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Serum Markers of Fibrosis. Serum biochemical tests do not reliably predict the stage of fibrosis. Non-specific tests are used in clinical practice, such as serum AST/ALT ratio,53,54 globulin and glutamyl transpeptidase levels, platelet count,54 or ferritin levels. Scores based on combi- nations of several biochemical tests have been assessed to predict liver fibrosis.55 Many studies have assessed the correlation between liver fibrosis serum markers of fibro- sis, such as type III procollagen peptide,56 type IV colla- gen 7S domain,56 hyaluronic acid,57 laminin,58 TGF-,59 and metalloproteinases or metalloproteinase inhibi- tors.59,60 Serum hyaluronic acid seems the best of these serum markers. None of these markers have been used in longitudinal studies to assess progression of fibrosis pro- spectively.

Currently available serum markers of fibrosis are not reliable, particularly in discriminating between mild and moderate degrees of fibrosis, and these tests do not have a good predictive value when used in an individual patient. Further studies are needed to determine and validate more reliable serum markers of fibrosis.

Necroinflammatory Activity on Liver Biopsy. The association between fibrosis progression and the necroin- flammatory activity scores on liver biopsy is controversial. On a single liver biopsy, there is little or no correlation between severity of the necroinflammatory activity and degree of fibrosis.15,16 However, necroinflammatory ac- tivity is a dynamic process in chronic hepatitis C and may fluctuate over time. The activity score likely reflects the severity of necrosis and inflammation at a given point. In some cross-sectional studies and in most longitudinal studies, the degree of necroinflammatory activity has been associated with the subsequent progression of fibro- sis18,19,61 (Table 2). There is reason to believe that the necroinflammatory process is implicated in the fibrogen- esis process, because the stellate cells are activated around the necroinflammatory lesions.62 Thus, severe degrees of inflammatory activity predict worsening of hepatic fibro- sis and constitute an indication for therapy independent of the current level of fibrosis.

Fibrosis. The stage of fibrosis on the initial biopsy was associated with progression of fibrosis in some stud- ies.10,18,61 This observation is consistent with the hypoth- esis that fibrosis may accelerate with duration of infection and/or that fibrosis by itself might enhance the fibrogen- esis process. However, estimates of the rate of fibrosis progression from a single liver biopsy have not always been predictive of subsequent progression or worsening of fibrosis in longitudinal studies.

Steatosis. Recently, the association between steatosis and the stage of fibrosis has been emphasized. In a cross- sectional study of 148 patients with chronic hepatitis C,

HEPATOLOGY, November 2002

the amount of steatosis was independently associated with the stage of fibrosis (P .03).48 At issue was whether the steatosis per se contributed to worsening of fibrosis. Ste- atosis on liver biopsy correlated significantly with obesity as measured by BMI (P .0001), and obesity, insulin resistance, or diabetes may have been the factors most responsible for worsening of liver disease. In another cross-sectional study of 211 patients, there was a signifi- cant association between the grade of steatosis and the stage of fibrosis (P .001) and the grade of necroinflam- mation (P .007).46 The grade of steatosis was associated with the BMI in patients with genotype 1 (P .001), but was independent of obesity in patients with HCV geno- type 3 infection (P .01). The mechanisms responsible for the association between steatosis and fibrosis are un- known. Some patients may have non-alcoholic steato- hepatitis due to obesity and metabolic disorders in addition to having chronic hepatitis C and the concur- rence of the two diseases may be synergistic in causing hepatic fibrosis. Alternatively, steatosis may itself worsen the fibrogenic stimuli that accompany chronic hepatitis C. Finally, steatosis may be the consequence of more se- vere cell injury and necroinflammation in chronic hepa- titis C (especially in patients infected with HCV genotype 3) and thus may be the effect of the more severe disease activity, rather than the direct cause of the worsening fibrosis. Direct cytopathogenic effects of the virus (espe- cially genotype 3) causing steatosis cannot be ruled out. At present, these hypotheses are all equally possible.


In the majority of patients with chronic hepatitis C, the progression of fibrosis is insidious and slow. Only a mi- nority of patients has rapid progression of fibrosis with early development of cirrhosis. Current knowledge on the factors that are responsible and that correlate with more rapid progression of fibrosis is limited, because it is based largely on cross-sectional studies using mathematical modeling and on a few, small scale prospective or retro- spective longitudinal studies of changes in hepatic fibro- sis. Carefully conducted prospective studies on untreated patients, mainly patients with mild disease in whom ther- apy is not indicated, are needed to validate the current hypothesis on the progression of fibrosis.

The mechanisms and factors associated with progres- sion of fibrosis are poorly understood. Older age, male gender, excessive alcohol consumption, overweight, and immune deficiency are associated with more rapid pro- gression of fibrosis. Therefore, counseling of patients should include abstinence from alcohol or minimal, oc- casional consumption and dietary measures to reduce overweight and metabolic disorders.

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