Low-phospholipid-associated cholelithiasis syndrome: Prevalence, clinical features, and comorbidities

Catherine Dong; Bertrand Condat; Magalie Picon-Coste; Yves Chrétien; Pascal Potier; Béatrice Noblinski; Lionel Arrivé; Marie-Pierre Hauuy; Véronique Barbu; Anware Maftouh; Farid Gaouar; Karima Ben Belkacem; Chantal Housset; Raoul Poupon; David Zanditenas; Olivier Chazouillères; Christophe Corpechot

doi:10.1016/j.jhepr.2020.100201

Low-phospholipid-associated cholelithiasis syndrome: Prevalence, clinical features, and comorbidities

JHEP Rep. 2020 Nov 6;3(2):100201. doi: 10.1016/j.jhepr.2020.100201. eCollection 2021 Apr.

Authors

Catherine Dong¹, Bertrand Condat^{2

3

4}, Magalie Picon-Coste^{3

4

5}, Yves Chrétien^{1

6}, Pascal Potier^{3

4

7}, Béatrice Noblinski⁸, Lionel Arrivé^{6

8}, Marie-Pierre Hauuy⁹, Véronique Barbu^{6

10}, Anware Maftouh¹¹, Farid Gaouar¹, Karima Ben Belkacem^{1

4}, Chantal Housset^{1

6}, Raoul Poupon¹, David Zanditenas^{3

4

12}, Olivier Chazouillères^{1

4

6}, Christophe Corpechot^{1

4

6}

Affiliations

¹ Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN RARE-LIVER, Saint-Antoine Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne University, Paris, France.
² Division of Gastroenterology and Hepatology, French Polynesia Hospital, Pirae, French Polynesia.
³ Association Nationale des Hépato-Gastroentérologues des Hôpitaux Généraux de France (ANGH), Montfermeil, France.
⁴ French National Cohort of Patients with LPAC syndrome (RaDiCo-COLPAC), RaDiCo, Inserm U933, Armand Trousseau Hospital, Paris, France.
⁵ Division of Gastroenterology and Hepatology, Aix-en-Provence Hospital, Aix-en-Provence, France.
⁶ Sorbonne University, INSERM, Centre de Recherche Saint-Antoine, Paris, France.
⁷ Division of Gastroenterology and Hepatology, Orléans Hospital, Orléans, France.
⁸ Radiology Department, Saint-Antoine Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
⁹ Radiology Department, Saint-Camille Hospital, Bry-sur-Marne, France.
¹⁰ Molecular Biology and Genetics Laboratory, Saint-Antoine Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹¹ Visceral Surgery Department, Saint-Camille Hospital, Bry-sur-Marne, France.
¹² Division of Gastroenterology and Hepatology, Saint-Camille Hospital, Bry-sur-Marne, France.

Abstract

Background & aims: Low-phospholipid-associated cholelithiasis (LPAC) syndrome, a rare genetic form of intrahepatic cholelithiasis in adults, is still poorly understood. We report the results of the largest-ever case-control study of patients with LPAC syndrome aiming to assess the prevalence, clinical features, and comorbidities of the disease.

Methods: We included all LPAC cases diagnosed between 2001 and 2016 in 11 French centres. Controls consisted of all patients who underwent a cholecystectomy for common gallstone disease in a single non-academic centre over 1 year. A logistic regression analysis was used to identify the clinical features associated with LPAC syndrome across several patient strata with increasing levels of diagnostic confidence. The ratio between the incident cases of LPAC syndrome and the total number of cholecystectomies for gallstones was used to assess the relative prevalence of the disease.

Results: In this study, 308 cases and 206 controls were included. LPAC syndrome accounted for 0.5-1.9% of all patients admitted with symptomatic gallstone disease. Age at first symptoms <40 years, absence of overweight, persistence of symptoms after cholecystectomy, intrahepatic micro- or macrolithiasis, common bile duct (CBD) lithiasis, and no history of cholecystitis were independently associated with LPAC diagnosis. ATP-binding cassette subfamily B member 4 (ABCB4) variants, present in 46% of cases, were associated with CBD lithiasis, chronic elevation of gamma-glutamyltransferase (GGT), and personal or family history of hepato-biliary cancer.

Conclusions: In this case-control study, LPAC syndrome accounted for approximately 1% of symptomatic cholelithiasis in adults. In addition to pre-established diagnostic criteria, normal weight, CBD lithiasis, and no history of cholecystitis were significantly associated with the syndrome. ABCB4 gene variations in patients with LPAC were associated with CBD lithiasis, chronic cholestasis, and a personal or family history of hepato-biliary cancer.

Lay summary: In the largest case-control study ever conducted in patients with LPAC syndrome, a rare genetic form of intrahepatic cholelithiasis in young adults, LPAC syndrome was found in approximately 1% of all patients admitted to the hospital for symptomatic gallstones and, in addition to the pre-established characteristics of the syndrome (age at first symptoms <40 years, recurrence of symptoms after cholecystectomy, and/or imaging evidence of intrahepatic microlithiasis), was associated with lower BMI, higher prevalence of common bile duct stones, and lower incidence of acute cholecystitis. ABCB4 gene variants, which were detected in about half of cases, were associated with common bile duct stones and a personal or family history of hepato-biliary cancer.

Keywords: ABCB4; ABCB4, ATP-binding cassette subfamily B member 4; CBD, common bile duct; Cancer; Cholestasis; ERCP, endoscopic retrograde cholangiopancreatography; FDR, false discovery rate; GGT, gamma-glutamyltransferase; ICP, intrahepatic cholestasis of pregnancy; LPAC; LPAC, low-phospholipid-associated cholelithiasis; MRCP, magnetic resonance cholangiopancreatography; Metabolic syndrome; Pregnancy; UDCA, ursodeoxycholic acid.