Challenges in Hepatic Fibrosis

Scott L. Friedman  Mount Sinai School of Medicine, New York, United States

The understanding of hepatic fibrosis, or the liver’s scarring  response has emerged as a major focus of current research in hepatology. There are several challenges evolving in the field. These include: (1)  We need better markers of fibrosis stage and disease activity,  (2) Which patients with chronic liver disease are most likely to progress?  (3) What makes cirrhotics decompensate?  (4)  We need a ‘proof-of-concept’ antifibrotic trial.

Hepatic stellate cells (HSC) are the primary source of extracellular matrix in normal and fibrotic liver. They undergo an “activation” or transdifferentiation in progressive stages yielding a cell type that is highly proliferative, fibrogenic and contractile. Activation of HSCs is the central event of fibrogenesis, combined with recruitment of other mesenchymal cells that also become activated myofibroblasts. Exciting progress has been made in understanding the molecular basis of this process. Major advances include: (1) elucidation of effects of key cytokines and their signaling pathways in HSC;  (2) understanding the transcriptional regulation of HSC activation; (3) characterization of matrix proteases and their inhibitors; (4) demonstration of apoptosis as an important event in resolution of hepatic fibrosis and identification of its mediators; (5) elucidation of the complex and dynamic interaction between HSC and matrix; (6) understanding of the role of other cellular elements in hepatic fibrosis and their interaction with HSC. In addition, clinical studies have begun to identify host genetic polymorphisms that may soon predict the risk of fibrosis progression.

Several new areas of rapid progress in the past 5~10 years have also taken root, including:  (1) identification of different fibrogenic populations apart from resident stellate cells, for example portal fibroblasts, fibrocytes and bone-marrow derived cells, as well as cells derived from epithelial mesenchymal transition; (2) emergence of stellate cells as finely-regulated determinants of hepatic inflammation and immunity;  (3) elucidation of multiple pathways controlling gene expression during stellate cell activation including transcriptional, post-transcriptional and epigenetic;  (4)  recognition of disease-specific pathways of fibrogenesis; (5) re-emergence of hepatic macrophages as determinants of matrix degradation in fibrosis resolution and the importance of matrix cross linking and scar maturation in determining reversibility;  (6)  hints that hepatic stellate cells may contribute to hepatic stem cell behavior, cancer and regeneration.  Clinical and translational implications of these advances have become clear, and have begun to impact significantly upon the management and outlook of patients with chronic liver disease.

The impact of cirrhosis on accelerating the risk of HCC is well established. At least six features of cirrhosis could predispose to HCC.  These include:  (1)  Enhanced oxidative stress and DNA damage,  (2) Matrix bound growth factors that promote survival and mitogenesis of hepatocytes, (3)  Telomere shortening,  (4)  Enhanced inflammation associated with fibrosis, (5) Reduced NK cell mediated killing of tumor cells,  (6)  Activated stellate cells may promote stem cell expansion.