Predicting Progression to Cirrhosis in Chronic Hepatitis C Virus Infection

A. J. Freeman, M. G. Law, J. M. Kaldor, G. J. Dore

Disclosures

J Viral Hepat. 2003;10(4) 

In This Article

Discussion

This report examines factors associated with progression to cirrhosis in people with chronic HCV infection. Following an extensive review of HCV natural history studies across four broad study categories, and including multivariate analysis of factors associated with disease progression, four were identified as independently influencing prognosis: gender, alcohol consumption, serum ALT level and histological grade of inflammation.

Heavy alcohol use has consistently been associated with more rapid progression to cirrhosis in patients with chronic HCV infection.[16,20,21,22,23,24,25,26,27,28,29,30,31] A cross-sectional study of 6664 referred patients demonstrated that cirrhosis was more frequent in those who reported heavy drinking (34.9% vs 18.2%).[32] A further study estimated the independent relative risk associated with high alcohol intake to be 1.9 (1.0-3.9)[33]; a figure similar to the pooled estimate reported here. The impact of low or moderate alcohol intake is less clear.[34,35,36,37]

With regard to gender, other studies have also demonstrated that men have a worse prognosis than women.[22,27,38,39] Low rates of cirrhosis in young women infected with contaminated anti-D support this association.[17,40] Alternatively, considering the association between male gender and heavy alcohol consumption in the analysis reported here, an apparent gender effect may relate to residual confounding because of under-reporting of alcohol use by men.

Despite the observation that the presence of an elevated ALT was associated with a higher HAI score, biochemical and histological evidence of hepatic inflammation were independently associated with more rapid progression to cirrhosis. Both cross-sectional[22,31] and longitudinal[41,42] studies have demonstrated that more active hepatic inflammation is associated with more rapid fibrosis progression. Therefore, in addition to stage of liver disease,[5] grade of hepatic inflammation influences prognosis. For people with mild hepatic fibrosis, the degree of hepatic inflammation may therefore be an important consideration in decisions relating to antiviral therapeutic intervention. People who have progressed to moderate or greater stages of hepatic fibrosis are generally recommended to commence antiviral therapy [43]

Serum transaminase levels fluctuate significantly in patients with chronic HCV infection and poorly predict the extent of liver damage.[44,45,46] However, cross-sectional[47,48] and recent longitudinal[49,50,51] studies have demonstrated slower disease progression rates for chronic HCV-infected patients with persistently normal ALT levels compared to patients with elevated ALT levels.[48,49,50] Our review supports an independent association between elevated serum transaminase levels and increased risk of progression to cirrhosis.

A number of studies have demonstrated that subjects infected at an older age develop cirrhosis over a shorter period.[22,39,52,53] In one study, among patients 50 years or older at the time of infection, the average time to development of cirrhosis was 9.8 years compared with 23.6 years for younger patients.[54] Children with chronic HCV infection have been shown to have disproportionably low rates of fibrosis progression.[22,55,56] However, in the analysis reported here, after adjusting for factors more clearly associated with disease progression, age at infection did not predict the development of cirrhosis. A possible explanation is that higher grade hepatic inflammation is more often established in people infected at an older age, thus providing the stimulus for more rapid development of hepatic fibrosis.

The analysis reported here was unable to examine the impact of coinfection with either HBV or HIV on HCV-related liver disease progression. It has been suggested that HBV infection increases fibrosis in patients with chronic HCV infection.[57,58] However, one large study considered HBV infection and demonstrated that while co-infection may increase the risk of cirrhosis, the effect was likely to be small (HBVs Ag-positive, 24.6% cirrhotic; HBVs Ag-negative, 21.2% cirrhotic).[32] Similarly, while some studies have demonstrated that concurrent HBV and HCV, infection significantly increases the incidence of hepatocellular carcinoma in patients with cirrhosis,[59,60,61] other evidence suggests that this may not be the case.[62]

In contrast to HBV, co-infection with HIV is highly likely to result in significantly more rapid disease progression.[29,63,64] In one study, mean interval from HCV acquisition to cirrhosis was 23.2 years for HIV-negative patients (n = 431), and 6.9 years for HIV-positive patients (n = 116).[65] HIV infection has been estimated to carry a relative risk of 2.2 (1.1-4.5) for the development of cirrhosis in patients with chronic HCV infection.[33] The corresponding relative risk in haemophiliacs with HIV is estimated to be 3.7 (1.3-11.1).[66] Worse outcomes among HIV-infected patients with chronic HCV infection are associated with immunosuppression as reflected by lower CD4-lymphocyte counts and increased HCV viral load.[67,68,69]

It is unclear whether viral factors, such as virulence of the infecting viral genotype, viral load and quasispecies diversity, impact on the development of HCV-related cirrhosis. Infection with HCV genotype 1, particularly subtype 1b, has been reported to increase the rate of progression to HCV-related cirrhosis.[70,71,72,73,74] Rather than a direct effect attributable to HCV genotype, it may be that genotype prevalence is changing, other genotypes are becoming more common and patients with genotype 1b have simply been infected for longer.[75,76] Studies that have considered other factors related to disease progression have typically failed to find any association between HCV genotype and cirrhosis.[16,27,31,36,53,58,77,78,79,80,81]

Progression to cirrhosis has also been associated with higher serum viral load in some studies.[74,82,83,84,85,86] In the analysis reported here, few studies provided viral load data, therefore the absence of an identifiable impact on disease progression must be interpreted with caution. However, recent evidence suggests that viral load does not influence disease progression in chronic HCV infection.[27,77,81,87,88,89,90,91,92] Similarly, data from a limited number of studies does not support a role for quasispecies diversity in influencing progression to cirrhosis.[93,94]

Ethnicity may influence the prevalence of cirrhosis in an HCV-infected population. This was not clarified in the analysis reported here as data regarding the ethnic distribution of the population studied was rarely available. Country of origin was extracted and no significant differences were seen. It has been reported that severe adverse effects are more common in Japan.[6] Certainly the rate of hepato-cellular carcinoma among HCV-infected Japanese is high[52,95] However, whether this is because of racial differences in the host response to the HCV, the environment or viral factors is uncertain.

Despite the limitations of ecologic analyses,[96] the relative risk of fibrosis progression related to significant cofactors in our analysis can be used to estimate risk of cirrhosis from time of infection. As the vast majority of people with chronic HCV infection present with established liver disease, further models are needed to predict both current stage of disease and predict future risk of disease progression.


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