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Adrenal insufficiency: Clinical practice

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Adrenal insufficiency: Clinical practice

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A 54-year-old woman comes to the clinic because of long-term fatigue, nausea, and continuous craving of salty foods. She has had several occasions of fainting after standing quickly. Her temperature is 37°C (98.6°F), pulse is 110/min, respirations are 20/minute, and blood pressure is 80/50 mm Hg. Physical examination shows increased pigmentation of the skin on her elbows and oral mucosa. She has a family history significant for myasthenia gravis. Laboratory studies show:
 
Which of the following is the most likely diagnosis? 

Transcript

Content Reviewers:

Rishi Desai, MD, MPH

Adrenal insufficiency is a condition in which the adrenal glands don’t produce enough adrenal hormones - particularly cortisol, but sometimes aldosterone can be deficient as well.

Cortisol production is normally under the control of the hypothalamus and pituitary.

The hypothalamus secretes corticotropin-releasing hormone, or CRH, which makes the pituitary gland secrete adrenocorticotropic hormone, or ACTH.

ACTH then stimulates the release of cortisol from the adrenal glands.

Aldosterone, on the other hand, is the final product of a physiological chain called the renin-angiotensin-aldosterone system, or RAAS for short.

Renin is produced by the kidneys, so aldosterone production is actually independent of hypothalamic and pituitary stimulation.

This is important, because adrenal insufficiency actually comes in three distinct flavors.

First, there’s primary adrenal insufficiency, or Addison’s disease, when there’s a problem with the adrenal glands themselves. In this case, both cortisol and aldosterone production are deficient.

The most common causes for primary adrenal insufficiency in high income countries is autoimmune destruction of the adrenal gland and adrenal metastases from cancer somewhere else in the body.

Worldwide, however, infectious adrenalitis is the most common cause of primary adrenal insufficiency - and this can be due to tuberculosis, HIV, or disseminated fungal infections.

Then, there’s secondary adrenal insufficiency, which occurs due to insufficient pituitary ACTH production.

Since ACTH only stimulates cortisol production, in this case there’s a cortisol deficiency, but aldosterone levels are normal. This can happen with panhypopituitarism, when the entire pituitary gland is affected, and all stimulatory hormones produced by it are deficient.

Panhypopituitarism can be a result of any condition that affects the entire pituitary - like when the pituitary is affected by trauma or compressed by large central nervous system tumor, either a pituitary tumor or another type of tumor growing in the vicinity.

And finally, there’s tertiary adrenal insufficiency which is due to insufficient CRH production - so once again, cortisol is deficient, but aldosterone levels are normal.

Similar to secondary adrenal insufficiency, this can also happen because of head trauma or intracranial tumors. But the most common causes of tertiary adrenal insufficiency are sudden withdrawal of chronic glucocorticoid therapy and resolution of Cushing’s syndrome.

In both these cases, there used to be high levels of circulating glucocorticoids - either because of medication, or, with Cushing’s, because of a tumor. This suppresses the hypothalamic production of CRH through negative feedback - so once medication is stopped, or the tumor is removed, individuals can have adrenal insufficiency for up to a year, until CRH levels return to normal.

All three types of adrenal insufficiency can be acute or chronic.

The acute presentation is called adrenal crisis, and rightly so - there’s usually a dramatic clinical picture, with hypotension or shock, vomiting, abdominal pain, fever, and mental status changes ranging from confusion to coma.

The chronic presentation is more insidious.

Some symptoms are nonspecific, like fatigue, weight loss, abdominal pain, and muscle and joint pain. Some, however, are rather specific - like skin hyperpigmentation, because of increased production of melanin, and salt craving, when aldosterone is also deficient.

Most frequently, individuals have chronic symptoms which may or may not go unnoticed, and then some sort of stress, like a serious illness, precipitates an adrenal crisis.

If acute adrenal insufficiency is suspected, a morning serum cortisol level below 3 micrograms per deciliter confirms the diagnosis, whereas a level above 18 micrograms per deciliter excludes adrenal insufficiency.

Now, if there’s adrenal insufficiency, if the serum ACTH is low, it suggests primary adrenal insufficiency, whereas if the serum ACTH is high, it suggests a central cause, either secondary or tertiary adrenal insufficiency.

When the morning serum cortisol level is between 3 and 18 micrograms per deciliter, an ACTH-stimulation test is needed both to confirm the diagnosis, and differentiate between primary and central disease. This is when the individual is given 250 micrograms of Cosyntropin, which is the synthetic analog of ACTH, and the serum cortisol before ACTH is given, and then taken again one hour later.

Serum cortisol levels above 18 micrograms per deciliter before or after the ACTH injection rule out adrenal insufficiency.

On the other hand, if serum cortisol is lower than 18 micrograms per deciliter, and cortisol levels stay the same following Cosyntropin administration, that confirms primary adrenal insufficiency.

If they rise, that means the adrenals are responding properly to ACTH, so the issue is central, either with the pituitary or the hypothalamus.

Treatment should be initiated as soon as the diagnosis of adrenal insufficiency is confirmed.

In an emergency setting where an individual has hemodynamic instability, intravenous fluids and an injection of 50 to 100 milligrams of hydrocortisone should be administered immediately, and then a 50 mg bolus of hydrocortisone is administered every 8 hours until medication can be taken orally and the individual’s vital signs improve.

Now, if the cause is primary, then aldosterone is also deficient - so samples for serum aldosterone and plasma renin activity should also be obtained.

Renin normally stimulates aldosterone release, so with primary adrenal insufficiency, there will be low aldosterone and high plasma renin activity.

Once aldosterone deficiency is confirmed, replacement treatment with fludrocortisone should be started, with a daily dose of 50 to 100 micrograms.

On the other hand, if there’s a central cause, then a CRH stimulation test can be done to differentiate between secondary and tertiary disease. That’s where an individual is given a CRH injection, and ACTH is measured four times - 5 minutes before the CRH injection, then again when the injection is given, and then 15 minutes later, and finally 30 minutes later.

No rise in serum ACTH compared to the basal value points towards a pituitary, or secondary, cause, and if serum ACTH increases, then the hypothalamus is to blame - so tertiary adrenal insufficiency.

Finally, it’s important to determine the underlying reason for adrenal insufficiency.

Addison’s disease should be suspected in all individuals with acute or chronic adrenal insufficiency, and can be diagnosed by identifying elevated levels of serum anti-adrenal antibodies, particularly anti-21-hydroxylase.

Addison’s disease can occur on it’s own, or it can be part of a polyglandular autoimmune syndrome type 1 or polyglandular autoimmune syndrome type 2. Both are inherited diseases that affect different endocrine glands.

Type I is rarer, and it’s associated with Addison’s disease, hypoparathyroidism, and chronic mucocutaneous candidiasis, most commonly affecting the mouth, skin, and nails.

Also, most individuals have primary hypogonadism - which means the gonads don’t make enough sex hormones because of a deficient pituitary production of follicle stimulating hormone, or FSH, and luteinizing hormone, or LH.