CONTROVERSIES IN MINERALOCORTICOID

HYPERTENSION:THE CASE OF PRIMARY ALDOSTERONISM

José A. Rodriguez-Portales, MD, FACP

Division of Internal MedicineDepartment of Endocrinology

Catholic University of Chile School of Medicine

JW Conn

Primary aldosteronism,

a new clinical syndrome.

J Lab Clin Med 1955

• Aldosterone-producing adenoma• Hypertension

• Hipokalemia• Metabolic Alkalosis

CONN’S SYNDROME20% of pts. with hypertension

have it

OK,10%

Are we missing the diagnosis

in 10% of our hypertensive patients?

Diagnosis of Primary AldosteronismDiagnosis of Primary Aldosteronism

Case-finding strategies

Confirmatory tests

Subtype evaluation tests

CLASSICAL TRIAD OF PRIMARY CLASSICAL TRIAD OF PRIMARY HYPERALDOSTERONISMHYPERALDOSTERONISM

HypertensionHypokalemiaSuppressed PRA

< 1% ofhypertensive pts.

have it

PRIMARY HYPERALDOSTERONISM:increased diagnosis in normokalemic patients

0

10

20

30

40

50

60

70

1985 86 87 88 89 90 91 92 93

K+ normalK+ low

# pa

tien

ts /

year

YearGordon RD, Lancet 1994; 344: 240-243.

FREQUENCY OF HYPOKALEMIA IN PATIENTS WITH PRIMARY ALDOSTERONISM

Mulatero P, Stowasser M, Loh K, Fardella CE et al. J Clin Endocrinol Metab. 2004.Mulatero P, Stowasser M, Loh K, Fardella CE et al. J Clin Endocrinol Metab. 2004.

Hypokalemia in only 25%

CASES OF 1ary ALDOSTERONISM DIAGNOSED BEFORE AND AFTER USING THE PA/PRA RATIO

Mulatero P, Stowasser M, Loh K, Fardella CE et al. J Clin Endocrinol Metab 2004Mulatero P, Stowasser M, Loh K, Fardella CE et al. J Clin Endocrinol Metab 2004..

15-FOLD INCREASE

CONFIRMATORY TESTSCONFIRMATORY TESTS

Oral sodium loading testNa intake > 13 g/day UNa V > 200 mEq/dayThird day: 24-h urine collection for Na, aldo, creatUAldo > 12 μg/24 h Autonomous secretionSensitivity 96% Specificity 93%

CONFIRMATORY TESTSCONFIRMATORY TESTS

Saline infusion:Isotonic saline infusion, 500 ml/h for 4 hours. Positive result: serum aldosterone > 5 ng/dl.

Aldosterone suppression with fludrocortisone: Fludrocortisone 0.1 mg/6h for 4 days. Diet supplemented with NaCl 6 g/day Serum potassium must be monitored daily Positive result: serum aldosterone > 5 ng/dl

0

20

40

60

80

0 50 100 150 200 250

Time (min)

ZGH

APA

Normal

ALDOSTERONE RESPONSE TO SALINE LOAD

Holland OB, Hypertension 1984

SERUM ALDOSTERONE/PRA RATIO IN NORMOTENSIVE SUBJECTS

Fardella C.E., Mosso L., Montero J. et al Rev. Med. Chile 2000Fardella C.E., Mosso L., Montero J. et al Rev. Med. Chile 2000

305 HYPERTENSIVE PATIENTS305 HYPERTENSIVE PATIENTS

PA/PRA

44 PA/PRA ≥ 25 261 PA/PRA < 25

13 classic 1ary aldo

PA > 16ng/dl

PRA < 0,5 ng/ml/h

PA/PRA > 50

31 probable 1ary aldo

29 1ary aldo (9.5%) Essential hypertension

13 (+) 16 (+)

Fludrocortisone

Fardella C.E., Mosso L., Montero J. et al J Clin Endocrinol Metab. 2000Fardella C.E., Mosso L., Montero J. et al J Clin Endocrinol Metab. 2000

546 (10.7)4994Total

61(6.0)Captopril>201020Japan2004Omura M

54 (18.0)Fludrocortisone>30300Australia2003Stowasser M

66 (6.3)Captopril>351046Italy2003 Rossi E

37 (6.1)Fludrocortisone>25609Chile2003Mosso LM

18 (20.0)PRA and Aldo ur c>2088bUSA2002Calhoun DA

106 (21.0)NA>20505USA2002Schwartz GL

15 (17.0)CT-NMR-I131 scan>10090USA2001Gallay BJ

22 (10.1)NA>36216South Africa2000Rayner BL

16 (4.6)Saline infusion>20350Singapore2000Loh KC

43 (9.2)Fludrocortisone>27465UK2000Lim PO

Prevalencen (%)

Confirmatorytest

Author (Ref) Year Country Patients (n) ARR (ng/dL / ng/mL·h)

29 (9.5)Fludrocortisone>25305Chile2000Fardella, CE

PREVALENCE OF HYPERALDOSTERONISM IN DIFFERENT POPULATIONS

William F YOUNG JrMayo, Rochester MN

Celso GOMEZ-SANCHEZJackson, MS

Carlos FARDELLALorena MOSSOSantiago, Chile

Paolo MULATEROFranco VEGLIO

Torino, Italy

Keh-Chuan LOHSingapore

Michael STOWASSERRichard D GORDONBrisbane, Australia

SUBTYPES OF 1ary HYPERALDOSTERONISM

Aldosterone-producing adenoma (APA) 35%

Bilateral Adrenal Hyperplasia (BAH) 65%

Unilateral Adrenal Hyperplasia (PAH) < 1%

Aldosterone-producing carcinoma (APC) < 1%

Aldosterone-producing carcinoma < 1%

FAMILIAL FORMS

Glucocorticoid-Remediable Aldosteronism (GRA) < 2%

Familial HA Type II (FH-II) < 2%

FREQUENCY OF ALDOSTERONE-PRODUCING ADENOMA

Mulatero P, Stowasser M, Loh K, Fardella CE et al. J Clin Endocrinol Metab 2004.Mulatero P, Stowasser M, Loh K, Fardella CE et al. J Clin Endocrinol Metab 2004.

APA only in 30% of 1ary aldo cases

DIAGNOSING SUBTYPES OF DIAGNOSING SUBTYPES OF HYPERALDOSTERONISMHYPERALDOSTERONISM

Adrenal CT Scan or MRI.

Adrenal veins catheterization with simultaneous sampling for aldosterone and cortisol.

Other tests: postural test, post spironolactone urinary aldosterone measurement, dexamethasone suppression test, 18 OH B, 18 OH cortisol derivatives, genetic testing.

ADENOMA CORTICO SUPRARRENAL ADRENAL CT SCAN IN HYPERALDOSTERONISM

Helpful in diagnosing APA if > 5 mm.

Helpful in diagnosing BAH if area > 10 mm.

Suggests adrenal cancer if > 6 cm.

Micro-macronodular hyperplasias may suggest a false diagnosis of APA

Main disadvantage: incidentalomas

Right Adrenal Vein

Inferior Vena Cava

Left Adrenal Vein

ADRENAL VEIN SAMPLING

Best method to detect lateralization

Adrenal vein/inferior vena cava cortisol ratio must be >2

Lateralization exists if Aldo/cortisol ratio is 4-fold higher than in contralateral adrenal vein

Adrenal vein catheterization may help avoid unnecesary surgery and identify microadenomas not detected by CT scanning.

Concordance: APA 8/15, BAH 4/21

Young WF. Clinical Endocrinology 2007; 66:607-618

Why is Primary Aldosteronism Why is Primary Aldosteronism important ?important ?

Primary aldosteronism may be one of the most frequent causes of secondary hypertension.

Hypertension can be cured or successfully treated with mineralocorticoid antagonists.

Aldosterone can cause vascular and cardiac damage independent from hypertension.

End-Organ Damage of AldosteroneEnd-Organ Damage of Aldosterone

PA patients compared with hypertensive patients:PA patients compared with hypertensive patients:Higher prevalence of metabolic syndromeHigher urinary albumin excretionIncreased arterial wall stiffnessGreater left ventricular massHigher rate of cardiovascular events

1,99

8,02

13,2

20

0

5

10

15

20

25

Stage1

Stage2

Stage3

Resistant

Calhoun D, Hypertension 2002Mosso L, Fardella C . Hypertension 2003

PREVALENCE OF 1ary ALDO BY SEVERITY OF HT (JNC VI)

Milliez P et al. J Am Coll Cardiol 2005

0

5

10

15

20

25

30

35

40

1ary ALDO EH 1ary ALDO EH

LVH-US LVH-ECG

p=0.01 p=0.001

PREVALENCE OF LEFT VENTRICULAR HYPERTROPHY IN PATIENTS WITH 1ary ALDO vs. EH

1ary ALDO EH

0

10

20

30

40

50

60 ACLVF

Rossi GP Hypertension 2002

DIASTOLIC DYSFUNCTION IN PATIENTS WITH 1ary ALDO vs. EH

0

10

20

30

40

50

60

70

80

PREVALENCE OF MICROALBUMINURIA IN PATIENTS WITH 1ary ALDO

Halimi JM, J Hypertens 1995

1ary ALDO LR-EH NR-EH

HYPERTENSION AFTER SURGERY IN PATIENTS WITH PRIMARY HYPERALDOSTERONISM

Rochester

66% 33%

1%

65%

35%

TorinoBrisbane

55%45%

Singapore

55% 40%

5%

Cured

Improved

No change

Santiago

30%70%

Mulatero P, Stowasser M, Loh K, Fardella CE et al. J Clin Endocrinol Metab 2004Mulatero P, Stowasser M, Loh K, Fardella CE et al. J Clin Endocrinol Metab 2004..

If aldosterone is an “evil” hormone and primary hyperaldosteronismis worse than hypertension alone, should we undertake a thorough

search for this condition in all patients with hypertension?

Who should be screened for PA?Who should be screened for PA?

Hypertension and hypokalemiaResistant hypertensionAdrenal incidentaloma and hypertensionOnset of hypertension <20 years of ageSevere hypertension (>160/100 mm Hg)Whenever considering secondary hypertension

Young WF. Clinical Endocrinology 2007; 66:607-618

How to screen?How to screen?

Plasma aldosterone/plasma renin activity ratioCorrect hypokalemiaLiberalize sodium intakeWithdraw MCH receptor blockers, OC 4 weeksUse α blockers + verapamil if needed for HT

CONCLUSIONSCONCLUSIONS

Primary hyperaldosteronism is a more frequent cause of hypertension than previously thought.

Primary hyperaldosteronism can be diagnosed by the combination of a high PA/PRA ratio and failure to suppress aldosterone with volume-expanding maneuvers.

At present time, case detection can be recommended only for selected patient groups.

Primary hyperaldosteronism should be diagnosed not only to treat hypertension but also because aldosterone by itself may be harmful for the cardiovascular system and kidneys.