Disorders of Vasopressin

Question 1

Describe posterior pituitary structure

Answer 1

Hypothalamic magnocellular neurons originate in hypothalamus and carry AVP and oxytocin respectively from the supraoptic nucleus and paraventricular nucleus respectively to the neurohypophysis, which is anatomically continuous with the hypothalamus.

Question 2

What are the 3 roles of vasopressin?

Answer 2

1. Opposes diuresis (urine production) by stimulating water reabsorption in renal collecting duct, concentrating urine, via action of V2 receptor.
2. Is a vasoconstrictor via action of V1 receptor.
3. Stimulates ACTH release from adenohypophysis.

Question 3

How does vasopressin concentrate urine?

Answer 3

AVP binds to the V2 receptor in the basolateral membrane of cells lining the renal collecting duct. This activates a G2 protein leading to adenylate cyclase activation and cAMP formation. cAMP activates protein kinase A which then stimulates binding of aquaporin 2 to apical membrane of cell. This allows a greater volume of water which is hence reabsorbed from urine. Osmotically moves into plasma through aquaporin 3.

Question 4

How is posterior pituitary visualised radiologically?

Answer 4

Through MRI. Appears as bright spot but absence on MRI is also normal.

Question 5

What are the 2 types of stimuli for vasopressin release?

Answer 5

Plays 2 roles: Vasoconstrictor and osmotic balancer. Therefore, there are osmotic reasons for release and non-osmotic reasons. Osmotic includes a rise in plasma osmolality sensed by osmoreceptors. Non-osmotic includes decrease in atrial pressure measured by atrial stretch receptors.

Question 6

What regions of the brain are responsible for osmotic stimulation of vasopressin release?

Answer 6

The organum vasculosum & subfornical organ.

1. Both nuclei are circumventricular as they sit around the 3rd ventricle.
2. These structures have no blood-brain barrier and highly vascularised - allows response to changes in systemic circulation.
3. Neurons from here project to supraoptic nucleus where vasopressinergic neurons are.

Question 7

How do osmoreceptors regulate vasopressin?

Answer 7

If there is a decrease in water levels, conc of extracellular Na+ increase. Increase in osmolality prompts water to leave osmoreceptor so cell shrinks and therefore increases action potentials. Leads to hypothalamic release of AVP.

Question 8

What is a non-osmotic reason for AVP release?

Answer 8

If there is a reduction in circulating volume e.g. due to a haemorrhage, atrial receptors are less stretched. They inhibit vasopressin release (via vagal afferents to hypothalamus) as they are stretched so less stretch results in less inhibition and so vasopressin levels are increased.

Question 9

What is the result of vasopressin release following a haemorrhage?

Answer 9

Vasopressin release results in increased water reabsorption in the kidney (some restoration of circulating volume) via V2 receptors. Vasoconstriction via V1 receptors and juxtaglomerular apparatus increases blood pressure.

Question 10

What is the physiological response to water deprivation?

Answer 10

Osmoreceptors are stimulated by an increased plasma osmolality which induces thirst and AVP release. More water is reabsorbed from collecting duct so urine volume reduces while while plasma osmolality decreases.

Question 11

What are 4 symptoms of diabetes?

Answer 11

Polyuria, polydipsia, nocturia and thirst. When caused by hyperglycaemia, indicate diabetes mellitus (osmotic diuresis) but when caused by AVP problems, indicate diabetes insipidus. However, most common cause of these symptoms is DM.

Question 12

What are the 2 types of diabetes insipidus?

Answer 12

Cranial DI - lack of AVP production by hypothalamus/neurohypophysis. Vasopressin insufficiency essentially as not made.
Nephrogenic DI - kidney doesn’t respond to AVP. Vasopressin resistance.

Question 13

What are causes of cranial diabetes insipidus?

Answer 13

Congenital causes very rare. Acquired causes include:
Traumatic brain injury
Pituitary surgery
Pituitary tumours
Metastasis to the pituitary gland eg breast
Granulomatous infiltration of pituitary stalk eg TB, sarcoidosis
Autoimmune
ST GAMB

Question 14

What are causes of nephrogenic diabetes insipidus?

Answer 14

This is much less common than CDI.
Congenital causes rare (e.g. mutation in gene encoding V2 receptor, aquaporin 2 type water channel)
Certain drugs e.g. lithium used in the treatment of bipolar disorder can cause this.

Question 15

Describe the presentation of diabetes insipidus APART from 4 core symptoms

Answer 15

1. Large volumes of hypo-osmolar urine
2. Hyper-osmolar plasma
3. Hypernatremia
4. Normal glucose

Question 16

Why do these symptoms occur in diabetes insipidus?

Answer 16

AVP problem leads to impaired concentration of urine in renal collecting duct so large volumes of dilute urine produced. Plasma osmolality increases as urine not concentrated enough. Osmoreceptors are stimulated causing thirst. If patient has access to water, circulating volume maintained but if not, can be fatal.

Question 17

What is psychogenic polydipsia?

Answer 17

AVP is normal but patient drinks too much water so symptoms mimic diabetes insipidus.

Question 18

How can psychogenic polydipsia and diabetes insipidus be differentiated?

Answer 18

Water deprivation test. Provide no access to water and measure urine volume, urine osmolality and plasma osmolality over an 8 hour time period. If normal, urine osmolality will increase (gradient will decrease over time but overall increase will occur). If psychogenic polydipsia, will mimic a normal trend but osmolality increase will overall be lower as too much water in the system already. If DI, no increase in urine osmolality.

Question 19

When should a water deprivation test be halted?

Answer 19

If patient loses over 3% of their body weight, test must be stopped as it is a marker of significant dehydration which can occur in DI.

Question 20

How is cranial & nephrogenic diabetes insipidus distinguished?

Answer 20

ddAVP (Desmopressin) given, is a synthetic vasopressin analogue. If CDI, will respond to vasopressin and urine osmolality will increase. If NDI, won’t respond as renal apparatus damaged.

Question 21

How can plasma osmolality differentiate DI from PP?

Answer 21

As patient drinks too much in PP, plasma sodium levels will be low due to excess water. However, in DI, AVP problems mean urine doesn’t concentrate properly and so plasma osmolality will be high.

Question 22

How is CDI treated?

Answer 22

Desmopressin prescribed to make up for vasopressin insufficiency. This is selective for V2 receptor as vasoconstriction not required. Can be taken as tablets or intranasally.

Question 23

How is NDI treated?

Answer 23

Harder to treat. Thiazide diuretics eg bendofluazide used. Mechanism unclear.

Question 24

What is Syndrome of Inappropriate Anti-Diuretic Hormone?

Answer 24

When there is an excess of AVP resulting in low urine output and water retention. Characterised by high urine osmolality, low plasma osmolality and dilutional hyponatraemia.

Question 25

What are the causes of SIADH?

Answer 25

1. CNS - Head injury, stroke, tumour,
2. Pulmonary disease - Pneumonia, bronchiectasis
3. Malignancy - Lung cancer (small cell)
4. Drug-related - Carbamazepine, Serotonin Reuptake Inhibitors (SSSRIs)
5. Idiopathic

Question 26

How is SIADH managed?

Answer 26

Fluid restriction and vaptan (vasopressin receptor antagonist but super expensive). SIADH is a common cause of prolonged hospital stay.