Morning Report Rick Hobbs PGY – 3.4ish

Frequency Endogenous Cushing syndrome –13 cases per million individuals 70% to Cushing disease 15% to ectopic ACTH 15% to a primary adrenal tumor

Patient Characteristics Female-to-male ratio 5:1 for Cushing syndrome due to adrenal or pituitary tumor Ectopic ACTH production is more frequent in men than in women because of the increased incidence of lung tumors in this population

Clinical History Weight gain, skin changes, bruising, proximal muscle weakness, menstrual irregularities, decreased libido, depression, cognitive dysfunction, emotional lability, HTN, diabetes, impaired wound healing, infections, osteoporotic fractures, headaches, vision changes, galactorrhea, virilization

Physical Exam Findings Obesity Increased adipose tissue w/moon facies, buffalo hump, and supraclavicular fat pads Central obesity w/ increased fat in mediastinum and peritoneum, and visceral fat on CT. Increased waist-to-hip ratio greater than 1 in men and 0.8 in women Skin Facial plethora Violaceous striae on abdomen, buttocks, lower back, upper thighs, upper arms, and breasts Ecchymoses Telangiectasias and purpura. Cutaneous atrophy with exposure of subcutaneous vasculature tissue and tenting of skin Increased lanugo facial hair. If glucocorticoid excess is accompanied by androgen excess, as occurs in adrenocortical carcinomas, hirsutism and male pattern balding may be present in women. Steroid acne over the face, chest, and back may be present Acanthosis nigricans, which is associated with insulin resistance and hyperinsulinism, may be present. Axilla, elbows, neck, and under breasts. Cardiovascular and renal Hypertension and possibly edema may be present due to cortisol activation of the mineralocorticoid receptor leading to sodium and water retention. Gastroenterologic Peptic ulceration particularly if patients are given high doses of glucocorticoids (rare in endogenous hypercortisolism). Endocrine Galactorrhea if anterior pituitary tumors compress the pituitary stalk, leading to elevated prolactin levels. Signs of hypothyroidism if anterior pituitary tumor whose size interferes with proper TRH and TSH function Decreased testicular volume due to low testosterone levels from inhibition of LHRH and LH/FSH function Skeletal/muscular Proximal muscle weakness Osteoporosis w/ fractures, kyphosis, height loss, axial skeletal bone pain. Avascular necrosis of the hip is also possible from glucocorticoid excess. Neuropsychological Emotional liability, fatigue, and depression. Visual-field defects, often bitemporal hemianopsia, and blurred vision with large ACTH-producing pituitary tumors that impinge on the optic chiasma. Adrenal crisis May occur in patients on steroids who stop taking their glucocorticoids or neglect to increase their steroids during an acute illness, or in patients who have recently undergone resection of an ACTH-producing or cortisol-producing tumor or who are taking adrenal steroid inhibitors. Hypotension, abdominal pain, vomiting, and mental confusion (secondary to low serum sodium or hypotension). Hypoglycemia, hyperkalemia, hyponatremia, and metabolic acidosis.

Physical Features

Labs Leukocytosis Hyperglycemia Hypokalemic metabolic alkalosis due to activation of the renal mineralocorticoid receptor

Okay, that’s my patient, how do I find the source?

Simplify. Step 1: Exogenous vs Endogenous Cortisol Excess? Step 2: ACTH-dependent or ACTH-independent? Step 3: ACTH from pituitary or ectopic?

Remember… Exogenous corticosteroids are the leading cause of Cushing’s Syndrome Exogenous steroids suppress the HPA axis, with full recovery taking as long as a year after cessation of glucocorticoid administration.

ACTH-producing pituitary adenoma ACTH -> adrenal cortical hyperplasia -> adrenal steroid overproduction Can also impair other anterior pituitary hormones as well as vasopressin (galactorrhea not uncommonly) Bitemporal hemianopsia

Primary adrenal lesions Adrenal adenoma, adrenal carcinoma, or macronodular or micronodular adrenal hyperplasia Excess androgen secretion is suggestive of an adrenal carcinoma rather than an adrenal adenoma

Ectopic ACTH Ectopic ACTH is sometimes secreted by oat cell or small-cell lung tumors or by carcinoid tumors Occurs later in life

Question 1 – Endogenous? Endogenous overproduction of cortisol requires the demonstration of inappropriately high serum or urine cortisol levels Four Methods: Urinary Free Cortisol Low Dose Dexamethasone Suppression Test Evening Serum and Salivary Cortisol Dexamethasone-Corticotropin-Releasing hormone test

UFC 3-4 times the upper limit of normal are highly suggestive of Cushing syndrome 3 negative UFC measurements excludes endogenous Cushing’s Syndrome

Dexamethasone Suppression Test Inhibit secretion of hypothalamic CRH and pituitary ACTH but does not directly affect adrenal cortisol production or ectopic production

Question 2 – ACTH Dependent? Undetectable plasma ACTH (<5pg/ml) with simultaneously elevated serum cortisol is diagnostic of ACTH-independent Cushing syndrome -> usually adrenal adenoma or carcinoma Measurements of adrenal androgen production, DHEAS and 24-hour urinary 17-ketosteroid can confirm adrenal tumor

Question 3- Okay, too much ACTH. But from where? ACTH >10-20 = dependent 8mg overnight dex suppression test and 48hr high-dose dex suppression test can differentiate pituitary from ectopic ACTH CRH administration will increase pituitary-driven ACTH and cortisol, but not affect ectopic sources

Imaging Wait! Not until biochemical testing performed given 10% prevalence of incidentalomas. Abdominal CT to eval for primary adrenal Pituitary MRI Chest CT for lung CA w/ectopic secretion Octreotide scintigraphy can localize some ectopic ACTH tumors

Inferior Petrosal Sinus Sampling Can identify a pituitary source of ACTH not revealed by MRI by measuring ACTH secretion in response to CRH in serum and petrosal samples and comparing the values Bilateral sampling can actually lateralize a microadenoma

Treatment Stop exogenous glucocorticoid Surgery Medication to control hypercortisolism Mitotane, ketoconazole, metyrapone, aminoglutethimide, trilostane, and etomidate Often fail Radiation if surgery not possible Must have stress-dose steroids pre-, intra-, post-op