Adrenal Venous Sampling and Primary Aldosteronism: in Search of the Perfect Denominator

Primary aldosteronism (PA) is a prevalent endocrine disease, recognized as the most common cause of secondary hypertension. PA is associated with higher cardiometabolic risk than primary hypertension because of the detrimental effects of aldosterone excess per se. To make this diagnosis is, indeed, of utmost importance, to provide targeted treatment (mineralocorticoid antagonism or adrenalectomy), which can mitigate the elevated health risks. Making this diagnosis is still an outstanding challenge in clinical practice.

The Endocrine Society guidelines for the management of PA outline the recommended diagnostic approach (1). First, the diagnosis must be made based on one of the accepted confirmatory tests. Second, it has to be determined whether increased aldosterone secretion origins from one or both adrenals. Conventional adrenal imaging with computed tomography is not particularly helpful; aldosterone-producing tumors are typically small, and incidental adrenal tumors of no significance are common. Hence, adrenal venous sampling (AVS) is the recommended procedure to determine lateralization of aldosterone overproduction. In their article published in JCEM, Buffolo et al revisit a crucial question pertinent to the validity of AVS: Is cortisol or metanephrine the most stable and reliable identifier of venous blood from the adrenals? (2).

Although AVS is usually helpful, the method comes with several problems. It is technically challenging, requires experienced personnel, and is not universally available. Correct catheter position must be confirmed, which is conventionally defined by high selectivity index (SI), given as the ratio of cortisol concentration in adrenal to peripheral veins. The catheter positions will inevitably be different within the adrenal veins on either side and allow differential dilution of venous blood with blood from peripheral veins. Hence, we cannot directly compare the concentrations of aldosterone on the two sides. By convention, the aldosterone level is normalized, that is, represented as the concentration ratio of aldosterone over cortisol. The lateralization index (LI) is the ratio between the dominant and the nondominant aldosterone over cortisol ratio. High LI indicates unilateral PA. Obviously, any difference in cortisol secretion between the two adrenals will complicate the interpretation of LI.

The two sides are typically sampled sequentially, allowing for time-shift in cortisol levels; this is usually considered a minor problem when the procedure runs unhindered. More importantly, it is now appreciated that a significant proportion of aldosterone-producing tumors cosecrete cortisol (3). To overcome variation in cortisol levels, one recommendation is to perform AVS under cosyntropin stimulation. The downside of this approach is that cosyntropin to some extent stimulates the aldosterone secretion and may both enhance or reduce the LI, thus disturbing the assessment we were to make in the first place (4).

Buffolo et al set out to determine the prevalence of asymmetric cortisol secretion, and to evaluate whether SI and LI, by applying metanephrine concentrations, would be superior to those using cortisol. In a retrospective study, they analyzed the results of AVS in 101 patients who had undergone the procedure either unstimulated, or both unstimulated and cosyntropin-stimulated, and compared those with results obtained when metanephrine substituted cortisol in the calculations of ratios. Assuming that metanephrine secretion is similar on both sides, they found asymmetrical cortisol secretion in 18% of the patients. Applying LI with metanephrine identified unilateral PA in 9%, who were missed by the standard approach in unstimulated AVS. Conversely, 5% of the patients diagnosed with unilateral PA by the standard approach were defined as bilateral PA when applying metanephrine as denominator.

Metanephrine was previously studied in AVS, mostly as a means for determination of catheter positioning (5-7). Based on the available data, it seems that secretion of metanephrine is more uniform than that of cortisol, and less prone to the fallacies, which have been revealed for cortisol.

However, the picture is blurred. Indeed, 3 patients operated on based on the metanephrine LI corresponding with cosyntropin stimulation, but not unstimulated LI, obtained biochemical cure. On the other hand, 2 patients were biochemically cured after standard unstimulated AVS interpretation; they would not have been operated on if metanephrine LI were applied. To be able to tell the true sensitivities and specificities of the tests, we would need to know what diagnoses are hidden among those not operated on.

Recently, Wu et al investigated whether functional imaging with ¹¹C-metomidate-positron emission tomography might outperform AVS as a standard method for localization studies of PA (8). Interestingly, they concluded that ¹¹C-metomidate-positron emission tomography identifies a similar number of patients with true unilateral disease as does AVS. More intriguingly, the 2 methods identify different patients; only in about half of the patients were the test results concordant and positive. From the results presented by Buffolo et al, we might speculate whether the various AVS procedures show different sensitivities to different subsets of PA patients, and that we need them all to solve the puzzle.

It may be time to reconsider the classification of PA as bilateral or unilateral. New insights into the histopathology and genetics of PA have identified several subsets of both unilateral and bilateral PA. Consequently, the term “lateralized” rather than “unilateral” PA is a more precise description of the continuum of PA subtypes observed. Moreover, the use of static cutoff values for the various tests does not take into account the rhythmicity of aldosterone secretion in PA. A future challenge is to embed aldosterone rhythms and the factors influencing them into the diagnostic workup. We believe that we are only beginning to see what precision diagnostics will unravel about this fascinating disease in the years to come.

Funding

Nothing to disclose.

Disclosures

None.

References

Abbreviations

 
• AVS

  adrenal vein sampling

 
• LI

  lateralization index

 
• PA

  primary aldosteronism

 
• SI

  selectivity index