hyperadrenal disorders

Question 1

what are the clinical features of cushings?

Answer 1

Too much cortisol
Centripetal obesity
Moon face and buffalo hump
Proximal myopathy
Hypertension and hypokalaemia
Red striae, thin skin and bruising
osteoporosis, diabetes

Question 2

list the causes of cushings?

cushings disease vs cushings syndrome

Answer 2

• Taking too many steroids
• Pituitary dependent Cushing’s disease
• Ectopic ACTH from lung cancer
• adrenal adenoma secreting cortisol

Question 3

what are the investigations to determine the cause of cushing’s sydrome?

Answer 3

-24 h urine collection for urinary free cortisol
-Blood diurnal cortisol levels
(cortisols usually highest at 9am and lowest at midnight, if asleep). In normals cortisol increases and then decreases throughout the 24hrs, but in patients with cushings, the cortisol doesn’t chnage much, just stays kinda high throughout
-low dose dexamethasone suppression test

Question 4

how does the low dose dexamethasone suppression test work?

Answer 4

0.5 mg 6 hourly for 48 hrs
Dexamethasone = artificial steroid
Dexamethasone is an exogenous steroid that provides negative feedback to the pituitary gland to suppress the secretion of adrenocorticotropic hormone (ACTH)
Normals will suppress cortisol to zero
Any cause of Cushing’s will fail to suppress

Question 5

difference between cushings disease and cushings syndrome

Answer 5

Cushing disease is caused by a pituitary gland tumor (usually benign) that over-secretes the hormone ACTH, thus overstimulating the adrenal glands’ cortisol production. Cushing syndrome refers to the signs and symptoms associated with excess cortisol in the body, regardless of the cause

Question 6

what are the values used to diagnose cushings?

Answer 6

Basal (9am) cortisol 800 nM

End of LDDST: 680 nM

Question 7

how can we treat cushings with drugs?

Answer 7

Pharmacological manipulation of steroids

• Enzyme inhibitors
• Receptor blocking drugs

Question 8

what are the drugs used in cushings?

Answer 8

Inhibitors of steroid biosynthesis:

• metyrapone
• ketoconazole

Question 9

what are the mechanisms of action for metyrapone?

Answer 9

Inhibition of 11b-hydroxylase
hence cortisol synthesis is blocked
ACTH secretion increased
plasma deoxycortisol increased

steroid synthesis in the zona fasciculata [and reticularis] is arrested at the 11-deoxycortisol stage

Question 10

what are the uses of metyrapone?

Answer 10

Control of Cushing’s syndrome prior to surgery.
- adjust dose (oral) according to cortisol (aim for mean serum cortisol 150-300 nmol/L)
- improves patient’s symptoms and promotes better post-op recovery (better wound healing, less infection etc)
Control of Cushing’s symptoms after radiotherapy (which is usually slow to take effect)

Question 11

what are the unwanted actions of metyrapone and how do they occur?

Answer 11

Hypertension on long-term administration
-deoxycorticosterone accumulates in z. glomerulosa; it has aldosterone-like (mineralocorticoid) activity, leading to salt retention and hypertension.

Hirsutism
Increased adrenal androgen production HIRSUTISM
in women

Question 12

what is the mechanism of action for ketoconazole?

Answer 12

block 17a hydroxylase
at higher concentrations, inhibits steroidogenesis – off-label use in Cushing’s syndrome

-blocks production of glucocorticoids, mineralocorticoids and sex steroids
(aldosterone, corticosterone and cortisol)

Question 13

what are the uses of ketoconazole?

Answer 13

USES (similar to metyrapone)
Cushing’s syndrome
- treatment and control of symptoms prior to surgery
- orally active

Question 14

what are the unwanted actions of ketoconazole?

Answer 14

Liver damage - possibly fatal - monitor liver function weekly, clinically and biochemically

Question 15

what are the options for treatment of cushings?

Answer 15

Depends on cause
Pituitary surgery (transsphenoidal hypophysectomy)
Bilateral adrenalectomy
Unilateral adrenalectomy for adrenal mass
medical treatment

Question 16

what is conn’s syndrome?

Answer 16

Benign adrenal cortical tumour (zona glomerulosa)
Aldosterone in excess
Hypertension and hypokalaemia

Primary hyperaldosteronism
Renin - angiotensin system should be suppressed (exclude secondary hyperaldosteronism)

Question 17

what drugs can be used to treat conn’s syndrome?

Answer 17

MR antagonist

spironolactone, epleronone

Question 18

how does spironolactone work? and what is it used for?

Answer 18

Primary hyperaldosteronism (Conn’s syndrome)

Converted to several active metabolites, including canrenone, a competitive antagonist of the mineralocorticoid receptor (MR).

Blocks Na+ resorption and K+ excretion in the kidney tubules (potassium sparing diuretic).

Question 19

what are the unwanted actions of spironolactone?

Answer 19

Menstrual irregularities (+ progesterone agonist)
Gynaecomastia (- androgen antagonist)

Question 20

how does epleronone work?

Answer 20

Also a mineralocorticoid receptor (MR) antagonist
Similar affinity to the MR compared to spironolactone
Less binding to androgen and progesterone receptors compared to spironolactone, so better tolerated

Question 21

what are phaeochromocytomas?

Answer 21

These are tumours of the adrenal MEDULLA which secrete catecholamines
(adrenaline or nor-adrenaline)

Question 22

what are the clinical features of a phaeo?

Answer 22

Hypertension in young people
Episodic severe hypertension     (after abdominal palpation)
More common in certain inherited conditions
sweating 
headache 
palor 
weakness 
dizziness 

Severe hypertension can cause myocardial infarction or stroke

High adrenaline can cause ventricular fibrillation + death

Thus this is a medical emergency

Question 23

management of phaeo

Answer 23

Eventually need surgery, but patient needs careful preparation as anaesthetic can precipitate a hypertensive crisis

Alpha blockade is first therapeutic step (required to prevent hypertensive crisis)
Patients may need intravenous fluid as alpha blockade commences
Beta blockade added to prevent tachycardia