Some patients with chronic hepatitis C develop progressive liver disease, including advanced fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), over a period of about 10-40 years.

Two studies presented at the recent Digestive Disease Week conference add to the evidence that steatosis (fatty liver) is a key risk factor for advanced fibrosis and liver cancer.

Steatosis, Fibrosis, and Genotype 1 HCV

The etiology of steatosis in people with hepatitis C varies by genotype. In those with genotype 3, the hepatitis C virus (HCV) itself is believed to initiate steatosis, while in those with genotype 1, steatosis appears to be associated with metabolic abnormalities.

The first study, by K. Corey and colleagues, aimed to assess the relationship between steatosis and fibrosis in a cohort of hepatitis C patients with genotype 1. They conducted a retrospective review of medical records of 223 patients with chronic hepatitis C who underwent liver biopsy. Biopsies were analyzed by a single pathologist and graded for necroinflammatory activity and fibrosis using the Ishak staging system, as well as the Brunt steatosis score. Steatosis was graded on a scale of 0-4:

0 = no steatosis
1= steatosis in < 5% of liver cells
2= steatosis in 5%-33% of hepatocytes
3= steatosis in 34%-66% of hepatocytes
4= steatosis in > 66% of hepatocytes

Results

Steatosis was observed in 66% of patients in this group; the mean steatosis score was 0.99 + 0.9.

Fibrosis was found on liver biopsy in 77% of patients; the mean fibrosis score was 2.51 + 1.47.

66% of genotype 1 patients had at least grade 1 steatosis, and 27% had grade 2 or higher.

Among genotype 3 patients, the corresponding percentages were 78% with grade 1 and 30% with grade 2 steatosis.

Overall, an absolute correlation between steatosis score and fibrosis stage was not observed.

However, when looking only at minimal to moderate fibrosis (stage 0-2) and severe fibrosis (stage 3-6), a significant relationship with steatosis was seen (P = 0.008).

A significant relationship between steatosis and fibrosis was also observed when looking only at patients with genotype 1 HCV (P = 0.05).

Conclusion
The authors concluded that the finding that increased steatosis is associated with worsening fibrosis "suggests a possible role for steatosis in the acceleration of liver disease in HCV patients, especially in genotype 1 patients." Thus, they added, "Efforts to control steatosis may therefore have an important role in halting HCV liver disease progression, particularly in persons who are non-responders to antiviral therapy."

Steatosis and Hepatocellular Carcinoma

The second study, by J. Pekow and colleagues, sought to determine whether liver steatosis is associated with HCC in a group of patients with hepatitis C-related cirrhosis.

The study included 94 consecutive patients for whom hepatitis C-related cirrhosis with or without HCC was the primary indication for liver transplantation between 1992 and 2005. Upon checking the explants (old removed livers), 34% had evidence of HCC malignancy. All explant specimens were re-graded for steatosis by a single, blinded pathologist using the same 0-4 scale described above. Univariate and multivariate analyses were conducted to analyze the association between HCC and steatosis, age, gender, body mass index, HCV viral load, HCV genotype, MELD score, chronic alcohol use, and diabetes.

Results

Overall, 69% of patients with HCC and 50% of patients without HCC showed evidence of steatosis ( >= grade 1).

The relative risks (RR) for the development of HCC for each grade of steatosis compared to grade 0 were:

grade 1: RR 1.41 (.69-2.85)
grade 2: RR 2.19 (1.07-2.48)
grades 3 or 4: RR 2.73 (1.04-7.17).

There was a significant association for the trend of increasing steatosis grade and risk of HCC (P = 0.03).

In a univariate analysis, having HCC was associated with steatosis (P = 0.03), age (56 vs 49; P < 0.02), AST (122.5 vs 91.5; P = 0.005), ALT (95.8 vs 57.2; P = 0.002), median HCV RNA (239,000 vs 496,500; P = 0.02), and biologic MELD score (21.8 vs 20.3; P = 0.03).

In a multivariate analysis including age, steatosis, AST, ALT, and MELD score, only age was significantly associated with HCC (P = 0.01), although steatosis trended toward significance (P = 0.08).

Conclusion

The researchers concluded that in patients with hepatitis C-related cirrhosis, the presence of liver steatosis is associated with an increased risk for development of hepatocellular carcinoma. They added that these findings suggest that having steatosis poses an additional risk factor for HCC, and that "increased vigilance should be practiced in persons with both HCV and steatosis."

Taken together, these two studies suggest that chronic hepatitis C patients with steatosis may have a more urgent need for treatment.

6/16/06

References

K Corey, AK Bhan, RT Chung. Steatosis associated with more severe fibrosis in chronic hepatitis C. Abstract S1056. Digestive Disease Week 2006 (DDW 2006). May 20-25, 2006. Los Angeles, CA.

J Pekow, AK Bhan, Z Hui, RT Chung. S1016. Hepatic steatosis is associated with increased frequency of hepatocellular carcinoma in patients with hepatitis C-related cirrhosis. Abstract S1016. DDW 2006. May 20-25, 2006. Los Angeles, CA.