Cushing’s Disease vs Cushing’s Syndrome

Cushing’s disease and Cushing’s syndrome are two very similar yet astronomically different conditions. Why? 
Look, one - they are similar for the obvious reason that they are named after the same person - Harvey Williams Cushing. 

Two - Most of their symptoms overlap! This is because the common problem is hypercortisolism (excess cortisol levels).

So what’s the difference? Cushing’s “disease” is a term solely used for ACTH-secreting pituitary adenoma - which can LEAD to endogenous Cushing’s syndrome!

Now, we can broadly divide the causes of Cushing’s “syndrome” into 2:

• Exogenous Cushing’s syndrome: As the name suggests, the excess cortisol comes from “outside” the body. For example, excessive iatrogenic administration of cortisol. 
  Interestingly, this remains the most common cause (MCC) for Cushingoid features.
   
• Endogenous Cushing’s syndrome: Here, the excess cortisol is produced within the body! This is where Cushing’s “disease” comes in. In fact, more than half of the cases of endogenous Cushing’s syndrome is Cushing’s disease!
  
  Yes, non-pituitary ACTH secreting tumors from the lungs, pancreas, thymus, adrenal, GIT, and thyroid can also cause endogenous Cushing’s syndrome. But, they are far less common than Cushing’s disease!

Simply put:

Wisdom from Grand Wizard Zeo:

“Bilateral adrenal hyperplasia is a result of endogenous corticosteroid excess due to pituitary causes (this is directly dependent on ACTH).
For example, Cushing’s disease increases ACTH production. This causes bilateral adrenal hyperplasia.

Whereas, in exogenous corticosteroid excess, the administration of cortisol decreases ACTH production due to the negative feedback mechanism. This causes bilateral adrenal atrophy!

So, in conclusion: Cushing’s disease WILL cause bilateral adrenal hyperplasia, but Cushing’s syndrome can present with either bilateral adrenal hyperplasia or atrophy!”

The patient

The typical presenting features of Cushing’s syndrome can be summed up by the name itself - C.U.S.H.I.N.G.O.I.D!

C - Cataracts and Central Obesity

Corticosteroids themselves can increase the risk of cataracts. In addition to this, Cushing’s syndrome patients are at an increased risk of developing diabetes mellitus, which can, in turn, cause snowflake cataract!

Obesity in Cushing’s syndrome is special because it is not the accumulation of fat all over the body. It’s the localized accumulation of fat along the trunk, giving rise to a pendulous abdomen, moon-like face, and buffalo hump between the shoulders.

U - Ulcers

Some studies indicate that Cushing’s syndrome can have an increased risk of developing peptic ulcers. 

However, these are NOT Cushing’s ulcers! 

Cushing’s ulcers are a totally different type of gastric ulcers which arise secondary to raised

Intracranial tension.

S - Skin changes: Striae, bruising, and thinning

Patients with Cushing’s syndrome have increased skin bruisability and purplish skin striae. These patients also have impaired wound healing. The patients with endogenous Cushing’s syndrome can have skin hyperpigmentation due to ACTH-secreting tumors!

H - Hypertension and Hirsutism

Patients with Cushing’s syndrome also tend to have an increase in facial hair. Since Cushing’s syndrome is much more common in females than males, hirsutism is considered as a significant finding.

I - Immunosuppression

The patient’s immune system is affected adversely, thus placing the patient at an increased risk of unusual bacterial and fungal opportunistic infections.

N - Necrosis

Avascular necrosis of bone is a phenomenon that often occurs in patients with Cushing’s syndrome.

G - Glycosuria

Glycosuria may or may not be present as hypercortisolism itself can cause polyuria and thirst. However, patients may also have increased thirst and polyuria due to insulin-resistant diabetes mellitus.

O - Osteoporosis and Oligomenorrhea

Hypercortisolism is also associated with osteoporosis and oligomenorrhea in females.

I - Infections

As mentioned before, immunosuppression puts the patient at an increased risk of opportunistic infections.

D - Diabetes mellitus 

Again, as mentioned before, hypercortisolism increases the risk of developing insulin-resistant diabetes mellitus.

Confirming you suspicion

So, what do you do if you suspect Cushing’s syndrome?

Confirm Hypercortisolism

First things first, you find a patient with features of Cushing’s - you need to confirm hypercortisolism. 

In this era of evidence-based medicine, this step is not a luxury. It is a necessity.

This can be done using:

• Late-night salivary cortisol determination:
  This is a very useful and non-invasive screening test for hypercortisolism. This test has relatively high sensitivity and specificity, particularly for ACTH-dependent hypercortisolism (pituitary causes).
  Late-night salivary cortisol levels are normally below 150 ng/dL, and anything more than 250 ng/dL is considered very abnormal.
  
  Now, the usual next question - what about the 150-250 grey zone? Don’t bother breaking your head for it. This is a screening test, not a confirmatory test. 
   
• Overnight dexamethasone suppression test (DST):
  This again, is an easy screening test, particularly for ACTH independent hypercortisolism (e.g., adrenal causes).
  In this test, 1 mg of dexamethasone is given orally in the night at around 11 PM. The next morning at around 8 AM, a blood sample is collected for cortisol determination.
  
  If the cortisol level measured is less than 1.8 μg/dL, we can safely ELIMINATE Cushing’s syndrome as a diagnosis. 
  
  Now begs the question, what could go wrong?
  
  False negatives: 
  Some patients with pituitary causes (Cushing’s disease) can have dexamethasone-suppressed cortisol levels too!
  
  False positives: 
  If the patient is on antiepileptics (phenytoin, phenobarbital) or antitubercular therapy (rifampicin) or oral contraceptive pills (OCPs) or HRT - all of these increase the metabolism of dexamethasone.
  
  This causes a lack of suppressibility, which causes increased early morning cortisol levels, giving rise to false-positive results!
   
• 24-hour urinary free cortisol and creatinine:
  When done in a patient with a high late-night salivary cortisol or an abnormal DST, 24-hour urinary free cortisol can CONFIRM hypercortisolism.
  
  HIGH 24-hour urinary cortisol (> 50 μg/day) and INCREASED urinary Cortisol:Creatinine ratio confirm hypercortisolism.

Great! So you confirmed that the patient has hypercortisolism. What next?

Is it ACTH dependent or ACTH independent?

Before you scan every patient of suspected Cushing’s, the presenting symptoms and the screening tests mentioned above can be considered.

Consider this,

A patient comes to you with Cushingoid features with visual disturbances (bitemporal hemianopia). You do the screening tests which reveal:

• Late-night salivary cortisol: Positive - increased (>250 ng/dL)
• DST: Negative (< 2 μg/dL)
• 24-hour urinary cortisol: Positive - increased (> 50 μg)

So what could be the diagnosis?

Yes, it’s obviously a pituitary tumor compressing on the chiasma producing too much ACTH - Cushing’s disease (ACTH-dependent Cushing’s syndrome).

In this patient, targeted imaging can be considered - MRI brain.

Yes, the patient CAN have another lesion too. BUT the likelihood of that happening is very, very low. Occam’s razor - The simplest explanation is most probably the correct explanation.

Note: IF an ectopic ACTH secreting tumor is suspected: The most sensitive scanning technique is a whole-body ⁶⁸Gallium-DOTATATE-PET scan. 

If the same patient presented with Cushingoid features without visual symptoms and the screening tests reveal:

• Late-night salivary cortisol: Positive - increased (>250 ng/dL)
• DST: Positive (> 2 μg/dL)
• 24-hour urinary cortisol: Positive - increased (> 50 μg)

This would mean that the patient has an ACTH-independent Cushing’s syndrome - Adrenal tumors or exogenous Cushing’s syndrome due to iatrogenic causes.

Now for such cases, a plain abdominal CT would essentially be sufficient to confirm the diagnosis.

Close Differentials

Hypercortisolism and other manifestations of Cushing’s syndrome can also be seen in:

• Alcoholics
• Pregnancy
• Critically Ill patients (hypercortisolism)

Managing a patient with Cushing’s Syndrome

The patient’s comorbid symptoms, osteoporosis, psychiatric manifestations, DM, hypertension, electrolyte disturbances, and infections have to be managed appropriately. 

The definitive treatment for Cushing’s syndrome is surgery. But where to perform the surgery would depend on the cause.

In pituitary causes (Cushing’s disease), the definitive option would be trans-sphenoidal hypophysectomy. 

In adrenal adenoma and in cases where the source is ectopic, adrenalectomy and local removal of the ectopic source(s) has to be done. 

Management of the patient doesn't end there. Hyponatremia is a common postoperative complication in the case of pituitary resection. Thus, serum sodium should be monitored frequently for these patients, particularly in the first 2 postoperative weeks. If present, hyponatremia should be corrected very slowly in order to avoid osmotic demyelination syndrome (one of the dreaded complications of rapid correction of hyponatremia).

What if the patient doesn’t want surgery?

If the patient declines surgery, or if the surgery was unsuccessful, medical management can be considered.

For Cushing’s disease:

Cabergoline and Pasireotide have been found to be useful to reduced hypercortisolemia in refractory ACTH secreting pituitary tumors.

For adrenaline gland causes:

There are basically three ways of approaching medical management in adrenal gland tumor secreting:

• Manage mineralocorticoid hypertension: Spironolactone, eplerenone, and amlodipine.
• Manage hyperandrogenism (especially in women): Flutamide
• Manage hypercortisolemia: Ketoconazole and metyrapone.

References:

1. Harrison’s Principles of Internal Medicine 20th edition, Page no: 2680 - 2682
2. Current Medical Diagnosis and Treatment 2020, Page no: 1191 - 1195
3. https://www.ncbi.nlm.nih.gov/books/NBK448184/
4. https://www.ncbi.nlm.nih.gov/books/NBK470218/
5. https://www.ncbi.nlm.nih.gov/books/NBK538239/

Author’s footnote

The difference between Cushing’s disease and Cushing’s syndrome is often misunderstood. They are indeed different entities but are also quite similar to one another. The screening and diagnostic techniques of hypercortisolism have been repeatedly tested in various entrance examinations.

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