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I C M Pelsma, K M.j.a. Claessen, Pieternella E Slagboom, D van Heemst, A M Pereira, H Kroon, Yolande F M Ramos, M Kloppenburg, N R Biermasz, and Ingrid M Meulenbelt

Introduction

Pathologically high growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels in patients with acromegaly are associated with arthropathy. Several studies highlight the potential role of the GH/IGF-1 axis in primary osteoarthritis (OA). We aimed to disentangle the role of IGF-1 levels in primary OA pathogenesis.

Methods

Patients from the Genetics osteoARthritis and Progression (GARP) Study with familial, generalized, symptomatic OA (N=337, mean age 59.8±7.4 years, 82% female) were compared to Leiden Longevity Study (LLS) controls (N=456, mean age 59.8±6.8 years, 51% female). Subjects were clinically and radiographically assessed, serum IGF-1 levels were measured, and 10 quantitative trait loci (QTL) in the FOXO3, IGBP3/TNS3, RPA3, SPOCK2 genes, previously related to serum IGF-1 levels, were genotyped. Linear or binary logistic generalized estimating equation models were performed.

Results

Serum IGF-1 levels were increased in OA patients, with male patients exhibiting the strongest effect (males OR=1.10 (1.04-1.17), P=0.002 vs. females OR=1.04 (1.01-1.07), P=0.02). Independent of the increased IGF-1 levels, male carriers of the minor allele of FOXO3 QTL rs4946936 had lower risk to develop hip OA (OR=0.41 (0.18-0.90), P=0.026). Additionally, independent of IGF-1 levels, female carriers of the minor alleles of RPA3 QTL rs11769597 had higher risk to develop knee OA (OR=1.90 (1.20-2.99), P=0.006).

Conclusion

Patients with primary OA had significantly higher IGF-1 levels compared to controls. Moreover, SNPs in the FOXO3 and RPA3 genes were associated with an altered risk of OA. Therefore, altered IGF-1 levels affect the development of OA, and are potentially the result of the pathophysiological OA process.

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Olaf M Dekkers and Rolf H.h. Groenwold

Immortal time bias should always be considered in an observational study if exposure status is determined based on a measurement or event that occurs after baseline. This bias can lead to an overestimation of an effect, but also to an underestimation, which is explained Several approaches are illustrated that can be used to avoid immortal time bias in the analysis phase of the study; a time-dependent analysis to avoid immortal time bias optimizes the use of available information.

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Adina F Turcu, Diala El-Maouche, Lili Zhao, Aya T Nanba, Alison Gaynor, Padma Veeraraghavan, Richard J Auchus, and Deborah P Merke

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João Pedro Ferreira, Zohra Lamiral, Constance Xhaard, Kévin Duarte, Emmanuel Bresso, Marie-Dominique Devignes, Edith Le Floch, Claire Dandine Roulland, Jean-François Deleuze, Sandra Wagner, Bruno Guerci, Nicolas Girerd, Faiez Zannad, Jean-Marc Boivin, and Patrick Rossignol

Objective:

Determining the factors associated with new-onset pre-diabetes and type 2 diabetes mellitus (T2D) is important for improving the current prevention strategies and for a better understanding of the disease.

Design:

To study the factors (clinical, circulating protein and genetic) associated with new onset pre-diabetes and T2D in an initially healthy (without diabetes) populational familial cohort with a long follow-up (STANISLAS cohort).

Methods:

A total of 1506 participants attended both the visit 1 and visit 4, separated by ≈20 years. Over 400 proteins, GWAS and genetic associations were studied using models adjusted for potential confounders. Both prospective (V1 to V4) and cross-sectional (V4) analyses were performed.

Results:

People who developed pre-diabetes (n = 555) and/or T2D (n = 73) were older, had higher BMI, blood pressure, glucose, LDL cholesterol, and lower eGFR. After multivariable selection, PAPP-A (pappalysin-1) was the only circulating protein associated with the onset of both pre-diabetes and T2D with associations persisting at visit 4 (i.e. ≈20 years later). FGF-21 (fibroblast growth factor 21) was a strong prognosticator for incident T2D in the longitudinal analysis, but not in the cross-sectional analysis. The heritability of the circulating PAPP-A was estimated at 44%. In GWAS analysis, the SNP rs634737 was associated with PAPP-A both at V1 and V4. External replication also showed lower levels of PAPP-A in patients with T2D.

Conclusions:

The risk of developing pre-diabetes and T2D increases with age and with features of the metabolic syndrome. Circulating PAPP-A, which has an important genetic component, was associated with both the development and presence of pre-diabetes and T2D.

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J C. Naafs, P H. Verkerk, E Fliers, A. S. van Trotsenburg, and N Zwaveling-Soonawala

Objective: To evaluate clinical characteristics of patients with central congenital hypothyroidism (CH), detected in the Dutch neonatal screening program. This included patients with isolated central CH but the majority have multiple pituitary hormone deficiencies (MPHD).

Design: nationwide, cross-sectional study.

Methods: Data was collected on clinical characteristics, endocrine tests and neuroimaging of central CH patients, detected by the Dutch neonatal screening and born between 1-1-1995 and 1-1-2015. Height and pubertal status were assessed during a study visit. Isolated central CH patients without a confirmed genetic diagnosis were offered genetic (re-)testing.

Results: During the 20-year period 154 central CH patients were detected (incidence of permanent central CH 1:25,642). After excluding deceased (15), severe syndromic (7) and transient patients (6), 92 of 126 eligible patients were included (57 MPHD; 79% male). Sixty-one patients (50 MPHD) had been hospitalized before screening results were reported, but central CH was diagnosed on clinical grounds in only three of them (5%). MRI abnormalities consistent with pituitary stalk interruption syndrome were seen in 50 (93%) MPHD patients. Among isolated central CH patients, 27 (84%) had an IGSF1, TBL1X or IRS4 gene variant (53%, 16% and 16% respectively).

Conclusion: Many patients with central CH have neonatal health problems, especially MPHD patients. Despite hospital admission of two-thirds of patients, almost none were diagnosed clinically, but only after the notification of an abnormal screening result was received. This indicates that central CH, especially if isolated, is an easily missed clinical diagnosis. (This investigator-initiated study received a support grant from Pfizer; WI219179).

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Hanneke M van Santen, Erik K Alexander, Scott A Rivkees, Eva Frey, Sarah C Clement, Miranda P Dierselhuis, Chantal A Lebbink, Thera P Links, Kerstin Lorenz, Robin P Peeters, Christoph Reiners, Menno R Vriens, Paul Nathan, Arthur B Schneider, and Frederik Verburg

The incidence of differentiated thyroid carcinoma (DTC) has increased rapidly over the past several years. Thus far, the only conclusively established risk factor for developing DTC is exposure to ionizing radiation, especially when the exposure occurs in childhood. Since the number of childhood cancer survivors (CCS) is increasing due to improvements in treatment and supportive care, the number of patients who will develop DTC after surviving childhood cancer (secondary thyroid cancer) is also expected to rise. Currently, there are no recommendations for management of thyroid cancer specifically for patients who develop DTC as a consequence of cancer therapy during childhood. Since complications or late effects from prior cancer treatment may elevate the risk of toxicity from DTC therapy, the medical history of CCS should be considered carefully in choosing DTC treatment. In this paper, we emphasize how the occurrence and treatment of the initial childhood malignancy affects the medical and psychosocial factors that will play a role in the diagnosis and treatment of a secondary DTC. We present considerations for clinicians to use in the management of patients with secondary DTC, based on the available evidence combined with experience-based opinions of the authors.

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Sung Hye Kong, Jung Hee Kim, and Chan Soo Shin

Objective:

To identify radiologic features that correlate with mild autonomous cortisol excess using planar and volumetric analysis.

Design:

Cross-sectional study.

Methods:

In the study, 64 patients with overt Cushing syndrome (CS), 59 patients with mild autonomous cortisol excess (MACE), and 64 patients with nonfunctioning adrenal tumors (NFAT) with evaluable CT scans were included. Patients with NFAT and MACE were BMI-matched with those with overt CS. Planar and volumetric analyses of CT scans were performed in DICOM images using OsiriX software.

Results:

The mean age was 56.6 ± 1.01 years, and 123 patients (65.1%) were female. In the order of NFAT, MACE, and overt CS, the diameters and volumes of the adenoma increased, while limb widths and volumes of the contralateral adrenal gland decreased. Patients with MACE or overt CS were more likely to have osteoporosis than those with NFAT (P = 0.006), and patients with overt CS were more likely to experience a fragility fracture than those with NFAT or MACE (P = 0.002). Among radiologic features, the limb width of the contralateral adrenal gland correlated with the cortisol level after overnight dexamethasone suppression test (r = −0.583, P < 0.001).

Conclusions:

The study showed that the contralateral adrenal limb thinning was a distinctive radiologic feature of autonomous cortisol excess in the planar and volumetric analysis.

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Kevin Stroek, Annemieke C Heijboer, Marelle J Bouva, Catharina P B van der Ploeg, Marie-Louise A Heijnen, Gert Weijman, Annet M Bosch, Robert de Jonge, Peter C J I Schielen, A S Paul van Trotsenburg, and Anita Boelen

Objective:

Congenital hypothyroidism (CH) is defined as thyroid hormone deficiency at birth due to disorders of the thyroid gland (thyroidal CH, CH-T), or the hypothalamus or pituitary (central CH, CH-C). The Dutch Newborn Screening (NBS) strategy is primarily based on determination of thyroxine (T4) concentrations in dried blood spots followed, if necessary, by thyroid-stimulating hormone (TSH) and thyroxine-binding globulin (TBG) measurement enabling detection of both CH-T and CH-C. A calculated T4/TBG ratio serves as an indirect measure for free T4. A T4/TBG ratio ≤ 17 in a second heel puncture is suggestive of CH-C.

Design and methods:

In the present study, we evaluated 11 years of Dutch CH NBS using a database of referred cases by assessing the contribution of each criterion in the unique stepwise T4-TSH-TBG NBS algorithm.

Results:

Between 2007 and the end of 2017, 1 963 465 newborns were screened in the Netherlands. Use of the stepwise algorithm led to 3044 referrals and the identification of 612 CH cases, consisting of 496 CH-T, 86 CH-C, and 30 CH of unknown origin diagnoses. We detected 62.8% of CH-C cases by the T4/TBG ratio in the second heel puncture. The positive predictive value (PPV) of the stepwise T4-TSH-TBG NBS algorithm was 21.0%.

Conclusion:

This evaluation shows that the Dutch stepwise T4-TSH-TBG NBS algorithm with a calculated T4/TBG ratio is of great value for the detection of both CH-T and CH-C in the Netherlands, at the cost of a lower PPV compared to TSH-based NBS strategies.

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Maria-Elina Mosorin, Annina Haverinen, Meri-Maija Ollila, Tanja Nordström, Jari Jokelainen, Sirkka Keinänen-Kiukaanniemi, Katri Puukka, Aimo Ruokonen, Juha Auvinen, Terhi Piltonen, Laure Morin-Papunen, and Juha S Tapanainen

Objective

The use of combined hormonal contraceptives (CHCs) worsens glucose tolerance, but the risk for glucose metabolism disorders remains controversial.

Design

The study is a prospective longitudinal population-based cohort study.

Methods

The study was based on a cohort population that comprised 1879 women born in 1966. At age 46, the women answered a questionnaire on contraceptive use and underwent an oral glucose tolerance test. Glucose metabolism indices were evaluated in current CHC (n=153), progestin-only contraceptive (POC, n=842), and non-hormonal contraceptive users (n=884).

Results

In the entire study population, current CHC use was significantly associated with prediabetes (OR 2.0, 95% CI 1.3-3.2) and type 2 diabetes (OR 3.3, 95% CI 1.1-9.7) compared to non-hormonal contraceptive use. After five years of use, the prediabetes risk increased 2.2-fold (95% CI 1.3-3.7) and type 2 diabetes risk increased 4.5-fold (95% CI 1.5-13.5). Compared with the current POC use, current CHC use was significantly associated with prediabetes (OR 1.9, 95% CI 1.2-3.0). Current POC use was not associated with any glucose metabolism disorders. The results prevailed after adjusting for body mass index and socioeconomic status.

Conclusions

CHC use in perimenopausal women was associated with a significantly increased risk of glucose metabolism disorders. This association should be considered in women with increased metabolic risk.

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Mark E Molitch

There can potentially be a number of clinical interactions that could adversely affect patient outcomes in a patient with a prolactinoma and psychiatric disease that might require antipsychotic and dopamine agonist treatment. Dopamine agonists stimulate the dopamine D2 receptor, resulting in a decrease in prolactin (PRL) levels and in prolactinoma size but action on dopamine receptors in the meso-limbic system may rarely cause psychosis and more commonly cause impulse control disorders. The psychiatric benefits of antipsychotic agents involve blocking the D2 and other dopamine receptors but this blockade often also causes hyperprolactinemia.

In patients with macroprolactinomas and psychosis, observation, estrogen/progestin replacement, and surgery can be considered in addition to dopamine agonists. In those who require dopamine agonists for PRL and tumor size control, the introduction of antipsychotics may blunt this effect, so that higher doses of the dopamine agonists may be needed. Alternatively, antipsychotics that have less of a blocking effect at the D2 receptor, such as aripiprazole, can be tried, if appropriate. For patients already on antipsychotic drugs who are found to have a macroprolactinoma for which dopamine agonists are required, dopamine agonists can be initiated at low dose and the dose escalated slowly. However, such patients require careful monitoring of psychiatric status to avoid the rare complication of exacerbation of the underlying psychosis. Again, if appropriate, use of antipsychotics that have less of a blocking effect at the D2 receptor may allow lower doses of dopamine agonists to be used in this situation.