title: Circulating tricarboxylic acid cycle metabolite levels in citrin-deficient children with metabolic adaptation, with and without sodium pyruvate treatment.
abstract: Citrin deficiency causes adult-onset type II citrullinemia (CTLN-2), which later manifests as severe liver steatosis and life-threatening encephalopathy. Long-standing energy deficit of the liver and brain may predispose ones to CTLN-2. Here, we compared the energy-driving tricarboxylic acid (TCA) cycle and fatty acid β-oxidation cycle between 22 citrin-deficient children (age, 3-13years) with normal liver functions and 37 healthy controls (age, 5-13years). TCA cycle analysis showed that basal plasma citrate and α-ketoglutarate levels were significantly higher in the affected than the control group (p<0.01). Conversely, basal plasma fumarate and malate levels were significantly lower than those for the control (p<0.001). The plasma level of 3-OH-butyrate derived from fatty acid β-oxidation was significantly higher in the affected group (p<0.01). Ten patients underwent sodium pyruvate therapy. However, this therapy did not correct or attenuate such deviations in both cycles. Sodium pyruvate therapy significantly increased fasting insulin secretion (p<0.01); the fasting sugar level remained unchanged. Our results suggest that citrin-deficient children show considerable deviations of TCA cycle metabolite profiles that are resistant to sodium pyruvate treatment. Thus, long-standing and considerable TCA cycle dysfunction might be a pivotal metabolic background of CTLN-2 development.
authors.affiliation: Department of Pediatrics, Takarazuka City Hospital, 4-5-1, Kohama, Takarazuka 665-0827, Japan. Electronic address: nagasaka@cnt-osaka.com.
authors.forename: Hironori
authors.initials: H
authors.lastname: Nagasaka
authors.affiliation: Department of Pediatrics, Toho University Sakura Medical Center, 564-1, Shimoshizu, Sakura 285-8741, Japan.
authors.forename: Haruki
authors.initials: H
authors.lastname: Komatsu
authors.affiliation: Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohamashi Tobu Hospital, 3-6-1 Shimosueyoshi, Tsurumi-ku, Yokohama 230-0012, Japan.
authors.forename: Ayano
authors.initials: A
authors.lastname: Inui
authors.affiliation: Department of Pediatrics, Takarazuka City Hospital, 4-5-1, Kohama, Takarazuka 665-0827, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Nakacho
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-Cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Morioka
authors.affiliation: Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-Cho, Kita-ku, Okayama 700-8558, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tsukahara
authors.affiliation: Department of Pediatrics, Tsuyama-Chuo Hospital, 1756 Kawasaki, Tsuyama City, Okayama 708-0841, Japan.
authors.forename: Shunsaku
authors.initials: S
authors.lastname: Kaji
authors.affiliation: Department of Clinical Laboratory Medicine, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hirayama
authors.affiliation: Department of Clinical Laboratory Medicine, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Miida
authors.affiliation: Department of Pediatrics, Kindai University Nara Hospital, 1248-1, Otoda-cho, Ikoma, Nara 630-0293, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kondou
authors.affiliation: Department of Pediatrics, Kyushu University Graduate School of Medical Science, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Department of Pediatrics, Oita University, Faculty of Medicine, 1-1. Idaigaoka, Hasama-machi, Yufu -city 879-5593, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ihara
authors.affiliation: Department of Pediatrics, Nikoniko House Medical & Welfare Center, 14-1, Azanakaichiriyama, Shimotanigami, Yamada-cho, Kita-ku, Kobe 651-1102, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Yagi
authors.affiliation: Department of Pediatrics, Kyoto Cross-Red Hospital, 15-749 Honmachi, Higashiyama-ku, Kyoto 230-0012, Japan.
authors.forename: Zenro
authors.initials: Z
authors.lastname: Kizaki
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, 2-2, Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Bessho
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2, Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kodama
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-Cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Kazumoto
authors.initials: K
authors.lastname: Iijima
authors.affiliation: Department of Molecular Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1, Sakuragaoka, Kagoshima 890-8544, Japan.
authors.forename: Takeyori
authors.initials: T
authors.lastname: Saheki
authors.affiliation: Division of Pediatric Endocrinology and Metabolism, Children's Medical Center, Osaka City General Hospital, 2-13-22 Miyakojima-hondori, Miyakojima, Osaka 534-0021, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Yorifuji
authors.affiliation: Joint Research Center and Division of Gastroenterology, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Chuou, Ami, Ibaraki 300-0395, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Honda
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D019343:Citric Acid / Q000097:blood; D002952:Citric Acid Cycle / Q000187:drug effects; D020159:Citrullinemia / Q000188:drug therapy* / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D005650:Fumarates / Q000097:blood; D006801:Humans; D007656:Ketoglutaric Acids / Q000097:blood; D008293:Malates / Q000097:blood; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D011773:Pyruvates / Q000008:administration & dosage* / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D005227:Fatty Acids; D005650:Fumarates; D007656:Ketoglutaric Acids; D008293:Malates; D011773:Pyruvates; D019343:Citric Acid; C030298:malic acid
keywords: Adaptation period; Adult-onset type II citrullinemia; Citrin deficiency; Free fatty acid β oxidation; Sodium pyruvate therapy; Tricarboxylic acid cycle