Conn Syndrome

Article Author:
Malvinder Parmar
Article Editor:
Steve Bhimji
Updated:
10/27/2018 12:31:29 PM
PubMed Link:
Conn Syndrome

Introduction

Conn syndrome was named after J. W. Conn who first decribed it in 1955, in a patient who had hypertension with an aldosterone-producing adenoma. The ademona 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.

Etiology

The syndrome may be secondary to adrenal hyperplasia, adrenal adenoma, aldosterone-secreting adrenal carcinoma (1%), or familial hyperaldosteronism (FH).

Various specific genetic alterations (see below) have been identified for rare familial forms of the disease. In a majority of these genetic alterations, the end point is Ca influx and membrane depolarization resulting in aldosterone hypersecretion.

Familial hyperaldosteronism (FH) type 1: Unequal crossing over between highly homologous CYP11B2 and CYP11B1 genes that code of aldosterone synthase and steroid 11 B-hydroxylase, resulting in a chimeric gene that is under adrenocorticotrophin (ACTH) rather than RAS control.

Familial hyperaldosteronism (FH) type 2: Autosomal dominant, heterogeneous, no response to dexamethasone suppression, possibly link with chromosome 7p22.

Familial hyperaldosteronism (FH) type 3: Mutations in the gene encoding the inwardly rectifying potassium channel Kir3.4 (KCNJ5 gene). Specific mutations in KCNJ5 gene, like those altering the G151E amino acid, are associated with a milder form of aldosteronism, compared to those with a G151R mutation that have a more severe form.

Mutations in three 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 that codes for mineralocorticoid receptor (MR) has been shown to be associated with increased activation of RAS and increased blood pressure in the general population.

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 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 two times more common in women than men.

Pathophysiology

Primary hyperaldosteronism is caused by aldosterone-producing adenomas, bilateral idiopathic adrenal hyperplasia, aldosterone-producing adrenal carcinoma, and familial aldosteronism. The increased amount of aldosterone potentiates renal sodium reabsorption and water retention, and potassium excretion. The increased sodium reabsorption by the kidneys results in plasma volume expansion which is 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 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.

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.

Evaluation

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

  • 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 method 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 of these confirmatory tests should be regarded as the gold standard to confirm or exclude the diagnosis; therefore, different tests are performed by different centers.
  • Once autonomous aldosterone production is established, next step is to evaluate for possible adenoma. CT scan may show an adenoma that accounts for 70% cases, but as milder forms are being recognized now, idiopathic hyperaldosteronism is the most common cause. However, CT may provide 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 unilateral nature of adrenal hypersecretion (lateralization) either by adrenal venous sampling (invasive, difficult and possible complications) or byiodocholesterol adrenal scan have limitations. 
  • Plasma 18-hydroxycorticosterone is elevated in adenoma and normal in adrenal hyperplasia.
  • A plasma aldosterone response to a two-hour upright position shows normal increase in adrenal hyperplasia but a paradoxical decrease in adrenal adenoma.

When 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

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.

Pearls and Other Issues

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

The ARR may be falsely elevated in patients with chronic kidney disease, 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 two weeks.