide use of antiviral drugs that cure HCV has had a significant effect on patients being admitted to hospital. Most patients with HCV and cirrhosis are treated (and often cured) in the community and, thus, the number of hospital admissions because of severe forms of HCV has decreased drastically. HCV is no longer the first cause of admission into liver units and, in only a few years from now, it is likely to be only a residual cause of hospitalisation.
    Viral Hepatitis
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    Rong Fan, George Papatheodoridis, Jian Sun, Hamish Innes, Hidenori Toyoda, Qing Xie, Shuyuan Mo, Vana Sypsa, Indra Neil Guha, Takashi Kumada, Junqi Niu, George Dalekos, Satoshi Yasuda, Eleanor Barnes, Jianqi Lian, Vithika Suri, Ramazan Idilman, Stephen T. Barclay, Xiaoguang Dou, Thomas Berg, Peter C. Hayes, John F. Flaherty, Yuanping Zhou, Zhengang Zhang, Maria Buti, Sharon J. Hutchinson, Yabing Guo, Jose Luis Calleja, Lanjia Lin, Longfeng Zhao, Yongpeng Chen, Harry L.A. Janssen, Chaonan Zhu, Lei Shi, Xiaoping Tang, Anuj Gaggar, Lai Wei, Jidong Jia, William L. Irving, Philip J. Johnson, Pietro Lampertico, Jinlin Hou
    Journal of Hepatology, Vol. 73, Issue 6, p1368–1378
    Open Access
Lay Summary:  In this international collaboration, we developed and externally validated a simple, objective and accurate prognostic tool (called the aMAP score), that involves only age, male, albumin–bilirubin and platelets. The aMAP score (ranged from 0 to 100) satisfactorily predicted the risk of hepatocellular carcinoma (HCC) development among over 17,000 patients with viral and non-viral hepatitis from 11 global prospective studies. Our findings show that the aMAP score had excellent discrimination and calibration in assessing the 5-year HCC risk among all the cohorts irrespective of aetiology and ethnicity.
Lay Summary:  One principal characteristic of autoimmune hepatitis (AIH), like for many other autoimmune diseases, is the accumulation of autoantibodies produced by B lymphocytes following their interaction with autoreactive CD4 T lymphocytes. In this study, we identified and characterised with high resolution these CD4 T cells. This will be essential to track, delineate, and potentially target them during AIH.
Lay Summary:  Biliary atresia is a poorly understood and devastating obstructive bile duct disease of newborns. It is often diagnosed late, is incurable and frequently requires liver transplantation. Using human and mouse ‘liver mini-organs in the dish’, we unexpectedly identified beta-amyloid deposition – the main pathological feature of Alzheimer's disease and cerebral amyloid angiopathy – around bile ducts in livers from patients with biliary atresia. This finding reveals a novel pathogenic mechanism that could have important diagnostic and therapeutic implications.
Lay Summary:  We have identified the mechanisms by which non-selective beta-blockers could impair survival in patients with refractory ascites. We show that peripheral vasodilation and sympathetic activation lead to increased left ventricle systolic function in patients with cirrhosis and ascites, which acts as an adaptive mechanism to maintain renal perfusion. When ascites becomes refractory, this compensatory cardiac response to vasodilation is critically dependent on sympathetic hyperactivation and is hardly able to maintain renal perfusion. In this setting, β-blockade blunts the sympathetic overdrive of cardiac function, hampers cardiac output, lowers renal perfusion pressure below the critical threshold and impairs renal function.
Lay Summary:  As a major complication of cirrhosis, clinically significant portal hypertension (CSPH) is associated with adverse clinical outcomes. Herein, we show that CSPH persists at 96 weeks in just over half of patients with HCV-related cirrhosis, despite HCV elimination by direct-acting antivirals. Despite viral cure, patients with CSPH at the start of antiviral treatment remain at long-term risk of hepatic complications and should be managed accordingly.
Lay Summary:  Acute-on-chronic liver failure (ACLF) is a condition marked by multiple organ failures in patients with cirrhosis and is associated with a high risk of death. Liver transplantation may be the only curative treatment for these patients. A score called model for end-stage liver disease-sodium (MELD-Na) helps guide donor liver allocation for transplantation in the United States. The higher the MELD-Na score in a patient, the more likely that a patient receives a liver transplant. Our study data showed that MELD-Na score underestimates the risk of dying at 90 days in patients with ACLF. Thus, physicians need to start liver transplant evaluation early instead of waiting for a high MELD-Na number.
    Hepatic and Biliary Cancer
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    Etienne Audureau, Fabrice Carrat, Richard Layese, Carole Cagnot, Tarik Asselah, Dominique Guyader, Dominique Larrey, Victor De Lédinghen, Denis Ouzan, Fabien Zoulim, Dominique Roulot, Albert Tran, Jean-Pierre Bronowicki, Jean-Pierre Zarski, Ghassan Riachi, Paul Calès, Jean-Marie Péron, Laurent Alric, Marc Bourlière, Philippe Mathurin, Jean-Frédéric Blanc, Armand Abergel, Olivier Chazouillères, Ariane Mallat, Jean-Didier Grangé, Pierre Attali, Louis d'Alteroche, Claire Wartelle, Thông Dao, Dominique Thabut, Christophe Pilette, Christine Silvain, Christos Christidis, Eric Nguyen-Khac, Brigitte Bernard-Chabert, David Zucman, Vincent Di Martino, Angela Sutton, Stanislas Pol, Pierre Nahon for the ANRS CO12 CirVir group
    Journal of Hepatology, Vol. 73, Issue 6, p1434–1445
Lay Summary:  Patients with HCV-related cirrhosis must be included in liver cancer surveillance programs, which rely on ultrasound examination every 6 months. Hepatocellular carcinoma (HCC) screening is hampered by sensitivity issues, leading to late cancer diagnoses in a substantial number of patients. Refining surveillance periodicity and modality using more sophisticated imaging techniques such as MRI may only be cost-effective in patients with the highest HCC incidence. Herein, we demonstrate how machine learning algorithms (i.e. data-driven mathematical models to make predictions or decisions), can refine individualized risk prediction.
Lay Summary:  Abnormally activated mammalian target of rapamycin (mTOR) signaling is associated with poor tumor differentiation, early tumor recurrence and worse overall survival in patients with hepatocellular carcinoma. Herein, we identify low VEPH1 expression as a potential cause of abnormally activated mTOR signaling in hepatocellular carcinoma tissues. mTOR inhibitors could thus be an effective treatment option for patients with HCC and low VEPH1 expression.
Lay Summary:  Certain tests may be used to provide a picture of how a tumour is escaping the immune system, allowing it to continue to grow and create more tumours. Therapies such as nivolumab are designed to help the immune system fight the tumour. These tests may be used to determine how effective such therapies will be in the treatment of advanced liver cancer.
Lay Summary:  Herein, we have identified the role of IRAK4 kinase activity in the development of alcohol-induced liver injury in mice. Hepatocyte-specific IRAK4 is associated with an acute phase response and release of proinflammatory cytokines/chemokines, which synergistically exacerbate alcohol-induced hepatocyte cell death ex vivo. Pharmacological inhibition of IRAK4 kinase activity effectively attenuates alcohol-induced liver injury in mice and could have therapeutic implications.
Lay Summary:  Nogo deficiency blocks high-carbohydrate diet-induced glucose intolerance and insulin resistance, while increasing glucose/lipid utilisation and energy expenditure. Thus, reduction of Nogo expression protects against high-carbohydrate diet-induced body-weight gain, hepatic lipid accumulation and the associated metabolic disorders, indicating that approaches inhibiting Nogo expression can be applied for the treatment of diseases associated with metabolic disorders.