Endocrinology Problem (Gunn)

Question 1

Define Diuresis

Answer 1

increased or excessive production of urine.

Question 2

A 6 year old boy presents to hospital severely unwell, clinically dehydrated and was breathing rapidly and deeply. His blood pressure was 75/40 mm Hg and heart rate was 140 per minute. He was drowsy, and passing little urine. His temperature is 38C. His parents described a 3 week history of worsening bedwetting and weight loss, and for the last 2 days (acute) he had mainly drunk coke and lemonade because of severe thirst.

Venous blood glucose: 85 mmol/L (normal 3.0-6.0 mmol/liter)

Venous serum Na+: 122 mmol/L (normal 135 -146 mmol/L)

Arterial sample: pH 6.85 (normal 7.36-7.44)

HCO3 : 5 mmol/L (normal 22-28 mmol/L)

paCO2 : 23 mmHg (normal 36-44 mmHg)

paO2 85 mmHg

He was given 30 ml/kg of normal saline (0.9% NaCl) before transfer to a specialist hospital, and a bolus dose of insulin 0.1 iu/kg. On arrival at the base hospital, he is passing copious urine, his serum glucose is 30 mmol/L and he is only intermittently responding to questions

What are some reasons why someone way have diuresis?

Answer 2

• drinking too much water (habit, physiological issues)
• excess loss of water
• renal (high output failure)
• endocrine (↓ ADH release or effect, excess release of naturetic peptised)

Question 3

A 6 year old boy presents to hospital severely unwell, clinically dehydrated and was breathing rapidly and deeply. His blood pressure was 75/40 mm Hg and heart rate was 140 per minute. He was drowsy, and passing little urine. His temperature is 38C. His parents described a 3 week history of worsening bedwetting and weight loss, and for the last 2 days (acute) he had mainly drunk coke and lemonade because of severe thirst.

Venous blood glucose: 85 mmol/L (normal 3.0-6.0 mmol/liter)

Venous serum Na+: 122 mmol/L (normal 135 -146 mmol/L)

Arterial sample: pH 6.85 (normal 7.36-7.44)

HCO3 : 5 mmol/L (normal 22-28 mmol/L)

paCO2 : 23 mmHg (normal 36-44 mmHg)

paO2 85 mmHg

He was given 30 ml/kg of normal saline (0.9% NaCl) before transfer to a specialist hospital, and a bolus dose of insulin 0.1 iu/kg. On arrival at the base hospital, he is passing copious urine, his serum glucose is 30 mmol/L and he is only intermittently responding to questions

What should we test first?

Answer 3

• test urine glucose/blood glucose
• clinical exam = general status
• clinical exam = evidence of dehydration VS water overload

o capillary refill time

o blood pressure

o JVP

o Skin turgor

* Don’t do fasting glucose because Anything above 12mmol/L is abnormal, therefore you do not need to do one. Also it takes time.

If he is dehydrated or volume contracted, cannot becess intake! However, neutral hydration status is not helpful

Question 4

A 6 year old boy presents to hospital severely unwell, clinically dehydrated and was breathing rapidly and deeply. His blood pressure was 75/40 mm Hg and heart rate was 140 per minute. He was drowsy, and passing little urine. His temperature is 38C. His parents described a 3 week history of worsening bedwetting and weight loss, and for the last 2 days (acute) he had mainly drunk coke and lemonade because of severe thirst.

Venous blood glucose: 85 mmol/L (normal 3.0-6.0 mmol/liter)

Venous serum Na+: 122 mmol/L (normal 135 -146 mmol/L)

Arterial sample: pH 6.85 (normal 7.36-7.44)

HCO3 : 5 mmol/L (normal 22-28 mmol/L)

paCO2 : 23 mmHg (normal 36-44 mmHg)

paO2 85 mmHg

He was given 30 ml/kg of normal saline (0.9% NaCl) before transfer to a specialist hospital, and a bolus dose of insulin 0.1 iu/kg. On arrival at the base hospital, he is passing copious urine, his serum glucose is 30 mmol/L and he is only intermittently responding to questions

What are the bedside tests you would do on this patient

Answer 4

1) Urine dipstick

• 2) No blood; trace protein
• 3) Glucose +++
• Could glucose reflect a 1 degree renal problem?
• 4) Ketones +++
• 5) Anything else?

2) Capillary glucose: High (> 30mmol/L)

Question 5

A 6 year old boy presents to hospital severely unwell, clinically dehydrated and was breathing rapidly and deeply. His blood pressure was 75/40 mm Hg and heart rate was 140 per minute. He was drowsy, and passing little urine. His temperature is 38C. His parents described a 3 week history of worsening bedwetting and weight loss, and for the last 2 days (acute) he had mainly drunk coke and lemonade because of severe thirst.

Venous blood glucose: 85 mmol/L (normal 3.0-6.0 mmol/liter)

Venous serum Na+: 122 mmol/L (normal 135 -146 mmol/L)

Arterial sample: pH 6.85 (normal 7.36-7.44)

HCO3 : 5 mmol/L (normal 22-28 mmol/L)

paCO2 : 23 mmHg (normal 36-44 mmHg)

paO2 85 mmHg

He was given 30 ml/kg of normal saline (0.9% NaCl) before transfer to a specialist hospital, and a bolus dose of insulin 0.1 iu/kg. On arrival at the base hospital, he is passing copious urine, his serum glucose is 30 mmol/L and he is only intermittently responding to questions

Glucose was found in his urine

What is the persumptive diagnosis?

Answer 5

New onset diabetes, with ketoacidosis

Question 6

A 6 year old boy presents to hospital severely unwell, clinically dehydrated and was breathing rapidly and deeply. His blood pressure was 75/40 mm Hg and heart rate was 140 per minute. He was drowsy, and passing little urine. His temperature is 38C. His parents described a 3 week history of worsening bedwetting and weight loss, and for the last 2 days (acute) he had mainly drunk coke and lemonade because of severe thirst.

Venous blood glucose: 85 mmol/L (normal 3.0-6.0 mmol/liter)

Venous serum Na+: 122 mmol/L (normal 135 -146 mmol/L)

Arterial sample: pH 6.85 (normal 7.36-7.44)

HCO3 : 5 mmol/L (normal 22-28 mmol/L)

paCO2 : 23 mmHg (normal 36-44 mmHg)

paO2 85 mmHg

He was given 30 ml/kg of normal saline (0.9% NaCl) before transfer to a specialist hospital, and a bolus dose of insulin 0.1 iu/kg. On arrival at the base hospital, he is passing copious urine, his serum glucose is 30 mmol/L and he is only intermittently responding to questions

Why is the patient thirsty?

Answer 6

• plasma glucose well over the tubular maxima (~ > 10mmol/L) (excess glucose is lost in urine)
• osmotic diuresis → high water loss, tending to iso-osmotic
• mechanisms:

o ↓ efficiency of loop of Henle

o ↑ flow → ↓ concentration

o osmotic effect of un-reabsorbed glucose retaining water in DCT/CD

• nonspecific mechanisms as well
  
  • ​→ nausea, general unwell → water intake ↓
• net dehydration, mainly pure water loss with compensation:

o aldosterone release → retain maximal amount of salt

o AVP release: aquaporins open → retain maximal water

Question 7

A 6 year old boy presents to hospital severely unwell, clinically dehydrated and was breathing rapidly and deeply. His blood pressure was 75/40 mm Hg and heart rate was 140 per minute. He was drowsy, and passing little urine. His temperature is 38C. His parents described a 3 week history of worsening bedwetting and weight loss, and for the last 2 days (acute) he had mainly drunk coke and lemonade because of severe thirst.

Venous blood glucose: 85 mmol/L (normal 3.0-6.0 mmol/liter)

Venous serum Na+: 122 mmol/L (normal 135 -146 mmol/L)

Arterial sample: pH 6.85 (normal 7.36-7.44)

HCO3 : 5 mmol/L (normal 22-28 mmol/L)

paCO2 : 23 mmHg (normal 36-44 mmHg)

paO2 85 mmHg

He was given 30 ml/kg of normal saline (0.9% NaCl) before transfer to a specialist hospital, and a bolus dose of insulin 0.1 iu/kg. On arrival at the base hospital, he is passing copious urine, his serum glucose is 30 mmol/L and he is only intermittently responding to questions

Why is he breathing rapidly and deeply?

Answer 7

• Kussmaul’s respirations

o severe metabolic acidosis (pH 6.85)

o respiratory compensation for metabolic acidosis, leading to hypocapnia

Question 8

What is the word for “increased or excessive production of urine.”

Answer 8

Diuresis

Question 9

A 6 year old boy presents to hospital severely unwell, clinically dehydrated and was breathing rapidly and deeply. His blood pressure was 75/40 mm Hg and heart rate was 140 per minute. He was drowsy, and passing little urine. His temperature is 38C. His parents described a 3 week history of worsening bedwetting and weight loss, and for the last 2 days (acute) he had mainly drunk coke and lemonade because of severe thirst.

Venous blood glucose: 85 mmol/L (normal 3.0-6.0 mmol/liter)

Venous serum Na+: 122 mmol/L (normal 135 -146 mmol/L)

Arterial sample: pH 6.85 (normal 7.36-7.44)

HCO3 : 5 mmol/L (normal 22-28 mmol/L)

paCO2 : 23 mmHg (normal 36-44 mmHg)

paO2 85 mmHg

He was given 30 ml/kg of normal saline (0.9% NaCl) before transfer to a specialist hospital, and a bolus dose of insulin 0.1 iu/kg. On arrival at the base hospital, he is passing copious urine, his serum glucose is 30 mmol/L and he is only intermittently responding to questions

Explain his serum Na+ of 122 mmol/L (normal 135 – 146 mmol/L) **** Is he hyponatraemic?

Answer 9

• (2 x measure sNa+) + serum glucose (learn this)
• 2 x 122 + 85 = 329 mmol/L (net hyperosmolar state!)

Therefore, she is in hyper-osmolar state.

• High serum glucose is causing water to move from ICF into ECF, which is then urinated (water and glucose excretion) since glucose prevents water reabsorption by collecting duct. Therefore, she presents with clinical dehydration.
• (Some Na⁺ may also be binding to BOHB due to DKA, hence further water loss.)

Glucose-Corrected Serum Sodium

Glucose-Corrected Serum Sodium (Empiric Formula) = Measured Serum Sodium + ([Glucose − 5.5] ´ 0.288)

132 + (29.5 – 5.5) 132 + (29.5-5.5)´0.3 = 139mmol/L

(0**.5mmol/L is average serum [glucose], 0.3 is good approximation to 0.288)

Therefore, she is not in hyponatraemia.

• Na⁺ is merely diluted by hyperglycaemia (water shift from ICF into ECF so dilute serum [Na+])
• This is a form of pseudohyponatreamia (serum [Na⁺] is actually normal after serum [glucose] correction)
• Glucose-corrected serum sodium =
  
  • measured serum sodium + ([glucose -5.5] x 0.2888)
  • 122+ (85-5.5) x 0.288 = 145mmol/L

Pseudohyponatremia (if you take the glucose out, his sodium level will be high)

i.e. he is NOT hyponatraemic, merely diluted by hyperglycaemia (i.e. water shifts out of cells -> ECF)

Question 10

A 6 year old boy presents to hospital severely unwell, clinically dehydrated and was breathing rapidly and deeply. His blood pressure was 75/40 mm Hg and heart rate was 140 per minute. He was drowsy, and passing little urine. His temperature is 38C. His parents described a 3 week history of worsening bedwetting and weight loss, and for the last 2 days (acute) he had mainly drunk coke and lemonade because of severe thirst.

Venous blood glucose: 85 mmol/L (normal 3.0-6.0 mmol/liter)

Venous serum Na+: 122 mmol/L (normal 135 -146 mmol/L)

Arterial sample: pH 6.85 (normal 7.36-7.44)

HCO3 : 5 mmol/L (normal 22-28 mmol/L)

paCO2 : 23 mmHg (normal 36-44 mmHg)

paO2 85 mmHg

He was given 30 ml/kg of normal saline (0.9% NaCl) before transfer to a specialist hospital, and a bolus dose of insulin 0.1 iu/kg. On arrival at the base hospital, he is passing copious urine, his serum glucose is 30 mmol/L and he is only intermittently responding to questions

Initially passing little urine, after partial rehydration began passing a large volume of urine

Answer 10

Initially, there is reduced urine output due to reduced RBF and GFR, which is caused by:

• Volume contraction (even though she is unable to concentrate urine or reabsorb water, she retains volume by reducing renal blood flow, hence pre-renal failure (note that particularly in older patients, acute renal failure can occur))
• Intense SNS (catecholamine causes constricted afferent arteriole)
• Increased angiotensin II (constricted efferent arteriole; glomerular mesangial cells contraction, which reduces surface area for glomerular filtration) (hence reduced GFR)

After rehydration with IV fluid, it restores GFR due to (1) volume expansion (increased ECF volume); (2) reduced SNS and AII.

As soon as GFR is restored, urine output massively increases, thus diuresis (but hyperglycaemia can still lead to glycosuria).

• profound volume contraction + intense SNS + Ang II → ↓ RBF and GFR
  
  • volume constriction by release of SNS (noradrenalin) and A2 which results in vasoconstriction of renal arteriole.
  • This is a compensation mechanism to preserve volume in the presence of hypovolumia
  • May or may not have severe hypertension at this point
• rehydration → restoration of GFR
  
  • _​_note, particularly in orlder patients acute renal failure can occur

Question 11

What is a common cause of morbidity and mortality in DKA patients?

How do you combat this?

Answer 11

Hypokalaemia and hyperkalemia (depending on their health at the onsent of DKA)

Patients are now typically supplemeted with i.v. KCl and sNa/K measured every 4 hours, and more oftenin intensive care

Question 12

A 6 year old boy presents to hospital severely unwell, clinically dehydrated and was breathing rapidly and deeply. His blood pressure was 75/40 mm Hg and heart rate was 140 per minute. He was drowsy, and passing little urine. His temperature is 38C. His parents described a 3 week history of worsening bedwetting and weight loss, and for the last 2 days (acute) he had mainly drunk coke and lemonade because of severe thirst.

Venous blood glucose: 85 mmol/L (normal 3.0-6.0 mmol/liter)

Venous serum Na+: 122 mmol/L (normal 135 -146 mmol/L)

Arterial sample: pH 6.85 (normal 7.36-7.44)

HCO3 : 5 mmol/L (normal 22-28 mmol/L)

paCO2 : 23 mmHg (normal 36-44 mmHg)

paO2 85 mmHg

He was given 30 ml/kg of normal saline (0.9% NaCl) before transfer to a specialist hospital, and a bolus dose of insulin 0.1 iu/kg. On arrival at the base hospital, he is passing copious urine, his serum glucose is 30 mmol/L and he is only intermittently responding to questions

Explain: Serum K+ = 5.1 mmol/L at admission but following IV fluids + insulin, the serum K+ = 2.8 mmol/L

Answer 12

Simple Explanation

There is whole body potassium depletion is due to DKA.

• However, this is initially masked by acidosis, insulin deficiency, etc. (shift of K+ from ICF to ECF to mask lost serum [K+])

Treatment leads to rapid shift of K+ into ICF, thus decreased serum [K+]. This is exposed (unmasked) by normal insulin, normalisation of osmolarity and correction of acidosis.

Complex Explanation

Initially (before treatment), multiple forces displacing K+ from cells into ECF (increased s[K+]):

• Lack of insulin ® ¯Na/K ATPase ® K out of cells (chronic shift)
• Acidosis ® ¯ Na/K ATPase (milder effect on serum [K+] with ketoacidosis than some forms of metabolic acidosis, since (1) DKA develops relatively progressively; (2) ketone acids have less effect)

When serum is hyperosmolar (due to hyperglycemia), water moves from ICF to ECF, which cause cellular volume contraction.

• This increase osmolarity inside cell, hence increase intracellular [K+].
• This increase [K+] gradient across membrane, thus greater K+ shift from ICF to plasma (ECF), leading to increased s[K+].

Once K+ is outside cells, it can lead to greater excretion in urine. This is due to:

• Increased aldosterone (stimulated by volume contraction, and high s[K+])
• Increased excretion independent of aldosterone when s[K+]>4.2mmol/L (high normal)
• Polyuria due to osmotic diuresis (greater dilution for urine [K+], thus better gradient for excretion)

Potential excretion inhibitor is effect of acidosis on Na/K ATPase. However, it does not affect much K+ excretion due to:

• Milder effect with DKA (develops progressively, ketone acids have less effect)
• Or just counterbalanced by above effect leading to net effect to increase excretion.

Therefore, evolving diabetes and DKA lead to progressive intracellular K+ loss (chronically), thus loss of whole body K+ store.

Treatments leads rapid shift of K+ into ICF, thus decreased serum [K+], hence unmask whole body potassium depletion:

• Replacement with insulin (increases Na/K ATPase to shift K+ from ECF back to ICF), and
• Normalisation of osmolarity (decreased ICF osmolarity favours K+ re-entry into ICF), and
• Correction of acidosis (favouring Na/K ATPase effects)
• whole body K+ depletion due to DKA
• treatment → rapid shift of K+ into cells
  
  • replacement with insulin
  • fall of osmolarity
  • correction of acidosis
• lack of insulin → ↓ Na/K ATPase → K+ out of cells
• acidosis → ↓ Na/K ATPase
  
  • Milder effect on sK with ketoacidosis than some forms of metabolic acidosis
    
    • ? because develops relatively progressively
    • ? ketoacids have less effect
• hyperosmolarity = ↑ gradient → greater K+ loss from cells → plasma
• once K+ in plasma, it is then excreted in urine
  
  • aldosterone, due to volume contraction + high K+
  • polyuria due to osmotic diuresis (greater dilution of urine → better gradient for excretion)
  • potential inhibitor → effect of acidosis on Na/K ATPase
• Thus progressive loss of intracellular K
  
  • exposed by normal insulin, normalisation of osmolarity and correction of acidosis
  • hypo and hyperkalaemia are common causes of death and morbidity during DKA

Question 13

A 6 year old boy presents to hospital severely unwell, clinically dehydrated and was breathing rapidly and deeply. His blood pressure was 75/40 mm Hg and heart rate was 140 per minute. He was drowsy, and passing little urine. His temperature is 38C. His parents described a 3 week history of worsening bedwetting and weight loss, and for the last 2 days (acute) he had mainly drunk coke and lemonade because of severe thirst.

Venous blood glucose: 85 mmol/L (normal 3.0-6.0 mmol/liter)

Venous serum Na+: 122 mmol/L (normal 135 -146 mmol/L)

Arterial sample: pH 6.85 (normal 7.36-7.44)

HCO3 : 5 mmol/L (normal 22-28 mmol/L)

paCO2 : 23 mmHg (normal 36-44 mmHg)

paO2 85 mmHg

He was given 30 ml/kg of normal saline (0.9% NaCl) before transfer to a specialist hospital, and a bolus dose of insulin 0.1 iu/kg. On arrival at the base hospital, he is passing copious urine, his serum glucose is 30 mmol/L and he is only intermittently responding to questions

Why did his serum glucose fall dramatically? (3 reasons)

Answer 13

1. Dilution: in part his s Glucose was high because of dehydration

o 30ml/kg bolus of 0.9% saline diluted the glucose

o total body water = 0.6 x wt (in boys)

o total ECF ~=1/3 x water = 0.6/3 = 0.2 L/kg = 200ml/kg

o i.e. diluted by ~~30/200 = 15%

2. Diuresis after fluid loading

o he had continued osmotic diuresis

o if urine is iso-osmotic, with maximal reabsorbtion of Na by aldosterone, could have lost up to 300mmol/L of glucose in urine

o actually must be less of course because of ketones + Na/K also in urine

3. Gave insulin

o activation of GLUT4 in fat/muscle, glycogen synthetase and pyruvate dehydrogenase

o glucose uptake & incorporation

o turn off gluconeogenesis/release

Question 14

A 6 year old boy presents to hospital severely unwell, clinically dehydrated and was breathing rapidly and deeply. His blood pressure was 75/40 mm Hg and heart rate was 140 per minute. He was drowsy, and passing little urine. His temperature is 38C. His parents described a 3 week history of worsening bedwetting and weight loss, and for the last 2 days (acute) he had mainly drunk coke and lemonade because of severe thirst.

Venous blood glucose: 85 mmol/L (normal 3.0-6.0 mmol/liter)

Venous serum Na+: 122 mmol/L (normal 135 -146 mmol/L)

Arterial sample: pH 6.85 (normal 7.36-7.44)

HCO3 : 5 mmol/L (normal 22-28 mmol/L)

paCO2 : 23 mmHg (normal 36-44 mmHg)

paO2 85 mmHg

He was given 30 ml/kg of normal saline (0.9% NaCl) before transfer to a specialist hospital, and a bolus dose of insulin 0.1 iu/kg. On arrival at the base hospital, he is passing copious urine, his serum glucose is 30 mmol/L and he is only intermittently responding to questions

He became confused, Explain his mental status after start of treatment

Answer 14

Pathophysiology of Cerebral Oedema

Prior to treatment, patient has been in a hyperosmotic state over several days, there has been increased intracellular osmolarity (hyperosmolarity) in brain to allow normal function (normalisation).

When treatment was initiated, rapid reduction in ECF osmolarity causes sudden osmotic shift, which causes brain swelling (cerebral oedema), hence reduced cerebral perfusion.

• With rapid rehydration (acute hyponatremia), sodium concentration is diluted in plasma, so plasma osmolarity decreases.
• This means water moves from ECF into ICF, so intracellular osmolarity decreases.
• This sudden osmotic shift causes increased in cell volume (swelling!) and potassium depletion.

Cerebral oedema is rare complication of treatment (~0.9%) with unclear aetiology (severe DKA and treatment?)

Slow correction seems to be safer!

• he has developed hyperosmotic state over several days, allowing normalisation

​

• cerebral oedema = rare complication, aetiology unclear
• intracellular hyperosmolarity has developed → rapid ↓ in ECF during treatment → brain swelling
• slow correction seems to be safe

Question 15

What are the risks of Cerebral oedema?

How do you treat this?

Answer 15

Known risks for cerebral oedema

• severe acidosis
• ketosis (anion gap)
• low PaCO2

treatment:

o insulin administered within an hour of fluid replacement

o volume given in first 4 hours

o use of bicarbonate

o rapid falls in blood glucose levels following start of insulin

Question 16

A 19 year old girl presents with a 5 month history of waking up once, sometimes twice a night, by the need to go to the bathroom. More recently, she has noticed that she needs to go to the bathroom during the day much more frequently than before, every few hours. At first she thought that her increased frequency of urination was due to the coffee, but when she cut her latte’s to one in the morning, she still needed to go to the bathroom just as often. In addition, she found herself never without a beverage in her hand or nearby.

Urine dipstick showed no glucose or blood

A random serum sodium level was 142 mmol/L

Urine osmolarity of 200 mOsm/L (15-1200 mosm/L)

You admit her to hospital to monitor paired blood and urine tests overnight, without drinking. The morning blood osmolarity of 305 mosml/L (normal 280-295 mosml/L), urinary osmolarity of 350 mosml/L (50- 1200 mosm/L).

You give her a subcutaneous dose of desmopressin (dDAVP, a synthetic form of vasopressin), her serum osmolarity falls to 290 mosm/L, with urine Osmolarity of 800 mosm/L. Explain the following:

Explain her initial serum Na+

Answer 16

• sNa+ = 142 mmol/L
  
  • A normal blood sodium level is between 135 and 145 milliequivalents per liter (mEq/L)
• normal because she has access to water and intact thirst
• differential diagnosis:

o diabetes insipidus

o excessive ‘psychological’ drinking

Question 17

A 19 year old girl presents with a 5 month history of waking up once, sometimes twice a night, by the need to go to the bathroom. More recently, she has noticed that she needs to go to the bathroom during the day much more frequently than before, every few hours. At first she thought that her increased frequency of urination was due to the coffee, but when she cut her latte’s to one in the morning, she still needed to go to the bathroom just as often. In addition, she found herself never without a beverage in her hand or nearby.

Urine dipstick showed no glucose or blood

A random serum sodium level was 142 mmol/L

Urine osmolarity of 200 mOsm/L (15-1200 mosm/L)

You admit her to hospital to monitor paired blood and urine tests overnight, without drinking. The morning blood osmolarity of 305 mosml/L (normal 280-295 mosml/L), urinary osmolarity of 350 mosml/L (50- 1200 mosm/L).

You give her a subcutaneous dose of desmopressin (dDAVP, a synthetic form of vasopressin), her serum osmolarity falls to 290 mosm/L, with urine Osmolarity of 800 mosm/L. Explain the following:

Explain changes in osmolarity next morning

Answer 17

• increase in early morning blood osmolarity due to excessive loss of free water overnight
• early morning _urinary osmolarity of 350 is ‘inappropriately normal’ (_failure to concentrate despire abnormally high sNa+/plasma osmolarity)
• Should have been around 1200.

Question 18

What is Diabetes Insipidus?

Answer 18

Diabetes insipidus (DI) is a condition characterized by large amounts of dilute urine and increased thirst.[1] Complications may include dehydration or seizures.[1]

There are four types of DI, each with a different set of causes.

1. [1] Central DI (CDI) is due to a lack of the hormone vasopressin (antidiuretic hormone).[1] This can be due to damage to the hypothalamus or pituitary gland or genetics.[1]
2. Nephrogenic diabetes insipidus (NDI) occurs when the kidneys do not respond properly to vasopressin.[1]
3. Dipsogenic DI is due to abnormal thirst mechanisms in the hypothalamus while gestational DI occurs only during pregnancy.[1]

Diagnosis is often based on urine tests, blood tests, and the fluid deprivation test.[1]

Question 19

A 19 year old girl presents with a 5 month history of waking up once, sometimes twice a night, by the need to go to the bathroom. More recently, she has noticed that she needs to go to the bathroom during the day much more frequently than before, every few hours. At first she thought that her increased frequency of urination was due to the coffee, but when she cut her latte’s to one in the morning, she still needed to go to the bathroom just as often. In addition, she found herself never without a beverage in her hand or nearby.

Urine dipstick showed no glucose or blood

A random serum sodium level was 142 mmol/L

Urine osmolarity of 200 mOsm/L (15-1200 mosm/L)

You admit her to hospital to monitor paired blood and urine tests overnight, without drinking. The morning blood osmolarity of 305 mosml/L (normal 280-295 mosml/L), urinary osmolarity of 350 mosml/L (50- 1200 mosm/L).

You give her a subcutaneous dose of desmopressin (dDAVP, a synthetic form of vasopressin), her serum osmolarity falls to 290 mosm/L, with urine Osmolarity of 800 mosm/L. Explain the following

Why did the urinary osmolarity rise after giving desmopressin?

Answer 19

• desmopressin = long acting ADH
• V2 → insertion of AQP in CD → allows maximal concentration of urine
• thus she has central diabetes insipidus

Question 20

A 19 year old girl presents with a 5 month history of waking up once, sometimes twice a night, by the need to go to the bathroom. More recently, she has noticed that she needs to go to the bathroom during the day much more frequently than before, every few hours. At first she thought that her increased frequency of urination was due to the coffee, but when she cut her latte’s to one in the morning, she still needed to go to the bathroom just as often. In addition, she found herself never without a beverage in her hand or nearby.

Urine dipstick showed no glucose or blood

A random serum sodium level was 142 mmol/L

Urine osmolarity of 200 mOsm/L (15-1200 mosm/L)

You admit her to hospital to monitor paired blood and urine tests overnight, without drinking. The morning blood osmolarity of 305 mosml/L (normal 280-295 mosml/L), urinary osmolarity of 350 mosml/L (50- 1200 mosm/L).

You give her a subcutaneous dose of desmopressin (dDAVP, a synthetic form of vasopressin), her serum osmolarity falls to 290 mosm/L, with urine Osmolarity of 800 mosm/L. Explain the following:

If the urine osmolarity had not increased, what would you suggest?

Answer 20

• renal resistance to ADH
  
  • aka. Nephrogenic Diabetes Insipidus
• acquired forms of NDI are more common in adults
• congenital causes are more common in children
• most patients with congenital NDI (90%) have an X-linked pattern of inheritance
• affected male patients do not concentrate their urine, even after administration of e_xogenous vasopressin_
• can diuresis 20 L per day, and may sleep only for 1 to 2h a time

Question 21

A 45 year old man comes to you with a 3 year history of feeling vaguely unwell, weak, “can’t shrug off cold or flus”. For 6 months he has had several episodes of fainting, intermittent vomiting, aches and pains.

On examination he is thin, tanned, blood pressure 85/50, heart rate 90bpm.

His serum sodium is 128mmol/L (135-145mmol/L), with potassium of 5.2mmol/L (normal 3.5-5.0mmol/L).

Baseline cortisol of 50mmol/L, and a peak of 280mmol/L (normal >550mmol/L).

Explain his initial serum Na+ 128mmol/L (135-145mmol/L)

Answer 21

• unable to retain sodium
• serum [Na+] depends on ADH response:
• unable to secrete aldosterone from zona glomerulosa of adrenal cortex, thus less sodium reabsorption, which means there is contraction of extracellular volume (i.e. dehydration), ↓ blood volume (BV)
• low BV and BP stimulates ADH secretion → water reabsorption → dilutes ECF → hyponatremia
• (set point shift to lower osmolality with steeper ADH slope)

ADH secretion has different sensitivity:

• Volume receptors tonically inhibit ADH release
  
  • _​_Sensitive to 5-10% change in volume.
  • it is possible to change volume (without change osmolarity) to change ADH secretion
  • with isotonic volume depletion <5%, there is no increase in ADH secretion
  • with isotonic volume depletion >5%, there is non-linear increase in ADH secretion
• more sensitive to changes in plasma osmolarity via osmoreceptors (1-2% change)
• linear relationship of ADH increase with isovolumic osmotic increase
• less sensitive to change in volume via volume receptors (5-10% change)
  
  • volume receptor tonically inhibit ADH release
• therefore, kidney conserves water despite ↓ osmolality

Question 22

A 45 year old man comes to you with a 3 year history of feeling vaguely unwell, weak, “can’t shrug off cold or flus”. For 6 months he has had several episodes of fainting, intermittent vomiting, aches and pains.

On examination he is thin, tanned, blood pressure 85/50, heart rate 90bpm.

His serum sodium is 128mmol/L (135-145mmol/L), with potassium of 5.2mmol/L (normal 3.5-5.0mmol/L).

Baseline cortisol of 50mmol/L, and a peak of 280mmol/L (normal >550mmol/L).

Explain his initial serum K+ 5.2mmol/L (normal 3.5-5.0mmol/L)

Answer 22

Patient is hyperkalemic, which suggests that:

• He is either aldosterone deficient or aldosterone resistant, since aldosterone acts to secrete potassium and reabsorb sodium.
• There is also cortisol deficiency, since cortisol binds to aldosterone receptors (20% efficiency) for potassium-sparing effects.
• Because patient is dehydrated and under physiological stress, he is expected to release cortisol to reduce s[K+] if there is no aldosterone action. However, since he is hyperkalemic, it means that cortisol is not achieving its desired effect in body either.

Note that aldosterone secretion is not dependent on ACTH, cortisol secretion is dependent on ACTH in normal indivudals.

Differential diagnosis includes:

• Primary Addison’s disease, thus primary adrenal insufficiency (e.g. tumour, autoimmune, TB)
  
  • Since short synacthen test shows baseline and peak cortisol is low, it indicates that adrenal gland is unable to respond to ACTH. Therefore, this is typical of severe primary Addison’s disease (primary adrenal insufficiency)
• Secondary (or central) Addison’s disease, thus secondary adrenal insufficiency (e.g. pituitary problem, severe stress)
  
  • If exogenous ACTH administration increase cortisol to normal levels, it would suggest that more central Addison’s disease (secondary adrenal insufficiency).
  • It can also present with hypovolemia/hypotension and high s[K+] during severe stress (e.g. acute gastroenteritis, trauma)

• _either aldosterone deficien_t or _aldosterone resistan_t, as aldosterone acts to secrete K+ and reabsorb Na+
• also cortisol deficiency, since cortisol binds to aldosterone receptors for K+-sparing effects
• because patient is dehydrated and under physiological stress, he is expected to release cortisol to ↓ s[K+] if there is no aldosterone action
• however, since he is hyperkalemic, it means that cortisol is not achieving its desired effect in body either
  
  • aldosterone secretion is not dependent on ACTH
  • 8cortisol secretion is dependent on ACTH in normal individuals

Question 23

A 45 year old man comes to you with a 3 year history of feeling vaguely unwell, weak, “can’t shrug off cold or flus”. For 6 months he has had several episodes of fainting, intermittent vomiting, aches and pains.

On examination he is thin, tanned, blood pressure 85/50, heart rate 90bpm.

His serum sodium is 128mmol/L (135-145mmol/L), with potassium of 5.2mmol/L (normal 3.5-5.0mmol/L).

Baseline cortisol of 50mmol/L, and a peak of 280mmol/L (normal >550mmol/L).

Differential diagnoses

Answer 23

• Primary Addison’s disease = primary adrenal insufficiency (e.g. tumour, autoimmune, TB)
  
  • baseline and peak cortisol is low → adrenal gland is unable to respond to ACTH
  • therefore, this is typical of severe primary Addison’s disease (primary adrenal insufficiency)
• Secondary (central) Addison’s disease = secondary adrenal insufficiency (e.g. pituitary problem, stress)
  
  • if exogenous ACTH administration ↑ cortisol to normal levels → central Addison’s disease
  • can also present with hypovolemia/hypotension and high s[K+] during severe stress
• (e.g. acute gastroenteritis, trauma)

Question 24

A 45 year old man comes to you with a 3 year history of feeling vaguely unwell, weak, “can’t shrug off cold or flus”. For 6 months he has had several episodes of fainting, intermittent vomiting, aches and pains.

On examination he is thin, tanned, blood pressure 85/50, heart rate 90bpm.

His serum sodium is 128mmol/L (135-145mmol/L), with potassium of 5.2mmol/L (normal 3.5-5.0mmol/L).

Baseline cortisol of 50mmol/L, and a peak of 280mmol/L (normal >550mmol/L).

Explain his initial arterial BP of 85/50mmHg

Answer 24

volume contraction due to l_oss of whole body NaCl_, caused by low aldosterone (low Na+ reabsorption)

• volume contraction is usually not present or mild in central Addison’s

l_ack of cortisol leads to decreased tone_

• cortisol interacts with β2 adrenergic stimulus to ↑ cardiac tone
• cortisol interacts with RAS and β2 stimulation to maintain peripheral tone
  
  • Note this interaction may also contribute to cardiac contractility

Question 25

A 45 year old man comes to you with a 3 year history of feeling vaguely unwell, weak, “can’t shrug off cold or flus”. For 6 months he has had several episodes of fainting, intermittent vomiting, aches and pains.

On examination he is thin, tanned, blood pressure 85/50, heart rate 90bpm.

His serum sodium is 128mmol/L (135-145mmol/L), with potassium of 5.2mmol/L (normal 3.5-5.0mmol/L).

Baseline cortisol of 50mmol/L, and a peak of 280mmol/L (normal >550mmol/L).

Why is he tanned?

Answer 25

• due to lack of cortisol release seen in primary Addison’s, there is high ACTH
• cleaved to form α-melanocyte stimulating hormone (α-MSH) → stimulates melanocytes to secrete melatonin
• causes t_anning of skin_, including areas not exposed to sun, e.g. skin creases, inside of cheek (buccal mucosa)

Question 26

A 45 year old man comes to you with a 3 year history of feeling vaguely unwell, weak, “can’t shrug off cold or flus”. For 6 months he has had several episodes of fainting, intermittent vomiting, aches and pains.

On examination he is thin, tanned, blood pressure 85/50, heart rate 90bpm.

His serum sodium is 128mmol/L (135-145mmol/L), with potassium of 5.2mmol/L (normal 3.5-5.0mmol/L).

Baseline cortisol of 50mmol/L, and a peak of 280mmol/L (normal >550mmol/L).

How would you treat this patient?

Answer 26

• replacement therapy with mineralocorticoid (e.g. aldosterone) and glucocorticoid (e.g. cortisol)
• also determine primary cause!

Question 27

mineralocorticoid (e.g. ________) and glucocorticoid (e.g. __________)

Answer 27

mineralocorticoid (e.g. aldosterone) and glucocorticoid (e.g. cortisol)