1 Introduction

Primary aldosteronism (PA) is the most common secondary cause of hypertension, affecting about 10 % of the general hypertensive population and 20 % of drug-resistant hypertension. The diagnosis of PA is critical not only to prevent and correctly treat the complications related to hypertension, but also to prevent the non-epithelial effects related to hyperaldosteronism. Indeed, there is great evidence that PA patients have an increased rate of cardio- and cerebro-vascular events and of metabolic complications compared to essential hypertensives [1, 2]. In fact, PA patients have an increased risk of stroke, myocardial infarction, arrhythmias, heart failure and type 2 diabetes [3]. As a result, the current Endocrine Society (ES) guidelines (a new version is expected to be published in 2016) recommend case detection of PA in patient groups with relatively high prevalence of PA, in an effort to maximize detection of subjects who may benefit from optimal specific management [4].

2 Who Should Be Screened?

Firstly, patients who should be screened include those with Joint National Commission stage 2 (160–179/100–109 mmHg) and stage 3 (>180/110 mmHg) hypertension and/or with hypertension resistant to 3 conventional antihypertensive drugs, including a diuretic. In fact, several studies demonstrated that the probability of having PA increases with the severity of hypertension, reaching a prevalence of about 20 % in resistant hypertensives [5, 6]. Secondly, PA screening is suggested in patients with hypertension and spontaneous or diuretic-induced hypokalemia. Although normokalemic hypertension constitutes the most common presentation of the disease, hypokalemia is much more frequent in PA patients compared to essential hypertension [7]. Hypertensive patients with adrenal incidentaloma represent another recommended patient subgroup, PA prevalence being about 1.6 % [8]. Finally, PA should be screened in hypertensive patients with a family history of early-onset hypertension or cerebrovascular accident at a young age (<40 years) and all hypertensive first-degree relatives of patients with PA: this could indicate in fact familial hyperaldosteronism type 1 (glucocorticoid-remediable aldosteronism) or type 2 [9] or type 3 [10]. However, other subgroups of patients with a potentially increased PA prevalence have subsequently identified. Jerome W. Conn firstly described the association between PA and impaired glucose tolerance in 1965 [11], but some reports did not confirm these results, partially because of the small sample of patients evaluated and the different criteria used to diagnose altered glucose metabolism and PA. A significant increased prevalence of metabolic syndrome, including hyperglycemia, was found in PA patients compared to essential hypertensives patients (41.1 vs 29.6 and 27 vs 15.2 %, respectively) [12], and a more recent study in a large German cohort confirmed a higher prevalence of type 2 diabetes mellitus in PA than in essential hypertensives [13]. Thus, an abnormal glucose metabolism due to insulin resistance appears to be linked to aldosterone overproduction, and appears to be the major contributor to metabolic dysfunction in PA [14, 15]. Many pathogenic mechanisms, both direct (aldosterone excess) and indirect (hypokalemia, oxidative stress) [16], have been suggested to explain this effect. Another interesting association has been described between hyperaldosteronism and severity of obstructive sleep apnea (OSA) in patients with resistant hypertension [17]. Addition of spironolactone to the ongoing antihypertensive therapy reduced the severity of OSA, probably due to its diuretic effect and the consequent reduction in pharyngeal edema and in upper airway resistance [18]. Moreover, a high prevalence of PA has been in fact found in patients with OSA [19]. This suggests to include patients with OSA among those to be investigated for PA. Table 1 reports patient groups indicated by the ES guidelines and those suggested to be screened for PA.

Table 1 Groups of patients with high prevalence of primary aldosteronism (PA)
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3 Which Screening Test Is Recommended?

The ES guidelines recommend the use of aldosterone-to-renin ratio (ARR) as the most reliable test to detect cases of PA. After its introduction, the prevalence of PA has in fact significantly increased, detecting PA in normokalemic cases and/or with normal plasma/urinary aldosterone values. The cutoff level of ARR is usually set between 20 and 40 (using aldosterone units of ng/dL and plasma renin activity as ng/mL/h), considering serum aldosterone levels greater than 15 ng/dL (416 pmol/L). To increase ARR accuracy, conditions of sampling are crucial: blood samples should be collected in the morning, after the patients have been out of bed for at least 2 h and usually after they have been seated for 5–15 min; ideally, patients should have unrestricted dietary salt intake and potassium-repleted before testing. Moreover, antihypertensive drugs (β-blockers, ACE-inhibitors, angiotensin II receptor antagonists, MR-antagonists and diuretics) and some conditions like advancing age and renal impairment, could affect the ARR measurements. Washout of interfering medications is feasible in patients with mild hypertension which can be controlled by α-antagonists and/or non-dihydropyridine calcium antagonists, which do not significantly affect ARR. If this switch is difficult, most investigators suggest to interpret the ARR considering the possible interferences, allowing the patient to proceed to confirmatory/exclusion testing without delay [4]. The measurement of PRA is time consuming and shows poor inter-laboratory variability. Recently, a monoclonal antibody against active renin has been used by several laboratories to measure plasma renin concentration (PRC) instead of PRA. However, more studies are needed to test this method for detection of PA cases [20], and it would be reasonable to consider the PRC only when its value is below the lower limit of detection for the assay.

4 Which Confirmatory Tests Should Be Performed?

The ES guidelines recommend that patients with a positive ARR should undergo confirmatory procedures, in order to avoid costly and potentially harmful lateralization procedures in subjects with false positive ARR. The four confirmatory tests recognized by the ES guidelines are: (1) oral salt loading; (2) saline infusion; (3) captopril challenge and (4) fludrocortisone suppression (see test protocols and diagnostic cut-offs in Fig. 1). None of these has been identified as a gold standard procedure to confirm PA. The oral salt loading test, after hypertension and hypokalemia are controlled, is quite inexpensive and does not require patient hospitalization: it is however associated with a risk of hypokalemia and its reliability depends on the accuracy of urine collection by the patient. The intravenous saline loading test is safe and relatively inexpensive, but it must be performed monitoring blood pressure and heart rate, being potentially harmful. The captopril challenge is associated with a significant rate of false positive and negative PA diagnosis, but it is the only test without risk of volume expansion and therefore suggested for patients with reduced cardiac or renal function or uncontrolled hypertension. The fludrocortisone suppression test is considered the most physiologic test for PA, but it is also the most expensive and requires a brief hospitalization due to the risk of severe hypokalemia. The use of interfering antihypertensive drugs (it is impossible to interpret data obtained from patients receiving MR-antagonists or direct renin inhibitors) must be always considered, and the optimal cutoff value for these tests depends on the assay used to measure aldosterone and PRA or PRC.

Fig. 1
figure 1

Flow-chart for confirmatory diagnosis of primary aldosteronism, including test protocols and cut-offs. PA primary aldosteronism, ARR aldosterone-to-renin ratio, U-Aldo urinary aldosterone, P-Aldo plasma aldosterone

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5 Conclusions

All patient groups with increased prevalence of PA, including hypertensive patients with type 2 diabetes mellitus and those with OSA, should be carefully screened, using the ARR as the most practical and initial test. Subsequent confirmatory tests are required to confirm the diagnosis and to avoid that patients with a false positive ARR (for example with low-renin hypertension) would inappropriately undergo costly and harmful lateralization procedures [21]. If confirmatory testing is positive, further investigations are directed toward determining the subtype of PA, as the treatment differs for each subtype.