TOPIC: Cushing’s Syndrome.
DEFINITION OF DISEASE: Cushing’s syndrome refers to hypercortisolism or elevated concentrations of serum cortisol. There are many etiologies, but the syndrome is generally classified into two categories- Adrenocorticotropic hormone (ACTH) dependent or ACTH independent. A third pseudo-Cushing’s syndrome is also discussed. The syndrome is named after American surgeon, Harvey Cushing, who described the condition in 1912 (Bruyere, 2009)
PATHOPHYSIOLOGY: Iatrogenic ACTH independent, is by far the most common type of Cushing’s syndrome, causing approximately half of all cases. It is generally caused by the administration of excessive amounts of a synthetic glucocorticoid, such as prescribed prednisone, or other oral, injected, topical or inhaled corticosteroids. The administration of this medication, often to treat autoimmune disorders, results in excessive amounts of circulating cortisol. This type of Cushing’s syndrome is reversible.
The second type of Cushing syndrome, ACTH dependent, is also known as Cushing’s disease. It is generally caused by the hyper-secretion of ACTH secondary to an adenoma or a benign pituitary tumor. Cushing’s disease may also be caused by the hyper-secretion of ACTH by non-pituitary tumors, such as small cell lung cancers. This type is also known as ectopic Cushing’s disease because the source of the hormone is outside of the neuroendocrine system. Finally, tumors of the adrenal gland and the hypothalamus can also cause excessive secretion of ACTH and result in elevated serum cortisol levels (Bruyere, 2009).
Pseudo-Cushing syndrome refers to hypercortisolism secondary to disorders other than Cushing syndrome. These include individuals who are physically stressed, severely obese, those with polycystic ovary syndrome, patients who have chronic alcoholism, malnutrition, anorexia nervosa, or participate in intense exercise and those with psychological stress, especially severe depressive disorder. All of these disorders can cause elevated serum cortisol levels (Nieman, 2012)
GENETICS: There does not appear to be any genetic link to Cushing syndrome.
EPIDEMIOLOGY: Cushing syndrome can occur at any age, but usual onset is between 30 and 50 years of age. It is two to three times more common in women than in men. However, Cushing syndrome caused by ectopic ACTH secretion is more prevalent in older adults, especially men. Cushing syndrome caused by adrenal tumors is more common in children, especially girls (Huether & McCance, 2004).
Risk factors include the ingestion or application of excessive amounts of corticosteroids. Cigarette smoking is also a risk factor as it can result in carcinoma of the lung.
SIGNS AND SYMPTOMS: Weight gain is the most common and recognized feature of Cushing’s syndrome and is due to increased adipose tissue accumulating in the trunk and face. This pattern of fat distribution is termed truncal obesity, moon face and/or buffalo hump.
Glucose intolerance occurs because excess cortisol causes insulin resistance and increased gluconeogenesis and glycogen storage. Diabetes mellitus develops in approximately 20% of people with Cushing’s syndrome.
Protein wasting is caused by the breakdown of muscle tissue. In addition, protein loss in the bone leads to osteoporosis, fractures, bone pain, kyphosis and loss of height. Furthermore, bone loss results in hypercalcinuria and the development of renal stones. Loss of collagen leads to thin and weakened skin and blood vessels which causes characteristic purple striae and increased bruising.
Other effects include hyperpigmentation secondary to high serum levels of ACTH, resulting in a characteristic brown or bronze coloring of the mucous membranes, hair and skin. Women may experience symptoms of virilization secondary to elevated androgen levels. These signs include facial hair, acne and oligomenorrhea. Elevated cortisol causes vasoconstriction, hypertension, sodium retention and hypokalemia. Immune suppression and increased susceptibility to infection are present and are a large cause of morbidity (Huether & McCance, 2004).
Finally, there is a large component of mental illness associated with Cushing’s syndrome. Alterations in mental status range from irritability and depression to severe psychiatric disturbances such as schizophrenia.
DIAGNOSIS: Diagnosis is difficult and involves three separate steps: suspicion based upon signs and symptoms, documenting increased cortisol levels through several laboratory tests and finally, determining tumor presence. Laboratory tests include urinary free cortisol, a midnight serum or salivary cortisol level, dexamethasone suppression test and plasma ACTH level. Pituitary tumors can be detected by MRI. CT scan can reveal the presence of other tumors.
TREATMENT: Treatment options vary and are dependent upon the underlying cause of the hypercortisolism. Therefore differentiation of the cause is essential for effective treatment. Treatment options include the elimination of glucocorticoid medication for iatrogenic ACTH independent Cushing’s syndrome. Cushing’s disease is treated by surgical removal of the pituitary tumor and subsequent hydrocortisone replacement therapy. Without treatment, 50% of affected individuals die within five years, generally due to infection, suicide, arteriosclerosis or hypertension (Huether & McCance, 2004).
LINKS: National Adrenal Diseases Foundation: www.nadf.us/diseases
REFERENCES: Bruyere, H.J. (2009). 100 Case studies in pathophysiology. Baltimore, MD: Lippincott Williams & Wilkins.
Huether, S.E., & McCance, K.L. (2004). Understanding Pathophysiology (3rd Ed.). St. Louis, MO: Mosby.
Nieman, L.K. (2012). Causes and pathophysiology of Cushing’s syndrome. In A. Lacroix and K.A. Martin (Eds.), UpToDate. Retrieved from http://www.uptodate.com/contents/causes-and-pathophysiology-of- cushings-syndrome