QuestionSBA
QuestionChoice
Mild hypercalcaemia is a feature of primary adrenal insufficiency of all causes. Infiltrative diseases such as sarcoidosis can cause primary adrenal insufficiency but this is rare
32302
e
Serum angiotensin-converting enzyme (ACE) levels
QuestionChoice
Pituitary disease can cause secondary adrenal insufficiency; however, this would not lead to hyperkalaemia (as potassium level homeostasis is not dependent on the pituitary-adrenal axis - it is mainly controlled by the renin-angiotensin-aldosterone system) or hyperpigmentation.

Hyperpigmentation and hyperkalaemia are suggestive of primary adrenal insufficiency
32299
b
CT pituitary
QuestionChoice
The clinical vignette and blood test findings are suggestive of primary adrenal insufficiency. This would need to be confirmed with a screening test (usually 9 am cortisol level) and, if positive, a short-synacthen test.

In a patient with previous lung cancer, the most likely cause of primary adrenal insufficiency would be metastatic adrenal disease, for which a CT scan is the best investigation of choice. Imaging of the chest and pelvis is useful to assess for further sites of metastasis
32298
a
CT scan of the chest abdomen and pelvis (CT CAP)
QuestionChoice
MRI is the best modality to image the pituitary; however, as described above the history and blood tests findings are more suggestive of primary adrenal insufficiency in this case
32300
c
MRI pituitary
QuestionChoice
Autoimmune disease is the most common cause of primary adrenal insufficiency in the UK. However, the history of recent lung cancer in an older patient makes metastatic disease more likely in this case
32301
d
Autoantibody screen
Concept
Chapter
# Summary

Adrenal insufficiency is a condition where destruction of the adrenal cortex leads to reduced glucocorticoid production. It can be classified as primary (Addison's disease) or secondary, each with different causes. Key signs and symptoms include hypotension, fatigue, weakness, gastrointestinal symptoms, and increased pigmentation. Initial investigations should focus on levels of sodium, potassium, glucose, cortisol, ACTH, renin, and aldosterone, while further tests should be used to establish the underlying cause. Management includes patient education on 'sick day' rules, glucocorticoid and mineralocorticoid replacement, and regular screening for complications like adrenal crisis and osteoporosis.

# Definition

Adrenal insufficiency is a clinical syndrome that arises due to the insufficient production of glucocorticoids and mineralocorticoids from the adrenal cortex. 

It can be categorized as primary, commonly known as Addison's disease, where the cause lies within the adrenal glands themselves, or secondary, where inadequate stimulation of the adrenal glands by the pituitary or hypothalamus is the culprit.


# Epidemiology

Adrenal insufficiency is a relatively rare disease. Primary adrenal insufficiency (Addison's disease) affects approximately 100-140 people per million in developed countries. Secondary adrenal insufficiency is considered more common but accurate prevalence rates are difficult to determine.

# Pathophysiology

Adrenal insufficiency can result from damage to the adrenal cortex or disruptions in the hypothalamus-pituitary-adrenal (HPA) axis. The HPA axis regulates adrenal hormone production. In primary adrenal insufficiency (Addison's disease), the adrenal glands are damaged, while secondary adrenal insufficiency is due to dysfunction in the hypothalamus or pituitary. The lack of cortisol then disrupts feedback mechanisms, leading to elevated adrenocorticotropic hormone (ACTH) levels.


Primary adrenal insufficiency (Addison's disease) can be caused by:

- Auto-immune destruction (most common)
- Surgical removal of the adrenal glands
- Trauma to the adrenal glands
- Infectious diseases, such as tuberculosis (more common in developing countries)
- Haemorrhage (e.g., Waterhouse-Friderichsen syndrome)
- Infarction
- Less commonly, neoplasms, sarcoidosis, or amyloidosis

Secondary adrenal insufficiency can occur due to:

- Congenital disorders
- Fracture of the base of the skull
- Pituitary or hypothalamic surgery or Neoplasms in the pituitary or hypothalamus
- Infiltration or infection of the brain
- Deficiency of corticotropin-releasing hormone (CRH)

# Signs and Symptoms 

Clinical features of adrenal insufficiency include:

- Hypotension
- Fatigue and weakness
- Gastrointestinal symptoms
- Syncope
- Skin pigmentation due to increased ACTH which stimulates production of alpha melanocyte stimulating hormone (MSH).

[lightgallery]

In the case of auto-immune Addison's disease, approximately 60% of patients may also have vitiligo or other autoimmune endocrinopathies.

[lightgallery1]

# Differential Diagnosis

Adrenal insufficiency can be misdiagnosed as several other conditions, including:

- Chronic fatigue syndrome: Presents with persistent fatigue, cognitive difficulties, and other non-specific symptoms
- Dehydration or septic shock: Hypotension and tachycardia can mimic adrenal insufficiency
- Primary psychiatric illnesses: Depression or other psychiatric illnesses may present with fatigue, decreased appetite, and weight loss.

# Investigations

* First line investigations are U+E and serum cortisol, where you may find:
	* Hyponatraemia (low sodium)
	* Hyperkalaemia (high potassium)
	* Low serum cortisol
- Glucose (typically low)
- Therefore in a patient with Addison's who is acutely unwell, you would expect a blood gas to show a **hyperkalaemic, hyponatraemic, hypoglycaemic metabolic acidosis**
- ACTH: High in primary insufficiency, low or low-normal in secondary insufficiency
- Renin (high in Addison's disease)
- Aldosterone (low in Addison's disease)

An ACTH (Short Synacthen) test is the gold standard investigation to confirm the diagnosis.

Further investigations to establish the cause can include:

- Testing for adrenal auto-antibodies
- Chest X-ray
- CT scan of the adrenal glands
- MRI of the brain

# Management

**Management of adrenal insufficiency involves:**

- Patient education on 'sick day' rules, carrying a steroid card, and wearing a medical alert bracelet
- Doubling the regular steroid medication dose during any intercurrent illness
- Replacement of both glucocorticoids (typically with hydrocortisone) and mineralocorticoids (typically with fludrocortisone)
- Regular screening for complications including an adrenal crisis and osteoporosis

**Management of Addisonian Crisis**

An Addisonian crisis, a life-threatening condition characterized by severe hypotension and electrolyte imbalances, should be managed with:

- Aggressive fluid resuscitation
- Administration of intravenous/IM (if no access) steroids STAT
- Glucose administration if hypoglycaemia is present

# Complications
* Addisonian crisis (life-threatening adrenal crisis)
* Severe electrolyte imbalances
* Cardiovascular collapse
* Hypoglycemia
* Side effects of long term corticosteroid use e.g. osteoporosis

# NICE Guidelines

[Click here for NICE CKS on Addison's disease](https://cks.nice.org.uk/topics/addisons-disease/)

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The appearance of acanthosis nigricans.
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The typical tanned appearnce seen in a woman with Addison's disease.
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Adrenal insufficiency and Addison's Disease
Topic
36
Clinical Chemistry
6460
A 67-year-old woman presents with increasing lethargy and dizziness on standing. Her past medical history is significant for lung cancer which was treated with chemotherapy two years ago.

On examination, there is hyperpigmentation of the buccal mucosa and a drop in blood pressure of 25mmHg on standing.

Blood tests show mild eosinophilia, mild hypercalcaemia, hyperkalaemia and hypotonic hyponatraemia.

Which of the following is most likely to identify the cause of this patient's symptoms?
a