Medium-chain triglycerides supplement therapy with a low-carbohydrate formula can supply energy and enhance ammonia detoxification in the hepatocytes of patients with adult–onset type II citrullinemia
Citrin, encoded by SLC25A13, constitutes the malate-aspartate shuttle, the main NADH-shuttle in the liver. Citrin deficiency causes neonatal intrahepatic cholestasis (NICCD) and adult–onset type II citrullinemia (CTLN2). Citrin deficiency is predicted to impair hepatic glycolysis and de novo lipogenesis, resulting in hepatic energy deficit. Secondary decrease in hepatic argininosuccinate synthetase (ASS1) expression has been considered a cause of hyperammonemia in CTLN2. We previously reported that medium–chain triglyceride (MCT) supplement therapy with a low–carbohydrate formula was effective in CTLN2 to prevent a relapse of hyperammonemic encephalopathy. We present the therapy for six CTLN2 patients. All the patients’ general condition steadily improved and five patients with hyperammonemic encephalopathy recovered from unconsciousness in a few days. Before the treatment, plasma glutamine levels did not increase over the normal range and rather decreased to lower than the normal range in some patients. The treatment promptly decreased the blood ammonia level, which was accompanied by a decrease in plasma citrulline levels and an increase in plasma glutamine levels. These findings indicated that hyperammonemia was not only caused by the impairment of ureagenesis at ASS1 step, but was also associated with an impairment of glutamine synthetase (GS) ammonia-detoxification system in the hepatocytes. There was no decrease in the GS expressing hepatocytes. MCT supplement with a low–carbohydrate formula can supply the energy and/or substrates for ASS1 and GS, and enhance ammonia detoxification in hepatocytes. Histological improvement in the hepatic steatosis and ASS1-expression was also observed in a patient after long-term treatment.
Neonatal intrahepatic cholestasis
Adult-onset type II citrullinemia
Argininosuccinate synthetase 1
Pancreatic secretory trypsin inhibitor
Body mass index
Carbamoyl phosphate transferase
Citrullinemia type 1
Peroxisome proliferator-activated receptor
This work was supported in part by a grant from the Ministry of Health, Labor and Welfare in Japan.
Compliance with ethical standards
Conflicts of interest
K. Hayasaka, C. Numakura, M. Yamakawa, T. Mitsui, H. Watanabe, H. Haga, M. Yazaki, H. Ohira, Y. Ochiai, T. Tahara, T. Nakahara, N. Yamashiki, T. Nakayama, T. Kon, H. Mitsubuchi, and H. Yoshida declare that they have no conflict of interest.
- Häussinger D (1983) Hepatocyte heterogeneity in glutamine and ammonia metabolism and the role of an intercellular glutamine cycle during ureogenesis in perfused rat liver. Eur J Biochem 133:269–275Google Scholar
- Saheki T, Song YZ (2017) Citrin deficiency. In: Adam MP, Ardinger HH, Pagon RA et al (eds) GeneReviews. University of Washington, SeattleGoogle Scholar
- Seifter S, Englard S (2009) Energy metabolism. In: Arias I, Wolkoff A, Boyer J et al (eds) The liver: biology and pathobiology, 5th edn. Raven, New York, pp 1–41Google Scholar
- Yazaki M, Fukushima K, Saheki T, Ikeda S (2013) Therapeutic strategy for patients with adult onset type II citrullinemia (CTLN2). Program and abstracts for the 3rd Asian Congress for Inherited Metabolic Diseases/the 55th Annual Meeting of the Japanese Society for Inherited Metabolic Diseases, Chiba, p 101Google Scholar