Cushing syndrome and Cushing disease: Clinical sciences

Cushing syndrome refers to a combination of clinical features and symptoms that arise as a result of long-term exposure to high glucocorticoid levels in the blood. Based on the underlying cause, Cushing syndrome can be iatrogenic, which occurs from exogenous administration of glucocorticoids; ACTH-independent, which is specific to adrenal cortisol hypersecretion; and ACTH-dependent, which can be due to either ectopic ACTH secretion by non-pituitary tumors or excessive pituitary ACTH secretion.

Moreover, Cushing syndrome caused by excessive secretion of ACTH by pituitary adenoma is called Cushing disease!

Now, if your patient presents with a chief concern suggesting Cushing syndrome, the first step is to obtain a focused history and physical examination as well as labs, including a basic metabolic panel or BMP.

High glucocorticoid levels in the blood affect almost every system in the body, so your patient will have various clinical manifestations. For example, history will often reveal central nervous system symptoms, such as irritability and depressed mood; as well as metabolic conditions, like glucose intolerance or diabetes mellitus. Next, high glucocorticoid levels can suppress gonadotropin secretion, so your patients might report symptoms involving the reproductive system, like decreased libido and amenorrhea.

The physical exam reveals the glucocorticoid effects on fat redistribution and findings like central obesity, moon facies or round face, and “buffalo hump”, which refers to fat accumulation on the back of the neck. Additionally, you might notice skin changes, such as thin skin, acne, hirsutism, and purple and broad abdominal striae!

Next, let’s take a look at cardiovascular findings! Normally, the kidneys inactivate cortisol by converting it into cortisone, which cannot bind mineralocorticoid receptors and exert cardiovascular effects.

But, in Cushing syndrome, there’s too much cortisol, so the kidneys are unable to inactivate everything from the blood. As a result, cortisol remains active and begins binding mineralocorticoid receptors in the kidneys, subsequently causing sodium reuptake and increasing potassium excretion! Ultimately, this leads to findings such as elevated blood pressure and peripheral edema.

Next, let’s take a look at muscles! Since glucocorticoids stimulate protein degradation, you might notice muscular atrophy, especially of gluteal and upper leg muscles!

Finally, as far as labs go, keep in mind that your patient is losing potassium through the kidneys, so you will often notice hypokalemia. Additionally, your patient might present with hyperglycemia due to glucose intolerance or uncontrolled diabetes mellitus.

Now, with these findings, you should suspect Cushing syndrome, so your next step is to determine the underlying cause!

First, check if there’s a long-term use of exogenous glucocorticoids. Exogenous glucocorticoids come in many forms, so be sure to specifically ask about all delivery methods of glucocorticoids, including oral, injection, inhaler, or topical, which are typically used to treat various inflammatory conditions!

Now, if your patient has been prescribed exogenous glucocorticoids to treat a specific inflammatory condition, you can clinically diagnose Iatrogenic Cushing syndrome!

In this case, the management consists of lowering the dosage, or if possible, gradually tapering off the medication.

On the flip side, if there is no exogenous glucocorticoid use, you need to assess if your patient’s blood cortisol levels are truly elevated before going any further.

To do this, you can obtain either a late-night salivary cortisol, a 24-hour urinary free cortisol level, or a low-dose overnight dexamethasone suppression test. Now, if cortisol levels are below, or within the reference range, then your patient does not have Cushing syndrome, so you should consider alternative diagnoses.

However, if cortisol levels exceed the reference range, you can confirm the diagnosis of Cushing syndrome. Your next step is to assess the underlying cause by obtaining a plasma adrenocorticotropic hormone or ACTH level test.

If the plasma ACTH level is below the reference range, diagnose ACTH-independent Cushing syndrome, which typically occurs due to excessive cortisol secretion by the adrenal glands.

Next, obtain an adrenal gland imaging, like CT or MRI. Imaging will typically reveal either an adrenal tumor or adrenal gland hyperplasia. With these findings, diagnose adrenal cortisol hypersecretion as the cause of Cushing syndrome!

Now, here’s a clinical pearl to keep in mind! Important conditions associated with adrenal cortisol hypersecretion include adrenocortical adenoma and adrenocortical carcinoma, as well as macronodular adrenal hyperplasia.

Once you determine the cause of ACTH-independent Cushing syndrome, consult your surgery team for tumor resection or bilateral adrenalectomy in case of adrenal hyperplasia. Following adrenalectomy, your patient will require a life-long glucocorticoid and mineralocorticoid replacement. Other treatment options include medical therapy with adrenal steroidogenesis inhibitors like mitotane, which can help manage symptoms of excess cortisol.