The Potential Role of Aldosterone-Producing Cell Clusters in Adrenal Disease

Abstract

Primary aldosteronism (PA) is the most common cause of secondary hypertension. The hallmark of PA is adrenal production of aldosterone under suppressed renin conditions. PA subtypes include adrenal unilateral and bilateral hyperaldosteronism. Considerable progress has been made in defining the role for somatic gene mutations in aldosterone-producing adenomas (APA) as the primary cause of unilateral PA. This includes the use of next-generation sequencing (NGS) to define recurrent somatic mutations in APA that disrupt calcium signaling, increase aldosterone synthase (CYP11B2) expression, and aldosterone production. The use of CYP11B2 immunohistochemistry on adrenal glands from normal subjects, patients with unilateral and bilateral PA has allowed the identification of CYP11B2-positive cell foci, termed aldosterone-producing cell clusters (APCC). APCC lie beneath the adrenal capsule and like APA, many APCC harbor somatic gene mutations known to increase aldosterone production. These findings suggest that APCC may play a role in pathologic progression of PA. Herein, we provide an update on recent research directed at characterizing APCC and also discuss the unanswered questions related to the role of APCC in PA.

Functional Characteristic and Significance of Aldosterone-Producing Cell Clusters in Primary Aldosteronism and Age-Related Hypertension

“…Similarly, a recent study using tandem mass spectrometry imaging verified Suguira et al’s findings in normal adrenals as elevated levels of aldosterone and 18-oxocortisol were found in APCC’s relative to the adjacent adrenal tissue in an adrenal obtained from a patient that had undergone radical nephrectomy for renal cell carcinoma ( 51 ). These studies support the steroidogenic activity of APCCs in producing aldosterone in normal adrenals as well as under suppressed renin conditions, as shown in PA patients’ adrenals ( 44 ). Accordingly, APCCs has been proposed to be the transitioning step to APAs ( 50 ).…”

“…IHC analysis has shown that compared to ZF cells that are generally negative for CYP11B2 and unrelated to aldosterone production, ZF-like looking cells of APCCs in the ZF has high levels of CYP11B2 and low levels of CYP11B1 or CYP17A1, both enzymes being involved in cortisol production ( 33 , 35 , 37 , 38 ). However, according to Lim & Rainey ( 44 ), APCCs may manifest various patterns of enzyme expression with some exhibiting homogeneous expression of CYP11B2 while others exhibit polarity with a declining expression of CYP11B2 aligned with the development of CYP17A1 expression. This pattern of expression indicates that some APCCs cells may go through a transition to a more ZF-like phenotype, at least partially ( 44 ), thus making CYP11B1 and CYP17A1 IHC useful to characterize APCCs ( 33 , 35 ).…”

“…However, according to Lim & Rainey ( 44 ), APCCs may manifest various patterns of enzyme expression with some exhibiting homogeneous expression of CYP11B2 while others exhibit polarity with a declining expression of CYP11B2 aligned with the development of CYP17A1 expression. This pattern of expression indicates that some APCCs cells may go through a transition to a more ZF-like phenotype, at least partially ( 44 ), thus making CYP11B1 and CYP17A1 IHC useful to characterize APCCs ( 33 , 35 ). Another published method to detect APCCs is in situ hybridization of CYP11B2.…”

“…This is as with age, there is a loss of the classical subcapsular CYP11B2-positive ZG due to the effects of trophic hormones that lead to the decline in total aldosterone production. Thus within this background of decreased ZG CYP11B2 expression, the number of CYP11B2-positive APCCs grows ( 34 , 44 ). Finally, the expansion of the mutation bearing APCCs leads to the generation of an aldosterone-producing adrenal lesion.…”

Progress in Primary Aldosteronism 2019: New Players on the Block?

“…In an original publication, Handgriff et al analyze the association between glucocorticoid co-secretion, assessed by the 1 mg dexamethasone suppression test, on the prevalence and the time course of thyroid antibodies in PA [13]. In a series of pathophysiologic manuscripts, the role of mast cells [14], expression of aldosterone synthase in adrenalectomy samples [15], the role of aldosterone producing cell clusters [16], and the methodologic advances obtained by tissue mass spectrometry imaging [17] are analyzed. Finally, the study of Gao et al [18] gives a comprehensive overview on calcium metabolism in PA, followed by an in-depth study on clinical determinants of surgical success by Naruse et al [19].…”