Targeted Molecular Characterization of Aldosterone-Producing Adenomas in White Americans

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.

Section: Overview Of Primary Aldosteronism (Pa)mentioning

confidence: 99%

Section: Overview Of Primary Aldosteronism (Pa)mentioning

confidence: 99%

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

Lim

Rainey

2020

“…Early studies of adenomas recognized by H & E staining found that 50-70 % of patients exhibited one of these mutations and that the relative incidence the types of mutations differed in patients of European or East Asian origin [44]. Recent studies using CYP11B2 immunohistochemistry to select areas for mutation analysis demonstrate that about 90 % of aldosterone-producing adenomas have a known aldosterone-driving mutation and confirm that the incidence of the various types of mutations differ between races and sexes [45,46]. However, the functional significance of all the new mutations have not been studied and is likely that some do not result in gain-of-function [47].…”

Section: Adrenal Immunohistochemistry In Primary Aldosteronismmentioning

confidence: 95%

Immunohistochemistry of the Human Adrenal CYP11B2 in Normal Individuals and in Patients with Primary Aldosteronism

Gómez-Sánchez

Nishimoto

2020

The CYP11B2 enzyme is the terminal enzyme in the biosynthesis of aldosterone. Immunohistochemistry using antibodies against CYP11B2 defines cells of the adrenal ZG that synthesize aldosterone. CYP11B2 expression is normally stimulated by angiotensin II, but becomes autonomous in primary hyperaldosteronism, in most cases driven by recently discovered somatic mutations of ion channels or pumps. Cells expressing CYP11B2 in young normal humans form a continuous band beneath the adrenal capsule; in older individuals they form discrete clusters, aldosterone-producing cell clusters (APCC), surrounded by non-aldosterone producing cells in the outer layer of the adrenal gland. Aldosterone-producing adenomas may exhibit a uniform or heterogeneous expression of CYP11B2. APCC frequently persist in the adrenal with an aldosterone-producing adenoma suggesting autonomous CYP11B2 expression in these cells as well. This was confirmed by finding known mutations that drive aldosterone production in adenomas in the APCC of clinically normal people. Unilateral aldosteronism may also be due to multiple CYP11B2-expressing nodules of various sizes or a continuous band of hyperplastic ZG cells expressing CYP11B2. Use of CYP11B2 antibodies to identify areas for sequencing has greatly facilitated the detection of aldosterone-driving mutations.

“…In men, CACNA1D is the most common mutation; in women, as noted earlier, it is KCNJ5. Patterns between Caucasian [19] and African-Americans [20] differ significantly: whether Africans from the West Coast of Africa, with putatively considerably less Caucasian genetic material, are even more different is to date moot. Some mutations are extremely rare: it thus seems likely that over the course of the next few years additional somatic mutations will be added to the present tally of 93-94 %: 'wild type' is perhaps better expressed as 'not yet identified'.…”

Section: Yet To Be Explained Variationmentioning

confidence: 98%

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

Funder

2020

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.