Endocrine Hypertension and Adrenal Incidentalomas

1. Endocrine Hypertension and Adrenal Incidentalomas

2. Goals and Objectives • Review indications for secondary workup of hypertension • Discuss major Endocrine causes for hypertension • Screening and confirmatory testing • Localization • Treatment • Discuss evaluation of adrenal incidentalomas • Initial diagnostic workup • Indications for surgery or biopsy • Long-term monitoring schedules

3. Secondary Hypertension • 2006 AACE Guidelines • Suspect secondary cause: • Sudden onset, intermittant, especially labile • Contributing factors absent • Abnormal clinical or lab features • Cushingoid habitus • Hypokalemia • Resistant to therapy • Uncontrolled with 3 medications including diuretic

4. Endocrine Hypertension

5. Primary Hyperaldosteronism • Incidence varies • Overall 6.1% • Stage 1 (<160/<100) 2% • Stage 2 (<180/<110) 8% • Stage 3 (>180/>110) 13% • Diagnostic clues • Hypokalemia (spontaneous or diuretic-induced) • Hypomagnesemia • Metabolic alkalosis

6. Primary Hyperaldosteronism • Indications for screening • Stage 2/3 HTN (BP >160/>100) • Resistant HTN (BP >140/>90 despite 3 BP meds) • 17-23% prevalence • Spontaneous or diuretic-induced hypokalemia • HTN with adrenal incidentaloma • 1-10% prevalence

7. Primary Hyperaldosteronism • Screening test • Aldosterone concentration (ng/dL):plasma renin activity (ng/mL/h) ratio • “Aldo renin ratio” or “ARR” • >20 • >30 • >40 • +/- Aldosterone concentration >15ng/dL • 16-37% of primary hyperaldo patients have aldo of 9-16ng/dL

8. Primary Hyperaldosteronism • Confirmatory tests • Saline load • Aldosterone remains >7ng/dL • Oral salt load • Ensure normal serum potassium • 2g sodium chloride TID for 4 days • 24-hr urine aldosterone on day 4-5 >12mcg/24-hr • Fludricortisone suppression test • Ensure renin activity <1ng/mL/h • Serum aldo >6ng/dL • Captopril challenge • <30% aldo suppression from initial level

9. Primary Hyperaldosteronism • Localization • Adrenal CT scan • Better spatial resolution than MRI • Adrenal venous sampling Young, W, et al. “Role for adrenal venous sampling in primary aldosteronism.” Surgery, 2004;136:1227-35.

10. Primary Hyperaldosteronism

11. Primary Hyperaldosteronism • Treatment • Goals • Normalize potassium • Normalize BP • Antagonize aldosterone’s effect on endothelium

12. Primary Hyperaldosteronism • Treatment • Adrenalectomy • Only for aldosterone producing adenomas (APA) or unilateral adrenal hyperplasia (UAH) • Medical therapy • Spironolactone • Eplerenone if limited by side effects • Amiloride, triamterene, ACE-I/ARB’s • (<1% of hyperaldo cases due to glucocorticoid-remediable aldosteronism) • (Usually suggested by FHx of HTN <20yo and hemorrhagic CVA) • (Diagnosed by genetic testing) • (Dexamethasone or prednisone in lowest effective doses)

13. Pheochromocytoma • Rare, mostly benign tumors of adrenal medulla • 2-8 cases per million per year • 10% extradrenal (“paragangliomas”) • 10% bilateral • 10% recur after initial treatment • 10% malignant • May be episodic or part of familial syndrome • HTN may be episodic or sustained • Symptoms include • Palpitations • Headaches • Diaphoresis • Orthostatic hypotension

14. Lenders, J, et al. “Biochemical diagnosis of pheochromocytoma: which test is best?” JAMA. 2002. 287(11):1427-34. Sensitivity: Specificity: • Multicenter cohort study of 214 patients with confirmed PC and 644 patients determined to not have PC • Plasma fractionated metanephrines (99%) • Urinary fractionated metanephrines (97%) • Urinary catecholamines (86%) • Plasma catecholamines (84%) • Urinary total metanephrines (77%) • Urinary VMA (64%) • Urinary VMA (95%) • Urinary total metanephrines (93%) • Plasma fractionated metanephrines (89%) • Urinary catecholamines (88%) • Plasma catecholamines (81%) • Urinary fractionated metanephrines (69%)

15. Lenders, J, et al. “Biochemical diagnosis of pheochromocytoma: which test is best?” JAMA. 2002. 287(11):1427-34. Sensitivity: Specificity: • Multicenter cohort study of 214 patients with confirmed PC and 644 patients determined to not have PC • Plasma fractionated metanephrines (99%) • Urinary fractionated metanephrines (97%) • Urinary catecholamines (86%) • Plasma catecholamines (84%) • Urinary total metanephrines (77%) • Urinary VMA (64%) • Urinary VMA (95%) • Urinary total metanephrines (93%) • Plasma fractionated metanephrines (89%) • Urinary catecholamines (88%) • Plasma catecholamines (81%) • Urinary fractionated metanephrines (69%)

16. Pheochromocytoma • Labs can be affected by: • Other medications • TCA • Antipsychotics • Levodopa • Amphetamines • Clonidine withdrawal • Phenoxybenzamine • Decongestants • Ethanol • Acetaminophen • Physical stressors • Stroke • Major operation • Myocardial infarction • Heart failure • Obstructive sleep apnea

17. Algorithmic Approach to Diagnosis • Determine if clinical suspicion is high • Past h/o treated PC and recurrent HTN or dizziness • FH of PC • MEN2 or other genetic syndrome • Von HippelLindau • Neurofibromatosis type 1 • Familial paraganglioma • Incidental adrenal mass with suggestive characteristics • High Hounsfield unit density • Delayed washout <50% in 10min • High intensity on T2 • Cystic and hemorrhagic changes • Bilateral • Large size >4cm)

18. Pheochromocytoma • Treatment • Volume expansion • Medications • Alpha Blockers • Phenoxybenzamine • Prazosin • Later BB’s or CCB’s (or both) • Surgical excision • Curative in 75% of cases • Can be done laparoscopically if • Tumor <6cm • No evidence of invasion into adjacent tissue • No regional or metastatic disease • Normal contralateral adrenal gland

19. Cushing’s Syndrome • Uncommon secondary cause of HTN • 75% have HTN • Subjective/objective findings • Centripetal obesity • Supraclavicular fat pad • Facial plethora • Hirsutism • Acne • Widened, purple striae • Glucose intolerance • Hypokalemia • Hypomagnesemia • Metabolic alkalosis

20. Cushing’s Syndrome • Diagnosis • Low dose DXM suppression (serum cortisol >5μg/dL) • 24-hr urine cortisol >50μg • Late night salivary cortisol >145ng/dL • Midnight serum cortisol >1.8μg/dL • Localization • ACTH or non-ACTH mediated • ACTH >5pg/mL • High dose (8mg) DXM suppression • Inferior petrosal vein sampling

21. Cushing’s Syndrome • Treatment • Surgical • Adrenalectomy • Trans-sphenoidal pituitary adenoma excision • (Bilateral adrenalectomy) • Medication • Ketoconazole • Mitotane

22. Other Hormonal and Enzymatic Causes for HTN • Adrenal • Enzyme deficiencies • 11β-hydroxylase • 17α-hydroxylase • 11β-hydroxysteroiddehydrogenase • 11-Deoxycorticosterone secreting tumors • Thyroid • Hyper- and hypo-thyroidism • Hyperparathyroidism • Pituitary • Acromegally • Renal • Renin-secreting tumor • Fibromuscular dysplasia • Renal artery stenosis • Liddle syndrome • Hypokalemia • Metabolic alkalosis • LOW aldosterone • Pregnancy • Gestational HTN • Eclampsia/HELLP • Hydatidiform mole

23. Adrenal Incidentalomas • Glomerulosa • Aldosterone • Fasciculata • Cortisol • Reticularis • DHEA • Androstenedione • Medulla • Epinephrine • Norepinephrine • Dopamine

24. Adrenal Incidentalomas • Definition • Unsuspected mass found on imaging • Incidence in autopsy series 8.7% • Diagnostic considerations • 1. Is the mass hormonally active? • 80% nonfunctioning • 5% subclinical Cushing Syndrome • 5% Pheochromocytoma • 1% aldosterone-producing adenoma (Conn’s tumor) • 2. Does it have worrisome radiologic features for malignancy? • 5% adrenocortical carcinoma • 3. Does the patient have a previous history of a malignant lesion? • 2.5% metastatic malignancies • Most commonly Lung, breast, stomach, kidney, melanomas, lymphomas

25. History and Physical • History • Weight change • Easy bruising • New HTN • New DM • Proximal muscle weakness • Edema • Fatigue • Virilization • Headaches • Anxiety • Sweating • Palpitations • Pallor • Low potassium • “B” symptoms • History of cancer • Current/prior smoking • Family history of Endocrine tumors or other cancers • Physical • Blood pressure • Pulse • Central obesity • Dorsocervical/supraclavicular fat pad • Facial plethora • Hirsutism • Acne • Ecchymoses • Striae • Muscle wasting

26. Suggested Evaluation • Biochemical evaluation • Cushing’s Syndrome • 1mg DXM suppression test • 24-hr urine free cortisol • Pheochromocytoma • Plasma fractionated metanephrines • 24-hr urine total metanephrines and fractionated catecholamines • Aldosterone concentration:plasma renin activity ratio • Only if hypertensive

27. Suggested Evaluation • Imaging • High resolution adrenal CT with contrast • Benign features • <10HU on noncontrast CT • 80-90HU with >50% washout on contrast CT • Pheochromocytomas generally enhance to >100HU • T2-weighted adrenal MRI • Benign features • High-signal enhancement on T2 • Highly characteristic of pheochromocytoma

28. Surgical Indications • Any lesion with concerning radiographic features • Most lesions >4cm • <4cm = 2% risk of malignancy • 4.1-6cm = 6% risk • >6cm = 25% risk • Unilateral hormone-producing adenomas • Except “Subclinical” Cushing’s Syndrome • Normal physical appearance, BP, potassium, insulin sensitivity, BMD • New hormonal activity or >1cm growth

29. Perioperative Management • Adrenocortical carcinoma • Full hormonal assessment • Open adrenalectomy recommended • Cortisol-producing adenoma • Rule out pheochromocytoma • Glucose and BP management • DVT and UGIB prophylaxis • Postoperative hydrocortisone • Pheochromoctyoma • Alpha blockade 1-3 weeks preoperatively • Long-term biochemical monitoring for recurrence • Aldosterone-producing adenoma • Rule out pheochromocytoma • BP, potassium, magnesium management

30. Long-term Monitoring of Adenomas • Biochemical • Annual for 5yrs • Risk of becoming hormonally active at 1, 2, and 5yrs • 17%, 29%, and 47%, respectively • Cushing’s Syndrome most likely to develop • Imaging • Re-assess size at 3-6mo • Annual for 1-2yrs • Risk of enlarging at 1, 2, and 5yrs • 6%, 14%, and 29%, respectively

31. References • Funder, J, et al. “Case detection, diagnosis, and treatment of patients with primary hyperaldosteronism: an Endocrine Society clinical practice guideline.” J ClinEndocrinol and Metab, 2008;93(9):3266-81. • Nieman, L, et al. “The diagnosis of Cushing’s Syndrome: an Endocrine Society clinical practice guideline.” J ClinEndocrinol and Metab, 2008;93(5):1526-40. • Torre, J, et al. “American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of hypertension.” Endo Pract, 2006;12(2):193-222. • Young, W, et al. “Role for adrenal venous sampling in primary aldosteronism.” Surgery, 2004;136:1227-35. • Zeiger, M, et al. “American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons medical guidelines for the management of adrenal incidentalomas.” Endo Pract, 2009;15(Suppl 1):1-20.