Patients may present with headaches, muscle weakness and fatigue. Muscle weakness is due to hypokalemia and may be accompanied by paresthesias such as sensations of tingling and warmness. Transient paralysis and/or muscle spasms may be observed .
Furthermore, CS patients often report excessive thirst and urination. Polyuria and polydipsia are indicative of water and electrolyte imbalances caused by aldosteronism. Hypernatremia, hypervolemia and hypokalemia are common.
Clinical examination may further reveal hypertension, and this finding may serve as an explanation for the above mentioned headaches .
Diagnosis of CS is facilitated if patients present with hypertension, hypokalemia and metabolic alkalosis. However, the majority of CS patients will not present with hypokalemia. Also, this symptom triad is typical for primary and secondary hyperaldosteronism, so additional diagnostic measures are needed to confirm diagnosis.
In this context, blood checkup should be conducted even though patients are normokalemic. Plasma aldosterone levels, renin activity and the ratio of aldosterone to renin should be evaluated . Since these parameters may be altered by ACE inhibitors, angiotensin antagonists, beta-sympatholytics or diuretics, such medication should be stopped at least one month before blood samples are obtained. The latter should ideally occur in the morning and from a recumbent patient. Increased plasma aldosterone (> 15 ng/dl), reduced renin activity (reference range is age dependent, unit is ng/ml/h) and augmented aldosterone to renin ratio (> 20) are indicative of CS. In contrast, patients showing increased plasma aldosterone and augmented renin activity most likely do suffer from secondary hyperaldosteronism. Patients showing both reduced plasma aldosterone and decreased renin activity presumably suffer from other pathological conditions, e.g. Cushing syndrome, Liddle syndrome or licorice poisoning. Cortisol, for instance, may mediate mineralocorticoid effects.
Additional laboratory analyses of bloods samples obtained up to four hours after the initial sampling and from a standing patient may help to distinguish adenoma and hyperplasia: If the patient suffers from adrenal adenoma, plasma aldosterone levels should decrease when compared with the blood sample obtained in the morning. If adrenal hyperplasia triggers CS, plasma aldosterone levels should increase.
This method is of low sensitivity and imaging techniques such as magnetic resonance imaging and computed tomography are usually required to detect the cause of CS, most likely adrenal adenoma or hyperplasia .
If images do not allow for a concluding diagnosis, catheterization of both adrenal veins is required to clarify if the patient suffers from unilateral adenoma or bilateral hyperplasia.
CS treatment aims at diminishing hypertension and correcting electrolyte imbalances, ideally by reducing plasma aldosterone levels .
In cases of adrenal adenoma, unilateral adrenalectomy is the therapy of choice and cure rates are very high. However, patients suffering from idiopathic bilateral adrenal hyperplasia do less frequently benefit from surgical intervention. Even if bilateral adrenalectomy is conducted, blood pressure does not return to physiological values and drug therapy is necessary. The latter also applies to patients that may not undergo surgery due to existing comorbidities. Such patients may also benefit from percutaneous injection of acetic acid or ethanol into adrenal neoplasms , but this technique is not well validated. Treatment for CS is symptomatic rather than causative .
Adrenal aldosterone production may be reduced by application of dihydropyridine calcium channel blockers. Such compounds interrupt signaling pathways by limiting calcium influx in adrenocortical cells and thus, inhibit stimulatory effects mediated by various triggers. In this line, nifedipine is generally administered. It effectively reduces blood pressure.
Mineralocorticoid antagonists mediate hypotensive effects by binding to mineralocorticoid receptors. Thereby, blood volume and pressure can be reduced and potassium levels can be increased. Spironolactone is the most widely used mineralocorticoid antagonist (50 mg, per os, qd, and increasing doses until the desired effect is achieved). It has been shown that combined administration of spironolactone and thiazide diuretics is even more effective to treat hypertension.
Certain cases of CS seem to be treatable with glucocorticoids. Short-acting glucocorticoids like hydrocortisone and prednisone should be administered at the lowest possible dose in order to avoid side effects. However, side effects will not be completely avoidable and patients should be monitored regularly.
Hypertension may also be regulated with ACE inhibitors and potassium-sparing diuretics like amiloride and triamterene may be helpful to improve hypokalemia, but are not generally recommended for CS treatment. Angiotension receptor blockers (ARBs) might be used as well.
Chronic hypertension is associated with a variety of potentially lethal events affecting the cardiovascular system, e.g. retinopathy, hypertensive nephropathy, stroke, myocardial infarction, hypertrophic cardiomyopathy and heart failure. It has been speculated that the risk for these cardiovascular diseases is higher in CS patients than in those suffering from hypertension of other origin. Severe hypokalemia may provoke cardiac arrhythmias and subsequent heart failure.
Certain morbidity and mortality may result from CS treatment, especially if surgical interventions are required to resect neoplasms. However, remission can be expected after complete resection of causative adenomas. Cure rates are lower in patients suffering from adrenal hyperplasia.
Symptoms associated with CS result either directly or indirectly from an excessive release of the mineralocorticoid aldosterone. This may result from neoplasms in the adrenal gland, almost exclusively adenomas and very rarely carcinomas, or hyperplasia of the adrenal gland. Rarely, genetic disorders account for aldosteronism, e.g., familial hyperaldosteronism and deficiency of 11β-hydroxylase . Familial hyperaldosteronism is inherited with a dominant trait.
Physiologically, aldosterone is produced in the adrenal cortex, and its main function is to regulate renal electrolyte excretion, blood volume and blood pressure . Therefor, it promotes reabsorption of sodium and water as well as excretion of potassium and hydrogen in renal tubules. Increased levels of aldosterone, also referred to as hyperaldosteronism or simply aldosteronism, thus mediate hypertension, hypokalemia and metabolic alkalosis. These conditions provoke muscle weakness and polyuria that, in turn, triggers polydipsia.
For a long time, CS was considered a rare disease. Further diagnostic measures were only realized in patients that showed the characteristic symptom triad of hypertension, hypokalemia and metabolic alkalosis. However, there are studies that show that the majority of CS patients are indeed normokalemic . Thus, in order to obtain realistic values concerning CS prevalence, patients suffering from hypertension, but not from hypokalemia should be examined for possible CS. The ratio of aldosterone to renin may serve as a valuable parameter in this context. It has been estimated that 80% of CS patients may only be recognized when adopting this policy. Of course, this also means that an adequate treatment can be provided and existing adrenal adenomas may be detected and removed.
Today, CS is widely recognized as a possible, and not rare cause for hypertension. CS presumably accounts for approximately 10% of all cases of normokalemic hypertension. In the UK, more than 300 CS patients have been treated for hyperaldosteronism in 2013. Prevalence seems to vary between 5% in Spain and Japan and 16% in Chile and Scotland . Elsewhere, lower and even higher prevalence of up to 32% have been observed . The overall prevalence of CS seems to be increasing, but this assessment needs to be interpreted keeping the above mentioned extended diagnostics in mind.
CS affects people across a wide range of age. Children less frequently develop adrenal adenoma and in pediatric patients CS is often related to adrenal hyperplasia or carcinoma. The incidence of adrenal hyperplasia is increased in the elderly.
The mineralocorticoid aldosterone mainly exerts its effects by enhancing the activity of sodium-potassium exchange pumps and the expression of sodium channels in renal tubules. These channels allow for an increased reabsorption of sodium and consequently of water. At the same time, renal excretion of potassium and hydrogen is stimulated . While the former result in hypertension, the latter account for hypokalemia and metabolic alkalosis.
Contrary to patients suffering from secondary hyperaldosteronism, renal blood flow is usually not decreased in CS patients. Also, dietary sodium intake is typically not altered. It has been suggested that CS patients who do not show the characteristic symptom triad of , hypokalemia, metabolic alkalosis and hypertension may additionally suffer from any pathologic conditions altering the aforementioned parameters. This particularly applies to the great share of normokalemic CS patients.
Of note, hypokalemia affects insulin-mediated cellular glucose uptake. Thus, approximately one in five CS patient shows reduced glucose tolerance. CS is, however, not related with an increased incidence of diabetes mellitus.
There are no diagnostic measures to detect CS before symptom onset except for genetic screens that should be offered to patients that may have inherited genetic disorders and could suffer from familial hyperaldosteronism . Such screens should be conducted regardless of existing hypertension, particularly because familial hyperaldosteronism is associated with a severe course of CS and high risks of cerebral infarction and early death. DNA isolated from peripheral blood is sufficient for genetic testing.
No direct preventive measures can be recommended in order to avoid adrenal adenoma or hyperplasia and diagnosis is usually made when symptoms already developed. While severe hypokalemia may provoke cardiac arrhythmias that require urgent assistance, morbidity and mortality of CS are generally associated with long-term consequences of hypertension. Thus, early detection of CS may allow for an adequate treatment and reduction of the risk for cardiovascular diseases.
Conn syndrome (CS) is an alternative denomination of primary hyperaldosteronism, a condition resulting from excessive aldosterone production in the adrenal glands. Most frequently, adrenal adenoma or hyperplasia cause CS . In rare cases, adrenal carcinoma or genetic disorders may account for the disease.
Aldosterone is an essential factor in blood pressure regulation through the renin-angiotensin-aldosterone system with angiotensin II being the trigger for aldosterone release. Aldosterone levels are further affected by pituitary ACTH. Aldosterone increases renal sodium and water reabsorption as well as potassium and hydrogen excretion. Therefore, increased aldosterone levels result in hypervolemia, hypertension, hypokalemia and metabolic alkalosis. In order to distinguish CS from other pathological conditions that are associated with hypertension, hypokalemia and metabolic alkalosis, laboratory tests must be conducted. Plasma aldosterone levels, renin activity and aldosterone to renin ratio may reveal the cause of the patient's water and electrolyte imbalances.
Conn syndrome (CS) is a metabolic disease characterized by excessive production of aldosterone, a mineralocorticoid hormone produced by the adrenal glands with diverse functions regarding the regulation of blood pressure and electrolyte balance.
Excessive aldosterone production can be caused by different pathological conditions. Aldosterone is normally produced in the cortex of the adrenal glands, which are small glands located in close proximity to the kidneys. Benign neoplasms called adenoma and adrenal hyperplasia are the most common causes for CS. In rare cases, malignant tumors or genetic disorders trigger the disease.
Aldosterone mediates renal sodium and water reabsorption as well as potassium and hydrogen excretion. Therefore, elevated aldosterone levels cause increase in sodium and plasma volume, reduced potassium and metabolic alkalosis. These water and electrolyte imbalances manifest in form of high blood pressure and headaches, muscle weakness and fatigue, excessive urination and thirst.
The most commonly detected symptom is hypertension. If routine measurements reveal increased blood pressure, diagnostic measures will be undertaken to clarify its source.
In order to do so, blood samples need to be analyzed for plasma aldosterone levels and related parameters. Also, electrolyte concentrations will be checked. If the physician detects alterations indicating CS, imaging techniques such as magnetic resonance imaging or computed tomography will be applied to revise the patient's adrenal glands.
In some cases, adrenal vein catheterization may be required to distinguish between the above mentioned causes of CS and to choose an adequate therapy.
Adrenal tumors such as adenoma and carcinoma should be removed surgically if the overall condition of the patient does not forbid such an intervention. Complete removal of adrenal tumors usually results in remission and normalization of blood pressure and electrolyte levels.
Surgery is less successful in patients suffering from adrenal hyperplasia and drug therapy is usually necessary to control blood pressure and electrolyte balances. Different compounds are available to reduce adrenal aldosterone production (calcium channel blockers like nifedipine) and to limit aldosterone-mediated effects by inhibiting the hormone's receptor (mineralocorticoid antagonists like spironolacton). Additional hypotensive treatment may be required if blood pressure and electrolyte levels cannot be sufficiently regulated with this medication.