Professor Peter Baylis
University of Newcastle

Control of body water balance requires adequate circulating concentrations of Vasopressin (the Anti-diuretic Hormone), a kidney responsive to vasopressin and an intact thirst mechanism. Vasopressin is synthesised in the Hypothalamus and transported along neurones to the posterior Pituitary gland. Water lost from the body causes the release of vasopressin to stimulate the kidneys to concentrate urine (conserve water). Thirst is also stimulated to increase water ingestion. When the body is water overloaded, vasopressin secretion is inhibited and excess water is removed in large volumes of dilute urine.

Plasma osmolality is a measure of solutes, such as sodium and glucose, circulating in the blood. As body water decreases plasma osmolality increases, as does the concentration of plasma sodium. Excessive body water causes plasma osmolality and plasma sodium to decrease.

Diabetes Insipidus (DI) is a condition characterised by the production of large volumes of dilute urine, with 24-hour urine volumes in excess of 2-3 litres. Three mechanisms can cause DI:

• Inappropriate excessive drinking (primary polydipsia or dipsogenic DI);
• Failure of the hypothalamus to produce adequate vasopressin (cranial DI); and
• Inadequate response of the kidney to normal circulating vasopressin (nephrogenic DI).

Methods of investigation in patients with excessive urine production include:

• Measurement of 24 hour urine output;
• Measurement of blood solutes, plasma osmolality, plasma sodium and other electrolytes and blood glucose;
• Water deprivation test;
• Measurement of plasma vasopressin response to osmotic stimulation with hypertonic saline infusion; and
• Therapeutic trial of Desmopressin (DDAVP), the synthetic drug used in the treatment of cranial DI.

Causes of cranial DI include:

• Genetic abnormalities: a number of mutations of the gene encoding vasopressin have been identified. Symptoms of genetic or familial cranial DI tend to occur between 6 months and 6 years after birth.
• Injury to the pituitary or hypothalamus, neurosurgery, craniopharyngiomas and inflammatory conditions of the hypothalamus, and occasionally pituitary tumours, can also cause cranial DI.

Treatment of cranial DI includes the following:

• Ensuring adequate intake of fluid by allowing patients to quench their thirst. Management of very mild cases of cranial DI can be confined to increased fluid intake without other specific treatments.
• Most patients will require drug therapy with DDAVP. This is a remarkably safe drug with very few side effects or complications. However, patients over-treated with DDAVP who continue to ingest water will develop Hyponatraemia (low plasma sodium), which indicates an increase in total body water. Symptoms of hyponatraemia can include dizziness, headaches and muscle cramps. Mild hyponatraemia may be asymptomatic so regular plasma sodium measurements are advisable.

If severe cranial DI is left untreated large volumes of urine pass through the renal tract and can cause bladder distension.

Matters discussed by the audience

• There are no dreadful consequences if a dose of DDAVP is missed. However, it is essential that patients drink to satisfy their thirst.
• If a patient is very sensitive to standard concentrations of DDAVP it may be advisable to dilute the standard dose 1:4. Optimal control of diabetes will include a urine output of approximately 2 litres per 24 hours with blood tests indicating normal plasma osmolality and plasma sodium.
• Drinking alcohol tends to reduce vasopressin secretion, which in turn causes an increase in urine output.
• Steroid deficiency (inadequate Hydrocortisone secretion) masks cranial DI symptoms or may reduce the amount of DDAVP required to control symptoms. It is essential that steroid deficient patients, usually due to hypopituitarism, are given adequate doses of steroids. This may unmask DI, which would then be treated with DDAVP.
• When the effect of DDAVP wears off many patients' thirsts increase but appetites reduce.
• The effects of oral DDAVP seem to last longer if taken without food.
• The ingestion of cold fluid quenches thirst more effectively than warm fluid.