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.

Adipsic Diabetes Insipidus—The Challenging Combination of Polyuria and Adipsia: A Case Report and Review of Literature

“…These patients did not have any structural abnormalities in the hypothalamus and detailed investigations revealed evidence of antibodies against the OVLT organs. These cases have been postulated to have an underlying autoimmune pathology (10, 33).…”

Characteristic clinical features of adipsic hypernatremia patients with subfornical organ-targeting antibody

“…Clinical findings of patients with adipsic hypernatremia, with ( 33 ) and without ( 13 , 14 ) structural lesions, are compared and summarized in Tables 1 and 2…”

“…There are still two unresolved points related to the pathophysiology of this disorder: the antigen eliciting the specific immune response to SFO, and the mechanism for producing this antibody. We attempted to identify the specific antigens of the autoantibodies in the three patients, but all attempts failed, suggesting that these antigen molecules are not abundant in the SFO ( 14 ). Nevertheless, immunohistochemistry using patients’ sera suggested that the antigen molecule is expressed specifically in the SFO area, but not other brain tissue.…”

“…Generally, the incident prompting the onset of an autoimmune disorder is thought to be inflammation triggered by tumors and infections in subjects with preexisting susceptibilities. Injection of patient Ig into mice led to complement deposition, infiltration of inflammatory cells, and damage to the mouse SFO area resulting from apoptosis ( 14 , 16 ). The classical complement pathway is activated by the interaction of an antigen-antibody complex with a C1 component on the cell-surface target.…”

“…These results suggest a new etiology for adipsic hypernatremia caused by autoimmune responses. Additionally, we recently reported that the serum of three patients, exhibiting adipsic hypernatremia without demonstrable hypothalamus-pituitary lesion, reacted with a mouse SFO, though their sera did not contain anti-Na x antibodies ( 14 ). Mice injected with a patient’s Ig exhibited similar pathophysiology as the patient, including hypernatremia and defects in thirst sensation and AVP release.…”