Endocrine Topic Review. Sethanant Sethakarun, MD
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1 Endocrine Topic Review Sethanant Sethakarun, MD
2
3 Definition Cushing's syndrome comprises a large group of signs and symptoms that reflect prolonged and in appropriately high exposure of tissue to glucocorticoids
4 Signs and Symptoms More specific: Reddish purple striae (>1 cm.wide) Facial plethora Proximal muscle weakness Easy bruising In children-weight gain with decreasing growth velocity
5 Signs and Symptoms High sensitivity Feature
6 Signs and symptoms
7 Pseudo-Cushing's Syndrome
8 Morbidity and Mortality Severe hypercortisolism: a median survival of 4.6 yr Most deaths caused by vascular (MI, CVA) or infectious complications. Treatment of patients with moderate to severe Cushing's syndrome clearly reduces mortality and morbidity.
9 Diagnosis
10 Severity of Cushingoid features depends on the potency of the preparation used, its dose, the route and duration of its administration. Current or recent use of these medication. Eg.skin creams, herbal medications, joint or nerve injections, synthetic progesterone derivative, etc. Exclude exogenous glucocorticoid exposure
11
12 Cushing's syndrome tends to progress, accumulation of new features increases the probability that the syndrome is present. In children, the sensitivity of combined reduced linear growth and increased weight is quite high. Patients with incidentally found adrenal nodule usually not present with overt clinical features of Cushing's syndrome, but biochemical hypercortisolism is present in a large fraction. Adrenal incidentaloma, usually not present with overt CS
13 False-positive results are reduced if case detection is limited to individuals with an increased pretest probability of having the disorder.
14 Diagnosis
15 Diagnosis
16 Initial testing
17 Initial testing ** **Not available in Thailand
18 Initial testing 4 recommended tests have acceptable diagnostic accuracy when the suggested cutoff points are used. If the initial testing results are normal, then the patient is very unlikely to have Cushing's syndrome. Initial testing!!
19 Estrogen increase the cortisol-binding globulin (CBG) in the circulation. Because serum assays measure total cortisol, false-positive rates for the overnight DST are seen in 50% of women taking the OCP. Estrogen-containing drugs should be withdrawn for 6 weeks before testing. Because the hypercortisolism of Cushing's syndrome can be variable, at least 2 measurements of urine or salivary cortisol are recommended.
20 Urine Free Cortisol (UFC) UFC reflects both urine metabolites and cortisol. Measures the cortisol that is not bound to CBG, which is filtered by the kidney unchanged. Values are significantly lower in patients with moderate to severe renal impairment. (GFR < 60 ml/min) UFC is not affected by conditions and medications that alter CBG!!
21 Urine Free Cortisol (UFC) Sample collection and instructions: Avoid the use of any glucocorticoid preparations. Because UFC levels in a patient with Cushing's syndrome are variable, at least two collections should be performed. Interpretation: UFC is 3 times higher than upper normal level -> positive
22 1-mg Overnight DST Supraphysiological dose of glucocorticoid results in suppression of ACTH and cortisol secretion. Endogenous Cushing's syndrome of any cause have a failure of this suppression.
23 1-mg Overnight DST Enzyme inducer drugs accelerate dexamethasone metabolism. Enzyme inhibitor drugs impair dexamethasone metabolism. OCP increase CBG and may falsely elevate cortisol.
24
25 1-mg Overnight DST Sample collection and instruction: 1 mg dexamethasone is given between , and cortisol is measured between the following morning. Interpretation: Suppresible when serum cortisol less than 1.8 microgram/dl.
26 Low-dose DST Sample collection and instruction: Dexamethasone is given in doses of 0.5 mg for 48 hrs, beginning at on day 1, at 6 hrs intervals. Serum cortisol is measured at 8.00 after the last dexamethasone dose. Interpretation: Suppresible when serum cortisol is less than 1.8 µg/dl. Improved specificity as compared with the 1-mg test
27 Some patients with Cushing's syndrome, usually those with mild or cyclic disease, may have discordant results.
28 Subsequent Evaluation
29 Subsequent Evaluation
30 Special Populations
31 Pregnancy: UFC excretion is normal in the first trimester, it increases up to 3-fold by term. Dexamethasone testing has an increased potential for false positive results in pregnancy.
32 Epilepsy: Anticonvulsants are enzyme inducer drugs. May cause false positive responses on testing.
33 Renal failure: Excreted urine cortisol values decrease below creatinine clearance of 60 ml/min, and quite low, below 20 ml/min.
34 Cyclic Cusing's syndrome: Measurement of UFC or salivary cortisol may best demonstrate cyclicity. If initial tests are normal but high suspicion, follow-up is recommended with repeat testing.
35 Adrenal incidentaloma: UFC appears to be less sensitive than the 1-mg DST or late night cortisol. A suppressed ACTH or dehydroepiandrosterone sulfate concentration supports the diagnosis of Cushing's syndrome in patients with adrenal mass.
36 Determining the Cause Determining the cause Plasma ACTH High-dose dexamethasone suppression test (HDDST)
37
38 Determining the Cause ACTH level
39 Plasma ACTH Collect plasma ACTH at and the sample should be kept cool all the time. Using EDTA tube
40 Plasma ACTH Interpretation: ACTH < 10 pg/ml ->ACTH-independent Cushing's syndrome. ACTH > 20 pg/ml ->ACTH-dependent Cushing's syndrome. ACTH pg/ml-> repeating ACTH levels.
41 High-dose DST For ACTH dependent Cushing's syndrome. Measure baseline morning cortisol. 2 methods: 1. HDDST-dexamethasone 8 mg at and measure serum cortisol at Standard HDDST-Dexamethasone 2 mg every 6 hrs for 48 hrs and measure serum cortisol 2-6 hrs after last dose of dexamethasone.
42 High-dose DST Interpretation: Suppressible if serum cortisol decrease from baseline 50% or more. If not suppressible: 1. Ectopic ACTH 2. Pituitary macroadenoma
43 Pituitary MRI Should be done in all patients with ACTHdependent Cushing's syndrome.
44 Bilateral Inferior Petrosal Sinus Sampling (BIPSS) For ACTH-dependent Cushing's syndrome with normal finding in pituitary MRI. Require experienced intervention radiologist. Measure petrosal:peripheral ACTH ratio, positive if ratio = 2 or >3 after CRH
45 Ectopic ACTH CT chest and Abdomen Eg. SCLC, carcinoid tumor, islet cell tumors, medullary thyroid cancer, pheochromocytoma "รถ" "แพน" "ค นเล ก" "หมอเม ด" "ให ฟร "
46 ACTH-independent CS CT or MRI adrenal glands -> Adrenal tumor.
47 Treatment Treat complication from hypercortisolism: HT, DM, osteoporosis, gonadal axis. Treat the cause: ACTH-independent: benign adrenal adenoma, adrenocortical carcinoma Pituitary adenoma Ectopic ACTH
48 Treatment Adrenal Adenoma: unilateral adrenalectomy Adrenocortical carcinoma: remove primary tumor followed with adrenolytic agent Pituitary micro/macroadenoma: transphenoidal pituitary surgery Ectopic ACTH: depend on the type of tumor
49 Treatment Adjuvant medical therapy: Inhibit corticosteroid synthesis: ketoconazole, metyrapone Block corticosteroid effect: mifepristone Cytotoxic to adrenal cortical cells: mitotane
50 Reference The Diagnosisn of Cushing's syndrome, The Endocrine Society's clinical guideline.(j Clin Endocrinol Metab93: , 2008) Evidence-based Clinical Practice Guidelines in Endocrinology, สาขาว ชาต อมไร ท อและเมตาบอล สม ภาคว ชาอาย รศาสตร คณะแพทยศาสตร จ ฬาลงกรณ มหาว ทยาล ย MKSAP 15, Endocrinology and Metabolism, American College of Physicians. Pocket Medicine, 4th Edition
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