Progressive familial intrahepatic cholestasis (PFIC) encompasses a heterogeneous group of rare genetic disorders characterized by defects in biliary epithelial transporters, leading to bile acid accumulation, severe pruritus, progressive fibrosis, and end-stage liver disease. Historically conceptualized as an exclusively pediatric disease defined by straightforward autosomal recessive inheritance, the clinical and diagnostic landscape of PFIC is rapidly evolving. Groundbreaking developments in genomic sequencing, variant classification, and targeted molecular therapies are uncovering adult-onset presentations and transforming patient management.

In this interview, Laura Bull, PhD, RDN, Professor of Medicine at the University of California, San Francisco (UCSF), discusses the evolving genetic and therapeutic paradigms in PFIC. Dr. Bull explores the therapeutic impact of ileal bile acid transporter (IBAT) inhibitors, the clinical implementation of nested genomic diagnostics, the rising recognition of adult genetic cholestasis, and the clinical utility of re-analyzing inconclusive genetic tests over time.

Expanding the Therapeutic Armamentarium

For decades, medical therapy for PFIC was largely confined to non-specific symptomatic relief with ursodeoxycholic acid (UDCA), with progressive cases requiring surgical biliary diversion or orthotopic liver transplantation. The recent regulatory approval and widespread adoption of IBAT inhibitors represent a major milestone in non-invasive disease modification. By selectively interrupting the enterohepatic circulation of bile acids, IBAT inhibitors decrease systemic and hepatic bile acid pools, significantly alleviating disabling pruritus and improving biochemical markers of cholestasis.

“The most prominent advance in treatment in the last couple of years has been the approval and increasing use of IBAT inhibitors to treat cholestasis,” Dr. Bull noted. “And along with all that is the accumulation of data and information on when those are most useful to help manage cholestasis and delay or avoid more invasive surgeries such as liver transplant.”

As real-world registry data and clinical trial evidence accumulate, clinicians are gaining clearer insights into which patient subsets and specific genetic variants derive the greatest long-term benefit, positioning these targeted agents as essential tools for preserving native liver survival.

Modernizing Diagnostics: Nested Genomic Sequencing and Variant Interpretation

The diagnostic approach to cholestatic liver disease has expanded from traditional single-gene assays to comprehensive expanded gene panels, whole exome sequencing (WES), and whole genome sequencing (WGS). However, balancing comprehensive genetic evaluation with the cognitive burden of managing vast genomic data remains a clinical challenge. Dr. Bull highlighted an increasingly adopted diagnostic strategy known as the “nested” genomic sequencing framework.

“One approach which I think is going to be increasingly applied is the use of a nested diagnostic approach, where the whole genome or whole exome is sequenced, but initially only a subset of genes that are considered most likely to contain mutations that cause cholestasis will be assayed and will be interpreted,” Dr. Bull explained. “And then if there are clear results from that, we don't need to move on to the rest of the data, but if there aren't clear results from that, then the rest of the data can be used. That helps with the balance of keeping things focused, but where necessary, being able to expand out and look for other causes. It also leaves flexibility to go back to that data in the future if additional PFIC cholestasis genes are identified.”

This workflow streamlines initial diagnostic turnarounds while preserving comprehensive genomic data for longitudinal re-examination as novel cholestasis-associated genes are characterized.

Driving Recognition in Adult Hepatology and Re-Analyzing Negative Findings

Genomic medicine is fundamentally altering clinical perceptions regarding patient demographics. Hepatologists are identifying a substantial subset of adult patients presenting with cryptogenic cirrhosis, drug-induced liver injury, or unexplained cholestasis who harbor pathogenic variants in PFIC-related transporter genes. Unlike pediatric presentations, adult genetic cholestasis often features complex polygenic inheritance, hypomorphic mutations, or non-coding regulatory alterations.

“It's becoming increasingly clear that there's a subset of adult patients with unexplained cholestasis who have genetic etiologies for their condition, and our genetic understanding and diagnosis of such cases is consistently improving,” stated Dr. Bull.

To prevent diagnostic closure and resolve diagnostic odysseys, Dr. Bull underscored the clinical necessity of periodic genetic re-evaluation. Negative or ambiguous tests from years past should not be considered definitive: “Some clinical bodies have started to recommend re-analysis of negative genetic results every few years, or if there's a whole genome or whole exome sequence available, go back and check that to see if now something is coming up as likely contributing to a disease that we didn't know about a few years ago; or if a patient only had a very focused testing that was negative, to consider going ahead and doing a broader test such as whole genome or whole exome.”

Dr. Bull also pointed out that classification schemes for variants of uncertain significance (VUS) are becoming more refined: “Depending on one's location, there are more nuanced approaches to the clinical interpretation of genetic variants that are in the process of being implemented, which will be helpful because oftentimes there are variants that we can't really say for sure if they're contributing to disease, but they might be sort of warm as opposed if we call ones that clearly are pathogenic hot.”

Genotype-Phenotype Correlations and Non-Coding Variants

The ongoing refinement of genotype-phenotype correlations is central to tailoring precision therapies. Distinguishing missense mutations with residual transporter activity from complete null alleles directly impacts therapeutic responsiveness to UDCA and IBAT inhibitors.

Furthermore, as diagnostic capabilities advance through whole genome sequencing, functional genomics, and advanced in silico computational prediction tools, researchers are uncovering non-coding variants located in promoter and enhancer regions that disrupt gene expression without altering protein amino acid sequences.

“As we identify these variants, we have a better chance of being able to tell which of them could be actually affecting the disease,” Dr. Bull concluded. “And that should allow us to have a higher hit rate in terms of finding the genetic etiologies of cholestasis in patients. This may be especially the case for adult cholestasis. Genetics is increasingly becoming an important part of adult hepatology. Maintaining, refreshing, and enhancing your understanding of clinical genetics and its applications to adult hepatology will help keep you current on the latest developments in this area.”

Key Takeaways

IBAT inhibitors have transformed the PFIC therapeutic landscape, effectively reducing serum bile acids, managing intractable pruritus, and serving as a disease-modifying strategy to delay or prevent liver transplantation.
A nested genomic diagnostic framework—sequencing the exome or genome while initially filtering for high-yield cholestasis genes—optimizes diagnostic speed while retaining comprehensive data for future analysis.
Clinicians should routinely re-evaluate patients with prior negative or inconclusive genetic testing every few years, as evolving variant databases and re-annotation frequently resolve previous variants of uncertain significance (VUS).
PFIC is increasingly recognized in adult hepatology; adults with cryptogenic cholestasis, recurrent drug-induced cholestasis, or unexplained fibrosis warrant comprehensive genetic screening.
Advanced functional assays and in silico prediction models are uncovering regulatory, non-coding, and promoter/enhancer variants that drive disease expression without altering coding protein sequences.
Ongoing multidisciplinary collaboration between adult and pediatric hepatologists, genetic counselors, and molecular pathologists is essential to successfully integrate genomic insights into everyday clinical practice.

About Dr. Bull

Laura Bull, PhD, RDN, is a Professor in the Department of Medicine at the University of California, San Francisco. Her research focuses on using genetic, physiologic, and mechanistic approaches to increase the understanding of genetic etiologies contributing to liver disease. Dr. Bull’s laboratory is currently leading genetic studies of familial hypercholanemia, phenotype-genotype correlation in hereditary cholestasis, and evaluation of genetic factors influencing susceptibility to secondary liver diseases. Dr. Bull has published numerous peer-reviewed publication and has presented her research at many national and international meetings.

Genomic Advances in Treatment and Diagnosis of PFIC