Primary Hyperaldosteronism

Cobb A, Aeddula NR.

Continuing Education Activity

Primary hyperaldosteronism (PA) is an underdiagnosed cause of hypertension. The classic presentation of PA includes
hypertension and hypokalemia. However, in reality, most patients will present without hyperkalemia. The two primary causes are
aldosterone-producing adenomas and bilateral adrenal hyperplasia of the zona glomerulosa. Familial cases have been found and are
classified into Type I, Type II, and Type III familial hyperaldosteronism. Diagnosis can initially be confirmed with the elevated
morning aldosterone to plasma renin activity ratio. If the ratio is higher than 20 to 1; then the excess aldosterone points to the
adrenal gland as the primary source. The preferred treatment is adrenalectomy in those with unilateral disease. Those who are poor
surgical candidates or have bilateral adrenal hyperplasia can be treated medically with mineralocorticoid antagonists as well as
antihypertensive agents for further blood pressure control. This activity reviews the evaluation and management of primary
hyperaldosteronism and highlights the role of the interprofessional team in identifying and treating this condition.

Objectives:

Describe the common presentation of primary hyperaldosteronism.

Review the evaluation of primary hyperaldosteronism.
Summarize the treatment options for primary hyperaldosteronism.
Identify interprofessional strategies regarding the evaluation and management of primary hyperaldosteronism to ensure
up-to-date best practices are employed, thereby improving patient outcomes.

Access free multiple choice questions on this topic.

Introduction
Primary hyperaldosteronism (PA) is an under-diagnosed cause of hypertension. The presentation is classically known to occur as a
patient with hypertension and hypokalemia. However, in reality, most patients will present without hyperkalemia. The two primary
causes are aldosterone-producing adenomas and bilateral adrenal hyperplasia of the zona glomerulosa. Some familial causes have
been found and are classified into Type I, Type II, and Type III familial hyperaldosteronism. Diagnosis can initially be confirmed
with the elevated morning aldosterone to plasma renin activity ratio. If the ratio is higher than 20 to 1; then the excess aldosterone
points to the adrenal gland as the primary source. The preferred treatment is adrenalectomy in those with unilateral disease. Those
who are poor surgical candidates or have bilateral adrenal hyperplasia can be treated medically with mineralocorticoid antagonists
as well as antihypertensive agents for further blood pressure control.

Etiology
The most prevalent cause of primary hyperaldosteronism is aldosterone-producing adenomas. Other causes include aldosterone-
producing adrenal carcinoma, ectopic aldosterone secretion from the kidneys or ovaries, and bilateral zona glomerulosa
hyperplasia. There are familial causes as well. Type I is glucocorticoid-remediable hyperaldosteronism that results from the
formation of a chimeric gene containing the regulator portion of 11B-hydroxylase (usually regulated by ACTH) and the synthetic
region of aldosterone synthase; as a result, ACTH stimulates aldosterone synthase and hence aldosterone production. Type II
causes are unclear; it correlates to a gene on 7p22 (band 11q13), and histologic findings are consistent with hyperplasia or
adenomas.[1] Type III results from a mutation in KCNJF which is a potassium channel coding gene. This mutation causes
increased calcium ion availability into the glomerulosa cells leading to increased aldosterone synthesis.[2][3]
Epidemiology
Primary hyperaldosteronism occurs worldwide, and no evidence suggests that there are more cases of primary hyperaldosteronism
in certain areas of the world. Aldosterone-producing adenomas occur more frequently in women than in men. Reports are that there
may be a higher prevalence in African Americans or persons from African origin; this is demonstrated more in the idiopathic
adrenal hyperplasia variant of the disease.[4][5]

History and Physical

A patient with suspected primary hyperaldosteronism will present with uncontrolled hypertension and will typically be
young. These patients will require up to three antihypertensive medications including a diuretic to maintain suboptimal blood
pressure control. They can also have a family history of early-onset hypertension or cerebral vascular disease at a younger age.
Patients may have severe muscle weakness, palpitations, fatigue, or muscle cramps due to symptoms related to hypokalemia.
Polydipsia and polyuria are present due to nephrogenic diabetes insipidus likely secondary to hypokalemia.

Hypokalemia has been considered one of the hallmark signs in the diagnosis of primary aldosteronism; however, estimates are now
that less than 37 percent of patients who have primary hyperaldosteronism will present with hypokalemia.[5] Patients who have
adequate sodium intake will often be more hypokalemic. Increasing sodium intake will allow more sodium delivery to the cortical
collecting tubules promoting further excretion of potassium in the setting of excess aldosterone.[5] Even though patients typically
do not present with hypokalemia; the diagnosis should be considered in a patient with drug-resistant hypertension and hypokalemia
in a patient starting a low dose of diuretic.

There are no physical exam characteristics that will lead to a diagnosis of primary hyperaldosteronism. However, due to excessive
hypertension and stress on the heart, left ventricular hypertrophy can occur leading to an S4 heart sound secondary to blood trying
to enter a noncompliant stiff ventricle during atrial contraction. Other findings related to longstanding hypertension can arise
throughout the body affecting the heart (heart failure), kidneys (proteinuria), eyes (hypertensive retinal changes), vasculature
(carotid bruits/stroke symptoms), muscle weakness, and mental status changes secondary to hypertensive encephalopathy.

Evaluation
The Endocrine Society recommends screening for specific patient presentations. Patients with hypertension on triple-drug therapy
and diuretic-induced hypokalemia; patients with hypertension and adrenal incidentaloma; hypertension with a family history of the
early-onset cerebral vascular accident; or patients with hypertension and first-degree relatives with confirmed primary
hyperaldosteronism.[6]

Suspect primary aldosteronism when a patient presents with hypertension at an early age with hypokalemia and poorly controlled
blood pressure despite medical therapy. The next step is to obtain a morning plasma aldosterone and renin activity. If the ratio of
morning aldosterone to plasma renin activity is higher than 20 to 1; then the excess aldosterone can be attributed to the adrenal
gland as the primary source. Next, any of the four confirmatory tests may follow: 1) oral sodium loading 2) saline infusion 3)
fludrocortisone suppression 4) captopril challenge, should suppress aldosterone; however, in a patient with primary aldosteronism,
there will be a lack of aldosterone suppression. Once primary aldosteronism is confirmed all suspected patients are recommended
to undergo Adrenal computed tomography scan as the initial study and to exclude possible adrenocortical carcinoma. It is then
recommended for the patient to have an adrenal venous sampling.[7]

The best diagnostic test involves the measurement of cortisol and aldosterone in bilateral adrenal venous effluent and a peripheral
vein before and during an ACTH infusion. Cortisol will be used to evaluate the catheter placement in the adrenal veins, as levels
from the two sides should be similar. When an adenoma is present, the aldosterone-to-cortisol ratio on one side is usually at least
five times greater than the other indicating suppression. Bilateral hyperplasia tends to produce similar values on each side. If the
 study points towards a unilateral adenoma, then laparoscopic adrenalectomy is the preferred treatment. If the patient declines
surgery or is not a surgical candidate, medical therapy is the recommended route. If the study points towards a bilateral cause, then
medical treatment with a mineralocorticoid antagonist is warranted.[8]

Treatment / Management
Treatment for primary hyperaldosteronism includes laparoscopic resection for adenomas. This procedure will usually
resolve the hypokalemia, but hypertension can persist in up to 65% of patients post adrenalectomy. Surgery is the preferred
treatment for patients with unilateral aldosterone-producing adenoma. After unilateral adrenalectomy, almost all patients have the
resolution of hypokalemia and moderate improvement in blood pressure control.[9] In those who are unable to undergo surgery or
have bilateral adrenal hyperplasia, mineralocorticoid antagonists such as spironolactone or eplerenone are an option. In a
randomized study, the antihypertensive effects between spironolactone and eplerenone in patients with primary hyperaldosteronism
were studied showing that spironolactone was more effective than eplerenone in controlling blood pressure.[10] Amiloride, a
sodium channel blocker, may be helpful in the treatment and other antihypertensive agents can be continued as needed to optimize
blood pressure control. Spironolactone is considered the first line agent for patients who cannot undergo surgical resection.

Di!erential Diagnosis
In patients with refractory hypertension, some other differentials to include are renal artery stenosis, secondary aldosteronism,
pheochromocytoma (spontaneous and drug-mediated),[11] deoxycorticosterone secreting tumors, renin-secreting tumor from the
juxtaglomerular apparatus, and renovascular ischemia.[12] Excessive licorice intake can lead to the impairment of conversion of
cortisol to cortisone in the kidneys; this is because the glycyrrhizinic acid portion of the licorice inhibits 11-beta-hydroxysteroid
dehydrogenase. Excess cortisol will then bind to mineralocorticoid receptors acting as a mineralocorticoid.[13]

Other genetic diseases presenting similar to primary hyperaldosteronism include but are not limited to:

Chrétien syndrome is a rare syndrome that is caused by excess secretion of POMC from pituitary adenoma leading to
adrenocortical hypertension.[14]

Gitelman syndrome, which is a loss of function of the sodium chloride cotransporter in the renal tubules, leading to salt wasting
and secondary hyperaldosteronism.[15]

Liddle syndrome is a pseudohyperaldosteronism which is a rare autosomal dominant disorder causing hyperactive renal epithelial
sodium channels with increased sodium reabsorption in the distal tubules. In this syndrome, levels of renin and aldosterone are
low.[16]

Prognosis
Studies show that morbidity and mortality of those with primary hyperaldosteronism are directly related to chronic elevated
hypertension leading to increased risk of cardiovascular disease including CAD, stroke, and congestive heart failure secondary to
left ventricular hypertrophy.[17][18] Other studies point to the increased risk of cardiac arrhythmias secondary to persistent
hypokalemia in those with primary hyperaldosteronism.[14] Research has shown in individual studies that surgical correction by
adrenalectomy leads to a better prognosis by a significant reduction in hypertension and hypokalemia when compared to those with
medical therapy.[19]

Complications
Cardiovascular risk is associated with patients who have primary aldosteronism because these patients will have greater mass
:
 measurements of the left ventricle as well as decreased left ventricular function when compared to patients with other types of
hypertension.[20][21] Other cardiovascular risks include stroke, atrial fibrillation, and myocardial infarction. There was a
prospective study done comparing 54 patients with primary hyperaldosteronism who had treatment with either spironolactone, a
mineralocorticoid receptor antagonist, or surgical resection of an adrenal adenoma. The control group was patients with primary
hypertension matched for age, gender, BMI, and duration of hypertension. The study found that before treatment, patients with
primary hyperaldosteronism had a greater prevalence of cardiovascular events than those with primary hypertension. After
treatment of the mineralocorticoid excess whether it be by surgical resection of adenomas or by spironolactone; there was no
longer an elevated cardiovascular risk for those with primary hyperaldosteronism. The patients received follow-up for roughly
seven years, and there was no significant difference between each group when it came to reaching the primary outcome of
myocardial infarction, revascularization procedure, sustained arrhythmia, or stroke.[22]

Metabolic syndrome is more common in those with primary hyperaldosteronism as compared to controls with similar blood
pressure, sex, age, and BMI.[23]

Increased aldosterone blood levels lead to increasing GFR and renal perfusion pressure. These patients will also have increased
urinary albumin excretion. A study of a series of 50 patients with primary aldosteronism treated with either adrenalectomy or
spironolactone was compared to those with primary hypertension on antihypertensive therapy. The results showed that at baseline,
patients with primary aldosteronism had higher GFRs and albumin excretion than patients with primary hypertension. However,
after a six-month follow-up of the treated primary aldosteronism patients, it was found that albuminuria was significantly
decreased in addition to the reduction in the GFR when compared to the primary hypertension group.[24] This research shows that
with surgical resection or medical therapy in those with primary hyperaldosteronism, an underlying renal insufficiency could be
present due to reversing the hyperfiltration state.

Prior stroke was found to be significantly higher in patients with primary hyperaldosteronism (12.9%) than those with primary
hypertension (3.4%) in a retrospective study comparing a total of 124 patients with primary hyperaldosteronism and 465 patients
with primary hypertension. The two groups had similar ages, genders, and mean blood pressure of 175/107.[25]

Consultations
Nephrology

Endocrinology

General surgery

Interventional radiology

Deterrence and Patient Education

Patients should be educated with the common symptoms of primary hyperaldosteronism and be aware of the common family
history findings to report to their physicians. Patients should be mindful of bringing up any early family history of hypertension or
stroke in an immediate family member. When diagnosed with hyperaldosteronism, patients should understand the importance of
compliance with medical therapy as this is the only treatment besides surgical intervention. Patients diagnosed with essential
hypertension at a young age that have been refractory to treatment on multiple medications should mention to the primary care
physicians of their compliance and provide a record of blood pressure readings as this will help their physician evaluate further
causes of hypertension.

Enhancing Healthcare Team Outcomes

:
 In patients with suspected primary hyperaldosteronism, it is critical to maintain interprofessional communication between the
primary care physician, endocrinologist, nurse practitioner, and the laboratory team. The workup of suspected primary
hyperaldosteronism involves an initial blood test of aldosterone to plasma renin activity, and this needs to be drawn early in the
morning, preferably before 8 am. Discussion between the healthcare provider and lab team should take place if working in the
hospital, or conversation with the patient if working up outpatient. Confirmatory tests including oral sodium loading or saline
infusion require timely blood draws by lab staff and careful instruction to the patient for sodium loading to allow for accurate
results. Once diagnosed, especially if by an endocrinologist, it is important to thoroughly document the steps of the workup and
goals of treatment as this will help the interprofessional communication with the primary care physician, nurse practitioner or
surgeon if the patient is a surgical candidate for adrenalectomy. A thorough explanation of the treatment options should be given to
the patient to allow them to be a part of the medical team.

Review Questions
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Comment on this article.

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 Publication Details

Author Information

Authors

Alexander Cobb1; Narothama R. Aeddula2.

A"liations

1 Michigan State/McLaren Greater Lansing

2 Deaconess HS, IN University School Med

Publication History

Last Update: August 10, 2022.

Copyright
Copyright © 2022, StatPearls Publishing LLC.

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NLM Citation

Cobb A, Aeddula NR. Primary Hyperaldosteronism. [Updated 2022 Aug 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.
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