Subclinical Cushing’s syndrome is highly under-diagnosed and under-treated. Unfortunately, despite subclinical Cushing’s syndrome being relatively common, causing significant problems for patients, referral for cure by an expert surgeon is oftentimes never done or delayed.  The diagnosis itself is rarely made in a timely manner (if at all). This leaves most subclinical Cushing’s syndrome patients fending for themselves. They need to advocate and research for themselves, trying to uncover the diagnosis and best possible treatment (surgery).

Subclinical Cushing’s Syndrome Treatment and Surgery

In this article, we'll detail:

• How can we better understand how common and what subclinical Cushing’s syndrome is?
• How is it different from Cushing’s syndrome?
• What are the difficulties in diagnosing it?
• Why are thousands of patients every year not being referred for surgery (the only opportunity for cure)?

Figure 1. An adrenal tumor producing too much cortisol causes subclinical Cushing’s syndrome

Subclinical Cushing’s Syndrome and Surgery: How common and What is it?

Subclinical Cushing’s syndrome is a relatively newly discussed and understood disease, first described in 2000, in a large Italian study of over 1000 patients with adrenal incidentalomas.  An adrenal incidentaloma is an adrenal mass newly discovered on abdominal imaging that is being done for another reason (most commonly, the emergency room CT scan for belly pain related to an inflamed appendix, trauma, gallstones, intestinal blockage, ovarian cyst, etc).  In this Italian study, the incidence of subclinical Cushing’s syndrome was greater than 9%.  Subsequent studies have placed the accepted incidence at roughly 5-30%.  Since adrenal incidentalomas are discovered in up to 7% of adults, the prevalence of subclinical Cushing’s syndrome is as high as 2% (same prevalence of primary hyperparathyroidism in women over age 50)! A prevalence of 2% means that at a concert venue holding 10,000 people, about 200 individuals at the concert has subclinical Cushing’s syndrome.

Cushing’s syndrome (sometimes called overt as opposed to subclinical) is a more-recognized diagnosis, described as a specific constellation of signs and symptoms directly related to a prolonged and inappropriately elevated exposure to glucocorticoid, or cortisol (overt production).  The excess cortisol is typically related to a tumor (benign adenoma) within the adrenal gland, cured with adrenal surgery to remove the affected gland. The schematic below presents the signs of overt Cushing’s syndrome.    

Figure 2: Signs and symptoms of overt Cushing’s syndrome                                                    

What are the causes of Cushing’s Syndrome?

Cushing’s syndrome is divided into two categories:

• ACTH Dependent (60%; ACTH, adrenocorticotropic hormone) made in the pituitary gland within the brain that stimulates cortisol production in the adrenal glands)
  1. Overproduction of the pituitary hormone ACTH
  2. Only rarely is adrenal surgery necessary in these cases
  3. Pituitary tumors (55%) and Lung cancers (5%)
• ACTH Independent (40%)
  1. Adrenal surgery is almost always curative in these cases
  2. Benign adrenal adenomas (30%) and Malignant adrenal tumors (10%)

What are the symptoms of Cushing syndrome?

• Hypertension (high blood pressure)
• Osteopenia (weak bones) or osteoporosis (really weak bones; higher risk for fracture)
• High blood sugar (pre-diabetes or diabetes)
• Hypokalemia (low blood potassium)
• Hyperlipidemia (elevated fat/cholesterol levels)

Subclinical Cushing’s syndrome has excess cortisol production, also typically from an adrenal tumor, in the absence of the classical signs and symptoms as pictured and listed above. Subclinical Cushing’s syndrome is also cured by adrenal surgery. Even though subclinical Cushing’s syndrome is not associated with all the classic signs and symptoms specific to hypercortisolism, the condition still leads to long-term consequences of cortisol excess (hypertension, obesity, type 2 diabetes, and osteoporosis).  Since these conditions are frequent among all individuals regardless of adrenal tumor status, and thus not specific to cortisol excess, we can begin to understand the reasons why thousands of such patients each year are not being appropriately and timely referred to an expert adrenal surgeon for removal of the offending tumor.

Further, several studies suggest that subclinical Cushing’s syndrome is likely underreported. It is known that diabetes mellitus and osteoporosis are frequently found in patients with cortisol excess.  Also, vertebral fractures may be the initial presenting symptom of an otherwise asymptomatic (subclinical) individual with cortisol excess. Thus, it has been proposed to screen for subclinical Cushing’s syndrome in:

• All with an adrenal incidentaloma (tumor over 1 cm)
• All patients with very low bone mineral density (osteoporosis) and/or vertebral fractures without other known causes of osteoporosis
• Type 2 diabetes patients with poor glucose control despite adequate diet, exercise, and medication treatment regimens; and, in particular, those also affected with osteoporosis and hypertension.

It is very important to identify patients with overproduction of cortisol (whether overt or subclinical Cushing’s syndrome) since a simple operation, Mini-Back Scope Adrenalectomy (MBSA), can dramatically improve the patient’s quality of life, cure high blood sugar (pre-diabetes) and hypertension, and prevent the risk of dying prematurely from heart disease and stroke.

Subclinical Cushing’s Syndrome and Surgery:  Why is it so hard to diagnose and refer for surgery?

One of the myths about subclinical Cushing's syndrome is that the diagnosis is very hard. 

Diagnosing adrenal Cushing’s syndrome is actually straightforward. Do not be confused!

Diagnosing Subclinical Cushing's Syndrome is done in two steps:

1. Prove that there is too much cortisol (also known as hypercortisolism).
   
   The best test is the low dose dexamethasone suppression test (LDDST). The patient simply takes a 1 mg dexamethasone pill at 11 PM and have the cortisol measured in the morning. If the cortisol is greater than 1.8 (not suppressed) this is consistent with too much cortisol.
   
   You can also measure the cortisol in the saliva as well as performing a 24-hour urine free cortisol (UFC) measurement. The latter is not very sensitive, so most people with subclinical Cushing’s syndrome will have a normal 24-hour urine free cortisol (UFC). However, if it is elevated it proves that indeed you have Cushing syndrome.
   
   
2. Prove that the cortisol excess is due to an adrenal problem (not a pituitary tumor).
   
   Measuring the ACTH (pituitary hormone) will clarify this.  Patients with adrenal Cushing’s syndrome have ACTH levels on the low side.
   
   You have adrenal Cushing’s syndrome (99%; nothing is 100% in medicine) if you have this constellation:
   
   ACTH = 10 or lower
   
   Cortisol after LDDST = 1.8 or higher.
   
   See, easy!  If your ACTH is on the low side and the cortisol is on the high side, you have too much cortisol.
   
   NOTE: if both your cortisol and your ACTH is high you probably have a pituitary problem.

We realize though, that making the diagnosis of cortisol excess can be cumbersome, particularly for the family medicine physician who does not routinely order these tests.  Blood testing the morning after taking an oral steroid at night, urine testing, saliva testing at various times during the day, are all difficult to obtain for the patient and order for the clinicians, particularly when their practices are not used to treating such patients. If the following terms make your head spin: “elevated cortisol levels after 1 mg dexamethasone suppression testing; high average daily serum cortisol; high 24-hour urine free cortisol levels; altered circadian cortisol rhythm; low basal ACTH levels; and, blunted ACTH response to CRH;” then, imagine how your primary care doctor is feeling when he or she knows there is something wrong, but doesn’t know how to order (much less interpret) the right tests to diagnose the problem. Wouldn’t it benefit everyone involved (particularly YOU) to have your existing data interpreted by an expert adrenal surgeon and his team to determine what still needs to be done and when you can be treated with a minimally invasive, 20-minute surgery to achieve cure?  

In some clinical studies, because the diagnosis can be challenging, it has been proposed that the gold standard for diagnosing subclinical Cushing’s syndrome should be weight loss and improvement in blood pressure, cholesterol levels, and fasting glucose after adrenalectomy.  We do know that those individuals with subclinical Cushing’s syndrome treated with surgery will typically show improvement in their hypertension, obesity, diabetes, and cholesterol levels.  These improvements in patients after surgery are when compared with similarly matched patients treated without surgery, and surgery has been proven to be the best treatment for subclinical Cushing’s syndrome.

Figure 3. Adrenal surgery can be performed via the Mini Back Scope Adrenalectomy (MBSA) operation, which is by far the best adrenal operation, suing small incisions on the patient’s flank

Subclinical Cushing’s syndrome and surgery: Adrenal surgery is the best and only curative treatment

Since most patients with subclinical Cushing’s syndrome present with an adrenal incidentaloma, (again, this is an adrenal tumor appearing on a Xray (scan) done for other reasons), the best treatment is surgery on the adrenal gland in which the benign tumor is growing. Laboratory tests are performed (best if done by an expert surgeon that can interpret and act on the results), confirming cortisol overproduction. In patients undergoing adrenalectomy, studies have proven that they demonstrate an improvement in their blood pressure (reducing number of medications needed), diabetes, obesity, and cholesterol levels, as well as glucose metabolism and lowered body weight. Importantly, adrenal surgery has been demonstrated to decrease the cardiovascular risk factors associated with subclinical Cushing’s syndrome. Occasionally, some doctors wish to treat patients with medications, such as Korlym (mifepristone) instead of adrenal surgery. This is a mistake. Adrenal surgery for subclinical Cushing’s syndrome is much more effective, less expensive than medication, and the only opportunity for cure. Korlym should be used in preparation for surgery or reserved for the rare patients when adrenal surgery is not possible. Per the medication’s description on its website,

The goal of treatment with Korlym is to decrease the symptoms of excess cortisol activity. Korlym does not decrease cortisol levels, [surgery does].

Korlym is a cortisol receptor blocker indicated to control [high blood sugar] secondary to [high blood cortisol levels] in adult patients with [subclinical or overt Cushing’s syndrome] who have type 2 diabetes, or glucose intolerance, and have failed surgery or are not candidates for surgery.

The clinical spectrum of subclinical Cushing’s syndrome can range from slightly disrupted circadian rhythm of cortisol release to complete shutdown (dormancy) of contralateral adrenal gland with lasting adrenal insufficiency after unilateral adrenalectomy.  Subclinical Cushing’s syndrome is more common than classic Cushing’s syndrome. Even though those with subclinical Cushing’s syndrome do not exhibit the typical signs and symptoms of those with overt Cushing’s syndrome, they do have a high incidence of hypertension, obesity, bone loss, elevated cholesterol levels, and type 2 diabetes. These increased morbidities worsen quality of life and increase the risk of death (increased risk of heart disease, stroke, frailty fractures, etc).  Clinical and hormonal features improve    after adrenalectomy making a difficult diagnosis imperative to save your life.

Additional Resources: 

• Learn more about the Carling Adrenal Center
• Learn more about Dr. Tobias Carling
• Learn more about our sister surgeons at the Norman Parathyroid Center, Clayman Thyroid Center and Scarless Thyroid Surgery Center
• Learn more about the Hospital for Endocrine Surgery