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Sequential appearance of intestinal mucosal cell types in the right and caudate liver lobes of furan‐treated rats

Furan rapidly induces in rat liver a unique, lobespecific pattern of development of intestinal metaplasia and associated cholangiofibrosis. To establish early cell‐precursor relationships in the genesis of this cholangiofibrosis, a time‐course study was conducted in which young adult male Fisher 344 rats received furan by gavage at a daily dose of 45 mg/kg body wt over a 32‐day treatment period. An analysis of individual liver lobes obtained at different time points from these animals during furan treatment revealed the following sequence of histopathological changes, which were located mainly in the right and, to a lesser extent, the caudate liver lobes: day 1, severe hepatonecrosis in zone 3 extending into zone 2 of the liver acini; days 3 to 5, presence of a diffuse inflammatory cell infiltrate in hepatonecrotic areas, which gradually resolved; day 7, prominent bile ductule hyperplasia in tissue sections exhibiting marked loss of normal liver parenchyma; day 9, continued replacement of injured liver by hyperplastic bile ductule tissue, which now contained occasional metaplastic glandular structures composed of columnar basophilic epithelial cells; days 12 to 16, increasing cell diversity in the developing metaplastic glands, with the sequential appearance of goblet cells, Paneth cells and serotonin‐positive neuroendocrine cells; and day 32, typical cholangiofibrosis defined by hyperplastic bile ductule–type structures in association with an increased number of metaplastic intestinal glands and progressively more dense fibrotic stroma. Interestingly, at 16 and 32 days the cellular composition of the newly formed metaplastic intestinal glands in liver closely resembled that of the crypts of Lieberkühn in the normal adult rat small intestine. These results strongly suggest that hyperplastic bile ductule cells differentiate preferentially along the small‐intestinal mucosa lineage in the right and caudate liver lobes of the furan‐treated rats. In addition, they support the view that small intestinal metaplasia is an important intermediate in the development of cholangiofibrosis in liver. (HEPATOLOGY 1992;16:1220–1226.)