Addison’s Disease

Question 1

Addison’s disease (primary adrenal insufficiency) is caused by destruction or dysfunction of the … …

Answer 1

Addison’s disease (primary adrenal insufficiency) is caused by destruction or dysfunction of the adrenal cortex.

Question 2

The adrenal glands sit atop each kidney, they are an important endocrine organ responsible for the release of catecholamines (adrenaline, noradrenaline), glucocorticoids, mineralocorticoids and sex hormones.

Adrenal insufficiency occurs when there is a reduction of glucocorticoid +/- mineralocorticoid production such that normal physiology is interrupted:

Answer 2

Primary adrenal insufficiency (Addison’s disease): caused by destruction or dysfunction of the adrenal cortex. This is the focus of this note.
Secondary adrenal insufficiency: caused by a reduction in adrenocorticotropic hormone release. May be seen as part of panhypopituitarism, an isolated deficiency, following brain injury or secondary to medications.
Tertiary adrenal insufficiency: caused by a reduction in corticotropin-releasing hormone, most commonly seen following chronic glucocorticoid steroid use.

Question 3

On occasion, patients can present with an ‘…. …’, which refers to a medical emergency caused by profound glucocorticoid and mineralocorticoid deficiency that may be triggered by intercurrent illness.

Answer 3

On occasion, patients can present with an ‘Addisonian crisis’, which refers to a medical emergency caused by profound glucocorticoid and mineralocorticoid deficiency that may be triggered by intercurrent illness.

Question 4

The adrenal cortex is the outermost aspect of the adrenal gland. It is composed of three layers:

Answer 4

Zona Glomerulosa: mineralocorticoids - aldosterone is the key mineralocorticoid, release primarily controlled by the renin-angiotensin system (described below).
Zona Fasciculata: glucocorticoids - release controlled by hypothalamic-pituitary-adrenal axis (described below).
Zona Reticularis: androgens - produces dehydroepiandrosterone (DHEA).

Question 5

In men the testes produce the majority of androgens, as such deficiency of adrenal production does not tend to cause symptoms. However, in women where the other site of production is the ovaries, absence of adrenal androgens may lead to symptoms (see ‘Clinical features’ below),

Answer 5

In men the testes produce the majority of androgens, as such deficiency of adrenal production does not tend to cause symptoms. However, in women where the other site of production is the ovaries, absence of adrenal androgens may lead to symptoms (see ‘Clinical features’ below),

Question 6

The innermost aspect of the adrenal gland, composed of a single layer. Responsible for the production of three hormones:

Answer 6

Adrenaline
Noradrenaline
Dopamine

Question 7

… secretion is controlled by the hypothalamus-pituitary-adrenal axis.

Answer 7

Cortisol secretion is controlled by the hypothalamus-pituitary-adrenal axis.

Question 8

1. Corticotropin-releasing hormone

Answer 8

Corticotropin-releasing hormone (CRH) is released by the paraventricular nucleus of the hypothalamus. It is transported via the hypophyseal portal system to the anterior pituitary where it stimulates the release of adrenocorticotropic hormone (ACTH).

Question 9

2. Adrenocorticotropic hormone

Answer 9

ACTH, released from the corticotrophs of the anterior pituitary, stimulates the release of cortisol.

The precursor of ACTH is POMC, this is also the precursor of beta-melanocyte-stimulating hormone. In addition, ACTH may be cleaved to form alpha-melanocyte-stimulating hormone. As a result ACTH excess results in hyperpigmentation (resulting from melanocyte stimulation), particularly affecting the oral mucosa and palmar creases.

ACTH excess is a feature of both Addison’s disease (primary adrenocortical insufficiency) and ACTH dependent Cushing’s syndrome.

Question 10

Cortisol is released from the adrenal cortex in response to …

Answer 10

Cortisol is released from the adrenal cortex in response to ACTH. It exerts negative feedback on the release of both ACTH and CRH.

Cortisol exhibits diurnal variation, that is to say, the plasma concentration of cortisol levels vary during a 24 hour period.

It reaches a zenith (highest point) at around 8 am and a nadir (lowest point) at around midnight to 1am.

Question 11

… release is primarily controlled by the renin-angiotensin system.

Answer 11

Aldosterone release is primarily controlled by the renin-angiotensin system.

Question 12

Renin, a proteolytic enzyme, is released by … cells of the juxtaglomerular apparatus in response to:

Renal artery hypotension
Sympathetic stimulation
Reduced sodium levels in the distal tubal
In the blood renin cleaves angiotensinogen into angiotensin I.

Answer 12

Renin, a proteolytic enzyme, is released by granular cells of the juxtaglomerular apparatus in response to:

Renal artery hypotension
Sympathetic stimulation
Reduced sodium levels in the distal tubal
In the blood renin cleaves angiotensinogen into angiotensin I.

Question 13

Angiotensin II has multiple functions: (5)

Answer 13

Angiotensin II has multiple functions:

Stimulates adrenal cortex to release aldosterone
Causes vasoconstriction
Increases sodium reabsorption
Stimulates the release of anti-diuretic hormone (ADH)
Increases sympathetic permissiveness

Question 14

Aldosterone is a mineralocorticoid released from the zona glomerulosa of the adrenal cortex. It is released in response to:

Answer 14

Angiotensin II (primary stimulus)
ACTH
Potassium levels

Question 15

Worldwide, the most common cause of adrenal insufficiency is ..

Answer 15

Worldwide, the most common cause of adrenal insufficiency is tuberculosis.

Question 16

Aetiology of Addison’s disease

Answer 16

Question 17

Autoimmune adrenalitis

Answer 17

The most common cause of adrenocortical insufficiency in the western world is the autoimmune destruction of the adrenal cortex. This is more common in women.

It is suggested that autoantibodies target enzymes involved in the biosynthesis of steroids. One of the main targets for autoimmune destruction is the enzyme 21-hydroxylase.

Question 18

Infective adrenalitis

Answer 18

Though rare in the UK, tuberculosis induced infective adrenalitis is the most common cause of adrenocortical insufficiency worldwide. This is the setting in which Thomas Addison first described the condition.

Other infective causes include HIV (and associated opportunistic infections), disseminated fungal infection and syphilis.

Question 19

Other rare causes of addison’s

Answer 19

The remaining causes of Addison’s disease are uncommon. In Waterhouse-Friderichsen syndrome adrenal haemorrhage occurs secondary to septicaemia.

Infiltrative disease as a result of malignant metastasis or amyloid deposits may cause adrenal insufficiency. Bilateral adrenalectomy is an iatrogenic cause of Addison’s disease.

Question 20

Addison’s disease is often diagnosed late - why?

Answer 20

Addison’s disease is often diagnosed late due to its non-specific presentation.
Addison’s disease may present with an acute Addisonian crisis or (more commonly) with chronic disease.

Question 21

In women features of androgen deficiency may be seen (this is rarely seen in men where the testes provide the majority of androgen production). This may include:

Answer 21

Loss of libido

Loss of hair in axillary/pubic regions

Question 22

Features of…a

Answer 22

Addison’s

Question 23

Addisonian crisis

Answer 23

An Addisonian crisis is a potentially life-threatening presentation of Addison’s disease. It is caused by a significant deficiency in glucocorticoids and mineralocorticoids. It is most commonly seen in tertiary adrenal insufficiency (termed an ‘adrenal crisis’) as a result of the sudden withdrawal of exogenous steroids.

Question 24

An Addisonian crisis is a potentially life-threatening presentation of Addison’s disease. It is caused by a significant deficiency in glucocorticoids and mineralocorticoids. It is most commonly seen in tertiary adrenal insufficiency (termed an ‘adrenal crisis’) as a result of the sudden withdrawal of …

In Addison’s disease it may occur following an acute decompensation where an additional stress (e.g. infection) results in an exacerbation of a pre-existing deficiency. Bilateral adrenal gland haemorrhage can also result in a crisis.

Answer 24

An Addisonian crisis is a potentially life-threatening presentation of Addison’s disease. It is caused by a significant deficiency in glucocorticoids and mineralocorticoids. It is most commonly seen in tertiary adrenal insufficiency (termed an ‘adrenal crisis’) as a result of the sudden withdrawal of exogenous steroids.

In Addison’s disease it may occur following an acute decompensation where an additional stress (e.g. infection) results in an exacerbation of a pre-existing deficiency. Bilateral adrenal gland haemorrhage can also result in a crisis.

Question 25

Signs and symptoms of addisonian crisis

Answer 25

Question 26

Biochemistry can be indicative. A deficiency in mineralocorticoids (aldosterone) may lead to …natreamia (seen in up to 90%) and …kalaemia (seen in around 30-50% of cases).

Answer 26

Biochemistry can be indicative. A deficiency in mineralocorticoids (aldosterone) may lead to hyponatraemia (seen in up to 90%) and hyperkalaemia (seen in around 30-50% of cases).

Question 27

What may be used as a screening tool for addisons?

Answer 27

Serum cortisol, measured at 8-9 am (when it should be highest in those with routine sleeping patterns) may be used as a screening tool. It should be noted this does not distinguish between types of adrenal insufficiency (i.e. primary, secondary, tertiary). In addition there is not clear ‘cut-off’ that can conclusively determine whether or not someone has adrenal insufficiency.

Question 28

< 100 nmol/L: adrenal insufficiency …
100–500 nmol/L: adrenal insufficiency …
> 500 nmol/L: adrenal insufficiency …

Answer 28

< 100 nmol/L: adrenal insufficiency very likely
100–500 nmol/L: adrenal insufficiency possible
> 500 nmol/L: adrenal insufficiency unlikely

Question 29

A plasma ACTH level may help distinguish between primary and secondary/tertiary adrenal insufficiency:

Answer 29

High: indicative of Addison’s disease (primary adrenal insufficiency)
Normal: inconclusive
Low: indicative of secondary/tertiary adrenal insufficiency

Question 30

2. Short synacthen test

Answer 30

This test involves the IV administration of 250 mcg of tetracosactide, a synthetic analogue of ACTH. Cortisol is measured at three time points: 0 (i.e. immediately before), 30 and 60 minutes following administration. The test is carried out in the morning, normally commencing at 8 am.

The baseline reading of cortisol should be >180-190 nanomol/L. Serum cortisol > 500–550 nanomol/L either before or following the ACTH is considered normal.

Question 31

The management of adrenal insufficiency involves replacement of …

Answer 31

The management of adrenal insufficiency involves replacement of deficient hormones.

Question 32

Glucocorticoids are replaced with …, 15-30 mg/day given in divided doses.

Answer 32

Glucocorticoids are replaced with hydrocortisone, 15-30 mg/day given in divided doses.

Question 33

Glucocorticoid replacement - addisons

Answer 33

Glucocorticoids are replaced with hydrocortisone, 15-30 mg/day given in divided doses.

An example regime may be 10 mg in the morning, 5 mg at noon and 5 mg in the evening. Regimes should follow the pattern of work in shift workers (i.e 10 mg dose on waking regardless of time of day).

Question 34

Mineralocorticoids are replaced with …, typically around 50-300 mcg per day.

Answer 34

Mineralocorticoids are replaced with fludrocortisone, typically around 50-300 mcg per day.

Question 35

Fludrocortisone is typically used, which has mineralocorticoid activity 125 times that of …. The dose of fludrocortisone can be adjusted to levels of exercise and metabolism.

Answer 35

Fludrocortisone is typically used, which has mineralocorticoid activity 125 times that of hydrocortisone. The dose of fludrocortisone can be adjusted to levels of exercise and metabolism.

Question 36

Androgen replacement

Answer 36

This is an area where our understanding and the evidence base is developing. There is some evidence that DHEA replacement in certain settings improves mood and quality of life in women.

Generally caution is advised until there is more long-term safety data. It may be considered by specialists in women with adequate glucocorticoid and mineralocorticoid replacement with significant ongoing mood or quality of life disturbance.

Question 37

Patient education - addisons

Answer 37

Patients must understand that treatment for Addison’s disease is (for the majority) lifelong. Intercurrent illness requires adjustment of the glucocorticoid dose. For example, a temperature > 37.5oC should prompt a doubling of dose.

Patients should be able to promptly identify an Addisonian crisis as well as carry a steroid card and MediAlert identification.

Question 38

Patients should be able to promptly identify an Addisonian crisis as well as carry a … card and … identification.

Answer 38

Patients should be able to promptly identify an Addisonian crisis as well as carry a steroid card and MediAlert identification.

Question 39

An Addisonian crisis is a medical emergency requiring prompt recognition and treatment.

Answer 39

It is managed with IV hydrocortisone (100mg) and IV fluid rehydration. Cardiac, electrolyte and blood sugar monitoring should be arranged.

Question 40

How is addisonian crisis managed?

Answer 40

It is managed with IV hydrocortisone (100mg) and IV fluid rehydration. Cardiac, electrolyte and blood sugar monitoring should be arranged.

Question 41

100mg of hydrocortisone has sufficient mineralocorticoid activity and acutely fludrocortisone is not necessary. Following initial resuscitation, a hydrocortisone/dextrose infusion may be given with a target of … of hydrocortisone over a 24 hour period. This will need to be reduced over the coming days, specialist input should be sought.

Answer 41

100mg of hydrocortisone has sufficient mineralocorticoid activity and acutely fludrocortisone is not necessary. Following initial resuscitation, a hydrocortisone/dextrose infusion may be given with a target of 400mg of hydrocortisone over a 24 hour period. This will need to be reduced over the coming days, specialist input should be sought.

Question 42

Question 1.
A 42 year old female with a past medical history of rheumatoid arthritis presents with a diarrhoea and vomiting for the past few days. Her regular medications include high-dose steroids and methotrexate (once weekly). The nurse calls you over to see her as she is complaining of dizziness and palpitations. She is apyrexial and normotensive but is noted to have postural drop in her blood pressure and has vomited twice.

What is the most appropriate management?

A 100 ml of 20% dextrose
B Slow IV fluids and place catheter to monitor fluid output
C 100 mg IV hydrocortisone and IV normal saline
D 0.5 ml 1 in 1000 IM adrenaline, IV hydrocortisone and IV chlorphenamine
E Septic screen and IV antibiotics

Answer 42

C
- 100 mg IV hydrocortisone and IV normal saline

The history of rheumatoid arthritis and steroid therapy, along with the vomiting should raise concerns that her medication has not been absorbed. Long-term administration of steroids leads to suppression of the normal hypothalamic-pituitary-adrenal (HPA) axis, leading to a reduction in ACTH. Immediately stopping steroids can lead to a profound secondary hypoadrenalism with circulatory collapse.

It is also important patients on long term steroids take greater doses when they are unwell as their stress response is blunted by the HPA suppression. The immediate management of acute adrenal insufficiency is IV corticosteroids and fluid rehydration.

Question 43

A 42-year-old female is seen in the endocrinology clinic with a history of fainting and postural dizziness. She also complains of vague abdominal pain and diarrhoea. Increased pigmentation in her palmar creases had been noted by her GP. The endocrinologist thinks this could be Addison’s disease.

What is the most appropriate test to confirm the diagnosis?

Answer 43

Short synacthen test

Question 44

… … test: this test is used to assess pituitary (hypopituitarism) function. It is considered the gold standard for the assessment of the hypothalamic-pituitary-adrenal axis.

Answer 44

Insulin tolerance test: this test is used to assess pituitary (hypopituitarism) function. It is considered the gold standard for the assessment of the hypothalamic-pituitary-adrenal axis.

Question 45

Low-dose … suppression test: can be used to establish a diagnosis of Cushing’s syndrome. 1 mg of dexamethasone is given at 11 pm and serum cortisol is then measured at 8 am. In a normal individual, the administration of dexamethasone should suppress the morning rise in serum cortisol. However, in patients with Cushing’s syndrome, there is a lack of suppression, which warrants further investigation.

Answer 45

Low-dose dexamethasone suppression test: can be used to establish a diagnosis of Cushing’s syndrome. 1 mg of dexamethasone is given at 11 pm and serum cortisol is then measured at 8 am. In a normal individual, the administration of dexamethasone should suppress the morning rise in serum cortisol. However, in patients with Cushing’s syndrome, there is a lack of suppression, which warrants further investigation.

Question 46

High-dose dexamethasone suppression test: can be used to identify the cause of an ACTH-dependent … ….

Answer 46

High-dose dexamethasone suppression test: can be used to identify the cause of an ACTH-dependent Cushing’s syndrome. ACTH-dependent disease occurs where cortisol excess is secondary to increased ACTH secretion. The increased ACTH may be due to a pituitary adenoma (Cushing’s disease) or ectopic ACTH production (e.g. some lung cancers). The high-dose test is used to differentiate between these causes. In the high-dose test a larger dose of dexamethasone is given, this high level will be sufficient to suppress ACTH produced by pituitary adenomas but not ectopic causes.

Question 47

Serum cortisol: cortisol exhibits diurnal variation, that is to say, the plasma concentration of cortisol levels varies during a 24 hour period. Early morning cortisol levels can be used in the work-up for adrenal insufficiency. High levels of cortisol (e.g. > 350nmol/L) make adrenal insufficiency less likely. Midnight cortisol can be used in the diagnosis of Cushing’s syndrome to demonstrate a loss of normal diurnal variation - levels should be low at midnight but may be elevated in Cushing’s syndrome.

Answer 47

Serum cortisol: cortisol exhibits diurnal variation, that is to say, the plasma concentration of cortisol levels varies during a 24 hour period. Early morning cortisol levels can be used in the work-up for adrenal insufficiency. High levels of cortisol (e.g. > 350nmol/L) make adrenal insufficiency less likely. Midnight cortisol can be used in the diagnosis of Cushing’s syndrome to demonstrate a loss of normal diurnal variation - levels should be low at midnight but may be elevated in Cushing’s syndrome.

Question 48

Aldosterone is a mineralocorticoid that promotes sodium and water … and potassium …

Answer 48

Aldosterone is a mineralocorticoid that promotes sodium and water reabsorption and potassium excretion.

Question 49

Which of the following blood results is suggestive of Addison’s disease?

A High ACTH, low Na+, high K+, low cortisol
B Low ACTH, low Na+, normal K+, low cortisol
C High ACTH, high Na+, low K+, high cortisol
D Low ACTH, high Na+, low K+, high cortisol
E High ACTH high Na+, high K+, high cortisol

Answer 49

A high ACTH (due to lack of negative feedback) and potassium with a low cortisol and sodium is typical of Addison’s disease.

Question 50

High Na+ and low K+ levels are suggestive of … syndrome.

Answer 50

High Na+ and low K+ levels are suggestive of Cushing’s syndrome.