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Adrenal insufficiency: Pathology review



Endocrine system


Adrenal gland disorders
Thyroid gland disorders
Parathyroid gland disorders
Pancreatic disorders
Pituitary gland disorders
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Polyglandular syndromes
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Endocrine system pathology review

Adrenal insufficiency: Pathology review


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USMLE® Step 1 style questions USMLE

13 questions

A 62-year-old male is evaluated post-operatively after a transsphenoidal pituitary tumor resection two days ago. He appears groggy and is unable to provide any clinical history. Past medical history is notable for Cushing disease, for which he underwent resection of the aforementioned pituitary tumor. The surgery was uncomplicated, and he is not on any medications. Temperature is 37.0°C (98.6°F), pulse is 101/min, respirations are 14/min, blood pressure is 110/60mmHg, and oxygen saturation is 97% on room air. Physical examination is notable for truncal obesity and striae. Initial laboratory findings are demonstrated below:

Which of the following laboratory findings is most representative of this patient’s clinical presentation?


Content Reviewers:

Yifan Xiao, MD

While doing your rounds, you see two individuals. First is Mike, a 50-year-old immigrant from Canada who comes in with a 5-month history of progressive fatigue, weight loss, and muscle pain. Personal history is unremarkable but there’s a family history of autoimmune disease. Examination reveals hypotension, and diffuse skin hyperpigmentation most pronounced around the oral mucosa, palmar creases, and knuckles.

Then you see Teresa, a 25-year-old who presents acute vomiting, abdominal pain, and fever. She was accompanied by her mother, who mentions Teresa recently underwent transsphenoidal resection of a pituitary tumor. Examination reveals severe hypotension and altered mental status.

Morning cortisol serum measurements showed decreased levels of serum cortisol in both individuals. Both people have adrenal insufficiency although their symptoms are very different.

Now, adrenal insufficiency is a condition where the adrenal glands don’t produce enough adrenal hormones, particularly cortisol and, sometimes, aldosterone. There are actually three types of adrenal insufficiency. First, primary adrenal insufficiency is when there’s a problem with the adrenal glands themselves. As a result, both cortisol and aldosterone production is deficient. It can be acute, usually due to a massive adrenal hemorrhage, or chronic, in which case it is called Addison disease. Now, a high yield concept to remember is that the most common cause for Addison in high income countries is autoimmune mediated damage to the adrenal glands. In the rest of the world, the most common cause is infection, especially from tuberculosis, but it can also be due to HIV or disseminated fungal infections. Finally, bilateral adrenal metastases of cancer from somewhere else in the body,can also cause chronic adrenal insufficiency.

Then, there’s central adrenal insufficiency which can be secondary or tertiary. In secondary adrenal insufficiency, the problem is not with the adrenal glands but with the pituitary, which secretes insufficient ACTH. And since ACTH only regulates cortisol production, in this case there’s cortisol deficiency, but aldosterone levels are normal. This can happen with panhypopituitarism, when the entire pituitary gland is affected, and all the hormones secreted by it are deficient. Panhypopituitarism can be a result of any condition that affects the entire pituitary, like trauma, and pituitary tumors or large central nervous system tumors in its vicinity. And finally, there’s tertiary adrenal insufficiency, where the problem originates with the hypothalamus and there’s insufficient CRH secretion.

So once again, because there’s no CRH to stimulate the pituitary to release ACTH, the adrenal glands won’t produce cortisol. And because CRH doesn’t influence its production, aldosterone levels are normal. Similar to secondary adrenal insufficiency, this can happen because of head trauma or intracranial tumors.

However, tertiary adrenal insufficiency is usually caused by sudden withdrawal of chronic glucocorticoid therapy and resolution of Cushing’s syndrome, which suppresses hypothalamic production of CRH through negative feedback.

Now, when it comes to symptoms, adrenal insufficiency can be acute or chronic. The acute presentation is high-yield and is called adrenal crisis. This typically occurs when the body is under stress, like when the person is ill or just undergone surgery, and the adrenal glands can’t meet the increased demand for cortisol. An adrenal crisis presents 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, anorexia and weight loss, weakness, abdominal pain, and muscle and joint pain. Sometimes, these can go unnoticed, because the body can partially compensate for low levels of cortisol and aldosterone. Sometimes, people with Addison disease can present with adrenal crisis from when they are under stress.

Moving on, there are some symptoms specific to each type of insufficiency as well. In primary adrenal insufficiency, you need to know that there’s hyperpigmentation, especially around the oral mucosa, palmar creases, and knuckles. Hyperpigmentation is caused by increased production of melanin due to a surge in melanocyte-stimulating hormone or MSH levels. This is because MSH is a byproduct of increased ACTH production since both have a common precursor called proopiomelanocortin. There can also be salt craving if aldosterone is deficient. Hyponatremia and hyponatremic volume contraction can also develop when aldosterone levels drop, since aldosterone normally enhances sodium reabsorption. The main result of volume contraction is hypotension. Another major function of aldosterone is to increase urinary potassium secretion, and without it, the kidneys won’t be able to get rid of excess potassium, which causes hyperkalemia and, subsequently, metabolic acidosis.

Additionally, on your test, there might also be either a personal or a family history of autoimmune disease, like diabetes or Hashimoto thyroiditis, which are commonly associated with autoimmune Addison disease.

Now, in secondary and tertiary adrenal insufficiency, because there’s no ACTH excess and aldosterone levels are normal, individuals won’t present with hyperpigmentation or hyperkalemia. However, they might have symptoms pertaining to the underlying cause of insufficiency, such as headaches, visual abnormalities like bitemporal hemianopia, and features of hypopituitarism in those with pituitary tumors. Others might have a history of prolonged glucocorticoid treatment. Adrenal insufficiency diagnosis is also very high yield. Testing begins with a morning or random serum cortisol measurement, where a low cortisol level confirms adrenal insufficiency.

Now, if there’s adrenal insufficiency, serum ACTH levels should also be tested. If it’s high, it suggests primary adrenal insufficiency, whereas if serum ACTH is low, it suggests a central cause, either secondary or tertiary adrenal insufficiency. Next, an ACTH-stimulation test can help confirm the diagnosis when the morning cortisol level is inconclusive, and it can also help differentiate between primary and central disease. In this test, the individual is given Cosyntropin, which is a synthetic analog of ACTH, and serum cortisol levels are measured before and after the analogue is given.

Low cortisol levels before and after Cosyntropin administration confirm primary adrenal insufficiency because adrenal pathology prevents the release of cortisol. In contrast, if cortisol levels rise following Cosyntropin administration, that means the adrenals are responding properly to ACTH or its analogue, confirming central adrenal deficiency, meaning the issue is either with the pituitary or the hypothalamus. Now, if this test is also inconclusive, a Metyrapone stimulation test can be performed.

Metyrapone is a drug that blocks the conversion of a precursor called 11-deoxycortisol to cortisol, and the test is based upon the principle that decreasing serum cortisol concentrations will result in an increase in ACTH if the pituitary and hypothalamus are normal. So, if after the test ACTH levels are high but 11-deoxycortisol levels are decreased, that confirms primary adrenal insufficiency. If both ACTH and 11-deoxycortisol are decreased, that is suggestive of secondary or tertiary adrenal insufficiency. Next, if we suspect primary insufficiency, then 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. 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 before and after. 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 it’s tertiary adrenal insufficiency.Treatment for adrenal insufficiency consists of lifelong hormone replacement therapy with glucocorticoids like hydrocortisone. Mineralocorticoids like fludrocortisone should also be added, in cases of primary adrenal insufficiency with decreased aldosterone. Individuals should also be advised to wear a bracelet that mentions they have adrenal insufficiency in case of adrenal crisis.

For this dangerous condition, treatment should be initiated as soon as the diagnosis is confirmed. In an emergency setting where an individual has severe hypotension, intravenous fluids and IV hydrocortisone, a synthetic corticosteroid, should be administered immediately.

Now that we’ve covered the basics of adrenal insufficiency, let’s talk about some specific causes. So starting with primary adrenal insufficiency, or Addison disease, if the cause is autoimmune in nature, it’s called autoimmune adrenalitis. This can occur on its own, or it can be a part of two inherited polyglandular autoimmune syndromes that affect different endocrine glands.

Polyglandular autoimmune syndrome Type I is associated with Addison disease, hypoparathyroidism, and chronic mucocutaneous candidiasis, most commonly affecting the mouth, skin, and nails. These individuals often have primary hypogonadism where the gonads are also damaged by autoantibodies. Polyglandular autoimmune syndrome type II is associated with Addison disease and autoimmune thyroiditis, in which case it’s known as Schmidt syndrome. In addition, hypogonadism and type I diabetes mellitus may also be present. Autoimmune adrenalitis can be diagnosed by identifying elevated levels of serum anti-adrenal antibodies, particularly anti-21-hydroxylase.

When it comes to Addison disease caused by an infection or malignancy, diagnosis is based on a workup which should include a chest X-ray and a tuberculin skin test to look for evidence of tuberculosis, and, if confirmed, anti tuberculosis medications can be given to treat the infection. Screening for HIV infection can be done with PCR or with antibody-antigen tests. If an HIV infection is the confirmed cause, antiretroviral therapy should be initiated.


Adrenal insufficiency occurs when the adrenal glands do not produce sufficient amounts of hormones. The most common type is hypoadrenalism, which refers to insufficient production of cortisol. This can lead to some symptoms and health problems, including fatigue, weakness, weight loss, and abdominal pain. In severe cases, it can even be life-threatening.

Adrenal insufficiency is divided into two types: primary and secondary. Primary adrenal insufficiency is due to a problem with the adrenal gland itself, while secondary adrenal insufficiency is due to a problem with the pituitary gland. The pituitary gland controls the production of cortisol by the adrenal gland.

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