Addison’s disease + Cushing’s syndrome

Question 1

What are the three parts of the adrenal cortex and what do they produce?

Answer 1

• Zona glomerulosa: Mineralocortiocoids (eg aldosterone)
• Zona fasiculata: Glucocorticoids (eg cortisol)
• Zona reticularis: Androgens

Question 2

Define Addison’s disease

Answer 2

Addison’s disease refers to chronic primary adrenal insufficiency resulting in reduced adrenocortical hormones (particularly cortisol and aldosterone).

In developed countries most cases are caused by autoimmune destruction of the adrenal glands.

Question 3

Adrenal insufficiency results in which electrolyte abnormalities?

Answer 3

• Metabolic acidosis
• Hyperkalaemia
• Hyponatraemia
• Hypoglycaemia

Question 4

Risk factors for Addison’s disease

Answer 4

• Female gender
• Other autoimmune conditions: T1DM, Hashimoto’s thyroiditis, rheumatoid arthritis

Question 5

Symptoms of Addison’s disease

Answer 5

• Lethargy and generalised weakness
• Nausea and vomiting
• Weight loss
• Salt cravings
• Collapse and shock: Addisonian crisis

Question 6

Signs of Addison’s disease

Answer 6

• Hyperpigmentation: particularly of the palmar creases; seen in 92%
• Vitiligo
• Loss of pubic hair in women
• Hypotension and postural drop
• Associated autoimmune conditions

Question 7

Primary investigations in Addison’s disease

Answer 7

• Early morning cortisol (8-9am)
  
  • <100nmol/L: highly suggestive of Addison’s, admit to hospital
  • 100-500nmol/L: refer the patient for an ACTH stimulation test
  • >500nmol/L: Addison’s is unlikely
• ACTH stimulation test (short Synacthen test): gold standard
• 8am ACTH: increased in Addison’s due to loss of negative feedback from cortisol
• Adrenal antibodies: anti-21-hydroxylase suggests autoimmune aetiology
• U&Es: mineralocorticoid deficiency causes hyponatraemia and hyperkalaemia

Question 8

Describe the short synacthen test

Answer 8

It is usually performed in the morning when the adrenal glands are more “fresh”.

The test involves giving synacthen which is synthetic ACTH.

The blood cortisol is measured at baseline, 30 minutes and 60 minutes after administration. The synthetic ACTH will stimulate healthy adrenal glands to produce cortisol and the cortisol level should at least double.

A failure of cortisol to rise to at least double the baseline indicated primary adrenal insufficiency.

Question 9

Addison’s disease management

Answer 9

• Hydrocortisone in 2-3 doses divided through the day with a total of 20-30mg
• Fludrocortisone once daily for mineralocorticoid replacement (50-300 micrograms)

Patient education:

• Advise patients to wear a MedicAlert bracelet or carry steroid cards in case of an Addisonian crisis
• Advise patients to double hydrocortisone dose if they develop an intercurrent illness

Question 10

What is an Addisonian crisis?

Answer 10

An acute presentation of severe Addisons where the absence of steroid hormone leads to a life threatening presentation.

It can be the first presentation of Addisons disease or triggered by infection, trauma or other acute illness in some one with established Addisons.

It can occur with previously normal adrenal function when patients suddenly stop long term steroid therapy.

Question 11

Clinical features of Addisonian crisis

Answer 11

Symptoms

• Nausea and vomiting
• Abdominal pain
• Trigger eg infection or MI

Signs

• Hypotension
• Hypovolaemic shock
• Reduced GCS

Question 12

Investigations in Addisonian crisis

Answer 12

• 12 lead ECG: hyperkalaemic changes include flat P waves, short QT interval, broad QRS, ST depression, and tented T waves
• VBG: can be conducted quickly and will reveal metabolic acidosis with hyponatraemia and hyperkalaemia. Patients may also be hypoglycaemic.
• U&Es: hyponatraemia and hyperkalaemia
• FBC and CRP: leukocytosis and raised inflammatory markers may suggest underlying infection as precipitant
• TFTs: hypothyroid states may mimic an Addisonian picture

Question 13

Management of Addisonian crisis

Answer 13

• IV fluids: for resuscitation; consider dextrose if hypoglycaemic
• Corticosteroid: hydrocortisone 100mg IV and a further dose 6 hours later
• Fludrocortisone is not required in the acute stage (as hydrocortisone exerts an effect at the mineralocorticoid receptor)

Question 14

Classes of causes of Cushing’s syndrome

Answer 14

• ACTH-independent causes (ACTH not raised):
• ACTH-dependent causes (ACTH raised)

Question 15

Describe the HPA pathway

Answer 15

• The hypothalamus releases CRH (corticotropin releasing hormone)
• The anterior pituitary releases ACTH (adrenocorticotropic hormone)
• The adrenal cortex releases cortisol
• Cortisol exerts negative feedback on ACTH and CRH

Question 16

ACTH independent causes of Cushing’s syndrome

Answer 16

• Iatrogenic: the most common cause of Cushing’s syndrome eg glucocorticoid use
• Primary disease: adrenal adenoma, hyperplasia or carcinoma (rare)

Question 17

ACTH dependent causes of Cushing’s syndrome

Answer 17

• Cushing’s disease: an ACTH secreting pituitary adenoma
• Ectopic ACTH production: small cell lung cancer, neuroendocrine tumours

Question 18

Clinical features of Cushing’s syndrome

Answer 18

Round in the middle with thin limbs:

• Round “moon” face
• Central obesity
• Abdominal striae
• Fat pad on upper back “buffalo hump”
• Proximal limb muscle wasting

High levels of stress hormone

• Hypertension
• Cardiac hypertrophy
• Hyperglycaemia
• Depression
• Insomnia

Other

• Osteoporosis
• Ecchymosis and fragile skin
• Menstrual irregularity

Question 19

Cushing’s syndrome is associated with:

Answer 19

Hypokalaemic metabolic alkalosis and impaired glucose tolerance

Question 20

Investigations for Cushing’s syndrome

Answer 20

• Exclude exogenous glucocorticoid use
• Confirm hypercorticolism:
  
  • Low dose dexamethasone suppression or
  • 24 hour urinary free cortisol
• Once hypercoricolism is confirmed:
  
  • High dose dexamethasone suppression test

Question 21

Describe the dexamethasone suppression test

Answer 21

Dexamethasone is given at 10pm (1mg for low dose or 8mg for high dose) and cortical is measured at 9am the next morning.

Question 22

Low dose dexamethasone suppression test interpretation

Low cortisol

High/normal cortisol

Answer 22

• Low cortisol is normal
• High or normal cortisol indicates Cushing’s syndrome

Question 23

High dose dexamethasone suppression test interpretation

Answer 23

• Low cortisol: Cushing’s disease
• High/normal cortisol:
  
  • ACTH low: Adrenal Cushings
  • ACTH high: Ectopic ACTH

Question 24

Other investigations for Cushing’s syndrome

Answer 24

• MRI brain if pituitary adenoma (Cushing’s disease)
• Chest CT if suspecting small cell lung cancer
• Abdominal CT if suspecting adrenal tumour

Question 25

Management of Cushing’s disease

Answer 25

Transpheonoidal resection of the pituitary

Question 26

Management of Cushing’s syndrome caused by an ectopic ACTH source

Answer 26

Treatment of the underlying cancer

Question 27

Management of iatrogenic Cushing’s disease

Answer 27

Review the need for medication and try weaning if possible

Question 28

Management of adrenal tumour

Answer 28

Tumour resection or adrenalectomy

Question 29

Complications of Cushing’s disease

Answer 29

• Cardiac: Hypertension and ischaemic heart disease
• Endocrine: T2DM
• MSK: Osteoporosis