Satoshi Hirayama1, Hironori Nagasaka2, Akira Honda3, Haruki Komatsu4, Takahiro Kodama5, Ayano Inui6, Ichiro Morioka7, Shunsaku Kaji8, Tsuyoshi Ueno1, Kenji Ihara9,10, Mariko Yagi11, Zenro Kizaki12, Kazuhiko Bessho13, Hiroki Kondou14, Tohru Yorifuji15, Hirokazu Tsukahara16, Kazumoto Iijima17, Takashi Miida1,18. 1. Department of Clinical Laboratory Medicine, Juntendo University School of Medicine, Tokyo, Japan. 2. Department of Pediatrics, Takarazuka City Hospital, Takarazuka, Japan. 3. Joint Research Center and Division of Gastroenterology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan. 4. Department of Pediatrics, Toho University Sakura Medical Center, Sakura, Japan. 5. Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Osaka, Japan. 6. Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohamashi Tobu Hospital, Yokohama, Japan. 7. Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan. 8. Department of Pediatrics, Tsuyama-Chuo Hospital, Okayama, Japan. 9. Department of Pediatrics, Kyushu University Graduate School of Medical Science, Fukuoka, Japan. 10. Department of Pediatrics, Oita University, Faculty of Medicine, Yufu, Japan. 11. Department of Pediatrics, Nikoniko House Medical & Welfare Center, Kobe, Japan. 12. Department of Pediatrics, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan. 13. Department of Pediatrics, Graduate School of Medicine, Osaka University, Osaka, Japan. 14. Department of Pediatrics, Kindai University Nara Hospital, Nara, Japan. 15. Division of Pediatric Endocrinology and Metabolism, Children's Medical Center, Osaka City General Hospital, Osaka, Japan. 16. Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. 17. Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan. 18. Department of Clinical Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Abstract
Context: Citrin-deficient infants present neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), which resolves at 12 months. Thereafter, they have normal liver function associated with hypercholesterolemia, and a preference for lipid-rich carbohydrate-restricted diets. However, some develop adult-onset type II citrullinemia, which is associated with metabolic abnormalities. Objectives: To identify the causes of hypercholesterolemia in citrin-deficient children post-NICCD. Design and Setting: We determined the concentrations of sterol markers of cholesterol synthesis, absorption, and catabolism by liquid chromatography-electrospray ionization-tandem mass spectrometry and evaluated serum lipoprotein profiles. Subjects: Twenty citrin-deficient children aged 5 to 13 years and 37 age-matched healthy children. Intervention: None. Main Outcome Measures: Relationship between serum lipoproteins and sterol markers of cholesterol metabolism. Results: The citrin-deficient group had a significantly higher high-density lipoprotein cholesterol (HDL-C) concentration than did the control group (78 ± 11 mg/dL vs 62 ± 14 mg/dL, P < 0.001), whereas the two groups had similar low-density lipoprotein cholesterol and triglyceride concentrations. The concentrations of markers of cholesterol synthesis (lathosterol and 7-dehydrocholesterol) and bile acids synthesis (7α-hydroxycholesterol and 27-hydroxycholesterol) were 1.5- to 2.8-fold and 1.5- to 3.9-fold, respectively, higher in the citrin-deficient group than in the control group. The concentration of 24S-hydroxycholesterol, a marker of cholesterol catabolism in the brain, was 2.5-fold higher in the citrin-deficient group. In both groups, the HDL-C concentration was significantly positively correlated with that of 27-hydroxycholesterol, the first product of the alternative bile acid synthesis pathway. Conclusions: HDL-C and sterol marker concentrations are elevated in citrin-deficient children post-NICCD. Moreover, cholesterol synthesis and elimination are markedly enhanced in the liver and brain of citrin-deficient children.
Context:Citrin-deficient infants present neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), which resolves at 12 months. Thereafter, they have normal liver function associated with hypercholesterolemia, and a preference for lipid-rich carbohydrate-restricted diets. However, some develop adult-onset type II citrullinemia, which is associated with metabolic abnormalities. Objectives: To identify the causes of hypercholesterolemia in citrin-deficient children post-NICCD. Design and Setting: We determined the concentrations of sterol markers of cholesterol synthesis, absorption, and catabolism by liquid chromatography-electrospray ionization-tandem mass spectrometry and evaluated serum lipoprotein profiles. Subjects: Twenty citrin-deficient children aged 5 to 13 years and 37 age-matched healthy children. Intervention: None. Main Outcome Measures: Relationship between serum lipoproteins and sterol markers of cholesterol metabolism. Results: The citrin-deficient group had a significantly higher high-density lipoprotein cholesterol (HDL-C) concentration than did the control group (78 ± 11 mg/dL vs 62 ± 14 mg/dL, P < 0.001), whereas the two groups had similar low-density lipoprotein cholesterol and triglyceride concentrations. The concentrations of markers of cholesterol synthesis (lathosterol and 7-dehydrocholesterol) and bile acids synthesis (7α-hydroxycholesterol and 27-hydroxycholesterol) were 1.5- to 2.8-fold and 1.5- to 3.9-fold, respectively, higher in the citrin-deficient group than in the control group. The concentration of 24S-hydroxycholesterol, a marker of cholesterol catabolism in the brain, was 2.5-fold higher in the citrin-deficient group. In both groups, the HDL-C concentration was significantly positively correlated with that of 27-hydroxycholesterol, the first product of the alternative bile acid synthesis pathway. Conclusions: HDL-C and sterol marker concentrations are elevated in citrin-deficient children post-NICCD. Moreover, cholesterol synthesis and elimination are markedly enhanced in the liver and brain of citrin-deficient children.