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Fig. 1. Progression of fibrosis from periportal fibrosis to cirrhosis according to the Metavir scoring system.9 F1, portal and periportal fibrosis only; F2, periportal fibrosis with few septa; F3, septal fibrosis and bridging without cirrhosis; F4, cirrhosis. PS, portal areas; CLV, centrolobu- lar veins. (Reprinted with permission.63)

inflammatory reaction. Fibrosis, therefore, is a physio- logic mechanism, which is at first beneficial, but which can become pathological if the viral infection and chronic hepatocellular injury persist.

Fibrosis is characterized by the deposition of collagen and other extracellular matrix proteins and their organi- zation in complex polymers, which are insoluble and in- duce loss of the liver architecture.2 In all forms of chronic hepatitis, including chronic hepatitis C, active fibrosis be- gins around the portal areas (periportal or zone 1 fibrosis) and gradually extends out into the lobules towards the central veins (zone 3) with septa formation and then bridging fibrosis3-5 (Fig. 1). The final stage of fibrosis constitutes cirrhosis with extensive fibrosis linking portal and central areas and nodular regeneration of the liver parenchymal.

Collagen and matrix proteins that constitute fibrosis are largely produced by activated hepatic stellate cells.6,7 The stellate cells are activated from a quiescent lipocyte phenotype to a fibroblastic phenotype. The activation oc- curs in 2 phases: initially activation of stellate cells by cytokines, chemokines, and other signalling molecules in- duced by the inflammatory process, followed by trans- formation of the stellate cells into a myofibroblastic phenotype, in which the cell can proliferate, attract leu- kocytes, and produce extracellular collagen and matrix proteins.

The steps in stellate cell activation and transformation have been demonstrated to occur in chronic hepatitis C.8 The major fibrogenic cytokine, transforming growth fac- tor (TGF)-, is increased in expression in the liver in patients with chronic hepatitis C, and mRNA levels for

HEPATOLOGY, November 2002

this cytokine are also increased.9,10 Serum levels of TGF-are present in increased amounts in patients with chronic hepatitis C,9,10 and levels of connective tissue growth fac- tor, which are associated with the expression of TGF-, are also markedly increased, serum levels correlating with the degree of liver fibrosis.11

During the fibrogenesis process, a basal membrane ap- pears separating the hepatocytes from sinusoidal blood and perturbing the exchange of nutrients between blood and hepatocytes, a process known as capillarization of the sinusoids. Also, the accumulation of the fibrosis compo- nents in the extracellular matrix is responsible for the storage of very reactive molecules (growth factors and cy- tokines) in an inactive form, which may be activated in certain circumstances.11 In addition, during the progres- sion of fibrosis, there is a quantitative increase of the extracellular matrix, but also qualitative changes in repar- tition of each different component. Indeed, liver fibrosis is characterized by the transformation from normal extra- cellular matrix (basal membrane) into a reticulated and dense matrix (fibrillar type), which is much more resistant to enzymatic degradation.

Assessment of Stage of Fibrosis

Liver biopsy remains the gold standard for assessment of hepatic fibrosis. Several systems for scoring liver fibrosis have been proposed, each based on visual assessment of collagen staining of liver biopsy samples. The more fre- quently used systems are the histology activity index (HAI: Knodell score),12 the Ishak modification of the HAI score,13 and the Metavir score.14

The HAI system scores necroinflammatory activity from 0 to 18 assessing periportal necrosis and inflamma- tion (0 to 10), lobular necrosis and inflammation (0 to 4), and portal inflammation (0 to 4).12 Fibrosis in the HAI system is staged as 0, 1, 3, or 4, with 1 indicating portal fibrosis only, 3 indicating bridging fibrosis, and 4 cirrho- sis. The discontinuous scale was used initially to allow for clear separation of mild (1) from extensive (3) fibro- sis, which was believed to have important prognostic value. The HAI system is simple and has been widely used, particularly in the large multicenter, registration trials of interferon and ribavirin combination therapy of chronic hepatitis C. However, the intra- and interob- server reproducibility of the HAI is only fair, and the lack of a score for stages between mild (1) and severe (3) fibrosis is problematic. In addition, the discontinuous scale complicates statistical analysis in clinical trials.

Ishak et al.13 have proposed a modification of the HAI scoring system, which uses similar scores for necroinflam- matory changes (activity: 0 to 18), but scores fibrosis on a scale from 0 to 6 with no missed numbers. Scores of 1 and

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