Primary aldosteronism (PA) is a common cause of secondary hypertension, characterized by autonomous aldosterone production [1]. In hypertensive patients, the prevalence of PA had been considered to be less than 1% [2,3] but, recently, it has come to be widely recognized as having a higher prevalence than previously thought. With the widespread use of the aldosterone/renin ratio (ARR) as a screening test, the range has increased, up to 5% to 13%, depending on the population selected and diagnostic values used [4,5].

Inappropriately elevated aldosterone acts as a mediator, causing cardiovascular injury via mineralocorticoid receptors (MRs) in the brain, heart, and blood vessels through mechanisms explained by inflammation and endothelial dysfunction [6]. In 2006, our center conducted a retrospective study [7] in 41 patients with PA who were diagnosed during the period between 1986 and 2005, and the results showed that they were at increased risk of target organ damage (TOD) compared with patients with essential hypertension. In many studies, it has been documented that appropriate treatment improves high blood pressure (BP) and reverses cardiovascular risks [8,9].

Thus, it is important to identify the existence of PA among hypertensive patients. To determine which patients should be suspected for PA and to manage them properly, understanding current trends in PA is helpful. However, few analyses have been conducted to assess the changes in clinical manifestations of PA in Koreans. Here, we retrospectively reviewed chronological changes of the clinical manifestations of aldosteronism since the previous report in 2006.

PA was first described by Conn [10] in 1955, and was characterized by hypertension, hypokalemia, and autonomous production of aldosterone, followed by suppressed renin activity. PA was previously considered to account for less than 1% of hypertensive patients [2,3] and hypokalemia was a determinant for pursuing diagnostic tests. However, it is now widely accepted that most patients do not present with hypokalemia, and the popular use of ARR by a simple blood test increased the detection of PA, up to 5% to 13% of all hypertensive patients [4,5]. Indeed, Young [11] reported a 10-fold increase in the prevalence of PA since the introduction of the ARR. Likewise, the detection of PA has increased in our clinic because the numbers of PA patients detected in 1986 to 2005 and 2006 to 2012 were similar. This was the result of increased investigations in normokalemic hypertensive patients, wide application of ARR, and the increased chance of discovering adrenal masses incidentally in CT scans.

In the past, several studies assumed hypokalemia was a hallmark for the diagnosis of PA but recent evidence has challenged this. Gordon [12] explained that normokalemic PA had not been recognized because it was not considered in screening; however, it clearly existed and its prevalence was simply underestimated. It has also been suggested that it is only valuable to screen for PA in hypokalemic patients based on the belief that most patients with normokalemic PA have IHA rather than APA and are almost surgically incurable [13]. According to our data, of the 41 patients with PA who were diagnosed during the period between 1986 and 2005 [7], the results showed that hypokalemia was predominant in APA as a common presentation. However, notably, we also observed that, in the later period, the patients presenting with hypokalemia were fewer in number, with an increasing trend towards IHA. This shift may be explained by earlier and more precise case detection. The hormonal and biochemical abnormalities are generally much milder in patients with IHA than in those with APA [14] and hypokalemia is usually considered to be more common in APA, especially in severe cases [15].

On the other hand, Rossi [16] stated that IHA is increasing because of the more general use of a sensitive screening test, and also by the lack of systematic use of AVS. In a large multicenter study [17], APAs were detected significantly more commonly in centers with AVS than without. Gordon et al. [18] were concerned that the prevalence of IHA could have been overestimated in centers not performing AVS, because of the low sensitivity of adrenal CT alone for the detection of small APAs. According to our data, more than half of patients with AVS were diagnosed with APA. Thus, we can expect that AVS may contribute to better estimating the true prevalence of PA subtypes.

AVS was first introduced in 1957 to differentiate the subtype of PA [19]. It is the most reliable method to date, although the criteria that indicate successful cannulation and lateralization remain controversial. In our study, most AVS (82.3%) were conducted in the later period. On adrenal CT, we observed several inconsistent findings-compared with AVS-and the concordance of CT and AVS was only 56.2%. In another report [19] of 203 PA patients, CT was accurate in 53% of patients, similar to our data. Consequently, AVS is essential in distinguishing the subtypes of PA; CT alone appears to be an inadequate diagnostic method. Nevertheless, CT should be performed in all patients with suspected PA to exclude large masses that may represent adrenal carcinomas [15].

In young patients the question of whether to perform AVS is controversial, because it is known that adrenal incidentalomas are uncommon in young patients [20]. In our study, 21 patients under 40 years old at the time of diagnosis underwent surgery without AVS because the CT scan and other clinical features, such as severe hypertension, spontaneous hypokalemia, and higher levels of aldosterone, were suspicious for APA. However, seven of them were finally diagnosed as having IHA and also needed MR antagonists for BP control. Thus, we can suggest that AVS has clinical importance in patients with PA, regardless of age, especially in those who require surgery.

Unilateral adrenalectomy is effective in patients with APA or UAH to normalize the hypokalemia and to improve BP, whereas medical therapy is the treatment of choice in patients with IHA in whom surgery rarely improves BP [15]. Thus, distinguishing the subtype of PA is important in assessing treatment plans [21,22] and AVS is the most accurate method to determine the etiology of PA.

We analyzed the BP outcome in APA patients treated with adrenalectomy and IHA patients treated with medical therapy. After treatment, the mean BP declined significantly in APA with adrenalectomy and IHA with medical therapy. According to the American Heart Association criteria [23], cure is defined as SBP < 140 mmHg and DBP < 90 mmHg without antihypertensive medications; and improvement is defined by either SBP < 140 mmHg or DBP < 90 mmHg or both, for patients remaining on the same or fewer medications. Cure and improvement are both considered to have benefit in BP. In our study population, cure was obtained in 53% of APA and in all UAH patients, and improvement was observed in 34% of APA and 87% of IHA patients, respectively. The benefit in BP was similar between APA and IHA. Particularly, among APA patients, all lateralized subjects-by AVS-benefitted from BP reduction after adrenalectomy. Additionally, in all UAH that was confirmed by pathology, BP was cured after adrenalectomy.

In several studies, it has been documented that PA patients are at an increased risk of TOD versus essential hypertensive patients, independent of BP [7,24,25]. We found that about 78.0% versus 86.3% of patients had at least one TOD at the time of diagnosis in the 1986 to 2005 and 2006 to 2012 periods, respectively. None of the values regarding TOD, including LVH, retinopathy, nephropathy, coronary artery disease, and cerebrovascular disease, showed a significant difference over the periods. There was a significant difference when comparing the subgroups between patients with and without TOD. Patients with TOD were much older and had a longer duration of hypertension. Thus, in the case of younger patients with hypertension, patients with adrenal masses, severe hypertension, or a family history of early-onset hypertension, suspicion and screening are important to prevent the occurrence of TOD in PA.

This study has some limitations. First, the study population was small; thus, there was no statistically significant difference in the prevalence of subtypes of PA. Second, because it was a retrospective study, there was a lack of unique criteria for screening PA to compare the precise prevalence. Third, AVS was almost entirely performed in the later period, so the subtypes in the earlier period might not be accurate. Despite these limitations, our study is worthwhile because it is the first conducted in Korea that compares changes in the clinical manifestations of PA over a long period.

In summary, the prevalence of PA is increasing and there is an increasing tendency to IHA. Additionally, hypokalemia is no longer a requisite for the diagnosis of PA. The identification of PA has substantial prognostic value because, after optimal treatment with surgery or medical treatment, BP declines significantly and, furthermore, the increased risk of TOD caused by excess aldosterone can be reduced significantly. Moreover, AVS plays a critical role in distinguishing the subtype of PA to guide proper management, especially in patients who need surgery. With the knowledge that PA is a potentially curable and treatable disease, extending screening, based on current trends, would result in better prognoses.

1. The prevalence of primary aldosteronism (PA) is increasing and there is an increasing tendency to idiopathic hyperaldosteronism.

2. More PA patients presented with normokalemia than previous period.

3. Adrenal vein sampling plays a critical role in distinguishing the subtype of PA, especially in patients who need surgery.

4. Early and accurate diagnosis of PA would prevent target organ damage.