Cushing’s syndrome Elżbieta Petriczko

Physiology of adrenal cortex: Adrenal cortex produces:  1) glucocorticoids (eg cortisol) which affect metabolic functions ( carbohydrate, lipid and protein metabolism)  mineralocorticoids (eg aldosterone)  androgens and oestrogens

Cushing syndrome ACTH dependentindependent ACTH Cortisol ACTH adenomacarcinoma 70% 12%10%8%

Clinical features: 1) skin changes: acne seborrhea increased growth of hair, especially pubic hair appearance of dark-colored striae due to weakening of collagenous connective tissue in the skin wasting of tissues ( myopathy, thin skin) truncal obesity ( waight gain 90%) due to increased protein catabolism and loss of muscle mass –the buffalo-hump is characteristic ; the latter is due to increased fat padding between the scapulae vascular changes consist of –hypertension ( 50% to 80%) –increased capillary fragility –and easy bruising abnormality of bone matabolism –with demineralization of the skeleton lead to pathological fractures –osteoporosis, –growth retardation is common

Clinical features: 7) water retention, oedema, plethoric moon-face, (broadening of the face with temporal fat padding, chubby cheeks and double chin) 9) predisposition to infection, ( bacteria, fungi, parasites) 10) poor wound healing, 11) hirsuitism, 12) amenorrhoea, 13) hyperglicaemia (30%) ; rarely, children may present with polyuria, polydipsia (resulting from glucocorticoid excess causing hyperglicaemia) 14) psychological disturbances ranging from mild personality changes to severe psychosis 15) growth retardation ( 83%) and delayed puberty 16) hyperpigmentation may be present with ACTH excess 17) virilization ( if the adrenal tumor is producing androgens as well as glucocorticoids) : premature pubarche, clitoromegaly, penile enlargement

Clinical features in children: Cushing’s syndrome is due to chronic glucocorticoid excess. The condition is rare in childhood. In infants and children one may not find the marked difference in obesity between the trunk and extremities that is often noted in adults. Short stature may be the only presenting symptom in some children. When Cushing’s syndrome occurs before 7 years, it typically implies the presence of an adrenal tumor. In contrast, after 7 years, most cases are due to increased ACTH- secreting pituitary tumor may be found.

Screening tests (out patient): 24h urine collection for urine free cortisol assay. Normal <700 nmol/24h or 25 to 75 ug/m2/24hr. In Cushing’s this is raised More than one collection is needed. !!!! * 3% of normal individuals have levels of urinary free cortisol exceeding the normal range on a single determination. * Normal values have been reported ion patients with confirmed Cusing syndrome.

Inpatient tests: Plasma cortisol measured at h and h The normal plasma cortisol concentration is 5-25 ug/dl ( 140 to 690 nmol/L in early morning, dropping to less than 50% in the late evening ( PM to midnight) Loss of diurnal variation is typical of Cushing syndrome. The false-negative rate of this test is only 3%. This pattern of diurnal variation often is not yet established in children less than 3 years old. Cusing’s suggested if level at 22.00h is about equal to that at 09.00h ( it is normally lower).

LABORATORY EVALUATION: –fasting hypergyceamia –normal sodium level –normal or low potassium level (resulting from the mineralocorticoid effect of high cortisol levels) –hypercalciuria (40%) with normal serum calcium and phosphorus –hyperinsulinemia –elevation of plasma lipoproteins –leukocytosis and lymphopenia

HORMONAL TESTS: No test has 100% sensitivity or specificity, …… so multiple testing in the same patient is necessary to confirm a specific diagnosis.

Short dexametazone test cortisol (plasma) < 5  g/dl Dexametazon 1 mg (-) test only confirm the hypercortisolis 5% false (-) 15 – 20% false (+)

Cushing disease ACTH Cortisol ACTH % microadenoma (<10 mm). ~50% < 5 mm ♀:♂ 8:1 ~1% adenoma out of pituitary gland

after Gd-DTPA Normal MRI microadenoma

Cushing disease A.K. ♀ l. 55 MRI: pituitary gland small, without signs of microadenoma presence diagnosis: microadenoma near pituitary gland

ectopic ACTH production: CRH Cortisol ACTH 50% bronchogenic carcinoma (~2% cases of ACTH- dependent Cushing syndrome) pancreas carcinoid pulmonis, thymi, pancreas, oviaries pheochromocytoma ♀:♂ 1:5 rare

Reasons of the elevated ACTH value ACTH pg/ml Cushing disease CAH Nelson syndrome ectopic ACTH production Adrenal insufficiency NORMA Cushing syndrome

Cushing disease TBC A.T. ♂ 40 l. death

Cushing disease R.S. ♂ lat 30 since10 years hypertension stroke Epilepsia and left hemiparesis

Cushing disease serious osteoporosis. A.K. ♂ lat 30 1 year height 170  160 cm

Treatment: In the case of excessive pituitary ACTH release, management includes transsphenoidal microsurgery, with a remission rate of 85%-95%. Irradiation of the pituitary gland – successful in 80%

The risk of hypopituitarism is high after irradiation. During and after surgery, glucocorticoid replacement is essential. TREATMENT of adrenal gland tumors consist of surgical removal with replacement of glucocorticoids until the remaining adrenal gland is functioning normally.

Pharmacotherapy Ketokonazol 600 – 1200 mg daily inhibit cytochrome P-450 action and cholesterol production Metyrapon inhibit 11  -hydroksylase Aminoglutetymid inhibit cholesterol conversion Mitotan

Cushing disease Before treatment After pituitary adenoma removal L.D. ♀ l. 39 Two years of diagnostic procedures: suspected dermatmiositis

Cushing disease Before treatment After pituitary adenoma removal B.D. ♀ l. 39 Four years of treatment because of: hirsutismus secondary amenorrhea

Cushing diasease Before treatment After pituitary adenoma removal M.S. ♀ l. 46 Two years of depression treatment:

ACTH-dependent Cushing syndrome After pituitary operation After bronchocarcinoma removal A.B. ♂ lat 21

ACTH-zależny zespół Cushinga ACTH: 790 pg/ml CgA: 168 U/l J.P. ♂ lat 60 RTG: zmiany pogruźlicze TK:guzy obu nadnerczy rak drobnokomórkowy meta

ACTH-zależny zespół Cushinga A.B. ♂ lat 21 Po operacji mikrogruczolaka przysadki oktreoscan TK kl. piersiowej Guz (rakowiak) prawego płuca skutecznie przygotowany analogami somatostatyny do operacji

Hydrocortison 30 mg/d ACTH pg/ml kortyzol mg% OPERACJAOPERACJA Sandostatin LAR 30 mg co 3 tyg. ACTH-zależny zespół Cushinga B.D. ♂ lat 47 Guz (rakowiak) lewego płuca skutecznie przygotowany analogami somatostatyny do operacji

ACTH-zależny zespół Cushinga Z.R. ♂ lat 41 Po operacji przysadki oktreoscan TK kl. piersiowej