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In the U.S., primary sclerosing cholangitis (PSC), an uncommon fibro-inflammatory cholestatic liver disease that attacks the biliary tree, only affects an estimated 1 to 16 people but the disease significantly impacts quality of life and healthcare resources.

A comprehensive update on the management of PSC was recently published in .

Lead author David N. Assis, MD, of Yale University School of Medicine in New Haven, Connecticut, discussed the present state of knowledge and management in the following interview with the Reading Room.

Why an update on PSC now?

Assis: There have been advances in our understanding of the disease and the approach to management that merit an update to providers. With respect to PSC itself, big challenges remain, most significantly in the continued lack of effective medical treatment. Other challenges include the disease's rarity and the heterogeneity of its clinical features.

What is the epidemiology of PSC?

Assis: Occurrence appears to be increasing in North America and Western Europe. However, conducting epidemiological studies in the U.S. has been quite challenging. The lack of a disease-specific ICD code until 2018 has significantly hampered high-quality studies.

Another challenge in assessing incidence is the shift in the time at which patients are diagnosed -- in older studies, most patients presented with symptoms such as jaundice, pruritus, or cholangitis, whereas now most patients are asymptomatic at diagnosis and the disease is discovered on the basis of labs and cholangiogram imaging with MRI/MR cholangiopancreatography.

Furthermore, some studies of inflammatory bowel disease (IBD) cohorts receiving screening MRI reveal that a much greater percentage of patients with IBD have strictures typical of PSC than previously suspected, even though many of these patients have no symptoms or laboratory abnormalities. Therefore, patients are being diagnosed often at earlier stages.

Who's at risk?

Assis: PSC can no longer be considered a disease limited to patients of Northern European heritage, as was traditionally believed. In fact, a study by the North American Consortium for Autoimmune Liver Disease that this condition is not rare in Black patients, with the percentage of affected African Americans at a given medical center appearing to mirror the percentage living in that region. Therefore, PSC must be considered in patients of all racial and ethnic backgrounds.

Overall, approximately 80% of patients with PSC have concurrent IBD, which can develop after diagnosis and may be asymptomatic and predominantly right-sided. Therefore, it is very important for patients diagnosed with PSC to receive an ileocolonoscopy with random biopsies to rule out IBD.

What level of burden does PSC impose?

Assis: Although rare, this disease has a disproportionate impact and burden of care within hepatology and the wider medical community.

It is associated with an elevated risk of cholangiocarcinoma and colon cancer, symptomatic biliary strictures, which may require endoscopic intervention, and regular laboratory and imaging studies for monitoring. The lack of effective medical treatment leads to an elevated risk of progression to decompensated cirrhosis and liver transplantation.

Symptoms, which affect more than 50%, can significantly impair quality of life and include fatigue, abdominal pain, pruritus, and jaundice.

What are some of the significant new developments?

Assis: has highlighted the central role of high-quality MRI as the diagnostic test of choice. Endoscopic retrograde cholangiopancreatography should no longer be used, although it still plays a key role in endoscopic therapy for patients with biliary obstruction and in the evaluation of patients with suspected cholangiocarcinoma.

Patients with small-duct PSC features without IBD should be considered for genetic testing, since there is an increased frequency of genetic mutations leading to cholestasis in this subgroup.

In another development, prognostication based on calculated risk scores has improved significantly over the past decade. for example, is a risk score developed from machine learning that can very accurately predict hepatic decompensation due to PSC.

Biomarkers as predictors of disease progression are also being studied, and the peripheral blood test correlates with increases in liver fibrosis over time. For now, transient elastography including FibroScan has become routine for monitoring and can help identify the risk of decompensation and the need for transplant.

What about liver transplantation?

Assis: Patients who require transplantation for recurrent cholangitis can now benefit from a change in the United Network for Organ Sharing policy that provides MELD (model for end-stage liver disease) exception points for patients with two or more hospitalizations for cholangitis and sepsis within a 1-year period.

In addition, there's an increasing ability for qualifying centers to offer transplant to PSC patients with early-stage hilar cholangiocarcinoma. It is critically important not to perform a percutaneous biopsy to sample the malignant lesion, since this would prevent consideration for transplant.

What's new in research?

Assis: Innovative research on the role of the microbiome has highlighted a possible key link between the gut-liver interaction in patients with PSC-IBD. This will hopefully lead to interventions against key pathogenic bacteria to reduce inflammation.

Our center is currently evaluating the possibility of antibacterial viral phages, or bacteriophages, to target pathogenic bacteria, but clinical applications from these studies are still premature.

Additionally, clinical trials of pharmacotherapeutic candidates are ongoing, with a phase III study of norursodeoxycholic acid in Europe and a planned phase II study of in the U.S.

What does future management look like?

Assis: Future management will hopefully incorporate a better approach to early diagnosis of PSC and accurate methods for risk stratification at diagnosis and over time.

We will also be able to categorize patients based on their immunological and microbiome profile and to offer effective medical therapies at key moments in the natural history of the disease, so the progression to end-stage liver disease and the development of malignancy can be significantly reduced.

We are not there yet, and studies of medical therapies have yet to be successful, but the goals for future care are emerging.

What do gastroenterologists need to know now?

Assis: There are likely more patients with PSC, particularly in IBD cohorts, than we previously recognized. Any IBD patient should have at least annual liver enzyme testing to screen for PSC. Although routine screening with MRI in all IBD patients is not currently recommended, a low threshold should be applied for further evaluation if PSC is suspected.

After diagnosis, cholangiocarcinoma should be ruled out with high-quality MRI/MR cholangiopancreatography at baseline, with annual screening thereafter. Patients should all have a baseline characterization of fibrosis using methods such as FibroScan. Patients who inquire about their individual risk should be counseled that calculated risk tools are available.

Finally, all patients with this rare and therapeutically orphaned disease should be connected to an experienced medical center that can offer clinical trials and the latest innovations in care. Hopefully in the years ahead, we will have significant and impactful innovations to reduce disease progression and increase survival.

You can read the abstract of the study here, and about the clinical implications of the study here.