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HEPATOLOGY, Vol. 36, No. 5, Suppl. 1, 2002

Table 1. Progression of Fibrosis in Three Series of Patients With Chronic Hepatitis C With Two Liver Biopsies




et al.17

et al.18

et al.19


Mean delay between the 2 biopsies (yrs)




Proportion of patients with progression




Progression of 1 point




Progression of 2 points




Progression of 3 points




Number of patients




This model has major implications for the prognosis of chronic hepatitis C. The model implies that progression of fibrosis is linear in each phase, but accelerates from phase to phase, increasing exponentially with age and time after onset of infection. According to this prediction, a patient might have minimal or no fibrosis after 2 decades of infection, but with subsequent decades and after the age of 50, fibrosis may develop rapidly. This model should be interpreted with caution, because it was based on a cross-sectional analysis of a selected population of pa- tients: patients from 16 referral centers and from random- ized controlled trials of antiviral therapy. In addition, only a small proportion of patients had an estimated duration of the disease of more than 20 years when the accelerated course was predicted to occur. Finally, a minority of pa- tients had bridging fibrosis (11%) or cirrhosis (9%), the outcome that is predicted to occur eventually in the ma- jority of patients.

Estimates From Longitudinal Studies. There have been 3 recent studies (1 prospective17 and 2 retrospec- tive18,19) of untreated patients with chronic hepatitis C who underwent 2 liver biopsies 3 to 8 years apart (Ta- ble 1).17-19 In these studies, 32% to 59% of patients showed a progression of fibrosis. In up to 24% of pa- tients, there was an apparent improvement in fibrosis. In 2 studies in which liver biopsies were 3 years apart, patients who showed progression mostly had only a 1-point worsening of fibrosis; a 2-point increase oc- curred in 2% to 9%, and no patient had a 3-point or more increase. In the study with 2 liver biopsies with a longer intervening period (averaging 8.3 years), 31% of patients had a 1-point, 15% a 2-point, and 13% a 3-point increase in fibrosis scores.19 These 3 studies showed similar average rates of progression of fibrosis that were consistent with the original reports from Poy- nard et al.15 that predicted the development of cirrhosis in the average patient after 30 to 40 years of infection. It should be stressed, however, that these studies were performed in referral centers, and the patients who were studied may not have been representative of the average patient with chronic hepatitis C.



Factors Associated With Fibrosis Progression

Most studies of liver histology and fibrosis have ana- lyzed factors that correlated with the degree of fibrosis and estimated rate of fibrosis progression. Factors identified in most studies included age, age at infection, male sex, and history of heavy alcohol use. Immune deficiency, such as due to HIV infection or inherited conditions of the im- mune system, has also been identified as correlating with more rapid progression of fibrosis in chronic hepatitis C. In recent reports, steatosis on liver biopsy, obesity, and diabetes have also been associated with more rapid pro- gression of fibrosis.

Age. Age at onset of infection has consistently been found to be a major factor influencing the rate of progres- sion of fibrosis in hepatitis C. Thus, studies of posttrans- fusion hepatitis in which most patients are over the age of 40 at the time of onset of infection have indicated that at least 20% of patients develop cirrhosis during the first 15 to 20 years of HCV infection.20-22 In contrast, in studies of young women infected as a result of exposure to HCV- contamined Rh immune globulin, less than 5% develop cirrhosis within the first 15 to 20 years of infection.23,24

In the analyses of fibrosis progression by Poynard et al.,15,16 the rate of progression of fibrosis was correlated directly with age of onset of infection. In univariate anal- yses, cirrhosis developed within 20 years in only 2% of patients infected before the age of 20, in 6% infected between 21 and 30 years, 10% infected between 31 and 40 years, 37% infected between 41 and 50 years, and 63% infected over the age of 50 years. In the hazard function model, virtually all patients infected after 40 years of age develop cirrhosis within 16 years (Fig. 3).16 Interestingly, in this model, the rate of progression of fibrosis accelerates after 50 years of age, regardless of the duration of infection up to that time. This model with a progressive accelera- tion of fibrosis progression needs to be validated in cohort studies.

The mechanisms responsible for the influence of age on fibrosis progression are not known, but might include immune factors, increased fibrogenesis, or decreased fi- brolysis.

Gender. Most studies of hepatic fibrosis have reported that male sex is significantly associated with progression of fibrosis.15,16,23-25 Two long-term retrospective-prospec- tive studies of hepatitis C in women who received HCV- contaminated Rh immune globulin also suggested an important role of gender in progression of fibrosis. In these 2 studies, only 2% and 0.4% of women had cirrhosis on histological evaluation 17 and 20 years after expo- sure.23,24 The mechanisms by which sex affects fibrosis

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