Thirst and water regulation is largely controlled by ADH (vasopressin), which is synthesized in the hypothalamus, and then migrates in neurosecretory granules along axonal pathways to the posterior pituitary. Pituitary damage alone without hypothalamic involvement does not therefore lead to ADH deficiency as the hormone can still ‘leak’ from the damaged end of the intact axon. Changes in plasma osmolality are sensed by osmoreceptors in the anterior hypothalamus. Vasopressin secretion is suppressed at levels below 280 mosmol kg “, thus allowing maximal water diuresis. Above this level, plasma vasopressin increases in direct proportion to plasma osmolality. At the upper limit of normal (295 mosmol kg-I) maximum antidiuresis is achieved and thirst is experienced at about 298 mosmol kg-I. Other factors affecting vasopressin release.
At normal concentrations the kidney is the predominant site of action. Via a cyclic AMP mechanism it allows the collecting tubule to become permeable to water, thus permitting reabsorption of hypotonic luminal fluid. At high concentrations vasopressin also causes vasoconstriction. Disorders of vasopressin secretion or activity include:
• Deficiency as a result of hypothalamic disease (diabetes insipidus)
• Inappropriate excess of the hormone
• ‘Nephrogenic’ diabetes insipidus-a condition in
which the renal tubules are insensitive to vasopressin, an example of a receptor abnormality While all these are uncommon, they need to be distinguished from the occasional patient with ‘hysterical water drinking’ and those whose renal tubular function has been impaired by electrolyte abnormalities, such as hypokalaemia or hypercalcaemia.
Diabetes insipidus (01)
Deficiency of vasopressin leads to polyuria, nocturia and compensatory polydipsia. Daily urine output may reach as much as 10-15 litres, leading to dehydration that may be very severe if the thirst mechanisms are impaired or the patient is denied fluid.
Causes of Dr are listed. The commonest is hypothalamic-pituitary surgery, following which transient Dr is common, frequently remitting after a few days or weeks. Primary overdrinking (polydipsia) is a common differential diagnosis.
Dr may be masked by simultaneous cortisol deficiency- cortisol replacement allows a water diuresis and Dr then becomes apparent. DIDMOAD syndrome (Wolfram syndrome) is a rare recessive disorder comprising diabetes insipidus, diabetes mellitus, optic atrophy and deafness.
• High or high-normal plasma osmolality with low urine osmolality (in primary polydipsia plasma osmolality tends to be low)
• Resultant high or high-normal plasma sodium
• Failure of urinary concentration with fluid deprivation
• Restoration of urinary concentration with vasopressin or an analogue
The latter two points may be studied with a formal waterdeprivation
test (see Appendix). In normal subjects, plasma osmolality remains normal while urine osmolality rises above 700 mosmol kg-I. In Dr, plasma osmolality rises while the urine remains dilute, only concentrating after exogenous vasopressin is given (cranial Dr) or not concentrating after vasopressin if renal Dr is present. This test can give equivocal results and measurement of vasopressin during the test is helpful.
Cranial diabetes insipidus
Pituitary with suprasellar extension
Hypothalamic tumour, e.g. glioma
Metastases, especially breast
Base of skull fracture
Post radiotherapy (to head)
Nephrogenic diabetes insipidus
Renal tubular acidosis
Synthetic vasopressin (desmopressin, DDA VP) is the treatment of choice. It is given intranasally as a spray 10- 20 JLgonce to three times daily or intramuscularly 2-4 JLg daily. Response is variable and must be monitored carefully with fluid input/output charts and plasma osmolality measurements. An oral preparation, 0.1-D.2 mg daily, is now available with shorter action than the spray. Alternative agents in mild Dr, probably working by sensitizing the tubules to endogenous vasopressin, include thiazide diuretics, carbamazepine 200-400 mg daily or chlorpropamide (200-350 mg daily). These are rarely used, especially with the risk of hypoglycaemia from chlorpropamide.
Nephrogenic diabetes insipidus In this condition, renal tubules are resistant to normal or high levels of plasma vasopressin. It may be inherited as a sex-linked recessive or can be acquired as a result of renal disease, drug ingestion, hypercalcaemia or hypokalaemia. Wherever possible the cause should be reversed. Other causes of polyuria and polydipsia.
Diabetes mellitus, hypokalaemia and hypercalcaemia are diagnoses to be considered. In the case of diabetes mellitus the cause is an osmotic diuresis secondary to glycosuria and this leads to dehydration and an increased perception of thirst due to hypertonicity of the extracellular fluid.
Primary or hysterical polydipsia is a relatively common cause of thirst and polyuria. It is a psychiatric disturbance characterized by the excessive intake of water. Plasma sodium and osmolality fall as a result and the urine produced is appropriately dilute. Vasopressin levels become virtually undetectable. Prolonged primary polydipsia may lead to the phenomenon of ‘renal medullary washout’, with a fall in the concentrating ability of the kidney. Characteristically the diagnosis is made by a waterdeprivation test. A low plasma osmolality is usual at the start of the test, and since vasopressin secretion and action can be stimulated, the patient’s urine becomes concentrated (albeit ‘maximum’ concentrating ability may be impaired); the initially low urine osmolality gradually increases with the duration of the water deprivation.
Syndrome of inappropriate
antidiuretic hormone (SIADH)
The presentation is usually vague, with confusion, nausea, irritability and, later, fits and coma. There is no oedema. Mild symptoms usually occur with plasma sodium levels below 125 mmol litre”! and serious manifestations are likely below ll5 mmol Iitre” ‘.
The syndrome must be distinguished from those causing similar dilutional hyponatraemia from excess infusion of dextrose/water solutions or diuretic administration (thiazides or amiloride.
The usual features are:
• Dilutional hyponatraemia due to excessive water retention
• Low plasma osmolality with higher ‘inappropriate’ urine osmolality
• Continued urinary sodium excretion >30 mmol litre:”
• Absence of hypokalaemia (or hypotension)
• Normal renal and adrenal and thyroid function
The underlying cause should be corrected where possible. For symptomatic relief:
FLUID INTAKE should be restricted to 500-1000 ml daily.
PLASMA OSMOLALITY AND SODIUM AND BODY WEIGHT should be measured frequently.
IF WATER RESTRICTION IS POORLY TOLERATED OR INEFFECTIVE, demethylchIortetracycline (600- 1200 mg daily) may be given; this inhibits the action of vasopressin on the kidney causing a reversible form of nephrogenic diabetes insipidus. It may, however, cause photosensitive rashes.
WHEN THE SYNDROME IS VERY SEVERE, hypertonic saline (300 mmol litre ” slowly i.v.) is rarely given and frusemide may be used. These should be used with extreme caution by specialists.
Small-cell carcinoma of lung
SLE, systemic lupus erythematosus.