Neurohypophyseal disorders Flashcards
Name the two main nuclei within which neurones of the neurohypophysis have their cell bodies. (2)
Paraventricular Nucleus
Supraoptic Nucleus
Describe the innervation pattern of the hypothalamic PVN and SON nuclei. (3)
- SON neurons are magnocellular
- PVN neurons predominantly magnocellular
- Magnocellular neurons extend into the posterior pituitary
- Some PVN neurons terminate at the median eminence and release e.g. ACTH into the hypophyseal system
What two hormones are produced by the neurohypophysis? (2)
Vasopressin
Oxytocin
What receptors does vasopressin bind to and what are the effects? (2)
- V1 - vasoconstriction
- V2 - increased water reabsorption
What is the mechanism of vasopressins anti-diuretic effect at the kidney? (4)
- Binds to V2 (a GPCR) to activate Ga
- Ga activates adenylate cyclase which produces cAMP from ATP
- cAMP activates PKA
- PKA mediates the cellular effects including:
- AQP2 synthesis/aggrophore insertion (into APICAL membrane)
- Water taken up from tubule lumen (via AQP2) and into interstitial space by AQP3/4 (constitutively active)
How is ADH release regulated? (3)
- Osmoreceptors in the organ vasculosum activated when there is low plasma osmolarity
- Water leaves their cell bodies and into the extracellular space so the cells shrink
- This activates the osmoreceptors and so get increased ADH release at the terminals
- At high plasma osmolarity water enters the neurons and reduces ADH release
List diseases associated with
i) Too little ADH
ii) Too much ADH
i) Diabetes insIpidus
ii) SIADH
What are the two forms of diabetes inspidus and what is the mechanism of each? (2)
1) Cranial DI: failure to produce sufficient ADH (1)
2) Nephrogenic DI: Failure to respond sufficiently to ADH
What is the cause of cranial (aka central) diabetes insipidus? (3)
- Traumatic brain injury
- Pituitary tumour/craniopharyngioma
- Surgery
- Metastasis (from breast cancer)
- Granulomatous infiitration (sarcoidosis)
- In rare cases can be congenital (though usually acquired)
What is the cause of nephrogenic diabetes insipidus? (2)
- In rare cases can be congenital (though usually acquired)
- E.g. mutation in V2 receptor
- Can be caused by drugs/medication e.g. lithium
State some signs and symptoms of diabetes insipidus. (3)
- Polyuria
- Polydipsia
- Hypo-osmolar urine
- Dehydration
- Possible disruption of sleep
- Possible electrolyte imbalance
How does psychogenic polydipsia present? (1)
Polydipsia (excessive thirst and drinking) + polyuria AND ability to produce/respond to ADH is preserved
Compare the biochemical features of diabetes insipidus with those of psychogenic polydipsia. (2)
- DI = hypernatraemia. Psychogenic polydipsia hyponatraemia (another way to see this is that in diabetes inspidus your plasma osmolarity is HIGHER than normal, whilst in psychogenic polydipsia your plasma osmolarity is LOW than normal)
- In diabetes insipidus you get raise plasma urea, you do not in psychogenic polydipsia
- In both you have hypo-osmolar urine
i) What test can you use to distinguish between psychogenic polydipsia and diabetes insipidus? (2)
ii) … between nephrogenic and cranial diabetes inspidus? (2)
i) Do a water deprivation test: as long as the individual can produce and respond appropriately to ADH in water deprived circumstances their urine will become hyperosmolar. In DI your urine will remain hypoosmolar even in water deprived circumstances. In psychogenic polydipsia your urine will become hyperosmolar (even if not quite as much as a normal person). NOTE BEWARE DO NOT WANT TO KILL THE DI PATIENTS!!!
ii) Administer desmopressin. Desmopressin is an ADH anaologue so in cranial DI it will in water deprived circumstances show a more normal response (urine will become hyperosmolar). This will not happen in nephrogenic DI because the problem is with the response to DI rather than the production of it.
How is diabetes insipidus treated? (2)
For cranial DI: desmopressin (an ADH analogue - V2 SPECIFIC)
For nephrogenic DI: thiazides
Why in a water deprivation test does the patient with psychogenic DI not have a urine osmolality which goes as high as a normal patient? (1)
- Medullary washout
- 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
What is the difference between desmopressin and terlipressin? (1)
Terlipressin is V1 specific
Desmopressin is V2 specific
How do thiazides help treat DI? (2)
Possible mechanism:
- Inhibits Na+/Cl- transport in distal convoluted tubule (→ diuretic effect)
- Compensatory increase in Na+ reabsorption from the proximal tubule (plus small decrease in GFR, etc.)
- Increased proximal water reabsorption
- Decreased fluid reaches collecting duct = reduced urine volume
What is SIADH? (1)
State a sign of SIADH (1)
- Syndrome of Inappropriate ADH = when the plasma vasopressin concentration is inappropriate for the existing plasma osmolality
- Decreased urine volume or Increased urine osmolality or Hyponatraemia
Describe the pathological sequelae of SIADH? (4)
Diagram on page 13
The main problem is HYPONATRAEMIA
State the symptoms of SIADH? (2)
Depends on level of Na
Can be symptomless
If Na < 120mM might be very tired, nausea, generalised weakness
If Na <110mM can go into a coma and eventually death
State some causes of SIADH. (3)
CNS: SAH (subarachnoid haemorrhage), stroke, tumour, TBI
Pulmonary disease: Pneumonia, bronchiectasis
Malignancy: Lung (small cell) (ectopic expression)
Drug-related: Carbamazepine (anti-convulsive), SSRI (selective serotonin re-uptake inhibitor)
Idiopathic
How is SIADH treated? (3)
Depends on cause
Acutely: fluid restriction
V2 receptor antagonists e.g. vaptans
Can treat the other cause e.g. surgically remove cancer
How do vaptans work?
- These are 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
Where are V1 and V2 receptors found? (3)
V1 (at least 1 of each) Vascular smooth muscle Non-vascular smooth muscle Anterior pituitary Liver Platelets CNS V2 Kidney Endothelial cells
