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Review

Diabetes insipidus Diabètes insipides Clara Leroy , Wassila Karrouz , Claire Douillard , Christine Do Cao , Christine Cortet , Jean-Louis Wémeau , Marie-Christine Vantyghem ∗ Service d’endocrinologie et maladies métaboliques, centre hospitalier régional universitaire de Lille (CHRU de LIlle), hôpital Huriez/Inserm U 859, 1, rue Polonovski, 59000 Lille, France

Abstract Diabetes insipidus (DI) is characterized by hypotonic polyuria greater than 3 liters/24 hours in adults and persisting even during water deprivation. It is mostly due to a defect in arginin-vasopressin (AVP) synthesis (central DI); other causes are: AVP resistance (nephrogenic DI), abnormal thirst regulation (primary polydipsia) or early destruction of AVP by placental enzymes (gestational DI). A thorough medical history is warranted to investigate nocturnal persistence of polyuria (night waking being a good sign of its organic nature) to specify the onset and duration of the trouble, the medication use and the potential hereditary nature of the disorder. The next step is based on weight and blood pressure measurements and especially the quantification of beverages and diuresis over a 24-hour cycle. Assessment of signs of dehydration, bladder distention, pituitary hormone hyperor hyposecretion, tumor chiasmatic syndrome, granulomatosis and cancer is required. The diagnosis is based on biological assessment, pituitary magnetic resonance imaging (MRI) and results of a desmopressin test. In severe forms of DI, urine osmolality remains below 250 mOsmol/kg and serum sodium greater than 145 mmol/L. In partial forms of DI (urine osmolality between 250 and 750), the water deprivation test demonstrating the incapacity to obtain a maximal urine concentration is valuable, together with vasopressin or copeptin measurement. The pituitary MRI is done to investigate the lack of spontaneous hyperintensity signal in the posterior pituitary, which marks the absence of AVP and supports the diagnosis of central DI rather than primary polydipsia (although not absolute); it can also recognize lesions of the pituitary gland or pituitary stalk. Acquired central DI of sudden onset should suggest a craniopharyngioma or germinoma if it occurs before the age of 30 years, and metastasis after the age of 50 years. Fifteen to 20% of head trauma lead to hypopituitarism, including DI in 2% of cases. Transient or permanent DI is present in 8–9% of endoscopic transphenoidal surgeries. Current advances in DI concern the etiological work-up, with in particular the identification of IgG4-related hypophysitis or many genetic abnormalities, opening the field of targeted therapies in the years to come. © 2013 Elsevier Masson SAS. All rights reserved. Résumé Le diabète insipide (DI) est caractérisé par une polyurie hypotonique supérieure à 3 litres/24heures chez l’adulte, persistant même en restriction hydrique. Il est le plus souvent secondaire à un défaut de synthèse de l’arginine-vasopressine (AVP) (DI central), parfois à une résistance à l’AVP (DI néphrogénique), une anomalie de la soif (polydipsie primaire) ou un catabolisme précoce de l’AVP par une enzyme placentaire (DI gestationnel). Un interrogatoire minutieux doit rechercher la persistance nocturne de la polyurie, bon signe d’organicité dont témoignent les réveils nocturnes, préciser le début et l’ancienneté des troubles, la notion de prise médicamenteuse et le caractère familial du trouble. L’étape suivante repose sur la mesure du poids, de la pression artérielle, et surtout la quantification nycthémérale des boissons et de la diurèse. Des signes de déshydratation, un globe vésical, des signes d’hyper- ou d’hyposécrétion hormonale hypophysaire, un syndrome tumoral, des signes de granulomatose ou de cancer doivent être recherchés. Le diagnostic positif repose sur les données biologiques, l’IRM hypophysaire et un test thérapeutique à la vasopressine. Dans les formes sévères, le diagnostic de DI est porté sur une osmolalité urinaire inférieure à 250 mOsmol/kg en regard d’une natrémie supérieure à 145 mmol/L. Dans les formes partielles (osmolalité urinaire comprise entre 250 et 750), le test de restriction hydrique montrant une incapacité à obtenir une concentration maximale des urines garde un intérêt, couplé au dosage de la vasopressine ou de la copeptine. L’IRM hypophysaire recherche : 1. l’absence d’hypersignal spontané de la post-hypophyse signant la carence en AVP, en faveur d’un DI central plutôt que d’une

∗

Corresponding author. E-mail address: [email protected] (M.-C. Vantyghem).

0003-4266/$ – see front matter © 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.ando.2013.10.002

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polydipsie, bien que ce signe ne soit pas absolu; 2. une anomalie de l’hypophyse ou de la tige hypophysaire. Un DI central acquis de révélation brutale doit évoquer un craniopharyngiome ou un germinome avant 30 ans et une métastase après 50 ans. Les traumatismes crâniens se compliquent dans 15 à 20 % d’hypopituitarisme, dont 2 % de diabète insipide. Le diabète insipide transitoire ou permanent s’observe dans 8–9 % des cas de chirurgie trans-sphénoidale par voie endoscopique. Les avancées actuelles concernent le bilan étiologique en particulier les hypophysites à IgG4 et de nombreuses anomalies génétiques, laissant espérer des thérapeutiques ciblées dans le futur. © 2013 Elsevier Masson SAS. Tous droits réservés.

1. Definition Diabetes insipidus (DI) is defined as a polyuric-polydipsic syndrome, in which voiding of hypotonic/dilute urine exceeds 3 liters in 24 hours, even in situations of water deprivation. Partial forms are defined as the incapacity to obtain a maximal urine concentration, corresponding to the urine osmolality that would be reached after administration of a vasopressin analog (at least for central DI). The etymology of these terms both of Greek origin (diaben: pass; betten: through; in sapidus: without taste) gives the litteral meaning. The differential diagnosis includes: • psychogenic polydipsia; • hypertonic or osmotic polyuria, defined by urine osmolality greater than 250 mOsmol/kg of water and negative free water clearance. Hypertonic polyuria is linked to: • glycosuria; • excretion of mannitol, contrast agent, urea (used in the treatment of inappropriate antidiuretic hormone secretion syndrome [SIADH]), glycerol; • acute tubular necrosis; • removal of obstruction secondary to uropathy. Loop diuretics rather induce isotonic polyuria. DI can be related to: • • • •

vasopressin deficiency (central DI); resistance to vasopressin (nephrogenic DI); thirst disorder (primary polydipsia); increased vasopressin metabolism (gestational DI).

2. Regulation of water metabolism The major steps in water metabolism are primarily controlled by vasopressin (or AVP for arginin-vasopressin) (Fig. 1) [1]. 2.1. Vasopressinergic stimuli A variation in plasma osmolality greater than 1% stimulates osmotic receptors that were recently identified both in the hypothalamus (TRPV1 - transient receptor potential vanilloid 1) [2] and the portal vein (TRPV4) [3].

Additionally, non-osmotic stimuli, particularly a variation in blood volume over 10%, are also capable of stimulating vasopressin secretion by means of angiotensin II receptors. Vasopressin synthesis can also be stimulated by nausea, pain, stress, hypoglycemia, hypoxia, interleukin-6 (IL6), brain natriuretic peptide (BNP), oxytocin (OCT) and various neuromediators. 2.2. Vasopressin synthesis A precursor of AVP synthesis, neurophysin-vasopressin prohormone, is found in the magnocellular neurons of the supraoptic and paraventricular nuclei. This pro-hormone is stored within the granules that circulate along the vasopressinergic neurons, in which maturation occurs (progressive cleavage of a signal peptide, then neurophysin-II). Besides magnocellular neurons, there are parvocellular neurons, which secrete both AVP and corticotropin-releasing hormone (CRH) and have their nerve terminals at the median eminence. 2.3. Vasopressin secretion Vasopressin, which is released after stimulation of the posterior pituitary, acts via: • the V1 receptors, located at the smooth muscle fibers, through which the hormone exerts its vasopressive activity and favours platelet aggregation [4]; • the V2 receptors, located at the kidney collecting ducts, by which the hormone exerts its antidiuretic effect by activating water channels, aquaporin 2 (AQP2) in particular, which reabsorbs water from the apical terminal to the basal terminal of the collecting duct cells [5,6]. Extra-renal V2 receptors probably exist, since desmopressin (or, synthetic analog of vasopressin) is capable of inducing secretion of factor VIII and Von Willebrand factor, and hypotension with subsequent secretion of renin and heart rate acceleration [7]. These effects provide evidence of the vasodilator action of the drug. V3 receptors, very similar to V1 receptors, have also been identified in the anterior pituitary. Brattleboro rat studies (model of central DI through deletion of a single nucleotide in the part of the AVP gene that codes for neurophysin-II) showed that AVP controlled the expression of aquaporin 2, as well as other proteins involved in urine concentration such as aquaporin 3, Na-K-Cl cotransporter (NKCC2) and urea transporters [8,9].

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Fig. 1. Regulation of water metabolism.

3. Diagnosis 3.1. General considerations The diagnosis of DI is based on the observation of a significant abnormal quantity of urine that is: • more than 3 liters/24 hours in adults (40 mL/kg/day) or 6.6 mL/kg/hour in children; • diluted, clear, dull, hypo-osmolar, urine i.e., with osmolality less than 250 mOsmol/kg of water [10]. This polyuric syndrome results in overbearing thirst, which leads to polydipsia related to plasma hyperosmolality and generates anxiety if water access is difficult. Nocturnal persistence of this polyuric-polydipsic syndrome is a sign of organic origin. The polyuric-polydipsic syndrome can lead to sleep problems and hinder social interaction. It is however often fairly well-tolerated if water intake is sufficient. If this is not the case, or in the event of disorders in alertness or thirst perception, there is a risk of dehydration or even circulatory collapse. Polyuria may be more difficult to assess if there is: • dilation of the urinary tract secondary to DI, particularly in children. In this case, dehydration tests and response to desmopressine (dDAVP) will be difficult to interpret due to some “dead” space;

• or adrenocorticotropic hormone insufficiency. In this case, polyuria would occur lately, after hydrocortisone replacement. With regards to laboratory tests, measurement of blood and urine electrolytes, creatinine, serum and urinary calcium, blood and urine glucose, plasma and urine osmolality are essential for the diagnosis. Measurement of anterior pituitary hormones helps to identify a central cause, and determines whether the posterior pituitary deficiency is isolated or not. Magnetic resonance imaging (MRI) often precedes the measurement of vasopressin and other biomarkers of central DI. The presence of vasopressin can be indirectly assessed by a spontaneous hyperintense signal of the posterior pituitary. The lack of this bright spot orientates towards central DI rather than towards primary polydypsia. Such sign is not absolute however, since hyperintensity lacks in approximately 20% of the normal population, more likely in elderly patients. Eventually, this bright spot could be decreased/absent both in central and nephrogenic diabetes insipidus (NDI) [11]. MRI can also display possible associated lesions (Fig. 2). 3.2. Clinical diagnosis Clinical work-up should assess the onset and duration of the symptoms, nocturnal awakening, medication used and the familial background to address the possible hereditary nature of the disorder.

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vasopressin levels are increased [12]. An isolated vasopressin value is not informative if not correlated to plasma osmolality. Measurement of vasopressin requires very strict sampling conditions (on ice, with rapid centrifugation and immediate freezing). If vasopressin measurement is not available, a desmopressin test will be done. A subsequent lack of urinary concentration suggests nephrogenic DI. 3.4. Water deprivation test and desmopressin test When urine osmolality ranges between 250 and 700 mOsmol/kg, a water deprivation test can be performed. The specific conditions of this test and its interpretation are shown in Tables 1a and 1b. This test is better performed in experienced team and is not beneficial in case of osmotic polyuria or associated corticotropin (ACTH) deficiency. Application is currently Table 1a Conditions for performing a water deprivation test. Fig. 2. Pituitary metastasis from a lung neoplasm that was manifest by central diabetes insipidus as a presenting symptom in a woman over the age of 50 years with tobacco intoxication (sagittal slice of T1-weighted magnetic resonance imaging).

The next step is based on measurements of weight, blood pressure and the quantification of beverages and diuresis over a 24-hour cycle. Examination should focus on signs of dehydration, possible bladder distention, anterior pituitary hormone hyper- or hyposecretion, tumoral syndrome (headache, bitemporal hemianopsia, diplopia), and systemic signs of granulomatosis or cancer. 3.3. Baseline laboratory diagnostic testing The laboratory diagnosis of DI is based on: • urine specific density less than 1005; • urine osmolality less than 250 mOsmol/kg of water; • a markedly positive free water clearance which demonstrates failure of urinary concentration mechanisms. This last calculation has interest mainly in clinical research. Free water clearance is the quantity of water that must be added or subtracted from the urine to result in isoosmotic excretion to the plasma. It is calculated as follows: free water clearance (CH2O = V × 1–urine osmolality/plasma osmolality), with V = urine output in mL/min over a given time. Also, plasma osmolaliry may be calculated using the formula: OsmP = 2 (natremia + kalemia) + blood glucose + blood urea (all values expressed in mmol/L). In conditions of free water access, blood electrolytes levels are normal in DI. Nevertheless, morning fasting sodium levels are often slightly elevated. Therefore, if urine osmolality is less than 200 mOsmol/kg with serum sodium over 145 mmol/L, DI is confirmed, and the water deprivation test is not useful and even dangerous. A low plasma concentration of vasopressin provides evidence of central DI; in nephrogenic DI, serum

Fluids stopped at 20:00, midnight or 06:00 At 08:00 Weight, intake/output, blood pressure (BP) Serum sodium, plasma and urine osmolality (Osm) Every hour from 09:00 to 16:00 Weight, heart rate, intake/output, BP Plasma and urine Osm End of fluid restriction at 17:00 Weight, heart rate, BP and urine volume Serum sodium, plasma and urine Osm After fluid restriction stopped, sub-cutaneous injection of 2 μg minirin Fluids resumed with volume limit of 1.5 L until following day at 08:00 Exception in case of confirmed insipidus diabetes: patient intake ad lib Following day at 08:00 Weight, intake/output, BP Plasma and urine Osm and serum sodium Test stopped if weight loss > 3–5% of baseline weight Increase of urine Osm < 30 mOsm/kg for 2 consecutive hours, urine Osm > 750 mOsm/kg Plasma Osm > 145–148 (sufficient for AVP stimulation > 3.5 ng/mL and urine Osm > 750) AVP: arginin-vasopressin. Table 1b Interpretation criteria. Urine Osm at end of test (mOsm/kg)

% of increase in urine Osm after dDAVP (2 ␮g IM)

Normal subjects > 750 < 9% < 250 > 50% Complete CDI 250–750 > 10% Partial CDI Complete NDI < 250 0 250–750 0 Partial NDI Primary polydipsia 250–750 < 9% AVP and plasma osmolality at end of test (46% diagnostic specificity) dDAVP test Other tests: blood copeptin; hypertonic saline infusion test AVP: arginin-vasopressin; CDI: central diabetes insipidus; NDI: nephrogenic diabetes insipidus; IM: intra-muscular; dDAVP: desmopressine.

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disputed since the measurement of AVP and plasma osmolality at the end of the test raises low diagnostic specificity (less than 50%). There are individual variations in the osmoregulation threshold of thirst and AVP secretion. In chronic polyuria, alterations in the concentration gradient of the renal medulla can affect the urine osmolality. Its maximum value may be reduced, even at satisfactory endogenous vasopressin concentrations. 3.5. Vasopressin measurement substitutes Different markers of vasopressin secretion have been proposed given vasopressin measurement issues. 3.5.1. Urinary aquaporin 2 Urinary aquaporin 2 using a commercial chemiluminescence kit is a marker of renal vasopressin activity, but has never been validated in clinical evaluation. 3.5.2. Blood neurophysins Blood neurophysins is not a very common assay due to the lack of a commercial kit [13]. They are released in an equimolar amount with vasopressin. As a result, the serum levels are low in patients with central DI. Abnormal circulating forms have been found in some families. 3.5.3. Copeptin Copeptin, the C-terminal part of provasopressin, currently draws attention [14]. AVP and copeptin share the same precursor peptide of 164 amino acids. Copeptin is released in the same proportions as AVP but has proved to be more stable at room temperature and easier to measure. This assay might reach 100% specificity and 86% sensitivity in the differential diagnosis of primary polydipsia, partial central DI and complete DI. There is however no gold standard for comparing the sensitivity and specificity. Published data (about 15 articles) focusing on copeptin interest in the differential diagnosis of DI are small series with water deprivation tests done under various conditions, without prospective validation of the diagnostic criteria. In addition, copeptin is also a marker of myocardial ischemia, heart failure, cerebral vascular accident and septicemia; it may therefore have less specificity than originally claimed. 3.5.4. Apelin Apelin, a diuretic neuropeptide, produced by hypothalamic neurons, besides several peripheral tissues, has not been studied in diabetes insipidus [15]. 3.6. Hypertonic saline infusion test The hypertonic saline infusion test is an osmotic stimulation test of vasopressin secretion. It consists in an infusion over 120 minutes of 5.0% hypertonic saline at a rate of 0.05 mL/kg of body weight/minute with the aim of increasing the serum sodium between 145 and 150 mmol/L. Plasma osmolality, urine osmolality and vasopressin are measured every 20 minutes, the first 3 hours after the start of the infusion.

This test is contraindicated in case of arterial hypertension and heart failure. It carries a risk of plasma hypertonicity and is of course contraindicated in the event of baseline hypernatremia. In central DI, this test shows the persistence of positive free water clearance with absence of increase in vasopressin plasma concentrations in the complete forms or very modest increase in the partial forms. In nephrogenic DI or primary polydipsia, stimulation of AVP secretion is normal. This test is rarely performed. It is especially informative to display partial forms of DI. 3.7. Non-osmotic vasopressin stimulation tests Non-osmotic stimulation tests of vasopressin secretion are rarely performed, but their knowledge has a physiopathological interest. The easiest test to perform is the measurement of vasopressin in lying, then standing positions, with concomitant measurement of plasma renin activity and aldosterone. Hypotension induced by changing to a standing position is a physiological stimulus of vasopressin. Low concordance between osmotic and non-osmotic stimuli responses has been reported in thirst disorders. 3.8. Conclusion In conclusion, the diagnosis of severe forms of DI is founded on baseline clinical and laboratory data, most often in association with a desmopressin test and pituitary MRI. In the partial forms, the water deprivation test is still important, together with measurement of vasopressin or copeptin (the best sensitivity and specificity of which should nevertheless be confirmed). At this stage, DI can be classified into 4 groups as cited in the introduction with the etiology specified. 4. Etiology and treatment of central diabetes insipidus 4.1. Acquired central diabetes insipidus 4.1.1. Acquired central diabetes insipidus of tumor origin Acquired central DI occurring after the age of 50 years suggests metastasis or craniopharyngioma and before the age of 30 years a germinoma or a craniopharyngioma. This DI is frequently associated with hypopituitarism and tumoral syndrome (headache, bitemporal hemianopsy) (Table 2). DI is a complication of 85% of pituitary metastases. It is the presenting symptom in 30% of cases. The most frequent primary neoplasms are breast and endometrium in women, prostate in men and lung, colon and melanomas in both genders. The MRI shows 1) loss of the spontaneous hyperintensity of the posterior pituitary, 2) a bilateral lobular mass related to rapid cellular proliferation with posterior-superior spread in contact with the floor of the third ventricle, and an intense and homogenous hyperintensity after gadolinium injection. Central DI that occurs before the age of 30 years is most often due to: • a craniopharyngioma in adults. This is a benign, slow-growing tumor with significant suprasellar development. It can be suspected when the tumor is heterogeneous on MRI, with solid

C. Leroy et al. / Annales d’Endocrinologie 74 (2013) 496–507 Table 2 Etiologies of central diabetes insipidus. Acquired Tumoral: < 30 years: craniopharyngioma, germinoma; > 50 years: meta ++ Post-trauma: postoperative, post-trauma (deceleration) Inflammatory/autoimmune/granulomatous(histiocytosis in children; sarcoidosis in adults) Infectious (MTB, toxoplasmosis, HIV, meningitis, encephalitis, etc.) Ischemic or anoxic: shock, Sheehan’s syndrome Malformation syndromes, hydrocephaly, cysts, degenerative diseases Toxic (ethanol, diphenylhydantoin, snake venom) Idiopathic: repeat MRI Familial Autosomal dominant: heterozygous mutation of the AVP precursor gene/recessive: wolfram holoprosencephaly-related Idiopathic (hepatic LXR mutation?) AVP: arginin-vasopressin; LXR: liver X receptor. Predilection for the posterior lobe is traditionally attributed to its direct vascularisation by the systemic arterial system, reaching either the part that codes for the signal peptide, or more often, that which codes for neurophysin II. The five mutations described at this time result in progrssive accumulation of the hormone at the posterior pituitary, enabling.

and cystic components and when calcifications are present (visible on standard X-ray or CT scan); • a sellar or suprasellar germinoma in children or adolescents. The appearance on MRI is non-specific, but thickening of the pituitary stalk occurs early, with again absence of the hyperintensity signal of the posterior pituitary. A positive diagnosis is based on cytology studies of the cerebrospinal fluid (CSF) and assays of beta chorionic gonadotrophin hormone (␤hCG) in the CSF and serum. These three tests usually enable the biopsy to be postponed. In 90% of cases, it is a malignant but very radiosensitive tumor. When no abnormality is visible on imaging, the exams should be repeated for evidence of micro-tumors, which can become visible secondarily. Invasive suprasellar pituitary adenomas can rarely cause central DI. The polyuric-polydipsic syndrome can be masked in case of associated corticotropin deficiency and then occur during treatment with hydrocortisone. Granular cell tumors or choristomas are very rare, slowgrowing, benign neuro-pituitary tumors, which occur after the age of 40 years and present as DI, generally associated with tumor chiasmatic syndrome. MRI of the pituitary reveals significant vascularization leading to intense and homogenous contrast uptake. Lymphoma or leukemia may exceptionally be the etiology of DI. 4.1.2. Post-traumatic and postoperative DI There are 3 presentations of post-traumatic or postoperative DI: • temporary, occurring suddenly in the first 24 hours following intra-sellar surgery or trauma, and then resolving within several days (the most common);

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• permanent, associated with proximal lesions of the pituitary stalk or the hypothalamus; • triphasic, a complication especially of hypothalamic surgery via subfrontal approach, and characterized by: ◦ DI that occurs in the first 5 days, related to saturation of the neurons, with absence of normal vasopressin release, ◦ the 2nd phase between the 5th and the 7th day is characterized by remission, which is sometimes marked by the syndrome of inappropriate antidiuretic hormone secretion in relation to vasopressin release, ◦ the 3rd phase is DI that is usually definitive (except when the lesion is located below the median eminence). DI that occurs after severe head trauma generally complicates the fractures at the base of the skull or face with lesions of the cranial nerves and anterior pituitary deficit. Head trauma is complicated in 15 to 20% of cases by hypopituitarism, especially concerning the somatotropic and corticotropic hormones. Two percent of the other axes, including the posterior pituitary, are each affected. The temporary or definitive character of this DI depends on the degree of involvement of the stalk: the more the involvement is close to the hypothalamic nuclei, the later the DI resolves. The frequency of DI after endoscopic trans-sphenoidal surgery was evaluated in a series of close to 200 cases. Each of the two forms of DI, temporary or permanent, occurred in 8–9% of cases [16]. The predictive factors of these postoperative types of DI are the tumor volume and the histopathology. Cysts in the Rathke’s pouch and craniopharyngiomas are the main causes of DI. Indicators for the development of postoperative DI are postoperative serum sodium greater than or equal to 145 mmol/L and a rise in the serum sodium between the pre- and postoperative assessments greater than or equal to 2.5 mmol/L. 4.1.3. Inflammatory and immune dysfunction causes The classification of inflammatory and immune dysfunction pituitary pathologies has been re-evaluated under the generic heading of “hypophysitis” [17]. This term, which was previously reserved for postpartum hypophysitis and necrotic neuroinfundibulitis, now encompasses the other autoimmune causes, granulomatosis and inflammatory diseases. Due to the heterogeneity of these pathologies, they are classified according to: • anatomic location (adeno-, infundibulo- or panhypophysitis); • the histological exam (lymphocytic, granulomatous, xanthomatous, necrotizing, IgG4, mixed); • or the primary (isolated DI or that associated with a systemic disease) or secondary (hypothalamic-pituitary disorder, immunomodulator treatments, systemic disease) etiology. Of these causes, we will discuss autoimmune hypophysitis, necrotic lymphocytic infundibuloneuro-hypophysitis, IgG4related hypophysitis, Langerhans cell histiocytosis in children and sarcoidosis in adults. In reason of the lack of autoimmune pituitary markers in clinical practice, a diagnosis of autoimmune hypophysitis is considered as likely when the symptoms occur during the

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postpartum period or when they are associated with a personal and/or family history of autoimmune diseases. In some rare reference centers, the so-called autoimmune hypophysitis is however better characterized through the identification of pituitary antibodies [18,19]. Ninety-five patients with autoimmune hypopituitarism who were positive for pituitary antibodies (60 without and 35 with histological or radiological signs of lymphocytic hypophysitis) were compared with 20 patients with postoperative hypopituitarism and 50 normal subjects. Hypothalamic antibodies directed against CRH-secreting cells were detected in some patients with corticotropic and somatotropic deficiencies, even though these patients only presented with pituitary antibodies against growth hormone (GH)-secreting cells. In addition, the presence of vasopressin antibodies can be used to identify patients most at risk of developing central autoimmune DI. Therefore, the presence of hypothalamus antibodies in these cases of lymphocytic hypophysitis shows that autoimmune involvement is not confined to the pituitary but may also involve the hypothalamus through a specific and not uniquely inflammatory process [13]. Moreover, the presence of TPIT (a corticotropin-specific transcription factor) antibodies was also found in 10% of patients who presented with lymphocytic hypophysitis [19]. The prevalence of DI in polyendocrine disorders is extremely rare. Only one case of DI has been reported in relation with an autoimmune type 1 polyendocrinopathy (PEAI 1 or APECED [autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy]) linked to a mutation of the AIRE gene), and only one case in relation with an autoimmune type 2 polyendocrinopathy (PEAI 2) (the genetic substratum of which is multifactorial) [20–22]. The case related to PEAI 1 occurred in an 8-year-old child who presented with onychomycosis and autoimmune hepatitis before manifesting slow corticoadrenal insufficiency, then finally DI. The presence of a mutation of the exon 11 of the AIRE gene was found (c1314-1326 del13/insGT). The case related to PEAI 2 concerned a young woman with thyroiditis who had presented with hemolysis, elevated liver enzymes and low platelet count syndrome (HELLP) during a previous pregnancy. With a subsequent pregnancy, this patient demonstrated acute adrenal insufficiency after an increase in the dose of L-thyroxine, which was justified by the pregnancy. Correction of the glucocorticoid deficiency resulted in DI, which thus shows how pregnancy can reveal pre-existing but compensated endocrine disorders. Cases of posterior or total necrotic lymphocytic infundibuloneuro-hypophysitis were reported in 1993 in two young men. They had presented with central DI, partial hypopituitarism, and increased volume of the pituitary gland with thickening of the stalk on MRI. The trans-sphenoidal surgery of both these patients resulted in a necrotic creamy substance involving both pituitary lobes as well as the stalk up to the median eminence of the hypothalamus. The microscopic exam confirmed extensive necrosis, lymphoplasmocytic infiltration and perinecrotic fibrosis with only several residual islet cells from healthy gland tissue. A new concept is that of IgG4-related hypophysitis, which may occur in conjunction with autoimmune pancreatitis, or with imunomodulatory treatments such as monoclonal anti-CTLA4

antibodies. Central DI was present in nearly half of these cases of autoimmune pancreatitis or IgG4-related sclerosing pancreatitis in the presence of exocrine pancreas cell antibodies, inflammatory adenopathies and retroperitoneal fibrosis [17]. The diagnosis of IgG4-related hypophysitis is based on the presence of major histopathological criteria (mononuclear infiltration of the pituitary gland, rich in lymphocytes and plasma cells, with more than 10 IgG4-positive cells per high-power field) or on the combination of radiological suspicion (sellar mass and/or thickened pituitary stalk) and a positive IgG4 histological lesion in another organ, or radiological suspicion with an IgG4 serum level > 140 mg/L and a response to glucocorticoids. Langerhans cell histiocytosis is a cause of DI and is a presenting sign in over 30% of cases, particularly in children. It frequently has a systemic scope and occurs as part of a classical triad in combination with exophthalmia and lytic bone lesions. Anterior hypopituitarism and delayed puberty are often present from the time of the diagnosis or may appear later (75% of anterior hypopituitarism cases are noted 3 years after the diagnosis). MRI reveals thickening of the pituitary stalk, absence of the spontaneous hyperintensity of the posterior pituitary and sometimes a tumor-like appearance. The mechanisms of histiocytosis remain unknown, and its prognosis is very heterogeneous. An activating BRAF(V600E) mutation was recently observed in 55% of cases of Langerhans cell histiocytosis or Erdheim-Chester disease, while this mutation was not present in other types of histiocytosis. In a series of 54 cases, the occurrence of the triad (central DI, hyperprolactinemia and thickening of the pituitary stalk) preceded the characteristic lytic bone lesions from 4 to 9 years in close to 10% of Langerhans cell histiocytosis cases [23]. Adult sarcoidosis, which is characterized by skin, bone and/or lung involvement, can be complicated by central DI or much more rarely by nephrogenic DI or primary polydipsia. In a multicenter series [24] of 24 patients (10 women and 14 men) who presented with hypopituitarism secondary to sarcoidosis, the median age at the diagnosis of sarcoidosis was 31 years (range 8 to 69 years). The presence of sarcoidosis was known before central DI appeared in close to 50% of cases. Practically, all the patients presented with anterior pituitary dysfunction, primarily gonadotropic (n = 21), then thyrotropic (n = 15) or finally hyperprolactinemia or DI (n = 12). The MRI showed an abnormal pituitary gland in 14 cases, thickening of the stalk in 12 cases, and infundibular involvement in 8 cases. Following corticosteroid therapy and a mean 4-year follow-up, the MRI abnormalities improved or resolved in over 50% of cases, unlike the hormonal deficiencies, thus demonstrating the absence of correlation between hormonal dysfunction and radiological findings. Patients with hypothalamic-pituitary sarcoidosis presented more frequently with sinus locations and required systemic treatment more often than patients who did not have pituitary sarcoidosis. 4.1.4. Central diabetes insipidus of infectious origin Tuberculosis, toxoplasmosis, meningococcal encephalitis and HIV infections may also be the cause of central DI, sometimes via a pituitary abscess, which then results in anterior hypopituitarism. These forms can completely resolve after treatment of the causative infection.

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4.1.5. Central diabetes insipidus of ischemic origin Sheehan syndrome following postpartum hemorrhage is the perfect example of cardiovascular collapse that can lead to hypopituitarism. However, some cases of hypopituitarism that are attributed to Sheehan syndrome (hemorrhage at delivery, absence of milk let-down, secondary amenorrhea), could also correspond to postpartum hypophysitis [25]. Cerebral or hypothalamic hemorrhaging through aneurysm rupture of the anterior communicating artery can also be the cause of central DI. 4.1.6. Other causes Malformation syndromes (hydrocephalus, cysts, degenerative diseases), toxic substances (ethanol, diphenylhydantoin, some snake venoms) can also be the cause of acquired central DI. If no cause has been identified and the pituitary MRI is normal, repeat imagery is required due to the possible secondary appearance of images consistent with germinoma or sarcoidosis. 4.2. Familial central DI Familial central DI may be related to a vasopressin gene mutation, DIDMOAD syndrome or syndromic holoprosencephaly [26]. 4.2.1. Mutations of the arginin-vasopressin neurophysin-II gene Heterozygote mutations of the arginin-vasopressin neurophysin-II gene located on chromosome 20 result in most of the time autosomal dominant isolated DI. It appears between 6 months and 15 years, and progressively worsens. Over 60 mutations have been described, particularly at the exon that codes for neurophysin-II. These mutations lead to a defect in the maturation of vasopressin with synthesis of an abnormal protein that remains imprisoned in the endoplasmic reticulum, where it accumulates and causes neuronal degeneration. The spontaneous hyperintensity on the T1 pituitary MRI is usually maintained, but is absent at times [27,28]. This DI is very sensitive to desmopressin. The diagnosis should be considered in the event of severe dehydration episodes, which if repeated can result in growth delay and even mental retardation. Megalocystis or ureterohydronephrosis may also occur. Rare autosomal recessive forms with early polyuria from the first week of life and X-related forms have also been reported. 4.2.2. DIDMOAD or Wolfram syndrome Wolfram syndrome, which is still referred to by the acronym DIDMOAD, combines insulin-dependent diabetes (diabetes mellitus or DM) due to a loss of ␤ cells, and bilateral, progressive optic atrophy (OA), which are two mandatory parts of the diagnosis. Central DI and perceptive deafness (D) combine with the two previous manifestations in slightly over 50% of cases. Finally, urinary tract abnormalities, possibly secondary to the severity of the polyuria but also to innervation abnormalities create a wider neurological scope (psychiatric disorders, mental retardation, dementia) and can lead to early death.

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Central DI is often partial, progressive and therefore inconsistent. It has to be distinguished from polyuria related to diabetes and can be complicated by hyperosmolar coma. Atrophy of the optic nerves can be seen on MRI, as well as frequently of the hypothalamus, the cerebellum and the brain. This suggests that Wolfram syndrome is a hereditary degenerative form of recessive autosomal transmission, since consanguinity is found in 30% of cases. Wolfram syndrome is classified as type 1 (WFS1) or type 2 (WFS2). WFS1, which is the only to be associated with DI, is related to a mutation of wolframin, an endoglycosidase of the neuronal endoplasmic reticulum, which is coded by a gene located on chromosome 4p16.1. WFS2 combines diabetes mellitus, optic atrophy and early deafness with decreased longevity and without DI. It is linked to a mutation of the CISD2 gene [29–31]. 4.2.3. Mutations in genes encoding hypothalamo-pituitary transcription factors Mutations in genes encoding several hypothalamo-pituitary transcription factors result in hypopituitarism [isolated GH deficiency and combined pituitary hormone deficiency. The presence of optic nerve hypoplasia was significantly associated with an absent septum pellucidum, an abnormal corpus callosum, stalk abnormalities, and diabetes insipidus, as well as thyrotrophin and ACTH deficiencies [32]. 4.2.4. Syndromic holoprosencephaly with normal karyotype Holoprosencephaly syndromes are complex brain malformations that include facial anomalies, mental retardation, and neurological disorders [33]. Endocrine disorders (DI, adrenal or thyroid hypoplasia, hypogonadism, growth hormone deficiency) are common. These syndromes encompass about 20 entities, including for example 1) CHARGE syndrome (acronym including coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, ear anomalies/deafness) (OMIM 214750); 2) Pallister-Hall syndrome, related to a mutation of the gli3 7p13 gene (OMIM 146510); 3) SmithLemli-Opitz syndrome (OMIM 270400); 4) Rubinstein-Taybi syndrome (related to a mutation of the CREBBP gene on chromosome 16p11.3; OMIM 180849); 5) Meckel syndrome (OMIM 249000); 6) pseudotrisomy 13 (OMIM 264480); 7) velocardiofacial syndrome (related to a mutation of the TBX1 22q11.2 gene; OMIM 192430). . . 4.2.5. LXR mutation (liver X receptor) Central DI due to an expression anomaly of renal aquaporin1 has only been reported up till now in mice with an inactivated LXR␤ receptor [6]. 4.3. Treatment of central DI In the event of dehydration, complete central DI may require urgent treatment with intravenous glucose solution or possibly pure water per feeding tube combined with dDAVP injection. dDAVP is a synthetic vasopressin analogue, with more antidiuretic and less vasopressive properties than natural vasopressin.

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Its half-life is of 3 hours and duration of action of 8 hours. Monitoring of the diuresis and serum sodium should be done twice daily at the initiation of treatment, followed by once daily [34]. Desmopressin can be given as an injection (1 to 2 ␮g, one or two times daily) or via endonasal route as a spray (5 to 20 ␮g, two to three times per day, with each spray providing 10 ␮g). Absorption may be difficult with this method due both to the endonasal administration and to possible intercurrent rhinitis. The most used and only oral form is a lyophilisate of 60, 120 or 240 ␮g, which is usually administered at 60 to 120 ␮g, 2 to 3 times per day. This lyophilisate is also the most expensive. This medication is not contraindicated during pregnancy. This treatment is usually started at the smallest dosage of 60 ␮g, twice daily, and progressively increased in the evening until there is no longer nocturnal miction. Signs of water intoxication (headaches, nausea, confusion) should be explained to the patient. Treatment should be stopped if they occur until polyuria returns. In order to avoid chronic hyponatremia, it is sometimes recommended that one dose or a half-dose be skipped once per week. Serum sodium should be monitored in case of undiagnosed corticotropin insufficiency. Clofibrate and chlorpropamide, which are traditional treatments for partial central DI, are no longer marketed in France. Carbamazepine (200 to 600 mg per day) might stimulate the vasopressin secretion and its renal action. It may be useful in cases with associated seizures. 5. Etiology of nephrogenic diabetes insipidus 5.1. Acquired forms Acquired nephrogenic DI forms are generally less severe than the familial forms and may be related to a kidney disorder, metabolic disturbances or an iatrogenic cause (Table 3) [35]. 5.1.1. Kidney disorders Nephrogenic DI may be due to kidney failure (both acute and chronic), kidney transplantation outcomes, liver and kidney polycystosis, obstructive nephropathy, myeloma, renal sarcoidosis, Sjögren’s syndrome, amylose, Fanconi syndrome and drepanocytosis via a vascular mechanism. 5.1.2. Metabolic disturbances Some metabolic disturbances, such as hypercalcemia and hypokalemia, lead to a temporary negative down regulation of aquaporin 2 through resistance to vasopressin (even though hypercalcemia may initially be the cause of hypertonic polyuria). 5.1.3. Iatrogenic causes Many drugs, particularly chemotherapy and systemic antifungal treatments, can promote the occurrence of nephrogenic DI (Table 3). Of these treatments, lithium was the cause in 12 to 30% of observed cases. This treatment could lead to a defect in the formation of cyclic adenosine monophosphate (AMP) and aquaporin 2 by AVP in the collecting ducts, as well as anomalies in the production of prostaglandin 2. Secondarily, it induces chronic tubulo-interstitial alterations, sometimes with

Table 3 Etiologies of nephrogenic diabetes insipidus. Familial forms Acquired forms, less severe Kidney disorders (defect of aquaporin 1, 2 and 3 expression) Acute and chronic kidney failure, post-kidney transplantation Kidney polycystosis, obstructive nephropathy Myeloma, sarcoidosis, amyloidosis Sjögren’s syndrome, Fanconi syndrome Vascular (drepanocytosis) Metabolic disturbances (temporary negative feedback of aquaporin 2) Hypercalcemia (+ associated with defect of aquaporin 1 and 3 expression and NKCC2) Hypokalemia (++ associated with defect of NKCC2 expression) Iatrogenic Demeclocycline (transient isolated tubular dysfunction; used to treat SIADH) Methoxyflurane Sulfonylureas Colchicine Vinblastine, cisplatin, cyclophosphamide, ifosfamide (associated Fanconi syndrome) Amphotericin B (antimycotic; reversible associated distal tubular acidosis) Foscarnet (anti-cytomegalovirus) Lithium+++ 12 to 40% of cases NKCC2: Na-K-Cl cotransporter; SIADH: syndrome of inappropriate secretion of vasopressin.

a definitive form of potentially severe DI. The distinctive feature of nephrogenic DI induced by lithium is the preservation of the hemodynamic and procoagulant response to dDAVP. The persistence of this response suggests resistance to vasopressin confined to the kidneys, since this response, attributed to the existence of extra-renal V2 receptors, provides evidence of the normalcy of those outside the kidney parenchyma. 5.2. Familial nephrogenic diabetes insipidus [36,37] 5.2.1. Mutation of the vasopressin V2 receptor gene Unlike familial central DI, familial nephrogenic DI begins in the neonatal period. The preservation of the posterior pituitary hyperintensity signal, since vasopressin is secreted in normal quantities, does not appear as a very specific sign. Most of these DI is transmitted in a X-linked recessive manner and are related to a mutation of the vasopressin V2 receptor gene, for which over 200 mutations have been reported. Phenotypes of partial DI have been described according to the type of mutation. Some mutations result in decreased affinity of vasopressin for the receptor; others result in an abnormality of intracellular trafficking, and some others in a decrease of the receptor transcription. 5.2.2. Mutation of the aquaporin 2 gene In more rare instances, autosomal recessive forms through homozygous mutation of the aquaporin gene have been reported. About 50 different mutations have been reported that affect either the transportation of aquaporin to the membrane or directly affect the formation of the water channel. Ten percent of cases of autosomal nephrogenic DI occur through dominant

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Table 4 Treatment of nephrogenic diabetes insipidus. Currently available Water supplementation (> 200 ml/kg) Hypo-osmotic diet: 1 mmol Na, 2–3 mmol K, 2–3 g protein/kg/day (breast milk) Thiazides (hydrochlorothiazide: 2–4 mg/kg/day) (increases expression of aquaporin 2) Combined with amiloride (20 mg/1.73 m2 /day) Modification of the renin-angiotensin system by spironolactone, angiotensin conversion enzyme (ACE) inhibitors (captopril) or angiotensin II receptor antagonists (candesartan) Indomethacin: 0.5 to 3mg/kg/day in 2 administrations, with meals; monitor urine BUN, protein Future V2 receptor antagonists/agonists likely to re-establish intracellular trafficking of certain V2 mutants Non-peptide V1, a receptor antagonists to refold some specific AVPR2 mutants EP2 and EP4 prostanoid receptor agonists or phosphodiesterase-5 inhibitors likely to activate aquaporin 2 by short-circuiting the vasopressin V2 receptor Increasing cGMP or inhibiting cAMP degradation Inhibition of the Hsp90 molecular chaperone (release of AQP2 from the endoplasmic reticulum) AQP2: aquaporin2; cGMP: cyclic guanosine monophosphate; BUN: blood urea nitrogen.

transmission and are also related to a mutation of aquaporin 2 in the C-terminal part of the gene. In all cases, the usual early occurrence of severe dehydration episodes created by nephrogenic DI and their neurological consequences justifies molecular diagnosis and genetic counseling for future pregnancies. Molecular diagnosis is also recommended in children with unexplained thickening of the pituitary stalk, even in the absence of family history. Finally, the phenotype of familial DI should be regularly reassessed since it may change according to age, especially because the renal ability to concentrate urine is reached progressively.

throughout its entire period, a decrease in the plasma osmolality of around 10 mOsmol/kg can be observed, while the mean serum sodium decreases slightly to around 135 ± 3 mmol/L. There is a joint decrease in the thirst threshold and the vasopressin secretion level, which results in hemodilution. Finally, a decrease in the metabolic clearance of vasopressin appears from the 2nd trimester in relation to placental vasopressinase secretion. Measurement of vasopressin during pregnancy requires the use of phenanthroline, which is a vasopressinase inhibitor. The performance of a water deprivation test during pregnancy is always difficult and requires fetal monitoring.

5.3. Treatment of nephrogenic diabetes insipidus

6.2. Classification

The main treatments for nephrogenic DI are shown in Table 4. The non-peptide V2 receptor antagonists would likely reestablish the intracellular trafficking of certain vasopressin V2 receptor mutants, but they are currently unavailable in France. Non-peptide V1a receptor antagonists have been used successfully to refold some specific V2 receptor mutants but these compounds have not been developed further by the pharmaceutical industry [38]. Considering the purely renal mechanism of these types of DI, the evolution to end stage renal failure that results in hemodialysis and especially kidney transplantation might represent a “healing” mode for nephrogenic DI, especially those induced by lithium, in the way that the exhausting polyuria-polydipsia syndrome disappears, leading to an improvement of the quality of life despite the burden of dialysis or immunosuppressive regimen. Nevertheless, with appropriate early “double voiding” patients with hereditary nephrogenic diabetes insipidus should not develop dilation of their urinary tract and progressive renal failure [39]. 6. Gestational diabete insipidus 6.1. Physiopathology Knowledge of the pathophysiology of water metabolism during pregnancy is essential to understanding gestational DI, which is extremely rare [40]. From the first weeks of gestation and

Gestational DI is classified according to its date of appearance relative to the pregnancy. DI can therefore: • be central, or more rarely, nephrogenic, pre-existing to the pregnancy; • occur during pregnancy; • or finally, occur in the postpartum period. 6.3. Pre-existing diabetes insipidus DI that exists before the pregnancy does not pose any particular diagnostic problem. The need for desmopressin increases in the 3rd trimester and decreases during lactation. 6.4. Diabetes insipidus occurring during pregnancy DI that occurs during pregnancy can be a central or partial nephrogenic DI that will be revealed in the 2nd trimester due to the increased metabolic clearance of vasopressin. But it can also correspond to a special mechanism: pure gestational DI is usually transient and sometimes recurs in subsequent pregnancies. It occurs in the 3rd trimester in relation to an increased secretion of placental vasopressinase. It is resistant to AVP (since it is degraded by placental vasopressinase) but is sensitive to desmopressin acetate (dDAVP, not degraded by placental vasopressinase). It is sometimes difficult to distinguish from urinary

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frequency at the end of pregnancy, and it resolves very quickly after delivery. It is more common in twin pregnancies due to the large placental volume. One case was recently reported after placental abruption, which enabled the mechanism relative to vasopressinase secretion to be confirmed [41]. Otherwise, gestational DI may be the presenting symptom for a liver function abnormality (acute steatosis, pre-eclampsia, HELLP syndrome). These rare pregnancy pathologies activate hepatic vasopressinase and therefore precipitate the degradation of AVP. 6.5. Postpartum diabetes insipidus The occurrence of postpartum DI should also prompt investigation of hemorrhagic Sheehan syndrome, lymphocytic hypophysitis or a hypothalamic-pituitary tumor. 7. Primary polydipsia Primary polydipsia or dipsogenic polydipsia suggests an organic hypothalamic involvement of the thirst threshold and can occur in association with central DI. Much more common than primary polydipsia, the functional or so-called psychogenic polyuric-polydipsic syndromes which are also called potomania, result in inhibition of vasopressin secretion through inflation of the extracellular fluid. Such inhibition creates an induced (or “functional”) DI which is associated with reduced efficacy of the renal cortical medullary concentration gradient. Thirst is sometimes worsened by iatrogenic mouth dryness, especially related to the use of psychotropic drugs. An acute dipsogenic access or compulsive drinking water may complicate a functional polyuro-polydipsic syndrome, resulting in transient but often severe hyponatremia. Clinical and laboratory evidence that is suggestive of primary polydipsia are: • polyuric-polydipsic syndrome with progressive onset; • a history of psychiatric affective disorders; • plasma osmolality that is often lower than in organic central DI. Finally, the posterior pituitary hyperintensity is persistent on MRI, unlike in central DI. Water deprivation testing results show a late increase in urine osmolality, which remains submaximal and does not increase after desmopressin is given. Vasopressin measurements and the hypertonic saline infusion test are sometimes necessary to differentiate primary polydipsia from partial central DI. 8. Conclusion Finally, hypotonic polyuria, urine osmolality greater than 750 should lead to the diagnosis of moderate primary polydipsia. If the urine osmolality is less than 250 mosmol/kg with natremia above 145mmol/L, DI is confirmed. A low AVP, blood level orientates towards a central origin, a high level towards a nephrogenic origin. If the AVP level is not available, a desmopressin challenge test should be done. If the urine osmolality rises after

Table 5 Etiological diagnostic approach to diabetes insipidus. Monitoring of fluid intake and output Daily blood and urine electrolytes Plasma and urine osmolality + AVP or copeptin ± Water deprivation test Anterior pituitary hormone work-up (corticotrope ++) MRI Family history of autoimmune diseases or diabetes insipidus Obvious context (surgery, trauma, cancer, granulomatosis, pregnancy) Non-obvious context (isolated diabetes insipidus) Testing of antibodies, immunoglobulin quantification Conversion enzyme Blood ␤HCG and CSF Serological testing for HIV, toxoplasmosis, CMV, MTB (blood and CSF ± abnormal cells) Thorax, bronchoalveolar lavage, bone scintigraphy ± biopsy (histiocytosis) Pituitary biopsy Mammography, chest CT, coloscopy AVP: arginin-vasopressin; MRI: magnetic resonance imaging; CSF: cerebrospinal fluid; CMV: cytomegalovirus; ␤HCG: beta chorionic gonadotrophin hormone.

desmopressin more than 50%, complete central DI is suggested; an increase of less than 50% indicates complete nephrogenic DI. When the urine osmolality is between 250 and 750 and then increases by less than 50% after desmopressin, the differential diagnosis between primary polydipsia, central DI and partial nephrogenic DI is made according to the clinical context and MRI imaging. Water deprivation should only be undertaken if the etiological diagnosis is not clarified by the nocturnal occurrence of the polyuric-polydipsic syndrome, pituitary MRI, hormonal work-up, systemic signs, and the potential hereditary nature of the DI. Copeptin measurement has currently not demonstrated superiority compared to the vasopressin assay or the desmopressin challenge test (Table 5). In terms of etiology, the diagnosis of autoimmune, inflammatory and granulomatous hypophysitis is progressively improving since the identification of auto-antibodies and new mechanisms such as IgG4-related hypophysitis. In addition, a number of genetic causes are now identified, even though these forms are still rare. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Vantyghem MC, Balavoine AS, Wémeau JL, Douillard C. Hyponatremia and antidiuresis syndrome. Ann Endocrinol (Paris) 2011;72:500–12. [2] Bourque CW. Central mechanisms of osmosensation and systemic osmoregulation. Nat Rev Neurosci 2008;9(7):519–31. [3] Lechner SG, Markworth S, Poole K, Smith ES, Lapatsina L, Frahm S, et al. The molecular and cellular identity of peripheral osmoreceptors. Neuron 2011;69:332–44. [4] Bichet DG, Arthus MF, Lonergan M. Platelet vasopressin receptors in patients with congenital nephrogenic diabetes insipidus. Kidney Int 1991;39:693–9.

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