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Mirela Diana Ilie, Véronique Raverot, François Tronc, Alexandre Vasiljevic, Francoise Borson-Chazot and Gerald 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 Gross, Carlos A 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 L. Jorgensen, Sylvere 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 todays assay methods are scarce. We therefore investigated large cohorts of healthy subjects of both sexes to define normal GHnadir concentrations for a modern, sensitive, 22kD-GH specific assay.

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

Methods: GH concentrations were measured by the IDS-iSYS immunoassay after oral application of 75g 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, Juergen Grulich-Henn, Norbert Jorch, Christian Kastendieck, Kirsten Mönkemöller, Oliver Razum, Claudia Seigleder-Schweiger, Michael Witsch and Reinhard Holl

Objective: With increasing migration to Europe, diabetes diagnosis and treatment of refugees became challenging. To describe 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 (ME vs. AFR vs. G/A: 72.3±1.0 vs. 75.0±1.4 vs. 66.0±0.1 mmol/mol, each p<0.001) and microalbuminuria (9.9 vs 13.6 vs. 6.5%, each p<0.05) was more prevalent. African children experienced severe hypoglycemia (17.8±4.3 vs. 25.4±8.7 vs. 11.5±0.3 per 100 patient years) significantly more often, whereas hypoglycemia with coma (5.1±1.1 vs. 4.1±1.6 vs. 2.6±0.1 per 100 patient years) and retinopathy (2.1 vs. n/a vs. 0.2%) 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 vs. 13.2 vs. 43.0%, each 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.

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Mario Rotondi, Andrea Carbone, Francesca Coperchini, Rodolfo Fonte and Luca Chiovato

IgG4-related disease (IgG4-RD) is fibro-inflammatory, immune-mediated, systemic disease recognized as a defined clinical condition only in 2001. The prevalence of IgG4-RD is 6/100 000, but it is likely to be underestimated due to insufficient awareness of the disease. The diagnostic approach is complex because of the heterogeneity of clinical presentation and because of rather variable diagnostic criteria. Indeed, high concentrations of IgG4 in tissue and serum are not a reliable diagnostic marker. The spectrum of IgG4-RD also includes well-known thyroid diseases including Riedel’s thyroiditis, Hashimoto’s thyroiditis and its fibrotic variant, Graves’ disease and Graves’ orbitopathy. Results from clinical studies indicate that a small subset of patients with the above-mentioned thyroid conditions present some features suggestive for IgG4-RD. However, according to more recent views, the use of the term thyroid disease with an elevation of IgG4 rather than IgG4-related thyroid diseases would appear more appropriate. Nevertheless, the occurrence of high IgG4 levels in patients with thyroid disease is relevant due to peculiarities of their clinical course.

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QiChang Wan, Lin Bai, Gege Zhao, Youjia Zhang, Qingjie Ma, Renjie Wang and Bin Ji

Purpose: To evaluate the accuracy of 18F-FDG-PET/CT for detection of recurrent and/or metastatic diseases in differentiated thyroid cancer (DTC) patients with thyroglobulin elevation and negative iodine scintigraphy. Whether PET/CT with TSH stimulation (sPET/CT) had better diagnostic performance than PET/CT without TSH stimulation (nsPET/CT) in this scenario was also evaluated.

Methods: PubMed and Embase was searched for eligible studies from January 2001 to December 2018. Only studies with clearly stated reference standard (histopathology confirmation and/or clinical/imaging follow-up) were included. Publication bias was assessed by funnel plot. The pooled sensitivity, specificity, diagnostic odds ratio (DOR), and the area under the summary receiver operating characteristics curve (AUC) for PET/CT was determined by random-effect analysis, respectively. sPET/CT and nsPET/CT was compared pair-wisely for all diagnostic estimate indexes using Z-test.

Results: We included 17 studies with 1195 patients in this meta-analysis. The pooled sensitivity, specificity, DOR, and AUC for PET/CT on patient-based data were 0.86 (95% CI; 0.79-0.91), 0.84 (95% CI; 0.72-0.91), 31.00 (95% CI; 12.00-80.00), and 0.91 (95% CI; 0.88-0.93), respectively. There was high heterogeneity (I2=80% for sensitivity, I2=82% for specificity) and possible publication bias (P=0.01). Z-test did not detect statistically significant difference between sPET/CT and nsPET/CT for all the diagnostic estimate indexes (All P>0.05).

Conclusions: On patient-based analysis, 18-FDG-PET/CT has high diagnostic accuracy for detection of recurrent and/or metastatic diseases in DTC patients with thyroglobulin elevation and negative iodine scintigraphy, but existing studies were limited by high heterogeneity and possible publication bias. The diagnostic performance of sPET/CT may be not superior to nsPET/CT.

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Hanne L Gulseth, Ingrid M F Gjelstad, Audrey C Tiereny, Danielle McCarthy, Julie A Lovegrove, Catherine Defoort, Ellen E Blaak, Jose Lopez-Miranda, Aldona Dembinska-Kiec, Ulf Risérus, Helen M Roche, Christian A Drevon and Kåre I Birkeland

Objective

Impaired insulin secretion and action contribute to the development of type 2 diabetes. Dietary fat modification may improve insulin sensitivity, whereas the effect on insulin secretion is unclear. We investigated the effect of dietary fat modification on insulin secretion in subjects with the metabolic syndrome.

Design

In a 12-week pan-European parallel, randomized controlled dietary intervention trial (LIPGENE), 486 subjects were assigned to four isoenergetic diets: high-fat diets rich in saturated fat (HSFA) or monounsaturated fat (HMUFA) or low-fat, high-complex carbohydrate diets with (LFHCC n-3) or without (LFHCC control) 1.2 g/day of n-3 PUFA supplementation. Insulin secretion was estimated as acute insulin response to glucose (AIRg) and disposition index (DI), modeled from an intravenous glucose tolerance test.

Results

There were no overall effect of the dietary intervention on AIRg and DI in the total cohort, in neither the high-fat nor LFHCC groups. We observed significant diet*fasting glucose category interactions for AIRg (P = 0.021) and DI (P = 0.001) in the high-fat groups. In subjects with normal fasting glucose and preserved first phase insulin secretion, the HMUFA diet increased, whereas the HSFA diet reduced AIRg (P = 0.015) and DI (P = 0.010).

Conclusions

The effects of dietary fat modification on insulin secretion were minor, and only evident in normoglycemic subjects. In this case, the HMUFA diet improved AIRg and DI, as compared to the HSFA diet.

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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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Andreas Stomby, Alireza Salami, Per Dahlqvist, Johan Arild Evang, Mats Ryberg, Jens Bollerslev, Tommy Olsson, Gudmundur Johannsson and Oskar Ragnarsson

Objective

Cushing’s syndrome is associated with long-term cognitive deficits and affective symptoms such as depression and anxiety. The alterations in brain function underlying these deficits after Cushing’s syndrome are unclear and therefore we aimed to explore alterations in resting-state functional connectivity in patients with Cushing’s syndrome in remission.

Design

Cross-sectional case–control study.

Methods

Nineteen women with Cushing’s syndrome in remission for a median time of 7 years (IQR: 6–10) and a mean age of 45 years were included at three university clinics. These patients and 38 age-matched female controls underwent brain imaging at a single center. The main outcome measure was functional connectivity at rest, measured with functional magnetic resonance imaging.

Results

The medial temporal lobe (MTL) and prefrontal cortex networks, exhibited elevated functional connectivity among patients compared to controls. The degree of elevated functional connectivity in the MTL was negatively associated with time in remission.

Conclusions

Resting-state functional connectivity within glucocorticoid receptor-rich regions, particularly the MTL and medial prefrontal cortex, was increased in patients. These differences in connectivity may provide a neural basis for the cognitive deficits and affective symptoms commonly experienced by patients with Cushing’s syndrome in remission.

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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: 8 patients with primary AI (female=5;age:56±21years;BMI:22.8±2kg/m2;mean blood pressure:140/83mmHg; hydrocortisone dose:21.9±5mg/day; fludrocortisone dose:0.061±0.03mg/day) and 8 matched healthy volunteers (female=5;age:52±21years;BMI:25.2±4kg/m2;mean blood pressure:135/84mmHg) 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), AngII (p=0.032), Ang1-7 and Ang1-5. 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 hyper-activated. The contribution of AngII 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.