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Nicole Prinz, Katja Konrad, Christoph Brack, Eva Hahn, Antje Herbst, Andrea Icks, Jürgen Grulich-Henn, Norbert Jorch, Christian Kastendieck, Kirsten Mönkemöller, Oliver Razum, Claudia Steigleder-Schweiger, Michael Witsch, Reinhard W Holl and the DPV Initiative

Objective

With increasing migration to Europe, diabetes diagnosis and treatment of refugees became challenging. To describe the current experience with pediatric refugees in Germany and Austria.

Design and Methods

43,137 patients (<21 years) with type 1 diabetes from the diabetes patient follow-up registry (DPV) were studied and divided by refugee status into patients born in Middle East (n = 365) or Africa (n = 175) and native patients (child and parents born in Germany/Austria; G/A: n = 42,597). Groups were compared using multivariable regression adjusted for age, sex and diabetes duration (SAS 9.4). In refugees the first year after arrival was studied, and for native children the most recent year of care.

Results

After adjustment, HbA1c was highest in refugees (1. ME and 2. AFR vs 3. G/A: 72.3 ± 1.0 and 75.0 ± 1.4 vs 66.0 ± 0.1 mmol/mol, 1 vs 3: P < 0.001 and 2 vs 3: P < 0.001) and microalbuminuria (9.9 and 13.6 vs 6.5%, 1 vs 3: P = 0.039 and 2 vs 3: P = 0.002) was more prevalent. African children experienced severe hypoglycemia (17.8 ± 4.3 and 25.4 ± 8.7 vs 11.5 ± 0.3 per 100 patient years, 1 vs 3: P > 0.05 and 2 vs 3: P = 0.045) significantly more often, whereas hypoglycemia with coma (5.1 ± 1.1 and 4.1 ± 1.6 vs 2.6 ± 0.1 per 100 patient years, 1 vs 3: P = 0.006 and 2 vs 3: P > 0.05) and retinopathy (2.1 and n/a vs 0.2%, 1 vs 3: P < 0.001) were significantly more common in children from Middle East compared to natives. Insulin pumps were used in a markedly larger proportion of native patients (7.4 and 13.2 vs 43.0%, 1 vs 3: P < 0.001 and 2 vs 3: P < 0.001).

Conclusions

A relevant number of pediatric refugees with type 1 diabetes are treated in German/Austrian diabetes clinics. Refugee children, parents and caregivers are faced with several problems in diabetes therapy and outcome that should be addressed more intensively by pediatric diabetes teams.

Open access

Mirjam Christ-Crain

Diabetes insipidus (DI), be it from central or nephrogenic origin, must be differentiated from secondary forms of hypotonic polyuria such as primary polydipsia. Differentiation is crucial since wrong treatment can have deleterious consequences. Since decades, the gold standard for differentiation has been the water deprivation test, which has limitations leading to an overall unsatisfying diagnostic accuracy. Furthermore, it is cumbersome for patients with a long test duration. Clinical signs and symptoms and MRI characteristics overlap between patients with DI and primary polydipsia. The direct test including vasopressin (AVP) measurement upon osmotic stimulation was meant to overcome these limitations, but failed to enter clinical practice mainly due to technical constraints of the AVP assay. Copeptin is secreted in equimolar amount to AVP but can easily be measured with a sandwich immunoassay. A high correlation between copeptin and AVP has been shown. Accordingly, copeptin mirrors the amount of AVP in the circulation and has led to a ‘revival’ of the direct test in the differential diagnosis of DI. We have shown that a baseline copeptin, without prior thirsting, unequivocally identifies patients with nephrogenic DI. In contrast, for the differentiation between central DI and primary polydipsia, a stimulated copeptin level of 4.9 pmol/L upon hypertonic saline infusion differentiates these two entities with a high diagnostic accuracy and is superior to the water deprivation test. Close sodium monitoring during the test is a prerequisite. Further new test methods are currently evaluated and might provide an even simpler way of differential diagnosis in the future.

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Yempabou Sagna, Carine Courtillot, Joseph Youssoufou Drabo, Abdellatif Tazi, Jean Donadieu, Ahmed Idbaih, Fleur Cohen, Zahir Amoura, Julien Haroche and Philippe Touraine

Objective: Langerhans Cell Histiocytosis (LCH) is a rare inflammatory myeloid neoplasm which can infiltrate any organ or tissue. Endocrine involvement has mostly been described in case reports and small retrospective studies. We aimed to describe endocrine manifestations in a large cohort of adulthood onset (AO) and childhood onset (CO) patients with LCH.

Design: single-center observational study conducted between January 2002 and December 2017 at Pitié-Salpêtrière University Hospital (Paris, France), a tertiary care hospital.

Method: Clinical, biological and morphological evaluations of pituitary, gonadal, adrenal, and thyroid function evaluations performed in 63 consecutive patients with LCH (AO patients:40, CO patients:23). Fifty-eight patients underwent follow-up assessments.

Results: Complete pituitary evaluation was performed in 38/63 patients (60.3%); at least 1 anterior pituitary dysfunction (APD) was found in 63.2% of them. In this subgroup of patients, the most prevalent deficiencies were diabetes insipidus (DI,) and GHD (55.3% each), followed by gonadotropin deficiency (34.2%) and thyrotropin deficiency (23.7%). In the subgroup of the 25 incompletely evaluated patients, we found DI in 44%, GHD in 50%, gonadotropin deficiency in 30.4% and thyrotropin deficiency in 16%. APD was more common in CO patients (p=0.003) but was not systematically associated with DI regardless of the age of onset.

Endocrine dysfunction was most often permanent; moreover, occurrence of new deficiencies has been described during follow-up.

Conclusion: The spectrum of endocrine disorders appears to be large in LCH (both in AO and CO patients) and should be evaluated carefully at diagnosis and during follow-up. APD was not always associated with DI.

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Kristina Laugesen, Jens Otto L. Jorgensen, 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 utilization 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 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 from 3.0/100 p-y in 1999 to 3.6/100 p-y in 2014. Concomitantly, the annual amount of e.g. methotrexate, azathioprine and tumor 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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Nik Daskas, Peta Sharples, Marcus Likeman, Stafford Lightman and Elizabeth Crowne

Context: TBI is a recognized 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 mcg/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=0.011 and p=0.020). 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 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 to 2015; most were seated position(n=5112) rather than supine(n=340). An international PPGL database demonstrated expected distribution of supine PNM-PMN.

Methods: All PNM-PMN from a tertiary referral laboratory were reviewed. Any PNM-PMN result greater than 2X upper reference limit(URL) was considered true PPGL. Results 1 – 2X URL were uncertain, requiring additional testing/follow up despite most being false positive given the rarity of PPGL. The rate of results in the 1-2X 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 > 2X URL. For patients over age 50, 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.

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Peter Wolf, Johanna Mayr, Hannes Beiglböck, Paul Fellinger, Yvonne Winhofer, Marko Poglitsch, Alois Gessl, Alexandra Kautzky-Willer, Anton Luger and Michael Krebs

Background

In patients suffering from primary adrenal insufficiency (AI) mortality is increased despite adequate glucocorticoid (GC) and mineralocorticoid (MC) replacement therapy, mainly due to an increased cardiovascular risk. Since activation of the renin–angiotensin–aldosterone system (RAAS) plays an important role in the modulation of cardiovascular risk factors, we performed in-depth characterization of the RAAS activity.

Methods

Eight patients with primary AI (female = 5; age: 56 ± 21 years; BMI: 22.8 ± 2 kg/m2; mean blood pressure: 140/83 mmHg; hydrocortisone dose: 21.9 ± 5 mg/day; fludrocortisone dose: 0.061 ± 0.03 mg/day) and eight matched healthy volunteers (female = 5; age: 52 ± 21 years; BMI: 25.2 ± 4 kg/m2; mean blood pressure:135/84 mmHg) were included in a cross-sectional case–control study. Angiotensin metabolite profiles (RAS-fingerprints) were performed by liquid chromatography mass spectrometry.

Results

In patients suffering from primary AI, RAAS activity was highly increased with elevated concentrations of renin concentration (P = 0.027), angiotensin (Ang) I (P = 0.022), Ang II (P = 0.032), Ang 1-7 and Ang 1-5. As expected, aldosterone was not detectable in the majority of AI patients, resulting in a profoundly suppressed aldosterone-to-AngII ratio (AA2 ratio, P = 0.003) compared to controls. PRA-S, the angiotensin-based marker for plasma renin activity, correlated with plasma renin activity (r = 0.983; P < 0.01) and plasma renin concentration (r = 0.985; P < 0.001) and was significantly increased in AI patients.

Conclusions

AI is associated with a unique RAAS profile characterized by the absence of aldosterone despite strongly elevated levels of angiotensin metabolites, including the potent vasoconstrictor AngII. Despite state-of-the-art hormone replacement therapy, the RAAS remains hyperactivated. The contribution of Ang II in cardiovascular diseases in AI patients as well as a potential role for providing useful complementary information at diagnosis and follow up of AI should be investigated in future trials.

Open access

Jeroen M.k. de Filette, Joeri J. Pen, Lore Decoster, Thomas Vissers, Bert Bravenboer, Bart J. Van der Auwera, Frans 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 (ICI).

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 1 or 2 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.

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A Ziagaki, D Blaschke, W Haverkamp and U Plöckinger

Objective

Growth hormone (GH) deficiency is related to increased cardiovascular mortality. We studied clinical status, concentration of amino-terminal-pro B-type natriuretic-peptide (NT-proBNP) and echocardiographic parameters during long-term GH replacement (GH-R).

Methods

Fifty-one patients (29 females), 45.9 ± 11.3 years (mean ± s.d.), median follow-up 36.2 months, echocardiography and laboratory determinations initially and at 12-months intervals.

Results

At the last follow-up (last observation carried forward) (LFU (LOCF)) insulin-like growth-factor-1 standard deviation score (IGF-1 SDS) was ±1 in 92% of the patients. The median NT-proBNP declined significantly and stabilized (−40.5%) at LFU (LOCF) due to patients with a basal NT-proBNP >125 ng/L (indicative of heart failure). The basal NT-proBNP and the final IGF-1 SDS were significant predictors of the NT-proBNP at LFU (LOCF). Initially left ventricular enddiastolic diameter (LVEDD), left ventricular posterior wall diameter (LVPWD) and ejection fraction (EF) were normal, while interventricular septum diameter (IVSD) and left ventricular mass index (LVMi) were slightly increased. LVPWD and IVSD had significantly declined by year three. The LVMi was moderately to severely abnormal in 37.3 and 52.0% of patients initially and at LFU (LOCF). At LFU (LOCF) LVMi and IGF-1 were significantly correlated in the 14 male patients of this subgroup.

Conclusion

Long-term GH-R of GHD positively affected ISVD and LVPWD. In a subgroup of patients with severe GHD, LVMi increased concomitantly to the decline in NT-proBNP and this was positively correlated to the final IGF-1 concentration. Whether this observation indicates a positive development in a structurally altered heart muscle (reversal of adverse remodelling) or poses a future risk for heart failure needs further follow-up.

Free access

Germano Gaudenzi, Alessandra Dicitore, Silvia Carra, Davide Saronni, Carlotta Pozza, Elisa Giannetta, Luca Persani and Giovanni Vitale

Neuroendocrine neoplasms (NENs) are traditionally considered as a single group of rare malignancies that originate from the highly spread neuroendocrine system. The clinical management is complex due to the high heterogeneity of these neoplasms in terms of clinical aggressiveness and response to the therapy. Indeed, a multidisciplinary approach is required to reach a personalization of the therapy, including cancer rehabilitation. In this review, we discuss the possibility to adopt a precision medicine (PM) approach in the management of NENs. To this purpose, we summarize current knowledge and future perspectives about biomarkers and preclinical in vitro and in vivo platforms, potentially useful to inform clinicians about the prognosis and for tailoring therapy in patients with NENs. This approach may represent a breakthrough in the therapy and tertiary prevention of these tumors.