Management Update – Prof. Nor Azmi Kamaruddin, MD

Adrenal Causes of Hypertension: Update with Emphasis on Primary Aldosteronism

Nor Azmi Kamaruddin Endocrine Unit

National University of Malaysia (UKM)

15th Asia-Oceania Congress of Endocrinology (AOCE) 10th October 2014

Radisson Blu Hotel, Cebu City, Philippines

Malaysian Endocrine & Metabolic Society

MEMS Established 1981

UKM

Disclosure of Financial Relationships with Pharmaceutical Companies (Conflict of Interest Declaration)

MEMS Malaysian Endocrine & Metabolic Society

Nor Azmi Kamaruddin MBBS, MMed, DIS, FACE, AM

Established 1981

Nothing

To Declare

Causes of Secondary Hypertension

n  Endocrine Mineralcorticoid Hypertension (hypokalemia + metabolic alkalosis)

Phaeochromacytoma Acromegaly Thyroid Dysfunction Hyperparathyroidism

Carcinoid

n  Renal Renal artery stenosis Glomerulonephritis

Pyelonephritis Interstitial nephritis

Obstructive nephropathy Polycystic disease

Obstructive uropathy

n  Vascular Coarctation of Aorta Takayashu’s

n  Drugs Steroids

Oral Contraceptives

Symphatomimetics Erythropoietin

Cyclosporin MAOi

Coccaine, Amphetamines

n  Sleep Apnoea

n  Pregnancy (Eclampsia)

Low Renin Low Aldosterone

Cortisol

Ectopic ACTH Cushing’s syndrome

Liddle’s Licorice AMEs DOC

11-β Hydroxylase Def 17-α Hydroxylase Def

High Normal Low

Lin SH, et al. Am J Med Sci 2003; 325: 153-156.

Causes of Mineralocorticoid Hypertension other than Primary Aldosteronism

Conditions with low renin (other than PA):

Mineralocorticoid Excess Hypercortisolism (Cushing's syndrome)

Glucocorticoid / cortisol resistance (Chrousos syndrome)

Apparent mineralocorticoid excess syndrome Licorice or carbenoxolone in excess

Congenital adrenal hyperplasia (11beta- and 17alpha-hydroxylase deficiencies)

11-Deoxycorticosterone (DOC), 18-hydroxy-DOC excess Geller Syndrome (Mutation in MR during pregnancy)

Familial hyperkalemic hypertension (Gordon's syndrome) Liddle's syndrome

Prevalence of Unrecognized PA in Patients with Hypertension

Author (Ref.) Country No. Screened Prevalence

Gordon et al (21) Australia 199 8.5%

Kumar et al (22) India 103 8.7%

Kreze et al (23) Slovakia 115 13.0%

Lim et al (24) United Kingdom 465 9.2%

Loh et al (25) Singapore 350 4.6%

Fardella et al (26) Chile 305 9.5%

Schwartz et al (27) United States 117 12.0%

Rossi et al (10) Italy 1,046 6.3%

Young WF Jr. Endocrinology 2003; 144(6):2208-2213

Total 5464994 )10.7(‏

61Captopril >20 1020 Japan 2004 Omura M)6.0(‏ 54Fludrocortisone >30 300 Australia 2003 Stowasser M )18.0(‏

66Captopril >35 1046 Italy 2003 Rossi E )6.3(‏

37Fludrocortisone >25 609 Chile 2003 Mosso LM )6.1(‏

18PRA and Aldo ur c >20 88b USA 2002 Calhoun DA )20.0(‏

106NA >20 505 USA 2002 Schwartz GL )21.0(‏

15CT-NMR-I131 scan >100 90 USA 2001 Gallay BJ )17.0(‏

22NA >36 216 South Africa 2000 Rayner BL )10.1(‏

16Saline infusion >20 350 Singapore 2000 Loh KC )4.6(‏

43Fludrocortisone >27 465 UK 2000 Lim PO )9.2(‏

Prevalence n (%) ‏

Confirmatory test

Author (Ref) ‏

Year

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

29Fludrocortisone >25 305 Chile 2000 Fardella, CE )9.5(‏

Prevalence Of Primary Aldosteronism In Different Populations

Classification of untreated and treated hypertensive subjects according to ARR, PAC and PRC.

Hannemann A et al. Eur J Endocrinol 2012;167:7-15

Why The Increase Incidence Of Aldosteronism

Hypokalemia not a requirement

Screening Much Simpler & Straight Forward

Screening does not require the stopping of most of the anti-hypertensives

The historic prevalence rates of 0.5% are now between 5-15%.

Percentage of patients with particular indications who were diagnosed with primary aldosteronism (n=198).

Myśliwiec J et al. Journal of Renin-Angiotensin-Aldosterone System 2012;13:367-371

Increased rate of CV events in PA

Events OR

CVA 4.2

MI 6.5

Atrial fib 12.1

Milliez 2005; J Am Coll Card

When to Screen for Aldosteronism

Hypertension and Spontaneous Hypokalemia

Hypertension and Adrenal Tumor

Resistant Hypertension (20% incidence)

BP > 160/100

Require more than 3 drugs (incl diuretics) Young Onset

Bilateral Adrenal Hyperplasia (BAH)( up to 80%) - both adrenals overproducing aldo

Aldosterone-producing Adenoma (APA)(Conn’s adenoma)

- a benign adrenal tumor overproducing aldo Unilateral adrenal hyperplasia Aldosterone-producing Carcinoma

- a malignant adrenal tumor overproducing aldo Glucocorticoid-remediable Aldosteronism (FH-2)

- a rare, genetic form of PA that runs in families Familial Hyperaldosteronism Type 1 (FH-I), Familial Hyperaldosteronism Type 3 (FH-3)

Subtypes Of Primary Aldosteronism

Three Genetic-familial primary aldosteronism

Type 1 Glucocorticoid-remediable aldosteronism (GRA) (1966). Responds clinically to small doses of glucocorticoids Chimeric gene product that combines the glucocorticoid-responsive promoter of the 11-beta-hydroxylase gene (CYP11B1) with the coding region of the aldosterone synthetase gene (CYP11B2).

Type 2

Not glucocorticoid sensitive (1991). Although the exact genetic abnormality for type 2 primary aldosteronism has not been identified, data suggest that the locus for this disease is on band 7p22.

Type 3

Due to KCNJ5 (potassium inwardly rectifying channel, subfamily J, member 5) potassium channel mutations (2011).

11ß-OHaseregulatorysequences

Aldo Synthasecoding

sequences

HYBRID GENE

Regulatedby ACTH

EncodesAldo Synthase

ALDO

Small doses of glucocorticoids, by suppressing ACTH, suppress the hybrid gene and ameliorate aldosteronism and hypertension

Familial Hyperaldosteronism Type I (FH-I, Glucocorticoid-Remediable Aldosteronism)

0

50

100

150

200

250

300

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

PRA (ng/ml/h)

Cortisol (nmol/L)

Aldo (ng/L)

0 1 2 3 4 5 6 7

Days of Dexamethasone

FH-1 - Response To Dex (0.5mg Q6h)

Requires only a single blood sample that can be sent from anywhere in the world

DNA Extraction:

Southern Blot Test: - Lifton, USA, 1992

Long-PCR Test: - Greenslopes, 1994

Lifton R, et al. Nat Genet 1992

Jonsson J, et al. BBRC 1995

Genetic Testing For FH-1

Primer specific for 11ßOHase

Primer specificfor Aldo Synthase

Primer specific for Aldo Synthase

Primer specificfor Aldo Synthase

REACTION 1:

REACTION 2:

Jonsson J, et al. BBRC 1995

Long-PCR Testing For FH-I

23.1

9.4 6.4 4.4

2.3 2.0

Aldo Synthase

Aldo Synthase

Hybrid Gene

Hybrid Gene

NORMAL FH-I

FH-I - Long PCR

The  renin-­‐angiotensin-­‐aldosterone  system    regula'ng  blood  pressure  

The  angiotensin-­‐renin-­‐aldosterone  system    regula'ng  blood  pressure  

Adrenal  glomerulosa  cells    in  the  zonaglomerulosa  

Choi  et  al.,  Science  2011  

Membrane  depolariza9on  by  either  eleva9on  of  extracellular  K+  or  closure  of  K+  channels  by  angiotesin  II  ac9vates  voltage-­‐gated  Ca2+  channels,  increasing  intraceullular  Ca2+  level.  

Channel  containing  KCNJ5  wit  G151R,  T158A,  or  L168R  muta9ons  conduct  Na+,  resul9ng  in  Na+  entry,  chronic  depolariza9on,  cons9tu9ve  aldosterone  produc9on,  and  cell  prolifera9on.  

Aldosterone renin ratio

Hiramatsu et al, 1981

Screening For Primary Aldosteronism

Percentage of patients diagnosed for primary aldosteronism (n=198), in which sitting plasma aldosterone concentration/plasma renin activity ratio exceeded consecutive cut-offs.

Myśliwiec J et al. Journal of Renin-Angiotensin-Aldosterone System 2012;13:367-371

False Negatives

Diuretics CCBs (esp DHPs) ACEIs, ARBs V. low salt intake Renovascular HT Malignant HT Hypokalemia SSRI antidepressants

False Positives

Beta blockers α-methyldopa, clonidine NSAIDs Renal impairment Ageing Females – luteal phase Some OCPs – Yaz

(A Ahmed, et al JCEM 2010 and 2011)

Screening For PA : Aldo/Renin Ratio (ARR)

Angiotensinogen

A-I

A-II

Renin (The enzyme)

PRA versus DRC

PRA: involves measurement of angiotensin I generated in plasma from the endogenous substrate angiotensinogen by the action of endogenous enzyme renin

DRC: direct measurement of active renin

(The product)

Could hormonal changes during the menstrual cycle affect the ARR?

Angiotensinogen

A-I

A-II

Renin

How might E2 affect ARR?

Oestrogen stimulates plasma angiotensinogen (renin substrate) production by the liver

The resultant rise in angiotensin II levels chronically inhibits renal renin secretion by a negative feedback mechanism +

-

Renin

Oestrogen

Progesterone antagonizes aldosterone action in the kidney (MR antagonist) - natriuretic effect which in turn stimulates renin and aldosterone secretion Braley et al., 1996

How might progesterone affect ARR?

Aldosterone

Na+ reabsorption

Progesterone

Na+ excretion

Renin/AngII

Distal

nephron

Menses Follicular phase (Day 10)

Luteal phase (Day 20)

P Value (Friedman Test)

LH (IU/L) 3.2 (1.1-4.5) 5.4 (3.4-10.6) 1.3 (0.8-11.7) <0.01

FSH (IU/L) 5.1 (3.1-10.3) 4.9 (3.4-35.9) 2.6 (1.3-15.2) <0.001

Oestrogen (pmol/L) 144 (80-313) 389 (202-820) 263 (104-777) <0.001

Progesterone (nmol/L) 0.6 (0.3-2.1) 0.5 (0.3-7.6) 39.8 (12.1-71.5) <0.001

Pituitary and Ovarian Hormones

Values presented as medians (range)

Ahmed A, et al JCEM 2010

Effects Of Phase Of Menstrual Cycle On The ARR

Menses

Follicular phase (Day 10)

Luteal phase (Day 20)

P Value (Freidman

test)

DRC (mU/L) 25 (12-50) 28 (10-58) 38 (15-78) <0.001

PRA (ng/ml/hr) 1.7 (1.0-4.4) 2.1 (1.0-5.7) 3.8 (1.6-9.2) <0.001

Aldo (pmol/L) 153 (107-389) 170 (133-524) 454 (181-1141) <0.001

ARR using DRC 7.9 (2.6-27.8) 8.3 (2.3-49.9) 14.2 (2.3-75.7) <0.001

ARR using PRA 107 (32-223) 109 (24-227) 133 (30-300) NS

Renin, Aldo and ARR

Values presented as medians (range) Ahmed A, et al JCEM 2010

Effects Of Phase Of Menstrual Cycle On The ARR

+P<0.001

ARR Aldosterone/DRC (pmol/

L)/(mU/L)

ARR Aldosterone/PRA

(pmol/L)/(ng/ml/hr)

Error bars indicate interquartile ranges

Ahmed A, et al JCEM 2010

Effects Of Phase Of Menstrual Cycle On The ARR

With outliers excluded

Ahmed A, et al JCEM 2010

+P=0.001

ARR Aldosterone/DRC (pmol/

L)/(mU/L)

ARR Aldosterone/PRA

(pmol/L)/(ng/ml/hr)

Error bars indicate interquartile ranges

Men   Women

Menses     Mid-­‐follicular   Mid-­‐luteal  

ARR using DRC

4.8 (3.8-10.0)

7.9* (2.6-27.8)

8.3* (2.3-49.9)

14.2* (2.3-75.7)

ARR using PRA

61 (21-160)

107* (32-223)

109* (24-227)

133* (30-300)

ARR in women (according to menstrual phase) versus men

Values presented as medians (range)

Ahmed A, et al JCEM 2010

*P<0.05 vs Men

Effects Of Phase Of Menstrual Cycle On The ARR

Conclusions ●  When screening women for PAL by ARR, avoiding the luteal phase

should minimise the possibility of false positives, and possibly the time of the menses might be optimal when estrogen and progesterone levels are at their lowest and the ARR range is closest to male

●  Should we consider different reference ranges for men and women?

Ahmed A, et al JCEM 2010

Effects Of Phase Of Menstrual Cycle On The ARR

Results:

Treatment with EE+D was associated with significant increases in aldo and PRA but decreases in DRC, leading to increases in ARR calculated by DRC but not by PRA

In contrast, treatment with subdermal ETO was associated with no significant changes in PRA, DRC, aldosterone or ARR at either one week or six weeks

Conclusion:

The combined oral contraceptive ethinylestradiol plus drospirenone is capable of significantly increasing ARR with risk of false positive results during screening for PA, but only if DRC is used to calculate the ratio

Ahmed A, et al JCEM 2011

Contraceptives And The ARR

Results: For both SSRI antidepressants, treatment was associated with rises in aldo,

DRC and PRA ARR fell significantly whether calculated using DRC or PRA Conclusions: SSRI antidepressants can significantly reduce ARR and therefore potentially

increase the risk of false negative results when screening for PA Further studies in hypertensive patients, including patients with confirmed PA,

are required

Antidepressants And The ARR

Confirmatory Tests for PA Oral sodium loading (6g x 3 days) and 24-h urinary aldosterone >12-14

mcg/d (>33-38 nmol/d (replace potassium adequately). Ur Na+ > 200 mmol/d

Saline 0.9% 2L/4 h infusion in supine posture: aldosterone at 4 h: > 277

nmol/L (10 ng/dL): PA; 138-276 nmol/L unclear

Fludrocortisone 100 mcg q6h x 4 days oral: K+ supplements and

monitoring q 8h. Aldo on day 4 > 6 ng/dL (>162 nmol/L) with PRA < 1 ng/ml/h

Captopril 25-50 mg oral after sitting 1 h. Aldo 1-2 hr later decreases <30% and PRA remains suppressed

24 hour urinary aldosterone following 3 days of oral salt loading (>200 mmol sodium/day) >12 ug/d

Interpretation of the CT Abdomen? A.  Normal

B.  Left adrenal adenoma

C.  Bilateral adrenal hyperplasia D.  Bilateral adrenal hyperplasia with a

left nodule on the junction of the 2 limbs of the adrenal

E.  The adrenal is abnormal since this is a case presentation on adrenal disease

A sensitivity of 100% was achieved when a mean limb width of greater than 3 mm was used to diagnose bilateral adrenal hyperplasia, and a specificity of 100% was achieved when the mean limb width was 5 mm or greater. AJR:181, September 2003

Bilateral Adrenal Hyperplasia (BAH)( up to 80%) - both adrenals overproducing aldo

Aldosterone-producing Adenoma (APA)(Conn’s adenoma)

- a benign adrenal tumor overproducing aldo Aldosterone-producing Carcinoma

- a malignant adrenal tumor overproducing aldo Glucocorticoid-remediable Aldosteronism

- a rare, genetic form of PA that runs in families Familial Hyperaldosteronism Type 1 (FH-I), Type 3 (FH-3)

Subtypes Of Primary Aldosteronism

Examples of APAs not detected by CT scanning

Aldosterone-producing Adenoma (APA)

Adrenal "Incidentaloma"

53

Seeing is believing???

Wrong side

Wrong side

Could be treated by surgery

Wrong side Ineffective operation

RAV

R Adrenal L Adrenal

LAV

IVC L renal V

The Right AV is usually harder to cannulate than the Left

<'92 '92 '93 '94 '95 '96 '97 '98 '9940

50

60

70

80

90

100 PERCENT SUCCESSFUL

RIGHT ADRENAL VENOUS SAMPLING

(First Attempts)

When 4 radiologists performed AVS in 60 patients, the success rate was only 42%. If limit to one or two radiologists, the AVS success rate can increase to 96%.

Harvey, A., Kline, G. & Pasieka, J.L. (2006) Adrenal venous sampling in primary hyperaldosteronism: comparison of radiographic with biochemical success and the clinical decision-making with ‘less than ideal’ testing. Surgery, 140, 847– 855.

Right Adrenal Venous Sampling

IVC

RAG

RAV

Use Of CT To Localize Adrenal Vein

Rapid cortisol estimation performed TDx analyser

Incubation time reduced to 6 min by following a test protocol on the analyser originally used for measuring ethosuximide

Only 50 uL sample volumes required: rapid centrifugation (4 min)

Total time from point of collection = approx 12 mins

Rapid Cortisol Assay For Real-time Confirmation of AV Cannulation

Angiographic location of the orifice of right adrenal vein.

Iwasaki T et al. Journal of Renin-Angiotensin-Aldosterone System 2012;14:156-160

Left panel shows right adrenal venogram of the patient with body mass index of 40.7 kg/m2.

Iwasaki T et al. Journal of Renin-Angiotensin-Aldosterone System 2012;14:156-160

Body mass index was significantly higher in Group A than in Group C, Group D, Group E or Group F.

Iwasaki T et al. Journal of Renin-Angiotensin-Aldosterone System 2012;14:156-160

*p<0.01 vs Group A.

Hypertension After Surgery In Patients With Primary Aldosteronism

Rochester

66% 33%

1%

65%

35%

Torino Brisbane

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 2004.

Role of Unilateral Adrenalectomy in Bilateral Primary Aldosteronism: A 22-Year Single Center Experience

1)  PA confirmed by fludrocortisone suppression testing;

3)  Bilateral aldosterone production, defined by lack of contralateral suppression on

5)  Unilateral adrenalectomy performed;

7)  Postoperative follow-up of at least 12 months;

8)  serum creatinine less than 170 mol/liter; and

9)  No treatment with aldosterone antagonists (spironolactone or amiloride) since adrenalectomy.

Only 40 of 51 patients satisfied the inclusion criteria.

The adrenal chosen for removal

Higher adrenal venous aldosterone/cortisol ratio on AVS.

The adrenal showing the greater degree of morphological abnormality (diffuse and/or nodular enlargement) on CT.

Sukor N et al. J Clin Endocrinol Metab 94: 2437–2445, 2009

Role of Unilateral Adrenalectomy in Bilateral Primary Aldosteronism: A 22-Year Single Center Experience

Hypertension was defined as

“Cured” if patients were normotensive (BP 140/90 mm Hg) without taking antihypertensive medications

“Improved” if fewer medications were needed to maintain or decrease the baseline BP (provided the dosage of none was increased) or if the dosage of one or more was at a reduced level (provided no additionalmedications were used).

Sukor N et al. J Clin Endocrinol Metab 94: 2437–2445, 2009

Role of Unilateral Adrenalectomy in Bilateral Primary Aldosteronism: A 22-Year Single Center Experience

Sukor N et al. J Clin Endocrinol Metab 94: 2437–2445, 2009

Role of Unilateral Adrenalectomy in Bilateral Primary Aldosteronism: A 22-Year Single Center Experience

Sukor N et al. J Clin Endocrinol Metab 94: 2437–2445, 2009

Summary

1.  Substantial proportion of EH is due to PA (5-8%)

2.  Take into consideration drugs (including SSRIs, OCPs) & menstrual cycle in ARR

3.  KCNJ5 mutation play an important roles in Familial and Sporadic PAs

4.  Strategies to improve AVS (R cannulation)

5.  Quality of life improved with Rx of PA

6.  Role of unilat adrenalectomy in resistant bilateral diseases ? Pat selection ?