The ursodeoxycholic acid story in primary biliary cirrhosis.

The ursodeoxycholic acid story in primary biliary cirrhosis The name ursodeoxycholic acid (UDCA) is derived from 'ursocholeinische saure' used by Hammarsten in 1902 to describe a bile acid discovered in polar bears. The bile acid he identified was actually chenodeoxycholic acid.1 UDCA is the 7P epimer of chenodeoxycholic acid and has the chemical structure 3a 7,B-dihydroxy-5p-cholan-24-oic acid.2 Ten years ago, Leuschner et al3 made the seren-dipitous observation that UDCA given for gall stone dissolution noticeably improved routine liver function tests in patients who also had chronic liver disease. Since then, there have been reports of potential benefits in a wide range of cholestatic and chronic inflammatory liver conditions ,4 but most is known about the use of UDCA in primary biliary cirrhosis (PBC). In this article, we first discuss the pathogenesis of PBC and possible mechanisms of action of UDCA, and then review its clinical efficacy. Mechanisms of action of UDCA The pathophysiology of PBC can be considered as two processes. Firstly, immune damage directed at the intra-hepatic bile ducts; and secondly, reduced bile flow (cholestasis) and retention of endogenous bile acids, which cause cytotoxic damage to the liver.4 5 There is accumulating evidence that UDCA may affect all these mechanisms. IMMUNOMODULATOR UDCA corrects some of the immune abnormalities previously described in PBC. Most prominent is the finding that UDCA reduces the aberrant expression of class 1 human leukocyte antigens (HLA 1) on hepatocytes.67 Although aberrant expression of major histocompatibility complexes is not a unique feature of PBC,8 they are important for recognition of hepatic tissue as targets by activated T lymphocytes. UDCA may also improve abnormalities in concentrations of circulating IgM9 10 interferon y,"l and activated T lymphocytes. 12 In vitro, the addition of UDCA can modulate the production of certain cytokines (inter-leukin 2, interleukin 4, and interleukin y) from human mononuclear cells.'3 14 UDCA is not the only bile acid that can affect immune function. The endogenous bile acid chenodeoxycholic acid can reduce in vitro cytokine production'5 and be immunosuppressive.16 Unfortunately , the importance of these findings is unclear as current understanding of the immune pathogenesis of PBC is limited. Taken together, these reports suggest that UDCA has some modulatory effects on immune function. BILE ACID RETENTION In a series of elegant physiological experiments on bile duct fistula rats, Kitani et al 17 showed that hydrophobic bile acids reduce bile flow. Co-administration of UDCA and its conjugates protects …