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Can unilateral forms of primary aldosteronism be excluded with confidence preoperatively by methods other than adrenal venous sampling? The search continues

Stowasser, Michael

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doi: 10.1097/HJH.0000000000002417
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In patients diagnosed as having primary aldosteronism, the differentiation of unilateral (affecting only one adrenal) from bilateral (affecting both) forms is of major clinical importance. From the treating physician's perspective, it is vital for guiding optimal management approach: unilateral adrenalectomy for most patients with unilateral primary aldosteronism and medical treatment with agents that antagonize aldosterone action (usually spironolactone, amiloride or eplerenone) for most with bilateral primary aldosteronism. It is now clear that the patients who do the best in terms of long-term cardiovascular outcomes are those with unilateral primary aldosteronism who have undergone unilateral adrenalectomy (c.f. those with bilateral primary aldosteronism who have been treated medically) [1,2]. This is not particularly surprising given that this procedure rids the patient of aldosterone excess completely by removing it at its source; medical treatment can only hope to ameliorate the situation with effects that may be suboptimal at maximum tolerated doses.

From the patient's perspective, there are numerous benefits from being diagnosed with unilateral primary aldosteronism and undergoing surgical treatment. Not only does this lead to biochemical cure in almost all and cure or improvement in hypertension control in the great majority (with the opportunity to cease or markedly reduce medications, which, in itself, is a highly desirable outcome in most patient's minds), but it also usually results in a rapid and often marked improvement in quality of life. This, of course, is difficult to measure scientifically but is probably more important to the patient than any other, more commonly studied outcome (such as rates of primary aldosteronism and hypertension cure, cardiovascular and renal events and mortality). Although we have previously reported on the superiority of adrenalectomy over medical treatment in terms of improvements in SF-36 quality of life survey scores in patients with primary aldosteronism [3,4], this does not do justice to the differential impact on patient wellbeing that is apparent to physicians who regularly manage primary aldosteronism in the clinical setting and who therefore are privy to their patients’ self-reported physical and psychological health status. Commonly expressed outcomes of surgery are immediate and sustained improvements in vitality, cognition and mood; resolution of fatigue, headache and nocturia (a very common symptom in primary aldosteronism, even in patients who are normokalemic); and reduction in levels of anxiety or anger. The reasons for these improvements are not entirely clear, but possible contributors could be the resolution of hypertension and the cessation of medications that could be causing side effects, correction of hypokalaemia, improved sleep resulting from reduction in nocturia or severity of obstructive sleep apnoea and reversal of other (including possibly central nervous system) direct effects of aldosterone excess.

For over 50 years, the mainstay of subtype differentiation has been adrenal venous sampling (AVS), as it is the most reliable means of lateralization. However, because it is invasive, difficult to perform and relatively expensive, alternative approaches have been sought and evaluated but with generally disappointing results. These have included a variety of imaging methods [including computed tomography (CT), MRI and several isotope techniques], posture stimulation studies (comparing recumbent with upright plasma aldosterone concentrations) and measurement of ‘hybrid steroids’ (18-hydroxy- and 18-oxocortisol). In each case, the degree of overlap has rendered these approaches insufficiently reliable to replace AVS. More recently reported have been measurement of plasma aldosterone/cortisol ratios after corticotrophin stimulation [5], steroid profiling using mass spectrometry to measure multiple steroid molecules [6] and measurement of plasma aldosterone responses during isotonic saline infusion testing, but all await further evaluation and validation [7].

From as early as 1970, investigators have reported on the use of clinical prediction scores to help identify patients likely to have unilateral or bilateral primary aldosteronism, respectively. These have mainly relied on the well recognized observation that, in general, patients with unilateral disease tend to have a more florid form of primary aldosteronism (e.g. with higher sodium, total carbon dioxide and plasma aldosterone concentrations and lower plasma potassium and renin concentrations) and are more likely to demonstrate unilateral adrenal nodules on CT than those with bilateral primary aldosteronism. However, these prediction models were often complex, remained untested outside of the region of origin or lacked reproducibility when tested on external cohorts. In this edition of the Journal, Puar et al. [8] have attempted to address these issues by developing a relatively simple prediction model (the plasma aldosterone/lowest plasma potassium ratio, APR) derived from multivariate analysis of nine variables initially tested in a Singaporean cohort of patients with primary aldosteronism, and then validated in a European cohort (the AVS arm of the SPARTACUS study). Strengths of the study are that the APR should be relatively easy to apply clinically and does not require complex modelling that could lead to overfitting, considerable efforts were made to avoid confounding factors (especially medications and uncorrected hypokalaemia) that might affect aldosterone levels, and the APR performed relatively well in both patient cohorts. There were also some potential concerns, however, including a tendency for selection bias towards more severe forms of primary aldosteronism (especially in the Asian but also in the European cohort) as evidenced by the higher than usually reported proportion of patients with unilateral primary aldosteronism (68 and 52%, respectively, compared with approximately 30% report by other institutions with high throughputs of primary aldosteronism); the absence of information on whether plasma aldosterone was measured in the seated or recumbent position and at what time of day and whether isotonic saline suppression testing was performed recumbent or seated (which we reported to be much more sensitive for primary aldosteronism [9]); the differing AVS criteria used in the two centres used to define successful cannulation and lateralization; the variable use of immunoassay versus mass spectrometry to measure aldosterone; and issues regarding the meaningfulness of the ‘lowest potassium level’ when this will depend on how often potassium was measured, whether in serum or plasma, and whether or not on diuretics or potassium supplements or during intercurrent illnesses (e.g. gastroenteritis). For a tool that contains only two variables, it might have been preferable to take as much care to avoid confounding factors with one (potassium) as with the other (aldosterone).

One of the main reasons for developing prediction scores such as this is to identify patients who are so unlikely to have unilateral primary aldosteronism that they can be spared AVS and simply be placed on medical treatment. However, the APR was less than 5, and therefore at a level that was considered reasonably reliable for exclusion of unilateral primary aldosteronism, in only 10% of the Asian cohort and 21% of the European cohort. Hence, in terms of reducing the number of AVS studies that need to be performed, the benefit of APR analysis might not be substantial. Furthermore, in the European cohort, almost one-third of the patients with APR less than 5 in fact had unilateral primary aldosteronism and would therefore had been denied the opportunity for AVS and potentially curative surgery if treatment had been APR-guided.

One of the prime motivations for seeking alternatives to AVS has been that primary aldosteronism is now widely acknowledged as being a common disorder, affecting as many as 5–13% of hypertensive individuals, and there is therefore potential to ‘flood the system’ if all patients with primary aldosteronism were to be offered AVS. However, several recent studies have drawn attention to the very low rate of screening for primary aldosteronism that exists in the primary care setting [10,11], despite the wealth of prevalence and treatment outcome data that would appear to support widespread screening among the hypertensive population (as is recommended by current guidelines). On the basis of these disappointing findings, it would seem unlikely that we are going to be flooded with AVS requests any time soon. Either way, there is a need for increased training and application of new innovative methods (such as the excellent point-of-care cortisol testing strips [12] that have proven highly effective at enhancing rates of successful cannulation to very high levels and are popular among practicing proceduralists) to keep up with the growing need for high-quality AVS services.

In their conclusions, Puar et al.[8] make the excellent point that the APR may help guide decision making in patients with AVS results that are inconclusive for one reason or another (most commonly failed cannulation on one or both sides), and this would also be the case for patients who decline the procedure. This is certainly true, and applies to most other approaches to subtype differentiation (including CT scanning and other imaging modalities, posture studies and hybrid steroid levels where available). They may not replace AVS necessarily, but they can still provide valuable complementary information towards choosing the best treatment option.

ACKNOWLEDGEMENTS

Conflicts of interest

There are no conflicts of interest.

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