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progression are unknown. Other confounding factors, such as age of onset of infection, lower levels of alcohol intake, and lower body mass index (BMI) may also help to explain the slower development of fibrosis in women than men with hepatitis C.

Alcohol. In almost all studies, a high consumption of alcohol (more than 50 g/d) has been found to be associ- ated with higher fibrosis stage.15,16,26-28 The effects of a lower level of alcohol consumption, between 10 and 40 g/d, have not been clearly defined. In univariate analysis, patients who drank moderate amounts of alcohol (50 g daily) had a slightly higher estimated rate of fibrosis pro- gression (0.143) than non-drinkers (0.125), but the difference was not statistically significant and was con- founded by other features, such as gender, body weight, and age. 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 fibro- sis is increased in hepatitis C is unknown. Because of the negative influence of high alcohol consumption, absti- nence or minimal consumption are usually recommended in patients with chronic hepatitis C.

Besides its direct effects on fibrogenesis, excess alcohol intake may have other adverse effects on the course of hepatitis C. Thus, alcohol may affect immune responses to HCV29,30 and may cause increases in HCV RNA levels in serum and liver, an effect that has been reported by some investigators,27,31 but not all.32

Immune Status. Immune status probably has a major affect on the natural history of hepatitis C and the devel- opment of cirrhosis. Several studies have shown that hep- atitis C is more likely to progress to cirrhosis, and that the rate of fibrosis progression is greater in HIV-coinfected patients. In a study from Spain, the mean estimated time to development of cirrhosis was 7 years in HIV-positive and 23 years in HIV-negative injection drug users with hepatitis C (P .01).33 In a study from France, the HAI score was significantly higher among 80 HIV-positive pa- tients compared with 80 HIV-negative injection drug us- ers (matched for age, gender, and duration of disease) (7.5 2.9 vs. 6.5 2.2, P .01).34 During a mean follow-up of 52 30 months, the incidence of cirrhosis was significantly higher among HIV-positive than -nega- tive patients (P .04) (Fig. 4).

In immunosuppressed liver transplant recipients, cir- rhosis of the graft occurs in up to 30% of patients within 5 years of transplantation, and the estimated mean time to development of cirrhosis is only 12 years.35,36 Most strik- ingly, fibrosis progression appears to be more rapid in patients who have undergone transplantation for hepatitis C in recent years compared with the initial studies of 5 to

HEPATOLOGY, November 2002

Fig. 4. Proportion of patients with cirrhosis on liver biopsy by duration after initial evaluation and presence or absence of HIV infection. (Re- printed with permission.34)

10 years ago. The recent increase in rate of fibrosis pro- gression is unexplained, but may be due to an increase in the average liver donor age.37 Other factors associated with fibrosis progression after liver transplantation were a history of acute hepatitis and the types of immunosup- pressive therapies.37

Viral Factors. In retrospective and cross-sectional stud- ies, virological factors, such as serum HCV RNA levels and HCV genotype, have not been associated with the rate of progression of fibrosis in chronic hepatitis C.15,16,18,19

Most cross-sectional studies have reported the absence of correlation between serum HCV RNA levels and the activity or grade of liver disease.38 Interestingly, patients with chronic HCV infection who have normal serum ala- nine aminotransferase (ALT) levels and nearly normal liver histology may have high serum HCV RNA levels.39 However, serum HCV RNA levels are an indirect reflec- tion of intrahepatic HCV replication, and the correlation between fibrosis and intrahepatic levels of HCV RNA has not been adequately investigated and should be included in prospective studies.40

The influence of viral genotype in the pathogenesis of the liver disease is not completely resolved. In several early stud- ies, HCV genotype 1b was found to be associated with a more severe liver disease, including a higher frequency of cirrhosis and hepatocellular carcinoma.41 However, many of these studies did not control for important confounding fac- tors, such as age, source, and duration of infection. Genotype 1b is more common among older than younger patients and has been commonly linked to spread by blood transfusion. In studies with adjustment for these variables, the association between genotype 1b and a more severe liver disease has not been found.15,38 Interestingly, the distribution of genotypes is not different in patients with chronic hepatitis C and nor- mal serum ALT levels, as compared with those with in- creased serum levels.42 Further studies are needed to better determine the possible role of genotype in the outcome of HCV-related liver disease.

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