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Woo Kyung Lee, Jandee Lee, Hyunji Kim, Seul Gi Lee, Sun Hyung Choi, Seonhyang Jeong, Hyeong Ju Kwon, Sang Geun Jung and Young Suk Jo

Objective

Tumor location in papillary thyroid microcarcinoma (PTMC) might determine tumor outgrowth from the thyroid gland. However, the clinical implications of tumor location and minimal extrathyroid extension (mETE) have not been well elucidated. We aimed to investigate the relationship between tumor location and mETE to predict the aggressiveness of PTMC.

Methods

A total of 858 patients with PTMC were grouped according to tumor location on ultrasonography: central (cPTMC) and peripheral PTMC (pPTMC). PTMC without mETE (PTMC-mETE(−)) was divided further according to margin shape: encapsulated (E−) or infiltrative (I−). To understand the molecular biologic characteristics of PTMC presenting with an I-margin and mETE, transcriptome data from TCGA-THCA were analyzed using Gene Set Enrichment Analysis (GSEA).

Results

pPTMC (n = 807, 94.1%) accounted for the majority of cases; mETE was identified only in pPTMC (403/807; 49.9%). pPTMC-mETE(+) showed aggressive clinical characteristics that increased the odds ratio (OR) for lymph node metastasis (LNM). Interestingly, subgroup analysis of PTMC-mETE(−) revealed that the I-margin also increased the OR for LNM, independent of other clinical factors. GSEA of TCGA-THCA data suggested coordinated upregulation of genes related to epithelial-mesenchymal transition (EMT) in PTC with mETE. Immunohistochemical staining for laminin subunit gamma 2 (LAMC2), CD59, E-cadherin and vimentin showed that these markers of EMT were associated with progressive changes in E-margin PTMC-mETE(−), I-margin PTMC-mETE(−) and pPTMC-mETE(+).

Conclusion

mETE related to peripheral location of PTMC is an important predictor of tumor invasiveness, as is the I-margin, which presents with EMT features similar to mETE. I-margin PTMC-mETE(−) and pPTMC-mETE(+) might reflect the pattern of invasive PTMC.

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Alena Welters, Ranna El-Khairi, Antonia Dastamani, Nadine Bachmann, Carsten Bergmann, Clare Gilbert, Emma Clement, Jane A Hurst, Nada Quercia, Jonathan D Wasserman, Thomas Meissner, Pratik Shah and Sebastian Kummer

Objective

Genetic aetiology remains unknown in up to 50% of patients with persistent hyperinsulinaemic hypoglycaemia (HH). Several syndromes are associated with HH. We report Rubinstein–Taybi syndrome (RSTS) as one of the possible causes of persistent HH. Early diagnosis and treatment of HH is crucial to prevent hypoglycaemic brain injury.

Design

Four RSTS patients with HH were retrospectively analysed.

Methods

Genetic investigations included next-generation sequencing-based gene panels and exome sequencing. Clinical characteristics, metabolic profile during hypoglycaemia and treatment were reviewed.

Results

Disease-related EP300 or CREBBP variants were found in all patients, no pathogenic variants were found in a panel of genes associated with non-syndromic HH. Two patients had classic manifestations of RSTS, three had choanal atresia or stenosis. Diagnosis of HH varied from 1 day to 18 months of age. One patient was unresponsive to treatment with diazoxide, octreotide and nifedipine, but responded to sirolimus. All required gastrostomy feeding.

Conclusions

Given the rarity of RSTS (1:125 000) and HH (1:50 000), our observations indicate an association between these two conditions. We therefore recommend that clinicians should be vigilant in screening for HH in symptomatic infants with RSTS. In children with an apparent syndromic form of HH, RSTS should be considered in the differential diagnosis.

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Ying Sun, Jiao Fang, Yuhui Wan, Puyu Su and Fangbiao Tao

Objective

Previous finding suggests that children growing up under chronic stress tend to experience earlier sexual maturity. The present study aims to examine polygenic risk by experience interaction in predicting pubertal timing, as well as provide insight regarding the relevance of two G × E paradigms.

Design and methods

Data were analyzed from a 3-year prospective puberty cohort in Anhui Province, China. Breast Tanner stage and testicular volume (TV) of 997 children were annually assessed. The polygenic risk score (PRS) was computed based on 17 SNPs for early pubertal timing. Hair cortisol concentrations (HCC) were assessed in the first 3 cm hair segment as a biological marker of chronic stress.

Results

Comparing with participants under moderate levels of stress as measured by HCC, the puberty-accelerating effects of chronic stress were only observed among girls with moderate (1.7 months earlier, P = 0.007) and low genetic susceptibility (2.2 months earlier, P < 0.001) and among boys with high genetic susceptibility (2.0 months earlier, P = 0.005). Polygenic differences (PRSs) in age at thelarche was most prominent in those with low levels of stress by HCC (9.06, 9.36 and 9.53 years for high, moderate and low PRS, respectively; F = 105.06, P < 0.0001), while polygenic differences in age at TV ≥4 mL was strongest in those under chronic stress (10.91, 11.06 and 11.17 years for high, moderate and low PRS, respectively; F = 100.48, P < 0.0001).

Conclusion

Chronic stress predicts earlier age at pubertal onset in a sex-specific and genetic background-dependent manner. The bioecological G × E model for girls and diathesis stress model for boys in pubertal timing warrants further investigation.

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Francisco de Paula Paranhos Neto, Leonardo Vieira Neto, Miguel Madeira, Aline Moraes, Laura Maria Carvalho de Mendonça, Inaya Correa Barbosa Lima, Claudia Lopes Rodrigues Chagas, Daisy Anne Lira, Juliana Fernandes Spitz, João Antonio Matheus Guimarães, Maria Eugênia Leite Duarte and Maria Lucia Fleiuss Farias

Introduction: The role of vitamin D on bone microarchitecture and fragility is not clear. Objective: To investigate whether vitamin D deficiency (25(OH)D <20 ng/mL) increases cortical bone loss and the severity of fractures. Design: Cross-sectional study of 287 elderly women with at least one prevalent low-impact fracture. Methods: Biochemistry, X-rays to identify vertebral fractures (VFs) and to confirm non-vertebral fractures (NonVFs), and high resolution peripheral quantitative computed tomography (HR-pQCT) to evaluate bone microstructure. Results: Serum 25(OH)D levels were associated with body mass index (BMI: r= -0.161 p=0.006), PTH (r= -0.165 p=0.005), CTX (r=-0.119 p=0.043) and vBMD at cortical bone (Dcomp: r= 0.132 p=0.033) and entire bone (D100: r= 0.162 p=0.009) at the distal radius, but not at the tibia. Age and PTH levels were potential confounding variables, but in the multiple linear regressions only BMI (95% CI 0.11 – 4.16; p<0.01), 25(OH)D (95% CI -0.007 – 1.70; p=0.05) and CTX (95% CI -149.04 – 21.80; p<0.01) predicted DComp, while BMI (95% CI 1.13 – 4.18; p<0.01) and 25(OH)D (95% CI 0.24 – 1.52; p<0.01) predicted D100. NonVFs predominated in patients with 25(OH)D<20 ng/mL (p=0.013). Logistic regression analysis showed a decrease in the likelihood of presenting grade 2-3 VFs / NonVFs for every increase in 25(OH)D (OR = 0.962, 95% CI 0.940 – 0.984; p=0.001), BMI (OR = 0.932, 95% CI 0.885 – 0.981; p=0.007) and D100 at radius (OR = 0.994, 95% CI 0.990 – 0.998; p=0.005). Conclusion: In elderly patients with prevalent fractures, vitamin D deficiency was associated with cortical bone loss and severity of fractures.

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Esben T Vestergaard, Niels Møller, René Frydensbjerg Andersen, Søren Rittig and Jens Otto Lunde Jørgensen

Objective

Acyl ghrelin, which is the endogenous ligand for the growth hormone secretagogue receptor, potently stimulates pituitary growth hormone release, and to some degree adrenocorticotropic hormone and prolactin. Ghrelin is also orexigenic and has recently been shown to stimulate renal sodium absorption in rodent models. Increased thirst sensation has been observed as a side effect of acyl ghrelin administration in some human studies. The objective of this clinical trial was to investigate the direct effects of acyl ghrelin on thirst sensation and sodium excretion in hypopituitary patients.

Design

Hypopituitary patients on stable replacement with hydrocortisone and growth hormone were investigated in two double-blind and placebo-controlled crossover studies. The patients received a 5-h intravenous infusion of acyl ghrelin (5 pmol/kg/min in the first study and 1 pmol/kg/min in the second study). Thirst sensation was measured on a Visual Analog Scale (VAS). In the second study plasma osmolality, vasopressin, copeptin, water intake, diuresis and urinary excretion of sodium and creatinine were measured.

Results

In the initial study, acyl ghrelin (5 pmol/kg/min) increased thirst sensation (time × treatment analysis of variance for the effect of acyl ghrelin infusion P = 0.003). In the second study acyl ghrelin (1 pmol/kg/min) also increased thirst (P = 0.04) but did not affect urinary excretion of either sodium or water.

Conclusions

We demonstrate that acyl ghrelin infusion increases thirst sensation, without affecting sodium excretion or diuresis in human subjects.

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Mirela Diana Ilie, Véronique Raverot, François Tronc, Alexandre Vasiljevic, Françoise Borson-Chazot and Gérald Raverot

Context

Cabergoline has been shown to have some effect in the treatment of moderate Cushing’s disease, but its effectiveness in Cushing’s syndrome of ectopic or occult origin remains to be investigated.

Case series

In this case series, cabergoline was used in combination with steroidogenesis inhibitors in nine patients with severe Cushing’s syndrome of ectopic or occult origin. Cabergoline’s effectiveness enabled rapid withdrawal of the steroidogenesis inhibitors and long-term control of the hypercortisolism in three of the cases.

Review of the literature

In the literature, we found only 11 cases of ectopic or occult Cushing’s syndrome treated with dopamine receptor agonists, alone or in combination. Yet of these 11 cases, 10 responded.

Conclusions

Although limited, the existing experience highlights the potential value of cabergoline in the treatment of ectopic or occult Cushing’s syndrome.

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Orit Twito, Simona Grozinsky-Glasberg, Sigal Levy, Gideon Bachar, David J Gross, Carlos Benbassat, Alon Rozental and Dania Hirsch

Objective

Multiple clinical, pathological and biochemical variables, including the response to initial treatment, are associated with medullary thyroid carcinoma (MTC) prognosis. Studies that include separate analyses of familial and sporadic MTC patients followed for long period are scarce. This study evaluated the association between baseline clinico-pathologic variables and response to initial treatment and short- and long-term disease outcomes in sporadic and familial MTC.

Methods

Patients treated for MTC at four tertiary medical centers were retrospectively analyzed. Clinical and pathological data were collected. The outcomes measured included disease persistence 1 year after diagnosis, disease persistence at last follow-up, disease-related mortality (DRM) and all-cause mortality.

Results

The study enrolled 193 patients (mean age: 48.9 ± 18.7, 44.7% males), of whom 18.1% were familial cases. The mean follow-up period was 10.1 ± 9.4 years (8.5 ± 8.1 in sporadic and 16.9 ± 11.6 in familial MTC). Disease persistence 1-year after diagnosis and at last follow-up was detected in 56.1 and 60.4% patients, respectively. All-cause and DRM were 28.5 and 12.6%, respectively. Extra-thyroidal extension (ETE) and distant metastases (DM) were associated with disease persistence at last follow-up. ETE and DM were also significantly associated with DRM. Complete remission 1 year after diagnosis had high correlation with no evidence of disease at last follow-up (Cramer’s V measure of association 0.884, P < 0.001) and with 100% disease-specific survival (Cramer’s V measure of association 0.38, P < 0.001).

Conclusions

Apart from clinico-pathologic parameters, close correlation was found between 1-year status and long-term prognosis. These results underscore the importance of combining classical and dynamic factors for both sporadic and familial MTC prognostication and treatment decision making.

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Katharina Schilbach, Christina Gar, Andreas Lechner, Shiva Sophia Nicolay, Laura Schwerdt, Michael Haenelt, Jakob Dal, Jens-Otto Lunde Jørgensen, Sylvère Störmann, Jochen Schopohl and Martin Bidlingmaier

Objective

Growth hormone (GH) nadir (GHnadir) during oral glucose tolerance test (OGTT) is an important tool in diagnosing acromegaly, but data evaluating the need to adjust cut-offs to biological variables utilizing today's assay methods are scarce. We therefore investigated large cohorts of healthy subjects of both sexes to define normal GHnadir concentrations for a modern, sensitive, 22 kD-GH-specific assay.

Design

Multicenter study with prospective and retrospective cohorts (525 healthy adults: 405 females and 120 males).

Methods

GH concentrations were measured by the IDS-iSYS immunoassay after oral application of 75 g glucose.

Results

GHnadir concentrations (µg/L) were significantly higher in lean and normal weight subjects (group A) compared to overweight and obese subjects (group B); (males (M): A vs B, mean: 0.124 vs 0.065, P = 0.0317; premenopausal females without estradiol-containing OC (OC-EE) (FPRE): A vs B, mean: 0.179 vs 0.092, P < 0.0001; postmenopausal women (FPOST): A vs B, mean: 0.173 vs 0.078, P < 0.0061). Age, glucose metabolism and menstrual cycle had no impact on GHnadir. However, premenopausal females on OC-EE (FPREOC) exhibited significantly higher GHnadir compared to all other groups (all P < 0.0001). BMI had no impact on GHnadir in FPREOC (A vs B, mean: 0.624 vs 0.274, P = 0.1228).

Conclusions

BMI, sex and OC-EE intake are the major determinants for the GHnadir during OGTT in healthy adults. Using a modern sensitive GH assay, GHnadir concentrations in healthy subjects are distinctly lower than cut-offs used in previous guidelines for diagnosis and monitoring of acromegaly.

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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.