1. SUPRARENAL GLANDS DISEASES Lecturer: Sakharova I.Ye. M.D.

2. A Close Look at the Adrenal Glands

4. Adrenal glands hyperfunction:

5. Adrenal glands hypofunction:

7. Cushing's syndrome is a multisystem disorder resulting from chronic exposure to inappropriately elevated concentrations of free circulating glucocorticoids.

8. Etiology of Cushing's syndrome Endogenous ( ACTH dependent 85%) Cushing's disease (pituitary) Ectopic ACTH syndrome (small cell lung carcinoma) Ectopic CRH syndrome (bronchial carcinoid tumours) ACTH independent 15% Common: Adrenal adenoma, adrenal carcinoma Less common: Micronodular hyperplasia, macronodular hyperplasia Rare: McCune-Albright syndrome, gastric inhibitory polypeptide

9. Exogenous ACTH treatment Glucocorticoid treatment Pseudo-Cushing's syndrome Major depressive disorder Alcoholism Obesity

10. Clinical features of Cushing's syndrome 90% - Central (truncal) obesity. Fat deposits may appear in the cheeks (moon facies), in the dorsocervical area (buffalo hump), and the supraclavicular area 85% - Hypertension 65% - Presence of multiple purple striae with a diameter >1 cm on the abdomen or proximal extremities 60% - Muscle wasting and weakness affect the proximal muscles of leg and shoulder girdle 40% - Easy bruising of the skin 40% - Osteoporosis

11. Hyperpigmentation (palmar creases and pressure points) in a patient with Cushing's syndrome strongly suggests an ACTH cause (Cushing's disease) Patients may have mild hirsutism and acne, but severe hirsutism and especially virilisation strongly suggest an adrenal carcinoma. Depression, lethargy, and insomnia often occur at the same time as other symptoms. In children the dominant clinical features are cessation of linear growth and weight gain; the clinical course is more aggressive than in adults.

12. Investigation of Cushing's syndrome Screening tests (outpatient) Urinary free cortisol The measurement of 24 hour excretion of cortisol in urine integrates the variations in plasma free cortisol concentrations seen during the entire day; three consecutive 24 hour urine specimens. There is a false negative rate of 5.6%, with false positives of 1% in normal people and 5% in obese individuals.

13. Dexamethasone suppression tests In normal subjects, administration of a supraphysiological dose of glucocorticoid results in suppression of ACTH and hence of cortisol secretion (cortisol <50 nmol/l). This is the basis of dexamethasone suppression tests, of which there are several types.

14. The 48 hour low dose test, which is the most sensitive and specific screening test, entails the administration of 0.5 mg dexamethasone at intervals of exactly 6 hours from 9 am on day one for eight doses, and measurement of serum concentrations of cortisol at 9 am on day three, exactly 6 hours after the last dose of dexamethasone. A negative result is indicated when the serum concentration of cortisol at 9 am on day three is suppressed to < 50 nmol/l. Over 98% of patients with Cushing's syndrome fail to "suppress" serum cortisol on the low dose test.

15. Confirmatory tests Insulin tolerance test In normal subjects and those with pseudo- Cushing's, insulin induced hypoglycaemia (blood glucose concentration <2.2 mmol/l) results in a rise of ACTH and cortisol concentrations. This response to hypoglycaemia is lost in most cases of Cushing's syndrome (90%). This test is contraindicated in anyone with a history of epilepsy or cardiac disease and in those with hypothyroidism and hypoadrenalism.

16. Treatment of Cushing's syndrome Transsphenoidal surgery Pituitary radio-therapy Bilateral or unilateral adrenalectomy Medical therapy

17. Metyrapone and ketoconazole are commonly used. Metyrapone blocks the 11-ß hydroxylase enzyme involved in the final step in cortisol synthesis, whereas ketoconazole acts at several levels and inhibits cortisol synthesis by a direct action on the P450 cytochrome enzyme. The adrenolytic agent, mitotane, has a cytotoxic effect on both normal and malignant adrenocorticol tissue. Its use is mainly in the management of adrenal carcinoma and rarely in Cushing's disease.

18. Conn's syndrome is a disease of the adrenal glands involving excess production of a hormone, called aldosterone. Another name for the condition is primary hyperaldosteronism.

19. Epidemiology of Conn's syndrome Represents under 1% of hypertension causes Peak age 30-50 years Most patients are women

20. Primary Hyperaldosteronism (Conn's syndrome) 1.Solitary adrenal adenomas (80-90%) 2.Bilateral adrenal hyperplasia (10-20%) 3. Adrenal Carcinoma (rare) 4. Unilateral Adrenal Hyperplasia (very rare)

21. Clinical features of Conn's syndrome Often asymptomatic Frontal headache Muscle weakness to flaccid paralysis decreased muscle strength (because of low potassium level) Polyuria and Polydipsia (carbohydrate intolerance) Hypertension

22. Investigation of Conn's syndrome A.Serum Electrolytes 1.Serum Potassium decreased 2.Serum Sodium increased (Mild) 3.Metabolic Acidosis B. Increased serum level of aldosterone C. Greatly decreased serum level of renin Blood may also be taken directly from the adrenal veins (via a catheter passed through a vein in the inguinal region) to determine whether both adrenals are over-secreting aldosterone.

23. Treatment of Conn's syndrome A.Adrenal Adenoma Surgical excision (unilateral adrenalectomy) B. Adrenal Hyperplasia Spironolactone (Aldactone)

24. Congenital adrenal hyperplasia (CAH) is a group of inherited autosomal-recessive disorders in which a genetic defect results in the deficiency of an enzyme essential for synthesis of cortisol and, at times, aldosterone.

25. The incidence of CAH is 0.06 to 0.08 in 1,000 live births. There are several forms of CAH, the most common of which is 21- hydroxylase (21-OH) deficiency, occurring in over 90% of all cases (AAP, 2000).

26. Pathophysiology In a child with CAH, cortisol synthesis is blocked by the lack of the enzyme 21-OH. This reduction of cortisol leads ton increased ACTH production by the anterior pituitary. Prolonged oversecretion of ACTH causes enlargement or hyperplasia of the adrenal glands and excess production of androgens.

27. Clinical features of CHA The enzyme deficiency of 21-OH exposes the fetus to excessive production of androgens. In the male fetus, this causes no physical changes; however, in the female, excessive androgens will virilize (to develop sexual characteristics of a male) the external genitalia, resulting in an enlarged clitoris (possibly to the extent of resembling the male phallus), fusion of the labial folds, and a rugated appearance to the labia. This is known as ambiguous genitalia or pseudohermaphrodism. The ovaries, fallopian tubes, and uterus are normal.

28. Approximately 75% of cases of 21-OH deficiency have salt wasting from a defect in ability to synthesize aldosterone. If not diagnosed at birth, the neonate with 21-OH deficiency and salt wasting will develop a life- threatening hyponatremia, hyperkalemia, and hypovolemia by day 10-14 of life. This is known as adrenal crisis.

29. Acute adrenal (addisonian) crisis Clinical features – fever, dehydration, nausea, vomiting, hypotension, that evolves rapidly to circulatory shock.

30. Treatment of acute adrenal (addisonian) crisis Hydrocortison (Cortef) IV 100 mg as a bolus Intravenous saline and glucose Hydrocortison 10-15 mg/kg as a continuous infusion for 24 hours Decrease one third of the hydrocortison daily dose every day until a maintenance dosage is reached within 5 days

31. Children with atypical 21-OH deficiency will present later (often in the toddler or preschool years) with premature adrenarche (pubic hair development), accelerated growth velocity, advanced bone age, acne, and hirsutism (excessive body hair in a masculine distribution pattern).

32. Investigation of CAH Molecular genetics Increased level of 17- hydroxyprogesteron in serum Increased level of 17-ketosteroids in urine Positive reaction to the glucocorticoid- therapy