What is the Role of Ursodeoxycholic Acid for the Future Management of Patients with Primary Sclerosing Cholangitis in the Clinic and in Trials? - European Medical Journal
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What is the Role of Ursodeoxycholic Acid for the Future Management of Patients with Primary Sclerosing Cholangitis in the Clinic and in Trials?

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3 Mins
Authors:
*Roger W. Chapman1,2
Citation
EMJ Hepatol. ;5[1]:56-57. Abstract Review No. AR8.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

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Primary sclerosing cholangitis (PSC) is a rare, progressive, cholestatic, immune-mediated hepatobiliary disease. It is characterised by inflammation, stricturing, and concentric obliterative fibrosis of the biliary system, ultimately leading to biliary cirrhosis, portal hypertension, and eventually, in the majority of patients, hepatic failure.

It is predominantly found in males (male–female ratio 2:1) and is closely associated with inflammatory bowel disease, usually in the form of ulcerative colitis (UC). PSC is a premalignant disease with a high prevalence of hepatobiliary and colonic malignancy. The overall median survival is 21 years; however, mortality rates are ≤30% at 6 years, with the majority of deaths (40–50%) due to cancer and around 30–40% due to liver failure. Phenotypes of patients who have a bad prognosis include male patients with associated UC and both intra and extrahepatic involvement of the biliary tree.

There is no proven medical therapy for PSC. Trials of immunosuppressants and antifibrotic agents have been unsuccessful. A naturally occurring bile acid, ursodeoxycholic acid (UDCA), has been established as first-line therapy in primary biliary cholangitis, improving survival. UDCA has a number of actions that should be of benefit in cholestatic liver disease, including producing a choleresis (increase in bile flow), beneficial anti-apoptotic effects, and an increase in biliary bicarbonate secretion. In addition, it decreases bile toxicity by reducing the level of toxic hydrophobic bile acids, cholic acid, and chenodeoxycholic acid in the total bile acid pool.

The efficacy of oral UDCA in the treatment of PSC remains controversial. All studies since the 1980s have shown a significant drop in serum alkaline phosphatase. However, trials of moderate dose UDCA (17–22 mg/kg/day) have not shown a clear benefit to survival, and indeed higher doses (25–30 mg/kg/day) may be harmful. Moderate doses of UDCA may have a positive chemoprotective effect in the reduction of colonic dysplasia and colonic cancer in patients with PSC and inflammatory bowel disease.

However, it seems that a subset of approximately 30% of patients may respond, as assessed by normalisation of serum alkaline phosphatase after 1 year of treatment to <1.5-times the upper limit of the normal range. This has been shown to correlate with increased survival in PSC. The most recent guidelines suggest a trial of 6 months of moderate-dose UDCA treatment in PSC patients with elevated alkaline phosphatase and continuing long-term therapy if normalisation of alkaline phosphatase is achieved.

PSC patients have been shown to have specific gut microbiota that differ from normal subjects and UC patients without PSC. New therapeutic strategies in PSC include clinical trials of alteration of the biome with antibiotic therapy and faecal transplantation. In addition, clinical trials of agents that may alter T cell function, preventing inappropriate homing of T cells to the liver and biliary system, are being evaluated. Also, trials of drugs that cause a reduction in biliary fibrosis and toxic bile are in progress. It is likely that bile acid therapy, either with UDCA or nor-UDCA, a C23 homologue of UDCA, may be a part of combination therapy for PSC in the future. A Phase III trial of nor-UDCA is in progress.