Adrenal Cortex Remodeling and Functional Zona Glomerulosa Hyperplasia in Primary Aldosteronism

Abstract

Abstract-Primary aldosteronism is the most common form of secondary hypertension with hypokalemia and suppressed renin-angiotensin system caused by autonomous aldosterone production. Our aim was to compare zona glomerulosa (ZG) structure and function between control adrenals and the peritumoral tissue from patients operated on for aldosterone-producing adenoma. ZG morphology and CYP11B1, CYP11B2, and disabled 2 expression were studied in 15 control adrenals and 25 adrenals with aldosterone-producing adenoma. A transcriptome analysis was done using publicly available data sets. In control adrenals, ZG was discontinuous, and CYP11B2 expression was focal or partly continuous and localized to 3 structures, foci, megafoci, and aldosterone-producing cell clusters. CYP11B2 expression was restricted to a limited number of ZG cells expressing Dab2 but not CYP11B1; aldosterone-producing cell clusters were composed of cells with an intermediate phenotype expressing CYP11B2 but not disabled 2 or CYP11B1. In peritumoral tissue, large remodeling of the adrenal cortex was observed with increased nodulation and decreased vascularization that were not correlated with CYP11B2 expression. In 17 out of 25 adrenals, hyperplasia of adjacent ZG was observed with persistent expression of CYP11B2 that was extended to the entire ZG. In all of the adrenals from patients with aldosterone-producing adenoma, CYP11B2 expression was present in foci, megafoci, and aldosteroneproducing cell clusters. Transcriptome profiling indicates a close relationship between peritumoral and control adrenal cortex. In conclusion, adrenal cortex remodeling, reduced vascularization, and ZG hyperplasia are major features of adrenals with aldosterone-producing adenoma. Transcriptional phenotyping is not in favor of this being an intermediate step toward the formation of aldosterone-producing adenoma. (Hypertension. 2010;56:885-892.)Key Words: zona glomerulosa hyperplasia Ⅲ aldosterone-producing adenoma Ⅲ secondary hypertension Ⅲ adrenal cortex remodeling Ⅲ aldosterone Ⅲ potassium Ⅲ transcriptome P rimary aldosteronism (PAL) is the most common form of endocrine hypertension with a prevalence of 7% to 10% of hypertensive patients. 1 In PAL, autonomous production of aldosterone is associated with suppressed renin activity, hypokalemia, and hypertension. The two principal forms are unilateral aldosterone-producing adenoma (APA), a benign tumor of the adrenal cortex, and bilateral adrenal hyperplasia, also known as idiopathic hyperaldosteronism. Whereas in APA the adjacent zona glomerulosa (ZG) is believed to be nonfunctional because of negative feedback regulation, bilateral adrenal hyperplasia involves the entire ZG of both adrenal glands. 2 Patients with PAL operated on the basis of an APA, and/or a lateralized aldosterone hypersecretion can be cured by unilateral adrenalectomy. However, only Ϸ70% of patients with lateralized aldosterone secretion are cured by surgery, 3 suggesting that, in some cases, residual aldosterone secretion from the contralateral adrenal g...

Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands

“…Of note, in addition to CYP11B2 (which we confirmed by qPCR), differentially expressed transcripts between APCC and ZG may have a role of APCC function. Interestingly, we did not see a decrease in DAB2 expression, which had previously been reported by Boulkroun et al (30). One possible explanation for this discrepancy is our differences in the definition of APCC.…”

“…Foci and megafoci expressed CYP11B2 and DAB2, whereas APCCs were defined as clusters that expressed CYP11B2 but not DAB2. It is likely that APCCs from our study would include some CYP11B2-expressing foci and megafoci based on the criteria by Boulkroun et al (30). With the detailed transcriptome analysis, we have identified additional potential protein markers for APCCs other than CYP11B2.…”

“…One possible explanation for this discrepancy is our differences in the definition of APCC. Boulkroun et al (30) had three categories for CYP11B2-expressing cell clusters that included foci, megafoci, and APCC. Foci and megafoci expressed CYP11B2 and DAB2, whereas APCCs were defined as clusters that expressed CYP11B2 but not DAB2.…”

MECHANISMS IN ENDOCRINOLOGY: Autocrine/paracrine regulatory mechanisms in adrenocortical neoplasms responsible for primary adrenal hypercorticism

“…In support of this hypothesis, it has been reported that CD34 immunoreactivity in Conn's adenoma is positively correlated with plasma aldosterone levels (74). By contrast, vascularization, which is reduced in peritumoral tissues of aldosterone-producing adenomas, is not correlated with expression of CYP11B2, the gene encoding aldosterone synthase, the key enzyme of aldosterone biosynthesis (76,77).…”

“…In addition, vasculature is disorganized in carcinomas with large vessels and irregular networks of microcapillaries (76), which could affect communication between endothelial and steroidogenic cells. In adenomas and macronodular hyperplasias, vascular architecture is equivalent to that of normal adrenal (76,77) and could allow endothelial cells to control the steroidogenic activity of tumor cells via a paracrine mechanism, as in normal tissue. In support of this hypothesis, it has been reported that CD34 immunoreactivity in Conn's adenoma is positively correlated with plasma aldosterone levels (74).…”