A possible mechanism of neonatal intrahepatic cholestasis caused by citrin deficiency
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.
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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
References (33)
- et al.
Infantile cholestatic jaundice associated with adult-onset type II citrullinemia
J Pediatr
(2001) - et al.
Possible clinical and histological manifestations of adult-onset type II citrullinemia in early infancy
J Pediatr
(2001) - et al.
Determination of 3-oxo-Δ4- and 3-oxo-Δ4,6-bile acids and related compounds in biological fluids of infants with cholestasis by gas chromatography-mass spectrometory
J Chromatogr B Biomed Sci Appl
(1997) - et al.
Neonatal and delayed-onset liver involvement in disorders of oxidative phosphorylation
J Pediatr
(1997) - et al.
Depletion of mitochondrial deoxyribonucleic acid in a family with fatal neonatal liver disease
J Pediatr
(1996) - et al.
Long-chain 3-hydroxyacyl-coenxyme A dehydrogenase deficiency with G1528C mutation: clinical presentation of thirteen patients
J Pediatr
(1997) - et al.
Pathogenesis of adult-onset type II citrullinemia caused by deficiency of citrin, a mitochondrial solute carrier protein: tissue and subcellular localization of citrin
Adv Enzyme Regul
(2001) - et al.
Antioxidants in pediatric gastrointestinal disease
Pediatr Clin North
(1996) - et al.
Physiologic cholestasis: elevation of the primary serum bile acid concentrations in normal infants
Gastroenterology
(1981) - et al.
Impaired ketogenesis in patients with adult-type citrullinemia
Gastroenterology
(1994)
Ratio of serum aspartate to alanine aminotransferase in chronic hepatitis. Relationship to cirrhosis
Gastroenterology
Urinary 7α-hydroxy-3-oxochol-4-en-24-oic and 3-oxochola-4,6-dien-24-oic acids in infants with cholestasis
J Hepatol
Effect of Phenobarbital on hyperbilirubinemia, bile acid metabolism, and microsomal enzyme activity in chronic intrahepatic cholestasis of childhood
J Pediatr
Type II citrullinemia (citrin deficiency): a mysterious disease caused by a defect of calcium-binding mitochondrial carrier protein
The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein
Nat Genet
Identification of two novel mutations in the SLC25A13 gene and detection of seven mutations in 102 patients with adult-onset type II citrullinemia
Hum Genet
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Thematic review series: Genetics of human lipid diseases - Genetic determinants of hepatic steatosis in man
2011, Journal of Lipid ResearchCitation Excerpt :Compensatory changes in the malate-citrin shuttle may favor fatty acid and triglyceride synthesis, in combination with increased fatty acid uptake capacity into hepatocytes, thereby promoting hepatic steatosis (92, 95). Mutations in the SLC25A13 gene can also cause another condition, neonatal intrahepatic cholestasis; the mechanism is thought to involve primary mitochondrial impairment associated with the delayed maturity of bile acid metabolism (96, 97). Severe hepatic steatosis and fibrosis is a common finding in these infants (98).
Neonatal intrahepatic cholestasis caused by citrin deficiency: Clinical and laboratory investigation of 13 subjects in mainland of China
2009, Digestive and Liver DiseaseCitation Excerpt :Since the expression pattern of the proteins mirror development and maturation of the liver [32], the delayed switch of AFP to albumin may reflect the immature liver development in NICCD. Actually, the bile acids metabolism in NICCD patients also showed an immature pattern as in the fetal period [33]. Therefore, we speculate that the delayed maturation of liver function is, at least partly, involved in the development of NICCD, although other factors such as hepatocellular destruction and regeneration are also likely to contribute to low albumin and high AFP.
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