Disponible en ligne sur

ScienceDirect
www.sciencedirect.com

Annales d’Endocrinologie 74 (2013) 496–507

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 hyper-
or 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: mc-vantyghem@chru-lille.fr (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
 C. Leroy et al. / Annales d’Endocrinologie 74 (2013) 496–507 497

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 Additionally, non-osmotic stimuli, particularly a variation in

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:
blood volume over 10%, are also capable of stimulating vaso-
pressin 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 neuro-
mediators.
2.2. Vasopressin synthesis
A precursor of AVP synthesis, neurophysin-vasopressin pro-
hormone, 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 neu-
rons, which secrete both AVP and corticotropin-releasing
hormone (CRH) and have their nerve terminals at the median
eminence.

• glycosuria; 2.3. Vasopressin secretion

• 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% stimu-
lates osmotic receptors that were recently identified both in the
hypothalamus (TRPV1 - transient receptor potential vanilloid 1)
[2] and the portal vein (TRPV4) [3].
Vasopressin, which is released after stimulation of the poste-
rior 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 activat-
ing 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 secre-
tion 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 concen-
tration such as aquaporin 3, Na-K-Cl cotransporter (NKCC2)
and urea transporters [8,9].
498 C. Leroy et al. / Annales d’Endocrinologie 74 (2013) 496–507
Fig. 1. Regulation of water metabolism.
3. Diagnosis
3.1. General considerations
The diagnosis of DI is based on the observation of a signifi-
cant 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 gen-
erates 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 replace-
ment.
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 mea-
surement of vasopressin and other biomarkers of central DI. The
presence of vasopressin can be indirectly assessed by a sponta-
neous 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 pop-
ulation, 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 famil-
ial background to address the possible hereditary nature of the
disorder.
 C. Leroy et al. / Annales d’Endocrinologie 74 (2013) 496–507 499

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 spe-
cific 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 associ-
ated 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 Fluids stopped at 20:00, midnight or 06:00
with tobacco intoxication (sagittal slice of T1-weighted magnetic resonance At 08:00
imaging). Weight, intake/output, blood pressure (BP)
Serum sodium, plasma and urine osmolality (Osm)
The next step is based on measurements of weight, blood Every hour from 09:00 to 16:00
pressure and the quantification of beverages and diuresis over Weight, heart rate, intake/output, BP
Plasma and urine Osm
a 24-hour cycle. Examination should focus on signs of dehy-
dration, possible bladder distention, anterior pituitary hormone End of fluid restriction at 17:00
hyper- or hyposecretion, tumoral syndrome (headache, bitempo- Weight, heart rate, BP and urine volume
Serum sodium, plasma and urine Osm
ral hemianopsia, diplopia), and systemic signs of granulomatosis
or cancer. 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
3.3. Baseline laboratory diagnostic testing
Following day at 08:00
Weight, intake/output, BP
The laboratory diagnosis of DI is based on: Plasma and urine Osm and serum sodium
Test stopped if weight loss > 3–5% of baseline weight
• urine specific density less than 1005; Increase of urine Osm < 30 mOsm/kg for 2 consecutive hours, urine
• urine osmolality less than 250 mOsmol/kg of water; Osm > 750 mOsm/kg
• a markedly positive free water clearance which demonstrates Plasma Osm > 145–148 (sufficient for AVP stimulation > 3.5 ng/mL
and urine Osm > 750)
failure of urinary concentration mechanisms. This last calcu-
lation has interest mainly in clinical research. AVP: arginin-vasopressin.

Free water clearance is the quantity of water that must be Table 1b

added or subtracted from the urine to result in isoosmotic Interpretation criteria.
excretion to the plasma. It is calculated as follows: free water Urine Osm at end % of increase in
clearance (CH2O = V × 1–urine osmolality/plasma osmolality), of test (mOsm/kg) urine Osm after
with V = urine output in mL/min over a given time. Also, plasma dDAVP (2 ␮g IM)
osmolaliry may be calculated using the formula: OsmP = 2 Normal subjects > 750 < 9%
(natremia + kalemia) + blood glucose + blood urea (all values Complete CDI < 250 > 50%
expressed in mmol/L). Partial CDI 250–750 > 10%
Complete NDI < 250 0
In conditions of free water access, blood electrolytes levels Partial NDI 250–750 0
are normal in DI. Nevertheless, morning fasting sodium levels Primary polydipsia 250–750 < 9%
are often slightly elevated. Therefore, if urine osmolality is less AVP and plasma osmolality at end of test (46% diagnostic specificity)
than 200 mOsmol/kg with serum sodium over 145 mmol/L, DI dDAVP test
is confirmed, and the water deprivation test is not useful and Other tests: blood copeptin; hypertonic saline infusion test
even dangerous. A low plasma concentration of vasopressin AVP: arginin-vasopressin; CDI: central diabetes insipidus; NDI: nephrogenic
provides evidence of central DI; in nephrogenic DI, serum diabetes insipidus; IM: intra-muscular; dDAVP: desmopressine.
500 C. Leroy et al. / Annales d’Endocrinologie 74 (2013) 496–507
disputed since the measurement of AVP and plasma osmola-
lity at the end of the test raises low diagnostic specificity (less
than 50%). There are individual variations in the osmoregula-
tion 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 pro-
posed 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 pre-
cursor 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 diagno-
sis of primary polydipsia, partial central DI and complete DI.
There is however no gold standard for comparing the sensitiv-
ity 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 condi-
tions, 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 stimula-
tion 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, stim-
ulation 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 physiopatholo-
gical interest. The easiest test to perform is the measurement
of vasopressin in lying, then standing positions, with concom-
itant 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 associa-
tion 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 sug-
gests metastasis or craniopharyngioma and before the age of
30 years a germinoma or a craniopharyngioma. This DI is fre-
quently 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 sus-
pected 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 vascu-
larisation 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 hyper-
intensity 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 visi-
ble on imaging, the exams should be repeated for evidence of
micro-tumors, which can become visible secondarily.
Invasive suprasellar pituitary adenomas can rarely cause cen-
tral 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, slow-
growing, 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 signifi-
cant 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 follow-
ing intra-sellar surgery or trauma, and then resolving within
several days (the most common);
501
• 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 charac-
terized 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 postopera-
tive 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 postopera-
tive 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 neuro-
infundibulitis, now encompasses the other autoimmune causes,
granulomatosis and inflammatory diseases. Due to the hetero-
geneity of these pathologies, they are classified according to:
• anatomic location (adeno-, infundibulo- or panhypophysitis);
• the histological exam (lymphocytic, granulomatous, xan-
thomatous, necrotizing, IgG4, mixed);
• or the primary (isolated DI or that associated with a sys-
temic disease) or secondary (hypothalamic-pituitary disorder,
immunomodulator treatments, systemic disease) etiology.
Of these causes, we will discuss autoimmune hypophysitis,
necrotic lymphocytic infundibuloneuro-hypophysitis, IgG4-
related 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
502 C. Leroy et al. / Annales d’Endocrinologie 74 (2013) 496–507
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 pitu-
itary 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 dys-
trophy]) linked to a mutation of the AIRE gene), and only one
case in relation with an autoimmune type 2 polyendocrinopa-
thy (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 hep-
atitis 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 pre-
sented 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 infil-
tration 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 pan-
creatitis 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 pre-
senting sign in over 30% of cases, particularly in children. It fre-
quently has a systemic scope and occurs as part of a classical triad
in combination with exophthalmia and lytic bone lesions. Ante-
rior 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 sponta-
neous 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 histiocy-
tosis. 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 mul-
ticenter 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 hyper-
prolactinemia 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 abnormali-
ties improved or resolved in over 50% of cases, unlike the
hormonal deficiencies, thus demonstrating the absence of corre-
lation 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, some-
times via a pituitary abscess, which then results in anterior
hypopituitarism. These forms can completely resolve after treat-
ment of the causative infection.
 C. Leroy et al. / Annales d’Endocrinologie 74 (2013) 496–507
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 deliv-
ery, 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, degenera-
tive 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 nor-
mal, 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 muta-
tion, 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, pro-
gressive 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 abnormal-
ities create a wider neurological scope (psychiatric disorders,
mental retardation, dementia) and can lead to early death.
503
Central DI is often partial, progressive and therefore inconsis-
tent. 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 reces-
sive 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 mel-
litus, 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 associ-
ated 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 malfor-
mations 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 includ-
ing 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) Smith-
Lemli-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 aquaporin-
1 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 antidi-
uretic and less vasopressive properties than natural vasopressin.
504 C. Leroy et al. / Annales d’Endocrinologie 74 (2013) 496–507
Its half-life is of 3 hours and duration of action of 8 hours. Mon-
itoring 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 intoxi-
cation (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 treat-
ments 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 sar-
coidosis, 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 anti-
fungal 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 fea-
ture 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 muta-
tions 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
 C. Leroy et al. / Annales d’Endocrinologie 74 (2013) 496–507 505

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 con-
sequences justifies molecular diagnosis and genetic counseling
for future pregnancies. Molecular diagnosis is also recom-
mended in children with unexplained thickening of the pituitary
stalk, even in the absence of family history. Finally, the pheno-
type 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 secre-
tion 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. Mea-
surement of vasopressin during pregnancy requires the use of
phenanthroline, which is a vasopressinase inhibitor. The perfor-
mance 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.
Gestational DI is classified according to its date of appearance
The non-peptide V2 receptor antagonists would likely re-
relative to the pregnancy. DI can therefore:
establish the intracellular trafficking of certain vasopressin V2
receptor mutants, but they are currently unavailable in France.
• be central, or more rarely, nephrogenic, pre-existing to the
Non-peptide V1a receptor antagonists have been used success-
pregnancy;
fully to refold some specific V2 receptor mutants but these
• occur during pregnancy;
compounds have not been developed further by the pharma-
• or finally, occur in the postpartum period.
ceutical industry [38].
Considering the purely renal mechanism of these types of DI,
6.3. Pre-existing diabetes insipidus
the evolution to end stage renal failure that results in hemodial-
ysis and especially kidney transplantation might represent a
DI that exists before the pregnancy does not pose any partic-
“healing” mode for nephrogenic DI, especially those induced
ular diagnostic problem. The need for desmopressin increases
by lithium, in the way that the exhausting polyuria-polydipsia
in the 3rd trimester and decreases during lactation.
syndrome disappears, leading to an improvement of the qual-
ity of life despite the burden of dialysis or immunosuppressive
regimen. Nevertheless, with appropriate early “double voiding” 6.4. Diabetes insipidus occurring during pregnancy
patients with hereditary nephrogenic diabetes insipidus should
not develop dilation of their urinary tract and progressive renal DI that occurs during pregnancy can be a central or partial
failure [39]. nephrogenic DI that will be revealed in the 2nd trimester due to
the increased metabolic clearance of vasopressin. But it can also
6. Gestational diabete insipidus correspond to a special mechanism: pure gestational DI is usu-
ally transient and sometimes recurs in subsequent pregnancies.
6.1. Physiopathology It occurs in the 3rd trimester in relation to an increased secre-
tion of placental vasopressinase. It is resistant to AVP (since
Knowledge of the pathophysiology of water metabolism dur- it is degraded by placental vasopressinase) but is sensitive to
ing pregnancy is essential to understanding gestational DI, which desmopressin acetate (dDAVP, not degraded by placental vaso-
is extremely rare [40]. From the first weeks of gestation and pressinase). It is sometimes difficult to distinguish from urinary
506 C. Leroy et al. / Annales d’Endocrinologie 74 (2013) 496–507
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, ges-
tational DI may be the presenting symptom for a liver function
abnormality (acute steatosis, pre-eclampsia, HELLP syndrome).
These rare pregnancy pathologies activate hepatic vasopressi-
nase 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 inhi-
bition creates an induced (or “functional”) DI which is associated
with reduced efficacy of the renal cortical medullary concentra-
tion 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 com-
plicate 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 dif-
ferentiate 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 nephro-
genic 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: cere-
brospinal 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 desmo-
pressin challenge test (Table 5).
In terms of etiology, the diagnosis of autoimmune, inflamma-
tory 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.
 C. Leroy et al. / Annales d’Endocrinologie 74 (2013) 496–507
[5] Sasaki S. Aquaporin 2: from its discovery to molecular structure and medi-
cal implications. Mol Aspects Med 2012;33:535–46.
[6] Gabbi C, Kong X, Suzuki H, Kim HJ, Gao M, Jia X, et al. Central dia-
betes insipidus associated with impaired renal aquaporin-1 expression in
mice lacking liver X receptor ␤. Proc Natl Acad Sci U S A 2012;109:
3030–4.
[7] Bichet DG, Razi M, Lonergan M, Arthus MF, Papukna V, Kortas C,
Barjon JN. Hemodynamic and coagulation responses to 1-desamino[8-
D-arginine]–vasopressin (dDAVP) infusion in patients with congenital
nephrogenic diabetes insipidus. N Engl J Med 1988;318:881–7.
[8] Fenton RA. Essential role of vasopressin-regulated urea transport processes
in the mammalian kidney. Pflugers Arch 2009;458:169–77.
[9] Fenton RA, Knepper MA. Mouse models and the urinary concentrating
mechanism in the new millennium. Physiol Rev 2007;87:1083–112.
[10] Fenske W, Allolio B. Clinical review: Current state and future perspectives
in the diagnosis of diabetes insipidus: a clinical review. J Clin Endocrinol
Metab 2012;97:3426–37.
[11] Ranadive SA, Ersoy B, Favre H, Cheung CC, Rosenthal SM, Miller
WL, Vaisse C. Identification, characterization and rescue of a novel
vasopressin-2 receptor mutation causing nephrogenic diabetes insipidus.
Clin Endocrinol (Oxf) 2009;71:388–93.
[12] Zerbe RL, Robertson GL. A comparison of plasma vasopressin measure-
ments with a standard indirect test in the differential diagnosis of polyuria.
N Engl J Med 1981;305:1539–46.
[13] Scantamburlo G, Hansenne M, Fuchs S, Pitchot W, Pinto E, Reggers
J, Ansseau M, Legros JJ. AVP- and OT-neurophysins response to apo-
morphine and clonidine in major depression. Psychoneuroendocrinology
2005;30:839–45.
[14] Fenske W, Quinkler M, Lorenz D, Zopf K, Haagen U, Papassotiriou J,
et al. Copeptin in the differential diagnosis of the polydipsia-polyuria
syndrome–revisiting the direct and indirect water deprivation tests. J Clin
Endocrinol Metab 2011;96:1506–15.
[15] Bodineau L, Hus-Citharel A, Llorens-Cortes C. Contribution of apelin to
water balance, blood glucose control, and cardiovascular functions. Ann
Endocrinol (Paris) 2010;71:249–56.
[16] Schreckinger M, Walker B, Knepper J, Hornyak M, Hong D, Kim JM, et al.
Post-operative diabetes insipidus after endoscopic transsphenoidal surgery.
Pituitary 2013;16:445–51.
[17] Leporati P, Landek-Salgado MA, Lupi I, Chiovato L, Caturegli P. IgG4-
related hypophysitis: a new addition to the hypophysitis spectrum. J Clin
Endocrinol Metab 2011;96:1971–80.
[18] De Bellis A, Sinisi AA, Pane E, Dello Iacovo A, Bellastella G, Di Scala G,
et al. Involvement of hypothalamus autoimmunity in patients with autoim-
mune hypopituitarism: role of antibodies to hypothalamic cells. J Clin
Endocrinol Metab 2012;97:3684–90.
[19] Smith CJA, Bensing S, Burns C, Robinson PJ, Kasperlik-Zaluska AA,
Scott RJ, et al. Identification of TPIT and other novel autoantigens in lym-
phocytic hypophysitis: immunoscreening of a pituitary cDNA library and
development of immunoprecipitation assays. Eur J Endocrinol 2012;166:
391–8.
[20] Lintas C, Cappa M, Comparcola D, Nobili V, Fierabracci A. An 8-year-old
boy with autoimmune hepatitis and Candida onychosis as the first symp-
toms of autoimmune polyglandular syndrome (APS1): identification of a
new homozygous mutation in the autoimmune regulator gene (AIRE). Eur
J Pediatr 2008;167:949–53.
[21] Krysiak R, Samborek M. Coexistence of autoimmune polyglandular
syndrome type 2 and diabetes insipidus in pregnancy. Am J Med Sci
2011;342:433–4.
[22] Kahaly GJ. Polyglandular autoimmune syndrome type II. Presse Med
2012;41(12 P 2):e663–70.
507
[23] Yin J, Zhang F, Zhang H, Shen L, Li Q, Hu S, et al. Hand-Schüller-Christian
disease and Erdheim-Chester disease: coexistence and discrepancy. Oncol-
ogist 2013;18:19–24.
[24] Langrand C, Bihan H, Raverot G, Varron L, Androdias G, Borson-Chazot F,
et al. Hypothalamo-pituitary sarcoidosis: a multicenter study of 24 patients.
QJM 2012;105:981–95.
[25] De Bellis A, Kelestimur F, Sinisi AA, Ruocco G, Tirelli G, Battaglia M,
et al. Anti-hypothalamus and anti-pituitary antibodies may contribute to
perpetuate the hypopituitarism in patients with Sheehan’s syndrome. Eur J
Endocrinol 2008;158:147–52.
[26] Babey M, Kopp P, Robertson GL. Familial forms of diabetes insipidus:
clinical and molecular characteristics. Nat Rev Endocrinol 2011;7:701–14.
[27] Bichet DG. Genetics and diagnosis of central diabetes insipidus. Ann
Endocrinol (Paris) 2012;73:117–27.
[28] Ye D, Dong F, Lu W, Zhang Z, Lu X, Li C, et al. A missense mutation in
the arginine-vasopressin neurophysin-II gene causes autosomal dominant
neurohypophyseal diabetes insipidus in a Chinese family. Clin Endocrinol
(Oxf) 2013;78:920–5.
[29] Pickett KA, Duncan RP, Hoekel J, Marshall B, Hershey T, Earhart GM.
Early presentation of gait impairment in Wolfram syndrome. Orphanet J
Rare Dis 2012;7:92.
[30] Hershey T, Lugar HM, Shimony JS, Rutlin J, Koller JM, Perantie DC, et al.
Early brain vulnerability in Wolfram syndrome. PLoS One 2012;7:e40604.
[31] Rigoli L, Di Bella C. Wolfram syndrome 1 and Wolfram syndrome 2. Curr
Opin Pediatr 2012;24:512–7.
[32] Mehta A, Hindmarsh PC, Mehta H, Turton JP, Russell-Eggitt I, Taylor
D, Chong WK, Dattani MT. Congenital hypopituitarism: clinical, molec-
ular and neuroradiological correlates. Clin Endocrinol (Oxf) 2009;71:
376–82.
[33] França MM, Jorge AAL, Carvalho LRS, Costalonga EF, Otto AP, Correa
FA, et al. Relatively high frequency of non-synonymous GLI2 variants in
patients with congenital hypopituitarism without holoprosencephaly. Clin
Endocrinol (Oxf) 2013;78:551–7.
[34] Chanson P, Salenave S. Treatment of neurogenic diabetes insipidus. Ann
Endocrinol (Paris) 2011;72:496–9.
[35] Moeller HB, Rittig S, Fenton RA. Nephrogenic diabetes insipidus: essen-
tial insights into the molecular background and potential therapies for
treatment. Endocr Rev 2013;34:278–301.
[36] Sasaki S, Chiga M, Kikuchi E, Rai T, Uchida S. Hereditary nephrogenic
diabetes insipidus in Japanese patients: analysis of 78 families and report of
22 new mutations in AVPR2 and AQP2. Clin Exp Nephrol 2012;17:338–44.
[37] Huang L, Poke G, Gecz J, Gibson K. A novel contiguous gene deletion
of AVPR2 and ARHGAP4 genes in male dizygotic twins with nephro-
genic diabetes insipidus and intellectual disability. Am J Med Genet A
2012;158A:2511–8.
[38] Bernier V, Morello JP, Zarruk A, Debrand N, Salahpour A, Lonergan
M, et al. Pharmacologic chaperones as a potential treatment for X-linked
nephrogenic diabetes insipidus. J Am Soc Nephrol 2006;17:232–43 [Erra-
tum in: J Am Soc Nephrol 2006;17:591].
[39] Ulinski T, Grapin C, Forin V, Vargas-Poussou R, Deschênes G, Bensman
A. Severe bladder dysfunction in a family with ADH receptor gene muta-
tion responsible for X-linked nephrogenic diabetes insipidus. Nephrol Dial
Transplant 2004;19:2928–9.
[40] Vantyghem MC, Hober C, Bouthors AS, Cappoen JP, Monnier JC, Lefeb-
vre J. Stratégie diagnostique et thérapeutique devant un diabète insipide
de la grossesse et du post-partum. Rev Fr Endocrinol Clin Nutr Metab
1993;34:379–86.
[41] Wallia A, Bizhanova A, Huang W, Goldsmith SL, Gossett DR, Kopp P.
Acute diabetes insipidus mediated by vasopressinase after placental abrup-
tion. J Clin Endocrinol Metab 2013;98:881–6.