9th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 19-21 July 2007, Sydney, Australia

PATHOGENESIS OF HEPATIC FIBROGENESIS

Antiviral Therapy 2007; 12(Suppl. 2):L3 (abstract no. PL-01)

SL Friedman
Mount Sinai School of Medicine, New York, NY, USA

The understanding of hepatic fibrosis or the liver’s scarring response has emerged as a major focus of current research in hepatology, and has begun to yield meaningful progress in predicting the risk of fibrosis in chronic liver disease, assessing its severity non-invasively, and establishing antifibrotic therapies.

Hepatic stellate cells (HSC) are the primary source of extracellular matrix in normal and fibrotic liver. These resident perisinusoidal cells 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. Exciting progress has been made in understanding the molecular basis of this process. There have been major advances in defining pathways of activation, mediators and mechanisms of fibrosis resolution. These advances in pathogenesis have led to rational new approaches to antifibrotic therapies, including: 1) treating the underlying liver disease etiology; 2) hepatoprotection to reduce liver cell injury and oxidant stress; 3) downregulating stellate cell activation; 4) inhibiting cytokine driven pathways of stellate cell proliferation, contractility and fibrogenesis; 5) stimulating stellate cell apoptosis; and 6) directly degrading scar matrix. Clinical trials are underway attacking a number of these pathways, primarily in patients with HCV and NASH.

Another major advance in understanding the natural history of chronic liver disease, especially, viral hepatits and NASH, has been the recognition that fibrosis progression can be predicted based on genetic markers, and varies tremendously between patients, independent of viral load or genotype in HCV. Large scale studies have begun to identify host genetic polymorphisms that predict risk of fibrosis progression. Fibrosis is also greatly accelerated in patients with HIV/HCV coinfection, but is slowed by HAART therapy. The development of accurate, non-invasive markers of liver fibrosis has become an urgent priority in order to allow the evaluation of antifibrotic and antiviral drugs in clinical trials. Interest is accelerating in new modalities, as well as refining existing methods including serum assays, elastography (Fibroscan), proteomics and Ultrasound/CT/MRI. In particular, Fibroscan is as an outstanding test to diagnose cirrhosis, and ongoing studies are assessing its utility in tracking disease over time in lieu of liver biopsy, particularly in HIV/HCV coinfection and NASH.

Ultimately, advances in the understanding of the molecular biology of hepatic fibrosis are critical to the development of effective, targeted antifibrotic therapy that may benefit millions of patients with chronic liver disease worldwide.

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2007-07-24
PL-01

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