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What is diabetes insipidus?

Diabetes insipidus is a disease characterised by the passage of large volumes (>3L/24hrs) of dilute urine (osmolality <300 mOsmol/Kg)¹. It affects approximately 3 in 100,000 people². In some cases the volume of urine produced can be as much as 20 litres in a 24 hour period and therefore rapid dehydration can easily occur, leading to death if not managed appropriately. Diabetes insipidus has a number of causes and therefore use of the correct investigations is essential to reach a definitive diagnosis.


Pathophysiology

1. Vasopressin (antidiuretic hormone) is produced by the hypothalamus in response to increased serum osmolality.

2. Vasopressin is then transported to the posterior pituitary gland.

3. Vasopressin is then released into the circulatory system via the posterior pituitary gland.

4. Vasopressin then travels to the kidneys where it binds to vasopressin receptors on the distal convoluted tubules.

5. This causes aquaporin-2 channels to move from the cytoplasm into the apical membrane of the tubules:

  • These aquaporin-2 channels allow water to be reabsorbed out of the collecting ducts and back into the bloodstream.
  • This results in both a decrease in volume and an increase in osmolality (concentration) of the urine being excreted.

6. The extra water that has been reabsorbed re-enters the circulatory system, reducing the serum osmolality.

7. This reduction in serum osmolality is detected by the hypothalamus and results in decreased production of vasopressin.


Causes

Neurogenic

Diabetes insipidus can occur as a result of decreased circulating levels of vasopressin (ADH). Vasopressin is responsible for instructing the kidneys to retain fluid, therefore decreased circulating levels of ADH results in the production of copious volumes of urine.  Vasopressin is produced by the hypothalamus and released by the posterior pituitary gland, meaning damage to either of these structures can cause diabetes insipidus.

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Familial

Mutations in the Vasopressin gene   (e.g. Autosomal dominant AVP-NPII)¹

  • Results in inadequate production of functional Vasopressin

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Acquired¹

Tumours – Pituitary adenomas (20%) / Craniopharyngiomas / Metastases
Trauma – 17% of cases
Neurosurgery – 9% of cases
Infections – meningitis
Vascular – Sheehan’s syndrome
  • Complication of pregnancy in which the pituitary blood supply is ↓ causing necrosis of the gland
Sarcoidosis – formation of granulomas in pituitary
Haemochromotosis – deposition of iron in pituitary/hypothalamic tissue causing damage
Langerhans’ cell histiocytosis – proliferation of Langerhans cells which form lesions in many organs including pituitary stalk³
Idiopathic – 25% of cases.

Nephrogenic

The kidneys are responsible for reabsorbing fluid when antidu binds to their receptors.  Anything which interferes with this binding or damages the kidneys has the potential to cause diabetes insipidus.

 

Familial

X-linked recessive – mutations in the ADH receptor gene¹

Autosomal recessive – aquaporin-2 gene – aquaporin 2 is responsible for the reabsorption of water from urine 4

..

Acquired 

Metabolic – hypercalcaemia / hyperglycaemia / hypokalaemia
Drugs – lithium / demeclocycline – both interfere with the binding of ADH¹
Chronic renal disease
Amyloidosis
Post obstructive uropathy¹

Dipsogenic

Dipsogenic diabetes insipidus occurs as a result of hypothalamic disease or trauma. The hypothalamus is responsible for controlling thirst which is a key component of maintaining an appropriate fluid balance¹. As a result the individual is excessively thirsty regardless of their fluid status.  The individual therefore consumes large volumes of fluid which suppresses secretion of vasopressin and increases urine output.  It is dangerous to give a vasopressin analogue such as desmopressin in these circumstances as the individual will continue to feel thirsty and consume large volumes of fluids which could result in fluid overload.

 

Gestational

Gestational diabetes insipidus only occurs during pregnancy.  During pregnancy the placenta produces vasopressinase which breaks down vasopressin.  Gestational diabetes insipidus is therefore thought to be caused by overproduction of vasopressinase by the placenta causing a lack of functional vasopressin.

 

Primary polydipsia 

Primary polydipsia is characterised by an individual consuming large volumes of fluids and as a result producing large volumes of dilute urine.  The symptoms of primary polydipsia are therefore very similar to those of diabetes insipidus however a fluid deprivation test can help distinguish the diseases.  Most often primary polydipsia is due to a behavioural disorder.


Symptoms and signs

Symptoms

Excessive urination (>3L/24hrs)

Excessive thirst (especially for ice cold water)

Nocturia

Dehydration – headache / dizziness / dry mouth

Signs

Hypotension

Dilute urine

Reduced capillary refill time


Investigations

Measure urine output – confirm more than 3000ml a day

Exclude diabetes mellitus – dipstick urine for glucose and assess blood glucose level

Exclude renal failure – check U&Es

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Check electrolyte levels

  • Hypokalaemia and Hypercalcaemia – nephrogenic DI¹
  • Hypernatraemia can develop due to dehydration

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Fluid deprivation test¹
  • Helps determine cause of DI – neurogenic / nephrogenic / primary polydipsia
  • Patient is allowed fluids overnight
  • Patient is then deprived of fluids for 8 hours (or until loss of 5% of body weight if earlier)
  • The patient is weighed hourly
  • Plasma osmolality is measured every 4 hours
  • Urine volume and osmolality is measured every 2 hours
  • At the end of the deprivation period the patient is given 2mcg of intramuscular desmopressin
  • Urine volume and serum osmolality are then measured over the next 4 hours

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MRI head – pituitary adenomas / craniopharyngiomas

Diagnosis

  • The fluid deprivation test is the most useful in diagnosing diabetes insipidus (DI)
  • It can confirm the presence of DI and suggest which type of DI the individual likely has
  • If the serum osmolality is >305mOsm/kg at any point the patient has DI (stop test)

 

Table demonstrating patterns of urine osmolality in the fluid deprivation test and their corresponding likely diagnosis¹

Neurogenic

If the diagnosis is Neurogenic DI the urine osmolality will be low after fluid deprivation but normalise after desmopressin is given. This is because neurogenic DI is caused by the lack of vasopressin production therefore giving a synthetic form of vasopressin such as desmopressin normalises levels of the hormone resulting in the normalisation of serum and urine osmolality.

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Nephrogenic

If the diagnosis is nephrogenic DI then the urine osmolality will remain low throughout regardless of desmopressin.  This is because the kidneys have a problem which prevents them from being able to respond to vasopressin.

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Primary polydipsia

If the diagnosis is primary polydipsia the urine osmolality will remain high after fluid deprivation as well as after desmopressin is given.  This is because the patient’s vasopressin axis is intact and otherwise completely normal.

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Partial DI or polydipsia

If the diagnosis is that of partial DI or polydipsia the picture may be mixed.  The patient may have a slightly low osmolality after fluid deprivation and may not reach normal urine osmolality after desmopressin.  This kind of picture would require more thorough investigation to determine a definitive cause.


Management

Neurogenic

Desmopressin¹

  • Vasopressin analogue
  • Binds to v2 receptors on kidney allowing water to be reabsorbed
  • Drug can be given orally, intranasally, parenterally or buccally
  • Dose varies significantly between patients
  • Serum osmolality and serum sodium need monitoring – can cause hyponatraemia or hypo-osmolality

 

Nephrogenic

Advise patient to maintain adequate fluid intake

Correct any metabolic derangements –  hypercalcaemia, hyperglycaemia, hypokalaemia¹

Stop any drugs that may be to blame –  lithium, demeclocycline – both interfere with the binding of ADH¹

High dose desmopressin

Thiazide diuretics / prostaglandin synthase inhibitors – reduce action of prostaglandins which can inhibit the action of vasopressin on the kidneys¹.

 

Partial diabetes insipidus

Advise patient to maintain adequate fluid intake – usually no drugs required

  • Thirst mechanism must be normal¹
  • Polyuria must be mild (<4L/24hrs)

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Primary polydipsia

Often very difficult to manage.

The underlying psychiatric disorder needs to be treated .


References

1. Oxford handbook of Endocrinology & Diabetes

2. Saborio, P.; Tipton, G. A.; Chan, J. C. M. (2000). “Diabetes Insipidus”. Pediatrics in Review 21 (4): 122–129

3. Makras P, Papadogias D, Kontogeorgos G, Piaditis G, Kaltsas G (2005). “Spontaneous gonadotrophin deficiency recovery in an adult patient with Langerhans cell histiocytosis (LCH)”. Pituitary 8 (2): 169–74

4. Wildin, Robert (2006). What is NDI?. The Diabetes Inspidus Foundation