Adverse clinical events in primary sclerosing cholangitis (PSC) happen too slowly to capture during clinical trials. Surrogate endpoints are needed, but no such validated endpoints exist for children with PSC. We evaluated the association between gamma glutamyltransferase (GGT) reduction and long-term outcomes in pediatric PSC patients. We evaluated GGT normalization (< 50 IU/L) at 1 year among a multicenter cohort of children with PSC who did or did not receive treatment with ursodeoxycholic acid (UDCA). We compared rates of event-free survival (no portal hypertensive or biliary complications, cholangiocarcinoma, liver transplantation, or liver-related death) at 5 years. Of the 287 children, mean age of 11.4 years old, UDCA was used in 81% at a mean dose of 17 mg/kg/day. Treated and untreated groups had similar GGT at diagnosis (314 versus 300, P= not significant [NS]). The mean GGT was reduced at 1 year in both groups, with lower values seen in treated (versus untreated) patients (99 versus 175, P= 0.002), but 5-year event-free survival was similar (74% versus 77%, P= NS). In patients with GGT normalization (versus no normalization) by 1 year, regardless of UDCA treatment status, 5-year event-free survival was better (91% versus 67%, P< 0.001). Similarly, larger reduction in GGT over 1 year (> 75% versus < 25% reduction) was also associated with improved outcome (5-year event-free survival 88% versus 61%, P= 0.005). Conclusion:A GGT < 50 and/or GGT reduction of > 75% by 1 year after PSC diagnosis predicts favorable 5-year outcomes in children. GGT has promise as a potential surrogate endpoint in future clinical trials for pediatric PSC.

Academic Medical Centre Amsterdam the Netherlands

Alder Hey Children's Hospital Liverpool United Kingdom

Children's Health Memorial Institute Warsaw Poland

Children's National Medical Center Washington DC

Columbia University College of Physicians and Surgeons New York NY

Dana Dwek Children's Hospital Tel Aviv Medical Center Tel Aviv University Tel Aviv Israel

Emory University School of Medicine Atlanta GA

Lille University Hospital of Lille Lille France

Mayo Clinic Rochester MN

Medical College of Wisconsin Milwaukee WI

Memorial University St John's Newfoundland and Labrador Canada

Nassau University Medical Center East Meadow NY

Nemours Alfred 1 duPont Hospital For Children Wilmington DE

Northwest Pediatric Gastroenterology LLC Portland OR

Palacky University Olomouc Czech Republic

Phoenix Children's Hospital Phoenix AZ

Sapienza University of Rome Rome Italy

Shaare Zedek Medical Center Jerusalem Israel

Teikyo University School of Medicine Tokyo Japan

Texas Children's Hospital Houston TX

University College Dublin Dublin Ireland

University of Alberta Edmonton Canada

University of Athens Athens Greece

University of Colorado School of Medicine Aurora CO

University of Helsinki Helsinki Finland

University of Liverpool Liverpool United Kingdom

University of Ljubljana Ljubljana Slovenia

University of Manchester Manchester United Kingdom

University of Manitoba Winnipeg Canada

University of Naples Federico 2 Naples Italy

University of Pittsburgh Medical Center Pittsburgh PA

University of Rochester Medical Center Rochester NY

University of Toronto Toronto Canada

University of Ulsan Seoul South Korea

University of Utah Salt Lake City UT

Yale University School of Medicine New Haven CT

Zobrazit více v PubMed

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

Deneau MR, El‐Matary W, Valentino PL, Abdou R, Alqoaer K, Amin M, et al. The natural history of primary sclerosing cholangitis in 781 children: a multicenter, international collaboration. Hepatology 2017;66:518‐527. PubMed

Karlsen TH, Folseraas T, Thorburn D, Vesterhus M. Primary sclerosing cholangitis—a comprehensive review. J Hepatol 2017;67:1298‐1323. PubMed

Dyson JK, Webb G, Hirschfield GM, Lohse A, Beuers U, Lindor K, et al. Unmet clinical need in autoimmune liver diseases. J Hepatol 2015;62:208‐218. PubMed

Lindor KD. Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing Cholangitis‐Ursodeoxycholic Acid Study Group. N Engl J Med 1997;336:691‐695. 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;48:792‐800. PubMed

Olsson R, Boberg KM, de Muckadell OS, Lindgren S, Hultcrantz R, Folvik G, et al. High‐dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5‐year multicenter, randomized, controlled study. Gastroenterology 2005;129:1464‐1472. PubMed

Lindor KD, Kowdley KV, Luketic VA, Harrison ME, McCashland T, Befeler AS, et al. High‐dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology 2009;50:808‐814. PubMed PMC

Wunsch E, Trottier J, Milkiewicz M, Raszeja‐Wyszomirska J, Hirschfield GM, et al. Prospective evaluation of ursodeoxycholic acid withdrawal in patients with primary sclerosing cholangitis. Hepatology 2014;60:931‐940. PubMed

Imam MH, Sinakos E, Gossard AA, Kowdley KV, Luketic VA, Edwyn Harrison M, et al. High‐dose ursodeoxycholic acid increases risk of adverse outcomes in patients with early stage primary sclerosing cholangitis. Aliment Pharmacol Ther 2011;34:1185‐1192. PubMed PMC

Chapman R, Fevery J, Kalloo A, Nagorney DM, Boberg KM, Schneider B, et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology 2010;51:660‐678. PubMed

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. J Pediatr Gastroenterol Nutr 2016;63:603‐609. PubMed

Feldstein AE, Perrault J, El‐Youssif M, Lindor KD, Freese DK, Angulo P. Primary sclerosing cholangitis in children: a long‐term follow‐up study. Hepatology 2003;38:210‐217. PubMed

Miloh T, Arnon R, Shneider B, Suchy F, Kerkar N. A retrospective single‐center review of primary sclerosing cholangitis in children. Clin Gastroenterol Hepatol 2009;7:239‐245. PubMed

Al Mamari S, Djordjevic J, Halliday JS, Chapman RW. Improvement of serum alkaline phosphatase to xxaaa1.5 upper limit of normal predicts better outcome and reduced risk of cholangiocarcinoma in primary sclerosing cholangitis. J Hepatol 2013;58:329‐334. 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;11:841‐846. 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. Dig Liver Dis 2011;43:309‐313. PubMed PMC

Cabrera‐Abreu JC, Green A. Gamma‐glutamyltransferase: value of its measurement in paediatrics. Ann Clin Biochem 2002;39:22‐25. PubMed

Freeman AJ, Ng VL, Harpavat S, Hrycko A, Apted Z, Bulut P, et al. Level of gamma‐glutamyltransferase in 2‐year‐old children with biliary atresia associates with progression of portal hypertension. Clin Gastroenterol Hepatol 2017;15:1133‐1135. PubMed

Spagnuolo MI, Iorio R, Vegnente A, Guarino A. Ursodeoxycholic acid for treatment of cholestasis in children on long‐term total parenteral nutrition: a pilot study. Gastroenterology 1996;111:716‐719. PubMed

Wang J, Wang ZL, Wang XH, Zhu QR, Zheng S. The prognostic value of serum gamma glutamyltransferase activity in Chinese infants with previously diagnosed idiopathic neonatal hepatitis. HK J Paediatr (new series) 2008;13:39‐45.

Wang JS, Tan N, Dhawan A. Significance of low or normal serum gamma glutamyl transferase level in infants with idiopathic neonatal hepatitis. Eur J Pediatr 2006;165:795‐801. PubMed

Oswari H, Widjaja RK, Rohsiswatmo R, Cleghorn G. Prognostic value of biochemical liver parameters in neonatal sepsis‐associated cholestasis. J Paediatr Child Health 2013;49:E6‐E11. PubMed

Classen M, Gotze H, Richter HJ, Bender S. Primary sclerosing cholangitis in children. J Pediatr Gastroenterol Nutr 1987;6:197‐202. PubMed

Debray D, Pariente D, Urvoas E, Hadchouel M, Bernard O. Sclerosing cholangitis in children. J Pediatr 1994;124:49‐56. PubMed

el‐Shabrawi M, Wilkinson ML, Portmann B, Mieli‐Vergani G, Chong SKF, Williams R,, et al. Primary sclerosing cholangitis in childhood. Gastroenterology 1987;92:1226‐1235. PubMed

Johnson DA, Cattau EL Jr, Hancock JE. Pediatric primary sclerosing cholangitis. Dig Dis Sci 1986;31:773‐777. PubMed

Kagalwalla AF, Altraif I, Shamsan L, Omojola M, Khan H, Kagalwalla YA. Primary sclerosing cholangitis in Arab children: report of four cases and literature review. J Pediatr Gastroenterol Nutr 1997;24:146‐152. PubMed

Sisto A, Feldman P, Garel L, Seidman E, Brochu P, Morin CL, et al. Primary sclerosing cholangitis in children: study of five cases and review of the literature. Pediatrics 1987;80:918‐923. PubMed

Werlin SL, Glicklich M, Jona J, Starshak RJ. Sclerosing cholangitis in childhood. J Pediatr 1980;96:433‐435. PubMed

Wilschanski M, Chait P, Wade JA, Davis L, Corey M, St. Louis P, et al. Primary sclerosing cholangitis in 32 children: clinical, laboratory, and radiographic features, with survival analysis. Hepatology 1995;22:1415‐1422. PubMed

Fickert P, Hirschfield GM, Denk G, Marschall HU, Altorjay I, Färkkilä M, et al. norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis. J Hepatol 2017;67:549‐558. PubMed

Corpechot C, El Naggar A, Poujol‐Robert A, Ziol M, Wendum D, Chazouilléres O, et al. Assessment of biliary fibrosis by transient elastography in patients with PBC and PSC. Hepatology 2006;43:1118‐1124. PubMed

Mayo Medical Laboratories . Alkaline phosphatase, total and isozymes, serum: clinical and interpretive. https://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/8340. Accessed August 31, 2018.

Ruemmele FM, Veres G, Kolho KL, Griffiths A, Levine A, Escher JC, et al. Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn's disease. J Crohns Colitis 2014;8:1179‐1207. PubMed

Manns MP, Czaja AJ, Gorham JD, Krawitt EL, Mieli‐Vergani G, Vergani D, et al. Diagnosis and management of autoimmune hepatitis. Hepatology 2010;51:2193‐2213. PubMed

Turner D, Levine A, Escher JC, Griffiths AM, Russell RK, Dignass A, et al. Management of pediatric ulcerative colitis: joint ECCO and ESPGHAN evidence‐based consensus guidelines. J Pediatr Gastroenterol Nutr 2012;55:340‐361. PubMed

Mileti E, Rosenthal P, Peters MG. Validation and modification of simplified diagnostic criteria for autoimmune hepatitis in children. Clin Gastroenterol Hepatol 2012;10(417–421):e1‐e2. PubMed PMC

Rupp C, Rossler A, Halibasic E, Sauer P, Weiss KH, Friedrich K, et al. Reduction in alkaline phosphatase is associated with longer survival in primary sclerosing cholangitis, independent of dominant stenosis. Aliment Pharmacol Ther 2014;40:1292‐1301. PubMed

de Vries EM, Wang J, Leeflang MM, Boonstra K, Weersma RK, Beuers UH, et al. Alkaline phosphatase at diagnosis of primary sclerosing cholangitis and one year later: evaluation of prognostic value. Liver Int 2016;36:1867‐1875. PubMed

FDA‐NIH Biomarker Working Group . Reasonably likely surrogate endpoint; in BEST (Biomarkers, EndpointS, and other Tools) resource. https://www.ncbi.nlm.nih.gov/books/NBK453485/. Accessed August 31, 2018.

U.S. Food and Drug Administration . FDA facts: biomarkers and surrogate endpoints. https://www.fda.gov/AboutFDA/Innovation/ucm512503.htm. 2017.

Ursodeoxycholic Acid Therapy in Pediatric Primary Sclerosing Cholangitis: Predictors of Gamma Glutamyltransferase Normalization and Favorable Clinical Course