Cystic fibrosis (CF) is the most common, lethal genetic disorder in the United States, occurring in one in three thousand live born children. The prevalence of liver disease increases with age among patients with CF, from less than ten percent in those under ten years old to thirty percent in those over twenty years old. CF patients with end stage liver disease die of cirrhosis, liver failure and hemorrhage from esophageal varices. Because of the likely development of gene therapy to treat the deficiency of the transmembrane conductance regulator (CFTR) protein in the lungs, CF research efforts will need to be directed toward treating other secondary manifestations of CF such as diabetes and liver disease. The prevalence of CF associated liver disease can be expected to increase as a greater proportion of CF patients survive into adulthood. The proposed study is a randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid (UDCA) to determine whether hepatobiliary clearance can be improved in patients with CF associated liver disease. Cholestasis and liver cell injury are the characteristic lesions of CF associated liver disease. UDCA may exert a beneficial effect by increasing choleresis (reversing cholestasis) and by displacing dihydroxy bile acids from the enterohepatic circulation and bile acid pool. Eighty patients will be enrolled from up to twelve clinics. UDCA and placebo will be prescribed in doses of 25 mg/kg with adjustment for weight change. Hepatobiliary clearance will be measured according to standardized procedures with technetium-labeled iminodiacetic acid scintigraphy; the hepatobiliary scintigrams will be evaluated in a Core Laboratory. The primary analysis will be based on a comparison of transit of technetium-labeled iminodiacetic acid from the liver (excretion half- time). This study will assess the impact of UDCA on stabilization or improvement of hepatobiliary abnormalities in patients with CF. Secondary analyses will be made of other scintigraphic variables, markers of liver injury, measures of growth, and nutritional status. A clinical trial is necessary at this time because clinicians are already beginning to use UDCA without proof of efficacy.
