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 (Anti-Diuretic Hormone) is produced by the hypothalamus in response to increased serum osmolality
2. Vasopressin is then transported to the posterior pituitary gland
3. It is then released into the circulatory system via the posterior pituitary gland
4. It 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 & back into the blood stream.
- This results in both a decrease in volume & an increase in osmolality (concentration) of the urine been 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 & 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. Because vasopressin is produced by the hypothalamus & released by the posterior pituitary gland, pathology impacting either of these glands has the potential to 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
- Complication of pregnancy in which the pituitary blood supply is ↓ causing necrosis of the gland
- Proliferation of Langerhans cells which form lesions in many organs including pituitary stalk³
Nephrogenic
The kidneys are responsible for reabsorbing fluid when ADH 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 urine4
Acquired
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Dipsogenic
Dipsogenic diabetes insipidus is caused by a defect or damage to the hypothalamus causing malfunction of the thirst mechanism¹. 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 psychological disorder.
Symptoms & Signs
Symptoms
Excessive urination (>3L/24hrs)
Excessive thirst (especially for ice cold water)
Nocturia
Dehydration – headache, dizziness, fainting, 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 & assess blood glucose level
Exclude renal failure
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Check electrolyte levels
- Hypokalaemia & Hypercalcaemia – nephrogenic DI¹
- Hypernatraemia can develop due to dehydration
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- 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 & Osmolality is measured every 2 hours
- At the end of the deprivation period the patient is given 2mcg of IM Desmopressin
- Urine volume & Serum osmolality are then measured over the next 4 hours
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Diagnosis
The fluid deprivation test is the most useful in diagnosing diabetes insipidus
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 & 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 been able to respond to vasopressin, therefore giving extra synthetic vasopressin will have no effect.
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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
Give Desmopressin¹
- Vasopressin analogue
- Binds to v2 receptors on kidney allowing water to be reabsorbed
- Drug can be given orally, intranasally, parenterally or bucally
- Dose varies significantly between patients
- Osmolality & Serum Sodium need monitoring – can cause hyponatraemia or hypo-osmolality
Chlorpropamide & Carbamazepine - can be used to increase activity of vasopressin¹
Nephrogenic
Advise patient to maintain adequate fluid intake
Correct any metabolic derangement’s - hypercalcaemia, hyperglycaemia, hypokalaemia¹
Stop any drugs that may be to blame - lithium, demeclocycline - both interfere with the binding of ADH¹
High dose Desmopressin – up to 5mcg IM
Thiazide diuretics / Prostaglandin Synthase Inhibitors – reduce action of prostaglandins which can inhibit vasopressin’s action on the kidney¹
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
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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