Recognising primary aldosteronism as a disorder in its own right

Elisabeth Ng and her colleagues report their very important investigation of aldosterone, renin, and blood pressure in this issue of the MJA.1 Those of us who care for people with hypertension or teach medical students should read and ponder the entire report, but here I summarise its context, major findings, and their implications.

Primary aldosteronism was first described by Jerome Conn more than sixty years ago (Conn's syndrome).2 Many of us were taught that it was a rare and relatively mild cause of secondary hypertension, but both these assessments are now known to be erroneous. Over the past decade, our knowledge of the pathophysiology of primary aldosteronism has expanded greatly, but its clinical management has lagged far behind. Different approaches to testing and diagnosis are applied at different expert centres, including the cut‐off values for renin and aldosterone levels, the use of confirmatory testing, and the use of adrenal venous sampling, to name the most egregious. Guidelines for treating primary aldosteronism suggest that 50% (United States Endocrine Society3) to 100% of people with hypertension (Japan Endocrine Society4) should be screened for primary aldosteronism; in no country are more than 1% screened.

Ng and colleagues examined three groups of people in previously established Northern Territory research cohorts: urban and remote Indigenous Australians in the Aboriginal Birth Cohort (ABC) and urban non‐Indigenous people in the Top End Cohort (TEC). Plasma aldosterone concentrations were similar in all three groups. Renin measurements for the remote Indigenous group may have been affected by the cooling required for sample transport, but results for the two urban groups could be compared.

The results of the study were clear. The urban ABC and TEC groups were similar with respect to age; mean weight and body mass index were higher for the urban Indigenous group, the proportion who smoked much larger (48% v 11%), and the proportion of women smaller (44% v 63%). Ng and colleagues defined the commonly used cut‐off aldosterone‐to‐renin ratio (ARR) value of 70pmol/mU as the signal for probable primary aldosteronism, but facilities for confirmatory testing were not available. Thirteen urban Indigenous (26%) and twenty‐one non‐Indigenous participants (28%) had ARRs exceeding this value; with the less strict ARR cut‐off of 50pmol/mU, test results were positive for sixteen urban Indigenous people (32%), and 32 non‐Indigenous participants (42%).1

What do these results tell us? First, that about one‐third of participants in the study had primary aldosteronism. The first study to report that a sizable proportion (36%) of people with “essential hypertension” actually had primary aldosteronism was published in 1980 (but had subsequently been forgotten).5 Second, these participants in the study by Ng and colleagues were young, and mean blood pressure (systolic/diastolic) was 117/74mmHg in the non‐Indigenous group and 121/79mmHg in the urban Indigenous group. Higher ARR values were associated with higher systolic blood pressure only in the non‐Indigenous group. In other studies, primary aldosteronism has been found in 10–12% of people with normal blood pressure.6 Third, as neither hypertension nor primary aldosteronism are common in people aged 30–32 years (or: they are not often identified in this age group), primary aldosteronism may have been the major cause of higher blood pressure for the people with the condition in this study. Fourth, the risk of cardiovascular events is three times as high for people with established hypertension and un‐ or undertreated primary aldosteronism as for patients with essential hypertension and similar blood pressure levels.7

There are four things we need to do. The first is to recognise that primary aldosteronism is a disorder in its own right, not just a driver of hypertension. The 2020 International Society of Hypertension global practice guidelines included 142 references, but only one regarding aldosterone: the same as for coffee or liquorice.8 Second, we need to screen everyone with hypertension and develop inexpensive methods for distinguishing between those who have primary aldosteronism and those who do not.9 Third, most newly discovered primary aldosteronism is in people with bilateral adrenal hyperplasia, whom we currently treat with mineralocorticoid receptor antagonists, spironolactone (occasionally eplerenone), antihypertensive drugs, or (inconsistently) epithelial sodium channel (ENaC) inhibitors. Spironolactone is inexpensive, but can cause unwelcome side effects. Non‐steroidal mineralocorticoid receptor antagonists, such as esaxerenone and finerenone, do not, but are considerably more expensive.

Finally, if fewer than 1% of people with hypertension are ever screened, let alone treated for primary aldosteronism, we have two problems. The first is, that if 25% of the eight billion people in the world have hypertension, more than half a billion may have undiagnosed primary aldosteronism and consequently higher morbidity and mortality. The other is not primarily a medical problem, but the major ethical question confronting those who allocate funding for managing what is no longer a minor health problem.