Cushing's Syndrome-- phys exam 2.pdf

Cushing's Syndrome Disease summary ○ Cushing syndrome is an endocrine disease with multiple etiologies and is characterized by a constellation of clinical manifestations that result from excessive concentrations of circulating cortisol (hypercortisolism)...

Cushing's Syndrome Disease summary ○ Cushing syndrome is an endocrine disease with multiple etiologies and is characterized by a constellation of clinical manifestations that result from excessive concentrations of circulating cortisol (hypercortisolism) ○ The syndrome is named after Harvey cushing, an american surgeon who first reported the condition in 1912 Prevalence ○ By far, the single most common cause of Cushing 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 prevalence of hypercortisolism from all other causes combined is only 3 cases per 1 million people nationally ○ The overall incidence is estimated as 2 new cases per 1 million persons per year ○ Females are 8 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 ○ 90% of all cases of cushing syndrome occur during adulthood ○ The incidence of cushing syndrome in children is estimated at approximately 0.2 cases per 1 million persons per year ○ The peak incidence of cushing syndrome due to adrenal or pituitary tumor occurs in persons 25 to 40 years of age Significance ○ The significance of cushing syndrome lies primarily in the multitude of complications that can result from hypercortisolism ○ Some complications: Others are purely bothersome (bruising with minimal trauma) some cause pain (e.g., osteoporosis), cosmetic (e.g., moon-shaped face and stretch marks) others are potentially life-threatening (e.g., hypertension, diabetes mellitus, and susceptibility to serious infections). Causes and risk factors: ○ Causes of Cushing syndrome are typically divided into two basic categories: Those that are adrenocorticotropic hormone (ACTH)-dependent (i.e., hypercortisolism is the result of elevated serum ACTH concentrations) those that are ACTH-independent. ○ The majority of cases diagnosed today are the result of administering supra-physiologic doses of corticosteroid drugs for various health conditions (e.g., autoimmune disease). ○ Common corticosteroids prescribed include prednisone, prednisolone, and methylprednisolone. ○ This type of Cushing syndrome is often referred to as iatrogenic Cushing syndrome and is a reversible form of the disorder. ○ Hypersecretion of ACTH by non-pituitary tumors (e.g., small cell lung carcinoma).  This is known as ectopic Cushing syndrome because the source of ACTH technically lies outside of the neuroendocrine system. Hypersecretion of cortisol from either a benign or a cancerous tumor (carcinoma) of the adrenal gland Hypersecretion of corticotropin-releasing hormone (CRH) by a benign tumor of the hypothalamus. Excessive circulating CRH causes excessive secretion of ACTH by the pituitary and, ultimately, elevates serum cortisol levels Signs?? ○ Back of the neck (so-called “buffalo hump”) ○ around the waist (truncal obesity) ○ increase in blood glucose levels by promoting hepatic gluconeogenesis and inhibiting glucose uptake by muscle and adipose tissue (i.e., causes insulin resistance and diabetes mellitus) ○ inhibition of both immune and inflammatory reactions that creates a susceptibility to infections (particularly fungal infections). ○ Cortisol specifically acts in this manner by decreasing T lymphocyte proliferation and suppressing the synthesis of important chemical mediators of inflammation (e.g., prostaglandins and leukotrienes). In patients with hypercortisolism that is ACTH-dependent: ○ hyperpigmentation of the skin and gums may occur (because ACTH indirectly stimulates melanin synthesis). ○ In addition, serum androgen levels may increase significantly (because ACTH stimulates androgen synthesis in the adrenal gland). ○ This latter pathophysiologic effect is especially problematic in females, who may suffer from excessive hair growth (especially facial hair), a more masculine sounding voice, acne (which can be androgen-induced), and decreased blood flow during menses. ○ If serum aldosterone is also significantly elevated, weight gain and blood pressure elevation from sodium and water retention may occur. ○ Excessive aldosterone levels may also induce a hypokalemic alkalosis (i.e., low serum K and H) in the patient. ○ Collection of fat in the cervical area and abdomen ○ Thin arms and legs ○ Elevated blood pressure ○ Back pain ○ Striae (stretch marks), especially in the thighs, breasts, and abdomen ○ Wide range of mental symptoms from an inability to concentrate to severe psychosis An abnormally high 24-hour urine-free cortisol (110 µg) helps to confirm hypercortisolism. ○ If the patient’s morning serum cortisol is 2 µg/dL (by high-performance liquid chromatography) after receiving 1 mg dexamethasone orally late the previous evening, Cushing syndrome can be ruled out with 98% certainty. ○ Once hypercortisolism is established, a baseline plasma ACTH is obtained. ○ A low ACTH level indicates ACTH-independent disease, while an elevated ACTH concentration is consistent with ACTH-dependent Cushing syndrome.  ○ With ACTH-dependent Cushing syndrome, an MRI scan of the pituitary will demonstrate a small, benign tumor in approximately half of all patients In patients with ACTH-DEPENDENT disease: ○ serum ACTH, cortisol, and androgen concentrations are elevated (as is, in some cases, serum aldosterone) In patients with ACTH-INDEPENDENT disease: ○ serum cortisol levels are high but serum ACTH concentrations low (due to negative feedback of cortisol on the hypothalamus and anterior pituitary gland) ○ Serum aldosterone is normal A midnight serum cortisol level 7.5 µg/dL or a midnight salivary cortisol level 550 ng/dL is highly suggestive of Cushing syndrome. More sx: ○ Patients are also highly susceptible to developing: acne Superficial skin infections Bruises glucose intolerance—which is manifested by excessive thirst (polydipsia) excessive glucose in the blood (hyperglycemia) and urine (glycosuria) frequent urination (polyuria). Adrenal Hyperplasia corresponds to findings of decreased ACTH, elevated cortisol, and elevated aldosterone levels. Females may also suffer from signs of androgen excess: such as amenorrhea and hirsutism. Prognosis ○ Varies from poor to excellent and also depends on the specific cause of hypercortisolism. ○ Since the patient with iatrogenic Cushing syndrome often develops adrenal cortical atrophy with virtually no source of natural cortisol, sudden discontinuation of corticosteroid may result in a life-threatening episode of acute adrenocortical insufficiency characterized by shock. ○ With slow tapering of corticosteroid doses, symptoms resolve and prognosis is excellent. ○ Following a successful adrenalectomy, patients with a benign adrenal tumor have a 95% 5-year survival rate and a 90% 10-year survival rate. ○ Surgery for pituitary tumors may have a rate of failure as great as 20%. ○ However, if surgery is successful, the 5-year survival rate exceeds 90%. ○ The prognosis for patients with ectopic ACTH-secreting neoplasms depends on the specific type of tumor and its extent of spread. ○ The 2-year survival rate for small cell lung carcinoma (a common ectopic source of ACTH hypersecretion) is very poor: 20% when confined to the lung and only 5% with dissemination and a 10-year survival rate of 55%. ○ Finally, the median survival time for patients with cortisol-secreting adrenal cancer (carcinoma) is only 7 months. ○ Ectopic ACTH-secreting tumors should also be surgically removed. ○ If tumors cannot be resected, laparoscopic removal of both adrenal glands is recommended. ○ When patients are not good candidates for surgery, a pharmacologic approach may be tried. ○ Ketoconazole may be used to suppress cortisol synthesis, but liver enzymes must be monitored for hepatotoxicity. ○ Metyrapone also inhibits cortisol synthesis but may promote masculinizing effects in females. ○ When given parenterally, the somatostatin analog octreotide suppresses ACTH secretion in approximately one third of cases.