1. Morning Report
Rick Hobbs
PGY – 3.4ish

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

3. 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

4. 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

5. 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.

6. Physical Features

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

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

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

10. 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.

11. 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

12. 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

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

14. 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

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

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

19. 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

20. 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

21. 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

22. 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

23. 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