scholarly journals Familial Hyperaldosteronism Type 3 with a Rapidly Growing Adrenal Tumor: An In Situ Aldosterone Imaging Study

2021 ◽  
Vol 44 (1) ◽  
pp. 128-138
Author(s):  
Nae Takizawa ◽  
Susumu Tanaka ◽  
Koshiro Nishimoto ◽  
Yuki Sugiura ◽  
Makoto Suematsu ◽  
...  
Keyword(s):  
Adrenal Gland ◽  
Primary Aldosteronism ◽  
Germ Line ◽  
Imaging Study ◽  
Adrenal Tumors ◽  
Adrenal Hyperplasia ◽  
Unilateral Adrenalectomy ◽  
Familial Hyperaldosteronism ◽  
Type 3

Primary aldosteronism is most often caused by aldosterone-producing adenoma (APA) and bi-lateral adrenal hyperplasia. Most APAs are caused by somatic mutations of various ion channels and pumps, the most common being the inward-rectifying potassium channel KCNJ5. Germ line mutations of KCNJ5 cause familial hyperaldosteronism type 3 (FH3), which is associated with severe hyperaldosteronism and hypertension. We present an unusual case of FH3 in a young woman, first diagnosed with primary aldosteronism at the age of 6 years, with bilateral adrenal hyperplasia, who underwent unilateral adrenalectomy (left adrenal) to alleviate hyperaldosteronism. However, her hyperaldosteronism persisted. At the age of 26 years, tomography of the remaining adrenal revealed two different adrenal tumors, one of which grew substantially in 4 months; therefore, the adrenal gland was removed. A comprehensive histological, immunohistochemical, and molecular evaluation of various sections of the adrenal gland and in situ visualization of aldosterone, using matrix-assisted laser desorption/ionization imaging mass spectrometry, was performed. Aldosterone synthase (CYP11B2) immunoreactivity was observed in the tumors and adrenal gland. The larger tumor also harbored a somatic β-catenin activating mutation. Aldosterone visualized in situ was only found in the subcapsular regions of the adrenal and not in the tumors. Collectively, this case of FH3 presented unusual tumor development and histological/molecular findings.

scholarly journals Potassium Channel Mutant KCNJ5 T158A Expression in HAC-15 Cells Increases Aldosterone Synthesis

Endocrinology ◽  
2012 ◽  
Vol 153 (4) ◽  
pp. 1774-1782 ◽  
Author(s):  
Kenji Oki ◽  
Maria W. Plonczynski ◽  
Milay Luis Lam ◽  
Elise P. Gomez-Sanchez ◽  
Celso E. Gomez-Sanchez
Keyword(s):  
Potassium Channel ◽  
Primary Aldosteronism ◽  
Calcium Influx ◽  
Fold Increase ◽  
Transitional Zone ◽  
Selectivity Filter ◽  
Adrenal Cortical Carcinoma ◽  
Aldosterone Secretion ◽  
Familial Hyperaldosteronism ◽  
Type 3

Primary aldosteronism is the most common cause of secondary hypertension, most frequently due to an aldosterone-producing adenoma or idiopathic hyperaldosteronism. Somatic mutations of the potassium channel KCNJ5 in the region of the selectivity filter have been found in a significant number of aldosterone-producing adenomas. There are also familial forms of primary aldosteronism, one of which, familial hyperaldosteronism type 3 which to date has been found in one family who presented with a severe abnormality in aldosterone and 18-oxocortisol production and hypertrophy and hyperplasia of the transitional zone of the adrenal cortex. In familial hyperaldosteronism type 3, there is a genomic mutation causing a T158A change of amino acids within the selectivity filter region of the KCNJ5 gene. We are reporting our studies demonstrating that lentiviral-mediated expression of a gene carrying the T158A mutation of the KCNJ5 in the HAC15 adrenal cortical carcinoma cell line causes a 5.3-fold increase in aldosterone secretion in unstimulated HAC15-KCNJ5 cells and that forskolin-stimulated aldosterone secretion was greater than that of angiotensin II. Expression of the mutated KCNJ5 gene decreases plasma membrane polarization, allowing sodium and calcium influx into the cells. The calcium channel antagonist nifedipine and the calmodulin inhibitor W-7 variably inhibited the effect. Overexpression of the mutated KCNJ5 channel resulted in a modest decrease in HAC15 cell proliferation. These studies demonstrate that the T158A mutation of the KCNJ5 gene produces a marked stimulation in aldosterone biosynthesis that is dependent on membrane depolarization and sodium and calcium influx into the HAC15 adrenal cortical carcinoma cells.

scholarly journals In situ Metabolite Mass Spectrometry Imaging: New Insights into the Adrenal Gland

2020 ◽  
Vol 52 (06) ◽  
pp. 435-447
Author(s):  
Fengxia Li ◽  
Annette Feuchtinger ◽  
Axel Walch ◽  
Na Sun
Keyword(s):  
Mass Spectrometry ◽  
Adrenal Gland ◽  
Mass Spectrometry Imaging ◽  
Neuroendocrine Cells ◽  
Adrenal Tumors ◽  
Analytical Methodology ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded ◽  
Clinically Significant

AbstractThe adrenal gland integrates catecholamine-producing neuroendocrine cells and steroid-producing cells with mesenchymal origin in a structured manner under one capsule and is a key regulator for vital bioactivity. In addition to adrenal-specific disease, dysregulation of adrenal hormones is associated with systemic effects, leading to undesirable metabolic and cardiovascular consequences. Mass spectrometry imaging (MSI) technique can simultaneously measure a broad range of biomolecules, including metabolites and hormones, which has enabled the study of tissue metabolic and hormone alterations in adrenal and adrenal-related diseases. Furthermore, this technique coupled with labeled immunohistochemistry staining has enabled the study of the pathophysiological adaptation of the adrenal gland under normal and abnormal conditions at different molecular levels. This review discusses the recent applications of in situ MSI in the adrenal gland. For example, the combination of formalin-fixed paraffin-embedded tissue microarray and MSI to tissues from patient cohorts has facilitated the discovery of clinically relevant prognostic biomolecules and generated promising hypotheses for new sights into physiology and pathophysiology of adrenal gland. MSI also has enabled the discovery of clinically significant tissue molecular (i. e., biomarker) and pathway changes in adrenal disease, particularly in adrenal tumors. In addition, MSI has advanced the ability to optimally identify and detect adrenal gland specific molecules. Thus, as a novel analytical methodology, MSI has provided unprecedented capabilities for in situ tissue study.

scholarly journals SUN-189 A Case of Delayed Hypoaldosteronism Following Unilateral Adrenalectomy for Primary Aldosteronism

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Julie Schommer ◽  
Amal A Shibli-Rahhal
Keyword(s):  
Adrenal Gland ◽  
Plasma Renin Activity ◽  
Potassium Chloride ◽  
Primary Aldosteronism ◽  
Plasma Renin ◽  
Renin Activity ◽  
Endocrine Society ◽  
Unilateral Adrenalectomy ◽  
One Year ◽  
Aldosterone To Renin Ratio

Abstract BACKGROUND: Hypoaldosteronism occurs in 6–30% of patients following unilateral adrenalectomy for primary aldosteronism. The Endocrine Society guidelines recommend discontinuing potassium supplementation and spironolactone postoperatively with repeat renin and aldosterone after surgery to monitor for cure. Clinical Case: A 69-year-old male with a 15-year history of hypertension on amlodipine 10 mg daily, atenolol 100 mg daily, terazosin 5 mg daily, valsartan 160 mg daily, spironolactone 50 mg three times daily, with longstanding hypokalemia on potassium chloride 20 mEq four times daily presented with an ischemic stroke and persistent hypertension (BP 182/79). Following discontinuation of spironolactone, evaluation revealed aldosterone concentration of 214 ng/dL (normal 4.0 - 31) and plasma renin activity of 0.1 ng/mL/hr (normal 0.5 - 4.0), giving an aldosterone-to-renin ratio of 2,140. CT of the abdomen showed a 3 cm right adrenal mass. He underwent uncomplicated right adrenalectomy for primary aldosteronism. Postoperative potassium was 3.4 mEq/L (normal 3.5–5.0) and hypertension persisted, so he was discharged on potassium chloride 10 mEq, losartan 100 mg daily, amlodipine 10 mg daily, and labetalol 200 mg twice daily. Two weeks later potassium level was 5.1 mEq/L and potassium chloride supplement was discontinued. Six months postoperatively, potassium was 5.7 mEq/L with well-controlled blood pressure, so losartan was discontinued. Labs over the subsequent several weeks showed persistent hyperkalemia up to 6.2 mEq/L and new hyponatremia to 128 mEq/L (normal 134 - 150). Repeat plasma renin activity was 0.51 ng/mL/hr and aldosterone concentration <1.0 ng/dL. Morning cortisol concentration was 18.3 ug/dL (normal 6.7 - 22.6) and ACTH 38 pg/mL (normal 6.0 - 50 pg/mL). He was diagnosed with postsurgical hypoaldosteronism. Potassium stabilized at 5.1 mEq/L and sodium stabilized at 134 mEq/L, so he was monitored without treatment for hypoaldosteronism. One year postoperatively his labs showed: potassium 5.1 mEq/L, sodium 135 mEq/L, renin 1.0 ng/mL/hr, and aldosterone 5.7 ng/dL. Conclusion: This patient had primary aldosteronism leading to suppression of aldosterone secretion from the contralateral healthy adrenal gland. This resulted in postoperative hypoaldosteronism once the affected adrenal gland was resected. This case demonstrates the need for continued monitoring of potassium, sodium, renin, and aldosterone following unilateral adrenalectomy for primary aldosteronism, especially in the setting of postoperative angiotensin receptor blocker use or other medications which can affect the renin-angiotensin-aldosterone system.

scholarly journals Steroidogenic Activity in Unresected Adrenals Associated With Surgical Outcomes in Primary Aldosteronism

Hypertension ◽  
2021 ◽  
Vol 77 (5) ◽  
pp. 1638-1646
Author(s):  
Kazuki Nakai ◽  
Yuya Tsurutani ◽  
Kosuke Inoue ◽  
Seishi Matsui ◽  
Kohzoh Makita ◽  
...  
Keyword(s):  
Adrenal Gland ◽  
Primary Aldosteronism ◽  
Surgical Outcomes ◽  
Area Under The Curve ◽  
Adrenal Venous Sampling ◽  
Central Vein ◽  
Venous Sampling ◽  
Unilateral Adrenalectomy ◽  
Complete Group ◽  
Success Group

In patients with primary aldosteronism diagnosed with unilateral lesions through adrenal venous sampling, excess aldosterone occasionally persists after adrenalectomy. We investigated whether aldosterone values from unresected adrenals would be associated with postoperative outcomes. Overall, 102 primary aldosteronism patients, who underwent segmental adrenal venous sampling and unilateral adrenalectomy, were assessed for biochemical success (as outlined in the PASO [Primary Aldosteronism Surgical Outcomes] Study) at 1 year after surgery by using the saline infusion test. We divided patients into the biochemical complete or incomplete success group. Eighty-seven and 15 patients had complete and incomplete biochemical success, respectively. The biochemical incomplete group, compared with the biochemical complete group, had higher maximum aldosterone in tributary veins (11 000 versus 7030 pg/mL, P =0.006), maximum aldosterone/cortisol in tributary veins (18.05 versus 9.13, P <0.001), aldosterone in the central vein (9260 versus 5800 pg/mL, P =0.011), and aldosterone/cortisol in the central vein (13.67 versus 8.08, P <0.001) of the unresected adrenal gland. In logistic regression analyses, maximum aldosterone/cortisol in tributary veins had the highest area under the curve (0.780). Aldosterone/cortisol in the central vein had a nearly equivalent area under the curve (0.775). The lateralization index showed no significant differences between the groups. The clinical incomplete group similarly had higher aldosterone and aldosterone/cortisol in the unresected adrenal gland than did the clinical complete group. Therefore, steroidogenic activity in unresected adrenals (eg, absolute aldosterone value and aldosterone/cortisol) were associated with surgical outcomes. Our results may aid clinicians in determining the surgical application for primary aldosteronism.

scholarly journals 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 ◽  
2006 ◽  
Vol 147 (2) ◽  
pp. 999-1006 ◽  
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.

scholarly journals DIAGNOSIS OF ENDOCRINE DISEASE: 18-Oxocortisol and 18-hydroxycortisol: is there clinical utility of these steroids?

2018 ◽  
Vol 178 (1) ◽  
pp. R1-R9 ◽  
Author(s):  
Jacques W M Lenders ◽  
Tracy Ann Williams ◽  
Martin Reincke ◽  
Celso E Gomez-Sanchez
Keyword(s):  
Primary Aldosteronism ◽  
Zona Glomerulosa ◽  
Zona Fasciculata ◽  
Endocrine Disease ◽  
Familial Hyperaldosteronism ◽  
High Concentrations ◽  
And Function ◽  
Type 3

Since the early 1980s 18-hydroxycortisol and 18-oxocortisol have attracted attention when it was shown that the urinary excretion of these hybrid steroids was increased in primary aldosteronism. The development and more widespread use of specific assays has improved the understanding of their role in the (patho)physiology of adrenal disorders. The adrenal site of synthesis is not fully understood although it is clear that for the synthesis of 18-hydroxycortisol and 18-oxocortisol the action of both aldosterone synthase (zona glomerulosa) and 17α-hydroxylase (zona fasciculata) is required with cortisol as main substrate. The major physiological regulator is ACTH and the biological activity of both steroids is very low and therefore only very high concentrations might be effectivein vivo. In healthy subjects, the secretion of both steroids is low with 18-hydroxycortisol being substantially higher than that of 18-oxocortisol. The highest secretion of both steroids has been found in familial hyperaldosteronism type 1 (glucocorticoid-remediable aldosteronism) and in familial hyperaldosteronism type 3. Lower but yet substantially increased secretion is found in patients with aldosterone-producing adenomas in contrast to bilateral hyperplasia in whom the levels are similar to patients with hypertension. Several studies have attempted to show that these steroids, in particular, peripheral venous plasma 18-oxocortisol, might be a useful discriminatory biomarker for subtyping PA patients. The current available limited evidence precludes the use of these steroids for subtyping. We review the biosynthesis, regulation and function of 18-hydroxycortisol and 18-oxocortisol and their potential utility for the diagnosis and differential diagnosis of patients with primary aldosteronism.

scholarly journals SAT-197 Unilateral Adrenalectomy Can Induce Control in ARMC5 Mutations Patients

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Maria João Ferreira ◽  
José Luis Castedo ◽  
Maria Manuel Costa ◽  
Davide M Carvalho
Keyword(s):  
Adrenal Gland ◽  
Ct Scan ◽  
Cushing Syndrome ◽  
Molecular Study ◽  
Pathogenic Mutation ◽  
Adrenal Tumors ◽  
Autosomal Dominant Disorder ◽  
Unilateral Adrenalectomy ◽  
Peripheral Blood Leucocyte ◽  
Nodular Hyperplasia

Abstract Primary macronodular hyperplasia (PMAH) is a rare cause of endogenous Cushing’s syndrome characterized by functioning adrenal macronodules and variable cortisol secretion. ARMC5 is the most frequent gene responsible for PMAH. Genetic mutations including inactivating germline mutations in armadillo repeat-containing 5 (ARMC5) gene have been identified. The occurrence of several other non adrenal tumors (meningioma, breast, colon, thyroid and parathyroid) has also been associated with PBMAH, suggesting a possible role of ARMC5 for the development of other neoplasias. The best treatment to this condition is not established. Clinical case: 64-year-old man, referred due to bilateral adrenal incidentalomas on a CT scan with characteristics of adenoma/hyperplasia. He had type-2 diabetes, hypertension and dyslipidemia for about 4 years. He was being treated with 4 different anti-hypertensive medications, gliclazide and simvastatin. Physical examination revealed thin and dry skin, obesity with centripetal fat distribution, multiple ecchymosis and facial erythrosis. He had a son and a daughter. No known familial relevant diseases. His laboratory workup revealed ACTH-independent hypercortisolism: failure to suppress on the overnight dexametasone suppression test - cortisol 27.6ug/dL- and on the low-dose dexamethasone test- cortisol 24ug/dL- associated to morning ACTH &lt;1ng/L. He underwent stimulation tests with tetracosactide, LHRH, TRH, vasopressin, metoclopramide, glucagon anddeambulation test, which were overall negative. It was decided to proceed to bilateral adrenalectomy. Due to surgical complications, only right adenalectomy was performed. Histology revealed adrenal nodular hyperplasia. Molecular study in DNA extracted from peripheral blood leucocyte and in the adrenal gland revealed the presence in heterozygosity of the pathogenic mutation c.1379T&gt;C in the ARMC5 gene. The patient underwent a cerebral CT scan which showed a meningioma in the posterior left temporal convexity. Genetic testing was also performed on the daughter and son of the patient, which revealed the same mutation. They were also tested for hypercortisolism and underwent adrenal and cerebral CT scan, which showed no abnormality. The adrenal CT scan of the daughter showed enlargement of the left adrenal gland, with aspects suggestive of nodular hyperplasia. Her blood tests revealed no sign of hypercortisolism - overnight dexametasone test- cortisol 1.0 ug/dL, morning ACTH 19.1 ng/L. The patient is currently with cortisol hypersecretion controlled. Conclusion: All patients with PMAH should be tested for ARMC5 mutations and if they are found, family screening is mandatory in this autosomal dominant disorder. Unilateral adrenalectomy could control the cortisol hypersecretion, however some of these patients can have subclinical Cushing Syndrome.

scholarly journals SAT-177 Relationship Between Visceral Fat and the Position of Adrenal Glands in Cranial-Caudal Direction in Patients with Primary Aldosteronism

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Yui Shibayama ◽  
Norio Wada ◽  
Shuhei Baba ◽  
Shinji Obara ◽  
Hidetsugu Sakai ◽  
...  
Keyword(s):  
Adrenal Gland ◽  
Visceral Fat ◽  
Primary Aldosteronism ◽  
Adrenal Glands ◽  
Subcutaneous Fat ◽  
Adrenal Tumors ◽  
Fat Percentage ◽  
Endocrine Society ◽  
Plasma Aldosterone Concentration ◽  
Caudal Direction

Abstract Context: Adrenal glands locate at the retroperitoneal space and could be affected their positions by some factors. Adrenal glands being surrounded by visceral adipose tissue (VAT), we have hypothesized that the VAT amount influences the position of adrenal glands in cranial-caudal direction. In patients with primary aldosteronism (PA), comprehending the position of adrenal glands in cranial-caudal direction might be useful to predict the position of adrenal veins before performing adrenal venous sampling. Objectives: To clarify the influence of VAT amount on the position of adrenal glands, we investigated the correlation of visceral fat parameters with the position difference of adrenal glands in cranial-caudal direction in patients with PA. Materials and methods: This retrospective observational study included patients with PA according to the guidelines of both the Japan Endocrine Society and the Japan Society of Hypertension. Those with adrenal tumors more than 10 mm in diameter in computed tomography (CT) were excluded. We measured the position difference of the adrenal glands in cranial-caudal direction, from the top of right adrenal gland to the top of left adrenal gland by CT. We correlated visceral fat percentage (VF%), visceral fat area (VFA), and subcutaneous fat area (SCFA) evaluated by CT studies with the position difference of adrenal glands in cranial-caudal direction. Results: We analyzed 150 patients [male (n = 50), female (n = 100)]. Patients’ characteristics: Age was 54.8 ± 11.4, body mass index 24.9 ± 3.8 kg/m2, plasma aldosterone concentration 133.5 [101–176] pg/ml, plasma renin activity 0.3 [0.2–0.5] ng/ml/h, VF% 25.8 [19.8–33.6] %, VFA 88.3 [60.9–125.0] cm2, and SCFA was 147.4 [105.6–193.4] cm2 (mean ± SD, or median [interquartile range]). The position difference of adrenal glands in cranial-caudal direction was 9.7 ± 10.0 mm. In 120 patients (80.0%), left adrenal glands locate at the upper position comparing to right adrenal glands. In 19 patients (12.7%), right adrenal glands were positioned at the upper comparing to left adrenal glands. A positive correlation of VF%, VFA with the position difference of adrenal glands in cranial-caudal direction were shown (r = 0.451, p &lt; 0.001, r = 0.426, p &lt; 0.001, respectively). No significant correlation of SCFA with the position difference of adrenal glands in cranial-caudal direction was shown (r = 0.122, p = 0.139). In patients with more VAT amount, right adrenal glands locate at the upper position comparing to left adrenal glands. In patients with less VAT amount, left adrenal glands locate at the upper position comparing to right adrenal glands. Conclusions: Regardless of the variation of the position of adrenal gland on each side, the correlation was found between VAT and the position difference of adrenal glands in cranial-caudal direction in PA.

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