Clinical and genetic features of neonatal intrahepatic cholestasis caused by citrin deficiency in northern China: A single-center analysis of 23 cases

Wenwen LIU; Xin MA; Meijuan WANG; Huijuan NING; Xuemei ZHONG

doi:10.3969/j.issn.1001-5256.2021.05.035

Volume 37 Issue 5

May 2021

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Article Navigation > Journal of Clinical Hepatology > 2021 > 37(5): 1158-1163

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Clinical and genetic features of neonatal intrahepatic cholestasis caused by citrin deficiency in northern China: A single-center analysis of 23 cases

DOI: 10.3969/j.issn.1001-5256.2021.05.035

Department of Gastroenterology, Children's Hospital, Capital Institute of Pediatrics, Beijing 100020, China

Received Date: 2020-10-16
Accepted Date: 2020-11-02
Published Date: 2021-05-20

Abstract

Abstract

Objective To investigate the clinical features and gene mutation characteristics of neonatal intrahepatic cholestasis caused citrin deficiency (NICCD) in northern China. Methods A total of 23 pediatric patients in northern China who were diagnosed with NICCD by blood tandem mass spectrometry and/or gene detection in Department of Gastroenterology, Children's Hospital Affiliated to Capital Institute of Pediatrics, from January 2015 to December 2018 were enrolled as NICCD group, and 36 pediatric patients with idiopathic neonatal cholestasis (INC) who had unclarified etiology after a series of examinations during the same period of time were enrolled as INC group. A retrospective analysis was performed for the clinical manifestation, laboratory examination, pathology, blood/urine metabolic screening, and gene sequencing results of the pediatric patients in the NICCD group, and follow-up was performed to observe their outcome; biochemical parameters were compared between the two groups. The independent samples t-test was used for comparison of normally distributed continuous data, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data; the chi-square test was used for comparison of categorical data between groups. Results Among the 23 patients in the NICCD group, 10 had hypoglycemia, 13 had hypoalbuminemia, 17 had hyperammonemia, and 15 had hyperlactacidemia; 15 had an increase in low-density lipoprotein, 6 had an increase in cholesterol, and 7 had an increase in triglyceride; 17 had prolonged prothrombin time, and 16 had prolonged activated partial thromboplastin time (APTT). Compared with the INC group, the NICCD group had significantly higher gamma-glutamyl transpeptidase (GGT), total bile acid (TBA), and APTT and a significantly lower albumin (Alb) level (Z=-2.487, Z=-3.528, t=3.532, t=-2.24, all P < 0.05). For the patients with NICCD, blood tandem mass spectrometry showed that the most common abnormalities were the increased levels of arginine, citrulline, methionine, free carnitine, and long-chain acylcarnitine, while urinary gas chromatography showed the increased levels of 4-hydroxyphenyllactic acid, galactose, galactitol, and galactonic acid. Gene detection was performed for all 23 patients and identified 16 pathogenic mutations, among which 7 were newly discovered, namely ivs14-9a>G, c1640 G>A, c.762T>A, c.736delG, c.1098 T del, c.851G>A, and c.550G>A. Except for the 2 patients who were lost to follow-up, the levels of aminotransferases and bilirubin gradually returned to normal in 21 patients after 2-6 months of treatment; none of them showed delayed growth and development after being followed up to the age of 1 year, and 2 of them developed dietary preference (they liked fish and meat and did not like staple food). Conclusion Abnormalities of blood GGT, TBA, Alb, and APTT may provide ideas for the differential diagnosis of NICCD and INC. NICCD gene mutations in northern China are heterogeneous and most patients tend to have a good prognosis.
- Cholestasis, Intrahepatic,
- High-Throughput Nucleotide Sequencing,
- Prognosis

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References

[1]	KOBAYASHI K, SINASAC DS, ⅡJIMA M, et al. The gene mutated in adult-onset type Ⅱ citrullinaemia encodes a putative mitochondrial carrier protein[J]. Nat Genet, 1999, 22(2): 159-163. DOI: 10.1038/9667.
[2]	SONG YZ, DENG M, CHEN FP, et al. Genotypic and phenotypic features of citrin deficiency: Five year experience in a Chinese pediatric center[J]. Int J Mol Med, 2011, 28(1): 3340. DOI: 10.3892/ijmm.2011.653.
[3]	SONG YZ, LI BX, HAO H, et al. Selective screening for inborn errors of metabolism and secondary methylmalonic aciduria in pregnancy at high risk district of neural tube defects: A human metabolome study by GC-MS in China[J]. Clin Biochem, 2008, 41(7-8): 616-620. DOI: 10.1016/j.clinbiochem.2008.01.025.
[4]	KOBAYASHI K, ⅡJIMA M, USHIKAI M, et al. Citrin deficiency[J]. J Jpn Pediatr Soc, 2006, 110: 1047-1059.
[5]	KIM Y, CHOI JY, LEE SH, et al. Malfunction in mitochondrial β-oxidation contributes to lipid accumulation in hepatocyte-like cells derived from citrin deficiency-induced pluripotent stem cells[J]. Stem Cells Dev, 2016, 25(8): 636-647. DOI: 10.1089/scd.2015.0342.
[6]	TANG CF, LIU SC, FENG Y, et al. Newborn screening program and blood amino acid profiling in early neonates with citrin deficiency[J]. Chin J Pediatr, 2019, 57(10): 797-801. DOI: 10.3760/cma.j.issn.0578-1310.2019.10.014. 唐诚芳, 刘思迟, 冯毅, 等. 希特林蛋白缺乏症新生儿早期血氨基酸谱特征及新生儿筛查评估[J]. 中华儿科杂志, 2019, 57(10): 797-801. DOI: 10.3760/cma.j.issn.0578-1310.2019.10.014.
[7]	CHEW HB, NGU LH, ZABEDAH MY, et al. Neonatal intrahepatic cholestasis associated with citrin deficiency (NICCD): A case series of 11 Malaysian patients[J]. J Inherit Metab Dis, 2010, 33(Suppl 3): S489-S495. DOI: 10.1007/s10545-010-9248-6.
[8]	SHIGEMATSU Y, HIRANO S, HATA I, et al. Newborn mass screening and selective screening using electrospray tandem mass spectrometry in Japan[J]. J Chromatogr B Analyt Technol Biomed Life Sci, 2002, 776(1): 39-48. DOI: 10.1016/s1570-0232(02)00077-6.
[9]	WANG Y, SUN M. GC/MS based metabonomie study of neonatal hepatitis syndrome[J]. Int J Pediatr, 2018, 45(7): 537-542. DOI: 10.3760/cma.j.issn.1673-4408.2018.07.011. 王洋, 孙梅. 基于气相色谱-质谱联用技术对婴儿肝炎综合征的代谢组学研究[J]. 国际儿科学杂志, 2018, 45(7): 537-542. DOI: 10.3760/cma.j.issn.1673-4408.2018.07.011.
[10]	ZHANG ZH, LIN WX, ZHENG QQ, et al. Molecular diagnosis of citrin deficiency in an infant with intrahepatic cholestasis: Identification of a 21.7kb gross deletion that completely silences the transcriptional and translational expression of the affected SLC25A13 allele[J]. Oncotarget, 2017, 8(50): 87182-87193. DOI: 10.18632/oncotarget.19901.
[11]	SONG YZ, ZHANG ZH, LIN WX, et al. SLC25A13 gene analysis in citrin deficiency: Sixteen novel mutations in East Asian patients, and the mutation distribution in a large pediatric cohort in China[J]. PLoS One, 2013, 8(9): e74544. DOI: 10.1371/journal.pone.0074544.
[12]	LIN WX, ZENG HS, ZHANG ZH, et al. Molecular diagnosis of pediatric patients with citrin deficiency in China: SLC25A13 mutation spectrum and the geographic distribution[J]. Sci Rep, 2016, 6: 29732. DOI: 10.1038/srep29732.
[13]	LIN WX, ZENG HS, ZHANG ZH, et al. Molecular diagnosis of pediatric patients with citrin deficiency in China: SLC25A13 mutation spectrum and the geographic distribution[J]. Sci Rep, 2016, 6: 29732. DOI: 10.1038/srep29732.
[14]	WANG L, CHENG XR, YAN L, et al. Analysis of clinical features and SLC25A13 gene mutations in a family affected with neonatal intrahepatic cholestasis[J]. Chin J Med Genetics, 2016, 33(5): 670-673. DOI: 10.3760/cma.j.issn.1003-9406.2016.05.020. 王玲, 程昕然, 鄢力, 等. 一个Citrin蛋白缺乏所致新生儿肝内胆汁淤积症家系的SLC25A13基因突变分析[J]. 中华医学遗传学杂志, 2016, 33(5): 670-673. DOI: 10.3760/cma.j.issn.1003-9406.2016.05.020.
[15]	ZHANG JL, SHU SN, CAI ZS, et al. Neonatal intrahepatic cholestasis caused by Citrin deficiency with hepatic cirrhosis ascites as the main manifestation: A case report[J]. J Clin Hepatol, 2019, 35(2): 372-375. DOI: 10.3969/j.issn.1001-5256.2019.02.026. 张建玲, 舒赛男, 蔡在胜, 等. 以肝硬化腹腔积液为特征表现的Citrin蛋白缺陷所致新生儿肝内胆汁淤积症1例报告[J]. 临床肝胆病杂志, 2019, 35(2): 372-375. DOI: 10.3969/j.issn.1001-5256.2019.02.026.

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Clinical and genetic features of neonatal intrahepatic cholestasis caused by citrin deficiency in northern China: A single-center analysis of 23 cases

DOI: 10.3969/j.issn.1001-5256.2021.05.035

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Clinical and genetic features of neonatal intrahepatic cholestasis caused by citrin deficiency in northern China: A single-center analysis of 23 cases

DOI: 10.3969/j.issn.1001-5256.2021.05.035

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