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MSc Endocrinology > Diabetes insipidus – pathophysiology and investigation > Flashcards

Diabetes insipidus – pathophysiology and investigation Flashcards

1
Q

What is Diabetes Insipidus?

A
  • Condition where the body in unable to conserve water which causes profound polyuria and polydipsia
  • Incidence approx 1:25,000
  • >3L water/d (up to 20L/d) excreted
  • Can be caused by either a lack of AVP or a defect in the kidneys response to AVP
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2
Q

Which hormones are secreted by Posterior Pituitary?

A
  • ADH: Acts on kidney tubules for water conservation
  • Oxytocin: Acts on mammary glands and Uterine muscles
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3
Q

What is the action of ADH?

A

ADH binds to ADH receptors (V2 receptor) on distal tubules and collecting duct. This causes the aquaporin-2 channels to move from the cytoplasm into the apical membrane

  • Aquaporin-2 channels allow water to be reabsorbed out of the collecting ducts and back into circulation
  • Causes decrease in urine volume and increase in urine osmolality
  • Reabsorbed water reduces the serum osmolality
  • Feedback on hypothalamus to reduce AVP secretion
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4
Q

How is ADH regulated?

A
  • Increased plasma osmolality or decreased effective circulating volume
  • Increased ADH leads to decreased Water excretion
  • Increased thirst leads to increased water ingestion
  • This leads to decreased plasma osmolality and increased effective circulating volume
  • This leads to decreased ADH and decreased thirst
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5
Q

What are main forms of Diabetes Insipidus?

A
  • Cranial diabetes insipidus (lack of AVP): 80-90% of the magnocellular neurones in the hypothalamus need to be damaged before symptoms of DI seen
  • Nephrogenic diabetes insipidus: defect in kidneys response to AVP
  • Gestational DI

Differential diagnosis includes primary polydipsia

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6
Q

What are causes of Cranial Diabetes Insipidus?

A
  • Head injury (17%)
  • Surgery (20-30% pituitary surgeries lead to transient DI, only 2-10% permanent)
  • Tumours (pituitary adenomas very rare cause)
  • Infection (meningitis)
  • Infiltration (sarcoidosis, haemochromatosis)
  • Loss of blood supply (Sheehan’s syndrome)
  • Mutation in AVP gene (AVP-NPII autosomal dominant) rare, even rarer X-linked or recessive
  • 25% cases idiopathic
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7
Q

What are causes of Nephrogenic Diabetes Insipidus?

A
  • Genetic (V2 receptor mutation, X-linked (90%), Mutations in AQP2 gene (10%))
  • Acquired forms more common, usually less severe
  • Drugs: lithium, amphotericin, demeclocyline
  • Hypercalcaemia
  • Polycystic kidney disease
  • Amyloidosis
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8
Q

What is the causes of Gestational Diabetes Insipidus?

A
  • Enzyme produced by the placenta cysteine aminopeptidase causes degradation of AVP
  • Gestational DI was thought to occur if there is overproduction of enzyme causing a lack of functional AVP, however hormone levels normal so probably more complex
  • Occurs only in pregnancy, resolves 2-3wks post partum
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9
Q

What is Primary Polydipsia?

A

Psychogenic polydipsia

  • Individual consumes large volumes of water/fluid producing large volumes of dilute urine
  • Most often a psychological disorder, has been assoc with drugs causing oral dryness

Dipsogenic

  • Dysfunction of the osmoreceptors results in impaired AVP response and thirst sensation leading to hypernatraemia and dehydration
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10
Q

What are clinical investigations of possible DI?

A

Symptoms

  • Excess urine (>3L/d)
  • Excess thirst
  • Nocturia
  • Dehydration: headaches, dizziness

Signs

  • Hypotension
  • Dilute urine
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11
Q

What is Polyuria?

A

Excess urine (>3L/d) with persistent urine osmolality <300 mOsm/kg

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12
Q

What are causes of Polyuria?

A
  • Osmotically active substances e.g. glucose, ketones so exclude diabetes mellitus
  • Tubular dysfunction- hypokalaemia, hypercalcaemia
  • Hyperthyroidism, hypoadrenalism
  • Chronic kidney disease
  • Urinary tract infections
  • Drugs: carbamazepine, chlorpropamide, lithium
  • DI, primary polydipsia
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13
Q

What is the investigations of Possible DI?

A
  • Confirm urine output (>3L/d)
  • Exclude other causes of polyuria and polydipsia
  • Na – hypernatraemia
  • Serum and urine osmolality
  • Random or overnight urine osmolality >750 mOsm/kg excludes DI
  • Strong clinical history eg. post pituitary surgery, initiate treatment without further investigations
  • Water deprivation test
  • Hypertonic saline infusion test
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14
Q

How is Preparation for Water Deprivation Test undertaken?

A
  • Do not restrict fluid or food intake prior to starting test
  • Tea, coffee, alcohol and tobacco are specifically excluded after midnight on the day of the test and during the test because they directly stimulate (vagus) the secretion of AVP independently of the osmoreceptors
  • Weigh patient before start of test
  • Document volume of all urine passes
  • Patient completes thirst chart
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15
Q

What is Water Deprivation test?

A
  • Patient deprived of fluid or food during test
  • Can be dangerous- patients unable to conserve water may become critically dehydrated within a few hours of water restriction
  • Must be performed under controlled conditions
  • Patients need to be monitored for Illicit water intake and Excessive weight loss
  • Need to weigh patients accurately and measure urine volume
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16
Q

How is the Water Deprivation test undertaken?

A
  • 08.00h - the patient should empty their bladder and this urine should be discarded
  • 09.00h - commence fluid restriction, weigh the patient and calculate 95% of their weight.

Begin the fluid balance chart. Take urine and serum samples for osmolality

  • 12.00h, 14.00h, 15.00h, 16.00h - Take samples for urine and serum osmolality and Weigh patient
17
Q

When would the test be stopped in Water Deprivation test?

A
  • Fall in weight of >5%
  • Plasma osmolality >300 mOsm/kg
18
Q

How is a DDAVP test undertaken?

A

Review the results:

  • If urine osmolality is <750 mOsm/kg or if urine osmolality failed to rise by more than 30 mOsm/kg over 3 successive urine samples, then administer 2µg DDAVP (0.3µg in Children) i.m. at 17.00h and allow food and fluids.

Do not allow patient to drink >500ml for 8 hours after DDAVP administration as the patient will be at risk of developing profound hyponatraemia

Check urine and serum osmolality at 2hr and 4hr post-DDAVP and the next morning.

19
Q

How are results interpreted for water deprivation test?

A

Normal

  • Post-Dehydration Osmolality: 283-293 in serum, >750 in urine
  • Post DDAVP osmolality: >750

Nephrogenic DI

  • Post-Dehydration Osmolality: >293 in serum, <300 in urine
  • Post DDAVP osmolality: <300

Cranial DI

  • Post-Dehydration Osmolality: >293 in serum, <300 in urine
  • Post DDAVP osmolality: >750

Primary Polydipsia

  • Post-Dehydration Osmolality: <293 in serum, 300-750 in urine
  • Post DDAVP osmolality: <750
20
Q

What are causes of equivocal results?

A
  • May be due to partial DI or patient drinking during the test. In these cases the test can be repeated fasting the patient from midnight the night before the test.
  • Chronic primary polydipsia can dissipate the renal medullary osmotic gradient, thereby reducing the renal response to endogenous and exogenous AVP. In severe cranial DI, maximal urinary concentration may be achieved only after repeated DDAVP.
  • Elderly patients may not achieve maximal concentration of their urine so results should be interpreted on a case by case basis.
  • If there remains clinical suspicion of DI then proceed to hypertonic saline infusion test.
21
Q

What is the Hypertonic Saline Infusion test?

A
  • An increase in plasma osmolality is a strong stimulus for AVP release via the hypothalamic osmoreceptors
  • Administration of hypertonic saline intravenously will produce a hyperosmolar state, causing maximal stimulation of AVP secretion
  • AVP is unstable and complex to assay
  • Copeptin (C-terminal glycoprotein of AVP prohormone) is measured as surrogate marker as secreted in equimolar concentrations, stable for 7d, easier to measure by immunoassay
  • Water is permitted during test
22
Q

How are patient prepared for Hypertonic Saline Infusion Test?

A
  • Must be performed under controlled conditions
  • Can be dangerous- patients unable to conserve water may become critically dehydrated within a few hours of water restriction
  • Patients need to be monitored. Excessive weight loss means need to weigh patients accurately and measure urine volume and bp
  • No tea, coffee, alcohol or smoking after midnight. Water only to be taken, no more than 500ml.
23
Q

How is the Hypertonic Saline Infusion test undertaken?

A
  • For each time point take sample for serum osmolality and copeptin
  • -30 mins take baseline
  • Infuse 5% saline 0.06ml/kg/min for 2 hours
  • Collect samples at 0, 30, 60, 90, 120 mins
  • Stop IV infusion
  • Collect final samples at 135 mins
24
Q

How s the hypertonic saline infusion test interperated?

A
  • Results that fall within the central area of the graph reflect a normal response.
  • For patients with primary polydipsia or nephrogenic diabetes insipidus have normal AVP/copeptin release in response to the hyperosmolar state induced by the procedure.
  • Patients with cranial diabetes insipidus have little or no rise in AVP/copeptin.
25
Q

How is Diabetes Insipidus treated?

A

Cranial

  • Vasopressin (desmopressin, DDAVP) tablets or nasal spray (vasopressin analogue)

Nephrogenic

  • Stop medication (may be irreversible esp Li)
  • High fluid intake
  • Indomethacin
  • Diuretics eg amiloride
  • Partial nephrogenic defect may be treated with desmopressin

MSc Endocrinology (16 decks)

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