Mechanisms of Disease: Mechanisms of Hepatic Fibrosis and Therapeutic Implications

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From Nature Clinical Practice Gastroenterology & Hepatology

Mechanisms of Disease: Mechanisms of Hepatic Fibrosis and Therapeutic

Implications

Posted 12/17/2004

L Friedman

Summary and Introduction

Summary

Hepatic fibrosis, or scarring of the liver, is emerging as a treatable

complication of advanced liver disease, following significant progress in

understanding its underlying mechanisms. Efforts have focused on the hepatic

stellate cell, as these cells can undergo 'activation' into proliferative

and fibrogenic myofibroblast-like cells during liver injury. Stimuli driving

stellate cell activation include hepatocellular necrosis due to oxidant

stress, apoptosis, and soluble growth factors. Specific lymphocyte subsets

can also stimulate fibrogenesis. A cascade of signaling and transcriptional

events in stellate cells underlies the fibrogenic response to liver injury,

with each step in the cascade being a potential target for antifibrotic

therapy. Disease-specific fibrogenic mechanisms have also been uncovered: in

hepatitis C, this may include direct stimulation of stellate cell activation

by viral infection; in nonalcoholic steatohepatitis, elevated levels of

leptin and increased leptin signaling by stellate cells increase

fibrogenesis. Determinants of fibrosis progression include both

environmental and genetic factors, with ongoing efforts to define specific

polymorphisms correlating with fibrosis progression rates. Human studies now

indicate that fibrosis and even cirrhosis could be reversible, especially if

the underlying disease is eradicated. A key challenge is to establish

noninvasive means of assessing fibrosis stage and progression using either

serum tests and/or imaging. In addition, endpoints of antifibrotic clinical

trials need to be established so that reliable evidence of benefit can be

identified. We are on the cusp of a new era in which antifibrotic therapies

could become important in treating chronic fibrosing liver disease.

Introduction

Hepatic fibrosis refers to the accumulation of interstitial or 'scar'

extracellular matrix after either acute or chronic liver injury. Cirrhosis,

the end-stage of progressive fibrosis, is characterized by septum formation

and rings of scar that surround nodules of hepatocytes. The composition of

extracellular matrix molecules in the fibrotic liver is similar to those of

other fibrosing parenchyma, including lung and kidney, and is also similar

among different etiologies of liver disease. Typically fibrosis requires

years or decades to become clinically apparent, but notable exceptions in

which cirrhosis develops over months may include pediatric liver disease

(e.g. biliary atresia), drug-induced liver disease, and viral hepatitis

associated with immunosuppression after liver transplantation.

Rapid progress in understanding the mechanisms of hepatic fibrosis

exemplifies how basic research has begun to yield meaningful prospects for

translation into new diagnostics and treatments for patients with liver

disease. These advances include the isolation and characterization of

fibrogenic cell types in liver, the clarification of general and

disease-specific pathogenic mechanisms, and the broader appreciation of the

natural history and reversibility of hepatic fibrosis. This article

highlights recent progress in the field and its impact on clinical practice,

and emphasizes persistent gaps in our knowledge that merit further study.

Recent reviews highlighting molecular mechanisms and historical aspects are

recommended to the reader for more detail.[1-5]

FULL TEXT: http://www.medscape.com/viewarticle/495340?src=mp