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ERC Advanced Grant Pathophysiology of Primary Aldosteronism (PAPA) 2017 - 2022

Arbeitsgruppe Prof. Dr. med. Martin Reincke


Primary aldosteronism (PA) was regarded for many years as a quantitative negligible cause of arterial hypertension, however, nowadays it is widely recognised as the most frequent endocrine cause of secondary arterial hypertension [1-3]. The two principle causes of sporadic PA are either an aldosterone producing adenoma (APA), which is treated by unilateral adrenalectomy, or the more common idiopathic adrenal hyperplasia (IAH), which is treated by life-long administration of mineralocorticoid receptor (MR) antagonists [4, 5]. Besides these sporadic forms, 1-5% of cases of PA are inherited familial forms named familial hyperaldosteronism (FH) types I, II or III [6, 7].

Patient based registries and biobanks, international networks and next generation sequencing technologies have emerged over the last years. The current review provides an overview of the most recent developments in the rapidly changing field of PA research: it will address the pathophysiological mechanisms causing PA and subtype differentiation by adrenal vein sampling (AVS).

Genetics of primary aldosteronism

Starting in 2011, the ground-breaking work of Choi et al. initiated immense efforts in elucidating the genetic causes of PA [8]. Next-generation sequencing methods identified somatic hot-spot mutations (initially the 2 variants Gly151Arg and Leu168Arg) in and near the selectivity filter of the potassium channel GIRK4 (encoded by KCNJ5) in 34-36% of Caucasian APA patients [9]. The mutations lead to a loss of channel selectivity and result in membrane depolarization and an increase in intracellular calcium concentration. This in turn causes an increase in aldosterone synthase (CYP11B2) expression and the production of aldosterone [8, 10, 11]. Mutations in genes encoding ATPases were subsequently identified (Na+/K+-ATPase 1 encoded by ATP1A1 and Ca2+-ATPase 3 encoded by ATP2B3) as well as gain of function mutations in a subunit of an L-type voltage-gated Ca2+-channel, Cav1.3 (encoded by CACNA1D), that lead to channel activation at less depolarized potentials [12]. Autonomous aldosterone production may be explained in 54% of all APAs, as demonstrated recently in a large European cohort of 474 APAs from the European Network for the Study of Adrenal Tumors (ENS@T) [13-17]. As described previously, the mutation status was associated to clinical correlates: patients with KCNJ5 mutations were more frequently female, younger and displayed a higher minimal plasma potassium concentration. Again, the variability in clinical characteristics across centers reflected different diagnostic procedures and ethnic backgrounds. Interestingly, KCNJ5 mutations are reported to be more common in patients of Asian heritage with a prevalence of 73% in East Asia compared to 39% in Western populations [18-20]. To overcome a potential selection bias in case series, the group of G.P. Rossi performed a meta-analysis of 13 studies on somatic KCNJ5 mutations in 1636 patients with APA [21]. The study revealed that KCNJ5 mutations were associated with more pronounced hyperaldosteronism, younger age, female gender, and larger tumors, while no significant association with blood pressure and serum potassium was found.

Compared to the sporadic forms, familial forms of PA only affect a small proportion of patients. The cause of FH I or glucocorticoid-remediable aldosteronism was elucidated in 1992, approximately 25 years after its first description by Sutherland et al. [22, 23]. It consists of a hybrid gene resulting from an unequal crossing-over between CYP11B1 (that encodes 11-hydroxylase) and CYP11B2 (that encodes aldosterone synthase) that both map to chromosome 8q24. The hybrid gene comprises 5’ sequences, including the adrenocorticotropic hormone (ACTH) responsive promoter region of CYP11B1 and 3’ sequences of CYP11B2. This results in the expression of the hybrid CYP11B1/B2 gene in the zona fasciculata and hyperaldosteronism [24]. FH I is inherited as an autosomal dominant disorder, affects 0.5 to 1% of PA patients and is distributed equally between male and female patients [25-27]. It is a heterogeneous disease with a wide range of clinical and biochemical characteristics, even within the same family [28]; usually, patients suffer from severe hypertension and from a high morbidity and mortality (risk of haemorrhagic stroke) at young age. Screening should be performed in patients < 20 years or in patients with a family history of hypertension and cerebral haemorrhage < 40 years [29-31]. Significant production of the steroids 18-hydroxycortisol (18OHF) and 18-oxocortisol (18oxoF) occurs. Adrenal imaging reveals bilateral hyperplasia in most cases [22, 32]. The diagnosis of FH I is usually confirmed by a long range polymerase chain reaction-based assay [33]. In FH I, because aldosterone production is regulated by ACTH rather than by the renin-angiotensin-aldosterone-system (RAAS), treatment is performed with low doses of dexamethasone, eventually in combination with MR antagonists in cases with insufficient blood pressure control [4, 34].

FH II, a form of non-glucocorticoid-remediable FH without chimeric CYP11B1/B2 gene, was first described in 1991 [35]. The genetic cause of FH II is still unknown, but an association with the chromosomal locus 7p22 has been described in some families [36-38]. The mode of inheritance is autosomal dominant [6, 34, 39]. FH II affects 1.2 to 6% of PA patients [6, 25, 40, 41]. The disease displays a wide clinical range with different subtypes (APA and IAH) even within the same family [6, 25, 42]. As it is clinically and biochemically indistinguishable from sporadic PA, diagnosis is based on the occurrence of PA in two or more first-degree members of the same family [4, 25].

Following the initial identification of the somatic mutations in APA, novel high-throughput genetic techniques have only recently led to the discovery of new germline mutations. FH III was first described in 2008 in a father and two daughters with severe, hypokalemic juvenile hypertension [43]. Non-glucocorticoid-remediable hyperaldosteronism was accompanied by high levels of 18OHF and 18oxoF. Bilateral adrenalectomy showed massive bilateral adrenal hyperplasia. Recently, FH III was shown to be caused by heterozygous gain-of-function mutation in GIRK4 (encoded by KCNJ5): the index family was affected by a Thr158Ala-mutation [8]. Four other families were identified by Scholl et al., of whom 2 families had a severe disease course similar to the index family; they were found to have a germline Gly151Arg mutation, identical to a somatic APA mutation identified previously [44]. In the two other families with a milder form of PA, a new germline Gly151Glu mutation was detected. The same mutation was found in a family studied as part of the European FH II consortium consisting of 21 European families [45]. In vitro, transfected cells showed an increased Na+-conductance that led to subsequent cell death. Another mutation (Ile157Ser) was identified in a mother and her daughter with severe PA, massive adrenal hyperplasia and refractory juvenile hypertension [46]. Different germline KCNJ5 mutations with autosomal dominant syndromes and variable clinical presentations and severity have been described in families with FH III [47, 48].

A new Mendelian syndrome consisting of PA, seizures, and neuromuscular disease was described in 2 cases as being caused by de novo germline CACNA1D mutations [17]. Using exome sequencing, the same group recently identified 5 independent occurrences of the identical germline gain of function mutation in CACNA1H among 40 patients with juvenile PA and without any additional shared symptoms, representing a new familial form of PA. This mutation was not previously described in APA. CACNA1H encodes the voltage-gated calcium channel Ca2+-channel Cav3.2 [49]. The mutation induces reduced channel inactivation and activation at more hyperpolarized potentials with an increase of intracellular calcium levels, triggering aldosterone production.

Aldosterone producing cell clusters (APCCs) with high expression of CYP11B2 have been identified by immunohistochemistry in normal adrenals and in adrenal tissue adjacent to APA, the latter under conditions characterized by a suppressed RAAS [50]. Higher APCC scores were identified in adrenals from women. These “nests” of cells are located under the adrenal capsule and protrude into cortisol-producing cells negative for CYP11B2, therefore differing from the conventional zonation. This led to the observation that aldosterone production may be constitutive in APCCs of the variegated zonation and inducible in the zona glomerulosa (ZG) of the conventional zonation. A recent study with microarray analysis demonstrated that APCCs display a transcriptome phenotype similar to the adjacent ZG but with an enhanced capacity to produce aldosterone [51]. Targeted next generation sequencing further revealed that APCCs harbor APA-related somatic mutations (CACNA1D and ATP1A1) resulting in renin-independent hyperaldosteronism. The spectrum of the mutations in APCCs was different than in APA; no KCNJ5 mutation was found in the APCCs. The authors concluded that APCCs arise from ZG cells as a consequence of somatic mutations and might represent a precursor of APA.

Autoimmune triggers in primary aldosteronism

Autoantibodies against the G protein-coupled angiotensin II Type 1 receptor (AT1-AA) have earlier been associated with conditions such as preeclampsia, renal-allograft rejection and hypertension [52-54]. Recently, AT1-AA were identified in patients with APA but not in patients with IAH with an ELISA-based essay [55]. In a study with cell-based functional assays, Kem et al. examined the potential of these autoantibodies to contribute to the pathophysiology of hyperaldosteronism and hypertension in PA [56]. The authors showed that the AT1-AA isolated from 13 patients with PA display losartan- and candesartan-sensitive AT1-receptor (AT1R) activation. In addition, the AT1-AA led to small resistance artery contraction and to a stimulation of aldosterone production in an adrenocortical carcinoma cell line (HAC15) in vitro. The latter was blocked by candesartan and enhanced in the presence of angiotensin II (AT2), suggesting that the AT1-AA may alter the allosteric configuration of the AT1R and facilitate AT2 binding. The authors postulated that the presence of these autoantibodies might be in part responsible for the persistence of hypertension in 50% of all APA after adrenalectomy (Figure 1). 

Interestingly, in contrast to the original study, a follow-up study by the same group in a larger cohort of PA patients showed a higher prevalence of AT1-AA in IAH compared to APA (75% versus 46%) [55, 57]. The activity of sera containing the AT1-AA was suppressible by AT1R blockade in vitro. The discrepancy between the studies might be caused by methodological differences and deserves further investigation in large cohorts. As discussed earlier, the chronic stimulation of the ZG by AT1-AA with a higher predisposition to somatic mutations might possibly elucidate the development of IAH and APA [58] (see Figure 2). 

Figure 1: AT1R activation by autoantibodies (from 27)
Figure 2: Hypothetical pathophysiologic model of the two ‘hit’ theory: agonistic AT1R autoantibodies and somatic driver mutations cause nodular remodelling of the adrenal cortex.

Objectives of the ERC-Advanced grant PAPA

The 5 objectives are:

  • Objective 1: defining the role of agonistic AT1R autoantibodies as pathophysiologic factor in plasma of patients with PA
  • Objective 2: studying the impact of AT1R autoantibodies on steroid excess and adrenal proliferation in adrenocortical cell lines with defined PA somatic driver mutations
  • Objective 3: analyzing the impact of AT1R autoantibodies on adrenal cortex growth and remodeling in mechanistic studies using genetically defined rodent models
  • Objective 4: analyzing the mineralocorticoid and glucocorticoid excess production using liquid chromatography / mass spectrometry to define the impact of agonistic AT1R autoantibodies and somatic driver mutations
  • Objective 5: developing a pathophysiology-based and targeted disease concept for the most prevalent form of secondary hypertension


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Further readings

Williams, T.A., et al., Genotype-Specific Steroid Profiles Associated With Aldosterone-Producing Adenomas. Hypertension, 2016. 67(1): p. 139-45.

Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension.
Beuschlein F, Boulkroun S, Osswald A, Wieland T, Nielsen HN, Lichtenauer UD, Penton D, Schack VR, Amar L, Fischer E, Walther A, Tauber P, Schwarzmayr T, Diener S, Graf E, Allolio B, Samson-Couterie B, Benecke A, Quinkler M, Fallo F, Plouin PF, Mantero F, Meitinger T, Mulatero P, Jeunemaitre X, Warth R, Vilsen B, Zennaro MC, Strom TM, Reincke M.
Nat Genet. 2013 Apr;45(4):440-4, 444e1-2. doi: 10.1038/ng.2550. Epub 2013 Feb 17.

The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline.
Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, Stowasser M, Young WF Jr.
J Clin Endocrinol Metab. 2016 May;101(5):1889-916. doi: 10.1210/jc.2015-4061. Epub 2016 Mar 2.PMID: 26934393