Adrenocortical Tumors in Children With Constitutive Chromosome 11p15 Paternal Uniparental Disomy: Implications for Diagnosis and Treatment.

Pediatric adrenocortical tumors (ACTs) are rare and heterogeneous. Approximately 50% of children with ACT carry a germline TP53 variant; however, the genetic underpinning of remaining cases has not been elucidated. In patients having germline TP53 variants, loss of maternal chromosome 11 and duplication of the paternal copy [paternal uniparental disomy, (UPD)] occurs early in tumorigenesis and explains the overexpression of IGF2, the hallmark of pediatric ACT. Beckwith-Wiedemann syndrome (BWS) is also associated with overexpression of IGF2 due to disruption of the 11p15 loci, including segmental UPD. Here, we report six children with ACT with wild type TP53 and germline paternal 11p15 UPD. Median age of five girls and one boy was 3.2 years (range 0.5-11 years). Two patients met the criteria for BWS before diagnosis of ACT. However, ACT was the first and only manifestation of paternal 11p15 UPD in four children. Tumor weight ranged from 21.5 g to 550 g. Despite poor prognostic features at presentation, such as pulmonary metastasis, bilateral adrenal involvement, and large tumors, all patients are alive 8-21 years after cancer diagnosis. Our observations suggest that children with ACT and wild type TP53, irrespective of their age, should be screened for germline abnormalities in chromosome 11p15.

Epidemiology and Comorbidity of Adrenal Cushing Syndrome: A Nationwide Cohort Study.

CONTEXT: Adrenal Cushing syndrome (CS) is a major subtype of CS and has a high surgical cure rate. However, only a few studies have investigated the epidemiology and long-term outcomes of adrenal CS. OBJECTIVE: We aimed to investigate the nationwide epidemiology, long-term prognosis, and postoperative glucocorticoid replacement therapies of adrenal CS in Korea. DESIGN: Retrospective cohort study. SETTING: A nationwide claim database. PATIENTS: Adrenal CS patients who were defined as having undergone adrenalectomy, a diagnosis code of CS, and not having pituitary gland surgery. MAIN OUTCOME MEASURES: Crude incidence and age-standardized incidence rates, long-term mortality, comorbidities diagnosed preoperatively or developed postoperatively, and the pattern of postoperative glucocorticoid replacement therapy. RESULTS: From 2002 to 2017, there were a total of 1199 new adrenal CS patients, including 72 patients with adrenocortical carcinoma (malignant adrenal CS), in Korea. The crude and age-standardized incidence rates were 1.51 and 1.27 per million person-years, respectively. The overall standardized mortality ratio was 3.0 (95% confidence interval [CI], 2.4-3.7) for benign adrenal CS and 13.1 (95% CI, 7.6-18.6) for malignant adrenal CS. Adrenal CS patients had a high risk of having coronary artery disease, stroke, metabolic diseases, and depression. A similar proportion of patients were diagnosed with these comorbidities both preoperatively and postoperatively, suggesting a significant residual risk even after adrenalectomy. The median time of postoperative glucocorticoid replacement therapy was 10.1 months, and the major types of glucocorticoids used were prednisolone (66.6%) and hydrocortisone (22.4%). CONCLUSIONS: Adrenal CS is associated with multiple comorbidities even after treatment, which necessitates meticulous postoperative care.

A Comparison of Adrenalectomy and Eplerenone on Vascular Function in Patients with Aldosterone-producing Adenoma.

CONTEXT: It remains unclear whether adrenalectomy has more beneficial effects than treatment with a mineralocorticoid receptor antagonist on vascular function in patients with aldosterone-producing adenoma (APA). OBJECTIVE: The aim of this study was to compare the effects of adrenalectomy and treatment with eplerenone on vascular function in patients with APA. DESIGN, SETTING, AND PATIENTS: Flow-mediated vasodilation (FMD), as an index of endothelium-dependent vasodilation, and nitroglycerine-induced vasodilation (NID), as an index of endothelium-independent vasodilation, were measured to assess vascular function before and after a 3-month treatment with eplerenone and at 3 months after adrenalectomy in 23 patients with APA. RESULTS: Flow-mediated vasodilation and NID after adrenalectomy were significantly higher than those before treatment with eplerenone (5.4 ± 2.6% vs 2.7 ± 1.9% and 14.8 ± 4.7% vs 9.6 ± 4.6%, P < 0.01, respectively) and those after treatment with eplerenone (5.4 ± 2.6% vs 3.1 ± 2.3% and 14.8 ± 4.7% vs 11.0 ± 5.3%, P < 0.01 and P = 0.03, respectively), while treatment with eplerenone did not alter FMD and NID compared with those before treatment with eplerenone. After adrenalectomy, the increase in FMD and NID were significantly correlated with a decrease in plasma aldosterone concentration and a decrease in the aldosterone-renin ratio. There were no significant relationships between FMD and changes in other parameters or between NID and changes in other parameters. CONCLUSIONS: Adrenalectomy, but not treatment with eplerenone, improved vascular function in patients with APA. Adrenalectomy may be more effective than treatment with eplerenone for reducing the incidence of future cardiovascular events in patients with APA. Clinical Trial Information: URL for the clinical trial: http://UMIN; Registration Number for the clinical trial: UMIN000003409.

Prevalence, diagnosis and outcomes of treatment for primary aldosteronism.

Primary aldosteronism (PA) is the most common potentially curable form of hypertension. The overproduction of aldosterone leads to an increased risk of cardiovascular and cerebrovascular events as well as adverse effects to the heart and kidney and psychological disorders. PA is mainly caused by unilateral aldosterone excess due to an aldosterone-producing adenoma or bilateral excess due to bilateral adrenocortical hyperplasia. The diagnostic work-up of PA comprises three steps: screening, confirmatory testing and differentiation of unilateral surgically-correctable forms from medically treated bilateral PA. These specific treatments can mitigate or reverse the increased risks associated with PA. Herein we summarise the prevalence, outcomes and current and future clinical approaches for the diagnosis of primary aldosteronism.

Modern Management of Mild Autonomous Cortisol Secretion.

Incidentally discovered adrenal tumors are reported in ~ 5% of adults undergoing cross-sectional imaging. Mild autonomous cortisol secretion (MACS) from the adrenal mass is demonstrated in 5-48% of patients with adrenal tumors. The diagnosis of MACS represents a challenge due to limitations of the currently used diagnostic tests, differences in the definitions of the clinically relevant MACS, and heterogeneity in an individual's susceptibility to abnormal cortisol secretion from the adrenal mass. Patients with MACS present with increased risk of cardiovascular risk factors, cardiovascular events, metabolic bone disease, and mortality. Adrenalectomy improves or reverses MACS-associated comorbidities in selected patients. The current review will address diagnostic and management challenges in the care of patients with MACS, discuss data on emerging biomarkers, and suggest future directions in the field of MACS.

Non-surgically treated case of nonfunctioning ruptured adrenal adenoma in a patient on hemodialysis.

OBJECTIVES: Herein, we report a case of rupture of nonfunctional adrenal adenoma treated by nonsurgical supportive management due to high risk for operation. METHOD AND CASE: A patient with end stage renal disease (ESRD) who was on hemodialysis visited our emergency room and complained of a sudden abdominal pain after a fall. A retroperitoneal hemorrhage with hematoma formation around the adrenal adenoma, which was caused by rupture of the adrenal adenoma, was detected by abdominal computed tomography (CT). RESULTS: Supportive management was performed, with serial CT follow-up instead of surgical adrenalectomy treatment because of high operative risk, due to hemodialysis. After 1 week, the patient's vital signs stabilized and the patient did not further complain about abdominal symptoms. However, supportive embolization was performed and the size of hematoma was more decreased. CONCLUSION: We report a case of a patient on hemodialysis who experienced a rupture of a nonfunctioning adrenal adenoma, which was caused by low-energy trauma. The patient's conditions improved with nonsurgical supportive management including embolization.

Resistant Hypertension: Diagnosis and Management.

Resistant hypertension is defined as high blood pressure requiring 3 or more medications for adequate control or controlled blood pressure requiring 4 or more medications. Considering the growing prevalence of hypertension and the strong link with cardiovascular disease, it is vital to understand the causes and treatment of resistant hypertension. This review article starts with an overview of the prevalence and little-known pathophysiology of resistant hypertension. Afterward, we discuss the evaluation and management of suspected secondary resistant hypertension in 2 broad categories: pseudoresistant hypertension and true resistant hypertension. Strategies for the identification and management of pseudoresistant hypertension are addressed. In addition, causes of true resistant hypertension, such as obstructive sleep apnea, primary aldosteronism, and renal artery stenosis, are examined along with their respective treatments. Finally, treatment of resistant hypertension is reviewed including pharmacologic treatments and novel procedural interventions for resistant hypertension. Overall, the review hopes to provide practitioners with a cohesive approach for the diagnosis and treatment of resistant hypertension.

Aldosterone-Producing Adenomas.

Aldosterone-producing adenomas (APA) are more common than initially anticipated. APA cause primary aldosteronism (PA), which affect 3-10% of the hypertensive population. Research during recent years has led to an increased knowledge of the background dysregulation of the increased aldosterone release, where mutation in the gene encoding the potassium channel GIRK4-KCNJ5-is the most common. Moreover, the discovery of aldosterone-producing cell clusters in apparently normal adenomas has also led to increased understanding of the development of PA, and presumably also APA. A continuum ranging from low-renin hypertension to APA and overt PA is reasoned, and the secondary effects of aldosterone on especially the cardiovascular system have also become more evident. Diagnostics of PA and APA is important in order to reduce cardiovascular morbidity and mortality, but the diagnostic methods are somewhat unspecific and insensitive, indicating the need for novel methods.

Autonomous hypercortisolism: definition and clinical implications.

In current practice, an adrenal adenoma usually comes as an unexpected byproduct of an imaging study performed for unrelated reasons, without any prior suspect of adrenal disease. Therefore, these tumors currently represent a public health challenge because they are increasingly recognized due to the widespread use of high-resolution cross-sectional imaging for diagnostic purposes. In radiology series, the prevalence of adrenal adenomas increases steeply with age, from around 3% below the age of 50 years up to 10% in the ageing population. These tumors may have clinical relevance because they are able to secrete cortisol autonomously, independently from the pituitary control, in up to 20-30% of patients. In most of the cases the resulting cortisol excess is insufficient to produce a typical Cushing phenotype but may have clinical consequences, such as hypertension, diabetes, obesity, dyslipidemia and osteoporosis. Despite some controversy on the most effective diagnostic algorithm to define this subtle hypercortisolism, there is mounting evidence that a simple approach by using the 1-mg overnight dexamethasone suppression test (DST) may stratify patients for their cardiovascular risk. Cross-sectional, retrospective studies showed that patients with increasingly higher cortisol following DST have an adverse cardiovascular risk profile and are at increased risk of death. Therefore, also a subtle autonomous cortisol excess is associated with increased morbidity and mortality, mainly of cardiovascular origin.

Cortisol Excess in Patients With Primary Aldosteronism Impacts Left Ventricular Hypertrophy.

Context: Primary aldosteronism (PA) represents the most frequent form of endocrine hypertension. Hyperaldosteronism and hypercortisolism both induce excessive left ventricular hypertrophy (LVH) compared with matched essential hypertensives. In recent studies frequent cosecretion of cortisol and aldosterone has been reported in patients with PA. Objective: Our aim was to investigate the impact of cortisol cosecretion on LVH in patients with PA. We determined 24-hour excretion of mineralocorticoids and glucocorticoids by gas chromatography-mass spectrometry and assessed cardiac remodeling using echocardiography initially and 1 year after initiation of treatment of PA. Patients: We included 73 patients from the Munich center of the German Conn's registry: 45 with unilateral aldosterone-producing adenoma and 28 with bilateral adrenal hyperplasia. Results: At the time of diagnosis, 85% of patients with PA showed LVH according to left ventricular mass index [(LVMI); median 62.4 g/m2.7]. LVMI correlated positively with total glucocorticoid excretion (r2 = 0.076, P = 0.018) as well as with tetrahydroaldosterone excretion (r2 = 0.070, P = 0.024). Adrenalectomy led to significantly reduced LVMI in aldosterone-producing adenoma (P < 0.001) whereas mineralocorticoid receptor antagonist therapy in bilateral adrenal patients with hyperplasia reduced LVMI to a lesser degree (P = 0.024). In multivariate analysis, the decrease in LVMI was positively correlated with total glucocorticoid excretion and systolic 24-hour blood pressure, but not with tetrahydroaldosterone excretion. Conclusion: Cortisol excess appears to have an additional impact on cardiac remodeling in patients with PA. Treatment of PA by either adrenalectomy or mineralocorticoid receptor antagonist improves LVMI. This effect was most pronounced in patients with high total glucocorticoid excretion.

Neonatal Cushing Syndrome: A Rare but Potentially Devastating Disease.

Neonatal Cushing syndrome (CS) is most commonly caused by exogenous administration of glucocorticoids and rarely by endogenous hypercortisolemia. CS owing to adrenal lesions is the most common cause of endogenous CS in neonates and infants, and adrenocortical tumors (ACTs) represent most cases. Many ACTs develop in the context of a TP53 gene mutation, which causes Li-Fraumeni syndrome. More rarely, neonatal CS presents as part of other syndromes such as McCune-Albright syndrome or Beckwith-Wiedemann syndrome. Management usually includes resection of the primary tumor with or without additional medical treatment, but manifestations may persist after resolution of hypercortisolemia.

18FDG-PET/CT for the Visualization of Inflammatory Component of Radiation-Induced Lung Injury After Stereotactic Radiotherapy.

Visualization and metabolic analysis of acute inflammation in the lung parenchyma plays a crucial role for the prediction and diagnosis of radiation-induced lung injury and is particularly important in medically inoperable patients because of a priori very limited pulmonary function. This case confirms that a radiation-induced lung injury is accompanied by acute inflammatory reaction in the lung parenchyma irradiated with a total dose of 12-40 Gy. This well-defined inflammation component could be exactly characterized with FDG-PET/CT.

[Clinical diagnosis and treatment of adrenocortical adenoma in patients aged 60 years or above].

OBJECTIVE: To investigate the clinical features of adrenocortical adenoma's diagnosis and treatment in patients aged 60 years or above. METHODS: A retrospective study was performed with a total of 249 patients aged 60 years or above who suffered from adrenocortical adenoma and treated in Peking Union Medical College Hospital from January 2004 to January 2014.The clinical features, treatments and prognosis of the 249 patients aged 60 years or above were compared with another 249 patients which were randomly selected during the same period aged from 30 to 50 years.t-test or χ(2) test was used to analyze the data between the two groups. RESULTS: Endocrine examinations were performed in all 249 patients aged 60 years or above.There were 144 patients diagnosed as non-functional adrenocortical adenoma, 94 cases as aldosterone-producing adenoma and 11 cases as Cushing adenoma.For the patients aged 60 years or above, the rate of cardio-cerebral vascular incident in non-functional adrenocortical adenoma group was 26.4%(38/144), which was significantly lower than that of the aldosterone-producing adenoma and Cushing adenoma group(54.3%, 57/105)(χ(2)=20.027, P=0.000). There were 91.5%(65/71) of the patients aged 60 years or above who got a relief in low blood potassium symptoms after the operation.Forty-nine point one percent(53/108) of the non-functional adrenocortical adenoma patients aged 60 years or above had a better control of their blood pressure level, while functional adrenocortical adenoma group were 64.0%(48/75) which indicated that the functional adrenocortical adenoma patients have a better control of their blood pressure then the non-functional adrenocortical adenoma patients after the operation(χ(2)=3.987, P=0.046). There were 37.1% of the patients aged 60 years or above whose fasting blood-glucose was higher than 7.1 mmol/L, while the patients aged from 30 to 50 years was 14.1%(χ(2)=22.02, P=0.000). The differences in plasma aldosterone and blood potassium between the patients aged 60 years or above and the patients aged from 30 to 50 years had statistical significance(t=10.48, -2.58; P=0.00, 0.01). CONCLUSIONS: Most of the adrenocortical adenoma in patients aged 60 years or above is non-functional adrenocortical adenoma.Among who, patients with aldosterone-producing adenoma tend to have lower plasma aldosterone concentration and higher blood potassium level then the patients aged from 30 to 50 years.The patients aged 60 years or above with functional adrenocortical adenoma are tend to have severe cardio-cerebral vascular incidence.A few of non-functional adrenocortical adenoma patients who combine with hypertension can benefit for the operation.

Metabolic reprogramming: a new relevant pathway in adult adrenocortical tumors.

Adrenocortical carcinomas (ACCs) are complex neoplasias that may present unexpected clinical behavior, being imperative to identify new biological markers that can predict patient prognosis and provide new therapeutic options. The main aim of the present study was to evaluate the prognostic value of metabolism-related key proteins in adrenocortical carcinoma. The immunohistochemical expression of MCT1, MCT2, MCT4, CD147, CD44, GLUT1 and CAIX was evaluated in a series of 154 adult patients with adrenocortical neoplasia and associated with patients' clinicopathological parameters. A significant increase in was found for membranous expression of MCT4, GLUT1 and CAIX in carcinomas, when compared to adenomas. Importantly MCT1, GLUT1 and CAIX expressions were significantly associated with poor prognostic variables, including high nuclear grade, high mitotic index, advanced tumor staging, presence of metastasis, as well as shorter overall and disease free survival. In opposition, MCT2 membranous expression was associated with favorable prognostic parameters. Importantly, cytoplasmic expression of CD147 was identified as an independent predictor of longer overall survival and cytoplasmic expression of CAIX as an independent predictor of longer disease-free survival. We provide evidence for a metabolic reprogramming in adrenocortical malignant tumors towards the hyperglycolytic and acid-resistant phenotype, which was associated with poor prognosis.

Primary aldosteronism and pregnancy.

Primary aldosteronism is the most common cause of secondary hypertension. Less than 50 cases of pregnancy in women with primary aldosteronism have been reported, suggesting the disorder is significantly underdiagnosed in confinement. Accurate diagnosis is complicated by physiological changes in the renin-angiotensin-aldosterone axis in pregnancy, leading to a risk of false negative results on screening tests. The course of primary aldosteronism during pregnancy is highly variable, although overall it is associated with a very high risk of fetal and maternal morbidity and mortality. The optimal management of primary aldosteronism during pregnancy is unclear, with uncertainty regarding the safety of mineralocorticoid antagonists and amiloride, their relative efficacy compared with the antihypertensive medications commonly used during pregnancy, and as to whether prognosis is improved by laparoscopic adrenalectomy where an adrenal adenoma can be demonstrated.

Effect of Treatment on Body Fluid in Patients with Unilateral Aldosterone Producing Adenoma: Adrenalectomy versus Spironolactone.

Aldosterone affects fluid retention in the body by affecting how much salt and water that the kidney retains or excretes. There is limited information about the effect of prolonged aldosterone excess and treatment on body fluid in primary aldosteronism (PA) patients. In this study, body composition changes of 41 PA patients with unilateral aldosterone producing adenoma (APA) were assessed by a bio-impedance spectroscopy device. Patients with APA receiving adrenalectomy, as compared with those treated with spironolactone, had significantly lower relative overhydration (OH) and urine albumin excretion, and significantly higher urine sodium excretion four weeks after treatment. These differences dissipated 12 weeks after the initial treatment. Independent factors to predict decreased relative OH four weeks after treatment were male patients and patients who experienced adrenalectomy. Patients who underwent adrenaelctomy had significantly decreased TNF-α and increased serum potassium level when compared to patients treated with spironolactone 4 and 12 weeks after treatment. In this pilot study, we found that adrenalectomy leads to an earlier increase in renal sodium excretion and decreases in body fluid content, TNF-α, and urine albumin excretion. Adrenalectomy yields a therapeutic effect more rapidly, which has been shown to ameliorate overhydration in PA patients.

Primary aldosteronism: challenges in diagnosis and management.

Primary aldosteronism (PA) is the main cause of endocrine hypertension, present in approximately 10% of hypertensive patients; about one-third is secondary to aldosterone-producing adenomas. Cardiovascular and renal morbidity are out of proportion to the degree of hypertension. Physicians have compelling rationale to correctly identify and treat PA. Physicians are challenged with patient selection for screening with the aldosterone/renin ratio (ARR), interpretation of ARR, and selecting a confirmatory test. Adrenal vein sampling is performed for subtype differentiation. The treatment depends on the disease subtype and results in control of hypertension and reversal of associated excess morbidity.

Adrenal mild hypercortisolism.

Adrenal incidentalomas have become detected more often as the use of abdominal imaging has increased. Up to one-third of these may be secreting low levels of cortisol, known as mild hypercortisolism or subclinical Cushing syndrome. These low levels of cortisol have been found to be associated with an increased in the metabolic syndrome, osteoporosis, cardiovascular events, and mortality. This article discusses in detail the epidemiology, diagnosis, clinical associations, and treatment options of mild hypercortisolism.

Management of adrenal tumors in pregnancy.

Adrenal diseases, including Cushing syndrome (CS), primary aldosteronism (PA), pheochromocytoma, and adrenocortical carcinoma, are uncommon in pregnancy; a high degree of clinical suspicion must exist. Physiologic changes to the hypothalamus-pituitary-adrenal axis in a normal pregnancy result in increased cortisol, renin, and aldosterone levels, making the diagnosis of CS and PA in pregnancy challenging. However, catecholamines are not altered in pregnancy and allow a laboratory diagnosis of pheochromocytoma that is similar to that of the nonpregnant state. Although adrenal tumors in pregnancy result in significant maternal and fetal morbidity, and sometimes mortality, early diagnosis and appropriate treatment often improve outcomes.