Hypoadrenal Disorders

Question 1

How many carbon atoms does cholesterol have?

Answer 1

27

Question 2

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

Answer 2

The combination of enzymes present in the different parts of the adrenal gland – hydroxylation in different positions of the cholesterol molecule gives different products.

Question 3

Which enzyme converts cholesterol to pregnenolone?

Answer 3

Cytochrome P450 (short chain cleavage)

Question 4

Which sets of enzymes are switched on by ACTH?

Answer 4

• Cortisol synthesis enzymes
• Sex steroid synthesis enzymes

Question 5

The pituitary gland produces ACTH in response to what?

Answer 5

Stress

Question 6

Which enzyme converts corticosterone to aldosterone?

Answer 6

Aldosterone synthase (includes 18-hydroxylase)

Question 7

State three causes of adrenocortical failure.

Answer 7

• Tuberculous Addison’s Disesae – most common cause worldwide
• Autoimmune Addison’s Disease – most common cause in the UK
• Congenital Adrenal Hyperplasia

General causes:

Adrenal gland destroyed OR enzymes in steroid synthetic pathway are not working properly.

Question 8

State some consequences of adrenocortical failure.

Answer 8

• Hypotension (due to lack of aldosterone)
• Hyperkalaemia
• Loss of salt (sodium) in urine
• Fall in blood glucose (due to lack of cortisol)
• High ACTH –> pigmentation
• Vitiligo
• Eventual death due to severe hypotension

Question 9

Why do Addison’s patients get vitiligo?

Answer 9

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

Question 10

Why does Addison’s cause skin pigmentation?

Answer 10

• The lack of cortisol stimulates the production of huge amounts of ACTH.
• ACTH is formed from the cleavage of POMC (pro-opiomelanocortin) to ACTH and alpha-MSH
• High ACTH also means high alpha-MSH –> skin pigmentation

Question 11

State some tests for Addison’s disease.

Answer 11

9 am cortisol (this should be high in a normal person)

You could measure ACTH and this should be high in Addison’s

Inject synthetic ACTH (synACTHen) and if they have functioning adrenals, they should start to produce cortisol

NOTE: 250 mg IM synacthem

Question 12

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

Answer 12

21-hydroxylase deficiency (recessive gene so both parents must carry it)

Question 13

What are the two degrees of CAH?

Answer 13

Partial or Complete (absence of the enzyme)

Question 14

Why are foetuses with CAH normally fine in utero?

Answer 14

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

• But as soon as the child is born you get an Addisonian crisis.
• Children are born with big adrenal glands which don’t work.
• Die of a SALT LOSING CRISIS where there is hypotension and loss of salt.
• Child will have a lot of extra testosterone before birth and after birth.

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

What will happen to a baby with complete 21-hydroxylase deficiency after they are born?

Answer 17

They will have a salt losing Addisonian crisis due to the lack of aldosterone - can probably only survive less than 24hr without treatment

Question 18

What are the two main features of 21-hydroxylase deficiency?

Answer 18

Hypotension

Virilisation (female babies will be born with ambiguous genitalia)

Question 19

Describe the presentation of partial 21-hydroxylase deficiency.

Answer 19

They may present much later because they don’t have a salt losing Addisonian crisis.

They will present once they start to see the effects of the excess adrenal sex steroids e.g. hirsuitism and precocious puberty (false puberty as it is not driven by hormones from testes/ovaries)

They will also be a little hypotensive

Question 20

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

Answer 20

• Excess of of 11-deoxycorticosterone, sex seroids and testosterone.
• 11-deoxycorticosterone has mineralocorticoid effects so they don’t have a salt losing Addisonian crisis – they will behave as if they have HIGH aldosterone
• They will be HYPERTENSIVE and HYPOKALAEMIC
• Problems: virilisation. hyperension, low K

NOTE: boys may be missed because they tend to look normal

Question 21

Describe and explain the presentation of 17-hydroxylase deficiency.

Answer 21

• Excess 11-deoxycorticosterone + aldosterone (mineralocorticoids)
• They will have high levels of aldosterone –> hypertensive and hypokalaemic
• They are missing cortisol and sex steroids so they will not go through puberty
• They will usually present around pubertal age –
• Problems: Hypertension, low K, sex steroid deficiency and glucocorticoid deficiency (low glucose).

NOTE: they will also have a lot of infections because you need cortisol to cope with the stress of infections

Question 22

What does 11-deoxycorticosterone behave like? What can it cause when in excess?

Answer 22

• 11 deoxycorticosterone behaves like aldosterone
• In excess it can cause hypertension and hypokalaemia

Question 23

Select True or False for each of the following statements:

a. Addison’s disease causes hypertension
b. Cushing’s disease causes hypertension
c. Addison’s disease causes hyperkalaemia
d. Cushing’s disease causes hyperkalaemia
e. Addison’s disease causes hyperpigmentation

Answer 23

False
True
True
False
True

Question 24

Select True or False for each of the following statements:

a. Cushing’s disease can be associated with hyperpigmentation
b. Congenital adrenal hyperplasia is caused by a deficiency in adrenal enzymes
c. The commonest variety of congenital adrenal hyperplasia is 21 hydroxylase deficiency

Answer 24

True
True
True
True
True

Question 25

Select True or False for each of the following statements:

a. Cushing’s syndrome is most commonly caused by an ACTH-producing adrenal adenoma
b. The discovery of a phaeochromocytoma is a medical emergency
c. Phaeochromocytomas can cause ventricular fibrillation
d. Patients with phaeochromocytomas will have high urinary cortisol levels
e. Surgery to remove a phaeochromocytoma must be performed immediately after the diagnosis is confirmed

Answer 25

False
True
True
False
False

Response Feedback:
Pituitary adenoma producing excess ACTH- is the commonest cause of endogenous Cushing’s syndrome

Although the discovery of a phaeochromocytoma is a medical emergency, surgery is dangerous until alpha and beta blockade are fully active. This can take several days.

Question 26

Select True or False for each of the following statements:

a. Beta blockade is the first therapeutic step in a patient with a phaeochromocytoma
b. Alpha blockade is the first therapeutic step in a patient with a phaeochromocytoma
c. Spironolactone is the first therapeutic step in a patient with a phaeochromocytoma
d. The discovery of a Conn’s adenoma is a medical emergency
e. Patients with Conn’s adenomas will have high urinary cortisol levels

Answer 26

False
True
False
False
False

Question 27

Select True or False for each of the following statements:

a. Patients with Conn’s adenomas will have high urinary catecholamine levels
b. Surgery to remove a Conn’s adenoma must be performed immediately after the diagnosis is confirmed
c. Beta blockade is the first therapeutic step in a patient with a Conn’s adenoma
d. Alpha blockade is the first therapeutic step in a patient with a Conn’s adenoma
e. Dexamethasone is useful in the investigation of patients with Cushing’s syndrome

Answer 27

False
False
False
False
True

Question 28

Select True or False for each of the following statements:

a. Glucose tolerance testing is useful in establishing the diagnosis of Cushing’s syndrome
b. Patients with Conn’s syndrome will have a high plasma renin activity
c. Spironolactone is an enzyme inhibitor
d. Ketoconazole is an enzyme inhibitor
e. Fludrocortisone is an enzyme inhibitor

Answer 28

False
False
False
True
False

Response Feedback: A GTT is useful to diagnose GH excess (it will fail to suppress) and has no role in assessing the cortisol axis. It may be useful to diagnose diabetes in a patient who has Cushing’s disease, but it is not useful in establishing the diagnosis of Cushing’s syndrome. Spironolactone an aldosterone receptor antagonist, ketoconazole is an enzyme inhibitor (inhibiting many of the enzymes on the pathway of steroid synthesis) and fludrocortisone is an aldosterone receptor agonist