Ultrastructural changes of intrahepatic bile ductules in griseofulvin fed mice

Intrahepatic bile ductules in male Swiss Webster mice, fed a diet containing 2.5 percent griseofulvin (GF), showed marked hypertrophy and hyperplasia within two weeks. Thereafter, this reaction gradually increased in prominence until nine weeks. Cytoplasmic acid phosphatase and succinic dehydrogenase deposits were more prominent and abundant after 12 to 14 weeks. Ultrastructural changes in ductular epithelial cells included enlargement of nuclei and nucleoli and increased abundance of cytoplasmic rough surfaced endoplasmic reticulum (RER), ribosomes and mitochondria until nine to 12 weeks. At this interval, duct lumina appeared widely dilated with small clumps of electron dense material at the periphery adjoining apical cell membranes with severely flattened or absent microvilli. Electron dense needle-like crystals resembling protoporphyrin were clustered centrally in the lumina. After twelve weeks occasional mitochondria were markedly swollen and contained vacuolated areas. Numerous multivesicular bodies were noted. Mallory bodies were seen in a few duct cells. The spectrum of duct cell changes just noted gives further evidence of extensive liver injury after GF feeding. These changes, in addition to diverse hepatocyte alterations previously reported, constitute morphologic features of GF induced murine porphyria, also common to human porphyria and human alcoholic liver disease.