Epidemic of Primary
Hyperaldosteronism:
Facts and Myths
Carla Sawan, MD
Division of Endocrinology
Saint George Hospital University Medical Center, Beirut
Epidemiology :
Types, prevalence, screening challenges
Clinical presentation
Diagnosis
Laboratory testing
Imaging modalities
Adrenal Vein Sampling and Subtype Differentiation
Treatment
Goals
Surgical treatment
Non-surgical treatment
Types of Hyperaldosteronism
 Bilateral idiopathic Hyperaldosteronism (IHA)  Most common form
60-70 % of cases of 1ary HA.
 Unilateral adenoma (APA)  30-40 % of cases of 1ary HA.
Somatic mutation in KCNJ5 gene in 40% of cases.
Other rare causes:
 Unilateral adrenal hyperplasia (PAH): similar clinical presentation and
outcome to APA.
 Familial Hyperaldosteronism types I, II and III. Germline muations in
KCNJ5 and CACNA1D.
 Aldosterone producing adrenocortical carcinomas/ ectopic aldosterone
secreting tumors (neoplams in ovary, kidney, etc)
Mattsson C, Young WF Jr. Nat Clin Pract Nephrol. 2006
Prevalence: wide variation
PA is responsible for 5 to 13% of HTN cases and makes up
0.6% of adrenal incidentalomas.
Conn 1964  the prevalence of PA in the hypertensive
population referred to him was 20%  Possible referral bias.
Primary aldosteronism prevalence is
 ~ 3% of HTN patients in primary care setting.
 ~ 39% of patients with resistant HTN.
 ~ 6-10% of HTN patients referred for difficult to manage
HTN or suspicion for PA. (Endocrine Society practice guidelines
2008).
With the (ARR) used as a screening tool, the prevalence of
primary hyperaldosteronism averaged 6% among patients
with HTN.
Kaplan NM. J Hypertens. Oct 2012
Prevalence of Primary Hyperaldosteronism
in Hypertensive Patients
Young, 2003
Prevalence of PA before and after
using of ARR for screening
Young et Al. JCEM 2004.
ARR detected more normokalemic PA
Young et Al. JCEM 2004.
Clinical Presentation
 Hypertension: usually substantial elevation
in both systolic and diastolic pressures
without malignant HTN.
 Hypokalemia: present in ~ 40% of cases.
IHA usually less hypokalemic than APA.
 Lack of edema: due to “aldosterone escape”
leading to increased diuresis.
 Metabolic alkalosis, hypomagnesemia,
mild hypernatremia.
Mulatero at al, JCEM 2004
Blumenfeld et al. Ann Intern Med 1994
Diagnosis
Why not using ARR as a routine screening tool?
• False-positive in about 50% of patients  confirmatory
testing is needed.
• Abnormal ARR level varies from 20 to as high as 69 in
various publications  wide range of positive results.
• PRA levels are low in about 30% of HTN individuals,
leading to falsely elevated ARR More False positives
in hypertensive patients.
• The lower limit of PRA changes from 0.6 ng/ml per h to
as low as 0.1 ng/ml per h  high ARR variability.
Kaplan. J Hypertens. 2012
Steps in the evaluation for PA
1) Case detection
2) Confirmatory testing
3) Subtype differentiation and Localization
Case detection rather than screening
•
•
•
•
•
HTN and spontaneous hypokalemia or hypokalemia on low
dose diuretic.
Severe HTN
• (>160 mmHg systolic or >100 mmHg diastolic)
• Drug-resistant hypertension (defined as suboptimallycontrolled hypertension on a 3-drug program that includes
an adrenergic inhibitor, vasodilator, and diuretic)
HTN with an adrenal incidentaloma (> 1 cm)
HTN and a family history of early-onset HTN or
cerebrovascular accident at age <40 years.
All HTN first-degree relatives of patients with primary
hyperaldosteronism.
Endocrine Society Practice Guidelines 2008
Paired Elevation in ARR and PAC
PAIRED
•
PAC/PRA ratio and Aldo level
Aldosterone concentration >15 ng/dL (416 pmol/L)
AND
• PAC/PRA ratio greater than 20.
• Usually PRA < than 1 ng/mL per hr (0.2778 ng/L per sec)
and undetectable PRC.
Tests are performed on blood sample obtained in
the morning in a seated ambulatory patient.
Confirmatory testing
Checking for Aldosterone suppression
• Orally administered NaCl and measurement of urine
aldosterone excretion.
OR
• IV NaCl loading and measurement of Aldo level.
Patients who don’t need confirmatory testing)
• Spontaneous hypokalemia.
• Undetectable PRA or PRC.
• PAC >30 ng/dL.
Caveats To Testing
• Most anti-HTN meds can be continued
• Posture stimulation is not required
• Discontinue spironolactone or epleronone 6
weeks prior to testing to avoid falsely low
ARR
Subtype Differentiation:
Why does It Matter
• In case of unilateral disease, surgery is curative.
– Unilateral adrenalectomy leads to resolution of hypoK
in all cases
– HTN is improved in all cases, cured in 30-60%
– Total adrenalectomy superior to partial
• In case of bilateral hyperplasia, no role for surgery.
– Unilateral or Bilateral adrenalectomy does not affect HTN
– Medical Therapy Improves BP control in all cases and
normalizes CV mortality
Subtype Differentiation:
Difficulties with Adrenal Vein Sampling
• AVS was first introduced in 1967
• Relies on finding a 4x difference in aldosterone
secretion between 2 sides, done under
cosyntropin stimulation.
• Abandoned as technically difficult and due to
unclear role in overall management paradigm.
Until …
Subtype Differentiation:
Critical Role of AVS
Primary aldosteronism: adrenal venous
sampling.
Young WF Jr, Stanson AW, Grant CS,
Thompson GB, van Heerden JA.
Surgery, Dec 1996
Subtype Differentiation:
Critical role of AVS
• 34 patients with confirmed PA and a spectrum of CT scan findings.
• Results:
– 40% patients with normal or minimal adrenal limb thickening had a
unilateral source of aldosterone
– 40% with apparent unilateral microadenoma had an ipsilateral APA
– 44% patients with bilateral adrenal masses had a unilateral source of
aldosterone secretion
– 3/4 patients with unilateral atypical adrenal macroadenomas had
ipsilateral aldosterone-producing adenomas.
Significant discordance
between CT scan findings
and real source of Aldo
excess found on AVS
Young et Al. Surgery, Dec 1996
Subtype Differentiation:
Critical Role of AVS
• 203 pts at Mayo Clinic with PA from 1990-2003
• Both adrenal veins catheterized in 194 patients
• Based on CT only
– 42 (25%) would have been excluded as
surgical candidates
– 48 (25%) would have had inappropriate
surgery.
Accuracy of CT was only ~ 53%
Young et Al, Surgery 2004
Treatment
Goals
Normalizing BP and decreasing cardiovascular mortality.
Milliez et al, J Am Coll of Cardiology 2005
 Broussais Hospital, Paris, between 1997-1999.
 Case-Control retrospective study
 124 patients with PA (65 pts with APA, 59 pts with
IHA) matched with 465 pts with essential HTN.
 Comparison of events between 2 groups:
 Prior strokes (12.9 % vs 3.4 %)
 Nonfatal myocardial infarction (4.0 % vs 0.6 %)
 Atrial fibrillation (7.3 % vs 0.6 %)
Difference was statistically significant, comparable
between IHA and APA.
Preoperative Preparation
1) HTN should be controlled, preferably with
mineralocorticoid receptor antagonist
2) HypoK should be corrected with K suppl.
BP response to spironolactone pre-op predicts
the BP response to unilateral adrenalectomy in
patients with unilateral disease.
Young et al. Ann Intern Med 2001
Postoperative Follow-Up
1. Plasma aldosterone should be measured the
day after surgery to assess for cure.
2. K supplements and spironolactone should be
discontinued and, if possible, antihypertensive
therapy should be decreased.
3. Patients should be monitored closely for
hyperkalemia 2/2 suppression of contralateral
adrenal gland
4. Na-rich diet on discharge
Possibly under-diagnosed disease?
• Persistent notion of “Conn’s Tumor” triad
for diagnosis to be made
• Treatment complexity
• 30% AVS failure rate in the US
Outcomes of surgery
1. HTN is cured in 40% of cases and
improved in all.
2. Hypokalemia and Hyperaldosteronism are
cured in all cases undergoing surgery.
References
1.
Slides obtained with courtesy of Dr Julia Kharlip at U.Penn, PA USA
2.
Hannemann A, Wallaschofski H. Prevalence of primary aldosteronism in patient’s
cohorts and in population-based studies: a review of the current literature. Horm
Metab Res 2012.
3.
Blumenfeld JD, Sealey JE, Schlussel Y, et al. Diagnosis and treatment of primary
hyperaldosteronism. Ann Intern Med 1994.
4.
Funder JW, Carey RM, Fardella C, et al. Case detection, diagnosis, and treatment
of patients with primary aldosteronism: an endocrine society clinical practice
guideline. J Clin Endocrinol Metab 2008.
5.
CONN JW. Aldosterone in clinical medicine; past, present, and future. AMA Arch
Intern Med 1956.
6.
Milliez P, Girerd X, Plouin PF, et al. Evidence for an increased rate of
cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol
2005.
7.
Sawka AM, Young WF, Thompson GB, et al. Primary aldosteronism: factors
associated with normalization of blood pressure after surgery. Ann Intern Med
2001.
8.
Young WF, Stanson AW, Thompson GB, et al. Role for adrenal venous sampling
in primary aldosteronism. Surgery 2004
Thank You