Adrenal

Question 1

What are the areas of the adrenal glands?

Answer 1

Capsule
Cortex -
zona glomerulosa - mineralocorticoids (e.g.aldosterone)
zona fasiculata - glucocorticoids (e.g. cortisol)
zona reticularis - androgens (e.g.DHEA+androtenedione)
Medulla - catecholamine (Adrenaline + NA) +enkephalins

Question 2

Where are corticosteroids produced?

Answer 2

cortex

Question 3

What are corticosteroids?

Answer 3

Cholesterol derivative (3 6-ring, 1 5-ring)
Lipid soluble (can diffuse through membranes)
Alter gene transcription directly/indirectly
Exact action depend on structure, ability to bind genes and recruit co-factors

Question 4

How does ACTH stimulate synthesis acutely?

Answer 4

Bind to GPCR > increase STAR production > increase cholesterol uptake by mitochondria
Effect on adrenal size - Increase ACTH > hyperplasia, Decrease ACTH > atrophy

Question 5

How are corticosteroid classified?

Answer 5

Pregnane derivatives (21C) - progesterone and corticoids
Androstane derivative (19C) - Androgens
Estrane derivative (18C) - e.g. oestrogen

Question 6

Glucocorticoids e.g. cortisol

Answer 6

Not water soluble, synth in z.f and z.r, permissive actions (effect only apparent in deficiency), diurnal rhythm, increase in stress

Actions: Increase lipolysis & gluconeogenesis, maintain circulation, immunomodulation (dampen immune response)

Cortisol - binds to mineralocorticoid receptor as well glucocorticoid receptor but system isn’t swamped as 11beta-HSD2 inhibits (cortisol>cortisone) by reducing affinity

Question 7

Mineralocorticoids e.g. aldosterone

Answer 7

Imp in salt and water balance, aldosterone increases Na reabsorption and K excretion

Question 8

What is congenital adrenal hyperplasia(CAH)?

Answer 8

Block in adrenal steroidogenesis that affects the synthesis of glucocorticoids, and occasionally mineralocorticoids.

Question 9

What is the commonest cause of CAH?

Answer 9

21-hydroxylase deficiency- usually due to autosomal recessive mutation in the CYP21 gene
Enzyme converts: 17OHP > deoxycortisol & Progesterone > deoxycorticosterone

Question 10

What will 21-hydroxylase deficiency do?

Answer 10

Loss of cortisol > stimulate increase in ACTH (due to -ve feedback)
> increased 17 OHP and progesterone and other precursors
> hyperplasia of adrenal glands > generate more cholesterol

Glucocorticoid cannot be produced therefore some steroid precursors e.g. 17-OHP are shunted to androgen synthesis (however increase in androgen production mainly due to ACTH stimulation of hyperplasia)

Question 11

How is CAH diagnosed and what are the symptoms & Signs?

Answer 11

Diagnosis: High levels of 17-OHP
Symptoms & signs: Androgen excess
Female - > virilisation of females infants (appearance of male genitalia with scrotum not containing testes - measure via Prader stage I - V)
Male - > more difficult to spot, salt wasting crisis due to lack of mineralocorticoids, and effects of lack of cortisol (Addison’s like symptoms)
Can pick up decreased linear growth in children

Question 12

Treatment of CAH?

Answer 12

Exogenous cortisol and aldosterone replacement -> decrease ACTH drive and lowers androgen excess
Excessive use of cortisol -> Cushing’s symptoms e.g. central obesity, moon face, striae, suppression of LH and FSH (->amenorrhea)
Lack of GC -> adrenal crisis and androgen excess (-> anovulation and oligiomenorrhea)

Question 13

What is a 46XX male?

Answer 13

When a female has androgen excess and develops a male appearance despite female anatomy

Question 14

What is an adrenal incidentaloma?

Answer 14

An incidentally discovered adrenal mass - commonly found in normal CT investigation. Usually benign endocrine inactive tumours but some may cause hormone excess or be a malignant growth or metastases.

Question 15

What is the difference between an adrenal carinoma and an adrenal adenoma?

Answer 15

Adenoma - benign fat based

Carcinoma - malignant, larger (usually >4cm), higher density, irregular edges

Question 16

How do you determine if there is hormone excess in an adrenal incidentaloma?

Answer 16

Cushing’s - excluded by 24-h urinary free cortisol followed by dexamethasone overnight test (should suppress ACTH release > lowering endogenous cortisol secretion below clinical detection i.e. high cortisol if secreting tumour)

Phaeochromocytoma - excluded with a 24-h urinary free catecholamines/ metanephrines (metabolite of catecholamines), or by measuring plasma metinephrine levels (high in phaeochromocytoma)

Primary hyperaldosteronism - Measurement of blood pressure and plasma K+ levels & renin (in primary hyperaldosteronism would have high BP, low plasma K+ and low renin despite high aldosterone)

CAH - excluded via measurement of DHEAs and 17-OHP

Question 17

Why is it important to rule out a hormone secreting tumour before operating on a patient with an adrenal incidentaloma?

Answer 17

If patient has phaeochromocytoma (overproducing catecholamines) > high intra-operative BP (potentially life threatening

Question 18

What is phaeochromocytoma?

Answer 18

Tumour of chromaffin tissue > increase in catecholamine production
Present in adrenal medulla/sympathetic ganglia (phaeoganglioma)

Question 19

Symptoms of phaeochromocytoma?

Answer 19

Headache, sweating, palpitations, nausea, tremor, pallor, hypertension, postural hypotension (due to low plasma volume), supraventricular tachycardia, myocardial ischaemia, cardiomyopathy (-> irreversible heart failure)

Question 20

What are the genes associated with phaeochromocytoma?

Answer 20

RET protooncogene 
Von Hippel Lindau syndrome (VHL)
NF-1
SDHC & SDHB tumour genes
Genetic causes account for 25% of phaeochromacytoma

Question 21

RET protooncogene

Answer 21

Will cause multiple endocrine neoplasia (MEN) type 2

• > phaeochromocytoma
• > medullary thyroid carcinoma,
• > parathyroid hyperplasia (MEN2A) / mucocutaneous neuroma (MEN2B) [present with multiple nodules on the tongue]

Question 22

Von Hippel Lindau syndrome (VHL)

Answer 22

Patients at risk of:
Haemangioblastoma (malignant tumours of cerebellum, retina or spinal cord cancer), phaeochromocytoma, renal angioma & renal cancer

Question 23

NF-1

Answer 23

• > neurofibromatosis type 1

- present with café au lait spots on the skin + benign tumours of the nerve endings (neuromas)

Question 24

SDHC & SDHB tumour genes

Answer 24

-> familial head and neck paragangliomas

SDHB -> phaeochromocytoma + extra-adrenal paragangliomas (frequently malignant)

Question 25

What % of phaeochromcytomas have genetic causes?

Answer 25

25%

Question 26

Diagnosis of phaeochromacytoma?

Answer 26

• 24-h urinary free catecholamines/ metanephrines
• Plasma metinephrine levels (high in phaeochromocytoma)
• Imaging using MRI
• 123 I- MIBG scintigraphy (precursor of NA - taken up by tumour and visualised with contrast)

Question 27

When are you more likely to have a malignancy than an adenoma?

Answer 27

> 4cm
irregular edges
Unenhanced HU CT: >10 (cutoff for surgery), >20 (strongly indicative of malignancy - favours surgery) - still high level of false-positive results but highly specific

Question 28

How do you distinguish between phaeochromacytoma and adrenocortical carcinoma?

Answer 28

You can’t

Question 29

When is surgery for an adrenal incidentaloma?

Answer 29

Tumour size - >4-5 cm
Imaging morphology - Inhomogenous mass with irregular margins
CT - Density > 20HU and delayed wash out
MRI - Irregular enhancement Strong enhancement and slow washout of gadolinium

Question 30

Why should you not biopsy a suspected malignant tumour?

Answer 30

Biopsy can disrupt tumour capsule -> metastasis

Question 31

Adrenocortical carcinoma (ACC) - give treatment

Answer 31

Rare, virilizing in women,
Poor 5 year survival
Treatment:
Complete surgical resection using expert surgeon. if not work - use drugs e.g. mitotane or cytotoxic chemotherapy

Question 32

What is the treatment for phaeochromocytoma?

Answer 32

alpha and beta blockers
Surgical resection if possible but must give alpha blockade prior with special anesthetic care to prevent hypertensive crisis (IV phentolamine in emergencies)

Malignant treated with - 131 I – MIBG therapy and DOTATOC therapy