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.
Highlights
The exact prevalence of Low phospholipid-associated cholelithiasis (LPAC) remains unknown
LPAC presents as a peculiar form of cholelithiasis characterized by cholecystitis, cholangitis and intrahepatic gallstone disease, and/or acute pancreatitis associated with biliary microlithiasis
Homozygous and heterozygous mutations in the MDR3 gene, the phosphatidylcholine translocator across the canalicular membrane, are thought to be responsible for progressive intrahepatic cholestasis type 3 (PFIC 3) [7], and heterozygous mutations have been reported in patients presenting with a history of intrahepatic cholestasis of pregnancy or with a cholangiopathy referred to as anti-mitochondrial antibody (AMA) negative primary biliary cirrhosis (PBC) [8,9,10,11]
Summary
Our results strongly support the role of an ABCB4 gene defect in LPAC syndrome and replace it in the context of ABCB4 gene-associated liver diseases in adults including attenuated form of PFIC 3, "atypical intrahepatic cholestasis of pregnancy", LPAC syndrome which might lead to adulthood biliary cirrhosis or bile duct dilatations associated with gallstones. A genetic test based on the present results may permit the molecular diagnosis of LPAC syndrome and the screening of high-risk subjects. Long-term curative or prophylactic UDCA therapy may be initiated early to prevent the occurrence or recurrence of this syndrome and its severe complications
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