Neurohypophyseal disorders

Question 1

How does the posterior pituitary gland appear on the MRI

Answer 1

‘bright spot’ on pituitary MRI

Question 2

Name the two main nuclei within which neurones of the neurohypophysis have their cell bodies.

Answer 2

Paraventricular Nucleus - BOTH MAGNOCELLULAR AND PARVOCELLULAR HORMONES
Supraoptic Nucleus- MAGNOCELLULAR HORMONES ONLY

Question 3

Which two hormones are produced by the neurohypophsyis

Answer 3

Vasopressin and Oxytocin

Question 4

Revise year 1 endocrinology

Answer 4

§ Magnocellular neurones – neurones that project into the neurohypophysis (with herring bodies).
§ 2 neurohypophysis hormones:
o Oxytocin.
o Vasopressin (ADH) – reduces urine output.
§ Vasopressin acts by increasing water reabsorption from renal cortical and medullary collecting ducts via V2 receptors.
§ Anti-diuretic = against increase in urine production.

Question 5

Summarise the principal effects of vasopressin

Answer 5

Principal effect of vasopressin = ANTI-DIURETIC ie increases water reabsorption from renal cortical and medullary collecting ducts via V2 receptors
Vasopressin also known as ADH – Anti Diuretic Hormone
Diuresis = increase in urine production

Question 6

What is the posterior pituitary gland composed of

Answer 6

Comprised of nerve axons descending through the pituitary stalk from their cell bodies in the hypothalamus, and numerous glial cells called pituicytes which make up the bulk of the neural lobe

Question 7

Describe the distinguishing features of the magnocellular neurones

Answer 7

Larger than normal neurones (parvocellular neurones)
Unmyelinated fibres, have the distinguishing features of herring bodies (swellings) along the axon, particularly near the nerve terminals. The nerve terminals, and indeed many of the herring bodies are in close contact with the walls of a capillary network in the neural lobe. The capillaries are typically fenestrated, allowing the passage of molecules released from nerve endings, and probably from the herring bodies, into the general circulation.

Question 8

Where are the paraventricular and supraoptic nuclei found

Answer 8

PVN- close to the walls of the 3rd ventricle

SON- above the optic chiasm

Question 9

Where do the parvocellular neurones terminate

Answer 9

In the median eminence or to other parts of the brain. The neurosecretions from the parvocellular fibres terminating in the median eminence reach the cells of the anterior pituitary via the hypothalamo-adenohypophysial portal system. The main one being vasopressin as a corticotrophin-releasing factor for corticotrophs.

In the CNS- their neurosecretions act as neurotransmitters or neuromodulators
Also synthesise somatostatin, CRH and TRH

Question 10

Why may it be possible for parvocellular neurones to have central effects

Answer 10

Increasing evidence that neurosecretions can be released at dendritic endings. Some parvocellular have dendritic endings abutting into the third ventricle- thus some hormones may be released into the CSF- particularly in parts of the brain devoid of vasopressinergic or oxytocinergic nerve endings but having abundant receptors.

Question 11

What is the principal action of vasopressin and how does it carry out this action?

Answer 11

Vasopressin’s main action is on the V2 receptors in the renal cortical and medullary collecting ducts
It stimulates the synthesis and assembly of aquaporin 2, which then increases water reabsorption and has an antidiuretic effect

Question 12

Describe the V2 receptor and its signalling pathway

Answer 12

The V2 receptor is linked to a Gs receptor- and the enzyme activated is adenyl cyclase - converting ATP to cAMP which then activates PKA, which in turn phosphorylates other intracellular proteins including CREB.

Question 13

How does vasopressin then illicit its effects

Answer 13

A key molecule influenced are the aquaporins. These are proteins which can be inserted into cell membranes where they act as pores through which water can pass, up an osmotic gradient.
The principal cells of the renal collecting ducts synthesise a vasopressin-dependent aquaporin (AQP2)
which is essential from the movement of water from the tubular fluid into the cells.
Vasopressin induces not only the synthesis of AQP2 but also its transport (within vesicles called aggraphores) to the apical membranes of the principal cells where they are inserted. Water moves out the principal cells via different aquaporins in the basolateral membranes (AQP3 and AQP4) and only AQP3 is vasopressin sensitive.

Question 14

Ultimately, what regulates vasopressin

Answer 14

Osmoreceptors- neurones which look at osmolality (how concentrated the solution is)
Not much change in osmolality on a daily basis

Question 15

Describe the osmoreceptors

Answer 15

The change is plasma osmolality is detected by osmosensitive (stretch-responsive) cells that are in contact with the general circulation but also able to communicate with the vasopressinergic in the hypothalamus. These osmoreceptors exist in certain structures called circumventricular organs, which are found in the anterior hypothalamus, close to the third ventircles, all of which importantly have fenestrated capillaries (i.e no BBB) and so are in contact with diffusible molecules, such as sodium ions in the blood.

Question 16

Where are these osmoreceptors found primarily

Answer 16

the organum vasculosum of the lamina terminalis and the sub-fornical organs from where axons contact the vasopressinergic neurones in the PVN and SON directly or indirectly.
They may well also influence other parts of the CNS, where they exert effects such as influencing drinking behaviour.
it is also worth noting that there is evidence to suggest that the firing rate of vasopressinergic neurones is also increased directly when the osmolality of the surrounding medium is increases, indicating that these neurones may be osmosensitive themselves.

Question 17

What happens to the osmoreceptors as plasma osmolality increases

Answer 17

When blood osmolarity goes up, water moves out of osmoreceptor cells and the osmoreceptors shrink which triggers them to send more signals to the hypothalamus to release VP.

Question 18

Describe the response seen in water deprivation

Answer 18

Increased blood plasma osmolarity - stimulation of osmoreceptors (thirst) - increased VP release - increased water reabsorption from renal collecting ducts - reduction in blood plasma osmolarity & reduced urine volume (but higher urine osmolarity).

Question 19

What else can stimulate vasopressin release

Answer 19

Low blood volume and BP ( baroreceptors both high pressure- responding to high BP and low pressure- responding to volume (venous blood volume)- normally have an inhibitory effect on VPP release- so when they are not stimulates- lose inhibition- leading to VPP release

Stressors- pain and surgery- visceral information (food being eaten) is associated with increased VPP released before any food constituents have been absorbed, via vagal afferent projections to the brainstem and hence the hypothalamus.

Question 20

What are the consequences of a lack of the neurohypophysial hormones?

Answer 20

Lack of Oxytocin – not clinically significant

Lack of Vasopressin – Diabetes Insipidus

Question 21

Ultimately, what is diabetes insipidus

Answer 21

Absence or lack of circulating vasopressin (cranial or central)

End-organ (kidneys) resistance to vasopressin (nephrogenic)- rarer

Can’t reabsorb water properly from the collecting duct

Question 22

Outline the causes of cranial diabetes insipidus

Answer 22

Acquired (more common)
Damage to Neurohypophysial system
Traumatic brain injury
Pituitary surgery- posterior lobe removed or damaged
Pituitary tumours, craniopharyngioma- benign anterior lobe disease does not usually affect the posterior lobe
Metastasis to the pituitary gland eg breast
Granulomatous infiltration of median eminence eg TB, sarcoidosis- neurones must pass down stalk through median eminence to reach the posterior lobe- so any inflammation here or damage may affect the function of the posterior lobe
Congenital - rare

Question 23

Outline the causes of nephrogenic diabetes insipidus

Answer 23

Congenital - rare (e.g. mutation in gene encoding V2 receptor, aquaporin 2 type water channel)
Acquired - Drugs (e.g. lithium, dimethyl chlortetracycline (DMCT) )- used to treat schizophrenia (can also cause primary hypothyroidism).

Question 24

Outline the signs and symptoms of diabetes insipidus

Answer 24

Large volumes of urine (polyuria)
Urine very dilute (hypo-osmolar)
Thirst and increased drinking (polydipsia)
Dehydration (and consequences) if fluid intake not maintained - can lead to DEATH
Possible disruption to sleep with associated problems- patients have to wake up repeatedly in the night to pass urine
Possible electrolyte imbalance

Question 25

Ultimately, what are patients with diabetes insipidus unable to do

Answer 25

Increase urine osmolality in response to water deprivation test (as they can't reabsorb water)- so urine osmolality stays low

Question 26

Describe the physiological response that occurs in patients with diabetes insipidus

Answer 26

INADEQUATE PRODUCTION OF/RESPONSE TO VP LARGE VOLUMES OF DILUTE (HYPOTONIC) URINE INCREASE IN PLASMA OSMOLALITY (AND SODIUM) REDUCTION IN EC FLUID VOLUME THIRST - POLYDIPSIA EC FLUID VOLUME EXPANSION

Question 27

What can happen to patients in diabetes insipidus if they don't have access to enough water

Answer 27

Dehydration and death | Can't reabsorb any water- so only way to reduce plasma osmolality and increase EC volume it by fluid intake

Question 28

State another cause of polydipsia that isn’t diabetes.

Answer 28

Psychogenic polydipsia | This is a central disturbance that increases the drive to drink

Question 29

Describe psychogenic polydipsia

Answer 29

Most frequently seen in psychiatric patients – aetiology unclear, may reflect anti-cholinergic effects of medication – ‘dry mouth’ Can be in patients told to ‘drink plenty’ by healthcare professionals Excess fluid intake (polydipsia) and excess urine output (polyuria) – BUT unlike DI, ability to secrete vasopressin in response to osmotic stimuli is preserved

Question 30

Describe the physiological response seen in patients with psychogenic polydipsia

Answer 30

INCREASED DRINKING (POLYDIPSIA) EXPANSION OF EC FLUID VOLUME, REDUCTION IN PLASMA OSMOLALITY LESS VP SECRETED BY POSTERIOR PITUITARY LARGE VOLUMES OF DILUTE (HYPOTONIC) URINE EC FLUID VOLUME RETURNS TO NORMAL INCREASED DRINKING (POLYDIPSIA)

Question 31

Difference between psychogenic polydipsia and diabetes insipidus

Answer 31

DI people will have a HIGH plasma osmolarity and PP people will have a LOW osmolarity (even though they both drink a lot of water – difference lies in differences in VP)

Question 32

Quantify the plasma osmolality values seen in patients with diabetes insipidus and compare this to the norm and in patients with psychogenic diabetes polydipsia

Answer 32

Normal- 270-290 mOsm/kg H2O Diabetes insipidus- >290mOsm/kgH20 Psychogenic polydipsia- <270 mOsm/kgH20

Question 33

What test can be used to distinguish between normal, psychogenic polydipsia, central DI and nephrogenic DI? Describe the results you would expect.

Answer 33

Fluid deprivation test · Normals and psychogenic polydipsia will show a rise in urine osmolality · Central and nephrogenic diabetes insipidus will show little or no change in urine osmolality Fluid deprivation with administration of DDAVP (Desmopressin) · Central diabetes insipidus will show a rise in urine osmolality · Nephrogenic DI will still have a low urine osmolality (because of end-organ resistance)

Question 34

Summarise the water deprivation test

Answer 34

§ Each column is a osmolarity test under different conditions. § DDAVP is synthetic AVP – differentiates cranial and central. § A cannula is inserted to take regular readings. § Patients’ weight is taken regularly to make sure they don’t become too dehydrated. § PP is very similar to normal as it’s mostly psychogenic! o PP is slightly lower because the polydipsia has ‘washed away’ the concentration gradient in the medulla slightly.

Question 35

What is classes as a low urine osmolarity

Answer 35

Less than 500 mOsm/khH2O

Question 36

Why do we need to monitor body weight in the water deprivation test

Answer 36

Losing more than 3kg of body weight- stop the test- marker of clinical dehydration which could result in death.

Question 37

State the biochemical features of diabetes insipidus

Answer 37

Hypernatraemia Raised urea Increased plasma osmolality Dilute (hypo-osmolar) urine - ie low urine osmolality

Question 38

Outline the biochemical features of psychogenic polydipsia

Answer 38

Mild hyponatraemia – excess water intake Low plasma osmolality Dilute (hypo-osmolar) urine - ie low urine osmolality

Question 39

Which tissues express the V1 receptor

Answer 39

``` Vascular smooth muscle Non-vascular smooth muscle Anterior pituitary Liver Platelets CNS ```

Question 40

Which tissues express the V2 receptor

Answer 40

Kidney | Endothelial cells

Question 41

Why is the urine osmolality of someone with psychogenic polydipsia lower (in the fluid deprivation test) than a normal subject?

Answer 41

Over time, the constant passage of large volumes of water through the kidneys will wash out the osmotic gradient that is necessary for AVP to exert its diuretic effect

Question 42

Describe the normal change in urine osmolality as plasma osmolality increases.

Answer 42

Normally, urine osmolality will increase as plasma osmolality increases (in a graph of urine osmolality against plasma osmolality it will show a sigmoid shape) In DI, there is little change in urine osmolality as plasma osmolality increases

Question 43

Describe changes in plasma vasopressin following administration of hypertonic saline in a normal subject, psychogenic polydipsia, central DI and nephrogenic DI.

Answer 43

Hypertonic saline will increase the plasma osmolality and hence will increase the vasopressin secretion in patients that have the capacity to produce vasopressin (normal, psychogenic polydipsia and nephrogenic DI) Patients with central DI can’t produce vasopressin at all so the hypertonic saline will show no change in plasma vasopressin

Question 44

What is the issue with various tissues expressing vasopressin receptors and how do we circumnavigate this in terms of treatment

Answer 44

§ Remember that ALL vasopressin receptors will be activated – we want to target just the V2 kidney receptors. § To treat cranial DI, we use selective VP receptor agonists: o V1 – Terlipressin. o V2 – Desmopressin (DDAVP)

Question 45

Summarise the use of DDAVP

Answer 45

Administration Nasally Orally SC Reduction in urine volume and concentration in cranial DI CARE – to tell patient starting this NOT to continue drinking large amounts of fluid – risk of hyponatraemia (used to drinking large amounts of water- but now they can reabsorb it all- leading to hyponatraemia)

Question 46

Describe the issue with giving DDAVP nasally

Answer 46

Makes the drug seem less important- especially if the patient has sinusitis- and so can impact drug adherence If the patient has had the pituitary gland removed- don't give nasally as they will have an inflamed nose from the operation.

Question 47

Describe the treatment of nephrogenic diabetes insipidus

Answer 47

Thiazide Diuretics (e.g. bendroflumethiazide) This inhibits the Na+/Cl- pump in the DCT leading to a diuretic effect This leads to volume depletion resulting in a compensatory increase in Na+ reabsorption from the PCT (plus a small decrease in GFR). This increases proximal water reabsorption so less water reaches the collecting duct This ultimately leads to reduced urine volume

Question 48

Why can't we use DDAVP to treat nephrogenic diabetes insipidus

Answer 48

This is the only drug we have (thiazides) and it’s not very effective but it is VERY hard to treat (as the problem lies in the kidneys, not in the hormone itself).

Question 49

What can V1 peptidergic agonists be used to treat

Answer 49

Have powerful vasconstrictive effects | Hence can be used to treat oesophageal varices and to reduce G.I bleeds

Question 50

Describe the DDAVP as a molecule

Answer 50

Had arginine in the VVP modified to give it a longer half life, so that patients do not need administration of the drug every 5 minutes, as they would with naïve vasopressin. By using a D-amino acid (rather than L-arginine as occurs in nature), the molecule is realtively resistant to the usual degradative pathways.

Question 51

What can happen post-operatively to patients who have had their pituitary gland removed

Answer 51

Following transphenoidal pituitary surgery, some patients have transient diabetes insipidus, and one or two doses may be used in the days following the surgery if the patient starts to become hypernatremic until the pituitary recovers

Question 52

Describe the different routes in which DDAVP can be administered

Answer 52

Patients usually take DDAVP intravenously twice daily, and by giving vast doses a tablet of DDAVP is just about viable. Most of an oral dose of DDAVP is digested, but enough survives to be reabsorbed and therapeutically useful- the oral dose is over 10 times that of the intranasal dose As a trial, 0.5-1.0mcg of DDAVP can be given subcutaneously or intravenously.- this dose and route are sometimes used immediately post-operatively. Patients who have permanent diabetes insipidus are usually offered intranasal therapy at a dse of about 10mcg per nostril once or twice daily, titrated to urine output and plasma sodium level. A tablet of 100mcg is also available, and patients need between one and three of these up to four times daily because most of the drug is still destroyed in the digestive system.

Question 53

Define SIADH

Answer 53

``` ADH (anti-diuretic hormone) = vasopressin By definition the plasma vasopressin concentration is inappropriately high for the existing plasma osmolality ```

Question 54

Describe the physiology of SIADH

Answer 54

Increased VPP INCREASED H20 REABSORPTION FROM RENAL COLLECTING DUCTS EXPANSION OF ECF VOLUME This leads to hyponatraemia and ANP release fron right atrium This caused natriuresis- leading to hyponatraemia and euvolemia

Question 55

What are the key signs of SIADH

Answer 55

raised urine osmolality, decreased urine volume (initially) | decreased p[Na+] (HYPONATRAEMIA) mainly due to increased water reabsorption

Question 56

What are the symptoms of SIADH

Answer 56

can be symptomless however if p[Na+] <120 mM: generalised weakness, poor mental function, nausea if p[Na+] <110 mM: CONFUSION leading to COMA and ultimately DEATH

Question 57

Outline the causes of SIADH

Answer 57

CNS SAH, stroke, tumour, TBI Pulmonary disease Pneumonia, bronchiectasis Malignancy Lung (small cell) Drug-related Carbamazepine (used to treat epilepsy), SSRI (selective serotonin reuptake inhibitors- depression- fluoxytine Idiopathic Ultimately, head or lung pathology So do Chest X-Ray and CT of the brain- to see cause

Question 58

Describe the biochemistry of SIADH

Answer 58

Increased urine osmolality | Decreased plasma sodium and osmolality- mainly due to increased sodium reabsorption

Question 59

State some other causes of SIADH

Answer 59

``` Neurohypophysial malfunction (e.g. meningitis, cerebrovascular disease) Thoracic disease (e.g. pneumonia) Endocrine disease (e.g. Addison’s) Physiological – it can happen under normal circumstances where AVP is release is stimulated by non-osmotic stimuli (e.g. hypovolaemia, pain, surgery) ```

Question 60

Summarise the treatment for SIADH

Answer 60

Appropriate treatment (e.g. surgery for tumour) To reduce immediate concern, i.e. hyponatraemia 1. Immediate: fluid restriction 2. Longer-term: use drugs which prevent vasopressin action in kidneys e.g. induce nephrogenic DI ie reduce renal water reabsorption - demeclocyline inhibit action of ADH - V2 receptor antagonists

Question 61

Briefly explain the treatments for SIADH

Answer 61

§ To reduce immediate concern (i.e. hyponatraemia): o Immediate – fluid restriction – thus won’t have water to reabsorb in the nephron. o Long-term – demeclocyline – induce nephrogenic DI – reduce renal water reabsorption. § These prevent VP action in the kidney

Question 62

What are vaptans

Answer 62

Non-peptide vasopressin receptor antagonists Tolvaptan = V2 receptor antagonist It is used to treat hyponatraemia associated with SIADH and may be useful in treating congestive heart failure

Question 63

Summarise vaptans

Answer 63

Non-competitive V2 receptor antagonists Inhibit aquaporin2 synthesis and transport to collecting duct apical membrane, preventing renal water reabsorption Aquaresis – solute-sparing renal excretion of water, contrast with diuretics (diuresis) which produce simultaneous electrolyte loss Licensed in the UK for treatment of hyponatraemia associated with SIADH Very expensive – limits their current use

Question 64

Why don't we give diuretics to patients with SIADH

Answer 64

Will also excrete electrolytes (inluciding Na+)- Na+ is already low-and so diuretics will just exacerbate problems

Question 65

Describe transient-pituitary driven SIADH

Answer 65

Lasts about a week, starting around 10 days after pituitary surgery. A well-described, but difficult to explain, pattern of events is for a transient diabetes insipidus to develop immediately following pituitary surgery for anterior pituitary disease, this being managed with careful fluid balance. Approximately 10 days later, some patients have an episode of SIADH that lasts about a week, and should be managed with fluid restriction. Patients who are unware of this sometimes feel thirsty and drink too much, resulting in transient hyponatraemia. An adequate fluid restriction is always sufficient to control this, and as it is transient any other therapy it is likely to cause an increased morbidity,

Question 66

Why is the use of ADH antagonists contra-indicted in transient SIADH

Answer 66

Will result in diabetes insipidus as soon as the patient normalises, and will confound further diagnostic tests

Question 67

State some clinical uses of Desmopressin.

Answer 67

Treatment of diabetes insipidus Treatment of nocturnal eneuresis Haemophilia (need V2 stimulation) NOTE: it is taken orally or nasally

Question 68

State some unwanted effects of Desmopressin

Answer 68

Nausea Headaches Abdominal pain Fluid retention and hyponatraemia