Histopathological Diagnosis of Primary Aldosteronism Using CYP11B2 Immunohistochemistry

Nanba, Kazutaka; Tsuiki, Mika; Sawai, Kuniko; Mukai, Kuniaki; Nishimoto, Katsutaro; Usui, Takeshi; Tagami, Tetsuya; Okuno, Hiroshi G.; Yamamoto, Tetsuro; Shimatsu, Akira; Katabami, Takuyuki; Okumura, Atsuko; Kawa, Gen; Tanabe, Akiyo; Naruse, Mitsuhide

doi:10.1210/jc.2012-3726

Cited by 102 publications

(109 citation statements)

References 25 publications

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“…More recently, generation of specific antibodies suitable for immunofluorescence has revealed that in APA a majority of cells express AS only, some cells express the 11b-and 17a-hydroxylases, but some cells are able to co-express the three enzymes . In 2013, two groups reported the use of specific antibodies against AS to improve the diagnosis of APA (Nanba et al 2013, Volpe et al 2013. However, similar to previous studies investigating CYP11B2 mRNA expression, in some APA AS is not detected.…”

Section: Familial Hyperaldosteronism Type IImentioning

confidence: 84%

“…However, similar to previous studies investigating CYP11B2 mRNA expression, in some APA AS is not detected. Semi-quantitative analysis revealed that AS expression was inversely correlated with tumor size and tumor volume, indicating that smaller tumors have higher AS expression per area and cell (Nanba et al 2013. These results may explain: i) why small APA below the detection limit of CT can result in clinical hyperaldosteronism and ii) why AS expression was not detectable in some large APA.…”

Section: Familial Hyperaldosteronism Type IImentioning

confidence: 95%

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An update on novel mechanisms of primary aldosteronism

Zennaro¹,

Boulkroun²,

Fernandes-Rosa³

2014

Journal of Endocrinology

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Primary aldosteronism (PA) is the most common and curable form of secondary hypertension. It is caused in the majority of cases by either unilateral aldosterone overproduction due to an aldosterone-producing adenoma (APA) or by bilateral adrenal hyperplasia. Recent advances in genome technology have allowed researchers to unravel part of the genetic abnormalities underlying the development of APA and familial hyperaldosteronism. Recurrent somatic mutations in genes coding for ion channels (KCNJ5 and CACNA1D) and ATPases (ATP1A1 and ATP2B3) regulating intracellular ionic homeostasis and cell membrane potential have been identified in APA. Similar germline mutations of KCNJ5 were identified in a severe familial form of PA, familial hyperaldosteronism type 3 (FH3), whereas de novo germline CACNA1D mutations were found in two cases of hyperaldosteronism associated with a complex neurological disorder. These results have allowed a pathophysiological model of APA development to be established. This model involves modifications in intracellular ionic homeostasis and membrane potential, accounting for w50% of all tumors, associated with specific gender differences and severity of PA. In this review, we describe the different genetic abnormalities associated with PA and discuss the mechanisms whereby they lead to increased aldosterone production and cell proliferation. We also address some of the foreseeable consequences that genetic knowledge may contribute to improve diagnosis and patient care.

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Section: Familial Hyperaldosteronism Type IImentioning

confidence: 84%

Section: Familial Hyperaldosteronism Type IImentioning

confidence: 95%

An update on novel mechanisms of primary aldosteronism

Zennaro¹,

Boulkroun²,

Fernandes-Rosa³

2014

Journal of Endocrinology

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“…Mechanisms responsible for such aldosterone gradient in the adrenal vein in non-PA patients remain to be elucidated. Whether aldosterone-producing cell clusters with CYP11B2 expression 26,27 has a pathological significance in the higher side of adrenal in these 8 patients requires further investigation. The aldosterone gradient in the gray zone (LI=2-4) should be carefully interpreted in the subtype diagnosis of PA to avoid inappropriate adrenalectomy.…”

Section: Discussionmentioning

confidence: 99%

Adrenal Venous Sampling in Patients With Positive Screening but Negative Confirmatory Testing for Primary Aldosteronism

et al. 2016

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Adrenal venous sampling is considered to be the most reliable diagnostic procedure to lateralize aldosterone excess in primary aldosteronism (PA). However, normative criteria have not been established partially because of a lack of data in non-PA hypertensive patients. The aim of the study was to investigate aldosterone concentration and its gradient in the adrenal vein of non-PA hypertensive patients. We retrospectively studied the results of cosyntropin-stimulated adrenal venous sampling in 40 hypertensive patients who showed positive screening testing but negative results in 2 confirmatory tests/captopril challenge test and saline infusion test. Plasma aldosterone concentration, aldosterone/cortisol ratio, its higher/lower ratio (lateralization index) in the adrenal vein with cosyntropin stimulation were measured. Median plasma aldosterone concentration in the adrenal vein was 25 819 pg/mL (range, 5154–69 920) in the higher side and 12 953 (range, 1866–36 190) pg/mL in the lower side ( P <0.001). There was a significant gradient in aldosterone/cortisol ratio between the higher and the lower sides (27.2 [5.4–66.0] versus 17.3 [4.0–59.0] pg/mL per μg/dL; P <0.001) with lateralization index ranging from 1.01 to 3.87. The aldosterone lateralization gradient was between 1 to 2 in 32 patients and 2 to 4 in 8 patients. None of the patients showed lateralization index ≥4. The present study demonstrated that plasma aldosterone concentration in the adrenal veins showed significant variation and lateralization gradient even in non-PA hypertensive patients. Adrenal venous sampling aldosterone lateralization gradients between 2 and 4 should be interpreted with caution in patients with PA because these gradients can be found even in patients with negative confirmatory testing for PA.

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“…These clusters or nests of cells, therefore, differ from the typical zonation seen in human and rodent adrenals [zona glomerulosa (ZG), ZF, and zona reticularis (ZR)]. Interestingly, APCCs are also frequently found in adrenal tissue adjacent to APA, despite the low circulating renin/angiotensin levels found in patients with APA, suggesting that APCC production of aldosterone is renin-independent (autonomous) (15)(16)(17). Although these studies suggest a role for APCCs in autonomous aldosterone production and potentially, PA, previous reports have been limited to immunohistochemical analysis.…”

mentioning

confidence: 96%

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

Nishimoto

Tomlins

Kuick

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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273

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Primary aldosteronism (PA) represents the most common cause of secondary hypertension, but little is known regarding its adrenal cellular origins. Recently, aldosterone-producing cell clusters (APCCs) with high expression of aldosterone synthase (CYP11B2) were found in both normal and PA adrenal tissue. PA-causing aldosteroneproducing adenomas (APAs) harbor mutations in genes encoding ion channels/pumps that alter intracellular calcium homeostasis and cause renin-independent aldosterone production through increased CYP11B2 expression. Herein, we hypothesized that APCCs have APArelated aldosterone-stimulating somatic gene mutations. APCCs were studied in 42 normal adrenals from kidney donors. To clarify APCC molecular characteristics, we used microarrays to compare the APCC transcriptome with conventional adrenocortical zones [zona glomerulosa (ZG), zona fasciculata, and zona reticularis]. The APCC transcriptome was most similar to ZG but with an enhanced capacity to produce aldosterone. To determine if APCCs harbored APA-related mutations, we performed targeted next generation sequencing of DNA from 23 APCCs and adjacent normal adrenal tissue isolated from both formalin-fixed, paraffin-embedded, and frozen tissues. Known aldosterone driver mutations were identified in 8 of 23 (35%) APCCs, including mutations in calcium channel, voltage-dependent, L-type, α1D-subunit (CACNA1D; 6 of 23 APCCs) and ATPase, Na + /K + transporting, α1-polypeptide (ATP1A1; 2 of 23 APCCs), which were not observed in the adjacent normal adrenal tissue. Overall, we show three major findings: (i) APCCs are common in normal adrenals, (ii) APCCs harbor somatic mutations known to cause excess aldosterone production, and (iii) the mutation spectrum of aldosteronedriving mutations is different in APCCs from that seen in APA. These results provide molecular support for APCC as a precursor of PA.primary aldosteronism | aldosterone | adrenal | somatic mutations | aldosterone-producing cell cluster P rimary aldosteronism (PA) accounts for 8% of hypertension and is the most common adrenal disease (1-4). PA patients can be classified into those with aldosterone-producing adenomas (APAs), idiopathic hyperaldosteronism, or familial hyperaldosteronism (FH), which is further divided into FH types 1-3 (FHI-FHIII) (5). In 1992, FHI was shown to result from a gene fusion of cytochrome P450, family 11, subfamily B, polypeptide 2 (CYP11B2: aldosterone synthase) and cytochrome P450, family 11, subfamily B, polypeptide 1 (CYP11B1; cortisol synthase) that resulted in zona fasciculata (ZF) expression of CYP11B2 and excess aldosterone production (6). For almost two decades after the original report, no other genetic abnormalities were identified in the other forms of PA.First reported in 2011, exome sequencing identified a series of germ-line and somatic mutations in genes that altered adrenal cell intracellular Ca 2+ in PA. The most common mutations are somatic mutations of the gene encoding the potassium inwardly rectifying channel, subfamily J, member 5 (KCNJ5)...

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Histopathological Diagnosis of Primary Aldosteronism Using CYP11B2 Immunohistochemistry

Abstract: The present study clearly demonstrates that CYP11B2 immunostaining is a powerful tool for histopathological diagnosis of aldosterone overproduction in PA and for subtype classification of APA, multiple APCCs, unilateral multiple adrenocortical micronodules, and diffuse hyperplasia.

Cited by 102 publications

References 25 publications

An update on novel mechanisms of primary aldosteronism

An update on novel mechanisms of primary aldosteronism

Adrenal Venous Sampling in Patients With Positive Screening but Negative Confirmatory Testing for Primary Aldosteronism

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

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