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.


Background: Urea cycle disorders (UCDs) are among the most common inborn errors of liver metabolism. As therapies for hyperammonemia associated with urea cycle dysfunction have improved, chronic complications, such as liver disease, have become increasingly apparent in individuals with UCDs. Liver disease in UCDs may be associated with hepatic inflammation, hepatic fibrosis, portal hypertension, liver cancer and even liver failure. However, except for monitoring serum aminotransferases, there are no clear guidelines for screening and/or monitoring individuals with UCDs for liver disease. Thus, we systematically evaluated the potential utility of several non-invasive biomarkers for liver fibrosis in UCDs.

Methods: We evaluated grey-scale ultrasonography, liver stiffness obtained from shear wave elastography (SWE), and various serum biomarkers for hepatic fibrosis and necroinflammation, in a cohort of 28 children and adults with various UCDs.

Results: Overall, we demonstrate a high burden of liver disease in our participants with 46% of participants having abnormal grey-scale ultrasound pattern of the liver parenchyma, and 52% of individuals having increased liver stiffness. The analysis of serum biomarkers revealed that 32% of participants had elevated FibroTest™ score, a marker for hepatic fibrosis, and 25% of participants had increased ActiTest™ score, a marker for necroinflammation. Interestingly, liver stiffness did not correlate with ultrasound appearance or FibroTest™.

Conclusion: Overall, our results demonstrate the high overall burden of liver disease in UCDs and highlights the need for further studies exploring new tools for identifying and monitoring individuals with UCDs who are at risk for this complication.

Trial registration: This study has been registered in (NCT03721367).

Keywords: ActiTest™; FibroTest™; Hepatic fibrosis; Hepatic steatosis; Liver dysfunction; Liver stiffness; Shear wave elastography.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Argininosuccinate Lyase / blood*
  • Biomarkers / blood
  • Child
  • Child, Preschool
  • Elasticity Imaging Techniques
  • Female
  • Genetic Diseases, Inborn / blood*
  • Genetic Diseases, Inborn / diagnostic imaging
  • Genetic Diseases, Inborn / genetics
  • Genetic Diseases, Inborn / pathology
  • Humans
  • Hyperammonemia / blood
  • Hyperammonemia / genetics
  • Hyperammonemia / metabolism
  • Hyperammonemia / pathology
  • Liver / diagnostic imaging
  • Liver / pathology
  • Liver Cirrhosis / blood*
  • Liver Cirrhosis / diagnostic imaging
  • Liver Cirrhosis / genetics
  • Liver Cirrhosis / pathology
  • Liver Diseases / blood*
  • Liver Diseases / genetics
  • Liver Diseases / metabolism
  • Liver Diseases / pathology
  • Male
  • Metabolism, Inborn Errors / genetics
  • Middle Aged
  • Ultrasonography
  • Urea Cycle Disorders, Inborn / blood*
  • Urea Cycle Disorders, Inborn / genetics
  • Urea Cycle Disorders, Inborn / metabolism
  • Urea Cycle Disorders, Inborn / pathology
  • Young Adult


  • Biomarkers
  • Argininosuccinate Lyase

Supplementary concepts

  • Hepatic Fibrosis, Congenital

Associated data