Cushings Syndrome Hasan AYDIN, M.D. Endocrinology and Metabolism
Yeditepe University Hospital Actions of Cortisol What Stresses Your Body Circadian Release of Cortisol Cushing's Syndrome In 1932, a physician by the name of Harvey Cushing described eight patients with central body obesity, glucose intolerance, hypertension, excess hair growth, osteoporosis, kidney stones, menstrual irregularity, and emotional liability. It is now known that these symptoms are the result of excess production of cortisol by the Definition Cushings Sydrome
Chronic glucocorticoid excess, whateverits cause Cushings diasease A spesific type ofCushings sydrome due to excessive pituitary ACTH secretion from a pituitary tumor. Cushings Syndrome: Major Causes
Exogenous (iatrogenic, factitious) ACTH-dependent: Pituitary adenoma 70% Ectopic ACTH syndrome 15% ACTH-independent: Adrenal adenoma 10% Adrenal carcinoma 5% Cushings Syndrome: Causes
ACTH-dependent: Pituitary adenoma 70% Ectopic ACTH syndrome 15% Ectopic CRH (ACTH dependent macronodular adrenal hyperplasia) Cushings Syndrome: Causes
ACTH-independent: Adrenal adenoma 10% Adrenal carcinoma 5% Bilateral macronodular hyperplasia Primary pigmented nodular adrenal disease (PPNAD) +/- Carney complex Ectopic ACTH Hypersecretion
15-20 % of patients with ACTH dependent Cushings Sydrome Tumors causing the ectopic ACTH syndrome small cell carcinoma of the lung (50% of cases) pancreatic islet tumors carcinoid tumors (lung,thymus,gut,pancreas,ovary) medullary carcinoma of the thyroid pheochromocytoma Rare Causes Bilateral Nodular Hyperplasia
ACTH independent, adrenal dependent Bilateral large nodules (3-6 cm in diameter) Food dependent hypercortisolism: The adrenal cortex expressed abnormal receptors for gastrointestinal inhibitory polypeptide (GIP).Food consumption stimulates GIP, which in turn binds to the receptors in the adrenal cortex,thereby stimulating adrenal growth and steroid biosynthesis. Adrenal Carcinoma Hypersecrete multiple adrenocortical steroids
Androgen excess is usually even greater than that of cortisol Hypertension and hypokalemia are frequent. Overlapping Conditions
Some clinical features of may be present Pregnancy Depression and other psychiatric conditions Alcohol dependence Glucocorticoid resistance Morbid obesity Poorly controlled diabetes mellitus Unlikely to have any clinical features Physical stress (hospitalization, surgery, pain) Malnutrition, Anorexia nervosa Intense chronic excercise Hypothalamic amenorrhea CBG excess (increased serum but not urine cortisol) Clinical Features of Cushings Sydrome
General obesity90 % hypertension 85% Skin plethora 70% hirsutism 75% striae 50% acne 35% bruising35% Musculoskeletal osteopenia 80% weakness Neuropsychiatric 85% emotional lability euphoria depression psychosis Gonadal dysfunction menstrual disorders 70% impotence,decreased libido 85% Metabolic glucose intolerance 75 % diabetes 20% hyperlipidemia 70% kidney stones 15% Clinical Features Cushings Syndrome Nonspecific findings Truncal obesity
Supraclavicular & dorsal fat pads Hypertension Hirsutism, acne Amenorrhea Depression Cushings Syndrome More specific findings: Thin skin Easy bruising
Red striae Facial plethora Muscle weakness Osteoporosis Growth failure Buffalo Hump Truncal Obesity Moon Face and Purple Striae Laboratory Findings High normal hemoglobin Eosinophils < 100 mL
Fasting hyperglycemia Serum calcium normal Serum phosporus low normal Hypercalciuria Diagnosis Demonstration of hypercortisolism
24-h urine free cortisol Midnight cortisol Low dose Dxm suppresion test Determination of ACTH dependence Plasma ACTH level Differentiation of ectopic ACTH from pituitary disease High dose DXM suppression test IPSS Diagnosis Urine free cortisol
in 24 hour urine samples mg/24 h is normal Discrimination between patients with hypercortisolism and obese-non cushing patients Diagnosis Absence of diurnal rhythm is the hallmark of diagnosis
Serum cortisol levels exceeding 7 mg/dL at midnight indicates absence ofdiurnal rhythm Dexametasone Supression Test
Diagnosis Dexametasone Supression Test Low dose for screening 1 mg dexametasone at bedtime (23 00hour) Determine plasma cortisol early following morning Plasma cortisol < 1,8 mg/dl- normal Dexamethasone 4 x 0.5 mg for two days 17 hydroxycorticosteroid excretion greater than 4 mg/24 hon the second day of dx administration= Cushing syndrome Diagnosis High dose Dx suppression test Overnight 8 mg Dx at bedtime
4 x 2 mgDxfor2 days. 2ndday urine steroid decreases< 50%- indicates pituitary disease Absence of supressionindicates primary adrenal disease or ectopic ACTH Overnight 8 mg Dx at bedtime Supression plasma cortisol < 50% at baselineconsistent with pituitary dependent Cushings syndrome Distinguish pituitary and nonpitutitaryACTH dependentCushings syndrome Pitfalls of Dexamethasone Testing
Compliance Taking dexamethasone Collecting urine Drug interference (eg phenytoin) Role of plasma dexamethasone measurement Other variation in dexamethasone metabolism Lack of validation with newer cortisol assays Drugs that may interfere with the tests
Drugs that accelerate DXM metabolism by inducing CYP 3A4 Phenobarbital Phenytoin Carbamazepine Primidone Rifampin, rifapentine Ethosuximide Pioglitazone Drugs that impair DXM metabolism by inhibiting CYP 3A4 Aprepitant/fosapritant Itraconazole Ritonavir Fluoxetine Diltiazem Cimetidine Drugs that increase CBG and may falsely elevate cortisol results Estrogens Mitotane Drugs that increase UFC results Carbamazepine (increase) Fenofibrate (increase if measured by HPLC) Some synthetic corticosteroids (immunoassays) Licorice, carbenexolone (inhibit 11-HSD2) Why is diagnosis is so hard?
Cortisol secretion is variable in normals & CS In some patients, CS is intermittent There may be overlap between mild CS and metabolic syndrome There are many different cortisol assays Differential Diagnosis
Plasma ACTH >15 pg/ml: ACTH dependent 10 pg/ml frequently greater than 52 pg/ml. Pituitary MRI ACTH-dependent patients adenoma on MRI likehood of cushing disease 98-99% Incidentaloma 10% Referral to neurosurgeon
If high dose dexamethasone test diagnostic of pituitary Cushings disease: Pituitary MRI Referral to neurosurgeon If urine cortisol very high or hypokalemia present:
If high dose dexamethasone test NOT diagnostic of pituitary Cushings disease: If urine cortisol very high or hypokalemia present: Chest & abdomen CT Octreotide scan O/W Petrosal sinus sampling Inferior Petrosal Sinus Sampling Inferior Petrosal Sinus Sampling
Distinguishing pituitary from non pituitary ACTH dependent Cushings syndrome Simultaneous inferior petrosal sinus and peripheral ACTH measurements before and after CRH stimulation IPS/P> pituitary ACTH secreting tumor IPS/P< ectopic ACTH Diagnostic accuracy 100% in the differantial dignosis of ACTH dependent Cushings syndrome If IPSS not diagnostic of CD:
Chest & abdomen CT Octreotide scan Cushings Syndrome Radiographic Localization CT of sella turcica
Unenhanced and gadolinium enhanced MRI Radionuclide imaging for somatostatin receptors >60% sensitive CT of chest/abdomen with 3 mm cuts through adrenal Adrenal hyperplasia Thickening and elongation of adrenal rami bilaterally Multinodularity of cortex bilaterally Cushings Syndrome Radiographic Localization CT of adrenal glands
Adenomas- usually >2cm but 5cm Necrosis, calcifications, irregularity, invasion MRI of adrenal- usually not needed Signal intensity much higher than in spleen = carcinoma Adjacent organ and/or vascular involvement Adrenal Nodule Adrenal Nodule Treatment of Cushings Syndrome
Obviously, the treatment of this disease depends upon the cause. Pituitary tumors are usually removed surgically and often treated with radiation therapy. Treatment Remove or destroy the basic lesion correct the hypersecretion of adrenal hormones microsurgery radiation therapy pharmocologic inhibition of ACTH secretion ketoconasole, metyrapone, amimoglutethimide, mitotane Cushings Syndrome Treatment: Surgical Cushings disease
Transphenoidal hypophysectomy >90% cure rate 1st time, 50% salvage cure 2nd attempt Exploration even if no obvious adenoma Transient post-op diabetes insipidus, adrenal insufficiency, CSF rhinorrhea, meningitis Tansphenoidal irradiation High success rate in kids (80%) Low success in adults (20%) Cushings Syndrome Treatment: Surgical Cushings disease
Bilateral adrenalectomy If failed pituitary surgery Nelsons syndrome (10-20%) Life-long steroid replacement Nelsons syndrome Rapid post-operative growth of ACTH-secreting pituitary adenomas that can be invasive Hyperpigementation Preoperative irradiation decreases incidence Cushings Syndrome Treatment: Surgical Adrenal lesions/carcinoma
Removal of primary lesion Survival based on underlying disease Ectopic ACTH lesions Remove lesion Survival based on primary disease May need bilateral adrenalectomy to control symptoms if primary tumor unresectable Cushings Syndrome Treatment: Medical
Used as prep for surgery or poor operative candidate Metyrapone- inhibits conversion of deoxycortisol to cortisol Aminoglutethimide-inhibits desmolase Cholesterol to pregnenolone Blocks synthesis of all 3 corticosteroids Side effects: N/V, anorexia, lethargy Ketoconazole- an imidazole that blocks cholesterol synthesis Mitotane (O-P-DDD)-inhibits conversion to pregnenolone Inhibits final step in cortisol synthesis Destroys adrenocortical cells (spares glomerulosa cells) Cushings syndrome: therapy
Before treatment After treatment Treated Cushing Syndrome T h a n kY o u