Patrick Marcellin, MD

NIH Consensus Development Conference on
Management of Hepatitis C: 2002 

Bethesda, Maryland
June 10-12, 2002

Chronic infection with HCV is associated with the typical histological features of chronic hepatitis including hepatocellular necrosis and inflammation (activity or grade) and fibrosis (stage). While the activity of the chronic liver disease can fluctuate over time, the stage of fibrosis is believed to be progressive and largely irreversible. In chronic hepatitis C, the rate at which fibrosis progresses varies markedly. In some individuals, fibrosis ultimately leads to cirrhosis, which is associated with the major complications of the liver disease: portal hypertension, liver failure, and hepatocellular carcinoma. In others, fibrosis does not appear to progress even after decades of infection. For these reasons, assessment of the stage and rapidity of progression of fibrosis can be helpful in determining the prognosis and the need for therapy in the individual patient. Factors associated with fibrosis progression are not well defined and the role of necroinflammatory activity is still controversial.

Assessment of the Stage of Fibrosis

Liver biopsy remains the gold standard to assess fibrosis. Several systems for scoring liver fibrosis have been proposed, each based upon visual assessment of portal and periportal fibrosis. The more frequently used systems are the Histology Activity Index (HAI: Knodell score), the Ishak modification of the HAI score, and the METAVIR. The HAI scoring system ranges from 0 to 22 and fibrosis is staged as 0, 1, 3, and 4. This discontinous scale was developed to allow for clear separation of mild (1+) from extensive (3+) fibrosis which has important prognostic value. The HAI system is simple and has been widely used, particularly in the large multicenter trials of interferon and ribavirin therapy of chronic hepatitis C. However, the intra- and inter-observer reproducibility of the HAI is not very good and distinction between stages 1 and 3 may be difficult. In addition, its discontinous scale complicates statistical analysis in clinical trials.

The modification of the HAI scoring system proposed by Ishak et al. is more sensitive in assessing fibrosis. Fibrosis stage is scored continuously from 0 to 6, which permits a better assessment of the effect of therapy on fibrosis. The Ishak score is better validated and gives a more accurate assessment of fibrosis. The METAVIR scoring system is simple; fibrosis stages are scored continuously from 0 to 4. This system has been carefully validated in large groups of patients with chronic hepatitis C and has shown good intra- and inter-observer reproducibility. Important limitations of these scoring systems should be emphasized. Hepatic fibrosis may not be homogenous throughout the liver and the liver specimen obtained by needle biopsy may not accurately reflect the overall average degree of fibrosis. The reliability of the assessment of fibrosis stage increases with the size of the liver sample. In most studies, a minimum length of 10 mm is required. Regardless of biopsy length, however, fibrosis may be underestimated and cirrhosis missed in some patients.

Factors Associated With the Stage of Fibrosis

Most cross-sectional studies of large numbers of liver biopsies have shown that the stage of fibrosis is associated with patient age, the age at onset of infection, male sex, a history of heavy alcohol consumption, and the presence of immune deficiency, such as HIV co-infection or immunosuppressive therapy. The mechanisms by which age and sex affect the degree of fibrosis are not known. Alcohol, which by itself can cause liver disease and fibrosis, may worsen fibrosis in hepatitis C at amounts that are not injurious in non-infected persons, but the amount of alcohol beyond which the progression of fibrosis is increased is unknown.

Serum biochemical tests do not reliably predict the stage of fibrosis. Currently available, indirect serum markers of fibrosis are not reliable, particularly in discriminating between mild and moderate degrees of fibrosis. In cross-sectional studies, serum alanine and aspartate aminotransferase (ALT and AST) levels do not correlate well with fibrosis. However, patients with documented, persistently normal ALT levels usually have mild degrees of hepatitis and either no or mild stages of fibrosis. The association between fibrosis stage and the necroinflammatory activity scores on liver biopsy is controversial. Necroinflammatory activity is a dynamic process in chronic hepatitis C and may fluctuate over time. Therefore, the activity score reflects the severity of necrosis and inflammation at a given point.

Factors Associated With Progression of Fibrosis

From retrospective studies and from some prospective studies done in patients infected by blood transfusion at a relatively older age, it is estimated that 20 percent of patients with chronic hepatitis C develop cirrhosis within 20 years of onset. In contrast, studies of cohorts of women who did not drink alcohol and who were infected by Rh immune globulin at a young age indicated that fewer than 5 percent developed cirrhosis within 20 years. These natural history studies validate the importance of age, sex, and alcohol intake in progression of fibrosis. Cross-sectional studies using mathematical modelling performed on cohorts of patients with a single liver biopsy suggest that the average rate of progression of fibrosis in chronic hepatitis C is 0.133 METAVIR points per year. Based on this rate, the estimate is that cirrhosis  develops in the average patient after 30 years. The average delay to the development of cirrhosis ranges from 13 years in infected men aged 40 or more years who drink more than 50 g of alcohol to 42 years in infected women under 40 years of age who do not drink alcohol. Furthermore, the progression of fibrosis is probably not linear. For instance, the time required to progress from stage 0 to 2 may be far longer than the time required to progress from stage 3 to 4. Moreover, fibrosis progression may accelerate with age (particularly after the age of 50). Finally, fibrosismay remain mild and stable for decades and may even regress spontaneously in some patients.

The progression of fibrosis is difficult to predict in the individual patient particularly based upon assessment at one point in time. There are no good clinical, biochemical, or virological tests that predict progression of fibrosis. High serum ALT levels have been associated with more active liver disease and more rapid progression of fibrosis in some prospective studies, which supports the use of monitoring of ALT levels in assessing prognosis and need for therapy. However, the validity of this approach and the level above which the ALT elevations are predictive of more rapid progression is not known. Virological factors such as serum HCV RNA level and HCV genotype are not predictive of fibrosis. Genotype 3 is associated with more liver steatosis than other genotypes, and steatosis itself, as well as other metabolic factors (such as lipid disorders, obesity, insulin resistance, and diabetes) may also predispose to more rapid progression of fibrosis.

Repeat liver biopsy is the only reliable means of assessing the progression of fibrosis and is commonly recommended every 3 to 5 years in untreated patients. A second liver biopsy can distinguish patients with rapidly progressive fibrosis, but may also merely indicate that the initial biopsy underestimated the degree of fibrosis. Overall, the risk of progression of fibrosis of more than one point in a 3 to 5 year period is low. In patients with factors associated with a higher risk of progression such as age beyond 50 years, alcohol consumption, or high serum ALT levels, liver biopsy may be recommended more frequently (2 to 3 years); in contrast, in the younger patient with no other risk factors, liver biopsies may be performed less frequently (every 5 to 6 years).

References

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2. Bedossa P, Poynard T. The METAVIR cooperative study group. An algorithm for the grading of activity in chronic hepatitis C. Hepatology 1996;24:289–93.

3. Tong MJ, El-Farra NS, Reijes AR, Co RL. Clinical outcomes after transfusion-associated hepatitis C. N Engl J Med 1995; 332:1463–6.

4. Poynard T, Bedossa P, Opolon P for the OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Natural history of liver fibrosis progression in patients with chronic hepatitis C. Lancet 1997;349:825–32.

5. Alter HJ, Seeff LB. Recovery, persistence, and sequelae in hepatitis C virus infection: a perspective on long-term outcome. Sem Liver Dis 2000;20:17–35.