Cushing syndrome and Cushing disease: Pathology review

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Case study0:00–1:13

On the endocrinology ward, two people came in with similar symptoms. One of them is 45 year old Samantha who complains of gaining a lot of weight.
Lately, Samantha also suffers from severe asthma for which she's taking oral glucocorticoids. She also had many viral and bacterial infections.
Lately. On clinical examination, there's truncal obesity, a large hump behind her neck and stria on her abdomen.
Her arterial pressure was elevated and she also had hyperglycemia. The other person is 38 year old Dan who is also obese and has an abnormally round face.
He has arterial hypertension and hyperglycemia. Unlike Samantha, Dan is not taking any medications.
A 24 hour urine free cortisol was done in both individuals and levels were high. Further investigations were done including ach levels.
Now, both individuals suffer from an endocrine disorder that involves high levels of cortisol. This is generally called Cushing's Syndrome.
Now, if Cushing's Syndrome results from a pituitary adenoma making excess ACTH, it's called Cushing's disease. Normally, the hypothalamus secretes corticotropin releasing hormone known as crh, which stimulates the pituitary gland to secrete adrenocorticotropic hormone known as ACTH ACTH travels to the adrenal glands where it targets cells in the adrenal cortex.

Physiology1:13–4:01

The adrenal cortex is the outer part of the adrenal gland and is subdivided into three layers. The zona glomerulosa, the zona fasciculata and the zona reticularis, zona fasciculata is the middle zone and also the widest zone and act specifically stimulates cells in this zone to secrete cortisol.
This is a class of steroids or lipid soluble hormones called glucocorticoids. Glucocorticoids are not soluble in water.
So most cortisol in the blood is bound to a special carrier protein and only about 5% is unbound or free. In fact, only this small fraction of free cortisol is biologically active and its levels are carefully controlled excess.
Free. Cortisol is filtered in kidneys and dumped into the urine free cortisol in the blood is involved in a number of things and it's part of the circadian rhythm.
Cortisol levels peak in the morning when the body knows we need to get up and go and then drop in the evening when we're preparing for sleep.
In times of stress. Cortisol increases gluconeogenesis, proteolysis and lipolysis.
Cortisol also helps maintain BP by increasing the sensitivity of peripheral blood vessels to catecholamines which further cause vasoconstriction.
Cortisol helps to dampen the inflammatory and immune response by reducing the production and release of inflammatory mediators as well as inhibiting the proliferation of T lymphocytes.
Finally, cortisol receptors are present in the brain where their full effect is still actually unclear but might influence things like mood and memory for all this to work properly.
Though the levels of free cortisol have to stay within the normal range to do that. The body uses negative feedback, which means that high levels of cortisol tell the hypothalamus and pituitary gland to decrease their secretion of crh and ACTH respectively.
Less crh also tells the pituitary to make less ACTH. So the pituitary ends up having two reasons not to make act with less act floating around the zona fasciculata gets less stimulation to make cortisol and eventually cortisol levels go back down to the normal range again.
Ok. Now, Cushing syndrome can be caused by exogenous cortisol, used as medications or endogenous cortisol, meaning that the excess cortisol is made by the body.
A very high yield fact is that the majority of cases of Cushing Syndrome occur in individuals using exogenous cortisol like predniSONE over a long period of time.

Exogenous Causes4:01–5:30

Often as a treatment for autoimmune and inflammatory conditions like rheumatoid arthritis or poorly controlled asthma. They have structures similar to endogenous cortisol and mimic its actions in various tissues.
In fact, exogenous cortisol can also cause negative feedback on the hypothalamus and the pituitary gland leading to a decrease in crh and ACTH which in turn shuts down cortisol production from the zona fasciculata.
Over time. This lack of stimulation can cause zona fasciculata of both adrenal glands to physically shrink or become atrophic.
Even though this results in less endogenous cortisol production, it still doesn't quite compensate for the huge levels of exogenous cortisol and that causes Cushings Syndrome to develop.
Now, if the medication is stopped too abruptly, the atrophied adrenal glands can't produce enough cortisol. So we get adrenal insufficiency.
If the cortisol level is low enough, it might trigger an adrenal crisis. This is a life threatening condition with symptoms like fever, hypotension, severe abdominal pain with vomiting and diarrhea, confusion, psychosis and coma.
In addition to taking exogenous steroid medications. Cushing syndrome can also result from increased levels of endogenous cortisol.
The most common cause is Cushing's disease where the pituitary releases too much act for your exams. Remember, the leading cause is a pituitary adenoma which is a benign tumor of the pituitary gland.

Endogenous Causes5:30–7:33

The exact reason for the development of this sort of benign tumor isn't known. And the pituitary adenoma simply grows in size and secretes excess act.
This causes the zona fasciculata of both adrenal glands to undergo hyperplasia and secrete excess cortisol. Apart from pituitary adenomas, there are ectopic sources of act such as paraneoplastic syndromes.
The high yield ones to remember are small cell lung cancer and bronchial carcinoids. In these cases, the excess ACTH is coming from somewhere other than the pituitary.
So these cases are not considered Cushing disease. Another common cause of endogenous Cushing syndrome is tumors of the adrenal glands that make excess cortisol like adrenal adenomas, which are benign tumors and adrenal carcinomas, which are malignant tumors in both adrenal adenomas and carcinomas.
The cells of the zona fasciculata within the adrenal cortex, start dividing abnormally and secrete excess cortisol as before the excess cortisol provides negative feedback to the hypothalamus and pituitary gland suppressing crh and ACTH production.
This doesn't have any effect on zona fasciculata of the involved adrenal gland. Since the neoplastic cells are autonomous, meaning that they grow independently from ACTH.
However, the zona fasciculata of the uninvolved adrenal gland shrinks and atrophies. This could be a clue to help you narrow down the cause to the adrenal gland.
The net result though is abnormally high levels of cortisol and that causes Cushing's Syndrome regardless of the cause. The symptoms of Cushing Syndrome are directly related to the effects of excess cortisol and other glucocorticoids on its various target tissues.
Since cortisol levels are elevated chronically, its effects will be exaggerated. Excess cortisol leads to severe muscle and skin breakdown, which are major sources of protein in the body.

Symptoms7:33–9:51

This leads to muscle wasting and thin extremities, skin thinning, easy bruising and abdominal stria or lines. The bones are also broken down for calcium.
So, fractures can occur due to osteoporosis. Next, there's elevated blood glucose level due to increased gluconeogenesis in the liver.
As a result, the insulin level goes up and eventually insulin resistance develops cortisol also increases appetite which can lead to weight gain.
This can manifest as truncal obesity, but there is also fat redistribution to the cheeks resulting in a round moons shaped face and to the back of the neck causing Buffalo Hump Cushing syndrome can also lead to arterial hypertension.
Thats because cortisol can amplify the effect of catecholamines on blood vessels. Second, cortisol is also a weak agonist for mineralocorticoid receptors.
So it can act like a weaker version of aldosterone and increase BP by causing the kidneys to retain more fluid and sodium.
Remember for your exam that this is called pseudo hyperaldosteronism. High levels of cortisol also inhibit the secretion of gonadotropin releasing hormone from the hypothalamus, which messes up normal ovarian and testicular function in biological females.
This leads to amenorrhea. Now, in cases with high levels of act such as Cushing disease act can also stimulate the production of androgen hormones leading to hirsutism in biological females, excess cortisol also dampens the inflammatory and immune response.
Making individuals develop a form of immunosuppression, making them more susceptible to infections. Finally, high levels of cortisol seem to impair normal brain function.
But the exact mechanism is unclear. Diagnosis of Cushing syndrome is a simple algorithm that's very high yield.
It's initially based on measuring the free cortisol in a 24 hour urine sample to confirm cortisol levels are high. Alternatively, blood or saliva tests at midnight can help check if there's a normal daily rise and fall of cortisol levels.
Another option is also the dexamethasone suppression test, which is when a person is given a low dose of dexamethasone, which is an exogenous steroid that suppresses act production in the pituitary gland.

Diagnosis9:51–12:14

Normally that should cause a decrease in serum cortisol levels. But if Cushings syndrome is caused by endogenous cortisol production, then the serum cortisol levels should remain unchanged.
If one of these tests is positive. The next step is to determine the exact cause of endogenous cortisol production and ACTH plasma levels can be checked.
Low ACTH levels can be seen in adrenal adenomas, adrenal carcinomas and exogenous glucocorticoids. Whereas high ac levels can be seen in cushing disease and ectopic ACTH production.
If the ACTH level is high. The next step is to give an injection of a high dose of dexamethasone.
And this is called a high dose dexamethasone suppression test if there's no suppression and the ACTH level remains the same.
It means there is an ectopic site of ACTH production. In which case a ct of the chest abdomen and pelvis can be done in order to find the source.
If levels of ACTH fall after the high dose dexamethasone test, then this means its cushing disease. In which case, an MRI of the pituitary is done to confirm an alternative to the high dose dexamethasone suppression test is the crh stimulation test where an individual is given synthetic crh.
Now, if there's no rise in ACTH and cortisol after the test, then this means ACTH secretion is ectopic and just as before a CT scan of the chest abdomen and pelvis is done.
If there's a rise in ACTH and cortisol. Then this means the pituitary responds to crh.
And we're talking about Cushing disease. In which case, an MRI of the pituitary is done.
All right. As a quick recap.
Cushing syndrome is a set of symptoms caused by high levels of glucocorticoids. The most common source is an exogenous cortisol like predniSONE, but it could also be caused by endogenous cortisol produced within the body.
Steroid medication can cause negative feedback in the hypothalamus and the pituitary gland leading to a decrease in crh and ACTH which in turn shuts down cortisol production over time.
Both adrenal glands can become atrophic in case of endogenous cortisol. The most common cause is excess act that usually happens due to a pituitary adenoma and this is referred to as Cushing disease.

Review12:14–14:57

The excess act causes both adrenal glands to undergo hyperplasia. Apart from pituitary adenomas, there are ectopic sources of act like para neoplastic syndromes associated with small cell lung cancer or bronchial carcinoids.
Another common cause of endogenous Cushing syndrome is tumors of the adrenal glands that make excess cortisol like adrenal adenomas or adrenal carcinomas.
And in this case, crh and ACTH production is suppressed and the normal adrenal gland atrophies. Symptoms of Cushing syndrome include arterial hypertension, weight gain and truncal obesity, moon face buffalo, hump, thinning and striae on the skin.
Hirsutism, osteoporosis, hyperglycemia, amenorrhea, and immunosuppression diagnosis of Cushing syndrome is based on a high 24 hour urine free cortisol test, a high late night salivary test or inadequate suppression on the dexamethasone suppression test.
Next to identify the cause act levels are taken. Low ACTH levels can be seen in adrenal adenomas, adrenal carcinomas and exogenous glucocorticoids.
Whereas high ACTH levels can be seen in cushing disease and ectopic ACTH production. If the ACTH level is high.
The next step is to do a high dose dexamethasone suppression test. If there's no suppression, then this means there's an ectopic site of act production.
In which case, a ct of the chest abdomen and pelvis can be done in order to find the primary tumor. If levels of act fall after the high dose dexamethasone test, then this means it's Cushing disease.
In which case, an MRI of the pituitary is done to confirm. Now, back to our cases, Samantha came in with arterial hypertension, truncal obesity, a Buffalo hump stria on the abdomen and hyperglycemia.
All of these are signs and symptoms of Cushing's syndrome. The cause is most likely the Glucocorticoids she's been taking for her asthma.
This decreased her immune response, which is the cause of the repeated viral and bacterial infections. A 24 hour urine free cortisol was done and levels were high.
Furthermore, ACTH levels were low, meaning that cortisol secretion is independent of ACTH. This confirms the diagnosis of Cushing Syndrome caused by exogenous glucocorticoids.
Now, Dan came in with similar symptoms as Samantha, but he didn't have a history of Glucocorticoid use tests showed high levels of urine free cortisol, but this time levels of ACTH were high and the high dose dexamethasone suppression test showed adequate suppression of act levels.

Summary14:57–15:29

This means that dan most likely has a pituitary adenoma thats responsible for the high levels of cortisol and act when a pituitary adenoma is the cause of Cushing syndrome, we call this Cushings disease.
An MRI of the pituitary will be done to confirm the diagnosis.