Gastroenterology

Gastroenterology

Volume 120, Issue 6, May 2001, Pages 1459-1467
Gastroenterology

Liver, Pancreas, and Biliary Tract
MDR3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis

https://doi.org/10.1053/gast.2001.23947Get rights and content

Abstract

Background & Aims: Many studies indicate that gallstone susceptibility has genetic components. MDR3 is the phosphatidylcholine translocator across the hepatocyte canalicular membrane. Because phospholipids are a carrier and a solvent of cholesterol in hepatic bile, we hypothesized that a defect in the MDR3 gene could be the genetic basis for peculiar forms of cholesterol gallstone disease, in particular those associated with symptoms and cholestasis without evident common bile duct stone. Methods: We studied 6 adult patients with a peculiar form of cholelithiasis. MDR3 gene sequence was determined by reverse-transcription polymerase chain reaction amplification of mononuclear cell RNAs followed by direct sequencing. Hepatic bile was analyzed in 2 patients. Results: All patients shared the following features: at least 1 episode of biliary colic, pancreatitis, or cholangitis; biochemical evidence of chronic cholestasis; recurrence of symptoms after cholecystectomy; presence of echogenic material in the intrahepatic bile ducts; and prevention of recurrence by ursodeoxycholic acid therapy. Hepatic bile composition showed a high cholesterol/phospholipid ratio and cholesterol crystals. In all patients, we found MDR3 gene mutations involving a conserved amino acid region. Conclusions: These preliminary observations suggest that MDR3 gene mutations represent a genetic factor involved in this peculiar form of cholesterol gallstone disease in adults. They require further studies to assess the prevalence of MDR3 gene defects in symptomatic and silent cholesterol gallstone disease.

GASTROENTEROLOGY 2001;120:1459-1467

Section snippets

Patients

In the present study, we studied 6 patients (2 men and 4 women, aged between 26 and 55 years) with the following peculiar features: presence of at least 1 episode of biliary colic, pancreatitis, or cholangitis; biochemical evidence of mild chronic cholestasis; recurrence of symptoms after cholecystectomy; presence of echogenic material in the intrahepatic bile ducts; and prevention of recurrence by UDCA therapy. In addition, 3 women had the above symptoms (i.e., biliary pain, cholestasis, and

Morphology and histopathology

Ultrasonography detected echogenic material suggestive of multiple small gallstones in the intrahepatic bile ducts of all the patients. An ultrasonography picture of these peripheral intrahepatic gallstones is presented in Figure 1A.

. Morphology and histopathology. (A) Ultrasound images of intrahepatic gallstones in patient 1. (B) Intrahepatic cholesterol gallstones in patient 3. (C, D) Histopathology of liver biopsy specimens obtained from patients 3 and 4.

Numerous radiolucent gallstones having

Discussion

We studied 6 adults with a peculiar form of cholesterol gallstone disease associated with mutations in the MDR3 gene.

Several lines of evidence suggest that an MDR3 gene defect is involved in this form of cholesterol cholelithiasis. First, the MDR3 protein is the physiologic translocator of phospholipids in bile. Secondly, phospholipids (mainly phosphatidylcholine) are the main carrier and solvent of biliary cholesterol. Third, all the patients showed evidence of both intrahepatic and

Acknowledgements

The authors thank the technical staff of the Laboratoire Commun de Biologie Moléculaire de la Fédération de Biochimie de l'Hôpital Saint-Antoine for their assistance.

References (38)

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Address requests for reprints to: Raoul Poupon, M.D., Service d'Hépatogastroentérologie, Hôpital Saint-Antoine, 184, rue du Faubourg St-Antoine, 75571 Paris Cédex 12, France. e-mail: [email protected]; fax: (33) 1-49-28-21-07.

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