contents
12.1 Introduction . . . 127
12.2 Diagnosis of Hyperaldosteronism . . . 127 12.3 Different Forms
of Primary Hyperaldosteronism . . . 127
12.4 Differentiation Between Aldosterone-Producing Adenomas and Bilateral Hyperplasia . . . 128 12.5 Treatment . . . 129
References . . . 130
12.1 Introduction
Primary aldosteronism was first described almost 50 years ago by Conn [2]. He predicted that aldostero- nism was a common cause of hypertension. For many years internists did not consider primary aldostero- nism to be common. It was thought that hypokalemia should be a prerequisite for investigating patients for primary aldosteronism. With this assumption about 0.5% of hypertensive patients had primary aldostero- nism.In addition,sampling of blood with a tourniquet induces an increase in serum potassium, also con- tributing to the low number of patients with primary aldosteronism. However, over the last 10 years there have been an increasing number of reports from all over the world that primary aldosteronism may be much more common [4, 5, 15].
Many more patients could benefit by screening for primary aldosteronism, using the ratio plasma aldos- terone/plasma renin activity or plasma renin levels. It is difficult to standardize the aldosterone/renin ratio as different laboratory methods are used and since plas- ma renin activity will with increasing frequency be re- placed by determination of plasma renin levels. Al- though it may be difficult to define the exact cut-off of the aldosterone/renin ratio, it is evident that such an increased ratio once confirmed is an excellent indica- tion for further endocrinologic workup. Several stud-
ies have shown a prevalence of primary aldosteronism of between 5% and 13% in patients with hypertension and even higher in some patients with continued high blood pressure in spite of treatment with several anti- hypertensive medications (see review by Young [16]).
Most of these patients are not hypokalemic.
12.2 Diagnosis of Hyperaldosteronism
In a patient with hypertension,a low plasma renin value and increased plasma and urinary aldosterone remains the cornerstone in the diagnosis and evaluation. Dur- ing this evaluation the patient should preferably be off all hypertensive drugs if possible. In particular spiro- nolactone and beta blocking agents may cause diag- nostic difficulties. The patient should also be normo- kalemic.Blood for aldosterone,renin and cortisol levels should be drawn from the patient in the morning at rest and at noon after being ambulatory. In addition, in- hibitory tests by, e.g., fludrocortisol may be used to in- crease the accuracy of the diagnosis of primary aldos- teronism [1]. The next step in the investigation, after confirmation of the diagnosis biochemically, is to ob- tain a high resolution computerized tomographic (CT) scan. The CT may show a unilateral enlargement, nor- mal adrenal glands or bilateral enlargement.
12.3 Different Forms
of Primary Hyperaldosteronism
▬ Bilateral hyperaldosteronism due to micro- or macronodular adrenocortical hyperplasia
▬ Aldosterone-producing adenoma
▬ Primary unilateral adrenal hyperplasia
▬ Adrenocortical carcinoma
▬ Familial hyperaldosteronism
– Type I glycocorticoid remediable aldosteronism – Type II familial adenoma or hyperplasia
12 Primary Aldosteronism: The Surgical Perspective
Bertil Hamberger
The most common types of hyperaldosteronism are aldosterone-producing adenomas (Fig. 1) and bilater- al aldosterone-producing hyperplasia. More uncom- mon forms are primary unilateral adrenocortical hy- perplasia and the extremely rare adrenocortical carci- noma-producing aldosterone. There are two familial forms, type I, glucocorticoid remediable aldostero- nism [8, 10], which is treated by oral administration of glucocorticoids, and type II, which is a recently dis- covered familial form with both adenoma and hyper- plasia being present [7].
12.4 Differentiation Between
Aldosterone-Producing Adenomas and Bilateral Hyperplasia
Patients with an aldosterone-producing adenoma should be offered surgical removal since this treat- ment cures the hyperaldosteronism and improves hypertension in virtually all patients [16] although about half remain hypertensive due to secondary arteriolar changes. On the other hand, patients with bilateral adrenal hyperplasia do not usually benefit from surgical removal of one adrenal unless there are large differences in aldosterone secretion between the two sides. Bilateral adrenalectomy creates more problems as a result of the need for substitution with
gluco- and mineralocorticoids and is not recom- mended.
As mentioned CT is the first investigation in line. A lesion of 1–2 cm in one gland and a completely normal contralateral gland may be sufficient for unilateral adrenalectomy. Magnetic resonance imaging (MRI) provides an excellent morphologic image but can also help to characterize an adrenal lesion and distinguish between a cortical and a medullary tumor [6]. Howev- er, MRI cannot give information on which steroid the cortical nodule may produce. Thus, in most cases a functional localization is required and recommended as well.
Adrenal venous sampling is the diagnostic method of choice for determining the release of aldosterone from the adrenal glands [11]. It is not an easy proce- dure and needs an experienced radiologist. It is essen- tial to be able to cannulate the more difficult right adrenal vein in addition to the left adrenal vein. For experienced radiologists the success rate of this technique is greater than 90%.Samples for aldosterone and cortisol levels are taken from both adrenal veins in addition to other locations including the left renal vein, the inferior vena cava and a peripheral vein. For positive lateralization, the aldosterone/cortisol ratio must be at least four times higher from the affected gland. In addition, the cortisol level must be three times higher in both adrenal veins when compared to Bertil Hamberger
128
Fig. 1. Schematic drawing of the effects of an aldosterone-producing adenoma
peripheral blood to prove that the sample was, in fact, taken from the adrenal vein. Clear lateralization with venous sampling is an excellent indicator for adrena- lectomy.
Scintigraphy after injection of iodine cholesterol may also provide an effective functional localization without invasive methods (Fig. 2 [9]). The drug is given intra- venously after inhibition of adrenal cortisol secretion by dexamethasone. Clear lateralization with scintigra- phy which is in accordance with the CT scan provides sufficient information for surgical intervention.
12.5 Treatment
In patients with clear lateralization by CT scanning, adrenal venous sampling or iodine cholesterol scintig-
raphy, there is an indication for unilateral adrenalec- tomy for an aldosterone-producing adenoma [13].
Usually aldosterone-producing adenomas are small (0.5–2 cm) (Fig. 3) and ideal for laparoscopic removal [11]. It is advantageous to correct hypokalemia pre- operatively using spironolactone. Surgical removal of an aldosterone-producing adenoma is very cost effec- tive especially in young patients compared to lifelong medical treatment. Cured patients should have nor- mal serum aldosterone, renin and potassium on fol- low-up.
Cure of hypertension after successful removal of any aldosterone-producing adenoma ranges between 40% and 70% [14, 12] and persistent hypertension needs conventional treatment. If the patient has per- sisting hyperaldosteronism, it is probable that the re- moved nodule was not producing aldosterone and the patient may have a small adenoma in the contralater- al adrenal gland or bilateral disease.Analysis of the re- moved tissue with in situ hybridization of steroid- ogenic enzymes can reveal the localization of aldos- terone production [3].
Patients with bilateral hyperplasia should be treated medically. Spironolactone is the most widely used drug in combination with other hypertensive drugs. The major problem is the occurrence of side effects, particularly painful gynecomastia and im- potence. A new drug, eplerenone, was introduced in 2003 to give an antimineralocorticoid effect on aldosterone receptors in the kidney [16]. This drug may be of great help in treating bilateral hyperplasia and may also prove to be useful in patients where surgical removal of an adenoma is contraindicated. In addition, primary adrenal hyperplasia and adrenal cortical carcinoma should be treated surgically. Pa- tients with adrenocortical carcinoma and hyper- aldosteronism will usually need an open adrenalecto- my, as radical surgery is the only chance for perma- nent cure.
12 Primary Aldosteronism: The Surgical Perspective 129
Fig. 2. Iodine cholesterol scintigraphy of a patient with pri- mary aldosteronism showing increased activity from the left adrenal.A 1.5-cm-large tumor was also seen on computed to- mography and the patient had an aldosterone-producing adenoma removed. (Courtesy of Dr. Hans Jacobsson, Dept. of Radiology, Karolinska Hospital)
Fig. 3. A typical aldosterone-producing adenoma with a yellow color to the right. To the left there is a nonhyperfunctioning nodule with a pale color. The adrenal cortex has a normal appearance
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