True unilateral primary aldosteronism exists, and unilateral adrenalectomy saves lives

Primary aldosteronism (PA) is the most frequent surgically curable form of arterial hypertension. It is textbook knowledge, that PA has two main forms: unilateral PA mostly caused by an aldosterone-producing adenoma and treated by unilateral adrenalectomy, and bilateral adrenal hyperplasia, which is currently treated by mineralocorticoid receptor blockade using spironolactone or eplerenone. This dichotomous black and white view of PA has become blurred in recent years due to the discovery of a multitude of adrenal histopathologic phenotypes. These were uncovered by immunohistochemistry using a highly specific antibody against the key enzyme for aldosterone synthesis, aldosterone synthase or CYP11B2 (1). It confirmed that there are classical histopathologic phenotypes with an aldosterone-producing adenoma (≥10 mm diameter) and those with a dominant aldosterone-producing nodule (<10 mm diameter). But it also uncovered non-classical adrenal histopathologies with multiple aldosterone-producing micronodules (formerly called aldosterone-producing cell clusters) and aldosterone-producing diffuse hyperplasia (2). In recent studies, non-classical histopathologies were present in 5–25% of cases (3, 4), exhibiting lower plasma aldosterone concentrations and lower biochemical cure rate after surgery. This suggests that similar histopathologies might be present in the contralateral unresected adrenal. Therefore, they rather represent asymmetric forms of bilateral adrenal hyperplasia. Indeed, a higher incidence of abnormal aldosterone secretion from the contralateral adrenal gland during adrenal vein sampling (3) has been confirmed in those patients. In summary, these data suggest that PA exists in many variants, with fully unilateral or bilateral aldosteronism being the two extremes on a continuous spectrum. Evidence from clinical practice supports this concept: only a minority of patients have fully suppressed contralateral aldosterone secretion during adrenal venous sampling results, and variable degrees of contralateral co-secretion is commonly observed.

This plethora of histopathological phenotypes complicates clinical care and calls into question the simple surgery-based algorithm for the treatment of PA. Instead, careful selection of candidates for unilateral adrenalectomy has to be based in most patients on a stepwise approach starting with case confirmation by confirmatory testing and ending with adrenal vein sampling to determine the degree of lateralization of aldosterone excess (5). Adrenalectomy in selected cohorts of unilateral PA can result in complete biochemical success in 83–100% (6). How do these high rates of biochemical cure fit with the frequency of non-classical histopathologies in PA of the recent HISTALDO consensus? This poses questions on the nature of PA. Overall, the white elephant in the room is if true unilateral PA really exists, and whether unilateral adrenalectomy really has the potential to cure the patient from PA. In a worst-case scenario, it could be rather a debulking procedure, like surgical treatment of other forms of adrenal hyperplasia, for example primary bilateral macronodular hyperplasia (PBMAH) (7, 8).

Patients with PA are at risk of major cardiovascular events. According to a meta-analysis of 31 studies including 3838 patients with PA and 9284 patients with essential hypertension, patients with PA had an increased risk of stroke (odds ratio (OR): 2.58), coronary artery disease (OR: 1.77), atrial fibrillation (OR: 3.52), heart failure (OR: 2.05), diabetes (OR: 1.33), metabolic syndrome (1.53), and left ventricular hypertrophy (2.29), with no difference between patients with aldosterone-producing adenoma and bilateral adrenal hyperplasia (9). Initially, it was unclear if patients treated by adrenalectomy for unilateral PA had a favorable outcome compared with mineralocorticoid receptor antagonist treatment. If PA can be a truly unilateral disease, a better cardiovascular long-term outcome and a survival benefit following surgery would be strong evidence supporting this position.

Over the years, a large amount of data has accumulated on long-term outcomes in PA. A recent review (10) on clinical and biochemical surrogate parameters concluded that evidence from 23 studies was in favor of adrenalectomy, 23 studies showed an equivalent outcome of adrenalectomy vs mineralocorticoid receptor antagonist treatment, but none of the studies demonstrated the superiority of mineralocorticoid receptor antagonist therapy. Despite this overwhelming evidence, the question of long-term cardiovascular morbidity and mortality remained unsolved. Two recent meta-analyses reached controversial conclusions: Satoh et al. did not find a lower incidence of cerebrovascular or cardiovascular disease between the two therapeutic strategies, whereas Jing et al. reported a higher risk of major cardiovascular events in medically treated patients with PA, but not in surgically treated cases, compared with patients with essential hypertension (11). More importantly, the risk of all-cause mortality was significantly only lower in surgically treated PA (OR 0.47) (12).

In a new study published recently in this Journal, Vin-Cent Wu and colleagues (13) provide an important and convincing piece of evidence in favor of true unilateral PA. Using a prospectively designed observational cohort study, the Taiwan Primary Aldosteronism Investigators enrolled 858 patients diagnosed with unilateral PA (from 2007 to 2017). The diagnosis was based on current guideline standards of case identification and confirmation of PA, with the important blemish that not all patients underwent adrenal vein sampling. The authors excluded all patients with baseline atrial fibrillation or heart failure. Of the remaining patients, 545 were treated surgically by unilateral adrenalectomy, and 313 with mineralocorticoid receptor antagonists. The control group comprised 1210 patients with essential hypertension. One year after surgery, outcomes were classified according to PASO criteria (6): complete clinical success (hypertension remission) was achieved in 50% of the 545 surgically treated PA patients. Follow-up for all-cause mortality and major cardiovascular events was 6.3 years. The main findings of the study were that patients with unilateral PA who underwent adrenalectomy had a lower rate of incident major cardiovascular events (15% vs 21%) and chronic heart failure (7% vs 14%), compared with those having unilateral PA treated with mineralocorticoid receptor antagonists. They also had a lower all-cause mortality (4% vs 7%). The hazard ratio for all-cause mortality was 0.54 in those with blood pressure remission and 0.61 in those with residual hypertension, compared with 0.95 in mineralocorticoid receptor antagonist-treated patients with unilateral PA. Finally, postoperative plasma aldosterone concentrations 1 year after surgery, but not plasma renin activity, predicted long-term mortality and major cardiovascular events in patients with surgical management, based on an internal cut-off of 27 ng/dL.

These data are strong evidence that true unilateral PA exists. The much lower rate of major cardiovascular events and mortality in surgically treated patients, especially in those with long-term remission of hypertension, are highly suggestive of complete resection of the aldosterone-producing adrenal source. The data also demonstrate that case selection for unilateral adrenalectomy is paramount: patients with postoperative persistence or recurrence of hyperaldosteronism do not benefit similarly from surgery.

Currently, we are lacking easy, cost-effective, and valid tools to identify those truly unilateral PA cases. Mineralocorticoid receptor antagonist enthusiasts advocating medical treatment in principle must face the reality that adrenalectomy is the better option for many patients.