Ask AI
Back Back

Confounding Cholestasis: Considerations for the Assessment of Late-Onset Disease

Clinical Thought
Clinical Thought
See Activity Information

Released: September 29, 2026

See Activity Collection

Step 1 of 2

1 ClinicalThought 2 Complete Activity

Late-onset genetic cholestasis, such as progressive familial intrahepatic cholestasis (PFIC) and Alagille syndrome (ALGS), is increasingly diagnosed in adolescents and adults with previously unexplained or persistent cholestatic symptoms, like jaundice or pruritus. Read this expert commentary to learn about factors that lead to suspicion of late-onset cholestasis, practical considerations for genetic testing and counseling, and the vital roles of patient networks.

Naim Alkhouri
Naim Alkhouri, MD, FAASLD, DABON
Confounding cholestasis considerations


Continue to Activity

Adolescents and adults with persistent or unexplained cholestatic symptoms, such as jaundice and pruritus, are increasingly diagnosed with late-onset genetic cholestasis. As genetic testing has become more accessible, it is proving to be a valuable tool in the early diagnostic process, particularly for patients without a clear diagnosis, those presenting with atypical features of a known condition, or those with a poor response to treatment.

Genetic testing should always be implemented as part of a detailed clinical evaluation that includes measurement of biochemical markers, imaging to rule out structural causes, and assessment of family history. This is important because understanding the underlying etiology of a cholestatic disorder can aid in selecting a more effective management strategy and open a window for the implementation of innovative therapies, like ileal bile acid transporter (IBAT) inhibitors. The IBAT inhibitors have demonstrated efficacy in alleviating pruritus in certain cholestatic conditions, including Alagille syndrome (ALGS) and some types of progressive familial intrahepatic cholestasis (PFIC), although their effectiveness may vary depending on the genetic variant involved.

Candidates for Genetic Testing
Genetic causes of late-onset cholestasis should be suspected in the following clinical scenarios:

  • Patients with unexplained cholestasis, including those with chronically elevated alkaline phosphatase and bilirubin levels and negative assessment for common causes, like primary biliary cholangitis (PBC)
  • Patients with atypical features of more common causes, such as small-duct primary sclerosing cholangitis or metabolic dysfunction–associated steatohepatitis (MASH)
  • All women with a history of intrahepatic cholestasis of pregnancy (ICP) or hormone-induced cholestasis triggered by birth control
  • Patients with a history of complicated gallstone disease, such as early-onset or intrahepatic gallstones

Of note, adolescents and adults with genetic cholestasis typically have distinct biochemical marker patterns on lab testing. These include elevated serum bile acid, alkaline phosphatase, and gamma-glutamyl-transferase levels, though the latter may be normal in some cases. In addition, elevation in alkaline phosphatase levels is generally more pronounced than elevations in alanine and aspartate aminotransferase levels.

Integrating Genetic Testing into Practice
Based on patients’ clinical presentation, healthcare professionals (HCPs) may choose to order genetic testing for late-onset cholestasis via a targeted gene panel, whole-exome sequencing (WES), or whole-genome sequencing (WGS).

A targeted gene panel provides information about the presence of genetic variants in the investigated genes; the interpretation of these results can be complex. The American College of Medical Genetics and Genomics and the Association for Molecular Pathology provide guidelines for classifying identified genetic variants into 5 distinct categories: pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, and benign. This classification is based on evidence from population data, computational predictions, functional studies, and segregation analyses. The classification of a genetic finding is crucial for determining its clinical relevance and guiding patient care.

In cases where targeted gene panels fail to identify mutations or patients have complex presentations that might suggest the presence of previously undescribed mutations, WES or, optimally, WGS should be recommended.

Genetic testing is necessary to determine the etiology of late-onset cholestasis, but genetic counseling plays a crucial role in providing education, facilitating informed decision-making, and offering support to patients and their families. Regardless of patients’ genetic testing results, genetic counseling helps them understand the implications of the findings and address the potential risks for family members and future offspring.

Patient Networks as Resources for HCPs
Networks for patients with rare diseases can provide valuable resources for HCPs who care for these patients. PFIC Network is an excellent example, functioning as a practical extension of the clinical team.

For HCPs who may see 1 or 2 patients with PFIC in their career, PFIC Network supplies essential disease-specific expertise that no single practice can maintain alone. HCPs can contact a PFIC Network Scientific Medical Advisory Board member for input on ambiguous phenotypes, VUS, and management decisions where published guidance is lacking. The PFIC Network Patient and Provider Outreach Program also offers packets that give patients and their families information on the network and PFIC. PFIC Network Provider Outreach packets give patients and families a structured way to open the conversation with an HCP and help them get a head start on communication so visits can be as productive as possible from the beginning of care. PFIC Network’s vast library of resources, including educational brochures, webinars, and a curated research database, keeps the care team current on all 13 PFIC-associated genes, surgical biliary diversion, and the rapidly evolving treatment landscape, including current evidence on IBAT inhibitors.

PFIC Network also fills evidence gaps that directly affect HCPs’ bedside decision-making. Its patient registry is building a much-needed natural history dataset, and its treatment experience app is capturing real-world response, tolerability, and symptom trajectories, including for pruritus, the outcome patients care about most. HCPs can request de-identified registry data, join the research consortium, apply for grants, and steer PFIC research priorities through its research roadmap.

Just as important, PFIC Network helps HCPs deliver comprehensive care to patients by assisting with services some practices cannot provide. This includes a financial assistance program, peer support, mental health resources, and a global directory that links patients to advocacy groups, nationwide organizations, and open clinical trial opportunities.

Your Thoughts
How often do you evaluate or manage patients with PFIC in your practice? You can get involved in the conversation by answering the poll question and posting a comment below.

Continue to Activity

Poll

1.

How often do you evaluate or manage patients with PFIC in your practice?

Submit