Diagnosis of PBC

Kris Kowdley, MD, FACP, FACG, AGAF, FAASLD: Let’s talk about how we diagnose PBC [primary biliary cholangitis] and how we risk stratify patients. Ed, tell us a little about how PBC is diagnosed and by whom. What should a gastroenterologist vs a hepatologist vs a primary care physician think about when diagnosing PBC?

Edward Mena, MD: First, thank you for the guidelines you wrote at the Chronic Liver Disease Foundation. Those were really good and very helpful. That was a robust data set of 4000-plus patients.

When I think about how we make the diagnosis and screening, the first thing we want to teach, especially for primary care providers, is abnormal liver enzymes. We need to look at abnormal alkaline phosphates and understand how that’s playing a role and how it’s balanced between AST [aspartate aminotransferase] and ALT [alanine aminotransferase]. The marker we typically use to confirm the diagnosis is the antimitochondrial antibody, which is a highly sensitive and specific test for primary biliary cholangitis.

One thing I learned in that paper is about those 3 scenarios you wrote about. Scenario No. 1 is to confirm the diagnosis is an elevated alkaline phosphatase with a positive antimitochondrial antibody. Scenario No. 2 is the elevated alkaline phosphatase, with possibly a negative antimitochondrial antibody [AMA] and a positive antinuclear antibody [ANA] with those other 2 specific markers. Scenario No. 3, which individuals do less these days, is the elevated alkaline phosphatase, with a liver biopsy showing primary biliary cholangitis. The way we all need to think about it, whether it’s a primary care physician or a gastroenterologist, is first to make the diagnosis. We’ll discuss treatment in a bit, but putting these patients on treatment sooner rather than later is probably the way to go.

Kris Kowdley, MD, FACP, FACG, AGAF, FAASLD: Great summary. We don’t need a biopsy. For the vast majority of patients, an AMA or disease-specific ANA is very useful. Does anybody have any comments? There are panels that you can order where you can get all the antibodies in 1 shot. It’s very convenient. Sonal, do you have anything to add about how you approach diagnosis as a hepatologist?

Sonal Kumar, MD, MPH: That’s in line with what I do. The only time we use liver biopsies is when the diagnosis is in question or you’re looking for coexisting liver diseases. But you don’t need it to diagnose PBC.

David Victor III, MD: One thing I have happen more often, now that patients are facile with the internet, is patients show up with a positive AMA. A positive AMA doesn’t completely equate to a diagnosis of PBC. You can have AMA positivity without the disease. It’s required, and patients and providers should know that it’s possible to have an autoantibody and not have the clinical manifestation of primary biliary cholangitis.

Kris Kowdley, MD, FACP, FACG, AGAF, FAASLD: This is an excellent point. We know that there’s an inexpensive ELISA [enzyme-linked immunosorbent assay]–based test. In the past, we used to get a titer, like 1 to 40 or 1 to 80. Now we get a number and a cutoff of 20 or 22, above which is reported as positive. Of course, there are a lot of false positive AMAs, so it’s important to reassure the patient and the referring doctor that it doesn’t necessarily equate to PBC. At the same time, there are patients who are AMA negative, so you need to consider the diagnosis even in patients who don’t have that.

Edward Mena, MD: That’s a great point. We get consults all the time for a normal alkaline phosphatase and a positive antimitochondrial antibody. I’ve been following them yearly in my clinic, but is there something different you all do?

Kris Kowdley, MD, FACP, FACG, AGAF, FAASLD: That’s a great question. How do you approach a positive AMA based on an ELISA test with a normal alkaline phosphatase? Sonal, we’ll start with you.

Sonal Kumar, MD, MPH: I’ll see them in my clinic or explain what it means to have a positive AMA. Then they can follow with their primary care physician and their annual labs. If the alkaline phosphatase is ever elevated, then they come back.

Kris Kowdley, MD, FACP, FACG, AGAF, FAASLD: David?

David Victor III, MD: In my clinical practice, I spend a little time defining what primary biliary cholangitis is. I engage them to read about it and bring them back 6 to 12 months later with repeat lab testing. I also talk to them about the delay in diagnosis that often could happen. I tell them that if they have an alkaline phosphatase elevated over any course, they should talk to me. Because of the timing to symptoms or timing to diagnosis delays of years for a lot of our studies, I ask the patient to invest in following their alkaline phosphatase going forward.

Kris Kowdley, MD, FACP, FACG, AGAF, FAASLD: That’s a good point. The point I want to make is that our thinking is evolving. We used to think that the subset of patients with a positive AMA, who have a normal alkaline phosphatase, are going to remain in that category indefinitely. But it’s becoming clearer that a high percentage of those patients, if you follow them, will develop an elevated alkaline phosphatase. The first point is that if the titer is low positive, then consider an immunofixation or immunofluorescence. For a more specific test, order that PBC panel if it’s available. If it’s strongly positive—if the number is over 50, 60, 80, 100, then that’s usually true positive—you’ll want to follow those patients because eventually they’ll get an elevated alkaline phosphate.

Steven Flamm, MD, FAASLD, FACG: First, this is a very uncommon scenario. Physicians aren’t checking AMA in patients who have normal alkaline phosphatase in the first place. The time I’ve seen it the most is if a family member has PBC and 1 of the other family members is checked to see if they have it, and an AMA is sent even with a normal alkaline phosphatase. It’s quite clear that if you follow those patients long enough, a high percentage of them will develop PBC. I send them back though to primary care and talk to the patient too the primary care physician. I say, “Check a liver panel every year. If that alkaline phosphatase starts to rise, please send them back.” That would indicate more concern for primary biliary cholangitis, and we’d want to treat it.

Kris Kowdley, MD, FACP, FACG, AGAF, FAASLD: That’s a good point. Usually, we see these patients because somebody was referred for a work-up of abnormal liver tests—liver enzymes, not alkaline phosphatase. A complete battery is ordered, and the AMA is weekly positive. Then they’re referred and you’re like, “What do I do? Is this patient PBC or not?” I must say that I continue to see patients who have PBC because they’ve had a biopsy. I’ve followed them for a long time, and they have elevated aminotransferase but not alkaline phosphatase. That’s a rare group. Most of these patients don’t have PBC, but the take-home message is that if the alkaline phosphatase is elevated and it’s a truly positive AMA, then follow the patient. Don’t say it’s negative and send them back.

Transcript edited for clarity