DEFINING THE GENETIC DRIVERS OF ADULT-ONSET CHOLESTATIC LIVER DISEASE

NCT ID: NCT07317193

Last Updated: 2026-01-05

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-11-01
• Study Completion Date: 2026-10-31

Brief Summary

Cholestatic disease in adults comprises a heterogeneous group of conditions characterized by intra- or extrahepatic alterations of bile flow that can lead to fibrosis or hepatic decompensation. Due to the heterogeneity of clinical manifestation, which is sometimes very subtle, diagnosis based on clinical, histological, and radiological evaluation is often very complicated. Genetic testing can be helpful in identifying the cause of the clinical phenotype, thereby allowing for targeted follow-up adequate to the patient's specific characteristics and risk factors. Although the utility of genetic analysis has been well documented for other liver diseases or in pediatric cohorts of children with cholestatic disease, the use and benefits of genetic testing in adults with cholestatic disease are still little explored and investigated. In this context, through the use of whole-genome sequencing (WGS), the FIRST project aims to evaluate the role of rare genetic variants in the pathogenesis of cholestatic disease and the utility of WGS in defining a genetic diagnosis.

Conditions

Cholestatic Liver Disease; Progressive Familial Intrahepatic Cholestasis

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

Evaluation of the Diagnostic Yield of WGS in Adult Patients with Idopathic Cholestasis

The FIRST study is a single-center, non-pharmacological, interventional investigation that aims to determine the diagnostic yield of Whole Genome Sequencing (WGS) in adult patients with unexplained cholestatic liver disease or with atypical clinical presentations (such as particular forms of PSC or PBC). The study design involves enrolling 60 patients ("Cases") who undergo WGS on peripheral blood samples, a procedure considered extra standard of care.

Group Type: EXPERIMENTAL

Advanced Whole Genome Sequencing to Identify Rare Pathogenic Variants in Unexplained Cholestatic Liver Disease

Intervention Type: OTHER

The intervention consists of advanced genetic analysis to identify the presence of rare harmful variants in genes known to be associated with cholestasis or in other genes related to liver disorders. The results from the cases will be compared with WGS data from a large group of 1025 healthy controls (previously collected within the FOGS study) to assess the enrichment of these variants. The primary objective is to establish the prevalence of pathogenic variants, while secondary objectives include identifying new potential genetic determinants to improve diagnostic accuracy and optimize the clinical management of these complex conditions.

Interventions

Advanced Whole Genome Sequencing to Identify Rare Pathogenic Variants in Unexplained Cholestatic Liver Disease

The intervention consists of advanced genetic analysis to identify the presence of rare harmful variants in genes known to be associated with cholestasis or in other genes related to liver disorders. The results from the cases will be compared with WGS data from a large group of 1025 healthy controls (previously collected within the FOGS study) to assess the enrichment of these variants. The primary objective is to establish the prevalence of pathogenic variants, while secondary objectives include identifying new potential genetic determinants to improve diagnostic accuracy and optimize the clinical management of these complex conditions.

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

Cases:

• Adults, aged > 18 years with:

1. persistent or intermittent elevations in serum alkaline phosphatase (ALP) or gamma-glutamyltransferase (GGT) for at least six months not explained following standard diagnostic assessment adhering to the guidelines of the European Association for the Study of the Liver (EASL), or with a positive family history of unexplained cholestasis or hepato-biliary cancer, negative to previous genetic tests (targeted panel for PFIC genes or WES);

2. primary sclerosing cholangitis (PSC) with unusual features: small-duct PSC, non-typical radiological findings according to radiological guidelines on PSC, absence of concomitant inflammatory bowel disease, negative to previous genetic tests (targeted panel for PFIC genes or WES) or who didn't perform previous genetic test;

3. primary biliary cholangitis (PBC) without specific anti-mitochondrial antibodies, negative to previous genetic tests (targeted panel for PFIC genes or WES) or who didn't perform previous genetic test.

• Signature of informed consent

Controls:

-Blood donors (age 18-65 years) without clinical signs of liver diseases based on the collected clinical parameters: anthropometric (BMI>18 and <25), haematological (Hb, white blood cells, platelets within the reference range), biochemical traits (albumin, bilirubin, AST, ALT, GGT, ALP within the reference range), medical history (negative for chronic or concomitant diseases, including immunological diseases)

• an already known genetic diagnosis explaining the clinical phenotype
• affected by other causes of liver disease such as viral or autoimmune hepatitis

Controls:

-Blood donors with clinical signs of liver diseases

Exclusion Criteria

Cases:

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

OTHER

Sponsor Role: lead

Responsible Party

Luisa Ronzoni

Principal Investigator, Medical Doctor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico - Istituto di Ricovero e Cura a Carattere Scientifico di natura pubblica

Milan, Milano, Italy

Site Status: RECRUITING

Countries

Italy

Central Contacts

Luisa Ronzoni, Doctor

Role: CONTACT

luisa.ronzoni@policlinico.mi.it

02.5503.4101

Facility Contacts

Luisa Ronzoni

Role: primary

luisa.ronzoni@policlinico.mi.it

02.5503.4101

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

FIRST

Identifier Type: -

Identifier Source: org_study_id