For many years, UDCA (Ursodeoxycholic acid, or Urso) was considered to be safe and beneficial in PSC, and its use has been well-established in primary biliary cholangitis (PBC).
Research trials of UDCA in PSC
Research reported positive results for the use of UDCA in PSC from the 1980s and studies continued with increasing doses on the grounds that higher doses might enhance the effects of the drug. For an excellent summary of UDCA trials (and other potential treatments) for PSC, see Dr Goode’s ‘Review of the medical treatment of primary sclerosing cholangitis in the 21st century’ 78 (free to access).
Goode’s 78 summary tells us that he early pilot studies were encouraging, finding that liver blood tests, biopsy results and symptoms improved in people with PSC who took low doses of UDCA, but the studies were small, often only including 20 PSC patients or fewer, or were short in duration, so definite conclusions could not be made. A trial in 2005 used a slightly higher dose (17-23mg per day) and found improved outcomes for the people taking UDCA (improved survival and longer time to transplant) but unfortunately, researchers could not recruit the 346 patients needed to truly know if this was a definite (statistically significant) effect.
High-dose research trial
In 2009, a high-dose trial of UDCA started. This high dose significantly improved ALP, but was prematurely terminated because the people taking high-dose UCDA (28-30 mg/kg/day) showed a higher risk of developing a serious liver-related complication, including cirrhosis, varices, cholangiocarcinoma, liver transplantation, or death 94.
Difficulties studying PSC
The UDCA trials reflect the difficulty in studying PSC.
It’s rare, so studies can sometimes struggle to recruit enough volunteers to take part. It is critical to have enough numbers to have confidence in the results.
PSC is a heterogenous disease, meaning that there are many differences between PSC patients. Today, researchers attempt to stratify (group) like-for-like PSC patients in trials to ensure similar groups are compared when testing a drug. The early trials were conducted at a time when we did not understand enough about these differences to adequately select those like-for-like groups.
A major issue for all PSC research trials is the selection of a measure or signal that will tell us if a drug is effective or not. This is called an endpoint. There is still not full agreement today but the whole PSC community is working on it!
It is possible that if those early trials of UDCA had been able to use today’s technology to evaluate, for example, fibrosis improvement or changes in the appearance of the bile ducts using advanced imaging technology, the results might have been different.
The use of UDCA then became controversial after the high-dose trial in 2009. Convinced about the benefits, some doctors continued to prescribe UDCA at lower doses whereas others stopped prescribing it based on the lack of evidence supporting the benefits.
The benefits of Urso?
UDCA was thought to have the following beneficial effects in conditions where bile does not flow properly:
- increase in bile flow;
- protection of cells both directly and indirectly;
- an immunomodulatory effect (has an effect on the immune system);
- an inhibitory effect on apoptosis (discourages cell death).
UDCA and Liver Blood Test Results
Even though the high-dose UDCA research trial was stopped, some interesting results were observed. Blood test results improved in the group taking UDCA even though their conditions were deteriorating 94. The fact that UDCA improved liver blood tests yet had no impact on overall outcomes such as long term survival 95,96 suggests that UDCA is not an effective treatment for PSC. However, patients who have reduced or normal levels of alkaline phosphatase (ALP) have been found to have longer survival times, regardless of whether they’ve received UDCA or not 97.
The UDCA conundrum
Therefore there are conflicting messages from these studies: UDCA reduces ALP. A reduced ALP level is associated with a better long-term outcome. But it has not been conclusively shown that UDCA itself is independently associated with a better long-term outcome.
The way doctors interpret this conundrum differs. Some doctors do not use UDCA at all as a result, and some doctors use UDCA but at levels considered safe (i.e. below the high doses mentioned above of 28mg/kg).
Does UDCA help prevent cancer of the colon?
UDCA may be protective for colon cancer, possibly also reducing the risk of dysplasia and cancer in the biliary tree, important in a disease like PSC which carries an increased risk of cancers 98. Some studies support this chemoprotective idea 99 but others have found the opposite: that long term use of high dose UDCA (i.e. the 28-30mg/kg dose) is associated with an increased risk of colorectal neoplasia in people with PSC and UC 100. It should be noted that the higher rate of colorectal neoplasia in the UDCA group included higher numbers of ‘low grade dysplasia’ (which does not always progress to cancer) and that the same number of ‘high grade dysplasia’ incidents was found in both groups.
Will taking UDCA stop me being eligible for clinical trials in PSC?
Taking UDCA could be a barrier to taking part in some trials. It is possible that continuing to take UDCA while testing the effects of a new drug will interfere with the study results, and indeed, some clinical trials state that UDCA cannot be taken by participants in the trial. If this is the case, you usually need to stop taking UDCA (with your doctor’s knowledge) well in advance of taking part in the research study. Most research studies, however, ask that you are on a ‘stable dose’ of UDCA, meaning you should have been taking the same dose for a certain length of time without stopping.
Is UDCA safe while breastfeeding?
A study in the Czech Republic looked at the use of UDCA while breastfeeding 101. They studied a woman with primary biliary cholangitis (PBC) who developed severe pruritus (itching) and elevated serum bile acids 3 weeks after giving birth. She was given UDCA in daily doses from 500mg (7.5mg/kg) up to 1500mg (25mg/kg) over the following 8 weeks. She continued on the higher dose of UDCA for the next 8 weeks.
They found that the UDCA treatment was associated with improved liver enzyme levels, reduced itch and reduced fatigue. They found ‘no effects on breast milk bile acid content’. They state that the ‘psychomotor development of the child was normal, and no apparent side-effects of the treatment were observed in either child or mother’. They conclude that breastfeeding while taking UDCA was safe.
UDCA is widely used for the treatment of cholestasis in pregnancy and is a naturally occurring bile acid. Only tiny amounts of UDCA get into our circulation and it is doubtful that any clinically significant amounts get into breast milk. Based on the conclusion that UDCA is safe to take while breastfeeding with PBC, it is reasonable to expect the same to hold true for PSC. Obviously it is important to discuss your medication with your liver specialist who knows your exact circumstances before making any decisions.
What is officially recommended for UDCA in PSC?
Based on the lack of strong evidence of the benefits of UDCA in PSC, some official guidelines on the management of PSC no longer recommend its use, whereas other guidelines simply state the lack of conclusive evidence to make a concrete recommendation.
We recommend that UDCA is not used for the routine treatment of newly diagnosed PSC. For patients already established on UDCA therapy, there is evidence of harm in patients taking high dose UDCA (28-30mg/kg/day) 58.
We recommend that UDCA is not used for the prevention of colorectal cancer or cholangiocarcinoma 58.
EASL 2009 Recommendations on the use of Urso (UDCA) 4
- The available database shows that UDCA (15–20mg/d) improves serum liver tests and surrogate markers of prognosis but does not reveal a proven benefit on survival. The limited data base does not yet allow a specific recommendation for the general use of UDCA in PSC.
- Currently there is suggestive but limited evidence for the use of UDCA for chemoprevention of colorectal cancer in PSC. UDCA may be particularly considered in high-risk groups such as those with a strong family history of colorectal cancer, previous colorectal neoplasia or longstanding extensive colitis.
AASLD 2010 Recommendations on the use of Urso (UDCA) 68
'In adult patients with PSC, we recommend against the use of UDCA [Urso] as medical therapy.'
American Journal of Gastroenterology (2015) ACG Clinical Guideline: Primary Sclerosing Cholangitis 102
'...many practitioners are using a dose of ~20 mg/kg/day, although data from well-controlled clinical trials are lacking.'
Even though there is not enough data to allow a specific recommendation for the general use of UDCA in PSC, Dr Roger Chapman says we should remember that there is suggestive but limited evidence that the use of UDCA may be ‘protective’ against bowel cancer in PSC. Note, regardless of taking UDCA and its possible chemoprotective effects, people with PSC should still undergo regular colonoscopies with biopsies.
Further bile acid research
In 2009, Dr Roger Chapman suggested further research was needed before bile acids were discounted completely, stating, ‘The role for UDCA in slowing the progression of PSC-related liver disease is as-yet unclear and indeed, high-dose UDCA (28-30 mg/kg/day) may be harmful. However, on current evidence it would be premature to exclude bile acids as therapy for PSC.’ 103. Research into bile acids continued and we can report that a decade later, the first Phase III clinical trial in PSC is testing a bile acid called norUrsodeoxycholic acid.
Should I stop taking UDCA?
Firstly, no one with PSC should be taking UDCA at a high dose (greater than 25mg/kg/day). If you are on a high dose, contact your doctor immediately for a review. Secondly, if you are taking UDCA, and you wish to stop taking it, please talk to your doctor before doing so.
If you stop taking UDCA, your liver blood tests are likely to get worse. A small study looked at what happened to 28 PSC patients 3 months after stopping low dose UCDA 104. After UCDA withdrawal they found that liver blood tests got worse, especially ALP, which increased by 76%. There was a deterioration of health-related quality of life (QoL) in some areas for some patients (although for others it improved). It should be noted that this was a small study, and that it was not blinded, that is, the participants knew they had stopped taking UDCA. There is a possibility that there was inadvertent bias in the health related QoL reporting.
Jury is still out on UDCA
It’s a good idea to talk to your doctor about the risks and benefits associated with UDCA. Without strong research to provide evidence about the benefits, clinical guidelines cannot recommend its use, and so the jury is still out on UDCA.
What are doctors doing about UDCA?
Some doctors prescribe UDCA at intermediate doses (less than 15-20mg/kg/day) and we know from our online communities that many patients want to continue to take it, just in case there is a benefit to them. Other doctors do not prescribe UDCA at all, arguing that there is no evidence to show that it improves survival in PSC, and that when their patients are not on UDCA, they may have more chances to be eligible for clinical trials.
They recommend trialling UDCA (17-23mg/kg/day) and checking that it actually has the desired effect on the liver blood tests at 6 months, as well as looking at other parameters, and then making a conscious decision at 6 months as to whether to continue or not. Whilst this is not an official guideline, some doctors and patients see it as a good approach given the unclear benefit of its use.