Neurohypophysial Disorders

Question 1

How can the PP be detected radiologically?

Answer 1

• Bright spot on MRI

Question 2

Give 2 hormones secreted from the PP?

Answer 2

• VP
• Oxytocin

Question 3

What are the 2 principle functions of VP (/ADH), including which receptor it acts on for each function, sites of action?

Answer 3

1. Anti-diuretic - via V2 receptors - acts on renal cortical and medullary collecting ducts
2. Vasoconstriction - via V1 receptors - acts on vasculature

Question 4

Outline the mechanism of the action of VP on collecting duct cells

Answer 4

• VP acts on V2 receptors
• Acts on adenylate cyclase via these G-protein linked V2 receptors
• Forms cyclic AMP (cAMP) using ATP
• cAMP activates PKA
• Activated PKA activates other cellular mediators
• Causes AQP2 synthesis which are packaged into aggraphores
• Migration of aggraphores containing AQP2 to the apical membrane
• AQP2 insertion into apical membrane
• H20 can now enter collecting duct cells from tubule via apical AQP2 via osmosis
• H20 now exits collecting duct cells via pre-existing AQP3,4 alrady on basolateral membrane into the bloodstream

Question 5

Where are osmoreceptors located and what are they connected to?

Answer 5

• Organum Vasculosum
• Project onto the hypothalamic para-ventricular and supra-optic nuclei

Question 6

Outline the mechanism regulation of VP release, in the example of increased serum osmolality (not drinking water)

Answer 6

• Serum osmolality increases, EC [Na⁺] increases
• H₂O exits osmoreceptors into EC space via osmosis
• Therefore the osmoreceptors shrink
• Osmoreceptor firing rate increases
• This stumulates VP release as initiated by hypothalamic paraventricular and supraoptic nuclei which these osmoreceptors project onto

Question 7

List and define the 2 types of diabetes insipidus

Answer 7

1. Cranial - ‘absence or lack of circulating VP’
2. Nephrogenic - ‘End-organ (kidney) resistance to VP

Question 8

Suggest some causes of cranial diabetes insipidus

Answer 8

Acquired - damage to PP

• Traumatic Brain Injury
• Pituitary Surgery
• Pituitary Tumours - craniopharyngiomas
• Granulomatous infiltration of median eminence e.g. TB, neurosarcoidosis

Congenital

Question 9

Give 2 possible congenital and 1 acquired cause of nephrogenic diabetes insipidus

Answer 9

Congenital

1. ​Mutated V2 receptor gene
2. Mutated AQP2 genes

Acquired

• Lithium - drug used to treat bipolar disorder

Question 10

Signs and symptoms of diabetes insipidus?

Answer 10

1. Polyuria
2. Polydispia
3. Hypo-osmolar urine
4. Sleep disruption (due to polyuria)
5. Dehydration and death if no access to water

Question 11

1) Describe the diabetes insipidus cycle if you have access to water?
2) If no access to water?

Answer 11

1)

1. Inadequate production of VP response
2. Large volumes of dilute (hypotonic) urine
3. Increase in plasma osmolarity (and sodium)
4. Hence reduction in EC fluid volume because H₂O moves from EC into plasma by osmosis due to high plasma osmolality
5. Thirst - polydipsia (as detected by osmoreceptors)
6. So you drink - polydipsia
7. So increase in EC fluid volume expansion and plasma osmolality falls (normalisation)

2)

• Same up until point 5, but afterm you cannot normalise ECF volume and plasma osmolality so dehydration and death occurs

Question 12

1) What is psychogenic polydipsia and how is it different to diabetes insipidus?
2) In whom is psychogenic polydipsia most common and why?

Answer 12

1)

• Central disturbance which increases the drive to drink (polydipsia) → XS fluid intake and thus xs urine output
• But, unlike in DI, the ability to secrete VP in response to osmotic stimuli is preserved

2)

1. In psychiatric patient - could be due to anti-cholinergic medication
2. Patients told to ‘drink plenty’

Question 13

List in order of highest to lowest plasma osmolality (including range values) people with DI, normal people and people with psychogenic polydipsia and why

Answer 13

1. Diabetes Insipidus - plasma v.salty in diabetes insipidus due to lack of / ineffective VP
2. Normal People (hydrated)
3. Psychogenic Polydipsia - plasma very dilute because you drink loads

Question 14

Biochemical features of Diabetes Insipidus?

Answer 14

• Hypernatraemia
• Raised urea
• Increased plasma osmolality
• Dilute (hypo-osmolar) urine - i.e. low urine osmolality

Question 15

Biochemical features of psychogenic polydipsia?

Answer 15

• Mild hyponatraemia due to XS water intake
• Low plasma osmolality
• Dilute (hypo-osmolar) urine - i.e. low urine osmolality

Question 16

1)

Name a V1 selective VP receptor peptidergic agonist?

2)

Name a V2 selective VP receptors peptidergic agonist?

Answer 16

1)

• Terlipressin

2)

• Desmopressin (DDAVP)

Question 17

1)

3 methods of desmopressin administration?

2)

What is desmopressin used to treat and why does it only work for this type?

3)

What should you warn patients about prior to its use?

Answer 17

1)

1. Nasally
2. Orally
3. Subcutaneous

2)

• Used to treat cranial DI as VP replacement
• Cannot work on nephrogenic DI as VP has no effect anyway

3)

• Normally you’d tell someone with Diabetes Insipidus to drink loads to prevent dehydration, but since you’re replacing VP, if you drink loads on top of the reabsorptive effects, you’d cause hyponatraemia

Question 18

1)

Treatment for nephrogenic diabetes insipidus? (a class of drugs and named example)

2)

How does this work?

Answer 18

1)

• Thiazide diuretics
• E.g. Bendroflumethiazide

2)

• Inhibits Na⁺ / Cl^- transport in DCT (this is how it would have its diuretic effect but this is irrelevant)
• Compensatory increase in Na⁺ reabsorption from the proximal tubule (plus small decrease in GFR)
• This causes water reabsorption at the PCT into the blood
• Also less fluid reaches the collecting duct which is what is resistant to VP in nephrogenic DI

Question 19

1)

Define SIADH

2)

SIADH process?

Answer 19

1)

• Syndrome of Inappropriate ADH
• ‘The plasma VP concentration is inappropriately high for the existing plasma osmolality’

2)

• ↑ VP → ↑ H₂O reabsorption from collecting duct → ↑ECF volume → directly causing hyponatraemia
• ANP is also released by the right atrium in response to the low plasma osmolality → causes natriuresis to increase urine excretion
• Aggravates hyponatraemia due to loss of Na⁺
• Euvolaemia (aka ECF volume is restored to normal)

Question 20

1)

Signs of SIADH?

2)

Symptoms of SIADH?

Answer 20

1)

• ↑ Raised urine osmolality
• ↓ Urine volume (initially prior to ANP compensation)
• Decreased p[Na⁺] mainly due to increased water reabsorption

2)

• Can be symptomless, however…

If p[Na⁺] < 120 mM:

• Generalised weaknesss
• Poor mental function
• Nausea

If p[Na⁺] < 110 mM:

• Confusion
• Death

Question 21

Give 5 cause types and examples for causes of SIADH

Answer 21

1. CNS - subarachnoid haemorrhage, stroke, tumour, TBI etc
2. Pulmonary disease - pneumonia, bronchiectasis
3. Malignancy - lung (small cell)
4. Drug-related - carbamazepine, SSRI
5. Idiopathic

Question 22

Treatment options of SIADH, including the main drug used and why is this drug useful in not aggravating any symtoms?

Answer 22

• Surgery
• Immediate fluid restriction to handle hyponatraemia
• Demeclocycline - induces nephrogenic Diabetes Insipidus to counteract XS ADH
• V2 receptor antagonists e.g. Vaptans - prevent AQP2 reabsorption
• Vaptans is useful because it only causes aquaresis (only water excretion), not diuresis (both water + electrolyte excretion) which would aggravate hyponatraemia