Diabetes insipidus (arginine vasopressin deficiency)

Definition

In arginine vasopressin deficiency (AVP-D), formerly central diabetes insipidus, the hormone vasopressin (ADH) is completely or partially lacking. The kidneys cannot concentrate urine adequately, resulting in large volumes of very dilute urine (polyuria) and intense thirst (polydipsia).

It is distinguished from arginine vasopressin resistance (AVP-R, formerly nephrogenic diabetes insipidus), in which vasopressin is present but the renal tubules do not respond adequately. Both forms may be complete or partial.

Classification

Forms and causes

• Primary AVP-D: markedly reduced vasopressin synthesis in the hypothalamic nuclei; autosomal dominant forms due to changes in the vasopressin gene on chromosome 20, many cases idiopathic; Wolfram syndrome (with diabetes mellitus, optic atrophy and sensorineural deafness).
• Secondary (acquired) AVP-D: after surgery on the pituitary, head injury (especially basal skull fractures), suprasellar and intrasellar tumors or metastases, Langerhans cell histiocytosis, lymphocytic hypophysitis, granulomas (sarcoidosis, tuberculosis), vascular lesions (aneurysm, thrombosis) and infections (encephalitis, meningitis).
• Gestational: in the second half of pregnancy placental vasopressinase degrades vasopressin; with limited hypothalamic capacity, polyuria and polydipsia develop.
• AVP-R: inherited, usually X-linked (vasopressin V2 receptor gene), rarely autosomal (aquaporin-2 gene); acquired e.g. in hypercalcemia, chronic hypokalemic nephropathy, polycystic kidney disease, sickle cell nephropathy, amyloidosis, Sjögren syndrome, myeloma or drug-induced.

Aetiopathogenesis

Vasopressin is synthesised in the supraoptic and paraventricular nuclei of the hypothalamus and stored and released by the posterior pituitary. The main stimuli for release are rising plasma osmolality and volume depletion. Vasopressin increases the water permeability of the distal tubule and thus conserves water.

As long as about 10 % of neurosecretory neurons remain intact, AVP-D does not develop. AVP-D therefore always requires damage to the hypothalamic nuclei or a major part of the pituitary stalk. It is rare in primary disorders of the anterior pituitary but common with lesions of the stalk and hypothalamus.

Clinical features

• Onset is insidious or abrupt, at any age.
• The cardinal symptoms are polydipsia and polyuria; in primary AVP-D they are the only symptoms.
• Large volumes (3–30 l/day) of very dilute urine are excreted (specific gravity usually below 1.005, osmolality below 200 mOsm/kg).
• Nocturia is almost always present.
• If losses are not matched by drinking, dehydration and hypovolaemia develop rapidly. People without free access to water or unable to express thirst (infants, older people with dementia) develop hypernatremia with neurological symptoms up to seizures and coma.
• In secondary AVP-D, signs of the underlying lesion are also present.

Diagnosis

Investigations

• 24-hour urine: polyuria above 50 ml/kg/day. A urine osmolality below 300 mOsm/kg indicates water diuresis (AVP-D or AVP-R), above 300 mOsm/kg solute diuresis, e.g. due to glycosuria.
• Serum sodium: only mildly raised (142–145 mmol/l) with free access to water.
• Water deprivation test: under constant medical supervision because severe dehydration may occur; measurement of body weight, serum osmolality and hourly urine osmolality. Stopped at orthostatic hypotension, weight loss of 5 % or more, or when urine osmolality no longer rises (less than 30 mOsm/kg). A desmopressin test with repeat urine measurement follows.
• Copeptin or vasopressin: at the end of dehydration or after saline loading, low in AVP-D and appropriately high in AVP-R; especially helpful in partial forms and equivocal water deprivation tests.
• Imaging: MRI of the hypothalamic–pituitary region to look for an acquired cause.

Interpreting the water deprivation test

• Normal: urine osmolality after dehydration very high (above 700–800 mOsm/kg), further rise after desmopressin below 5 %.
• Complete AVP-D: urine osmolality remains below plasma osmolality; rise after desmopressin of 50 to more than 100 %.
• Partial AVP-D: urine is concentrated above plasma osmolality (at least 300 mOsm/kg); rise after desmopressin of 15–50 %.
• AVP-R: no concentration above plasma osmolality; rise after desmopressin below 50 mOsm/kg, up to 45 % in the partial form.
• Primary polydipsia: usually no nocturia; with long duration, impaired concentration as in partial AVP-D, but no rise after desmopressin; basal vasopressin low.

Keep learning in the app

Further reading (open access)

1. MSD Manual Professional: Arginine Vasopressin Deficiency (Central Diabetes Insipidus)
2. MSD Manual Professional: Arginine Vasopressin Resistance
3. MSD Manual Professional: Generalized Hypopituitarism

Cross-references