Continuing Education Activity

Hyperaldosteronism occurs due to the excess production of aldosterone from the adrenal gland. Hyperaldosteronism can initially present as essential and refractory hypertension and can often go undiagnosed. This disorder can be of primary or secondary origin, both presenting similarly but differentiated by a set of lab values and diagnostic studies. This activity reviews the cause of hyperaldosteronism and highlights the role of the interprofessional team in its management.

Objectives:

• Recall the causes of hyperaldosteronism.
• Describe the laboratory features of hyperaldosteronism.
• Summarize the treatment of hyperaldosteronism.
• Explore modalities to improve care coordination among interprofessional team members in order to improve outcomes for patients affected by hyperaldosteronism.

Introduction

Aldosterone is a mineralocorticoid hormone. It is secreted by the zona glomerulosa, the outermost layer of the Adrenal cortex. Excess production of aldosterone is referred to as hyperaldosteronism. Hyperaldosteronism can initially present as mild or severe to refractory hypertension but can often go undiagnosed. Hyperaldosteronism can be of primary or secondary origin, presenting similarly but differentiated by a set of lab values and diagnostic studies. Treatment is specific to the individual causes of hyperaldosteronism.[1][2][3][4]

Etiology

The cause of the excess production of aldosterone differentiates primary from secondary hyperaldosteronism.[5]

Primary hyperaldosteronism is due to the excess production of the adrenal gland, more specifically the zona glomerulosa. It can present more commonly as a primary tumor in the gland known as Conn syndrome or bilateral adrenal hyperplasia. Rarer forms of primary hyperaldosteronism are unilateral adrenal hyperplasia, ectopic aldosterone-secreting tumors, aldosterone-producing adrenocortical carcinomas, and familial hyperaldosteronism type 1.

Secondary hyperaldosteronism occurs due to excessive activation of the renin-angiotensin-aldosterone system (RAAS). This activation can be due to a renin-producing tumor, renal artery stenosis, or edematous disorders like left ventricular heart failure, pregnancy, cor pulmonale, or cirrhosis with ascites.

Epidemiology

Primary hyperaldosteronism can be seen in about 10% of hypertensive patients [6]. However, some studies have shown an overestimation of cases. The prevalence of primary hyperaldosteronism has varied from 4.6 % to 16.6 % in different studies, depending on patient selection, diagnostic methods, and severity of hypertension [7]. Secondary hyperaldosteronism is diagnosed less often than primary hyperaldosteronism. Both primary and secondary hyperaldosteronism present more frequently in women. 

Pathophysiology

Primary hyperaldosteronism (PHA) occurs due to the excess aldosterone production by the adrenal gland. The most common cause of PHA (in two-thirds of the patients) is idiopathic bilateral adrenal hyperplasia. In the remaining one-third of patients, a tumor in the zona glomerulosa, known as Conn syndrome, can directly cause an increase in aldosterone. These patients are usually asymptomatic but can typically present with hypertension and hypokalemia.

Secondary hyperaldosteronism (SHA) occurs due to the excess stimulation of the RAAS. It can happen due to physiologic state of transient RAAS activation such as hypovolemia but can be seen in pathological states of sustained RAAS activation. Renal artery stenosis (atherosclerosis or fibromuscular dysplasia) causes decreased blood flow through the kidneys, simulates a false sense of hypovolemia, and activates aldosterone secretion. In left-sided congestive heart failure and cor pulmonale, a decrease in cardiac output leads to aldosterone stimulation. In patients with cirrhosis and ascites, the reduction in circulating fluid volume leads to decreased perfusion through the kidneys and results in increased aldosterone secretion. Less commonly found is a renin-producing tumor in the juxtaglomerular cells. Both primary and secondary hyperaldosteronism can present with a broad clinical range. [6]

Aldosterone is the primary mineralocorticoid in the body. Aldosterone acts on the epithelial sodium channels (ENaC) in the collecting tubules and causes sodium reabsorption. This creates a negative potential in the tubular lumen and, in turn, causes movement of cations (primarily potassium and hydrogen ions) into the tubular lumen to maintain electrical neutrality, resulting in hypokalemia and metabolic alkalosis. The increased reabsorption of sodium leads to hypertension and volume expansion. [6]

Histopathology

Histopathology is not a standard tool for the diagnosis of hyperaldosteronism. Immunohistochemical staining of CYP-11B2 in aldosterone-producing adenomas has been found to be valuable. This can be useful to differentiate the variable types and subtype classifications of adenomas,  micronodules, and aldosterone-producing cell clusters.

History and Physical

Patients often can present asymptomatically, but this varies with the severity of hyperaldosteronism. First-occurrence and resistant hypertension are the most common presenting symptoms for these patients, and the sequelae of fatigue, headache, polyuria, and polydipsia commonly occur with it. Metabolic alkalosis observed in these patients is attributable to the same mechanism that happens in contraction alkalosis.

Patients with aldosteronism can be asymptomatic or symptomatic. Blood pressure can range from normotensive to severe hypertension and sometimes refractory hypertension. Sodium reabsorption, volume expansion, and increased peripheral vascular resistance are the causative factors for hypertension in aldosteronism. [6] Symptoms are usually due to moderate to severe high blood pressure or secondary to hypokalemia. High blood pressure can cause headaches, dizziness, vision problems, chest pain, and dyspnea. 

Patients with secondary hyperaldosteronism can present with different blood pressure measurements. Renal artery stenosis and coarctation of Aorta have higher blood pressure. Patients with diuretic use have hypovolemia as can patients with heart failure, cirrhosis, and nephrotic syndrome. Patients with Gitelman’s and Bartter’s syndromes have mild hypotension. [6]

Moderate to severe hypokalemia can cause neuromuscular symptoms such as fatigue, muscle weakness, muscle cramps, paresthesias, and cardiac arrhythmias. Also, antidiuretic hormone resistance in renal tubule due to hypokalemia has been implicated in diabetes insipidus in aldosteronism. [6]

Evaluation

Laboratory findings are typically consistent with hypokalemia, mild hypernatremia, and mild hypomagnesemia.[8][9][10]

Plasma renin concentration (or PRC) and plasma renin activity (or PRA) are the initial laboratory measurements in the diagnosis of hyperaldosteronism. In primary hyperaldosteronism, the PRC and PRA are low (less than 1 ng/mL/hour and undetectable, respectively) as the excess aldosterone originates from the zona glomerulosa itself and not an extrinsic pathway. In secondary hyperaldosteronism, the PRC and PRA are high, as renin is the primary mediator for the excess production of aldosterone. These levels are usually measured in the morning after patients have been out of bed. The results are more accurate when the labs are drawn at least two hours after the patient is out of bed and at least five minutes in sitting position.

PAC/ PRA ratio (Plasma aldosterone concentration/plasma renin activity) is a confirmatory test for primary hyperaldosteronism. Most studies support an elevated PAC/PRA (> 30) and PAC (> 20 ng/dL) levels with a sensitivity and specificity of over 90%. However, a PAC/PRA ratio greater than 20 and PAC greater than 15 ng/dL have been reported to be sufficient. In secondary hyperaldosteronism, both PRA and PRC are increased, but the PAC/PRA is less than primary hyperaldosteronism.[11] [12] [13]

The role of 24-hour urine collection in hyperaldosteronism is controversial. However, it can be used to detect inappropriate potassium wasting (> 30 mEq/day). This test can be useful in evaluating the role of extrarenal losses and diuretic abuse in hypokalemia, especially when the increase in aldosterone is barely detectable to mild.

Confirmation of hyperaldosteronism diagnosis typically requires Aldosterone suppression. Testing usually comprises of sodium loading and subsequent measurement of aldosterone. This is achieved with oral sodium loading over three days (5000 mg sodium in diet or 90 mEq sodium tablet). Subsequently urine aldosterone is measured, and a value > 12 mcg/day is used to confirm the diagnosis of hyperaldosteronism. Alternatively, a two-liter intravenous isotonic saline infusion over 4 hours ca be used. With the saline infusion, PAC levels greater than 10 ng/dL are consistent with hyperaldosteronism; however, the saline infusion has a false negative rate of 30%.[12]

Radiological imaging such as computed tomography (CT scan) can be used to distinguish adenomas from bilateral adrenal hyperplasia, but studies have found that CT cannot distinguish the two reliably. All patients with primary aldosteronism should undergo imaging to rule out large masses or carcinomas. [12]

Adrenal vein sampling (AVS) is used to differentiate unilateral from bilateral pathology if radiological imaging is not helpful. An incongruence in levels (usually a 4 fold increase on the side of the adenoma) indicates unilateral origin, whereas equivalent levels indicate a bilateral source. AVS is not recommended in patients younger than 35 years with spontaneous hypokalemia, marked levels of aldosterone, and highly suspicious adrenal adenoma on CT imaging. [12]

Genetic testing is advised in primary aldosteronism seen in very young patients (less than 20 years) with a family history. Familial hyperaldosteronism could be type I (FH-I or glucocorticoid remediable aldosteronism) or type III (FH-III). [12]

Metabolic alkalosis is frequently observed in hyperaldosteronism. The historically wee documented association with hypokalemia has been observed to be less than 40% in studies. Mild hypernatremia and hypomagnesemia some of the other lab abnormalities found in these patients.

Treatment / Management

Surgery is the preferred treatment in primary hyperaldosteronism caused by unilateral disease. Laparoscopic adrenalectomy is preferred as it is associated with fewer complications and a shorter hospital stay than compared to open adrenalectomy. Complete adrenalectomy is preferred to partial adrenalectomy due to greater efficacy and resolution of symptoms. For nonsurgical candidates, mineralocorticoid receptor antagonists (MRA) were preferred as a medical therapy.[14][15][16]

For bilateral hyperplasia in primary hyperaldosteronism, MRAs are the treatments of choice. Spironolactone or eplerenone is the most commonly used. Selection among these agents depends on the adverse effect profile. According to the 2016 Endocrine Society Guidelines, the spironolactone starting dose is 12.5 to 25 mg daily and titrated every two weeks upward. Eplerenone is usually started at 50 mg daily and titrated upward. The clinical course ultimately dictates the increase and frequency in dosage. Combination therapy consisting of medications, restriction of sodium (less than 100 mEq/day), avoidance of alcohol, smoking cessation, aerobic exercise, and maintenance of ideal body weight is shown to produce the best results.[17][18]

For secondary hyperaldosteronism, treatment of the underlying disease will lead to the resolution of the symptoms. Renal artery stenosis might need intervention/ revascularization to control the blood pressure.

ACE inhibitors (ACE I) and angiotensin receptor blockers (ARB) are the agents of choice for controlling blood pressure due to their renal protective benefits. Salt restriction also is recommended for better efficacy.

Differential Diagnosis

Similar presentations have been observed in essential hypertension, Liddle syndrome, syndrome of apparent mineralocorticoid excess, congenital adrenal hyperplasia, primary glucocorticoid resistance, and ectopic adrenocorticotropic hormone (ACTH) syndrome.

Essential hypertension presents with a normal PAC/PRA ratio. Liddle syndrome will have low aldosterone levels and will typically present in childhood. Syndrome of apparent mineralocorticoid excess will present with low aldosterone levels, high urinary free cortisol levels, hereditary implications, and/or a history of excessive licorice consumption. Congenital adrenal hyperplasia will have a family history of 11-beta-hydroxylase or 17-alpha-hydroxylase deficiency and low aldosterone levels. Primary glucocorticoid resistance will have low aldosterone levels, an elevated ACTH and cortisol, and a family history of this syndrome. Ectopic ACTH syndrome will have elevated ACTH that cannot be suppressed with high-dose dexamethasone, and these patients will have an underlying tumor.

Prognosis

Few studies have been performed on the mortality rates of either form of hyperaldosteronism, but 10-year-survival rates have been reported between 90% - 95% in patients treated. The most common morbidity associated with this disorder is cardiovascular. Cardiovascular mortality is increased in these patients, but all-cause mortality is not significantly different.

If hypokalemia persists, it may lead to weakness, paralysis, constipation, and polyuria. Hypokalemia also impairs the secretion of insulin and promotes the development of diabetes mellitus.

Complications

The most common complication and comorbidity associated with these patients is the increased risk of cardiovascular mortality. This is related to excessive aldosterone secretion and can present as atrial fibrillation, left ventricular hypertrophy, myocardial infarction, and stroke.

Postoperative and Rehabilitation Care

Salt restriction (less than 100 mEq/day), alcohol cessation, smoking cessation, maintenance of ideal body weight, and aerobic exercise are beneficial in postoperative and post-treatment care.

Consultations

Endocrinologists and nutritionists can better manage these patients on a long-term basis. Surgery is indicated for a subset of this disorder.

Enhancing Healthcare Team Outcomes

The diagnosis and management of hyperaldosteronism are complex and best done by an interprofessional team that includes a radiologist, pathologist, internist, endocrinologist, nurse practitioner, pharmacist, and a surgeon. Surgery is the preferred treatment in primary hyperaldosteronism caused by unilateral disease. Laparoscopic adrenalectomy is preferred as it is associated with fewer complications and a shorter hospital stay as compared to open adrenalectomy. Complete adrenalectomy is preferred to partial adrenalectomy due to greater efficacy and resolution of symptoms. For nonsurgical candidates, mineralocorticoid receptor antagonists (MRA) were preferred as a medical therapy.

If the patient has bilateral hyperaldosteronism, then medical therapy is preferred. The drug of choice is spironolactone. The pharmacist should assist the clinical team and educate the patient on the importance of drug compliance. In addition, the patient needs to be told that there is a small risk of developing gynecomastia.

The primary care providers, nurses, and dietitians should educate the patient on the importance of salt restriction, alcohol cessation, smoking cessation, maintenance of ideal body weight, and aerobic exercise. Follow up is necessary as the risk of adverse cardiac events is high in these patients.[18]

Only a team approach with close communication between the members can the morbidity of hyperaldosteronism be lowered. [16]