[Disorders of the adrenal gland

Endocrinology

What are the learning outcomes for the HPA axis disorders lecture? (5 points)

1. Review the anatomy of the adrenal glands 2. Discuss the functions of adrenal hormones and critique the role of the hypothalamic-pituitary-adrenal axis in maintaining homeostasis 3. Describe the signs and symptoms of adrenal underactivity and overactivity 4. Outline the pathophysiology and diagnosis of different types of adrenal insufficiency and overactivity 5. Detail therapies and treatment regimens for adrenal insufficiency and overactivity

What is the normal anatomy and function of the adrenal glands? (6 points)

1. The adrenal glands are triangular organs situated above each kidney 2. They consist of two distinct areas 3. The adrenal medulla is the middle layer 4. The adrenal cortex is the outer layer 5. The adrenal cortex has three regions 6. These regions are the zona glomerulosa, zona fasciculata and zona reticularis

What hormones are produced by each adrenal cortex region? (3 points)

1. Zona glomerulosa secretes aldosterone, a mineralocorticoid 2. Zona fasciculata secretes cortisol, a glucocorticoid 3. Zona reticularis secretes androgens

What does the normal adrenal anatomy/function diagram show? (2 points)

1. It shows the adrenal glands positioned above the kidneys 2. It shows the adrenal medulla and adrenal cortex as separate functional regions

What does the HPA axis diagram show? (5 points)

1. The hypothalamus releases signals that control the pituitary 2. The pituitary releases ACTH 3. ACTH stimulates the adrenal cortex 4. The adrenal cortex releases cortisol 5. Cortisol provides negative feedback to regulate the axis

What are the metabolic actions of glucocorticoids? (3 points)

1. They create a tendency towards hyperglycaemia 2. They promote protein catabolism 3. They cause redistribution of fats

What are the regulatory actions of glucocorticoids? (4 points)

1. Negative feedback via the HPA axis 2. Vasoconstriction 3. Effects on bone metabolism 4. Inflammatory and immune control

What are the actions of mineralocorticoids? (2 points)

1. Mineralocorticoid receptors are mainly restricted to the kidneys 2. They are responsible for hydrogen and potassium loss and sodium reabsorption

How are disorders of the HPA axis classified? (6 points)

1. HPA axis disorders can be divided into adrenal underactivity/insufficiency and adrenal overactivity 2. Adrenal underactivity is deficiency in one or more adrenal hormones 3. Primary adrenal insufficiency is also called Addison’s disease 4. Secondary adrenal insufficiency involves pituitary-related ACTH deficiency 5. Tertiary adrenal insufficiency involves hypothalamic CRH deficiency 6. Adrenal overactivity involves excess adrenal hormones and may occur with high or low ACTH

What section is introduced after HPA axis pathophysiology? (1 point)

1. Pathophysiology and treatment of adrenal underactivity

What are the signs and symptoms of adrenal insufficiency? (7 points)

1. Fatigue or lethargy 2. Muscle weakness 3. Low mood or depression 4. Loss of appetite or weight loss 5. Urinary frequency or increased thirst 6. Craving salty foods, seen in primary adrenal insufficiency only 7. First presentation can be a life-threatening adrenal crisis

What causes primary adrenal insufficiency and what hormones are affected? (5 points)

1. Primary adrenal insufficiency is caused by damage to the adrenal cortex itself 2. Autoimmune adrenalitis/Addison’s disease can cause it 3. Adrenoleukodystrophy can cause it 4. Congenital adrenal hypoplasia can cause it 5. It results in underproduction of all adrenal hormones

How is primary adrenal insufficiency diagnosed? (2 points)

1. Confirm low morning cortisol with raised ACTH 2. Perform a short Synacthen test using synthetic ACTH

How is primary adrenal insufficiency treated? (4 points)

1. Treatment requires both mineralocorticoid and glucocorticoid replacement 2. Hydrocortisone 20–25 mg/day is given in divided doses 3. Two-thirds of hydrocortisone dose should be given in the morning and the remaining one-third no later than 18:00 4. Fludrocortisone 50–200 micrograms/day is titrated according to blood pressure and U&Es

What causes secondary adrenal insufficiency? (5 points)

1. Secondary adrenal insufficiency is caused by problems with the pituitary gland 2. Causes include pituitary tumours or irradiation 3. Causes include infection or infiltration 4. Causes include pituitary apoplexy 5. Causes include genetic disorders

What happens in secondary adrenal insufficiency and how is it diagnosed? (5 points)

1. It results in underproduction of hormones controlled by the pituitary 2. It occurs secondary to insufficient ACTH secretion 3. Diagnosis includes confirmation of low morning cortisol 4. Diagnosis includes confirmation of low morning ACTH 5. Diagnosis may use insulin tolerance testing, CRF testing or long Synacthen test

How is secondary adrenal insufficiency treated? (1 point)

1. Treatment requires glucocorticoid replacement only, plus replacement of any other deficient pituitary hormones

What causes tertiary adrenal insufficiency? (4 points)

1. Tertiary adrenal insufficiency is caused by deficient CRH secretion from the hypothalamus 2. The most common cause is HPA axis suppression from long-term high-dose glucocorticoids 3. It can occur in patients cured of Cushing’s disease 4. It can be drug-induced by mifepristone, antipsychotics or antidepressants

How is tertiary adrenal insufficiency diagnosed and treated? (3 points)

1. It is diagnosed by morning cortisol, with or without short Synacthen test 2. Treatment involves slow withdrawal of steroids 3. Full recovery may take 9–12 months

What other considerations are important in adrenal insufficiency? (6 points)

1. Untreated hyperthyroidism requires a 2–3 fold increase in glucocorticoid dose because of increased clearance 2. Thyroxine treatment should not be started until adrenal insufficiency is treated or excluded 3. Starting thyroxine too early can trigger adrenal crisis 4. Pregnancy is a physiological state of hypercortisolism 5. Enzyme inducers such as rifampicin, carbamazepine, phenytoin and phenobarbital increase cortisol clearance 6. Enzyme inhibitors such as antiretrovirals reduce cortisol clearance

What is acute adrenal crisis and how does it present? (4 points)

1. Acute adrenal crisis is a life-threatening emergency caused by acute cortisol deficiency 2. Symptoms can be vague 3. Symptoms include dizziness, weakness, sweating, abdominal pain, nausea and vomiting 4. It may cause loss of consciousness

How is acute adrenal crisis treated? (3 points)

1. Prompt treatment is needed to save lives 2. Give IV hydrocortisone 50–100 mg four times daily or 200 mg by continuous IV infusion over 24 hours 3. Provide fluid support

What section is introduced after adrenal underactivity? (1 point)

1. Pathophysiology and treatment of adrenal overactivity

What are the signs and symptoms of adrenal overactivity? (10 points)

1. Emotional disturbance 2. Moon face or buffalo hump 3. Osteoporosis or muscle weakness 4. Cardiac hypertrophy and hypertension 5. Obesity 6. Adrenal tumour or hyperplasia 7. Thin or wrinkled skin 8. Amenorrhoea 9. Skin ulcers, poor wound healing or purpura 10. Abdominal striae

What causes adrenal overactivity with high ACTH? (2 points)

1. Pituitary disease/Cushing’s disease due to excess ACTH secretion 2. Ectopic ACTH production from an ACTH-secreting tumour

What causes adrenal overactivity with low ACTH/Cushing’s syndrome? (2 points)

1. Adrenal adenoma 2. Excessive doses of exogenous corticosteroids

What are the primary tests for hypercortisolism? (4 points)

1. Overnight dexamethasone suppression test 2. Long dexamethasone suppression test 3. Drugs that interfere with interpretation should be considered 4. Serum ACTH is measured after hypercortisolism testing

How is the overnight dexamethasone suppression test performed and interpreted? (3 points)

1. Give 1 mg dexamethasone at 23:00–00:00 2. Measure serum cortisol at 09:00 3. Cortisol below 35 nmol/L is probably normal

How is the long dexamethasone suppression test performed and interpreted? (3 points)

1. Give dexamethasone 500 micrograms four times daily for 48 hours 2. Measure serum cortisol at 09:00 3. Cortisol below 50 nmol/L is probably normal and has less chance of false positive

What can interfere with dexamethasone suppression test interpretation? (3 points)

1. Oestrogens 2. Inducers of steroid metabolism 3. Exogenous steroids

How is serum ACTH interpreted after confirming hypercortisolism? (4 points)

1. Low serum ACTH suggests an adrenal cortex problem 2. High serum ACTH requires identification of the ACTH source 3. Imaging may be needed 4. If necessary, corticorelin and bilateral inferior petrosal sampling may be used; if ectopic, the source must be found

How is adrenal overactivity treated when ACTH is high? (4 points)

1. Pituitary disease/Cushing’s disease is treated with pituitary surgery 2. Ectopic ACTH production requires identification of the source 3. The source should be removed where possible 4. Adrenalectomy may be required

How is adrenal overactivity treated when ACTH is low? (3 points)

1. Excision of adrenal adenoma 2. Adrenalectomy 3. Gradual withdrawal of exogenous glucocorticosteroid therapy

When is medical management used in adrenal overactivity? (1 point)

1. Medical management is used to control symptoms before surgery

How does metyrapone work and how is it dosed? (4 points)

1. Metyrapone is a competitive inhibitor of 11β-hydroxylase 2. It inhibits cortisol and aldosterone synthesis 3. Starting dose is 250 mg three times daily, increasing to 750 mg three times daily 4. Maximum dose is 1.5 g four times daily and dose is tailored to cortisol production

How does ketoconazole work and how is it dosed? (4 points)

1. Ketoconazole is a potent inhibitor of cortisol and aldosterone synthesis 2. It inhibits 17α-hydroxylase and 11-hydroxylation 3. Starting dose is 400–600 mg daily in 2–3 divided doses 4. Dose can increase to 800–1200 mg daily, with maintenance usually 400–800 mg daily

What is hyperaldosteronism and what causes it? (3 points)

1. Hyperaldosteronism is increased serum aldosterone 2. Primary hyperaldosteronism is most commonly due to an adenoma of the zona glomerulosa/Conn’s syndrome 3. Secondary hyperaldosteronism is due to inappropriate activation of the renin-angiotensin system

What are the signs and treatment of hyperaldosteronism? (5 points)

1. Signs include hypokalaemia 2. Signs include hypertension due to sodium reabsorption 3. Signs include metabolic alkalosis 4. Treatment is primarily surgical 5. Spironolactone 100–400 mg daily can be used while waiting for surgery or long-term if surgery is inappropriate

What toxicology issue is linked with systemic corticosteroids? (3 points)

1. Systemic corticosteroids such as prednisolone are used for many conditions 2. Serious risks are more likely at higher doses 3. Serious risks are more likely with prolonged use

What adverse effects are associated with long-term systemic corticosteroids? (4 points)

1. Osteoporosis 2. Cardiovascular disease 3. Altered glucose and lipid metabolism 4. Psychiatric disturbances

What toxicology issues are associated with metyrapone, ketoconazole and spironolactone? (7 points)

1. Metyrapone causes build-up of cortisol precursors 2. Metyrapone can increase testosterone and cause hirsutism 3. Ketoconazole is associated with hepatotoxicity 4. Ketoconazole is associated with QTc prolongation 5. Ketoconazole requires baseline LFTs and periodic monitoring depending on treatment duration 6. Ketoconazole requires baseline ECG and repeat ECG within a week of starting treatment 7. Spironolactone can cause gynaecomastia and hyperkalaemia

What counselling or precautions are needed with ketoconazole treatment? (3 points)

1. Effective contraception is needed for women of childbearing potential 2. Treatment is contraindicated during breastfeeding 3. Monitoring should follow SPC guidance, including LFTs and ECG

What learning outcomes are reviewed at the end of the lecture? (5 points)

1. Review the anatomy of the adrenal glands 2. Discuss the functions of adrenal hormones and the role of the HPA axis in maintaining homeostasis 3. Describe signs and symptoms of adrenal underactivity and overactivity 4. Outline pathophysiology and diagnosis of different types of adrenal insufficiency and overactivity 5. Detail therapies and treatment regimens for adrenal insufficiency and overactivity

```Which hormone is released from the zona glomerulosa of the adrenal cortex in response to stimulation from the renin-angiotensin system?

Cortisol

Aldosterone

Corticotrophin-releasing hormone (CRH)

 

Adrenocorticotropic hormone (ACTH)

 

Dehydroepiandrosterone (DHEA)

Aldosterone

Aldosterone is secreted from the zona glomerulosa of the adrenal cortex in response to stimulation from the renin-angiotensin system.

Which of the following is NOT a toxicity associated with long-term use of glucocorticosteroids?

 

Weight loss

Mood disturbances

 

Hypertension

 

Loss of bone mineral density

 

Gastrointestinal haemorrhage

Weight loss: Long term use of systemic glucocorticosteroids is associated with numerous toxicities but not weight loss (they in fact cause weight gain) - see the lecture notes for full details.

 

Which of the following would be an appropriate initial treatment regime for a patient with primary adrenal insufficiency (Addison's disease)?

 

Hydrocortisone 50mg QDS + fludrocortisone 100mcg OD

 

Hydrocortisone 100mg QDS

 

Hydrocortisone 5mg OM + 5mg lunch + 10mg teatime and fludrocortisone 100mcg OD

 

Hydrocortisone 10mg OM + 10mg ON and fludrocortisone 100mcg OD

 

Hydrocortisone 10mg OM + 5mg lunch + 5mg teatime and fludrocortisone 100mcg OM

Hydrocortisone 10mg OM + 5mg lunch + 5mg teatime and fludrocortisone 100mcg OM

Treatment requires both glucocorticoid (hydrocortisone) mineralocorticoid (fludrocortisone) replacement​.

Generally a dose of hydrocortisone 20-25mg/day (divided with 2/3 of the dose given in the morning and the remaining 1/3 no later than 18:00)​ is a sensible starting regime. Fludrocortisone 50-200mcg/day titrated according to BP and U&Es​ is usually also added.

Thinking about the 'sick day rules' for patients with adrenal insufficiency, which of the following would be appropriate advice to give to a patient with primary adrenal insufficiency (Addison's disease)?

 

If unwell, double all of their usual doses of hydrocortisone

​

 

Continue with their usual treatment unless vomiting and unable to keep anything down in which case they should seek medical advice

 

They should not self-administer hydrocortisone injection, but seek medical attention to assist with this

 

Diarrhoea is unlikely to affect their disease and should not be worried about

 

Omit hydrocortisone on days when they are unwell and resume once recovered

If unwell, double all of their usual doses of hydrocortisone

Patients should be told about the ‘sick day rules’ to manage illness (especially if febrile)​:

• Double all of the usual doses if unwell or in any doubt

• Take 20mg PO and sip fluids (ideally Dioralyte) if severe nausea / headache​

• Take 20mg PO in the event of major injury (although 100mg IM may be required for serious trauma)​

• Use (self-administer) emergency hydrocortisone injection and seek immediate medical advice if unwell and vomiting​

• If diarrhoea, seek advice from their endocrinologist​

• If undertaking strenuous exercise, may need to double the dose of both hydrocortisone and fludrocortisone and increase fluid intake​

• For less strenuous exercise, may need to take an additional 5-10mg hydrocortisone before starting​

Outline what the short Synacthen test entails. Include in your answer details of what agent is used, its physiological effects on both healthy individuals and someone with the disease state it is used to diagnose, the monitoring of response and how to interpret the results. You do NOT need to give specific values or reference ranges in your answer.

Synacthen is synthetic ACTH. It is administered via IM or IV injection after checking baseline cortisol levels first thing in the morning. A repeat cortisol level is then taken 30 minutes later. As ACTH stimulates the release of cortisol from the adrenal cortex, a healthy individual will experience a significant rise in cortisol level at 30 minutes, whereas someone with adrenal insufficiency would experience a blunted response (i.e., a smaller rise in cortisol).