In primary aldosteronism (PA), two subtypes are distinguished: aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH). In general, these are treated by adrenalectomy (ADX) and ...mineralocorticoid receptor antagonists (MRA), respectively.
To compare the effects of surgical treatment and medical treatment on quality of life (QoL).
Post hoc comparative effectiveness study within the Subtyping Primary Aldosteronism: A Randomized Trial Comparing Adrenal Vein Sampling and Computed Tomography Scan (SPARTACUS) trial.
Twelve Dutch hospitals and one Polish hospital.
Patients with PA (n = 184).
ADX or MRAs.
At baseline and 6-month and 1-year follow-up, we assessed QoL by two validated questionnaires: RAND 36-Item Health Survey 1.0 (RAND SF-36) and European Quality of Life-5 Dimensions (EQ-5D).
At baseline, seven of eight RAND SF-36 subscales and both summary scores, as well as three of five EQ-5D dimensions and the visual analog scale, were lower in patients with PA compared with the general population, especially in women. The beneficial effects of ADX were larger than for MRAs for seven RAND SF-36 subscales, both summary scores, and health change. For the EQ-5D, we detected a difference in favor of ADX in two dimensions and the visual analog scale. Most differences in QoL between both treatments exceeded the minimally clinically important difference. After 1 year, almost all QoL measures had normalized for adrenalectomized patients. For patients on medical treatment, most QoL measures had improved but not all to the level of the general population.
Both treatments improve QoL in PA, underscoring the importance of identifying these patients. QoL improved more after ADX for suspected APA than after initiation of medical treatment for suspected BAH.
Differentiating patients with primary aldosteronism caused by aldosterone-producing adenomas (APAs) from those with bilateral adrenal hyperplasia (BAH), which is essential for choice of therapeutic ...intervention, relies on adrenal venous sampling (AVS)-based measurements of aldosterone and cortisol. We assessed the utility of LC-MS/MS-based steroid profiling to stratify patients with primary aldosteronism.
Fifteen adrenal steroids were measured by LC-MS/MS in peripheral and adrenal venous plasma from AVS studies for 216 patients with primary aldosteronism at 3 tertiary referral centers. Ninety patients were diagnosed with BAH and 126 with APAs on the basis of immunoassay-derived adrenal venous aldosterone lateralization ratios.
Among 119 patients confirmed to have APAs at follow-up, LC-MS/MS-derived lateralization ratios of aldosterone normalized to cortisol, dehydroepiandrosterone, and androstenedione were all higher (P < 0.0001) than immunoassay-derived ratios. The hybrid steroids, 18-oxocortisol and 18-hydroxycortisol, also showed lateralized secretion in 76% and 35% of patients with APAs. Adrenal venous concentrations of glucocorticoids and androgens were bilaterally higher in patients with BAH than in those with APAs. Consequently, peripheral plasma concentrations of 18-oxocortisol were 8.5-fold higher, whereas concentrations of cortisol, corticosterone, and dehydroepiandrosterone were lower in patients with APAs than in those with BAH. Correct classification of 80% of cases of APAs vs BAH was thereby possible by use of a combination of steroids in peripheral plasma.
LC-MS/MS-based steroid profiling during AVS achieves higher aldosterone lateralization ratios in patients with APAs than immunoassay. LC-MS/MS also enables multiple measures for discriminating unilateral from bilateral aldosterone excess, with potential use of peripheral plasma for subtype classification.
•LC–MS/MS based quantification of 15 steroids in peripheral and adrenal venous samples.•Sensitivity sufficient for reliable aldosterone measurements in peripheral plasma.•Utility for clinical work-up ...of primary aldosteronism due to included hybrid steroids.•AV/pV step-ups for most other steroids higher than for cortisol.•Cosyntropin stimulation during AVS changes relative adrenal secretion of steroid.
Steroid profiling for diagnosis of endocrine disorders featuring disordered production of steroid hormones is now possible from advances in liquid chromatography with tandem mass spectrometry (LC–MS/MS). Adrenal venous (AV) measurements of aldosterone and cortisol are a standard practice in the clinical work-up of primary aldosteronism, but do not yet take advantage of steroid profiling.
A novel LC–MS/MS based method was developed for simultaneous measurement of 15 adrenal steroids: aldosterone, corticosterone, 11-deoxycorticosterone, progesterone, pregnenolone, cortisone, cortisol, 11-deoxycortisol, 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone-sulfate, 21-deoxycortisol, 18-oxocortisol and 18-hydroxycortisol. These were compared in peripheral venous (pV) and AV plasma from 70 patients undergoing AV sampling with and without cosyntropin stimulation. Aldosterone and cortisol levels measured by LC–MS/MS were compared with those measured by immunoassay.
Reproducibility of measurements with coefficients of variation ≤10% as well as analytical sensitivity sufficient to measure low pV levels particularly of aldosterone demonstrate the utility of the assay for profiling adrenal steroids in primary aldosteronism. Method comparisons indicated assay and concentration dependent differences of cortisol and aldosterone concentrations measured by immunoassay and LC–MS/MS. Median AV/pV ratios of 11-deoxycortisol (53.0), 17-hydroxyprogesterone (33.4), pregnenolone (62.4), androstenedione (40.6) and dehydroepiandrosterone (33.3) were 2.9- to, 5.4-fold larger than those for cortisol (11.6), with additionally generally larger increases than for cortisol with than without cosyntropin stimulation.
Our LC–MS/MS assay, in addition to improvements over existing immunoassay measurements of aldosterone and cortisol, offers profiling of 13 other adrenal steroids, providing a potentially useful method for the clinical work-up of patients with primary aldosteronism. In particular, the larger AV/pV ratios of several steroids compared to cortisol suggest more sensitive alternatives to the latter for assessing positioning of AV sampling catheters.
Prediction models have been developed to predict either unilateral or bilateral primary aldosteronism, and these have not been validated externally. We aimed to develop a simplified score to predict ...both subtypes and validate this externally.
Our development cohort was taken from 165 patients who underwent adrenal vein sampling (AVS) in two Asian tertiary centres. Unilateral disease was determined using both AVS and postoperative outcome. Multivariable analysis was used to construct prediction models. We validated our tool in a European cohort of 97 patients enrolled in the SPARTACUS trial who underwent AVS. Previously published prediction models were also tested in our cohorts.
Backward stepwise logistic regression analysis yielded a final tool using baseline aldosterone-to-lowest-potassium ratio (APR, ng/dl/mmol/l), with an area under receiver-operating characteristic curve of 0.80 (95% CI 0.70-0.89). In the Asian development cohort, probability of bilateral disease was 90.0% (with APR <5) and probability of unilateral disease was 91.4% (with APR >15). Similar results were seen in the European validation cohort. Combining both cohorts, probability of bilateral disease was 76.7% (with APR <5), and probability for unilateral was 91.7% (with APR >15). Other models had similar predictive ability but required more variables, and were less sensitive for identifying bilateral PA.
The novel aldosterone-to-lowest-potassium ratio is a convenient score to guide clinicians and patients of various ethnicities on the probability of primary aldosteronism subtype. Using APR to identify patients more likely to benefit from AVS may be a cost-effective strategy to manage this common condition.
Adrenal vein sampling is used to establish the origins of excess production of adrenal hormones in primary aldosteronism. Correct catheter positioning is confirmed using adrenal vein measurements of ...cortisol, but this parameter is not always reliable. Plasma metanephrine represents an alternative parameter. The objective of our study was to determine the use of plasma metanephrine concentrations to establish correct catheter positioning during adrenal vein sampling with and without cosyntropin stimulation. We included 52 cosyntropin-stimulated and 34 nonstimulated sequential procedures. Plasma cortisol and metanephrine concentrations were measured in adrenal and peripheral venous samples. Success rates of sampling, using an adrenal to peripheral cortisol selectivity index of 3.0, were compared with success rates of metanephrine using a selectivity index determined by receiver operating characteristic curve analysis. Among procedures assessed as selective using cortisol, the adrenal to peripheral vein ratio of metanephrine was 6-fold higher than that of cortisol (94.0 versus 15.5; P<0.0001). There were significant positive relationships between adrenal to peripheral vein ratios of cortisol and metanephrine for cosyntropin-stimulated samplings but not for nonstimulated samplings. Receiver operating characteristic curve analysis indicated a plasma metanephrine selectivity index cutoff of 12. Using this cutoff, concordance in sampling success rates determined by cortisol and metanephrine was substantially higher in cosyntropin-stimulated than in nonstimulated samplings (98% versus 59%). For the latter procedures, sampling success rates determined by metanephrine were higher (P<0.01) than those determined by cortisol (91% versus 56%). In conclusion, metanephrine provides a superior analyte compared with cortisol in assessing the selectivity of adrenal vein sampling during procedures without cosyntropin stimulation.
Context:
For health care planning and allocation of resources, realistic estimation of the prevalence of primary aldosteronism is necessary. Reported prevalences of primary aldosteronism are highly ...variable, possibly due to study heterogeneity.
Objective:
Our objective was to identify and explain heterogeneity in studies that aimed to establish the prevalence of primary aldosteronism in hypertensive patients.
Data Sources:
PubMed, EMBASE, Web of Science, Cochrane Library, and reference lists from January 1, 1990, to January 31, 2015, were used as data sources.
Study Selection:
Description of an adult hypertensive patient population with confirmed diagnosis of primary aldosteronism was included in this study.
Data Extraction:
Dual extraction and quality assessment were the forms of data extraction.
Data Synthesis:
Thirty-nine studies provided data on 42 510 patients (nine studies, 5896 patients from primary care). Prevalence estimates varied from 3.2% to 12.7% in primary care and from 1% to 29.8% in referral centers. Heterogeneity was too high to establish point estimates (I2 = 57.6% in primary care; 97.1% in referral centers). Meta-regression analysis showed higher prevalences in studies 1) published after 2000, 2) from Australia, 3) aimed at assessing prevalence of secondary hypertension, 4) that were retrospective, 5) that selected consecutive patients, and 6) not using a screening test. All studies had minor or major flaws.
Conclusions:
This study demonstrates that it is pointless to claim low or high prevalence of primary aldosteronism based on published reports. Because of the significant impact of a diagnosis of primary aldosteronism on health care resources and the necessary facilities, our findings urge for a prevalence study whose design takes into account the factors identified in the meta-regression analysis.
A systematic review of 39 studies from primary care and referral centers shows that gross study heterogeneity precludes a reliable estimate of the prevalence of primary aldosteronism in hypertensive patients.
Primary aldosteronism comprises 2 main subtypes: unilateral aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia. Somatic KCNJ5 mutations are found in APA at a prevalence of around ...40% that drive and sustain aldosterone excess. Somatic APA mutations have been described in other genes (CACNA1D, ATP1A1, and ATP2B3) albeit at a lower frequency. Our objective was to identify genotype-specific steroid profiles in adrenal venous (AV) and peripheral venous (PV) plasma in patients with APAs. We measured the concentrations of 15 steroids in AV and PV plasma samples by liquid chromatography-tandem mass spectrometry from 79 patients with confirmed unilateral primary aldosteronism. AV sampling lateralization ratios of steroids normalized either to cortisol or to DHEA+androstenedione were also calculated. The hybrid steroid 18-oxocortisol exhibited 18- and 16-fold higher concentrations in lateralized AV and PV plasma, respectively, from APA with KCNJ5 mutations compared with all other APA combined together (P<0.001). Lateralization ratios for the KCNJ5 group were also generally higher. Strikingly, we demonstrate that a distinct steroid signature can differentiate APA genotype in AV and PV plasma. Notably, a 7-steroid fingerprint in PV plasma correctly classified 92% of the APA according to genotype. Prospective studies are necessary to translate these findings into clinical practice and determine if steroid fingerprinting could be of value to select patients with primary aldosteronism who are particularly suitable candidates for adrenal venous sampling because of a high probability of having an APA.
At least 5% of individuals with hypertension have adrenal aldosterone-producing adenomas (APAs). Gain-of-function mutations in KCNJ5 and apparent loss-of-function mutations in ATP1A1 and ATP2A3 were ...reported to occur in APAs. We find that KCNJ5 mutations are common in APAs resembling cortisol-secreting cells of the adrenal zona fasciculata but are absent in a subset of APAs resembling the aldosterone-secreting cells of the adrenal zona glomerulosa. We performed exome sequencing of ten zona glomerulosa-like APAs and identified nine with somatic mutations in either ATP1A1, encoding the Na(+)/K(+) ATPase α1 subunit, or CACNA1D, encoding Cav1.3. The ATP1A1 mutations all caused inward leak currents under physiological conditions, and the CACNA1D mutations induced a shift of voltage-dependent gating to more negative voltages, suppressed inactivation or increased currents. Many APAs with these mutations were <1 cm in diameter and had been overlooked on conventional adrenal imaging. Recognition of the distinct genotype and phenotype for this subset of APAs could facilitate diagnosis.
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