Aldosterone Levels Research Articles

Subunit-Specific Developmental Roles of PI3K in SF1-Expressing Cells.

Phosphatidylinositol 3-kinase (PI3K) regulates cellular development and energy homeostasis. However, the roles of its subunits in organ development remain largely unknown. We explored the roles of PI3K catalytic subunits in steroidogenic factor 1 (SF1)-expressing cells through knockout (KO) of the p110α and p110β subunits. We examined mice with a double KO of p110α and p110β in SF1-expressing cells (p110αβ KOSF1). Although these animals exhibited no significant changes in the development of the ventromedial hypothalamus, we noted pronounced hypotrophy in the adrenal cortex, testis, and ovary. Additionally, corticosterone and aldosterone levels were significantly reduced. The absence of these subunits also resulted in decreased body weight and survival rate, along with impaired glucose homeostasis, in p110αβ KOSF1 mice. The data demonstrate the specific roles of PI3K catalytic subunits in the development and function of SF1-expressing organs.

The effect of adrenalectomy on bleomycin-induced pulmonary fibrosis in mice.

Progressive lung fibrosis is often fatal and has limited treatment options. Though the mechanisms are poorly understood, fibrosis is increasingly linked with catecholamines such as adrenaline (AD) and noradrenaline (NA), and hormones such as aldosterone (ALD). The essential functions of the adrenal glands include the production of catecholamines and numerous hormones, but the contribution of adrenal glands to lung fibrosis remains less well studied. Here, we characterized the impact of surgical adrenal ablation in the bleomycin model of lung fibrosis. Wild type mice underwent surgical adrenalectomy or sham surgery followed by bleomycin administration. We found that while bleomycin-induced collagen over-deposition in the lung was not affected by adrenalectomy, histologic indices of lung remodeling were ameliorated. These findings were accompanied by a decrease of lymphocytes in bronchoalveolar lavage (BAL) and macrophages in lung tissues, along with concomitant reductions in alpha smooth muscle actin (⍺SMA) and fibronectin. Surgical adrenalectomy completely abrogated AD, not NA, detection in all compartments. Systemic ALD levels were reduced after adrenalectomy while ALD levels in lung tissues remained unaffected. Taken together, these results support the presence of a pulmonary-adrenal axis in lung fibrosis and suggest that adrenalectomy is protective in this disease. Further investigation will be needed to better understand this observation and aid in the development of novel therapeutic strategies.

Safety, tolerability and blood pressure lowering of the innovative guanylyl cyclase a-receptor activator MANP in an ethnically diverse resistant hypertension population: a phase 1B clinical trial

Abstract Background/Introduction MANP is a novel atrial natriuretic peptide (ANP) analog bioengineered as a particulate guanylyl cyclase A receptor (GC-A) activator with superior receptor binding, resistance to neprilysin degradation, natriuretic, aldosterone suppressing and blood pressure (BP) lowering properties than native ANP. MANP is now under clinical development for resistant hypertension (RH). The rationale for its design was the fundamental role of the ANP/GC-A system in BP homeostasis through which GC-A activation with MANP leads to BP reduction through renal, vascular, and hormonal mechanisms mediated by the second messenger cGMP. Purpose We investigated the safety, tolerability, cGMP activation and BP reductions of MANP compared to placebo in subjects with RH. Methods We performed a double-blind, placebo controlled randomized trial in 36 RH patients comprised of approximately 50% non-African Americans (NAA) and 50% AA. MANP was administered in 6 cohorts receiving ascending subcutaneous (SQ) doses of MANP once daily from 3 ug/kg to a maximal dose of 7 ug/kg or placebo for 5 days and then followed for 21 days after dosing. Endpoints included safety, cGMP activation and changes in systolic BP (SBP), aldosterone (Aldo) levels and glomerular filtration rate (GFR). Results MANP was safe and well tolerated. One patient in the 7 ug/kg cohort was discontinued due to symptomatic hypotension. Compared to baseline, plasma cGMP increased in all MANP groups on Day 1 and Day 5 with no change in the placebo group. The maximal SBP reduction in the MANP group on Days 1 (D1) and 5 (D5) was -17.5 (D1) and -16 mmHg (D5) with 3 ug/kg (lowest dose) and -39.5 (D1) and -36.3 mmHg (D5) with 7 ug/kg (highest dose); Changes in the Placebo group were -6.3 (D1) and -16.7 mmHg (D5). Notably, the SBP reductions in AA were greater than NAA in the 4 and 7 ug/kg cohorts. After the 1-hour timepoint on both the first and fifth days, Aldo and percentage of Aldo reduction generally remained suppressed compared to baseline. Twenty-one days after MANP dosing, SBP remained lower in three groups receiving SQ MANP (4, 4.5 and 7 ug/kg) compared to placebo in association with a preservation of GFR. There were no reported drug related serious adverse events. Conclusions This clinical trial demonstrates that once a day SQ administration of MANP in RH subjects activates cGMP, without attenuation over 5 days, and reduces SBP and preserves GFR. At higher doses of MANP, SBP reductions were greater in AA compared to NAA. MANP also demonstrated Aldo inhibiting actions compared to placebo. Importantly, MANP was overall safe and well-tolerated. Our findings support the continued clinical development of MANP as a novel GC-A activating peptide for the treatment of RH.

Challenges in diagnosing and treating Liddle syndrome in resource-limited settings: A case report from Indonesia

Liddle syndrome, a rare form of monogenic hypertension, poses significant diagnostic and therapeutic challenges due to its phenotypic variability and the need for genetic testing. The rarity of the condition, coupled with the limited availability of first-line treatments such as epithelial sodium channel (ENaC) blockers, makes this case report particularly urgent and novel, highlighting alternative management strategies in resource-limited settings. The aim of this case report was to present the diagnostic challenges, therapeutic strategies, and clinical outcomes of a patient with Liddle syndrome who did not have access to ENaC blockers, emphasizing the importance of early recognition and personalized treatment. A 35-year-old female presented with resistant hypertension (190/100 mmHg) and bilateral limb weakness. Laboratory results revealed persistent hypokalemia, hypernatremia, and metabolic alkalosis. Low aldosterone levels, alongside clinical and family history, led to the diagnosis of Liddle syndrome. Genetic testing was not conducted due to resource limitations, and ENaC blockers were unavailable. The patients were managed with a combination of alternative antihypertensive agents, potassium supplementation, and a low-sodium diet. Although this approach led to modest improvements in blood pressure and motor strength, persistent hypokalemia and hypernatremia underscored the suboptimal control of the syndrome's underlying pathophysiology in the absence of ENaC blockers. This case highlights the challenges faced in resource-limited settings and the need for innovative strategies to manage rare conditions like Liddle syndrome. Liddle syndrome's diagnostic and therapeutic challenges underscore the critical importance of early recognition and access to targeted therapies. In the absence of ENaC blockers, alternative treatment strategies can provide some benefit, but they often fall short of optimal management. This case emphasizes the need for enhanced clinical awareness, improved access to genetic testing, and the development of personalized treatment approaches to achieve better patient outcomes.

Sex differences in the adrenal circadian clock: A role for BMAL1 in the regulation of urinary aldosterone excretion and renal electrolyte balance in mice.

Brain and muscle ARNT-Like 1 (BMAL1) is a circadian clock transcription factor that regulates physiological functions. Male adrenal-specific Bmal1 (ASCre/+::Bmal1) KO mice displayed blunted serum corticosterone rhythms, altered blood pressure rhythm, and altered timing of eating, but there is a lack of knowledge in females. This study investigates the role of adrenal BMAL1 in renal electrolyte handling and urinary aldosterone levels in response to low salt in male and female mice. Mice were placed in metabolic cages to measure 12-hour urinary aldosterone after a standard diet and 7 days low salt diet, as well as daily body weight, 12-hour food and water intake, and renal sodium and potassium balance. Adrenal glands and kidneys were collected at ZT0 or ZT12 to measure expression of aldosterone synthesis genes and clock genes. Compared to littermate controls, ASCre/+::Bmal1 KO male and female mice displayed increased urinary aldosterone in response to a low salt diet, although mRNA expression of aldosterone synthesis genes was decreased. Timing of food intake was altered in ASCre/+::Bmal1 KO male and female mice, with a blunted night/day ratio. ASCre/+::Bmal1 KO female mice displayed decreases in renal sodium excretion in response to low salt, but both male and female KO mice had changes in sodium balance that were time-of-day-dependent. In addition, sex differences were found in adrenal and kidney clock gene expression. Notably, this study highlights sex differences in clock gene expression that could contribute to sex differences in physiological functions.

Primary and "Pre-Primary" Aldosteronism in Resistant Hypertension: A Practical, Pragmatic, and Prudent Approach in Resource-Limited Milieu.

Introduction Primary aldosteronism (PA), once considered rare, is now recognized as the most common cause of secondary hypertension, accounting for almost a quarter of resistant hypertension (RH) cases. Despite this, PA remains underdiagnosed, with an extremely low percentage of RH patients undergoing screening. Methods In a specialty diabetes-endocrinology clinic, the aldosterone:renin ratio (ARR) was assessed in 115 consecutive RH patients (ages 21-93 years; 47% male; 87% with type 2 diabetes). Fasting blood samples were drawn in a standing position after 30 minutes of walking. Adrenal imaging (CT/MRI) was performed for those with an ARR >20. Results ARR values ranged from 0.4 to 227 (ARR <10 (35%); 11-20 (19%), 21-40 (25%), and >40 (21%)), with corresponding stepwise decreasing plasma renin activity (PRA) (P= 1E-6) and increasing serum aldosterone (SA) (P= 8E-7). Increasing ARR tended to be associated with an increase in serum creatinine (R= 0.23; P= 0.03) and a decrease in estimated glomerular filtration rate (eGFR) (R= -0.24; P= 0.02) and an increase in urine albumin: creatinine ratio. The ARR> 40 group displayed the highest serum creatinine, lowest eGFR, higher urine albumin: creatinine ratio, highest serum sodium, lowest serum potassium, and highest (44%) abnormal adrenal imaging (bilateral hyperplasia diffuse/nodular; solitary adenoma), reflecting a later stage of the pathological spectrum. PA treatment with mineralocorticoid receptor antagonists (MRAs) had a salutary effect. Conclusions Our observations further reinforce that PA is not a binary condition, but exists as a spectrum disorder responsive to MRAs, even in patients with mildly elevated or normal aldosterone levels. Early disease detection/recognition ("renin-independent aldosterone production") can be facilitated by marking "pre-primary" aldosteronism (ARR 11-20), followed by monitoring progression (periodic rescreening) and optimizing treatment, with hopeful mitigation of end-organ damage in RH.

Vitamin D-Parathyroid Hormone-Fibroblast Growth Factor 23 Axis and Cardiac Remodeling.

Cardiac remodeling is a compensatory adaptive response to chronic heart failure (HF) altering the structure, function, and metabolism of the heart. Many nutritional and metabolic diseases can aggravate the pathophysiological development of cardiac remodeling. Vitamin D deficiency leads to cardiac remodeling by activating the renin-angiotensin-aldosterone system (RAAS), resulting in enhanced inflammation and directly promoting cardiac fibrosis and extracellular matrix deposition. Hyperparathyroidism upregulates protein kinase A or protein kinase C, enhances intracellular calcium influx, promotes oxidative stress, activates RAAS, and increases aldosterone levels, thereby aggravating cardiac remodeling. Besides, fibroblast growth factor 23 (FGF23) plays a direct role in the heart, resulting in ventricular hypertrophy and myocardial fibrosis. Vitamin D deficiency leads to hyperparathyroidism, which in turn increases the level of FGF23. Elevated levels of FGF23 further inhibit vitamin D synthesis. Evidence exists that vitamin D deficiency, hyperparathyroidism, and marked elevations in FGF23 concentration form a vicious cycle and are believed to contribute directly to cardiac remodeling. Therefore, the purpose of this article is to introduce the specific effects of the above substances on the heart and to explain the significance of understanding the vitamin D-parathyroid hormone-FGF23 axis in improving or even reversing cardiac remodeling, thus contributing to the treatment of patients with HF.

Role of aldosterone in various target organ damage in patients with hypertensive emergency: a cross-sectional study

BackgroundHypertensive emergency is a critical disease that causes multiple organ injuries. Although the renin-angiotensin-aldosterone system (RAS) is enormously activated in this disorder, whether the RAS contributes to the development of the organ damage has not been fully elucidated. This cross-sectional study was conducted to characterize the association between RAS and the organ damage in patients with hypertensive emergencies.MethodsWe enrolled 63 patients who visited our medical center with acute severe hypertension and multiple organ damage between 2012 and 2020. Hypertensive target organ damage was evaluated on admission, including severe kidney impairment (eGFR less than 30 mL/min/1.73 m2, SKI), severe retinopathy, concentric left ventricular hypertrophy (c-LVH), thrombotic microangiopathy (TMA), heart failure with reduced ejection fraction (HFrEF) and cerebrovascular disease. Then, whether each organ injury was associated with blood pressure or a plasma aldosterone concentration was analyzed.ResultsAmong 63 patients, 31, 37, 43 and 8 cases manifested SKI, severe retinopathy, c-LVH and ischemic stroke, respectively. All populations with the organ injuries except cerebral infarction had higher plasma aldosterone concentrations than the remaining subset but exhibited a variable difference in systolic or diastolic blood pressure. Twenty-two patients had a triad of SKI, severe retinopathy and c-LVH, among whom 5 patients manifested TMA. Furthermore, the number of the damaged organs was correlated with plasma aldosterone levels (Spearman’s coefficient = 0.50), with a strong association observed between plasma aldosterone (≥ 250 pg/mL) and 3 or more complications (odds ratio = 9.16 [95%CI: 2.76–30.35]).ConclusionIn patients with hypertensive emergencies, a higher aldosterone level not only contributed to the development of the organ damage but also was associated with the number of damaged organs in each patient.

Hipertensão arterial resistente: um desafio diagnóstico

Introduction: Primary hyperaldosteronism is a leading cause of secondary arterial hypertension, affecting approximately 10% to 20% of the hypertensive population worldwide and in Brazil. This condition involves excessive aldosterone production due to factors such as adrenal adenoma, hyperplasia, or, less commonly, adrenal carcinoma and familial hyperaldosteronism. This study reports a case of resistant hypertension secondary to aldosterone-producing adenoma. Clinical Case: A 70-year-old male patient presented with episodes of dizziness, syncope, cramps, and asthenia. His medical history included resistant hypertension for over 30 years, despite treatment with five classes of antihypertensive medications. Additionally, he had a history of dyslipidemia, type 2 diabetes mellitus, non-dialysis chronic renal failure, and obstructive coronary arterydisease. Physical examination showed a BMI of 29 kg/m² (overweight), mean blood pressure of 140/90 mmHg (right arm) and 150/100 mmHg (left arm), and palpable nodules in both thyroid lobes, classified as Bethesda V based on aspiration cytopathology. Subsequently, he underwent total thyroidectomy and lymph node dissection. Laboratory tests revealed high plasma aldosterone levels with suppressed renin and an elevated aldosterone-renin ratio, raising suspicion of primary hyperaldosteronism. This diagnosis was confirmed by a computed tomography scan, which identified a 1.2 cm nodule in the right adrenal gland consistent with an adenoma. The patient underwent unilateral laparoscopic adrenalectomy. Two years post-surgery, the patient’s blood pressure was well-controlled with three antihypertensive medications, and his blood sugar, aldosterone, and renin levels were normal. Discussion and Conclusion: Most patients undergoing unilateral adrenalectomy for aldosterone-producing adenomas experience significant clinical improvement. Early screening and diagnosis of primary hyperaldosteronism are crucial for effective management, reducing the risk of complications in the cardiovascular and renal systems.

Severe hydronephrosis complicated with primary aldosteronism: a case report and review of the literature

BackgroundPrimary aldosteronism is characterized by high plasma aldosterone and low renin. The plasma aldosterone-to-renin ratio is recommended for screening. Severe hydronephrosis leads to renal parenchymal ischemia, resulting in increased renin secretion. Since nonsuppression of renin may cause a negative result in the aldosterone-to-renin ratio test, severe hydronephrosis and primary aldosteronism occurring simultaneously in a patient are challenging to diagnose.Case presentationA 54-year-old Chinese man of Han ethnicity was diagnosed with hypertension and severe hypokalemia (minimum 1.57 mmol/L) 13 years prior, and was also diagnosed with severe hydronephrosis due to congenital ureteral stenosis on the left side. His clinical features suggested primary aldosteronism, but the aldosterone-to-renin ratio result of the patient was negative every time he underwent the primary aldosteronism screening test. No further treatment for primary aldosteronism was performed, which led the patient to suffer from severe hypokalemia, such that he was taking 12–15 g/day potassium chloride orally to keep his blood potassium between 3.0 and 3.5 mmol/L (reference value, 3.5–5.5 mmol/L) for 13 years, and the patient needed to be hospitalized in the intensive care unit for rescue several times. At admission, although the aldosterone-to-renin ratio result of the patient was negative, we still did the saline stress test and captopril inhibition test, and the results showed that the plasma aldosterone level was not lower after the test than before the test. Adrenal enhanced computed tomography suggested an adenoma in the left adrenal gland, and the results of adrenal vein sampling suggested that the left side was the dominant side. Therefore, laparoscopic total resection of the left adrenal gland was performed, and 2 weeks later, the patient developed short-term renal function impairment and hyperkalemia, but his renal function and blood potassium returned to normal after treatment that included fluid rehydration. The patient’s biochemical test results and clinical symptoms were completely normal after 1 year.ConclusionWe suggest that for patients with a high suspicion of primary aldosteronism in the clinic, comprehensive analysis must be performed in combination with clinical characteristic assessments, such as severe hydronephrosis, if renin is within the normal range or if the aldosterone-to-renin ratio result is negative at screening and diagnostic tests, and adrenal vein sampling should be performed if necessary. It can help avoid misdiagnoses and contribute to the treatment of patients with severe hydronephrosis and primary aldosteronism.

7561 Maternal Sucrose Consumption During Gestation Alone Does Not Affect Glucocorticoids and Aldosterone in the Fetal Brain and Blood of Rats

Abstract Disclosure: M.M. Jung: None. D.R. Seib: None. M. Idrissi: None. H.W. Chen: None. K.K. Soma: None. Sucrose (table sugar) is a common added sugar in foods and beverages. Sucrose intake is high worldwide, yet little is known about how sucrose affects the brain and hormones. We designed an isocaloric, macro/micro-nutrient matched control diet (1% kcal sucrose) and high-sucrose diet (26% kcal sucrose) paradigm where the two diets only differ in kcal from sucrose. In this paradigm, maternal high-sucrose diet intake alters glucocorticoids (GCs) which are steroid hormones that regulate numerous physiological processes including the stress response. 16 wk of maternal sucrose intake (10 wk before mating, 3 wk during gestation, and 3 wk during lactation) increases blood and brain corticosterone levels in adult female offspring. Moreover, 13 wk of maternal sucrose intake (10 wk before mating and 3 wk during gestation) increases 11-deoxycorticosterone (DOC, corticosterone precursor) and 11-dehydrocorticosterone (DHC, corticosterone metabolite) in maternal serum, and increases aldosterone in fetal blood and brain at embryonic day 19.5 (E19.5). These results suggest that long-term maternal sucrose intake is a stressor that alters GC and aldosterone signalling. It is unclear whether a maternal high-sucrose diet only during gestation alters fetal steroid levels, or whether long-term sucrose consumption before mating is necessary. Here, we investigate the effects of maternal sucrose intake during gestation only on GCs and aldosterone in the fetal blood and brain. We hypothesize that maternal sucrose intake only during gestation will alter GC and aldosterone signaling in the fetus. We predict that maternal sucrose consumption during gestation alone will increase GC and aldosterone levels in the fetal blood and brain. Female Long-Evans rats were fed either a high-sucrose diet or a control diet starting E0.5 (day of mating confirmation) (n=15/diet). On E19.5, we collected fetal brain and blood and microdissected the regions of the fetal brain that are sensitive to GCs and aldosterone: nucleus accumbens, amygdala, hypothalamus, ventral hippocampus, and ventral tegmental area. We measured a panel of 15 steroids including GCs and aldosterone in the fetal brain (0.8-1.6 mg/region) and blood (5 µL) using liquid chromatography-tandem mass spectrometry, the gold standard for steroid quantification. Maternal high-sucrose diet intake during gestation alone did not alter maternal food intake, maternal body mass, or litter size, but increased the percentage of male offspring per litter. Maternal sucrose intake did not alter DOC, corticosterone, or DHC levels in the fetal blood and brain regions. Aldosterone was not detected in the fetal blood and brain. These results suggest that maternal sucrose intake during gestation alone does not alter GC and aldosterone levels in the developing fetus and that a longer duration of maternal sucrose intake is needed to alter offspring endocrine physiology. Presentation: 6/1/2024

7094 Post Unilateral Adrenalectomy Hyporeninemic Hypoaldosteronism: Requiring Long Term Fludrocortisone In Managing Hyperkalemia And Renal Dysfunction

Abstract Disclosure: R. Rani: None. K. Bidani: None. R. Roy: None. Adrenalectomy, seen as a potentially curative measure for unilateral aldosterone-producing adenoma (APA), targets both biochemical and clinical resolution. However, postoperative challenges may arise, including acute renal failure and hyperkalemia, due to inadequate aldosterone secretion, a consequence of prolonged suppression of the renin-angiotensin-aldosterone system (RAAS) on the contralateral side. Our case underscores the postoperative challenge of isolated aldosterone deficiency leading to renal function deterioration and hyperkalemia, necessitating fludrocortisone therapy. We are presenting case of 71-year-old male with a history of uncontrolled hypertension for over 30 years with hypokalemia (taking KCL 20mEq daily). Initial laboratory findings revealed elevated aldosterone levels 79ng/dL and an aldosterone-to-renin ratio (ARR)&amp;gt; 20, K- 3.2mmol/L, creatinine 1.32mg/dl, Na-145 mmol/L with normal cortisol and plasma metanephrines levels. CT abdomen disclosed a 21 x 18 mm right adrenal adenoma, with subsequent confirmation of lateralization through Adrenal vein sampling. The patient underwent right adrenalectomy. Two weeks post-surgery, he presented to the emergency department with symptoms of fatigue and weakness. Laboratory results indicated hyperkalemia (K- 6.5 mmol/L) and elevated creatinine (3.52mg/dl) with undetectable aldosterone and renin levels. Urinalysis and CT abdomen ruled out other causes of acute renal injury. Initial management included intravenous fluids and Potassium supplementation. However, due to persistent hypokalemia, the patient was initiated on fludrocortisone (0.1 mcg daily). Subsequent follow-up demonstrated improvement in renal function and potassium levels, however, his aldosterone and renin levels remain undetectable. Hyperkalemia incidence post-adrenalectomy in primary aldosteronism (PA) ranges from 6.3% to 29.1%. Notably, older age and preexisting impaired renal function, particularly in cases with prolonged hypertension are identified as potential risk factors for postoperative hyperkalemia and renal failure. Understanding the potential for a further decline in the glomerular filtration rate (GFR) post-surgery becomes crucial. This decline might manifest as a transient or permanent issue, necessitating prolonged fludrocortisone treatment. This case highlights the importance of tailored preoperative assessment and postoperative management to mitigate complications in high-risk populations. Presentation: 6/1/2024

6701 Bilateral Adrenal Hematomas As Initial Presenting Sign Of Lung Adenocarcinoma

Abstract Disclosure: S. Gumireddy: None. R. Panta: None. Y. Shaikh: None. Introduction: Lung cancer typically presents with dyspnea, chest pain, hemoptysis, weight loss, or recurrent pulmonary infections. This case illustrates primary lung adenocarcinoma presenting with abdominal pain and bilateral adrenal hematomas. Clinical Case: 51-year-old male presented to the emergency department with left sided abdominal pain persisting for one week. CT abdomen showed a left suprarenal mass measuring 4.5 x 5 x 4.3cm indicating an acute adrenal hematoma. An MRI showed a partially solid left adrenal lesion that had hemorrhaged and a 1.3cm hemorrhagic nodule in the right adrenal gland. The patient remained hemodynamically stable. Hormonal evaluation done while patient was in the hospital showed renin level 0.417ng/mL/hr, aldosterone level &amp;lt;1.0ng/dL, epinephrine level 312pg/mL, norepinephrine level 333pg/mL, cortisol 11.3, ACTH level 13, plasma metanephrine levels 93pg/mL, plasma normetanephrine levels 111.7pg/mL, DHEA-S 151mcg/dL, potassium 4.1mmol/L, raising concern for hypersecretion. Patient was discharged with plans for outpatient follow-up but was readmitted in two months due to worsening abdominal pain. Repeat imaging revealed an increase in size of adrenal lesions, measuring 3.3 x 3.6 cm within the right adrenal gland and a 6.7 x 6.3 cm heterogeneously enhancing lesion within the left adrenal gland concerning for metastatic disease to bilateral adrenals and to the ileum causing small bowel obstruction. Chest imaging showed a 2.2cm irregular right apical nodule. Subsequent hormonal evaluation showed normalization of plasma metanephrine levels at 15.8pg/mL, renin level 3.314ng/mL/hr, aldosterone level 4.3ng/dL, deoxycorticosterone level 4.8ng/dL, androstenedione level 40ng/dL, plasma normetanephrines 146.4pg/mL. The patient underwent left adrenal gland mass biopsy which showed metastatic poorly differentiated adenocarcinoma of pulmonary origin. Tumor cells were positive for keratin cocktail, TTF1 and synaptophysin supporting the morphologic interpretation. Patient is currently receiving treatment with carboplatin, pemetrexed, and pembrolizumab. Conclusion: Adrenal masses can be unilateral (85%) or bilateral (15%). While most unilateral adrenal masses are benign and nonfunctional, bilateral adrenal masses are likely to be metastatic disease, hemorrhage, infiltrative disease, congenital adrenal hyperplasia, macronodular Cushing’s syndrome, or bilateral cortical adenomas. Although uncommon, our case highlights the importance of considering metastatic disease to the adrenal glands as a potential initial manifestation of primary cancers. The most likely primary cancers to metastasize to the adrenal glands are breast, lung, colon, kidney, and esophagus. Presentation: 6/1/2024

12293 Dynamic Clinical Evolution: Why Patients Require Long-Term Follow-up Over Time

Abstract Disclosure: A. Attre: None. A. Syeda: None. A. Khan: None. B. Esayag-Tendler: None. Dynamic Clinical Evolution: Why Patients Require Long-Term Follow-up Over Time Introduction Primary Hyperaldosteronism (PHA) is an increasingly recognized cause of secondary hypertension amenable to specific therapy. We describe a case of PHA with change in management trajectory over time. Case A 48-year-old woman was diagnosed with PHA in 2009 based on an aldosterone level of 42.7 ng/dL, plasma renin activity of &amp;lt;0.1 ng/mL/hr, and a low potassium of 3.4 mmol/L. At that time, simultaneous adrenal venous sampling (AVS) had revealed a bilateral etiology of aldosterone excess. Original imaging with CT scan had shown fullness on both adrenal glands, and she was treated with 50mg daily spironolactone. Follow-up with CT scan in 2018 revealed similar imaging phenotype. When she established care with us in 2020, the abdomen MRI revealed a 2.5 cm x 1.9 cm right adrenal nodule. In addition, the blood pressure readings were noted to be high despite increasing doses of spironolactone to 150mg. Her laboratory results revealed aldosterone 151 ng/dL [&amp;lt; 31 ng/dL], cortisol 0.8 µg/dL, plasma renin activity 0.8 ng/mL/hr [0.2 ng/mL/hr - 1.6 ng/mL/hr], ACTH 12.5 pg/mL [7.2 pg/mL - 63.3 pg/mL], normal plasma metanephrine and a normal thyroid panel. A decision was made to repeat AVS in 2023 following Dr. Doppman’s protocol. The patient’s spironolactone was held before AVS and the plasma renin activity before the procedure was 0.4-0.8 ng/mL/hr. Results: Repeat AVS in 2023 showed mean pre-ACTH right to left lateralization index (LI) of 29.9 and mean post-ACTH LI of 9.7 (cutoff &amp;gt;4). This is concordant with the right adrenal nodule noted on imaging. The selectivity index confirmed adequate adrenal venous sampling data. Analysis of our findings confirmed right adrenal excess and left adrenal suppression compared to the IVC results. This patient underwent a laparoscopic right adrenalectomy in 2023. This patient's aldosterone levels were measured two days postoperatively and were found to be 4.2 ng/dL, showing immediate improvement. Six months postoperatively, our patient’s home and clinic blood pressures are in 120s/60s mmHg range without any medications. The aldosterone remains less than 6 ng/dL and the plasma renin activity is no longer low. Her potassium remains around 4.9 mmol/L. Discussion Based on current literature, surgical treatment is preferred when there is a confirmed unilateral cause of PHA. Adrenalectomy is recommended in patients with confirmed unilateral hyperaldosteronism especially when they do not achieve clinical and biochemical goals (renin plasma activity &amp;gt;1 ng/mL/hr, resolution of hypokalemia and optimal BP control) despite the use of MRA at appropriate doses. Suppressed renin is known to be associated with increased cardiovascular morbidity. This case serves as an important example of the need to follow patients long-term because PHA is a dynamic clinical entity that affects quality of life. Presentation: 6/3/2024

9388 Unusual Case Of Ectopic Adrenocorticotropic Hormone Syndrome Secondary To Non-small Cell Lung Cancer

Abstract Disclosure: A. TakallooBakhtiari: None. G.L. Nunlee-Bland: None. V. Ganta: None. A. Zenebe: None. H. Abdalla: None. A. Elobeid: None. W.A. Odonkor: None. Introduction: Ectopic adrenocorticotropic hormone syndrome (EAS) is a rare condition due to adrenocorticotropic hormone (ACTH) release from non-pituitary tumors. It increases the mortality of affected patients thus finding and removal of the ACTH-producing source allows for curing or reduction of symptoms and serum cortisol levels. The most common cause of EAS is lung cancer. Cushing syndrome (CS) due to EAS is an uncommon paraneoplastic phenomenon in non-small cell lung cancer. Clinical case: The patient is an 80-year-old man with a past medical history of hypertension, dementia, stroke, schizophrenia, and recently diagnosed lung adenocarcinoma. He presented with a few weeks history of dysuria and generalized fatigue. There was no family history for any endocrine disorders. He has a 40 pack-year history of tobacco use. He denied alcohol or illicit drug use. Upon initial evaluation, VS: BP 155/95 mmHg, HR 82 beats/min, Ht 77 inches, Wt 125 lb with a BMI 14.7 Kg/m2. He had no typical symptoms of CS. A physical exam showed a cachectic man with no other remarkable findings. Laboratory tests on admission showed severe hypokalemia of 1.8 mEq/L (3.5-5 mEq/L) with hypochloremic metabolic alkalosis. (bicarbonate 45 mEq/L (22-28 mEq/L) and chloride 79 mEq/L (96-106 mEq/L)). Patient was normoglycemic with HbA1c of 5.0%. Random morning cortisol was 55 μg/dL (13-24 μg/dL). Supine renin and aldosterone levels were 0.45 ng/ml/h (0.25-5.8 ng/ml/h) and 1.0 ng/dL (3-16 ng/dL), respectively, excluding hyperaldosteronism. Beside urinary tract infection, other biochemical workup revealed elevated 24-h urinary free cortisol level 5233 mcg/24h (4.0-50.0 mcg/24h) with creatinine 0.7 g/24h (0.5-2.15 g/24h). Failure to suppress cortisol with low dose dexamethasone suppression test (LDDST) was evident: morning cortisol &amp;gt;60.0 g/dL , with concurrent serum dexamethasone 299 ng/dL (180-550 ng/dL). Plasma ACTH level was elevated 327 pg/ml (6-50 pg/ml), favoring ACTH-dependent CS. A magnetic resonance imaging (MRI) of the sella and computed tomography (CT) of the abdomen did not show pituitary or adrenal masses. Therefore, a diagnosis of ectopic CS due to lung cancer was established. Pathology of the lung mass showed tumor cells were negative for synaptophysin, chromogranin, and CD52. The immunohistochemically findings support primary adenocarcinoma of the lung. Patient refused surgical or medical treatment and was discharged to a hospice facility. Conclusion: The clinical presentation of EAS ranges from the abrupt onset of the signs and symptoms of severe hypercortisolism, including hypertension, hypokalaemia, metabolic alkalosis as in our patient to the gradual and slow onset of the classical signs and symptoms of CS. Though EAS with adenocarcinoma of the lung is rare, it is important to consider it within the differential diagnosis of any adenocarcinoma of the lung presenting with the relevant symptoms. Presentation: 6/3/2024

7652 Functional Adrenocortical Carcinoma Presenting As Uncontrolled Hypertension

Abstract Disclosure: B.R. Bedell: None. M. Fariduddin: None. J. Sanchez Perez: None. S.C. Kukreja: None. R.M. Sargis: None. Adrenocortical carcinoma is a rare malignancy, with approximately 2,000 cases reported in the United States since 1970.[1] Many secrete excess adrenocortical hormones, adding to morbidity and mortality. Surgery can be curative or prolong survival if diagnosis is made early, but prognosis remains poor due to delayed detection.[2] We present a case of metastatic functional adrenocortical carcinoma that presented with consequences of long-standing uncontrolled hypertension. A 59-year-old male with history of hypertension and CAD presented to the hospital with worsening bilateral pitting edema, dyspnea on exertion, palpitations, headaches, and proximal muscle weakness over for multiple months. His hypertension (HTN) was noted to be uncontrolled despite use of multiple antihypertensives (daily Lasix 20 mg, Lisinopril 40 mg, Metoprolol Succinate 100 mg and Amlodipine 10 mg). Hypokalemia of 3.0 mmol/l (3.5 - 5.2 mmol/l) was noted. Echocardiogram revealed new heart failure with preserved ejection fraction. A subsequent nuclear stress test incidentally revealed a right-sided 15 cm retroperitoneal mass, invading the IVC and the right hepatic lobe. An AM dexamethasone suppression test was notable for a cortisol of 39 ug/dl (&amp;lt;1.8 ug/dl) and an undetectable ACTH level of &amp;lt;1.5 pg/ml (7.2 - 63.3 pg/mL), suggestive of primary hypercortisolism. 24-hour urine cortisol was 930.6 ug/d, (&amp;lt;=60.0 ug/d), DHEA-s 1105 ug/dL (52 - 295 ug/dL), Androstenedione 2.641ng/mL (0.230 - 0.890 ng/mL), and 17-Hydroxyprogesterone 299.87 ng/dL (&amp;lt;=138.00 ng/dL). Plasma metanephrines were normal and aldosterone levels were undetectable, confirming cortisol and its precursor excess as the cause of hypertension. Biopsy of the mass was consistent with adrenocortical carcinoma. Due to disease extent, the patient was not a candidate for surgical debulking, and radiation therapy was commenced. Ketoconazole 200 mg and Spironolactone 150 mg twice daily led to improvement in HTN and hypokalemia. His course was further complicated by bacteremia and acute pulmonary embolism. The patient eventually elected to pursue hospice care. Adrenocortical carcinoma remains challenging to detect at early stages given a paucity of symptoms. This case highlights the need to have a high index of suspicion for hypercortisolism in patients with uncontrolled HTN and hypokalemia, as this may be indicative of a functional adrenal cancer. This could be a potential strategy for earlier diagnosis, thereby increasing survival rates by improving disease amenability to surgical intervention. (1.) Sharma E, Dahal S, Sharma P, et al. The Characteristics and Trends in Adrenocortical Carcinoma: A United States Population Based Study. J Clin Med Res. 2018;10(8):636-640. doi:10.14740/jocmr3503w (2.) Vaidya A, Nehs M, Kilbridge K. Treatment of Adrenocortical Carcinoma. Surg Pathol Clin. 2019;12(4):997-1006. doi:10.1016/j.path.2019.08.010 Presentation: 6/2/2024

7764 A Case of Primary Hyperaldosteronism With Negative Imaging Findings -Diagnostic Approach and Outcome in a Decade

Abstract Disclosure: U.D. Gupta: None. M. Al-Ghuraibawi: None. R. Abdulhussein: None. K. Panigrahi: None. Z. Deribe: None. Distinguishing between the various subtypes of primary hyperaldosteronism (PHA) poses a clinical challenge. Nevertheless, it is notable that primary hyperaldosteronism is a prominent contributor to secondary hypertension, accounting for less than 1% of cases. The triad of hypertension, hypokalemia, and metabolic alkalosis demands screening for PHA. While bilateral adrenal hyperplasia and aldosterone-producing adenomas (APA) are common, rarer forms like unilateral adrenal hyperplasia and glucocorticoid-responsive aldosteronism can also occur. In our case, a 61-year-old patient has been diagnosed and treated for primary hyperaldosteronism for last 10-years. Presently, the patient is undergoing management for blood pressure with a medication regimen comprising Amiloride, Nifedipine, Minoxidil, Atenolol, and Eplerenone over the past decade. No abnormal findings were observed in the computed tomography or magnetic resonance imaging of the adrenal gland, and adrenal venous sampling test results were non-conclusive. The patient has exhibited favorable outcomes with medications, also subsequent imaging has not revealed the presence of an adrenal mass. This case is presented as unique due to its atypical presentation, characterized by the absence of anatomical lesions in the adrenal gland and non-conclusive sampling test results. Nevertheless, the patient responded positively to treatment, supported by the diagnostic significance of preliminary lab tests for primary hyperaldosteronism (aldosterone level: 20.5; plasma renin activity: 0.19, initially aldosterone levels were 17 and 7 before and after saline infusion). Notably, literature acknowledges that the aldosterone-producing adenomas (APAs) can be very small, sometimes &amp;lt;3 mm in diameter, and lesions &amp;lt;1 cm may be overlooked on CT scans. The limitation of adrenal venous sampling (AVS) is the challenge in obtaining good sample due to technical difficulties and variations in local expertise, success rates in AVS may vary. This case exemplifies the diagnostic complexities encountered in primary hyperaldosteronism cases, where imaging and adrenal venous sampling, though frequently recommended, may pose challenges. In conclusion, we share insights from this case and its treatment outcome. Clinically, a thorough assessment of symptoms, along with laboratory results, is crucial for diagnosis and treatment and further categorization may be challenging without imaging and adrenal venous sampling. Presentation: 6/3/2024

6657 A rare case of a composite pheochromocytoma and ganglioneuroma in a 47-year-old male

Abstract Disclosure: C. Ekladios: None. M.J. Levine: None. Introduction: Pheochromocytoma is a rare tumor that originates from adrenal chromaffin cells. It remains a diagnostic challenge due to its diverse clinical manifestations. We present a case of pheochromocytoma, shedding light on its atypical presentation and diagnostic complexity.Case reportA 47-year-old male was referred to our clinic with a recent diagnosis of pheochromocytoma. Patient started having symptoms approximately two months prior to referral to our office. He initially presented to the emergency department (ED) with generalized weakness for three days, accompanied by feelings of “rushing of blood to the head” and a “rush of blood in the arms” every time he laid down. Symptoms would last for a few seconds and resolve without intervention. Vitals signs and physical examination (PE) were within normal limits. He had basic laboratory studies including BMP and CBC without any abnormalities. He was discharged home with instructions to follow-up outpatient. He returned to the ED two days after with a chief complaint of left sided chest pain associated with palpitations, pain was non-persistent, lasting a few seconds. On presentation his blood pressure was 142/89 mmHg, Pulse: 66 bpm, Temperature: 98.4 °F, and oxygen Saturation 100%. On PE, he had clear bilateral air entry and regular heart rate with no murmurs noted, EKG demonstrated no ischemic changes. Chest Xray showed no evidence of cardiopulmonary disease. A CTA revealed no pulmonary embolism, pleural effusion, or pneumothorax. However, a large heterogeneous adrenal mass was partially visualized, measuring 8.3 cm anteroposteriorly concerning for adrenal cortical carcinoma. His labs were pertinent for Metanephrine level of 0.52 nmol/L (nl:0-0.49) and Normetanephrine of 4.22 nmol/L (nl:0-0.89). Aldosterone level is 16.2 ng/dL and Renin activity was 0.1ng/mL. An abdominal CT scan confirmed a left adrenal mass measuring approximately 9.2 x 8.8 cm transaxially and 9.9 cm craniocaudal. He was seen in our office after discharge, at that time he was still experiencing tingling in both lower extremities that sometimes would wake him up from sleep. His blood pressure at the office was 125/83 mm Hg. In preparation for the surgery, we started treatment with Prazosin, followed by addition of Metoprolol succinate. Further work-up included a dexamethasone suppression test that ruled out Cushing’s syndrome and a negative RET proto-oncogene, ruling out MEN 2. Patient underwent laparoscopic left adrenalectomy without complications. Pathology results interestingly showed a composite pheochromocytoma and ganglioneuroma constituting 5 % of the mass volume, Ki-67 proliferative index was less than 1% for the pheochromocytoma and overall findings were consistent with a benign tumor.ConclusionOur case report emphasizes the necessity of a high index of suspicion for diagnosing pheochromocytoma in the absence of the classic symptoms. Presentation: 6/2/2024

8233 Cushing Disease Presenting As Severe Persistent Hypokalemia

Abstract Disclosure: G. Palaguachi: None. A. Randhawa: None. M. Sattar: None. G. Mahajan: None. J. Karam: None. Introduction: The clinical presentation of Cushing Disease represents a wide spectrum of clinical and laboratory findings, including electrolyte derangements such as hypokalemia. In this case report, we describe a patient in whom the admission for severe persistent hypokalemia prompted the diagnosis of Cushing Disease. Clinical Case: A 35-year-old woman with history of type 2 diabetes, hypertension, and hyperlipidemia, presented to the Emergency Department with worsening bilateral lower extremities swelling, impairing her ability to walk, found to have severe hypokalemia with K level of 2.8 (3.4-4.8 mmol/L), in additional to right pubic rami fracture, left breast abscess, oral thrush, and severe hyperglycemia with HbA1C of 15.4%. Additional history was relevant for hirsutism, scalp hair thinning, weight gain, and amenorrhea of few months duration. Physical examination was significant for round face, thin scalp hair, oral thrush, facial hirsutism, central obesity, wide abdominal striae, onychomycosis, thin skin with multiple ecchymoses, bilateral lower extremity edema, and thin extremities. Her hypokalemia was resistant to therapy and K level remained in 3.2-3.5 mmol/L range on the third week of admission despite oral and intravenous potassium replacements and spironolactone high dose therapy at 100mg twice a day. Additional laboratory testing showed Cortisol 25.0 (6.70 - 27.60 ug/dL) and normal Aldosterone and renin levels. Given absence of otherwise clear etiology of hypokalemia, and presence of multiple features of Cushing’s syndrome, further inpatient evaluation included 24-hour Urine Free Cortisol level that came back at 2754 (3.5 - 45.0 mcg/24hour), 1 mg Dexamethasone Suppression Test Cortisol of 24.9 (6.70 - 27.60 ug/dL), ACTH of 151.0 (7.2 - 63.3 pg/mL), and 8 mg Dexamethasone Suppression Test Cortisol of 14.2 (6.70 - 27.60 ug/dL). MRI Pituitary showed a pituitary adenoma (0.7 x 0.3 cm) with cavernous sinus involvement. A diagnosis of Cushing disease was made and the patient underwent transsphenoidal surgery on the fourth week of hospital stay with diffuse ACTH staining of the tumor. Postoperatively, cortisol levels were not suppressed suggesting persistent disease, but hypokalemia resolved while on Spironolactone. Conclusion: This patient had several classical features of hypercortisolemia with associated hyperglycemia, recurrent infections, and bone fractures, however the finding that connected the dots and prompted establishing her diagnosis was her severe refractory hypokalemia. Although not a defining feature of Cushing Disease, and usually more pronounced with ectopic ACTH secretion, severe and/or persistent hypokalemia can be part of the presenting symptoms. This case demonstrates the importance of including Cushing Disease as part of the differential diagnosis of persistent hypokalemia in correlation with other clinical signs and diagnostics. Presentation: 6/2/2024

8659 Aldosterone-Secreting Adrenocortical Carcinoma: A Rare Cause Of Primary Hyperaldosteronism Associated With Dismal Outcome

Abstract Disclosure: S. Beeby: None. C.H. Huzita: None. F.Q. Aratani: None. L.S. Motomia: None. F. Coelho: None. M. Polo: None. C.R. Victor: None. A.O. Hoff: None. J. Chambo: None. V. Srougi: None. F. Ledesma: None. A. Latronico: None. M.Q. Almeida: None. B.B. Mendonca: None. M.C. Fragoso: None. Background: Adrenocortical carcinoma (ACC) is a rare and one of the most aggressive solid tumors, with an incidence of 1-2 cases per million. In adults, hormonal excess is usually manifested by ACTH-independent Cushing's syndrome or mixed endocrine syndrome due to cortisol and androgen production. Isolated aldosterone secretion is an extremely rare condition, with an estimated 2.5% of patients with ACC. We aimed to describe two patients with aldosterone-secreting ACC with poor outcomes. Case 1 - A 34-year-old male who was diagnosed with hypertension at 29 years of age, associated with hypokalemia needing intravenous potassium replacement therapy. Diagnosis of primary hyperaldosteronism was established with aldosterone levels of 72 ng/dL (RR &amp;lt; 23.1 ng/dL) and renin activity of 1.1 ng/mL/h (RR 0.3 to 5.8 ng/mL/h. An abdominal CT scan identified a tumor mass of 9.5 x 8.0 x 4.5 cm. He underwent a left adrenalectomy and histological and immunohistochemistry data suggested an adrenocortical carcinoma (modified Weiss score 5/7, Ki67 40%). Initial staging was ENSAT III and a Helsinki score of 48. There was transient improvement, however recent laboratory studies showed an increase in aldosterone (66,9 ng/dL) accompanied by new episodes of hypokalemia. CT scans on follow-up showed recurrence of disease, with the presence of nodules on the surgical site and abdominal wall. He received 3 lines of systemic chemotherapy and mitotane and underwent 2 other surgical procedures to treat the metastatic lesions. Currently, overall survival is 3 years. Case 2 - A 44-year-old female incidentally found a right adrenal mass (6.6 x 6.4 cm) on MRI during the investigation of elevated liver enzymes and abdominal pain. Laboratory studies showed hypokalemia, with potassium levels of 2 mEq/L (RR 3.5-5 mEq/L), aldosterone levels of 243 ng/dL (RR &amp;lt; 23.1 ng/dL), and renin of 12.2 uUI/mL (RR 4.4 - 46.1 uUI/mL). She underwent right adrenalectomy and histology and immunohistochemistry data showed a modified Weiss 7/7 and Ki67 of 80%. The patient had a germline pathogenic variant of TP53 (p.R337H). Initial staging was ENSAT III and a Helsinki score of 88. She received adjuvant mitotane and systemic chemotherapy. Even so, follow-up imaging showed hepatic metastatic disease, with an elevated aldosterone production surpassing 1000 ng/dL. The patient's overall survival was 2 years and she passed away during surgical procedure for resection of liver metastases. Discussion: ACC is a rare and aggressive tumor, and isolated aldosterone production by such tumors is extremely rare. We presented two cases with poor prognostic features and in which despite adjuvant mitotane and systemic chemotherapy there was disease progression. Due to the rarity of this condition, data on patient outcomes is limited, and further understanding of the molecular signature of these tumors could bring new insights on the tumorigenesis process. Presentation: 6/3/2024