Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, Box 1616, New York, NY, 10029, USA.
Division of Pediatric Endocrinology, Yale School of Medicine, New Haven, CT, USA.
Orphanet J Rare Dis. 2021 Apr 28;16(1):190. doi: 10.1186/s13023-020-01642-y.
The spectrum of disorders associated with hyperinsulinemic hypoglycemia (HHI) has vastly increased over the past 20 years with identification of molecular, metabolic and cellular pathways involved in the regulation of insulin secretion and its actions. Hereditary tyrosinemia (HT1) is a rare metabolic disorder associated with accumulation of toxic metabolites of the tyrosine pathway due to a genetically mediated enzyme defect of fumarylacetoacetate hydrolase. Transient tyrosinemia of the newborn (TTN) is a benign condition with a maturational defect of the enzymes associated with tyrosine metabolism without any genetic abnormalities.
We describe two rare cases of HHI, one in a patient with HT1 and for the first time, in a patient with TTN. Each of our patients presented in the neonatal period with persistent hypoglycemia that on biochemical evaluation was consistent with HHI. Each patient received diazoxide therapy for 3.5 months and 17 months of life, respectively and HHI resolved thereafter.
Despite the fact that HHI has been described in HT1 for several decades, no specific mechanism has been delineated. Although we considered the common embryonal origin of the liver and pancreas with the hepatotoxic effect in HT1 also impacting the latter, this was not a possible explanation for TTN. The commonality between our two patients is the accumulation of certain amino acids which are known to be insulinotropic. We therefore hypothesize that the excess of amino acids such as leucine, lysine, valine and isoleucine in our patients resulted in HHI, which was transient. Both patients responded to diazoxide. This novel presentation in TTN and the reassuring response in both HT1 and TTN to diazoxide will be useful to inform physicians about managing HHI in these patients. Further studies are required to delineate the mechanism of HHI in these infants.
在过去的 20 年中，与高胰岛素血症性低血糖（HHI）相关的疾病谱大大增加，涉及胰岛素分泌及其作用的调节的分子、代谢和细胞途径已被确定。遗传性酪氨酸血症（HT1）是一种罕见的代谢疾病，由于延胡索酰乙酰乙酸水解酶的遗传介导酶缺陷，导致酪氨酸途径的有毒代谢物积累。新生儿一过性酪氨酸血症（TTN）是一种良性疾病，与酪氨酸代谢相关的酶存在成熟缺陷，而无任何遗传异常。
我们描述了两种罕见的 HHI 病例，一种发生在 HT1 患者中，这是首次在 TTN 患者中发现。我们的每位患者在新生儿期均表现为持续性低血糖，生化评估与 HHI 一致。每位患者分别接受了 3.5 个月和 17 个月的二氮嗪治疗，此后 HHI 得到解决。
尽管 HHI 在 HT1 中已被描述了数十年，但尚未确定具体的机制。尽管我们考虑到肝脏和胰腺的共同胚胎起源以及 HT1 中的肝毒性作用也会影响后者，但这并不是 TTN 的可能解释。我们的两位患者之间的共同点是某些氨基酸的积累，已知这些氨基酸具有胰岛素刺激作用。因此，我们假设患者体内过量的氨基酸，如亮氨酸、赖氨酸、缬氨酸和异亮氨酸，导致了短暂的 HHI。两位患者均对二氮嗪有反应。这种在 TTN 中的新表现以及 HT1 和 TTN 对二氮嗪的令人放心的反应，将有助于告知医生如何管理这些患者的 HHI。需要进一步研究以阐明这些婴儿中 HHI 的机制。
