Diabetes insipidus

Overview

DI results from insufficient ADH (central) or renal insensitivity to ADH (nephrogenic), causing dilute polyuria. Distinguished from diabetes mellitus by normal blood glucose and absence of glycosuria.

Presentation

•Polyuria - urine output >3 litres/24 hours

•Polydipsia - intense thirst; preference for ice-cold water (distinguishing clue vs psychogenic polydipsia)

•Nocturia and nocturnal enuresis in children

•Hypernatraemia - when losses exceed intake; causes confusion, irritability, decreased consciousness

Investigations

🥇 First-line

•serum osmolality (raised >295 mOsmol/kg in true DI), urine osmolality (inappropriately low <300 mOsmol/kg), blood glucose and urine dipstick (exclude diabetes mellitus), U&Es, calcium, potassium

🏆 Gold standard

•water deprivation test with desmopressin challenge

🥈 Second-line

•MRI pituitary and hypothalamus (structural cause in confirmed central DI)

Water deprivation test interpretation
ConditionSerum osmolalityUrine after deprivationUrine after desmopressin
Central DIHighLowRises (responds)
Nephrogenic DIHighLowStays low (no response)
Primary polydipsiaNormal or lowConcentrates normallyNormal

Condition	Serum osmolality	Urine after deprivation	Urine after desmopressin
Central DI	High	Low	Rises (responds)
Nephrogenic DI	High	Low	Stays low (no response)
Primary polydipsia	Normal or low	Concentrates normally	Normal

Differential diagnosis

•Diabetes mellitus - raised blood glucose, glycosuria on dipstick, raised HbA1c; acanthosis nigricans suggests type 2 DM not DI

•Primary polydipsia - serum osmolality normal or low; urine concentrates normally on water deprivation

•SIADH - euvolaemic hyponatraemia with inappropriately concentrated urine; opposite biochemistry to DI

🎯
Acanthosis nigricans (hyperpigmentation and hyperkeratosis in axilla/groin) in a patient with polyuria, polydipsia, and hypertension points to type 2 diabetes mellitus - not DI.

Management

•Central DI - first-line: desmopressin (synthetic ADH analogue; intranasal, sublingual, or oral) + treat underlying cause

•Nephrogenic DI - first-line: remove/treat cause (stop lithium if safe, correct hypercalcaemia/hypokalaemia); low-sodium low-protein diet; thiazide diuretics (e.g. bendroflumethiazide) - paradoxically reduce urine volume via mild volume depletion increasing proximal tubular reabsorption

•Nephrogenic DI - second-line: NSAIDs (e.g. indomethacin) - reduce prostaglandins, partially restoring collecting duct ADH sensitivity

•Gestational DI: desmopressin - resistant to placental vasopressinase; resolves post-partum

⚠️
Desmopressin can cause dilutional hyponatraemia if fluid intake is not monitored, and must be used cautiously in ischaemic heart disease due to risk of vasoconstriction.

Types and causes

Central vs nephrogenic DI
FeatureCentral DINephrogenic DI
MechanismInsufficient ADH synthesis/releaseRenal insensitivity to ADH
Key acquired causesIdiopathic (25%), pituitary surgery, craniopharyngioma, sarcoidosis, haemochromatosis, head injuryLithium (most common drug cause, 10-15% of long-term users), hypercalcaemia, hypokalaemia, Sjögren's syndrome
Congenital causesAVP-NPII gene mutation (AD); Wolfram syndrome (DIDMOAD)X-linked V2 receptor mutation (90%); AQP2 mutation (10%)
ADH levelLowHigh (compensatory)
Response to desmopressinUrine osmolality risesUrine osmolality stays low

Feature	Central DI	Nephrogenic DI
Mechanism	Insufficient ADH synthesis/release	Renal insensitivity to ADH
Key acquired causes	Idiopathic (25%), pituitary surgery, craniopharyngioma, sarcoidosis, haemochromatosis, head injury	Lithium (most common drug cause, 10-15% of long-term users), hypercalcaemia, hypokalaemia, Sjögren's syndrome
Congenital causes	AVP-NPII gene mutation (AD); Wolfram syndrome (DIDMOAD)	X-linked V2 receptor mutation (90%); AQP2 mutation (10%)
ADH level	Low	High (compensatory)
Response to desmopressin	Urine osmolality rises	Urine osmolality stays low

💡
Haemochromatosis causes central DI via iron deposition in hypothalamic neurons. Suspect when DI is accompanied by arthralgia, lethargy, raised ferritin, or family history of 'regular venesection'. It is autosomal recessive and can skip generations - confirm with serum ferritin.