Interesting case Interesting case ConferenceConference

11/13/200811/13/2008

Ashish Ashish Dhungel Dhungel

Susan Susan Steigerwalt Steigerwalt

CaseCase History of present illnessHistory of present illness

31 Yr Caucasian female31 Yr Caucasian female

HTN- 2 years . No hypertension or HTN- 2 years . No hypertension or preeclampsia with pregnancies 4 and preeclampsia with pregnancies 4 and 6 years prior to presentation. 6 years prior to presentation. Referred by Primary due to Referred by Primary due to presentation with BP 160/112 mmHg.presentation with BP 160/112 mmHg.

Past Medical HistoryPast Medical History

HeadacheHeadache Social HistorySocial History

Smoke tobacco 1 pk /day- 13 yr, no drug Smoke tobacco 1 pk /day- 13 yr, no drug use, no alcohol useuse, no alcohol use

High stress job. Sleeps 6 hours/ nightHigh stress job. Sleeps 6 hours/ night Family historyFamily history

Father –DMFather –DM

Mother- healthyMother- healthy

MedicationMedication

Norvasc 5 mg daily; unknown oral Norvasc 5 mg daily; unknown oral

contraceptive( intermittently for 8 contraceptive( intermittently for 8 years)years)

Review of symptomsReview of symptoms General-exhaustion, feels excessive hot General-exhaustion, feels excessive hot andand

coldcold CVS- palpitationCVS- palpitation GI- heartburnGI- heartburn Neuro- Headache, tingling of hands and Neuro- Headache, tingling of hands and feetfeet

Physical examPhysical exam B.PB.P 140/88 (sitting) 140/88 (sitting)

147/91 (standing)147/91 (standing)

PulsePulse-88, Wt 146 lb, BMI- 22-88, Wt 146 lb, BMI- 22 HEENTHEENT No ThyromegalyNo Thyromegaly ChestChest No wheezeNo wheeze

SkinSkin-- No striae, no rashNo striae, no rash CardiovascularCardiovascular

No murmur, No carotid bruitNo murmur, No carotid bruit AbdomenAbdomen

No organomegaly, No bruitNo organomegaly, No bruit NeurologicalNeurological

Normal examNormal exam

InvestigationInvestigation

CBC- Hb 12.3 ,WBC, platelets CBC- Hb 12.3 ,WBC, platelets wnlwnl

CMP- sodium 141, potassium 3.8, CMP- sodium 141, potassium 3.8, bicarb 29, creatinine 0.7 bicarb 29, creatinine 0.7

U/A - no proteinuriaU/A - no proteinuria

Differential Diagnosis- Differential Diagnosis- young woman with stage 2 young woman with stage 2

hypertensionhypertension

Differential Diagnosis- Differential Diagnosis- young woman with stage 2 young woman with stage 2

hypertension hypertension Essential HypertensionEssential Hypertension Medications: oral Medications: oral contraceptives, illicit drugscontraceptives, illicit drugs

PCOS PCOS Primary aldosteronismPrimary aldosteronism Fibro muscular dysplasiaFibro muscular dysplasia Liddle’s syndromeLiddle’s syndrome

Additional Evaluation?Additional Evaluation?

Additional Evaluation?Additional Evaluation?

Aldosterone 76!!!!Aldosterone 76!!!! PRA< 0.5!!!! Guess what she has!!!!PRA< 0.5!!!! Guess what she has!!!! Best part- no invasive work up prior Best part- no invasive work up prior to lab evaluation- we saved money!!!to lab evaluation- we saved money!!!

CT scan showed left adrenal adenomaCT scan showed left adrenal adenoma She was referred for AVS…She was referred for AVS…

GuidelineGuideline

Approach to pt with Approach to pt with suspected suspected

Primary Primary AldosteronismAldosteronism

IntroductionIntroduction

Primary aldosteronism is the Primary aldosteronism is the syndrome from the autonomous syndrome from the autonomous hyper secretion of hyper secretion of aldosterone , almost always aldosterone , almost always from the adrenal cortex.from the adrenal cortex.

Conn‘s syndromeConn‘s syndrome was based on a thirty-four-year-old was based on a thirty-four-year-old patient who entered the university hospital patient who entered the university hospital in in 1954 1954 complaining of seven years of complaining of seven years of episodic muscle weakness that often episodic muscle weakness that often resulted in virtual paralysis of her lower resulted in virtual paralysis of her lower legs. At Central Society for Clinical legs. At Central Society for Clinical Research on Research on October 29, 1954October 29, 1954, he present , he present for the first time his extensive clinical for the first time his extensive clinical investigations of this new syndrome, which investigations of this new syndrome, which he called he called primary aldosteronism. primary aldosteronism.

Jerome W.Conn 09 /24/1907 –06/ 11 1981

IncidenceIncidence

CONN JW.CONN JW. Primary aldosteronism.Primary aldosteronism. J Lab Clin Med. 1955 J Lab Clin Med. 1955 Apr;45(4):661-4Apr;45(4):661-4

In unselected patients – 0.5% of In unselected patients – 0.5% of hypertensive (Gifford,1969;kaplan hypertensive (Gifford,1969;kaplan 1967;Sinclair 1987)1967;Sinclair 1987)

20% in referred patients 20% in referred patients (Mulatero,2004;Stowasser et al 2003)(Mulatero,2004;Stowasser et al 2003)

IncidenceIncidence

Using ARR ,prevalence 5-13% of Using ARR ,prevalence 5-13% of all hypertensives.all hypertensives.

Forms of PAForms of PA

Aldosterone producing adenoma (APA)Aldosterone producing adenoma (APA) Bilateral idiopathic hyperplasia Bilateral idiopathic hyperplasia (IHA) most common!!!!(IHA) most common!!!!

Primary (unilateral) adrenal hyperplasiaPrimary (unilateral) adrenal hyperplasia Aldosterone producing adrenocortical Aldosterone producing adrenocortical carcinomacarcinoma

Familial hyperaldosteronism (FH)Familial hyperaldosteronism (FH) Glucocorticoid remediable aldosteronism ( type I)Glucocorticoid remediable aldosteronism ( type I)

FH type II (APA or IHA)FH type II (APA or IHA)

Clinical featuresClinical features 30- 50 years30- 50 years AldosteronismAldosteronism

Hypertension Hypertension ↑↑Na Na reabsorptionreabsorption

↑ ↑Plasma volume Plasma volume ↑↑ K K excretionexcretion

Suppressed Suppressed Hypokalemia Hypokalemia

renin-angiotensinrenin-angiotensin

AldosteroneAldosterone

Various deleterious effectsVarious deleterious effects

Endothelial stiffness Endothelial stiffness (Oberleithner,2005)(Oberleithner,2005)

Vascular damage Vascular damage (Schmidt ,2003)(Schmidt ,2003)

Myocardial fibrosis (GP Rossi,2002)Myocardial fibrosis (GP Rossi,2002) Proteinuria (Calhoun,2008)Proteinuria (Calhoun,2008)

Hypertension in PAHypertension in PA

Severe hypertensionSevere hypertension

Aldosterone stimulate ENaC Aldosterone stimulate ENaC activity in apical membranes. activity in apical membranes.

Slightly expanded plasma volume, Slightly expanded plasma volume, increased total body Na content increased total body Na content and increased peripheral and increased peripheral resistanceresistance

Hypokalemia in PAHypokalemia in PA

9-37% 9-37% Normokalemic HTN – most common Normokalemic HTN – most common Less common in pt diagnosed Less common in pt diagnosed early in course of disease.early in course of disease.

Diuretic induced hypokalemia.Diuretic induced hypokalemia.

DiagnosisDiagnosis

Patients with HTN that are at risk of PA

Case detection using ARR

Case confirmation

Adrenal CT

AVS

Subtype testing

Importance of case Importance of case detectiondetection

Pt with PA have higher cardiovascular Pt with PA have higher cardiovascular morbidity and mortality then age and morbidity and mortality then age and sex matched pt with Essential HTN and sex matched pt with Essential HTN and the same degree of B.P controlthe same degree of B.P control

Rossi GP, at el, Rossi GP, at el, 2006 Renal damage in primary aldosteronism: results of the PAPY Study. 2006 Renal damage in primary aldosteronism: results of the PAPY Study. Hypertension 48:232–238Hypertension 48:232–238

Milliez P, at el Milliez P, at el 2005 Evidence for an increased rate of cardiovascular 2005 Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism.J Am Coll Cardiol 45:1243–events in patients with primary aldosteronism.J Am Coll Cardiol 45:1243–12481248

Strong evidence linking reduction Strong evidence linking reduction in aldosterone level to improved in aldosterone level to improved cardiac and cerebrovascular cardiac and cerebrovascular outcomeoutcome

Rossi GP, Sacchetto A, Visentin P, Canali C, Graniero GR, Palatini P, Rossi GP, Sacchetto A, Visentin P, Canali C, Graniero GR, Palatini P, Pessina AC.Pessina AC.

Changes in left ventricular anatomy and function in hypertension and Changes in left ventricular anatomy and function in hypertension and primary aldosteronism.primary aldosteronism.

Hypertension. 1996 May;27(5):1039-45Hypertension. 1996 May;27(5):1039-45

Case detectionCase detection JNC Stage 2 and stage 3 HTN *(>160/110)JNC Stage 2 and stage 3 HTN *(>160/110) Drug Resistant hypertension Drug Resistant hypertension Hypertension and spontaneous or diuretic Hypertension and spontaneous or diuretic induced hypokalemiainduced hypokalemia

Hypertension with adrenal incidentalomaHypertension with adrenal incidentaloma Hypertension and family history of early Hypertension and family history of early onset HTN or CVA at young age (< 40)onset HTN or CVA at young age (< 40)

Hypertensive First degree relatives of Hypertensive First degree relatives of patient with PApatient with PA

Aldosterone to Renin Ratio Aldosterone to Renin Ratio (AAR)(AAR)

Aldosterone 5- 20 ng /dlAldosterone 5- 20 ng /dl Plasma renin activity 1-3 ng /ml per hrPlasma renin activity 1-3 ng /ml per hr Currently the most reliable for Currently the most reliable for screeningscreening

Associated with False + and –veAssociated with False + and –ve PAC:PRA ratio > 20ng/dl per ng/ml per hrPAC:PRA ratio > 20ng/dl per ng/ml per hr Should be repeated if results are Should be repeated if results are inconclusive or difficult to interpret.inconclusive or difficult to interpret.

A)A) Preparation for ARR measurementPreparation for ARR measurement

1.1. Attempt to correct hypokalemiaAttempt to correct hypokalemia

2.2. Encourage patient to liberalize Na Encourage patient to liberalize Na intakeintake

3.3. Withdraw agents affecting ARR Withdraw agents affecting ARR (4wk) Spironolactone, (4wk) Spironolactone, Eplerenone, amiloride, Eplerenone, amiloride, triamterene, K wasting diuretics, triamterene, K wasting diuretics, tobacco, licoricetobacco, licorice

4 . If results off the above agents are not 4 . If results off the above agents are not diagnostic and if HTN can be controlled diagnostic and if HTN can be controlled with relatively non interfering with relatively non interfering medication, withdraw meds that affect ARR medication, withdraw meds that affect ARR (2wk)(2wk)

- B blocker, clonidine, methyldopa, NSAIDs- B blocker, clonidine, methyldopa, NSAIDs

- ACEI, ARB, Renin inhibitors, - ACEI, ARB, Renin inhibitors, dihydropyridine ca ch blockerdihydropyridine ca ch blocker

5 If necessary to maintain B.P - Verapamil, 5 If necessary to maintain B.P - Verapamil, hydralazine, pazosine, terazosinehydralazine, pazosine, terazosine

B) B) Collection of bloodCollection of blood

Mid morning, after pt has Mid morning, after pt has been up (sitting, standing or been up (sitting, standing or walking) for at least 2 hr and walking) for at least 2 hr and seated for 5- 15 minseated for 5- 15 min

Factors affecting ARRFactors affecting ARR

Case ConfirmationCase Confirmation

11 Oral Sodium loadingOral Sodium loading

22 Saline infusionSaline infusion

33 Fludrocortisone suppressionFludrocortisone suppression

44 Captopril challengeCaptopril challenge

Choice of test is determined by local Choice of test is determined by local expertise.expertise.

Meds with min or no effect in RAS should Meds with min or no effect in RAS should be used for B.P controlbe used for B.P control

Oral Sodium loading Oral Sodium loading testtest

Saline infusion testSaline infusion test

Fludrocortisone Fludrocortisone suppression testsuppression test

Captopril challenge Captopril challenge testtest

Subtype classificationSubtype classification

11 CT scanCT scan All pt with PA should undergo CT scan All pt with PA should undergo CT scan as initial study in subtype testingas initial study in subtype testing

MRI has no advantage over CTMRI has no advantage over CT CT finding along with AVS is used in CT finding along with AVS is used in combination to guide treatment combination to guide treatment decisiondecision

Sensitivity and specificity 78% and Sensitivity and specificity 78% and 75%75%

Limitation of CTLimitation of CT

Small APA can be interpreted as IHA Small APA can be interpreted as IHA on basis of CT finding of bilateral on basis of CT finding of bilateral nodularity or normal appearing nodularity or normal appearing adrenalsadrenals

Adrenal micro adenomas may actually Adrenal micro adenomas may actually represent areas of hyperplasia represent areas of hyperplasia

Non functioning unilateral adrenal Non functioning unilateral adrenal macro adenoma are indistinguishable macro adenoma are indistinguishable from APAs on CT.from APAs on CT.

CT detected fewer than 25% of CT detected fewer than 25% of APA <1 cm APA <1 cm Gordon RD Gordon RD 2001 Diagnostic investigations in 2001 Diagnostic investigations in primary aldosteronism,Zanchetti A, ed. Clinical medicine series on primary aldosteronism,Zanchetti A, ed. Clinical medicine series on hypertensionhypertension

CT was accurate in only 53% of CT was accurate in only 53% of pt in comparision to both CT and pt in comparision to both CT and AVS.AVS.

Young WF, Stanson AW, Thompson GB, Grant CS, Farley DR, van HeerdenJA Young WF, Stanson AW, Thompson GB, Grant CS, Farley DR, van HeerdenJA 2004 Role 2004 Role for adrenal venous sampling in primary aldosteronismfor adrenal venous sampling in primary aldosteronism

Concordance between CT and AVS Concordance between CT and AVS was found only in 54% was found only in 54%

Nwariaku FE, Miller BS, Auchus R, Holt S, Watumull L, Nwariaku FE, Miller BS, Auchus R, Holt S, Watumull L, Dolmatch B, Nesbitt, Dolmatch B, Nesbitt, 2006 Primary hyperaldosteronism: effect of 2006 Primary hyperaldosteronism: effect of adrenal vein sampling on surgical outcome.Arch Surg 141:497–502adrenal vein sampling on surgical outcome.Arch Surg 141:497–502

AVSAVS

22 Adrenal venous samplingAdrenal venous sampling AVS is essential in directing AVS is essential in directing appropriate therapy.appropriate therapy.

Differentiate Uni /Bilateral Differentiate Uni /Bilateral diseasedisease

Invasive and expensiveInvasive and expensive Sensitivity and specificity is Sensitivity and specificity is 95% and 100%95% and 100%

AVS ProtocolAVS Protocol

1.1. Unstimulated AVSUnstimulated AVS

2.2. Unstimulated AVS followed by Unstimulated AVS followed by cosyntropincosyntropin

3.3. Continuous cosyntropin with AVS Continuous cosyntropin with AVS ( used HFH ) ( used HFH )

- minimize stress induced - minimize stress induced fluctuation in fluctuation in

aldosterone secretionaldosterone secretion

Cortisol corrected aldosteroneCortisol corrected aldosterone ratioratio- - Dividing PAC by respective Cortisol Dividing PAC by respective Cortisol concentration to correct for dilutional concentration to correct for dilutional effect of phrenic vein flowing into effect of phrenic vein flowing into adrenal veinadrenal vein

Cortisol corrected aldosterone ratio, Cortisol corrected aldosterone ratio, from high side to low sidefrom high side to low side > 4:1 > 4:1

indicate unilateral aldosterone indicate unilateral aldosterone excessexcess

Ratio < 3:1Ratio < 3:1 suggest bilateral suggest bilateral aldosterone secretionaldosterone secretion

Ratio between 3:1 and 4:1Ratio between 3:1 and 4:1 may may have either ,and result should have either ,and result should be interpreted in conjunction be interpreted in conjunction with CT and clinical setting.with CT and clinical setting.

TreatmentTreatment

Unilateral PA (APA,UAH)Unilateral PA (APA,UAH) Unilateral adrenalectomyUnilateral adrenalectomy

-B.P, K improve in 100% pt and HTN-B.P, K improve in 100% pt and HTN

cured in 35-60%cured in 35-60%

- Medical management who do not go - Medical management who do not go for for

surgerysurgery

Spironolactone, EplerenoneSpironolactone, Eplerenone

TreatmentTreatment

Bilateral disease (IHA, Bilateral disease (IHA, bilateral APA,GRA)bilateral APA,GRA)

9% cure rate after uni 9% cure rate after uni /Bilateral adrenalectomy/Bilateral adrenalectomy

Medical management.Medical management.

SpironolactoneSpironolactone

Starting dose 12.5 -25 mg dailyStarting dose 12.5 -25 mg daily Eplerenone 25 mg daily/bidEplerenone 25 mg daily/bid

GRAGRA

Glucocorticoid to suppress Glucocorticoid to suppress Pit ACTHPit ACTH

Dexamethasone 0.125-Dexamethasone 0.125-0.25 mg daily0.25 mg daily

Prednisone 2.5-Prednisone 2.5-5 mg daily5 mg daily

Back to our patient-Back to our patient-wow!wow!

ARR - 152ARR - 152 CT scan - Lt adrenal mass CT scan - Lt adrenal mass AVSAVS VeinVein AldosteronAldosteron

eeCortisoCortisoll

A/C ratioA/C ratioCortisol Cortisol corrected corrected aldosterone ratioaldosterone ratio

L:RL:R

R R adrenal adrenal veinvein

600600 322322 1.81.8

L L adrenal adrenal veinvein

1263012630 236236 53.5153.51 >4:1>4:1

IVCIVC 315315 26.726.7 1.171.17

Our patientOur patient

Unilateral ( Lt) Aldosterone Unilateral ( Lt) Aldosterone Producing Adenoma (APA)Producing Adenoma (APA)

Pt referred for Laparoscopic Lt Pt referred for Laparoscopic Lt Adrenalectomy Adrenalectomy

Questions ???Questions ???