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Kristina Laugesen, Jens Otto Lunde Jørgensen, Irene Petersen and Henrik Toft Sørensen

Objective

Glucocorticoid treatment of inflammatory disorders is associated with significant adverse effects related to glucocorticoid excess as well as adrenal insufficiency. This necessitates awareness of its use. We therefore investigated trends in systemic glucocorticoid use as well as morbidity and comedications among users.

Design

Cross-sectional drug utilisation study.

Methods

We conducted a population-based study of 926,314 users of systemic glucocorticoids (oral and injectable formulations) from 1999 to 2014 using Danish nationwide registries. We computed annual prevalence and incidence of systemic glucocorticoid use and prevalence of comedications and morbidity. Further, we assessed the annual amount of disease-modifying drug use.

Results

Of the 926,314 users of systemic glucocorticoids, 54% were female and median age at first-time use was 55 years. The annual prevalence was ≈ 3%, while the incidence was ≈ 1.4/100 person years (p-y). Both figures remained constant from 1999 to 2014. In the elderly, the annual prevalence was 6.7–7.7% (60–79 years of age) and 9.7–11% (≥80 years of age). Incidence increased among persons aged ≥80 years from 3.0/100 p-y in 1999 to 3.6/100 p-y in 2014. Concomitantly, the annual amount of for example methotrexate, azathioprine and tumour necrosis factor (TNF)-alpha agents increased and new biological agents emerged. The most frequent comedications were antibiotics (49%), cardiovascular drugs (38%) and NSAIDs (37%).

Conclusions

Our findings confirm a widespread use of systemic glucocorticoids, especially in the elderly, which prevails despite increased use of disease-modifying drugs. The continuously prevalent use of glucocorticoid use constitutes a challenge for the endocrine community.

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N Daskas, P Sharples, M Likeman, S Lightman and E C Crowne

Context

Traumatic brain injury (TBI) is a recognised cause of hypopituitarism in adults but the prevalence after childhood TBI remains controversial.

Objective

To investigate long-term endocrine outcomes and quality of life (PedsQL and QoL-AGHDA (Quality of Life in Adult Growth Hormone Deficiency Assessment)) following childhood TBI.

Design

Prospective study.

Methods

Participants with moderate/severe TBI (n = 31) and controls (n = 17). Mean (range) age: 19.8 ± 4.2 (11–26), time post TBI: 9 (7–11) years. Detailed endocrine evaluation of stimulated (insulin tolerance test (ITT)) and spontaneous GH secretion (overnight profile) was undertaken in the TBI group; QoL and neuroimaging in both groups.

Results

No participant had seizures, short stature, precocious puberty or hypothyroidism. In 6/25 the ITT GH response was below age-defined cut-offs and cortisol <500 nmol/L in 2/25. Mean spontaneous GH secretion was <3.1 µg/L in 16/22 but peak GH was low only in 1/22 profiles. One patient had abnormal spontaneous and stimulated GH secretion and hypogonadism. Fatigue and depression scores were higher in TBI patients (P = .011 and P = .020). Fatigue correlated with measures of spontaneous but not stimulated GH secretion. Overall QoL (PedsQL) did not differ between groups but specific attributes of health state (cognition, memory) were impaired in TBI patients. Pituitary neuroimaging was normal in all participants.

Conclusions

Fatigue and depression were common 8–10 years post childhood TBI. One individual had GHD (1/22) using rigorous diagnostic criteria. A single ITT potentially over-diagnosed GHD in 25% (6/25) without clear correlation with symptoms underlying the importance of using two diagnostic tests in TBI survivors.

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Jessica Boyd, Alexander A Leung, Hossein SM Sadrzadeh, Christina Pamporaki, Karel Pacak, Timo Deutschbein, Stephanie Fliedner and Gregory A Kline

Objective

Determine rate of high plasma normetanephrine or metanephrine (PNM-PMN) in a large sample of patients according to PNM-PMN posture and age-adjusted references.

Design

Retrospective re-analysis of PNM-PMN from a Canadian reference laboratory (n = 5452), 2011–2015; most were in seated position (n = 5112) rather than supine (n = 340). An international PPGL database demonstrated expected distribution of supine PNM-PMN in PPGL patients.

Methods

All PNM-PMN from a tertiary referral laboratory were reviewed. Any PNM-PMN result greater than 2× upper reference limit (URL) was considered likely true PPGL. Results 1–2× URL were uncertain, requiring additional testing/follow-up despite most being false positive given the rarity of PPGL. The rate of results in the 1–2× URL category were calculated for each group according to collection posture and differing published URL: seated, supine or supine age adjusted.

Results

When collected and interpreted by seated URL, 19.6% of PNM required additional testing; only 4.6% being >2× URL. For patients over age 50 years, the abnormal rate was 24.9%. When collected supine, interpreted by supine age-adjusted URL, only 5.3% of PNM were mildly elevated. Possible false positives may be even lower when considering PMN or plasma methoxytyramine which were commonly high in true PPGL despite mild PNM elevations.

Conclusions

In a general medical population, seated PNM has a high rate of abnormal results, far exceeding expected prevalence. Supine measurement with supine, age-adjusted interpretation is strongly preferred prior to costly or invasive PPGL investigations.

Summary

Review of 5452 plasma normetanephrine measurements showed 20% to be high, likely false positives for most. Supine, age-adjusted measures were half as likely to be elevated.

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Alexander Faje, Kerry Reynolds, Leyre Zubiri, Donald Lawrence, Justine V Cohen, Ryan J Sullivan, Lisa Nachtigall and Nicholas Tritos

Objective

Little has been published describing hypophysitis after nivolumab or pembrolizumab treatment. We aimed to (i) assess the risk of hypophysitis following nivolumab or pembrolizumab treatment, (ii) characterize the clinical presentation and outcomes in these patients and (iii) compare these patients to hypophysitis following ipilimumab and ipilimumab plus nivolumab (combo). We hypothesized that headaches, pituitary enlargement on MRI and multiple anterior pituitary hormone deficiencies would occur less often in the nivolumab/pembrolizumab group versus ipilimumab or combo hypophysitis patients.

Design and methods

We conducted a multi-center retrospective review utilizing the Research Patient Database registry to evaluate individuals diagnosed with hypophysitis following treatment with nivolumab/pembrolizumab (n = 22), ipilimumab (n = 64) and combo (n = 20). Encounter notes, radiologic imaging and laboratory results for these patients were comprehensively reviewed.

Results

Hypophysitis was rare following treatment with nivolumab/pembrolizumab (0.5%, 17/3522) compared to ipilimumab (13.6%, 34/250), P < 0.0001. Hypophysitis was diagnosed later in nivolumab/pembrolizumab (median: 25.8 weeks, interquartile range (IR): 18.4–44.0) compared to ipilimumab (9.3, IR: 7.2–11.1) or combo patients (12.5, IR: 7.4–18.6), P < 0.0001 for both. Headache and pituitary enlargement occurred less commonly in nivolumab/pemrolizumab patients (23% and 5/18, respectively) compared to ipilimumab (75%, 60/61) and combo (75%, 16/17) treatment groups (P < 0.0001 versus ipilimumab and P = 0.001 versus combo for headache and P < 0.0001 for both for enlargement).

Conclusions

This study represents the first comprehensive cohort analysis of nivolumab or pembrolizumab-associated hypophysitis in a large patient group. Hypophysitis occurs rarely with these medications, and these patients have a distinct phenotype compared to hypophysitis after treatment with ipilimumab or ipilimumab plus nivolumab.

Open access

Jeroen M K de Filette, Joeri J Pen, Lore Decoster, Thomas Vissers, Bert Bravenboer, Bart J Van der Auwera, Frans K Gorus, Bart O Roep, Sandrine Aspeslagh, Bart Neyns, Brigitte Velkeniers and Aan V Kharagjitsingh

Objective

To better define the rare adverse event (AE) of diabetes mellitus associated with immune checkpoint inhibitors (ICIs).

Design and methods

We report the case of a lung cancer patient with diabetic ketoacidosis (DKA) and autoimmune thyroiditis during pembrolizumab treatment. We provide a systematic review of all published cases (PubMed/Web of Science/Cochrane, through November 2018) of autoimmune diabetes mellitus related to blockade of the cytotoxic T-lymphocyte antigen 4 (CTLA-4)-, programmed cell death 1 (PD-1) receptor or its ligand (PD-L1) or combination (ICI) therapy.

Results

Our literature search identified 90 patient cases (our case excluded). Most patients were treated with anti-PD-1 or anti-PD-L1 as monotherapy (79%) or in combination with CTLA-4 blockade (15%). On average, diabetes mellitus was diagnosed after 4.5 cycles; earlier for combination ICI at 2.7 cycles. Early-onset diabetes mellitus (after one or two cycles) was observed during all treatment regimens. Diabetic ketoacidosis was present in 71%, while elevated lipase levels were detected in 52% (13/25). Islet autoantibodies were positive in 53% of patients with a predominance of glutamic acid decarboxylase antibodies. Susceptible HLA genotypes were present in 65% (mostly DR4). Thyroid dysfunction was the most frequent other endocrine AE at 24% incidence in this patient population.

Conclusion

ICI-related diabetes mellitus is a rare but often life-threatening metabolic urgency of which health-care professionals and patients should be aware. Close monitoring of blood glucose and prompt endocrine investigation in case of hyperglycemia is advisable. Predisposing factors such as HLA genotype might explain why some individuals are at risk.

Free access

Frédérique Albarel, Frédéric Castinetti and Thierry Brue

In recent years, the development of immunotherapy has constituted a revolution in the therapy for many cancers, with a specific toxicity profile including endocrine immune-related adverse events. Immune check point inhibitors (ICI)-induced hypophysitis is a common endocrine side effect, particularly with CTLA-4 antibodies and combination therapy, with frequent hormonal deficiencies at diagnosis. It can be difficult to evoke such diagnosis as the initial clinical symptoms are not specific (headache, asthenia…); thus, patients receiving such immunomodulatory therapies should be closely monitored by systematic hormone measurements, especially in the first weeks of treatment. Usually, hormonal deficiencies improve, except for corticotroph function. Despite a lack of large prospective studies on ICI-induced hypophysitis, some detailed longitudinal cohort studies have focused on such cases of hypophysitis and allow for optimal monitoring, follow-up and management of patients with this immune-related adverse event. In the case of ICI-induced hypophysitis, patients need long-term multidisciplinary follow-up, with specific education for those patients with corticotropin deficiency to allow them to be autonomous with their treatment. In this review, based on a clinical case, we detail the most relevant and novel aspects related to the incidence, diagnosis, treatment, evolution and management of hypophysitis induced by immunotherapy, with a focus on possible mechanisms and current recommendations and guidelines. Lastly, we emphasize several key points, such as the absence of indication to systematically treat with high-dose glucocorticoid and the pursuit of immunotherapy in such hypophysitis. These points should be kept in mind by oncologists and endocrinologists who treat and monitor patients treated by immunotherapy.

Free access

Grigoris Effraimidis

Prediction models are of a great assistance for predicting the development of a disease, detecting or screening undiagnosed patients, predicting the effectiveness of a treatment and helping toward better decision-making. Recently, three predictive scores in the field of autoimmune thyroid disease (AITD) have been introduced: The Thyroid Hormones Event Amsterdam (THEA) score: a predictive score of the development of overt AITD, the Graves’ Events After Therapy (GREAT) score: a prediction score for the risk of recurrence after antithyroid drugs withdrawal and the Prediction Graves’ Orbitopathy (PREDIGO) score: a prediction score for the development of Graves’ orbitopathy in newly diagnosed patients with Graves’ hyperthyroidism. Their construction, clinical applicability, the possible preventative measurements which can be taken to diminish the risks and the potential future developments which can improve the accuracy of the predictive scores are discussed in this review.

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Yufei Xu, Yirou Wang, Niu Li, Ruen Yao, Guoqiang Li, Juan Li, Yu Ding, Yao Chen, Xiaodong Huang, Yuling Chen, Yanrong Qing, Tingting Yu, Yongnian Shen, Xiumin Wang, Yiping Shen and Jian Wang

Context

Diagnosis of non-chromosomal type disorders of sex development (DSD) has long been challenging. There is still no research on overview of a large Chinese DSD cohort.

Objective

To determine the etiologic diagnosis through unbiased large-scale panel sequencing and whole-exome sequencing (WES) within a large Chinese DSD cohort.

Design

Patients were recruited according to the inclusion criteria of DSD. The applied panel contains 2742 known disease-causing genes, including all known diagnostic genes for DSD.

Methods

Targeted panel sequencing (TPS) was performed, and identified candidate variants were verified. Variant pathogenicities were evaluated according to established guidelines. WES was performed for randomly selected negative samples.

Results

This study included 125 patients. Seventy-five variants were identified by TPS and 31 variants were reported for the first time. Pathogenic and likely pathogenic variants accounted for 38.7 and 30.7%, respectively. On the basis of clinical certainty, etiologic diagnostic rates of 46.9 and 10.3% were obtained for 46,XY and 46,XX DSD patients, respectively. We reported novel candidate genes (BMPR1B, GNAS, GHR) and regions of copy number variants outside the expected DSD genotype–phenotype correlation and determined a founder mutation (SRD5A2 p.R227Q) in patients with 5α-reductase deficiency. Further WES in randomly selected negative samples identified only one among 14 negative samples as a variant of uncertain significance, indicating that WES did not improve the diagnostic rate.

Conclusions

This is the first report of the applying unbiased TPS in a large Chinese cohort of patients with 46,XY and 46,XX DSD. Our findings expand the gene, mutation and phenotype spectra of the rare types of DSD in the Chinese population and provide new insight into the current understanding of the etiologies of DSD.

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Marco Castellana, Camilla Virili, Andrea Palermo, Francesco Giorgino, Luca Giovanella and Pierpaolo Trimboli

Objective

Despite the improvements in ultrasound (US) and scintigraphy, 10–20% of patients with primary hyperparathyroidism (PHPT) still have discordant findings. We performed a systematic review and meta-analysis to assess the safety and the diagnostic performance of US-guided PTH washout (FNA-PTH) in patients with PHPT, a suspected parathyroid lesion on US but negative or equivocal scintigraphy.

Methods

The review was registered on PROSPERO (CRD42019124249). PubMed, Scopus, CENTRAL and Web of Science were searched until February 2019. Original articles reporting complications and diagnostic performance of FNA-PTH in biochemically and histopathologically diagnosed PHPT were selected. The risk of bias of included studies was assessed through QUADAS-2. Summary operating points were estimated using a random-effects model.

Results

Out of 2573 retrieved papers, nine cohort studies were included in the review. No major procedure-related complications were found. Pooled sensitivity was 95% (95% CI: 91–98; I 2: = 14%) and positive predictive value was 97% (95% CI: 93–100; I 2: = 39%). There were not enough data for specificity and negative predictive value to perform a meta-analysis. However, pooling results of all lesions, they were estimated to be 83 and 73%, respectively.

Conclusions

In patients with biochemically proven PHPT and discordant imaging, FNA-PTH was a safe and accurate procedure. In this specific setting of patients, FNA-PTH could be used as a rule-in test for minimally invasive parathyroidectomy.

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Akiyuki Kawashima, Masakatsu Sone, Nobuya Inagaki, Yoshiyu Takeda, Hiroshi Itoh, Isao Kurihara, Hironobu Umakoshi, Takamasa Ichijo, Takuyuki Katabami, Norio Wada, Yoshihiro Ogawa, Junji Kawashima, Megumi Fujita, Shozo Miyauchi, Shintaro Okamura, Tomikazu Fukuoka, Toshihiko Yanase, Shoichiro Izawa, Yuichiro Yoshikawa, Shigeatsu Hashimoto, Masanobu Yamada, Tatsuya Kai, Tomoko Suzuki, Mitsuhide Naruse and the JPAS and JRAS groups

Objective

Several clinical studies have reported that renal impairments are sometimes observed in patients with primary aldosteronism (PA). We analyzed the prevalence of renal impairments in PA patients and identified parameters that increase the risk for them.

Design

This is a retrospective cross-sectional study. We assessed the PA database established by the multicenter Japan PA study (JPAS). Data were also collected from patients with essential hypertension (EHT).

Methods

We compared the prevalences of proteinuria and lowered estimated glomerular filtration rate (eGFR) between patients with PA and age, sex, blood pressure and duration of hypertension-matched patients with EHT. We also performed logistic regression analysis to identify parameters that increase the risk for these renal impairments.

Results

Among 2366 PA patients, the prevalences of proteinuria and lowered eGFR were 10.3 and 11.6%, respectively. The prevalence of proteinuria was significantly higher in PA patients than matched-EHT patients (16.8 vs 4.4%), whereas there was no significant difference in the prevalence of lowered eGFR (17.2 vs 15.0%). The logistic regression analysis also showed that the plasma aldosterone concentration (PAC) significantly increases the risk of proteinuria and lowered eGFR, independent of other known risk factors.

Conclusion

Plasma aldosterone levels are closely associated with renal impairment in patients with PA. This is contrast to our earlier finding that the PAC was not itself linearly associated with cardiovascular events such as stroke or ischemic heart disease. The mechanism underlying the kidney damage in patients with PA may differ from that affecting the cardiovascular system.