# Clinical-Res-Project3

> **NIH NIH U54** · CHILDREN'S RESEARCH INSTITUTE · 2022 · $100,000

## Abstract

PROJECT 3 - SUMMARY/ABSTRACT
 Hepatocellular injury, hepatic fibrosis, and cirrhosis leading to liver failure have been described in a
subset of patients with urea cycle disorders (UCD). In addition, there are reports of abnormal liver function
during acute episodes of hyperammonemia in several disorders, including ornithine transcarbamylase
deficiency (OTCD), and there are single case reports of hepatocellular carcinoma in UCD. Common
histopathologic findings in the liver of individuals with UCD include hepatocyte enlargement, increased
glycogen deposition, and steatosis. However, there are no recommendations for long-term surveillance for
chronic hepatic complications. Although serum aminotransferases and markers of synthetic function are used
to monitor hepatic disease, the sensitivity of such assays to detect progression of liver disease is low.
 Recently, several non-invasive biomarkers for liver fibrosis including serum biomarker panels and
various forms of elastography have been validated for predicting the degree of fibrosis in patients with a variety
of chronic liver diseases. In this project, we propose to use these non-invasive tools to assess the extent and
prevalence of liver disease in a large cohort of individuals with UCD. Data from the Longitudinal Study of UCD,
Urea Cycle Disorders Consortium (UCDC) Project 1, show that the risk for chronic hepatocellular injury is
higher in distal UCD (e.g., argininosuccinate lyase deficiency – ASLD, citrullinemia – ASS1D, and arginase
deficiency - ARG1D) compared to OTCD, a proximal UCD. We hypothesize that liver fibrosis, as measured by
non-invasive biomarkers, is also a significant and underestimated complication of distal UCD and that both
steatosis and glycogen accumulation contribute to the etiology of the liver disease. To test this hypothesis, we
will compare serum biomarkers for fibrosis in individuals with ASS1D, ASLD, and ARG1D vs. OTCD, and we
will test whether elevation in serum biomarkers for fibrosis correlate with liver stiffness as measured by
magnetic resonance elastography (MRE). Lastly, we will histopathologically score fibrosis stage and steatosis
grade, and quantify the glycogen content in hepatic explants and biopsies from two UCDC liver transplant
centers in order to determine the prevalence of these complications in UCD. Overall, this will be the largest,
comprehensive study of liver disease in UCD. This study will inform our understanding of the natural history of
liver disease in UCD, provide the basis for the development of new biomarkers for assessing liver disease in
UCD, and validate endpoints that could be used in the future to assess efficacy of interventions for the
prevention and/or therapy of liver disease in UCD.

## Key facts

- **NIH application ID:** 10463798
- **Project number:** 5U54HD061221-19
- **Recipient organization:** CHILDREN'S RESEARCH INSTITUTE
- **Principal Investigator:** Lindsay C Burrage
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $100,000
- **Award type:** 5
- **Project period:** 2003-09-30 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10463798

## Citation

> US National Institutes of Health, RePORTER application 10463798, Clinical-Res-Project3 (5U54HD061221-19). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10463798. Licensed CC0.

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