Improving clinical diagnostics for the management of primary aldosteronism with mass spectrometry

The endocrine disorder primary aldosteronism (PA) accounts for up to 10% of all hypertension cases.¹ PA is characterized by overproduction of the hormone aldosterone by the adrenal glands causing hypertension and sometimes hypokalemia. If not treated early, the disease can also lead to injury of the cardiovascular system and kidneys, increasing mortality in patients.^2,3

It is becoming more evident that PA is underdiagnosed or misdiagnosed due to a lack of biochemical standards, along with high testing costs, and diagnostic complexity.⁴ The latest hypertension guidelines recommend widespread screening in all persons with hypertension (new European guidelines), but if screening/diagnosis is not understood, this can lead to a lost opportunity for highly effective treatment in affected patients. Therefore, lab leaders must utilize improved tools to ensure that PA is accurately and reliably diagnosed. By doing so, labs can help clinicians make informed decisions for safe and effective treatment strategies and impact patient care.

The aldosterone-to-renin ratio (ARR) is the recommended biochemical screening tool in patients presenting with hypertension and clinical suspicion of PA. Development and improvement in the performance of aldosterone and renin determinations have permitted more reliable screening and diagnosis of PA. Current diagnostic methods for PA are not always ideal because measuring aldosterone accurately can be challenging, and other structurally similar compounds may interfere with its detection.⁵  Considering the high prevalence of immunoassay inaccuracies, if such results do not clearly fit the patient's situation, a repeat test by LC-MS/MS is often very useful but represents a second (delayed) step.

Therefore, labs are turning to liquid chromatography-tandem mass spectrometry (LC-MS/MS) in first-line testing. This technology, which offers high sensitivity and specificity, has the potential to improve diagnostic accuracy for PA. When interpreting the data, cautions Kline, it should be noted that the numeric results of mass spectrometry tests differ from those of the immunoassays used to date, and global diagnostic reference standards and ranges are needed in order to make the most of the advantages of mass spectrometry offers.

Historically considered a rare disease, it is now known that primary aldosteronism (PA) is actually highly prevalent affecting more than 1 billion people worldwide.⁶  However, it has been estimated that PA is missed or misdiagnosed approximately 95% of the time.⁴

Given the wide range of disease severity and definition, along with variable immunoassays used in different centers at different times over the past 20 years, there has been a lack of globally agreed diagnostic standardization for PA diagnosis.^4,6  The varying practices in multi-step testing has resulted in inconsistencies in diagnostic recommendations at different medical centers creating a barrier to accurate diagnosis. Additionally, costly and complex adrenal venous sampling procedures for diagnosing PA are not readily available in most medical facilities, leading to delays in diagnosis.⁴

Beyond hypertension and hypokalemia, PA can lead to severe cardiovascular complications and kidney problems or failure, causing increased mortality compared to primary hypertension.^3,7 Studies demonstrate that accurate diagnosis and screening, along with appropriate and early interventions, can prevent these end-stage and irreversible complications.^7,8 However, choosing the correct treatment approach can be challenging since options are based on the accurate diagnosis of the PA subtype. The two subtypes include 1) unilateral adrenal aldosterone excess, which is best managed with surgical adrenalectomy, and 2) bilateral adrenal hyperplasia, which is typically treated with mineralocorticoid receptor antagonists.^9,10

Because these two subtypes differ dramatically in treatment approaches, and both differ from essential hypertension, there is a significant need to improve early diagnostic capabilities such that patients receive the best care possible. Therefore, accurate and reliable detection of circulating aldosterone concentrations are essential for personalized, targeted care.

Conventional immunoassays that measure plasma aldosterone levels offer clinical labs an affordable, easy-to-use technique to support the diagnosis of primary aldosteronism (PA). However, cross-reactivity due to structurally similar endogenous steroids or the identification of low levels of molecules remains a challenge in the field. Regardless of the numeric minimum aldosterone threshold used in PA-directed testing, accurate measurement of aldosterone remains critical; any mode of interference that artifactually raises aldosterone levels will increase the risk of misdiagnosis or miscategorization.

As a potentially complementary approach to immunoassays, LC-MS/MS provides enhanced analytical detection of low molecular weight analytes and minimizes cross-reactivity which might otherwise raise apparent aldosterone levels. Known for its high sensitivity and specificity and a broad dynamic range to detect multiple molecular species, LC-MS/MS can add significant value to the endocrinology field.¹¹ It can also expand endocrine diagnostics into new patient cohorts and disease subtypes, and lead to more informed treatment decisions. 

Studies show that LC-MS/MS can accurately detect PA compared to traditional approaches.¹² More specifically, mass spectrometry could offer highly precise and reliable support for subtyping PA, especially when overdiagnosis and misdiagnosis could lead to unnecessary surgical treatment procedures as described by Eisenhofer et al 2022.¹³ As LC-MS/MS becomes more mainstream and integrated into routine medical workflows, efforts are ramping up to improve the standardization and reference methods, including the determination of appropriate cut-off values, to enhance the reliability of this technology.^5,14-15

Steroid hormones can be difficult to detect due to structural similarities with competing compounds or the low presence of associated metabolites. Detection of these compounds and metabolites is critical to the accurate diagnosis of endocrine conditions such as primary aldosteronism (PA). Because such diseases can lead to downstream clinical complications such as cardiovascular disease and renal failure, it is essential for lab leaders to leverage technologies with better sensitivity and specificity. 

Today, LC-MS/MS is becoming more accessible across the healthcare industry, especially within large and medium-sized academic teaching hospitals and regional clinical labs.^11,16 This can be attributed to the introduction of automated LC-MS/MS processes, which will offer easier workflows for medical laboratories and their personnel.¹⁷

LC-MS/MS has the ability to provide physicians with more accurate, more informative clinical data that can lead to enhanced care. Current methodologies like immunoassays offer labs a simple and streamlined way of evaluating PA, but LC-MS/MS can provide comprehensive and complementary patient information. LC-MS/MS enables labs to expand their screening and diagnostic services into new patient populations and disease areas, and significantly advance precision medicine, early disease detection, and personalized treatment strategies.