Chronic liver disease and impaired hepatic glycogen metabolism in argininosuccinate lyase deficiency.

Lindsay C Burrage,Bridget M Stroup,Zixue Jin,Racel Cela,Xiaohui Li,Danielle Guffey,Terry Bertin,Brendan Lee,Deborah Schady,Deeksha Bali,Simran Madan,Daniel H Leung,Prakash Masand,Benjamin L Shneider,Charles G Minard,Saima Ali,Jinghong Dai ,Milton J Finegold ,Mingming Jiang ,Mahmoud A Mohammad ,Juan C Marini ,Sandesh C.s Nagamani

doi:10.1172/jci.insight.132342

Abstract

BACKGROUNDLiver disease in urea cycle disorders (UCDs) ranges from hepatomegaly and chronic hepatocellular injury to cirrhosis and end-stage liver disease. However, the prevalence and underlying mechanisms are unclear.METHODSWe estimated the prevalence of chronic hepatocellular injury in UCDs using data from a multicenter, longitudinal, natural history study. We also used ultrasound with shear wave elastography and FibroTest to evaluate liver stiffness and markers of fibrosis in individuals with argininosuccinate lyase deficiency (ASLD), a disorder with high prevalence of elevated serum alanine aminotransferase (ALT). To understand the human observations, we evaluated the hepatic phenotype of the AslNeo/Neo mouse model of ASLD.RESULTSWe demonstrate a high prevalence of elevated ALT in ASLD (37%). Hyperammonemia and use of nitrogen-scavenging agents, 2 markers of disease severity, were significantly (P < 0.001 and P = 0.001, respectively) associated with elevated ALT in ASLD. In addition, ultrasound with shear wave elastography and FibroTest revealed increased echogenicity and liver stiffness, even in individuals with ASLD and normal aminotransferases. The AslNeo/Neo mice mimic the human disorder with hepatomegaly, elevated aminotransferases, and excessive hepatic glycogen noted before death (3-5 weeks of age). This excessive hepatic glycogen is associated with impaired hepatic glycogenolysis and decreased glycogen phosphorylase and is rescued with helper-dependent adenovirus expressing Asl using a liver-specific (ApoE) promoter.CONCLUSIONOur results link urea cycle dysfunction and impaired hepatic glucose metabolism and identify a mouse model of liver disease in the setting of urea cycle dysfunction.TRIAL REGISTRATIONThis study has been registered at ClinicalTrials.gov (NCT03721367, NCT00237315).FUNDINGFunding was provided by NIH, Burroughs Wellcome Fund, NUCDF, Genzyme/ACMG Foundation, and CPRIT.

Highlights

We demonstrate a high prevalence of elevated ALT in argininosuccinate lyase deficiency (ASLD) (37%)
The AslNeo/Neo mice mimic the human disorder with hepatomegaly, elevated aminotransferases, and excessive hepatic glycogen noted before death (3–5 weeks of age)
Argininosuccinic aciduria (MIM 207900) is an autosomal recessive disorder caused by a deficiency of argininosuccinate lyase (ASL) [1]

Summary

Introduction

Argininosuccinic aciduria ( referred to as argininosuccinate lyase deficiency; ASLD) (MIM 207900) is an autosomal recessive disorder caused by a deficiency of argininosuccinate lyase (ASL) [1]. ASL is an enzyme in the urea cycle that converts argininosuccinic acid (ASA) to arginine and fumarate. ASLD is characterized by arginine deficiency and accumulation of ASA, the diagnostic metabolite, in plasma and urine. In addition to this catalytic function, ASL has a structural role as a component of a protein complex with nitric oxide synthase (NOS) that channels extracellular arginine to NOS for nitric oxide (NO) production [2]. Individuals with ASLD may have both urea cycle dysfunction with arginine deficiency from decreased catalytic activity and NO deficiency if the structural integrity of the protein complex required for the synthesis of NO is deficient [2, 3].

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Conclusion