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Diabetes insipidus
This uncommon disorder is characterised by the persistent excretion of excessive
quantities of dilute urine and by thirst. Diabetes insipidus is classified into two types:


cranial diabetes insipidus, in which there is deficient production of ADH by the
hypothalamus
nephrogenic diabetes insipidus, in which the renal tubules are unresponsive
to ADH.
Causes of diabetes insipidus
Cranial
Structural hypothalamic or high stalk lesion
Idiopathic Genetic defect
 Dominant (AVP gene mutation)
 Recessive (DIDMOAD syndrome-association of diabetes
insipidus with diabetes mellitus, optic atrophy, deafness)
Nephrogenic Genetic defect
 V2 receptor mutation
 Aquaporin-2 mutation

Cystinosis
Metabolic abnormality
 Hypokalaemia

Hypercalcaemia
Drug therapy

Lithium

Demeclocycline

Heavy metals
Poisoning
Chronic kidney disease
 Polycystic kidney disease
 Sickle-cell anaemia

Infiltrative disease
Clinical features
The most marked symptoms are polyuria and polydipsia. The patient may pass 5-20
L or more of urine in 24 hours. This is of low specific gravity and osmolality. If the
patient has an intact thirst mechanism, is conscious and has access to oral fluids,
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then he or she can maintain adequate fluid intake. However, in an unconscious
patient or a patient with damage to the hypothalamic thirst centre, diabetes insipidus
is potentially lethal. If there is associated cortisol deficiency, then diabetes insipidus
may not be manifest until glucocorticoid replacement therapy is given. The most
common differential diagnosis is primary polydipsia, caused by drinking
excessive amounts of fluid in the absence of a defect in ADH or thirst control.
Investigations
Diabetes insipidus can be confirmed if serum ADH is undetectable or the urine is not
maximally concentrated (i.e. is < 600 mOsm/kg) in the presence of increased plasma
osmolality (i.e. > 300 mOsm/kg). Sometimes, the diagnosis can be confirmed or
refuted by random simultaneous samples of blood and urine, but more often a
dynamic test is required. The water deprivation test is widely used, but an alternative
is to infuse hypertonic (5%) saline and measure ADH secretion in response to
increasing plasma osmolality. Thirst can also be assessed during these tests on a
visual analogue scale.
How and when to do a water deprivation test
Use

To establish a diagnosis of diabetes insipidus, and
differentiate cranial from nephrogenic causes


No coffee, tea or smoking on the test day
Free fluids until 0730 hrs on the morning of the test, but
discourage patients from 'stocking up' with extra fluid in
anticipation of fluid deprivation
No fluids from 0730 hrs
Attend at 0830 hrs for body weight, plasma and urine
osmolality
Record body weight, urine volume, urine and plasma
osmolality and thirst score on a visual analogue scale every
2 hrs for up to 8 hrs
Stop the test if the patient loses 3% of body weight
If plasma osmolality reaches > 300 mOsm/kg and urine
osmolality < 600 mOsm/kg, then administer DDAVP (see
text) 2 μg i.m.
Protocol





Interpretation




Diabetes insipidus is confirmed by a plasma osmolality >
300 mOsm/kg with a urine osmolality < 600 mOsm/kg
Cranial diabetes insipidus is confirmed if urine osmolality
rises by at least 50% after DDAVP
Nephrogenic diabetes insipidus is confirmed if DDAVP does
not concentrate the urine
Primary polydipsia is suggested by low plasma osmolality at
the start of the test
In primary polydipsia, the urine may be excessively dilute because of chronic diuresis
which 'washes out' the solute gradient across the loop of Henle, but plasma
osmolality is low rather than high. DDAVP should not be administered to patients with
‫احمد حسين جاسم‬.‫د‬
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primary polydipsia, since it will prevent excretion of water and risks severe water
intoxication if the patient continues to drink fluid to excess. In nephrogenic diabetes
insipidus appropriate further tests include plasma electrolytes, calcium and
investigation of the renal tract
Management
Treatment of cranial diabetes insipidus is with des-amino-des-aspartate-arginine
vasopressin (desmopressin, DDAVP), an analogue of ADH which has a longer halflife. DDAVP is usually administered intranasally. An oral formulation is also available
but bioavailability is low and rather unpredictable. In sick patients, DDAVP should be
given by intramuscular injection. The dose of DDAVP should be adjusted on the
basis of serum sodium concentrations and/or osmolality. The principal hazard should
be excessive treatment resulting in water intoxication and hyponatraemia.
Conversely, inadequate treatment results in thirst and polyuria. The ideal dose
prevents nocturia but allows a degree of polyuria from time to time before the next
dose (e.g. DDAVP nasal dose 5 μg in the morning and 10 μg at night).
The polyuria in nephrogenic diabetes insipidus is improved by thiazide diuretics (e.g.
bendroflumethiazide 5-10 mg/day), amiloride (5-10 mg/day) and NSAIDs (e.g.
indometacin 15 mg 8-hourly), although the last of these carries a risk of reducing
glomerular filtration rate.
DISEASES AFFECTING MULTIPLE ENDOCRINE GLANDS
Multiple endocrine neoplasia (MEN)
These rare autosomal dominant syndromes are characterised by hyperplasia and
formation of adenomas or malignant tumours in multiple glands. They fall into two
groups, Some other genetic diseases also have an increased risk of endocrine tumours;
for example, phaeochromocytoma is associated with von Hippel-Lindau syndrome and
neurofibromatosis type 1.
Multiple endocrine neoplasia (MEN) syndromes
MEN 1 (Werner's syndrome)



Primary hyperparathyroidism
Pituitary tumours
Pancreatic
neuro-endocrine
gastrinoma)
tumours
(insulinoma,
MEN 2 (Sipple's syndrome)
 Primary hyperparathyroidism
 Medullary carcinoma of thyroid
 Phaeochromocytoma
In addition, in MEN 2b syndrome there are phenotypic changes (including
marfanoid habitus, skeletal abnormalities, abnormal dental enamel, and
multiple mucosal neuromas).
MEN syndromes should be considered in all patients with two or more endocrine
tumours and in patients with solitary tumours who report other endocrine tumours in
their family. MEN 1 results from inactivating mutations in MENIN, a tumour
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suppressor gene on chromosome 11, whereas MEN 2 is caused by mutations in the
RET proto-oncogene on chromosome 10. This causes constitutive activation of the
membrane-associated tyrosine kinase RET, which controls the development of cells
that migrate from the neural crest. Different mutations causing loss of function of the
RET kinase are associated with Hirschsprung's disease . Genetic testing can be
performed on relatives of affected individuals, after appropriate counselling .
Individuals who carry mutations associated with MEN should be entered into a
surveillance programme. In MEN 1, this typically involves annual history, examination
and measurements of serum calcium, gastrointestinal hormones and prolactin; MRI
of the pituitary is performed at less frequent intervals. In individuals with MEN 2,
annual history, examination and measurement of serum calcium and urinary
catecholamine metabolites should be performed. Because the penetrance of
medullary carcinoma of the thyroid is 100% in individuals with a RET mutation,
prophylactic thyroidectomy should be performed in early childhood.
Autoimmune polyendocrine syndromes (APS)
Two distinct autoimmune polyendocrine syndromes are known: APS types 1 and 2.
Autoimmune polyendocrine syndromes (APS)*
Type 1 (APECED)




Addison's disease
Hypoparathyroidism
Type 1 diabetes
Primary hypothyroidism



Chronic mucocutaneous candidiasis
Nail dystrophy
Dental enamel hypoplasia
Type 2 (Schmidt's syndrome)
 Addison's disease
 Primary hypothyroidism
 Graves' disease
 Pernicious anaemia
 Primary hypogonadism




Type 1 diabetes
Vitiligo
Coeliac disease
Myasthenia gravis
The most common is APS type 2 (Schmidt's syndrome) which typically presents in
women between the ages of 20 and 60. It is usually defined as the occurrence in the
same individual of two or more autoimmune endocrine disorders, The mode of
inheritance is autosomal dominant with incomplete penetrance and there is a strong
association with HLA-DR3 and CTLA-4. APS type 2 may be further subdivided,
depending on the precise combination of endocrine disorders observed, but this is of
limited value.
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APS type 1, which is also termed autoimmune polyendocrinopathy-candidiasisectodermal dystrophy (APECED), is much rarer and is inherited in an autosomal
recessive fashion. It is caused by mutations in the autoimmune regulator gene
(AIRE). AIRE is responsible for the presentation of self-antigens to thymocytes in
utero, which is essential for the deletion of thymocyte clones that react against selfantigens and hence for the development of immune tolerance .