Primary aldosteronism
1. Define primary aldosteronism.
Primary aldosteronism (PA) is a generic term for a group of disorders in which excessive production of aldosterone by the zona glomerulosa of the adrenal cortex occurs independently of normal renin-angiotensin stimulation. These primary disorders of the adrenal system are distinct from forms of secondary hyperaldosteronism due to excessive renin (renal artery stenosis, renin-producing tumors). The four most important clinical entities constituting PA are bilateral hyperplasia of the zona glomerulosa (commonly termed idiopathic hyperaldosteronism [IHA]), solitary aldosterone-producing adenoma (APA), adrenal carcinoma, and glucocorticoid-remediable aldosteronism. IHA and APA are the most important causes of PA.
2. How common are these disorders?
The most common manifestation of excess aldosterone secretion is hypertension. Cross-sectional and prospective studies indicate that up to 12% of the hypertensive population may have PA.
3. Aside from hypertension, what are the common clinical manifestations of primary aldosteronism?
Aldosterone normally acts at the renal distal convoluted tubule to stimulate reabsorption of sodium ions (Na), as well as secretion of potassium (K) and hydrogen ions (H) and at the cortical and medullary collecting ducts to cause direct secretion of H. Excess secretion of aldosterone in PA results in hypertension, potassium loss, and metabolic alkalosis; hypomagnesemia may also occur (Fig. 27-1). Spontaneous hypokalemia (K < 3.5 mmol/L), however, is an uncommon presenting manifestation of PA, occurring in only 9% to 37% of cases of PA. Therefore, normokalemic hypertension is the most common presentation. Vague symptoms are manifestations of hypokalemia: weakness, muscle cramping, paresthesias, headaches, hyperglycemia (insulinopenia), palpitations, polyuria, and polydipsia.
4. Who should be screened for primary aldosteronism?
Hypertension affects 29% of the adult U.S. population; screening for PA must be judicious. Case detection should be targeted to four groups of patients:
Hypertensive patients with spontaneous or diuretic-induced hypokalemia; PA prevalence 50%.
Patients with adrenal incidentalomas who have hypertension; PA prevalence 1% to 10%.
Hypertension due to aldosterone excess causes enhanced perivascular inflammation and myocardial fibrosis; end-organ damage is therefore more severe than in essential hypertension. Screening and confirmation of the diagnosis are described in questions 14 and 16.
5. What is the most common form of primary aldosteronism?
Of the four causes mentioned in question 1, IHA is most common, accounting for up to 70% of cases in most series. IHA, also known as bilateral adrenal hyperplasia, is characterized by bilateral hyperplasia (diffuse and focal) of the zona glomerulosa layer of both adrenal glands. The most likely cause is supranormal sensitivity of the zona glomerulosa in affected adrenal glands to physiologic concentrations of angiotensin II.
6. What is the second most common cause of primary aldosteronism?
APAs account for up to 30% of cases of PA. APAs are small (< 2 cm), occur more commonly in the left adrenal gland, and are composed of zona glomerulosa cells, zona reticularis cells, and hybrid cells with characteristics of both layers. APAs are also known as Conn’s syndrome.
7. Why differentiate between IHA and APA?
APAs are a surgically curable form of PA; IHA is not. APAs produce greater amounts of aldosterone than other forms of PA; consequently, the degrees of hypertension and biochemical abnormalities tend to be more severe. APAs demonstrate partial autonomy of function, secreting aldosterone in response to stimulation by corticotropin (ACTH) but not by angiotensin II. Aldosterone synthesis by these tumors, therefore, parallels the normal circadian rhythm of ACTH secretion, with the highest serum aldosterone concentrations occurring in the mornings and the lowest in the evenings.
8. How do symptoms of IHA differ from symptoms of APA?
Aldosterone is produced in smaller amounts in IHA than in APA; therefore the degree of hypertension, hypokalemia, hypomagnesemia, and metabolic alkalosis is less dramatic. Serum aldosterone levels tend to rise during upright posture, perhaps owing to greater sensitivity to angiotensin II.
9. How commonly does adrenal cancer cause primary aldosteronism?
Adrenal carcinoma as a cause of PA is rare. The tumors are very large (> 6 cm) and commonly metastatic at the time of diagnosis. All cases of PA should be imaged with computed tomography (CT) to exclude this rare cause of PA.
10. What is glucocorticoid-remediable aldosteronism?
In this rare cause of PA, production of mineralocorticoid is stimulated solely by ACTH. The disorder is inherited in an autosomal-dominant fashion.
11. How is aldosterone synthesis normally regulated in the zona glomerulosa?
Humans possess two mitochondrial 11β-hydroxylase isoenzymes that are responsible for cortisol and aldosterone synthesis (designated CYP11B1 and CYP11B2). Both are encoded on chromosome 8. CYP11B1, which is responsible for conversion of 11-deoxycortisol to cortisol, is expressed only in the zona reticularis. CYP11B2, which is responsible for the conversion of corticosterone to aldosterone, is expressed only in the zona glomerulosa. CYP11B1 activity is stimulated by ACTH, whereas CYP11B2 is stimulated by angiotensin II or hyperkalemia.
