Can large cell change and high proliferative activity predict hepatocellular carcinoma in patients with hereditary hemochromatosis?

OBJECTIVE: Patients with hereditary hemochromatosis are at high risk of developing hepatocellular carcinoma. This study was undertaken to define whether large cell change and nucleolar organizer regions proliferative index (marker of high proliferative activity) predict hepatocellular carcinoma development in hereditary hemochromatosis. METHODS: Histological staining for large cell change and high proliferative activity were done on baseline liver biopsies of 74 patients with hereditary hemochromatosis (52 with and 22 without cirrhosis), prospectively followed-up for 83 +/- 53 months (range, 1-230 months). RESULTS: Large cell change and high proliferative activity were found only in cirrhotic patients; 16 of 52 patients (31%) had either the large cell change or high proliferative activity. Large cell change was more frequent in patients with hepatitis B surface antigen than in those positive for hepatitis C virus (57% vs 14%, p = 0.04). Hepatocellular carcinoma developed in 7 of 16 (44%) and in 6 of 36 patients (16%) of the patients positive or negative for these morphological variables. The probability of developing hepatocellular carcinoma at 7 yr of follow-up was significantly higher in patients with large cell change or high proliferative activity than in those without. The length of follow-up from baseline histology to hepatocellular carcinoma occurrence was shorter in patients with large cell change or high proliferative activity than in those without these changes (46 +/- 36 and 109 +/- 34 months, p = 0.01). A multivariate analysis indicated that in patients with cirrhosis, large cell change or high proliferative activity (considered as a single variable), and age >55 yr were the only independent variables significantly associated with the risk of developing hepatocellular carcinoma, with a risk ratio of 4.8 (confidence interval 1.2-18.2) and 4.0 (confidence interval 1.1-15.6), respectively. CONCLUSIONS: In hereditary hemochromatosis, the presence of large cell change or high proliferative activity in patients older than 55 yr with cirrhosis should be considered a strong predictor of hepatocellular carcinoma development, especially if hepatitis B virus infection coexists.