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EDITORIAL COMMENTARY

Primary aldosteronism diagnosis: is cosyntropin stimulation in adrenal venous sampling still convincing?

Pizzolo, Francesca

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doi: 10.1097/HJH.0000000000002955
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Primary aldosteronism is now recognized as the most frequent form of secondary hypertension, characterized by a higher burden of organ damage compared with primary hypertension. Once diagnosed, targeted therapy leads to control of hypertension, resolution of hypokalaemia, and reverses increased cardiovascular risk. In the last two decades, awareness of the importance of a correct diagnosis has progressively increased, mirrored by a consensual increase in patient screening and primary aldosteronism diagnosis in the two principal subtypes: aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH). However, it is well known that the diagnostic process remains cumbersome, with variation in all stages (screening test, confirmatory test, and subtyping procedure) in different centres, as testified by international guidelines [1].

The main focus of the study by Saito et al. [2], published in this issue, is subtype-specific trends in the clinical presentation of primary aldosteronism over time. Data for this study was obtained from a very large Japanese PA registry. Moreover, an interesting comparison is made by examining APA diagnosis with or without cosyntropin stimulation at adrenal venous sampling (AVS).

In the entire primary aldosteronism population, subtype diagnoses were APA in 952 patients (34%), BAH in 1634 patients (58%), and undetermined in 218 patients (8%). The authors found a reduction in the proportion of APA over time, with a concomitant increase in BAH, characterized by a progressively milder phenotype. Such differences in primary aldosteronism population trends could be expected. It is evident that the greater proportion of BAH diagnosed over time (more than doubled) is attributable to the screening of a larger number of hypertensive patients with a less florid clinical expression, and typically those patients are affected by BAH, not APA. Similar findings of a lower prevalence of unilateral subtype and a milder phenotype diagnosed over time were reported by the German Conn's registry from 2008 to 2016 [3]; nevertheless, the number of patients included in the present analysis was significantly higher (2800 vs. <800), and strength of the results that has already been described in other populations.

In addition to the main result, this manuscript is noteworthy in that it makes use of the very high number of patients with data on both cosyntropin-stimulated and unstimulated AVS (2213 on 2362 AVS procedures), allowing a comparison between the two protocols.

AVS is the gold standard for subtype definition of primary aldosteronism, and the distinction between unilateral aldosterone hypersecretion (mainly because of APA) and bilateral disease (typically BAH). The procedure consists of the selective cannulation of both the left and right adrenal veins, with measurement of plasma cortisol (PCC) and aldosterone concentration (PAC) in the adrenal veins and inferior vena cava to demonstrate a lateralized aldosterone excess. The selectivity index, calculated as the ratio of PCC in the adrenal vein to PCC in the infra-adrenal vena cava, is essential to establish if catheterization is successful. Only AVS studies that are defined as bilaterally successful by selectivity index should be used to determine lateralization. The second crucial index for the interpretation of AVS is the lateralization index, calculated as the ratio of the higher (dominant) to the lower (nondominant) PAC/PCC ratios in the adrenal veins.

There is great variability in the selectivity index and lateralization index cut-off values used for the interpretation of the AVS results in different referral centres. A further source of variability is the possible presence of pharmacological stimulation with cosyntropin (administered either as a bolus or constant infusion) during AVS in order to maximize the cortisol gradient from the adrenal vein to the inferior vena cava, and the aldosterone secretion by APA, thus facilitating the assessment of selective adrenal vein cannulation and lateralization.

The cut-off values of both lateralization index and selectivity index are generally higher at centres that perform AVS with pharmacologic stimulation than at those without pharmacological stimulation, ranging from 1.1 to 4 for selectivity index, and from 2 to 5 for lateralization index.

As reported by the authors of a large international retrospective study on AVS (AVIS) [4], most centres use a selectivity index of at least 2.0 for AVS performed under unstimulated conditions, and at least 3.0 for AVS performed during cosyntropin stimulation.

In 2018, the results from phase II of a large international registry of individual AVS studies (AVIS2 study) were published, investigating the diagnostic accuracy of the different indices for the identification of unilateral aldosterone secretion [5]. As expected, the analysis of 1625 AVS individual studies demonstrated that the rate of biochemically confirmed bilateral AVS success progressively decreased with increasing selectivity index cut-offs, and a higher rate of bilaterally successful AVS was reported for cosyntropin-stimulated studies than for unstimulated ones. The registry also included 402 AVS procedures performed under both unstimulated and cosyntropin-stimulated conditions in the same patient. In this population, cosyntropin increased the confirmed rate of bilateral selectivity for selectivity index cut-off at least 2.0 but reduced lateralization rates. Moreover, using the postcosyntropin selectivity as a reference, it was found that the unstimulated selectivity index cut-off with the best combination of sensitivity and specificity was 1.4.

Saiti et al. [2] reclassified the large subgroup of patients with both cosyntropin-stimulated and unstimulated AVS, according to precosyntropin-stimulation AVS data as suggested by the AVIS 2 study. In this alternative model, primary aldosteronism subtypes were retrospectively reclassified using an selectivity index at least 1.4, for successful cannulation without cosyntropin stimulation and lateralization index greater than 2 for lateralization. According to these parameters, a total of 1943 patients had successful cannulation during AVS in a precosyntropin-stimulated condition and were re-classified as APA (1241 patients, 64%) or BAH (702 patients, 36%), inverting the relative prevalence of the two subtypes.

Results are confirmatory, in a larger and different population, that the use of cosyntropin is associated with a higher rate of AVS success but a lower number of APA diagnoses. This finding is of undoubted interest and addresses a hot topic. The questions of stimulated vs. unstimulated AVS and selectivity index/lateralization cut-offs are a matter of debate among specialists, and marked differences remain in the use of AVS even at major referral centres.

Whenever choosing the AVS protocol, clinicians must be aware that implementing cosyntropin stimulation during AVS provides the undeniable advantage of a higher rate of AVS success, but comes with the consequence of under-identification of APA, especially in patients with mild or early cases.

Given the high prevalence of primary aldosteronism among hypertensive patients and the detrimental effect of untreated aldosterone excess (e.g. high risk of target organ damage and cardiovascular events), a correct and timely diagnosis of the disease is essential. Targeted therapy is either surgical, for unilateral disease, or medical, with mineralocorticoid receptor antagonist, for bilateral disease or when lateralization is unknown. Adrenalectomy is a potentially curative treatment for APA, and the duration of hypertension is considered an important predictor of whether adrenalectomy will significantly ameliorate or even resolve hypertension control. Both the first and more recent international guidelines recommend that the presence of a unilateral form of primary aldosteronism should be established by an experienced radiologist, and whenever present, optimally treated by laparoscopic adrenalectomy. If, in relation to cosyntropin stimulation during AVS, a proportion of APA cases are not correctly diagnosed, those primary aldosteronism patients would not have added any diagnostic benefit from the AVS procedure, and the ideal surgical treatment will be precluded.

It is to be emphasized that the selectivity index of 1.4 used by authors in unstimulated AVS, according to AVIS 2 indications, is not widely used in referral centres at present. Generally, referral centres implement higher cut-off values (often >2, or higher), and a definitive validation of this cut-off requires further studies, possibly prospective outcome-based diagnostic trials. However, at a minimum, a warning concerning the use of cosyntropin stimulation should be considered, especially regarding the resultant decrease in diagnosis of lateralization, thus masking true unilateral disease in a considerable proportion of cases.

The international guidelines do not provide advice concerning the use of cosyntropin during AVS as there are arguments both in favour and against its use [1,3–7], with the suggestion by some experts that the use of cosyntropin stimulation can be justified only at centres that have a low experience/success rate in achieving bilateral selectivity [7]. Nevertheless, taking into account the results from the study by Saito et al. [2], I favour unstimulated AVS following procedural recommendations to maximize success rate: adjust antihypertensive agents before and during AVS, correct hypokalaemia if present, perform the procedure in the morning after an hour of supine rest, and wherever possible, adopt the rapid intraprocedural cortisol measurement.

ACKNOWLEDGEMENTS

Conflicts of interest

There are no conflicts of interest.

REFERENCES

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