ArticlesNatural history of liver fibrosis progression in patients with chronic hepatitis C
Introduction
Chronic hepatitis C has a prevalence of at least 1% worldwide.1 Mortality associated with chronic hepatitis C results mainly from the development of liver fibrosis and the subsequent occurrence of cirrhosis, with complications such as hepatocellular carcinoma.2 However, most studies of the natural history of chronic hepatitis C defined liver lesions according to so-called activity grades–ie, classification of necrosis and inflammation without identification of fibrosis stages. In such studies patients were classified as having chronic persistent or active hepatitis, but the development of fibrosis itself was not assessed.3, 4 These activity grades have been used for cost-effective analysis5 and investigations of the severity of the disease.2 Some studies suggest that activity and fibrosis should be separated, because the association between these two pathological features is not known in chronic hepatitis C.3, 4 The time course of earlier fibrosis stages and the factors associated with the rate of fibrosis progression are not known. In theory, the best way to investigate fibrosis in chronic hepatitis C would be to prospectively follow a large representative sample of patients from infection to death, with repeated liver biopsies and no treatment. But this type of study is unethical and unfeasible. Studies that have investigated biopsy samples were retrospective and included few and selected patients.6, 7, 8, 9, 10, 11, 12
Our cross-sectional study was designed to describe the natural history of liver fibrosis progression and to identity risk factors in a large group of patients who had undergone a single liver biopsy and a standard assessment of fibrosis stage. This standard assessment classifies liver fibrosis into five stages (F0, F1, F2, F3, F4) and has been validated by the METAVIR group.13, 14 Although histological assessment of liver fibrosis is more commonly done in patients for whom the duration of infection is known, its validity has been checked by indirect estimates of age at biopsy and in two smaller-scale longitudinal studies in which repeated biopsy samples were obtained.15, 16, 17, 18, 19
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Methods
We recruited patients from three populations: the Observatoire de 1′Hépatite C (OBSVIRC) population,20 the Cohorte Hépatite C Pitié-Salpêtriére (DOSVIRC) population, and the original population from the METAVIR scoring-system validation study.13, 14 The characteristics of the three populations are shown in table 1. All these patients had chronic hepatitis C with at least a second-generation ELISA test positive for the presence of hepatitis C virus (HCV) antibodies and a liver biopsy sample
Estimation of rate of fibrosis progression
The mean rate of fibrosis progression per year among the 1157 patients with chronic hepatitis C for whom the duration of infection was known 0·252 (95% CI 0·227–0·277). This rate was not distributed normally, with a median of 0·133 (0·125–0·143). At this rate of fibrosis progression, the median duration from infection to cirrhosis was 30 years (28–32)-ie, 4 METAVIR units divided by 0·133. When divided into seven classes of median expected time to cirrhosis, the age distribution of patients was:
Discussion
An understanding of the natural history of hepatitis C is important for making rational decisions about public health, be they screening or therapeutic.21 Because there are no predictive surrogate markers of fibrosis, only studies with liver biopsy samples are useful. There have been only a few studies of the time period required for the development of fibrosis.6, 7, 8, 9, 10, 11, 12, 22 In those mostly retrospective studies, the number of patients was small, biopsy samples were assessed by
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