Download PDF
Eur J Pediatr Surg 2016; 26(03): 255-259
DOI: 10.1055/s-0035-1551566
Original Article
Georg Thieme Verlag KG Stuttgart · New York

Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency Differentiated from Biliary Atresia

Zhenhua Gong
1   Department of Pediatric Surgery, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
,
Wei-Jue Xu
1   Department of Pediatric Surgery, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
,
Guo-Li Tian
2   Neonatal Screening Center, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
,
Ting Zhang
3   Department of Gastroenterology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
,
Zhibao Lv
1   Department of Pediatric Surgery, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
› Author Affiliations
Further Information

Publication History

13 November 2014

15 February 2015

Publication Date:
19 May 2015 (online)

    Permissions and Reprints

Abstract

Purpose The aim of this article is to differentiate neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) from biliary atresia (BA) by total hexose.

Methods A total of 11 patients with NICCD, 29 patients with BA, and 4,898 children as controls were involved in this study. The blood concentration of amino acids, carnitine, acylcarnitines, and total hexose were measured in dry blood spots (DBS) using tandem mass spectrometry (MS/MS).

Results In the patients with NICCD, the blood concentration of the total hexose (15.3 ± 9.0 mmol/L vs. 7.3 ± 2.7 mmol/L; p < 0.001), citrulline (Cit) (197.9 ± 93.7 µmol/L vs. 17.5 ± 7.4 µmol/L; p < 0.001) were higher than those of patients with BA. Using total hexose (> 10 mmol/L), Cit (> 55 µmol/L) to diagnose NICCD, the sensitivity and specificity were 66.7 and 97.8% and 90.0 and 99.1%, respectively, and all of the areas under the receiver–operating characteristic curves were greater than 0.85.

Conclusion Elevated total hexose in DBS measured by MS/MS associated with elevated amino acids, especially Cit can be used to diagnose NICCD and differentiate it from BA.

Keywords

biliary atresia - neonatal intrahepatic cholestasis caused by citrin deficiency - hexose - tandem mass spectrometry
 

  • References

  • 1 Moyer V, Freese DK, Whitington PF , et al; North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Guideline for the evaluation of cholestatic jaundice in infants: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2004; 39 (2) 115-128
    CrossrefPubMedGoogle Scholar
  • 2 Del Arco A, Agudo M, Satrústegui J. Characterization of a second member of the subfamily of calcium-binding mitochondrial carriers expressed in human non-excitable tissues. Biochem J 2000; 345 (Pt 3) 725-732
    CrossrefPubMedGoogle Scholar
  • 3 Kobayashi K, Sinasac DS, Iijima M , et al. The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein. Nat Genet 1999; 22 (2) 159-163
    CrossrefPubMedGoogle Scholar
  • 4 Saheki T, Kobayashi K. Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD). J Hum Genet 2002; 47 (7) 333-341
    CrossrefPubMedGoogle Scholar
  • 5 Tazawa Y, Kobayashi K, Ohura T , et al. Infantile cholestatic jaundice associated with adult-onset type II citrullinemia. J Pediatr 2001; 138 (5) 735-740
    CrossrefPubMedGoogle Scholar
  • 6 Vitoria I, Dalmau J, Ribes C , et al. Citrin deficiency in a Romanian child living in Spain highlights the worldwide distribution of this defect and illustrates the value of nutritional therapy. Mol Genet Metab 2013; 110 (1–2) 181-183
    CrossrefPubMedGoogle Scholar
  • 7 Chen ST, Su YN, Ni YH , et al. Diagnosis of neonatal intrahepatic cholestasis caused by citrin deficiency using high-resolution melting analysis and a clinical scoring system. J Pediatr 2012; 161 (4) 626-31.e2
    CrossrefPubMedGoogle Scholar
  • 8 Ohura T, Kobayashi K, Tazawa Y , et al. Clinical pictures of 75 patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). J Inherit Metab Dis 2007; 30 (2) 139-144
    CrossrefPubMedGoogle Scholar
  • 9 Tazawa Y, Kobayashi K, Abukawa D , et al. Clinical heterogeneity of neonatal intrahepatic cholestasis caused by citrin deficiency: case reports from 16 patients. Mol Genet Metab 2004; 83 (3) 213-219
    CrossrefPubMedGoogle Scholar
  • 10 Song YZ, Li BX, Chen FP , et al. Neonatal intrahepatic cholestasis caused by citrin deficiency: clinical and laboratory investigation of 13 subjects in mainland of China. Dig Liver Dis 2009; 41 (9) 683-689
    CrossrefPubMedGoogle Scholar
  • 11 Wang JS, Wang XH, Zheng YJ , et al. Biochemical characteristics of neonatal cholestasis induced by citrin deficiency. World J Gastroenterol 2012; 18 (39) 5601-5607
    CrossrefPubMedGoogle Scholar
  • 12 Gong Z, Tian G, Huang Q, Wang Y, Ge Q. Quantification of total hexose on dry blood spot by tandem mass spectrometry. Clin Biochem 2012; 45 (18) 1673-1677
    CrossrefPubMedGoogle Scholar
  • 13 Streiner DL, Cairney J. What's under the ROC? An introduction to receiver operating characteristics curves. Can J Psychiatry 2007; 52 (2) 121-128
    PubMedGoogle Scholar
  • 14 Saheki T, Inoue K, Tushima A, Mutoh K, Kobayashi K. Citrin deficiency and current treatment concepts. Mol Genet Metab 2010; 100 (Suppl. 01) S59-S64
    CrossrefPubMedGoogle Scholar
  • 15 Shigeta T, Kasahara M, Kimura T , et al. Liver transplantation for an infant with neonatal intrahepatic cholestasis caused by citrin deficiency using heterozygote living donor. Pediatr Transplant 2010; 14 (7) E86-E88
    CrossrefPubMedGoogle Scholar
  • 16 Song YZ, Deng M, Chen FP , et al. Genotypic and phenotypic features of citrin deficiency: five-year experience in a Chinese pediatric center. Int J Mol Med 2011; 28 (1) 33-40
    PubMedGoogle Scholar
  • 17 Dimmock D, Kobayashi K, Iijima M , et al. Citrin deficiency: a novel cause of failure to thrive that responds to a high-protein, low-carbohydrate diet. Pediatrics 2007; 119 (3) e773-e777
    CrossrefPubMedGoogle Scholar
  • 18 Yeh JN, Jeng YM, Chen HL, Ni YH, Hwu WL, Chang MH. Hepatic steatosis and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) in Taiwanese infants. J Pediatr 2006; 148 (5) 642-646
    CrossrefPubMedGoogle Scholar
  • 19 Lee NC, Chien YH, Kobayashi K , et al. Time course of acylcarnitine elevation in neonatal intrahepatic cholestasis caused by citrin deficiency. J Inherit Metab Dis 2006; 29 (4) 551-555
    CrossrefPubMedGoogle Scholar
  • 20 Kawana S, Nakagawa K, Hasegawa Y, Yamaguchi S. Simple and rapid analytical method for detection of amino acids in blood using blood spot on filter paper, fast-GC/MS and isotope dilution technique. J Chromatogr B Analyt Technol Biomed Life Sci 2010; 878 (30) 3113-3118
    CrossrefPubMedGoogle Scholar
  • 21 Nagasaka H, Okano Y, Tsukahara H , et al. Sustaining hypercitrullinemia, hypercholesterolemia and augmented oxidative stress in Japanese children with aspartate/glutamate carrier isoform 2-citrin-deficiency even during the silent period. Mol Genet Metab 2009; 97 (1) 21-26
    CrossrefPubMedGoogle Scholar
  • 22 Kuhara T, Ohse M, Inoue Y, Cooper AJ. A GC/MS-based metabolomic approach for diagnosing citrin deficiency. Anal Bioanal Chem 2011; 400 (7) 1881-1894
    CrossrefPubMedGoogle Scholar
  • 23 Wahjudi PN, Patterson ME, Lim S, Yee JK, Mao CS, Lee WN. Measurement of glucose and fructose in clinical samples using gas chromatography/mass spectrometry. Clin Biochem 2010; 43 (1–2) 198-207
    CrossrefPubMedGoogle Scholar
  • 24 Baadenhuijsen H, Scholten R, Willems HL, Weykamp CW, Jansen RT. A model for harmonization of routine clinical chemistry results between clinical laboratories. Ann Clin Biochem 2000; 37 (Pt 3) 330-337
    CrossrefPubMedGoogle Scholar
  • 25 Lee HH, Wong ES, Chan AY, Choi MM. Development of a galactose biosensor with galactose oxidase-immobilized epidermis of Solanum lycopersicum: potential point-of-care testing for citrin deficiency in high-prevalence areas. Clin Chim Acta 2011; 412 (3–4) 391-392
    CrossrefPubMedGoogle Scholar
  • 26 Mizoguchi N, Ono H, Eguchi T, Sakura N. Galactose metabolites in blood from neonates with and without hypergalactosaemia detected by mass screening. Eur J Pediatr 2000; 159 (11) 851-853
    CrossrefPubMedGoogle Scholar
  • 27 Kono T, Hiki T, Kuwashima S, Hashimoto T, Kaji Y. Hypergalactosemia in early infancy: diagnostic strategy with an emphasis on imaging. Pediatr Int 2009; 51 (2) 276-282
    CrossrefPubMedGoogle Scholar