RaDiCo-COLPAC - National Cohort on the Epidemiology, Clinical and Genetic Heterogeneity of "Low Phospholipid‐Associated Cholelithiasis" (LPAC) Syndrome FRESH-PEF74147-en Sonia GUEGUEN RaDiCo-COLPAC - National Cohort on the Epidemiology, Clinical and Genetic Heterogeneity of "Low Phospholipid‐Associated Cholelithiasis" (LPAC) Syndrome RaDiCo-COLPAC FRESH-PEF74147-en FRESH-PEF74147 C16-14 COLPAC NCT05961826 14238ND DC-2015-2480 Christophe CORPECHOT INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE (INSERM) Epidemiology France Portal (PEF) AGENCE NATIONALE DE LA RECHERCHE (ANR) MINISTERE DE L’ENSEIGNEMENT SUPERIEUR, DE LA RECHERCHE ET DE L’ESPACE null Juliette;CARTON CPP CNIL Other LPAC Syndrome Gallstones Rare disease Quality of Life Gastroenterology Cohort Gastroenterology Hepatology Internal medicine Medical genetics Paediatrics Public, environmental and occupational health Radiology and nuclear medicine Surgery Cholelithiasis Socio-demographic and economic determinants Socio-demographic and economic determinants: Age Behavioral determinants Behavioral determinants: Addiction Behavioral determinants: Physical activity Biological determinants Biological determinants: Genetic predisposition Biological determinants: Sex The main objective is to describe the clinical, biological and radiological manifestations of LPAC syndrome, defined according to current diagnostic criteria or according to criteria extended to any recurrent symptomatic gallstone disease, and to characterize its different possible courses. The secondary objectives are to estimate the prevalence of LPAC syndrome among patients referred for gallstone disease, to describe diagnostic and therapeutic practices, to identify new diagnostic criteria, to evaluate the response to medical and interventional treatments as well as the prognostic factors associated with an inadequate response, and finally to assess the impact of the syndrome on patients’ quality of life. The exploratory objectives aim to document the mode of genetic transmission and the penetrance of LPAC syndrome based on the phenotypes and genotypes of patients and their first-degree relatives, to deepen the genotype/phenotype correlations of the ABCB4 gene, and to search for new predisposition or modifier genes in patients with or without an ABCB4 mutation. LPAC syndrome is a rare, symptomatic form of intrahepatic cholesterol gallstone disease that primarily affects young individuals (under 40 years of age) and has a genetic origin; it is characterized by frequent recurrence after cholecystectomy and a good therapeutic response to ursodeoxycholic acid (UDCA) in many cases; this syndrome exhibits significant clinical and genetic heterogeneity, and its prevalence in the general population remains unknown to date. This is an observational study—both retrospective and prospective—involving the collection of biological samples, conducted as part of the routine care of patients at reference and competence centers for rare diseases; It primarily includes adult patients meeting the diagnostic criteria for LPAC syndrome, as well as a few pediatric cases, and blood samples will be collected from index cases and their relatives to study the transmission and segregation of the identified mutations and to validate the genetic diagnosis. The RaDiCo-COLPAC cohort is a national, multicenter, non-interventional, observational, longitudinal, descriptive, retrospective, and prospective study sponsored by Inserm and coordinated by the RaDiCo platform. It involves pediatric patients (ages 13 and older) and adults with LPAC (Low Phospholipid-Associated Cholelithiasis) syndrome who are being treated at Reference and Center of Excellence Centers for Inflammatory Biliary Tract Diseases (MIVB network, FILFOIE network) as well as in hepatogastroenterology departments affiliated with the ANGH. As of August 18, 2026, 614 patients have been enrolled across 20 different centers. Patients will be followed for 5 years after enrollment, with at least one annual visit. The projected end date for the study is June 30, 2029. LPAC syndrome is a rare genetic disorder associated with a constitutional abnormality in bile composition, resulting in an abnormally low concentration of phospholipids in the bile. This abnormality leads to intrahepatic cholesterol gallstones, which cause recurrent biliary pain—particularly after cholecystectomy—and may be complicated by cirrhosis or cholangiocarcinoma. The disease may be associated with cholestasis of pregnancy and a family history of symptomatic gallstones (40% of cases). It is characterized by significant clinical and genetic heterogeneity. Its prevalence is unknown but is estimated to be less than 1% of patients with gallstones. The study population includes prevalent and incident patients, aged 13 years or older, with LPAC syndrome meeting either the standard diagnostic criteria (at least 2 of the 3 criteria: onset before age 40, radiological evidence of intrahepatic gallstones, recurrence after cholecystectomy) or the expanded criteria (a single criterion). Liver transplant recipients are not included. An exploratory genetic study is offered to first-degree relatives (aged 18 and older) of the index cases to assess the penetrance of genetic abnormalities; their refusal does not affect the index case’s participation. Patients are recruited from referral and specialty centers for inflammatory biliary tract diseases (MIVB network, FILFOIE program) and from hepatogastroenterology departments affiliated with the ANGH, either during a routine follow-up visit (prevalent cases) or at the first post-diagnosis consultation (incident cases). The study does not alter patient care and does not require any additional tests; data are collected from medical records and routine care. A single, non-additional blood sample will be used to contribute to a proposed DNA bank. The cohort combines retrospective and prospective data. The data collected include administrative data, general and specific clinical data (initial symptoms, diagnosis, biliary manifestations), comorbidity data, medication data (particularly UDCA), family history data, laboratory data (liver function tests, glucose and lipid parameters), imaging data (hepatobiliary ultrasound, MRI cholangiography), histological and elastometric data, if available, genotypic data (ABCB4 and candidate genes), as well as quality of life data (SF-36), collected at least once a year. A sample is collected for a DNA bank and a plasma bank and stored at the CRB-HUEP. The RaDiCo-COLPAC cohort thus brings together longitudinal data from multiple centers on pediatric and adult patients with a rare disease. The harmonized collection of clinical, biological, radiological, and genetic data, combined with a genomic DNA and plasma bank, provides a structured foundation for analyzing the evolution of heterogeneity in LPAC syndrome. France Auvergne Rhône-Alpes Bourgogne Franche-Comté Centre-Val de Loire Grand Est Hauts-de-France Ile-de-France Normandie Nouvelle-Aquitaine Provence - Alpes - Côte d'Azur Individus Patients population Female Male Adolescent (13 to 18 years) Young Adult (19 to 24 years) Adult (25 to 44 years) Middle Aged (45 to 64 years) Aged (65 to 79 years) Aged, 80 and over (80 years and more) Any patient over 13 years of age, prevalent or incident, meeting the usual diagnostic criteria - Symptomatic gallstones with at least 2 out of 3 LPAC syndrome criteria - Symptomatic gallstones with only one out of 3 LPAC syndrome criteria LPAC syndrome diagnostic criteria (first symptoms before the age of 40, radiological images consistent with the existence of intrahepatic lithiasis, recurrence of symptoms after cholecystectomy) Patients who have undergone liver transplantation. Clinical data Paraclinical data (non-biological) Paraclinical data (non-biological) : Imaging Paraclinical data (non-biological) : Anthropometry Paraclinical data (non-biological) : Other Biological data Socio-demographic data Environmental / exposure data Genetic / genomic data Participant-reported health data Clinical and phenotypic data are structured using appropriate medical thesauri and nomenclatures including Orphanet and HPO to ensure consistent coding and better organization of the collected data. Steering Committee: Christophe CORPECHOT, Pierre-Antoine SORET, Olivier CHAZOUILLERES, David ZANDITENAS, Damien LABARRIERE, Raphael POIGNET, Angela LEBURGUE, RaDiCo + DSO Project Team. Scientific Committee: Christophe CORPECHOT, Pierre-Antoine SORET, Olivier CHAZOUILLERES, Nathalie CARRIE, Damien LABARRIERE, Raphael POIGNET; David ZANDITENAS, Angela LEBURGUE, RaDiCo + DSO Project Team. Data quality is ensured under the Data Management Plan and the Data Validation Plan with continuous data management. Data collected in the eCRF undergo consistency and completeness checks in particular through automatic control rules and a query system. Checks are carried out to identify data that are missing inconsistent or require clarification from the investigating centres. Corrections are made after verification with the centres concerned in accordance with research data management procedures. Data management process flowcharts are also used to document the data processing and validation circuits the various quality control points and the responsibilities of those involved at each stage. Health events / morbidity and mortality: manifestations of LPAC syndrome and course over time. The primary assessment is based on the description of the clinical, biological and radiological manifestations of LPAC syndrome and their course in adult and pediatric patients meeting the usual or extended diagnostic criteria. The variables used include: • Clinical characteristics: personal and family medical history related to the disease, clinical manifestations, medical complications and comorbidities; • Mortality data: occurrence of death, age at death and cause of death; • Biological parameters: results of liver biochemistry tests and glucose and lipid profile; • Radiological data: presence and location of stones or signs of intrahepatic, gallbladder or main bile duct microlithiasis, taking into account the radiologist’s experience; • Genetic characteristics: presence or absence of an ABCB4 gene mutation and type of mutation identified. The assessment covers data at diagnosis, at inclusion and during follow-up, in particular at visits and significant clinical events, such as a hospitalization or a consultation prompted by disease progression. The follow-up planned in the protocol is five years, with at least one annual visit. 1. Relative prevalence of LPAC syndrome among patients treated for gallstones The criteria are the relative prevalence and relative incidence of LPAC syndrome at the participating centers during the period specified in the protocol. They are based, respectively, on the number of LPAC cases divided by the number of gallstone cases, and on the number of new LPAC cases divided by the number of new gallstone cases. 2. Diagnostic and therapeutic practices and treatment approaches The assessment is based on the nature and sequence of the steps that led to the diagnosis, the time between the onset of symptoms and the diagnosis, and the duration of the diagnostic odyssey. The variables studied also include the medical and interventional treatments proposed, the healthcare professionals consulted, the tests performed, the frequency of follow-up, monitoring for complications, and the adjustment of treatment to the progression of the disease. 3. Identification of New Diagnostic Criteria The evaluation is based on the clinical, biological, and radiological characteristics of patients who meet the standard or expanded diagnostic criteria, as well as on available data from their first-degree relatives. Variables include, in particular, age at onset of symptoms, radiological signs of intrahepatic lithiasis or microlithiasis, and recurrence of symptoms after cholecystectomy. 4. Response to Medical and Interventional Treatments Response to ursodeoxycholic acid (UDCA) and to endoscopic, radiological, or surgical treatments is assessed based on changes in the frequency and intensity of pain episodes, the number of complications, liver function tests, radiological signs of intrahepatic lithiasis, and quality of life. An inadequate response is characterized by a lack of reduction in pain episodes or complications, a lack of improvement or normalization in liver function tests, a lack of regression in radiological findings, or a lack of improvement in quality of life and social functioning. 5. Prognostic factors associated with an unfavorable outcome or poor response to treatment The assessment is based on the association between clinical, biochemical, radiological, and therapeutic characteristics and the occurrence of complications—whether fatal or nonfatal—or death from liver-related causes or other causes. 6. Quality of Life / Perceived Health The criterion is the score on the various dimensions of the SF-36 questionnaire and its change over the course of the study. Patients complete the questionnaire at enrollment and then every 12 months, with the option to complete it every 3 months if they wish. Other Data is collected annually for 5 years per patient. Complete enumeration (including consecutive recruitment) Through organizations (health services or institutions schools businesses etc.) [500-1000[ individuals Converting or copying information into a structured record Interview with the participant (including clinical) Measurements and tests Physical/biological measurements (blood pressure, weight, biochemistry, imaging, etc.) Psychological tests/clinical scales (depression, cognition, quality of life, etc.) Observation (clinical or behavioural) Recording (audio, video, electrophysiological, imaging) Self-administered questionnaire Observational Study Observational Study Cohort study Monitoring by participant visit to the investigation center 621 au 01/10/2026 Ongoing study The data is hosted in France, within the France Cohortes secure environment, by a hosting provider certified as a Health Data Host (HDS). It is collected and centralized in a secure eCRF, accessible only to duly authorized individuals in accordance with current security and access management procedures. Restricted access The available data files consist of data collected as part of the cohort and selected based on the purpose of the access request. Certain collected data may not be included in the files provided if they are subject to regulatory, ethical, or personal data protection restrictions. Access to information regarding the cohort is contingent upon compliance with the confidentiality obligations applicable to the data, documents, and information made available. Authorized users agree to use this information solely for the approved purposes and not to disclose it to unauthorized third parties. These obligations may be formalized in specific agreements or contracts governing access to the data. Access to the dataset is governed by an access request procedure. Data access takes place exclusively within the France Cohortes secure environment, with no possibility of extracting raw data to an external environment. The data are not freely distributed, and their use is limited to authorized research projects in accordance with the cohort’s governance rules. Users must comply with the access conditions, confidentiality agreements, personal data protection rules, and data utilization guidelines established by the cohort. Juliette;CARTON Prior to any publication, the PRS holder—in consultation with the PRS manager, if applicable—shall determine, by mutual agreement with the relevant project committee and based on each party’s respective intellectual contributions, the authorship structure and the number of authors from each entity participating in the project. Publications must include at least one author from the sponsor. Provided that this practice is accepted by the publishers of these scientific journals, RaDiCo will be listed as a co-author of the publication. In the event of a refusal by the publisher, the members of the RaDiCo Consortium Agreement will provide the PRS manager or the PRS lead with the list of co-authors. Before publication, manuscripts are submitted to the relevant project committee for review. Users who wish to publish must take into account all comments made by the relevant committee, provided that such comments are well-founded and not arbitrary. The terms and conditions for publication and dissemination are specified in the PRS contract. According to the cohort’s Resource Access Charter, requests must be submitted as a research project synopsis to colpac@radico.fr (reviewed within one month by the RaDiCo-COLPAC Scientific Committee). Requests for access to RaDiCo-COLPAC data (aggregated or individual) will be reviewed by the Scientific Committee following submission of a Specific Research Project (SRP) summary, as defined in the Resource Access Charter. Data access is restricted to specific research projects (SRP). Any data access request is submitted by a user and assessed by the cohort’s relevant bodies, including a scientific review by the Scientific Committee and a feasibility, regulatory and legal analysis by the teams concerned. Once approved by the relevant bodies, the terms of data access and use are set out in a specific agreement. Results from the projects may be disseminated as scientific publications, presentations or reports, in compliance with confidentiality and the regulations applicable to health data.