Diabetes insipidus

Stephen Ball
Abstract
Diabetes insipidus (DI) describes the excess production of dilute urine. It is
caused by the lack of production or action of the hormone vasopressin
(AVP). Diagnosis requires a targeted history and examination. Conrmation
requires referral to specialist services with expertise in diagnosis and man-
agement. Lack of AVP can be treated with synthetic vasopressin analogues.
Additional approaches may be needed for specic forms of DI. Combined
defects in AVP production and thirst perception require a structured pro-
gramme of uid intake and antidiuresis. Clinicians need to be aware of
both systemic and locally progressive pathologies that can present with DI.
Keywords adipsia; diabetes insipidus; hypernatraemia; hyponatraemia;
polydipsia; polyuria; vasopressin
Diabetes insipidus (DI) is characterized by excess production of
dilute urine e more than 40 ml/kg/24 hours in adults and more
than 100 ml/kg/24 hours in children.
Urine concentration is regulated by vasopressin (AVP), a nine-
amino-acid peptide produced by magnocellular neurones within
the supra-optic nucleus (SON) and para-ventricular nucleus
(PVN) of the hypothalamus. AVP is released into the circulation
from nerve terminals in the posterior pituitary gland. Production
is directly related to plasma osmolality and inversely related to
plasma volume. The principal site of action of AVP is the kidney,
where it increases the synthesis and assembly of water channels
(aquaporin 2, AQP2), leading to increased free water reabsorp-
tion. These effects are mediated through interaction with a G-
protein coupled cell surface receptor (AVP-R2), found on target
cells lining the luminal surface of the distal nephron.
1
Classication and aetiology
There are three sub-types of DI, each reecting a specic element
of the physiology and/or pathophysiology of the AVP axis.
2
Cranial or hypothalamic diabetes insipidus (HDI): relative
or absolute lack of AVP.
Nephrogenic diabetes insipidus (NDI): partial or total
resistance to the renal antidiuretic effects of AVP.
Dipsogenic diabetes insipidus (DDI, primary polydipsia):
inappropriate, high uid intake in excess of ability to
excrete free water.
Hypothalamic diabetes insipidus
Presentation with HDI occurs when 80% of hypothalamic mag-
nocellular neurone AVP production has been lost. Several path-
ological processes can be involved. All lead to either the
destruction of AVP neurones, or the interruption of the transport
or processing of AVP as it moves along the axons of these neu-
rones for release at nerve terminals in the posterior pituitary
(Table 1). The condition can appear for the rst time or become
worse in pregnancy as residual AVP is degraded by increased
placental (vasopressinase) enzyme activity. Up to 50% of chil-
dren and young adults with HDI have an underlying tumour or
CNS malformation.
3
Familial HDI comprises 5% of cases.
4
Nephrogenic diabetes insipidus
Renal resistance to AVP can be the result of the adverse effects of
specic drugs (e.g. lithium toxicity). These effects may be tem-
porary, but sometimes persist. NDI may also occur following
obstructive nephropathy, acute kidney injury and electrolyte
disturbances (e.g. hypokalaemia, hypercalcaemia). Prolonged
polyuria of any cause can result in partial NDI through disruption
of the intra-renal solute gradient that is an obligatory require-
ment for production of concentrated urine. X-linked familial NDI
results from loss-of-function mutations in the renal AVP-R2 re-
ceptor. Autosomal recessive NDI is caused by loss-of-function
mutations in the AVP-dependent water channel, AQP2.
5
Dipsogenic diabetes insipidus
Persistent inappropriate uid intake leads to appropriate poly-
uria. If it exceeds the limit of renal free water excretion it may
result in hyponatraemia. DDI can be associated with the
following abnormalities in thirst perception:
low threshold for thirst
exaggerated thirst response to osmotic challenge
inability to suppress thirst at low plasma osmolalities.
Structural lesions may be present, but neuroimaging is normal in
most cases. DDI is associated with affective disorders.
Epidemiology
DI is rare. Prevalence of HDI is estimated at 1/25,000 with equal
gender distribution. The prevalence of the other forms is unclear.
While most cases present in adults, familial HDI and NDI char-
acteristically present in childhood.
Whats new?
C
Better understanding of the regulation of vasopressin secretion
and its mechanism of action
C
New insights into the molecular genetics of inherited diabetes
insipidus
C
Evolving approaches and novel tools to aid differential
diagnosis
Stephen Ball BSc PhD FRCP is Senior Lecturer and Honorary Consultant,
Newcastle University and Newcastle Hospitals NHS Trust, UK. SB
studied Basic Science at Birmingham University before pursuing
undergraduate and postgraduate Medical Studies in London. Middle
grade training in Diabetes and Endocrinology included a period in the
USA as a Medical Research Council (UK) and Howard Hughes Fellow. He
combines clinical medicine, research and teaching. He is a member of
Council of the Society for Endocrinology and a Senior Editor of Clinical
Endocrinology. He is also a European Endocrine Society representative
within European Guideline groups. Conicts of interest: none declared.
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Diagnosis and investigations
DI presents with polyuria and polydipsia. History and examina-
tion may reveal important features suggestive of:
systemic disease
associated endocrinopathy
an associated neurological problem suggestive of struc-
tural disease
drug toxicity.
Polyuria must be distinguished from simple frequency without
excess urine volume.
The initial approach should be to conrm excess urine volume
and exclude simple metabolic causes such as hyperglycaemia
and hypercalcaemia. Denitive diagnosis requires referral to an
endocrine service for testing of AVP production and action in
response to osmolar stress. The water deprivation test measures
renal concentrating capacity in response to dehydration, and is
an indirect assessment of the AVP axis. It is usually followed by
assessment of renal response to the synthetic AVP analogue
DDAVP. Characteristic ndings are as follows.
In DDI, urine concentration is normal in response to
dehydration.
In HDI, urine concentration fails in response to dehydra-
tion, but not to DDAVP.
In NDI, urine concentration fails in response to both
manoeuvres.
In practice, many results are indeterminate.
6
Direct measurement of AVP production during graded hyper-
osmolar stimulation is the gold-standard method for diagnosing
and classifying DI (Figure 1). Recent data suggest that measure-
ment of co-peptin, an inactive fragment of the AVP precursor that
is released in proportion to AVP, may prove to be an alternative.
7
Conrmation of HDI should lead to further pituitary function
testing and cranial MRI. NDI requires renal tract imaging and
additional renal function studies.
Diabetes insipidus and hypernatraemia
There is a close neuroanatomical relationship between the hy-
pothalamic structures responsible for osmoregulation of thirst
and AVP production. Certain structural, neurovascular and
neuro-developmental lesions are thus associated with combined
defects in both processes. Absent or reduced thirst (adipsia) in
association with HDI predisposes to hypernatraemic dehydra-
tion. Diagnosis follows the protocol for HDI, but benets from
the parallel assessment of thirst perception.
8
Management
Mild forms of HDI may not require treatment. Signicant polyuria
and polydipsia are treated effectively with oral or intranasal
DDAVP. In NDI, causal drugs should be withdrawn where possible
and precipitating electrolyte disturbances corrected. NDI may
respond partly to high-dose DDAVP. Thiazide diuretics and non-
steroidal anti-inammatory drugs can be of additional benet,
but may not normalize urine production. The only rational
approach to DDI is reduction in uid intake. DDAVP treatment
must be avoided in DDI, because of the risk of hyponatraemia.
Follow-up
Following initiation of DDAVP, patients may require frequent
review by an endocrine service for dose titration. Thereafter,
they can be seen annually to assess symptom control and check
serum sodium to avoid over-treatment. The combination of HDI
with adipsia requires meticulous follow-up in a specialist service,
with a structured approach to uid intake and antidiuresis.
Prognosis
Isolated HDI has an excellent prognosis and patients should
anticipate a normal quality of life. When HDI is associated with
pituitary hormone deciency, structural or systemic disease,
prognosis is determined by the natural history of the underlying
pathology and co-morbidities. HDI following trauma may
resolve.
9
NDI is difcult to treat, and the symptoms seldom
Aetiology of hypothalamic diabetes insipidus
Primary Genetic Wolframs syndrome, autosomal
dominant, autosomal recessive
Developmental
syndromes
Septo-optic dysplasia
Idiopathic
Secondary Trauma Head injury, post-surgery
(transcranial, trans-sphenoidal)
Tumour Craniopharyngioma, germinoma,
metastases, pituitary
macroadenoma
Inammatory Sarcoidosis, histiocytosis,
meningitis, encephalitis,
infundibuloneurohypophysitis,
GuillaineBarre syndrome,
autoimmune
Vascular Aneurysm, infarction
Classication describes primary and secondary (acquired) causes. All result in
decreased production of vasopressin (AVP) through direct or indirect damage
to hypothalamic AVP magnocellular neurones.
Table 1
Diagnosis and classification of diabetes insipidus by
measurement of plasma vasopressin in response to
graded hyperosmolar stimulation
The shaded area depicts the normal-range response of plasma vasopressin
as plasma osmolality is raised. Patients with hypothalamic diabetes insipidus
have a response below the normal range. Those with dipsogenic diabetes
insipidus have a normal response. Patients with nephrogenic diabetes
insipidus have a response at the top of the reference range but coincident
urine osmolalities that are dilute, consistent with vasopressin resistance.
P
l
a
s
m
a

v
a
s
o
p
r
e
s
s
i
n
(
p
m
o
l
/
l
i
t
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)
20
15
10
0
Plasma osmolality (mOsmol/kg)
310 300 290 280 320
5
Nephrogenic
Dipsogenic
Hypothalamic
Figure 1
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respond completely. Future developments may further help early
diagnosis and guide appropriate intervention.
10
A
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