An endocrine disorder caused by hyperaldosteronism presenting with symptoms associated with hypertension and hypokalemia.
Primary Hyperaldosteronism; Familial Hyperaldosteronism Type I-IV; Aldosteronism; Aldosteronoma.
Named after the American physician Jerome W. Conn (1907-1994), who in 1955 described primary hyperaldosteronism (PHA) secondary to benign bilateral adrenal masses.
PHA accounts for approximately 5% of all hypertensive patients, but increases to 15 to 20% in patients with treatment-resistant hypertension. However, due to patient selection and the diagnostic criteria used, prevalence rates vary significantly.
Most cases are sporadic; however, rarely familial cases with a genetic basis and autosomal dominant inheritance have also been identified. Depending on the underlying genetic defect, four different types of Familial Hyperaldosteronism can be distinguished (Type II is caused by hyperaldosteronism due to adrenal cortical hyperplasia [diffuse or nodular], adrenal adenoma).
|Familial Hyperaldosteronism ||Genetic Defect ||Chromosomal Location |
|Type I ||Hybrid CYP11B1/CYP11B2 (Cytochrome P450, Subfamily XIB, Polypeptide 1/2) ||8q24.3 |
|Type II ||— ||7p22 |
|Type III ||KCNJ5 (Inwardly Rectifying Potassium Channel, Subfamily J, Member 5) ||11q24.3 |
|Type IV ||CACNA1H (T-Type Voltage-Dependent Calcium Channel, Alpha-1H Subunit) ||16p13.3 |
PHA with autonomous aldosterone overproduction is the most frequent endocrine cause of secondary arterial hypertension in 5 to 20% of hypertensive patients. PHA is a high-aldosterone, low-renin state that results from excessive aldosterone synthesis and release. Most commonly, PHA is caused by an adrenocortical adenoma or idiopathic bilateral adrenal hyperplasia and results not only in excessive sodium reabsorption in the distal nephron with hypertension and suppression of the renin-angiotensin II system, but also in increased urinary losses of potassium and hydrogen ions (in exchange with sodium) leading to hypokalemia (in <20% of patients) and metabolic alkalosis. Recent research points to the possibility of an independent ligand secreted by adipose tissue that promotes aldosterone biosynthesis and secretion, which at least in part could explain the concurrent presence of obesity and therapy-resistant arterial hypertension, which in up to 20% occurs to be secondary to PHA. In keeping with this finding, a higher rate of obstructive sleep apnea, diabetes mellitus Type 2/metabolic syndrome has been found in adult PA patients.
Based on the clinical findings (arterial hypertension, polyuria, polydipsia, fatigue, tinnitus, paresthesia, episodic muscular weakness or paralysis, muscle cramps or tetany of variable duration, muscle wasting, failure to thrive). Hypokalemia (<3.5 mmol/L; is present in approximately 20% of patients), metabolic alkalosis associated with inappropriate kaliuresis, hypernatremia, increased plasma levels of aldosterone (>40 ng/dL), decreased plasma renin activity (<0.3 ng/mL/hour), non-suppressible aldosterone response to ambulation, and a pathologic fludrocortisone suppression test confirm the diagnosis. Dexamethasone does not suppress aldosterone levels (except in Familial Hyperaldosteronism Type I, where small doses of dexamethasone can be used therapeutically). MRI-scanning is the diagnostic imaging tool of choice. It shows that the left adrenal gland is four times more often involved than the right. In some centers, all patients with PHA undergo adrenal CT-scanning to exclude adrenocortical carcinoma. Familial PHA Type III is associated with severe arterial hypertension in early childhood, hypokalemia, and macronodular, bilateral hyperplasia. In patients with severe and/or refractory hypertension, bilateral adrenalectomy may be indicated to manage hypertension. Determining the plasma aldosterone-renin ratio and selective adrenal venous sampling to exclude/prove unilateral disease have been recommended.
Morbidity in Conn Syndrome results mainly from hypertension, which can range from mild to severe and be associated with significant headache. Increasing evidence indicates that excess aldosterone can trigger adverse cardiovascular sequelae (myocardial infarction, stroke, atrial fibrillation, myocardial remodeling, and fibrosis) that cannot entirely be attributed to arterial hypertension. It has been hypothesized that prolonged and sustained exposure to high-aldosterone levels may result in renal and metabolic effects, myocardial and/or vascular remodeling, and endothelial dysfunction. These processes could result in premature atherosclerosis, impaired endothelial function, abnormal arterial stiffness from thickening and fibrosis of the wall, increased risk of vascular dissection, and left ventricular hypertrophy. Aldosterone appears to induce vascular smooth muscle cell hypertrophy and/or hyperplasia and hypertrophy of ...