Hypoadrenal disorders

Question 1

How many carbon atoms does cholesterol have?

Answer 1

27

Question 2

Which enzyme converts cholesterol to pregnenolone?

Answer 2

Cytochrome P450 (short chain cleavage)

Question 3

Which sets of enzymes are stimulated by ACTH?

Answer 3

Cortisol synthesis enzymes

Sex steroid synthesis enzymes

Question 4

The pituitary gland produces ACTH in response to what?

Answer 4

Stress (mediated by hypothalamus)

Question 5

Which enzyme converts corticosterone to aldosterone?

Answer 5

Aldosterone synthase (via 18-hydroxycorticosterone)

Question 6

What determines which steroids the different parts of the adrenal gland produce? Which parts produce what?

Answer 6

The combination of enzymes present in the different parts of the adrenal gland

CORTEX:

z. glomerulosa = Mineralocorticoids (corticosterone, aldosterone)
z. fasciculata = Glucocorticoids (cortisol)
z. reticularis = Sex steroids (testosterone, oestradiol)

MEDULLA (chromaffin cells):
Catecholamines (adrenaline, noradrenaline, little dopamine)

Question 7

What are the two potential reasons for adrenocortical failure?

Answer 7

• Adrenal glands destroyed

- Enzymes in the steroid synthetic pathway not working

Question 8

What are the three main causes of adrenocortical failure? State which is most common worldwide and in the UK.

Answer 8

• Tuberculous Addison’s disease (commonest worldwide)
• Autoimmune Addison’s disease (commonest in UK)
• Congenital adrenal hyperplasia

Question 9

List and explain the consequences of adrenocortical failure

Answer 9

• Hypotension (due to lack of aldosterone) especially postural
• Loss of sodium in urine and hyperkalaemia (due to lack of aldosterone)
• Fall in blood glucose (due to lack of cortisol)
• High ACTH => increased pigmentation*
• Vitiligo*
  Eventual death due to severe hypotension

Also, Weight loss and Muscular weakness in Addison’s

Question 10

Why do Addison’s patients get vitiligo?

Answer 10

Vitiligo is an autoimmune disease where you have antibodies against melanin.
Autoimmune diseases tend to go hand-in-hand

Question 11

Why does Addison’s cause skin pigmentation?

Answer 11

• The lack of cortisol => production of huge amounts of ACTH
• ACTH is formed from the cleavage of POMC (pro-opiomelanocortin) to ACTH and alpha-MSH (and endorphins and enkephalins and other peptides)
• High ACTH = high alpha-MSH => skin pigmentation

Question 12

State some tests for Addison’s disease.

Answer 12

• Low 9am cortisol (this should be high in a normal person)
• Measure ACTH and this should be high in Addison’s
• IM injection of 250 ug of synthetic ACTH (synacthen) and if they have functioning adrenals, they should start to produce cortisol (Short Synacthen Test)

Question 13

What is the most common cause of congenital adrenal hyperplasia (CAH)?

Answer 13

21-hydroxylase deficiency

Question 14

What are the two degrees of CAH?

Answer 14

Partial or Complete (absence of the enzyme)

Question 15

Which hormones are absent in complete 21-hydroxylase deficiency?

Answer 15

Cortisol and Aldosterone

Question 16

What effect does 21-hydroxylase deficiency have on sex steroid synthesis?

Answer 16

It funnels the precursors towards the steroid synthesis pathway so you get an increase in adrenal sex steroids.

Question 17

Why are foetuses with CAH normally fine in utero?

Answer 17

In utero, the foetus will have maternal cortisol and aldosterone so don’t need to rely on their own endogenous production

Question 18

What will happen to a neonate with complete 21-hydroxylase deficiency?

Answer 18

They will have a salt losing Addisonian crisis due to the lack of aldosterone

Question 19

How may a girl with 21-hydroxylase deficiency present?

Answer 19

Girls might have ambiguous genitalia (virilised by adrenal testosterone)

Question 20

Which hormones are deficient and which hormones are in excess in Partial 21-hydroxylase deficiency?

Answer 20

• Cortisol and aldosterone

- Sex steroids and testosterone

Question 21

What is the clinical presentation of partial 21-hydroxylase deficiency, and when?

Answer 21

Main problem in later life is hirsutism and virilisation in girls, and precocious puberty in boys due to adrenal testosterone

Question 22

Describe and explain the presentation of complete 11-hydroxylase deficiency.

Answer 22

• Cortisol and aldosterone deficient
• Sex steroids and 11-deoxycorticosterone in excess
• High 11-deoxycorticosterone => hypertension and hypokalaemia
  (behaves like aldosterone)
• High sex steroids => virilisation

Question 23

Describe and explain the presentation of complete 17-hydroxylase deficiency

Answer 23

• Cortisol and sex steroids deficient
• 11-deoxycorticosterone and aldosterone in excess

- High 11-deoxycorticosterone => hypertension and hypokalaemia
(behaves like aldosterone)
- Borderline hypoglycaemic 
- Absent puberty
- Prone to infection

Note that 17-hydroxylase converts progesterone to 17-hydroxyprogesterone which is required glucocorticoid synthesis pathway.