Etiologic significance of defects in cholesterol, phospholipid, and bile acid metabolism in the liver of patients with intrahepatic calculi

Citation
J. Shoda et al., Etiologic significance of defects in cholesterol, phospholipid, and bile acid metabolism in the liver of patients with intrahepatic calculi, HEPATOLOGY, 33(5), 2001, pp. 1194-1205
Citations number
56
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Gastroenerology and Hepatology","da verificare
Journal title
HEPATOLOGY
ISSN journal
0270-9139 → ACNP
Volume
33
Issue
5
Year of publication
2001
Pages
1194 - 1205
Database
ISI
SICI code
0270-9139(200105)33:5<1194:ESODIC>2.0.ZU;2-5
Abstract
Intrahepatic calculi, highly prevalent in the Far East, including Japan, ar e characterized clinically by chronic proliferative cholangitis with freque nt stone recurrences. Intrahepatic calculi consist of 2 groups, i.e., brown pigment stones, including a high cholesterol content, and cholesterol ston es, with the former predominating. To gain insights into the pathogenesis o f intrahepatic calculi, cholesterol and bile acid biosynthesis, as well as alterations in intracellular transport and/or canalicular secretion of phos pholipid and bile acid were investigated in liver of patients with intrahep atic calculi. Enzyme activities of 3-hydroxy-3-methylglutaryl-coenzyme A (H MG-CoA) reductase were increased (12.8 +/- 1.9 pmol/min/mg protein, mean +/ - SEM vs. 5.5 +/- 0.4 in controls; P < .01) and cholesterol 7 alpha -hydrox ylase activities were decreased (1.3 +/- 0.4 vs. 4.9 +/- 0.6; P < .01) in l iver specimens of patients with brown pigment stones. In addition, messenge r RNA (mRNA) levels of multidrug resistance P-glycoprotein 3 (MDR3 Pgp) and phosphatidylcholine transfer protein (PCTP) were markedly low in the liver specimens compared with the levels in specimens of control subjects, gallb ladder stone patients, and patients with obstructive cholestasis. The prote in levels and the immunohistochemical staining were decreased for MDR3 Pgp and PCTP in the liver. Consistently, the concentrations of phospholipid wer e markedly reduced in the hepatic bile from both affected and unaffected he patic segments. In patients with intrahepatic calculi, biliary cholesterol supersaturation and the formation of cholesterol-rich brown pigment as well as cholesterol stones may be attributed to decreased hepatic transport and biliary secretion of phospholipids, in the setting of increased cholestero genesis and decreased bile acid synthesis.