1. Endocrine Physiology The Adrenal Medulla, Pheochromocytoma Dr. Khalid Alregaiey

2. Adrenal Medulla: A Modified Sympathetic Ganglion

3. Mechanism: Norepinephrine Release and Recycling

4. Review of Efferent Pathways: Motor and Autonomic

5. Adrenergic Receptors Alpha-Adrenergic Receptors  1 : vasoconstriction, intestinal relaxation, uterine contraction, pupillary dilation  2 :  presynaptic NE (clonidine), platelet aggregation, vasoconstriction,  insulin secretion Beta-Adrenergic Receptors  1 :  HR/contractility,  lipolysis,  renin secretion  2 : vasodilation, bronchodilation,  glycogenolysis  3 :  lipolysis,  brown fat thermogenesis

6. Functions of catecholamine 1. Effect on carbohydrate metabolism: Both of them can increase glycogenolysis and gluconeogenesis and decrease glycogenesis. i. Catecholamine promote the release of glucose from liver and decrees its utilization by muscle; ii. Epinepherine inhibits insulin secretion but promote glucagon secretion. 2. Effect on lipid metabolism: Both of them enhance the breakdown of TAG in adipose tissue. This cause increase in the free fatty acid in the circulation which are effectively utilized by the heart and muscle as fuel source. 3. Effect on physiological function: Cateccholamines increase cardiac output, blood pressure and oxygen consumption. They cause smooth muscle relaxation in bronchi, GIT and blood vessels supplying skeletal muscle.

7. Pheochromocytoma Neuroendocrine tumour of the medulla of the adrenal glands Originates from the chromaffin cells along the paravertebral sympathetic chain extending from pelvis to base of skull >95% are abdominal >90% in adrenal medulla Secretes excessive amounts of epinephrine and norepinephrine 80% occur unilateral Surgically correctable forms of hypertension

8. History First recognized by Von Frankel (1886) Name (pheochromocytoma, dark-colored cell tumor) coined by Pick in 1912 Successful surgery for excision of tumor- Roux & Mayo ( 1926-27)

9. MEN (multiple endocrine neoplasia )

10. Tumor Secretion: Large Pheo: more metabolites (metabolized within tumor before release) Small Pheo: more catecholamines Sporadic Pheo: Norepi > Epi Familial Pheo: Epi > Norepi Paraganglioma: Norepi

11. Clinical Features Hypertension: often severe, occasionally malignant, and may be resistant to treatment with standard antihypertensive drugs Paroxysms or Crisis: frequent or sporadic, occurring at intervals as long as weeks or months. With time, the paroxysms usually increase in frequency, duration, and severity

12. Other Distinctive Clinical Features Increased metabolic rate, such as profuse sweating and mild to moderate weight loss Sinus tachycardia, sinus bradycardia, supraventricular arrhythmias, and ventricular premature contractions have all been noted. Angina and acute myocardial infarction Headache 80% Perspiration71% Palpitation64% Pallor42%

13. Diagnosis The diagnosis is established by the demonstration of increased production of catecholamines or catecholamine metabolites: metanephrine and VMA (vanillylmandelic acid) in plasma and/or urine. The diagnosis can usually be made by the analysis of a single 24-h urine sample, provided the patient is hypertensive or symptomatic at the time of collection.metanephrinevanillylmandelic acid Imaging: CT, MRI, MIBG

14. Tyrosine L-DopaDopamine Norepinephrine Epinephrine Catecholamines Normetanephrine Metaneprine PNMT DBH COMT Metabolites Homovanillic acid (HVA) MAO, COMT Vanillymandelic Acid (VMA) MAO TH Metabolism

15. 24h Urine Collection Positive results (> 2-3 fold elevation): 24h U catechols > 2-fold elevation 24h U total metanephrines > 1.2 ug/d (6.5 umol/d) 24h U VMA > 3-fold elevation Detected by high performance liquid chromatography

16. Plasma Catecholamines Drawn with patient fasting, supine, with an indwelling catheter in place > 30 min Plasma total catechols > 11.8 nM (2000 pg/mL) False positives: same as for 24h urine testing, also with diuretics, smoking

17. Plasma Metanephrines Not postural dependent: can draw normally Secreted continuously by pheo False Positive: acetaminophen