Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan.
Department of Pediatrics, Miyukikai Hospital, Kaminoyama, Japan.
J Inherit Metab Dis. 2021 Jan;44(1):110-117. doi: 10.1002/jimd.12294. Epub 2020 Aug 26.
Citrin deficiency is a hereditary disorder caused by SLC25A13 mutations and manifests as neonatal intrahepatic cholestasis (NICCD), failure to thrive and dyslipidemia (FTTDCD), and adult-onset type II citrullinemia (CTLN2). Citrin is a component of the malate-aspartate nicotinamide adenine dinucleotide hydrogen (NADH) shuttle, an essential shuttle for hepatic glycolysis. Hepatic glycolysis and the coupled lipogenesis are impaired in citrin deficiency. Hepatic lipogenesis plays a significant role in fat supply during growth spurt periods: the fetal period, infancy, and puberty. Growth impairment in these periods is characteristic of citrin deficiency. Hepatocytes with citrin deficiency cannot use glucose and fatty acids as energy sources due to defects in the NADH shuttle and downregulation of peroxisome proliferator-activated receptor α (PPARα), respectively. An energy deficit in hepatocytes is considered a fundamental pathogenesis of citrin deficiency. Medium-chain triglyceride (MCT) supplementation with a lactose-restricted formula and MCT supplementation under a low-carbohydrate diet are recommended for NICCD and CTLN2, respectively. MCT supplementation therapy can provide energy to hepatocytes, promote lipogenesis, correct the cytosolic NAD /NADH ratio via the malate-citrate shuttle and improve ammonia detoxification, and it is a reasonable therapy for citrin deficiency. It is very important to administer MCT at a dose equivalent to the liver's energy requirements in divided doses with meals. MCT supplementation therapy is certainly promising for promoting growth spurts during infancy and adolescence and for preventing CTLN2 onset. Intravenous administration of solutions containing fructose is contraindicated, and persistent hyperglycemia should be avoided due to glucose intoxication for patients receiving hyperalimentation or with complicating diabetes.
Citrin 缺乏症是一种由 SLC25A13 基因突变引起的遗传性疾病，表现为新生儿肝内胆汁淤积症（NICCD）、生长不良和血脂异常（FTTDCD）以及成年起病型 II 型瓜氨酸血症（CTLN2）。Citrin 是苹果酸-天冬氨酸 NADH 氢（NADH）穿梭系统的组成部分，是肝脏糖酵解的必需穿梭系统。Citrin 缺乏症会损害肝脏糖酵解和偶联的脂肪生成。肝脂肪生成在生长突增期（胎儿期、婴儿期和青春期）对脂肪供应起着重要作用。这些时期的生长障碍是 Citrin 缺乏症的特征。由于 NADH 穿梭缺陷和过氧化物酶体增殖物激活受体 α（PPARα）下调，Citrin 缺乏的肝细胞不能将葡萄糖和脂肪酸用作能源。肝细胞能量不足被认为是 Citrin 缺乏症的基本发病机制。中链甘油三酯（MCT）补充乳糖限制配方和低碳水化合物饮食下的 MCT 补充分别推荐用于 NICCD 和 CTLN2。MCT 补充治疗可以为肝细胞提供能量，促进脂肪生成，通过苹果酸-柠檬酸穿梭纠正细胞溶质 NAD/NADH 比，并改善氨解毒，是治疗 Citrin 缺乏症的合理方法。非常重要的是，要根据每餐的需要将 MCT 以等分剂量给予，以满足肝脏的能量需求。MCT 补充治疗肯定有望促进婴儿期和青春期的生长突增，并预防 CTLN2 的发病。静脉内给予含有果糖的溶液是禁忌的，由于高营养支持或并发糖尿病的患者存在葡萄糖中毒，应避免持续高血糖。
