Use of Ursodeoxycholic Acid Therapy in the Treatment of Cholestatic Liver Diseases

Use of Ursodeoxycholic Acid Therapy in the Treatment of Cholestatic Liver Diseases

Harnois Denise M
US Gastroenterology Review 2007 - Issue II - October 2007
Published: October 2008
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Our understanding of the chemical structure and potential therapeutic properties of ursodeoxycholic acid (UDCA) dates back to the 1930s.1 However, it was not until the 1970s that its use became more widespread in clinical trials investigating its value in the dissolution of gallstones.2 These studies showed that candidates with radiolucent stones less than 2cm in diameter and a patent cystic duct were potential candidates for treatment with UDCA 8–10mg/kg/day. A dissolution rate of 30–60% was reported.3 However, the advent of less invasive surgical techniques with laparoscopic surgery has now limited the use of this therapy, predominantly only to those who are otherwise not reasonable candidates for surgical cholecystectomy.

This remained the primary use of UDCA therapy until 1985, when Leuschner et al. first reported biochemical improvement in chronic active hepatitis in patients undergoing treatment for gallstones.4 This study then led to a series of investigations looking into the potential benefits of UDCA therapy in the treatment of cholestatic liver diseases. UDCA is a hydrophilic dihydroxy bile acid, which in humans accounts for 4% of the bile acid pool.5 UDCA is not synthesized in the liver, but rather is produced by colonic bacteria and absorbed by the colonic mucosa into the portal circulation; it then becomes part of the bile acid pool. In humans, the half-life of UDCA is 3.5–5.8 days.6,7 The predominant pathway of UDCA elimination from the body is in the stool. UDCA exerts its effects in the hepatobiliary system through several mechanisms of action, including alteration of the bile acid pool, increasing the amount of hydrophilic bile acids while decreasing the amount of hydrophobic bile acids. These hydrophobic bile acids are believed to be toxic to the system, promoting apoptosis, necrosis, and fibrosis. Other postulated mechanisms of action include cytoprotection of the hepatocytes and bile duct epithelial cells.8,9 Immunomodulatory effects of therapy include decreased expression of major histocompatibility complex class I and II, correction of defective natural killer cell activity, reduction of peripheral eosinophils, and protection against T-helper-1-mediated liver injury.10–15

Clinical Use of Ursodeoxycholic Acid Therapy

Scenario 1
A 52-year-old female presents to her local primary care physician complaining of fatigue. She also complains of itching. Her primary care physician completes her annual screening exams: she has a negative colonoscopy and osteoporosis—her primary care physician starts her on treatment with calcium and biophosphonates—and her cholesterol is elevated—her primary care physician recommends fish oil initially. When her labs also show elevated alkaline phosphatase levels (three times higher than normal), she is referred to you, her local gastroenterologist. You order an antimitochondrial antibody (AMA) test, which is positive with negative viral serologies and other autoimmune markers. A liver biopsy shows periportal inflammation and stage 2 fibrosis consistent with primary biliary cirrhosis. You diagnose primary biliary cirrhosis (PBC) and start her on UDCA therapy at a dose of 13–15mg/kg/day.

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