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The surface epithelium of 28 gallbladders removed during elective cholecystectomies and pathology collection was studied ultrastructurally. Focusing on 10 of the 28 cases that were diagnosed as cholecystitis, we found that the epithelium displayed numerous apical mucous granules and bulging apical apices. Mucous granule changes included 1) hyperproduction of secretory granules of neutral type containing an electron-dense proteinaceous spherule, similar to that described in other mucus-producing glands of the digestive system, and 2) production of anionic, osmiophilic secretory mucus. Other alterations of the surface epithelial cells included the production of bizarre surface appendages resembling primitive cilia without axoneme and epithelial excrescences.

This report reviews previously published studies from our laboratory and shows some recent morphological data obtained with scanning and transmission electron microscopy regarding gallstone formation and alteration of the gallbladder epithelium in the Syrian hamster model. Both male and female hamsters were treated with female sex steroids (estradiol alone, estradiol and medroxyprogesterone, medroxyprogesterone alone) during one month. The results show that the Syrian hamster is a good model to study bile changes, gallbladder structure changes, including gallstone formation, and the regulation of cholesterol metabolism at the molecular level. Arguments in favor of this animal model are presented and, during gallstone formation, epithelial cell changes, anionic mucus secretion, and formation of gallbladder luminal deposits can be demonstrated. Recent molecular biology observations related to the effect of female sex steroids on liver cholesterol 7 alpha-hydroxylase (CYP7) gene suggest that progestin alone or primed by estrogen down regulates CYP7 transcription and activity. In addition, progesterone in cell culture systems has been shown to enhance intracellular accumulation of free cholesterol by increasing its uptake and synthesis and by decreasing its esterification by inhibiting the activity of acylcoenzyme A: cholesterol acyltransferase. Non-esterified cholesterol is free to migrate to the extracellular spaces and may contribute to nucleation within the bile. It is suggested that these effects of progesterone on cholesterol metabolism combined with the CYP7 gene down regulation, physical changes in the mucus and the hypomotility of the gallbladder and biliary ducts result in hypersaturation of cholesterol in the bile which favors gallstone formation.