Long-term Prospective Study of the Effect of Ursodeoxycholic Acid on Cystic Fibrosis-related Liver Disease Sanda Nousia-Arvanitakis, M.D., Maria Fotoulaki, M.D., Hippolyti Economou, M.D., Mairy Xefteri, M.D., and Assimina Galli-Tsinopoulou, M.D. Abstract Goals: To evaluate the efficacy of UDCA in arresting the progres- sion of the early multifocal hepatic lesion to overt CF-related NBC. Background: Focal biliary cirrhosis is an early hepatic pathologic change related to the ion transport defect in cystic fi- brosis. The factors involved in the progression of focal to nodular biliary cirrhosis are not clear. Ursodeoxycholic—a hydrophilic, nontoxic, choleretic, and hepatoprotective exogenous bile acid— has been reported to be effective in the management of cholestatic liver disease. Study: For 10 years at 6-month intervals, 70 indi- viduals with cystic fibrosis (38 men and 32 women; age range, 2–29 years) were examined using hepatosplenomegaly, liver func- tion tests, and ultrasound liver scan. Patients demonstrating evi- dence of liver involvement at the onset or during the study received ursodeoxycholic acid 20 mg/kg body weight. Results: After the administration of ursodeoxycholic acid, the progression of nodular biliary cirrhosis ultrasound changes was arrested, he- patic function was preserved, and no variceal bleeding was ob- served. No case of focal biliary cirrhosis progressed to nodular biliary cirrhosis. Furthermore, the multifocal, multilobular changes suggestive of focal biliary cirrhosis on ultrasound scan were re- versed to normal. Conclusion: Ursodeoxycholic acid is effective in improving cholestasis and hepatic dysfunction in nodular biliary cirrhosis and, also, in reversing the early sonography findings sug- gestive of focal biliary cirrhosis. It is speculated that ursodeoxy- cholic acid may prove to affect the natural history of cystic fibrosis-related liver disease. Key Words: Cystic fibrosis-related liver disease—Focal biliary cirrhosis—Nodular biliary cirrhosis—Ursodeoxycholic acid— Cystic fibrosis. C ystic fibrosis (CF), an inherited metabolic disease, re- sults from mutations of a gene located in the long arm of chromosome 7. 1 The defective protein coded by the mu- tated gene, CF transmembrane conductance regulator, is a transmembrane chloride channel. 2 Cystic fibrosis trans- membrane conductance regulator is localized at or near the apical membrane of epithelial cells in organs, which are characterized by the presence of ducts. The demonstration of CF transmembrane conductance regulator in the bile duct epithelial cells has improved the understanding of the mechanism by which liver involvement develops in CF. 3 Normally, exposure to secretin increases cyclic adenosine monophosphate levels and opens the CF transmembrane conductance regulator-associated chloride channels in the bile duct cells. This leads to the efflux of chloride into the lumen, resulting in paracellular movement of sodium and water and dilution of the bile. In CF, the chloride channel defect within the bile ducts gives rise to dehydrated viscous secretions that, in turn, produce localized stasis and focal obstruction. This obstruction represents the earliest hepatic abnormality in CF. The release of inflammatory mediators in the obstructed bile ducts (along with free radical damage) leads to progressive liver involvement. 4 The process begins focally in the liver, possibly because of interductal connec- tions that may allow adequate bile drainage of some areas. 5 This early pathologic change is referred to as focal biliary cirrhosis. As the fibrogenic process proceeds, bridging fi- brosis develops into multilobular nodular biliary cirrhosis (NBC). This progression from cholestasis to focal biliary cirrhosis to NBC may take years, or decades. Focal biliary cirrhosis is the most common hepatic feature in CF. It is a pathologic finding at autopsy 4 and may have no clinical or biochemical manifestations. Multifocal multilobular hepatic changes suggestive of focal biliary cirrhosis may be de- tected by ultrasonography. 6–9 Ursodeoxycholic acid (UDCA) is a nontoxic exogenous, hydrophilic bile acid, which possesses choleretic, hepato- protective, and immunomodulatory properties. 10–12 Ursode- oxycholic acid has been reported to be effective in the management of patients with cholestatic liver disease. 13 In the CF hepatobiliary tract, UDCA may decrease bile vis- cosity, stimulate bile flow, and prevent the obstruction of bile ductules. 13,14–16 We have shown that UDCA, adminis- tered to adolescents with CF having advanced hepatic dis- ease (NBC), was effective in dramatically improving the biochemical indices of liver function during a 6-year study period. 17 The aim of this prospective study was to evaluate Submitted April 4, 2000. Accepted July 18, 2000. From the Fourth Department of Pediatrics (S.N-A., M.F., M.X., A.G-T.) and the Department of Radiology (H.E.), Aristotle University of Thessaloniki, Greece. Address correspondence and reprint requests to Dr. Sanda Nousia- Arvanitakis, PO Box 322, Thermi, 57001 Thessaloniki, Greece. E-mail: sarvanit@med.auth.gr J Clin Gastroenterol 2001;32(4):324–328. © 2001 Lippincott Williams & Wilkins, Inc. 324