Iatrogenic complications of steroid treatments

Question 1

Describe the diurnal pattern of cortisol release?

Answer 1

Three spikes correspond to meals (involved in glucose regulation)

Very low during early morning

Question 2

Describe how cortisol is converted to cortisol, and vice versa?

Answer 2

In liver, 11b-HSD1 converts cortisone to cortisol

In kidney, 11b-HSD2 converts cortisol to cortisone

Question 3

Cortisol has high affinity for mineralocorticoid receptors in the kidney. Describe why it does not activate these receptors?

Answer 3

11b-HSD2 colocalised with mineralocorticoid receptor in kidney > cortisol converted to inactive metabolite cortisone > cortisone does not activate receptors

Question 4

Describe the difference in half-life between cortisol, cortisone, and cortisol regenerated from cortisone?

Answer 4

Cortisol: short (~30 mins)

Cortisone: longer (~60 mins)

Regenerated cortisol: longer (~60 mins) (similar to the cortisone that it was regenrated from)

PICTURE SLIDE 10

Question 5

Describe the clinical presentation of cortisol deficiency?

Answer 5

Weakness

Fatigue

Anorexia

Nausea

Vomiting

Hypotension

Hypoglycaemia

Question 6

In cortisol deficiency due to primary adrenal hypofunction, which other deficiency also occurs?

Answer 6

Mineralocorticoid deficiency

Question 7

Describe the clinical signs of mineralocorticoid deficiency?

Answer 7

Hyperkalaemia

Hyponatremia

Acidosis

Dehydration

Question 8

Why is adrenocortical insufficiency difficult to diagnose?

Answer 8

Presneting signs and symptoms are very nonspecific

Disorder rarely occurs without concomitant injury

Question 9

Describe the consequences of untreated adrenocortical insufficiency?

Answer 9

Dismal prognosis

Death

Question 10

Describe how treatment for adrenocortical insufficiency is administered?

Answer 10

Cortisol or cortisone

Short half-life > multiple doses a day

Divide doses to mimic physiological time course

Extra doses for infections and periods of stress (cortisol usually rises during these periods)

Add fludrocortisone if required (to replace aldosterone in primary adrenal insufficiency)

Question 11

Describe the side effects of treatment with cortisol/cortisone?

Answer 11

No side effects from well managed treatment

But: Cushingoid syndrome, adrneal suppression, immunosuppression, peptic ulcers, osteoporosis, inhibition of linear growth in children

Question 12

List the iatrogenic complications of glucocrticoid therapy?

Answer 12

Cushingoid syndrome

Adrenal suppression

Immunosuppression

Peptic ulcers

Osteoporosis

Inhibition of linear growth in children

Question 13

Why do iatrogenic complications of glucocorticoid therapy often occur?

Answer 13

Often given in supra-physiological doses

Question 14

Describe why adrenal suppression may occur as an iatrogenic complication of glucocorticoid therapy?

Answer 14

Increased cortisool > negative feedback to ACTH

Question 15

Why may immunosuppression be a problem as an iatrogenic complication of glucocorticoid therapy?

Answer 15

Reactivation of latent infection (eg. TB)

Question 16

Describe why immunosuppression occurs with glucocorticoid therapy?

Answer 16

Glucocrticoids inhibit inflammatory cytokines released from macrophages amd other inflammatory mediators

Question 17

Describe the effects of hypercortisolism?

Answer 17

Weight gain

Wasting of muscle, skin and bone

Hyperglycaemia

Hypertension

Inhibition of linear growth

Question 18

Describe the difference between transactivation and transrepression?

Answer 18

Transactivation: activation of gene transcription via GREs

Transrepression: reduction of gene transcription via inhibition of AP-1 and NF-kB

Question 19

What determines the level of adrenal suppression that occurs as an iatrogenic complication of glucocorticoid therapy?

Answer 19

Dose and duration of therapy

Varies between drugs

Varies between patients

Question 20

How can adrenal suppression due to glucocorticoid administration be minimised?

Answer 20

Allow for ACTH secretion: avoid long lasting drugs, alternate day dosing, morning dosing

Minimise systemic absorption: inhaled or topical

Use third generation glucocorticoid drugs

Question 21

Describe the third generation glucocorticoid drugs?

Answer 21

Have reduced systemic effects because they are pro-drugs, lipohilic, have low oral bioavailability and are highly protein bound in plasma

Question 22

Describe the role that glucocorticoids play in the development of petic ulcers?

Answer 22

Causal role is debatable

Mostly occurs in patients also taking NSAIDs (possible synergistic action)

Cortisol seems to be protective in rats

Question 23

Describe why glucocorticoid administration promotes osteoporosis?

Answer 23

Glucocorticoid administration leads to maturation of osteoclasts, via decreasing OPG and increasing RANKL

Osteoclast activation leads to bone resorption

(RANKL stimulates RANK receptor on osteoclast precursors, whereas OPG binds RANLK and prevents binding to RANK)

Question 24

Describe the effect of glucocrticoid treatment on growth in childhood?

Answer 24

Children taking glucocorticoids lag a little in growth, but can recover later in treatment

Modest effect size with moderate dosing

However, growth suppression may be worse if disease is not treated