DEFINING THE GENETIC DRIVERS OF ADULT-ONSET CHOLESTATIC LIVER DISEASE (FIRST)

Institute of Hospitalization and Scientific Care (IRCCS)

Status: Enrolling

Conditions: Progressive Familial Intrahepatic Cholestasis; Cholestatic Liver Disease

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

Study type: Interventional

Funder types: Other

Identifiers

NCT07317193

FIRST

Details and patient eligibility

About

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.

Enrollment: 60 estimated patients

Sex: All

Ages: 18 to 65 years old

Volunteers: Accepts Healthy Volunteers

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)

Exclusion criteria

Cases:

• Patients who do not possess the above inclusion criteria or have at least one of the following exclusion criteria:
• 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

Trial design

Primary purpose: Prevention

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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60 participants in 1 patient group

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

Experimental group

Description:

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.

Treatment:

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