The care pathway and unmet needs in primary biliary cholangitis, a rare autoimmune disease of the liver: an interview with Prof Singal
An overview of primary biliary cholangitis (PBC) by Prof Singal, professor at the University of South Dakota, Sanford School of Medicine, United States
What is PBC?
In an autoimmune disease like PBC, a person’s immune system attacks its own tissues. In the case of PBC, the person’s immune system reacts to an antigen in a population of epithelial biliary cells (called cholangiocytes) found in the bile ducts within the liver. So the bile ducts, the small bile ducts and the ductules (tiny ducts) within the liver are exposed to the autoimmune process and they become inflamed. The chronic inflammation, like in any other tissue, results in the development of diffuse fibrosis, and in the case of the liver, cirrhosis (where liver cells are damaged and replaced by scar tissue) and other complications.
What symptoms and complications might happen?
It’s important to remember that PBC can be completely asymptomatic. The only sign of the condition may be elevated levels of an enzyme (a protein) called alkaline phosphatase (ALP), which is made by the biliary cells. The biliary cells are very sensitive, and they respond to inflammation or pressure by increasing their production of this enzyme, leading to elevated levels of it in the blood.
PBC typically starts in the middle-age group (people who are 40–60 years old) and in females. So, if you have a female patient in that age group with elevated levels of ALP in their liver tests, you will have a high suspicion of PBC as a potential diagnosis.
Once PBC becomes symptomatic, the most common symptom is fatigue (tiredness). There may also be itching, called pruritus. This happens once there is inflammation and some scarring to these biliary cells. Then the bile (a clear yellow or orange fluid produced by the liver) cannot flow easily, which leads to the retention of bile acids. These bile acids are very irritating to the skin and that causes itching.
Vitamin deficiency is an important manifestation too, especially deficiency of fat-soluble vitamins (vitamins A, D, E and K), because bile has an important role in absorbing these from the diet. I think, clinically, vitamin D is most important, because people tend to be deficient in that vitamin already because of less exposure to sunlight.
And on top of that, especially because the typical patient is female and middle aged, I think bone disease—osteopenia and osteoporosis—should be kept in mind. I tell all my patients who have PBC to have bone scans so that we can also address their bone health when we are treating them.
What may happen in the later stages of the disease?
If a patient’s PBC is more advanced, they can develop jaundice, typically not in the late early phases but in the late phases, especially when there is cirrhosis of the liver. (Jaundice is a condition in which a person’s skin and the whites of the eyes are discoloured yellow due to an increased level of bile pigments in the blood.)
In any liver condition, patients may develop varices (widely dilated veins) if they have portal hypertension and cirrhosis, but I want to highlight that patients with PBC may develop varices even in the absence of cirrhosis.
Further complications of PBC include cirrhosis and the complications associated with that: hepatic encephalopathy, ascites (accumulation of fluid in the abdomen), variceal bleeding and liver cancer.
Are any other conditions associated with PBC?
PBC patients may have associated autoimmune conditions too. When the autoimmune process starts, PBC can overlap with autoimmune hepatitis (a form of liver inflammation in which the body’s immune system attacks hepatocytes (the most common type of liver cells). I have seen a small handful of cases where PBC overlaps with another autoimmune condition called PSC (primary sclerosing cholangitis), a chronic, progressive liver disease, but this is a rare overlap.
The most common autoimmune conditions outside the liver associated with PBC are Sjögren’s syndrome (in which the mouth and eyes become extremely dry) and Hashimoto’s thyroiditis (in which there is reduced functioning of the thyroid gland, known as hypothyroidism).
How is PBC diagnosed?
A diagnosis of PBC is suggested by a “cholestatic profile” with levels of alkaline phosphatase in the blood that are relatively high compared to other enzymes. The confirmatory serological test is for anti-mitochondrial antibody (AMA), an antibody against the mitochondria of the biliary cells. Liver biopsy, if performed, shows inflammation around the bile ducts, also known in early stage as florid duct lesion.
You only need two of the three tests to make a diagnosis: elevated levels of ALP with a cholestatic liver profile, a positive test for AMA or a biopsy. So if somebody has a predominantly cholestatic profile and positive AMA, you don’t need a biopsy to make the diagnosis.
As about 10% of PBC patients are negative for AMA (mostly in males), liver biopsy is needed in these patients to diagnose PBC. However, a liver biopsy may also be performed to stage the disease and estimate the degree of fibrosis.
How is the stage of the disease diagnosed?
Once you’ve made a diagnosis of PBC you want to know the stage of the disease because the prognosis depends on that. Biopsy of the liver (examination of tissue samples taken from the liver) is the best way to find this out because it shows you how much fibrosis there is. If there’s no fibrosis, it’s stage zero; if there’s minimal fibrosis around the portal tracts, it’s stage one; if the fibrosis has expanded out of the portal tracts, it’s stage two; if it bridges with the central vein of the liver, it’s stage three, and if there’s fibrosis all over, it’s stage four, also known as cirrhosis.
What is the first-line treatment for PBC?
Ursodeoxycholic acid (UDCA) is a specific treatment for PBC that can help prevent or delay liver damage in most people, particularly when treatment starts in the early stages of the condition.1 Studies suggest that treatment with UDCA improves liver transplant-free survival for patients.2 Typically within six months to one year of the start of treatment, ALP, which is the marker you use to follow these patients, should either normalise or, at least, decrease significantly. A patient on UDCA is defined as a responder to treatment when the ALP either normalises or is below 1.5 × upper limit of normal after 6–12 months of treatment.
Are second-line treatments available?
Some patients may not tolerate UDCA and may have side effects, including diarrhoea. So if, for some reason, UDCA is not tolerated by the patient, or if the patient’s disease does not respond to UDCA within 6 to 12 months, you want to use a second-line treatment.
How are associated symptoms and complications treated?
A patient may need additional therapies for symptoms such as pruritus. If the pruritus is very mild, I use local emollients and moisturisers. But if it is significant, then cholestyramine is the first-line medication. This binds the bile acids in the gut so the amount of bile acid in circulation goes down, improving the pruritus.
It’s very important to highlight that patients with PBC should have adequate intake of vitamin D and calcium. If they are at risk of osteopenia or osteoporosis based on their bone scans, you should treat them accordingly. Patients should also be monitored every one to two years for TSH (thyroid stimulating hormone), and if they have hypothyroidism they will need treatment for that. Also, if they have symptoms of Sjögren’s syndrome or any other associated autoimmune condition, they should be treated for that.
If the patient has cirrhosis, they should be treated for the complications and followed up in the liver disease clinic every three to six months.
What unmet needs are there in PBC?
There are two ways the test for AMA is reported. One way is to report that it is positive or negative, with the levels of AMA. The second way—a better way—is to give the titres (concentration), but many labs will only give you the levels, which has no diagnostic significance, unless the level of AMA is really high and so gives a positive result.
The second unmet need is that there are seven or eight mitochondrial antigens, but only one of these is attacked by the autoimmune process in PBC. But the test we use is not specific to that antigen, so you can have false positives and end up misdiagnosing patients as having PBC when you should be looking for other conditions.
And I think another unmet need is around non-invasive testing. You can’t biopsy everybody, because it’s invasive and costly, so you need a non-invasive test. Non-invasive tests—serological tests and radiological tests (like FibroScan or MR elastography)—have been very well developed for fatty liver disease (a condition where excess fat builds up in the liver), but I think we need more data on the PBC population to understand where the cuts-off are between fibrosis and cirrhosis when we look at these tests.
Also, I think there may currently be unmet need around prognostic models. We have excellent models, from the UK and from the US, which can tell people about their prognosis (the probable course and outcome of the disease) depending on their lab results and their profiles. With these, I can tell the patient, ‘If you take this medication, you’ll definitely improve your chance of survival and of not reaching a place where you’ll need a transplant.’ But there are patients with PBC who go on to develop cirrhosis—even with treatment. I think a model is needed so we can say, ‘Okay, this is your risk of developing cirrhosis over time, in spite of taking the medicine.’
Do you have any final reflections to share with our readers?
I think PBC is one disease in which we have made a fair degree of advance, in that we have specific drugs available; we know how to treat people who do not respond to first-line treatment; we know how to treat complications. Over the last two decades, the number of liver transplants needed for this condition has gone down significantly.
There are two reasons for this. Firstly, we diagnose this condition early. Twenty or thirty years ago, primary care doctors were not routinely ordering liver tests. Now they are. So they’re picking up more people who don’t have symptoms but do have elevated levels of ALP. And then they send the tests to a hepatologist who then screens them for AMA and makes the diagnosis. Secondly, we have effective drugs. People are taking the medication and they’re living their lives without needing a transplant or developing cirrhosis.
Prof Singal is a professor at the University of South Dakota, Sanford School of Medicine in the United States. His clinical and research interests include alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), porphyria, renal injury in cirrhosis and liver transplantation.
 Primary biliary cholangitis – Treatment. nhs.uk. Published November 30, 2017. Accessed 26 April 2023. https://www.nhs.uk/conditions/primary-biliary-cholangitis-pbc/treatment/
 Harms MH, van Buuren HR, Corpechot C, et al. Ursodeoxycholic acid therapy and liver transplant-free survival in patients with primary biliary cholangitis. J Hepatol. 2019;71(2):357-365. doi:10.1016/j.jhep.2019.04.001
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