Liver Disease in Urea Cycle Disorders

Noninvasive Biomarkers of Hepatic Fibrosis in Urea Cycle Disorders

This is a multi-center, cross-sectional study to assess risk for liver fibrosis and hepatic injury in individuals with urea cycle disorders (UCDs) using serum biomarkers, Fibroscan, and MRE. This study will be conducted at 5 sites of the Urea Cycle Disorders Consortium: Baylor College of Medicine in Houston, TX, Seattle Children's Hospital in Seattle, WA, Children's Hospital Colorado in Aurora, CO, Children's Hospital of Philadelphia in Philadelphia, PA, and Children's National Medical Center in Washington D.C.

Study Overview

• Status: Recruiting
• Conditions: Ornithine Transcarbamylase Deficiency; Urea Cycle Disorder; Argininosuccinic Aciduria; Hyperargininemia; Citrullinemia 1; ARGI Deficiency; ASL Deficiency; ASS Deficiency

Detailed Description

Urea cycle disorders (UCDs) are among the most common inborn errors of liver metabolism. With early diagnosis and improved treatments, the survival of individuals with UCDs has improved, and this improved survival has led to unmasking of some long-term complications such as hepatic dysfunction and progressive fibrosis in a subset of patients. Hepatic complications in UCDs are quite variable and dependent upon the specific metabolic defect.

Currently, there are no guidelines for monitoring hepatic complications or extent of liver disease in UCDs. The gold standard for staging of fibrosis or confirming cirrhosis has traditionally been liver biopsy, an invasive procedure with inherent risks, particularly in the setting of a UCD and compromised coagulation. Recently, non-invasive serum and imaging-based biomarkers have been introduced to assess hepatic fibrosis in adults and children who are at increased risk. Utilization of these technique in individuals with UCDs could be invaluable in both the research and clinical arenas.

The purpose of this study is:

1) To assess risk for increased fibrosis using serum biomarkers and/or VCTE in distal disorders (ASS1D, ASLD and ARG1D) as compared to OTCD 2 ) To assess risk for hepatic fibrosis (liver stiffness as measured by MRE) in individuals with UCDs who have abnormal serum biomarkers and/or VCTE as those who have normal values

• Study Type: Observational
• Enrollment (Anticipated): 62

Contacts and Locations

• Study Contact: Name: Saima Ali, MSN; Phone Number: 832-822-4183; Email: saima.ali@bcm.edu

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Not yet recruiting
      • Children's Hospital Colorado
      • Contact: Brittany Murphy; Phone Number: 720-777-8591; Email: Brittany.Murphy@childrenscolorado.org
      • Principal Investigator: Shawn McCandless, MD
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Recruiting
      • Children's National Medical Center
      • Contact: Kara Simpson, MS, CGC; Phone Number: 202-476-6216; Email: ksimpson@childrensnational.org
      • Principal Investigator: Nicholas A Mew, MD
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Not yet recruiting
      • The Children's Hospital of Philadelphia
      • Principal Investigator: Can Ficicioglu, MD, PhD
      • Contact: Bianca Ferreira, MPH; Phone Number: 267-426-1368; Email: ferreirab@email.chop.edu
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • Baylor College of Medicine
      • Contact: Saima Ali; Phone Number: 832-822-4183; Email: saima.ali@bcm.edu
      • Principal Investigator: Lindsay C Burrage, MD, PhD
  • Washington
    • Seattle, Washington, United States, 98105
      • Not yet recruiting
      • Seattle Children's Hospital
      • Contact: Linnea Brody, CRA; Phone Number: 206-987-3012; Email: Linnea.brody@seattlechildrens.org
      • Principal Investigator: Christina Lam, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Individuals with urea cycle disorders

Description

Stage A

Inclusion Criteria:

• Age > 6 years and < 65 years
• Weight ≥ 11 kg at time of screening
• A molecular or biochemical diagnosis of OTCD, ASS1D, ASLD, or ARG1D.

Exclusion Criteria:

• Prior liver transplantation
• Episode of acute hyperammonemia (≥100 umol/L) in the 30 days prior to enrollment
• Confirmed diagnosis of chronic viral hepatitis, autoimmune liver disease, short gut, small bowel syndrome, alcohol liver disease, TPN requirement, or TPN-related cholestatic disease
• Adults with BMI ≥ 45 kg/m2
• Current pregnancy
• Open wound near expected Fibroscan® probe application site
• Use of implantable active medical device such as cardiac pacemaker or implantable cardioverter-defibrillator

Stage B Inclusion Criteria

• Participation in Stage A of this study

Exclusion Criteria

• Individuals with claustrophobia or other inability to complete
• Known diagnosis of hemochromatosis
• Presence of implants or devices incompatible with MRI
• Inability to breath-hold for 20 seconds for the elastography sequence
• Current pregnancy
• Confirmed diagnosis of chronic viral hepatitis, autoimmune liver disease, short gut, small bowel syndrome, alcohol liver disease, TPN requirement, or TPN-related cholestatic disease
• Episode of documented acute hyperammonemia (ammonia ≥ 100 umol/L) in the 30 days prior to scheduled visit for Stage B

Study Plan

How is the study designed?

Design Details

• Observational Models: Other
• Time Perspectives: Cross-Sectional

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fibrotest	Fibrotest(TM)	One measurement made on the 1 day of the study visit (stage A)
Fibroscan (liver stiffness)	Liver stiffness (kPa) as assessed by Fibroscan®	One measurement made on the 1 day of the study visit (stage A)
Fibroscan (CAP)	Controlled Attenuation Parameter (CAPTM in dB/m) as assessed by Fibroscan®	One measurement made on the 1 day of the study visit (stage A)
MRE	Liver stiffness (kPa) as measured by MRE	One measurement made on the 1 day of the study visit (stage B)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Albumin	Albumin	One measurement made on the 1 day of the study visit (stage A)
Liver Enzymes	Aspartate aminotransferase, Alanine aminotransaminase, and Gamma glutamyl transferase	One measurement made on the 1 day of the study visit (Stage A)
Total Bilirubin	Total Bilirubin	One measurement made on the 1 day of the study visit (stage A)
Prothrombin time	Prothrombin time	One measurement made on the 1 day of the study visit (stage A)
INR	INR	One measurement made on the 1 day of the study visit (stage A)
AST-to-Platelet Ratio (APRI)	AST-to-Platelet Ratio (APRI)	One measurement made on the 1 day of the study visit (stage A)
GGT-to-Platelet Ratio (GPR)	GGT-to-Platelet Ratio (GPR)	One measurement made on the 1 day of the study visit (stage A)
Fibrosis-4 (FIB-4) Index	Fibrosis-4 (FIB-4) Index	One measurement made on the 1 day of the study visit (stage A)
MRE	Fat fraction (%) as measured by MRE	One measurement made on the 1 day of the study visit (stage B)

Collaborators and Investigators

• Sponsor: Baylor College of Medicine
• Collaborators: Children's Hospital of Philadelphia; Children's Hospital Colorado; Seattle Children's Hospital; Children's National Research Institute
• Investigators: Principal Investigator: Lindsay Burrage, MD, PhD, Baylor College of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): November 4, 2021
• Primary Completion (Anticipated): December 31, 2023
• Study Completion (Anticipated): December 31, 2023

Study Registration Dates

• First Submitted: October 22, 2020
• First Submitted That Met QC Criteria: October 27, 2020
• First Posted (Actual): November 3, 2020

Study Record Updates

• Last Update Posted (Estimate): May 5, 2023
• Last Update Submitted That Met QC Criteria: May 4, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Liver disease; Fibrotest; Fibroscan; Magnetic resonance elastography
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Amino Acid Metabolism, Inborn Errors; Ornithine Carbamoyltransferase Deficiency Disease; Urea Cycle Disorders, Inborn; Citrullinemia; Argininosuccinic Aciduria; Hyperargininemia
• Other Study ID Numbers: H-50295

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No