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Open access

Unni Syversen, Mats Peder Mosti, Ida Maria Mynarek, Trude Seselie Jahr Vedal, Kristin Aasarød, Trude Basso, Janne E Reseland, Per Medbøe Thorsby, Bjorn O Asvold, Erik Fink Eriksen, and Astrid Kamilla Stunes

Objective

Type 1 diabetes (T1D) is associated with substantial fracture risk. Bone mineral density (BMD) is, however, only modestly reduced, suggesting impaired bone microarchitecture and/or bone material properties. Yet, the skeletal abnormalities have not been uncovered. Men with T1D seem to experience a more pronounced bone loss than their female counterparts. Hence, we aimed to examine different aspects of bone quality in men with T1D.

Design and Methods

In this cross-sectional study, men with T1D and healthy male controls were enrolled. BMD (femoral neck, total hip, lumbar spine, whole body) and spine trabecular bone score (TBS) were measured by dual x-ray absorptiometry, and bone material strength index (BMSi) was measured by in vivo impact microindentation. HbA1c and bone turnover markers were analyzed.

Results

Altogether, 33 men with T1D (43 ± 12 years) and 28 healthy male controls (42 ± 12 years) were included. Subjects with T1D exhibited lower whole-body BMD than controls (P = 0.04). TBS and BMSi were attenuated in men with T1D vs controls (P = 0.016 and P = 0.004, respectively), and T1D subjects also had a lower bone turnover. The bone parameters did not differ between subjects with or without diabetic complications. Duration of disease correlated negatively with femoral neck BMD but not with TBS or BMSi.

Conclusions

This study revealed compromised bone material strength and microarchitecture in men with T1D. Moreover, our data confirm previous studies which found a modest decrease in BMD and low bone turnover in subjects with T1D. Accordingly, bone should be recognized as a target of diabetic complications.

Open access

Sara Storvall, Helena Leijon, Eeva Ryhänen, Johanna Louhimo, Caj Haglund, Camilla Schalin-Jäntti, and Johanna Arola

Introduction

Parathyroid carcinoma represents a rare cause of primary hyperparathyroidism. Distinguishing carcinoma from the benign tumors underlying primary hyperparathyroidism remains challenging. The diagnostic criteria for parathyroid carcinoma are local and/or metastatic spreading. Atypical parathyroid adenomas share other histological features with carcinomas but lack invasive growth. Somatostatin receptors are commonly expressed in different neuroendocrine tumors, but whether this also holds for parathyroid tumors remains unknown.

Aim

Our aim is to examine the immunohistochemical expression of somatostatin receptor 1–5 in parathyroid typical adenomas, atypical adenomas and carcinomas.

Methods

We used a tissue microarray construct from a nationwide cohort of parathyroid carcinomas (n = 32), age- and gender-matched typical parathyroid adenomas (n = 72) and atypical parathyroid adenomas (n = 27) for immunohistochemistry of somatostatin receptor subtypes 1–5. We separately assessed cytoplasmic, membrane and nuclear expression and also investigated the associations with histological, biochemical and clinical characteristics.

Results

All parathyroid tumor subgroups expressed somatostatin receptors, although membrane expression appeared negligible. Except for somatostatin receptor 1, expression patterns differed between the three tumor types. Adenomas exhibited the weakest and carcinomas the strongest expression of somatostatin receptor 2, 3, 4 and 5. We observed the largest difference for cytoplasmic somatostatin receptor 5 expression.

Conclusions

Parathyroid adenomas, atypical adenomas and carcinomas all express somatostatin receptor subtypes 1–5. Somatostatin receptor 5 may serve as a potential tumor marker for malignancy. Studies exploring the role of somatostatin receptor imaging and receptor-specific therapies in patients with parathyroid carcinomas are needed.

Open access

Cheng Han Ng, Yip Han Chin, Marcus Hon Qin Tan, Jun Xuan Ng, Samantha Peiling Yang, Jolene Jiayu Kiew, and Chin Meng Khoo

Purpose:

Primary hyperparathyroidism (PHPT) is a common condition affecting people of all ages and is mainly treated with parathyroidectomy. Cinacalcet has been widely used in secondary or tertiary hyperparathyroidism, but the use of cinacalcet in PHPT is less clear.

Methods:

Searches were conducted in Medline and Embase for cinacalcet use in PHPT from induction to 10 April 2020. Articles and conferences abstracts describing the use of cinacalcet for PHPT in prospective or retrospective cohorts and randomized controlled trials restricted to English language only. We initially identified 1301 abstracts. Each article went extraction by two blinded authors on a structured proforma. Continuous outcomes were pooled with weight mean difference (WMD). Quality of included articles was assessed with Newcastle Ottwa Scale and Cochrane Risk of Bias 2.0.

Results:

Twenty-eight articles were included. Normalization rate of serum Ca levels was reported at 90% (CI: 0.82 to 0.96). Serum levels of Ca and PTH levels were significantly reduced (Ca, WMD: 1.647, CI: −1.922 to −1.371; PTH, WMD: −31.218, CI: −41.671 to −20.765) and phosphate levels significantly increased (WMD: 0.498, CI: 0.400 to 0.596) after cinacalcet therapy. The higher the baseline Ca levels, the greater Ca reduction with cinacalcet treatment. Age and gender did not modify the effect of cinacalcet on serum Ca levels.

Conclusion:

The results from the meta-analysis support the use of cinacalcet as an alternative or bridging therapy to treat hypercalcemia in people with PHPT.

Open access

Lizhi Zhang, Jinwei He, Xiang Sun, Dongyue Pang, Jingjing Hu, and Bo Feng

Our previous studies have demonstrated that there is a correlation between GLP-1R SNP and the BMD in postmenopausal women. GLP-1 and GIP are both incretins. Whether the mutation of GIPR gene affects bone metabolism. SNP rs10423928 is a GIPR gene polymorphism that has been studied more frequently. The aim of this study was to investigate the association between GIPR SNP rs10423928 and bone-mineral density (BMD) in postmenopausal women in Shanghai. The GIPR SNP rs10423928 was detected in 884 postmenopausal women in Shanghai, the correlation between the GIPR SNP and BMD was further assessed. The dominant T/T genotype of the GIPR SNP rs10423928 was significantly related to BMD of the femoral neck (P = 0.035) and Ward’s triangle area (P = 0.033). Our research found that the dominant T/T genotype of GIPR SNP rs10423928 in postmenopausal women is significantly associated with higher BMD. The T/T genotype seems to have bone protection.

Open access

Maria Mizamtsidi, Constantinos Nastos, George Mastorakos, Roberto Dina, Ioannis Vassiliou, Maria Gazouli, and Fausto Palazzo

Primary hyperparathyroidism (pHPT) is a common endocrinopathy resulting from inappropriately high PTH secretion. It usually results from the presence of a single gland adenoma, multiple gland hyperplasia or rarely parathyroid carcinoma. All these conditions require different management, and it is important to be able to differentiate the underlined pathology, in order for the clinicians to provide the best therapeutic approach. Elucidation of the genetic background of each of these clinical entities would be of great interest. However, the molecular factors that control parathyroid tumorigenesis are poorly understood. There are data implicating the existence of specific genetic pathways involved in the emergence of parathyroid tumorigenesis. The main focus of the present study is to present the current optimal diagnostic and management protocols for pHPT as well as to review the literature regarding all molecular and genetic pathways that are to be involved in the pathophysiology of sporadic pHPT.

Open access

Kate E Lines, Mahsa Javid, Anita A C Reed, Gerard V Walls, Mark Stevenson, Michelle Simon, Kreepa G Kooblall, Sian E Piret, Paul T Christie, Paul J Newey, Ann-Marie Mallon, and Rajesh V Thakker

Multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder caused by MEN1 germline mutations, is characterised by parathyroid, pancreatic and pituitary tumours. MEN1 mutations also cause familial isolated primary hyperparathyroidism (FIHP), a milder condition causing hyperparathyroidism only. Identical mutations can cause either MEN1 or FIHP in different families, thereby implicating a role for genetic modifiers in altering phenotypic expression of tumours. We therefore investigated the effects of genetic background and potential for genetic modifiers on tumour development in adult Men1+/- mice, which develop tumours of the parathyroids, pancreatic islets, anterior pituitary, adrenal cortex and gonads, that had been backcrossed to generate C57BL/6 and 129S6/SvEv congenic strains. A total of 275 Men1+/- mice, aged 5–26 months were macroscopically studied, and this revealed that genetic background significantly influenced the development of pituitary, adrenal and ovarian tumours, which occurred in mice over 12 months of age and more frequently in C57BL/6 females, 129S6/SvEv males and 129S6/SvEv females, respectively. Moreover, pituitary and adrenal tumours developed earlier, in C57BL/6 males and 129S6/SvEv females, respectively, and pancreatic and testicular tumours developed earlier in 129S6/SvEv males. Furthermore, glucagon-positive staining pancreatic tumours occurred more frequently in 129S6/SvEv Men1+/- mice. Whole genome sequence analysis of 129S6/SvEv and C57BL/6 Men1+/- mice revealed >54,000 different variants in >300 genes. These included, Coq7, Dmpk, Ccne2, Kras, Wnt2b, Il3ra and Tnfrsf10a, and qRT-PCR analysis revealed that Kras was significantly higher in pituitaries of male 129S6/SvEv mice. Thus, our results demonstrate that Kras and other genes could represent possible genetic modifiers of Men1.

Open access

W N H Koek, N Campos-Obando, B C J van der Eerden, Y B de Rijke, M A Ikram, A G Uitterlinden, J P T M van Leeuwen, and M C Zillikens

Background

Sex differences in calcium and phosphate have been observed. We aimed to assess a relation with age.

Methods

We used the laboratory values of serum calcium, phosphate and albumin from three different samples ( 2005, 2010 and 2014 years) using the hospital information system of Erasmus MC, Rotterdam. The samples were divided into three age groups: 1–17, 18–44 and ≥45 years. Sex differences in calcium and phosphate were analyzed using ANCOVA, adjusting for age and serum albumin. Furthermore, sex by age interactions were determined and we analyzed differences between age groups stratified by sex.

Results

In all three samples there was a significant sex × age interaction for serum calcium and phosphate, whose levels were significantly higher in women compared to men above 45 years. No sex differences in the younger age groups were found. In men, serum calcium and phosphate levels were highest in the youngest age group compared to age groups of 18–44 and ≥45 years. In women, serum calcium levels were significantly higher in the age group 1–17 and the age group ≥45 years compared to the 18–44 years age group. In women, serum phosphate was different between the three different age groups with highest level in the group 1–17 years and lowest in the group 18–44 years.

Conclusion

There are age- dependent sex differences in serum calcium and phosphate. Furthermore, we found differences in serum calcium and phosphate between different age groups. Underlying mechanisms for these age- and sex- differences are not yet fully elucidated.

Open access

Pinaki Dutta, Bhuvanesh Mahendran, K Shrinivas Reddy, Jasmina Ahluwalia, Kim Vaiphei, Rakesh K Kochhar, Prakamya Gupta, Anand Srinivasan, Mahesh Prakash, Kanchan Kumar Mukherjee, Viral N Shah, Girish Parthan, and Anil Bhansali

The effectiveness and short-term safety of recombinant human GH (r-hGH) in acromegaly patients with GH deficiency (GHD) after treatment are not well established. The study includes ten subjects with acromegaly who had GHD treated with r-hGH for 6 months. Control groups consisted of ten age-, gender-, and BMI-matched healthy subjects and ten active acromegaly patients who were treatment naïve. Body composition, quality of life (QoL), muscle strength, lipid profile, and cardiovascular risk factors were assessed in all subjects at baseline, and the same parameters were reassessed after 6 months of therapy with r-hGH in acromegaly with GHD. Repeat magnetic resonance imaging of the sella was performed in treated subjects. Optical colonoscopy was done and biopsies were taken from multiple sites for proliferation indices (Ki67). The median duration of GHD was 17.8 months and dose of r-hGH administered was 5.7±1.5 μg/kg per day. There was improvement in bone mineral content (P=0.01), bone mineral density (P=0.04), muscle strength (P<0.001), total cholesterol (P=0.003), high-density cholesterol (P<0.001), and QoL – score (P=0.005), and reduction in low-density cholesterol (P=0.003) and triglyceride (P=0.004) after treatment. There was no change in lean body mass, total body fat, hsCRP, lipoprotein (a), and fibrinogen levels. There was a modest increase in plasminogen activator inhibitor 1 (P=0.002), but it was lower compared with healthy controls and treatment naïve acromegalics (P=0.007). Six month-r-hGH therapy improves body composition, atherogenic lipid profile, QoL, and muscle strength in GHD patients who had acromegaly. Long-term prospective studies are needed to evaluate the effect of r-hGH therapy in these patients.

Open access

Elena Pardi, Stefano Mariotti, Natalia S Pellegata, Katiuscia Benfini, Simona Borsari, Federica Saponaro, Liborio Torregrossa, Antonello Cappai, Chiara Satta, Marco Mastinu, Claudio Marcocci, and Filomena Cetani

Inactivating germline mutations of the CDKN1B gene encoding the nuclear cyclin-dependent kinase inhibitor P27kip1 protein have been reported in patients with multiple endocrine neoplasia type 4 (MEN4), a MEN1-like phenotype without MEN1 mutations. The aim of this study was to characterize in vitro the germline CDKN1B mutation c.374_375delCT (S125X) we detected in a patient with MEN4. The proband was affected by primary hyperparathyroidism due to multiglandular parathyroid involvement and gastro–entero–pancreatic tumors. We carried out subcellular localization experiments by transfection with plasmid vectors expressing the WT or mutant CDKN1B cDNA into the eukaryotic human cervix adenocarcinoma (HeLa) and GH3 cell lines. Results from western blotting studies indicated that fusion proteins were expressed at equal levels. The mutated protein was shorter compared with the WT protein and lacked the highly conserved C-terminal domain, which includes the bipartite nuclear localization signal at amino acids 152/153 and 166/168. In HeLa and GH3 cells, WT P27 localized in the nucleus, whereas the P27_S125X protein was retained in the cytoplasm, predicting the loss of tumor-suppressive function. The proband's tumoral parathyroid tissue did not show allelic loss, because both WT and mutant alleles were determined to be present by sequencing the somatic DNA. Immunohistochemistry revealed a complete loss of nuclear expression of P27 in a parathyroid adenoma, which had been removed by the second surgery in the patient. In conclusion, our results confirm the pathogenic role of the c.374_375delCT CDKN1B germline mutation in a patient with MEN4.

Open access

Louise Vølund Larsen, Delphine Mirebeau-Prunier, Tsuneo Imai, Cristina Alvarez-Escola, Kornelia Hasse-Lazar, Simona Censi, Luciana A Castroneves, Akihiro Sakurai, Minoru Kihara, Kiyomi Horiuchi, Véronique Dorine Barbu, Francoise Borson-Chazot, Anne-Paule Gimenez-Roqueplo, Pascal Pigny, Stephane Pinson, Nelson Wohllk, Charis Eng, Berna Imge Aydogan, Dhananjaya Saranath, Sarka Dvorakova, Frederic Castinetti, Attila Patocs, Damijan Bergant, Thera P Links, Mariola Peczkowska, Ana O Hoff, Caterina Mian, Trisha Dwight, Barbara Jarzab, Hartmut P H Neumann, Mercedes Robledo, Shinya Uchino, Anne Barlier, Christian Godballe, and Jes Sloth Mathiesen

Objective

Multiple endocrine neoplasia type 2A (MEN 2A) is a rare syndrome caused by RET germline mutations and has been associated with primary hyperparathyroidism (PHPT) in up to 30% of cases. Recommendations on RET screening in patients with apparently sporadic PHPT are unclear. We aimed to estimate the prevalence of cases presenting with PHPT as first manifestation among MEN 2A index cases and to characterize the former cases.

Design and methods

An international retrospective multicenter study of 1085 MEN 2A index cases. Experts from MEN 2 centers all over the world were invited to participate. A total of 19 centers in 17 different countries provided registry data of index cases followed from 1974 to 2017.

Results

Ten cases presented with PHPT as their first manifestation of MEN 2A, yielding a prevalence of 0.9% (95% CI: 0.4–1.6). 9/10 cases were diagnosed with medullary thyroid carcinoma (MTC) in relation to parathyroid surgery and 1/10 was diagnosed 15 years after parathyroid surgery. 7/9 cases with full TNM data were node-positive at MTC diagnosis.

Conclusions

Our data suggest that the prevalence of MEN 2A index cases that present with PHPT as their first manifestation is very low. The majority of index cases presenting with PHPT as first manifestation have synchronous MTC and are often node-positive. Thus, our observations suggest that not performing RET mutation analysis in patients with apparently sporadic PHPT would result in an extremely low false-negative rate, if no other MEN 2A component, specifically MTC, are found during work-up or resection of PHPT.