Original article
Hepatic steatosis and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) in Taiwanese infants

https://doi.org/10.1016/j.jpeds.2005.12.020Get rights and content

Objectives

To explore the prevalence of hepatic steatosis and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) in Taiwanese infants with idiopathic intrahepatic cholestasis.

Study design

The liver specimens from 69 infants with idiopathic intrahepatic cholestasis were reviewed (1993-2004); 11 of them (14.7%) had hepatic steatosis. Six patients with hepatic steatosis participated in the genetic study for the SLC25A13 gene under parental consent.

Results

Infants with cholestasis and hepatic steatosis had lower aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels than those with cholestasis alone. Three of the six infants in the genetic study had homozygous 851del4 mutation; for the others, homozygous 1638ins23 mutation, compound heterozygous 851del4/IVS6+5G→A mutation, and heterozygous IVS6+5G→A mutation were found for each one. Eleven of the total 12 alleles (91.7%) were demonstrated to have SLC25A13 gene mutations.

Conclusions

Metabolic and genetic studies for NICCD should be performed in Asian infants with idiopathic intrahepatic cholestasis and hepatic steatosis. The 851del4 mutation on the SLC25A13 gene accounts for the major genotype expression of patients with NICCD in Taiwan.

Section snippets

Definition

In this study, idiopathic intrahepatic cholestasis of infancy was defined as intrahepatic cholestasis with patent extrahepatic biliary tract and adequate interlobular bile duct portal area ratio (>0.6). To fulfill the criteria, the patient must also have no combined infection, such as syphilis, herpes virus, enterovirus, toxoplasma, or rubella infection. The only allowed exception is cytomegalovirus (CMV) infection, which is highly prevalent in Taiwanese infants. The presence of CMV infection

Results

Hepatic steatosis was found in 10 of the 68 infants (14.7%) who were previously diagnosed with “idiopathic” intrahepatic cholestasis of infancy. As shown in Table I, the aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase levels were lower in our 11 infants with hepatic steatosis than in the 58 infants without steatosis (P = .013, P <.001, P = .003, respectively). The CMV infection rate was similar between the two groups (steatosis vs non-steatotic group:

Discussion

The laboratory parameters in infants with idiopathic hepatic steatosis, non-steatotic intrahepatic cholestasis of infancy, or NICCD differ widely. Our infants with hepatic steatosis and the infants with NICCD from the literature have lower AST and ALT levels than the non-steatotic patients with idiopathic intrahepatic cholestasis of infancy. This can be explained by the histological findings that infants with NICCD usually have lower lobular activity than those with non-steatotic idiopathic

References (26)

  • F. Nishinomiya et al.

    Relationships between clinical and histological profiles of non-familial idiopathic neonatal hepatitis

    Acta Paediatr Jpn

    (1996)
  • Y. Tazawa et al.

    Idiopathic neonatal hepatitis presenting as neonatal hepatic siderosis and steatosis

    Dig Dis Sci

    (1998)
  • Y. Tazawa et al.

    Neonatal intrahepatic cholestasis with hepatic siderosis and steatosis

    Acta Paediatr Jpn

    (1998)
  • Cited by (40)

    • Histologic patterns of metabolic liver diseases

      2018, Practical Hepatic Pathology: A Diagnostic Approach: Second Edition
    • Molecular analysis of SLC25A13 gene in human peripheral blood lymphocytes: Marked transcript diversity, and the feasibility of cDNA cloning as a diagnostic tool for citrin deficiency

      2012, Gene
      Citation Excerpt :

      The protein encoded by SLC25A13, which has been designated as citrin, acts as a liver-type calcium-binding/stimulated aspartate–glutamate carrier that plays important roles in the metabolic pathways of aerobic glycolysis, gluconeogenesis, urea cycle, and synthesis of proteins and nucleotides (Kobayashi and Saheki, 2003; Palmieri et al., 2001; Saheki and Kobayashi, 2005; Saheki et al., 2004, 2006). SLC25A13 mutations lead to citrin deficiency (CD)(Kobayashi et al., 2012; Saheki et al., 2011), which has been well recognized as a worldwide panethnic disease entity (Ben-Shalom et al., 2002; Dimmock et al., 2009; Fiermonte et al., 2011; Ohura et al., 2007; Song et al., 2009a, 2011; Tabata et al., 2008; Tazawa et al., 2004; Takaya et al., 2005; Thong et al., 2010; Yeh et al., 2006) that encompasses different clinical phenotypes including adult-onset citrullinemia type II (CTLN2) (Komatsu et al., 2008; Saheki et al., 2002), neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD)(Saheki and Kobayashi, 2002; Saheki et al., 2002; Yamaguchi et al., 2002), and failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD), a post-NICCD state before CTLN2 onset which was proposed very recently (Kobayashi et al., 2012; Song et al., 2009b, 2011). SLC25A13 mutation analysis could provide reliable evidences for CD definitive analysis.

    • Diagnosis of neonatal intrahepatic cholestasis caused by citrin deficiency using high-resolution melting analysis and a clinical scoring system

      2012, Journal of Pediatrics
      Citation Excerpt :

      With informed consent from the parents, these 20 patients were enrolled in this study to detect mutations and single-nucleotide polymorphisms (SNPs) in the SLC25A13 gene. Of them, 11 patients had already been tested by direct sequencing of the 7 exons containing the most frequently reported mutations.7 This study was approved by the institutional review board of the National Taiwan University Hospital.

    • Multiple ovarian antral follicles in a preterm infant with neonatal intrahepatic cholestasis caused by citrin deficiency: A clinical, genetic and transcriptional analysis

      2012, Gene
      Citation Excerpt :

      In 2002, Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD, OMIM # 605814) was designated as a specific term standing for the CD phenotype during infancy (Saheki and Kobayashi, 2002; Saheki et al., 2002; Yamaguchi et al., 2002). In the past 10 years, more and more NICCD patients were diagnosed, not only in Japan (Kimura et al., 2010; Ohura et al., 2003,2007; Tabata et al., 2008; Takaya et al., 2005; Tamamori et al., 2002; Tazawa et al., 2004; Tokuhara et al., 2007), but also in other Asian countries or regions (Ben-Shalom et al., 2002; Fu et al., 2010, 2011; J.M. Ko et al., 2007; J.S. Ko et al., 2007; Lin et al., 2011; Song et al., 2009, 2011; Thong et al., 2010; Yeh et al., 2006), north America (Dimmock et al., 2007, 2009; Wong et al., 2008) and Europe (Fiermonte et al., 2011). NICCD has been recognized as a world-wide panethnic disease nowadays.

    • Neonatal Cholestasis

      2012, Gastroenterology and Nutrition: Neonatology Questions and Controversies
    • Neonatal Cholestasis

      2012, Gastroenterology and Nutrition
    View all citing articles on Scopus
    View full text