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52 Cards in this Set
- Front
- Back
Cushing’s syndrome:
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Comprises the symptoms and signs associated with prolonged exposure to inappropriately elevated levels of free plasma glucocorticoids
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cushing
central obesity and relative thinning of extremities |
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cushing
moon facies and red face |
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cushing
abdominal striae; dark, wide, abdominal and axillary |
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cushing
buffalo hump and hirsuitism |
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relative freq of symptoms in cushing:
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Relatively Specific Features in cushing:
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Facial plethora
Wide purple striae Spontaneous ecchymoses Proximal muscle weakness |
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Why “central” obesity in CS?
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*Glucocorticoids stimulate adipogenesis and adipocyte differentiation
-But this doesn’t explain the central nature of CS obesity *Other possibilities -Muscle atrophy makes the extremities look relatively thin -Increased expression of glucocorticoid receptor and type 1 isoenzyme of 11β-hydroxysteroid dehydrogenase (converts cortisone to cortisol) in omental fat compared with subcutaneous fat |
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Other fat deposits in CS besides central:
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Dorsocervical = “buffalo hump”
Supraclavicular Cheeks and temples = “moon facies” Epidural space – leads to neurologic deficits |
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Hypertension in CS:
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*75% of cases
*Increase sensitivity to catecholamines and angiotensin II in vascular smooth muscle *Increase angiotensinogen *Decrease NO-mediated endothelial dilatation *Sodium retention from mineralocorticoid activity |
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How can cortisol act as a mineralocorticoid in CS?
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*Your body has taken multiple steps to separate the regulation of cortisol and the regulation of aldosterone
*YET cortisol is a strong agonist of MR *Renal MR are “protected” from cortisol by 11B-HSD2 which locally converts cortisol (MR agonist) to cortisone (not an MR agonist) *In CS, there is so much cortisol that 11B-HSD2 is overwhelmed, and the MR are activated by cortisol -Sodium retention --> HTN -Potassium loss and H+ loss --> Hypokalemic alkalosis |
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Diabetes mellitus in CS:
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*1/3 of patients
*Glycogen deposition in the liver *Increase hepatic glucose output *Decrease peripheral glucose utilization *Activation of lipolysis *Permissive effect upon catecholamines and glucagon |
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Mood changes in CS:
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*Brain is an important target tissue of GC
*Psychiatric abnormalities in 50% of patients with CS -Agitated depression and lethargy -Memory and cognitive dysfunction -Insomnia -Paranoia and psychosis (esp in hospital after high dose steroids) |
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Describe issues in CS with:
-gonadal -thyroid -osteoporosis -muscles -skin |
*Gonadal dysfunction
Inhibited GnRH pulsatility and LH and FSH release *Thyroid dysfunction--Suppress thyroid axis *Osteoporosis Inhibit osteoblast function Induce negative calcium balance and increase PTH *Muscle weakness--Reduced muscle protein synthesis with muscle atrophy *Plethora/Ecchymoses/Striae Catabolic effects of GC lead to atrophy of epidermis and underlying connective tissue *Acne/Hirsutism--Increased adrenal androgens |
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Who should be screened for CS?
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*Patients with unusual features for age (e.g. osteoporosis, hypertension)
*Patients with multiple and progressive features *Patients with adrenal incidentaloma compatible with adenoma |
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Steps to take in evaluating a pt for CS:
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*Most important thing is to exclude exogenous steroids!!
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CS due to exogenous glucocorticoids:
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*By far the most common cause of CS
*Widespread use of GC to treat a variety of diseases *CS most commonly from longterm oral GC use, but can be from any route of delivery, even “local” *Megestrol--a progesterone derivative used to treat metastatic breast CA or to stimulate appetite in AIDS wasting--can act as an agonist at GR, causing CS |
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Describe the 1-mg Dexamethasonesuppression test:
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*Dexamethasone 1-mg at 11 PM
*Fasting plasma cortisol next day at 8-9 AM *Cortisol > 1.8 μg/dL [sensitivity >95%; specificity 80%] *False-positive results - increased CBG (estrogens); 50% of women on OCP have false-positive DST - increased metabolism of dexamethasone (antiseizure meds) *False-negative results - reduced dexamethasone clearance in liver or kidney failure |
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Describe Urine Free Cortisol testing:
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*Measures plasma free cortisol
*Not affected by CBG levels *Requires accurate 24 hour urine collection *Sensitivity of 90%; specificity of 95% *False-positive -High fluid intake (>5 liter/day) -Essentially any cause of Psuedo-Cushing’s *False-negative -Renal impairment -Cyclic or mild CS *Values above 4 times the upper limit of normal are diagnostic |
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Describe testing for Late-night Salivary Cortisol:
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*Cortisol concentration in saliva is highly correlated with plasma free cortisol
*The loss of circadian rhythm with absence of a late-night cortisol nadir is a consistent biochemical abnormality in Cushing’s *Sensitivity 93-100%; Specificity >92% |
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How is the cortisol circadian rhythm in CS?
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Causes of Cushing’s syndrome:
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Summary of HPA axis:
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Levels of ACTH in CD vs Adrenal tumor vs ectopic ACTH:
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Causes of Cushing’s syndrome:
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Describe CS due to Adrenal Tumor:
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*Benign (adenoma) or malignant (carcinoma) neoplasms of adrenal origin
*ACTH is suppressed but hormone secretion by adrenal neoplams is ACTH-independent |
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Primary pigmented nodular adrenocortical disease (PPNAD):
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-50 % familial as part of “Carney complex”
Autosomal dominant disorder of regulatory subunit of cAMP-dependent protein kinase A -Carney complex Mesenchymal tumors (atrial myxoma) Spotty skin pigmentation Peripheral nerve tumors (schwannomas) GH-secreting pituitary tumor Testicular tumor |
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carney complex associated with CS
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Bilateral adrenal disorders causing CS:
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-PPNAD
-McCune-Albright Syndrome -AIMAH |
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McCune-Albright syndrome:
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-Activating mutation of G-protein subunit
-Constitutive steroidogenesis -Fibrous dysplasia -Cutaneous pigmentation (coast of maine cafe au lait) -Pituitary/adrenal, thyroid, gonadal hyperfunction |
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Coast of Maine cafe au lait in Mccune albright syndroms
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Various clinical manifestations of McCune Albright:
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ACTH-independent macronodular adrenal hyperplasia (AIMAH):
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Abberant regulation of cortisol production and adrenal growth mediated by the abnormal adrenal expression of receptors for a variety of hormones (e.g. GIP, HCG-LH, serotonin)
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Receptors involved in AIMAH:
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Caused by aberrant expression of hormone receptors on GC-secreting cells
Cortisol secretion driven by a hormone that is not suppressed by cortisol-mediated negative feedback (e.g. GIP, catecholamines, LH/hCG, vasopressin) |
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macronodular adrenal hyperplasia in AIMAH
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ACTH-secreting Pituitary Adenoma (aka Cushing’s DISEASE)
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Pituitary neoplasm that secretes ACTH
Impairment of normal feedback suppression results in continued ACTH secretion despite high levels of cortisol |
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CS due to Ectopic ACTH secretion:
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Non-pituitary neoplasms may secrete ACTH
Cortisol production suppresses pituitary ACTH production but not the ectopic ACTH production |
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Ectopic ACTH Syndromes:
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Small-cell lung carcinoma
Bronchial carcinoid tumors Pancreatic islet cell tumors Medullary thyroid carcinoma Pheochromocytoma Carcinoma of the liver, prostate, breast and melanoma *all rare |
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Using ACTH in the diagnostic algorithm:
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The problem of ACTH-dependent CS:
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Imaging is not reliable
Pituitary MRI is normal in up to 50% patients with ACTH-secreting pituitary adenoma 10% of general population will have incidental pituitary tumor on MRI Biochemical testing High-dose dexamethasone test CRH stimulation test |
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Discuss the usefulness of the HDDST:
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Describe uses of the CRH test:
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ACTH-secreting pituitary adenomas remain responsive to CRH
Most ectopic ACTH-producing tumors are not responsive Therefore can also be used to distinguish between ACTH-dependent causes of Cushing’s syndrome |
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Describe the purpose of Inferior Petrosal Sinus Sampling:
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Last resort!
Used to establish if pituitary is source of ACTH Frequently needed because of the ambiguous nature of imaging and biochemical testing in ACTH-dependent CS |
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Management of Cushing’s Syndrome due to ACTH-secreting pituitary ademoma (aka Cushing’s disease):
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1st line: Neurosurgical resection of the pituitary tumor
If not curative-- Pituitary irradiation Antiadrenal agents Bilateral adrenalectomy |
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Pituitary irradiation for Cushing’s disease:
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Used in patients with persistent disease activity after surgery
May take many years to be effective Often results in deficiencies of other hormonal axes |
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Antiadrenal agents:
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*generally inhibit one or more enzymes in the steroid biosynthetic pathway
-examples are ketoconazole, mifepristone |
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Bilateral adrenalectomy for Cushing’s disease:
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Definitive
Patients need lifelong GC and MC replacement (i.e. they now have adrenal insufficiency) Leads to Nelson’s syndrome -Lack of feedback from high levels of GC results in aggressive growth of the remaining ACTH-secreting pituitary adenoma -Very high levels of ACTH cause hyperpigmentation (see discussion of adrenal insufficiency) |
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Management of Cushing’s Syndrome due to cortisol-secreting adrenal adenoma
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Surgery is curative
yay!!!! |
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Management of Cushing’s Syndrome due to adrenal carcinoma
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Surgery (usually not curative)
Antiadrenal agents |
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Mitotane:
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Cousin of the insecticide DDT
Inhibits multiple steroidogenic enzymes Cytotoxic to adrenocortical cells Treatment of choice for adrenal cancer Severe side effects (GI, neurologic) Treatment dose limited by side effects |
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Management of Cushing’s Syndrome due to the ectopic ACTH syndrome:
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Treatment of primary tumor (surgery, chemotherapy)
Antiadrenal agents Bilateral adrenalectomy |
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Pseudo-Cushing’s syndrome:
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Presence of some or all of the clinical features of Cushings syndrome together with some evidence for hypercortisolism
Alcoholism Depression Eating disorders Chronic pain |