Disorders Of Vasopressin

Question 1

Where does vasopressin come from?

Answer 1

Vasopressin = antidiuretic hormone =AVP

Comes from posterior pituitary, magnocellular neurones

Question 2

What is the posterior pituitary like?

Answer 2

Anatomically continuous with the hypothalamus

Neural tissue. No blood system

Hypothalamic magnocellular neuroma contain AVP or oxytocin

Neurones are long and originate in supraoptic and paraventricular hypothalamic nuclei

Nuclei -> stalk -> posterior pituitary

Question 3

What is the action and mechanism of action of vasopressin?

Answer 3

Anti diuretic hormone :. Stops you peeing/concentrates the urine

It does this by stimulating water reabsorbtion in the renal collecting duct

It acts to reabsorb water via the V2 receptor in the kidney

also acts as a vasoconstrictor via the V1 receptor. Acts via a G protein coupled receptor to cause aquaporin 2 channels to bind to the apical membrane (near the urine). This means more water is absorbed.

And stimulates ACTH release from the anterior pituitary

Question 4

How can the posterior pituitary be viewed radiologically?

Answer 4

MRI

Appears as a bright spot

But not necessarily seeing in all healthy individuals

The optic chias can be seen at the top, then the pituitary stalk (infundibulum). And then the posterior pituitary. (Anterior is much larger)

Question 5

What are the stimuli for vasopressin release?

Answer 5

Osmotic:

Rise in plasma osmolality (concentration - so more ions) sensed by osmoreceptors

Non-osmotic:

Decrease in atrial pressure sensed by atrial stretch receptors

Question 6

What is osmolality?

Answer 6

Basically concentration

Higher osmolality means more concentrated, so less water and more ions

Question 7

How, specifically, does osmotic stimulation of vasopressin release work?

Answer 7

Stimuli is an increase in plasma osmolality

Detected by the organum vasculosum and subfornical organ. These are both nuclei that sit around the 3rd ventricle

There is no blood brain barrier here so the neurones can respond directly to changes in osmolality in the systemic circulation

Organum vasculosum and subfornical organ are highly vascularised

Their brutes project into the supraoptic nucleus, the site of vasopressinergic neurones

Question 8

How do osmoreceptors work and regulate vasopressin release?

Answer 8

The osmoreceptors are in direct contact with plasma.

If there is an increase in extra cellular (so plasma) concentration (osmolality increases), water flows out of the receptor

This causes it to shrink and change shape

This leads to osmoreceptor firing

Leading to vasopressin release from hypothalamic neurones

Question 9

How do atrial stretch receptors work and regulate vasopressin release?

Answer 9

Atrial stretch receptors detect pressure in the right atrium

Vagal afferents to the hypothalamus inhibit vasopressin release

Reduction in circulating volume (eg. After haemorrhage) means LESS stretch receptor firing so LESS INHIBITION of vasopressin release

Vasopressin release increases following haemorrhage to restore some of the blood volume and blood pressure. Increases water reabsorbtion through V2, and vasoconstricts through V1
The renin-angiotensin system will also be important, sensed by juxtaglomerular appratus

Question 10

What is the physiological response to water deprivation?

Answer 10

Increased plasma osmolality (due to less water intake) ->

Stimulation of osmoreceptors ->

Thirst AND
Increased AVP release ->

Increased water absorption from renal collecting ducts ->

Reduced urine volume, increased urine osmolality (more concentrated/yellow) ->

Reduction in plasma osmolality

Question 11

What is diabetes insipidus?

Answer 11

Hyper glycaemia

But unlike mellitis, which is due to insulin problems, insipidus is due to problems with arginine vasopressin

It is way less common than diabetes mellitus

In mellitus excessive peeing is due to osmotic diuresis (lots of glucose in blood, not all can be reabsorbed in the kidney so is left in urine. Higher conc of urine means more water is drawn into pee, so more volume of pee)

In insipidus, excessive peeing is due to problems with vasopressin (none produced or resistance)

Question 12

What are the symptoms and presentation of diabetes insipidus?

Answer 12

Polyuria
Nocturia
Polydipsia

Urine:
Very dilute (hypo osmolar)
Large volumes

Plasma:
Increased concentration (hyper osmolar) as patient becomes dehydrated
Increased sodium (hyper natraemia)
GLUCOSE IS NORMAL

These symptoms may be kept under control though if they are drinking enough water to compensate

Question 13

What are the two types of diabetes insipidus?

Answer 13

Cranial:
Problem with hypothalamus and/or posterior pituitary

Unabated to make AVP

CRANIAL= VASOPRESSIN DEFICIENCY

Nephrogenic:
Can make Vasopressin (ie. hypothalamus and PP are normal)

V2 receptors on kidney collecting duct are unable to respond to it

NEOHROGENIC= VASOPRESSIN RESISTANCE

Question 14

What are some causes of cranial diabetes insipidus?

Answer 14

Aquired (more common):
Traumatic brain injury 
Pituitary surgery 
Pituitary tumour
Metastasis
Granulomatous infiltration of stalk (such as in TB or sarcoidosis). Causes thickening of stalk, visible on MRI 
Autoimmune 

Congenital:
Rare

Question 15

What are some causes of nephrogenic diabetes insipidus?

Answer 15

(Much less common than cranial)

Acquired:
Drugs (eg. Lithium)

Congenital:
Rare
Eg. Mutation in gene encoding V2 receptor, aquaporin 2 type water channel

Question 16

Why do the symptoms of diabetes insipidus occur?

Answer 16

Not enough/ not responding to AVP->

Impaired concentration of urine in renal collecting duct ->

Large volumes of dilute urine ->

Increase in plasma osmolality ->

Stimulation of osmoreceptors ->

Thirst - polydipsia ->

Maintains circulating volume as long as patient has access to water

If the patient doesn’t doesn’t have access to water ->

Dehydration and death

Question 17

What is psychogenic polydipsia?

Answer 17

Has similar presentation to diabetes insipidus

Polyuria
Polydipsia
Nocturia

But unlike diabetes insipidus, there is no problem with AVP

Problem is they just drunk way too much water for whatever reason. So pee all the time

May be a side effect of some psychiatric drug’s

In diabetes insipidus plasma osmolality is high. In psychogenic polydipsia plasma osmolality is low

Question 18

What is the mechanism of psychogenic polydipsia?

Answer 18

Patient drinks a lot (polydipsia) ->

Plasma osmolality falls ->

Less osmoreceptor firing ->

Less vasopressin secretion by posterior pituitary ->

Less water reabsorbed from the urine ->

Large volumes of dilute urine ->

So plasma osmolality returns to normal

Question 19

What test is done to distinguish between diabetes insipidus and psychogenic polydipsia?

Answer 19

Water deprivation test:

No access to anything to drink

Measure urine volume, urine concentration and plasma concentration over time

You also have to look out for weight. A >3% loss of body weight is a trigger to stop the test as these people will have insipidus, and this is a marker of significant dehydration which is dangerous

Normal results:
As time increases without water, urine osmolality increases as more water is retained in the body

Psychogenic polydipsia:
As time without water increases, urine osmolality increases but not as much as normal. This is because AVP reabsorbs some water but there is still excess water in the body

Diabetes insipidus:
No increase in urine osmolality as the body is unable to use AVP, so no water is reabsorbed and it is all peed out. They can’t concentrate their urine. Even if they don’t drink they still pee loads this leads to dehydration

Question 20

What test is done to distinguish between cranial and nephrogenic diabetes insipidus, and what are the results of this?

Answer 20

Give ddAVP
This is synthetic AVP
But it only acts on V2 receptors. So no vasoconstriction as this could be dangerous

It induces the same effects as vasopressin

Cranial response:
Can’t make vasopressin
But responds, so water is reabsorbed and urine osmolality (concentration) increases

Nephrogenic response:
Resistance to vasopressin
ddAVP still cannot bind to V2 receptors in kidney collecting ducts. So no water reabsorbtion. Urine remains dilute (low osmolality). Plasma osmolality remains high

Question 21

How is cranial diabetes insipidus treated?

Answer 21

Desmopressin - vasopressin replacement

Selective for V2 receptor. V1 (vasoconstriction) would be unhelpful

Comes in tablet and nasal spray form

Patients on desmopressin must be allowed this and must be given access to water, or they could die. This happens sometimes as insipidus is not very well known so people assume mellitus and people don’t get the treatment they need

Question 22

How is nephrogenic diabetes insipidus treated?

Answer 22

Much rarer

Much harder to treat

Thiazide diuretics used.
Eg. Bendofluazide

No one knows why this works
It is paradoxical

Question 23

What is syndrome of inappropriate ADH (SIADH)?

Answer 23

Too much AVP->

Water retention and reduced urine output

High urine osmolality
Low plasma osmolality
Dilutional hyponatremia (very low sodium makes you feel unwell)

Commonly idiopathic

Question 24

What are causes of SIADH?

Answer 24

CNS:
Head injury
Stroke
Tumour

Pulmonary disease:
Pneumonia
Bronchiectasis

Malignancy:
Lung cancer

Drug related:
Carbamazepine
SSRIs

Idiopathic

Question 25

How is SIADH managed?

Answer 25

It is often a cause of prolonged hospital stay

Fluid restriction

You can use a vasopressin antagonist (vaptan) - but this is reallllly pricey so never done