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PBC Guideline Gaps
Personalized Medicine in PBC? Filling the Guideline Gap

Released: November 04, 2025

Alan Bonder
Alan Bonder, MD, AGAF
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Key Takeaways
  • The goals in PBC treatment guidelines do not account for newer data and treatment options.
  • The future of PBC treatment might be more like personalized medicine.

We are at an interesting crossroads with managing primary biliary cholangitis (PBC) as new treatments have recently been approved as second-line agents, but the guidelines have not yet been updated.

When the European Association for the Study of the Liver guidelines were published in 2015, we had no treatment for PBC except ursodeoxycholic acid (UDCA). And when the American Association for the Study of Liver Diseases guidelines were published in 2019, it was fewer than 2 years after obeticholic acid had been approved, an agent that will soon no longer be available in the US.

Until the guidelines are updated to account for the more recently approved second-line agents—the PPAR agonists elafibranor and seladelpar—I think the first question we need to ask ourselves when managing PBC is, “Who are the best patients for which we should move on to adding the currently approved second-line therapies?”

Time and Goal
To answer this question, I think we need to start defining what a biochemical response means. After starting UDCA, we wait 6-12 months to see if there is a biochemical response—if the alkaline phosphatase (ALP) goes below 1.67 times the upper limit of normal (ULN).

You could argue that's a relatively arbitrary time. Why in some patients 6 months, and in others 12 months? In which patients should we wait longer to see if the UDCA works? In which patients should we start thinking about starting second-line therapy sooner to more quickly prevent disease progression?

The other part of this question is whether the threshold should be 1.67 times the ULN. This was the threshold used in the POISE trial of obeticholic acid, but should we change our endpoint? Should an ALP any amount higher than the ULN be treated? Should the new the normal be completely normal, and not less than 1.67 times the ULN as outlined in the Toronto criteria?

For example, if a patient has an elevated stage of fibrosis, such as a liver stiffness of 9 or 10, but their ALP is 1.4 times the ULN, I would argue they have an incomplete biochemical response, but they will not qualify for second-line therapy based on the Toronto criteria.

A recently published study revealed that ALP response that is “adequate” but not normalized (ie, 1.1-1.5 times ULN) is associated with worse outcomes, especially among patients with advanced fibrosis or younger age. Emerging data indicate that a “deep response” is associated with improved prognosis. In a cohort study from the GLOBAL PBC Study Group, normalization of ALP or total bilirubin ≤0.6 times the ULN was associated with the lowest risk of liver transplantation or death.

I think the real question is how to risk stratify patients, with all the tools we have, to choose how long to wait for ALP improvement before adding second-line therapy, whether that’s 3, 6, or 12 months, or even not at all. When judging whether PBC has responded to first-line UDCA, perhaps we should also consider the person’s fibrosis, level, risk factors, and even symptoms.

Symptoms
One area where I feel we are completely in the gray zone is in addressing symptoms. We know that the symptoms of PBC—pruritus, fatigue—are overwhelming. We know that they affect quality of life. But these symptoms don't correlate with the biochemical response. So if a patient has a biochemical response and still has a poor quality of life, how are we going to approach this patient so we can actually try second-line therapies?

There are now data on second-line therapies showing promise in controlling symptoms and improving quality of life, as measured in the PBC-40 quality of life questionnaire. Personally, I believe treating PBC in the future will look like personalized medicine—not only what we have in the trials but using the specific drugs for a specific patient with specific needs. If we can reach that goal for PBC, I think we will see that we're not only going to be curing our patients, we will also by giving them a good quality of life.

Your Thoughts
How do you determine whether and when to move to second-line PBC treatment? Join the conversation in the comments below.

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