Journal of Inherited Metabolic Disease

, Volume 41, Issue 5, pp 777–784 | Cite as

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

  • Kiyoshi Hayasaka
  • Chikahiko Numakura
  • Mitsunori Yamakawa
  • Tetsuo Mitsui
  • Hisayoshi Watanabe
  • Hiroaki Haga
  • Masahide Yazaki
  • Hiromasa Ohira
  • Yasuo Ochiai
  • Toshiyuki Tahara
  • Tamio Nakahara
  • Noriyo Yamashiki
  • Takahiro Nakayama
  • Takashi Kon
  • Hiroshi Mitsubuchi
  • Hiroshi Yoshida
Original Article


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


Medium-chain triglycerides


Argininosuccinate synthetase 1


Glutamine synthetase


Pancreatic secretory trypsin inhibitor


Body mass index


Gamma-glutamyl transpeptidase




Aspartate aminotransferase


Alanine aminotransferase


Lactate dehydrogenase


Leucine aminopeptidase


Alkali phosphatase


Carbamoyl phosphate transferase


Ornithine transcarbamylase


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.

Supplementary material

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Suppl. Fig. 1a

Changes in the level of blood ammonia, plasma citrulline, plasma glutamine, and Fischer ratio. (a) blood ammonia, (b) plasma citrulline, (c) glutamine, (d) Fischer ratio. Open circle: case 1, open triangle: case 2, open square: case 3, closed circle: case 4, closed triangle: case 5, closed square: case 6. Normal range is shown by the area within the box (JPEG 356 kb)

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Suppl. Fig. 2

Immunohistochemical localization of argininosuccinate synthetase 1 (ASS1) in the livers from case 6 before treatment and after treatment. (a) case 6 before treatment (×100), (b) case 6 after about 3 years of treatment (×100). Arrows indicate the patchy areas of ASS1-negative hepatocytes. ASS1-negative hepatocytes were decreased after treatment (JPEG 1277 kb)

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Copyright information

© SSIEM 2018

Authors and Affiliations

  • Kiyoshi Hayasaka
    • 1
    • 2
  • Chikahiko Numakura
    • 1
  • Mitsunori Yamakawa
    • 3
  • Tetsuo Mitsui
    • 1
  • Hisayoshi Watanabe
    • 4
  • Hiroaki Haga
    • 4
  • Masahide Yazaki
    • 5
  • Hiromasa Ohira
    • 6
  • Yasuo Ochiai
    • 7
  • Toshiyuki Tahara
    • 7
  • Tamio Nakahara
    • 8
  • Noriyo Yamashiki
    • 9
  • Takahiro Nakayama
    • 10
  • Takashi Kon
    • 11
  • Hiroshi Mitsubuchi
    • 12
  • Hiroshi Yoshida
    • 13
  1. 1.Department of PediatricsYamagata University School of MedicineYamagataJapan
  2. 2.Department of PediatricsMiyukikai HospitalKaminoyamaJapan
  3. 3.Department of Pathological DiagnosticsYamagata University School of MedicineYamagataJapan
  4. 4.Department of GastroenterologyYamagata University School of MedicineYamagataJapan
  5. 5.Department of Biological Sciences for Intractable Neurological Disorders, Institute for Biomedical SciencesShinshu UniversityNaganoJapan
  6. 6.Department of GastroenterologyFukushima Medical University School of MedicineFukushimaJapan
  7. 7.Department of GastroenterologySaiseikai Utsunomiya HospitalTochigiJapan
  8. 8.Department of GastroenterologyHikone Municipal HospitalHikoneJapan
  9. 9.Organ Transplantation UnitKyoto UniversityKyotoJapan
  10. 10.Division of Internal MedicineNihonkai General HospitalSakataJapan
  11. 11.Department of GastroenterologyYonezawa Municipal HospitalYonezawaJapan
  12. 12.Department of PediatricsGraduate School of Medical Sciences, Kumamoto UniversityKumamotoJapan
  13. 13.Department of PediatricsTsuruoka Municipal Shonai HospitalTsuruokaJapan

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