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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.

Free access

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.

Free access

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.

Open access

John-Paul Fuller-Jackson, Aimee L Dordevic, Iain J Clarke and Belinda A Henry

Objective:

Retrospective studies suggest that women have more active brown adipose tissue (BAT) than men, but little is known of the effect of fluctuating sex steroids across the menstrual cycle on thermogenesis in women.

Design:

To characterise the effects of sex and sex steroids on BAT activity we recruited healthy weight men (n = 14) and women at two stages of the menstrual cycle (luteal, n = 9; follicular, n = 11).

Methods:

Infrared thermography measured supraclavicular temperature to index BAT thermogenesis in response to both cold (immersion of one hand in water at 15°C) and meal (Ensure, 10 kcal/kg body weight) stimuli.

Results:

Adaptive BAT temperature responses were greater (P < 0.05) in women than men, irrespective of stage of menstrual cycle. Whereas during cold exposure, the increase in BAT temperature was abrogated (P < 0.05) in women during follicular phase compared to men and women during luteal phase. Plasma concentrations of progesterone, 17β-estradiol, testosterone and cortisol were measured. Regression analyses demonstrated that baseline BAT temperature was positively correlated (P < 0.05) with progesterone levels, but was inversely associated (P < 0.05) with cortisol concentration. Both cold- and meal-induced changes in BAT temperature mildly correlated (P = 0.07; P < 0.05) with 17β-estradiol levels, but not with testosterone concentrations.

Conclusions:

Baseline supraclavicular temperature is elevated in women during the luteal phase of the menstrual cycle, which correlated with elevated progesterone concentrations. Women exhibited greater thermogenic responses than men, irrespective of the state of the menstrual cycle, which was associated with plasma levels of 17β-estradiol. We conclude that sex steroids may regulate BAT thermogenesis in healthy adults.

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Qiao Hou, Jiayu Wu, Yaguang Zhao, Xinying Wang, Fang Jiang, Dan-Na Chen, Ruizhi Zheng, Meichao Men and Jia-Da Li

Objective:

To identify CCDC141 variants in a large Chinese cohort with congenital hypogonadotropic hypogonadism (CHH) and to assess the contribution of CCDC141 to CHH.

Design:

Detailed phenotyping was conducted in CHH patients with CCDC141 variants and co-segregation analysis was performed, when possible.

Methods:

Whole-exome sequencing was performed in 177 CHH patients and 450 unrelated, ethnically matched controls from China.

Results:

Seven novel CCDC141 rare sequencing variants (RSVs) were identified in 12 CHH pedigrees. Four of the variants were private mutations; however, p.Q409X, p.Q871X and p.G1488S were identified in more than one patient. Up to 75% (9/12) of patients had mutations in other CHH-associated genes, which is significantly higher than CHH patients without CCDC141 RSVs. The co-segregation analysis for eight CHH families showed that 75% (6/8) CCDC141 RSVs were inherited from their fertile parents. Over half (58.3%, 8/18) of the patients exhibited other clinical deformities in addition to hypogonadism. One patient harbouring a CCDC141 RSV showed a reversal of CHH after sex-steroid replacement.

Conclusions:

Our results broaden the genotypic spectrum of CCDC141 in CHH, as CCDC141 RSVs alone do not appear sufficient to cause CHH. The phenotypic spectrum in patients with CCDC141 RSVs is much wider than originally believed.

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Benjamin Bouillet, Thomas Gautier, Damien Denimal, Maxime Samson, David Masson, Jean Paul Pais de Barros, Guillaume Maquart, Marion Xolin, Alexandra Grosfeld, Héloïse Dalle, Bruno Vergès, Marthe Moldes and Bruno Fève

Objective:

Glucocorticoids (GC) are associated with increased cardiovascular morbidity despite increased HDL-C concentration. HDL-mediated cholesterol efflux, a major anti-atherogenic property of HDL particles, is negatively associated with CVD risk. We aimed to determine whether HDL-mediated cholesterol efflux was influenced by GC.

Design:

Prospective, observational study.

Methods:

Lipid parameters, HDL composition, HDL-mediated cholesterol efflux, cholesteryl ester transfer protein, phospholipid transfer protein and lecithin cholesterol acyl-transferase (LCAT) activities were determined in ten patients with giant cell arteritis before and 3 months after GC introduction and in seven control subjects. HDL concentration and composition, HDL-mediated cholesterol efflux and LCAT activity were determined in GC-treated mice.

Results:

In patients, HDL-C concentration was higher after than before treatment GC-treatment (P = 0.002), while HDL-mediated cholesterol efflux was decreased (P = 0.008) and negatively associated with the proportion of cholesteryl ester in HDL (P = 0.04), independently of CRP. As well, in mice, HDL-C level was increased after GC exposure (P = 0.04) and HDL-mediated cholesterol efflux decreased (P = 0.04). GC-treated patients had higher cholesteryl ester content in HDL, higher HDL2-to-HDL3 ratio and higher LCAT activity than before treatment (P = 0.008, P = 0.02 and P = 0.004, respectively).

Conclusions:

We report, for the first time, that in patients with giant cell arteritis and mice treated with GC, HDL-mediated cholesterol efflux was impaired by GC besides an increased HDL-C level. This impaired HDL functionality, possibly related to HDL enrichment in cholesteryl ester, could contribute to the increased CVD risk observed in GC-treated patients. Further studies are needed in larger populations, to further decipher the effect of GC on HDL.

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Henrik Olsen, Albin Kjellbom, Magnus Löndahl and Ola Lindgren

Objective:

Autonomous cortisol secretion and possible autonomous cortisol secretion (ACS/pACS) are associated to an increase of cardiovascular risk factors such as hypertension, diabetes mellitus and dyslipidaemia. To our knowledge, the prevalence of smoking, another well-established risk factor for cardiovascular disease, has not been studied in detail in people with ACS/pACS or adrenal incidentalomas.

Methods:

Patients with adrenal incidentalomas were examined with the 1-mg overnight dexamethasone suppression test (cortisolONDST). Information about current smoking was collected from the patient’s records.

Results:

We studied 1044 patients, of whom 370 (35%) were current smokers. Of these, 22% had bilateral AI compared to 12% of the non-smokers (P < 0.001). Among patients with unilateral adrenal incidentalomas, smokers had larger adrenal incidentalomas than non-smokers (22 mm vs 19 mm, P < 0.001). Smokers also more often had cortisolONDST ≥50 nmol/L than non-smokers, 54% vs 40% (P < 0.001), a finding independent of the size of the adrenal incidentaloma in patients with unilateral adrenal incidentalomas.

Conclusions:

In the present study of patients with adrenal incidentalomas, the prevalence of current smoking was higher than in the general population. Furthermore, smokers had larger unilateral adrenal incidentalomas, more often bilateral adrenal incidentalomas, and more frequently ACS/pACS. Whether smoking is a risk factor for adrenal incidentalomas and ACS/pACS or our findings are due to case selection needs to be further studied.

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Sneha Arya, Ankita Tiwari, Anurag Ranjan Lila, Vijaya Sarathi, Vishwambhar Vishnu Bhandare, Bajarang Vasant Kumbhar, Khushnandan Rai, Ambarish Kunwar, Hemangini Thakkar, Kunal Thakkar, Saba Samad Memon, Virendra Patil, Kranti Khadilkar, Swati S Jadhav, Nalini S Shah and Tushar Bandgar

Objective:

To evaluate the pathogenic role of a few benign variants and hypomorphic pathogenic variants in SRD5A2.

Design and methods:

We retrospectively analyzed phenotypes and genotypes in 23 Indian patients with genetically proven steroid 5α-reductase 2 (SRD5A2) deficiency. The interactions of the SRD5A2 enzymes resulting due to the most common benign variant (p.Val89Leu), the most common (hypomorphic) pathogenic variant (p.Arg246Gln) and the double variants (p.Val89Leu and p.Arg246Gln) in SRD5A2 were compared with that of the wild type (WT) enzyme by molecular dynamics (MD) simulation.

Results:

The majority (n = 19, 82.61%) of patients presented for atypical genitalia and had male gender identity (16/20). Including the two novel ones (p.Leu83Pro, p.Ala28Leufs*103), a total of nine different pathogenic variants were observed. p.Arg246Gln was the most common pathogenic variant (n = 12). Homozygous p.Arg246Gln (n = 9) variant was associated with milder undervirilization (Sinnecker score of ≤3a: 8/9 vs 6/14, P = 0.04) and had concurrent homozygous p.Val89Leu in all patients. Interestingly, asymptomatic fathers of two index patients were homozygous for p.Arg246Gln which questioned the pathogenicity of the variation as a sole factor. Unlike all symptomatic homozygous p.Arg246Gln patients who were also homozygous for p.Val89Leu, asymptomatic homozygous p.Arg246Gln fathers were heterozygous for p.Val89Leu. On MD simulation SRD5A2 p.Val89Leu-Testeosterone (T) and SRD5A2 p.Arg246Gln-T complexes, but not SRD5A2 p.Val89Leu and p.Arg246Gln-T complex, demonstrated close interaction between NADPH and T as that of SRD5A2 WT-T.

Conclusions:

p.Arg246Gln may not be pathogenic as a sole variation even in the homozygous state; additional contribution of homozygous p.Val89Leu variant may be essential for the pathogenicity of p.Arg246Gln in SRD5A2.