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Journal of Inherited Metabolic Disease

, Volume 29, Issue 4, pp 551–555 | Cite as

Time course of acylcarnitine elevation in neonatal intrahepatic cholestasis caused by citrin deficiency

  • Ni-Chung Lee
  • Yin-Hsiu Chien
  • Keiko Kobayashi
  • Takeyori Saheki
  • Huey-Ling Chen
  • Pao-Chin Chiu
  • Yen-Hsuan Ni
  • Mei-Hwei Chang
  • Wuh-Liang Hwu
Original Article

Summary

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.

Keywords

Carnitine Cholestasis Citrulline Intrahepatic Cholestasis Free Carnitine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 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.PubMedGoogle Scholar
  2. 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.PubMedCrossRefGoogle Scholar
  3. 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.PubMedCrossRefGoogle Scholar
  4. Inui Y, Kuwajima M, Kawata S, et al (1994) Impaired ketogenesis in patients with adult-type citrullinemia. Gastroenterology 107: 1154–1161.PubMedGoogle Scholar
  5. 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.PubMedCrossRefGoogle Scholar
  6. 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.PubMedGoogle Scholar
  7. 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.PubMedCrossRefGoogle Scholar
  8. 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.Google Scholar
  9. 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.PubMedCrossRefGoogle Scholar
  10. 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.Google Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 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.PubMedCrossRefGoogle Scholar
  13. 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.PubMedCrossRefGoogle Scholar
  14. 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.PubMedCrossRefGoogle Scholar
  15. 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).Google Scholar

Copyright information

© SSIEM and Springer 2006

Authors and Affiliations

  • Ni-Chung Lee
    • 1
  • Yin-Hsiu Chien
    • 1
    • 2
  • Keiko Kobayashi
    • 3
  • Takeyori Saheki
    • 3
  • Huey-Ling Chen
    • 2
  • Pao-Chin Chiu
    • 4
  • Yen-Hsuan Ni
    • 2
  • Mei-Hwei Chang
    • 2
  • Wuh-Liang Hwu
    • 1
    • 2
  1. 1.Department of Medical GeneticsNational Taiwan University Hospital and National Taiwan University College of MedicineTaipeiTaiwan
  2. 2.Department of PediatricsNational Taiwan University HospitalTaipeiTaiwan
  3. 3.Department of Molecular Metabolism and Biochemical GeneticsKagoshima University Graduate School of Medical and Dental SciencesKagoshimaJapan
  4. 4.Kaohsiung Veterans General HospitalKaohsiungTaiwan

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