Fibrosis in Patients with Hepatitis C: Detection and Significance: Detection and Significance

Thierry Poynard, M.D.; Ph.D.; Vlad Ratziu, M.D.; Yves Benmanov, M.D.; Vincent Di Martino, M.D.; Pierre Bedossa, M.D., Ph.D.; Pierre Opolon, M.D.

Semin Liver Dis. 2000;20(1) 

In This Article

Fibrosis Stages and Necroinflammatory Activity Grades

Activity (necroinflammation) and fibrosis are two major histologic features of chronic hepatitis C included in different proposed classifications. One of the few validated scoring systems is called the METAVIR scoring system. This system assesses histologic lesions in chronic hepatitis C using two separate scores, one for necroinflammatory grade (A for activity) and another for the stage of fibrosis (F). These scores are defined as follows; stages of fibrosis (F) (Fig. 1): F0, no fibrosis; F1, portal fibrosis without septa; F2, portal fibrosis with rare septa, F3, numerous septa without cirrhosis; F4, cirrhosis. Grade for activity (A): A0, no histologic necroinflammatory activity; A1, minimal activity, A2, moderate activity, A3, severe activity. The degree of activity was assessed by integration of the severity of the intensity of both piecemeal (periportal) necrosis and lobular necrosis as described in a simple algorithm. The intra- and interobserver variations of this METAVIR scoring system are lower than those of the widely used Knodell scoring system. For METAVIR fibrosis stages there is an almost perfect concordance (kappa = 0.80) among pathologists.

As did others, we observed that fibrosis stage and inflammatory grade were correlated. However, for 36% of patients, there was a discordance (178 of 500). If recommendations for treatment had been based on activity grades, 56% of patients without significant activity (119 of 214) would not have been treated despite significant fibrosis. In these patients who were infected for more than 10 years, fibrosis progression was therefore not related to significant activity, which also raises questions concerning the pathophysiology of fibrosis. The other discordant cases were 59 patients with nonsignificant fibrosis despite significant activity. This observation raises the question of the utility of treatment of significant inflammatory damages if fibrosis does not occur. To summarize, clinicians should not take "significant activity" as a surrogate marker of "severe disease." Fibrosis stage is the result of the imbalance between synthesis and degradation of extracellular matrix components. Hepatic stellate cells are the major cell types involved in extracellular matrix production (i.e., collagens, fibronectin, and laminin). Although hepatic stellate cells produce extracellular matrix under the influence of various stimuli (growth factors, cytokines, and lipid peroxydation products), they also produce a set of matrix metalloproteinases (MMPs) that control degradation. MMPs are a family of related zinc-dependent endopeptidases capable of degrading all extracellular matrix components, playing a major role in extracellular matrix remodeling. Finally, proteolytic activity of MMPs can be inhibited by the tissue inhibitors of metalloproteinases, a group of proteins also produced by hepatic stellate cells. Activity grade, which represents necrosis is not a good predictor of fibrosis progression. In fact, fibrosis alone is the best marker of ongoing fibrogenesis. So far there is no study demonstrating clearly that activity grades are predictive of fibrosis progression independently of fibrosis stage.


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