Pediatric Evaluation and Registry for Liver Cholestasis in Canada

Overview

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.

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. The primary objective of this study is to establish a national, multi-center, longitudinal registry for children with ALGS and GIC in Canada, incorporating both prospective enrollment and retrospective data collection, and ensuring standardized, high-quality data capture across participating pediatric hepatology centers. The secondary objectives are: to characterize the natural history of ALGS and GIC, including disease progression, clinical outcomes, and complications over time, to evaluate the real-world effectiveness and safety of ileal bile acid transporter (IBAT) inhibitors and other therapeutic interventions in routine clinical practice, to assess long-term outcomes associated with different treatment strategies and identify unmet clinical needs to inform future research priorities and therapeutic development, to generate real-world evidence to support clinical decision-making and inform healthcare policy, including equitable access to specialized care and emerging therapies for rare pediatric cholestatic disorders, and to support the development and dissemination of standardized clinical care frameworks and best-practice recommendations across Canadian pediatric hepatology centers. 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. Other novel PFIC-like conditions continue to be identified and may be included in the registry. If additional conditions are identified for inclusion in the registry, a protocol amendment will be submitted for REB approval. * Enrollment within Canadian pediatric liver centers participating in the registry. These include: Children's Hospital of Eastern Ontario (Ottawa, ON, Lead Site), CHU Sainte-Justine (Montreal, QC), McMaster Children's Hospital (Hamilton, ON), Montreal Children's Hospital (Montreal, QC), Alberta Children's Hospital (Calgary, AB), Stollery Children's Hospital (Edmonton, AB), Janeway Children's Health and Rehabilitation Centre (St. John's, NL), Jim Pattison Children's Hospital (Saskatoon, SK), Children's Hospital LHSC (London, ON), Children's Hospital IWK Health Centre (Halifax, NS), BC Children's Hospital (Vancouver, BC), HSC Winnipeg Children's Hospital (Winnipeg, MB), Hôpital de l'Enfant-Jésus (Quebec City, QC) * 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. Methodology for Retrospective Participants * Participants diagnosed between January 1, 2022, and the site's date of PEARL Registry activation are eligible for retrospective enrollment. * Participating sites will complete a Retrospective Enrollment Form, capturing data available at or near the time of diagnosis, including: * Demographics and baseline clinical characteristics * Genetic testing results * Baseline laboratory and imaging data * Growth parameters * Initial disease manifestations and treatment history * To balance data completeness with feasibility, the registry will not require reconstruction of every historical routine clinic visit i.e every 4-6month till enrollment. Instead: o Annual (8-12-month interval) retrospective follow-up forms may be completed for the period between diagnosis and formal registry consent. o These forms are intended to capture key intermediate outcomes that may not meet criteria for major clinical events which will be captured in special clinical event form as below. * Special Clinical Event Forms will be used to capture major events occurring prior to consent, including: * Liver transplantation or listing * Biliary diversion or other surgical interventions * Hospitalizations related to liver disease * Hepatic decompensation or malignancy * Once informed consent is obtained and the participant is formally enrolled, retrospective participants will transition to the standard prospective follow-up schedule, identical to newly enrolled prospective participants. * To facilitate data management and minimize site burden, separate REDCap instruments and entry links will be used for retrospective and prospective enrollment. Retrospective participants will be clearly flagged within REDCap to permit stratified analyses and appropriate handling of follow-up time. Transition of Retrospective Participants to Prospective Follow-Up For participants enrolled through the retrospective arm, follow-up will be structured to ensure continuity and analytic consistency once informed consent is obtained. By design, retrospective data collection is limited to annual (8-12-month interval) follow-up periods prior to enrollment, after which all participants transition to the standard prospective follow-up schedule. For example, a participant diagnosed in 2022 who is enrolled into the registry in 2025 may have up to three annual retrospective follow-up forms completed, in addition to the Retrospective Enrollment Form, capturing key clinical milestones and treatment exposures during the interval between diagnosis and enrollment. Upon provision of informed consent, this participant will then transition to the standardized prospective follow-up cycle, consisting of visits every 4-6 months, identical to participants enrolled prospectively at diagnosis. In such cases, while prospective follow-up formally begins at the time of consent, the participant's disease trajectory will be anchored to the date of initial diagnosis. Accordingly, retrospective follow-up data will contribute to the early portion of the longitudinal dataset, with the first prospective visit occurring approximately 36-40 months after diagnosis, depending on the timing of enrollment. This approach ensures that clinically meaningful pre-enrollment data are captured without requiring exhaustive reconstruction of historical visits, while maintaining a uniform prospective follow-up framework after consent. For participants diagnosed closer to the time of enrollment (e.g., in 2023 or 2024), fewer annual retrospective follow-up forms may be completed, and those diagnosed near the date of consent may transition directly into prospective follow-up with minimal or no retrospective follow-up forms. This flexible design balances feasibility with data completeness and allows appropriate handling of variable follow-up duration in subsequent time-to-event analyses. Methodology for Prospective Participants * Participants newly diagnosed with ALGS or GIC/PFIC at or after the date of site activation into the PEARL Registry are eligible for prospective enrollment. * Sites will complete the standard Enrollment Form at the time of consent and enrollment. * All prospective participants will undergo structured follow-up at 6 months thereafter, using predefined clinical, laboratory, imaging, elastography, and medication review forms. * Clinical events (e.g., liver transplant, hospitalization) occurring between scheduled visits will be recorded through the Special Clinical Event Form. Participants will participate in the study until transition to adult care, unless the registry is closed, participant withdrawal, or until the study doctor decides to end participation early; whichever comes first. If the latter, the reason will be discussed with the participant. The informed consent process is essential to the ethical conduct of human research. In accordance with the Tri-Council Policy Statement: Ethical conduct for research involving human (TCPS2-2022), evidence of consent may be contained either as a signed consent form or as documentation by the researcher with another appropriate means of consent. All research-related activities conducted within will be done only after the researcher has sought the appropriate permissions from recruiting participants. The potential participant will be informed that participation is voluntary, and that he/she/they may withdraw from the research study at any time. Once screened based on study inclusion criteria, eligible potential participants will be asked by a member of the participant's circle of care if they are interested in discussing participation with the research staff. Recruitment materials No recruitment materials will be used, as participants are being recruited directly from clinics. Consent Process and Documentation Capacity will be assessed by the Principal Investigator (PI) during their clinic visit. Capacity assessment will then be relayed to clinical research study staff. It will be encouraged for the participant to sign the consent themselves if they have the capacity (determined by the PI) to do so, otherwise parental consent will be obtained. Participants unable to provide consent will be provided with an assent form to read and sign depending on the capacity, along with parental consent. Once the potential participant has been introduced to the research team, the research team will describe the goals and processes of the study to them. They will be given a paper copy of the consent form depending on preference and to read it carefully and ask any questions they might have. If they and their parent(s), as applicable, feel they have adequate information about the study and would like to participate, consent will be obtained. If they need more time to consider the study, they will be encouraged to take the consent form home; the research team will follow up should the participant request further time to review the consent or to discuss with family or friends. If they choose to consent thereafter, they can bring their signed consent form, or receive a new copy at their next scheduled clinic visit. Data collection of retrospective participants will begin after written consent is obtained. From the date consent is obtained, study visits will follow the prospective calendar for data collection. If consent is refused or withdrawn, data collection will cease for the participant. If a participant withdraws their consent during the study, data that is already collected will remain in the study database, but no further data will be collected. After Consent/Assent: * Participants will be assigned a unique study ID, recorded in the study master list and flagged in EPIC as enrolled. This study ID will also be used in REDCap. * The research team will document any participants who decline or withdraw. Data points captured at Baseline (Enrollment Data): * Name of Person Reporting the Case: Since there are many sites, having the name of the person reporting makes it easier in case we have to review missing data, inconsistencies, etc. * Demographics: Age at diagnosis, sex, ethnicity and family history of liver disease * Clinical Data: o Symptoms including pruritus, jaundice, fatigue o Signs including hepatosplenomegaly, and growth data. * Comorbidities such as cardiac defects (ALGS), hearing impairment (ATP8B1 deficiency) or others. * Current medications, previous therapies, and response to treatments. * Laboratory Data: * Liver enzymes (ALT, AST, GGT, alkaline phosphatase), bilirubin (total and direct), INR, albumin, total protein. Serum Bile acid (if available) * Fasting lipid profile, bile acids, CBC, and vitamin levels (A, D, E, K). * AFP * Imaging: o Liver ultrasound with Doppler for signs of portal hypertension or biliary abnormalities. * Genetic Data: o JAG1, NOTCH2 for ALGS; ATP8B1, ABCB11, ABCB4, TJP2, NR1H4, MYO5B for PFIC subtypes, and other relevant genetic data for other GIC disorders. (Genetic results are limited to pathogenic/likely pathogenic variants relevant to cholestatic liver disease diagnosis as documented in the clinical record will be collected. We will not collect broad genomic data etc, the genetic test done for these participants only includes mutations seen and not extended data as these are disease specific panels.) * Fibroscan (Elastography): o Liver stiffness and CAP score for non-invasive fibrosis assessment. * Liver biopsy * Growth \& Nutrition: o Height-for-age z score, weight-for-age z-score, BMI z-score, and head circumference (\<2 years), MUAC in cm. * Clinical Events: * Surgical history (e.g., biliary diversion, liver transplant), hospitalizations, and disease-related complications (ascites, upper gastrointestinal bleeding, spontaneous bacterial peritonitis, hepatic encephalopathy, hepatocellular carcinoma, liver transplant, death). Follow-up (6-monthly Visits): * Reassessment of clinical symptoms, medications, laboratory tests, imaging, Fibroscan, Liver biopsy and growth parameters. * Documentation of new events, including decompensation, transplant, hospitalizations, and mortality. Potential Risks \& Benefits Risk: As this is a non-interventional study, participants are not at risk directly. However, there is a risk of a data breach of personal health information, and we will take all necessary steps to prevent this from occurring. To minimize this risk, a unique study ID number will be assigned to each participant. A password-protected file linking study ID number and PHI will be stored on an encrypted computer at the local center. Only personnel at the local site will have access to the linking log. We will ensure that the personal information collected during the study is kept private, encrypted, and locked with only key research team members having access to it. However, even with these safeguards, there is a risk of a data breach. These risks are mitigated by using coded data, access controls, sit-level linking logs, and de-identified exports. These risks also exist with future uses of data, but is mitigated by only sharing coded data. Benefit: There may not be any potential benefit to participants, but we hope that the information we learn from this registry will help those with pediatric liver cholestasis in the future. Statistical Analysis Plan We will be using the Clinical Research Unit (CRU) at the Children's Hospital of Eastern Ontario (CHEO) for statistical analysis. Descriptive statistics will be applied to collected data. We will calculate median and interquartile range (IQR) or mean and standard deviation (SD) for continuous variables depending on the distribution. Categorical variables will be reported as count and numeric proportions. Continuous variables will compare with rank-sum analyses/t-test and proportions with chi-square analyses as appropriate. We will perform unadjusted as well as adjusted logistic regression analysis. Sample Size Justification The PEARL Registry aims to enroll approximately 220 pediatric participants diagnosed with Alagille Syndrome (ALGS) or Genetic Intrahepatic Cholestasis (GIC), including defined PFIC subtypes. Primary Endpoint Analysis The primary endpoint is Event-Free Survival (EFS), defined as survival without liver transplantation, biliary diversion surgery, hepatic decompensation, or death. Time-to-event analyses will be conducted using Kaplan-Meier methods, with comparison between treatment-exposed and non-exposed groups performed using the log-rank test. Cox proportional hazards regression will be used to estimate hazard ratios and adjust for relevant covariates, including but not limiting to: * Age at diagnosis * Disease category (ALGS vs. GIC/PFIC) * Genotype (where available) * Baseline disease severity markers * Treatment exposure (e.g., IBAT inhibitors) Data Collection and Management We will use a Centralized electronic database (Redcap) with robust data security measures. REDCap is a secure web application for building and managing online surveys and databases. While REDCap can be used to collect virtually any type of data, it is specifically geared to support online or offline data capture for research studies and quality operations. The REDCap Consortium, a vast support network of collaborators, is composed of thousands of active institutional partners in over one hundred countries who utilize and support REDCap in various ways. Individual sites may choose to collect the data sets on paper or other electronic formats prior to transcribing the information into the registry, but the security of any site-specific processes will be addressed and if needed approved by the center with their specific ethics committee. At CHEO, we will transcribe data directly into the registry and will not maintain a separate data file. REB approval is required at each participating institution with DTA/DUA contracts with primary site. Participant information such as name or hospital number will not be collected. Date of birth will be collected in order to calculate age at follow-up time points but will not be included in any summary data reports. Data will be de-identified and stored with strict confidentiality protocols. We have developed standardized SOPs (Standard Operating Procedures) to maintain consistency and high data quality. Futures uses of data/ Data Sharing Data collected for this research may be used in future research within or beyond the general area of research of the current study (futures uses of data). Researchers outside of this specific study may request access to the coded data for new research purposes. Participants will not be asked to provide additional informed consent for the use of their data for future research. Future research may be conducted inside Canada. Data sharing outside Canada is not planned initially. If future international collaboration is proposed, only de-identified data would be shared under agreements and with appropriate REB approvals. Future access requests (internal or external) will require: written proposal, steering committee review for alignment with objectives/scientific merit, feasibility, overlap/duplication, and ethics requirements. Any approved additional collections will proceed with appropriate REB review (and data-sharing agreements as applicable). Budget Industry support from pharmaceutical companies (Mirum, Medison) for sustainable funding to support operational costs per participant per enrollment and the primary site to manage the registry. As well as funding for the CRU/REDCap development teams for their support in this project. Mirum and Medison will not have any role in the scientific conduct of the registry, including study design, data collection, analysis, interpretation, or publication decisions, and/or ownership of the study data. Manuscripts, Abstracts, and Knowledge Dissemination All centers that actively participate in data collection and contribute to participant enrollment will be recognized in all major knowledge dissemination outputs, including abstracts, presentations, and manuscripts. Authorship on peer-reviewed publications will follow International Committee of Medical Journal Editors (ICMJE) guidelines, ensuring that all contributing investigators are fairly represented as authors or group contributors. Proposed manuscripts or analyses utilizing registry data will require Steering Committee review and approval before proceeding to ensure alignment with registry goals, prevent duplication of efforts, and maintain scientific rigor.