Hypercortisolism

(Cushing’ s Syndrome)

A constellation of clinical abnormalities due

to chronic exposure to excess of cortisol or

related corticosteroid

Definition

It is rare disorder It occurs as a result of primary tumors of adrenal gland that

hypersecrete cortisol excess ACTH secretion that may be of

pituitary or nonpituitary sources

Anatomy and Histology

Cortex Medulla

Adrenal Gland

aldosterone cortisol Adrenal androgen

catecholamines

Zona glomerulosa

Zona fasciculata

Zona reticularis

Pulsatile secretion

Circadian rhythm

Normal pattern of ACTH and cortisol secretion

When stimulated by ACTH, the adrenal gland secretes cortisol and other steroid hormones. ACTH is produced by the pituitary gland and released into the petrosal venous sinuses in response to stimulation by corticotropin-releasing hormone (CRH) from the hypothalamus

TABLE 204-2. CAUSES OF CUSHING’ S SYNDROME

ACTH-dependent causesACTH-secreting pituitary tumor ( Cushing’ s disease )

Pituitary CRH-secreting neoplasm ( ectopic CRP syndrome )

Nonpituitary ACTH-secreting neoplasm ( ectopic ACTH syndrome )

ACTH-independent causes Adrenal adenoma

Adrenal carcinoma

Micronodular adrenal disease

McCune-Albright syndrome

Massive macronodular adrenal diease

Pseudo-cushing Syndrome

Factitious or surreptitious glucocorticoid administration

Etiology and Pathophysiology

TABLE 204-3. COMMON CAUSES OF ECTOPIC ACTH SECRETION

Small cell carcinoma of the lung 50%Endocrine tumors of foregut origin 35%

Thymic carcinoidIslet cell tumor Medullary carcinoma thyroidBronchial carcinoid

Pheochromocytoma 5%Ovarian tumors 2%

Clinical manifestations

Lab findings◦ Plasma cortisol and rhythm (RIA)

◦ Urinary free cortisol

17-hydroxycortisteriod

17-ketosteriods

◦ Plasma ACTH

Diagnosis

Clinical Features

Hypercotisolism

Lipid mobilization Lipid catabolism

Lipid redistribution

Moon-face

buffalo hump

truncal obesity

Violaceous striae

Hepatic glucose production

Insulin resistance

Glucose intolerance

protein metabolism negative nitrogen balance

disruption of water and electrocytes metabolism

Proximal muscle weakness

Dependent edema

Hypertension

Hypokalemic metabolic

alkalosis

TABLE 204-1. CLINICAL FEATURES OFGLUCOCORTICOID EXCESS

Frequency(%)

Weight gain 90“Moon facies” 75Hypertension 75

Violaceous striae 65Hirsutism 65Glucose intolerance 65Proximal muscle weakness 60Plethora 60Menstrual dysfunction 60Acne 40Easy bruising 40Osteopenia 40Dependent edema 40Hyperpigmentation 20Hypokalemic metabolic alkalosis

15

FIGURE . Multiple wide striae on the abdomen of a patient with Cushing's disease.

Screening test

◦ 1mg DX P.O at midnight

◦ Plasma cortisol (PF) at 7-8 am next day

◦ PF suppressed: Normal

◦ PF NOT suppressed: Cushing’ s Syndrome

Suppression tests

Low dose DX suppression test

◦ DX 0.5 mg q6h P.O 2 days

◦ Urinary free cortisol decreased: Normal

◦ Urinary free cortisol NOT decreased: Cushing’ s

Syndrome

Suppression tests

Large dose DX suppression test◦ D.X 2mg q6h P.O 2 days

◦ Urinary free cortisol reduced 50%: Cushing’s disease (Pituitary adenoma)

◦ Urinary free cortisol NOT reduced 50%:Adrenal tumor, carcinoma, ectopic ACTH Syndrome

Suppression tests

ACTH 25u intravenously 8h 2-5 fold increase in urinary free cortisol in

Cushing’ s disease Plasma cortisol and urinary free cortisol

increase in half of adrenal adenoma patients

No response in adrenal carcinoma

ACTH Stimulation test

Etiology diagnose (especially for pituitary ACTH-dependent or ectopic ACTH syndrome)

A newer approach is to combine a CRH stimulation test with a dexamethasone suppression test(4mg ).

method : 1 µg / kg of CRH is administered intravenously. ACTH and cortisol levels are measured before

CRH injection and 15, 30, 45, 60, 90 and 120 minutes after injection.

A rise in the cortisol value of 20 percent or more above basal level or a rise in the ACTH value of at least 50 percent above basal level is considered evidence for an ACTH-dependent lesion

CRH stimulation test

Etiology diagnose (especially for pituitary or adrenal)

◦ Metyrapone 2-3g (30mg/kg) P.O at midnight

◦ Urinary 17-OHCS, Plasma ACTH,11-deoxycortisol more above basal level : Cushing’s disease (Pituitary adenoma)

◦ No response in adrenal carcinoma , tumor, ectopic ACTH Syndrome

Metyrapone Test

Pituitary CT has a sensitivity of about 50% for identifying microadenomas

MRI has increased sensitivity but is not 100% predictive

If diagnostic doubt need bilateral inferior petrosal sinus sampling for ACTH

Adrenal ultrasonography---first choice Abdominal CT will allow identification of

adrenal pathology Somatostatin scintigraphy to identify

sites of ectopic hormone production

Imaging diagnosis

Cushing’ s disease:

Adrenal adenoma:

Adrenal carcinoma:

Ectopic ACTH Syndrome:

Chronic, moderate clinical features can be suppressed by large dose test

Shorter course , mild features can NOT be suppressed by large dose test

Acute onset, progressive course, hyperandrogenic effect predominate, palpable mass, low ACTH

Appear suddenly, progress rapidly, not typical manifestation of Cushing’s syndrome, hyperpigmentation, hypokalemia, high ACTH

Etiological diagnosis

Simple obesity◦ General obesity, long history, over nourished◦ Narrow and short striae◦ Urinary free cortisol can be suppressed by screening ( overnight ) test and/or

low-dose DX suppression test◦ Normal diurnal rhythm, almost normal plasma cortisol

Type 2 DM◦ Normal plasma cortisol and rhythm◦ Once blood glucose controlled, urinary free cortisol turns to normal

Alcoholic Cushingnoid Syndrome◦ No drinking for one week, plasma cortisol and urinary free cortisol become

normal

Depression ◦ Lack of clinical manifestation of Cushing’s Syndrome

Differential diagnosis

Cushing’s disease◦ Transsphenoidal microadenomectomy◦ Pituitary radiation◦ Bilateral total adrenolectomy◦ Drugs

Adrenal adenoma and carcinoma◦ Surgical removal◦ Drugs ( mitotane, metyrapone, ketoconazole ) for

nonresectable or metastatic carcinoma Ectopic ACTH Syndrome

◦ Surgical removal of the ectopic tumor◦ Chemotherapy, radiotherapy◦ Drugs ( mitotane, metyrapone, ketoconazloe )

Treatment

Purpose

◦ Correct metabolic abnormalities before

attempted surgical cure

◦ Palliate surgically noncurable disease

◦ Achieve remission in patients for whom

surgery is unlikely to achieve satisfactory long

term results

Medical therapy of Cushing’ s Disease

Steroidogenic inhibition◦ Mitotane◦ Metyrapone)◦ Aminoglutethimide◦ Ketoconazole

Neuromodulatory treatment◦ Bromocriptine◦ Cyproheptadin◦ Valproic acid◦ Octreotide

Glucocorticoid receptor antagonist◦ RU486

What is etiology and classification of Cushing’ s Syndrome ？

What is clinical manifestations of Cushing’ s Syndrome ?

Consideration question