Game Changer: Aldosterone-Driven Hypertension More Common Than Thought
“Our findings show a high prevalence of unrecognized yet biochemically overt primary aldosteronism [PA] using current confirmatory diagnostic thresholds. They highlight the inadequacy of the current diagnostic approach that heavily relies on the ARR [aldosterone renin ratio] and, most important, show the existence of a pathologic continuum of nonsuppressible renin-independent aldosterone production that parallels the severity of hypertension,” wrote Jennifer M. Brown, MD, and co-investigators in a report published in Annals of Internal Medicine on May 25. “These findings support the need to redefine primary aldosteronism from a rare and categorical disease to, instead, a common syndrome that manifests across a broad severity spectrum and maybe a primary contributor to hypertension pathogenesis,” they wrote in the report.
The results, showing an underappreciated prevalence of both overt and subtler forms of aldosteronism that link with hypertension, won praise from several experts for the potential of these findings to boost the profile of excess aldosterone as a common and treatable cause of high blood pressure, but opinions on the role for the ARR as a screen to identify affected patients were more mixed.
“ARR is still the best screening approach we have” for identifying people who likely have PA, especially when the ratio threshold for finding patients who need further investigation is reduced from the traditional level of 30 ng/dL to 20 ng/dL, commented Michael Stowasser, MBBS, professor of medicine at the University of Queensland in Brisbane, Australia, and director of the Endocrine Hypertension Research Centre at Greenslopes and Princess Alexandra Hospitals in Brisbane. “I strongly recommend ARR testing in all newly diagnosed hypertensives.”
The study results “showed that PA is much more common than previously perceived, and suggest that perhaps PA in milder forms than we typically recognize contributes more to ‘essential’ hypertension than we previously thought,” said Anand Vaidya, MD, senior author of the report and director of the Center for Adrenal Disorders at Brigham and Women’s Hospital in Boston. The researchers found adjusted PA prevalence rates of 16% among 115 untreated patients with stage 1 hypertension (130-139/80-89 mm Hg), 22% among 203 patients with untreated stage 2 hypertension (at least 140/90 mm Hg), and 22% among 408 patients with treatment-resistant hypertension. All three prevalence rates were based on relatively conservative criteria that included all 726 patients with hypertension in the analysis (which included 289 normotensive subjects) regardless of whether or not they also had low serum renin levels. These PA prevalence rates were also based on a “conservative” definition of PA, a level of at least 12 mcg excreted in a 24-hour urine specimen.
When the researchers applied less stringent diagnostic criteria for PA or focused on the types of patients usually at highest risk for PA because of a suppressed renin level, the prevalence rates rose substantially and, in some subgroups, more than doubled. Of the 726 people with hypertension included in the analysis, 452 (62%) had suppressed renin (seated plasma renin activity < 1.0 mcg/L per hour or supine plasma renin activity < 0.6 mcg/L per hour). Within this subgroup of patients with suppressed renin, the adjusted prevalence of PA by the threshold of 24-hour urine aldosterone secretion of at least 12 mcg was 52% in those with treatment-resistant hypertension; among patients with stage 1 or 2 hypertension, the adjusted prevalence rates were just slightly above the rates in the entire study group. But among patients with suppressed renin who were judged to have PA by a more liberal definition of at least 10 mcg in a 24-hour urine sample, the adjusted prevalence rates were 27% among untreated stage 1 hypertensives, 40% among untreated stage 2 patients, and 58% among treatment-resistant patients, the report showed.
Hypertension and Primary Aldosteronism
Primary aldosteronism, as described by Conn (7) in 1955, had been thought to be an uncommon cause of hypertension, with a prevalence of <1% among general hypertensive patients (7–9). However, beginning in the early 1990s with reports from Gordon and associates in Brisbane, Australia, the prevalence of primary aldosteronism is considerably higher. In the earliest study, Gordon et al. (10) screened 52 hypertensive individuals who responded to a newspaper advertisement for participation in a hypertensive drug trial and found that 12% of the individuals were positive for primary aldosteronism. In a subsequent evaluation of 199 individuals referred to the hypertension clinic in Brisbane, the prevalence of primary aldosteronism was at least 8.5% and probably 12% (11). These results were remarkable in suggesting that primary aldosteronism was not rare but rather a common cause of hypertension.
Since these earlier studies by Gordon, multiple investigators worldwide have confirmed a prevalence of primary aldosteronism of 5 to 15% in general or selected hypertensive populations (12–20). Two of these studies are particularly noteworthy because of their scientific rigor and the clinical implications of the results.
The studies that reported a high prevalence of primary aldosteronism have been criticized for lax diagnostic criteria, confounding effects of ongoing treatment, and/or lack of testing to confirm the absence of aldosterone suppression with volume expansion. Schwartz and Turner (18) avoided such limitations by prospectively evaluating 118 individuals who had primary hypertension after withdrawal from antihypertensive treatment and who had confirmation of the diagnosis of primary aldosteronism with a demonstration of lack suppression aldosterone excretion after 4 d of dietary salt loading. With the application of these stringent diagnostic criteria, primary aldosteronism was diagnosed in 13% of individuals.
In the study by Mosso et al. (20), >600 hypertensive patients were screened for primary aldosteronism by measuring the plasma aldosterone/PRA ratio. Patients with a high ratio were then evaluated by fludrocortisone suppression testing to confirm the diagnosis of primary aldosteronism. At some point before their biochemical evaluation, all patients had their antihypertensive mediations withheld. The authors were able to relate the prevalence of primary aldosteronism to the severity of hypertension. Overall, the prevalence of primary aldosteronism was 6.1%. However, the prevalence increased about the severity of hypertension (Figure 1). In patients with mild hypertension (<160/100 mmHg), primary aldosteronism was uncommon (2%). In patients with moderate hypertension (160 to 179/100 to 109 mmHg), the prevalence of primary aldosteronism was 8%, and in patients with severe hypertension (≥180/110 mmHg), aldosteronism was diagnosed in 13% of patients. These results of these two studies are clinically significant in providing rigorous confirmation of a high prevalence of primary aldosteronism in general hypertensive populations and in demonstrating that the likelihood of primary aldosteronism is much higher in patients with more severe hypertension.
Figure 1.
Prevalence of primary aldosteronism in patients according to Sixth Joint National Committee (JNC VI) stages of severity of hypertension (stage 1, 140 to 159/90 to 99 mmHg; stage 2, 160 to 179/100 to 109 mmHg; stage 3, ≥180/110 mmHg) (20).
Although originally defined as an essential characteristic of Conn’s syndrome, recent evaluations indicate that hypokalemia is uncommon in patients with demonstrable aldosterone excess when not part of the diagnostic criteria. In the study by Schwartz and Turner, none of the patients diagnosed with primary aldosteronism had a history of unprovoked hypokalemia. Of the 37 patients confirmed to have primary aldosteronism by Mosso et al. (20), all but one had normal potassium levels at the time of the diagnosis. These results suggest that hypokalemia is a late manifestation of aldosterone excess long preceded by the development of hypertension.
Resistant Hypertension and Primary Aldosteronism
Resistant hypertension is defined as BP that remains elevated despite using three antihypertensive agents, ideally one of which is a diuretic. The prevalence of resistant hypertension is unknown; however, cross-sectional and hypertension outcome studies suggest a common clinical problem. In the most recent National Health and Nutrition Examination Survey (NHANES 1999 to 2000), only 53% of individuals who were being treated for hypertension were controlled to <140/90 mmHg (21). Among older individuals (≥60 yr), control rates were worse, with only 44% at or below 140/90 mmHg. In a cross-sectional evaluation of patients with diabetes, only 23% of black and 31% of white patients were controlled to <130/80 mmHg despite being prescribed an average of 2.7 and 2.2 antihypertensive medications, respectively (22).
Prospective hypertensive trials confirm a high occurrence of treatment resistance. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), participants were provided medications at no charge, titration was dictated for uncontrolled hypertension. At the end of the study, medication adherence was monitored, 34% of participants’ hypertension remained uncontrolled, with an average use of 2.0 antihypertensive medications, and 27% of participants received three or more medications (23). These studies indicate that resistant hypertension is common and undoubtedly will become even more so as the population ages and becomes increasingly obese, two of the strongest predictors of the development of resistant hypertension (24).
Studies from separate laboratories suggest that primary aldosteronism is a common cause of resistant hypertension, with a prevalence of approximately 20% in patients with difficult-to-control hypertension (Figure 2). In an evaluation of 88 consecutive patients who were referred to the University of Alabama at Birmingham for resistant hypertension, primary aldosteronism was diagnosed in 18 or 20% of the patients based on a suppressed PRA (<1.0 mg/ml per h) and high urinary aldosterone excretion (>12 μg/24 h) during high dietary salt intake (sodium > 200 mEq/24 h) (25). In this evaluation, which included an equal number of black and white patients, primary aldosteronism was equally common regardless of race.
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