Hyperadrenal Disorders Flashcards
Describe the effects of excess cortisol on protein and fat synthesis.
Decrease protein synthesis
Increase fat synthesis
Explain why people with Cushing’s disease get stretch marks.
They are putting on a lot of fat quickly, which stretches the skin. Because protein synthesis is switched off, you can’t make the protein required for skin growth so the skin tears.
Describe the clinical features of Cushing’s syndrome.
- Too much cortisol
- Moon face
- Interscapular fat pad (buffalo hump)
- Proximal myopathy
- Easy bruising, striae, thin skin
- Osteoporosis , diabetes
- Centripetal adiposity (lemon on sticks)
- Hypertension and hypokalaemia
Why does Cushing’s syndrome cause hypertension and hypokalaemia?
At high concentrations, cortisol can have mineralocorticoid effects –> increased sodium absorption and potassium excretion
State four causes of Cushing’s syndrome.
- Pituitary adenoma
- Ectopic ACTH e.g. from lung cancer
- Oral glucocorticoid drugs
- Adrenal adenoma secreting cortisol
What are the three main tests used to diagnose Cushing’s syndrome?
- 24-hour urine free cortisol
- Blood diurnal cortisol levels (or midnight serum cortisol when it should be lowest; highest at 9am)
- Low dose dexamethasone suppression test
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.
You would expect lower cortisol at night in a normal subject and high cortisol in the morning.
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.
What is dexamethasone? How much is given in the low dose dexamthasone suppression test?
0.5 mg 6 hourly for 48 hrs
Dexamethasone = artificial steroid
Explain the scientific basis of the low dose dexamethasone suppression test.
- Dexamethasone is a glucocorticoid so by giving this extra glucocorticoid, it should suppress ACTH and reduce cortisol production.
- 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.
State some surgical treatments for Cushing’s syndrome.
Treatment is dependent on cause:
- Transsphenoidal Hypophysectomy (for Cushing’s disease)
- Bilateral adrenalectomy
- Unilateral adrenalectomy for adrenal mass
State two drugs that are used to treat Cushing’s syndrome before surgery.
Metyrapone
Ketoconazole
Draw the adrenal steroid synthesis pathway.
-
Which enzyme is inhibited by metyrapone?
11-Beta-hydroxylase
What effect does metyrapone have?
- cortisol synthesis blocked
- ACTH secretion increased
- plasma deoxycortisol increased
What is the mechanism of action of metyrapone?
- Inhibition of 11beta-hydroxylase
- Steroid sythesis in zona fasciculata (and reticularis) is arrested at the 11-deoxycortisol stage
- 11-deoxycortisol has no negative feedback on hypothalamus and pituitary
State two uses of metyrapone.
- Preparation of a Cushing’s patient for surgery (improves their healing abilities and makes them better surgical candidates)
- Treatment of Cushing’s syndrome symptoms following radiotherapy (radiotherapy has a delayed effect)
State two negative aspects of metyrapone.
Metyrapone –> accumulation of 11-deoxycorticosterone (because it doesn’t have any negative feedback effects on the ACTH axis). Since 11-deoxycorticosterone has mineralocorticoid effects so causes SALT RETENTION and HYPERTENSION.
Metyrapone inhibits two limbs of the steroid synthesis pathway so it funnels the precursors towards the sex steroid synthesis pathway. –> increased adrenal androgens, which has effects such as hirsuitism.
State some unwanted effects of metyrapone.
- Hypertension on long-term administration
- Hirsutism
What is ketoconazole and why is it no longer used?
Ketoconazole is an anti-fungal, which had an effect on the steroidsynthesis pathway.
- It is no longer used because of its hepatotoxicity.
Off label use for Cushing’s - treatment and control of symptoms prior to surgery. Orally active.
What are the effects of ketoconazole on steroid production?
Ketoconazole inhibits cytochrome P450 short chain cleavage enzyme.
This enzyme converts cholesterol –> pregnenolone
This means that it inhibits the production of glucocorticoids, mineralocorticoids and sex steroids. - off-label use in Cushing’s
State some unwanted actions of ketoconazole.
LIVER DAMAGE (could be fatal) - monitor liver function weekly, clinically and biochemically
What is Conn’s syndrome?
Aldosterone secreting adenoma of the adrenal gland (zona glomerulosa)
What are the two main features of Conn’s syndrome?
Hypertension
Hypokalaemia
What is primary hyperaldosteronism?
Hyperaldosteronism caused by an adrenal adenoma.
