CUSHING'S SYNDROME
Excess production of corticosteroid hormones is a heterogeneous group of disorders which present with somewhat common symptoms. In order to understand how these disorders are produced, it is necessary to understand the function of two glands in the body. The first is the pituitary gland which is the so-called master gland of the body. It is located just in front of the base of brain and is a very small structure. It produces a group of releasing hormones which have their end effects on other glands in the body such as the thyroid gland, the ovaries, the testis, the parathyroid glands and of course the adrenal gland. In the particular instance that we are discussing, the part of the adrenal gland that is of interest is the adrenal cortex. The adrenal glands are located on the top of the kidneys and are in the posterior portion of the abdomen just below the ribs.
The pituitary releases adrenocorticotropic hormone abbreviated as ACTH. This hormone then has effects on the adrenal gland to cause production of cortisol and other related hormones that produce masculinization. To add an element of complexity to this regulatory scheme, ACTH production in the pituitary is itself regulated by corticotrophin releasing hormone abbreviated CRH which is released by another central nervous system component called the hypothalamus and also by vasopressin which is itself produced in a portion of the pituitary gland.
ACTH is not released evenly throughout the day, but is released more in the morning and with a second pulse later in the evening. The morning release of ACTH causes plasma cortisol levels to be higher in the morning than in the evening in the average person. The pituitary stops producing ACTH when it sees that there is an adequate amount of cortisol in the blood, again this being in the average person.. The average value of cortisol in the morning is between 10 and 25 micrograms per deciliter and in the evening between 2 and 10 micrograms per deciliter.
Symptoms
The symptoms of excess cortisol include obesity, hypertension, diabetes, kidney stones, osteoporosis or loss of bone mineral's, easy bruising, mental disturbance to the point of psychosis, disturbance of menstrual periods, impotence, abnormal growth of body and facial hair, extremity swelling, loss of serum potassium, difficulty healing wounds, and susceptibility to infection. Full-blown Cushing's syndrome has a characteristic puffy looking face, bruising and a characteristic truncal obesity with a hump in the back.
Diabetes may lead to excessive urination at night and even to coma.
Causes
As can be seen by the above explanation, cortisol excess can be produced by several different mechanisms. Overproduction could be caused by corticotrophin releasing hormone acting to release ACTH which in turn acts to release excess cortisol from the adrenal gland.
ACTH can be produced in excess and this in turn can lead the adrenal glands to overproduce cortisol.
A different substance can mimic the action of corticotrophin releasing hormone or ACTH, again leading to the overproduction of cortisol by the adrenal glands.
Finally the adrenal glands can over produce cortisol either as a result of overactivity or as a result of the overactivity of a tumor in the adrenal glands.
Syndromes
1) classical Cushing's disease is produced by the overproduction of ACTH by the pituitary, most commonly by small tumors in the pituitary gland called adenomas or microadenomas. The excess ACTH causes the adrenal glands to grow larger and to over produce the hormone cortisol.
In classical Cushing's disease, there is elevation of the level of cortisol in the urine and there is a loss of the daily rhythm of cortisol production. There is a loss of the ability of medically administered cortisol or cortisol analogs to suppress the release of ACTH from the pituitary gland. However very high doses of a cortisol analog, dexamethasone, 2 mg every 6 hours for 2 days will suppress ACTH production and will cause urinary steroid production to fall to less than half of the previous measured levels.
2) production of ACTH by tissue other than the pituitary gland can cause elevation of serum cortisol and Cushing's syndrome. The usual cause of this is by malignant tumors, commonly small cell carcinoma of the lung, or tumors of the thymus, pancreas, and kidney. These are so-called paraneoplastic syndromes. The patients present with low serum potassium causing other metabolic problems such as alkalosis, weakness and weight loss. Once again the daily variation in cortisol production is lost. In this case, the overproduction of steroid is not diminished by a two-day administration of dexamethasone at high doses.
3) excess production of the releasing hormone corticotrophin releasing hormone can cause overproduction of ACTH again followed by overproduction of cortisol. Most frequently this is caused by carcinoid tumors and these are most frequently found in the chest. With this presentation of Cushing's disease, 90 percent of the carcinoid tumors are found in the chest. Carcinoid tumors can however be found in other areas of the body, particularly associated with the appendix, the small bowel, and other portion of the intestine.
4) adrenal gland tumors can produce cortisol. This accounts for approximately one third of presentations of Cushing's syndrome. The benign variety of adrenal tumor (adrenal adenoma) generally produces cortisol without without larger amounts of masculinizing hormones. Adrenal tumors that are cancerous, frequently produce large amounts of masculinizing hormone also and produce excess growth of body hair, loss of menstrual periods in women and a masculine appearance in women. Many adrenal cancers will present with a mass in the flank that can be felt (approximately 50 percent). These tumors also present with a loss of the daily variability in cortisol production and the two-day test of high dose dexamethasone fails to decrease the amount of cortisol produced.
5) bilateral nodular hyperplasia of the adrenal gland is diffuse enlargement of both adrenal glands with discrete nodules which cause an excess production of cortisol. This may be a late stage of uncontrolled production of ACTH by the pituitary. ACTH levels may be normal or elevated in this disease.
6) bilateral micronodular dysplasia is enlargement of the adrenal glands with small nodules. There may be an antibody that acts on ACTH receptors as though it was ACTH hormone itself.
7) there is a variant of nodule or adrenal hyperplasia which is stimulated by certain kinds of food and acts through the mechanism of another hormone, gastric inhibitory polypeptide. This is a very rare cause.
8) unfortunately there are people, frequently those people involved in the health-care industry, that self administer cortisol, ACTH or other hormones and produce the Cushing's syndrome for some sort of secondary gain. This is known as factitious production of Cushing's syndrome and always needs to be considered in the differential diagnosis.
Conditions that can mimic Cushing's syndrome
Simple obesity can mimic Cushing's syndrome in both in the changes in body habitus and in some of the secondary manifestations such as the secondary development of diabetes, and presence of stria or abnormal skin markings on the body.
Alcoholism can also mimic Cushing's syndrome especially with regard to some of the mental status changes that can accompany alcoholism. Alcoholism can present with decreased platelet count which can cause easy bruising and also can cause weakness and fatigue.
Diagnostic Tests
With such complex hormonal inter relations, the diagnosis of the various types of Cushing's syndrome is complicated and is based on hormonal measurement. A scheme has been developed by Mayo Clinic that addresses this complexity.
The first step in suspected Cushing's syndrome is to actually confirm that Cushing's syndrome is present. This is done by a screening test, either a 24-hour urinary free cortisol level whose normal is generally less than 120 micrograms or by a test in which the patient is administered 1 mg of dexamethasone and the serum cortisol level at 8:00 in the morning is measured. Normal is less than 5 micrograms per deciliter. If the patient has normal values on either of these tests, Cushing's syndrome should not be present.
If the 8:00 in the morning cortisol is greater than 5 micrograms per deciliter, there is a pretty strong suspicion that Cushing's syndrome is present. The next step would be to measure the plasma ACTH level along with the plasma cortisol level at the same time. If the cortisol level is less than 15 micrograms per deciliter and the ACTH level is less than 10-pg per milliliter , the elevation in cortisol is not driven by ACTH and pituitary hormone is not the problem.
If both cortisol is elevated greater than 25 micrograms per deciliter and ACTH is normal or elevated, this represents suspected Cushing's syndrome on the basis of excess production of ACTH. The patient is then given dexamethasone 1/2 mg every 6 hours for 48 hours. If plasma cortisol is now less than 5 micrograms per deciliter , then this does not represent Cushing's syndrome. If plasma cortisol is greater than 5 micrograms per deciliter Cushing's syndrome is confirmed.
If Cushing's syndrome is confirmed then a high dose test with dexamethasone is done during which the patient is administered 2 mg of dexamethasone every 6 hours for 48 hours. If plasma cortisol is less than 10 micrograms per deciliter after this, the patient is presumed to have Cushing's disease which is excess production of pituitary ACTH. If plasma cortisol is greater than 10 micrograms per deciliter, this represents Cushing's syndrome that is now diagnosed as being not associated with the pituitary gland.
Plasma ACTH is then measured. If the plasma ACTH is less than 10pg per milliliter, the presumption is that the patient has an adrenal tumor or adrenal hyperplasia. If the plasma ACTH is high, usually > 50pg per milliliter, this represents production of ACTH by a source other than the pituitary such as a peripheral tumor.
If the plasma ACTH is high, magnetic resonance imaging or CT scan imaging of the pituitary probably will show the presence of the tumor.
If the plasma ACTH is low, C. T. or MRI of the adrenal glands will frequently reveal the diagnosis.
When the plasma ACTH is high and the above scans do not show presence of a pituitary tumor, then CT scan of the chest can be done. This will usually show the carcinoid tumor or the peripheral cancer that is producing ACTH outside of the pituitary.
The above scheme is sufficient to make the diagnosis in more than 90 percent of patients. Some additional refinements can be performed if the diagnosis is still in question. There can be a very small tumor of the pituitary gland that is not visualized by CT scan or MRI. Selective vein sampling of the veins exiting the pituitary gland after stimulating the pituitary gland with corticotropin releasing hormone can reveal the location of this small tumor.
Treatment
The most common cause of Cushing's syndrome is Cushing's disease and this is related to a tumor in the pituitary gland. The usual treatment for this is a neurosurgical technique to remove the tumor. Cure rates are as high as 90 percent. If the pituitary tumor cannot be adequately removed or if removal does not lead to remission of Cushing's syndrome, radiation of the pituitary gland, especially in children can give good results. Failure of these treatment modalities can be salvaged by removing both adrenal glands, but the patient will be almost certainly hypoadrenal and will require lifelong replacement of hormones.
Drugs that can treat Cushing's syndrome include amino glutethimide which blocks cortisol production, metyrapone also reduces cortisol production as does mitotane. Of these metyrapone is the least toxic and drug therapy is usually limited to a presurgical treatment to reduce symptoms.
If an adrenal tumor which is functioning is found, removal of the tumor is the treatment of choice, including adrenal cancer.
Carcinoid tumors are treated by removal and if they have not already metastasized, typically have a high cure rate, particularly for the typical variant of carcinoid. Further information on this can be found under the heading of lung cancer.
Small cell carcinoma of the lung, unless it is caught very early, is generally not a surgical disease but is treated with a combination of chemotherapy and radiotherapy. Some very intense chemotherapy protocols are currently being investigated at tertiary centers. More details on this are also found in the section on lung cancer.
Complications
After removal of pituitary tumor, meningitis can occur which is treated with antibiotics.
After removal of a pituitary tumor there can be a temporary problem with diabetes insipidus which is production of large volumes of very dilute urine. This is usually temporary and is usually treated with medication.
After removal of the pituitary tumor, many patients will have low serum cortisol is and may need to take steroid medications for up to 6 months.
Similarly after removing both adrenal glands, the patient will probably require lifelong steroid replacement therapy. After removing a functioning adrenal gland tumor, it is likely that steroid replacement therapy will be necessary for several months during which the adrenal gland on the opposite side can recover.
So-called Nelson syndrome consists of excess dark pigment of the skin associated with a new tumor of the pituitary gland which can be associated with disturbances of vision.