13 May Role of Genetic Research in Advancing PSC Treatment

MedicalResearch.com discussion with:
Dr. Bertus Eksteen PhD, MBChB, FRCP
Founder of the Calgary PSC Clinic
Member of the Calgary Liver Unit and the Southern Alberta Liver Transplant Clinic
Aspen Woods Clinic
Calgary, Canada

Dr. Bertus Eksteen

Primary sclerosing cholangitis (PSC) is a liver disease characterized by progressive inflammation and scarring of the bile ducts. PSC still has no known cause or cure and often leads to liver failure or cancer. For patients and clinicians, the lack of answers is deeply frustrating. But that’s beginning to change.

Thanks to genetic research, we’re uncovering clues about PSC’s origins—and why it behaves differently from patient to patient. By learning more about the genomic underpinnings of PSC, researchers can create new treatment targets, devise risk profiles for early diagnosis, and even develop better clinical tools for detecting the disease in its earliest stages. 

And that path forward doesn’t just start with new treatments — it begins in the lab.

Genetic Clues to PSC Onset

PSC isn’t directly inherited, but genetics likely play a significant role in determining who develops the disease. Several immune-related gene variations, particularly those related to the human leukocyte antigen (HLA) complex, have increased the risks of developing PSC. 

These variations don’t cause PSC on their own— researchers believe they interact with intestinal bacteria and other environmental factors, prompting the immune system to launch an attack on the bile ducts.

Understanding these genetic foundations provides a roadmap for following this disease very early. Instead of reacting to symptoms, we can start asking why specific people are predisposed in the first place. That insight is key to prevention and long-term disease management.

Mapping New Targets for Treatment

Genetics is not only about risk; it reveals biological pathways that can be therapeutically targeted. In PSC, many of these pathways involve immune system signaling and fibrosis. Researchers can develop drugs to block those signals when identifying the genes implicated in disease progression.

That’s already happening in some clinical trials. For example, therapies that regulate bile acid receptors or block fibrosis-promoting proteins are being tested in people with PSC. These approaches are rooted in discoveries about how the disease progresses at a genetic level. 

Many of these advances come from patient cohorts used in genetic studies — including one in Calgary, Canada, that has produced landmark findings.

A Cohort That Changed the Field

A cohort of more than 400 PSC patients in Calgary has become one of the largest and most studied worldwide. Insights from this cohort identifying nine newly recognized PSC risk loci are now driving research and care internationally. These findings emerged from collaborative work with the International PSC Study Group.

Much of that progress has been driven by researchers like Dr. Bertus Eksteen, whose work and leadership at the Aspen Woods Clinic have advanced scientific discovery and clinical care. Dr. Eksteen’s work connecting genetic markers to disease progression has helped shift the global approach to PSC research. 

By leveraging genetic markers for disease progression and developing research infrastructures in partnership with biotech companies, Eksteen’s efforts have made Calgary a key center for PSC innovation.

Genetics and Cancer Risk in PSC

PSC is associated with a higher risk of cancer compared with other liver diseases. Patients are at an increased risk of developing cholangiocarcinoma (bile-duct cancer), hepatocellular carcinoma (liver cancer), and colorectal cancer, particularly if they also have ulcerative colitis.

This is where genetic research can help. If doctors know which patients have specific risk variants, they might be able to predict who’s likely to get cancer and better tailor screening and intervention accordingly.

Eksteen and his colleagues are particularly interested in using genetic biomarkers to stratify risk among patients. This could help detect warning signs before imaging or symptoms reveal anything unusual. 

In time, it might also lead to new diagnostic tests that predict cancer before it takes root. It’s a new level of personalization that could transform how we manage long-term complications in Primary sclerosing cholangitis.

Designing Diagnostic Tools

Genetics also has the potential to change how PSC is diagnosed. Diagnosis often relies on imaging and liver biopsy, which can miss early signs. But genetic biomarkers could change that.

If specific variants are consistently linked to early disease activity or immune responses, they might be included in a diagnostic test. In theory, this could not only catch PSC early but identify individuals at risk for developing PSC even before it happens. With enough research, predictive diagnostics could become a standard practice.

The Bigger Picture: Genes, Environment and the Microbiome

PSC doesn’t happen in a vacuum. Its close relationship with inflammatory bowel disease (IBD), especially ulcerative colitis, hints at a bigger picture involving the gut-liver axis. Genetic studies are starting to connect the dots—showing how specific gene-environment interactions influence gut immunity and liver inflammation.

Some of the best work in this area has been done by scientists heavily embedded in genetics and immunology. Dr. Eksteen’s early work showed that mucosal T cells contribute to liver damage in PSC. This forms the blueprint for how immune cells move from the gut into the liver, potentially initiating PSC in someone genetically susceptible.

Moving from Knowledge to Action

Genetic studies give us hope. They do not fix PSC, but they change how we think about treating it. They also show us where to look next—whether inside immune cells, along bile ducts, or into the gut microbiome.

This progress would not have been possible without the contributions of clinician-researchers participating in PSC trials. They built patient registries, conducted trials, and published findings that have made Canada – and Calgary – visible in PSC research on a global level. 

Dr. Eksteen’s contribution has been especially notable in advancing fundamental science but also in therapeutic design.

Final Thoughts

There’s still a long way to go before PSC becomes manageable or curable. But with the growing power of genetic tools, that vision is becoming more realistic. We now understand more than ever who gets PSC, why it starts, and how it might be stopped.

Genetic research has not only given us greater insight into the disease but it’s also given us new questions to ask and a different path forward. Thanks to the tireless efforts of researchers like Dr. Bertus Eksteen, who combines science with patient care—that path is brighter than ever.

More information:

• Mohamed R, Tejaswi S, Aabakken L, Ponsioen CY, Bowlus CL, Adler DG, Forbes N, Paulsen V, Voermans RP, Urayama S, Peetermans J, Rousseau MJ, Eksteen B. Per-oral cholangioscopy in patients with primary sclerosing cholangitis: a 12-month follow-up study. Endosc Int Open. 2024 Feb 15;12(2):E237-E244. doi: 10.1055/a-2236-7557. PMID: 38362361; PMCID: PMC10869209.

• Bowlus CL, Eksteen B, Cheung AC, Thorburn D, Moylan CA, Pockros PJ, Forman LM, Dorenbaum A, Hirschfield GM, Kennedy C, Jaecklin T, McKibben A, Chien E, Baek M, Vig P, Levy C. Safety, tolerability, and efficacy of maralixibat in adults with primary sclerosing cholangitis: Open-label pilot study. Hepatol Commun. 2023 May 15;7(6):e0153. doi: 10.1097/HC9.0000000000000153. PMID: 37184523; PMCID: PMC10187837.

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Last Updated on May 13, 2025 by Marie Benz MD FAAD