[Show abstract][Hide abstract] ABSTRACT: Co-existing prolactinoma-primary aldosteronism (PA) is infrequently reported.
Identify patients with prolactinoma-PA and test the hypothesis that elevated prolactin (PRL) concentrations play a role in PA pathogenesis.
Hyperprolactinemia/prolactinoma was diagnosed in PA patients from 2 referral centres (Munich and Turin) and in essential hypertensive (EH) patients from 1 center (Turin). PRL receptor (PRLR) gene expression was determined by microarrays on aldosterone-producing adenomas (APA) and normal adrenals and validated by qPCR. H295R adrenal cells were incubated with 100 nM PRL and gene expression levels were determined by qPCR and aldosterone production was quantified.
Seven patients with prolactinoma-PA were identified: 4 out of 584 and 3 out of 442 patients from the Munich and Turin PA cohorts, respectively. A disproportionate number presented with macroprolactinomas (5 out of 7). There were 5 cases of hyperprolactinemia with no cases of macroprolactinoma out of 14,790 patients in a general EH cohort. In a population of PA patients case-control matched 1:3 with EH patients there were 2 cases of hyperprolactinemia out of 270 PA patients and no cases in the EH cohort (n=810). PRLR gene expression was significantly upregulated in APA compared to normal adrenals (1.7-fold and 1.5-fold by microarray and qPCR, respectively). In H295R cells, PRL treatment resulted in 1.3-fold increases in CYP11B2 expression and aldosterone production.
Elevated PRL caused by systemic hyperprolactinemia may contribute to the development of PA in those cases where the two entities co-exist.
The Journal of Clinical Endocrinology and Metabolism 07/2015; DOI:10.1210/JC.2015-2422 · 6.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pheochromocytomas and paragangliomas (PPGLs) are rare neoplasms often releasing cathecolamines, mainly originating from adrenals but occasionally observed in sympathetic and parasympathetic ganglia, with a genetic base up to 25% of the cases. After radical surgery of these tumors, disease recurrence was believed to be under 10% but recent studies reported a higher rate even after many years. Apart from familiar forms, little evidence exist about predictors of disease relapse, so we aimed to research predictors of recurrence with a retrospective analysis on patients referred to our Centers from 2000.
We collected data of patients with diagnosis of PPGL that underwent radical surgery. 76 subjects were recorded (Men/women: 42/34, Age: 45.9 ± 16.2 years) for a mean follow up of 64.9 ± 66.5 months. Genetic test for mutation of known susceptibility genes was performed in 37 cases, resulting positive in 23.
20/76 (26.3%) patients had disease recurrence. These patients were younger (30.7 ± 14.8 vs 51.4 ± 12.9 years; p = 0.000), had higher rate of positive familiarity and genetic mutations (53.3% vs 13.0%; p = 0.002 and 75% vs 14.3%; p = 0.000, respectively), lower rate of abnormal metanephrines levels (27.3% vs 64.4%, p = 0.003), larger tumors (72.4 ± 37.6 vs 45.3 ± 20.2 mm; p = 0.000) and lower biochemical normalization rate (66.6% vs 96.3%, p = 0.004). We also analysed data on follow-up with Kaplan Meier curves, searching for variables associated with cumulative incidence of recurrence by Log Rank test: age at diagnosis < 45 years (p = 0.003), neoplasm dimension > 40 mm (p = 0.009), positive familiarity (p = 0.007) or genetic test (p = 0.000) and lack of biochemical normalization after surgery (p = 0.004) were associated to disease recurrence.
Recurrence in PPGLs develops more frequently in young subjects, in patients with mutations in susceptibility genes, larger tumors, normal levels of metanephrines and incomplete normalization of biochemical markers after radical surgery. Patients with these characteristics should be monitored with strictly follow-up.
[Show abstract][Hide abstract] ABSTRACT: Primary aldosteronism (PA) is the most frequent cause of secondary hypertension responsible for an increased rate of cardiovascular events. According to the Endocrine Society Guidelines, up to 50% of hypertensive patients should be screened for PA, using the aldosterone to renin (or plasma renin activity, PRA) ratio (AARR and ARR, respectively). The automated Diasorin LIAISON® chemiluminescent immunoassay for renin and aldosterone measurement became available and in many laboratories is currently used instead of the classical radioimmunometric PRA and aldosterone assay. Aim of the study was to prospectively compare the diagnostic accuracy of AARR and ARR as screening test for PA and the two aldosterone assays also during confirmatory test in patients with a positive screening test.
One hundred patients were screened for PA and 44 patients underwent confirmatory test (either by intravenous saline load or by captopril challenge test). We considered as cut off for the AARR 2.7 (ng/dL/mU/L) and for the ARR 30 (ng/dL/ng/mL/h). All patients positive to one of the two screening test underwent confirmatory test; patients with positive confirmatory test underwent subtype diagnosis by CT scanning and adrenal vein sampling.
Seventy three patients were diagnosed as essential hypertensives, 22 had bilateral adrenal hyperplasia and 5 had an aldosterone producing adenomas (APA). The AARR displayed a sensitivity of 78% and a specificity of 100%, whereas the ARR had a sensitivity of 96% and a specificity of 90%. Of the 6/27 PA patients missed by AARR, none resulted to be affected by APA. All PA patients were correctly diagnosed by chemiluminescence at confirmatory test. In the overall sample of 181 measurements available both the correlation for the PRA with renin and for aldosterone in chemiluminescence and radioimmunoassay were highly significant (Rho = 0.66, p < 0.0001 and Rho = 0.80, p < 0.0001, respectively). On ROC curves, the AUC for AARR was 0.905 (95% CI 0.821-0.988) and for ARR 0.947 (95% CI 0.903-0.991) and they were not significantly different.
The automated aldosterone and renin chemiluminescent assay is a reliable alternative to the well-established radioimmunometric method, especially for the detection of APA.
[Show abstract][Hide abstract] ABSTRACT: Adrenal vein sampling (AVS) is recognized by Endocrine Society guidelines as the only reliable mean to distinguish between aldosterone producing adenomas and bilateral adrenal hyperplasia, the two most common subtypes of primary aldosteronism (PA). However, despite being the gold-standard procedure, AVS protocols are not standardized and vary widely between centers. The objective of the present study was to assess whether the presence or absence of contralateral adrenal (CL) suppression has an impact on the postoperative clinical and biochemical parameters in patients who underwent unilateral adrenalectomy for PA.
The study was retrospectively carried out in eight referral hypertension centers in Italy, Germany and Japan. Case detection and subtype differentiation were performed according to the Japan Endocrine Society and The Endocrine Society guidelines and a total of 234 AVS procedures were included in the study. CL suppression was defined as aldosterone/cortisol non dominant adrenal vein/aldosterone/cortisol peripheral vein less than 1.
Overall, 82% of patients displayed CL suppression at AVS, with no statistically significant differences among centers. This percentage was significantly higher in ACTH-stimulated compared with basal procedures (90% vs 77%). The contralateral ratio was inversely correlated with the aldosterone level at diagnosis and, among AVS parameters, with the lateralization index (P < 0.02 and P < 0.01, respectively). To investigate whether the presence of CL suppression was correlated with response to adrenalectomy, we analyzed the CL suppression status with regard to the patient's clinical and biochemical postoperative parameters. No differences were observed between the two groups for the main clinical and biochemical parameters (systolic and diastolic blood pressure, aldosterone, PRA, PRC, K+, number of drugs, reduction of blood pressure levels, and the number of classes of drugs assumed), but patients with CL suppression underwent a significantly larger reduction in aldosterone levels after adrenalectomy.
For patients with lateralization indices of greater than 4 (which comprised the great majority of subjects in this study), contralateral suppression should not be required to refer patients to adrenalectomy because it is not associated with a larger blood pressure reduction and might exclude patients from curative surgery.
[Show abstract][Hide abstract] ABSTRACT: Primary aldosteronism (PA) is associated with a high rate of cardio- and cerebrovascular complications and metabolic alterations. PA is also recognized as the most frequent, although often unrecognized, secondary form of hypertension. Guidelines have been released to assist clinicians in the diagnostic work-up and subtype differentiation of PA. In this review we discuss and compare the available guidelines in the context of our professional experience and evaluate diagnostic and therapeutic aspects that are still a matter of debate.
High Blood Pressure & Cardiovascular Prevention 04/2015; DOI:10.1007/s40292-015-0084-5
[Show abstract][Hide abstract] ABSTRACT: Patients with autonomic failure are characterized by orthostatic hypotension, supine hypertension, high blood pressure variability, blunted heart rate variability, and often have a "non-dipping" or "reverse dipping" pattern on 24-h ambulatory blood pressure monitoring. These alterations may lead to cardiovascular and cerebrovascular changes, similar to the target organ damage found in hypertension. Often patients with autonomic failure are on treatment with anti-hypotensive drugs, which may worsen supine hypertension. The aim of this review is to summarize the evidence for cardiac, vascular, renal, and cerebrovascular damage in patients with autonomic failure.
Clinical Autonomic Research 03/2015; 25(3). DOI:10.1007/s10286-015-0275-0 · 1.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The prevalence of orthostatic hypotension (OH) in hypertensive patients ranges from 3 to 26%. Drugs are a common cause of non-neurogenic OH. In the present study, we retrospectively evaluated the medical records of 9242 patients with essential hypertension referred to our Hypertension Unit. We analysed data on supine and standing blood pressure values, age, sex, severity of hypertension and therapeutic associations of drugs, commonly used in the treatment of hypertension. OH was present in 957 patients (10.4%). Drug combinations including α-blockers, centrally acting drugs, non-dihydropyridine calcium-channel blockers and diuretics were associated with OH. These pharmacological associations must be administered with caution, especially in hypertensive patients at high risk of OH (elderly or with severe and uncontrolled hypertension). Angiotensin-receptor blocker (ARB) seems to be not related with OH and may have a potential protective effect on the development of OH.Journal of Human Hypertension advance online publication, 29 January 2015; doi:10.1038/jhh.2014.130.
Journal of Human Hypertension 01/2015; DOI:10.1038/jhh.2014.130 · 2.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Essential hypertension arises from the combined effect of genetic and environmental factors. A pharmacogenomics approach could help to identify additional molecular mechanisms involved in its pathogenesis.
The aim of SOPHIA study was to identify genetic polymorphisms regulating blood pressure response to the angiotensin II receptor blocker, losartan, with a whole-genome approach.
We performed a genome-wide association study on blood pressure response in 372 hypertensives treated with losartan and we looked for replication in two independent samples.
We identified a peak of association in CAMK1D gene (rs10752271, effect size -5.5 ± 0.94 mmHg, p = 1.2 × 10(-8)). CAMK1D encodes a protein that belongs to the regulatory pathway involved in aldosterone synthesis. We tested the specificity of rs10752271 for losartan in hypertensives treated with hydrochlorothiazide and we validated it in silico in the GENRES cohort.
Using a genome-wide approach, we identified the CAMK1D gene as a novel locus associated with blood pressure response to losartan. CAMK1D gene characterization may represent a useful tool to personalize the treatment of essential hypertension. Original submitted 7 May 2014; Revision submitted 29 July 2014.
[Show abstract][Hide abstract] ABSTRACT: Context: Adrenal vein sampling (AVS) is the only reliable means to distinguish between aldosterone producing adenoma and bilateral adrenal hyperplasia, the two most common subtypes of primary aldosteronism (PA). AVS protocols are not standardized and vary widely between centers. Objective: To retrospectively investigate whether the presence of contralateral adrenal (CL) suppression of aldosterone secretion was associated with improved postoperative outcomes in patients who underwent unilateral adrenalectomy for PA. Setting: The study was carried out in 8 different referral centers in Italy, Germany and Japan. Patients: From 585 consecutive AVS in patients with confirmed PA, 234 procedures met the inclusion criteria and were used for the subsequent analyses. Results: Overall, 82% of patients displayed contralateral suppression. This percentage was significantly higher in ACTH stimulated compared to basal procedures (90% vs 77%). CL ratio was inversely correlated with aldosterone level at diagnosis and, amongst AVS parameters, with lateralization index (p=0.02 and 0.01, respectively). The absence of contralateral suppression was not associated with a lower rate of response to adrenalectomy in terms of both clinical and biochemical parameters and patients with CL suppression underwent a significantly larger reduction in aldosterone levels after adrenalectomy. Conclusions: For patients with lateralizing indices of > 4 (which comprised the great majority of subjects in this study), CL suppression should not be required to refer patients to adrenalectomy, since it is not associated with a larger blood pressure reduction after surgery and might exclude patients from curative surgery.
[Show abstract][Hide abstract] ABSTRACT: The risk of thoracic aortic dissection is strictly related to the diameter of the ascending aorta. Arterial hypertension represents a major risk factor for the development of aortic dissection and is thought to be directly involved in the pathogenesis of aortic aneurysms. Recent studies have suggested a high prevalence of aortic root enlargement in the hypertensive population, but evidence of a direct link between blood pressure values and size of the aortic root has been inconclusive so far. The aim of the current study was to evaluate prevalence of aortic root dilatation (ARD) in the hypertensive population and to assess the correlates of this condition.
Journal of Hypertension 06/2014; 32(10). DOI:10.1097/HJH.0000000000000286 · 4.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patients with autonomic failure experience orthostatic hypotension (OH) often leading to syncope. Arrhythmias may cause severe syncope, characterized by an increased risk of mortality. We report two cases of patients with primary autonomic neuropathy suffering from both severe OH and arrhythmic syncope.
Clinical Autonomic Research 05/2014; 24(4). DOI:10.1007/s10286-014-0246-x · 1.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Primary aldosteronism comprises subtypes that need different therapeutic strategies. Adrenal vein sampling is recognised by Endocrine Society guidelines as the only reliable way to correctly diagnose the subtype of primary aldosteronism. Unfortunately, despite being the gold-standard procedure, no standardised procedure exists either in terms of performance or interpretation criteria. In this Personal View, we address several questions that clinicians are presented with when considering adrenal vein sampling. For each of these questions we provide responses based on the available evidence, and opinions based on our experience. In particular, we discuss the most appropriate way to prepare the patient, whether adrenal vein sampling can be avoided for some subgroups of patients, the use of ACTH (1-24) during the procedure, the most appropriate criteria for interpretation of adrenal vein cannulation and lateralisation, the use of contralateral suppression, and strategies to improve success rates of adrenal vein sampling in centres with little experience.