Cushing's Syndrome

Welcome to PT 635 Pathophysiology of Complex Patient Problems This is a wiki created by and for the students in the School of Physical Therapy at Bellarmine University in Louisville KY. Please do not edit unless you are involved in this project, but please come back in the near future to check out new information!!

Original Editors - Jessica Stevenson from Bellarmine University's Pathophysiology of Complex Patient Problems project.

Lead Editors - Your name will be added here if you are a lead editor on this page.  Read more.

Definition/Description 

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
  

Prevalence

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.

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.

Characteristics/Clinical Presentation

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. 

Associated Co-morbidities

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   

Medications

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.

ADD DIAGNOSTIC TABLE

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.

Causes

 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.

Systemic Involvement

add text here

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)

add text here

Alternative/Holistic Management (current best evidence)

add text here

Differential Diagnosis 

Differential diagnoses for Cushing’s syndrome are obesity, diabetes, polycystic ovarian syndrome, other metabolic and endocrine problems.

Case Reports

add links to case studies here (case studies should be added on new pages using the case study template)

Resources

add appropriate resources here

Recent Related Research (from Pubmed)

see tutorial on Adding PubMed Feed

References

see adding references tutorial.