Who and How Should We Screen for Primary Aldosteronism?

There are mounting data that at least 30% of hypertensives who are appropriately screened have primary aldosteronism (PA), rather than the commonly reported figure of 5% to 10%. Second, there are similar data that undertreated patients with PA have a 3-fold higher risk profile than essential hypertensives with the same blood pressure levels. Third, clinicians managing hypertension measure success as sustainable lowering of blood pressure; untreated hypertensive patients with PA are thus in double jeopardy. Finally, and crucially, fewer than 1% of patients with hypertension are ever screened-let alone investigated-for PA. Accordingly, for "Who should we screen?" the answer is simple-all patients with hypertension. For "How they should be screened?" the answer is also simple-add spironolactone 25 mg/day for 4 weeks and measure the blood pressure response. In established hypertension, a fall of <10 mm Hg means PA is unlikely; above 12 mm Hg PA, it is probable. Newly presenting hypertension is much the same-hold off on first-order antihypertensive(s) and prescribe spironolactone 25 mg/day for 4 weeks. If blood pressure falls into the normal range, continue; if it does not, prescribe a standard antihypertensive. It is likely that the above protocols-a first start, amenable to refinement-will find additional hypertensives with unilateral PA; it is probable that the overwhelming majority will have bilateral disease. What this means is that we have a major public health issue on our hands: how can this be the case?

Primary Aldosteronism: Where Are We Now? Where to From Here?

Primary aldosteronism, the most common secondary form of hypertension, is thought to be present in ≈5% to 10% of hypertensive adults. However, recent studies indicate that its prevalence may be at least 3-fold higher based on the identification of renin-independent (autonomous) aldosterone production that is not suppressible with dietary sodium loading in a large fraction of adults with primary hypertension. Currently, the screening rate for primary aldosteronism in adults with primary hypertension is <1%. This review summarizes current thinking about primary aldosteronism from the standpoint of 3 key questions: Where are we now? Where to from here? So how do we get there?

Primary aldosteronism.

In 1955 Dr Jerome Conn first documented primary aldosteronism (PA). Since then, screening, diagnosis and treatment have developed, in the process both refining and complicating management. Currently, screening requires 4-6 weeks of lead-up, including major changes in antihypertensive therapy, followed by a blood draw for plasma aldosterone concentration (PAC) and plasma renin activity (PRA) or concentration (PRC). Screening is considered indicative of PA on the basis of the PAC and the aldosterone to renin ratio (ARR). This is then followed by one or more of 6 confirmatory/exclusion tests. Three things have changed. First is now incontrovertible evidence that a single spot PAC is a deeply flawed index of true aldosterone status, so that many referred patients with PA fall at the first hurdle. A valid index of aldosterone status is an integrated value, measured as urinary aldosterone excretion (UEA) over 24 h. On the basis of the UEA, the prevalence of PA appears to be 3-5 times higher than the currently accepted figure of 5-10% of hypertensives. The second is the recognition that inadequately treated PA has a cardiovascular risk profile ~threefold that of matched essential hypertensives. Third is the realization that <1% of hypertensives are ever screened for PA, who are thus in double jeopardy for the risks of untreated PA on top of those for hypertension per se. Taken together, this a major if occult public health issue; if it is to be addressed, radical changes in management are needed. Some are in screening, which needs to be simply done on all newly-presenting hypertensives; others are major simplifications of screening in established hypertension. The front-line actors need to be Internists/Primary Care Providers; the costs will be significant, but much less than those of increased morbidity/premature mortality in unrecognized PA. Possible suggestions as to how best to address this constitute the final chapter of this article.

A tumour suppressive relationship between mineralocorticoid and retinoic acid receptors activates a transcriptional program consistent with a reverse Warburg effect in breast cancer.

BACKGROUND: The role of nuclear receptors in both the aetiology and treatment of breast cancer is exemplified by the use of the oestrogen receptor (ER) as a prognostic marker and treatment target. Treatments targeting the oestrogen signalling pathway are initially highly effective for most patients. However, for the breast cancers that fail to respond, or become resistant, to current endocrine treatments, the long-term outlook is poor. ER is a member of the nuclear receptor superfamily, comprising 48 members in the human, many of which are expressed in the breast and could be used as alternative targets in cases where current treatments are ineffective. METHODS: We used sparse canonical correlation analysis to interrogate potential novel nuclear receptor expression relationships in normal breast and breast cancer. These were further explored using whole transcriptome profiling in breast cancer cells after combinations of ligand treatments. RESULTS: Using this approach, we discovered a tumour suppressive relationship between the mineralocorticoid receptor (MR) and retinoic acid receptors (RAR), in particular RARß. Expression profiling of MR expressing breast cancer cells revealed that mineralocorticoid and retinoid co-treatment activated an expression program consistent with a reverse Warburg effect and growth inhibition, which was not observed with either ligand alone. Moreover, high expression of both MR and RARB was associated with improved breast cancer-specific survival. CONCLUSION: Our study reveals a previously unknown relationship between MR and RAR in the breast, which is dependent on menopausal state and altered in malignancy. This finding identifies potential new targets for the treatment of breast cancers that are refractory to existing therapeutic options.

Primary Aldosteronism: Where Are We Now? Where to from Here?

The past nine years have seen major advances in establishing the etiology of unilateral primary aldosteronism, and very possibly that of bilateral hyperaldosteronism, in response to somatic mutations in aldosterone synthase expressing cells. Though there have been important advances in the management of primary aldosteronism, in small but convincing studies, they represent minor changes to current guidelines. What has been totally absent is consideration of the public health issue that primary aldosterone represents, and the public policy issues that would be involved in addressing the disorder. In his introduction to PiPA 6, Martin Reincke calculated that only one in a thousand patients in Germany with primary aldosteronism were treated appropriately, an astounding figure for any disease in the 21st century. Towards remedying this totally unacceptable public health issue, the author proposes a radical simplification and streamlining of screening for primary aldosteronism, and the management of most patients by general practitioners. The second bottle-neck in current management is that of mandatory adrenal venous sampling for all but 1-2% of patients, a costly procedure requiring rare expertise. Ideally, it should be reserved - on the basis of likelihood, enhanced imaging, or peripheral steroid profiles - for a small minority of patients with clear evidence for unilateral disease. Only when costs are minimized and roadblocks removed will primary aldosteronism be properly treated as the public health issue that it is.

Primary aldosteronism: Treatment of the disease, and new therapeutic approaches.

Primary aldosteronism is currently considered to represent 5-13% of hypertension, yet fewer than 1% of patients with the disorder are ever diagnosed and treated. Current management of patients screened and confirmed positive for primary aldosteronism involves imaging, and with very few exceptions adrenal venous sampling to lateralize (or not) hyperaldosteronism. Unilateral disease is treated by adrenalectomy: bilateral disease by mineralocorticoid receptor antagonists and conventional antihypertensives as/if required. New therapeutic approaches include (i) routine screening on first presentation for hypertension; (ii) harmonisation of cut-offs for renin and aldosterone, plus use of 24-h urinary rather than spot plasma values for the latter; (iii) adoption of a dexamethasone enhanced seated saline suppression test for confirmation exclusion; (iv) enhanced imaging and steroid profiles as partial replacement for adrenal venous sampling; and finally (v), inclusion of low dose spironolactone in first-line therapy for hypertension.

Aldosterone Research: 65 Years, and Counting.

Aldosterone was characterized as the major mineralocorticoid hormone 65 years ago, and since then its physiologic role in epidural electrolyte homeostasis the province of nephrologists. In epithelia it acts via the mineralocorticoid receptor (MR) to retain Na+ and excrete K+; MRs, however, are widely expressed in organs not known to be aldosterone target tissues. MRs are not merely "aldosterone receptors," as they have equivalently high affinity for the physiologic glucocorticoids, and for progesterone. In epithelia (plus in the blood vessel wall and in the nucleus tractus solitarius of the brain) MRs are "protected" by coexpression of the enzyme 11ß-hydroxysteroid dehydrogenase. This enzyme converts cortisol-which circulates at much higher concentrations than aldosterone-to receptor-inactive cortisone, thus allowing aldosterone selectively to activate "protected" MR. In tissues which do not express 11ß-hydroxysteroid dehydrogenase, the default MR ligand is cortisol, which circulates at ≥100-fold higher plasma free concentrations than aldosterone. In such tissues there is as yet scant evidence for the physiologic role of cortisol-occupied MR: over the past decade, however, it has become clear that in damaged tissues cortisol can act as an MR-agonist, mimicking the effects seen with aldosterone under experimental conditions, in vitro and in vivo. Many pathophysiologic roles have been attributed to aldosterone: on the current evidence there are none outside its long established epithelial actions, those on the blood vessel wall and on the nucleus tractus solitarius.

Primary Aldosteronism: Present and Future.

Primary aldosteronism (PA), currently recognized to be 5-10% of hypertension, has a cardiovascular risk profile double that in age-, sex-, and blood pressure-matched essential hypertensives. Screening for PA is by determining the plasma aldosterone to renin ratio (ARR), followed by one of half a dozen confirmatory/exclusion tests. Unilateral hyperaldosteronism normally reflects an aldosterone producing adenoma; bilateral disease is the more common form, and termed idiopathic hyperaldosteronism (IHA). Subjects confirmed undergo imaging, followed by adrenal venous sampling (AVS) for lateralization. Unilateral lesions undergo laparoscopic adrenalectomy, to normalize aldosterone levels, and in approximately half reduction of BP/antihypertensive use. Bilateral hyperaldosteronism is treated by low dose mineralocorticoid receptor antagonists MRAs, plus amiloride/conventional antihypertensives, if/as indicated.In the future, what is needed is recognition that inappropriate aldosterone levels for sodium status (i.e., PA) represents up to 50% of "essential" hypertensives; all hypertensive should thus be screened by a modified ARR, using 24-h urinary aldosterone rather than a single plasma aldosterone. The current reluctance to do so reflects the costs of AVS if PA is confirmed-optimally by a standard seated saline suppression test-followed by surgery or life-long MRAs. Increasingly AVS will be replaced by plasma steroid assays capable of discriminating APA from the far more common IAH. Third generation MRAs (as selective as eplerenone, as potent as spironolactone, non-steroidal) are in development; in the interim, to minimize side effects and maximize compliance, spironolactone dosage should be set at 12.5-25 mg/day.