What is Cushing Disease?
Cushing disease is a medical condition caused by the excess production of a hormone from the pituitary gland, leading to an overproduction of cortisol from the adrenal glands. It is typically the result of a small tumor in the pituitary gland, or due to an overproduction of another hormone from the hypothalamus. The symptoms may vary and can include generalized weakness, high blood pressure, diabetes, irregular periods, and changes in mental health. Visible signs of the disease may include a round face, hump on the back, easy bruising, stretch marks, obesity, redness in face, and excess body hair.
Notably, many people with Cushing disease don’t experience a specific vision problem known as ‘bitemporal hemianopsia’. This is because most of these cases are caused by small pituitary tumors (less than 10mm in size).
What Causes Cushing Disease?
People suffering from Cushing disease usually have a tumor in the pituitary gland, which is not always detected by medical imaging. There are rare instances where it’s caused by overgrown corticotroph cells in the pituitary gland, even if there’s no unusual release of corticotropin-releasing hormone (CRH). These tumors are typically small, referred to as microadenomas, and are less than 10mm in size. Only about 5 to 10 percent are larger tumors, known as macroadenomas.
It’s interesting to note that larger tumors are more likely to result in abnormally high concentration of ACTH, a hormone that regulates levels of the steroid hormone cortisol, compared to smaller ones. Scientific research shows that this happens 83 percent of the time with large tumors, versus 45 percent with smaller ones.
Different genetic mutations can be responsible for the growth of these tumors. The most frequently occurring mutation is called USP8, or ubiquitin specific peptidase 8. These mutations lead to unusual growth factors, which when paired with ACTH, results in higher levels of cortisol.
Risk Factors and Frequency for Cushing Disease
Cushing’s disease is the second most common cause of Cushing syndrome, with the primary cause being the external use of steroids. On average, about 2.4 new cases occur yearly per million people. The disease is typically diagnosed 3 to 6 years after symptoms start, and it most commonly affects women between the ages of 50 and 60. High blood pressure and disturbances in glucose metabolism are key indicators of the disease. If left untreated, these can lead to serious health issues. The disease has a mortality rate of roughly 10% to 11%.
- Cushing’s disease is the second most common cause of Cushing syndrome, after external steroids use.
- Around 2.4 new cases appear per million people each year.
- The diagnosis usually happens 3 to 6 years after symptoms begin.
- Most commonly, women between the ages of 50 and 60 are affected.
- High blood pressure and abnormalities in glucose metabolism can occur, leading to potential health complications.
- The mortality rate is approximately 10% to 11%.
Signs and Symptoms of Cushing Disease
Patients with hypercortisolism, a condition where the body produces too much cortisol, may experience a wide range of symptoms. These can vary greatly among patients, so a high level of awareness is needed for accurate diagnosis. Not all patients will have all symptoms, and they might present differently.
- Weight gain (in about 50% of patients)
- High blood pressure
- Easy bruising
- Purple or reddish stretch marks
- Acne
- Redness of the face
- Slow healing of cuts and wounds
- Swelling in the lower legs
- Tiredness
- Difficulty processing sugar
- Weak and brittle bones
- Darkening of the skin
- Changes in mood and memory
- Stoppage of menstrual periods
- Excessive hair growth in women
- Decreased sex drive
- Frequent infections
In rare cases, large pituitary tumors, called macroadenomas, can cause other issues due to their size and pressure on surrounding structures. In these instances, patients may experience symptoms such as impaired peripheral vision or headaches.
Testing for Cushing Disease
Over half of the people who have Cushing disease – a condition that causes the body to produce too much of the stress hormone cortisol – have a small tumor less than 5 mm in size on their pituitary gland. However, only 10% of these tumors are large enough to impact the brain tissue and surrounding regions. Therefore, the majority of these cases are detected due to symptoms of excess cortisol and androgen, hormones that control a range of functions such as immune response and metabolism.
To confirm the presence of excess cortisol, doctors may conduct a range of tests. These include salivary and blood cortisol tests, a 24-hour urine test for cortisol, and a dexamethasone suppression test. The late-night salivary cortisol test, which measures cortisol levels in saliva, is increasingly popular due to its simplicity. It has a success rate of 95% to 98% in identifying Cushing syndrome.
The urine test measures the amount of cortisol passed through urine. If the results are three times higher than normal and another test also shows abnormal results, this is usually attributed to Cushing syndrome. However, as this test has a success rate of 81%, it must be carried out three times to avoid misdiagnoses.
Dexamethasone suppression tests involve giving the patient a dose of medication and then measuring their cortisol levels. If the cortisol level is less than 1.8 mcg/dL, it’s considered normal. The sensitivity and specificity of the test are 100% and 88% respectively, with a 92% chance of correctly identifying Cushing’s Syndrome and an 89% chance of correctly ruling it out.
If two or more of these initial tests come back positive and the person is already thought to likely have the disease, it’s usually considered a biochemically confirmed diagnosis of Cushing syndrome.
After Cushing syndrome is diagnosed, the next step is to understand the cause by measuring a specific hormone in the bloodstream. If levels are consistently over a certain threshold, it’s classified as a particular type of Cushing syndrome. Further testing, such as pituitary MRI or a particular type of dexamethasone suppression test, may be used.
An MRI scan may provide images of the pituitary tumor, but it doesn’t always detect it. In some cases, an invasive method, called inferior petrosal sinus sampling, is used to confirm diagnosis. This involves measuring the variation in hormone levels between different regions of the body. Despite its high success and specificity rates, this method is rarely used due to its expense and invasiveness.
Treatment Options for Cushing Disease
If doctors discover a tumor that is causing an overproduction of ACTH (a hormone), the first course of action is typically to remove the tumor through surgery. This type of surgery is often done through the nose or under the lip, based on the surgeon’s preference. If the tumor is identified during the initial surgery, the chances of successfully removing it are higher. Generally, the success rates for these surgeries are between 65% and 90% for smaller tumors and less than 65% for larger ones. Sometime, if the disease persists after the first surgery, patients may go through another surgery, although it’s less successful and might result in a reduced pituitary function. Common complications post-surgery can include the onset of diabetes insipidus, changes in fluid and electrolyte levels, and neurological issues. Also, patients who are above the age of 64 stand a higher chance of facing adverse outcomes.
Another treatment option, namely radiation therapy, can be considered if the initial surgery isn’t successful. This treatment is particularly successful among younger patients, with cure rates between 80% to 88%. However, it might lead to hypopituitarism, a condition where the pituitary gland doesn’t produce enough hormones, causing growth hormone deficiency. This side effect has been reported in 36% to 68% of patients.
In severe cases, both adrenal glands can be removed to quickly decrease cortisol levels in patients with Cushing’s disease. But, these patients will need lifelong replacement therapy for the hormones glucocorticoid and mineralocorticoid. A major complication of this treatment could be Nelson syndrome, characterized by the growth of large ACTH-secreting tumors. This occurs between 8% to 29% of patients, usually around 15 years after the adrenal glands were removed.
After treatment, tests will be conducted on urine and blood samples to measure cortisol levels. If a test called the desmopressin test becomes negative after surgery, it can suggest that the tumor was completely removed and thus, there’s a lower chance of it recurring. Despite this, recurrence post-treatment is not unusual and affects about a third of patients. As such, lifelong monitoring is required, with late-night salivary cortisol tests being one of the best predictors of recurrence.
For patients suffering from persistent or returning Cushing’s disease, medications can be used to manage the hormonal imbalances. Such medicines can help inhibit ACTH secretion, reduce the production of steroids in the adrenal gland, or block the action of glucocorticoids.
Certain drugs, such as pasireotide and cabergoline, have been effective in regulating this disease in 35% to 40% of cases. Pasireotide therapy has also been beneficial in reducing tumor size in over 40% of patients. However, these medications might exacerbate high blood sugar levels, so they must be used cautiously in patients with diabetes. Certain adrenal steroidogenesis inhibitors, like ketoconazole, metyrapone, etomidate, mitotane, and osilodrostat, have shown to normalize lab results in over 60% of cases that last over two years. Side effects include liver damage, though this can be reversed by reducing the drug dosage or stopping the medication.
Mifepristone is a medication that blocks the action of glucocorticoids and can help in controlling several symptoms of Cushing’s disease. Although the testing of cortisol levels isn’t viable due to this medication, symptom-review is helpful for diagnosing adrenal insufficiency and treating patients with appropriate cortisol replacement therapy.
Some treatments, like retinoic acid and silibinin, have shown promise but their high cost and side effects limit their usage. More studies are being conducted to further understand their effects.
What else can Cushing Disease be?
Cushing’s disease can be confused with some other conditions due to similar symptoms. These include:
- Cushing’s syndrome, which is similar but caused by different factors
- Abnormal secretion of a hormone called ACTH (ectopic ACTH secretion)
- The use of steroid medication (exogenous corticosteroid use)
- Pseudo-Cushing syndrome, which has similar symptoms but isn’t true Cushing’s
- An elevated level of cortisol for natural reasons, like stress (physiological hypercortisolism)
These possibilities all need to be carefully considered and ruled out through appropriate tests to accurately diagnose Cushing’s disease.
What to expect with Cushing Disease
If Cushing disease isn’t treated, it can eventually lead to death. This is primarily due to the body’s overproduction of glucocorticoids – hormones that can bring about numerous health issues including heart problems and a weakened immune system. After undergoing surgery, patients must continue to take glucocorticoids for the rest of their lives.
Possible Complications When Diagnosed with Cushing Disease
If Cushing’s disease is not treated, it can lead to several complications. These include:
- Osteoporosis, which is a condition that weakens bones making them more likely to break. This often affects the foot bones and ribs.
- High blood pressure
- Type 2 diabetes, a condition that affects your body’s blood sugar control
- An increased risk of infections due to a weakened immune system
- Loss of muscle mass
- Depression and other mental health problems
Preventing Cushing Disease
It’s important for patients to understand that Cushing’s disease often arises due to another underlying health condition. Therefore, they need to follow the treatment plans prescribed for both conditions. By doing so, they can help ease the symptoms of their disease.
