Chronic Liver Disease in Urea Cycle Disorders

Prospective Cross-Sectional Non-invasive Assessment of Chronic Liver Disease in Urea Cycle Disorders

This is a pilot, cross-sectional study to assess liver stiffness and markers of hepatic injury, function, and fibrosis in patients with urea cycle disorders. This study will be conducted at 3 UCDC sites: Baylor College of Medicine in Houston, Texas, University of California San Francisco (UCSF), San Francisco, California and Seattle Children's Hospital, Seattle,Washington

Study Overview

• Status: Completed
• Conditions: Urea Cycle Disorder
• Intervention / Treatment: Other: Diagnostic Ultrasound

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 purpose of this study is: 1) To determine whether liver stiffness is higher in individuals with ASS1D, ASLD, and ARG1D as compared to females with OTCD, and to assess liver stiffness in other UCDs (citrin deficiency, NAGSD, CPS1D, and males with OTCD), 2) To test whether markers of hepatocellular injury and function and novel serum biomarker panels for hepatic fibrosis provide evidence of chronic liver disease in individuals with ASS1D, ASLD, and ARG1D as compared to OTCD and to assess these sample markers of hepatocellular injury and function and novel serum biomarker panels for hepatic fibrosis in other UCDs (citrin deficiency, NAGSD, CPS1D, and males with OTCD).

• Study Type: Observational
• Enrollment (Actual): 28

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 60 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Individuals with urea cycle disorders

Description

Inclusion Criteria:

1. Age > 5 years and < 60 years
2. Weight ≥ 11 kg
3. Males or females with a diagnosis of OTCD based on molecular or enzymatic testing. Males or females with a diagnosis of CPS1D, citrin deficiency, NAGSD, ASS1D, ASLD or ARG1D based on biochemical OR molecular, OR enzymatic testing

Exclusion Criteria:

1. History of hyperammonemia (blood ammonia greater than 100 micromoles/L) documented in the medical record or reported by the patient in the 30 days preceding enrollment visit
2. History of Liver transplantation
3. Current pregnancy
4. Confirmed diagnosis of chronic viral hepatitis, autoimmune liver disease, or alcohol liver disease

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Urea Cycle Disorders	Other: Diagnostic Ultrasound; All individuals will undergo a blood draw for measurement of biomarkers of liver disease and an ultrasound with shear-wave elastography.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Liver Stiffness as Measured by Shear Wave Elastography	Shear wave elastography in m/s is a measure of liver stiffness, a surrogate measure for hepatic fibrosis. Normal liverstiffness is < 1.35 m/s and abnormal liver stiffness is >1.35 m/s	One measurement made on the day of study visit
Grey Scale Ultrasound Findings	Grey scale ultrasound findings	Baseline, once

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fibrotest	Fibrotest is a blood test that is a surrogate measure for hepatic fibrosis. F0 is normal. >F0 predicts at least minimal fibrosis.	Baseline, once

Collaborators and Investigators

• Sponsor: Baylor College of Medicine
• Collaborators: Seattle Children's Hospital; University of California, San Francisco

Publications and helpful links

General Publications

• Nagamani SCS, Ali S, Izem R, Schady D, Masand P, Shneider BL, Leung DH, Burrage LC. Biomarkers for liver disease in urea cycle disorders. Mol Genet Metab. 2021 Jun;133(2):148-156. doi: 10.1016/j.ymgme.2021.04.001. Epub 2021 Apr 8.
• Burrage LC, Madan S, Li X, Ali S, Mohammad M, Stroup BM, Jiang MM, Cela R, Bertin T, Jin Z, Dai J, Guffey D, Finegold M; Members of the Urea Cycle Disorders Consortium (UCDC); Nagamani S, Minard CG, Marini J, Masand P, Schady D, Shneider BL, Leung DH, Bali D, Lee B. Chronic liver disease and impaired hepatic glycogen metabolism in argininosuccinate lyase deficiency. JCI Insight. 2020 Feb 27;5(4):e132342. doi: 10.1172/jci.insight.132342.

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 29, 2017
• Primary Completion (ACTUAL): June 1, 2020
• Study Completion (ACTUAL): June 1, 2020

Study Registration Dates

• First Submitted: June 20, 2018
• First Submitted That Met QC Criteria: October 24, 2018
• First Posted (ACTUAL): October 26, 2018

Study Record Updates

• Last Update Posted (ACTUAL): February 10, 2023
• Last Update Submitted That Met QC Criteria: February 8, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Amino Acid Metabolism, Inborn Errors; Liver Diseases; Urea Cycle Disorders, Inborn
• Other Study ID Numbers: H-40988; UCDC 5118 (OTHER: Urea Cycle Disorders Consortium)

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