Time course of acylcarnitine elevation in neonatal intrahepatic cholestasis caused by citrin deficiency
Tóm tắt
Citrin is a mitochondrial membrane aspartate–glutamate carrier, and citrin deficiency causes both hyperammonaemia in adults (adult-onset type II citrullinaemia, CTLN2) and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), with metabolic derangements in gluconeogenesis, aerobic glycolysis, urea synthesis, UDP-galactose epimerase activity, and possibly fatty acid synthesis and utilization. Through neonatal screening and case review, four patients with NICCD who had an acylcarnitine profile during infancy were all found to have an elevation of free carnitine, C2-carnitine, and long-chain acylcarnitines. These metabolic abnormalities appeared after the rise of citrulline and bilirubin, but before the elevation of alanine aminotransferase and aspartate aminotransferase. Although the rise of free carnitine and acylcarnitines seems to be a benign condition, the sequential changes of these metabolic derangements may give clues to the pathogenesis of this interesting disorder.
Tài liệu tham khảo
Costa CC, de Almeida IT, Jakobs C, Poll-The BT, Duran M (1999) Dynamic changes of plasma acylcarnitine levels induced by fasting and sunflower oil challenge test in children. Pediatr Res 46: 440–444.
Hachisu M, Oda Y, Goto M, et al (2005) Citrin deficiency presenting with ketotic hypoglycaemia and hepatomegaly in childhood. Eur J Pediatr 164: 109–110.
Imamura Y, Kobayashi K, Shibatou T, et al (2003) Effectiveness of carbohydrate-restricted diet and arginine granules therapy for adult-onset type II citrullinemia: a case report of siblings showing homozygous SLC25A13 mutation with and without the disease. Hepatol Res 26: 68–72.
Inui Y, Kuwajima M, Kawata S, et al (1994) Impaired ketogenesis in patients with adult-type citrullinemia. Gastroenterology 107: 1154–1161.
Kobayashi K, Sinasac DS, Iijima M, et al (1999) The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein. Nature Genetics 22: 159–163.
Lang C, Schafer M, Serra D, Hegardt F, Krahenbuhl L, Krahenbuhl S (2001) Impaired hepatic fatty acid oxidation in rats with short-term cholestasis: characterization and mechanism. J Lipid Res 42: 22–30.
Lang C, Berardi S, Schafer M, et al (2002) Impaired ketogenesis is a major mechanism for disturbed hepatic fatty acid metabolism in rats with long-term cholestasis and after relief of biliary obstruction. J Hepatol 37: 564–571.
Millington DS (2003) Tandem mass spectormetry in clinical diagnosis. In: Blau N, Duran M, Blaskovics ME, Gibson KM, eds. Physician's Guide to the Laboratory Diagnosis of Metabolic Diseases. Berlin: Springer-Verlag, 57–75.
Saheki T, Kobayashi K (2002) Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD). J Hum Genet 47: 333–341.
Saheki T, Kobayashi K (2005) Physiological role of citrin, a liver-type mitochondrial aspartate–glutamate carrier, and pathophysiology of citrin deficiency. Recent Res Devel Life Sci 3: 1–15.
Saheki T, Kobayashi K, Iijima M, et al (2002) Pathogenesis and pathophysiology of citrin (a mitochondrial aspartate glutamate carrier) deficiency. Metab Brain Dis 17: 335–346.
Saheki T, Kobayashi K, Iijima M, et al (2004) Adult-onset type II citrullinemia and idiopathic neonatal hepatitis caused by citrin deficiency: involvement of the aspartate glutamate carrier for urea synthesis and maintenance of the urea cycle. Mol Genet Metab 81(Supplement 1): S20–S26.
Socha P, Koletzko B, Swiatkowska E, Pawlowska J, Stolarczyk A, Socha J (1998) Essential fatty acid metabolism in infants with cholestasis. Acta Paediatr 87: 278–283.
Ventura FV, Ruiter JP, Ijlst L, de Almeida IT, Wanders RJ (1996) Inhibitory effect of 3-hydroxyacyl-CoAs and other long-chain fatty acid beta-oxidation intermediates on mitochondrial oxidative phosphorylation. J Inherit Metab Dis 19: 161–164.
Yeh CN, Jeng YM, Chen HL, et al (2006) Hepatic steatosis and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) in Taiwanese infants. J Pediatr (in press).