MRI Based Biomarkers in Pediatric Autoimmune Liver Disease

Study Overview
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Brief Summary
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Autoimmune liver diseases (AILD), which include Primary Sclerosing Cholangitis (PSC) and Autoimmune Hepatitis (AIH) are a common etiological factors for chronic liver disease among adolescents. In all these conditions, autoimmune lymphocyte responses are thought to orchestrate inflammatory injury against hepatocytes (primarily in AIH) or cholangiocytes (in PSC). In this proposal we aim to evaluate the Magnetic Resonance Imaging (MRI) modalities; MR cholangiopancreatography (MRCP) and MR elastography (MREL), as non-invasive biomarkers to assess two primary pathophysiological processes of AILD: bile duct damage and liver fibrosis. In this cross-sectional study MRI based findings of bile duct injury and liver fibrosis will be correlated with both liver histology and circulating biomarkers of these disease processes.

Official Title
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Cross-sectional Study for Assessment of MRI Based Biomarkers of Bile Duct Injury and Hepatic Fibrosis in Pediatric Onset Autoimmune Liver Disease

Conditions
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Autoimmune Liver Disease, Primary Sclerosing Cholangitis, Autoimmune Hepatitis

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 6-23 years old. Established or suspected clinical diagnosis of AIH or PSC. Exclusion Criteria: History of liver transplantation. Chronic Hepatitis B or untreated hepatitis C virus infection. Pregnancy. Absolute contraindication for MRI (e.g. pacemaker, metallic implants, claustrophobia). Diagnosis of cystic fibrosis or biliary atresia Diagnosis of cardiac hepatopathy. Diagnosis of Wilson's disease, Alpha-1 Antitrypsin deficiency, or Glycogen storage disease. Skin conditions which could be aggravated by MREL (i.e. Epidermolysis bullosa).

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 23 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients with autoimmune liver disease<br>Patients (6-23 y.o.) with established clinical diagnosis of AIH or suspected diagnosis of AIH based on elevated serum AST or ALT, elevated IgG level >1.1 ULN, elevated titer of autoantibodies, including ANA, SMA, LKM, LC-1 or SLA, which is consistent with the simplified criteria for the diagnosis of AIH in children will be enrolled. Patients (6-23 y.o.) with established clinical diagnosis of PSC or Suspected diagnosis of PSC supported by abnormal cholangiogram (ERCP or MRCP) or elevated GGT>1.5 ULN and dilated bile ducts by liver ultrasound will be enrolled. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MRI based outcomes | MRCP based assessment of intrahepatic and extrahepatic duct irregularities by Majoie classification (on 4 and 5 point scale of 0-3 and 0-4 respectively; 0: No visible abnormalities, 1: minimal dilatation/irregularities, 2: saccular dilatations/segmental stricture, 3: severe pruning, 4: Extremely irregular margin). MREL based quantification of mean shear stiffness (kPa) of liver. | 36 months | 
| Liver histopathology based assessment of bile duct injury by ISHAK Score | Assessment of bile duct injury by ISHAK Score (Confluent necrosis: on the 7 point scale of 0-6; Focal necrosis on the 4 point scale of 0-4 and portal inflammation on the 4 point scale of 0-4). | 36 months | 
| Liver histopathology based assessment of bile duct injury by Ludwig score | Assessment of bile duct injury by Ludwig score (on five point scale of 0-4; 0: No ductal injury, 1: portal inflammation, 2: periportal inflammation, 3: Portal bridging, 4: Nodular cirrhosis). | 36 months | 
| Liver histopathology based assessment of liver fibrosis by Nakanuma score | Assessment of liver fibrosis by Nakanuma score for on the 4 point scale of 0-3 (0; No portal fibrosis, 1; Portal fibrosis; 2; Bridging fibrosis, 3; Liver cirrhosis) . | 36 months | 
| Liver histopathology based assessment of liver fibrosis by Ishak score | Assessment of liver fibrosis by Ishak score on the 7 point scale of 0-6 (0; Absent, 1; confluent necrosis, 2; necrosis in some areas, 3; necrosis in most areas, 4; necrosis with occasional portal-central bridging necrosis, 5; necrosis with multiple portal-central bridging necrosis, 6; Panacinar or multiacinar necrosis). | 36 months | 
| Liver histopathology based assessment of cholangitis and hepatic activity | Cholangitis and hepatic activity by Nakanuma score for on the 4 point scale of 0-3 (0; No bile duct loss, 1; Bile duct loss in <1/3 of portal tracts; 2; Bile duct loss in 1/3-2/3 of portal tracts, 3; Bile duct loss in >2/3 of portal tracts). | 36 months | 
| Serum based outcome | Quantification of serum alkaline phosphatase (ALP in U/L) and Gamma-glutamyl transpeptidase (GGT in U/L). | 36 months | 
| Enhanced Liver Fibrosis (ELF) score | Assesment of Enhanced Liver Fibrosis (ELF) score on continuous scale of 1-10; <7.7 none -mild. ≥7.7 -<9.8 moderate, >9.8 sever). | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MR T1rho, T1, T2 Imaging | Mean of MR T1rho, T1, T2 signal in msec to measure the inflammation. | 36 Months | 
| Liver Morphometry | Collagen deposition in percent area fibrosis by image analysis | 36 Months | 
| Liver histopathology based outcomes | Liver histopathology based grade of inflammation by Scheuer score on 5 point scale of 0-4; (0: No ductal injury, 1: portal inflammation, 2: periportal inflammation, 3: Portal to portal bridging, 4: Nodular cirrhosis). | 36 Months | 
| Serum based outcomes | Quantification of serum fractionated ALP (U/L) | 36 Months | 
| Serum MMP7 | Quantification of serum MMP7 (pg/mL) | 36 Months |