Characteristics of a Novel ATP2B3 K416_F418delinsN Mutation in a Classical Aldosterone-Producing Adenoma

In patients with primary aldosteronism (PA), the prevalence of ATP2B3 mutation is rare. The aim of this study is to report a novel ATP2B3 mutation in a PA patient. Based on our tissue bank of aldosterone-producing adenomas (APA), we identified a novel somatic ATP2B3 K416_F418delinsN mutation. The affected individual was a 53 year-old man with a 4 year history of hypertension. Computed tomography (CT) showed bilateral adrenal masses of 1.6 (left) and 0.5 cm (right) in size. An adrenal venous sampling (AVS) showed a lateralization index (LI) of 2.2 and a contralateral suppression index (CLS) of 0.12; indicating left functional predominance. After a left unilateral adrenalectomy, he achieved partial biochemical and hypertension–remission. This classical adenoma harbored a novel ATP2B3 K416_F418delinsN somatic mutation, which is a deletion from nucleotides 1248 to 1253. The translated amino acid sequence from 416 to 418, reading as lysine-phenylalanine-phenylalanine, was deleted; however, an asparagine was inserted due to merging of residual nucleotide sequences. The CYP11B2 immunohistochemistry staining demonstrated strong immunoreactivity in this classical adenoma. The ATP2B3 K416_F418delinsN mutation is a functional mutation in APA, since HAC15 cells, a human adrenal cell line, transfected with the mutant gene showed increased CYP11B2 expression and aldosterone production.

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Does Contralateral Suppression at Adrenal Venous Sampling Predict Outcome Following Unilateral Adrenalectomy for Primary Aldosteronism? A Retrospective Study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2014-3676 ◽

2015 ◽

Vol 100 (4) ◽

pp. 1477-1484 ◽

Cited By ~ 47

Author(s):

Martin J. Wolley ◽

Richard D. Gordon ◽

Ashraf H. Ahmed ◽

Michael Stowasser

Keyword(s):

Retrospective Study ◽

Primary Aldosteronism ◽

Median Number ◽

Antihypertensive Medications ◽

Unaffected Side ◽

Unilateral Adrenalectomy ◽

Contralateral Suppression ◽

Biochemical Cure ◽

Lateralization Index

Context: In primary aldosteronism (PA), adrenal vein sampling (AVS) distinguishes unilateral and bilateral disease by comparison of aldosterone/cortisol (A/F) ratios. There is controversy about the criteria for interpretation, however, and in particular it is not clear whether contralateral suppression (CS) (defined as A/Fadrenal ≤ A/Fperipheral on the unaffected side) is important. We therefore performed a retrospective study to determine whether CS in surgically treated unilateral PA was associated with blood pressure (BP) and biochemical outcomes. Setting and Design: Patients who underwent unilateral adrenalectomy for PA after successful AVS were included if the lateralization index (A/Fdominant:A/Fnondominant) was ≥2. Cases were reviewed at 6 to 24 months follow-up for outcomes with respect to the presence and degree of CS. Results: Sixty-six of 80 patients had CS. Baseline characteristics were similar. At postoperative follow-up, those with CS had lower systolic BP (SBP) (128 mm Hg vs 144 mm Hg, P = .001), a greater proportion with cure or improvement of hypertension (96% vs 64%, P = .0034), a greater proportion with biochemical cure of PA on fludrocortisone suppression testing (43 of 49 [88%] vs 4 of 9 [44%], P = .002) and were taking a lower median number of antihypertensive medications (0 vs 1.5, P = .0032). In a multivariate model, the degree of CS and preoperative SBP were both significantly correlated with postoperative SBP, but the lateralization index, sex, and age were not. Conclusion: In this study, the presence of CS correlated with good BP and biochemical outcomes from surgery. This finding suggests that CS should be a factor in deciding whether to offer surgery for treatment of PA.

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Analysis of Unilateral Adrenal Hyperplasia with Primary Aldosteronism from the Aspect of Messenger Ribonucleic Acid Expression for Steroidogenic Enzymes: A Comparative Study with Adrenal Cortices Adhering to Aldosterone-Producing Adenoma

Endocrinology ◽

10.1210/en.2005-0765 ◽

2006 ◽

Vol 147 (2) ◽

pp. 999-1006 ◽

Cited By ~ 15

Author(s):

Kazuto Shigematsu ◽

Kioko Kawai ◽

Junji Irie ◽

Hideki Sakai ◽

Osamu Nakashima ◽

...

Keyword(s):

Primary Aldosteronism ◽

Zona Glomerulosa ◽

Adrenal Hyperplasia ◽

Steroidogenic Enzymes ◽

Unilateral Adrenalectomy ◽

Messenger Ribonucleic Acid ◽

Unilateral Adrenal Hyperplasia ◽

Aldosterone Production ◽

Long Term Follow Up ◽

Aldosterone Producing Adenoma

Unilateral adrenal hyperplasia with primary aldosteronism is very rare and shows similar endocrine features to aldosterone-producing adenoma and bilateral adrenal hyperplasia. In this study, the mRNA expression of steroidogenic enzymes in unilateral adrenal hyperplasia was examined by in situ hybridization. We found subcapsular micronodules composed of spironolactone body-containing cells, which showed intense expression for 3β-hydroxysteroid dehydrogenase, 11β-hydroxylase, 18-hydroxylase, and 21-hydroxylase but not 17α-hydroxylase, indicating aldosterone production. This expression pattern was the same as that in unilateral multiple adrenocortical micronodules, reported recently. Additionally, it was noted that a nodule with active aldosterone production was closely adjacent to one showing intense 17α-hydroxylase expression. In the adrenal cortices adhering to aldosterone-producing adenoma, the majority of hyperplastic zona glomerulosa and hyperplastic nodules demonstrated a decreased steroidogenic activity. However, minute nodules indicative of active aldosterone production were found at high frequency. These results suggest that the subcapsular micronodules observed might be the root of aldosterone-producing adenoma. Furthermore, we emphasize the need for long-term follow-up after unilateral adrenalectomy or enucleation of the adenoma because of the possibility that buds with autonomous aldosterone production may still be present in the contralateral or remaining adrenal tissue.

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Lack of influence of somatic mutations on steroid gradients during adrenal vein sampling in aldosterone-producing adenoma patients

Acta Endocrinologica ◽

10.1530/eje-13-0551 ◽

2013 ◽

Vol 169 (5) ◽

pp. 657-663 ◽

Cited By ~ 17

Author(s):

Andrea Oßwald ◽

Evelyn Fischer ◽

Christoph Degenhart ◽

Marcus Quinkler ◽

Martin Bidlingmaier ◽

...

Keyword(s):

Contralateral Side ◽

Adrenal Vein ◽

Genetic Modifiers ◽

Adrenal Vein Sampling ◽

Unilateral Adrenalectomy ◽

Mutation Status ◽

Mutation Carriers ◽

Contralateral Suppression ◽

Aldosterone Producing Adenoma ◽

Index Ratio

ObjectiveAdrenal vein sampling (AVS) is a technically demanding procedure required for the identification of suitable candidates for unilateral adrenalectomy in primary aldosteronism. Recently, somaticKCNJ5K+-channel mutations in aldosterone-producing adenoma (APA) patients have been shown to influence steroid gradients during AVS. These and other recently identified genetic modifiers (ATP1A1andATP2B3) might affect the final diagnosis and treatment of the affected patients.DesignFifty-nine patients with APAs who had undergone successful AVS (adrenal vein cortisol:peripheral cortisol ratio ≥2) and had undergone a mutation analysis of their tumor tissue were studied. The mutation status of the APAs was as follows: 19KCNJ5mutations, eight ATPase mutations (fiveATP1A1and threeATP2B3), and 32 patients with none of these mutations.MethodsThe lateralization index (ratio of aldosterone:cortisol on the side of the adenoma to aldosterone to cortisol on the contralateral side) and the contralateral suppression index (ratio of aldosterone:cortisol on the contralateral side to aldosterone to cortisol in the periphery) were calculated for theKCNJ5-mutated, ATPase-mutated, and theKCNJ5/ATPase mutation-negative APA patients.ResultsThe lateralization indices of the ATPase mutation carriers had a median of 19.9 compared with a median of 16.0 in theKCNJ5mutation carriers and that of 20.5 in theKCNJ5/ATPase mutation-negative patients. The contralateral suppression indices of the ATPase-mutated patients had a median of 0.1 compared with a median of 0.4 in theKCNJ5mutation carriers and that of 0.2 in theKCNJ5/ATPase mutation-negative patients. The differences between the genetic groups were not statistically significant.ConclusionsWe did not find evidence for a clinically important impact of mutation status on steroid gradients during AVS.

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Gonadotropin-Releasing Hormone Stimulate Aldosterone Production in a Subset of Aldosterone-Producing Adenoma

Medicine ◽

10.1097/md.0000000000003659 ◽

2016 ◽

Vol 95 (20) ◽

pp. e3659 ◽

Cited By ~ 9

Author(s):

Rui Kishimoto ◽

Kenji Oki ◽

Masayasu Yoneda ◽

Celso E. Gomez-Sanchez ◽

Haruya Ohno ◽

...

Keyword(s):

Gonadotropin Releasing Hormone ◽

Releasing Hormone ◽

Aldosterone Production ◽

Aldosterone Producing Adenoma

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A Case of Persistent Hyperkalemia After Unilateral Adrenalectomy for Aldosterone-Producing Adenoma

Journal of Korean Endocrine Society ◽

10.3803/jkes.2009.24.3.201 ◽

2009 ◽

Vol 24 (3) ◽

pp. 201

Author(s):

Min Jae Yang ◽

Seung Jin Han ◽

Min Seok Lee ◽

Eun Kyung Kim ◽

Hae Jin Kim ◽

...

Keyword(s):

Unilateral Adrenalectomy ◽

Aldosterone Producing Adenoma

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Unilateral Adrenalectomy for Primary Bilateral Macronodular Adrenal Hyperplasia: Analysis of 71 Cases

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/a-0998-7884 ◽

2019 ◽

Vol 128 (12) ◽

pp. 827-834

Author(s):

Mohammad Sheikh-Ahmad ◽

Gabriel Dickstein ◽

Ibrahim Matter ◽

Carmela Shechner ◽

Jacob Bejar ◽

...

Keyword(s):

Medical Center ◽

Urinary Free Cortisol ◽

Adrenal Hyperplasia ◽

Unilateral Adrenalectomy ◽

Long Period ◽

Pubmed Database ◽

Free Cortisol ◽

Adrenal Masses ◽

Current Article

Abstract Objective Primary bilateral macronodular adrenal hyperplasia (PBMAH) is characterized by benign bilateral enlarged adrenal masses, causing Cushing’s syndrome (CS). The aim of the current article is to define the role of unilateral adrenalectomy (UA) in treating patients with CS related to PBMAH. Methods A PubMed database search was conducted to identify articles reporting UA to treat PBMAH. We also report cases of PBMAH from our medical center treated by UA. Results A total number of 71 cases of PBMAH (62 cases reported in the literature and 9 cases from our center) are presented. Most patients were women (73.2%) and most UA involved the left side (64.3%). In most cases, the resected gland was the larger one. Following UA, 94.4% of cases had remission of hypercortisolism. Recurrence rate of CS was 19.4% and hypoadrenalism occurred in 29.6%. After UA, when the size of the remained adrenal gland was equal or greater than 3.5 cm, CS persisted in 21.4% of cases, and recurrence occurred in 27.3% of cases (after 20±9.2 months). However, when the size of the remained gland was less than 3.5 cm, CS resolved in all cases and recurrence occurred in 21.2% of cases after a long period (65.6±52.1 months). High levels of urinary free cortisol (UFC) were not correlated with post-surgical CS recurrence or persistence. Conclusions UA leads to beneficial outcomes in patients with CS related to PBMAH, also in cases with pre-surgical elevated UFC or contralateral large gland.

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ADRENAL VEIN SAMPLING WITHOUT DISCONTINUATION OF MINERALOCORTICOID RECEPTOR ANTAGONIST THERAPY

Endocrine Practice ◽

10.4158/ep-2019-0599 ◽

2020 ◽

Vol 26 (9) ◽

pp. 953-959

Author(s):

Malini Ganesh ◽

Shabirhusain S. Abadin ◽

Leon Fogelfeld

Keyword(s):

Plasma Renin Activity ◽

Mineralocorticoid Receptor ◽

Plasma Renin ◽

Plasma Aldosterone ◽

Adrenal Vein ◽

Adrenal Vein Sampling ◽

Mineralocorticoid Receptor Antagonist ◽

Plasma Aldosterone Concentration ◽

Contralateral Suppression ◽

Lateralization Index

Objective: Guidelines recommend withdrawing mineralocorticoid-receptor antagonists (MRAs) for 4 weeks prior to adrenal vein sampling (AVS), but this is not always feasible because of hypertension and hypokalemia. This retrospective study of primary aldosteronism (PA) patients who underwent AVS between 2008 and 2018 assessed the effect of continuing MRA on the AVS procedure. Methods: Clinical data including antihypertensive regimen defined by the World Health Organization Daily Defined Dose (DDD) system were collected for 19 patients with adequate cannulation and lateralization during AVS. Results were compared between 5 patients who continued and 14 patients who discontinued MRA therapy (MRA and non-MRA groups). Results: At diagnosis, plasma renin activity, plasma aldosterone concentration (PAC), potassium (K) doses, and DDD were not significantly different between groups. Aldosterone-renin ratio was significantly higher in the MRA group (median, 375.0; interquartile range [IQR], 224.8 to 544.3 vs. 148.7, 118.4 to 192.1; P = .034). No difference was found in lateralization index (median 48.3; IQR, 23.6 to 52.1 vs. 8.7; 4.9 to 20.2; P = .10). Contralateral suppression, defined as aldosterone-cortisol ratio of unaffected adrenal to periphery, trended lower in the MRA group (median, 0.17; IQR, 0.03 to 0.39 vs. 0.51; 0.27 to 1.1; P = .056). All five MRA patients underwent successful adrenalectomy with at least 50% reduction in DDD and PAC and normal K postoperatively. One MRA patient did not lateralize, which was confirmed on repeat AVS, after MRA withdrawal. Conclusion: Continuation of MRA may not interfere with AVS lateralization or affect contralateral adrenal suppression. Continuation of MRA in preparation for AVS may be considered, especially in patients with severe PA, to avoid uncontrolled hypertension and severe hypokalemia. Abbreviations: ACTH = adrenocorticotropic hormone; APA = aldosterone-producing adenoma; ARR = aldosterone-renin ratio; AV = adrenal vein; AVS = adrenal vein sampling; CS = contralateral suppression; DDD = daily defined dose; IQR = interquartile range; K = potassium; LI = lateralization index; MRA = mineralocorticoid receptor antagonist; PA = primary aldosteronism; PAC = plasma aldosterone concentration; PRA = plasma renin activity

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Aldosterone Suppression on Contralateral Adrenal During Adrenal Vein Sampling Does Not Predict Blood Pressure Response After Adrenalectomy

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2014-2345 ◽

2014 ◽

Vol 99 (11) ◽

pp. 4158-4166 ◽

Cited By ~ 33

Author(s):

Silvia Monticone ◽

Fumitoshi Satoh ◽

Andrea Viola ◽

Evelyn Fischer ◽

Oliver Vonend ◽

...

Keyword(s):

Blood Pressure ◽

Blood Pressure Response ◽

Blood Pressure Reduction ◽

Great Majority ◽

Adrenal Vein ◽

Curative Surgery ◽

Adrenal Vein Sampling ◽

Unilateral Adrenalectomy ◽

Contralateral Suppression ◽

Bilateral Adrenal Hyperplasia

Context: Adrenal vein sampling (AVS) is the only reliable means to distinguish between aldosterone-producing adenoma and bilateral adrenal hyperplasia, the two most common subtypes of primary aldosteronism (PA). AVS protocols are not standardized and vary widely between centers. Objective: The objective of the study was to retrospectively investigate whether the presence of contralateral adrenal (CL) suppression of aldosterone secretion was associated with improved postoperative outcomes in patients who underwent unilateral adrenalectomy for PA. Setting: The study was carried out in eight different referral centers in Italy, Germany, and Japan. Patients: From 585 consecutive AVS in patients with confirmed PA, 234 procedures met the inclusion criteria and were used for the subsequent analyses. Results: Overall, 82% of patients displayed contralateral suppression. This percentage was significantly higher in ACTH stimulated compared with basal procedures (90% vs 77%). The CL ratio was inversely correlated with the aldosterone level at diagnosis and, among AVS parameters, with the lateralization index (P = .02 and P = .01, respectively). The absence of contralateral suppression was not associated with a lower rate of response to adrenalectomy in terms of both clinical and biochemical parameters, and patients with CL suppression underwent a significantly larger reduction in the aldosterone levels after adrenalectomy. Conclusions: For patients with lateralizing indices of greater than 4 (which comprised the great majority of subjects in this study), CL suppression should not be required to refer patients to adrenalectomy because it is not associated with a larger blood pressure reduction after surgery and might exclude patients from curative surgery.

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

Hormone and Metabolic Research ◽

10.1055/a-1139-2079 ◽

2020 ◽

Vol 52 (06) ◽

pp. 421-426

Author(s):

Celso E. Gomez-Sanchez ◽

Elise P. Gomez-Sanchez ◽

Koshiro Nishimoto

Keyword(s):

Somatic Mutations ◽

Older Individuals ◽

Clinically Normal ◽

Normal People ◽

Normal Individuals ◽

Continuous Band ◽

Aldosterone Production ◽

Heterogeneous Expression ◽

Normal Humans ◽

Aldosterone Producing Adenoma

AbstractThe 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.

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Polycystic liver in two adult llamas

Journal of Veterinary Diagnostic Investigation ◽

10.1177/1040638718824736 ◽

2019 ◽

Vol 31 (2) ◽

pp. 280-283

Author(s):

Tatiane T. Negrão Watanabe ◽

Francisco R. Carvallo Chaigneau ◽

John M. Adaska ◽

Benjamín Doncel-Díaz ◽

Francisco A. Uzal

Keyword(s):

Laboratory Tests ◽

Incidental Finding ◽

Single Layer ◽

Infectious Agents ◽

Hepatic Cysts ◽

Polycystic Liver ◽

History Of ◽

Lama Glama ◽

Strong Immunoreactivity ◽

Unrelated Adult

Polycystic liver is usually considered an incidental finding in human and veterinary medicine. Two unrelated adult llamas ( Lama glama) with a history of marked anorexia and weight loss were received for autopsy and diagnostic workup. The main gross change in the liver of both animals was multiple variably sized cysts randomly distributed throughout the parenchyma. Histologically, the cysts compressed the adjacent parenchyma and were lined by a single layer of cuboidal-to-columnar epithelium, surrounded by a fibrous collagen capsule. The lumen of the cysts contained finely granular-to-homogeneous basophilic material. The lining epithelium displayed strong immunoreactivity for pancytokeratin AE1/AE3 and cytokeratins 7, 8, 8/18, and 19, and was negative for vimentin, confirming the biliary epithelial origin of the cysts. No parasitic or infectious agents, or neoplastic changes, were detected. All other laboratory tests performed in both llamas were negative or non-diagnostic, suggesting that the congenital hepatic cysts described may have been at least partly responsible for clinical disease in both animals.

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