Liver Fibrosis

Liver fibrosis is at the epicenter of clinical hepatology, contributing to most complications of chronic liver disease and often dictating long-term outcome. In the past three decades, there have been tremendous advances in the knowledge of the natural history as well as the genetic and environmental factors that influence the progression of liver fibrosis. Moreover, we have gained deep insight into fibrogenic cell types in the liver, identified several key molecular drivers that trigger fibrogenic responses, and developed improved methods to monitor fibrosis progression and regression. Current efforts are focused on translating our improved understanding of the underlying biological processes to clinical hepatology.

The recent achievements in the treatment of viral hepatitis have led the field to start refocusing on the next important challenges in hepatology. With the key role of fibrosis in clinical hepatology, increased appreciation of the concept of fibrosis reversibility, and recent Food and Drug Administration approval of antifibrotics in other organs, there is a revived enthusiasm about antifibrotic treatment in the field, which has led to the first large-scale antifibrotic trials. Ironically, the recent successes of new antivirals in hepatitis C may result in a large number of patients that are cured of the underlying disease, but not the accompanying fibrosis—further promoting interest in antifibrotic treatments. Moreover, the shift of the patient spectrum from viral hepatitis to increasing numbers of patients with nonalcoholic steatohepatitis (NASH) and the unchanged high number of patients with alcoholic liver disease (ALD) will require the basic and clinical research communities to better understand how fibrosis arises and how it can be treated in these settings.

In this issue of Seminars in Liver Disease, we not only focus on opportunities to translate our knowledge of liver fibrosis from the bench to bedside, but also discuss the many challenges that the field needs to address. Although large-scale studies with antifibrotics are on the way, identification of mechanisms of fibrosis, including disease-specific pathways and fibrogenic cell types, remains relevant in order to reveal additional targets. Hence, this issue covers both basic mechanisms of fibrogenesis as well as clinical aspects and translation studies. Rebecca Wells and Robert Schwabe review the role of different fibrogenic cell types in specific disease settings with a particular focus on recent fate-tracing studies and the role of hepatic stellate cells and portal fibroblasts. Michael Wallace, Scott Friedman, and Derek Mann discuss the concept of core versus disease-specific pathways and also review emerging profibrogenic pathways. Mechanisms underlying the resolution of liver fibrosis are reviewed by Prakash Ramachandran, John Iredale, and Jonathan Fallowfield. This contribution is followed by articles reviewing pathogenesis and clinical implication of fibrosis in the setting of nonalcoholic fatty liver disease (Anna Mae Diehl, Mariana Verdelho Machado, Paul Angulo) and ALD (Bin Gao, Ramon Bataller). The impact of novel antivirals on hepatitis C virus-induced fibrosis is discussed by Massimo Pinzani. Advances in the diagnostic assessment of liver fibrosis, and monitoring of fibrosis and fibrosis regression is highlighted by Keyur Patel, Pierre Bedossa, and Laurent Castera. Finally, Wajahat Mehal and Detlef Schuppan discuss current and future efforts to translate our knowledge of the underlying biology and pathophysiology into clinical treatments for liver fibrosis.

We dedicate this issue of Seminars to Paul Angulo, coauthor of the review on fibrosis in NASH, who continued to contribute to this review despite his illness, and who passed away shortly before publication of this issue. As part of this dedication, we would like to recognize Paul's contribution to the field, in particular his work on fatty liver disease.