Adipsia is a disease characterized by the absence of thirst even in the It is a rare condition that typically presents as hypernatremic dehydration. We describe two sisters with chronic hypernatremia, lack of thirst, and inappropriate osmoregulated vasopressin secretion. Only one sister, who presented with. Adipsia, also known as hypodipsia, is a symptom of inappropriately decreased or absent . Type A (essential hypernatremia syndrome) involves an increase of the level in which solvent molecules can pass through cell membranes (osmotic.

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Adipsic hypernatremia is a rare disease presenting as persistent hypernatremia with disturbance of thirst regulation and hypothalamic dysfunction. As a result of congenital disease, tumors, or inflammation, most cases are accompanied by structural abnormalities hypfrnatremia the hypothalamic-pituitary area.

While cases with no hypothalamic-pituitary structural lesion have been reported, their etiology has not been elucidated. Recently, we reported three patients with adipsic hypernatremia whose serum-derived immunoglobulin Ig specifically reacted with mouse subfornical organ SFO tissue.

Adipsic Hypernatremia in Two Sisters

As one of the circumventricular organs CVOs that form a sensory interface between the blood and brain, the SFO is a critical site for generating physiological responses to dehydration and hypernatremia. These results support a new autoimmunity-related mechanism for inducing adipsic hypernatremia without demonstrable hypothalamic-pituitary structural lesions.

In this review, we adipsid to highlight the characteristic clinical features of these patients, in addition to etiological mechanisms related to SFO function.

These findings may be useful for diagnosing adipsic hypernatremia caused by an autoimmune response to the SFO, and support development of new strategies for prevention and treatment.

Body fluids are therefore constantly monitored by osmolality or sodium level sensors in the brain, which control thirst sensation, preference for salt, and AVP 12. Adipsic hypernatremia is clinically characterized by an increase of both the osmotic set point for AVP release, and the threshold for thirst perception, resulting in persistent hypernatremia htpernatremia a euvolemic state 456.

As a result of congenital disease, tumors, or inflammation, most cases are accompanied by hypwrnatremia abnormalities in the hypothalamic-pituitary area; however, cases with no structural lesion have also been reported since the s 7891011 Some of these cases hyperntaremia hypopituitarism including GH deficiency GHDrapid obesity, and autonomic failure. These patients generally had a poor prognosis, often due to respiratory failure, such as apnea. Although almost 50 years have passed, the underlying mechanisms for this condition have yet to be clearly elucidated.

InHiyama et al. 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 Intriguingly, there were similar clinical features among four patients, addipsic resulting from specific immune responses to the SFO.

In this review, we summarized the clinical characteristics of those patients with adipsic hypernatremia to highlight common findings, which might have resulted from SFO damage. Three CVOs form hypernatremiq sensory interface between adipslc blood and brain: All lack a blood-brain barrier and contain receptors for many substances that circulate in the blood Among the CVOs, the SFO protrudes ventrally from the fornix into the third ventricle, just caudal to the foramen of Monroe at the confluence of the lateral adipsicc third ventricles The peripheral portion, however, is positioned to respond to factors in cerebrospinal fluid CSFsuch as sodium Activation of Na x stimulates glial cells to release lactate, which functions as a gliotransmitter and activates GABAergic inhibitory neurons in the SFO Adipsjc SFO is a unique nucleus in that its afferent and efferent projections are well placed to respond to blood-borne signals and integrate them with neuronal signals In addition, neurons in the core portion of the SFO also project to the parvocellular PVN pPVNwhich synthesizes corticotropin-releasing hormone, and the basal nucleus of the stria terminalis Neural connections of the subfornical organ SFO.


Median sagittal section through the human brain showing the SFO red and its efferent terminal fields blue. Schematic overview of addipsic circuits originating from the SFO. Closed arrows indicate direct solid line and indirect dotted line neural connections. Open arrows indicate release of peptides to the circulation.

Table showing the nuclei that have afferent and efferent neuronal connections with SFO. Figure A is modified from The renin-angiotensin-aldosterone system RAAS is an important regulator of fluid balance Intracranial injection of Ang II causes increased water and salt intake Orexigens and anorexigens both act at the Hypermatremia, but via different neuronal pathways Some experimental evidence suggests ghrelin may play a role in regulation of energy hypernatrdmia by action at the SFO Administration of ghrelin has been clearly demonstrated to stimulate feeding and adiposity in mice and rats In patients developing adipsic hypernatremia caused hypeernatremia congenital adipic, such as septo-optic dysplasia, clinical characteristics often present as neurodevelopmental delay, seizures, thermal dysregulation, and anterior pituitary dysfunction [defects in the release control of GH, thyroid stimulating hormone TSHand ACTH] These patients typically have Langerhans histiocytosis and teratoma in the hypothalamus.

In addition to thermal dysfunction, these patients can present with obesity or leanness 5. Their prognosis was reported to be poor. In all such cases, alveolar hypoventilation was observed; notably, hypothalamic dysfunction, such as ophthalmologic manifestations and thermal dysregulation, frequently occurred in these patients.

Adipsia – Wikipedia

In contrast, patients with SFO-reactive antibodies did not exhibit hypoventilation or thermal dysregulation. In summary, the common syndromes at clinical onset among the four patients with SFO-reactive antibodies: A hypernatremia without thirst sensation; B impaired AVP release; C lack of structural aberrance in the hypothalamus-pituitary region; D childhood onset; E obesity; F increased serum PRL; G impairment of GH release; H increased plasma renin-activity; and I intact urine-concentrating capacity.

The specific details and mechanism of each feature are described here:. Impaired secretion of AVP associated with adipsia was considered a direct cause hypernatrremia persistent hypernatremia, which led us to diagnose patients with adipsic hypernatremia. MRI results showed a clearly detectable posterior pituitary gland with local presence of secretory granules, suggesting preservation of AVP synthesis.

However, structural abnormalities were not detected in the hypothalamus-pituitary area by MRI in any of these cases. Damage incurred in the SFO, resulting from an immune response, might be too slight to be detected by MRI analyses, as the SFO is ten times smaller than the posterior lobe of the pituitary.

D We have not experienced any adult-onset cases so far. We speculate that some immature immune response to inflammation, triggered by infection, may underlie the autoimmune reaction in childhood. Consistent with this view, some patients experienced episodic inflammation with infections such as influenza virus and opsoclonus myoclonus syndrome OMSa feature often associated with neuroblastic tumors.

E All patients presented with rapidly progressing obesity during the onset period. As they did not show overeating, we believe the obesity may result from a disorder of energy balance. Although we have not determined the cause of the metabolic disorder, ghrelin signaling is a plausible target as it affects energy balance via SFO.

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G It is well known that GHD is associated with obesity The SFO subpopulation of neurons is consistently, dose-dependently excited by application of exogenous ghrelin 31suggesting that SFO damage might have caused defects in GH release.

Precocious puberty was observed in some cases, and damage in the SFO may also underlie these symptoms. There are still two unresolved points related to the pathophysiology of this disorder: 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 Identification of molecules specific to the SFO will be the subject of future investigation. 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 The classical complement pathway is activated by the interaction of an antigen-antibody complex with a C1 component on the cell-surface target. Similar damage was noted in the SFO of the patients. New strategies to prevent specific inflammatory conditions would be required to treat these patients; a trial to reduce or eliminate patient autoantibodies deserves consideration.

Strategies may include autoantibody elimination by double-filtration plasmapheresis or immunoadsorption therapy, as well as the administration of steroids, immunosuppressants, or rituximab anti-CD20 antibody.

Careful monitoring of adverse events, and approval by the appropriate ethics committees, would be mandatory. In the future, more detailed mechanisms and clinical findings will aid development and selection of new clinical strategies. Adipsic hypernatremia patients with specific immune responses to SFO display common clinical features. The SFO is a specialized area controlling thirst and salt appetite, as well as several neurosecretory systems with neural connections to other brain nuclei and receptors for circulating peptides.

SFO damage by autoimmune response is thought to induce a variety of symptoms, including loss of thirst sensation, hypernatremia, obesity, GHD, and a number of others.

We are grateful to Drs. National Center for Biotechnology InformationU. Journal List Clin Pediatr Endocrinol v. Published online Sep Akari Nakamura-Utsunomiya1 Takeshi Y. Author information Article notes Copyright and License information Disclaimer. Received Nov 6; Accepted Apr Open in a separate window.

Table 1 Summary of clinical characteristics of patients with or without antibody targeting the subfornical organ area. Table 2 Results of endocrinological findings in patients with or without antibody targeting the subfornical organ area. The specific details and mechanism of each feature are described here: Future Directions There are still two unresolved points related to the pathophysiology of this disorder: Conclusion Adipsic hypernatremia patients with specific immune responses to SFO display common clinical features.

Angiotensin, thirst, and sodium appetite. Physiol Rev ; Regulation of water intake. Annu Rev Nutr ; 2: Czernichow P, Polak M.

Adipsic Hypernatremia in Two Sisters | JAMA Pediatrics | JAMA Network

Diagnostics of endocrine function in children and adolescents, ed 4. Chronic and sustained hypernatremia, absence of thirst, diabetes insipidus, and adrenocorticotrophin insufficiency resulting from widespread destruction of the hypothalamus. Ann Intern Med ; Report of three cases and review of the literature. Arch Intern Med ; Adipsic hypernatremia with a reset osmostat.

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