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Y2 LCRS 1 - Endocrinology > Hyperadrenal Disorders > Flashcards

Hyperadrenal Disorders Flashcards

1
Q

Describe the effects of excess cortisol on protein and fat synthesis.

A

Excess cortisol:

  • Decreases protein synthesis
  • Increases fat synthesis*

*Explanation:

  • The main aim of cortisol is to increase blood glucose concentraion as it is part of the stress response and stress is metabolically (energy) demanding
  • At a physiological level, cortisol promotes lipolysis so that fatty acids can be used in gluconeogenesis
  • In order to increase blood glucose levels cortisol opposes the effects of insulin
  • This leads to insulin concentration in the blood increasing
  • Insulin inhibits lipolysis (and promotes lipogenesis) in adipocytes → increased fat synthesis
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2
Q

Describe the clinical features of Cushing’s syndrome.

A
  • Centripetal obesity (lemon on sticks)
  • Moon face and interscapular fat pad (buffalo hump)
  • Proximal myopathy
    • Cortisol causes muscle protein breakdown
  • Red striae, thin skin, easy bruising
    • Cortisol causes breakdown of protein in the skin
    • Abdominal growth and thin skin → striae (stretch marks)
  • Osteoporosis
    • Cortisol causes breakdown of bone protein, reducing bone density
  • Diabetes
  • Hypertension and hypokalaemia
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3
Q

Explain why excess cortisol causes centripetal obesity, moon face and interscapular fat pad.

A
  • Cortisol increases fat synthesis by increasing insulin concentrations
  • Central (abdomen and face) adipocytes are much more sensitive to insulin than peripheral adipocytes
  • So excess glucose in the blood due to cortisol action is converted to fat and stored in the central adipocytes → LEMON
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4
Q

Explain why excess cortisol causes diabetes.

A
  • Cortisol is opposing the effects of insulin and acting to increase blood glucose concentration
  • Because insulin cannot work properly due to the excess cortisol, glucose tolerance is said to be impaired
  • This causes high blood glucose concentration → DIABETES
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5
Q

Explain why excess cortisol causes hypertension and hypokalaemia.

A
  • Cortisol can bind to MR as well as GR
  • Usually cortisol can’t bind to the MR receptors in the kidneys as it is metabolised by an enzyme (11b-hydroxysteroid dehydrogenase 2)
  • At very high levels of cortisol, the enzyme becomes saturated
  • Therefore cortisol can bind to the MR and carry out the effects of aldosterone
    • Aldosterone causes increased Na+ reabsorption → increased water reabsorption → higher BP
    • Increased Na+ reabsorption means increased K+ excretion (due to Na+/K+ pump action)
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6
Q

State four causes of Cushing’s syndrome.

A
  • Taking too many steroids
    • Means you already have an excess of steroids which can act in the body to have a similar effect to cortisol (or any other glucocorticoid)
  • Pituitary dependent Cushing’s disease
    • Pituitary adenoma (of corticotrophs) producing too much ACTH
    • Cushing’s disease because cause is known
  • Ectopic ACTH from lung cancer
    • Some lung cancer cells can start to produce ACTH
    • Ectopic = in the wrong place
  • Adrenal adenoma secreting cortisol
    • Adenoma of the adrenal cortex
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7
Q

What are the three main tests used to diagnose Cushing’s syndrome?

A
  • 24-hour urine collection for urinary free cortisol
    • High levels in circulation will mean that some will enter urine - abnormal
  • Blood diurnal cortisol levels
  • Low dose dexamethasone suppression test

NOTE: These test will identify Cushing’s (i.e. excess cortisol) but will not be helpful in identifying the cause

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8
Q

Describe the results you’d expect from a normal subject AND a patient with Cushing’s syndrome in the 24-hour urine free cortisol and blood diurnal cortisol tests.

A

You would expect lower cortisol at night in a normal subject and high cortisol in the morning.

  • Cortisol is usually highest at 9am and lowest at midnight, if asleep
  • This is because cortisol is released in a diurnal (or cicardian) rhythm = daily 24 hour cycle, regulates sleep-wake cycle responds to light and dark in the organism’s environment

In someone with Cushing’s syndrome they would have high cortisol all the time

NOTE: a problem with this test is that the cortisol levels are affected by stress.

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9
Q

Explain the scientific basis of the low dose dexamethasone suppression test.

A
  • Dexamethasone is an artificial steroid (glucocorticoid)
  • Giving this extra glucocorticoid should suppress ACTH production due to negative feedback
    • Give 0.5mg every 6 hours for 48 hours
  • This should herefore lead to redduce cortisol production as there is no ACTH to stimulate the adrena cortex to proudce cortisol
  • So in a normal subject undertaking the dexamethasone suppression test, you would expect zero cortisol
  • In a Cushing’s patient, cortisol will remain high despite the presence of dexamethasone - cortisol production is no longer regulated by ACTH

NOTE: Any cause of Cushing’s will result in failure of dexamethasone to supresss cortisol production

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10
Q

What results are used to confirm a diagnosis of Cushing’s?

A
  • Basal (9am) cortisol is high - 800 nM or more
  • Based on this result you carry out LDDST
  • End of LDDST - 680 nM or more
  • Confirms Cushing’s
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11
Q

What are two drug types that can be used when you have an excess of a certain steroid hormone?

A

Enyme inhibition - reduces steroid synthesis

Receptor blocking drugs - reduces effect of steroid on target organs

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12
Q

State two drugs that are used to treat Cushing’s syndrome.

A
  • Metyrapone
  • Ketoconazole

NOTE: Both these drugs inhibit steroid biosynthesis

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13
Q

Draw the adrenal steroid synthesis pathway.

A

NOTE: P450SCC = cholesterol side-chain cleavage enzyme (member of cytochrome P450 superfamily of enzymes)

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14
Q

What is the mechanism of action of metyrapone?

A

It inhibits the 11β-hydroxylase enzyme

  • Disrupts the steroid biosysthesis pathway
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15
Q

What effect does metyrapone have on the steroid synthesis pathway? What are the consequences of this?

A

It prevents the conversion of:

  • 11-deoxycorticosterone → corticosterone
  • 11-deoxycortisol → cortisol
    • Therefore steroid synthesis in the zona fasciculata (and zona reticularis) is arrested at the 11-deoxycortisol stage
  • This means that no/reduced corticosterone or CORTISOL is produced - has consequences:
    • ACTH secretion from the anterior pituitary increases (lack of negative feedback from cortisol)
    • Plasma deoxycortisol increases
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16
Q

State two uses of metyrapone.

A
  • Control of Cushing’s syndrome prior to surgery
    • Adjust dose (oral) according to serum cortisol levels (aim for mean serum cortisol 150-300 nmol/L)
    • Treatment improves patient’s symptoms and promotes better post-op recovery (better wound healing, less infection etc. because supraphysiological levels of cortisol have an immunosupressive effect)
  • Control of Cushing’s symptoms after radiotherapy (which is usually slow to take effect)
17
Q

State two negative aspects of metyrapone.

A

Problem 1

  • Metyrapone causes the accumulation of 11-deoxycorticosterone (in the zona gomerulosa
  • 11-deoxycorticosterone has mineralocorticoid (aldosterone-like) effects so causes salt retention and HYPERTENSION
    • This is on long-term administration (takes time for 11-deoxycorticosterone to accumulate, esp when the precursors are being funnelled towards the sex steroid synthesis pathway as well)

Problem 2

  • Metyrapone inhibits two limbs of the steroid synthesis pathway so it funnels the precursors towards the sex steroid synthesis pathway
  • This leads to increased adrenal androgens, which has effects such as HIRSUTISM (excessive male-pattern hair growth)
18
Q

What was ketoconazole originally used for and why is it no longer used for this?

A
  • Ketoconazole was mainly used as an anti-fungal
  • It was withdrawn in 2013 due to risk of hepatotoxicity (i.e. it caused liver damage)
19
Q

What are the effects of ketoconazole on steroid production?

A
  • Ketoconazole inhibits the cholesterol side-chain cleavage enzyme (P450SCC)
  • This enzyme converts cholesterol → pregnenolone
    • Pregnenolone is the precursor for all the different pathways of steroid hormone production
  • This means that it inhibits the production of glucocorticoids, mineralocorticoids and sex steroids
20
Q

What is ketoconazole used for now?

A

Treatment of Cushing’s syndrome and control of symptoms prior to surgery (similar to metyrapone)

  • At higher concentrations, it inhibits steroidogenesis
  • However, this is off-label use - i.e. the drug is being used for a different purpose to the one that is stated on the license/label)

NOTE: Ketoconazole is orally active

21
Q

State some unwanted actions of ketoconazole.

A

Liver damage - possibly fatal so it is important monitor liver function weekly: clinically and biochemically

22
Q

State some surgical treatments for Cushing’s syndrome.

A

Treatment (i.e. type of surgery) is dependent on cause

  • Transsphenoidal Hypophysectomy (for Cushing’s disease)
    • i.e. removal of pituitary gland in Cushing’s disease, where the cause is known to be a pituitary adenoma
  • Bilateral adrenalectomy
    • i.e. removal of both adrenal glands
  • Unilateral adrenalectomy for adrenal mass
    • i.e. removal of just one adrenal gland if there is a mass/tumour, affecting just one of them
23
Q

What is Conn’s syndrome?

A

Benign adrenal cortical tumour

  • Tumour of the zona glomerulosa → excess aldosterone

NOTE: Conn’s syndrome = primary hyperaldosteronism

24
Q

What are the two main features of Conn’s syndrome?

A
  • Hypertension
  • Hypokalaemia

Explanation:

  • Excess aldosterone leads to excessive Na+ reabsorption
  • This is done via the Na+/K+ pump - so the more Na+ that is reabsorbed, the more K+ is excreted
  • This leads to hypokalaemia
  • The increased Na+ reabsorption creates an osmotic gradient which leads to increased water reabsoprtion
  • This results in increased blood volume and hence increased blood pressure - hypertension
25
Q

What is secondary hyperaldosteronism?

A

High aldosterone in response to activation of the renin-angiotensin-aldosterone system

26
Q

What can you test to exclude secondary hyperaldosteronism?

A

Check for suppression of the renin-angiotensin system

  • Measure aldosterone levels in the blood
  • If aldosterone is high (hyperaldosteronism), measure blood renin concentration
    • Renin levels should be low because its release would be suppressed by the high blood pressure (high renal perfusion pressure) caused by the high aldosterone
27
Q

Which drugs can be used to treat Conn’s syndrome?

A

Mineralocorticoid receptor (MR) antagonists:

  • Spironolactone
  • Epleronone
28
Q

What is the mechanism of action of spironolactone?

A
  • Spironolactone is converted to several active metabolites in the body, including canrenone
  • Canrenone is a competitive antagonist of the MR
  • Therefore, it inhibits Na+ reabsorption and K+ excretion in the kidney tubules (potassium sparing diuretic)
29
Q

State some unwanted effects of spironolactone.

A

Spironolactone is not very specific to the MR which leads to side effects

  • Progesterone receptor agonist → menstrual irregularities Androgen receptor antagonist → gynaecomastia
    • Gynaecomastia = enlargement of male breasts due to benign increase in glandular tissue
30
Q

Name another mineralocorticoid receptor antagonist and explain it’s advantages comapared to spironolactone

A

Eplerenone

  • Similar affinity to the MR compared to spironolactone
  • Less binding to androgen and progesterone receptors compared to spironolactone, so better tolerated (i.e. fewer side effects)
31
Q

What is phaeochromocytoma?

A

Tumour of the adrenal medulla that is producing excessive amounts of catecholamines (adrenaline and noradrenaline)

32
Q

What are the features of phaeochromocytoma?

A
  • Hypertension in young people (as you do not usually see hypertension in young people)
  • Episodic severe hypertension
    • This can be triggered by palpation of the adrenal tumour when doing an abdominal examination
  • More common in certain inherited conditions
    • e.g. von Hippel-Lindau syndrome = genetic condition associated with tumors arising in multiple organ
33
Q

What are the clinical features of phaeochromocytoma?

A
  • Severe hypertension can cause myocardial infarction or stroke
  • It can cause ventricular fibrillation and death
    • Ventricular fibrillation = rapid and disorganised electrical activity in ventricles means that the ventricles quiver instead of pumping blood
    • This is because NA/adrenaline can influence the electrical activity of the heart to try to increase heart rate, so it makes sense that excessive NA/adrenaline would lead to a disruption in electrical activity
    • Ventricular fibrillation would lead to cardiac arrest (sudden loss of blood flow) and hence death
  • Thus this is a MEDICAL EMERGENCY
34
Q

What is the management plan for phaeochromocytoma?

A

They would eventually need surgery, but patient needs careful preparation as anaesthetic can precipitate a hypertensive crisis

Therapeutic management prior to surgery:

  • Alpha-blockers to prevent the vasoconstriction caused by catecholamines binding to alpha-receptors
    • Alpha-blockers cause a drop in blood pressure so they are usually given with IV fluid to prevent hypotension
  • Beta-blockers to prevent tachycardia.
  • Once all the receptors are blocked, it means that a massive release in adrenaline (and NA) will not be able to have its effects
35
Q

What percentage of phaeochromocytoma is intra-adrenal?

A

90%

  • 10% of phaeochromocytomas are malignant and 10% are bilateral (affects both adrenal glands)
  • 10% are extra-adrenal meaning in the sympathetic chain → excessive sympathetic activation

NOTE: Phaeochromocytoma is a very rare condition

Y2 LCRS 1 - Endocrinology (20 decks)

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