title: Sustaining hypercitrullinemia, hypercholesterolemia and augmented oxidative stress in Japanese children with aspartate/glutamate carrier isoform 2-citrin-deficiency even during the silent period.
abstract: Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) shows diverse metabolic abnormalities such as urea cycle dysfunction together with citrullinemia, galactosemia, and suppressed gluconeogenesis. Such abnormalities apparently resolve during the first year of life. However, metabolic profiles of the silent period remain unknown. We analyzed oxidative stress markers and profiles of amino acids, carbohydrates, and lipids in 20 asymptomatic children with aspartate/glutamate carrier isoform 2-citrin-deficiency aged 1-10 years, for whom tests showed normal liver function. Despite normal plasma ammonia levels, the affected children showed higher blood levels of ornithine (p<0.001) and citrulline (p<0.01)--amino acids involved in the urea cycle--than healthy children. Blood levels of nitrite/nitrate, metabolites of nitric oxide (NO), and asymmetric dimethylarginine inhibiting NO production from arginine were not different between these two groups. Blood glucose, galactose, pyruvate, and lactate levels after 4-5h fasting were not different between these groups, but the affected group showed a significantly higher lactate to pyruvate ratio. Low-density and high-density lipoprotein cholesterol levels in the affected group were 1.5 times higher than those in the controls. Plasma oxidized low-density lipoprotein apparently increased in the affected children; their levels of urinary oxidative stress markers such as 8-hydroxy-2'-deoxyguanosine and acrolein-lysine were significantly higher than those in the controls. Results of this study showed, even during the silent period, sustained hypercitrullinemia, hypercholesterolemia, and augmented oxidative stress in children with citrin deficiency.
authors.affiliation: Division of Metabolism, Chiba Children's Hospital, 579-1 Heta Cho, Midori-ku, Chiba 266-0007, Japan. nagasa-hirono@k2.dion.ne.jp
authors.forename: Hironori
authors.initials: H
authors.lastname: Nagasaka
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Okano
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tsukahara
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Shigematsu
authors.forename: Toru
authors.initials: T
authors.lastname: Momoi
authors.forename: Junko
authors.initials: J
authors.lastname: Yorifuji
authors.forename: Takashi
authors.initials: T
authors.lastname: Miida
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Ohura
authors.forename: Keiko
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Takeyori
authors.initials: T
authors.lastname: Saheki
authors.forename: Kenichi
authors.initials: K
authors.lastname: Hirano
authors.forename: Masaki
authors.initials: M
authors.lastname: Takayanagi
authors.forename: Tohru
authors.initials: T
authors.lastname: Yorifuji
mesh_terms: D000596:Amino Acids / Q000097:blood; D001053:Apolipoproteins / Q000097:blood; D044466:Asian People; D015415:Biomarkers / Q000652:urine; D002241:Carbohydrates / Q000097:blood; D002648:Child; D002675:Child, Preschool; D020159:Citrullinemia / Q000097:blood / Q000150:complications* / Q000503:physiopathology; D005215:Fasting / Q000097:blood; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000150:complications* / Q000503:physiopathology; D007223:Infant; D007564:Japan; D050356:Lipid Metabolism; D008099:Liver / Q000473:pathology / Q000503:physiopathology; D008111:Liver Function Tests; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency*; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins / Q000172:deficiency*; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress; D014508:Urea / Q000378:metabolism; D014810:Vitamin E / Q000097:blood
chemical_list: D000596:Amino Acids; D001053:Apolipoproteins; D015415:Biomarkers; D002241:Carbohydrates; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; C119629:SLC25A13 protein, human; D014810:Vitamin E; D009569:Nitric Oxide; D014508:Urea