Continuing Education Activity

Conn syndrome was named after JW Conn, who first described it in 1955 in a patient who had hypertension with an aldosterone-producing adenoma. The adenoma is characterized by increased aldosterone secretion from the adrenal glands, suppressed plasma renin, hypertension, and hypokalemia. Later, many other cases of adrenal hyperplasia with inappropriately elevated aldosterone secretion were described, and now the term primary hyperaldosteronism is used to describe Conn syndrome irrespective of whether the patient has an adenoma or not. This activity reviews the pathophysiology, cause, and presentation of Conn syndrome and highlights the role of the interprofessional team in its management.

Objectives:

• Identify the etiology of Conn syndrome.

• Differentiate the laboratory features of Conn syndrome.

• Identify the treatment and management options available for Conn syndrome.

• Communicate interprofessional team strategies for improving care coordination and communication to advance the treatment of Conn syndrome and improve outcomes.

Introduction

Conn syndrome was named after JW Conn, who first described it in 1955 in a patient who had hypertension with an aldosterone-producing adenoma. The adenoma is characterized by increased aldosterone secretion from the adrenal glands, suppressed plasma renin, hypertension, and hypokalemia. Later, many other cases of adrenal hyperplasia with inappropriately elevated aldosterone secretion were described, and now the term primary hyperaldosteronism is used to describe Conn syndrome irrespective of whether the patient has an adenoma or not.[1][2]

The diagnosis of Conn syndrome is not always easy, but recognition is important as this condition can help cure hypertension with surgical or medical management. However, it is important to distinguish aldosteronoma from idiopathic adrenal hyperplasia. Aldosteronomas are removed surgically, whereas idiopathic adrenal hyperplasia is managed with medications. At the same time, one has to be aware that there are conditions that cause elevated aldosterone levels, including familial disease and aldosterone-producing renin-responsive adenomas. ectopic secretion (from kidneys and ovary) and adrenocortical carcinomas.

Etiology

The syndrome may be secondary to adrenal hyperplasia, adrenal adenoma, aldosterone-secreting adrenal carcinoma (1%), or familial hyperaldosteronism.[3][4][5] Various genetic alterations (see below) have been identified for rare familial forms of the disease. In most genetic alterations, the endpoint is Ca influx and membrane depolarization, resulting in aldosterone hypersecretion.

• Familial hyperaldosteronism type 1: Unequal crossing over between highly homologous CYP11B2 and CYP11B1 genes that code for aldosterone synthase and steroid 11 B-hydroxylase results in a chimeric gene that is under adrenocorticotrophin (ACTH) rather than RAS control.
• Familial hyperaldosteronism type 2: It is autosomal dominant, heterogeneous, and does not respond to dexamethasone suppression. It is possibly linked to chromosome 7p22.
• Familial hyperaldosteronism type 3: Mutations in the gene encoding the inwardly rectifying potassium channel Kir3.4 (KCNJ5 gene). Specific mutations in the KCNJ5 gene, like those altering the G151E amino acid, are associated with a milder form of aldosteronism than those with a G151R mutation that has a more severe form.

Mutations in 3 other genes encoding for membrane proteins (Na/K-ATPase (ATP1A), ca ATPase (ATP2B3), and Ca1.3 (CACNAID) are associated with Ca influx and/or activated calcium signaling pathways leading to increased production of aldosterone by CYP11B2 gene. Recently, a single-nucleotide polymorphism (c.-2G>C) of the NR3C2 gene, which codes for the mineralocorticoid receptor (MR), has been associated with increased activation of RAS and increased blood pressure in the general population. In most cases, the aldosteronomas arise from the zona fasciculata. There is often significant glandular hyperplasia.

Epidemiology

Primary hyperaldosteronism is the most common cause of secondary hypertension and occurs in about 6% to 20% of adult hypertensive patients, higher in patients with resistant hypertension. The prevalence of 10% was noted when consecutive patients with hypertension were evaluated. However, the prevalence increased to 30% when the aldosterone-to-renin ratio (ARR) was used as a screening method in general practice.

Aldosterone-producing adenoma is present in 50% to 60%, and the remaining is idiopathic or bilateral adrenal hyperplasia. It is about 2 times more common in women than in men.

Pathophysiology

Aldosterone-producing adenomas, bilateral idiopathic adrenal hyperplasia, aldosterone-producing adrenal carcinoma, and familial aldosteronism cause primary hyperaldosteronism. The increased aldosterone potentiates renal sodium reabsorption, water retention, and potassium excretion. The increased sodium reabsorption by the kidneys results in plasma volume expansion, the primary initiating mechanism for hypertension. This may induce tissue inflammation and heightened sympathetic drive, with subsequent development of fibrosis in vital organs, such as the heart, kidneys, and vasculature. As a result, this may lead to the development of chronic kidney disease, atrial fibrillation, stroke, ischemic heart disease, and congestive heart failure.[6][7]

Besides the elevation in sodium, patients often develop hypokalemia and metabolic alkalosis. Nearly one-fifth of patients with Conn syndrome have impairment in glucose tolerance, which is due to the inhibitory effects of hypokalemia on insulin secretion.

Histopathology

Histopathology is often heterogeneous, ranging from micronodular or macronodular hyperplasia with adenoma formation with atrophy or diffuse or nodular hyperplasia of the adjacent adrenal cortex.

History and Physical

Often, the patients are asymptomatic but may present with symptoms of fatigue, muscle weakness, cramping (secondary to potassium wasting), headaches, and palpitations. They can also have polydipsia and polyuria from hypokalemia-induced nephrogenic diabetes insipidus.

Many patients are discovered to have Conn syndrome as a result of persistent hypokalemia and hypertension. Others may present with serious arrhythmias after being started on diuretics for hypertension. Finally, some patients present with hypertension that is refractory to treatment.

Physical findings include:

• Hypertension
• Abdominal distension
• Ileus associated with hypokalemia
• Hypertension-associated bruits, altered mental status, retinopathy

It is important to note that Conn syndrome is not associated with edema because of spontaneous natriuresis.

Evaluation

Hypokalemia in a hypertensive patient is the most common clue for primary hyperaldosteronism. However, normal serum potassium may present in up to 38% of patients, especially those with adrenal hyperplasia or familial aldosteronism.[8][9]

Blood work reveals hypokalemia, hypernatremia, and metabolic alkalosis due to the actions of aldosterone on the distal convoluted tubule.

• Urinary potassium excretion is elevated (more than 30 mmol/day).
• Diagnosis depends on the demonstration of expanded extracellular fluid (ECF) volume (suppressed plasma renin) and non-suppressible aldosterone secretion.
• ARR (aldosterone: renin ratio): The lack of uniform assay methods and diagnostic protocols in assessing the results creates a high variability in cut-off values among various investigators. A ratio of 40 or more (20 ng/dL/h to 40 ng/dL/h) or more than 135 (68 pmol/mU to 135 pmol/mU) has a sensitivity of 73% to 93% and a specificity of 71% to 84%, indicating the need for further confirmatory studies with salt-loading (failure to lower plasma aldosterone level less than 10 ng/dL), fludrocortisone suppression test, or captopril suppression test. The Endocrine Society's clinical practice guidelines do not specify which confirmatory tests should be regarded as the gold standard to confirm or exclude the diagnosis; therefore, different centers perform different tests.
• Once autonomous aldosterone production is established, the next step is to evaluate for a possible adenoma. A CT scan may show an adenoma that accounts for 70% of cases, but as milder forms are being recognized now, idiopathic hyperaldosteronism is the most common cause. However, CT may provide an incorrect diagnosis because of the common occurrence of non-functional adrenal adenomas (incidentalomas) that may be present in 4% of the general population.
• The studies to confirm the unilateral nature of adrenal hypersecretion (lateralization) either by adrenal venous sampling (invasive, difficult, and possible complications) or byiodocholesterol adrenal scans have limitations. 
• Plasma 18-hydroxycorticosterone is elevated in adenoma and normal in adrenal hyperplasia.
• A plasma aldosterone response to a 2-hour upright position shows a normal increase in adrenal hyperplasia but a paradoxical decrease in adrenal adenoma.

It is important to know the hormone's diurnal rhythm before measuring aldosterone levels. The lowest aldosterone levels are observed around midnight, and the highest values are seen in the morning between 7 and 8 am. This diurnal rhythm is preserved in patients with Conn syndrome but rare in idiopathic adrenal hyperplasia. 

It is important to screen:

• Patients with stage 2 or stage 3 hypertension
• Resistant hypertension
• Hypertension with spontaneous or diuretic-induced hypokalemia
• Hypertension with adrenal incidentaloma
• Hypertension with a family history of early-onset hypertension or cerebrovascular disease
• Patients with first-degree relatives diagnosed with Primary aldosteronism
• Any patient with suspected secondary hypertension

Treatment / Management

Treatment goals include normalizing blood pressure, electrolytes, and aldosterone levels. The treatment depends on the cause. Unilateral adrenalectomy in patients with a unilateral adenoma (Conn syndrome) cures hypertension in 30% to 60% of cases, but the mean cure rate is only 19% after unilateral or bilateral adrenalectomy in patients with idiopathic hyperaldosteronism whose treatment mainly is medical. This treatment includes aldosterone antagonists such as spironolactone, eplerenone, or other potassium-sparing diuretics like amiloride.

Patients need to be optimized preoperatively to decrease the risks of elevated blood pressure during surgery. Aldosterone antagonists like eplerenone and spironolactone are associated with survival benefits. Spironolactone is preferred to lower blood pressure as it normalizes serum potassium levels and plasma volume. Low doses of corticosteroids can help control blood pressure in a small group of patients with glucocorticoid-mediated hyperaldosteronism. Nonsurgical treatment is an option for patients who are frail and have numerous comorbidities. In addition, bilateral adrenal hyperplasia is also managed medically. Adrenalectomy is used to excise unilateral lesions. Before surgery, the patient has to be treated with spironolactone for 4-6 weeks. Today, laparoscopic adrenalectomy is widely used to excise the adrenal gland.

Results

About two-thirds of patients become normotensive after surgery, but the blood pressure may take 6-12 months to stabilize. Over 5 years, only about 50% of patients remain normotensive. Those who fail to respond to spironolactone before surgery most likely continue to be hypertensive after surgery.

Differential Diagnosis

The differential diagnoses for Conn syndrome include the following:

• Hypertension
• Metabolic alkalosis
• Renal artery stenosis
• Malignant hypertension
• Preeclampsia
• Licorice intake
• Gitelman syndrome
• Barter syndrome
• Adrenal carcinoma

Prognosis

Conn syndrome is associated with high morbidity and mortality if it is left untreated. The primary cause of morbidity is linked to hypertension and hypokalemia; the latter is known to cause cardiac arrhythmias that can be fatal.

Complications

Complications are often related to the underlying chronic hypertension that can cause acute myocardial infarction, stroke, and heart failure. Most important, hypertension can also lead to retinopathy and end-stage renal disease. The surgery for Conn syndrome can also lead to complications.

Postoperative and Rehabilitation Care

After surgery, the blood pressure has to be monitored for many months. Some patients may develop significant hyperkalemia that may require treatment with diuretics. A low-salt diet is recommended, especially since it helps manage hypertension.

Pearls and Other Issues

Key facts to keep in mind about Conn syndrome are as follows:

• Normal serum potassium levels do not exclude primary hyperaldosteronism. Several studies have shown that 7% to 38% of patients with primary hyperaldosteronism have normal baselines.
• Serum potassium levels, especially patients with hypertension, are often advised to restrict their salt intake. The hypokalemia becomes evident with the liberalization of dietary sodium intake.

Enhancing Healthcare Team Outcomes

The diagnosis and management of Conn syndrome is best done with an interprofessional team. The disorder can be difficult to diagnose because of the lack of standardized tests. In addition, the ARR may be falsely elevated in patients with chronic kidney disease and patients on potassium supplements or beta-blockers. Diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers may cause false-negative results. If the clinical suspicion is high, ARR should be repeated after holding these agents for 2 weeks.

Unilateral adrenalectomy in patients with a unilateral adenoma (Conn syndrome) cures hypertension in 30% to 60% of cases, but the mean cure rate is only 19% after unilateral or bilateral adrenalectomy in patients with idiopathic hyperaldosteronism whose treatment mainly is medical. This treatment includes aldosterone antagonists such as spironolactone or eplerenone or other potassium-sparing diuretics like amiloride.

Due to the challenges of managing this disease, the pharmacist should be involved in diuretic selection and dosing. The pharmacist should check for drug-drug interaction and report concerns to the clinical interprofessional team. The clinicians monitoring the patient should be familiar with the pathophysiology and expected abnormalities in laboratory testing. Due to the precarious challenges of abnormal potassium, the clinician should be prepared to report to the clinical team quickly any untoward abnormalities as daily lab screens are reported. The best results can be achieved only through interprofessional team involvement and close monitoring.[10]