S P E C I A L F E A T U R E

C l i n i c a l R e v i e w

Current State and Future Perspectives in the

Diagnosis of Diabetes Insipidus: A Clinical Review

Wiebke Fenske and Bruno Allolio

Department of Internal Medicine I, Endocrine and Diabetes Unit, University Hospital Würzburg, 97080
Würzburg, Germany

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Context: The differential diagnosis of diabetes insipidus (DI) is often challenging but essential,
because treatment may vary substantially. This article analyzes the database and performance of
currently used differential diagnostic tests for DI and discusses future perspectives for diagnostic
improvement.

Evidence Acquisition: A review of electronic and print data comprising original and review articles
retrieved from the PubMed or Cochrane Library database up to January 2012 was conducted. The
search term “polyuria polydipsia syndrome” was cross-referenced with underlying forms of disease
and associated clinical, diagnostic, and therapeutic MeSH terms. In addition, references from re-
view articles and textbook chapters were screened for papers containing original data. Search
results were narrowed to articles containing primary data with a description of criteria for the
differential diagnosis of DI.

Evidence Synthesis: Fifteen articles on differential diagnosis of DI were identified, mainly con-
sisting of small series of patients, and mostly covering only part of the differential diagnostic
spectrum of DI. Test protocols differed, and prospective validation of diagnostic criteria was con-
sistently missing. Inconsistent data were reported on the diagnostic superiority of direct plasma
arginine vasopressin determination over the indirect water deprivation test. Both test methods
revealed limitations, especially in the differentiation of disorders with a milder phenotype.

Conclusion: The available data demonstrate limitations of current biochemical tests for the dif-
ferential diagnosis of DI, potentially leading to incorrect diagnosis and treatment. The newly
available assay for copeptin, the C terminus of the vasopressin precursor, holds promise for a higher
diagnostic specificity and simplification of the differential diagnostic protocol in DI. (J Clin Endo-
crinol Metab 97: 3426 –3437, 2012)

iabetes insipidus (DI) belongs to the spectrum of poly-
D uric and polydipsic diseases, a group of hereditary
or acquired disorders mainly associated with an inade-
quate arginine vasopressin (AVP) secretion or renal re-
sponse to AVP, which clinically results in hypotonic poly-
uria and a compensatory or underlying polydipsia.
Under physiological conditions, body water and os-
motic homeostasis are balanced by a sensitively regulated
AVP system essentially depending on two determinants,
the serum osmolality and arterial blood volume (1). AVP
activates the renal vasopressin-2 receptor (V2R) at the
basolateral membrane of the principal cells and increases
the tubular fluid permeability via cAMP-induced phos-
phorylation and insertion of the water channels aquaporin
2 (AQP2) into the apical membrane (2). Thirst serves as an
important backup mechanism, becoming indispensable in
the moment when pituitary and renal mechanisms fail to
maintain body fluid homeostasis. Under these circum-
stances, intact thirst sensation is essential to restore nor-
mal osmolality, but often at the expense of a clinically
pronounced polyuria and polydipsia. Differentiating pri-
mary polydipsia (PP) from secondary polydipsia is impor-

ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2012 by The Endocrine Society
doi: 10.1210/jc.2012-1981 Received April 17, 2012. Accepted July 2, 2012.
First Published Online August 1, 2012
Abbreviations: AQP2, Aquaporin 2; AVP, arginine vasopressin; CDI, central (or neurogenic)
DI; cMRI, cranial magnetic resonance imaging; DI, diabetes insipidus; NDI, nephrogenic DI;
PP, primary polydipsia; V2R, vasopressin-2 receptor.

3426 jcem.endojournals.org J Clin Endocrinol Metab, October 2012, 97(10):3426 –3437

J Clin Endocrinol Metab, October 2012, 97(10):3426 –3437
tant because incorrect treatment may lead to serious
complications. Although simple dehydration should the-
oretically enable the differentiation of both disorders, this
approach often fails, especially in mild forms of DI (3).
The purpose of this review is to provide a comprehen-
sive discussion of the available database on the differential
diagnosis of DI to better appreciate the diagnostic evi-
dence and strengths, but also the limitations and pitfalls of
the currently available test concepts.
Clinical Spectrum of the Underlying
Disorders
Central diabetes insipidus
Central or neurogenic DI (CDI) is the most common
form of polyuric and polydipsic disorder, which occurs
mainly due to lesions of the neurohypophysis or the hy-
pothalamic median eminence resulting in deficient syn-
thesis and/or release of AVP. A number of acquired and
congenital disorders may cause CDI (Table 1) (4 – 6) with
variable clinical manifestation, depending on the extent of
neuronal destruction. Usually 80 to 90% of the magno-
cellular neurones in the hypothalamus need to be damaged
before symptoms of DI arise (7).
Acquired CDI mostly results from transsphenoidal sur-
gery or head trauma. Twenty to 30% of pituitary surgeries
lead to transient CDI, and 2–10% lead to permanent dis-
ease (8, 9), with a risk of postoperative neuronal damage
depending on the height of hypothalamic-hypophyseal
tract destruction; sections above the median eminence
cause a permanent form of disease, whereas sections be-
low the median eminence produce only transient CDI (10).
CDI due to pituitary adenomas is extremely rare (11,
12), even when associated with complete anterior pitu-
itary insufficiency (13). Similarly rare, but important to
consider, is an autoimmune destruction of the neurohy-
pophysis caused by lymphocytic infundibuloneurohy-
pophysitis, an entity presenting with a thickened pituitary
stalk and enlargement of the neurohypophysis in cranial
magnetic resonance imaging (cMRI) (14 –16), which in
individual cases may spontaneously go into remission (6,
14, 17). This autoimmune process has also been described
in a subset of patients initially classified as idiopathic CDI
(14). But idiopathic CDI, accounting for about 25% of
disease in adulthood, provides no clinical evidence of in-
jury or diseases that could be linked to DI, and cMRI
generally reveals no abnormality other than the absence of
the posterior pituitary bright spot and sometimes varying
degrees of thickening of the pituitary stalk (6).
Much more rare are the congenital forms of CDI (Table
1), mostly presenting with an autosomal dominant mode
jcem.endojournals.org 3427
TABLE 1. Etiologies to consider in the differential
diagnosis of central diabetes insipidus
Central diabetes insipidus
Acquired
Trauma (surgery, deceleration injury)
Vascular (cerebral hemorrhage, infarctionanterior
communicating artery aneurysm or ligation,
intrahypothalamic hemorrhage)
Neoplastic (craniopharyngioma, meningioma, germinoma,
pituitary tumor or metastases)
Granulomatous (histiocytosis, sarcoidosis)
Infectious (meningitis, encephalitis)
Inflammatory/autoimmune (lymphocytic
infundibuloneurohypophysitis)
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Drug/toxin-induced (ethanol, diphenylhydantoin, snake
venom)
Other disorders (hydrocephalus, ventricular/suprasellar
cyst, trauma, degenerative diseases)
Idiopathic
Congenital
Congenital malformations
Autosomal dominant: AVP-neurophysin gene mutations
Autosomal recessive (21, 22): Wolfram Syndrome
(DIDMOAD) (23)
X-linked recessive (24)
Idiopathic
Nephrogenic diabetes insipidus
Acquired
Drug-induced (demeclocycline, lithium, cisplatin,
methoxyflurane, etc.)
Hypercalcemia, hypokalemia
Infiltrating lesions (sarcoidosis, amyloidosis, multiple
myeloma, Sjoergen’s disease)
Vascular (sickle cell disease)
Congenital
X-linked recessive (OMIM 304800): AVP V2 receptor gene
mutations
Autosomal recessive: AQP2 water channel gene mutations
Primary polydipsia
Psychogenic
Dipsogenic (downward resetting of thirst threshold)
Increased AVP metabolism
Pregnancy
of inheritance (18 –20), and only very infrequently due to
an autosomal recessive (21–23) or X-linked recessive in-
heritance (24). Underlying mutations, located in the cod-
ing region of the AVP-neurophysin precursor gene medi-
ate the generation of an abnormal precursor protein,
which accumulates within the neuron and causes cell ap-
optosis (25). Therefore, congenital CDI typically develops
months to years after birth and then gradually progresses
(26, 27). Only rare cases of congenital CDI were reported,
which later went into remission (28, 29) without evidence
for recovered AVP release (30).
Osmoreceptor dysfunction
Different lesions in the anterior hypothalamus near the
third ventricle may entail a dysfunction of the osmorecep-
tors resulting in an impaired AVP responsivity and thirst
sensation (Table 1) (31, 32). Patients manifest with dehy-
dration and hypernatremia, sometimes resulting in serious
3428 Fenske and Allolio Differential Diagnosis of Diabetes Insipidus
cardiovascular complications like hypotension, renal fail-
ure, and hypovolemic shock (33). The severity of the neu-
rological signs is closely related to the degree of hyperto-
nicity, ranging from irritability to disorientation, seizures,
and coma (34). Importantly, patients can still demonstrate
a physiological antidiuretic response to baroreceptor-me-
diated (35) and other non-osmotic stimuli of AVP release
(36, 37).
Nephrogenic diabetes insipidus
Nephrogenic DI (NDI) results from renal resistance to
the antidiuretic action of AVP, which may also be due to
acquired or inherited conditions (Table 1).
The acquired form of NDI is much more common
than the congenital form, but it is rarely severe. The
ability to elaborate a hypertonic urine is usually pre-
served, despite the impairment of the maximal concen-
trating ability of the nephron. Therefore, the symptoms
of disease are usually more moderate with a polyuria
and polydipsia seldom above 3 to 4 liters/d. Lithium
therapy poses the most frequent cause of acquired NDI
(38), involving about 10 –20% of patients treated long
term (39). Even at therapeutic concentrations, lithium
may interfere with the cAMP system (40, 41), leading to
decreased renal AQP2 expression (42) with subsequent
polyuria and tubular acidosis (40, 43, 44). This defect
in AQP2 is slow to correct (45, 46), and in some cases
may even persist when associated with glomerular or
tubulointerstitial nephropathy (47).
Also, electrolyte disorders like hypokalemia or hyper-
calcemia may involve NDI, probably due to a temporary
down-regulation of AQP2 expression (45, 48, 49). But the
manifestation is reversible once electrolytes are corrected.
Almost 90% of the more infrequent congenital NDI is
inherited in an X-linked recessive manner due to muta-
tions in the V2R gene. Only 10% of congenital diseases are
due to autosomal mutations in the AQP2 gene (50). More
than 200 putative disease-causing mutations within the
V2R gene have been described (51), and functional char-
acterization of some of these mutant receptors revealed
reduced binding affinity for AVP (type 1), defective intra-
cellular trafficking (type 2), or reduced receptor transcrip-
tion (type 3) (50). The genetic form normally presents
from birth with basal serum sodium levels being either
normal or elevated if fluid administration is also impaired.
Primary polydipsia
PP differs from the other causes of DI in that it does not
arise from a deficient AVP secretion or activity, but rather
results from an excessive fluid intake practiced over an
extended period of time (52, 53). PP comprises subjects
with a defective thirst mechanism or increased thirst sen-
J Clin Endocrinol Metab, October 2012, 97(10):3426 –3437
sation (dipsogenic DI) and patients with a more unknown
motive for polydipsia frequently associated with psychi-
atric disorders (psychogenic polydipsia) (3, 54, 55). The
starting point of disease is always the same: an excessive
consumption of fluids, resulting in excessive body fluid,
decreased serum osmolality, and suppressed AVP release.
The subsequent increase in water excretion compensates
for the high fluid intake, and the tonicity stabilizes at a new
set point around the osmotic threshold for AVP secretion.
Therefore, despite intact pituitary and renal function, pa-
tients with PP share essential characteristics of DI.
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Because dipsogenic DI can be caused by the same hypo-
thalamic lesions as found in CDI (Table 1), it is essential to
perform cMRI scans in all patients with PP before idiopathic
or psychiatric illness can be diagnosed (56). PP may also have
an iatrogenic origin, either due to drug intake associated with
oral dryness (57) or due to the medical advice to increase fluid
intake for certain health benefits (58). These patients have
generally no signs of mental illness or increased thirst, and the
term “habitual polydipsia” may be the more accurate de-
scription of this disorder.
Gestational diabetes insipidus
For the sake of completeness, the gestational form of DI
should also be mentioned. The manifestation is triggered
by the degradation of AVP by the placental enzyme cys-
teine aminopeptidase (59 – 61), although the hormone lev-
els are often normal (62), suggesting that pregnancy un-
masks a subtle underlying deficiency of AVP (59, 63).
Although spontaneous remission of gestational DI nor-
mally occurs within 2 to 3 wk postpartum, diagnostic eval-
uation for possible underlying disorders should be con-
sidered (Table 1).
Differential Diagnosis
Once hypotonic polyuria has been confirmed, patient his-
tory and clinical presentation can provide useful diagnos-
tic clues. But very often, clinical data are of limited help
(64) because patients with a preserved thirst mechanism
do biochemically not differ significantly. And although the
assessment of the integrity of the neurohypophyseal sys-
tem may be conceptually simple and should theoretically
allow a straightforward diagnostic differentiation of DI,
interpretational difficulties often arise (65) and not seldom
lead to misclassification (64, 66, 67) with a high risk of
inappropriate therapy. Therefore, a reliable and generally
applicable diagnostic approach to suspected DI is ex-
tremely important (3, 68, 69).
To better understand and characterize the limitations
and pitfalls of current diagnostic test standards, we per-
J Clin Endocrinol Metab, October 2012, 97(10):3426 –3437
formed an extensive literature review, incorporating elec-
tronic and manual components with the search term
“polyuria polydipsia syndrome” and its underlying dis-
eases. The electronic search was conducted using the
PubMed and the Cochrane Library database (up to Jan-
uary 2012) with the following MeSH terms: “diagnosis of
polyuria/polydipsia/diabetes insipidus/(posterior) pitu-
itary disease/hypopituitarism”; “psychogenic polydip-
sia”; “compulsive water drinking”; “water deprivation
test”; “hypertonic saline infusion test”; “impaired urinary
concentration”; “desmopressin”; and “vasopressin.” In
addition, the scientific work of individual authors with
exceptional activity in this field (including G. L. Robert-
son, J. G. Verbalis, D. G. Bichet, P. H. Baylis, and C. J.
Thompson) was analyzed separately. Data and references
from major textbooks (70 –74) were also included in the
analysis. Fifteen original articles dealing with the evalua-
tion of differential diagnostic test concepts in DI were re-
trieved. Design, endpoints, and main findings of these
studies are chronologically summarized in Table 2, and
the diagnostic key issues in differentiation of DI are dis-
cussed in the following paragraphs against this database.
The urinary concentration test as an indirect
measure of AVP activity
Our current diagnostic test concepts of DI date back to
animal studies from Gilman and Goodman (75, 76) in the
1930s, which first demonstrated that osmotic stimulation
by dehydration (75, 76) or hypertonic saline infusion (77)
induces an antidiuretic urinary response that is not ob-
served in hypophysectomized dogs (78).
Hickey and Hare (79) first applied these findings to
man, demonstrating that patients with CDI (n ⫽ 2) have
a higher tubular chloride reabsorption and a higher water
diuresis during osmotic stimulation than patients with PP
(n ⫽ 1) (Table 2). Carter and Robbins (80) equally re-
ported a much lower reduction in urine flow in subjects
with CDI (n ⫽ 8) when compared with PP (n ⫽ 3) (Table
2). Both studies, therefore, suggest that the urinary con-
centration capacity may provide useful information in the
diagnostic differentiation of DI. But the urinary concen-
tration mechanism may be disturbed under certain cir-
cumstances (e.g. in states of anterior pituitary insuffi-
ciency, overhydration, or reduced glomerular filtration
rate), essentially limiting the test validity (64) (Table 2).
An important modification of the urine concentration
test was proposed in the 1950s by Barlow and de War-
dener (3). The authors aimed to improve the diagnostic
value of urine concentration by adding the evaluation of
the urine response to a subsequent injection of pitressin
(3). They hypothesized that patients with CDI should re-
spond with a further concentration of their urine, whereas
jcem.endojournals.org 3429
patients with PP should not. In fact, except for two pa-
tients, all subjects in their study with PP (n ⫽ 8) revealed
a greater urine concentration after dehydration than after
pitressin, despite significant variations in the absolute
urine concentration during dehydration (Table 2). In con-
trast, all patients with CDI (n ⫽ 12) consistently showed
a higher urine concentration after pitressin than after de-
hydration. Similar findings were reported by Dies et al.
(64), who found a decrease in urine osmolality after va-
sopressin injection in patients with PP (n ⫽ 2), but an
increased urine concentration in CDI (n ⫽ 2) (Table 2).
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Thus, this test concept seemed much more promising than
the evaluation of the absolute urine concentration alone.
But, its validation in a larger series of patients showing the
entire differential diagnostic spectrum of DI has long been
missing.
A first standardized test protocol with detailed diag-
nostic test criteria was proposed by Miller et al. (67) in
1970 after the evaluation of 36 patients with different
disorders of polyuria and polydipsia syndrome (Table 2).
Patients with severe CDI (n ⫽ 18) were reported to fail in
concentrating the urine above the level of plasma osmo-
lality during dehydration but to feature a more than 50%
urine osmolality increase (range, 51–792%) after exoge-
nous vasopressin injection; patients with NDI (n ⫽ 2)
showed a further rise of only 39 and 45%. In contrast,
subjects with mild forms of CDI (n ⫽ 11) were able to
concentrate their urine above their plasma osmolality but
still demonstrated a further rise in urine concentration
after vasopressin by more than 9% (range, 9 – 67%). A
much higher urine concentrating ability was found in pa-
tients with PP (n ⫽ 5), who showed only a minor further
increase in urine concentration after vasopressin, ranging
between 2 and 13%.
Unfortunately, the diagnostic criteria derived from this
study (67) (see Table 2 for details) have never been vali-
dated in an independent, prospective approach, and sen-
sitivity and specificity for identification of differential di-
agnoses of DI have not been defined. Furthermore, it was
shown that some patients with partial CDI may demon-
strate quite normal urine concentrations, in particular in
case of a decreased glomerular filtration rate (3, 64, 81).
And the urine concentration ability may be variably re-
duced in different forms of chronic polyuria (82), leading
to overlapping degrees of pathologically diminished uri-
nary responses to osmotic stimulation (67). This diagnos-
tic problem is not surprising, given some principles of kid-
ney physiology. First, chronic polyuria itself can decrease
the urinary concentration capacity (83– 85), probably
through a washout mechanism of the renal medullary con-
centration gradient as well as by down-regulation of kid-
ney AQP2 water channels. Both may explain the some-
3430 Fenske and Allolio Differential Diagnosis of Diabetes Insipidus
TABLE 2. Collection of the original data on the differential diagnosis of central diabetes insipidus in chronological order
Year of
study Method of testing
(Ref.) AVP reactivity
1944 (79) 2.5% NaCl infusion
1947 (65) 2.5% NaCl infusion
followed by pitressin
injection
1957 (96) Serial infusion of nicotine,
2.5% NaCl, and
pitressin under constant
water-loading
1959 (3) Serial testing of
vasopressin, 24-h
dehydration alone, and
followed by vasopressin
1961 (64) Serial testing of
dehydration, 0.5 mg
nicotine, vasopressin,
and 3% NaCl
1963 (66) Dehydration
1967 5% NaCl infusion
(108)
1970 (67) Dehydration followed by
vasopressin injection
1980 (89) 5% NaCl infusion
1981 (86) 5% NaCl infusion
1981 (82) 5% NaCl infusion vs.
dehydration test
1983 (69) 5% NaCl infusion vs.
dehydration test
1991 (97) 5% NaCl infusion followed
by hydration-induced
AVP suppression test
1992 (99) T1-weighted magnetic
resonance imaging of
the pituitary
2011 (68) Dehydration test
FWC, Free water clearance; S-Osm, serum osmolality; U-flow, urine flow; U-Na⫹, urine sodium excretion; chloride R/P ratio, relation of chloride
concentration in the reabsorbate to that in plasma; U-Osm, urine osmolality; WDT, water deprivation test.
Key endpoints
1. Tubular chloride reabsorbate
(chloride R/P ratio); 2. urine flow
(U-flow)
U-flow
FWC
1. Maximum U-Osm during
dehydration; 2. change in U-Osm
after vasopressin
1. Maximum U-Osm; 2. change in
U-Osm due to vasopressin; 3.
FWC
Urine-to-serum osmolality ratio
1. U-flow; 2. U-Osm; 3. urine sodium
excretion (U-Na⫹)
1. Maximum U-Osm during
dehydration; 2. change in U-Osm
after vasopressin
Direct plasma AVP response to
osmotic stimulation
Direct plasma AVP response to
osmotic stimulation
Consistency in diagnoses of plasma
AVP vs. urine concentration
measurement 关as described by Miller
et al. (as described in Ref. 67)
Same endpoints as in Ref. 82
Diagnostic specificity of thirst rating
on a visual analog scale for
differing PP from CDI
Diagnostic specificity of the
neurohypophyseal bright spot for
differing PP from CDI
Direct comparison of: 1. the urine
concentration tests (as described in
Ref. 67); 2. direct plasma AVP
measurement (as described in Ref.
89); and 3. direct plasma copeptin
measurement against an
independent diagnostic reference
standard
J Clin Endocrinol Metab, October 2012, 97(10):3426 –3437
No. of patients: cc
(complete CDI), c (partial
CDI), n (NDI), p (PP), and
v (volunteers)
cc ⫽ 2, p ⫽ 1, v ⫽ 1
cc ⫽ 8, p ⫽ 3, v ⫽ 9
cc ⫽ 3, p ⫽ 3
cc ⫽ 12, p ⫽ 8, v ⫽ 14
cc ⫽ 1, c ⫽ 1, p ⫽ 2
cc ⫽ 13, p ⫽ 3, v ⫽ 25
cc ⫽ 10, p ⫽ 3, v ⫽ 38
cc ⫽ 18, c ⫽ 17, n ⫽ 2,
p ⫽ 5, v ⫽ 10
cc ⫽ 3, c ⫽ 3, p ⫽ 4, v ⫽
11
cc ⫽ 5, c ⫽ 5, p ⫽ 4
AVP: cc ⫽ 7, c ⫽ 8, n ⫽ 1,
p ⫽ 7.
WDT: cc ⫽ 7, c ⫽ 6, n ⫽ 0,
p ⫽ 10
AVP: cc ⫽ 4, c ⫽ 9, n ⫽ 2,
p ⫽ 6.
WDT: cc ⫽ 7, c ⫽ 7, n ⫽ 0,
p⫽7
cc ⫽ 7, p ⫽ 7, v ⫽ 7
cc ⫽ 8, n ⫽ 4, p ⫽ 6, v ⫽
92
cc ⫽ 17, c ⫽ 9, n ⫽ 2,
p ⫽ 22, v ⫽ 30
Major findings in patients with CDI
1. Chloride R/P is elevated at baseline and further
increases during 2.5% saline infusion, but decreases
in volunteers; 2. water diuresis persists during saline
infusion
Unchanged U-flow during saline infusion; prompt
decrease after pitressin injection
Normal response to nicotine and pitressin, but no
response to NaCl in 3 subjects with posterior
pituitary damage; abnormal response to nicotine and
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normal response to NaCl in patients with PP
1. Maximum U-Osm reduced; 2. vasopressin-induced
rise in U-Osm higher compared to PP
U-Osm during dehydration was lower and rise in U-Osm
after vasopressin was higher compared to PP. Three
subjects with CDI showed a partial response of FWC
to nicotine, vasopressin, and saline; one subject with
PP had a partial response to nicotine, but a good
response to saline; the other one had completely
normal responses
Urine-to-serum osmolality ratio is lower than in PP and
volunteers
No change in U-flow, U-Osm, or U-Na⫹, contrary to
patients with PP and volunteers
In severe CDI and NDI, U-Osm remains below S-Osm
during dehydration, and further rises by ⬎50% (CDI)
or ⬍50% (NDI) after vasopressin. In partial CDI and
PP, U-Osm rises to levels above S-Osm during
dehydration, and further rises by ⬎9% (partial CDI)
or ⬍9% (PP) after vasopressin
Plasma AVP response was found to be nondetectable
(complete CDI, n ⫽ 3), subnormal (partial CDI, n ⫽
3), or comparable (PP, n ⫽ 4) to healthy volunteers
(n ⫽ 11)
Undetectable AVP levels in complete CDI (n ⫽ 5),
subnormal levels in partial CDI (n ⫽ 5), and normal
levels in PP (n ⫽ 4)
Both tests correctly identified complete CDI (n ⫽ 7).
Two of six patients with partial CDI and three of 10
patients with PP, according to the dehydration test,
had normal or subnormal AVP levels, respectively
Both tests correctly identified PP (n ⫽ 6). Two of 4
subjects with undetectable AVP levels were
confirmed as complete CDI by the dehydration test;
one subject was diagnosed as partial CDI, one as NDI
according to dehydration. And 8 of 9 patients with
subnormal AVP levels were confirmed as partial CDI
by the dehydration test, one patient was diagnosed
as NDI
Thirst sensation rises with elevating S-Osm, but is still
consistently lower compared to PP. Oral hydration
results in an immediate decrease in thirst, which is
not seen in PP
Absent hyperintense signal of the posterior pituitary gland in
all patients with CDI (n ⫽ 8), persistent signal in all
patients with PP (n ⫽ 6), 3 of 4 patients with NDI, and in
90 of 92 patients without sellar disease
Urine concentration tests with maximum U-Osm and
change in U-Osm to vasopressin reached a diagnostic
accuracy of 70%; plasma AVP correctly identified
38% of patients, and plasma copeptin identified
72% of patients
J Clin Endocrinol Metab, October 2012, 97(10):3426 –3437
times lower than expected urinary response to injected
vasopressin in CDI (86). Second, an enhanced antidiuretic
response to low levels of plasma AVP has been reported
(81, 87), possibly due to an up-regulated V2R expression
in chronic states of CDI (88). On the other hand, patients
with acquired NDI are often only incompletely resistant to
AVP, and therefore may resemble patients with partial
CDI. Thus, the consequence of these mechanisms is a con-
vergence of different underlying disorders to a similar uri-
nary phenotype. Accordingly, when we recently evaluated
in a prospective study the diagnostic accuracy of the pre-
viously described urine concentration test (67) in 50 pa-
tients presenting the entire differential diagnostic spec-
trum of DI, we only found a total diagnostic accuracy of
41% (68) (Table 2).
Direct measurement of plasma AVP activity
With the availability of a first sensitive and specific AVP
RIA in the 1970s, it was hoped that direct plasma AVP
measurement would overcome the limitations of the urine
concentration tests and allow a less cumbersome differ-
ential diagnosis of DI (87). The new test method, first
implemented by Baylis and Robertson in the early 1980s
(89, 90), exploited the direct assessment of AVP release in
response to a 2-h hypertonic saline infusion test, and the
data were interpreted as a function of the corresponding
serum osmolality (Table 2 and Fig. 1). The conceptual
superiority of this method was assumed to consist of an
intact AVP responsivity to osmotic stimulation even after
a long period of overhydration or dehydration (54). If
compared with the normal physiological relationship be-
tween plasma AVP and serum osmolality (Fig. 1, gray
area), patients with CDI were hypothesized to demon-
strate data pairs below this area of normality, whereas
patients with NDI or PP show data pairs above or within
this normative area (89, 90) (Fig. 1 and Table 2).
FIG. 1. Plasma AVP and osmolality response to hypertonic saline
infusion. The shaded area defines the normal response. Red triangle
symbolizes PP, and green circle symbolizes CDI. LD is the limit of
detection of plasma AVP (modified from Ref. 90).
jcem.endojournals.org 3431
Two peer-reviewed studies investigating the diagnostic
performance of direct AVP measurements in differential
diagnosis of DI are available in the literature. The first
study, from Zerbe and Robertson (82) (Table 2), com-
pared the diagnostic performance of plasma AVP mea-
surement with that of the urine concentration test (67) in
23 patients. Patients with complete CDI (n ⫽ 7) could be
easily identified by both test methods. Discrepant results,
however, were found in patients with partial CDI and PP:
two of six subjects diagnosed as partial CDI based on their
urine levels revealed an entirely normal AVP response; one
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was later diagnosed as PP, the other as NDI. Vice versa,
three of 10 patients diagnosed as PP by urine concentra-
tion had suppressed plasma AVP levels, clearly suggestive
of AVP deficiency (82).
Similar diagnostic discrepancies between both test
methods were reported by Milles et al. (69), who repeated
the study in another 19 patients (Table 2). Both tests came
to the diagnosis of PP in the same six patients, and also
eight of nine patients with subnormal AVP levels could be
confirmed as partial CDI by the urine test results; only one
patient was diagnosed as NDI. But, two of four patients
with undetectable plasma AVP levels were categorized as
partial CDI (n ⫽ 1) or NDI (n ⫽ 1) according to their urine
results.
An important difficulty in the interpretation of both
studies is the lack of a diagnostic “gold standard” with
which the test results could be compared. Thus, the final
diagnosis and, therefore, the diagnostic accuracy of both
test methods remain undetermined. Another critical point
refers to the area of normality describing the physiological
behavior of plasma AVP release in relation to the corre-
sponding serum osmolality. The exact definition of this
area is the fundamental basis for the identification of ab-
errant AVP secretion in patients tested for disease. On this
crucial point, however, both studies (89, 90) relied on a
previously described slope model of linear regression cal-
culated on the basis of a very small number of healthy
volunteers and without the definition of the correspond-
ing reference area or stability limit (69, 87, 89). But more
recent evidence, from a higher number of healthy controls,
suggests that the relation between AVP and serum osmo-
lality is less linear and close than has previously been de-
scribed (68). Consequently, a total diagnostic accuracy of
only 46% could be found when direct AVP measurement
was prospectively tested in 50 patients with polyuria poly-
dipsia disease (68) (Table 2). Finally, the well-character-
ized technical difficulties of the AVP assay with its high
preanalytical instability (87, 91, 92) certainly also account
for the still extremely low acceptance of the AVP assay in
the differential diagnosis of DI.
3432 Fenske and Allolio Differential Diagnosis of Diabetes Insipidus
FIG. 2. The ratio of ⌬ copeptin (increase between 8 and 16 h) to the
serum sodium concentration measured at 16 h calculated during a
dehydration test and illustrated as standard box and whisker plots for
the control group, and for patients PP, partial CDI, and complete CDI.
a, P ⬍ 0.05 compared with controls; b, P ⬍ 0.05 compared with
partial CDI (68).
Direct measurement of plasma copeptin
(C-terminal proAVP)
A possibly novel approach to the diagnosis of DI offers
the measurement of plasma copeptin in response to an
appropriate osmotic stimulus. Within the last few years,
copeptin, the C-terminal glycoprotein of the AVP prohor-
mone, has been established as an easy to measure and
stable surrogate for endogenous plasma AVP (91, 93, 94).
Recent data have also promoted copeptin as a promising
diagnostic marker for identification of patients with severe
neurohypophyseal damage after transsphenoidal surgery
(n ⫽ 38) (95).
Based on these findings, another prospective study
evaluated the diagnostic potential of copeptin across the
FIG. 3. Sagittal T1-weighted magnetic resonance imaging scans of the hypothalamic-pituitary
region in a patient with PP (A) and a patient with CDI (B). A, A normal anterior pituitary
(arrowhead) and pituitary stalk (thin white arrow) and hyperintensity of the posterior pituitary
(thick white arrow). B, Sagittal T1-weighted scan obtained in patient with CDI due to lymphoma
shows a massively thickened pituitary stalk (thin white arrow) and an absent hyperintense signal in
the posterior pituitary gland (arrowhead).
J Clin Endocrinol Metab, October 2012, 97(10):3426 –3437
full differential diagnostic spectrum of DI (n ⫽ 50) (68)
(Table 2). In accordance with the direct AVP test
method (see The Urinary Concentration Test as an In-
direct Measure of AVP Activity and Fig. 1), osmotically
stimulated copeptin release was interpreted by plotting
the hormone levels together with the corresponding se-
rum osmolality into a nomogram and estimating the
data pairs as to their position to the area of normality.
In this way, copeptin revealed an overall diagnostic ac-
curacy of 83%, whereas patients with complete CDI
(n ⫽ 7) and NDI (n ⫽ 2) could already be identified at
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plasma baseline values. With respect to the particularly
challenging differentiation of patients with PP and partial
CDI, the ratio of copeptin increase during an 8-h dehydration
period to the serum sodium concentration measured after
16 h of water deprivation (⌬Copeptin[8 –16 h]/S-Na⫹[16 h])
proved to be a highly useful parameter, providing a di-
agnostic yield of 94%, and a specificity and sensitivity
of 100 and 86%, respectively, to separate PP (n ⫽ 22)
from partial CDI (n ⫽ 17) (Fig. 2). The main criticism
to this approach, again, is the missing “gold standard”
test with which the copeptin results could have been
compared. To cope with this problem, the reference
diagnosis in this study was made retrospectively, with
consideration of patient history, clinical presentation,
and treatment response. Moreover, the clinical use of
copeptin levels as a surrogate of AVP secretion during os-
motic stimulation still requires a larger database of normal
and abnormal responses, and the reported diagnostic cutoff
values that were determined in a post hoc analysis still need
to be validated prospectively. Also important to note is the
fact that the sandwich immunoluminometric copeptin as-
say (LUMItest CT-proAVP) is not yet commercially
available in countries outside Europe, currently limiting
its clinical implementation as a new
diagnostic standard.
Further proposed test procedures
As might be expected, most patients
with DI also exhibit a subnormal antidi-
uretic response to nonosmotic stimuli
such as nicotine (96), hypotension, nau-
sea, and hypoglycemia (90). But for di-
agnostic purposes, these nonosmotic
tests of neurohypophyseal function do
not provide advantages over the osmotic
stimuli because they are difficult to con-
trol or quantitate and generally cause a
markedly variable AVP response (90,
96). Moreover, they can lead to false-pos-
itive or false-negative test results because
there are patients who exhibit little or no
J Clin Endocrinol Metab, October 2012, 97(10):3426 –3437 jcem.endojournals.org 3433

rise in AVP after hypotension or emesis, yet lack polyuria show a normal response to induced hypotension (35) or
and have a normal response to osmotic stimuli. Con- nicotine infusion (96) (Table 2).
versely, patients with osmoreceptor dysfunction exhibit An interesting diagnostic test method has been pursued
little or no antidiuretic response to hypertonicity but by Thompson et al. (97) (Table 2), who examined the

Diagnostic Approach to Differential Diagnosis of Diabetes Insipidus

Water Deprivation Test

(after hypotonic polyuria has been confirmed)

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> 800mOsm/kg H2O Maximum Urine Osmolality < 300mOsm/kg H2O

Mild Increase in Urine Osmolality

>300 to <800mOsm/kg H2O
Primary Polydipsia following desmopressin

>50% <50%

Increase in Urine Osmolality Complete Complete

following desmopressin Central DI Nephrogenic DI

<50%

Recommended further diagnostic considerations to reliably differentiate between

suspected diagnoses of:

Primary Partial Partial

Polydipsia Central DI Nephrogenic DI

(A) Patient, familiy history and clinical data

+
(B) Cranial MRI of the hypothalamic-pituitary region on T1-weighted images

(+)
(C) Therapeutic trial with a standard dose of desmopressin

Primary Partial Partial

Polydipsia * Central DI ** Nephrogenic DI ***

FIG. 4. Diagnostic approach to a patient with suspected diabetes insipidus. *, Findings suggestive for PP include: 1) history of psychiatric disease or neurotic
personality, fluctuating symptoms and gradual onset of polydipsia; 2) posterior pituitary bright spot and normal thickness of the pituitary stalk; and 3) persistent
polydipsia, development of hyponatremia after a therapeutic trial with desmopressin. **, Findings suggestive for partial CDI include: 1) previous head trauma or
pituitary surgery, family history of DI, recent and distinct onset of symptoms, consistent need of fluid intake during the night; preference for cold fluids; 2) missing
pituitary bright spot and/or enlargement of the pituitary stalk beyond 2–3 mm; and 3) abolishment of thirst, polydipsia, and polyuria without development of
hyponatremia after a standard dose of desmopressin. ***, Findings suggestive for partial nephrogenic diabetes insipidus include: 1) history of lithium or other
drug therapies (e.g. cisplatin) interfering with urine concentration, presence of electrolyte disorders (like hypercalcemia or hypokalemia); 2) posterior pituitary
bright spot and normal pituitary stalk; and 3) no effect of desmopressin on polyuria or polydipsia.
3434 Fenske and Allolio Differential Diagnosis of Diabetes Insipidus
regulation of thirst sensation in patients with PP compared
with DI. They found that patients with PP have a lower
osmotic threshold for thirst than patients with DI and also
show a resistance to nonosmotic inhibition of thirst. But
similar to the urine-to-serum osmolality ratio, proposed
by Dashe et al. (66) for differentiation between CDI (n ⫽
13) and PP (n ⫽ 3) (Table 2), both test methods did not
gain wide acceptance in clinical routine and also lack
validation.
In recent years, cMRI has emerged as another useful
addition to the biochemical tests in the diagnosis of DI.
The physiological bright spot in the posterior pituitary of
the sella turcica, best seen in sagittal views on T1-weighted
images (98), is persistent in patients with PP (n ⫽ 6) (99)
(Table 2 and Fig. 3A) and is absent in CDI (n ⫽ 8) (Fig. 3B).
But also here, individual cases of CDI with persistent pi-
tuitary bright spot have been reported (100, 101) most
likely due to an early stage of the disease, whereas an
age-related absence of the signal has been described in up
to 20% of normal subjects (102). Conversely in NDI, the
bright spot is present in some patients and absent in others
(103). Consequently, the role of cMRI as a diagnostic test
in patients with DI remains to be clarified. It has been
suggested that cMRI is a more useful tool for ruling out
than for ruling in a diagnosis of CDI (104). A very similar
conclusion also seems to apply to measurements of the
pituitary stalk, whose enlargement beyond 2–3 mm has
been considered to be pathological (105), but not neces-
sarily to be specific for idiopathic CDI (106). The situation
is quite different when the cMRI scan shows both thick-
ening of the stalk and an absent neurohypophyseal bright
spot; in this case, idiopathic CDI and systemic diseases
should seriously be considered (104).
A therapeutic trial with a standard dose of desmopres-
sin for several days may be another useful approach in case
of persistent diagnostic uncertainty (107) (Fig. 4). Al-
though such a therapeutic trial is a plausible diagnostic
concept, sufficient evidence for its diagnostic accuracy is
still missing, and it may carry significant risks. Thus, it
should be conducted under close supervision.
Diagnostic Implementations and Future
Perspectives
Our analysis reveals a surprisingly poor database without
sufficient validation of the current diagnostic test stan-
dards for differentiation of DI. The data reported also
make clear that no agreement exists today regarding how
to biochemically best diagnose DI, and also that the com-
monly followed test protocols suffer from poor diagnostic
accuracy. These limitations are important to know and
J Clin Endocrinol Metab, October 2012, 97(10):3426 –3437
should encourage the clinician to interpret the diagnostic
test results with great caution. For the time being, we con-
sider the water deprivation test followed by a desmopres-
sin challenge as the most plausible test standard to validate
the adequacy of AVP function (Fig. 4). In patients with a
seriously impaired urine concentration capacity (urine os-
molality ⬍300 mOsm/kg), increases in urine osmolality in
response to desmopressin administration of more than
50% reliably indicate complete CDI, and responses of less
than 50% indicate complete NDI. Responses between less
than 0 and less than 50% in patients with only mild or
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moderately impaired urine concentration capacity (urine
osmolality ⬎300 to ⬍800 mOsm/kg) are diagnostically
indeterminate. In these cases, measurement of plasma
AVP may be useful, provided that it is performed with a
sensitive and validated assay for AVP, reliable preanalyti-
cal handling of samples is guaranteed, and corresponding
serum osmolality is in the hypertonic range, preferably
above 300 mOsm/kg. Otherwise, the differentiation be-
tween PP, partial CDI, and partial NDI should currently
rely on a comprehensive assessment of patient and family
history, clinical data, cMRI imaging of the hypothalamic-
pituitary region, and a therapeutic trial with desmopressin
(Fig. 4).
There are emerging data on copeptin measurement in
the differential diagnosis of DI to suggest that this surro-
gate provides a novel and more robust test concept of
neurohypophyseal function than current test standards.
But importantly, before its implementation in differential
diagnostic routine procedures, previous findings on co-
peptin in DI still need to be confirmed in larger prospective
trials. The ultimate aim should be to use the diagnostic
potential of copeptin for a simplification of the currently
still cumbersome diagnostic workup of DI.
Acknowledgments
Address all correspondence and requests for reprints to: Dr.
Wiebke Fenske, M.D., and Prof. Bruno Allolio, M.D., University
Hospital of Würzburg, Department of Medicine, Division of En-
docrinology and Diabetology, Oberdürrbacher-Str. 6, 97080 Wür-
zburg, Germany. E-mail: Fenske_w@medizin.uni- wuerzburg.de
and Allolio_b@medizin.uni-wuerzburg.de.
W.F. was supported by the German Research Society (DFG).
Disclosure Summary: The authors have nothing to declare.
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