title: Medium-chain triglyceride supplementation under a low-carbohydrate formula is a promising therapy for adult-onset type II citrullinemia.
abstract: BACKGROUND
  Citrin, encoded bySLC25A13, is a component of the malate-aspartate shuttle, which is the main NADH-transporting system in the liver. Citrin deficiency causes neonatal intrahepatic cholestasis (NICCD), which usually resolves within the first year of life. However, small numbers of adults with citrin deficiency develop hyperammonemic encephalopathy, adult-onset type II citrullinemia (CTLN2), which leads to death due to cerebral edema. Liver transplantation is the only definitive therapy for patients with CTLN2. We previously reported that a lactose (galactose)-restricted and medium-chain triglyceride (MCT)-supplemented formula is notably effective for patients with NICCD. Citrin deficiency may impair the glycolysis in hepatocytes because of an increase in the cytosolic NADH/NAD+ratio, leading to an energy shortage. MCT administration can provide energy to hepatocytes and was expected to have a good effect on CTLN2.
  
  
  METHODS
  An MCT supplementation therapy under a low-carbohydrate formula was administered to five patients with CTLN2. Four of the patients had episodes of hyperammonemic encephalopathy, and one patient had postprandial hyperammonemia with no symptoms.
  
  
  RESULTS
  One of the patients displaying hyperammonemic encephalopathy completely recovered with all normal laboratory findings. Others notably improved in terms of clinical and or laboratory findings with no hyperammonemic symptoms; however, the patients displayed persistent mild citrullinemia and occasionally had postprandial mild hyperammonemia most likely due to an irreversible change in the liver.
  
  
  CONCLUSIONS
  An MCT supplement can provide energy to hepatocytes and promote hepatic lipogenesis, leading to a reduction in the cytosolic NADH/NAD+ratio. MCT supplementation under a low-carbohydrate formula could be a promising therapy for CTLN2 and should also be used to prevent CTLN2 to avoid irreversible liver damage.
authors.affiliation: Dept. of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Hayasaka
authors.affiliation: Dept. of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Chikahiko
authors.initials: C
authors.lastname: Numakura
authors.affiliation: Dept. of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Toyota
authors.affiliation: Dept. of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Kakizaki
authors.affiliation: Dept. of Gastroenterology, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Hisayoshi
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Dept. of Gastroenterology, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Haga
authors.affiliation: Dept. of Internal Medicine, Prefectural Ninohe Hospital, Iwate, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Dept. of Neurology, Hematology, Metabolism, Endocrinology, and Diabetology, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Dept. of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Mieko
authors.initials: M
authors.lastname: Kaneko
authors.affiliation: Dept. of Pathological Diagnostics, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Yamakawa
authors.affiliation: Division of Pediatrics, Dept. of Reproductive and Developmental Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nunoi
authors.affiliation: Dept. of Neurology, Hematology, Metabolism, Endocrinology, and Diabetology, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Kato
authors.affiliation: Dept. of Gastroenterology, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ueno
authors.affiliation: Dept. of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Masatomo
authors.initials: M
authors.lastname: Mori
keywords: ALP, serum alkali phosphatase; ALT, alanine aminotransferase; ASS1, argininosuccinate synthetase 1; AST, aspartate aminotransferase; Adult-onset type II citrullinemia (CTLN2); BMI, body mass index; CTLN2, adult-onset type II citrullinemia; ChE, cholinesterase; Citrin deficiency; LDH, lactate dehydrogenase; MCFA, medium-chain free fatty acids; MCT, medium-chain triglycerides; Malate-aspartate shuttle; Medium-chain triglycerides (MCT); NICCD, neonatal intrahepatic cholestasis; Neonatal intrahepatic cholestasis (NICCD); PPAR, peroxisome proliferator-activated receptor; PSTI, pancreatic secretory trypsin inhibitor; SLC25A13; TIBC, total iron-binding capacity; UIBC, unsaturated iron-binding capacity; γ-GTP, gamma-glutamyl transpeptidase