Abstract
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.
Highlights
Serum activities of alanine and aspartate aminotransferases (ALT and AST) are used as gold standard biomarkers for the diagnosis of hepatocellular injury
To assess the impact of underlying muscle impairment on serum glutamate dehydrogenase (GLDH) levels in human subjects, we examined GLDH activity in serum samples from adult subjects with acute and chronic muscle impairments and pediatric patients with Duchene muscular dystrophy (DMD), a chronic muscle disease that exhibits extensive muscle injury in the absence of liver injury
Higher GLDH levels in the other three subjects could be attributed to underlying liver injury as their gamma-glutamyl transferase (GGT) or alkaline phosphatase (ALP) levels were above the reference range, did not meet exclusion criteria ( 3x and 2x ULN, respectively)
Summary
Serum activities of alanine and aspartate aminotransferases (ALT and AST) are used as gold standard biomarkers for the diagnosis of hepatocellular injury. In hepatocytes, both enzymes are present in cytoplasm and released into the circulation when the integrity of the hepatocellular membrane is disrupted. ALT and AST are highly sensitive biomarkers of liver. Serum glutamate dehydrogenase detection of liver injury in subjects with muscle impairments 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
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