In the present cohort of Alaska Native and American Indian persons with chronic HCV infection, we examined predictors of advanced fibrosis on liver biopsy. We developed two models for multivariate analysis. In the first, which included surrogate markers of liver inflammation (ALT, AST/ALT ratio and AFP), Knodell HAI and AFP level of 8 ng/mL or higher were significantly associated with advanced fibrosis on biopsy (Ishak score of 3 to 6). When these markers were removed to distinguish factors that actually contribute to disease progression, the presence of steatosis on biopsy, type 2 diabetes mellitus and duration of HCV infection by 10-year intervals were independent predictors of severe disease.
We previously reported (15
) an association of steatosis with fibrosis in this cohort, also finding that HCV genotype 3 was associated with the presence of moderate to severe steatosis. Many others (16
) have noted the association of steatosis and HCV genotype 3, which has been attributed to viral factors, whereas steatosis in HCV genotype 1 infection has usually been attributed to metabolic factors. Although it has not been well studied and the mechanism is unclear, type 2 diabetes mellitus also has been shown to be a risk factor for the progression of liver fibrosis (20
). In one study (21
), type 2 diabetes was independently associated with more severe fibrosis or the presence of cirrhosis in patients with chronic HCV. While other studies (3
) have reported HCV infection duration to be a risk factor for development of severe disease, its determination has been difficult and sometimes controversial. However, the Arctic Investigations Program of the Centers for Disease Control and Prevention and the Alaska Native Tribal Health Consortium have maintained a serum bank for more than 30 years from previous research projects conducted in Alaska, thus, facilitating our ability to more accurately determine duration of infection than previous studies (14
We found significant progression of fibrosis in the 52 persons in the present cohort who had undergone multiple biopsies, which were performed a mean of 6.2 years apart. This progression was associated with age at initial biopsy and risk factors (specifically, less progression with transmission by intravenous drug use). Independent association of age at time of biopsy with histological cirrhosis has been previously reported (5
). Likewise, the association of advanced fibrosis on biopsy with transmission by blood transfusion has been reported (22
). Our associations were only significant after adjustment for the initial Ishak score. These associations were not found in our overall biopsied cohort of 253 persons and, therefore, cannot be used to validate our findings in the present cohort. The small sample size of persons with repeat biopsies limited our power to establish risk factors for disease progression in a multivariate analysis.
We determined the incidence of developing decompensated liver disease according to baseline Ishak score in those with two or more liver biopsies. The incidence of progression to decompensated liver disease was 14 times higher in those with cirrhosis on initial liver biopsy (Ishak score of 5 to 6) than in those with an initial Ishak score of 4 or lower.
The current study had several limitations. Liver biopsies were performed in the present cohort for clinical reasons only, primarily as part of an evaluation for possible hepatitis C treatment. Subsequent liver biopsies were also performed only for clinical reasons to determine whether disease progression occurred in persons not treated after a preceding biopsy, as suggested by clinical guidelines (10
). Those biopsied had higher median ALT, AST and AFP levels, higher HCV RNA levels and were younger at age of consent than those not biopsied. This represents a selection bias and, therefore, limits our ability to generalize these findings to individuals who were not biopsied.