Original Editors - Jessica Stevenson from Bellarmine University's Pathophysiology of Complex Patient Problems project.
- 1 Definition/Description
- 2 Prevalence
- 3 Characteristics/Clinical Presentation
- 4 Associated Co-morbidities
- 5 Medications
- 6 Diagnostic Tests/Lab Tests/Lab Values
- 7 Causes
- 8 Systemic Involvement
- 9 Medical Management (current best evidence)
- 10 Physical Therapy Management (current best evidence)
- 11 Differential Diagnosis
- 12 Case Reports
- 13 Resources
- 14 References
Cushing’s syndrome is a general term for increased secretion of cortisol by the adrenal cortex. When corticosteroids are administered externally, a condition of hypercortisolism called iatrogenic Cushing’s syndrome occurs.  When the hypercortisolism results from an oversecretion of ACTH from the pituitary, the condition is called Cushing’s disease. The clinical presentation is the same for all of these conditions. 
- ACTH: Adrenocorticotropic hormone
By far, the single most common cause of Cushing's syndrome today (as many as 12 cases/1 million people) is the use of corticosteroid medications to treat a wide variety of disease states, including rheumatoid arthritis, asthma, and multiple sclerosis. The prevelance of hypercotisolism from all other causes combined is only 13 cases per 1 million people nationally. The overall incidence is estimated as 2 new cases per 1 million persons per year. 
Females are eight times more likely than males to develop hypercortisolism from a pituitary tumor and three times more likely to develop a cortisol-secreting adrenal tumor: However, hormone-producing lung tumors that cause hypercortisolism are more common in males. 
Ninety percent of all cases of Cushing's syndome occur during adulthood. The incidence of Cushing's syndrome in children is estimated at approximately 0.2 cases per 1 million persons per year: The peak incidence of Cushing's syndrome due to an adrenal or pituitary tumor occurs in persons 25-40 years of age. 
Non-iatrogenic Cushing’s syndrome occurs mainly in women, with an average age of onset of 20 to 40 years, although it can be seen in people up to age 60 years. 
Clinical manifestations include “moon” face (very round), buffalo hump (truncal obesity with prominent supraclavicular and dorsal cervical fat pads) , protuberant abdomen with accumulation of fatty tissue and stretch marks with purple striae, muscle wasting and weakness, thin extremities, decreased bone density (especially spine), kyphosis and back pain (secondary to bone loss), easy bruising and poor wound healing due to thin and atrophic skin , acne, psychiatric or emotional disturbances, impaired reproductive function (decreased libido and changes in menstrual cycle, and diabetes mellitus. In women, masculinizing effects such as hypertrichosis, breast atrophy, voice changes, and other signs of virilism are noted. Cessation of linear growth is characteristic in children.  
Cushing’s syndrome involves the HPA axis causing excess cortisol release from the adrenal glands. When the normal function of the glucocorticoids becomes exaggerated, a wide range of physiologic responses can be triggered. 
Co-morbidities involved with Cushing’s disease are persistent hyperglycemia, cardiac hypertrophy and hypertension, proximal muscle wasting (protein tissue wasting), osteopenia or osteoporosis, hypokalemia, mental changes and memory loss, depression, renal calculi, increased susceptibility to infection, adrenal hyperplasia and adrenal tumors   
Initially, the patient’s general condition should be supported by high protein intake and appropriate administration of vitamin K. If clinical manifestations are severe, it may be reasonable to block corticosteroid secretion with metyrapone 250 mg to 1 g pot id or ketoconazole 400 mg po once/day, increasing to a maximum of 400 tid. Ketoconazole is more readily available but slower in onset and sometimes hepatatoxic. 
Adrenal inhibitors, such as metyrapone 500 mg pot id (and up to a total of 6 g/day) or mitotane 0.5 g po once/day, increasing to a maximum of 3 to 4 g/day, usually control severe metabolic disturbances (eg. Hypokalemia). When mitotane is used, large doses of hydrocortisone or dexamethasone may be needed. Measures of cortisol production may be unreliable, and severe hypercholesterolemia may develop. Ketoconazole 400 to 1200 mg po once/day also blocks corticosteroid synthesis, although it may cause liver toxicity and can cause addisonian symptoms. Alternatively, the corticosteroid receptors can be blocked with mifepristone (RU 486). Mifepristone increases plasma cortisol but blocks effects of the corticosteroid. Sometimes ACTH-secreting tumors respond to long-acting somatostatin analogs, although administration for > 2 years requires close follow-up, because mild gastritis, gall stones, cholangitis, and malabsorption may develop. 
Diagnostic Tests/Lab Tests/Lab Values
Although there is a classic cushingoid appearance in persons with hypercortisolism and diagnosis is usually suspected based on the characteristic symptoms and signs, diagnostic laboratory studies, including hormonal and imaging tests, are used to confirm the diagnosis.   Also, reviewing the history of receiving corticosteroids is important.
In some centers, testing begins with measurement of urinary free cortisol (UFC), the best assay for urinary excretion. UFC is elevated > 120 µg/24h (>331 nmol/24h) in almost all patients with Cushing’s syndrome. However, many patients with UFC elevations between 100 and 150 µg/24h (276 and 414 nmol/24h) have obesity, depression, or polycystic ovaries but not Cushing’s syndrome. A patient with suspected Cushing’s syndrome with grossly elevated UFC (> 4 times the upper limit of normal) almost certainly has Cushing’s syndrome. Two to three normal collections virtually exclude the diagnosis. Slightly elevated levels generally necessitate further investigation. 
If the initial laboratory tests are positive (elevated cortisol levels), then a dexamethasone suppression test may be done to determine the cause.  An amount of 1, 1.5, or 2 mg of dexamethasone is administered po at 11 to 12 PM and plasma cortisol is measured at 8 to 9 AM the next morning. In most normal patients, this drug suppresses morning plasma cortisol to ≤ 1.8 µg/mL (≤ 50 nmol/L), whereas patients with Cushing’s syndrome virtually always have a higher level. A more specific but equally sensitive test is to give dexamethasone 0.5 mg po q 6 h for 2 days (low dose). In general, a clear failure to suppress levels in response to low-dose dexamethasone establishes the diagnosis. 
If the results of these tests are indeterminate, the patient is hospitalized for measurement of serum cortisol at midnight, which is more likely to be conclusive. Cortisol normally ranges from 5 to 25 µg/dL (138 to 690 nmol/L) in the early morning (6 to 8 AM) and declines gradually to < 1.8 µg/dL (< 50 nmol/L) at midnight. Patients with Cushing’s syndrome occasionally have a normal morning cortisol level but lack normal diurnal decline in cortisol production, such that midnight plasma cortisol levels are above normal and the total 24-hr cortisol production is elevated. Alternatively, salivary cortisol samples may be collected and stored in the refrigerator at home. Plasma cortisol may be spuriously elevated in patients with congenital increases of corticosteroid-binding globulinor in those receiving estrogen therapy, but diurnal variation is normal in these patients. 
Serum ACTH levels help determine whether Cushing’s syndrome is ACTH-dependent (pituitary tumor) or ACTH-independent (adrenal tumor).  Undetectable levels, both basally and particularly in response to corticotrophin-releasing hormone (CRH), suggest a primary adrenal cause. High levels suggest a pituitary cause. If ACTH is detectable (ACTH-dependent Cushing’s syndrome), provocative tests help differentiate Cushing’s disease from ectopic ACTH syndrome, which is rarer. In response to high-dose dexamethasone (2 mg po q 6 h for 48 h), the 9 AM serum cortisol falls by > 50% in most patients with Cushing’s disease but infrequently in those with ectopic ACTH syndrome. Conversely, ACTH and cortisol rise by >50% and 20%, respectively, in response to human or ovine-sequence CRH ( 100 µg IV or 1 µg/kg IV) in most patients with Cushing’s disease but very rarely in those with ectopic ACTH syndrome. An alternative approach to localization, which is more accurate but more invasive, is to catheterize both petrosal veins (which drains the pituitary) and measure ACTH from these veins 5 min after a bolus of CRH 100 µg or 1 µg/kg. A central-to-peripheral ACTH ratio >3 virtually excludes ectopic ACTH syndrome, whereas a ratio <3 suggests a need to seek such a source. 
Pituitary imaging is done if ACTH levels and provocative tests suggest a pituitary cause; gadolinium-enhanced MRI is most accurate, but some microadenomas are visible on CT. If testing suggests a nonpituitary cause, imaging includes high-resolution CT of the chest, pancreas, and adrenals; scintiscanning with radiolabeled octreotide; and PET scanning. 
X-rays or DEXA scans may be needed to assess for fractures or to rule out osteopenia or osteoporosis, respectively. These tests may be conducted to obtain a baseline measurement of bone density or they may be obtained in response to an individual’s report of musculoskeletal symptoms such as bone pain or backache. 
In children with Cushing’s disease, pituitary tumors are very small and usually cannot be detected with MRI. Petrosal sinus sampling is particularly useful in this situation. MRI is preferred to CT in pregnant women to avoid fetal exposure to radiation. 
The primary causes of Cushing’s syndrome are hyperphysiologic doses of adrenocorticosteroids and adrenocortical tumors.  Hyperfunction of the adrenal cortex can be ACTH-dependent or ACTH independent. 
ACTH-dependent Cushing’s syndrome may result from hypersecretion of ACTH by the pituitary gland, secretion of ACTH by a nonpituitary tumor, such as small cell carcinoma of the lung or a carcinoid tumor (ectopic ACTH syndrome), or administration of exogenous ACTH. 
ACTH-independent Cushing’s syndrome usually results from therapeutic administration of corticosteroids or from adrenal adenomas or carcinomas. Rare causes include primary pigmented nodular adrenal dysplasia (usually in adolescents) and macronodular dysplasia (in older patients). 
Pseudo-Cushing’s syndrome occurs when conditions such as depression, alcoholism, estrogen therapy, or eating disorders cause changes similar to those of Cushing’s syndrome. In pseudo-Cushing’s syndrome, the symptoms will go away when the cause is eliminated. 
Cushing’s syndrome involves the HPA axis causing excess cortisol release from the adrenal glands. Cortisol has a key role in glucose metabolism and a lesser part in protein, carbohydrate, and fat metabolism. Cortisol also helps maintain blood pressure and cardiovascular function while reducing the body’s inflammatory responses. Overproduction of cortisol causes liberation of amino acids from muscle tissue with resultant weakning of protein structures (specifically muscle and elastic tissue). The end result may include a protuberant abdomen with purple striae, poor wound healing, thinning of skin, generalized muscle weakness, and marked osteoporosis that is made worse by an excessive loss of calcium in the urine.   In severe cases of prolonged Cushing’s syndrome, muscle weakness and demineralization of bone may lead to pathological fractures and wedging of the vertebrae, kyphosis, osteonecrosis (especially in femoral head), bone pain, and back pain. 
The effect of circulating levels of cortisol on the muscles varies from slight to marked. Muscle wasting can be so extensive that the condition simulates muscular dystrophy. Marked weakness of the quadriceps muscle often prevents affected people from rising out of a chair unassisted.  
It is important to remember whenever corticosteroids are administered, the increase in serum cortisol levels triggers a negative feedback signal to the anterior pituitary gland to stop its secretion of ACTH.  This decrease in ACTH stimulation of the adrenal cortex results in adrenocortical atrophy during the period of exogenous corticosteroid administration. If these medications are stopped suddenly rather than reduced gradually, the atrophied adrenal gland will not be able to provide the cortisol necessary for physiologic needs. A life-threatening situation known as acute adrenal insufficiency can develop, requiring emergency cortisol replacement. 
Medical Management (current best evidence)
Treatment to restore hormone balance and reverse Cushing’s syndrome or disease may require radiation, drug therapy, or surgery, depending on underlying cause (e.g. resection of tumors). For individuals with muscle wasting or at risk for muscle atrophy, a high-protein diet may be prescribed. Prognosis depends on the underlying cause and ability to control the cortisol excess. Cortisol-secreting tumors can recur, thus follow-up screening is advised. 
Pituitary tumors that produce excessive ACTH are removed surgical or extirpated with radiation. If no tumor is demonstrated on imaging but a pituitary source is likely, total hypophysectomy may be attempted, particularly in older patients. Younger patients usually receive supervoltage irradiation of the pituitary, delivering 45 Gy. Improvement usually occurs in <1 yr. However, in children, irradiation may reduce secretion of growth hormone and occasionally cause precocious puberty. In special centers, heavy particle beam irradiation, providing about 100 Gy, is often successful, as is a single focused beam of radiation therapy given as a single dose-radiosurgery. Response to irradiation occasionally requires several years, but response is more rapid in children. 
Bilateral adrenalectomy is reserved for patients with pituitary hyperadrenocorticism who do not respond to both pituitary exploration (with possible adenomectomy) and irradiation. Adrenalectomy requires life-long corticosteroid replacement. 
Adrenocortical tumors are removed surgically. Patients must receive cortisol during the surgical and postoperative periods because their nontumorous adrenal cortex will be atrophic and suppressed. Benign adenomas can be removed laparoscopically. With multinodular adrenal hyperplasia, bilateral adrenalectomy may be necessary. Even after a presumed total adrenalectomy, functional regrowth occurs in few patients. 
Physical Therapy Management (current best evidence)
Therapists are more likely to treat people who have developed medication-induced Cushing’s syndrome. This condition occurs after these individuals have received a large dose of cortisol (also known as hydrocortisone) or cortisol derivitives. Exogenous steroids are administered for a number of inflammatory and other disorders such as asthma or rheumatoid arthritis. 
- Because cortisol suppresses the inflammatory response of the body, it can mask early signs of infection. Any unexplained fever without other symptoms should be a warning to the physical therapist of the need for medical follow-up. 
- Consult MD before beginning any exercise program. 
Get regular exercise to help maintain muscles and bone mass and prevent weight gain. To maintain muscle and bone mass, weight-bearing exercises such as push-ups, sit-ups, or lifting weights are helpful. To prevent weight gain, aerobic exercise is good to increase your heart rate. Examples of aerobic exercise include fast walking, jogging, cycling, and swimming. 
Education on avoiding falls and removing loose rugs and other hazards in the home. Falling may lead to broken bones and other injuries. 
Pay close attention to all wounds. Too much cortisol slows wound healing. Education on proper wound healing and cleansing is important. Clean all wounds immediately with antibacterial soap and use antibiotic ointment and dressings to prevent infection. 
Differential diagnoses for Cushing’s syndrome are obesity, diabetes, polycystic ovarian syndrome, other metabolic and endocrine problems. 
Differentiation of Cushing syndrome from pseudo–Cushing syndrome can sometimes be a challenge. A pseudo-Cushing state is defined as having some of the clinical features and biochemical evidence of Cushing syndrome. However, resolution of the primary condition results in disappearance of the cushingoid features and biochemical abnormalities. 
In patients who chronically abuse alcohol, clinical and biochemical findings suggestive of Cushing syndrome are often encountered. Discontinuation of alcohol causes disappearance of these abnormalities, and, therefore, this syndrome is often specifically referred to as alcohol-induced pseudo-Cushing syndrome. 
Patients with depression often have perturbation of the HPA axis, with abnormal cortisol hypersecretion. These patients rarely develop clinical Cushing syndrome. Because excess glucocorticoids can lead to emotional liability and depression, distinguishing between depression and mild Cushing syndrome is often a diagnostic challenge. 
Click on links below to view case studies of patient's with Cushing's syndrome:
<u</u>Cushing's Syndrome Support Group: http://www.cushings-help.com/cushing-causes.htm
100 Case Studies in Pathophysiology.
Differential Diagnosis for Physical Therapists: Screening for Referral.
The Merck Manual of Diagnosis and Therapy 18th edition.
Pathology: Implications for Physical Therapists 3rd edition.
Cushing's Syndrome Support Website (http://www.cushings-help.com/cushing-causes.htm)
Endocrine Pathology case study (http://path.upmc.edu/cases/case144.html)
Medscape Today from WebMD (http://www.medscape.com/medscapetoday)
Society for Endocrinology (http://www.endocrinology.org/)
U.S. National Library of Medicine. National Institute of Health. NCBI (http://www.nlm.nih.gov/)
- Goodman CC, Snyder KS. Differential Diagnosis for Physical Therapists: Screening for Referral. Philadelphia : W.B. Saunders Company; 2006: 473-475
- Goodman CC, Fuller KS. Pathology: Implications for the Physical Therapist 3rd ed. St. Louis: Saunders Elsevier; 2009: 481-483.
- Harold J Bruyere: 100 Case Studies in Pathophysiology. Lippincott Williams & Wilkins; October 2008: Case Study 52.
- Beers MH, Porter RS, Jones TV, Kaplan JL, Berkwits M. The Merck Manual of Diagnosis and Therapy 18th ed. Whitehouse Station:Merck Research Laboratories; 2006: 1212-1214.
- MauiMaryRN. Cushing's Disease. Available from: http://www.youtube.com/watch?v=OlIVt-Yv6I4 [last accessed 22/03/13]
- Caroline Rea. Cushing's Syndrome. YahooHealth. last updated 4/29/2008. http://health.yahoo.com/hormone-living/cushing-s-syndrome-home-treatment/healthwise--hw71687.html
- Gail K Adler, MD, PhD, FAHA, Assistant Professor, Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School Cushing Syndrome: Differential Diagnoses & Workup Updated: Oct 1, 2009
- N Kieffer. Leicester Royal Infirmary, UHL NHS Trust Endocrine Nurses Training Course 10-12 September 2003: St Aidan's College, University of Durham, Windmill Hill, Durham DH1 3LJ
- Sanja Dacic, MD and Prabha B. Rajan, MD Endocrine Pathology Case Study. Published on-line in April 1998
- Ashley B Grossman; Philip Kelly; Andrea Rockall; Satya Bhattacharya; Ann McNicol; Tara Balwick[Case Study]: Cushing's Syndrome Caused by an Occult Source: Difficulties in Diagnosis and ManagementPosted: 11/21/2006; Nat Clin Pract Endocrinol Metab. 2006;2(11):642-647. © 2006 Nature Publishing Group
- P Gerry Fegan, Derek D Sandeman, Nils Krone, Deborah Bosman, Peter J Wood, Paul M Stewart and Neil A Hanley. Cushing's syndrome in women with polycystic ovaries and hyperandrogenism. J Endocrinol Invest. 2004 Apr;27(4):375-9.
- Tung SC, Wang PW, Huang TL, Lee WC, Chen WJ. Bilateral adrenocortical adenomas causing ACTH-independent Cushing's syndrome at different periods: a case report and discussion of corticosteroid replacement therapy following bilateral adrenalectomy. Department of Internal Medicine, Division of Endocrinology and Metabolism, Kaohsiung Chang Gung Memorial Hospital, Taiwan. [email protected]