{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T04:46:33Z","timestamp":1791002793278,"version":"4.1.0"},"reference-count":56,"publisher":"American Society for Clinical Investigation","issue":"4","funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["U54HD061221,K08DK106453,P30DK56338,R01DK102641,HD024064,U54 HD083092"],"award-info":[{"award-number":["U54HD061221,K08DK106453,P30DK56338,R01DK102641,HD024064,U54 HD083092"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Urea Cycle Disorders Foundation","award":["National Urea Cycle Disorders Foundation Fellowship"],"award-info":[{"award-number":["National Urea Cycle Disorders Foundation Fellowship"]}]},{"DOI":"10.13039\/100000861","name":"Burroughs Wellcome Fund","doi-asserted-by":"crossref","award":["Burroughs Wellcome Fund Career Award for Medical Scientists"],"award-info":[{"award-number":["Burroughs Wellcome Fund Career Award for Medical Scientists"]}],"id":[{"id":"10.13039\/100000861","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000011","name":"Howard Hughes Medical Institute","doi-asserted-by":"crossref","award":["Howard Hughes Med into Grad Scholarship"],"award-info":[{"award-number":["Howard Hughes Med into Grad Scholarship"]}],"id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100004329","name":"Genzyme","doi-asserted-by":"crossref","award":["Genzyme\/ACMG Foundation for Genetic"],"award-info":[{"award-number":["Genzyme\/ACMG Foundation for Genetic"]}],"id":[{"id":"10.13039\/100004329","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100004329","name":"Genzyme","doi-asserted-by":"crossref","award":["Genomic Medicine Medical Genetics Training Award in Clinical Biochemical Genetics"],"award-info":[{"award-number":["Genomic Medicine Medical Genetics Training Award in Clinical Biochemical Genetics"]}],"id":[{"id":"10.13039\/100004329","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100004917","name":"Cancer Prevention and Research Institute of Texas","doi-asserted-by":"crossref","award":["CPRIT Pre-Doctoral Fellowship"],"award-info":[{"award-number":["CPRIT Pre-Doctoral Fellowship"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,2,27]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>Liver 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      We 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\n                      <jats:italic>\n                        Asl\n                        <jats:sup>Neo\/Neo<\/jats:sup>\n                      <\/jats:italic>\n                      mouse model of ASLD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      We demonstrate a high prevalence of elevated ALT in ASLD (37%). Hyperammonemia and use of nitrogen-scavenging agents, 2 markers of disease severity, were significantly (\n                      <jats:italic>P<\/jats:italic>\n                      &lt; 0.001 and\n                      <jats:italic>P<\/jats:italic>\n                      = 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\n                      <jats:italic>\n                        Asl\n                        <jats:sup>Neo\/Neo<\/jats:sup>\n                      <\/jats:italic>\n                      mice mimic the human disorder with hepatomegaly, elevated aminotransferases, and excessive hepatic glycogen noted before death (3\u20135 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\n                      <jats:italic>Asl<\/jats:italic>\n                      using a liver-specific (\n                      <jats:italic>ApoE<\/jats:italic>\n                      ) promoter.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>Our 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>TRIAL REGISTRATION<\/jats:title>\n                    <jats:p>This study has been registered at ClinicalTrials.gov (NCT03721367, NCT00237315).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>FUNDING<\/jats:title>\n                    <jats:p>Funding was provided by NIH, Burroughs Wellcome Fund, NUCDF, Genzyme\/ACMG Foundation, and CPRIT.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1172\/jci.insight.132342","type":"journal-article","created":{"date-parts":[[2020,1,28]],"date-time":"2020-01-28T16:27:59Z","timestamp":1580228879000},"source":"Crossref","is-referenced-by-count":18,"title":["Chronic liver disease and impaired hepatic glycogen metabolism in argininosuccinate lyase deficiency"],"prefix":"10.1172","volume":"5","author":[{"given":"Lindsay C.","family":"Burrage","sequence":"first","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA."},{"name":"Texas Children\u2019s Hospital, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simran","family":"Madan","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA."},{"name":"Interdepartmental Program in Translational Biology and Molecular Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohui","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saima","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud","family":"Mohammad","sequence":"additional","affiliation":[{"name":"USDA\/ARS Children\u2019s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA."},{"name":"Department of Food Science and Nutrition, National Research Centre, Dokki, Giza, Egypt."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9755-7937","authenticated-orcid":true,"given":"Bridget M.","family":"Stroup","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Ming","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Racel","family":"Cela","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terry","family":"Bertin","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixue","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Duke Health, Durham, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3721-614X","authenticated-orcid":true,"given":"Danielle","family":"Guffey","sequence":"additional","affiliation":[{"name":"Dan L. 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