Diabetes insipidus

There are two major forms of DI:

• Cranial DI: decreased secretion of ADH. Decreased secretion of ADH reduces the ability to concentrate urine and so causes polyuria and polydipsia.

• Nephrogenic DI: decreased ability to concentrate urine because of resistance to ADH in the kidney.

There are two other forms of DI (both caused by deficiencies in ADH; however, the deficiencies do not result from a defect in the neurohypophysis or kidneys):

• Gestational DI: results from degradation of vasopressin by a placental vasopressinase¹ . Gestational DI may be associated with increased complications of pregnancy, including pre-eclampsia.

• Primary polydipsia (dipsogenic DI): caused by a primary defect in osmoregulation of thirst. Dipsogenic DI has been reported in tuberculous meningitis, multiple sclerosis and neurosarcoidosis.

Epidemiology

• The combined prevalence of cranial DI and nephrogenic DI combined is estimated at 1 in 25,000² .

• DI can complicate up to 1 in 30,000 pregnancies³ .

• Nephrogenic DI is the most common adverse effect of lithium and occurs in up to 40% of patients⁴ .

• Inherited causes account for approximately fewer than 10% of all cases of DI.

Aetiology⁵

Cranial DI

This is usually due to disease of the hypothalamus or surrounding tissues. Posterior pituitary disease tends not to cause DI, as secretion continues in the hypothalamus, unless a pituitary tumour extends above the sella, putting pressure on the hypothalamus. See also the separate Hypopituitarism article.

• Acquired:
  

  • Idiopathic.

  • Tumours - craniopharyngioma, germinoma, hypothalamic metastases (especially breast carcinoma), hypothalamic glioma, large pituitary tumours with suprasellar extension, lymphoma (see the separate Brain Tumours in Adults and Brain Tumours in Children articles).

  • Intracranial surgery.

  • Head injury.

  • Granulomata - sarcoidosis, tuberculosis (TB), granulomatosis with polyangiitis (granulomatosis with polyangiitis), histiocytosis.

  • Infections - encephalitis, meningitis, cerebral abscess.

  • Vascular disorders - haemorrhage/thrombosis, aneurysms, sickle cell disease, Sheehan's syndrome (postpartum pituitary necrosis).

  • Post-radiotherapy.

• Inherited:
  

  • Autosomal recessive combination of DI, diabetes mellitus, optic atrophy, deafness (DIDMOAD) - Wolfram's syndrome⁶ .

  • Autosomal dominant mutations of vasopressin gene.
    

Nephrogenic DI

• Acquired nephrogenic DI:
  

  • Idiopathic.

  • Hypokalaemia.

  • Hypercalcaemia.

  • Chronic kidney disease.

  • Other metabolic derangements.

  • Drugs - eg, ofloxacin, orlistat, lithium⁴ .

  • Renal tubular acidosis.

  • Pregnancy (combined renal hyposensitivity to ADH, increased placental elimination of ADH, lowered thirst threshold and effect of fluid retention)⁷ .

  • Post-obstructive uropathy.

• Congenital/genetic nephrogenic DI:
  

  • X-linked mutation in V2 ADH-receptor gene⁸ .

  • Autosomal recessive defect in aquaporin 2 (AQP2) gene - water channel in distal renal tubule⁹ .

  • Sporadic nephrogenic DI with general learning disability and intracerebral calcification (exceedingly rare)¹⁰ .

Presentation

Symptoms

The onset of symptoms can be vague and insidious, such that the person affected may suspect nothing untoward, despite having a urinary volume that would be very troubling had it come on acutely:

• Patients may experience marked polyuria. The daily urine volume is relatively constant for each patient but polyuria is generally defined as urine output exceeding 3 litres per day in adults.

• Polydipsia and chronic thirst are usually a feature and there may be a predilection for very cold drinks, and usually water.

• Nocturia occurring several times per night is common, particularly in older adults. Children may develop nocturnal enuresis, where they have previously been continent.

• Infants may present with irritability, failure to thrive, protracted crying, fever, anorexia and fatiguability or feeding problems.

• If there is damage to the bladder through chronic overdistension, then urinary incontinence may ensue. This is a particular problem in those who have inborn causes of nephrogenic DI, particularly AQP2 mutations.

Signs

• There may be signs of dehydration and the bladder can be grossly enlarged and palpable.

• 24-hour urinary collection will show urine volume >3 litres/24 hours.

Differential diagnosis

Other causes of polyuria and thirst¹¹ .

• Psychogenic or primary polydipsia (PP).

• Diabetes mellitus.

• Cushing's syndrome.

• Hypercalcaemia.

• Hyperkalaemia.

• Diuretic abuse.

Investigations⁵

See also the separate Pituitary Function Tests article.

• Biochemistry - plasma glucose, U&Es, urine specific gravity and and simultaneous plasma and urine osmolality.

• 24-hour urine collection to measure urine volume.

• Fluid deprivation test with response to desmopressin. The patient is deprived of fluids for up to eight hours or 5% loss of body weight, following which desmopressin (DDAVP®) 2 micrograms (IM) is given. See the table below for interpretation of the results.

• MRI of the pituitary, hypothalamus and surrounding tissues, including the pineal gland, may be contributory in helping to determine the underlying cause.

• Renal tract ultrasound or intravenous pyelogram (IVP) may be used to assess for obstructive complications caused by the high urinary back-pressure.

Classification of causes of diabetes insipidus on basis of water deprivation and DDAVP® response

Management

Cranial DI

• As the primary problem is a hormone deficiency, physiological replacement with desmopressin is usually effective. This can be given orally, intranasally or parenterally.

• Mild cases of DI (urine output 3-4 litres/24 hours) can be managed by ingestion of water to quench thirst.

• It is essential to avoid chronic overdosage with desmopressin, which will cause hyponatraemia.

• Long-term management:
  

  • Because of the risk of hyponatraemia, occasional (1- to 3-monthly) measurements of serum sodium are advised.

  • Some endocrinologists recommend missing desmopressin treatment one day each week to avoid the development of hyponatraemia.

Nephrogenic DI¹¹

• If daily urine volume is <4 litres/24 hours and the patient does not have severe dehydration then definitive therapy is not always necessary.

• It is important for patients always to have access to drinking water and to drink enough to satiate their thirst.

• Correct any metabolic abnormality.

• Stop any drugs that may be causing the problem.

• High-dose DDAVP® may be used with success in mild-to-moderate cases of nephrogenic DI.

• Combination treatment with a thiazide diuretic and a non-steroidal anti-inflammatory drug may be effective in reducing the volume of urine produced.

• Patients with nephrogenic DI undergoing surgery need careful multidisciplinary management with close attention to fluid regimens and DDAVP® administration.

• Patients with genetic causes or severe nephrogenic DI may need to practise clean, intermittent catheterisation to reduce urinary tract back-pressure complications.

Complications

• DDAVP® can worsen myocardial ischaemia in susceptible patients; there may be a need for nitrates/other anti-anginal medications.

• Patients with DI need careful monitoring of fluid balance and therapy following surgery, with multidisciplinary care.

• Patients with genetic causes of nephrogenic DI are prone to bladder dysfunction and hydro-ureter/hydronephrosis if the condition is undiagnosed or untreated for an appreciable period of time¹² .

Prognosis

• Outlook is usually very good once treatment or correct fluid management has been instituted¹³ . Specialist follow-up is required to monitor for complications and response to therapy.

• Death is rare in adults, as long as water is available. Affected children, the elderly and any adult with acute illness or surgery are more at risk of severe dehydration, hypernatraemia, fever, cardiovascular collapse and death.

• Patients with inborn errors are more likely to experience complications as the underlying cause cannot be removed.

Prevention

It is important to monitor for the complication of lithium use through at least annual review of symptoms of nephrogenic DI and 24-hour urinary volume measurement. Patients on lithium should be made aware of this potential complication and warned about symptoms that should prompt them to seek medical review.