Primary Sclerosing Cholangitis in Children

Официальное название

Prospective Observational Study of Primary Sclerosing Cholangitis (PSC) in Children

Обзор

Primary sclerosing cholangitis (PSC) is a rare liver disease that damages the liver's bile ducts. Bile ducts are tiny tubes that carry bile from the liver to the small intestine. Bile is a liquid produced by the liver that helps us absorb and use the nutrients in the food we eat. In people with PSC, the bile backs up into the liver and will damage it, causing scarring of the liver. The purposes of this study are to: * Collect medical and other data to learn more about PSC, how it progresses, and identify factors that may cause the disease to progress more quickly. * Ask questions about how PSC symptoms affect your child's life to learn more about its impact on your child's daily functioning * Children with PSC who are seen at one of the participating clinical sites in the Childhood Liver Disease Research Network (ChiLDReN) will be asked to contribute information, DNA, and other specimens. The information and specimens will be available to investigators to carry out approved research aimed at learning more about the possible causes and long-term effects of PSC.

Подробное описание

Pediatric primary sclerosing cholangitis (PSC) is a rare autoimmune biliary fibrosing disease that leads to significant morbidity, the need for liver transplantation in \~50% of patients, and an increased risk for biliary and colorectal cancers in adulthood. The progression of the biliary disease in children is variable and risk factors associated with a more rapid progression of disease have not been adequately studied. Importantly, pediatric hepatologists have never previously collaborated with inflammatory bowel disease (IBD) specialists to rigorously explore interactions between colonic inflammation and liver disease. New non-invasive imaging modalities to measure fibrosis have not been explored in pediatric PSC. Furthermore, the impact that PSC has on the global functioning of children is not well understood, and likely underappreciated.

The natural history of pediatric PSC is poorly understood. This study aims to determine risk factors, including activity of co-existent IBD, associated with more rapid progression of disease, characterize the impact of PSC on global functioning, define the spectrum and prognostic value of biliary tract disease and liver fibrosis based on novel imaging techniques, and establish a biobank of specimens for future mechanistic studies aimed at discovering biomarkers pertaining to etiology and severity of PSC and novel mechanisms of immunopathogenesis of disease. This comprehensive observational and longitudinal study will delineate unique aspects of the natural history and severity of pediatric PSC and of associated IBD and provide necessary data for future therapeutic trials. It aims to provide a platform to discover and validate circulating and imaging biomarkers, which may serve as surrogate endpoints in future interventional studies.

Первичные конечные точки

• To characterize the major phenotypes of PSC including patients with large duct or small duct disease, with and without Inflammatory Bowel Disease (IBD), and with and without Auto Immune Hepatitis (AIH) [Срок оценки: up to 10 years]

Вторичные конечные точки (3)

• To identify the symptoms of PSC in children and the affects of those symptoms on the functional health of children. [Срок оценки: up to 10 years]
• Utilizing imaging modalities measuring liver fibrosis, and large duct injury to correlate with other markers of fibrosis and biliary injury and predict progression of disease. [Срок оценки: up to 10 years]
• Development of a repository for formalin fixed paraffin embedded (FFPE) liver biopsy tissue, serum, plasma, peripheral blood mononuclear cells (PBMCs), DNA and stool. [Срок оценки: up to 10 years]

Критерии участия

Критерии включения

Patients with the clinical diagnosis of large or small duct PSC made at any time prior to enrollment are screened for eligibility to participate in this prospective cohort study. The site PI will determine eligibility following review of MRCP or ERCP images with the site radiologist to confirm presence of an abnormal cholangiogram at the time of diagnosis of large duct PSC. Liver histopathology obtained at the time of diagnosis of small duct PSC will be reviewed with the site pathologist prior to enrollment.

Individuals must meet all of the Inclusion criteria in order to be eligible to participate in the study:

• Aged 2 through 25 years at time of screening.
• Diagnosis of large duct PSC based on review of cholangiogram by MRC, ERC, or intraoperative cholangiogram (IOC) by the site radiologist and interpreted to be consistent with PSC, based on one or more of the following:

• Focal structuring of the bile duct(s)
• Dominant stricture of the common bile duct
• Saccular dilatation of bile duct(s)
• Beaded appearance of bile duct(s)
• Pruning appearance of the distal bile duct branches

AND/OR

• Diagnosis of small duct PSC based on review of liver histopathology by the site pathologist and interpreted to be compatible with PSC:

• Probable small duct PSC: biopsy with ≥3 of 5 criteria: periductal edema, concentric inflammation, bile duct injury, ductular reaction, and neutrophils in bile ducts (cholangitis) OR...
• Definitive small duct PSC: Periductal fibrosis/ "onion skinning" around interlobular bile ducts or smaller profiles
• Stated willingness to comply with all study procedures and availability for the duration of the study.
• Able to provide informed consent/assent

Participants for the imaging study are eligible if they are:

• Aged 8 through 25 years at the time of screening
• No absolute contraindication to MRI
• No skin condition that could be aggravated by MREL
• Meet all other eligibility criteria of the PSC Observational Study
• For whom none of the exclusion criteria apply

Критерии исключения

An individual who meets any of the following criteria at baseline will be excluded from participation in this study.

• History of liver transplantation
• History bone marrow transplantation
• History of primary or acquired immunodeficiency predisposing to secondary sclerosing cholangitis, for instance: hyper-IgM syndrome, severe combined immunodeficiency (SCID) syndrome, common variable immunodeficiency (CVID) syndrome, cartilage hair hypoplasia syndrome, or HIV/AIDS
• History of histiocytosis, including Langerhans cell histiocytosis (LCH), or hemophagocytic lymphohistiocytosis (HLH)
• History of ischemic cholangitis
• History of portal vein thrombosis with biliopathy, veno-occlusive disease, or abdominal radiation vasculopathy
• History of recurrent pyogenic cholangitis
• History of biliary tract surgery for cholecystolithiasis prior to cholangiogram/liver biopsy evaluated to determine enrollment
• History of biliary tract surgery for choledochal cyst
• History of hepatocellular carcinoma, or hepatoblastoma
• History of surgical biliary trauma
• History of congenital cytomegalovirus (CMV) hepatitis
• History of Sickle Cell Disease
• History of cystic fibrosis, biliary atresia, Caroli disease/congenital hepatic fibrosis, or progressive familial intrahepatic cholestasis type 3/MDR3 disease
• History of cardiac hepatopathy.
• History of metabolic disorders, including Wilson's disease, glycogen storage disorder, Alpha-1 Antitrypsin deficiency
• Diagnosis of systemic lupus erythematosus (SLE)
• Concurrent pregnancy at the time of enrollment -

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

США · 11 центров

• Children's Hospital of Los Angeles — Los Angeles
• Children's Hospital Colorado — Aurora
• Children's Healthcare of Atlanta — Atlanta
• Ann & Robert H Lurie Children's Hospital — Chicago
• Riley Hospital for Children — Indianapolis
• Cincinnati Children's Hospital Medical — Cincinnati
• The Children's Hospital of Philadelphia — Philadelphia
• UPMC Children's Hospital of Pittsburgh — Pittsburgh
• … и ещё 3 центра

Канада · 1 центр

• The Hospital for Sick Children — Toronto

Публикации

• Hirschfield GM, Karlsen TH, Lindor KD, Adams DH. Primary sclerosing cholangitis. Lancet. 2013 Nov 9;382(9904):1587-99. doi: 10.1016/S0140-6736(13)60096-3. Epub 2013 Jun 28. PMID 23810223
• Eaton JE, Talwalkar JA, Lazaridis KN, Gores GJ, Lindor KD. Pathogenesis of primary sclerosing cholangitis and advances in diagnosis and management. Gastroenterology. 2013 Sep;145(3):521-36. doi: 10.1053/j.gastro.2013.06.052. Epub 2013 Jul 1. PMID 23827861
• Bambha K, Kim WR, Talwalkar J, Torgerson H, Benson JT, Therneau TM, Loftus EV Jr, Yawn BP, Dickson ER, Melton LJ 3rd. Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community. Gastroenterology. 2003 Nov;125(5):1364-9. doi: 10.1016/j.gastro.2003.07.011. PMID 14598252
• Deneau M, Jensen MK, Holmen J, Williams MS, Book LS, Guthery SL. Primary sclerosing cholangitis, autoimmune hepatitis, and overlap in Utah children: epidemiology and natural history. Hepatology. 2013 Oct;58(4):1392-400. doi: 10.1002/hep.26454. Epub 2013 Aug 13. PMID 23686586
• Toy E, Balasubramanian S, Selmi C, Li CS, Bowlus CL. The prevalence, incidence and natural history of primary sclerosing cholangitis in an ethnically diverse population. BMC Gastroenterol. 2011 Jul 18;11:83. doi: 10.1186/1471-230X-11-83. PMID 21767410
• Olsson R, Danielsson A, Jarnerot G, Lindstrom E, Loof L, Rolny P, Ryden BO, Tysk C, Wallerstedt S. Prevalence of primary sclerosing cholangitis in patients with ulcerative colitis. Gastroenterology. 1991 May;100(5 Pt 1):1319-23. PMID 2013375
• Ricciuto A, Kamath BM, Griffiths AM. The IBD and PSC Phenotypes of PSC-IBD. Curr Gastroenterol Rep. 2018 Mar 28;20(4):16. doi: 10.1007/s11894-018-0620-2. PMID 29594739
• Mieli-Vergani G, Vergani D, Baumann U, Czubkowski P, Debray D, Dezsofi A, Fischler B, Gupte G, Hierro L, Indolfi G, Jahnel J, Smets F, Verkade HJ, Hadzic N. Diagnosis and Management of Pediatric Autoimmune Liver Disease: ESPGHAN Hepatology Committee Position Statement. J Pediatr Gastroenterol Nutr. 2018 Feb;66(2):345-360. doi: 10.1097/MPG.0000000000001801. PMID 29356770

Идентификаторы

NCT: NCT04181138 · PSC Study - ChiLDReN Network · 2U24DK062456

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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