Long-Term Ursodeoxycholic Acid Therapy Does Not Alter Lithocholic Acid Levels in Patients with Cystic Fibrosis with Associated Liver Disease.
To evaluate the fasting and postprandial serum bile acid composition in patients with cystic fibrosis-associated liver disease (CFLD) after chronic administration of ursodeoxycholic acid (UDCA) (20 mg/kg/day). The aim was to specifically focus on the extent of biotransformation of UDCA to its hepatotoxic metabolite, lithocholic acid, because of recent concerns regarding the safety of long-term, high-dose UDCA treatment for CFLD.



Twenty patients with CFLD (median age 16 years, range: 2.4-35.0) prescribed UDCA therapy for at least 2 years were studied. Total and individual serum bile acids were measured by stable-isotope dilution mass spectrometry, in fasting and 2-hour postprandial samples taken during chronic UDCA (20 mg/kg/day) administration.



During chronic UDCA administration (median duration 8 years, IQR: 6-16), UDCA became the predominant serum bile acid in all patients (median, IQR: 3.17, 1.25-5.56 μmol/L) and chenodeoxycholic acid concentrations were greater than cholic acid (1.86, 1.00-4.70 μmol/L vs 0.40, 0.24-2.71 μmol/L). The secondary bile acids, deoxycholate and lithocholate, were present in very low concentrations in fasted serum (<0.05 μmol/L). After UDCA administration, 2-hour postprandial concentrations of both UDCA and chenodeoxycholic acid significantly increased (P < .01), but no significant changes in serum lithocholic acid concentrations were observed.



These data do not support recent suggestions that enhanced biotransformation of UDCA to the hepatotoxic secondary bile acid lithocholic occurs when patients with CFLD are treated with relatively high doses of UDCA.
Cystic Fibrosis Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy. Electronic address: carla.colombo@unimi.it.
Carla
C
Colombo
Division of Internal Medicine and Liver Unit, School of Medicine Ospedale San Paolo, Università degli Studi di Milano, Milan, Italy.
Andrea
A
Crosignani
Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.
Gianfranco
G
Alicandro
Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Wujuan
W
Zhang
Cystic Fibrosis Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Arianna
A
Biffi
Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
Valentina
V
Motta
Cystic Fibrosis Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Fabiola
F
Corti
Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.
Kenneth D R
KDR
Setchell
D000293:Adolescent; D000328:Adult; D001647:Bile Acids and Salts / Q000097:blood*; D001711:Biotransformation; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000097:blood / Q000188:drug therapy*; D003840:Deoxycholic Acid / Q000097:blood; D005260:Female; D006801:Humans; D008095:Lithocholic Acid / Q000097:blood*; D008107:Liver Diseases / Q000097:blood / Q000188:drug therapy*; D008297:Male; D053719:Tandem Mass Spectrometry; D014580:Ursodeoxycholic Acid / Q000009:adverse effects / Q000627:therapeutic use*; D055815:Young Adult
D001647:Bile Acids and Salts; D003840:Deoxycholic Acid; D008095:Lithocholic Acid; D014580:Ursodeoxycholic Acid
bile acid metabolism; bile acids; cholestasis; cystic fibrosis