đCushing Syndrome Flashcards
(14 cards)
What is Cushing Sydrome?
Clinical condition caused by prolonged exposure to elevated levels of excess glucocorticoids (Cortisol) by ACTH dependent or independent causes.
Can be divided into:
- ACTH Dependent
- ACTH independent
What are other examples of ACTH or CRH producingn ectopic tumour?
- Small cell Lung Ca
- Carcinoid of Thymus
- Bronchial ca.
Tumors associated with the paraneoplastic ACTH syndrome include :
- pancreatic endocrine neoplasms
- MTC
- thymic carcinoids
- pheochromocytomas
- bronchogenic small cell carcinoma.
Epidemiology
- Incidence : 1.3/100,000. Breakdown of disease as above.
- F:M ratio : 5:1
- Age : 25 â 40 years old
Presentation of Cushing Syndrome or disease
Cushingâs Syndrome: as per diagram
- Recent weight gain.
- Proximal muscle weakness ( as high Cortisol will have minerolocortisoid effect â> decreased in potassium)
Cushingâs Disease:
- Pituitary tumor (especially if large macroadenoma): Headache, galactorrhea.
- â visual acuity, homonymous hemianopia - the classical presentation of optic chiasma compression.
- Cranial nerve 3, 4, 6 may be affected.
Subclinical Cushingâs Syndrome
- Hypercortisolism without clinical manifestations of Cushingâs syndrome
- Most frequent hormonal abnormality in adrenal incidentalomas
Investigation for Cushing Syndrome
Screening - 2 Tests
- Cortisol ( Serum, late night/evening salivary or 24 urine free cortisol)
- Low dose dexamethasone suppresion test
Confirmation - 3 Tests (Suppression test)
- High dose Dexamethasonen suppersion test
- CRH stimulation test
- Serum ACTH
Localization - 2 Tests
- ACTH dependent : MRI pituitary
- ACTH Independent: CT adrenals protocol
Screening tests for Cushing
Serum Cortisol morning and evening â 1st line, loss of diurnal variation.
Late-night/ evening salivary cortisol - correlate with free plasma cortisol, normally lowest at night.
24H Urine Free Cortisol (UFC)
- > 3 - 4x normal - suggestive.
- < 3 - 4x - inconclusive, pseudo-Cushing syndrome (Micronodular Hyperplasia, Macronodular Hyperplasia, Iatrogenic, Alcoholism, Major depressive disorder).
Low dose dexamethasone suppression test
- Overnight, 1 mg test
- Two-day, 2 mg test
Overnight, 1 mg test: Prescribe 1 mg of oral dexamethasone at 11 PM â next morning at 8 AM, cortisol and dexamethasone level are drawn.
- If 8 AM cortisol < 1.8 mcg/dL, normal or exogenous cause if patient taking
- Cortisol between 1.8 and 5.0 mcg/dL may represent mild cortisol excess:
- Repeat DST annually for 5 years.
- Failure to suppress below 5.0 mcg/dL raises concern for cortisol excess â 24-hour urinary cortisol and refer to Endocrinology or Endocrine Surgery.
Two-day, 2 mg test: Dexamethasone 0.5 mg is administered orally every 6 hours (9 AM, 3 PM, 9 PM, 3 AM) for two days (total dose 4 mg). Serum cortisol level is drawn 6 hours (9 AM) after the last administered dose.
Comfirmation tests for Cushing disease
Aim to identify ACTH dependent or independent.
High Dose Dexamethasone Suppression Test - evaluation of endogenous Cushing syndrome (CS), by assessing for the lack of suppression of the hypothalamic-pituitary-adrenal (HPA) axis by exogenous corticosteroids.
- When HPA axis is intact, exogenously administered corticosteroids exert feedback inhibition on the production of serum CRH and ACTH by binding to the hypothalamic and pituitary glucocorticoid receptors, respectively, that subsequently causes suppression of the synthesis and secretion of serum cortisol.
- Overnight, 8mg test
- Two-day, 8 mg test
Overnight, 8mg test: Baseline morning serum cortisol is measured, and oral dexamethasone 8 mg is administered between 11 PM and midnight. Repeat serum cortisol is drawn the next morning (between 8 and 9 AM).
Two-day, 8 mg test: On day 1, a baseline morning serum cortisol or 24-hour urinary free cortisol (UFC) from the day before is obtained. Then oral dexamethasone 2 mg every 6 hours((9 AM, 3 PM, 9 PM, 3 AM) is given for 2 days (total dose 16 mg between Day 1 and Day2) with simultaneous collection of a urine sample for UFC. Serum cortisol levels are checked 6 hours after the last dose (9 AM)
- Reduction in UFC, or serum cortisol > 50% in the overnight, or two-day HDDST makes Cushing disease (CD) the likely source of ACTH-dependent Cushing syndrome.
CRH Stimulation Test
CRH stimulates release of ACTH from corticotrophs of anterior pituitary. Patients with
- CRH administered (100 microgram human or bovinne CRH by increasing ACTH and cortisol secretion)
- Cushingâs disease â excessive increase in plasma cortisol
Ectopic ACTH secretion â no excessive increase in plasma cortisol - Occasionally, patients with ectopic ACTH secretion have a positive CRH test, so reducing this testâs specificity
Serum ACTH - 100 Âľg of IV human- or bovine-sequence CRH (CRH-41) administered, cortisol and ACTH measured over two hours.
- 50% â ACTH and serum cortisol â 20% - highly suggestive of Cushingâs Disease.
- Ectopic ACTH syndrome rarely respond.
localization for Cushing
ACTH-independent Cushingâs
- CT Abd - mass > 4cm suspicious of carcinoma.
- CT adrenal protocol; thin sliced CT (2-3mm) with 4 phase of
acquisition (non-contrast, early arterial (60-90s), venous and delayed (10/15 minutes) - AVS - if imaging equivocal.
- I31I-NP-59 (Iodine 131-6-β iodomethyl-19-norcholesterol) scintigraphy or single-photon emission computed tomography (SPECT/CT) - concentrated in steroid hormone synthesizing tissue and is able to localize.
ACTH-dependent Cushingâs Syndrome
- Pituitary MRI brain with gadolinium - an obvious tumor > 5cm will be diagnostic, false +ve may happen as 10% may have non functioning adenoma.
- CT Brain - identify only 50% of pituitary lesions.
-
Inferior petrosal sinus sampling (IPSS) if MRI inconclusive.
- Pituitary gland drains laterally into cavernous sinuses and then into the inferior petrosal sinuses.
- Performed by sampling ACTH peripherally and from both IPSs before and after CRH administration.
- Lateralization accuracy of the test is in the range of 70%
- Sinus : peripheral ACTH of 2:1 diagnostic for pituitary. Accuracy improved with CRH stimulation.
Ectopic
- CT TAP
- 18-FDG PET/CT - to detect ectopic secreting ACTH.
- Octreotide scintigraphy - ectopic may have somatostatin receptor.
Overview of Cushingâs syndrome/disease investigation
Management of Cushingâs syndrome and Disease
Can be divided into:
- Medical
- Surgical
1) Medical therapy
Metyrapone or Ketoconazole : these are adrenal enzyme inhibitors which reduce cortisol production temporarily, usually given prior to surgery to improve patientâs clinical condition.
Mitotane : an adrenocorticolytic agent used primarily in adrenocortical carcinoma.
2) Surgery
Preoperative
- Co morbid control - DM/HPT
- Correct electrolyte imbalance: Cortisol has mineralocorticoid activity. âK, âNa
- DVT prophylaxis : Higher risk of DVT.
- Antibiotic prophylaxis : Patient DM with immunosuppression â risk of infection
Operative for primary and recurrence
- IV Hydrocortisone intraoperative and post-operative (Risk of Addisonâs crisis)
ACTH-independent Cushingâs
- Unilateral adrenalectomy: open, laparoscopic or retroperitoneoscopic is performed for an adenoma (10%).
- Bilateral adrenalectomy is performed in patient with primary pigmented nodular adrenocortical disease (PPNAD) or also known as micronodular adrenal hyperplasia.
ACTH-dependent Cushingâs
- Tran sphenoidal micro adenectomy - cure rate 80-90% (less in macroadenomas)
Post operative management
Postoperative
Hormone replacement
- Prolonged glucocorticoid secretion by tumor lead to suppression of contralateral adrenal gland. Therefore, hormone replacement is always required post operatively (temporary/permanent).
- IV Hydrocortisone 80 â 100mg t.d.s. before start of surgery and first 24 hour
- Good response post op â change to oral glucocorticoid over 1-2 days.
- Post pituitary resection/ bilateral adrenalectomy â lifelong glucocorticoid & mineralocorticoid.
If Operation is for ACTH independent Cushingâs Syndrome:
- steroid replacement will be required until it recovers functionality.
- This should be confirmed with a Synacthen test before complete withdrawal of steroid supplements (this may take up to a year)
How to management Persistent or Recurrent Disease
- Reoperation is less successful and may be complicated with other pituitary hormone deficiencies. (panhypopituitarism)
- Irradiation of the pituitary : long latency period. ( Delayed effect on circulating cortisol level and also risk panhypopituitarism)
- Medical adrenalectomy: usually given while receiving radiotherapy and not as definitive treatment.
- Bilateral adrenalectomy : suitable for patients with severe hypercortisolisme, need for rapid cure and failed other therapy.
- Patients will be on lifelong cortisol (to avoid Addisonian crises) and run the risk of Nelson syndrome (an enlarging pituitary tumor with progressive hyperpigmentation due to very high plasma ACTH).
The results of bilateral adrenalectomy for the treatment of pituitary ACTH-dependent Cushingâs syndrome ( if recurrence)
- Following bilateral adrenalectomy for Cushingâs disease, loss of negative feedback from circulating cortisol may result in hyperpigmentation, enlarge- ment of the ACTH-secreting tumour and increased secretion of ACTH; this is called Nelsonâs syndrome and its incidence may be reduced, or at least de- layed, with prior radiotherapy to the pituitary
HPE of Cushing
HPE (Cushingâs - Pituitary (ACTH) or Hypothalamic (CRH))
- Glands have rounded contours, rather than the sharp outlines typical of normal glands. The inner portion of the cortex is widened and often appears pale brown or tan. The outer layers of the cortex are typically yellow.
- Cortex may appear nodular with individual nodules measuring
- < 0.5 or 1.0 cm in diameter -diffuse and micronodular hyperplasia.
- > 1 cm in diameter -diffuse and macronodular hyperplasia.
Addisonian Crisis
