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Fibrosis and Disease Progression in Hepatitis C

Patrick Marcellin, Tarik Asselah, and Nathalie Boyer

The progression of fibrosis in chronic hepatitis C determines the ultimate prognosis and thus the need and urgency of therapy. Fibrogenesis is a complex dynamic process, which is mediated by necroinflammation and activation of stellate cells. The liver biopsy remains the gold standard to assess fibrosis. Scoring systems allow a semiquantitative assessment and are useful for cross-sectional and cohort studies and in treatment trials. The rate at which fibrosis progresses varies markedly between patients. The major factors known to be associated with fibrosis progression are older age at infection, male gender, and excessive alcohol consump- tion. Viral load and genotype do not seem to influence significantly the progression rate. Progression of fibrosis is more rapid in immunocompromised patients. Hepatic steatosis, obesity, and diabetes may also contribute to more rapid progression of fibrosis. There are no tests that reliably predict the rate of progression of fibrosis in an individual patient. High serum alanine aminotransferase (ALT) levels are associated with a higher risk of fibrosis progression, and worsening of fibrosis is uncommon in patients with persistently normal serum aminotransferase levels. Serum markers for fibrosis are not reliable and need to be improved and validated. Liver biopsy provides the most accurate information on the stage of fibrosis and grade of necroinflammation, both of which have prognostic significance. Re- peating the liver biopsy, 3 to 5 years after an initial biopsy is the most accurate means of assessing the progression of fibrosis. (HEPATOLOGY 2002;36:S47-S56.)

T he typical histological features of chronic hepati- tis C are variable degrees of hepatocellular necro- sis and inflammation (referred to as the activity or grade of disease) and fibrosis (referred to as stage of dis- ease). While the activity of the liver disease can fluctuate, worsening and improving over time, the stage of fibrosis is believed to be progressive and largely irreversible. Impor- tantly, it is the progression of fibrosis that ultimately leads to architectural distortion of the liver and cirrhosis. For these reasons, the rate of progression of fibrosis is the defining feature of the natural history of chronic hepa- titis C.

In chronic hepatitis C, the rate at which fibrosis progresses varies markedly from person to person and may

vary over time. In some individuals, the rate of fibrosis is rapid so that cirrhosis eventually develops and, with it, the major complications of hepatitis C: end-stage liver dis- ease, portal hypertension, and hepatocellular carcinoma. In other patients, fibrosis does not develop or progresses so slowly that after decades of infection, little or no fibro- sis is found on liver biopsy. Such patients are unlikely to suffer the long-term complications of chronic hepatitis C. For these reasons, assessment of the stage and rapidity of progression of fibrosis are helpful in determining the prognosis and the need of therapy in the individual pa- tient. Factors associated with fibrosis progression in hep- atitis C are not well defined and the role of the accompanying necroinflammatory activity is still contro- versial.

Abbreviations: HCV, hepatitis C virus; TGF-, transforming growth factor-; HAI, histology activity index; ALT, alanine aminotransferase; AST, aspartate ami- notransferase; HIV, human immunodeficiency virus.

From the Service d’He´patologie and INSERM U 481, Hoˆpital Beaujon, Clichy, France.

Dr. Marcellin is a consultant for Hoffmann-La Roche, Gilead Sciences, Glaxo- SmithKline, Bristol-Meyer-Squibb, Triangle Pharmaceuticals, Vertex, Bayer and Ortho Diagnostics and has received research grants from Hoffmann-LaRoche, Schering Plough Research Institute, and Bayer.

Address reprint requests to: Professor Patrick Marcellin, M.D., Hoˆpital Beaujon, Service d’He´patologie, 100, Blvd du Ge´ne´ral Leclerc, 92110, Clichy, France. E-mail: marcellin@bichat.inserm.fr; fax: 33-1-47-30-94-40.

Copyright © 2002 by the American Association for the Study of Liver Diseases. 0270-9139/02/3605-1006$35.00/0 doi:10.1053/jhep.2002.36993

Fibrogenesis

Chronic infection with hepatitis C virus (HCV) typi- cally induces injury and inflammation of the liver, which appear to be responsible for the associated fibrogenesis. Fibrogenesis is a dynamic process characterized by the synthesis of constituents of the extracellular matrix, which is a complex mixture of glycoproteins (collagen, elastin, fibronectin, laminin) and proteoglycans organized in a tridimensional network.1 Fibrogenesis is a non-specific mechanism, which lasts as long as injury persists in the liver and is believed to help limit the extension of the

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