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.

Primary objectives:

• 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 children's lives to learn more about its impact on their 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 to learn more about the possible causes and long-term effects of PSC

Primary outcome measure:

1. 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).
• Data will be collected on all phenotypes of PSC but attention is focused on how the intestinal inflammation and clinical activity of Inflammatory Bowel Disease (IBD) affect the progression of PSC, better classification of patients with features of Auto Immune Hepatitis (AIH), and the implications of bacterial cholangitis amongst all PSC phenotypes.
• Collection of retrospective clinical and laboratory data from the time of diagnosis of PSC and annual timepoints thereafter. Information regarding clinically important timepoints, laboratory data and FibroScan Liver Stiffness Measurements (LSM) are collected prospectively.
• Slides/images (if available) from each liver biopsy obtained at the time of diagnosis of PSC and thereafter and from the explanted liver recovered at the time of liver transplantation will undergo central review.
• Cholangiography results (MRCP, ERCP) will also undergo central review.

Secondary outcome measures:

1. To identify the symptoms of PSC in children and the affects of those symptoms on the functional health of children.
• Identify deficits in the functional health of children with PSC and explore the association of these functional parameters with biochemical markers of liver disease severity and IBD activity. Symptoms and the impact the symptoms on the functional health of children is measured through the use of "Patient Reported Outcomes" and performance-based metrics.
• The burden of disease on the quality of life for children with PSC is measured utilizing the Peds-QL questionnaires (parent proxy and self-report). Child self-report: 8-12 years, and 13-18 years. Young adult self-report: 18-25 years. Parent proxy report: 2-4 years, 5-7 years, 8-12 years, and 13-17 years.
• Itch and fatigue identified as predominant symptoms in PSC are measured through the administration (at every visit) of the 5-D ITCH scale and the PedsQL multidimensional fatigue and PROMIS Sleep Scales.
• Frailty parameters in children with PSC are measured through the Fried frailty criteria at every visit.
2. 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.
• The imaging modalities are utilized to explore the two pathophysiological processes of PSC, liver fibrosis and bile duct damage. Quantitative MRI techniques may be more sensitive to disease progression than standard clinical and laboratory tests, as the liver and bile ducts are being explored directly.
3. Development of a repository for formalin fixed paraffin embedded (FFPE) liver biopsy tissue, serum, plasma, peripheral blood mononuclear cells (PBMCs), DNA and stool.
• Samples of peripheral blood mononuclear cells (PBMC), serum, plasma, DNA and stool are collected from participants at baseline and serum/plasma will be collected annually. In addition, any liver tissue previously collected or collected for clinical purposes in the future will be analyzed along with the PBMC, serum, plasma, DNA and stool within future mechanistic ancillary studies related to the diagnostic/prognostic biomarkers, and genetic, immune and microbial theories of pathogenesis.

Inclusion criteria:

• 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

Exclusion criteria:

• 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

This study is ongoing.