Serum glutamate dehydrogenase activity enables early detection of liver injury in subjects with underlying muscle impairments

Serum activities of alanine and aspartate aminotransferases (ALT and AST) are used as gold standard biomarkers for the diagnosis of hepatocellular injury. Since ALT and AST lack liver specificity, the diagnosis of the onset of hepatocellular injury in patients with underlying muscle impairments is s...

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Bibliographic Details
Published in:	PloS one Vol. 15; no. 5; p. e0229753
Main Authors:	Schomaker, Shelli, Potter, David, Warner, Roscoe, Larkindale, Jane, King, Nicholas, Porter, Amy C, Owens, Jane, Tomlinson, Lindsay, Sauer, John-Michael, Johnson, Kent, Aubrecht, Jiri
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 14-05-2020 Public Library of Science (PLoS)
Subjects:	Acetaminophen Alanine Amino acids Analysis Aspartate Atrophy Biological markers Biology and Life Sciences Biomarkers Clinical trials Complications and side effects Creatine Creatine kinase Critical path Dehydrogenase Dehydrogenases Diagnosis Disabilities Disease Diseases Drug development Dystrophy Enzymes Glutamate Glutamate dehydrogenase Hypoxia Injury prevention Kinases Liver Liver diseases Medical records Medicine and Health Sciences Muscles Muscular diseases Muscular dystrophy Mutation Personal information Product safety Research and Analysis Methods Researchers Rhabdomyolysis Risk factors United States Ann Arbor Michigan United States > US
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Summary:	Serum activities of alanine and aspartate aminotransferases (ALT and AST) are used as gold standard biomarkers for the diagnosis of hepatocellular injury. Since ALT and AST lack liver specificity, the diagnosis of the onset of hepatocellular injury in patients with underlying muscle impairments is severely limited. Thus, we evaluated the potential of glutamate dehydrogenase (GLDH) as a liver specific alternative biomarker of hepatocellular injury. In our study, serum GLDH in subjects with Duchene muscular dystrophy (DMD) was equivalent to serum GLDH in age matched healthy subjects, while serum ALT was increased 20-fold in DMD subjects. Furthermore, serum GLDH in 131 subjects with variety of muscle impairments was similar to serum GLDH of healthy subjects while serum ALT corelated with serum creatine kinase, a widely accepted biomarker of muscle impairment. In addition, significant elevations of ALT, AST, and CK were observed in a case of a patient with rhabdomyolysis, while serum GLDH stayed within the normal range until the onset of hypoxia-induced liver injury. In a mouse model of DMD (DMDmdx), serum GLDH but not serum ALT clearly correlated with the degree of acetaminophen-induced liver injury. Taken together, our data support the utility of serum GLDH as a liver-specific biomarker of liver injury that has a potential to improve diagnosis of hepatocellular injury in patients with underlying muscle impairments. In drug development, GLDH may have utility as a biomarker of drug induced liver injury in clinical trials of new therapies to treat muscle diseases such as DMD.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Current address: Takeda Pharmaceuticals, Cambridge, MA, United States of America Competing Interests: The project was funded by Pfizer Inc. in forms of research grants to K.J.J and R.W. (University of Michigan). Critical Path Institute provided salary support to J.L., A.C.P., and J-M.S. Pfizer Inc. provided support in the form of salaries for authors [S.J.S., J.O., T.L., and J.A.]. Critical Path Institute and Pfizer Inc reviewed the final manuscript, but the funding organizations did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. None of the authors serve on the editorial board of PLOS ONE. None of the authors have acted as an expert witness in relevant legal proceedings. None of the authors have sat or currently sit on a committee for an organization that may benefit from publication of the paper. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0229753