Adipsic hypernatremia without hypothalamic lesions accompanied by autoantibodies to subfornical organ

Abstract

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.

Keywords: adipsic hypernatremia; autoimmune disease; essential hypernatremia; sensory circumventricular organs.

Figure 1

Patients showed impaired vasopressin release without demonstrable hypothalamic structural lesions. A. Relationship between serum osmolality and plasma vasopressin levels. The green area indicates the normal range (40). B. Sagittal T1‐weighted MRI.

Figure 2

Sera of patients contained antibodies specifically reactive to mouse sCVOs. Immunostaining of the coronal brain sections of mice with the sera of patients and a control healthy subject. All sera examined were reactive to the SFO. The serum of Case 3 was also reactive to the OVLT. SFO, subfornical organ; OVLT, organum vasculosum laminae terminalis; PVN, paraventricular nucleus; SON, supraoptic nucleus; ME, median eminence. Scale bars, 100 μm.

Figure 3

Mice injected with patient Ig showed an abnormal NaCl preference under water‐restricted conditions. A. Strategy of the food preference test. Mice were injected with Ig obtained from a patient (Case 1) or healthy control subjects 30 days before the test (day −30) and housed under usual conditions (day −30 to day 0). Na‐depleted and Na‐repleted food were served from days 0 to 5, and mice had ad libitum access. The amount of drinking water was restricted to 0.5 mL/day from days 0 to 3. B. Preference ratio for Na‐repleted food. **P < 0.01 by the two‐tailed t‐test (n = 10 for each group). C. Plasma Na⁺ levels ([Na⁺]) were monitored at the indicated time points, as shown in A. *P < 0.05 and **P < 0.01 by the two‐tailed t‐test (n = 10 for each group). D–F. Water intake volumes during the dark period (12 h) (D), plasma vasopressin levels (E), and urine volumes (F) of mice that received the passive transfer of the patient or control Ig. *P < 0.05 and **P < 0.01 by the two‐tailed t‐test (n = 10 for each group).

Figure 4

Infiltrates of reactive microglia and cell death were observed in the SFO of mice that received the passive transfer of a patient's Ig. A. TUNEL staining of tissue sections of the SFO, OVLT, PVN, SON, and pituitary gland from mice, 3 days after the injection of control (uppers) or patient Ig (lowers). Magnified view of the squared region in the SFO is shown below. Arrow heads indicate TUNEL‐positive cells. Scale bars, 100 μm. B. Summary of TUNEL assays. **P < 0.01 (significantly different from control Ig in the same brain region), by a two‐tailed t‐test (n = 10 for each group). C. Anti‐P2Y₁₂ immunostaining of the SFO, OVLT, PVN, SON, and pituitary gland of mice 3 days after the injection of control Ig (upper panels) or patient Ig (lower panels). Arrow heads indicate P2Y₁₂‐positive microglia. Scale bars, 100 μm.