Biomarkers for liver disease in urea cycle disorders

Sandesh C S Nagamani, Saima Ali, Rima Izem, Deborah Schady, Prakash Masand, Benjamin L Shneider, Daniel H Leung, Lindsay C Burrage, Sandesh C S Nagamani, Saima Ali, Rima Izem, Deborah Schady, Prakash Masand, Benjamin L Shneider, Daniel H Leung, Lindsay C Burrage

Abstract

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 ClinicalTrials.gov (NCT03721367).

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

Conflict of interest statement

Declaration of Competing Interest The authors have declared that no conflict of interest exists.

Copyright © 2021. Published by Elsevier Inc.

Figures

Figure 1.. Liver stiffness in participants ages…
Figure 1.. Liver stiffness in participants ages 5–17 years.
The median liver shear wave velocity in m/s, a marker of liver stiffness, for each participant is plotted based on age. The top of each grey box represents the 97.5th %tile of the liver stiffness from a published cohort of healthy children of the same age using the GE Logiq E9 equipment used in this study[39]. The red line indicates the manufacturer’s cutoff for normal stiffness in adults.
Figure 2.. Liver explant tissue from individual…
Figure 2.. Liver explant tissue from individual with OTC deficiency who had liver transplantation after biomarker evaluations.
A. Trichrome staining (100x) shows stage 1 fibrosis. B. Hematoxylin and eosin staining (40x) shows mild expansion of portal tracts by fibroconnective tissue. C. PAS stain without diastase (40x) demonstrates strong staining suggestive of hepatic glycogen accumulation. D. PAS with diastase (40x) shows markedly reduced intra-hepatic PAS staining which is consistent with hepatic glycogen.
Figure 3.. Liver explant tissue from individual…
Figure 3.. Liver explant tissue from individual with ARG1 deficiency who had liver transplantation after biomarker evaluations.
A. Trichrome staining (40x) shows stage 3 fibrosis. B. Hematoxylin and eosin staining (100x) shows variable hepatocyte tinctorial change with many hepatocytes showing pale to moderate eosinophilic cytoplasmic staining with clusters of hepatocytes with clear cytoplasm. C. PAS stain without diastase (100x) suggests excess glycogen with patchy areas with little to no glycogen accumulation corresponding to the areas of clear cytoplasm on H&E. D. PAS stain with diastase (100x) indicates that the PAS stained positive material noted in the absence of diastase is consistent with hepatic glycogen.
Figure 4.. Repeat biomarker evaluation.
Figure 4.. Repeat biomarker evaluation.
Repeat biomarker evaluation was performed on 13 participants approximately one year after initial evaluation. The year 1 and year 2 values for each biomarker for each individual are shown. The red line indicates the cutoff for normal vs. abnormal values provided by manufacturer or laboratory for liver stiffness obtained by SWE, ActiTest™ and FibroTest™. For FIB-4 and APRI, the red line indicates cutoffs determined in individuals with hepatitis C [36, 37].

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Source: PubMed

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