Diabetes Insipidus (DI)

This is caused by hyposecretion of, or hyporesponsiveness to Anti Diuretic Hormone (ADH), i.e .arginine vasopressin.¹ ADH is synthesised in the hypothalamus and transported as neurosecretory vesicles to the posterior pituitary where it is released into the circulation, governed by plasma osmolality. Its deficiency or failure to act causes an inability to concentrate urine in the distal renal tubules; leading to the passage of copious volumes of dilute urine. Usually the sufferer passes >3litres/24 hours of low osmolality (<300 mOsmol/kg) urine.²

There are two types:

This is caused by a deficiency of circulation-osmoregulated ADH. It is usually due to disease of the hypothalamus or surrounding tissues. Posterior pituitary disease tends not to cause diabetes insipidus, as secretion continues in the hypothalamus, unless pituitary tumour extends above the sella, putting pressure on the hypothalamus.

Causes

Acquired

• Idiopathic (30%)
• Tumours (25%) - craniopharyngioma, germinoma, hypothalamic metastases (especially breast carcinoma), hypothalamic glioma, large pituitary tumours with suprasellar extension, lymphoma
• Intracranial surgery (20%)
• Head injury (16%)
• Granulomata - sarcoidosis, Tuberculosis, histiocytosis
• Infections - TB, encephalitis, meningitis, cerebral abscess
• Vascular disorders - haemorrhage/thrombosis, aneurysms, sickle-cell disease, Sheehan's Syndrome (post-partum pituitary necrosis)
• Post-radiotherapy

• DIDMOAD (Wolfram Syndrome) - autosomal recessive (combination of diabetes insipidus, diabetes mellitus, optic atrophy, deafness)⁴
• Autosomal dominant mutations of vasopressin gene

This is caused by renal hyporesponsiveness to adequate vasopressin levels. Causes include:

• Idiopathic
• Hypokalaemia
• Hypercalcaemia
• Drugs - e.g. lithium, demeclocycline and other antibiotics, chlorpropamide, glibenclamide, foscarnet, clozapine, antifungals, antivirals^6,7
• Renal tubular acidosis
• Pregnancy (due to combined renal hyposensitivity to ADH, increased elimination ADH by placenta, lowered thirst threshold and endocrine water retention)^8,9
• Familial - X-linked (V2 ADH-receptor gene) or autosomal recessive (Aqua Porin AQP2 gene - water channel in distal renal tubule)^2,10,11
• Chronic interstitial renal disease, post-obstructive uropathy, solute 'washout'

Symptoms

The predominant symptoms in older patients are polyuria (large output of urine with micturition up to every 30 minutes), polydypsia, nocturia, and, in children, enuresis. Infants tend to suffer failure to thrive, irritability, protracted crying, anorexia and fatiguability.

Signs

Bladder enlargement may occur. Signs of dehydration may be present. Confirm that the urine volume output >3 l/24 hours.

• Psychogenic polydypsia (PP)
• Osmotic diuresis (esp. diabetes mellitus)
• Diuretic abuse

• Biochemistry - plasma glucose, urea and electrolytes, and plasma and urine osmolality should all be measured.
• Fluid deprivation test with response to desmopressin - this should be used if glucose and electrolyte levels are normal. The patient is deprived of fluids for up to 8 hours or 5% loss of body weight, following which desmopressin (DDAVP) 2g IM is given. See Table I for interpretation of the results.
• Plasma vasopressin levels and osmolality in response to infusion of 5% hypertonic saline at 0.05 ml/kg/min for 2 hours may be measured in cases of diagnostic difficulty.
• A therapeutic trial of low dose desmopressin is another option, with careful monitoring of plasma osmolality or serum sodium. CDI patients improve, and those with NDI are unaffected. Those with PP develop hyponatraemia and may stop drinking.
• MRI of the pituitary, hypothalamus and surrounding tissues, including pineal gland may be contributory in helping to determine the underlying cause.

Non-drug

If the urine output is < 4 litres/24 hour specific therapy may not be required. However, patients should be advised that they must drink enough to satisfy their thirst. Metabolic abnormalities should be corrected. Medication regimes should be reviewed to identify any drugs likely to cause NDI.

Drugs

• CDI If a large urinary volume is produced use desmopressin orally, intranasally or injected. Monitor serum sodium or plasma osmolality to prevent hyponatraemia or hypo-osmolality from chronic overdose.
• Mild to moderate NDI Use high dose desmopressin
• Severe NDI¹³ Options include desmopressin plus:
  • Thiazides¹⁴
  • Chlorpropamide
  • Carbamazepine
  • Clofibrate
  • Indomethacin (limited efficacy)

Once diagnosed the condition should respond well to appropriate therapy. This should be initiated and supervised by a physician with appropriate experience.

Patients with diabetes insipidus need careful monitoring of fluid balance and therapy following surgery, with multidisciplinary care.^15,16,