Genotype correlates with the natural history of severe bile salt export pump deficiency

Genotype correlates with the natural history of severe bile salt export pump deficiency · SciRah

^aPediatric Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, The Netherlands
^bKing's College London, United Kingdom
^cService d'Hépatologie et de Transplantation Hépatique Pédiatriques, Bicêtre Hôspital, AP-HP, Université Paris-Sud, Paris Saclay, Inserm UMR-S 1174, France
^dEuropean Reference Network on Hepatological Diseases (ERN RARE-LIVER)
^eGastroenterology, Hepatology, Nutritional Disorders and Paediatrics, The Children's Memorial Health Institute, Warsaw, Poland
^fUniversité
^gCatholique de Louvain, Cliniques St Luc, Brussels, Belgium
^hService de Biochemie, Bicêtre Hôspital, AP-HP, Université Paris-Sud, Paris Saclay, Inserm UMR-S 1174, France
ⁱLiver & SB Transplant & Hepatobiliary-Pancreatic Surgery, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
^jAlfaisal University, College of Medicine, Riyadh, Saudi Arabia
^kPediatric Hepatology, Gastroenterology and Transplantation, Ospedale Papa Giovanni XXIII, Bergamo, Italy
^lLiver Unit, Birmingham Women's and Children's Hospital, Birmingham, United Kingdom
^mServizio Di Epatologia e Nutrizione Pediatrica, Fondazione Irccs Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
ⁿPediatric Digestive Diseases, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
^oPaediatric Surgery, University Medical Centre Groningen, Groningen, The Netherlands
^pPaediatric and Liver Unit, Meyer Children's University Hospital of Florence
^qKoc University School of Medicine, Paediatric GI and Hepatology Liver Transplantation Centre, Kuttam System in Liver Medicine, Istanbul, Turkey
^rHospital Umraniye Training and Research Hospital, Istanbul, Turkey
^sUnité; d'hépatologie Pédiatrique et Transplantation, Hôpital Necker, Paris, France
^tUnité
^ud'hépatologie Pédiatrique et Transplantation, Hôpital Necker, Paris, France
^vCoimbra University Hospital Center, Coimbra, Portugal
^wPediatric Liver Service, La Paz University Hospital, Madrid, Spain

Abstract

BACKGROUND & AIMS Mutations in ABCB11 can cause deficiency of the bile salt export pump (BSEP), leading to cholestasis and end-stage liver disease. The rarity of the disease has prevented determination of associations between genotype and either natural history or the effect of surgical biliary diversion (SBD) on long-term outcome (liver transplantation (LTx), hepatocellular carcinoma (HCC), death). We aimed to determine these associations by assembling the largest genetically defined cohort of severe BSEP deficiency patients to date. METHODS This multicentre, retrospective cohort study of patients with homozygous or compound heterozygous pathological ABCB11 mutations included 264 patients. Patients were categorized according to genotypic severity (BSEP1, BSEP2, BSEP3). The predicted residual BSEP transport function decreased with each category. RESULTS Genotype severity was strongly associated with native liver survival (NLS, BSEP1 median 20.4y; BSEP2, 7.0y; BSEP3, 3.5y; P<.001). At age 15y, the proportion of patients with HCC was 4% in BSEP1, 7% in BSEP2 and 34% in BSEP3 (P=0.001). SBD was associated with significantly increased NLS (HR:0.50; 95%CI 0.27-0.94, P=.03) in BSEP1 and BSEP2. A serum bile acid (sBA) concentration below 102 μmol/L and a decrease in sBA by at least 75%, each shortly after SBD, reliably predicted NLS of at least 15 years after SBD (each P<.001). CONCLUSIONS The genotype of severe BSEP deficiency strongly predicts the long-term native liver survival, the risk to develop hepatocellular carcinoma, and the chance that surgical biliary diversion increases native liver survival. Serum bile acid parameters shortly after surgical biliary diversion allow the reliable identification of patients with long-term native liver survival.

TL;DRThe genotype of severe BSEP deficiency strongly predicts the long-term native liver survival, the risk to develop hepatocellular carcinoma, and the chance that surgical biliary diversion increasesnative liver survival. (Semantic Scholar)

Genotype correlates with the natural history of severe bile salt export pump deficiency

Abstract

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