Hypoadrenal disorders Flashcards
How many carbon atoms does cholesterol have?
27
What enzyme converts cholesterol to pregnenolone and where is it found?
P450scc
Zona glomerulosa
How can cholesterol be converted to aldosterone?
In the adrenal cortex.
Add OH groups in different positions.
Following conversion to pregnenolone, hydroxylate position 3, add further OH groups at different positions (21, 11 and 18), and oxidise further.
What are all steroids derived from?
Cholesterol
Where are glucocorticoids produced?
Zona fasciculata, because it has slightly different enzymes to the zona glomerulosa (which produces mineralocorticoids).
Where are the sex steroid pathways present?
Ovaries
Testes
What activates glucocorticoid synthesis enzymes and sex steroid synthesis enzymes?
ACTH
What triggers ACTH release from the pituitary?
Stress
What does ACTH release from the pituitary result in?
Cortisol production
How is cortisol produced from pregnenolone?
Add OH groups at position 17, 21 and 11.
What triggers aldosterone production?
Renin and angiotensin II activate enzymes in the mineralocorticoid pathway to make aldosterone.
What is the most common cause of adrenal failure worldwide?
Tuberculous Addison’s disease- particularly occurs when the course of treatment is stopped prematurely.
What is the most common cause of adrenal failure in the UK?
Autoimmune Addison’s disease- immune system mistakenly wipes out adrenal gland.
When may adrenocortical failure occur?
When the adrenal glands are destroyed.
When enzymes in the steroid synthesis pathway are not working.
What can cause adrenal failure, other than autoimmune and tuberculous Addison’s?
Congenital adrenal hyperplasia.
What is congenital adrenal hyperplasia?
Patient is born with large adrenal glands.
Caused by enzyme deficiency- adrenals cannot make hormones properly.
Adrenals are therefore stimulated and become enlarged.
What are the consequences of adrenal failure?
Fall in blood pressure (no aldosterone)
Loss of salt in urine (no aldosterone, rise in plasma potassium)
Increased plasma potassium
Fall in glucose (due to glucocorticoid deficiency)
High ACTH resulting in increased pigmentation
Eventual death due to severe hypotension (Addisonian crisis)
Where is proopiomelanocortin (POMC) synthesised?
Pituitary
What is POMC broken down into?
ACTH MSH (melanocyte stimulating hormone) Endorphins Enkephalins Other peptides
What is the link between adrenal failure and hyperpigmentation?
No adrenal gland No cortisol No negative feedback High ACTH High MSH Increased pigmentation
In a typical Addison’s patient, what would you expect their 9am cortisol and ACTH levels to be compared to normal?
9am cortisol low (around 100, normal range is 270-900)
ACTH high
How can Addison’s be tested for?
Administer 250mg i.m. synacthen to a patient with low 9am cortisol and high ACTH. Half an hour later, cortisol level will not have changed in Addison’s patient- can’t make cortisol despite large dose of ACTH, so adrenals are abnormal.
What is the most common cause of congenital adrenal hyperplasia?
21-hydroxylase deficiency- can be complete or partial.
What does complete 21-hydroxylase deficiency result in?
Complete aldosterone and cortisol deficiency.
Excess sex steroids (especially testosterone).
<24hrs survival.
How do neonates present with 21-hydroxylase deficiency?
Salt-losing Addisonian crisis.
Girls might have ambiguous genitalia (virilised by adrenal testosterone).
What does partial 21-hydroxylase deficiency result in?
Deficient cortisol and aldosterone, with sex steroids in excess.
When does partial 21-hydroxylase deficiency present?
Can present at any age.
What are the main problems caused by 21-hydroxylase deficiency?
Hirsutism
Virilisation in girls
Precocious puberty in boys- adrenal testosterone
What is 11-beta hydroxylase deficiency?
High 11-deoxycorticosterone (active aldosterone receptor agonist). Hypertensive in childhood. Hypokalaemia. Cortisol and aldosterone deficiency. Sex steroids in excess. Virilisation. (No salt-losing crisis).
What is 17-hydroxylase deficiency?
High aldosterone- hypertension and hypokalaemia.
Cortisol deficiency.
Sex steroid deficiency- no puberty.
Glucocorticoid deficiency- borderline hypoglycaemia.
What are the consequences of adrenocortical failure?
Fall in blood pressure
Loss of salt in urine
Increased plasma potassium
Fall in glucose due to glucocorticoid deficiency
High ACTH resulting in increased pigmentation
Eventual death due to severe hypotension
Craving salt
