Bosch, De Lange & Koning Division of Endocrinology 25 February 2011

1. A RARE CAUSE OF CURABLE HYPERTENSION Bosch, De Lange & KoningDivision of Endocrinology25 February 2011

2. History • Mrs TM 31 yr black † G5P1 married hairdresser Fouriesburg O

3. History • No current main complaint • Hypertension • Dx 2005 (at age 26) • Associated with poor obstetrical history (G5P1)related to previously uncontrolled hypertension • Requiring more than 3 anti-HPT drugs • Family history: mom and dad has HPT

4. 3 Stillbirths & 1 Miscarriage Date GestationFetus Blood pressure 06/2005 7 /12 † Preg induced HPT (PIH) 09/2007 5/12 † PIH 10/2008 5/12 † PIH 10/2009 5/12 † PIH   HPT 07/2010 7/12 Alive Superimposed pre-eclamp

5. 07/2010 - 5th pregnancy: • Superimposed pre-eclampsia • Post-partum cardiomyopathy (resolved) • Paroxysms of a feeling of impending doom associated with hypertension Triggered by micturition

6. Medication • Post partum blood pressure control • Ridaq 25 mg dlypo • Atenolol 50 mg dlypo • Pharmapress 10 mg bdpo • Amlodipine 10 mg dlypo

7. Further enquiry • No previous stroke • No previous DVT/PE • No risk factors for atherosclerosis • No triad of headache/palpitations/sweating • No history of glucocorticoid use • No symptoms of hypothyroidism

8. Examination • Vitals: • BP 122/70 • PR 89/min regreg • BMI 18.59 • General examination: NAD • All systems normal • No evidence of TOD • No renal artery bruits • All pulses even

9. Baseline special investigations • U-dipstick: NAD • ECG: No LVH • UEC: Na 139 K 4.1 Ur 6.0 Creat 81 • Renal sonar: R kidney 97 mm L kidney 94 mm • Creatininclearence 77.9 ml/min & prot excretion 0.15 g/24 hr • HIV non-reactive

10. Summary… Differential diagnosis? • Young hypertensive • Resistant hypertension • Multiple fetal losses due to hypertension • Paroxysm of hypertension feeling of impending doom triggered by micturition

11. Secondary HYPERTENSION • It is important to be aware of the clinical clues suggesting the possible presence of secondary hypertension • Many of these disorders can be cured, leading to partial or complete normalization of the blood pressure • It is not cost effective to perform a complete evaluation in every hypertensive patient 1Who should be screened for renovascular or other causes of secondary hypertension? Uptodate 18.1

12. Who to screen for SECONDARY HPT? • Severe or resistant hypertension Resistant HPT: the persistence of hypertension despite concurrent use of three antihypertensive agents of different classes • Malignant hypertension Patients with severe HPT and signs of TOD such as ARF, retinal hemorrhages or papilledema, heart failure, or neurologic disturbance 1Who should be screened for renovascular or other causes of secondary hypertension? Uptodate 18.1

13. Who to screen for SECONDARY HPT? • Age < 30 years • in non-obese • non-black patients • with a confirmed negative family history of • and no other risk factors (eg, obesity) for HPT • Proven age of onset before puberty • An acute rise in blood pressure over a previously stable value 1Who should be screened for renovascular or other causes of secondary hypertension? Uptodate 18.1

14. Disorder Suggestive clinical features Renovascular Acute  s-creatinine 30 % after initiating ACE inhibitor or ARB disease Moderate to severe HPT with diffuse atherosclerosis, a unilateral small kidney, or a asymmetry in renal size  1.5 cm that cannot be explained by another reason Moderate to severe HPT with recurrent episodes of flash pulmonary edema Onset of stage II hypertension after age 55 years Systolic or diastolic bruit (not very sensitive) Primary renal Elevated serum creatinine concentration disease Abnormal urinalysis Oral contraceptives New elevation in blood pressure temporally related to use Pheochromocytoma Paroxysmal elevations in blood pressure Triad of headache (usually pounding), palpitations, and sweating Primary Unexplained hypokalemia with urinary potassium wasting aldosteronism however, more than one-half of patients are normokalemic Cushing's syndrome Cushingoidfacies, central obesity, proximal muscle weakness, and ecchymoses May have a history of glucocorticoid use Sleep apnea Primarily seen in obese men who snore loudly while asleep syndrome Daytime somnolence and fatigue and morning confusion Coarctation of HPT in the arms with diminished/delayed femoral pulses + low/unobtainable BP in legs the aorta Left brachial pulse is diminished and equal to the femoral pulse if origin of the left subclavian artery is distal to the coarct Hypothyroidism Symptoms of hypothyroidism Elevated serum thyroid stimulating hormone Primary Elevated serum calcium hyperparathyroidism 1Who should be screened for renovascular or other causes of secondary hypertension? Uptodate 18.1

15. Approach to the patient with possible Pheochromocytoma Adler J T, Meyer-Rochow GY, Chen H, Benn DE, Robinson BG, Sippel RS and Sidhu SB. Pheochromocytoma: Current Approaches and Future Directions. The Oncologist 2008;13:779–793

16. Tricyclic antidepressants , Levodopa Amphetamines, ProchlorperazineReserpine Buspirone and most psychoactive agents Withdrawal from clonidine and other drugs Ethanol , Acetaminophen Drugs containing adrenergic receptor agonists eg, decongestants • Typical triad (headache, palpitations, sweating)  HPT • Patients with spells that relate to paroxysmal elevations in BP Spells = a sudden onset of a symptom/symptoms that are recurrent, self-limited, and stereotypic in nature • Paroxysmal hypertension • Adrenal incidentalomas • High risk for pheochromocytoma • familial syndromes: MEN2, von Hippel-Lindau syndrome • previously surgically cured pheochromocytomas /paragangliomas Adler J T, Meyer-Rochow GY, Chen H, Benn DE, Robinson BG, Sippel RS and Sidhu SB. Pheochromocytoma: Current Approaches and Future Directions. The Oncologist 2008;13:779–793

17. 24 hr urine collection • Metadrenaline 1539 nmol (264-1729) • Metnoradrenaline227 641 (480-2424) • Vanillylmandelic acid 514.2umol (10.1-35.4) • Homovanillic acid 133.1umol (20.3-42.3)

18. CT Abdomen

19. Localisation – MRI Abdomen

20. Mrs. TM Illustration • Intra partum • Post partum • Spells of • Impending doom • Post micturition • When in supine position • Paroxysmal hypertension

21. Evaluation and treatment of catecholamine-producing tumors. Uptodate 18.1

22. 123 I – MIBG scan

23. Evaluation and treatment of catecholamine-producing tumors. Uptodate 18.1 Initiated Cardura XL Surgery referral

24. PHOTO TAKEN BY Dr. Michael Ackermann Surgical Resection

25. PHOTO TAKEN BY Dr. Michael Ackermann

26. PHOTO TAKEN BY Dr. Michael Ackermann ADRENALIN PHENIELEPHRINE TNT REMIFENTANIL

27. Arterial Supply tied off 9 minutes of MAP < 60mmHg Trendelenburg Packed Cellsx2 Adrenalin Bolus total 700µg Adrenalin infusion 0,2µg/kg/min Phenielephrine infusion 1µg/kg/min CaGluconate SoluCortef Aortic Compression TNT 0,1-0,2 µg/kg/min Remifentanil 0,3-0,4µg/kg/min MgSO4 1g/hr MAC 1,5 Propofol bolus Packed Cells x2 Adrenalin 0,2µg/kg/min Phenielephrine 1µg/kg/min Tumour removed Haemorrhage By Dr. Michael Ackermann

28. PHOTO TAKEN BY Dr. Michael Ackermann PLT X1 FFP X4 CRYO X8 PACKED CELLS X8

29. PHOTO TAKEN BY Dr. Michael Ackermann

30. Location of Paragangliomas • Paraganglionic system occupies four families • 1) branchiomeric • 2) intra-vagal • 3) aortico-sympathetic • 4) visceral-autonomic Whalen RK, Althausen AF and Daniels GH. Extra-adrenal pheochromocytoma. Review article. The Journal of Urology 147:1-10.

31. H&E stain: Para-aortic paraganglioma showing pleomorphic tumour cells arranged in well defined nests (Zellballen) set in a fibrovascularstroma (background). High magnification demonstrating occasional bizarre nuclei termed endocrine atypia . PHOTOS TAKEN BY Dr. Jacqueline Goedhals

32. Immunohistochemical stain for chromogranin (left) and synaptophysin (right) demonstrating strong cytoplasmic positivity PHOTO TAKEN BY Dr. Jacqueline Goedhals PHOTO TAKEN BY Dr. Jacqueline Goedhals

33. Pheochromocytoma: Current Approaches and Future Directions. The Oncologist 2008;13:779–793

34. Rule of P’s Characteristics % • 20% are extra-adrenal • 10% are bilateral • 25% are familial • 10% are not associated • with hypertension • 15% are malignant • hematogenous and lymphatic spread: bone, liver, and lung • <10% recurrence • 75% HPT cure post  • B: >95% 5yr survival • M: +- 50% 5yr survival • Palpitations • Pallor • Perspiration • Pain (headache) • Pressure • 0.1 % of HPT cases secondary to pheochromocytoma or paragangliomas Davidson’s Principles & Practice of Medicine 21st Ed. & Harrisons Principles of Internal Medicine 16th Ed.

35. Outcome • 1 healthy baby boy • NORMOTENSIVE • On no antihypertensive drugs • Will be followed up in 6 months for possible recurrence or metastases

36. Take home message… It is important to have a high clinical index of suspicion for a pheochromocytoma or paraganglioma as a rare, secondary and often curable cause of hypertension in young patients

37. References • Who should be screened for renovascular or other causes of secondary hypertension? Uptodate 18.1 • Adler J T, Meyer-Rochow GY, Chen H, Benn DE, Robinson BG, Sippel RS and Sidhu SB. Pheochromocytoma: Current Approaches and Future Directions.The Oncologist 2008;13:779–793 (www.TheOncologist.com) • Evaluation and treatment of catecholamine-producing tumors. Uptodate 18.1 • Melicow M. One hundred cases of pheochromocytoma (107 tumors) at the Columbia-presbyterian medical center, 1926-1976. A Clinicopathological Analysis. Cancer 40:1987-2004, 1977. • Whalen RK, Althausen AF and Daniels GH. Extra-adrenal pheochromocytoma. Review article. The Journal of Urology 147:1-10. • Davidson’s Principles & Practice of Medicine 21st Ed. • Harrisons Principles of Internal Medicine 16th Ed.