QuestionSBA
QuestionChoice
Aldosterone is also produced by the adrenal glands, alongside cortisol. It can also be deficient in Addison's disease and fludrocortisone replacement may be required alongside hydrocortisone in these cases. However, the first step in suspected Addison's disease is to evaluate the cortisol insufficiency since this is the most classical feature. A short syncathen test evaluates cortisol levels in response to exogenous ACTH administration and is the definitive initial test. In the case of Addison's disease (primary adrenal insufficiency), there will not be a rise in cortisol levels after ACTH administration.
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Aldosterone and renin levels
QuestionChoice
Cortisol levels fluctuate during the course of the day and with stress, such as that induced by surgery. Although the levels of a random cortisol may be within a normal range, it is still possible that the patient could have a diagnosis of adrenal insufficiency since even apparently normal values may be insufficient for that patient at that particular moment in time. Therefore, a random cortisol will not provide adequate definitive diagnostic information.
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Random cortisol level
QuestionChoice
Assessment of adrenal size and architecture can be useful for the evaluation of adrenal insufficiency, especially if there is concern that there may be an underlying cause, such as malignancy or infection. This is unlikely in this patient since there is no suggestion of there being an underlying cause; it is most likely that this patient has autoimmune Addison's disease, especially given the history of vitiligo.
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CT abdomen
QuestionChoice
Secondary adrenal insufficiency is caused by insufficient production of adrenocorticotropic hormone (ACTH) from the pituitary gland. Assessment of the size and architecture of the pituitary gland could be useful if this was suspected. This usually comes to light during a short synacthen test, where the baseline ACTH is evaluated, which would be low in the case of secondary adrenal insufficiency. Secondary adrenal insufficiency responds normally to short synacthen with a rise in cortisol; however, prolonged secondary adrenal insufficiency may result in underactive adrenal glands that do not respond well to short synacthen; in this case, a long synacthen test will be needed to stimulate cortisol release.
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MRI pituitary
QuestionChoice
This patient is presenting with an addisonian crisis postsurgery, as evidenced by refractory hypotension, hyperkalaemia, low-normal sodium and the past medical history of autoimmune disease. A 9 a.m. cortisol < 50 is usually sufficient to make the diagnosis and > 550 to rule out the diagnosis. In between, further testing is required. For primary adrenal insufficiency (Addison's disease), this test will be a short synacthen test.
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Short synacthen test
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).

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

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# 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
5
Endocrinology
10651
The Short Synacthen Test is used to diagnose Addison's disease by evaluating the adrenal glands' ability to produce cortisol in response to synthetic ACTH stimulation, with a low or absent cortisol response indicating adrenal insufficiency.
A 58-year-old man has been referred to intensive care by the anaesthetic registrar in orthopaedic theatre. He has had a knee replacement but has developed a persistent vasopressor requirement despite extensive intravenous fluids. His past medical history is significant for type 2 diabetes, hypertension, osteoarthritis and vitiligo. His blood gases reveal the following: 


||||
|---------------------------|:-------:|--------------------|
|Sodium|137 mmol/L|135 - 145|
|Potassium|6.2 mmol/L|3.5 - 5.3|
|Fasting Glucose|3.9 mmol/L|3.5 - 5.5|


What is the definitive investigation for his underlying disease?
a