Protective potential of the gallbladder in primary sclerosing cholangitis

Nora Cazzagon; Ester Gonzalez-Sanchez; Haquima El-Mourabit; Dominique Wendum; Dominique Rainteau; Lydie Humbert; Christophe Corpechot; Olivier Chazouillères; Lionel Arrivé; Chantal Housset; Sara Lemoinne

doi:10.1016/j.jhepr.2022.100649

Protective potential of the gallbladder in primary sclerosing cholangitis

JHEP Rep. 2022 Dec 17;5(4):100649. doi: 10.1016/j.jhepr.2022.100649. eCollection 2023 Apr.

Authors

Nora Cazzagon^{1

2

3}, Ester Gonzalez-Sanchez^{1

4

5

6}, Haquima El-Mourabit¹, Dominique Wendum^{1

7}, Dominique Rainteau^{1

8}, Lydie Humbert^{1

8}, Christophe Corpechot^{1

9}, Olivier Chazouillères^{1

9}, Lionel Arrivé¹⁰, Chantal Housset^{1

9}, Sara Lemoinne^{1

9}

Affiliations

¹ Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France.
² Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
³ European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Azienda Ospedale-Università Padova, Padova, Italy.
⁴ TGF-β and Cancer Group. Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet De Llobregat, Barcelona, Spain.
⁵ Oncology Program, Ciberehd, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto De Salud Carlos III, Spain.
⁶ Department of Physiological Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Spain.
⁷ Assistance Publique-Hôpitaux de Paris (AP-HP). Sorbonne Université. Department of Pathology, Saint-Antoine Hospital, Paris, France.
⁸ Assistance Publique-Hôpitaux de Paris (AP-HP). Sorbonne Université. Department of Clinical Metabolomics, Saint Antoine Hospital, Paris, France.
⁹ Assistance Publique-Hôpitaux de Paris (AP-HP). Sorbonne Université. Department of Hepatology, Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis (CRMR MIVB-H), ERN RARE-LIVER, Saint-Antoine Hospital, Paris, France.
¹⁰ Assistance Publique-Hôpitaux de Paris (AP-HP). Sorbonne Université. Department of Radiology, Saint-Antoine Hospital, Paris, France.

Abstract

Background & aims: Gallbladder enlargement is common in patients with primary sclerosing cholangitis (PSC). The gallbladder may confer hepatoprotection against bile acid overload, through the sequestration and cholecystohepatic shunt of bile acids. The aim of this study was to assess the potential impact of the gallbladder on disease features and bile acid homeostasis in PSC.

Methods: Patients with PSC from a single tertiary center who underwent liver MRI with three-dimensional cholangiography and concomitant analyses of serum bile acids were included. Gallbladder volume was measured by MRI and a cut-off of 50 ml was used to define gallbladder enlargement. Bile acid profiles and PSC severity, as assessed by blood tests and MRI features, were compared among patients according to gallbladder size (enlarged vs. normal-sized) or presence (removed vs. conserved). The impact of cholecystectomy was also assessed in the Abcb4 knockout mouse model of PSC.

Results: Sixty-one patients with PSC, all treated with ursodeoxycholic acid (UDCA), were included. The gallbladder was enlarged in 30 patients, whereas 11 patients had been previously cholecystectomized. Patients with enlarged gallbladders had significantly lower alkaline phosphatase, a lower tauro-vs. glycoconjugate ratio and a higher UDCA vs. total bile acid ratio compared to those with normal-sized gallbladders. In addition, gallbladder volume negatively correlated with the hydrophobicity index of bile acids. Cholecystectomized patients displayed significantly higher aspartate aminotransferase and more severe bile duct strictures and dilatations compared to those with conserved gallbladder. In the Abcb4 knockout mice, cholecystectomy caused an increase in hepatic bile acid content and in circulating secondary bile acids, and an aggravation in cholangitis, inflammation and liver fibrosis.

Conclusion: Altogether, our findings indicate that the gallbladder fulfills protective functions in PSC.

Impact and implications: In patients with primary sclerosing cholangitis (PSC), gallbladder status impacts on bile acid homeostasis and disease features. We found evidence of lessened bile acid toxicity in patients with PSC and enlarged gallbladders and of increased disease severity in those who were previously cholecystectomized. In the Abcb4 knockout mouse model of PSC, cholecystectomy causes an aggravation of cholangitis and liver fibrosis. Overall, our results suggest that the gallbladder plays a protective role in PSC.

Keywords: ABC, ATP-binding cassette transporter; Abcb4 knockout mice; BA, bile acid; Bile acids; C4, 7α-hydroxy-4-cholesten-3-one; CFTR, cystic fibrosis transmembrane conductance regulator; CK19, cytokeratin 19; Cholecystectomy; FGF19, fibroblast growth factor 19; Gallbladder volume; HPLC-MS/MS, high-performance liquid chromatography coupled to tandem mass spectrometry; IBD, inflammatory bowel disease; MRC, magnetic resonance cholangiography; Magnetic resonance imaging; PSC, primary sclerosing cholangitis; UDCA, ursodeoxycholic acid; ULN, upper limit of normal.