Low phospholipid associated cholelithiasis: association with mutation in the MDR3/ABCB4 gene

Abstract

Low phospholipid-associated cholelithiasis (LPAC) is characterized by the association of ABCB4 mutations and low biliary phospholipid concentration with symptomatic and recurring cholelithiasis. This syndrome is infrequent and corresponds to a peculiar small subgroup of patients with symptomatic gallstone disease. The patients with the LPAC syndrome present typically with the following main features: age less than 40 years at onset of symptoms, recurrence of biliary symptoms after cholecystectomy, intrahepatic hyperechoic foci or sludge or microlithiasis along the biliary tree. Defect in ABCB4 function causes the production of bile with low phospholipid content, increased lithogenicity and high detergent properties leading to bile duct luminal membrane injuries and resulting in cholestasis with increased serum gamma-glutamyltransferase (GGT) activity. Intrahepatic gallstones may be evidenced by ultrasonography (US), computing tomography (CT) abdominal scan or magnetic resonance cholangiopancreatography, intrahepatic hyperechogenic foci along the biliary tree may be evidenced by US, and hepatic bile composition (phospholipids) may be determined by duodenoscopy. In all cases where the ABCB4 genotyping confirms the diagnosis of LPAC syndrome in young adults, long-term curative or prophylactic therapy with ursodeoxycholic acid (UDCA) should be initiated early to prevent the occurrence or recurrence of the syndrome and its complications. Cholecystectomy is indicated in the case of symptomatic gallstones. Biliary drainage or partial hepatectomy may be indicated in the case of symptomatic intrahepatic bile duct dilatations filled with gallstones. Patients with end-stage liver disease may be candidates for liver transplantation.

Figure 1

Ultrasound images of intrahepatic hyperechoic foci in patients with the LPAC syndrome. In these patients, a careful US examination detected intrahepatic hyperechoic foci with diffuse topography compatible with lipid deposits along the luminal surface of the intrahepatic biliary tree (Arrows). These multiple dots, less than 1 mm in diameter, cast short echogenic trail without acoustic shadows and looked like comet tails. They were typically distributed along the portal arborizations and may be associated with intrahepatic sludge or microlithiasis casting typical acoustic shadows.

Figure 2

Localization of the DCMs in the different domains of the ABCB4 protein in the complete series of patients with LPAC.

Figure 3

LPAC syndrome associated with the presence of intrahepatic non cystic bile duct dilatations filled with cholesterol gallstones.