1. Epidemic of Primary Hyperaldosteronism: Facts and Myths Carla Sawan, MD Division of Endocrinology Saint George Hospital University Medical Center, Beirut

2. Epidemiology : Types, prevalence, screening challenges Clinical presentation Diagnosis Laboratory testing Imaging modalities Adrenal Vein Sampling and Subtype Differentiation Treatment Goals Surgical treatment Non-surgical treatment

3. Types of Hyperaldosteronism  Bilateral idiopathic Hyperaldosteronism (IHA)  Most common form 60-70 % of cases of 1ary HA.  Unilateral adenoma (APA)  30-40 % of cases of 1ary HA. Somatic mutation in KCNJ5 gene in 40% of cases. Other rare causes:  Unilateral adrenal hyperplasia (PAH): similar clinical presentation and outcome to APA.  Familial Hyperaldosteronism types I, II and III. Germline muations in KCNJ5 and CACNA1D.  Aldosterone producing adrenocortical carcinomas/ ectopic aldosterone secreting tumors (neoplams in ovary, kidney, etc) Mattsson C, Young WF Jr. Nat Clin Pract Nephrol. 2006

4. Prevalence: wide variation PA is responsible for 5 to 13% of HTN cases and makes up 0.6% of adrenal incidentalomas. Conn 1964  the prevalence of PA in the hypertensive population referred to him was 20%  Possible referral bias. Primary aldosteronism prevalence is  ~ 3% of HTN patients in primary care setting.  ~ 39% of patients with resistant HTN.  ~ 6-10% of HTN patients referred for difficult to manage HTN or suspicion for PA. (Endocrine Society practice guidelines 2008). With the (ARR) used as a screening tool, the prevalence of primary hyperaldosteronism averaged 6% among patients with HTN. Kaplan NM. J Hypertens. Oct 2012J Hypertens.

5. Surgically Curable HTN ??

6. Prevalence of Primary Hyperaldosteronism in Hypertensive Patients Young, 2003

7. Prevalence of PA before and after using of ARR for screening Young et Al. JCEM 2004.

8. ARR detected more normokalemic PA Young et Al. JCEM 2004.

9. Clinical Presentation

10.  Hypertension: usually substantial elevation in both systolic and diastolic pressures without malignant HTN.  Hypokalemia: present in ~ 40% of cases. IHA usually less hypokalemic than APA.  Lack of edema: due to “aldosterone escape” leading to increased diuresis.  Metabolic alkalosis, hypomagnesemia, mild hypernatremia. Mulatero at al, JCEM 2004 Blumenfeld et al. Ann Intern Med 1994

11. Diagnosis

12. Why not using ARR as a routine screening tool? False-positive in about 50% of patients  confirmatory testing is needed. Abnormal ARR level varies from 20 to as high as 69 in various publications  wide range of positive results. PRA levels are low in about 30% of HTN individuals, leading to falsely elevated ARR  More False positives in hypertensive patients. The lower limit of PRA changes from 0.6 ng/ml per h to as low as 0.1 ng/ml per h  high ARR variability. Kaplan. J Hypertens. 2012 J Hypertens.

13. Steps in the evaluation for PA 1) Case detection 2) Confirmatory testing 3) Subtype differentiation and Localization

14. Case detection rather than screening HTN and spontaneous hypokalemia or hypokalemia on low dose diuretic. Severe HTN (>160 mmHg systolic or >100 mmHg diastolic) Drug-resistant hypertension (defined as suboptimally- controlled hypertension on a 3-drug program that includes an adrenergic inhibitor, vasodilator, and diuretic) HTN with an adrenal incidentaloma (> 1 cm) HTN and a family history of early-onset HTN or cerebrovascular accident at age <40 years. All HTN first-degree relatives of patients with primary hyperaldosteronism. Endocrine Society Practice Guidelines 2008

15. Paired Elevation in ARR and PAC PAIRED PAC/PRA ratio and Aldo level Aldosterone concentration >15 ng/dL (416 pmol/L) AND PAC/PRA ratio greater than 20. Usually PRA < than 1 ng/mL per hr (0.2778 ng/L per sec) and undetectable PRC. Tests are performed on blood sample obtained in the morning in a seated ambulatory patient.

16. Confirmatory testing Checking for Aldosterone suppression Orally administered NaCl and measurement of urine aldosterone excretion. OR IV NaCl loading and measurement of Aldo level. Patients who don’t need confirmatory testing) Spontaneous hypokalemia. Undetectable PRA or PRC. PAC >30 ng/dL.

17. Caveats To Testing Most anti-HTN meds can be continued Posture stimulation is not required Discontinue spironolactone or epleronone 6 weeks prior to testing to avoid falsely low ARR

18. Subtype Differentiation: Why does It Matter In case of unilateral disease, surgery is curative. –Unilateral adrenalectomy leads to resolution of hypoK in all cases –HTN is improved in all cases, cured in 30-60% –Total adrenalectomy superior to partial In case of bilateral hyperplasia, no role for surgery. –Unilateral or Bilateral adrenalectomy does not affect HTN –Medical Therapy Improves BP control in all cases and normalizes CV mortality

19. Subtype Differentiation: Difficulties with Adrenal Vein Sampling AVS was first introduced in 1967 Relies on finding a 4x difference in aldosterone secretion between 2 sides, done under cosyntropin stimulation. Abandoned as technically difficult and due to unclear role in overall management paradigm. Until …

20. Subtype Differentiation: Critical Role of AVS Primary aldosteronism: adrenal venous sampling. Young WF JrYoung WF Jr, Stanson AW, Grant CS, Thompson GB, van Heerden JA.Stanson AWGrant CS Thompson GBvan Heerden JA Surgery, Dec 1996

21. Subtype Differentiation: Critical role of AVS 34 patients with confirmed PA and a spectrum of CT scan findings. Results: –40% patients with normal or minimal adrenal limb thickening had a unilateral source of aldosterone –40% with apparent unilateral microadenoma had an ipsilateral APA –44% patients with bilateral adrenal masses had a unilateral source of aldosterone secretion –3/4 patients with unilateral atypical adrenal macroadenomas had ipsilateral aldosterone-producing adenomas. Young et Al. Surgery, Dec 1996 Significant discordance between CT scan findings and real source of Aldo excess found on AVS

22. Subtype Differentiation: Critical Role of AVS 203 pts at Mayo Clinic with PA from 1990-2003 Both adrenal veins catheterized in 194 patients Based on CT only – 42 (25%) would have been excluded as surgical candidates –48 (25%) would have had inappropriate surgery. Accuracy of CT was only ~ 53% Young et Al, Surgery 2004

23. No AVS needed

24. Treatment

25. Goals Normalizing BP and decreasing cardiovascular mortality.

26. Milliez et al, J Am Coll of Cardiology 2005  Broussais Hospital, Paris, between 1997-1999.  Case-Control retrospective study  124 patients with PA (65 pts with APA, 59 pts with IHA) matched with 465 pts with essential HTN.  Comparison of events between 2 groups:  Prior strokes (12.9 % vs 3.4 %)  Nonfatal myocardial infarction (4.0 % vs 0.6 %)  Atrial fibrillation (7.3 % vs 0.6 %) Difference was statistically significant, comparable between IHA and APA.

27. Preoperative Preparation 1) HTN should be controlled, preferably with mineralocorticoid receptor antagonist 2) HypoK should be corrected with K suppl. BP response to spironolactone pre-op predicts the BP response to unilateral adrenalectomy in patients with unilateral disease. Young et al. Ann Intern Med 2001

28. Postoperative Follow-Up 1.Plasma aldosterone should be measured the day after surgery to assess for cure. 2.K supplements and spironolactone should be discontinued and, if possible, antihypertensive therapy should be decreased. 3.Patients should be monitored closely for hyperkalemia 2/2 suppression of contralateral adrenal gland 4.Na-rich diet on discharge

29. Possibly under-diagnosed disease? Persistent notion of “Conn’s Tumor” triad for diagnosis to be made Treatment complexity 30% AVS failure rate in the US

30. Outcomes of surgery 1.HTN is cured in 40% of cases and improved in all. 2.Hypokalemia and Hyperaldosteronism are cured in all cases undergoing surgery.

31. References 1.Slides obtained with courtesy of Dr Julia Kharlip at U.Penn, PA USA 2.Hannemann A, Wallaschofski H. Prevalence of primary aldosteronism in patient’s cohorts and in population-based studies: a review of the current literature. Horm Metab Res 2012. 3.Blumenfeld JD, Sealey JE, Schlussel Y, et al. Diagnosis and treatment of primary hyperaldosteronism. Ann Intern Med 1994. 4.Funder JW, Carey RM, Fardella C, et al. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2008. 5.CONN JW. Aldosterone in clinical medicine; past, present, and future. AMA Arch Intern Med 1956. 6.Milliez P, Girerd X, Plouin PF, et al. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol 2005. 7.Sawka AM, Young WF, Thompson GB, et al. Primary aldosteronism: factors associated with normalization of blood pressure after surgery. Ann Intern Med 2001. 8.Young WF, Stanson AW, Thompson GB, et al. Role for adrenal venous sampling in primary aldosteronism. Surgery 2004

32. Thank You