Pathologic hypercortisolism may be caused by either
a pituitary or nonpituitary (ectopic) ACTH secreting neoplasm or by benign or malignant adrenal tumors.
sypmtoms of ACTH Dependent Hypercortisolism
• weight gain • facial fullness/plethory • supraclavicular fat • diabetes • osteoporosis • BP • Myopathy • Neuropsych disoerders • edema • hypogonadism • androgen excess
________neoplasms have a much higher set point for glucocorticoid negative feedback and diurnal rhythm is disrupted.
The earliest biochemically-detectable finding of hypercortisolism is the
lack of nadir of cortisol secration late at night
What is the pathophysiology behind ACTH Dependent Hypercoricolism?
ACTH secreating tumor in the pituitary acting independent of negative feedback
see adrenal gland hyperplasia and increased cortisol secreation with low CRH
• Incidentally discovered • Intermittent cortisol excess • Hypertension • Hyperglycemia/metabolic syndrome • Osteoporosis • Vertebral compression Fx • Very long duration, 10-40 yrs.
signs of Adrenal dependent hypercorticolism
due to a solitary benign or malignant tumor and sometimes bilateral adrenal nodular disease. As expected, ACTH is low in these patients due to cortisol negative feedback and, as a result, the contralateral adrenal is usually small
ACTH-independent (adrenal-dependent) hypercortisolism
Whats the difference btwn ACTH dependent and adrenal dependent cushings?
How do pts with ACTH INDEPENDENT cushings present different than Dependent?
have very mild hypercortisolism and usually present with incidentally discovered adrenal nodules (during abdominal imaging studies for unrelated symptoms) without overt clinical evidence of cortisol excess
What types of things can lead to hypercorticolism that are more related to physiologic adaptions?
• Stress • Alcohol • Neuropsych disorders • Starvation
What signs/symptoms should raise your index of suspicion for Cushing syndrome?
Weight gain (unexplained) in truncal distribution
Increased supraclavicular and dorsocervical fat accumulation
Facial rounding and plethora
Proximal muscle weakness
Hirsutism/androgen excess in women
Wide violaceous striae
Cutaneous wasting (skin fold thickness in dorsum of hand <2 mm)
Easy bruising Neuropsychiatric problems
Cognitive difficulty, depression, psychosis Growth retardation (children)
What diagnosis may raise your suspicion for Cushing syndrome?
Diabetes/Hypertension/Metabolic syndrome Approximately 0.5-1.0% of this patient population Osteoporosis: 3% of patients with osteoporosis
Adrenal nodules; 10-30% of patients with incidental adrenal nodules
You suspect a pt has Cushings syndrome and excluced the cause to be d/t glucocorticoid medicine, what three tests could you perform next? which is the most accurate?
Late night salivary cortisol level
overnight low-dose dexamethasone suppression test
24 hours free cortisol
(written in order of most to least accurate)
How is teh overnight dexamethesone suppression test performed?
Overnight low-dose (1 mg) dexamethasone suppression test Simple, sensitive test for Cushing: 1 mg dexamethasone is given orally at 11pm with measurement of cortisol the following morning: normal suppression= cortisol <1.8 µg/dL (50 nmol/L). Particularly sensitive in patients with adrenal nodules, but there are many false positives limiting specificity
Your pt you suspected of cushings has abnromally high cortisol levels, what is your next step?
Measure ACTH levels!
What does it mean if your patient that has elevated cortisol levels has normal or elevated ACTH levels?
likely have ACTH DEPENDENT Cushings; get MRI of pituitary
Your attending informs you your pt came it with symproms of Cushings; both cortisol and ACTH levels were elevated and asks you what does this mean and how do we proceed?
means pts has ACTH dependent Cushings
get MRI of pituitary; if abnromal = CUSHIGS diesease
if normal, do bilateral petrosal sinus sampling to check for pituitary ACTH gradient
You perform a bilateral petrosal sinus pituitary gradient for pts with ACTH dependent cushings that has normal pituitary MRI, what are we looking for?
see a pituitary gradient means you have cushings disease
no gradient, we have occult ectopic ACTH production
If you have elevated coritsol and low ACTH levels, what is our Dx?
What is our next step?
ACTH INdependent Cushigns syndrome, get adrenal CT
What is the Tx for Cushings Disease?
The best treatment for Cushing syndrome always depends on an accurate differential diagnosis. Surgery: Remove the offending tumor (pituitary/adrenal) Pituitary surgery has 70-85% remission rate w/ experienced surgeons, but 10- 20% recurrence rate over 10 years
When is bilateral adrenalectomy recommend for pts with Cushings
indicated in patients who have failed other modalities of treatment; definitive therapy but confers decreased quality of life issues associated with life-long dependence on steroid (glucocorticoid and mineralocorticoid) support; also concern regarding re-growth of the pituitary tumor (as a result of loss of glucocorticoid negative feedback)—this is called Nelson’s syndrome
When is radiotherapy recommend for Cushings?
When is it not?
Used in pituitary Cushing as adjunctive therapy after failed surgery; modest success rates (15-50%) in inducing a remission of hypercortisolism and there is a high incidence of hypopituitarism within 5-10 years after pituitary radiation
***Not indicated in adrenal Cushing
Pituitary-directed somatostatin receptor analog (agonist) – This somatostatin analog is used specifically for the treatment of Cushing's disease in patients for whom pituitary surgery is not an option or has not been curative. T
Side effects of paseriotide
diarrhea, nausea, hyperglycemia, headache
Adrenal steroid inhibitor: available with compassionate use; 11-beta hydroxylase inhibitor
potent inhibitor of glucocorticoid and progesterone receptor
used for Cushings when surgery has failed