Conn’s syndrome

Conn’s syndrome

Conn’s syndrome also called primary hyperaldosteronism, is classically known to occur as a patient with hypertension and hypokalemia. However, in reality, most patients will present without hypokalemia 1. In 1954, J. W. Conn first reported the clinical syndrome of hypertension, hypokalemia, and metabolic alkalosis resulting from autonomous production of aldosterone due to an adrenal adenoma – a syndrome that continues to bear his name 2. The aldosterone-producing adenoma is characterized by increased aldosterone secretion from the adrenal glands, suppressed plasma renin, hypertension, and hypokalemia 1. And now the term primary hyperaldosteronism is used to describe Conn syndrome irrespective of whether the patient has an adenoma or not 2.

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 2. The prevalence of 10% was noted when consecutive patients with hypertension were evaluated. However, the prevalence increased to 30% when aldosterone to renin ratio was used as a screening method in general practice. Disparity in these percentages is probably due to the use of different laboratory screening techniques, different definitions of a positive screening study indicative of primary aldosteronism, study design, and varying population ethnicity and sampling source 3.  Accumulating evidence suggests that approximately 10% of hypertensive individuals (mostly sampled from specialty clinics) may have primary hyperaldosteronism 3. In patients with resistant hypertension, the addition of a mineralocorticoid antagonist has been associated with substantial efficacy in blood pressure lowering, suggesting that subclinical hyperaldosteronism may be more prevalent than recognized 4.

Conn’s syndrome or 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 5.

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 1.

Conn’s syndrome 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.

Figure 1. adrenal gland anatomy

Conn’s syndrome causes

The most prevalent cause of Conn’s syndrome or primary hyperaldosteronism is aldosterone-producing adenomas 2. Other causes include aldosterone-producing adrenal carcinoma (1%), ectopic aldosterone secretion from the kidneys or ovaries, and bilateral adrenal hyperplasia of the zona glomerulosa. There are familial hyperaldosteronism causes as well 6.

Various specific genetic alterations have been identified for rare familial forms of Conn’s syndrome. In a majority of these genetic alterations, the end point is Calcium influx and membrane depolarization resulting in aldosterone hypersecretion.

  • Familial hyperaldosteronism type 1: Familial hyperaldosteronism type 1 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. 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 type 2: Familial hyperaldosteronism type 2 causes are unclear. It is autosomal dominant, heterogeneous, no response to dexamethasone suppression, possibly link with a gene on chromosome 7p22 (band 11q13) and histologic findings are consistent with hyperplasia or adenomas 7.
  • Familial hyperaldosteronism type 3: Familial hyperaldosteronism type 3 results from a mutation 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. This KCNJ5 gene mutation causes increased calcium ion availability into the glomerulosa cells leading to increased aldosterone synthesis 8.

Mutations in three other genes encoding for membrane proteins (Na/K-ATPase (ATP1A), ca ATPase (ATP2B3) and Ca1.3 (CACNAID) are associated with Calcium 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 renin-angiotensin system (RAS) and increased blood pressure in the general population.

Conn’s syndrome symptoms

A patient with suspected Conn’s syndrome or primary hyperaldosteronism will present with uncontrolled hypertension and will typically be young 2. 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 present with symptoms of severe muscle weakness, headaches, palpitations, fatigue, or muscle cramps due to symptoms related to hypokalemia (secondary to potassium wasting). Polydipsia and polyuria are present due to hypokalemia-induced nephrogenic diabetes insipidus.

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 9. 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 9. 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.

Conn’s syndrome complications

Cardiovascular risk is associated with patients who have Conn’s syndrome 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 10. 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, body mass index (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 11.

Metabolic syndrome is more common in those with primary hyperaldosteronism as compared to controls with similar blood pressure, sex, age, and BMI 12.

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 13. 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 14.

Conn’s syndrome diagnosis

The Endocrine Society recommends screening for specific patient presentations. Hypokalemia in a hypertensive patient is the most common clue for Conn’s syndrome or primary hyperaldosteronism. However, normal serum potassium may be present in up to 38% of patients, especially in patients with adrenal hyperplasia or familial aldosteronism 15. 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 16.

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 17.

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 18.

  • 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.

Once the biochemical diagnosis of primary hyperaldosteronism has been confirmed, further testing is required to determine the cause and location of the disorder. Distinguishing between aldosterone-producing adenoma, bilateral adrenal hyperplasia, and less common forms of primary hyperaldosteronism, such as glucocorticoid-remediable aldosteronism, is important. Unilateral adrenalectomy cures hypertension in 30-70% of patients with aldosterone-producing adenoma or unilateral adrenal hyperplasia, and invariably reverses hypokalemia 19. In contrast, bilateral adrenalectomy in bilateral adrenal hyperplasia cures hypertension in only <20% of patients 19. Hence, the treatment of choice is surgical in aldosterone-producing adenoma or unilateral adrenal hyperplasia, and medical therapy is generally favored in bilateral adrenal hyperplasia and glucocorticoid-remediable aldosteronism.

Biochemical characteristics can assist with the diagnosis of the various causes of primary hyperaldosteronism. Young age (<50 years old), severe hypokalemia (<3.0 mmol/L), high plasma aldosterone concentrations (> 25 ng/dl), and high urinary aldosterone excretion (>30 ug/24hr) favor the diagnosis of aldosterone-producing adenoma versus bilateral adrenal hyperplasia. The presence of a classical unilateral Conn’s adenoma in addition to a serum potassium < 3.5 mmol/L or estimated glomerular filtration rate > 100 mL/min/1.73 m² is nearly 100% specific for an aldosterone-producing adenoma 20. However, while sensitive or specific, these clinical tools lack validation in large cohorts, and therefore cannot be relied upon as a means to determine the underlying etiology in individual patients 21.

Patients with primary hyperaldosteronism should undergo radiographic evaluation of the adrenal glands to localize the source and define the anatomy for potential surgical approaches. Computed tomography (CT) scanning with thin-slice (3mm) spiral technique is the best radiographic procedure to visualize the adrenal glands, and serves primarily to exclude large masses that may represent adrenocortical carcinoma, which are usually more than 4 cm in size. Observation of a solitary hypodense adrenal nodule, usually < 2 cm in size, supports the diagnosis of Aprimary hyperaldosteronism. Adrenal adenomas typically are lipid-rich on CT scan (<10 HU), and have a greater than 50% washout of contrast after 10-15 minutes. However, even when biochemical features suggestive of aldosterone-producing adenoma are present, only one-third to one-half of patients have positive CT findings for a solitary adenoma 22. It is also not uncommon for both adrenal glands to be anatomically abnormal in patients with primary aldosteronism. Furthermore, it is emphasized that a radiographic abnormality does not correlate with a functional equivalent. Non-functioning adrenal ‘incidentalomas’ are not rare, especially in patients above the age of 40; these are radiographically indistinguishable from Aprimary hyperaldosteronism, and can co-exist with an Aprimary hyperaldosteronism in the ipsilateral or contralateral adrenal gland. Therefore, data suggest that adrenal anatomy determined by CT scanning may wrongly predict etiology as well as lateralization of the aldosterone source in a significant proportion of patients 23.

Adrenal vein sampling is a localization technique that is considered to be the ‘gold standard’ for distinguishing unilateral versus bilateral disease in primary hyperaldosteronism 24. Adrenal vein sampling involves sampling from the right and left adrenal veins, as well as from the inferior vena cava (IVC), for measurement of aldosterone and cortisol concentrations. Many favor performing adrenal vein sampling with adrenocorticotropin (ACTH) stimulation, which can be administered continuously or as a bolus, and may minimize stress-induced fluctuations in aldosterone secretion during the procedure as well as maximize aldosterone secretion from an Aprimary hyperaldosteronism 25. However, other studies indicate that ACTH does not significantly improve the diagnostic accuracy of the procedure, in part because it may increase secretion from the contralateral side more than from the Aprimary hyperaldosteronism and therefore blunt lateralization 26.

Multiple variables derived from adrenal vein sampling can be used to determine lateralization of aldosterone hypersecretion 27. Cortisol-corrected aldosterone ratios (A/C ratio) are determined by dividing the aldosterone concentrations from each location sampled by the cortisol concentration in the same location to correct for dilutional effects.

Conn’s syndrome treatment

Treatment for Conn’s syndrome or primary hyperaldosteronism includes laparoscopic resection for adrenal 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 28. 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 29. 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.

Conn’s syndrome 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 coronary artery disease, stroke, and congestive heart failure secondary to left ventricular hypertrophy 30. Other studies point to the increased risk of cardiac arrhythmias secondary to persistent hypokalemia in those with primary hyperaldosteronism 31. 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 32.

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