Fibrosis and Cirrhosis

Progressive hepatic fibrosis leading to cirrhosis is the major complication of chronic HCV infection and accounts for almost all HCV-related morbidity and mortality. Early studies suggested little, if any, fibrosis progression during the first decade of infection, followed by a slow, regular progression during the next 15 years, increasing to an intermediate rate during the subsequent decade. In a German cohort study of 1833 women infected with HCV-contaminated immunoglobulin, 0.5% of patients developed cirrhosis after 25 years. Similarly, in a study of 376 HCV-infected women conducted by the Irish Hepatology Research Group, 51% of patients had fibrosis after 17 years, but only 2% had probable/definite cirrhosis. These estimates of cirrhosis rates are considerably lower than those from the US multicohort study and the widely cited US military study (approximately 35%). Fibrosis outcomes of 184 women from the same cohort were followed up for the subsequent 5 years; 49% showed no change in fibrosis, 24% showed regression, and 27% showed progression.

Recent data reinforce the potential for severe liver disease to develop in some patients. Among 485 plasma donors infected during the early 1970s, 34% had stage F3/F4 fibrosis (bridging fibrosis), cirrhosis, or HCC after 31 years; their 35-year cumulative survival was 84% versus 91%–95% for the general population. Similarly, a study of 300 black and white Americans with untreated HCV infection found that 29% of patients had stage F3/F4 fibrosis after 20 years, and 4.7% had confirmed cirrhosis. It should be noted, however, that these studies could have selected patients with severe disease.

The nonlinear progression of fibrosis was recently confirmed in a meta-analysis of 111 HCV studies. The mean annual stage-specific transition probabilities were 0.117 for stage F0 to F1, 0.085 for F1 to F2, 0.120 for F2 to F3, and 0.116 for F3 to F4. Although the estimated prevalence of cirrhosis was 16% after 20 years, there was wide variation between studies, suggesting that fibrosis is a highly unpredictable process.

Infection duration is a major risk factor for severe fibrosis, with the progression rate in a 50-year-old being almost 3 times that in a 20-year-old. Age at time of infection is also important. In a biopsy analysis of 247 treatment-naïve HCV patients, progression rates were 0.13, 0.14, 0.27, and 0.36 fibrosis units/year for patients aged =19, 20–24, 25–36, and >36 years at infection, respectively. Age >36 years (vs =36 years) at time of infection was independently associated with faster progression. Men infected before age 50 have been identified as comprising the majority of cases of cirrhosis today (73.6%), whereas men aged >50 years when infected have faster disease progression compared with other age groups.

Several other factors, including sex, baseline fibrosis, HCV genotype, HIV/HBV coinfection, and alcohol consumption, also influence fibrosis progression. Identifying these factors can be useful when determining prognosis and advising patients on minimizing liver damage. Indeed, a recent study suggested that HCV genotype 3 might pose a particularly high risk of progressive fibrosis. Insulin resistance has been linked with fibrosis, and several studies have reported that this relationship remains significant, irrespective of HCV genotype. In addition, serum aminotransferase level elevations and the degree of hepatocellular necrosis/inflammation on biopsy have been found to predict fibrosis progression. Genetic factors might also play a role in fibrosis progression. Recent data indicate that the cirrhosis risk score, which is based on the association of 7 host genes, might help to differentiate HCV patients at high versus low risk of progressing toward cirrhosis, including those with early or mild CHC. Steatosis has also been linked to fibrosis progression, as has regular cannabis use. There is evidence of an association between cigarette smoking and hepatitis fibrosis, but not all studies have verified such an association.