OBJECTIVE: To investigate patient factors predictive of gamma glutamyltransferase (GGT) normalization following ursodeoxycholic acid (UDCA) therapy in children with primary sclerosing cholangitis. STUDY DESIGN: We retrospectively reviewed patient records at 46 centers. We included patients with a baseline serum GGT level ≥50 IU/L at diagnosis of primary sclerosing cholangitis who initiated UDCA therapy within 1 month and continued therapy for at least 1 year. We defined "normalization" as a GGT level <50 IU/L without experiencing portal hypertensive or dominant stricture events, liver transplantation, or death during the first year. RESULTS: We identified 263 patients, median age 12.1 years at diagnosis, treated with UDCA at a median dose of 15 mg/kg/d. Normalization occurred in 46%. Patients with normalization had a lower prevalence of Crohn's disease, lower total bilirubin level, lower aspartate aminotransferase to platelet ratio index, greater platelet count, and greater serum albumin level at diagnosis. The 5-year survival with native liver was 99% in those patients who achieved normalization vs 77% in those who did not. CONCLUSIONS: Less than one-half of the patients treated with UDCA have a complete GGT normalization in the first year after diagnosis, but this subset of patients has a favorable 5-year outcome. Normalization is less likely in patients with a Crohn's disease phenotype or a laboratory profile suggestive of more advanced hepatobiliary fibrosis. Patients who do not achieve normalization could reasonably stop UDCA, as they are likely not receiving clinical benefit. Alternative treatments with improved efficacy are needed, particularly for patients with already-advanced disease.

1st Pediatric Clinic University of Athens Athens Greece

Department of Gastroenterology Hepatology and Nutrition Children's National Medical Center Washington DC

Department of Pediatrics and Child Health University of Manitoba Winnipeg Manitoba Canada

Department of Pediatrics and Pediatric Neuropsychiatry Sapienza University of Rome Rome Italy

Department of Pediatrics Cincinnati Children's Hospital Medical Center Cincinnati OH

Department of Pediatrics Emory University School of Medicine Atlanta GA

Department of Pediatrics Harvard University Boston MA

Department of Pediatrics Medical College of Wisconsin Milwaukee WI

Department of Pediatrics Oklahoma University Oklahoma City OK

Department of Pediatrics Palacky University Olomouc Czech Republic

Department of Pediatrics Texas Children's Hospital Houston TX

Department of Pediatrics The Children's Hospital of Philadelphia Philadelphia PA

Department of Pediatrics The Hospital for Sick Children University of Toronto Toronto Ontario Canada

Department of Pediatrics University of California San Francisco San Francisco CA

Department of Pediatrics University of Colorado School of Medicine Aurora CO

Department of Pediatrics University of Helsinki Helsinki Finland

Department of Pediatrics University of Naples Federico 2 Naples Italy

Department of Pediatrics University of Pittsburgh Medical Center Pittsburgh PA

Department of Pediatrics University of Rochester Medical Center Rochester NY

Department of Pediatrics University of Utah Salt Lake City UT

Department of Pediatrics Yale University School of Medicine New Haven CT

Division of Gastroenterology Liver and Nutrition The Dana Dwek Children's Hospital Tel Aviv University Tel Aviv Israel

Zobrazit více v PubMed

Hirschfield GM, Karlsen TH, Lindor KD, Adams DH. Primary sclerosing cholangitis. Lancet. 2013;382(9904):1587–1599. PubMed

Deneau MR, El-Matary W, Valentino PL, et al. The natural history of primary sclerosing cholangitis in 781 children: A multicenter, international collaboration. Hepatology. 2017;66(2):518–527. PubMed

Karlsen TH, Folseraas T, Thorburn D, Vesterhus M. Primary sclerosing cholangitis - a comprehensive review. Journal of hepatology. 2017. PubMed

Dyson JK, Webb G, Hirschfield GM, et al. Unmet clinical need in autoimmune liver diseases. J Hepatol. 2015;62(1):208–218. PubMed

Galle PR, Theilmann L, Raedsch R, Otto G, Stiehl A. Ursodeoxycholate reduces hepatotoxicity of bile salts in primary human hepatocytes. Hepatology. 1990;12(3 Pt 1):486–491. PubMed

Stiehl A, Rudolph G, Raedsch R, et al. Ursodeoxycholic acid-induced changes of plasma and urinary bile acids in patients with primary biliary cirrhosis. Hepatology. 1990;12(3 Pt 1):492–497. PubMed

Calmus Y, Gane P, Rouger P, Poupon R. Hepatic expression of class I and class II major histocompatibility complex molecules in primary biliary cirrhosis: effect of ursodeoxycholic acid. Hepatology. 1990;11(1):12–15. PubMed

Lindor KD. Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing Cholangitis-Ursodeoxycholic Acid Study Group. N Engl J Med. 1997;336(10):691–695. PubMed

Cullen SN, Rust C, Fleming K, Edwards C, Beuers U, Chapman RW. High dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis is safe and effective. J Hepatol. 2008;48(5):792–800. PubMed

Olsson R, Boberg KM, de Muckadell OS, et al. High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-year multicenter, randomized, controlled study. Gastroenterology. 2005;129(5):1464–1472. PubMed

Harnois DM, Angulo P, Jorgensen RA, Larusso NF, Lindor KD. High-dose ursodeoxycholic acid as a therapy for patients with primary sclerosing cholangitis. The American journal of gastroenterology. 2001;96(5):1558–1562. PubMed

Lindor KD, Kowdley KV, Luketic VA, et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology. 2009;50(3):808–814. PubMed PMC

Chapman R, Fevery J, Kalloo A, et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology. 2010;51(2):660–678. PubMed

Al Mamari S, Djordjevic J, Halliday JS, Chapman RW. Improvement of serum alkaline phosphatase to <1.5 upper limit of normal predicts better outcome and reduced risk of cholangiocarcinoma in primary sclerosing cholangitis. Journal of hepatology. 2013;58(2):329–334. PubMed

Lindstrom L, Hultcrantz R, Boberg KM, Friis-Liby I, Bergquist A. Association between reduced levels of alkaline phosphatase and survival times of patients with primary sclerosing cholangitis. Clin Gastroenterol Hepatol. 2013;11(7):841–846. PubMed

Stanich PP, Bjornsson E, Gossard AA, Enders F, Jorgensen R, Lindor KD. Alkaline phosphatase normalization is associated with better prognosis in primary sclerosing cholangitis. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2011;43(4):309–313. PubMed PMC

Deneau MR, Mack C, Abdou R, et al. Gamma glutamyltransferase reduction is associated with favorable outcomes in pediatric primary sclerosing cholangitis. Hepatology Communications (In Press - accepted 13-Jul-2018). 2018. PubMed PMC

Valentino PL, Wiggins S, Harney S, Raza R, Lee CK, Jonas MM. The Natural History of Primary Sclerosing Cholangitis in Children: A Large Single-Center Longitudinal Cohort Study. Journal of pediatric gastroenterology and nutrition. 2016;63(6):603–609. PubMed

Laboratories MM. Alkaline Phosphatase, Total and Isozymes, Serum: Clinical and Interpretive. http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/89503. Accessed August 18, 2016.

Mileti E, Rosenthal P, Peters MG. Validation and modification of simplified diagnostic criteria for autoimmune hepatitis in children. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2012;10(4):417–421 e411–412. PubMed PMC

Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377–381. PubMed PMC

Black DMC, Kerkar N, Miloh T, Sundaram S, Anand R, Gupta A, Alonso E, Arnon R, Bulut P, Karpen S, Lin C, Rosenthal P, Ryan M, Squires R, Valentino P, Schneider B. Initial Results of the WUPPSC Study - Prospective Multicenter Withdrawal of Ursodeoxycholic Acid in Pediatric Primary Sclerosing Cholangitis [Abstract}. Gastroenterology. 2018;154(6 S1):S1209.

Weismuller TJ, Trivedi PJ, Bergquist A, et al. Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis. Gastroenterology. 2017;152(8):1975–1984 e1978. PubMed PMC

Tse CS, Loftus EV Jr., Raffals LE, Gossard AA, Lightner AL. Effects of vedolizumab, adalimumab and infliximab on biliary inflammation in individuals with primary sclerosing cholangitis and inflammatory bowel disease. Alimentary pharmacology & therapeutics. 2018;48(2):190–195. PubMed

Peng X, Luo X, Hou JY, et al. Immunosuppressive Agents for the Treatment of Primary Sclerosing Cholangitis: A Systematic Review and Meta-Analysis. Dig Dis. 2017;35(5):478–485. PubMed

Sabino J, Vieira-Silva S, Machiels K, et al. Primary sclerosing cholangitis is characterised by intestinal dysbiosis independent from IBD. Gut. 2016;65(10):1681–1689. PubMed PMC