Disorders of Vasopressin Flashcards
What part of the pituitary gland is anatomically continuous with the hypothalamus?
Posterior pituitary gland
What hormones do hypothalamic magnocellullar neurones contain?
Describe the structure and pathway of hypothalamic magnocellular neurones.
AVP and oxytocin
Long, originate in supraoptic and paraventricular hypothalamic nuclei
Nuclei > Stalk > Posterior pituitary
What is another name for vasopressin?
ADH
What is the main physiological action of vasopressin?
Stimulation of water reabsorption in the renal collecting duct. This concentrates urine.
Acts through V2 receptor in the kidney.
What is the other physiological function of vasopressin and via what receptor?
Vasoconstrictor via V1 receptor
Stimulates ACTH release from anterior pituitary
Is the posterior pituitary visible on an MRI scan for all healthy patients?
No therefore absence may be a normal variant
How does vasopressin concentrate urine?
- AVP binds onto G-protein coupled V2 receptors on the basolateral membrane of tubule cells.
- Triggers intracellular signalling cascade (adenylate cyclase activity to form cAMP)
- Protein Kinase A activates aquaporin-2 and 3 genes and migration of channels
- Aquaporin-2 channels embed within the apical membrane to increase water permeability and facilitate water movement into the cell.
- Aquaporin-3 channels insert into the basolateral membrane to facilitate movement of water out of the cell into the plasma.
What is the name for the image of the posterior pituitary gland on an MRI scan?
‘bright spot’
Name the types of stimuli for vasopressin release and briefly explain them.
Osmotic - Rise in plasma osmolality sensed by osmoreceptors.
Non-osmotic - Decrease in atrial pressure sensed by stretch receptors.
What are the name of the 2 nuclei that sit around the 3rd ventricle and are for the osmotic stimulation of vasopressin release?
Organum vasculosum and subfornical organ
Why is the fact that organum vasculosum and subfornical organ (the 2 nuclei) have no blood brain barrier advantageous for responding to the osmotic stimulation of vasopressin release?
So that neurones can respond to changes in the systemic circulation.
Where do the nuclei for the osmotic stimulation of vasopressin release project to?
Supraoptic nucleus
Which nucleus is the site of vasopressinergic neurones?
Supraoptic
How do osmoreceptors regulate vasopressin?
Osmoreceptors are sensitive to changes in plasma osmolarity (increase in extracellular sodium ions), sensing around the third ventricle. Osmoreceptor shrinks (Water flows down osmotic gradient). Increased osmoreceptor firing due to change of shape. AVP is released from magnocellular hypothalamic neurones from the supraoptic nucleus.
Non-osmotic stimulation of vasopressin release
Atrial stretch receptors detect pressure in right atrium. AVP release is inhibited via vagal afferents to hypothalamus. Reduction in circulating volume (e.g. haemorrhaging) leads to hypovolaemia. Decreased stretch stimulation onto atrial receptors. Less vasopressin inhibition.
Why is vasopressin released following a haemorrhage (in reduction in circulating volume)?
Vasopressin release results in increased water reabsorption in the kidney (circulating volume restoration) – V2 receptors.
Vasoconstriction via V1 receptors (Renin-aldosterone system involved with water retention, sensed by the juxtaglomerular apparatus).
Outline the physiological response to water deprivation.
Increased plasma osmolality, which stimulates osmoreceptors (shape change)
Increased AVP release from supraoptic nuclei + increased thirst
Increased water reabsorption from renal collecting ducts
Reduced urine volume and increase in urine osmolality. Reduced plasma osmolality.
What is diabetes insipidus?
Vasopressin disorder (Impaired water reabsorption, thus there is an increase in urine volume manifesting as the following osmotic symptoms).
List the osmotic symptoms seen in diabetes insipidus (these are more common diabetes mellitus).
Polyuria
Nocturia
Thirst - often extreme
Polydipsia
In diabetes mellitus (hyperglycaemia), these symptoms are due to osmotic diuresis.
In diabetes insipidus, these symptoms are due to a problem with AVP
Name the 2 different types of diabetes insipidus.
Cranial and nephrogenic
Explain the difference between cranial and nephrogenic DI.
Cranial - Posterior pituitary/hypothalamus dysfunction > Impaired AVP synthesis. VASOPRESSIN INSUFFICIENCY
Nephrogenic - Can make AVP (normal hypothalamus and posterior pituitary). Kidney (collecting duct) unable to respond to it. VASOPRESSIN RESISTANCE
List the causes of cranial DI
Acquired:
Traumatic brain injury
Pituitary surgery
Pituitary tumours
Metastasis to the pituitary gland (e.g., breast)
Granulomatous infiltration of pituitary stalk (TB, sarcoidosis)
Autoimmune
Congenital - Rare
List the causes of nephrogenic DI
Congenital:
Rare (e.g. mutation in gene encoding V2 receptor, aquaporin 2 type water channel)
Acquired:
Drugs (e.g. Lithium)
Which type of DI is more common?
Cranial
What is the typical presentation of DI?
Urine:
Very dilute (hypo - osmolar)
Large volumes
Plasma: Increased concentration (hyper-osmolar) as patient becomes dehydrated Increased sodium (hypernatraemia) Glucose normal (make sure you ALWAYS check this in a patient with these symptoms)
Explain why the symptoms of DI occur.
AVP problem (CDI - not enough; NDI - not responding). Impaired concentration of urine in renal collecting duct. Large volumes of dilute (hypotonic) urine. Increase in plasma osmolality (and sodium). Stimulation of osmoreceptors. Thirst - polydipsia. Maintains circulating volume as long as patient has access to water.
Can DI cause death.
Yes:
If the patient has no access to water > Dehydration > Death
Psychogenic polydipsia
Can mimic diabetes insipidus
Similar presentation of osmotic symptoms: Polydipsia, polyuria and nocturia.
Patient drinks water all the time so passes large volumes of dilute urine.
Explain how the symptoms of polydipsia arise from drinking too much water
Increased drinking (polydipsia) > plasma osmolality falls > less AVP secreted by posterior pituitary > large volumes of dilute (hypotonic relief) > plasma osmolality returns to normal
What is the difference between DI and psychogenic polydipsia?
Unlike DI in PP there is no problem with AVP.
How do we distinguish between DI and PP?
Carry out the water deprivation test
No access to anything to drink. Over time, measure urine volumes, urine concentration (osmolality) and plasma concentration.
When and why should you stop the water deprivation test?
Stop test once patient has lost >3% body weight (a marker of significant dehydration that can occur in DI).
What would the urine osmolality be like in a patient with DI after hours of water deprivation?
Around the same urine osmolality.
How do we distinguish between cranial and nephrogenic DI?
The administration of ddAVP and the subsequent rise in urine concentration (osmolality) can be used to differentiate the form of diabetes insipidus. If there is no response to ddAVP the patients’ most likely diagnosis is Nephrogenic diabetes insipidus.
What is the treatment for CDI?
Desmopressin (Replaces AVP)
Selective for V2 receptor (V1 receptor activation is unhelpful)
Different preparations: Tablets or intranasal
Poorly managed DI is a cause of death. Explain why.
Diabetes insipidus is NOT the same as diabetes mellitus
Desmopressin nasal spray can be easily disregarded as ‘not important’ on admission to hospital
Preventing a patient with diabetes insipidus from drinking or not giving fluids if unable to drink can cause death
What is the treatment for NDI?
Thiazide diuretics – Bendofluazide (Paradoxical + unclear mechanism)
Nephrogenic DI is rare.
What is Syndrome of Inappropriate ADH (SIADH)?
Too much AVP leading to reduced urine output and increased water retention.
What are the causes of SIADH?
CNS: Head injury, stroke and tumour Pulmonary disease: Pneumonia, bronchiectasis Malignancy: Lung cancer (Small cell) Drug-related: Carbamazepine, SSRIs Idiopathic
Management of SIADH
Fluid restriction
Vaptan (Vasopressin antagonist) – binds to V2 receptor on the kidney, preventing aquaporin migration. However, this is expensive.
(SIADH is a common cause of prolonged hospital stay).
Case history
A 48 year old mother of two teenage children sees her GP to discuss some symptoms that have been troubling her. For the last few months she has had very disrupted sleep. She has no difficulty falling asleep but wakes up at least three times per night needing to pass urine. She also notices that before she goes back to sleep, she needs to drink a large glass of water because she is so thirsty. She works as a school administrator and has noticed that she is also passing urine frequently in the daytime, having to leave her desk to go to the toilet at least six times per day. She has a large bottle of water at her desk at work and fills this up several times per day.
What is the differential diagnosis?
Diabetes mellitus (glucose exceeds renal threshold therefore leaks out of kidneys taking more water out of the body with it).
Diabetes insipidus (ADH doesn’t work)
Psychogenic polydipsia
Anxiety
Case history
A 48 year old mother of two teenage children sees her GP to discuss some symptoms that have been troubling her. For the last few months she has had very disrupted sleep. She has no difficulty falling asleep but wakes up at least three times per night needing to pass urine. She also notices that before she goes back to sleep, she needs to drink a large glass of water because she is so thirsty. She works as a school administrator and has noticed that she is also passing urine frequently in the daytime, having to leave her desk to go to the toilet at least six times per day. She has a large bottle of water at her desk at work and fills this up several times per day.
Thinking about your differential diagnosis, what tests could the GP do next and how could these help?
Measure blood glucose levels - HbA1C, fasting glucose, random glucose, OGTT (75g sugar; wait 2 hours)
Water deprivation test - done in Hospitals (not done by GPs)
GP could also check blood and urine sodium levels (osmolality would be high in urine - darker urine) - for DI you’re expecting concentrated blood and dilute urine.
Case history
A 48 year old mother of two teenage children sees her GP to discuss some symptoms that have been troubling her. For the last few months she has had very disrupted sleep. She has no difficulty falling asleep but wakes up at least three times per night needing to pass urine. She also notices that before she goes back to sleep, she needs to drink a large glass of water because she is so thirsty. She works as a school administrator and has noticed that she is also passing urine frequently in the daytime, having to leave her desk to go to the toilet at least six times per day. She has a large bottle of water at her desk at work and fills this up several times per day.
You receive the patient’s blood results:
Fasting plasma glucose - 5.4mmol/L
HbA1C (<42 mmol/mol) - 36 mmol/mol
Serum sodium (133-145 mmol/L) - 148 mmol/L
How do these results help you with the differential diagnosis?
Serum sodium is high suggesting the patient has diabetes insipidus.
Most likely not diabetes mellitus because HbA1c and fasting glucose are normal.
The patient is then referred to the Endocrinology clinic at the local hospital and the decision is made to further investigate the patient using a water deprivation test.
This was closely monitored, with body weight measured before the urine sample collection on each occasion. The clinical staff carrying out the test were told to stop the test if the patient lost more than 3% of her body weight.
Work through the water deprivation test results. What would be the response to water deprivation in a healthy person? How does that compare to the test results here?
In a healthy person, the high serum osmolality would be detected by osmoreceptors and the posterior pituitary gland would release AVP in order to increase the reabsorption of water in the renal collecting duct. Also urine osmolality would increase as the hours of water depression increases.
This patients urine osmolality is low therefore urine is dilute however blood is very concentrated. Indicative of diabetes insipidus.
DDAVP done to differentiate between cranial and neurogenic diabetes insipidus. Patient’s urine osmolariy increases therefore this person responds to DDAVP suggesting the patient has diabetes insipidus due to a lack of vasopressin. Hence the diagnoses is cranial diabetes insipidus.
Why do we monitor weight during the water deprivation test?
So that in case the patient lose >3% of their initial body weight the test should be stopped as the patient has excessive hydration.
How should this patient be treated?
Want to replace vasopressin with desmopressin which is selective for V2 receptor (V2 receptor agonist).
