Pediatric Evaluation and Registry for Liver Cholestasis in Canada
brief summary
The purpose of this study is to create a national, multi-centre registry for children with Alagille syndrome (ALGS) and Genetic Intrahepatic Cholestasis (GIC) that follows participants long-term, ensuring standardized, high-quality data capture across all participating pediatric hepatology centres. Inclusion criteria: • Pediatric participants (\<18 years old) with genetically confirmed or clinically diagnosed ALGS or any of the various subtypes of GIC, each associated with a distinct genetic mutation: A. PFIC Type 1 (FIC1 Deficiency) - Mutation in ATP8B1 gene. B. PFIC Type 2 (BSEP Deficiency) - Mutation in ABCB11 gene. C. PFIC Type 3 (MDR3 Deficiency) - Mutation in ABCB4 gene. D. PFIC Type 4 (TJP2 Deficiency) - Mutation in TJP2 gene. E. PFIC Type 5 (FXR Deficiency) - Mutation in NR1H4 gene. F. PFIC Type 6 (MYO5B-Associated) - Mutation in MYO5B gene. G. Progressive cholestasis of northwestern Quebec (PCNQ)-Mutation in UTP4 gene. * Enrollment within Canadian pediatric liver centers participating in the registry. * Written informed consent obtained from participant if they have the capacity, or parents/guardians, and assent from participants as appropriate. Exclusion criteria: • Inability to comply with follow-up requirements (lost to follow-up). Participants will be recruited from our hepatology clinics retrospectively (diagnosed on or after January 1, 2022) and prospectively (newly diagnosed). Written consent/assent will be obtained from all participants prior to data collection from the participants' medical chart.
detailed description
Cholestatic liver diseases of genetic origin represent a major cause of chronic liver disease, morbidity, and liver transplantation in children. Among these, Alagille syndrome (ALGS) and the spectrum of disorders traditionally grouped as Progressive Familial Intrahepatic Cholestasis (PFIC) account for a substantial proportion of pediatric cholestasis worldwide. Advances in molecular genetics have demonstrated that PFIC represents only a subset of a broader and expanding group of monogenic disorders affecting bile formation, secretion, and transport. As such, the term Genetic Intrahepatic Cholestasis (GIC) has emerged as a more inclusive and biologically accurate classification, encompassing both classical PFIC disorders and genetically defined cholestatic conditions that do not fit existing PFIC subtypes.
Genetic Intrahepatic Cholestasis (GIC) refers to a heterogeneous group of inherited disorders characterized by impaired bile acid synthesis, transport, or canalicular excretion, leading to chronic intrahepatic cholestasis beginning in infancy or childhood. This category includes, but is not limited to, disorders caused by pathogenic variants in genes such as ATP8B1, ABCB11, ABCB4, TJP2, NR1H4, MYO5B, and others, as well as newly described or ultra-rare conditions that are not yet formally classified. Importantly, the clinical course, treatment response, and long-term outcomes of GIC vary widely by genotype, underscoring the need for granular, longitudinal, genotype-phenotype-linked data. Alagille syndrome, a multisystem disorder most commonly caused by pathogenic variants in JAG1 or NOTCH2, represents a distinct but related cholestatic condition with significant variability in hepatic severity and outcomes. Despite overlapping therapeutic strategies with GIC particularly the increasing use of ileal bile acid transporter (IBAT) inhibitors. ALGS has unique clinical trajectories that warrant dedicated, disease-specific investigation within a unified registry framework.
The Canadian Pediatric Hepatology Research Group (CPHRG) is a national collaborative network comprising all academic pediatric hepatology centers across Canada. The group is dedicated to advancing research, improving clinical outcomes, and informing health policy for children with liver diseases through coordinated, multi-center initiatives. Despite this unified national infrastructure, Canada currently lacks a dedicated pediatric hepatology registry focused on genetic cholestatic disorders.
Participants will be recruited from our hepatology clinics retrospectively (diagnosed on or after January 1, 2022) and prospectively (newly diagnosed). Written consent/assent will be obtained from all participants prior to data collection from the participants' medical chart.
official title
PEARL - Pediatric Evaluation and Registry for Liver Cholestasis in Canada