Adrenal gland hyperfunction

Objectives Define Cushing’s syndrome. At the end of this lecture, the student should be able to: Define Cushing’s syndrome. Recognize the etiology of Cushing’s syndrome. Describe the clinical features and complication of Cushing’s disease Outline the diagnosis and treatment options. Classify hyperaldosteronism. Describe clinical features of Conn’s syndrome State diagnosis and treatment

CASE SCENARIO A 28 y old unmarried female presented with weight gain, bruising easily, menstrual irregularity and striae. On examination she is hypertensive. Her blood tests reveal hypokalemia. What is the most likely diagnosis?

Cushing’s Syndrome A multisystem disorder resulting from chronic exposure to inappropriately elevated concentrations of free circulating glucocorticoids. Incidence of 1–2 per 100,000 population per year.

Causes of Cushing's Syndrome ACTH- Dependent Cushing‘s 1- Cushing's disease 2- Ectopic ACTH syndrome (by bronchial or pancreatic carcinoid tumors, small cell lung cancer, medullary thyroid carcinoma, pheochromocytoma ) F/M(1:1) ACTH- Independent Cushing‘s F/M (4:1) Adrenocortical adenoma, Adrenocortical CA Rare: primary pigmented nodular adrenal disease; ACTH-independent massive adrenal hyperplasia.  

Exogenous ACTH treatment Glucocorticoid treatment Pseudo-Cushing's syndrome chronic activation of (HPA), usually mild and temporary. Major depressive disorder Alcoholism Obesity, PCOS Obstructive sleep apnea

Cushing’s Disease (ACTH- producing pituitary adenoma) Most common cause of Cushing’s syndrome (in 90%) F/M (4:1), more in male in prepuberty cases 3rd or 4th decade of life

Clinical features Truncal obesity Moon face Fat deposits (supraclavicular fossa and buffalo hump) HTN Hirsutism Amenorrhea and impotence Depression Thin skin Easy bruising Hypercoagulation Purplish wide abdominal striae Proximal muscle weakness Osteoporosis Diabetes Mellitus Avascular necrosis Wound healing impaired Pysch symptoms Hyperpigmentation Hypokalemic alkalosis

 

Ectopic ACTH All the previous symptoms but….. Ectopic dominated by : Hypokalemic alkalosis (dominant feature) Fluid retention HTN Glucose intolerance Steroid psychosis Absence of other features may be explained by more sudden onset by acquired ACTH from tumor.

Complications of Cushing's if Untreated Diabetes HTN Osteoporotic fractures and avascular necrosis Infections Psychosis

Screening Test Overnight dexamethasone suppression test (1 mg at 11 pm, cortisol measured at 8-9 am) plasma cortisol> 50 nmol/L Or 24 hour urine free cortisol increased > 50 microgram/ day Midnight plasma or salivary cortisol > 130 nmol/L

False Positives False negatives Severe depression Severe stress Estrogen (pregnancy or oral CP) Morbid obesity False negatives Phenytoin/phenobarbital/rifampin (accelerated metabolism of dexamethasone)

Confirmatory Test Low dose dexamethasone suppression test Dexamethasone 0.5 mg q 6 x 48 hours plasma cortisol > 50 nmol/L Or Measure urine cortisol during the last 24 hours (urine free cortisol >40 micrograms/d)

Differential diagnosis 1 ACTH levels may distinguish: ACTH independent (adrenal or exogenous glucocorticoids) from ACTH dependent (pituitary, ectopic ACTH) ACTH independent- low ACTH to<5 pg/ml ACTH dependent-ACTH normal or high>15pg/ml In addition ectopic ACTH levels are usually 8x higher than pituitary caused ACTH secreting adenomas

ACTH independent CT adrenals: Bilateral micronodular or macronodular hyperplasia or unilateral adrenal mass ( adrenal tumor workup)

ACTH- dependent Differential diagnosis 2 MRI pituitary CRH test (ACTH increase>40% at 15- 30 min & cortisol > 20% at 45- 60 min after CRH 100 µg IV) High dose DEX test (cortisol suppression > 50 % after q6h 2 mg DEX for 2 days)

Positive (Cushing’s disease) Negative test (Ectopic ACTH) Equivocal (Inferior petrosal sinus sampling) petrosal/ peripheral ACTH ratio > 2 at baseline, > 3 at 2-5 min after CRH 100 µg i.v

Inferior petrosal sinus sampling Positive (Cushing’s disease) Negative ( locate and remove ectopic ACTH source)

Treatment Transsphenoidal surgery Pituitary radio-therapy Bilateral or unilateral adrenalectomy Medical therapy

Treatment Cushing’s Disease: Transphenoidal resection of pituitary adenoma Adrenal neoplasms: resection Ectopic ACTH: resection if possible Bilateral adrenal hyperplasia: may need adrenalectomies (lifelong glucocorticoid and mineralcorticoid replacement)

‘Medical’ Adrenalectomy Medications that inhibit steroidogenesis Ketoconazole (600 to 1200 mg/day) inhibits cortisol synthesis by a direct action on the P450 cytochrome enzyme Metyrapone, blocks the 11-ß hydroxylase enzyme (exacerbates female virilization) (2-3 g/day) Mitotane(2-3 g/day)- has a cytotoxic effect on both normal and malignant tissue. Aminoglutethinide (1g/day) Ocreotide, major side effect is adrenal insufficiency, therefore start at lowest dose and titrate

Mineralocorticoid Excess

Primary Hyperaldosteronism (high aldosterone and low renin) Adrenal (Conn's) adenoma Bilateral (micronodular) adrenal hyperplasia

Secondary hyperaldosteronism (high aldosterone and renin) Diuretics, HF, liver F, NS, RAS Renin secreting renal tumor Low aldosterone and renin Congenital adrenal hyperplasia (high DOC) Liquorice misuse Liddle's syndrome

Conn's syndrome An aldosterone-producing adrenal adenoma Represents 5- 12% of hypertension causes Peak age 30-50 years Most patients are women

Clinical features Often asymptomatic Proximal muscle weakness to flaccid paralysis (because of low potassium level) Hypokalemic Hypertension Leg edema due to sodium retention

Investigations Low K and high bicarbonate Upper normal Na Screening test: Aldosterone renin ratio > 750pmol/L:ng/ml/h and aldosterone > 450 pmol/L Confirmation of diagnosis: saline infusion( 2Lsaline over 4h IV), oral Na test, fludrocortisone suppression test

If still negative: Abdominal CT (unilateral adrenal mass, bilateral hyperplasia or normal adrenal morphology) Adrenal vein catheterization to measure aldosterone Iodo- noncholesterol scanning

Management A. Unilateral Adrenal Adenoma and age<40 y Unilateral adrenalectomy preceded by medical treatment for few weeks If >40y and still surgery is indicated we depend on result of vein sampling(if positive then surgery but if negative treat by drugs). B. Bilateral Adrenal Hyperplasia Spironolactone (Aldactone) up to 400mg/d and Amiloride (10- 40mg/d)

References Davidson’s Principles of Internal Medicine 20th Edition. Harrison’s Principles of Internal Medicine 18th Edition.

1- A cushinoid appearance would be an expected finding in all of the following conditions EXCEPT: a- Chronic alcohol abuse. b- Pituitary microadenoma. c- ACTH- secreting bronchial carcinoma. d- Adrenocortical adenoma. 2- The typical clinical features of Conn's syndrome include all of the following EXCEPT: a- Hypertension b- Muscle weakness c- Hypokalemic alkalosis d- High aldosterone and high renin