Current and future anti-fibrotic therapies for chronic liver disease

Abstract

Chronic injury results in a wound healing response that eventually leads to fibrosis. The response is generalized, with features common among multiple organ systems. In the liver, various different types of injury lead to fibrogenesis, implying a common pathogenesis. Although several specific therapies for patients who have different liver diseases have been successfully developed, including antiviral therapies for those who have hepatitis B and hepatitis C virus infection, specific and effective antifibrotic therapy remains elusive. Over the past 2 decades, great advances in the understanding of fibrosis have been made and multiple mechanisms underlying hepatic fibrogenesis uncovered. Elucidation of these mechanisms has been of fundamental importance in highlighting novel potential therapies. Preclinical studies have indicated several putative therapies that might abrogate fibrogenesis. This article emphasizes mechanisms underlying fibrogenesis and reviews available and future therapeutics.

Figure 1. Stellate cell activation

The current consensus is that the key pathogenic feature underlying liver fibrosis and cirrhosis is activation of hepatic stellate cells. This process is complex, both in terms of the events that induce activation and the effects of activation. Multiple and varied stimuli participate in the induction and maintenance of activation, including, but not limited to cytokines, peptides, and the extracellular matrix itself. Key phenotypic features of activation include production of extracellular matrix, loss of retinoids, proliferation, of upregulation of smooth muscle proteins, secretion of peptides and cytokines (which have autocrine effects), and upregulation of various cytokine and peptide receptors (From reference 129). It is likely that other effector cells (fibroblasts, fibrocytes, bone marrow derived-cells), similarly undergo activation and contribute to the fibrogenic response. With permission, Rockey DC: Antifibrotic therapy in chronic liver disease. Clin Gastroenterol Hepatol 3:95, 2005