In patients with primary aldosteronism, specific treatment provides prognostic benefit over optimal antihypertensive therapy and is therefore crucial to reduce mortality and morbidity in this subgroup of patients with hypertension. Prognostic relevance has been shown for adrenalectomy in unilateral disease and for medical treatment with mineralocorticoid receptor antagonists in bilateral adrenal hyperplasia. Collectively, evidence points to the superiority of surgical treatment compared to medical treatment. The causal approach of removing the mineralocorticoid excess, as well as the often-accompanying glucocorticoid excess, might provide one biologically plausible explanation for the observation of slightly better outcomes with surgical therapy. However, in patients living with primary aldosteronism, medical treatment is often insufficient for three major reasons. First and foremost, no marker of sufficient aldosterone blockade has yet been established and therefore adequate treatment of the aldosterone excess is often dismissed as a treatment goal. Second, side effects often limit patient compliance. Third, as recommendations differ from other indications like heart failure, drug dosing is often inadequate. The aim of this review is first to provide an overview over medical treatment options and second to review potential markers for treatment surveillance in patients with primary aldosteronism.
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Benjamin Lechner, Katharina Lechner, Daniel Heinrich, Christian Adolf, Finn Holler, Holger Schneider, Felix Beuschlein and Martin Reincke
Daniel J Lobatto, Amir H Zamanipoor Najafabadi, Friso de Vries, Cornelie D Andela, Wilbert B van den Hout, Alberto M Pereira, Wilco C Peul, Thea P M Vliet Vlieland, Wouter R van Furth and Nienke R Biermasz
Although widely advocated, applying Value Based Health Care (VBHC) in clinical practice is challenging. This study describes VBHC-based perioperative outcomes for patients with pituitary tumors up to 6 months postoperatively.
A total of 103 adult patients undergoing surgery were prospectively followed. Outcomes categorized according to the framework of VHBC included survival, degree of resection, endocrine remission, visual outcome (including self-perceived functioning), recovery of pituitary function, disease burden and health-related quality of life (HRQoL) at 6 months (Tier 1); time to recovery of disease burden, HRQoL, visual function (Tier 2); permanent hypopituitarism and accompanying hormone replacement (Tier 3). Generalized estimating equations (GEEs) analysis was performed to describe outcomes over time.
Regarding Tier 1, there was no mortality, 72 patients (70%) had a complete resection, 31 of 45 patients (69%) with functioning tumors were in remission, 7 (12%, with preoperative deficits) had recovery of pituitary function and 45 of 47 (96%) had visual improvement. Disease burden and HRQoL improved in 36–45% at 6 months; however, there were significant differences between tumor types. Regarding Tier 2: disease burden, HRQoL and visual functioning improved within 6 weeks after surgery; however, recovery varied widely among tumor types (fastest in prolactinoma and non-functioning adenoma patients). Regarding Tier 3, 52 patients (50%) had persisting (tumor and treatment-induced) hypopituitarism.
Though challenging, outcomes of a surgical intervention for patients with pituitary tumors can be reflected through a VBHC-based comprehensive outcome set that can distinguish outcomes among different patient groups with respect to tumor type.
Fernando Santos-Pinheiro, Marta Penas-Prado, Carlos Kamiya-Matsuoka, Steven G Waguespack, Anita Mahajan, Paul D Brown, Komal B Shah, Gregory N Fuller and Ian E McCutcheon
Pituitary carcinoma (PC) is an aggressive neuroendocrine tumor diagnosed when a pituitary adenoma (PA) becomes metastatic. PCs are typically resistant to therapy and develop multiple recurrences despite surgery, radiotherapy and chemotherapy. Recently, treatment with temozolomide (TMZ) has shown promising results, although the lack of prospective trials limits assessment of benefit.
We describe a single-center multidisciplinary experience in managing PC patients over a 22-year period and review previously published PC series.
Seventeen patients were identified. Median age at PC diagnosis was 44 years (range 16–82 years), and the median time from PA to PC transformation was 5 years (range 1–29 years). Median follow-up time was 28 months. Most PCs were hormone-positive (n = 12): ACTH (n = 5), PRL (n = 4), LH/FSH (n = 2) and GH (n = 1). All patients underwent at least one resection and at least one course of radiation after PC diagnosis. Immunohistochemistry showed high Ki-67 labeling index (>3%) in 10/15 cases. Eight patients (47%) had only central nervous system (CNS) metastases; six (35%) had combined CNS and systemic metastases. The most commonly used chemotherapy was TMZ, and TMZ-based therapy was associated with the longest PFS in 12 (71%) cases, as well as the longest period from PC diagnosis to first progression (median 30 months). The 2, 3 and 5-year survival rate of the entire cohort was 71, 59 and 35%, respectively. All patients surviving >5 years had been treated with TMZ-based therapy.
PC management benefits from multidisciplinary care and multimodality therapy. TMZ-based regimens were associated with high survival rates and long disease control.
Domenico Corica, Chiara Zusi, Francesca Olivieri, Marco Marigliano, Claudia Piona, Elena Fornari, Anita Morandi, Massimiliano Corradi, Emanuele Miraglia del Giudice, Davide Gatti, Maurizio Rossini, Riccardo C Bonadonna and Claudio Maffeis
Vitamin D may potentially play a central role in glucose homeostasis and β-cell function (BCF), although studies are not consistent. Aim of our study was to test the hypotheses of a direct relationship between vitamin D, insulin sensitivity (IS) and BCF in overweight and obese non-diabetic children.
Design and methods
Cross-sectional study carried out at the Childhood Obesity Outpatient Clinic, University Hospital of Verona. One hundred twenty-two Caucasian overweight and obese children (age: 12.8 ± 0.2 years) were enrolled. Exclusion criteria: genetic or endocrine causes of obesity, chronic diseases or therapies. Patients underwent oral glucose tolerance test. HOMA-IR, Matsuda index and insulinogenic index were calculated. BCF was reconstructed by mathematical modeling and described by Derivative and Proportional Control. Total 25-hydroxyvitamin D and vitamin D-binding protein (VDBP) were measured. Two SNPs (rs4588 and rs7041) in the VDBP gene were studied, and bioavailable vitamin D (BVD) was calculated.
Hypovitaminosis D was documented in 90% of patients. Forty-seven subjects were homozygous for both SNPs. Total vitamin D was positively correlated with Matsuda index (P = 0.002), VDBP (P = 0.045), and negatively with BMI SDS (P = 0.043), HOMA-IR (P = 0.008), HOMA-B (P = 0.001), IGI (P = 0.007), derivative control (P = 0.036) and proportional control (P = 0.018). Total vitamin D, adjusted for age, gender, BMI SDS, puberty and seasonality of vitamin D measurement, was a predictor of Matsuda index, HOMA-IR, HOMA-B, IGI, proportional control (all P < 0.05). BVD was positively correlated with total vitamin D (P < 0.001) and negatively with BMI SDS (P = 0.041).
Hypovitaminosis D negatively influences BCF and IS, suggesting that vitamin D levels might be implicated in glucose metabolism impairment in overweight and obese individuals.
Jaap Deinum, Hans Groenewoud, Gert Jan van der Wilt, Livia Lenzini and Gian Paolo Rossi
Notwithstanding the high prevalence of primary aldosteronism (PA), probably the most common form of secondary hypertension, the diagnosis of PA is often neglected or delayed, thus precluding target treatment, which is curative in many cases. For selection of the most appropriate treatment, a fundamental step is the distinction between a lateralized form, mainly aldosterone-producing adenoma (APA), and bilateral adrenocortical hyperplasia (BAH), also known as idiopathic hyperaldosteronism (IHA). To this aim all current guidelines recommend adrenal vein sampling (AVS), a technically challenging procedure that often fails, particularly in non-experienced hands. Cosyntropin (synthetic ACTH) is administered in the attempt to maximize adrenal cortisol secretion and avoid pulsatile adrenocortical hormone secretion in about 40% of the referral centres around the world. However, the Endocrine Society guidelines do not advise about the use or not of cosyntropin as stimulus during AVS, as there are arguments in favour and against its use. These arguments are presented in this debate article reflecting the views of groups that currently use and do not use cosyntropin.
Muhamad Badarna, Ruth Percik, Genya Aharon-Hananel, Inbal Uri and Amit Tirosh
Patients with pancreatic neuroendocrine tumors (PNET) have variable prognosis, even with comparable tumor grade and stage. In the current study we aimed to evaluate the prognostic utility of the intrapancreatic PNET anatomical site.
Cohort study based on the Surveillance Epidemiology and End Results database.
Patients diagnosed with non-functioning PNET between 2004 and 2015 were compared by anatomic site for disease-specific mortality and all-cause mortality, using log-rank test and by multivariable cox regression analysis.
Overall, 4171 patients (1839 women (44.1%), median age strata 60–64 years, range 10–14 to ≥85 years) were included in our analysis. Patients with PNETs located at the head vs body/tail of the pancreas had comparable tumor diameter, as well as ethnicity, gender and age distributions, but had higher rates of grade III and IV NET (13.2 vs 6.6% and 4.4 vs 1.9%, respectively, P < 0.001). NETs located at the head vs body/tail of pancreas were more likely to be locally advanced (32.2 vs 19.9%) with no difference in distant metastases (36.4 vs 33.5%, respectively, P < 0.001). Patients with NETs of the head vs. body/tail of the pancreas had higher disease-specific mortality risk in univariate (log-rank test, P < 0.001) and multivariable analysis (hazard ratio (HR): 1.34, 95% confidence interval: 1.10–1.65, P = 0.004). Multivariable analysis for all-cause mortality also showed increased risk for patients with pancreatic head vs. body/tail PNET (HR: 1.23, P = 0.013).
PNET anatomical location is associated with the mortality risk and should be considered as a prognostic factor, and as an additional consideration in directing patients management.
Giulia Gava, Ilaria Mancini, Isabella Orsili, Silvano Bertelloni, Stefania Alvisi, Renato Seracchioli and Maria Cristina Meriggiola
Objectives. To assess bone health in adult women with complete androgen insensitivity syndrome (CAIS) and removed gonads compared with age-matched healthy controls. To evaluate the effects of transdermal estradiol 2 mg or oral estradiol valerate 2 mg on bone, biochemical and clinical characteristics. Design. Cohort study. Methods. Bone, body composition and anthropometric parameters were assessed in 32 adult CAIS and 32 healthy controls. In 28 CAIS evaluations of metabolic, bone and body composition were performed also after a maximum of six years of therapy. Results. Lumbar, femoral and total body bone mineral density (BMD) were significantly lower in those with CAIS when compared with controls. The prevalence of vertebral osteoporosis and osteopenia was significantly higher in the CAIS group (p=0.038 OR=9.67, 95% CI 1.13-82.83 and p=0.012 OR 3.85, 95% CI 1.34-11.16, respectively). Prevalence of femoral osteopenia was significantly higher in the CAIS group (p=0.0012, OR=7.93 95% CI 2.26-27.9). During follow-up, lumbar BMD significantly increased suggesting a significant effect of treatment on BMD (p=0.0016), while femoral and total body BMD did not show any significant change. Total body BMD values were positively associated to the duration and route of estrogen administration and to serum estradiol levels. Transdermal administration of estrogens was associated with better total body BMD in comparison to oral administration. Conclusions. Our results reinforce the importance of adequate hormonal treatment in women living with CAIS, suggesting a better effect from the transdermal route over the oral route.
Flávia R Oliveira, Marcelo Mamede, Mariana F Bizzi, Ana L Rocha, Cláudia N Ferreira, Karina Braga Gomes, Ana Lúcia Cândido and Fernando M Reis
Objective: To evaluate whether brown adipose tissue (BAT) activity is altered in women with polycystic ovary syndrome (PCOS), and whether BAT activity correlates with plasma levels of irisin, a myokine that can induce BAT formation.
Design: We performed a cross-sectional study including women with PCOS (n=45) and a healthy control group (n=25) matched by age and body mass index (BMI).
Methods: BAT activity was measured using 18F-FDG positron emission tomography-computed tomography (PET-CT) and plasma irisin levels were measured by a validated enzyme immunoassay.
Results: Total BAT activity was significantly reduced in women with PCOS (maximal standardized uptake value [SUVmax]: median 7.4 g/ml, interquartile range 0.9 to 15.4) compared to controls (median 13.0 g/ml, interquartile range 4.7 to 18.4, p=0.047). However, this difference was no longer significant after adjustment for waist circumference, a surrogate marker of central adiposity. In the PCOS group, BAT activity correlated negatively with BMI (Spearman’s r = -0.630, p=0.000) and waist circumference (r = -0.592, p=0.000) but not with plasma irisin levels.
Conclusions: BAT activity was reduced in women with PCOS possibly due to increased central adiposity. In PCOS women, BAT activity did not correlate with plasma irisin levels.
Ravi Kumar Dutta, Thomas Arnesen, Anette Heie, Martin K Walz, Piero Alesina, Peter Söderkvist and Oliver Gimm
To screen for CLCN2 mutations in apparently sporadic cases of aldosterone producing adenomas (APAs).
Recently, CLCN2, encoding for the voltage-gated chloride channel protein 2 (ClC-2), was identified to be mutated in familial hyperaldosteronism II (FH II). So far, somatic mutations in CLCN2 have not been reported in sporadic cases of APAs. We screened 80 apparently sporadic APAs for mutations in CLCN2. One somatic mutation was identified at p.Gly24Asp in CLCN2. The male patient had a small adenoma in size but high aldosterone levels preoperatively. Postoperatively, the patient had normal aldosterone levels and was clinically cured.
In this study, we identified a CLCN2 mutation in a sporadic APA comprising about 1% of all APAs investigated. This mutation was complementary to mutations in other susceptibility genes for sporadic APAs and may thus be a driving mutation in APA formation.
Peter J Trainer and Phillip Monaghan