Elsevier

Hepatology Research

Volume 31, Issue 3, March 2005, Pages 168-171
Hepatology Research

A possible mechanism of neonatal intrahepatic cholestasis caused by citrin deficiency

https://doi.org/10.1016/j.hepres.2005.01.001Get rights and content

Abstract

For this study, we investigated why cholestasis develops into neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), and concluded that primary mitochondrial impairment associated with the delayed maturity of bile acid metabolism may contribute to the occurrence of NICCD.

Introduction

Citrullinemia caused by an argininosuccinate synthetase deficiency (ASS) has been classified into two groups; classical citrullinemia types I and III having a generalized defect in ASS activity, and adult-onset citrullinemia type II (CTLN2) which has a reduction of ASS protein specifically in the liver [1]. Recently, the responsible gene for CTLN2 was uncovered as SLC25A13, located on chromosome 7q21.3 [2], 14 mutations having been reported [2], [3], [4], [5]. The product of the SLC25A13 gene, designated citrin, has been disclosed to be a Ca2+-stimulated aspartate/glutamate carrier (AGC) in mitochondria [6], a special shuttle systems carrying reducing equivalents from cytosolic NADH into the mitochondria. The most active NADH shuttle is called the malate-aspartate shuttle [7], [8]. The transporter, AGC, catalyzes an irreversible step in this aspartate-malate NADH shuttle [7].

Hyperammonemia and fatty liver, which develop around the 20th year of life, are clinical core features of CTLN2 [1]. However, advances in molecular biology have discovered neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) [9], [10], [11], [12]. In adult-onset CTLN2, intrahepatic cholestasis is rare [13], but NICCD patients have transient neonatal intrahepatic cholestasis [9], [10], [11], [12]. In this study, we preliminary investigated why cholestasis develops in NICCD.

Section snippets

Materials and methods

Fourteen patients, from 19 to 167 (mean ± S.D., 80 ± 52) days of life, who were proven to be homozygotes or compound heterozygotes for SLC25A13 gene mutations, were recruited for this study. Gene analysis [5] were performed with the informed consent of their parents. Six of the 14 patients had been previously reported [9], [10]. Twelve of the 14 patients examined had diffuse fatty liver, and parenchymal cellular infiltration associated with hepatic fibrosis. Another 14 patients with idiopathic

Results

In comparison with INH and EBA patients, NICCD patients had a lower level of serum direct bilirubin, or serum ALT, and had a higher level of serum total bile acids, total bile acids/direct bilirubin ratio, serum ALP, and AST/ALT ratio. Furthermore, these patients had a higher level of serum γ-GTP, and a lower level of serum AST activity than those of INH (Table 1).

The three NICCD patients who underwent urinary bile acid analysis had no significant urinary excretion of 3-oxo-Δ4 bile acids, or

Discussion

Among CTLN2, intrahepatic cholestasis is rare [13], but NICCD patients have transient intrahepatic cholestasis. In NICCD, mitochondrial morphological abnormalities have been reported [9]. However, we do know whether mitochondrial diseases are often associated with intrahepatic cholestasis [15], [16], [17], [18]. Citrin is a protein localized in the inner membranes of human mitochondria [6], [19]. Citrin dysfunction leads to NADH paucity and ATP depletion in mitochondria. On the other hand,

Acknowledgements

We thank Drs. Hideaki Sanjou, Michiyo Sakamoto, Masabumi Kudo, Mutumi Watanabe, Michiko Nakagawa, Masaaki Yamada, Fujihiko Nishinomiya, Junichirou Aikawa, Shinobu Ishizawa, Yasuro Oyake, Mariko Yamashita, Yukinori Ando, Yasuhisa Kajino, and Kunihiro Fujii for their help. We also thank Prof. Masayoshi Kage, Emitus Profs. Tasuke Konno, Kazuo Shiraki, Kuniaki Narisawa, and Keiya Tada for their support and thoughtful advice. First author (Y.T.) would like to thank the deceased Emitus Prof. Tsuneo

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