Progress in Primary Aldosteronism

In July 2009, the international symposium “Progress in Primary Aldosteronism” was held in the beautiful surroundings of the Carl Friedrich von Siemens Foundation in the vicinity of Nymphenburg Palace in Munich, Germany.

Primary aldosteronism has been a topical issue since the discovery that it represents the most frequent secondary cause of hypertension worldwide. Depending on screening methods, assay procedures, and pretest likelihood of aldosteronism, the estimates range from 4.5–13 % of subjects in hypertensive cohorts at tertiary hospitals. Primary aldosteronism is even more likely to be found in patients with resistant hypertension and patients with hypokalemic hypertension. Although there has been significant progress in understanding the pathophysiology of primary aldosteronism, the accuracy of diagnostic tests, and the outcome of various therapeutic measures, there are still many areas of uncertainty. This is also highlighted by the recently published Endocrine Society practice guidelines for the diagnosis and treatment of primary aldosteronism [1]. Comparison with another secondary cause of hypertension, pheochromocytoma, is striking in this context ([Table 1]). Whereas pheochromocytoma can nowadays easily be diagnosed by measuring the highly sensitive and specific plasma metanephrines, the sensitivity and specificity of the aldosterone to renin ratio is far from sufficient for definite diagnosis of primary aldosteronism. The same holds true for imaging procedures: computed tomography and magnet resonance imaging, in combination with functional radionucleotide imaging procedures, provides almost 100 % accuracy for localizing pheochromocytoma. In contrast, the differential diagnosis between idiopathic bilateral hyperplasia and aldosterone-producing adenomas in primary aldosteronism is challenging. Currently, imaging by CT and MRI does not sufficiently distinguish between these two entities. Selective adrenal venous sampling, the so called gold standard for differential diagnosis, is not available for technical reason in many centers, leaving the distinction of unilateral from bilateral disease obscure in many cases. The genetic basis of familial pheochromocytoma has been elucidated over the last 15 years; the genetic basis of most cases of primary aldosteronism is still a hidden “Schatz der Nibelungen” – a treasure – waiting to be discovered. However, it can be expected that some of the above-mentioned problems in the care of patients with primary aldosteronism will be solved within the next few years. The generous support of the German Research Society (DFG) and the Carl Friedrich von Siemens Foundation made it possible to gather most of the internationally renowned researchers in this field, who presented their data on progress in their respective areas of expertise and discussed the mysteries which remain to be solved. Bright sunshine, midsummer temperatures, and the amenities of the venue all contributed to the symposium’s success.

Table 1 Characteristics of pheochromocytoma and primary aldosteronism.

	Pheochromocytoma	Primary aldosteronism
Sensitivity/specificity of screening test1	~95 %/~95 %	~70–80 %/~70–90 %
Sensitivity/specificity of CT and/or MRI for localization of ­functional tumors	85–95 %/~90 %	~50–60 %/~50 %
Prevalence of genetic syndromes as predisposing factor	~25–30 %	< 1 %
Rate of blood pressure normalization following unilateral adrenalectomy	> 80 %	~30–50 %

¹Plasma metanephrines in pheochromocytoma and aldosterone to renin ratio in primary aldosteronism

This volume includes a selected number of invited articles which summarize the presentations given at the symposium. They cover a wide range of questions, starting with basic research and ending in clinical management of primary aldo­steronism. Some authors have also been asked to review the state of the art of their respective areas of expertise.

A special feature of the symposium was the four predefined wrap-up sessions between thematic blocks, which allowed extensive discussions of critical issues of primary aldosteronism. The article by Gomez-Sanchez et al. nicely summarizes some of those issues raised during the course of the symposium [2]. As the authors point out, the pathophysiology of aldosterone excess in PA is still ill-defined. Only a very low percentage of cases seem to be caused by one of the three familial syndromes of aldosterone excess [3].

Animal and human data related to autonomy of aldosterone production in PA are consistent with the hypothesis that one or several unidentified stimuli can drive aldosterone overproduction and the expansion of an aldosterone-producing cell phenotype. This would explain the histopathologic findings in unilateral aldosterone excess, namely the multinodular appearance of the resected adrenals [2]. The situation is reminiscent of the toxic multinodular goiter of patients with long term multinodular goiters, which develop adenomas that produce thyroid hormone autonomously due to activating mutations of the TSH receptor or G-protein alpha-subunit. Recent studies summarized in the review by Mazzuco et al. identified overexpression or malfunctioning of several G-protein coupled receptors as a potential cause for excess aldosterone production in APA and in bilateral idiopathic hyperaldosteronism [4]. These receptors have been shown to be expressed in aldosterone-producing adrenal tumors in vitro and to regulate aberrantly renin-independent aldosterone secretion in vivo. The identification of aberrant adrenal G-protein coupled receptors offers the potential for novel pharmacological therapies to suppress the endogenous ligands or block the receptor with specific antagonists. As potassium channels control the membrane voltage of aldosterone-producing zona glomerulosa cells, they are responsible for the unique potassium sensitivity of these cells. The potassium channels TASK1 and TASK3 are strongly expressed in the adrenal cortex. Disruption of the TASK1 gene in mice results in an autonomous aldosterone production and causes a remarkable aberrant expression of aldosterone synthase in zona fasciculata cells that normally produce glucocorticoids [5]. These genetically modified mice are interesting models to study mechanisms of auto­nomous aldosterone production and suggest that modifications of the adrenocortical potassium conductances could contribute to autonomic aldosterone production and primary hyperaldo­steronism. Other mouse models with defined genetic modification are currently developed by several groups using different approaches and are expected to prove functional relevance of predefined candidate genes in the future [6]. These animal models can also be used to investigate cardiovascular and metabolic consequences of unopposed aldosterone secretion and potential restoration of these parameters through pharmacologic interventions.

The article by Tomaschitz and Pilz [7] covers the current data related to the renin to aldosterone ratio as a screening test for primary aldosteronism. This test is clearly far away from being a ‘100 % test’, as sensitivity and specificity ranges from 70 to 90 %, respectively. Appropriate definition of those subjects at risk for primary aldosteronism is essential as the pretest probability of PA influences negative and positive predictive value of an elevated aldosterone to renin ratio. Special attention has to be given to the laboratory methods, the influence of the medication and the impact of dietary salt intake during the procedure, as these factors influence test results dramatically. It is possible that currently used cut-off levels of the aldosterone to renin ratio in clinical care are too high. In the first large population based study reported so far by Hannemann et al. [8], the upper reference limit for the aldosterone to renin ratio was 14.2 and 20.3 (ng/l//ng/l) in young men and women, and 22.4 and 25.5 in old men and women, respectively, much lower than the conventionally reported cutoff of 25 or even 30 (ng/l//ng/l). These data emphasize the need to take the influence of age and gender into account when interpreting screening results in primary aldo­steronism. Considering the inherent difficulties of the aldosterone to renin ratio new diagnostic tests would be desirable, especially to identify subjects with surgically amendable forms of primary aldosteronism. Manolopoulou et al. [9] report on the development of a sensitive salivary aldosterone test, which shows some promise as a screening tool: sensitivity and specificity of salivary aldosterone in the morning was 77 and 82 % for PA versus essential hypertensives, superior to plasma aldosterone (78 % and 60 %). This test can also be used to study the diurnal rhythm of aldosterone secretion: patients with surgically confirmed aldosterone producing adenoma usually showed a strong decline of aldosterone in samples from morning to late night, which was not seen in patients with bilateral idiopathic hyperplasia.

Confirmatory testing following an abnormal screening test is currently recommended by most authors in order to definitively confirm or exclude the diagnosis of primary aldosteronism. Since low-renin hypertension comprises up to 30 % of hypertensive patients, a considerable number of hypertensive patients would otherwise inappropriately undergo costly and potentially harmful procedures without a definitive diagnosis. Four tests are currently used, but there is no consensus which of the tests may be considered the gold standard. These tests may differ in terms of sensitivity, specificity, and reliability. The choice of confirmatory test is commonly determined by considerations of cost, patient compliance, laboratory routine, and local expertise, as summarized beautifully in the manuscript by Mulatero et al. [10].

Most adrenal adenomas detected by adrenal imaging are nonfunctional. Therefore, functional adrenal tumors cannot be identified using imaging criteria alone. In addition, some aldosterone producing adenomas are too small to be detected by even the most sensitive CT and MRI techniques. Adrenal vein sampling has emerged as the only reliable method to determine the source of aldosterone excess. However, the methodology and criteria for lateralization have been determined empirically with little prospective data. Different centers use various protocols and strategies to perform adrenal vein sampling. The review article by Auchus et al. [11] summarizes some of the advances in the execution of this procedure, the variations in procedure, and the issues that need to be resolved in the future.

Several studies have shown that patients with PA have more cardiovascular events than age-, sex-, and blood pressure-matched

patients with essential hypertension [12]. Cross-sectional comparisons with patients with essential hypertension have demonstrated that patients with PA are at higher risk of cardiovascular events, have more frequent left ventricular hypertrophy and diastolic dysfunction, have greater urinary albumin losses as a marker of a hemodynamic intrarenal adaptation, and are insulin resistant. Blood pressure independent end-organ damage is attributed to direct proinflammatory effects of aldosterone in a high sodium environment. Another important finding is that aldosterone may induce DNA damage by increased oxidative stress as reported in the manuscript by Schupp et al. in this issue [13].

Early detection of primary aldosteronism has the potential to prevent cardiovascular complications if treated appropriately. Unilateral adrenalectomy or treatment with mineralocorticoid receptor antagonists is effective in correcting hypertension and hypokalemia. Normalization of blood pressure and correction of hypokalemia are not the only goals in treating PA. Effective prevention of organ damage has become a more recent focus of research in these patients [14]. The long-term efficacy of adrenalectomy and MR antagonists on the cardiovascular, renal, and metabolic outcomes reported in small patient series seems to justify the increased costs for screening and diagnosing of PA, but require confirmation in larger cohorts.

Another finding in PA is the observation that aldosterone excess is associated with impaired glucose homeostasis. In a case-control study published in this issue, Reincke et al. demonstrates that diabetes mellitus is more prevalent in patients with PA than in hypertensives matched for age, sex, and blood pressure level [15]. This finding is intriguing since recent population based studies support the notion that high plasma aldosterone concentrations are associated with the metabolic syndrome. This observation may form the basis of a bi-directional causal relation: On the one hand factors secreted by the adipose tissue can stimulate aldosterone release from the zona glomerulosa constituting a novel mechanism of obesity-mediated hypertension [16]. On the other hand high aldosterone levels may directly impair pancreatic beta cell function and insulin sensitivity. Therefore, targeting inappropriate aldosterone secretion may also provide novel therapeutic strategies for the metabolic syndrome.

Management of primary aldosteronism is work-in-progress, and advances may come directly from the clinic or from basic studies. Published earlier in 2010, well after our symposium was held, was a paper by Doi et al. on salt-sensitive hypertension in circadian clock-deficient Cry-null mice [17]. In a beautiful study, these authors reported that in contrast to wild-type mice, those with deletion of the genes coding for Cryptochrome-1 and Cryptochrome-2 show very high levels of plasma aldosterone, reflecting derepression of adrenal Hsd3b6. This enzyme is expressed only in the glomerulosa, as is its human homologue HSD3B, and is normally repressed by the clock gene products. The implications for our understanding of rate limiting steps in aldosterone biosynthesis, and for primary aldosteronism, the metabolic syndrome, and sleep apnoea, remain to be explored.

We as guest editors hope that this special issue will provide the reader with information useful not only for solving problems in clinical care, but also as a touchstone for future research in primary aldosteronism.

• References

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