Pathogenesis and Management of Citrin Deficiency

• Published in: Internal Medicine Vol. 63; no. 14; pp. 1977 - 1986
• Main Author: Hayasaka, Kiyoshi
• Format: Journal Article
• Language: English
• Published: Japan The Japanese Society of Internal Medicine 15.07.2024; Japan Science and Technology Agency
• Subjects: adult-onset type 2 citrullinemia; Brain injury; Calcium-Binding Proteins - deficiency; Calcium-Binding Proteins - genetics; Carbohydrates; Cholestasis; Cholestasis, Intrahepatic - etiology; Cholestasis, Intrahepatic - genetics; Cholestasis, Intrahepatic - therapy; citrin; Citrullinemia - diagnosis; Citrullinemia - genetics; Citrullinemia - therapy; Dietary Supplements; Dyslipidemia; Glycolysis; Hepatocytes; Hepatocytes - metabolism; Humans; Lipogenesis; Liver; medium-chain triglycerides; Mitochondrial Membrane Transport Proteins - genetics; Mutation; neonatal intrahepatic cholestasis caused by citrin deficiency; Neonates; Organic Anion Transporters - deficiency; Organic Anion Transporters - genetics; Quality of life; SLC25A13; Triglycerides - metabolism; medium-chain triglycerides; neonatal intrahepatic cholestasis caused by citrin deficiency; citrin; adult-onset type 2 citrullinemia; SLC25A13
• ISSN: 0918-2918; 1349-7235; 1349-7235
• DOI: 10.2169/internalmedicine.2595-23

Citrin deficiency (CD) is a hereditary disorder caused by SLC25A13 mutations that manifests as neonatal intrahepatic cholestasis caused by CD (NICCD), failure to thrive and dyslipidemia caused by CD (FTTDCD), and adult-onset type 2 citrullinemia (CTLN2). Citrin, an aspartate-glutamate carrier primarily expressed in the liver, is a component of the malate-aspartate shuttle, which is essential for glycolysis. Citrin-deficient hepatocytes have primary defects in glycolysis and de novo lipogenesis and exhibit secondarily downregulated PPARα, leading to impaired β-oxidation. They are unable to utilize glucose and free fatty acids as energy sources, resulting in energy deficiencies. Medium-chain triglyceride (MCT) supplements are effective for treating CD by providing energy to hepatocytes, increasing lipogenesis, and activating the malate-citrate shuttle. However, patients with CD often exhibit growth impairment and irreversible brain and/or liver damage. To improve the quality of life and prevent irreversible damage, MCT supplementation with a diet containing minimal carbohydrates is recommended promptly after the diagnosis.