Unresolved basic issues in hepatology

Unresolved basic issues in hepatologyBasic research and comparative human medical advances during the last decades and centuries have significantly improved diagnostic and treatment modalities in Hepatology.However, the evolution of this area has sparked not only scientific and clinical benefits but also controversies.The focused series "Unresolved Basic Issues in Hepatology" contains 13 reviews from leading experts from Australia, Austria, Canada, China, France, Germany, India, UK and USA highlighting current perspectives on hot and often controversial discussed topics in the field of Hepatology (Figure 1).In their article "Revisiting hemochromatosis: genetic vs. phenotypic manifestations", Anderson and Bardou-Jacquet report about the high phenotypic variability in hereditary hemochromatosis that can be largely explained by a range of environmental, genetic and physiological factors.They strengthen the point that variations in penetrance between individuals might be due to the fact that some genes involved in the pathogenesis of iron homeostasis disorders are still not know yet and that both co-morbidities and genetic polymorphisms that do not affect iron levels per se could influence or determine the propensity of the disease.The review "Autoimmune hepatitis: is histology conclusive?" by Beer and Dienes critically discuss the diagnostic value of liver biopsy in the diagnosis and management of autoimmune hepatitis.The authors provide some clues on the histological difference between clinical subtypes of autoimmune hepatitis showing that a definitive diagnosis of autoimmune hepatitis is not possible by histology alone and should be better based on combined criteria including the presence of autoantibodies, immunoglobulin G elevations, and graded histopathology.Cai and Boyer discuss "The role of bile acids in cholestatic liver injury" focusing on their direct effects on hepatocytes, cholangiocytes, stellate cells and immune cells.From their contribution it became clear that despite the fundamental insights in the pathogenesis of cholestatic liver injury, important mechanistic details on the effects of bile acids on specific liver cells are still not understood.Ding and colleagues highlight the current knowledge on "Exosomes as therapeutic vehicles in liver diseases".They describe the role of exosomes and their cargo as potential therapeutic tools to treat or to alleviate liver injury caused by various factors.As the authors discuss, there are still many problems to be solved before the wealth of encouraging findings obtained with these membrane-bound extracellular vesicles in preclinical studies can be applied clinically.In the review "It's all about the spaces between cells: Role of extracellular matrix in liver fibrosis" Khurana and colleagues critically discuss the advances in the understanding of the physiological role of factors contributing to extracellular matrix homeostasis, turnover and impairment.Particularly, it is discussed how the knowledge of individual mediators can be harnessed for the therapy of hepatic fibrosis.In their article "Liver failure-future challenges and remaining questions" Lemmer and colleagues describe controversial aspects in the classification of liver failure.They propose that it is necessary to differentiate three types of liver failure, namely acute liver failure, acute-on-chronic liver failure, and acute-on-liver-cirrhosis that mainly can be discriminated by changes in coagulation factors and inhibitors.Melnik reviewed molecular mechanisms that may explain dairy-induced hepatocancerogenesis.In his article entitled "Dairy consumption and hepatocellular carcinoma risk" he highlights how abundant constitutes of milk proteins and milk exosomes and their cargo might contribute to the pathogenesis of hepatocellular carcinoma.Based on accumulating evidence from a large number of epidemiological and translational studies, he concluded that several milk products need to be listed as dairyrelated risk factors for hepatocellular carcinoma.The article "Non-alcoholic fatty liver diseases: current challenges and future directions" written by Roeb provides information about critical issues in the pathogenesis of non-alcoholic fatty liver disease (NAFLD).It summarizes comprehensively the actual knowledge about relevant risk factors and management strategies.In her article she nicely illustrates that key questions related to disease definition, diagnosis, therapy, and long-term management are still only partially answered.In line with this assumption, Rosso and colleagues argued that there is an urgent need to identify better biomarkers for the diagnosis of NAFLD.In their contribution "Diagnostic management of nonalcoholic fatty liver disease: a