Adrenal insufficiency: Pathology review

Definitions & Key takeaways

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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Case study0:00–0:58

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.

Primary adrenal insufficiency0:58–2:04

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.

Secondary adrenal insufficiency2:04–2:48

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.

Tertiary adrenal insufficiency2:48–3:34

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.

Symptoms3:34–6:09

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.

Diagnosis6:09–8:58

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.

Treatment8:58–9:43

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.

Autoimmune adrenalitis9:43–10:48

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.

Infection or malignancy10:48–11:39

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.Finally, a CT scan can also identify adrenal metastases, which most frequently come from lung, breast, stomach and colon cancer, or lymphoma.
In these cases, treatment with hydrocortisone and fludrocortisone should also be initiated before surgery or chemo and radiotherapy.Another rare cause of primary adrenal insufficiency is adrenoleukodystrophy, which is an inherited disease that predominantly affects young males.

Adrenoleukodystrophy11:39–12:48

The condition is an X-linked recessive disorder. The defect is actually a mutation in the ABCD1 gene, and it interferes with fatty acid beta oxidation.
As a result, very long chain fatty acids accumulate in various tissues, and they particularly affect the white matter of the brain, the adrenal cortex, and testes.
So, besides adrenal insufficiency, they will also have neurological problems like seizures, blindness, quadriparesis, and cognitive developmental delay.
In severe cases, it can result in dementia, coma and even death. Diagnosis begins with blood tests which show elevated plasma concentration of very long chain fatty acids or VLCFAs.
In individuals with elevated VLCFAs, molecular genetic testing confirms the diagnosis, for which lifelong therapy with hydrocortisone is required.Another important cause of adrenal insufficiency is congenital adrenal hyperplasia, or CAH.

Congenital adrenal hyperplasia12:48–18:34

This is a group of autosomal recessive diseases caused by mutations in the genes that encode the enzymes involved in cortisol and aldosterone biosynthesis.
As a general note, if the deficient enzyme starts with 1, it causes hypertension and if the deficient enzyme ends with 1, it causes virilization in females.When it comes to 21-hydroxylase deficiency, remember that 21-hydroxylase converts progesterone into 11-deoxycorticosterone, an aldosterone precursor, and 17-hydroxyprogesterone to 11-deoxycortisol, a cortisol precursor.
It’s impaired function leads to low levels of cortisol and aldosterone, and high levels of ACTH, resulting in adrenal gland hyperplasia.
It also leads to excess production of androgen precursors, since their production is also regulated by ACTH. It’s important to know that 21-hydroxylase deficiency can lead to three distinct syndromes depending on the residual activity of the enzyme.First is the classic salt-wasting type, which is caused by severe 21-hydroxylase deficiency.
In this case, females present with ambiguous genitalia at birth due to excess androgen precursors; and males present with failure to thrive during the first 1-2 weeks.
They can also have symptoms like dehydration, vomiting, and hypotension, mostly due to aldosterone deficiency. Second is the classic non-salt-wasting type, which is due to moderate 21-hydroxylase deficiency.
This is when females develop ambiguous genitalia at birth, and males develop signs of early virilization, like pubic hair, accelerated growth, and a large phallus at 2 to 4 years.
And third, there’s the non-classic, delayed type which is associated with mild enzyme deficiency. This is when school-age boys present with early onset of puberty or sexual prematurity, and, in addition, females develop acne, hirsutism, and menstrual irregularity.
Ok, so screening for 21-hydroxylase deficiency involves measuring serum levels of 17 hydroxyprogesterone, which are usually higher or very high in affected individuals due to them not being converted by 21-hydroxylase.In the salt-wasting type, another clue is that blood work might also show hyponatremia and hyperkalemia due to aldosterone deficiency.
Other characteristic findings include decreased levels of mineralocorticoids and cortisol, increased levels of sex hormones, and decreased renin activity.
And finally, something else to keep in mind is that treatment consists of hormonal replacement with gluco- and mineralocorticoids to suppress pituitary secretion of ACTH, which will also normalize androgen levels.OK, so there are two more types of CAH to remember.
First is 11b-hydroxylase deficiency, and this enzyme converts 11-deoxycorticosterone to corticosterone and 11-deoxycortisol to cortisol.
It presents similarly to 21-hydroxylase deficiency, with the important difference being that it causes the accumulation of 11-deoxycorticosterone, a mild mineralocorticoid.
This can lead to hypertension and hypokalemia even though renin and aldosterone levels are low. And then there’s 17a-hydroxylase deficiency, which is very rare.The enzyme is active in both the adrenal and the gonads, where it converts pregnenolone to 17-hydroxypregnenolone and progesterone to 17-hydroxyprogesterone.
This means 17a-hydroxylase deficiency leads to impaired synthesis of androgens, estrogens, and cortisol but does not affect mineralocorticoid production.On the contrary, high ACTH levels cause excessive production of 11-deoxycorticosterone and corticosterone, which are mineralocorticoids that cause hypertension.
The clinical picture here is dominated by the lack of androgens in utero. This means males will have external genitalia that appear female at birth, without having any internal female genitalia, whereas females will have the typical internal and external female genitalia.
At puberty, due to low levels of sex hormones, male individuals won’t develop secondary sex characteristics, like body hair, breast enlargement, and voice deepening.
Additionally, menstrual bleeding won’t be triggered in females.Individuals might also experience symptoms suggestive of mineralocorticoid overproduction.
When it comes to blood work, in 11b-hydroxylase deficiency you can typically find decreased levels of aldosterone, cortisol, potassium and renin activity, and increased levels of 11-deoxycorticosterone and sex hormones.
In 17a-hydroxylase deficiency, there’s increased levels of mineralocorticoids, and decreased levels of cortisol, sex hormones, potasium, and androstenedione.
As a quick summary of the 3 types of CAH; 21-hydroxylase deficiency and 11b-hydroxylase deficiency cause females to develop ambiguous genitalia at birth, while 17a-hydroxylase deficiency cause males to have external genitalia that appear female at birth.
11b-hydroxylase and 17a-hydroxylase deficiency cause hypertension but 21-hydroxylase deficiency does not.Okay, let’s move on!
The last cause of primary adrenal insufficiency we’ll go over is Waterhouse-Friderichsen syndrome.This is an acute syndrome caused by bilateral adrenal hemorrhage, usually associated with severe bacterial infection.

Waterhouse-Friderichsen syndrome18:34–20:10

Although many microbes can cause this, the most likely scenario to appear on your exams is severe septicemia due to Neisseria meningitidis infection.
Key things to look for are disseminated intravascular coagulation, or DIC, endotoxic shock, petechial rash, and headache with neck stiffness if meningitis is also present.
Diagnosis is based on clinical features of adrenal insufficiency as well as identifying the causative pathogen.If meningitis is suspected, a lumbar puncture is performed to obtain cerebrospinal fluid for analysis and culture.
In all other instances, blood cultures should be obtained. Additionally, blood work could show a sudden fall in hemoglobin and hematocrit, leukocytosis, and progressive hyperkalemia, hyponatremia, and volume contraction.
Remember that DIC will cause thrombocytopenia and extremely elevated PT and PTT. Treatment should be focused on correcting fluids, electrolyte, and hematological deficits as well as treating the infection with antibiotics.
IV Hydrocortisone can be used to address adrenal insufficiency.Okay, let’s look at the causes of secondary adrenal insufficiency.
The most common is a non-functional pituitary macroadenoma. This type of adenoma is a benign tumor of the pituitary greater than 1 centimeter.

Pituitary macroadenoma20:10–21:08

If the tumor is large enough, it can compress the normal pituitary tissue, so, in time, some or all the pituitary hormones become deficient, which is called hypopituitarism.
Regarding symptoms, the tumor can cause headaches, and as the tumor compresses on the nearby nerves, visual abnormalities.
Individuals can also develop signs of adrenal insufficiency and hypopituitarism. Diagnosis is based on a head MRI to identify the tumor’s size and location, and pituitary hormone serum measurements to look for hypopituitarism.
Treatment is usually transsphenoidal resection - which is when the tumor is removed through the nose.And finally, the more commonly tested causes of tertiary adrenal insufficiency are sudden withdrawal of glucocorticoid therapy.
Another cause is when a person was treated for Cushing syndrome and a tumor secreting ACTH in the pituitary or cortisol in the adrenal gland gets removed.

Glucocorticoid withdrawal21:08–22:00

Both Glucocorticoid therapy and a tumor secreting cortisol will lead to inhibition of the hypothalamic-pituitary-adrenal axis, and consequently, decrease natural production of CRH.
But when the cause of high cortisol levels is removed suddenly, it can take more than a year for CRH production to go back to normal, resulting in adrenal insufficiency.
Diagnosis is based on a combination of history, clinical findings, imaging, and serum cortisol, ACTH and CRH measurements.
Treatment is hormone replacement therapy.All right, as a quick recap… Adrenal insufficiency can be primary, when the adrenal glands don’t work properly, or central, when there is a problem with either the hypothalamus or the pituitary.
With primary adrenal insufficiency, there is low cortisol, high ACTH and no increase in cortisol level after the ACTH stimulation test.

Review22:00–23:55

There can also be low aldosterone and high plasma renin activity. With central adrenal insufficiency, there is low cortisol and low ACTH, an increase in cortisol after ACTH administration, but no aldosterone deficiency.
Central adrenal insufficiency can further be secondary or tertiary. With secondary insufficiency, there’s no increase in ACTH after a CRH injection, whereas with tertiary disease, ACTH levels increase after CRH.Causes of primary adrenal insufficiency, or Addison disease, can be autoimmune, when there are anti-adrenal antibodies present, or non-autoimmune, which can happen because of adrenal infections, bilateral adrenal metastases or hemorrhages.
Secondary adrenal insufficiency is usually due to a pituitary tumor or a central nervous system tumor.Finally, tertiary adrenal insufficiency can occur either because of sudden withdrawal of glucocorticoid therapy or after the removal of a tumor causing Cushing syndrome.
Primary insufficiency can cause hyperpigmentation, hypotension, hyperkalemia, and metabolic acidosis. Secondary and tertiary adrenal insufficiency can be associated with headaches, visual abnormalities, and hypopituitarism.
Both primary and central adrenal insufficiency can present acutely, as an adrenal crisis with symptoms like fever, shock, abdominal pain, and altered mental status.
Treatment consists mostly of lifelong hormone replacement therapy.Now, back to our cases… Mike presents with chronic symptoms like fatigue, weight loss, and muscle pain, and a family history of autoimmune disease.
Examination reveals hypotension and skin hyperpigmentation. Together, these symptoms are highly suggestive of primary adrenal insufficiency, most likely from an autoimmune cause given his family history and the fact that he’s from Canada, a high income country.
The diagnosis was partially confirmed by low serum cortisol levels, so the next step would be obtaining serum ACTH, aldosterone, and anti-21-hydroxylase antibodies levels plus an ACTH stimulation test to confirm that the insufficiency is indeed primary.Teresa, on the other hand, presented with acute symptoms like vomiting, abdominal pain, hypotension, and altered mental status.

Summary23:55–25:07

Now, these are rather unspecific, but adding the fact that she underwent transsphenoidal resection of a pituitary tumor and her low serum cortisol levels, suggests adrenal crisis due to tertiary adrenal insufficiency.
A CRH stimulation test would be needed to confirm the diagnosis. She was started on IV fluids and hydrocortisone immediately.
acute symptoms, like vomiting abdominal pain, hypotension and altered mental status. Now, these are rather on specific but adding the fact that she underwent transfer title resection of a pituitary tumor and her low serum cortisol levels, suggest adrenal crisis due to tertiary adrenal insufficiency.
The crh stimulation test would be needed to confirm. The diagnosis.
She was started on IV fluids