Cholestatic Liver Disease, Hepatobiliary Cancers, Progressive Familial Intrahepatic Cholestasis (PFIC)
Conditions
Brief summary
This is a cross-sectional, multicenter tissue study with an exploratory aim to estimate the prevalence of genetic mutations that predispose individuals to diseases in the context of cholestatic disorders and hepatobiliary neoplasms. It is intended as a hypothesis-generating study for future empirical investigations.
Detailed description
This is a multicenter, cross-sectional tissue study designed to explore the prevalence of genetic mutations associated with cholestatic liver diseases and hepatobiliary neoplasms. It aims to generate hypotheses for future empirical research. Patient data will be collected, including medical history, imaging tests (e.g., abdominal ultrasound, CT, and MRI), and liver function tests, along with \[BA\] levels. Non-invasive liver fibrosis assessment (FibroScan or Shear-Wave elastography) and, where applicable, liver biopsies will be included, all referenced to the time of genetic testing. Molecular genetic analysis of PFIC will be conducted using a multiplex PCR NGS panel covering 37 genes. If clinical suspicion remains high despite negative NGS results, Whole Exome Sequencing (WES) will be used to identify previously unknown PFIC-related genes. WES will prioritize patients with hepatobiliary cancers on a healthy liver or without advanced fibrosis and those with a family history of PFIC or related conditions. Variants will be filtered based on clinical significance, gene-disease associations, and functional predictions, using resources like ClinVar, HGMD, and Personal Genomics PGVD. WES analysis will include at least one affected parent when available, with de novo mutations considered when both parents are involved. Only pathogenic or potentially pathogenic variants will be reported, confirmed by Sanger sequencing. Genetic counseling will be offered for patients with significant findings. Tumor tissue samples will also be analyzed for somatic mutations, potentially guiding therapeutic decisions or family screening. NGS for somatic mutations will use tumor samples collected for clinical purposes, with findings compared to germline mutations. This may inform treatment options and surveillance protocols for relatives. The data will be stored in an electronic archive using REDCap and analyzed by clinical staff. The collected data will include clinical history, liver function tests, response to ursodeoxycholic acid, liver fibrosis stage, and molecular results, along with relevant family histories and therapies. For patients undergoing surgery, the data will also cover pre-operative assessments, surgical techniques, and post-operative outcomes.
Interventions
None listed
Sponsors
IRCCS Azienda Ospedaliero-Universitaria di Bologna
Study design
Observational model
OTHER
Time perspective
OTHER
Eligibility
Sex/Gender
ALL
Age
12 Months to No maximum
Healthy volunteers
No
Inclusion criteria
* Instrumental or histological diagnosis of HBCs, defined as primary liver and/or biliary tumors (hepatocellular carcinoma, cholangiocarcinoma, hepatocholangiocarcinoma) occurring in patients without apparent underlying chronic liver disease or in the context of cryptogenic chronic liver disease; * Curative treatment through surgical resection of the neoplasm or liver transplantation * Diagnosis of CCLDs defined as: 1. GGT and/or alkaline phosphatase \>1.5 times the normal values in two or more measurements taken at least 6 months apart, 2. A history of pruritus combined with \[BA\] \>10 mmol/l for a period of ≥6 months. * Obtaining written informed consent
Exclusion criteria
* Other documented causes of chronic liver disease that can justify the clinical phenotype include: Primary biliary cholangitis Primary sclerosing cholangitis IgG4-related cholangiopathy Obstructive jaundice excluded by the demonstration of normal bile duct anatomy Negative virological tests for HBV, HCV, HEV Alcohol abuse Hemochromatosis Wilson's disease Alpha-1 antitrypsin deficiency
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Prevalence of Pathogenic and Variant Mutations in PFIC Genes in HBCs and CCLDs Patients | 3 years | To estimate the prevalence of pathogenic germline mutations, probably pathogenic mutations, variants of uncertain significance, probably benign variants, and benign variants in the genes responsible for PFIC in individuals diagnosed with HBCs who have undergone liver resection or liver transplantation, and in a population of patients with CCLDs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Identifying New PFIC-Associated Genes in HBCs and CCLDs Patients Negative for NGS Analysis via WES | 3 years | Estimate the percentage of patients carrying newly identified genes potentially responsible for PFIC, discovered through WES |
| Identification of Somatic Mutations in Tumor Tissue Samples from Patients Undergoing Liver Resection or Transplantation for HBCs | 3 years | Estimate percentage of patients carrying somatic mutations identified through NGS (in PFIC-related genes) or through WES. |
| Laboratory and Clinical Features of HBCs and CCLDs Patients | 3 years | Estimate percentage of patients with PFIC gene mutations and BRIC, LPAC, ICP, DIC phenotype, advanced fibrosis, pruritus, and/or neonatal jaundice |
| Comparison of Allelic Frequency of PFIC-Related Mutations in the NGS Panel between the Study Population and gnomAD Database | 3 years | Estimate the proportion of a specific allele among the total alleles identified in the NGS genetic analysis. |
Countries
Italy
Contacts
Primary ContactGiovanni Vitale
Outcome results
None listed