In an attempt to clarify the role of oval cells in the emergence of
hepatocellular carcinoma, we fed rats a
choline-free diet containing 0%, 0.05% or 0.1%
ethionine. The incidence and nature of premalignant and malignant hepatic lesions were then related to the degree of oval cell proliferation. Intake of
choline-free diet alone for up to 12 mo was associated with minimal oval cell proliferation; cholangiofibrosis, hepatocellular nodules and
hepatocellular carcinoma were observed in 55%, 23% and 14% of the animals, respectively. When rats were given the
choline-free diet with 0.05%
ethionine, proliferation of oval cells was more pronounced; after a 6- to 12 mo feeding period, cholangiofibrosis (57%) was again observed. However, hepatocellular nodules (91%) and
hepatocellular carcinoma (74%) were the most common lesions seen with this feeding regimen. Finally, rats fed the
choline-free diet with 0.1%
ethionine had massive oval cell proliferation and progressive loss of parenchymal liver tissue. Most of these animals died before they had consumed the
choline-free diet with 0.1%
ethionine for 12 mo. Rats in this group (96%) exhibited large and numerous cholangiofibrotic lesions, but hepatocellular nodules and
carcinoma were not detected. In all animals of each experimental group, hyperplastic bile duct cells in areas of cholangiofibrosis and oval cells were positive for
cytokeratin 19, an intermediate filament
protein present only in bile duct cells in normal liver. Hepatocellular nodules and
hepatocellular carcinoma were invariably negative for
cytokeratin 19. We interpret these findings to suggest that oval cells are not involved in the histogenesis of
hepatocellular carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)