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 ?