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How to spot zebras - diabetes insipidus

Dr Niki Karavitaki with advice on spotting diabetes insipidus

Diabetes insipidus is a condition attributed to deficient synthesis or release of arginine vasopressin (AVP) (cranial or central diabetes insipidus) or to renal insensitivity or resistance to the actions of AVP (nephrogenic diabetes insipidus).

AVP is a peptide synthesised in the hypothalamus. One of its main actions is the control of water metabolism through the regulation of water resorption in the kidneys. Diabetes insipidus can be acquired or familial. The most common causes are shown in the table below.

Causes of DI

Central DINephrogenic DI

Neurosurgical interventions

Drug induced (e.g., lithium, demeclocycline, cisplatin)

Traumatic brain injury

Metabolic (hypercalcaemia, hypokalaemia)

(Para)sellar tumours (e.g., craniopharyngioma, germinoma)

Infiltrative diseases (e.g., renal amyloidosis, renal sarcoidosis, multiple myeloma, Sjögren’s disease)

Vascular (e.g., aneurysm, arteriovenous malformations, subarachnoid haemorrhage)

Vascular (sickle cell disease)

 

Infections (e.g., meningitis, encephalitis)

Genetic causes (e.g., aquaporin-2 defects [autosomal recessive], AVP V2-receptor defect [X-linked recessive])

Infiltrative/inflammatory diseases (eg, sarcoidosis, histiocytosis, lymphocytic hypophysitis)

Chronic renal disease (e.g., polycystic kidneys)

Metastasis to pituitary gland (particularly breast and lung cancer)

 

Autoimmune

 

Genetic causes (e.g., vasopressin-neurophysin gene mutations [autosomal dominant], DIDMOAD syndrome [diabetes insipidus, diabetes mellitus, optic atrophy, deafness] [autosomal recessive], X-linked recessive)

 

Congenital (e.g., septo-optic dysplasia)

 

Drug/toxin induced (e.g., ethanol, snake venom)

 

Idiopathic

 

Prevalence

Diabetes insipidus is uncommon althoughaccurate epidemiological data are not available. Acquired central diabetes insipidus usually results from transsphenoidal surgery or head trauma. After pituitary surgery, 20-30% of the patients develop transient central diabetes insipidus and 2–10% of them have permanent disease. Based on data from Denmark, the prevalence of medically treated central diabetes insipidus is 7-10/100,000 population.

Presentation

Diabetes insipidus presents as:

  • Hypotonic polyuria – >3l of dilute urine (urine osmolality <300mOsmol/kg) per 24 hours.
  • Polydipsia.
  • Nocturia with craving for cold fluids.
  • Also, in children, nocturnal enuresis and failure to thrive.

Dehydration and hypovolaemic hypernatraemia will develop if thirst response is not intact and the patient has no free access to water to compensate renal fluid losses. Hypotonic polyuria is the most important biochemical finding that should initially make the GP consider diabetes insipidus in a patient who complains of polyuria.

Differential diagnosis

Differential diagnosis includes diuretic use and other conditions causing polyuria such as psychogenic polydipsia, diabetes mellitus and renal failure.

Investigation

The diagnosis of diabetes insipidus should be considered in patients who are excreting large volumes of dilute urine and have polydipsia. While the presence of diabetes insipidus may be obvious in the appropriate clinical scenario (for instance, after pituitary surgery), in cases with a not previously known pathology able to cause this condition, diagnostic delays may be encountered. Initial investigations include confirmation of polyuria with 24-hour urine collection. Further tests after this include blood sampling for assessment of kidney function, sodium, potassium, calcium, glucose and measurement of urine and serum osmolalities, (combined with urine dipstick for glycosuria); these tests need to be done simultaneously.

Features of volume depletion should be looked for (dry mucous membranes, tachycardia, hypotension), although these may be absent when there is unrestricted access to water and an intact thirst centre. History will guide for hypothalamo-pituitary pathology (headaches, visual deterioration, manifestations of anterior hypopituitarism, presence of systemic infiltrative disease) or for conditions causing nephrogenic diabetes (see left).

Diagnosis

The diagnosis in a patient with polyuria is strongly suggested by the presence of high serum osmolality (>295mOsm/kg) and low urine osmolality (<300mOsm/kg) after exclusion of hyperglycaemia. Delay in diagnosis may lead to dehydration and hypernatraemia, with adverse sequelae. In cases with partial inability to concentrate urine, these tests may not be diagnostic and investigations in specialised units will be needed.

Follow-up

The gold standard test for confirming diabetes insipidus is the water deprivation test. This assesses the ability to concentrate urine during controlled water deprivation and is then followed by assessment of response to desmopressin (DDAVP, a synthetic AVP analogue) to confirm renal sensitivity, facilitating the differential diagnosis between central and nephrogenic diabetes insipidus.

In cranial diabetes insipidus, imaging of the hypothalamo-pituitary area and assessment of the pituitary function are needed and the results will guide further investigations. In cases with mild polyuria (<4l/24 hours), patients with an intact thirst mechanism can be managed by advising an adequate fluid intake. With more severe symptoms, treatment includes administration of DDAVP (subcutaneously, orally, intranasally or sublingually as a melt) in individualised therapeutic schedules (the lowest dose that allows adequate rest at night and causes minimal disruption of individual daytime activities). Patients should be educated about the risk of overdosing and hyponatraemia.

In nephrogenic diabetes insipidus, underlying causes should be corrected and causative drugs withdrawn,

although their effects are not always reversible. Patients should maintain adequate fluid intake. High-dose DDAVP may be effective in partial nephrogenic diabetes insipidus. Thiazide diuretics can also be helpful. In addition, prostaglandin synthase inhibitors, such as indometacin, may be effective as prostaglandins locally inhibit the renal actions of vasopressin.

Patient education on adherence to dose regimen, fluid intake in response to thirst and regular monitoring of water and electrolyte balance by an endocrine specialist are of major importance.

Dr Niki Karavitaki is a senior clinical lecturer in endocrinology and honorary consultant endocrinologist at the University Hospitals Birmingham NHS Foundation Trust

Conflicts: none declared

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