Diabetes insipidus Flashcards
Which hormones does the posterior pituitary secrete and how?
Hypothalamus synthesises:
- arginine vasoPressin/ADH in the paraventricular nucleus
- oxytocin in the supraoptic nucleus
ADH & oxytocin are transported down axoplasm of neurones in the pituitary stalk & stored in the posterior pituitary gland (neurohypophysis.)
- ADH is released from posterior pituitary when plasma osmolality is high
Function & mechanism of ADH
ADH is secreted from posterior pituitary gland when plasma osmolality is high & it acts to increase H20 reabsorption in collecting ducts, resulting in decreased plasma osmolality & increased urine osmolality (blood becomes more dilute; urine becomes more concentrated). In prinical cells:
- ADH binds to V2R receptor on basolateral membrane which is a Gs protein-coupled receptor.
- Activates adenylate cyclase which converts ATP-> cAMP. Activation of protein kinase A results in increased expression & insertion of aquaporin-2 channels into apical membrane of principal cells-> increased water reabsorption.
- Plasma osmolality decreases & urine osmolality decreases.
Definition
Passage of large volumes of dilute urine, typically >3L/day, due to either:
- deficiency in ADH secretion from posterior pituitary or production in hypothalamus = cranial DI (AVP deficiency)
- impaired response of kidneys to ADH = nephrogenic DI
Pathophysiology
Kidneys can’t concentrate urine. In diabetes inspidus the patient will be dry inside so plasma osmolality will be high & urine osmolality will be low (very dilute urine) as water is not rebasorbed in collecting ducts. Charcterised by high urine output & low urine osmolality.
Causes of cranial DI
Deficiency in ADH secretion from posterior pituitary or production in hypothalamus = cranial DI
- Brain tumours e.g.pituitary adenoma, craniopharyngioma
- **Head injury **(damages hypothalamus/pituitary stalk/posterior pituitary)
Brain infections- tuberculosis, meningitis, encephalitis - ADH gene mutation
- infiltrative disease e.g. sarcoidosis- granulomas in brain & spinal cord = neurosarcoidosis
- idiopathic
Causes of nephrogenic DI
- most common = mutations in AVPR2 gene or mutations in aquaporin-2 gene
- Drugs- lithium (bipolar affective disorder), Demeclocycline (used for SIADH), Glibenclamide (sulfonylurea used for T2DM)
- CKD, renal tubular acidosis
- Electrolyte imbalance: hypercalcemia & hypokalemia (NOTE: these can also cause polyuria & polydipsia which is a differential diagnosis)
- sickle cell anaemia
Signs & symptoms (+ explanation)
Polyuria - typically >3L/day (deficiency of ADH/impaired response to ADH means less water reabsorption in collecting ducts & more water excretion in urine)
Polydipsia
Due to hypernatremia (Na+ is the main serum electrolyte & gets concentrated): confusion, lethargy, weakness
Severe dehydration (high plasma osmolality)
Differential diagnosis for polyuria & polydipsia
- Diabetes mellitus (exlcude by measuring plasma glucose)
- Hypercalemia
- Hypokalmeia
- Primary polydipsia (psychiatric disorder characterised by excessive drinking; patient has functioning ADH system so after 8hr fluid deprivation test, urine osmolality is high as kidneys concentrate urine)
Investigations
(2)
- 1st line + GS
1st line:
- Urine volume- DI is unlikely if urine output <3L/day. DI patients typically produce urine 3-20L/day. If >3L/day SUSPECT DI.
- Serum osmolality- normal or high
- Urine osmolality- low
- Blood glucose- exclude diabetes mellitus
- U & E - may show hypernatremia (& elevated urea due to volume depletion)
- Urine dipstick (urinalysis)- check for proteinuria & haematuria indicating CKD as the underlying cause of nephrogenic DI. Check for glycosuria to exclude DM.
Gold standard:
Fluid deprivation test (8hr fast with no food or fluids, check urine osmolality hourly)- to determine whether it is DI or primary polydipsia
Then if DI diagnosed, do **desmopressin stimulation test*8- to distinguish between cranial & nephrogenic DI
Explain gold standard test for diagnosing DI?
Fluid deprivation test (8hr fast with no food or fluids, check urine osmolality hourly)- to determine whether it is DI or primary polydipsia
- Cranial DI - high urine output, low urine osmolality
- Nephrogenic DI - high urine output, low urine osmolality
- Primary polydipsia - low urine output, high urine osmolality (in response to raised plasma osmolality, ADH secretion increases linearly-> increased H20 reabsorption in kidneys decreases urine osmolality). This EXCLUDE DI & there is no need to progress to desmopressin stimulation test.
Then if DI diagnosed, do desmopressin stimulation test (administer 2 microgram SC Desmopressin (synthetic ADH)) - to distinguish between cranial & nephrogenic DI:
- Cranial DI - urine osmolality increases & urine output decreases (ADH acts on collecting ducts to reabsorb water concentrate urine)
- Nephrogenic DI - urine osmolality remains low, urine output remains high (as kidneys have impaired response to ADH)
Treatment for cranial DI
Oral desmopressin (synthetic ADH analogue) - as there is ADH deficiency
Treatment for nephrogenic DI
Mainstay = thiazide diruetics
1) Treat underlying cause (e.g. CKD, electrolyte imbalance, renal tubular acidosis, stop drug (Lithium for bipolar disorder, Glibenclamide for T2DM, Demeclocylcine for SIADH) + thiazide diuretics (e.g. Bendroflumethiazide) + NSAIDS (inhibit prostaglandin synthesis, prostaglandins locally inhibit ADH action)
Why do we give Thiazide diuretics for Nephrogenic DI?
Thiazide diuretics (e.g. Bendroflumethiazide) produce mild hypovolemia by causing increased water excretion in DCT (by inhibiting NaCl symporter)-> kidneys try to offset water loss by reabsorbing more Na+ & thus water in PCT-> urine osmolality increases & plasma osmolality decreases & urine output decreases.
