Dr. Donald Perry-Keene, Endocrinologist, Brisbane
What is Diabetes Insipidus (DI)?
Diabetes insipidus is a condition of excessive thirst (polydipsia) due to excessive urine output (polyuria) causes by deficiency of production or action of AVP.
Complete DI leads to large volume loss, and severe dehydration that is life threatening if not recognised and treated immediately.
Partial DI may be mild - just a nuisance, requiring the patient to drink more water to maintain hydration – or moderate, requiring treatment.
Before considering DI further, some knowledge of normality is required.
Some background physiology:
The normal mechanism for water conservation by the body is:
- Recognition of thirst – this depends on the osmolality of blood being interpreted by the thirst centre in the hypothalamus.
- Dehydration causes a rise in osmolality. This stimulates the thirst centre by increase in osmolality from an individual’s set-point activating the production of vasopressin-neurophysin in the cells of the neurohypophysis. This compound is cleaved into the two component molecules migrating own the nerve fibres, with release of both neurophysin2 and AVP from the posterior pituitary.
- AVP circulates in blood and is uniquely recognised by the specialised AVP receptor (AVPR V2) in the cell membrane of the collecting duct part of the renal tubule.
- Binding of AVP to its receptor activates a complex process within the cell which allows transit of water from within the hollow tubule through the cell back into the blood (water reabsorption).
- Aquaporins 3 and 4 are cell surface molecules activated by the process of AVP stimulation. They actively transport the water through the tubule cell from the tubule lumen back into the blood vessels. Thus the osmolality of blood is maintained within very tight margins – 280 to 290 milliosmols/l, and whereas about 180 litres of urine are produced by the kidney per day, the renal tubules do a fine reabsorption job in reducing that huge volume to an average 1.5 litres/day of concentrated urine. Body hydration is thus maintained – remembering that 66% of our body is water. AVP is essential in this process.
DI can be further subdivided into:
Central or cranial DI – due to deficiency of production of AVP from the posterior pituitary, Nephrogenic DI – due toineffective action of AVP at the renal tubule level.
A condition called Primary Polydipsia (habitual excessive water intake, usually in excess of 5-6 litres per day) can mimic DI but is driven by intake rather than failure of urinary concentration, and must be excluded by Doctors by appropriate history and investigation.
Diagnosis of DI
DI is suspected clinically because of excessive thirst and polyuria, usually occurring quite abruptly, with a preference for cold water to slake the thirst. Measuring the urine volume over a day can be helpful to document excess, particularly in cases of partial DI.
When suspected, appropriate investigations include:
- Measurement of blood and urine concentration (osmolality) at the same time – this is best done first thing in the morning. In severe cases immediate sampling at the time of presentation may be sufficient to confirm the diagnosis.
- If not simply confirmed, then a water deprivation test is done.
- At the time of diagnosis, distinction of cranial from nephrogenic DI should occur by observing the effect of a test dose of desmopressin on plasma and urine osmolality.
Principles of a water deprivation test.
This involves close observation of the patient by staff during the test.
- Initial samples of blood (plasma) and urine are taken to measure sodium (Na) levels and osmolality, and urine specific gravity (SG). SG is a simple bedside test to track progress. Weight is measured at each sample time. Food and water are withheld for the duration of the test.
- Depending on severity, hourly or second hourly sampling is done until either urine osmolality stabilises at inappropriately dilute levels while plasma osmolality is higher than normal, or if weight declines by 5% or more.
- The test is terminated by the administration of desmopressin, allowing the patient to drink, and measuring the blood and urine again following that.
For infants with DI, usually congenital nephrogenic DI, water deprivation is hazardous, and diagnosis should be made on an immediate blood and urine sample and response (or lack of response) to desmopressin.
Confirmation of the diagnosis of DI.
DI is confirmed if, at any time, urine is found to be inappropriately dilute in the presence of elevated (>295 or 300 mosm/kg) plasma osmolality.
With cranial DI the urine will concentrate and plasma osmolality normalise after administration of desmopressin.
Nephrogenic DI is distinguished by lack of response to desmopressin.
When DI is confirmed, treatment should commence using desmopressin for cranial DI, or other options for nephrogenic DI as described below.
Causes of DI
This can be “idiopathic” most likely autoimmune, or due to injury to the neurohypophysis by trauma of head injury, pituitary and suprasellar tumours, surgery to the pituitary or hypothalamus, or infiltrative or inflammatory disorders such as sarcoidosis, histiocytosis, or infundibulo-hypophysitis. The commonest tumour presenting in childhood is craniopharyngioma.
Magnetic Resonance Imaging (MRI) of the region assists in diagnosis of cause.
Resistance to the action of AVP at the kidney tubule can by genetic, usually appearing in infancy or early childhood, or acquired, usually in adult life.
Genetic causes can be X chromosome linked mutations of the AVPR2 gene, or autosomal recessive or dominant mutations affecting the Aquaporin-2 gene.
Acquired DI can be seen in patients with hypercalcaemia (high calcium levels in blood) – reversible with correction of calcium, or those taking chronic lithium therapy – which is usually irreversible. Rarely amyloidosis, sarcoidosis and other conditions can cause nephrogenic DI.
Treatment of DI
Treatment focuses on relief of symptoms of thirst and polyuria. If mild, simply encouraging regular and increased fluid intake in response to thirst is sufficient.
Desmopressin is given in doses that relieve thirst by appropriately concentrating the urine and preventing polyuria. The initial object is to relieve polyuria overnight allowing a good sleep pattern by administering an evening dose. If required a morning dose is given and is invariably required in complete DI. Desmopressin has an action time of 12 or more hours, so should not need to be given more often than twice per day.
As well as correcting thirst, occasional checks of serum Na should be done under medical guidance to ensure dosage safety. Overdosage plus too much fluid intake can lead to hyponatraemia (too low blood sodium), with adverse consequences.
Desmopressin is available in several forms, and is PBS subsidised for cranial DI. These include:
- Nasal solution for puffing into the nose for absorption by the nasal membrane, with ability to vary the dose.
- Nasal pump spray which conveniently delivers a dose of 10micrograms per puff.
- Tablets taken orally.
- An injectable preparation used in hospitals when it is not possible to use the above preparations, for example after nasal or pituitary surgery.
The dose administered under medical supervision is determined by response, and, once established, does not usually change, and for most people needs to be taken permanently.
Under some circumstances cranial DI may not be permanent, and desmopressin can be withdrawn.
Temporary DI may be seen immediately after pituitary or related surgery, after head injury, or with recovery from neurohypophysitis. This depends on the level at which injury occurs in the neurohypophysis.
Higher level injury at hypothalamus or at the base of the pituitary stalk is more likely to cause permanent loss of ADH secretion.
Another circumstance where temporary DI can be seen is during pregnancy in females who have partial DI, either cranial or nephrogenic which is mild, even unrecognised, and compensated by increased fluid intake. The normal placenta in pregnancy produces vasopressinases (proteins that break down AVP) and if there is borderline deficiency before pregnancy, then DI requiring therapy with desmopressin (which is not broken down) is needed during such pregnancy. This may apply to women with a past history of temporary DI after pituitary surgery.
Because the kidney is unresponsive to the action of AVP, other strategies are used with variable success. These include –
Restriction of salt and protein in diet to reduce the filtered load of solute for the kidney. Protein restriction is difficult to achieve in very young children.
The next step is the use of a thiazide diuretic. Non steroidal anti-inflammatory agents such as indomethacin can be useful.
The addition of high dose desmopressin to the above measures may be required.
Research into substitutes for, or compounds activating AVPR2 or aquaporin, is in progress.
Special issue and caution
When a person with DI cannot respond to thirst by drinking, that person is in danger.
This must be considered during any fasting procedure as for endoscopy or operation, or if unconscious for any reason. Desmopressin must be continued, and careful supervision of fluid balance attended by medical or paramedical staff if necessary with intravenous fluids.
Particular danger exists for those rare DI patients who, after head injury or brain surgery, also have lost their sense of thirst, and cannot themselves detect a need to drink. Their fluid intake needs to be closely regulated by on the clock regular intake of measured amounts, supervised by others if necessary.
As in anyone requiring life essential medication, every patient with DI should wear or carry some form of Medical Alertto warn other carers of that need.
Some terms used:
ADH = antidiuretic hormone also AVP (arginine vasopressin) – the hormone produced by the posterior pituitary, circulates in blood and acts on the kidney to promote water reabsorption.
Anterior = at the front.
Aquaporin = a renal tubule cell protein, activated by ADH, producing active water reabsorption
Central or Cranial = from the head end of the system.
Diabetes – from the Greek “diabatuw” = to go through – in this case much urine:
Mellitus = of honey - as in sweet tasting glucose in urine (glycosuria) ie “sugar diabetes”.
Insipidus = spurious, not having glycosuria.
Diuresis = increased flow of urine. Therefore Antidiuresis = reduced flow of urine.
Hypothalamus = the lower part of the forebrain intimately linked to the pituitary.
Infundibulum = lower part of the hypothalamus including the pituitary stalk.
Nephrogenic = of the kidney – the lower end of the system.
Neurophysin (N) = part of a larger molecule co-released with ADH (N2) or oxytocin (N1)
Osmotic = concentration effect due to dissolved substances in a fluid:
Hyperosmotic – high concentration.
Hypoosmotic – low concentration.
Isosmotic – normal concentration.
Pituitary = the master hormone producing gland in the head:
Anterior – derived from gut structure and controlled by hypothalamic releasing hormones.
Posterior – extension of brain tissue – directly releases ADH, oxytocin and neurophysin.
Polydipsia = increased fluid intake, as in excessive thirst.
Polyuria = increased urine output.
Posterior = at the back.
Primary = first or main problem or source of problem.
Renal = of the kidney.
Secondary = a consequence from another problem.
Stalk = that part of the pituitary complex linking hypothalamus with pituitary – has vascular and neural tissue components.
Tubule = that part of the kidney’s microscopic structure where exchanges of water and other compounds occurs.
120 ARETAEUS of Capadocia – described diabetes (mellitus).
1020 AVICENNA – noted sweet taste of urine in diabetes mellitus.
1674 Thomas WILLIS coined the term diabetes mellitus (verus or true as in glycosuria).
1794 Johann Peter FRANK recognised diabetes insipidus (spurious, not having glycosuria).
1877 Samuel GEE noted congenital (familial) diabetes insipidus - later proven nephrogenic.
1908 SCHAEFER and HERRING described a diuretic principle in posterior pituitary.
1912 Alfred Erich FRANK showed the posterior pituitary (PP) to be neural tissue.
1928 KAMM et al identified separate oxytocic and vasopressin compounds in the PP.
1954 du VIGNEAUD et al – analysis and synthesis of oxytocin and vasopressin.
1956 ACHER et al – demonstrated neurophysins co-secreted with oxytocin and AVP.
1973 Synthesis and use of desmopressin, replacing pitressin tannate in oil (injected) and short acting nasal spray lysine vasopressin.