Editorials

Ursodeoxycholic acid and primary biliary cirrhosis

The results of four large, well designed, double blind, placebo controlled trials are now available.*RF 2-5* All studied patients for two years and reported broadly similar results - that ursodeoxycholic acid greatly improves serum concentrations of bilirubin and liver enzymes. Serum bilirubin concentration of untreated patients with primary biliary cirrhosis is an independent predictor of outcome. Alkaline phosphatase and (gamma)-glutamyl transpeptidase values reflect cholestasis, and serum transaminase values indicate the degree of hepatocellular damage.

Although these results are encouraging, their long term importance is unclear. In particular, the prognostic importance of a fall in serum bilirubin concentration during treatment has not been established. Improvements in features such as pruritus and fatigue were found in some trials but not in others. These variables are subjective, difficult to assess, and influenced by a large placebo effect.³

Improvements in histological variables have also been reported, such as decrease in the amount of piecemeal necrosis and inflammatory cell infiltration and preservation of the bile duct. No significant improvement in the overall stage of the disease has been detected; however, assessment of liver histology by needle biopsy can be affected by sampling error. The inability of ursodeoxycholic acid to affect fibrosis is supported by the lack of improvement in serum markers of fibrogenesis such as procollagen III P and hyaluronate.⁶

The studies discussed above were designed to assess surrogate end points, but the improvements that were found do not necessarily translate into clinical efficacy.⁷ To be confident of the benefit of ursodeoxycholic acid in primary biliary cirrhosis one would like to see increased survival. Unfortunately, none of the recent trials was designed to evaluate this. Although these trials were large - each with 150-200 patients - the number of deaths in two years was small. To assess these end points accurately a double blind, placebo controlled trial would need about 1000 patients, running for about 10 years.³ This may not be feasible in an uncommon condition like primary biliary cirrhosis.

Long term follow up of patients in open trials suggests that the biochemical improvement induced by ursodeoxycholic acid is sustained and may improve survival and reduce the need for liver transplantation. Leuschner et al have followed up a small cohort of patients for more than 10 years⁸ and Poupon et al recently reported the outcome in 129 patients.⁹ There were significantly fewer liver transplantations and deaths in those who had been given ursodeoxycholic acid for four years than in those initially treated with placebo. Data on liver transplantation rates must, however, be treated with caution as criteria for referring patients for transplantation may vary within and among centres.

Aside from trials on clinical efficacy much effort has been spent on examining the effects of ursodeoxycholic acid on the pathophysiology of primary biliary cirrhosis. Data from our unit show that ursodeoxycholic acid reduces retention of bile acids and increases their hepatic excretion.¹⁰ Endogenous bile acids are hydrophobic and damage hepatocytes.¹¹ In vitro, they harm hepatocyte membranes and impair the ability of cells to produce energy.^12,13 Treatment with ursodeoxycholic acid reduces the amount of these bile acids in the bile acid pool and partially replaces them with ursodeoxycholic acid.¹⁴ Ursodeoxycholic acid, a hydrophilic bile acid, is not only less damaging but seems to reduce the damage caused by hydrophobic bile acids.

Effect on immune system

Primary biliary cirrhosis is thought to be primarily an immune disorder. Intriguingly, ursodeoxycholic acid also has some effect on the immune system. It reduces the level of hepatic expression of human leucocyte antigens (HLA class I).¹⁵ Although aberrant presentation of these antigens is not the primary immune abnormality in primary biliary cirrhosis, these antigens are targets for cell mediated immune damage. Patients with primary biliary cirrhosis treated with ursodeoxycholic acid have lower serum IgM concentrations.² In vitro, ursodeoxycholic acid reduces production by peripheral mononuclear cells of IgG, IgA, and IgM as well as cytokines such as interleukin 2, interleukin 4, and interleukin 6.¹⁶

Ursodeoxycholic acid may be beneficial in primary biliary cirrhosis, and we now have a clearer understanding of how it may work. Unfortunately, the nature of the disease makes it difficult to show definitive long term benefit. A meta-analysis of double blind placebo controlled data is planned and may be helpful. In comparison with previously suggested agents ursodeoxycholic acid is well tolerated and non-toxic. It should be used in patients with primary biliary cirrhosis except those with end stage disease, who should be considered for liver transplantation.

Professor Northfield has been carrying out studies on the mechanism of action of UDCA and is about to carry out a trial to determine its optimum dose in primary biliary cirrhosis funded by the pharmaceutical industry.

A G Lim, T C Northfield 

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