Abstract
Context
Malignant pheochromocytoma (PHEO) and paraganglioma (PGL) are rare and knowledge of the natural history is limited.
Objective
We aimed to describe baseline characteristics and ...outcomes of patients with malignant PHEO and PGL (PPGL) and to identify predictors of shorter survival.
Design
Retrospective review of patients with malignant PPGL evaluated from 1960 to 2016.
Setting
Referral center.
Patients
The group comprised 272 patients.
Main Outcome Measures
Baseline description, survival outcomes, and predictors of shorter survival were evaluated in patients with rapidly progressive (n = 29) and indolent disease (n = 188).
Results
Malignant PPGL was diagnosed at a median age of 39 years (range, 7 to 83 years), with synchronous metastases in 96 (35%) patients. In 176 (65%) patients, metastases developed at a median of 5.5 years (range, 0.3 to 53.4 years) from the initial diagnosis. Median follow-up was 8.2 years (range, 0.01 to 54.1 years). Median overall and disease-specific survivals were 24.6 and 33.7 years, respectively. Shorter survival correlated with male sex (P = 0.014), older age at the time of primary tumor (P = 0.0011), synchronous metastases (P < 0.0001), larger primary tumor size (P = 0.0039), elevated dopamine (P = 0.0195), and not undergoing primary tumor resection (P < 0.0001). There was no difference in the type of primary tumor or presence of SDHB mutation.
Conclusions
The clinical course of patients with malignant PPGL is remarkably variable. Rapid disease progression is associated with male sex, older age at diagnosis, synchronous metastases, larger tumor size, elevated dopamine, and not undergoing resection of primary tumor. An individualized approach to patients with metastatic PPGL is warranted.
We studied patients with malignant pheochromocytoma and paraganglioma. Overall and disease-specific survivals were 24.6 and 33.7 years, respectively. Patients had a markedly variable clinical course.
Primary aldosteronism is a common cause of secondary hypertension associated with excess cardiovascular morbidities. Primary aldosteronism is underdiagnosed because it does not have a specific, ...easily identifiable feature and clinicians can be poorly aware of the disease. The diagnostic investigation is a multistep process of screening, confirmatory testing, and subtype differentiation of unilateral from bilateral forms for therapeutic management. Adrenal venous sampling is key for reliable subtype identification, but can be bypassed in patients with specific characteristics. For unilateral disease, surgery offers the possibility of cure, with total laparoscopic unilateral adrenalectomy being the treatment of choice. Bilateral forms are treated mainly with mineralocorticoid receptor antagonists. The goals of treatment are to normalise both blood pressure and excessive aldosterone production, and the primary aims are to reduce associated comorbidities, improve quality of life, and reduce mortality. Prompt diagnosis of primary aldosteronism and the use of targeted treatment strategies mitigate aldosterone-specific target organ damage and with appropriate patient management outcomes can be excellent. Advances in molecular histopathology challenge the traditional concept of primary aldosteronism as a binary disease, caused by either a unilateral aldosterone-producing adenoma or bilateral adrenal hyperplasia. Somatic mutations drive autonomous aldosterone production in most adenomas. Many of these same mutations have been identified in nodular lesions adjacent to an aldosterone-producing adenoma and in patients with bilateral disease. In addition, germline mutations cause rare familial forms of aldosteronism (familial hyperaldosteronism types 1-4). Genetic testing for inherited forms in suspected cases of familial hyperaldosteronism avoids the burdensome diagnostic investigation in positive patients. In this Review, we discuss advances and future management approaches in the diagnosis of primary aldosteronism.
Adrenal incidentalomas are commonly encountered because of the widespread use of high-resolution cross-sectional imaging. Adrenal incidentalomas may be benign or malignant, and also may demonstrate ...hormonal hypersecretion, so all patients with adrenal masses should undergo further assessment. Clinicians should have a basic understanding of adrenal incidentalomas, their workup, and when follow-up and referral are warranted.
Adrenal insufficiency continues to be a challenge for patients, their physicians, and researchers. During the past decade, long-term studies have shown increased mortality and morbidity and impaired ...quality of life in patients with adrenal insufficiency. These findings might, at least partially, be due to the failure of glucocorticoid replacement therapy to closely resemble physiological diurnal secretion of cortisol. The potential effect of newly developed glucocorticoid drugs is a focus of research, as are the mechanisms potentially underlying increased morbidity and mortality. Adrenal crisis remains a threat to lives, and awareness and preventative measures now receive increasing attention. Awareness should be raised in medical teams and patients about adrenal insufficiency and management of adrenal crisis to improve clinical outcome.
Adrenal masses are highly prevalent, found in 5% of the population. Differentiation of benign adrenocortical adenoma from adrenocortical carcinoma is currently hampered by the poor specificity and ...limited evidence base of imaging tests. This review summarizes the results of studies published to date on urine steroid metabolite profiling for distinguishing benign from malignant adrenal masses.
Three studies have described cohorts of at least 100 patients with adrenal tumors showing significant differences between urinary steroid metabolite excretions according to the nature of the underlying lesion, suggesting significant value of steroid metabolite profiling as a highly accurate diagnostic test.
Steroid profiling is emerging as a powerful novel diagnostic tool with a significant potential for improving the management for patients with adrenal tumors. Although the current studies use gas chromatography-mass spectrometry for proof of concept, widespread use of the method in routine clinical care will depend on transferring the approach to high-throughput tandem mass spectrometry platforms. The use of computational data analysis in conjunction with urine steroid metabolite profiling, that is, steroid metabolomics, adds accuracy and precision.
Context:
The diagnosis of adrenal insufficiency is clinically challenging and often requires ACTH stimulation tests.
Objective:
To determine the diagnostic accuracy of the high- (250 mcg) and low- (1 ...mcg) dose ACTH stimulation tests in the diagnosis of adrenal insufficiency.
Methods:
We searched six databases through February 2014. Pairs of independent reviewers selected studies and appraised the risk of bias. Diagnostic association measures were pooled across studies using a bivariate model.
Data Synthesis:
For secondary adrenal insufficiency, we included 30 studies enrolling 1209 adults and 228 children. High- and low-dose ACTH stimulation tests had similar diagnostic accuracy in adults and children using different peak serum cortisol cutoffs. In general, both tests had low sensitivity and high specificity resulting in reasonable likelihood ratios for a positive test (adults: high dose, 9.1; low dose, 5.9; children: high dose, 43.5; low dose, 7.7), but a fairly suboptimal likelihood ratio for a negative test (adults: high dose, 0.39; low dose, 0.19; children: high dose, 0.65; low dose, 0.34). For primary adrenal insufficiency, we included five studies enrolling 100 patients. Data were only available to estimate the sensitivity of high dose ACTH stimulation test (92%; 95% confidence interval, 81–97%).
Conclusion:
Both high- and low-dose ACTH stimulation tests had similar diagnostic accuracy. Both tests are adequate to rule in, but not rule out, secondary adrenal insufficiency. Our confidence in these estimates is low to moderate because of the likely risk of bias, heterogeneity, and imprecision.
Abstract
Context
Modern pheochromocytomas (PHEOs) are often discovered by incidental finding on cross-sectional imaging or mutation-based genetic case detection testing. Little is known about how ...these PHEOs behave.
Objective
To describe the characteristics and behavior of PHEOs discovered incidentally on imaging or through mutation-based genetic case detection testing.
Design
Retrospective study.
Setting
Referral center.
Patients
Consecutive patients with pathology-confirmed PHEOs, treated from 2005 to 2016.
Main Outcome Measure(s)
Tumor size, plasma/urine fractionated metanephrines and catecholamines, and preoperative management.
Results
Two hundred seventy-one patients (52% women, median age 52.0 years) presented with 296 PHEOs. Discovery method was most often incidental finding on cross-section imaging (61%) rather than PHEO-related symptoms (27%) or mutation-based case detection testing (12%). Patients with incidentally discovered PHEOs were older than symptomatic and mutation-based case detection testing patients (median age 56.6 vs 43 vs 35 years, P < 0.0001). Mutation-based case detection PHEOs were smaller than those discovered due to symptoms (median size 29.0 vs 50.5 mm, P = 0.0027). Patients with PHEOs discovered due to symptoms had the highest median concentration of 24-hour urinary metanephrines and total plasma metanephrines (P < 0.0001). These patients required a higher cumulative phenoxybenzamine dose than patients with incidental or case detection PHEO (median 450 vs 375 vs 270 mg, P = 0.029).
Conclusions
PHEOs are primarily discovered due to incidental finding on cross-sectional imaging rather than PHEO-related symptoms. PHEOs discovered through mutation-based genetic case detection testing were smaller and required less α-adrenergic blockade preoperatively compared with PHEOs found due to symptoms, which supports routine case detection testing for patients genetically predisposed for PHEOs.
Pheochromocytomas found by mutation-based case detection testing are less biochemically active and require less preoperative α-adrenergic blockade compared with those found due to symptoms.
Steroid profiling is a promising diagnostic tool with adrenal tumors, Cushing syndrome (CS), and disorders of steroidogenesis. Our objective was to develop a multiple-steroid assay using ...liquid-chromatography, high-resolution, accurate-mass mass spectrometry (HRAM LC-MS) and to validate the assay in patients with various adrenal disorders.
We collected 24-h urine samples from 114 controls and 71 patients with adrenal diseases. An HRAM LC-MS method was validated for quantitative analysis of 26 steroid metabolites in hydrolyzed urine samples. Differences in steroid excretion between patients were analyzed based on
-score deviation from control reference intervals.
Limits of quantification were 20 ng/mL. Dilution linearity ranged from 80% to 120% with means of 93% to 110% for all but 2 analytes. Intraassay and interassay imprecision ranged from 3% to 18% for all but 1 analyte. Control women had lower excretion of androgen and glucocorticoid precursors/metabolites than men (
< 0.001), but no difference in mineralocorticoids was seen (
= 0.06). Androgens decreased with age in both sexes (
< 0.001). Compared with patients with adrenocortical adenoma (ACA), patients with adrenocortical carcinoma (ACC) had 11 steroids with increased
scores, especially tetrahydro-11-deoxycortisol (14 vs 0.5,
< 0.001), pregnanetriol (7.5 vs -0.4,
= 0.001), and 5-pregnenetriol (5.4 vs -0.4,
= 0.01). Steroid profiling also demonstrated metabolite abnormalities consistent with enzymatic defects in congenital adrenal hyperplasia and differences in pituitary vs adrenal CS.
Our HRAM LC-MS assay successfully quantifies 26 steroids in urine. The statistically significant differences in steroid production of ACC vs ACA, adrenal vs pituitary CS, and in congenital adrenal hyperplasia should allow for improved diagnosis of patients with these diseases.
Individuals with congenital adrenal hyperplasia (CAH) require glucocorticoid therapy to replace cortisol and to control androgen excess. We sought to evaluate the effects of glucocorticoid therapy on ...cardiovascular and metabolic outcomes in individuals with CAH.
We searched bibliographical databases through January 2016 for studies evaluating cardiovascular risk factors in individuals with CAH treated with glucocorticoids compared with controls without CAH. We used a random-effects model to synthesize quantitative data.
We included 20 observational studies (14 longitudinal, six cross-sectional) with a moderate to high risk of bias. The average dose of glucocorticoids (in hydrocortisone equivalents) was 9 to 26.5 mg/m2/d. In the meta-analysis (416 patients), compared with controls without CAH, individuals with CAH had increased systolic blood pressure weighted mean difference (WMD), 4.44 mm Hg; 95% CI, 3.26 to 5.63 mm Hg, diastolic blood pressure (WMD, 2.35 mm Hg; 95% CI, 0.49 to 4.20 mm Hg), homeostatic model assessment of insulin resistance (WMD, 0.49; 95% CI, 0.02 to 0.96), and carotid intima thickness (WMD, 0.08 mm; 95% CI, 0.01 to 0.15 mm). No statistically significant differences were noted in fasting blood glucose, insulin level, glucose, or insulin level after 2-hour glucose load or serum lipids. Data on cardiac events were sparse, and most of the literature focused on surrogate outcomes.
Individuals with CAH demonstrate a high prevalence of cardiovascular and metabolic risk factors. The current evidence relies on surrogate outcomes. Long-term prospective studies are warranted to assess strategies for reducing cardiovascular risk in individuals with CAH.
Abstract
Context
Chronic opioid use may lead to adrenal insufficiency because of central suppression of the hypothalamic-pituitary-adrenal axis. However, the prevalence of opioid-induced adrenal ...insufficiency (OIAI) is unclear.
Objective
To determine the prevalence of OIAI and to identify predictors for the development of OIAI in patients taking opioids for chronic pain.
Design
Cross-sectional study, 2016-2018.
Setting
Referral center.
Patients
Adult patients taking chronic opioids admitted to the Pain Rehabilitation Center.
Main outcome measure
Diagnosis of OIAI was considered if positive case detection (cortisol < 10 mcg/dL, ACTH < 15 pg/mL, and dehydroepiandrosterone sulfate < 25 mcg/dL), and confirmed after endocrine evaluation. Daily morphine milligram equivalent (MME) was calculated.
Results
In 102 patients (median age, 53 years range, 22-83, 67% women), median daily MME was 60 mg (3-840), and median opioid therapy duration was 60 months (3-360). Abnormal case detection testing was found in 11 (10.8%) patients, and diagnosis of OIAI was made in 9 (9%). Patients with OIAI were on a higher daily MME (median, 140 20-392 mg vs 57 3-840 mg, P = 0.1), and demonstrated a 4 times higher cumulative opioid exposure (median of 13,440 vs 3120 mg*months, P = 0.03). No patient taking <MME of 20 mg/day developed OIAI (sensitivity of 100% for MME > 20 mg); however, specificity of MME cutoff >20 mg was only 19%. After opioid discontinuation, 6/7 patients recovered adrenal function.
Conclusion
The prevalence of OIAI was 9%, with MME cumulative exposure being the only predictor for OIAI development. Patients on MME of 20 mg/day and above should be monitored for OIAI.
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