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 (CTLN2), 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 5–13 years and thirty-seven 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 HDL-cholesterol (HDL-C) concentration than the control group (75 ± 10 vs. 60 ± 25 mg/dL, p < 0.01), while the two groups had similar LDL-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- 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. Copyright © 2018 Endocrine Society
Journal of Clinical Endocrinology and Metabolism – Oxford University Press
Published: Apr 5, 2018
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