Elsevier

The Lancet

Volume 349, Issue 9055, 22 March 1997, Pages 825-832
The Lancet

Articles
Natural history of liver fibrosis progression in patients with chronic hepatitis C

https://doi.org/10.1016/S0140-6736(96)07642-8Get rights and content

Summary

Background

Our aim was to assess the natural history of liver fibrosis progression in hepatitis C and the factors associated with this progression.

Methods

We recruited 2235 patients from the Observatoire de i'Hépatite C-(OBSVIRC) population, the Cohorte Hépatite C Pitié-Salpêtrière (DOSVIRC) population, and the original METAVIR population. All the patients had a biopsy sample compatible with chronic hepatitis C as assessed by the METAVIR scoring system (grades the stage of fibrosis on a five-point scale, FO=no fibrosis, F4=cirrhosis, and histological activity on a four-point scale, AO=no activity, A3=severe activity). No patient had received interferon treatment before the liver biopsy sample was obtained. We assessed the effect of nine factors on fibrosis progression: age at biopsy; estimated duration of infection; sex; age at infection; alcohol consumption; hepatitis C virus C (HCV) genotype; HCV viraemia; cause of infection; and histological activity grade. We defined fibrosis progression per year as the ratio between fibrosis stage in METAVIR units and the duration of infection (1 unit=one stage, 4 units=cirrhosis).

Findings

The median rate of fibrosis progression per year was 0·133 fibrosis unit (95% CI 0·125-0-143), which was similar to the estimates from previous studies (0·146 to 0·154). Three independent factors were associated with an increased rate of fibrosis progression: age at infection older than 40 years, daily alcohol consumption of 50 g or more, and male sex. There was no association between fibrosis progression and HCV genotype. The median estimated duration of infection for progression to cirrhosis was 30 years (28–32), ranging from 13 years in men infected after the age of 40 to 42 years in women who did not drink alcohol and were infected before the age of 40. Without treatment, 377 (33%) patients had an expected median time to cirrhosis of less than 20 years, and 356 (31%) will never progress to cirrhosis or will not progress for at least 50 years.

Interpretation

The host factors of ageing, alcohol consumption, and male sex have a stronger association with fibrosis progression than virological factors in HCV infection.

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

Section snippets

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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