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Adrenal Insufficiency

Adrenal Insufficiency (AI)

Overview:

Adrenal insufficiency is associated with high morbidity and mortality, which increase when diagnosis is delayed.

Adrenal Crisis

We should be suspicious of adrenal crisis in patients who present with acute shock that is refractory to vasopressors and fluid replacement. Adrenal crisis can be fatal.

Primary vs Central

We can broadly classify adrenal insufficiency as primary vs central.

Primary adrenal insufficiency (PAI), also called Addison's disease, is rare, and is caused by adrenal gland dysfunction.

All adrenal cortex hormones are potentially affected (cortisol, aldosterone, and androgens).
Primary AI affects slightly more women than men and is typically diagnosed in patients 30-50 years old.

Central adrenal insufficiency is more common and is caused by a deficiency in CRH and/or ACTH; thus, it primarily affects cortisol and androgen secretion (recall that aldosterone secretion is primarily directed by the renin-angiotensin-aldosterone system).

Chronic AI:

In chronic AI, adrenal reserves may initially maintain basal hormone levels, but with impaired ACTH stress response. Eventually, however, even basal levels of hormones drop. As we'll see, these nuances in progression of AI can complicate its diagnosis.

Treatment:

Glucocorticoid, and, in the case of primary AI, mineralocorticoid replacement.

However, we have to beware of over-treatment, especially with glucocorticoids, given that excessive cortisol exposure produces Cushing's syndrome.

Primary AI, aka, Addison Disease

Cortisol and aldosterone deficiency are of primary concern. Without the negative feedback effects of cortisol, ACTH levels rise.

As a result of elevated ACTH production, patients with Primary AI have characteristic hyperpigmentation of the skin and mucosa; we show this around the gums and in the folds of the hands.

John F Kennedy Jr, the 35th President of the United States, had a famously "bronzed" look due to Addison Disease.

Patients are also hypotensive and hyponatremic, with hyperkalemia and metabolic acidosis.

Causes of Chronic PAI:

Autoimmune diseases: In the United States and other countries where tuberculosis is no longer endemic, autoimmune diseases are the most common causes of primary AI.

In these patients, anti-adrenal antibodies destroy the adrenal cortex.

Some important examples of autoimmune disorders resulting in Primary AI are: Autoimmune Polyendocrine Syndrome Type 1 (APS-1): onset is typically in childhood, and the disorder is characterized by adrenal insufficiency, hypoparathyroidism, and mucocutaneous candidiasis.

In children, recurrent mucocutaneous candidiasis is a potential indicator of APS-1 – we show thrush and angular cheilitis, which are common manifestations.

Autoimmune Polyendocrine Syndrome Type 2 (APS-2) is associated with adrenal insufficiency, Hashimoto's thyroiditis, and Type I diabetes mellitus.

Be aware that patients with APS are likely to have additional endocrine-related disorders.

Infections are another important cause of Primary AI, particularly in countries where TB and/or HIV are endemic.

Signs/Symptoms of Chronic PAI:

Patients with chronic Primary AI experience symptoms and signs that reflect loss of cortisol and aldosterone:

Weakness, fatigue, weight loss, gastrointestinal problems, and possibly salt cravings.

Acute adrenal crisis occurs when patients with adrenal insufficiency face additional stressors, including infections, trauma, surgery, and dehydration.

Acute adrenal crisis is a life-threatening situation: look for shock, fever, dehydration, nausea, vomiting, hypoglycemia, apathy, and weakness.

Treatment: IV fluids & glucocorticoids.

To avoid acute adrenal crisis in patients with diagnosed adrenal insufficiency, we provide additional doses of glucocorticoids when stressors, such as surgery, are expected. Patients can also carry medical cards that warn of their condition in the case of accidental trauma, etc.

Causes of Acute PAI:

Bilateral adrenal hemorrhage: It is thought that the anatomy of the adrenal gland blood supply makes it especially vulnerable to venous congestion and hemorrhaging, so we'll show that each adrenal gland is supplied by three arteries but drained by only one vein.

Risk factors for bilateral adrenal hemorrhage include:

Anti-coagulation therapy and disorders that increase the risk of venous blood clots, such as antiphospholipid antibody syndrome and systemic lupus erythematosus.
In children, we watch for the development of Waterhouse-Friderichsen Syndrome, in which adrenal bleeding and dysfunction is caused by septicemia, most often associated with meningococcal or pseudomonas infections.

Additional Causes of PAI:

Adrenoleukodystrophy (X-linked)
Infiltrative disorders (i.e., metastatic, sarcoidosis)
Familial glucocorticoid deficiency
Congential adrenal hypoplasia
Cortisol resistance due to abnormal receptors
Drug effects
Disorders of aldosterone synthesis & action

Signs and symptoms of Acute PAI:

Fever, nausea, vomiting, tachycardia, cyanosis, and flank and abdominal pain and tenderness.

Labs:

ACTH stimulation test - see below.
Electrolyte abnormalities (hyponatremia, hyperkalemia, hypercalcemia)
Hypoglycemia after fasting
Normocytic anemia, eosinophilia

*Central AI

Be aware that some authors further divide central into secondary and tertiary, where secondary AI refers to pituitary/ACTH dysfunction and tertiary refers to hypothalamic/CRH dysfunction; however, others lump tertiary in with secondary. Thus, we use "central" to avoid confusion.

Central AI is characterized by cortisol and androgen deficiencies due to ACTH deficiency. As mentioned in the introduction, aldosterone secretion is maintained in the absence of ACTH.

Central AI (CAI) is more common than Primary AI.

Causes of Central AI:

Most commonly caused by long-term exogenous steroid use.

Central AI can develop as a result of sudden cessation of the drugs or by the inability of the HPA axis to respond to additional stressors.

Central AI may also be caused by dysfunction in the pituitary or hypothalamus, including tumors, infections, and drugs.

Some examples of drugs that interrupt ACTH production include immune checkpoint inhibitors, high-dose progestins, and opioids.
Pituitary and/or hypothalamic dysfunction is often associated with deficiencies of other pituitary hormones.

Signs/Symptoms of Central AI:

Chronic and nonspecific due to glucocorticoid deficiencies.

Thus, manifestations are similar to what we see in Primary AI, with important exceptions:
There is no hyperpigmentation in central AI, since ACTH is deficient, and,
There is less hypovolemia or hypotension, since aldosterone secretion is normal.

We still need to watch for and avoid acute adrenal crisis in these patients.

Distinguish between PAI & CAI

When AI is suspected, we do a rapid ACTH stimulation test, which, in a healthy person, would raise cortisol levels.

If the patient has abnormal cortisol levels after the ACTH stimulation test, then we know that the patient has some form of adrenal insufficiency.

If plasma ACTH is high, then the patient has Primary AI; if plasma ACTH is low or normal, then the patient has Central AI.

On the other hand, if the ACTH stimulation test results are normal, then we know that the patient does not have primary adrenal insufficiency.

But, we'll need to make sure that the test results aren't simply reflecting decreased ACTH reserves, as we'd see in someone in early stages of central adrenal insufficiency.

So, to test for this, we can give the patient metyrapone, which prevents cortisol synthesis, or, we can give an insulin tolerance test, and measure cortisol levels.

If plasma cortisol is normal after the test, we can exclude adrenal insufficiency.
If plasma cortisol is low, then the patient has central adrenal insufficiency, and we'll need to investigate the causes.

For references, please see full tutorial.

Adrenal Insufficiency

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