HEPATOCELLULAR PROLIFERATION AND DEVELOPMENT OF HEPATOCELLULAR-CARCINOMA - A CASE-CONTROL STUDY IN CHRONIC HEPATITIS-C

Patients with hepatitis C have an increased risk of developing hepatoc ellular carcinoma (HCC). This is related to the stage of chronic liver disease, as characterized histologically by hepatic fibrosis and arch itectural distortion, but it is unclear whether histological markers c an define the risk of developing HCC. We conducted a case-control immu nohistochemical study of Ki-67, a marker for hepatocellular proliferat ion, in livers of 18 patients who had developed HCC more than 2 years after the biopsy specimen had been taken. Using conditional logistic r egression analysis, the results were compared with 18 selected control s, who were age-matched patients with hepatitis C of similar histologi cal stage who had not developed HCC. We also examined livers for cellu lar dysplasia, p53 mutations, and bcl-2 overexpression, and assessed w hether the results could be correlated with demographic and disease-re lated variables, such as gender, region of birth, alcohol consumption, severity of liver disease, HCV genotype, and markers of hepatitis B v irus (HBV) infection. Livers from patients who developed HCC were more often positive for Ki-67 (13 of 18 [72%] v 9 of 18 [50%]; P =.06) and tended to have higher mean Ki-67 scores (6 +/- 7.5 v 3 +/- 4.4; P =.1 0) compared with control cases. In the HCC-predisposed group, three li vers showed large cell dysplasia, two were positive for p53 mutations, and two for beta overexpression. In contrast, in the non-HCC group, o nly one case had dysplasia, and none were positive for immunostaining for p53 or bcl-2 mutations. With the exception of one case, all livers with large cell dysplasia or p53 mutations and bcl-2 overexpression w ere also positive for Ki-67. Twelve (55%) of the 22 Ki-67-positive cas es were anti-HBc-positive in the serum, in contrast to 2 of 14 (14W) p atients in the Ki-67-negative group (P =.01). Patients with evidence o f past infection with HBV were more often Ki-67 positive than those wh o had no evidence of past infection (85% [11 of 13] v 45% [10 of 22]; P =.02). There were no other associations between demographic or disea se-related variables and Ki-67 expression. Increased hepatocellular pr oliferative activity, as assessed by Ki-67 expression, may be one fact or indicative of an increased risk of developing HCC among patients wi th chronic hepatitis C. Furthermore, past infection with HBV appears t o be an important correlate of increased hepatocellular proliferation in hepatitis C. Copyright (C) 1998 by W.B. Saunders Company.