Adrenal

Question 1

Where is cortisol secreted from?

Answer 1

Cortisol is secreted by the two adrenal glands, which sit above each kidney.

Question 2

What is released from the hypothalamus and what does it stimulate in the pituitary in the adrenal axis?

Answer 2

The hypothalamus releases corticotropin-releasing hormone (CRH). CRH stimulates the anterior pituitary to release adrenocorticotropic hormone (ACTH). ACTH stimulates the adrenal glands to release cortisol.

Question 3

When is cortisol secreted during the day?

Answer 3

Cortisol is released in pulses throughout the day and in response to a stressful stimulus. It is a “stress hormone”.

It has diurnal variation, meaning it is high and low at different times of the day. Typically cortisol peaks in the early morning, triggering us to wake up and get going, and is at its lowest late in the evening, prompting us to relax and fall asleep.

Question 4

The adrenal-axis is controlled by negative feedback, how does this work?

Answer 4

When the levels get too high cortisol is sensed by the hypothalamus and anterior pituitary, suppressing the release of CRH and ACTH. This results in lower amounts of cortisol. This way, cortisol is closely regulated to keep it within normal limits.

Question 5

What actions does cortisol have within the body?

Answer 5

Increases alertness
Inhibits the immune system – inhibits the production of several inflammatory cytokines
Inhibits bone formation – chronically elevated cortisol can lead to osteoporosis)
Raises blood glucose – stimulating gluconeogenesis (synthesis of glucose from non-carbohydrate sources)
Increases metabolism – promoting breakdown of proteins which can result in muscle wasting in chronic states of cortisol elevation
An initial surge in cortisol levels triggers lipolysis, however, chronically elevated cortisol promotes lipogenesis.

Question 6

What is Cushing’s syndrome?

Answer 6

Cushing’s syndrome refers to the features of prolonged high levels of glucocorticoids (cortisol) in the body.

Question 7

What are the symptoms of Cushing’s syndrome?

Answer 7

Symptoms:
* Weakness
* Facial fullness
* Weight gain
* Low mood
* Decreased libido
* polydipsia
* polyuria
* Increased frequency of infection

Question 8

What are the presenting features of Cushing’s syndrome upon inspection?

Answer 8

Round face (known as a “moon face”)
Central (truncal) obesity
Abdominal striae (stretch marks)
Enlarged fat pad on the upper back (known as a “buffalo hump”)
Proximal limb muscle wasting (with difficulty standing from a sitting position without using their arms)
Male pattern facial hair in women (hirsutism)
Easy bruising and poor skin healing
Hyperpigmentation of the skin in patients with Cushing’s disease (due to high ACTH levels)
ACTH is stimulating melanocytes to produce melanin
This is absent if the cause is an adrenal adenoma or exogenous steroids
Hypertension
Signs of tumour in Cushing’s disease e.g. headaches, visual field defects

Question 9

What are the metabolic effects of Cushing syndrome?

Answer 9

• Hypertension
• Cardiac hypertrophy
• Type 2 diabetes
• Dyslipidaemia (raised cholesterol and triglycerides)
• Osteoporosis

Question 10

What are the endogenous causes of Cushing’s syndrome?

Answer 10

• Cushing’s disease = pituitary adenoma secreting excessive adrenocorticotropic hormone (ACTH), stimulating excessive cortisol release from the adrenal glands.
  ○ Around 80% of endogenous cases
• Cushing’s syndrome can also be caused by adrenal adenomas and adrenal carcinomas, these are corticotropin-independent

Question 11

What are the exogenous causes of Cushing’s syndrome?

Answer 11

• The prolonged use of exogenous corticosteroids, such as prednisolone or dexamethasone, often causes Cushing’s syndrome.

Question 12

You can remember the causes of Cushing syndrome by CAPE, what does this stand for?

Answer 12

• C – Cushing’s disease (a pituitary adenoma releasing excessive ACTH)
• A – Adrenal adenoma (an adrenal tumour secreting excess cortisol)
• P – Paraneoplastic syndrome – ACTH is released from a tumour somewhere other than the pituitary gland (ectopic ACTH) stimulating excessive cortisol release from the adrenal gland e.g. small cell lung cancer
• E – Exogenous steroids (patients taking long-term corticosteroids)

Question 13

What is a dexamethasone suppression test?

Answer 13

Only used on endogenous causes.
The normal response to dexamethasone = is suppressed cortisol due to negative feedback.

• Dexamethasone causes negative feedback on the hypothalamus, reducing the corticotropin-releasing hormone (CRH) output.
• It causes negative feedback on the pituitary, reducing the ACTH output.
  -The lower CRH and ACTH levels result in a low cortisol output by the adrenal glands.
  -A lack of cortisol suppression in response to dexamethasone suggests Cushing’s syndrome.

Question 14

There are 3 types of dexamethasone suppression tests, what are they?

Answer 14

• Low-dose overnight test (used as a screening test to exclude Cushing’s syndrome)
  
  • Low-dose 48-hour test (used in suspected Cushing’s syndrome)
• High-dose 48-hour test (used to determine the cause in patients with confirmed Cushing’s syndrome)

Question 15

How does a High-dose 48-hour test indicate a cause?

Answer 15

• higher dose is enough to suppress the cortisol in Cushing’s syndrome caused by a pituitary adenoma (Cushing’s disease),
• but not when it is caused by an adrenal adenoma or ectopic ACTH.

Question 16

ACTH levels can be measured directly, how do they indicate the cause of Cushing’s dyndrome?

Answer 16

• ACTH is suppressed due to negative feedback on the pituitary when excess cortisol comes from an adrenal tumour (or endogenous steroids)
• ACTH is high when produced by a pituitary tumour or ectopic ACTH (e.g., small cell lung cancer)

Question 17

What other blood tests would you request and why?

Answer 17

• Full blood count may show a high white blood cell count
• U&Es may show low potassium if an adrenal adenoma is also secreting aldosterone
• MRI brain for a pituitary adenoma
• CT chest for small cell lung cancer
• CT abdomen for adrenal tumours

Question 18

What is the treatment for Cushing’s syndrome?

Answer 18

Surgery to remove the relevant tumor of the cause.
If exogenous steroids - reduce the dose where possible

Where surgical removal of the cause is not possible, another option is to surgically remove both adrenal glands (adrenalectomy) and give the patient life-long steroid replacement therapy.

Question 19

What is Nelson’s syndrome?

Answer 19

The development of an ACTH-producing pituitary tumour after the surgical removal of both adrenal glands due to a lack of cortisol and negative feedback. It causes skin pigmentation (high ACTH), bitemporal hemianopia and a lack of other pituitary hormones.

Question 20

What are the complications of Cushing’s syndrome?

Answer 20

hypertension
diabetes
obesity
Metabolic syndrome
Osteoporosis

Question 21

What is adrenal insufficiency?

Answer 21

Adrenal insufficiency is where the adrenal glands do not produce enough steroid hormones, particularly cortisol and aldosterone. Steroids are essential for life. Therefore, the condition is life-threatening unless the hormones are replaced.

Question 22

What is Addison’s disease?

Answer 22

when the adrenal glands are damaged -> reduced cortisol and aldosterone secretion, the most common cause is autoimmune.

Question 23

What is secondary adrenal insufficiency?

Answer 23

inadequate adrenocorticotropic hormone (ACTH) and a lack of stimulation of the adrenal glands, leading to low cortisol.
This is the result of loss or damage to the pituitary gland.

Question 24

What is the cause of secondary adrenal insufficiency?

Answer 24

▪ Tumours (e.g., pituitary adenomas)
▪ Surgery to the pituitary
▪ Radiotherapy
▪ Sheehan’s syndrome = where major post-partum haemorrhage causes avascular necrosis of the pituitary gland
▪ Trauma

Question 25

What is tertiary adrenal insufficiency?

Answer 25

inadequate corticotropin-releasing hormone (CRH) release by the hypothalamus.

Question 26

What is the common cause of adrenal insufficiency?

Answer 26

○ Usually the result of patients taking long-term oral steroids (for more than 3 weeks), causing suppression of the hypothalamus (via negative feedback)
○ When the exogenous steroids (originating outside the body) are suddenly withdrawn, the hypothalamus does not “wake up” fast enough, and endogenous steroids (originating inside the body) are not adequately produced
○ Long-term steroids must be tapered slowly to allow the adrenal axis to regain normal function.

Question 27

What are the causes of addison’s disease?

Answer 27

Autoimmune (more common in women)
Infective (TB, HIV, fungal, synphilis)
Hemorrhage, malignant invasion)

Question 28

What are the symptoms of Addisons disease?

Answer 28

• Fatigue
  
  • Muscle weakness
  • Muscle cramps
  • Dizziness and fainting
  • Thirst and craving salt
  • Weight loss
  • Abdominal pain
  • Depression
  • Reduced libido (mainly in women)
• Loss of hair in axillary/pubic regions (mainly in women)

Question 29

What are the clinical signs of Addison’s disease?

Answer 29

• Bronze hyperpigmentation of the skin (particularly in creases, scars, lips and buccal mucosa) = excessive ACTH stimulates melanocytes to produce melanin
• Hypotension (particularly postural hypotension – with a drop of more than 20 mmHg on standing)

Question 30

What blood tests would you investigate in suspected Addison’s disease?

Answer 30

• Hyponatraemia (low sodium) is a key biochemical finding. This may be the only presenting feature.
  Other potential biochemical findings may occur. Normal results do not exclude the diagnosis:
  ○ Hyperkalaemia (high potassium)
  ○ Hypoglycaemia (low glucose)
  ○ Raised creatinine and urea due to dehydration
  ○ Hypercalcaemia (high calcium)

ACTH -> directly measured to suggest the cause
Antibodies -> autoimmune adrenal insufficieny

Question 31

What imaging tests would you request?

Answer 31

CT or MRI of the adrenal glands can be helpful if suspecting structural pathology. They are not routinely required.
MRI of the pituitary gives further information about pituitary pathology.

Question 32

What is the main test for diagnosing adrenal insufficiency and how does it work?

Answer 32

Short Synacthen Test.

• The test involves giving a dose of Synacthen (synthetic ACTH)/ IV administration of 250mcg of tetracosactide (synthetic ACTH). The blood cortisol is checked before and 30 and 60 minutes after the dose.

○ Normal = cortisol level should at least doubel,synacthen will stimulate healthy adrenal glands to produce cortisol.
○ Failure of cortisol to double indicates either:
▪ Primary adrenal insufficiency (Addison’s disease)
▪ Very significant adrenal atrophy after a prolonged absence of ACTH in secondary adrenal insufficiency

Question 33

What is the management of adrenal insufficiency?

Answer 33

Replacement steroids titrated to signs, symptoms, and electrolytes.
* Hydrocortisone 15-30mg/day divided into doses (a glucocorticoid) is used to replace cortisol.
* Fludrocortisone 50-300mcg/day (a mineralocorticoid) is used to replace aldosterone, if aldosterone is also insufficient.

Question 34

What is the presentation of an adrenal crisis?

Answer 34

• Reduced consciousness
  
  • Hypotension
  • Hypoglycaemia
  • Hyponatraemia and hyperkalaemia
    Abdominal pain, nausea, vomiting, hypermigmentation.

Question 35

What can cause an adrenal crisis?

Answer 35

It may be the initial presentation of adrenal insufficiency or triggered by infection, trauma or other acute illness in established adrenal insufficiency.