Hepatic Fibrosis -- Role of Hepatic Stellate Cell Activation

Scott L. Friedman, MD

In This Article

Clinical Aspects of Hepatic Fibrosis

Fibrosis Progression and Reversibility

The rate of progression of fibrosis in an individual patient with chronic liver disease cannot be predicted with certainty. However, some general rules apply, as discussed below.

1. Fibrosis usually requires at least several months to years of ongoing insult. In adults, two exceptions to the latter are veno-occlusive disease and mechanical biliary obstruction, in which cases fibrosis can progress more rapidly. In patients with hepatitis C virus (HCV) infection, a median time to progression overall has been estimated at 30 years,[46] with a range from 13 to 42 years, depending on the presence of other risk factors. Independent risk factors for more rapid progression include alcohol abuse, older age at the time of infection, and male sex.[46] Even in patients with similar risk factors, some variability in progression was noted, which also may reflect host phenotype.

2. Severity of inflammation and injury usually correlate with rate of progression, as documented in studies of alcoholic liver disease and hepatitis C.[46] No independent correlation with HCV genotype and fibrosis has been observed in the largest series to date.[46]

3. Concurrent hepatic insult by more than 1 agent is synergistic for the progression of fibrosis. This has been especially well documented in patients with HCV infection who abuse alcohol,[46] but is also true for viral coinfection, including hepatitis B virus (HBV) infection with either hepatitis C or delta viruses,[47] as well as HCV with HIV.[48]

Iron overload and increased steatosis are also associated with increased fibrosis in patients infected with HCV[27] or who have nonalcoholic steatohepatitis (NASH). Other risk factors for fibrosis in patients with NASH include older age, obesity, and presence of diabetes mellitus.[49]

4. The precise moment at which fibrosis becomes irreversible is not known, either in terms of a histologic marker or a specific change in the matrix composition or content. It is important to realize that even advanced stages of fibrosis/cirrhosis may be reversible as clinical trials of antifibrotics emerge. Well-documented reversibility of cirrhosis has been reported in a number of diseases, including alcoholic liver disease, biliary obstruction, HBV following treatment with antivirals, and even HCV following response to interferon/ribavirin.

5. Host genotype is an intrinsic determinant of fibrosis progression Efforts are under way to exploit the human genome sequencing in order to identify polymorphisms that predict more rapid fibrosis in chronic liver disease. Identification of host immune factors contributing to fibrosis could represent an important insight into the pathogenesis of fibrosis in humans.


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