The use of recombinant human thyrotropin (rhTSH) testing in the diagnosis and therapy of differentiated thyroid cancer (DTC) has been adopted over the last two decades as an alternative to the classical thyroid hormone withdrawal avoiding the threat of hypothyroidism. Serum thyroglobulin (Tg) measurement is crucial for monitoring DTC patients over time. Until about a decade ago, optimal sensitivity of Tg assays for the detection of smaller disease foci required Tg measurement after thyrotropin (TSH) stimulation, carried out following thyroid hormone withdrawal or rhTSH administration. In very recent years, significant improvements in assay technology have resulted in highly sensitive Tg (hsTg) assays, sufficiently sensitive to obviate the need for rhTSH stimulation in most DTC patients. The aim of this paper is to review and discuss, via a ‘pros and cons’ approach, the current clinical role of rhTSH to stimulate radioiodine (RAI) uptake for treatment and/or imaging purposes and to increase the clinical sensitivity of Tg measurement for monitoring DTC patients when high-sensitive Tg assays are available.
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Luca Giovanella and Leonidas H Duntas
Andrew A Crawford, Stefan Soderberg, Clemens Kirschbaum, Lee Murphy, Mats Eliasson, Shah Ebrahim, George Davey Smith, Tommy Olsson, Naveed Sattar, Debbie A Lawlor, Nicolas J Timpson, Rebecca M Reynolds and Brian R Walker
The identification of new causal risk factors has the potential to improve cardiovascular disease (CVD) risk prediction and the development of new treatments to reduce CVD deaths. In the general population, we sought to determine whether cortisol is a causal risk factor for CVD and coronary heart disease (CHD).
Design and methods
Three approaches were adopted to investigate the association between cortisol and CVD/CHD. First, we used multivariable regression in two prospective nested case-control studies (total 798 participants, 313 incident CVD/CHD with complete data). Second, a random-effects meta-analysis of these data and previously published prospective associations was performed (total 6680 controls, 696 incident CVD/CHD). Finally, one- and two-sample Mendelian randomization analyses were performed (122,737 CHD cases, 547,261 controls for two-sample analyses).
In the two prospective nested case–control studies, logistic regression adjusting for sex, age, BMI, smoking and time of sampling, demonstrated a positive association between morning plasma cortisol and incident CVD (OR: 1.28 per 1 SD higher cortisol, 95% CI: 1.06–1.54). In the meta-analysis of prospective studies, the equivalent result was OR: 1.18, 95% CI: 1.06–1.31. Results from the two-sample Mendelian randomization were consistent with these positive associations: OR: 1.06, 95% CI: 0.98–1.15.
All three approaches demonstrated a positive association between morning plasma cortisol and incident CVD. Together, these findings suggest that elevated morning cortisol is a causal risk factor for CVD. The current data suggest strategies targeted at lowering cortisol action should be evaluated for their effects on CVD.
Aikaterini Geroula, Timo Deutschbein, Katharina Langton, Jimmy Masjkur, Christina Pamporaki, Mirko Peitzsch, Stephanie Fliedner, Henri J L M Timmers, Stefan R Bornstein, Felix Beuschlein, Anthony Stell, Andrzej Januszewicz, Aleksander Prejbisz, Martin Fassnacht, Jacques W M Lenders and Graeme Eisenhofer
Hypertension and symptoms of catecholamine excess are features of pheochromocytomas and paragangliomas (PPGLs). This prospective observational cohort study assessed whether differences in presenting features in patients tested for PPGLs might assist establishing likelihood of disease.
Design and methods
Patients were tested for PPGLs because of signs and symptoms, an incidental mass on imaging or routine surveillance due to previous history or hereditary risk. Patients with (n = 245) compared to without (n = 1820) PPGLs were identified on follow-up. Differences in presenting features were then examined to assess the probability of disease and relationships to catecholamine excess.
Hyperhidrosis, palpitations, pallor, tremor and nausea were 30–90% more prevalent (P < 0.001) among patients with than without PPGLs, whereas headache, flushing and other symptoms showed little or no differences. Although heart rates were higher (P < 0.0001) in patients with than without PPGLs, blood pressures were not higher and were positively correlated to BMI, which was lower (P < 0.0001) in patients with than without PPGLs. From these differences in clinical features, a score system was established that indicated a 5.8-fold higher probability of PPGLs in patients with high than low scores. Higher scores among patients with PPGLs were associated, independently of tumor size, with higher biochemical indices of catecholamine excess.
This study identifies a complex of five signs and symptoms combined with lower BMI and elevated heart rate as key features in patients with PPGLs. Prevalences of these features, which reflect variable tumoral catecholamine production, may be used to triage patients according to likelihood of disease.
Leonie van Hulsteijn, Renato Pasquali, Felipe F. Casanueva, Martin Haluzik, Severine Ledoux, Mp Monteiro, Javier Salvador, Ferruccio Santini, Hermann Toplak and Olaf M Dekkers
Objective: The increasing prevalence of obesity is expected to promote the demand for endocrine testing. To facilitate evidence guided testing, we aimed to assess the prevalence of endocrine disorders in patients with obesity. The review was carried out as part of the Endocrine Work-up of Obesity Guideline of the European Society of Endocrinology.
Design: Systematic review and meta-analysis of the literature.
Methods: A search was performed in MEDLINE, Embase, Web of Science and COCHRANE Library for original articles assessing the prevalence of hypothyroidism, hypercortisolism, hypogonadism (males) or hyperandrogenism (females) in patients with obesity. Data were pooled in a random-effects logistic regression model and reported with 95% Confidence Intervals (95% CI).
Results: 68 studies were included, concerning a total of 19.996 patients with obesity. The pooled prevalence of overt (newly diagnosed or already treated) and subclinical hypothyroidism was 14.0% (95% CI 9.7-18.9) and 14.6% (95% CI 9.2-20.9), respectively. Pooled prevalence of hypercortisolism was 0.9% (95% CI 0.3-1.6). Pooled prevalence of hypogonadism when measuring total testosterone or free testosterone was 42.8% (95% CI 37.6-48.0) and 32.7% (95% CI 23.1-43.0), respectively. Heterogeneity was high for all analyses.
Conclusions: The prevalence of endocrine disorders in patients with obesity is considerable, although the underlying mechanisms are complex. Given the cross-sectional design of the studies included, no formal distinction between endocrine causes and consequences of obesity could be made.
Daniel A Heinrich, Christian Adolf, Marcus Quinkler, Finn Holler, Benjamin Lechner, Nina Nirschl, Lisa Sturm, Veronika Görge, Felix Beuschlein and Martin Reincke
Saline infusion test (SIT) and captopril challenge test (CCT) are standard confirmatory procedures routinely used in the diagnostic work-up of primary aldosteronism (PA). However, side effects and complications during testing have not been systematically studied.
We performed a cohort study with patients undergoing SIT and/or CCT in two centers from 2016 until 2018.
We studied 272 study participants with suspected PA enrolled at two outpatient centers in Germany. We assessed the frequency and severity of side effects during adjustment of blood pressure medication and during SIT and CCT.
During the adjustment phase prior confirmatory testing, side effects including palpitations, headaches, edema and hypertensive episodes occurred in 18.4% of study participants. Side effects were associated with higher defined daily doses (DDD) (r = 0.25, P < 0.005), number of antihypertensive drugs (r = 0.285, P < 0.005) and higher blood pressure (r = 0.145, P = 0.019). During SIT, 17.5% of study participants had side effects, associated with higher blood pressure (systolic: r = 0.541, P < 0.0005; diastolic: r = 0.426, P < 0.0005) and DDDs (r = 0.727, P < 0.0005). During CCT, only 1.5% of study participants developed side effects.
In contrast to the high rate of side effects during SIT, CCT appears to be the safer test with a very low event rate. This makes CCT especially suitable for severely hypertensive patients.
Lucie Coppin, Margaux Dufosse, Pauline Romanet, Sophie Giraud, Marie-Odile North, Catherine Cardot-bauters, Francoise Borson-Chazot, Laurence Duchesne, Mélanie Metallo, Tonio Lovecchio, Anne Barlier and Marie-Françoise Odou
Objective: Primary hyperparathyroism (PHPT) is a disease with either sporadic or inherited presentation. Germline mutations responsible for this disease can be found in different genes, the most frequently involved being MEN1, CDC73=HRPT2 and CASR. During the last few years, new genes have been described as responsible for development of PHPT such as GCM2. These genes are not systematically included in PHPT genetic screening yet. The aim of this work was to assess the importance of GCM2 genetic analysis in PHPT to determine if this gene should be included in gene panel investigated for this disease.
Design, and Methods: The TENGEN network (French Oncogenetic Network of Neuroendocrine Tumors) collected and interpreted allelic variants according to the clinical characteristics of the GCM2-positive patients identified through genetic testing performed in French laboratories (713 patients with PHPT).
Results: From 713 patients with PHPT included in this study, 85 (6.6%) carried at least one GCM2 variant. A total of 12 variants classified as uncertain significance or likely pathogenic were reported in 47 patients. Their mean age at PHPT diagnosis was 49 years. Additionnally, the investigation of a large family showed that GCM2 variants could be associated with low penetrancy.
Conclusion: We provide a description and interpretation for GCM2 variants identified in French population. We suggest that this gene should be included in genetic screening of patients with PHPT and propose the follow-up of calcemia for asymptomatic patients carrying such variants.
Laurence Pacot and Eric Pasmant
In the October 2019 issue of the European Journal of Endocrinology, Lin et al. reported a de novo heterozygous nonsense variant in the PHEX gene in an X-linked hypophosphatemic rickets patient. Lin et al. described a germline mosaicism in the sperm of the unaffected father of the proband, providing the opportunity to discuss the concept of isolated germline mosaicism. Upon fertilization, a human zygote inherits half of its genome from the mother via the oocyte and the other half from the father through the sperm. In addition to the genetic information passed on from generation to generation, each of us is born with a small number of novel genetic changes - de novo mutations - that occurred either prezygotically or postzygotically. A typical human genome varies at 4 to 5 million positions compared with the human reference genome. All of this genetic variation must have occurred as a de novo germline mutation in an individual at least once in human evolution. The occurrence of novel mutations in each generation explains why reproductively lethal disorders continue to occur ...
Benjamin Lechner, Katharina Lechner, Daniel Heinrich, Christian Adolf, Finn Holler, Holger Schneider, Felix Beuschlein and Martin Reincke
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.
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.