L02 - The Adrenal Gland

Question 1

What is congenital adrenal hyperplasia (CAH)?

Answer 1

A group of autosomal recessive disorders characterised by a deficiency of mineralocorticoids and glucocorticoids

Question 2

Which enzyme is most commonly deficient in congenital adrenal hyperplasia?

Answer 2

21-hydroxylase

Question 3

Which gene codes for 21-hydroxylase?

Answer 3

CYP21A2

Question 4

Why does congenital adrenal hyperplasia cause high sex steroid hormone levels?

Answer 4

• There is no negative feedback from mineralocorticoids or glucocorticoids as they are no longer produced
• This increases the level of ACTH in the blood
• The adrenals respond by increasing sex steroid hormone production

Question 5

What are the consequences of congenital adrenal hyperplasia (other than changes in hormone levels)?

Answer 5

1 - Adrenal gland become hyperplasia

2 - Newborn girls with the condition are virilised (a condition known as 46,XX disorder of sex development) as they are producing male sex hormones (androgens).

Question 6

Which molecule, when in excess, is used as an indicator of 21-hydroxylase deficiency?

Answer 6

17-hydroxyprogesterone (17OHP) - a precursor for cortisol

Question 7

Why do more males die from congenital adrenal hyperplasia than females?

Answer 7

• Congenital adrenal hyperplasia causes excessively high androgen production
• Since these are male sex hormones, females with the condition are more easy to identify as the female genitalia is virilised, whereas the male genitalia is unchanged
• More males are therefore undiagnosed at birth and die from losing the functions of mineralocorticoids and glucocorticoids (‘salt-wasting’ crisis)

Question 8

How is congenital adrenal hyperplasia treated?

Answer 8

By replacing lost glucocorticoids and mineralocorticoids

Question 9

List 3 symptoms of glucocorticoid excess.

Answer 9

1 - Obesity

2 - Osteoporosis

3 - Suppression of LH and FSH due to increased negative feedback, causing amenorrhoea

Question 10

List 2 symptoms of glucocorticoid insufficiency.

Answer 10

1 - Anovulation

2 - Oligomenorrhea

• Due to androgen excess

Question 11

List 5 clinical signs of androgen excess.

Answer 11

1 - Hirsutism

2 - Acne

3 - Androgenic alopecia

4 - Virilisation in women

5 - Hypertension

Question 12

What is polycystic ovarian syndrome (PCOS)?

Answer 12

• A syndrome characterised by at least 2 of the following 3 criteria:

1 - Chronic (or intermittent) anovulation

2 - Androgen excess

3 - Polycystic appearance of ovaries on ultrasound

Question 13

List 5 conditions that people with PCOS are at higher risk of developing.

Answer 13

1 - Insulin resistance

2 - Hypertension

3 - Type 2 diabetes

4 - Liver disease

5 - Cardiovascular disease

Question 14

What causes of androgen excess must be ruled out before a diagnosis of PCOS is made?

Answer 14

1 - Congenital adrenal hyperplasia

2 - Ovarian hyperthecosis

3 - Cushing’s syndrome

4 - Adrenocortical carcinoma

5 - Adrenocortical adenoma

Question 15

Define adrenal incidentaloma.

Answer 15

An unsuspected tumour in the adrenal glands found by chance during a CT/ultrasound for another condition

Question 16

List 2 investigations that must be done when an adrenal incidentaloma is discovered.

Answer 16

1 - Is the tumour malignant?

2 - Is the tumour functional (hormone excess)?

Question 17

Give an example of a problem with adrenal imaging.

Answer 17

It cannot differentiate between an adrenocortical carcinoma or a phaeochromocytoma

Question 18

What is the procedure for attributing a known adrenal tumour as the cause of excess adrenal hormone production?

Answer 18

1 - Exclude primary aldosteronism

2 - Exclude Cushing’s

3 - Exclude adrenal androgen excess

4 - Exclude phaeochromocytoma

Question 19

How is primary aldosteronism diagnosed?

Answer 19

To exclude primary hyperaldosteronism, blood pressure should be measured (aldosterone increases BP), as well as the aldosterone/renin ratio (the ratio will be increased in hyperaldosteronism).

Question 20

How is Cushing’s syndrome diagnosed?

Answer 20

• To exclude Cushing’s disease, perform a Dexamethasone 1mg overnight test
• Dexamethasone binds to glucocorticoid receptors in the anterior pituitary gland, suppressing the production of ACTH via negative feedback
• In normal patients, this will suppress levels of cortisol, but in patients with Cushing’s disease, cortisol levels will remain high

Question 21

How is a phaeochromocytoma diagnosed?

Answer 21

To exclude phaeochromocytoma (tumour within the adrenal medulla), plasma metanephrines (i.e. adrenaline metabolites) are measured

Question 22

What is a phaeochromocytoma?

Answer 22

Catecholamine over-secreting tumours located in the adrenal medulla

Question 23

List 2 characteristics of adenomas that are used to differentiate them from carcinomas in imaging.

Answer 23

1 - If the size of the tumour is <4cm, it is unlikely to be malignant & therefore is an adrenocortical adenoma

2 - If there is a low HU (<10) on a non-contrast CT, there is a high likelihood of an adenoma

Question 24

When is an adrenal biopsy recommended?

Answer 24

Adrenal biopsy is not recommended in diagnostic work up unless there is a history of extra-adrenal malignancy & all of the following criteria are fulfilled:

1 - Lesion hormonally inactive (phaeochromocytoma excluded)

2 - Lesion not conclusively characterised as benign by diagnostic imaging

3 - Management would be altered by knowledge of histology

Question 25

What results from mutation of the RET proto-oncogene?

Answer 25

Results in multiple endocrine neoplasia (MEN) type 2. This will cause:

• Phaeochromocytoma
• Medullary thyroid carcinoma
• Either parathyroid hyperplasia (MEN2A) or mucocutaneous neuroma (MEN2B)

It will also present with multiple nodules on the tongue

Question 26

What is Von Hippel Lindau syndrome?

Answer 26

Von Hippel-Lindau syndrome (VHL) is a hereditary condition associated with tumors arising in multiple organs. It causes:

• Phaeochromocytoma
• Renal angioma
• Renal cancer
• Haemangioblastinoma: malignant tumours of blood vessels in the cerebellum, retina and spinal cord

Question 27

What can mutations in the NF-1 gene cause?

Answer 27

Neurofibromatosis type 1. This will lead to café au lait spots on the skin, as well as multiple benign tumours of the nerve endings (neuromas)

Question 28

What are the treatments for phaeochromocytomas?

Answer 28

• Medical therapy involves the use of ⍺-blockades (antagonists for adrenaline – e.g. phenoxybenzamine, doxazosin) and β-blockades (treatment of tachycardia – e.g. propranolol)
• Surgery should not be attempted without the use of an α-blockade, and requires special anaesthesiology care

Question 29

Why is alpha blockade necessary before surgery to remove a phaeochromocytoma?

Answer 29

To treat hypertension & prevent hypertensive crisis in surgery