Primary Aldosteronism Is Everywhere But Does Anyone See It?

Gregory Kline


Clin Endocrinol. 2021;95(3):410-411. 

For the past decade, it has become de rigueur for authors writing about primary aldosteronism (PA) to have an introductory sentence that makes reference to how common PA is known to be among people with hypertension. But that has not always been the case. After Conn's seminal case report in 1955,[1] he quickly became aware of many other cases,[2] leading him to predict that PA would not be a rare disease. However, it was not until researchers like Gordon and others starting doing systematic screening for PA in hypertension patients 40 years later[3] that we began to see population data supporting Conn's prediction. Since then, there have appeared a number of studies showing similar results from around the globe including North America, South America, many countries within the European and Australasian regions, South Africa and China among others. In the present issue of Clinical Endocrinology, Alam et al[4] have added to this list with the first PA prevalence study from another major population group, this time in India. Like prior studies, the researchers prospectively and systematically looked for PA among younger-aged patients referred to a hypertension specialty clinic and reported a prevalence rate of nearly 20%.

It has proved challenging for global PA researchers to agree upon a specific PA disease prevalence statistic[5] likely owing to wide variation in the populations surveyed according to age, ethnicity, severity of disease, primary vs specialist care settings and selection/referral biases around 'red flag' factors such as hypokalaemia or adrenal masses. An additional albeit perhaps under-appreciated factor affecting apparent prevalence is the issue of disease definition itself. If PA was exclusively caused by adrenal aldosteronomas, one could easily do high-quality prevalence studies based on surgical pathology and outcomes, similar to pheochromocytomas. However, PA encompasses a wide range of aetiopathogeneses including aldosteronomas, germline mutations affecting aldosterone production,[6] aberrant adrenal stimuli,[7] stimulatory auto-antibodies,[8] obesity[9] and maybe even aldosterone hyper-responsiveness from bio-psycho-social stress[10,11] such that defining a measurement-oriented concept such as 'aldosterone excess' has become an exercise in choosing the meaning of 'excess' when based upon biochemical measures drawn from a continuous distribution.[12]

Nonetheless, despite the caveats of population-specific estimates and vagaries of PA disease definition, the unmistakable signal from the collected evidence is that PA, in some form, is not rare. With disease prevalence estimates ranging from 3% to 13% in primary care and up to 30% in hypertension referral centres across the globe,[5] there is little value to continued haggling over the best single point estimate. If anything, further attempts to narrow the accepted prevalence interval may be short-sighted; recent multi-centre studies have now shown that 'aldosterone excess' likely exists with meaningful frequency even among people with normotension[13] or pre-hypertension[14] and this too may not be benign.[15] If true, these new data suggest we may be arriving at the diagnosis far too late in people who do not come to attention until they have had hypokalaemia or a cardiovascular complication. The point is that if pathologic and medically dangerous[16,17] aldosterone excess co-exists to a significant degree among people with hypertension across the world, then it is time for the next stage of PA research to come with a public health focus and design.

In the meantime, there is a practical and more immediate problem also highlighted by Alam et al in their report: even those who do eventually come to a PA diagnosis are likely waiting a very long time to do so, despite the presence of 'red flag' signals. The investigators noted that of 202 consecutive patients in their early 40's, the median duration of prior hypertension in those with PA was 10 years, 30% were already on 4 or more anti-hypertensives and two-thirds had hypokalaemia. These are not subtle PA cases. Unfortunately, this phenomenon of delayed or missed diagnosis is not limited to the authors' experience either. A study of US Veterans showed that of over 260,000 patients with treatment-resistant hypertension, only 1.6% were ever tested for possible PA; those who did get testing and disease-specific treatment were the few who eventually achieved better blood pressure control.[18] Another 2016 report showed that the majority of primary care doctors in a large German-Italian sample were not aware of or participating in PA case finding.[19] Therefore, it is one thing to talk about PA prevalence among pre-hypertensive patients but the data show that PA is not even getting diagnosed or treated in most of the obvious cases.

What is the way forward to better PA care for the most patients? Undoubtedly, the answer(s) will be as disparate as the global geographies from which studies like Alam et al originate. If adrenal vein sampling has to be part of the diagnosis, then this will necessarily put a hard limit on the number of people who may benefit from access to diagnosis. The first step may be to have feasibility-sensitive recommendations that are more suitably adapted for low to high-resource health systems.[20] A strong argument may be made for earlier introduction of empiric spironolactone in resistant hypertension,[21] an intervention that should be made comfortable for all primary care physicians. Simplification of the PA diagnostic pathway might be a critical step to removing barriers to care; the classical extra step of 'confirmatory testing' should be actively discouraged in situations where adrenal vein sampling or surgery is not available or anticipated. Laboratory result reports for aldosterone and renin should be generated in collaboration with local endocrinologists in order to produce reports that are meaningful and give clear direction for physicians less familiar with aldosterone-renin-ratio interpretation. Ultimately, a paradigm shift in the way we think about, teach and treat hypertension may be coming; better matching of underlying endocrine mechanisms to more targeted therapies for better outcomes in all patients is the dream. Until then, endocrinologists can play a leading role, imitating the example of Alam and colleagues by proactively looking for PA in patients with hypertension and letting our students and referring physicians see the results that may be achieved when we all start to take the prevalence data seriously.