For many years, Urso (Ursodeoxycholic acid, or UDCA) was considered to be safe and beneficial in PSC, and has been well established for its use in Primary Biliary Cirrhosis but recently it has been the subject of much discussion. Should we take it or not?
The benefits of Urso?
Is thought to have the following beneficial effects in chronic cholestasis (where bile does not flow properly):
- increases bile flow;
- protects cells both directly and indirectly;
- has an immunomodulatory effect (has an effect on the immune system);
- has an inhibitory effect on apoptosis (discourages cell death).
Studies with positive results for Urso and PSC were found in research in the 90s, and research continued with increasing doses on the grounds that higher doses might enhance the effects of the drug, until a high-dose trial in America (Lindor, 2009) was prematurely terminated due to unexpected results. The group taking high dose Urso (28-30 mg/kg/day) showed a higher risk for or liver transplantation or development of varices. Interestingly, despite these adverse effects, serum biochemical features improved in the whole Urso group, that is, the liver function tests were improved in the Urso group, even though their conditions were deteriorating.
High dose Urso trial prematurely terminated
The unexpected results of the high-dose Urso trial by Lindor (2009) caused PSC Specialists all over the world to review their use of Urso in PSC, leading to differences in whether or not Urso was prescribed, and the dose prescribed. Furthermore, Volk (2011) in a commentary on the risks of using Urso in PSC noted that Urso has been shown to improve liver enzymes but has no impact on clinical outcomes (Poropat et al., 2011).
Does Urso help prevent cancer of the colon?
Urso is also thought to be chemoprotective for colon cancer, possibly reducing the risk of dysplasia and cancer in the biliary tree and/or the colon. Volk (2011) argues that we must also consider impact of Urso on Ulcerative Colitis (UC), because of the increased risk of PSCers with IBD getting colorectal cancer (about 30% by 20 years; J Hepatol 2009;50:158). He cites studies that support the chemoprotective idea (eg Pardi et al., 2003) but acknowledges other studies have found conflicting results.
Eaton et al (2011) looked at impact of Urso on development of colorectal neoplasia in PSCers with UC. They looked at the patients with UC in the high dose Urso group from Lindor’s 2009 high dose Urso study, and found that long term use of high dose Urso was associated with increased risk of colorectal neoplasia in PSCers with UC. This is the opposite of being chemoprotective! Volk comments that Eaton et al (2011) was a well-designed study with no major methodological flaws, although when we asked, Roger Chapman did not share this view. It should be noted that the higher rate of colorectal neoplasia in the Urso group included higher numbers of ‘low grade dysplasia’ (which does not normally progress to cancer) and that the same number of ‘high grade dysplasia’ incidents was found in both groups. Volk says these results add weight to the case against the use of Urso. He states that “…at the present time the data suggests that for the majority of patients with PSC, routine use of UDCA [Urso] should be avoided.”
What is officially recommended for Urso in PSC?
Europe: EASL 2009 Recommendations on the use of Urso (UDCA)
1.The available data base 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.
2.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.
America: AASLD 2010 Recommendations on the use of Urso (UDCA)
In adult patients with PSC, we recommend against the use of UDCA [Urso] as medical therapy.
Roger Chapman is one of the contributors to both the EASL Guidelines and the AASLD Guidelines.
So, the American PSC guidelines recommend against using Urso in PSC but European Guidelines don’t specifically recommend against the use of Urso (at low doses), but they certainly don’t specifically recommended it to treat PSC either.
The key here is dosage. Roger Chapman’s explanation of this apparent contradiction is that “high dose UDCA is not indicated for the treatment of PSC” not Urso per se. Even though there is not enough data to allow a specific recommendation for the general use of Urso in PSC, Chapman says we should remember that there is suggestive but limited evidence that the use of Urso may be ‘protective’ against colorectal cancer (CRC) in PSC. Note, regardless of taking Urso and its potential chemoprotective effects, PSCers should still undergo regular colonoscopies with biopsies.
Chapman (2009) says, “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.” Chapman talks about the potential benefits of 24-norursodeoxycholic acid (Nor Urso) and is about to take part in an international clinical trial of Nor Urso in PSC, which looks very promising. He suggests that further research is needed before bile acids are discounted completely, accounting for the separate PSC phenotypes that are emerging.
So, is Urso prescribed in the UK?
In 2011, Roger Chapman confirmed to PSCers attending the annual Oxford PSC Support Meeting that he continued to prescribe Urso for PSC , but at low dose, which is up to 20mg/kg body weight. Similarly, David Adams at the 2012 Birmingham PSC Support meeting said the same.
Reviewed by RC 15/4/12