Aldosterone is the major electrolyte-regulating steroid of the adrenal cortex. Production is stimulated by ACTH but is also influenced by serum sodium or potassium levels. In addition, aldosterone can be secreted under the influence of the renin-angiotensin system in quantities sufficient to maintain life even without ACTH. In plasma, some aldosterone is probably bound to alpha globulins. There is a circadian rhythm that corresponds to that of cortisol, with peak levels occurring in the early morning and low levels (50% or less of A.M. values) in the afternoon. Ninety percent of breakdown and inactivation takes place in the liver. Aldosterone acts primarily on the distal convoluted tubules of the kidney, where it promotes sodium reabsorption with compensatory excretion of potassium and hydrogen ions.

Primary aldosteronism (Conn’s syndrome) results from overproduction of aldosterone, usually by an adrenal cortex adenoma (carcinoma, nodular hyperplasia, and glucocorticoid-suppressible aldosteronism are rare etiologies). Symptoms include hypertension, weakness, and polyuria, but no edema.

Secondary aldosteronism refers to overproduction of aldosterone in certain nonadrenal conditions:

1. Hyponatremia or low salt intake
2. Potassium loading
3. Generalized edema (cirrhosis, nephrotic syndrome, congestive heart failure)
4. Malignant hypertension
5. Renal ischemia of any etiology (including renal artery stenosis)
6. Pregnancy or use of estrogen-containing medications

Current explanations for the effects of these conditions on aldosterone point toward decreased effective renal blood flow (Fig. 30-4). This triggers certain pressure-sensitive glomerular afferent arteriole cells called the “juxtaglomerular apparatus” into compensatory release of the enzyme renin. Renin acts on an alpha-2 globulin from the liver called “renin substrate” to produce a decapeptide, angiotensin I, which, in turn, is converted to an octapeptide, angiotensin II, by angiotensin-converting enzymes in lung and kidney. Angiotensin II has a very short half-life (< 1 minute), and is both a powerful vasoconstrictor and a stimulator of the adrenal cortex to release aldosterone. There are several feedback mechanisms, one of which is mediated by retention of salt (and accompanying water) by increased aldosterone, leading to increase in plasma volume, which, in turn, induces the juxtaglomerular apparatus of the kidney to decrease renin secretion directly. The autonomic nervous system also affects renin output. Normally, renin production follows a circadian rhythm that roughly (not exactly) parallels that of cortisol and aldosterone (highest values in early morning). There are reports that renin normal values diminish somewhat with age. Upright posture is a strong stimulus to renin secretion. Atrial natriuretic factor (a hormone produced in the atrial appendage of the heart that affects the kidney) acts as antagonist to aldosterone and to renin.

Renal pressor system

Fig. 30-4 Renal pressor system.

General laboratory findings

Hypokalemia is the most typical abnormality, and the combination of hypertension and hypokalemia in a person who is not taking diuretics suggests the possibility of primary aldosteronism. However, about 20% (range, 0%-66%) of patients with primary aldosteronism have serum potassium levels within population reference range. Most of these normokalemic patients have a serum potassium value that does not exceed 4.0 mEq/L (4 mmol/L). Also, hypokalemia in a person with hypertension who is taking diuretics does not mean that hypokalemia is invariably due only to the diuretic unless the patient had already been adequately investigated for Conn’s syndrome. Some other diseases that may be associated with both hypertension and hypokalemia include Cushing’s syndrome, essential hypertension combined with diuretic therapy, potassium-losing renal disease, licorice abuse, malignant hypertension, Bartter’s syndrome, and the 11-b-hydroxylase variant of congenital adrenal hyperplasia.

Other frequent laboratory findings in primary aldosteronism include mild alkalosis and a low urine specific gravity. Postprandial glucose tolerance (but not the fasting glucose) is abnormal in about 50% of patients. Hypernatremia is occasionally found in classic cases, but most patients have high-normal or normal serum sodium levels. Excretion of 17-OHCS and 17-KS is normal. Hemoglobin values and white blood cell counts are also normal.

Diagnostic tests

Serum potassium loading. Diagnosis of primary aldosteronism may be suggested by failure to raise serum potassium levels on regular diet plus 100 mEq of potassium/day. (In addition, urine potassium excretion should increase during potassium loading, assuming a normal salt intake of 5-8 gm/day.)

Plasma or urine aldosterone. Patients with primary aldosteronism secrete more aldosterone than normal persons, so that aldosterone levels are increased in 24-hour urine specimens and, under proper conditions, in plasma specimens. Although RIA methods are now being used, these are still too difficult for the average laboratory. Even reference laboratories are not always dependable, especially for plasma aldosterone assay. Urine assay has the advantage that short-term fluctuations are eliminated, and there appears to be less overlap between normal and abnormal values. Accurate collection of the 24-hour specimen is the major drawback. Plasma is much more convenient to obtain, but plasma levels are more likely to be affected by short-term influences and other factors. Among these are diurnal variation (lower values in the afternoon than in the morning) and upright position (which greatly increases plasma aldosterone), whereas a 24-hour urine collection dampens the effects of these changes and instead reflects integrated secretion rate. Both plasma and urine aldosterone levels are increased by low-sodium diets and by lowered body sodium content and are decreased in the presence of high sodium intake. A low serum magnesium level also stimulates production of aldosterone. Potassium has an opposite effect: high potassium levels stimulate aldosterone secretion, whereas hypokalemia inhibits it.

Since hypertensive patients are frequently treated by sodium restriction or diuretics that increase sodium excretion, and since the body may be sodium depleted while still maintaining serum sodium within a normal range, it is advisable to give patients a high-sodium diet or salt supplements for several days before collecting specimens for aldosterone (renin assay is invalidated by salt loading and would have to be done previously or at some other time). One investigator suggests adding 10-12 gm of salt/day for 5-7 days plus one additional day while a 24-hour urine for aldosterone is collected. Salt loading should not affect aldosterone values in primary aldosteronism, since the hormone is secreted autonomously and therefore production is not significantly affected by normal feedback mechanisms. As a further check, the 24-hour specimen (if urine is assayed) or a random urine specimen (if plasma is used) should be assayed for sodium. Urine sodium values less than 30 mEq/L (mmol/L) suggest decreased sodium excretion, implying a sodium deficit and therefore a falsely increased aldosterone level. Several investigators have used a saline infusion procedure (1.5-2.0 L of saline infused between 8 and 10 A.M., with plasma aldosterone samples drawn just before and after the infusion). Some data indicate that aldosterone normal values, like those of renin, decrease somewhat with age. Certain drugs may increase aldosterone secretion; most of these are agents that increase plasma renin (hydralazine [Apresoline], diazoxide [Hyperstat], nitroprusside, and various diuretics such as furosemide [Lasix]). Glucose ingestion temporarily lowers plasma aldosterone levels.

Plasma renin. Plasma renin characteristically is decreased in primary aldosteronism. Plasma renin assay is complicated by the fact that renin cannot be measured directly, even by RIA. Instead, angiotensin I generation is estimated. This situation is standard in laboratory measurement of enzymes: usually the action of the enzyme on a suitable substrate is measured rather than direct reaction of a chemical or antibody with the enzyme. Two related techniques are used: plasma renin activity (PRA) and plasma renin concentration (PRC). The PRA reflects the rate of angiotensin I formation per unit of time. However, renin substrate (on which renin acts) is normally not present in sufficient quantities for maximal renin effect. In PRC, excess renin substrate is added to demonstrate maximal renin effect; the result is compared with standard renin preparations to calculate the patient’s renin concentration. In most cases PRA is adequate for clinical purposes and is technically a little more easy. Estrogens increase renin substrate, so PRC would be more accurate in that circumstance.

Plasma renin is an immunoassay technique of moderate or moderately great difficulty; accurate results are highly dependent on the manner in which a laboratory performs the test. In addition, optimum conditions under which the assay should be performed are not yet standardized. Although several kits are now commercially available, these kits demonstrate considerable variation in results when tested on the same plasma samples. In short, most laboratories cannot be depended on to produce accurate results, and even reference laboratories may at times have problems, especially with some of the kits. Renin is a very unstable enzyme, and for usable results it must be drawn into an ethylenediamine tetraacetic acid (EDTA) hematology tube at room temperature and centrifuged at room temperature within 6 hours. After centrifugation, the plasma must be frozen in a nondefrosting freezer until assay. Heparin cannot be used. The tourniquet should be removed before the blood sample is drawn, since stasis may lower renin levels considerably. Certain factors influence renin secretion. Sodium depletion, hypokalemia, upright posture, various diuretics, estrogens, and vasodilating antihypertensive drugs (hydralazine, diazoxide, and nitroprusside) increase plasma renin levels. Methyldopa (Aldomet), guanethidine, levodopa, and propranolol decrease renin levels. Changes in body sodium have parallel effects on renin and aldosterone (e.g., low sodium level stimulates production of both), whereas changes in potassium have opposite effects (low potassium level stimulates renin but depresses aldosterone).

Although Conn’s syndrome is typically associated with low plasma renin levels, other conditions (Table 30-2) may produce similar decreased values. In addition, nearly 25% of hypertensive patients have decreased plasma renin levels without having Conn’s syndrome. In Conn’s syndrome, low-salt diet plus 2 hours of upright posture may increase previously low renin values but not enough to reach the normal range. In patients who do not have Conn’s syndrome, a renin level that is temporarily decreased for some reason will be stimulated enough to rise above the lower limits of normal. It has been advised not to use diuretics in addition to a low-salt diet plus upright posture, since the additional stimulation of renin production may overcome renin suppression in some patients with Conn’s syndrome. Four hours of continual upright posture was originally thought to be necessary; subsequent data indicated that 2 hours is sufficient.

Typical renin-aldosterone patterns in various conditions

Table 30-2 Typical renin-aldosterone patterns in various conditions

Several screening tests for renin abnormality have been suggested. The furosemide test seems to be the one most widely used.

Unilateral renal disease is another cause of hypertension that is potentially curable. It is estimated that 5% (or even more) of hypertensive persons have this condition, which makes it much more common than primary aldosteronism. Plasma renin is frequently elevated. Since renin assay may already be considered in a hypertensive patient to rule out Conn’s syndrome, it could also serve as a screening test for unilateral renal disease. However, about one half of patients (literature range, 4%-80%) who have curable hypertension due to unilateral renal disease have normal peripheral vein plasma renin levels.

Summary of tests in primary aldosteronism

Hypokalemia in a patient with hypertension should raise the question of possible Conn’s syndrome. The typical laboratory pattern for primary aldosteronism is that of increased aldosterone and decreased renin levels. Other conditions have symptoms or laboratory findings that might suggest primary aldosteronism, but these can be differentiated by the combination of aldosterone and renin (see Table 30-2). Some patients with Conn’s syndrome have aldosterone values in the upper normal area rather than definitely elevated values. At times, either the renin or the aldosterone assay will have to be repeated to obtain a correct diagnosis.

Adrenal localization procedures in aldosteronism

Primary aldosteronism actually comprises a group of at least three conditions. First is Conn’s syndrome, produced by unilateral adrenal tumor (adenoma, rarely carcinoma). This syndrome comprises about 70% (range, 54%-90%) of primary aldosteronism cases. Second is idiopathic aldosteronism, caused by bilateral nodular adrenal hyperplasia or associated with apparently normal adrenals. This category comprises about 25%–30% (range, 10%-45%) of primary aldosterone cases. Third is glucocorticoid-suppressible aldosteronism, in which elevated aldosterone levels are suppressible and treatable by cortisol or similar glucocorticoids. This condition is uncommon; is hereditary (autosomal dominant transmission); and is diagnosed by elevation of urine 18-oxocortisol (a metabolite of cortisol) greater than urine aldosterone.

Of these, Conn’s syndrome is responsible for about 75% of cases and is the only condition that is surgically curable. Several procedures have been advocated to help verify the diagnosis of Conn’s syndrome, to help differentiate it from the other categories of primary aldosteronism, and to establish which adrenal contains the adenoma. Currently, CT visualization of the adrenals is the most widely used technique. CT is reported to detect about 75% (60%-90%) of aldosterone-producing adenomas. Radionuclide adrenal scanning using one of several new radioactive agents concentrated by the adrenal is also useful in those few institutions that do the procedure. If CT or radionuclide scans are normal, some medical centers proceed to adrenal vein catheterization for aldosterone assay from the adrenal vein on each side. A considerable difference in concentration between the two sides suggests adenoma.