Adrenal hypercortisolism (AHC), formerly called MACS or subclinical Cushing 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, which gained wide attention in 2000 through 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 have 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 (ACTH, adrenocorticotropic hormone, is made in the pituitary gland at the base of the brain and 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 (most of these cases; this is Cushing’s disease) and, less often, ACTH-producing tumors elsewhere in the body (for example in the lung)
• ACTH Independent (the cortisol comes from the adrenal glands themselves)
  1. Adrenal surgery is almost always curative in these cases
  2. Benign adrenal adenomas (the large majority) and malignant adrenal tumors (rare)

What are the signs and consequences 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, improve or resolve high blood sugar (pre-diabetes) and hypertension, and may lower 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 has the cortisol measured in the morning. If the cortisol is greater than 1.8 µg/dL (not suppressed) this is consistent with too much cortisol. A result between 1.2 and 1.8 is “possible” hypercortisolism: it must be interpreted together with ACTH and DHEA-S and is worth repeating.
   
   You can also measure the cortisol in the saliva late at night as well as performing a 24-hour urine free cortisol (UFC) measurement. These tests are not very sensitive, so most people with subclinical Cushing’s syndrome will have normal results, and a normal result does not rule the disease out. However, if the 24-hour urine free cortisol is elevated it strongly supports that 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 almost certainly have adrenal Cushing’s syndrome (nothing is 100% in medicine) if you have this constellation:
   
   ACTH = low (below 20 pg/mL in mild disease, below 10 in moderate disease and below 5 in severe disease)
   
   Cortisol after LDDST = above 1.8 µg/dL.
   
   See, easy!  If your ACTH is on the low side and the cortisol is on the high side, you have too much cortisol coming from the adrenal glands.
   
   NOTE: if both your cortisol and your ACTH are 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 operation, which typically takes about 20 minutes, to achieve cure?  

In some older clinical studies, because the diagnosis can be challenging, it was even proposed that the diagnosis of subclinical Cushing’s syndrome should be confirmed by 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 seen when compared with similarly matched patients treated without surgery. A randomized trial (CHIRACIC, Lancet Diabetes & Endocrinology 2025) found that adrenalectomy improved blood pressure control compared with conservative care (the blood pressure endpoint was met in 46% versus 15% of patients). Adrenalectomy is the only cure and, in our view, the best treatment for subclinical Cushing’s syndrome.

Figure 3. Adrenal surgery can be performed via the Mini Back Scope Adrenalectomy (MBSA) operation, which we believe is the best adrenal operation for most patients, using 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 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 mild disease the decision for surgery is individualized, based on cortisol-related conditions (hypertension, diabetes or pre-diabetes, osteoporosis or fractures, weight gain), whether one or both adrenal glands are involved, age, surgical risk and the patient’s preference. In patients undergoing adrenalectomy, studies have shown 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 mifepristone instead of adrenal surgery. For patients who are candidates for surgery, we believe 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. Mifepristone should be used in preparation for surgery or reserved for the rare patients when adrenal surgery is not possible. According to the manufacturer’s own description:

The goal of treatment with mifepristone is to decrease the symptoms of excess cortisol activity. Mifepristone does not decrease cortisol levels (surgery does).

Mifepristone is a cortisol receptor blocker used to control high blood sugar caused by high blood cortisol levels in adult patients with 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, fragility fractures, etc).  Clinical and hormonal features improve after adrenalectomy, which is why making this sometimes difficult diagnosis is so important.

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