1925 Mo1925 Mo

Quando il surrene è causa di Quando il surrene è causa di ipertensioneipertensione

Alberto MorgantiAlberto Morganti

Centro di Fisiologia Clinica e Ipertensione , Centro di Fisiologia Clinica e Ipertensione , Ospedale Policlinico, MilanoOspedale Policlinico, Milano

Giornate Mediche FiorentineGiornate Mediche FiorentineFirenze 7-9 Novembre 2014Firenze 7-9 Novembre 2014

CLINICAL CASE: MEDICAL HISTORYCLINICAL CASE: MEDICAL HISTORY

Female, black, 21 years old.Female, black, 21 years old. No relevant medical history.No relevant medical history. In April 2011 occasional diagnosis of severe systo-diastolic In April 2011 occasional diagnosis of severe systo-diastolic

hypertension , asymptomatic. Treatment is started with hypertension , asymptomatic. Treatment is started with hydrochlorotiazide 12.5 mg/d and lercanidipine 10 mg/d.hydrochlorotiazide 12.5 mg/d and lercanidipine 10 mg/d.

In June 2011 the patient is seen in the Emergency Department In June 2011 the patient is seen in the Emergency Department of San Giuseppe Hospital for dizziness and paresthesias.of San Giuseppe Hospital for dizziness and paresthesias.

• PA 190/120 mmHg,PA 190/120 mmHg, HR 100 bpm. HR 100 bpm. No significant abnormalities except for a systolic 2/6 murmur No significant abnormalities except for a systolic 2/6 murmur on the apex at cardiac examination.on the apex at cardiac examination.

• ECG: signs of left ventricular hypertrophy and overload, QTc ECG: signs of left ventricular hypertrophy and overload, QTc prolongation.prolongation.

CLINICAL CASE: BASELINE WORK-UPCLINICAL CASE: BASELINE WORK-UP

The patient is admitted in the Hypertension Unit for diagnostic The patient is admitted in the Hypertension Unit for diagnostic work-up:work-up:•Routine laboratory data:Routine laboratory data: Cr 0.68 mg/dl, Az 59 mg/dl, Na 141 Cr 0.68 mg/dl, Az 59 mg/dl, Na 141 mEq/l, K 2.5 mEq/l,mEq/l, K 2.5 mEq/l, Cl 103 mEq/l, Gl 105 mg/dl, Cholesterol Cl 103 mEq/l, Gl 105 mg/dl, Cholesterol 213 mg/dl, HDL 48 mg/dl, LDL 143 mg/dl, TG 60 mg/dl, Uric 213 mg/dl, HDL 48 mg/dl, LDL 143 mg/dl, TG 60 mg/dl, Uric acid 3.1 mg/dl,Ca 10.5mg/dl Hb 13.0 g/dl, WBC 3590/mm3, PLT acid 3.1 mg/dl,Ca 10.5mg/dl Hb 13.0 g/dl, WBC 3590/mm3, PLT 189000/mm3.189000/mm3.•Urinalysis:Urinalysis: pH 7.0, sw 1017, no proteins, glucose or blood. pH 7.0, sw 1017, no proteins, glucose or blood. Microalbuminuria 10 mg/24 hs.Microalbuminuria 10 mg/24 hs.•Echocardiography:Echocardiography: concentric left ventricular hypertrophy (IVS concentric left ventricular hypertrophy (IVS 13 mm, PW 13 mm, LVM 120 g/m2).13 mm, PW 13 mm, LVM 120 g/m2).•Abdominal ultrasonography and EchocolorDoppler ultrasound of Abdominal ultrasonography and EchocolorDoppler ultrasound of the carotid and renal arteries:the carotid and renal arteries: normal. normal.

306306

Indici Clinici di Sospetto Iperaldosteronismo Primitivo (IA)Indici Clinici di Sospetto Iperaldosteronismo Primitivo (IA)

AnamnesticiAnamnestici-- Storia di ipertensione lieve-moderata resistente ai comuni farmaci Storia di ipertensione lieve-moderata resistente ai comuni farmaci

antipertensiviantipertensivi-- Gravi ipopotassiemie in corso di trattamento con diureticiGravi ipopotassiemie in corso di trattamento con diuretici

Obiettivi / soggettiviObiettivi / soggettivi-- Astenia-fascicolazioni-parestesieAstenia-fascicolazioni-parestesie-- ParalisiParalisi-- PoliuriaPoliuria-- PolidipsiaPolidipsia

LaboratoristiciLaboratoristici-- IpopotassiemiaIpopotassiemia-- IpomagnesiemiaIpomagnesiemia-- pH urinario alcalino (alcalosi metabolica)pH urinario alcalino (alcalosi metabolica)-- Alterazioni della ripolarizzazione (onda U) e aritmie all’ECGAlterazioni della ripolarizzazione (onda U) e aritmie all’ECG

1308 Mo1308 Mo

Prevalence of Primary Hyperaldosteronism in ItalyPrevalence of Primary Hyperaldosteronism in ItalyPAPI StudyPAPI Study

Patients recruitedPatients recruited

Primary hyperaldosteronismPrimary hyperaldosteronism

AldosteronomaAldosteronoma

Adrenal hyperplasiaAdrenal hyperplasia(mono / bilateral)(mono / bilateral)

Rossi GP et al., JACC 2006Rossi GP et al., JACC 2006

11211121

118 (10.5%)118 (10.5%)

49 (41%)49 (41%)

69 (59%)69 (59%)

Aldosterone and Cardiovascular Damage

Pro-hypertensiveEffects on the Brain

Prothrombotic Effects

Potassium and Magnesium Loss

Inflammation andVascular Damage

Fibrosis and Ventricular Remodeling

Endothelial Dysfunction

Ventricular Arrhythmias

SodiumRetention

Potentiation of Catecholamines

and Angiotensin II

Pathological Effects of

Aldosterone

Cardiovascular Disease

Stroke Ischaemia Hypertension Heart Failure End-StageRenal Disease

Impaired Vascular

Compliance

Reduction in BRS and HRV

Struthers AD Cardiovasc Res 2004Mulatero P Cardiovasc Hematol Ag 2006

0

2

4

6

8

10

12

14p=0.001 p=0.005 p=0.0001

%

Cardiovascular Events in Patients with Primary Aldosteronism vs Essential Hypertensives

PA EHT PA EHT PA EHT

Stroke Myocardial Infarction

AtrialFibrillation

Milliez P et al. J Am Coll Cardiol 20053 years follow-up

Renin-angiotensin-aldosterone-system

Aldosterone increase

Renin suppresion

BP elevation

+ Na

- K

Flow chart for screening hyperaldosteronism

Primary hypertension

Normal ARR

Surgery

Adenoma

Medical treatment

Hyperplasia

CT + Adrenal vein sample

Not suppressed

Primary hypertension

Suppressed

Florinef \Saline suppression test

Elevated ARR

Aldosterone/Renin-ratio (ARR)

1310 Mo1310 Mo

Number of Diagnosed Cases of PA per Year Number of Diagnosed Cases of PA per Year Before and After Using ARR for ScreeningBefore and After Using ARR for Screening

Mulatero P et al., J Clin Endocrinol Metab 2004; 89: 1045-1050Mulatero P et al., J Clin Endocrinol Metab 2004; 89: 1045-1050

Torino Rochester Brisbane Singapore Santiago0

10

20

30

40

50

60

70

80

90

Before ARR

After ARR

ENDOKRINOLOGISCHES LABORMEDIZINISCHE KLINIK UND POLIKLINIK IV

KLINIKUM DER UNIVERSITÄT MÜNCHEN®

11

ARR cut-off - JCEM Guidelines and units

Educational Workshop EuroMedLab Milano 2013Educational Workshop EuroMedLab Milano 2013

• Variability between different assays

• Additional source of confusion:

- Aldosterone in ng/dL, pg/mL or pmol/L

- Renin activity in ng/mL*h or pmol/L*min

- Renin concentration in mU/L or ng/L

21.05.201321.05.2013

CLINICAL CASE: ENDOCRINOLOGIC WORK UPCLINICAL CASE: ENDOCRINOLOGIC WORK UP

Cortisol 3.86 µg/dl Cortisol 3.86 µg/dl (nv 6.70-22.60)(nv 6.70-22.60)ACTH 4.44 pg/ml ACTH 4.44 pg/ml (nv 5-80) (nv 5-80) UFC 30 µg/24 hs UFC 30 µg/24 hs (nv 28-213)(nv 28-213)Renin supine <0.5 mU/l Renin supine <0.5 mU/l (nv 2.8-39.9) (nv 2.8-39.9) Aldosterone supine 187 ng/dlAldosterone supine 187 ng/dl(nv 0.75-15)(nv 0.75-15)ARR 374 ARR 374 (nv<3.7) (nv<3.7) Renin standing <0.5 mU/lRenin standing <0.5 mU/l(nv 4.40-46.10)(nv 4.40-46.10)Aldosterone standing 190 ng/dlAldosterone standing 190 ng/dl(nv 3.5-30)(nv 3.5-30)

TSH 1.39 TSH 1.39 μμUI/mlUI/ml

(nv 0.34-5.6)(nv 0.34-5.6)

S-DHEA 66 µg/dl S-DHEA 66 µg/dl

(nv 35-430) (nv 35-430)

U-Catecholamines 25 µg/24 hsU-Catecholamines 25 µg/24 hs

(nv <120 µg) (nv <120 µg)

U-Metanephrines U-Metanephrines

60 µg/24 hs (nv <400 µg)60 µg/24 hs (nv <400 µg)

U-Normetanephrines 163 µg/24 hs U-Normetanephrines 163 µg/24 hs

(nv <800 µg)(nv <800 µg)

Saline infusion 2L NaCl 0,9%

ALDng/dl

0

8

16

24

32

0 h 2 h 4 h

Saline infusion 2L NaCl 0,9%

ALDng/dl

0

8

16

24

32

0 h 2 h 4 h

CLINICAL CASE: ENDOCRINOLOGIC WORK UPCLINICAL CASE: ENDOCRINOLOGIC WORK UP

Aldosterone Suppression testAldosterone Suppression test

At centers with experience with AVS, the complication rate is 2.5% or less

Complications may include:-Symptomatic groin hematoma

-Adrenal hemorrhage

-Dissection of an adrenal vein

-Adrenal venous thrombosis

-Adrenal infarction

Primary Aldosteronism The Role of Adrenal Venous Sampling (AVS)

Mayo Clinics Recommendations

2902 Mo2902 Mo

Precautions to be taken to optimize AVS resultsPrecautions to be taken to optimize AVS results

Perform the procedure in the morningPerform the procedure in the morning

Correct hypokalemia prior to AVSCorrect hypokalemia prior to AVS

Adjust anti-HT treatment with alpha-blocker or calcium Adjust anti-HT treatment with alpha-blocker or calcium antagonistsantagonists

Withdraw RAS and MR antagonists (4 weeks)Withdraw RAS and MR antagonists (4 weeks)

Visualize right adrenal vein with CTVisualize right adrenal vein with CT

Minimize stress prior to and during AVSMinimize stress prior to and during AVS

Simultaneous sampling from the adrenal veins (because of pulsatile Simultaneous sampling from the adrenal veins (because of pulsatile secretion of aldosterone)secretion of aldosterone)

Inject the least possible amount of dye into adrenal veinInject the least possible amount of dye into adrenal vein

CLINICAL CASE: CONFIRMATION OF LATERALIZATIONCLINICAL CASE: CONFIRMATION OF LATERALIZATION

Adrenal vein samplingAdrenal vein sampling

Aldosterone Cortisol Aldo/Cortisol

Right adrenal vein 187 91.5 2.04

Left adrenal vein 52 30.6 1.7

Vena cava 56 14.8 0.3

CLINICAL CASE: IMAGINGCLINICAL CASE: IMAGING

Adrenal CT scan:Adrenal CT scan: right adrenal mass, 27 x 15 x 27 mm, right adrenal mass, 27 x 15 x 27 mm, hypodense (10 HU), with light enhancement after iodine hypodense (10 HU), with light enhancement after iodine contrast medium.contrast medium.

Iodocholesterol Adrenal scintigraphy Iodocholesterol Adrenal scintigraphy after after dexamethasone suppression: rigth adrenal hyper-uptake dexamethasone suppression: rigth adrenal hyper-uptake of the tracer.of the tracer.

2905 Mo2905 Mo

Clinical characteristics associated with greater chances of Clinical characteristics associated with greater chances of cure of hypertension following adrenalectomycure of hypertension following adrenalectomy

Young ageYoung age

Short duration of HT (5-10 yrs)Short duration of HT (5-10 yrs)

Fewer anti-HT medicationsFewer anti-HT medications

Higher pre-operative blood pressureHigher pre-operative blood pressure

Pre-operative normal renal functionPre-operative normal renal function

BMI < 25 kg/mBMI < 25 kg/m22

Female genderFemale gender

Lack of family history of HTLack of family history of HT

No evidence of CV organ damage No evidence of CV organ damage

2735 Mo2735 Mo

Estimated costs of medical and surgical therapyEstimated costs of medical and surgical therapy

AdrenalectomyAdrenalectomy

Adrenalectomy plus ongoing Adrenalectomy plus ongoing antihypertensive medicationantihypertensive medication

Estimated cost of medical therapy aloneEstimated cost of medical therapy alone

Estimated cost savings for adrenalectomy Estimated cost savings for adrenalectomy per patientper patient

Cost (Canadian $)Cost (Canadian $)

84638463

1996019960

3908039080

3113231132

Sywak M et al., Br J Surg 2002; 89: 1587-1593Sywak M et al., Br J Surg 2002; 89: 1587-1593

2744 Mo2744 Mo

Anti-aldosterone medicationsAnti-aldosterone medications

Aldosterone receptor Aldosterone receptor antagonist (ARA)antagonist (ARA)

Non-steroidsNon-steroids

Aldosterone biosynthesis Aldosterone biosynthesis inhibitor (ASI)inhibitor (ASI)

DenominationDenomination

SpironolactoneSpironolactone

CanrenoneCanrenone

EplerenoneEplerenone

Some DHP CCBsSome DHP CCBs(nimodipine, felodipine,(nimodipine, felodipine,

nitrendipine)nitrendipine)

BR-4628, FAD 286, BR-4628, FAD 286, LCI 1699LCI 1699

DevelopmentDevelopment

Early 1960sEarly 1960s

1980s1980s

2000s2000s

2000s2000s

2010s2010s

0 1 2 3 4 5 6 7 8 9 10 11 120

5

10

15

20

25

30

Essential hypertension

Primary aldosteronism

0 1 2 3 4 5 6 7 8 9 10 11 120

5

10

15

20

25

30

Adrenalectomy

Spironolactone

2336 Mo2336 Mo

Incidence of Combined CV End-point in Patients with PA and EH Incidence of Combined CV End-point in Patients with PA and EH

Treated with Adrenalectomy or Aldosterone AntagonistsTreated with Adrenalectomy or Aldosterone Antagonists

Catena C et al., Arch Intern Med 2008; 168: 80-85Catena C et al., Arch Intern Med 2008; 168: 80-85

Patients (%)Patients (%)

Follow-up (y)Follow-up (y)

Patients (%)Patients (%)

Follow-up (y)Follow-up (y)

CLINICAL CASE: TREATMENTCLINICAL CASE: TREATMENT

DIAGNOSIS: Primary hyperaldosteronism DIAGNOSIS: Primary hyperaldosteronism due to aldosterone producing adenomadue to aldosterone producing adenoma

Antihypertensive therapy was initiated with Antihypertensive therapy was initiated with potassium canrenoate 100 mg, nifedipine GITS 60 potassium canrenoate 100 mg, nifedipine GITS 60 mg and doxazosin 4 mg.mg and doxazosin 4 mg.After 4 weeks blood pressure and kalemia were After 4 weeks blood pressure and kalemia were normalised: normalised: • PA 125/80 mmHg.PA 125/80 mmHg.• Na 138 mEq/l, K 4.1 mEq/l. Na 138 mEq/l, K 4.1 mEq/l.

CLINICAL CASE: TREATMENTCLINICAL CASE: TREATMENT

In February 2012 elective laparoscopic right In February 2012 elective laparoscopic right adrenalectomy was perfomed.adrenalectomy was perfomed.Hystologic diagnosis: adrenal adenoma.Hystologic diagnosis: adrenal adenoma.After 5 weeks blood pressure, kalemia and After 5 weeks blood pressure, kalemia and renin/aldosterone profile were normalised without renin/aldosterone profile were normalised without any therapy: any therapy: • PA 110/75 mmHg.PA 110/75 mmHg.• Na 137 mEq/l, K 4.5 mEq/l. Na 137 mEq/l, K 4.5 mEq/l. • Renin supine 14.9 mU/l, Aldosterone supine 3 Renin supine 14.9 mU/l, Aldosterone supine 3 ng/dl, ARR 0.2ng/dl, ARR 0.2

2902 Mo2902 Mo

ConclusionsConclusions

The prevalence of Primary Aldosteronism (PA) among patients The prevalence of Primary Aldosteronism (PA) among patients with hypertension is about 10%, being due in similar percentages with hypertension is about 10%, being due in similar percentages to aldosteronoma and to adrenal hyperplasia.to aldosteronoma and to adrenal hyperplasia.

Because of the deleterious actions of excess aldosterone, PA is Because of the deleterious actions of excess aldosterone, PA is associated with high prevalence of CV disorders.associated with high prevalence of CV disorders.

Resistance to conventional anti-hypertensive agents and Resistance to conventional anti-hypertensive agents and hypokaliemia are clinical features strongly suggestive of PA.hypokaliemia are clinical features strongly suggestive of PA.

Aldosterone / renin ratio (ARR), aldosterone suppressive test and Aldosterone / renin ratio (ARR), aldosterone suppressive test and adrenal veins sampling (AVS) are the three screening tests adrenal veins sampling (AVS) are the three screening tests required for the diagnosis of PA and for subtype classification.required for the diagnosis of PA and for subtype classification.

Adrenalectomy is indicated for treatment of aldosteronoma but Adrenalectomy is indicated for treatment of aldosteronoma but antialdosterone agents are suitable alternatives.antialdosterone agents are suitable alternatives.

In patients with aldosteronoma, adrenalectomy is more cost-In patients with aldosteronoma, adrenalectomy is more cost-effective than medical treatment.effective than medical treatment.