Hiyama Takeshi Y, Utsunomiya Akari N, Matsumoto Masahito, Fujikawa Akihiro, Lin Chia-Hao, Hara Keiichi, Kagawa Reiko, Okada Satoshi, Kobayashi Masao, Ishikawa Mayumi, Anzo Makoto, Cho Hideo, Takayasu Shinobu, Nigawara Takeshi, Daimon Makoto, Sato Tomohiko, Terui Kiminori, Ito Etsuro, Noda Masaharu
Division of Molecular Neurobiology, National Institute for Basic Biology (NIBB), Okazaki, Aichi, 444-8787, Japan.
School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi, 444-8787, Japan.
Brain Pathol. 2017 May;27(3):323-331. doi: 10.1111/bpa.12409. Epub 2016 Aug 2.
Adipsic (or essential) hypernatremia is a rare hypernatremia caused by a deficiency in thirst regulation and vasopressin release. In 2010, we reported a case in which autoantibodies targeting the sensory circumventricular organs (sCVOs) caused adipsic hypernatremia without hypothalamic structural lesions demonstrable by magnetic resonance imaging (MRI); sCVOs include the subfornical organ (SFO) and organum vasculosum of the lamina terminalis (OVLT), which are centers for the monitoring of body-fluid conditions and the control of water and salt intakes, and harbor neurons innervating hypothalamic nuclei for vasopressin release. We herein report three newly identified patients (3- to 8-year-old girls on the first visit) with similar symptoms. The common features of the patients were extensive hypernatremia without any sensation of thirst and defects in vasopressin response to serum hypertonicity. Despite these features, we could not detect any hypothalamic structural lesions by MRI. Immunohistochemical analyses using the sera of the three patients revealed that antibodies specifically reactive to the mouse SFO were present in the sera of all cases; in one case, the antibodies also reacted with the mouse OVLT. The immunoglobulin (Ig) fraction of serum obtained from one patient was intravenously injected into wild-type mice to determine whether the mice developed similar symptoms. Mice injected with a patient's Ig showed abnormalities in water/salt intake, vasopressin release, and diuresis, which resultantly developed hypernatremia. Prominent cell death and infiltration of reactive microglia was observed in the SFO of these mice. Thus, autoimmune destruction of the SFO may be the cause of the adipsic hypernatremia. This study provides a possible explanation for the pathogenesis of adipsic hypernatremia without demonstrable hypothalamus-pituitary lesions.
无渴感（或特发性）高钠血症是一种罕见的高钠血症，由口渴调节和抗利尿激素释放缺陷引起。2010年，我们报告了一例病例，其中靶向感觉室周器官（sCVOs）的自身抗体导致了无渴感高钠血症，而磁共振成像（MRI）未显示下丘脑结构病变；sCVOs包括穹窿下器官（SFO）和终板血管器（OVLT），它们是监测体液状况以及控制水和盐摄入的中枢，并且含有支配下丘脑核以释放抗利尿激素的神经元。我们在此报告三名新确诊的患者（初诊时年龄为3至8岁的女孩），她们有相似的症状。这些患者的共同特征是存在严重高钠血症但无任何口渴感，以及抗利尿激素对血清高渗反应存在缺陷。尽管有这些特征，我们通过MRI未检测到任何下丘脑结构病变。使用这三名患者的血清进行免疫组织化学分析显示，所有病例的血清中均存在与小鼠SFO特异性反应的抗体；在一例病例中，这些抗体也与小鼠OVLT发生反应。将一名患者血清的免疫球蛋白（Ig）组分静脉注射到野生型小鼠体内，以确定小鼠是否会出现类似症状。注射了患者Ig的小鼠在水/盐摄入、抗利尿激素释放和利尿方面出现异常，最终发展为高钠血症。在这些小鼠的SFO中观察到明显的细胞死亡和反应性小胶质细胞浸润。因此，SFO的自身免疫性破坏可能是无渴感高钠血症的病因。本研究为无明显下丘脑 - 垂体病变的无渴感高钠血症的发病机制提供了一种可能的解释。
