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  • Bone and Mineral Metabolism x
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Rong Xu Center for Endocrine Metabolism and Immune Diseases, Lu He Hospital, Capital Medical University, Beijing, China
Beijing Key Laboratory of Diabetes Research and Care, Beijing, China

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Difei Lian Center for Endocrine Metabolism and Immune Diseases, Lu He Hospital, Capital Medical University, Beijing, China
Beijing Key Laboratory of Diabetes Research and Care, Beijing, China

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Yan Xie Center for Endocrine Metabolism and Immune Diseases, Lu He Hospital, Capital Medical University, Beijing, China
Beijing Key Laboratory of Diabetes Research and Care, Beijing, China

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Lin Mu Center for Endocrine Metabolism and Immune Diseases, Lu He Hospital, Capital Medical University, Beijing, China
Beijing Key Laboratory of Diabetes Research and Care, Beijing, China

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Yali Wu Center for Endocrine Metabolism and Immune Diseases, Lu He Hospital, Capital Medical University, Beijing, China
Beijing Key Laboratory of Diabetes Research and Care, Beijing, China

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Zhilei Chen Center for Endocrine Metabolism and Immune Diseases, Lu He Hospital, Capital Medical University, Beijing, China
Beijing Key Laboratory of Diabetes Research and Care, Beijing, China

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Baoyu Zhang Center for Endocrine Metabolism and Immune Diseases, Lu He Hospital, Capital Medical University, Beijing, China
Beijing Key Laboratory of Diabetes Research and Care, Beijing, China

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Osteoporosis (OP) is a systemic bone disease in which bone density and quality decrease and bone fragility increases due to a variety of causes, making it prone to fractures. The development of OP is closely related to oxidative stress. Uric acid (UA) is the end product of purine metabolism in the human body. Extracellular UA has antioxidant properties and is thought to have a protective effect on bone metabolism. However, the process of UA degradation can lead to intracellular oxidative stress, which together with UA-induced inflammatory factors, leads to increased bone destruction. In addition, UA can inhibit vitamin D production, resulting in secondary hyperparathyroidism and further exacerbating UA-associated bone loss. This review summarizes the relationship between serum UA levels and bone mineral density, bone turnover markers, and so on, in the hope of providing new insights into the pathogenesis and treatment of OP.

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Marcela Moraes Mendes Department of Nutrition, Faculty of Health Sciences, University of Brasília, Distrito Federal, Brazil
Department of Nutrition, Institute of Life Sciences, Federal University of Juiz de Fora, Governador Valadares, Minas Gerais, Brazil
Department of Nutrition, Faculty of Health and Medical Sciences, University of Surrey, University of Surrey, Guildford, UK

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Patricia Borges Botelho Department of Nutrition, Faculty of Health Sciences, University of Brasília, Distrito Federal, Brazil

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Helena Ribeiro Department of Environmental Health, Faculty of Public Health, University of São Paulo, São Paulo, Brazil

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Vitamin D enhances calcium absorption and bone mineralisation, promotes maintenance of muscle function, and is crucial for musculoskeletal health. Low vitamin D status triggers secondary hyperparathyroidism, increases bone loss, and leads to muscle weakness. The primary physiologic function of vitamin D and its metabolites is maintaining calcium homeostasis for metabolic functioning, signal transduction, and neuromuscular activity. A considerable amount of human evidence supports the well-recognised contribution of adequate serum 25-hydroxyvitamin D concentrations for bone homeostasis maintenance and prevention and treatment strategies for osteoporosis when combined with adequate calcium intake. This paper aimed to review the literature published, mainly in the last 20 years, on the effect of vitamin D and its supplementation for musculoskeletal health in order to identify the aspects that remain unclear or controversial and therefore require further investigation and debate. There is a clear need for consistent data to establish realistic and meaningful recommendations of vitamin D status that consider different population groups and locations. Moreover, there is still a lack of consensus on thresholds for vitamin D deficiency and optimal status as well as toxicity, optimal intake of vitamin D, vitamin D supplement alone as a strategy to prevent fractures and falls, recommended sun exposure at different latitudes and for different skin pigmentations, and the extra skeletal effects of vitamin D.

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Nancy Martini Laboratorio de Investigaciones en Osteopatías y Metabolismo Mineral (LIOMM-UNLP-CICPBA), Facultad de Ciencias Exactas, Universidad Nacional de La Plata, La Plata, Argentina

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Lucas Streckwall Laboratorio de Investigaciones en Osteopatías y Metabolismo Mineral (LIOMM-UNLP-CICPBA), Facultad de Ciencias Exactas, Universidad Nacional de La Plata, La Plata, Argentina

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Antonio Desmond McCarthy Laboratorio de Investigaciones en Osteopatías y Metabolismo Mineral (LIOMM-UNLP-CICPBA), Facultad de Ciencias Exactas, Universidad Nacional de La Plata, La Plata, Argentina

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In post-menopausal women, aged individuals, and patients with diabetes mellitus or chronic renal disease, bone mineral density (BMD) decreases while the vasculature accumulates arterial calcifications (ACs). AC can be found in the tunica intima and/or in the tunica media. Prospective studies have shown that patients with initially low BMD and/or the presence of fragility fractures have at follow-up a significantly increased risk for coronary and cerebrovascular events and for overall cardiovascular mortality. Similarly, patients presenting with abdominal aorta calcifications (an easily quantifiable marker of vascular pathology) show a significant decrease in the BMD (and an increase in the fragility) of bones irrigated by branches of the abdominal aorta, such as the hip and lumbar spine. AC induction is an ectopic tissue biomineralization process promoted by osteogenic transdifferentiation of vascular smooth muscle cells as well as by local and systemic secreted factors. In many cases, the same regulatory molecules modulate bone metabolism but in reverse. Investigation of animal and in vitro models has identified several potential mechanisms for this reciprocal bone–vascular regulation, such as vitamin K and D sufficiency, advanced glycation end-products–RAGE interaction, osteoprotegerin/RANKL/RANK, Fetuin A, oestrogen deficiency and phytooestrogen supplementation, microbiota and its relation to diet, among others. Complete elucidation of these potential mechanisms, as well as their clinical validation via controlled studies, will provide a basis for pharmacological intervention that could simultaneously promote bone and vascular health.

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Heng Yeh Department of Emergency Medicine, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
College of Medicine, Chang Gung University, Taoyuan, Taiwan

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Hsuan Yeh College of Medicine, Chang Gung University, Taoyuan, Taiwan
Department of Nephrology, Clinical Poison Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan

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Chun-Cheng Chiang College of Medicine, Chang Gung University, Taoyuan, Taiwan
Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan

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Ju-Ching Yen College of Medicine, China Medical University, Taichung, Taiwan

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I-Kuan Wang College of Medicine, China Medical University, Taichung, Taiwan
Department of Nephrology, China Medical University Hospital, Taichung, Taiwan

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Shou-Hsuan Liu College of Medicine, Chang Gung University, Taoyuan, Taiwan
Department of Nephrology, Clinical Poison Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan

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Cheng-Chia Lee College of Medicine, Chang Gung University, Taoyuan, Taiwan
Department of Nephrology, Clinical Poison Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan

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Cheng-Hao Weng College of Medicine, Chang Gung University, Taoyuan, Taiwan
Department of Nephrology, Clinical Poison Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan

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Wen-Hung Huang College of Medicine, Chang Gung University, Taoyuan, Taiwan
Department of Nephrology, Clinical Poison Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan

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Ching-Wei Hsu College of Medicine, Chang Gung University, Taoyuan, Taiwan
Department of Nephrology, Clinical Poison Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan

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Tzung-Hai Yen College of Medicine, Chang Gung University, Taoyuan, Taiwan
Department of Nephrology, Clinical Poison Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan

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Secondary hyperparathyroidism (SHPT) is a common complication of end-stage kidney disease (ESKD). Hungry bone syndrome (HBS) occurs frequently in patients on maintenance dialysis receiving parathyroidectomy for refractory SHPT. However, there is scanty study investigating the clinical risk factors that predict postoperative HBS, and its outcome in peritoneal dialysis (PD) patients. We conducted a single-center retrospective study to analyze 66 PD patients who had undergone parathyroidectomy for secondary hyperparathyroidism at Chang Gung Memorial Hospital between 2009 and 2019. The patients were stratified into two groups based on the presence (n=47) or absence (n=19) of HBS after parathyroidectomy. Subtotal parathyroidectomy was the most common surgery performed (74.2%), followed by total parathyroidectomy with autoimplantation (25.8%). Pathological examination of all surgical specimens revealed parathyroid hyperplasia (100%). Patients with HBS had lower levels of postoperative nadir corrected calcium, higher alkaline phosphate (ALP), and higher potassium levels compared with patients without HBS (all P<0.05). A multivariate logistic regression model confirmed that lower preoperative serum calcium level (OR 0.354, 95% CI 0.133–0.940, P=0.037), higher ALP (OR 1.026, 95% CI 1.008–1.044, P=0.004), and higher potassium level (OR 6.894, 95% CI 1.806–26.317, P=0.005) were associated with HBS after parathyroidectomy. Patients were followed for 58.2±30.8 months after the surgery. There was no significant difference between HBS and non-HBS groups in persistence (P=0.496) or recurrence (P=1.000) of hyperparathyroidism. The overall mortality rate was 10.6% with no significant difference found between both groups (P=0.099). We concluded that HBS is a common complication (71.2%) of parathyroidectomy for SHPT and should be managed appropriately.

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Lu Yang Department of Nuclear Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China

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Xingguo Jing Department of Nuclear Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China

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Hua Pang Department of Nuclear Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China

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Lili Guan Department of Nuclear Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China

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Mengdan Li Department of Nuclear Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China

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In this review, we discuss the definition, prevalence, and etiology of sporadic multiglandular disease (MGD), with an emphasis on its preoperative and intraoperative predictors. Primary hyperparathyroidism (PHPT) is the third-most common endocrine disorder, and multiglandular parathyroid disease (MGD) is a cause of PHPT. Hereditary MGD can be definitively diagnosed with detailed family history and genetic testing, whereas sporadic MGD presents a greater challenge in clinical practice, and parathyroidectomy for MGD is associated with a higher risk of surgical failure than single gland disease (SGD). Therefore, it is crucial to be able to predict the presence of sporadic MGD in a timely manner, either preoperatively or intraoperatively. Various predictive methods cannot accurately identify all cases of sporadic MGD, but they can greatly optimize the management of MGD diagnosis and treatment and optimize the cure rate. Future research will urge us to investigate more integrative predictive models as well as increase our understanding of MGD pathogenesis.

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Keiko Ohkuwa Department of Surgery, Ito Hospital, Tokyo, Japan

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Kiminori Sugino Department of Surgery, Ito Hospital, Tokyo, Japan

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Ryohei Katoh Department of Pathology, Ito Hospital, Tokyo, Japan

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Mitsuji Nagahama Department of Surgery, Ito Hospital, Tokyo, Japan

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Wataru Kitagawa Department of Surgery, Ito Hospital, Tokyo, Japan

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Kenichi Matsuzu Department of Surgery, Ito Hospital, Tokyo, Japan

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Akifumi Suzuki Department of Surgery, Ito Hospital, Tokyo, Japan

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Chisato Tomoda Department of Surgery, Ito Hospital, Tokyo, Japan

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Kiyomi Hames Department of Surgery, Ito Hospital, Tokyo, Japan

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Junko Akaishi Department of Surgery, Ito Hospital, Tokyo, Japan

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Chie Masaki Department of Surgery, Ito Hospital, Tokyo, Japan

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Kana Yoshioka Department of Surgery, Ito Hospital, Tokyo, Japan

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Koichi Ito Department of Surgery, Ito Hospital, Tokyo, Japan

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Objective

Parathyroid carcinoma is a rare tumor among parathyroid tumors. Aspiration cytology and needle biopsy are generally not recommended for diagnostic purposes because they cause dissemination. Therefore, it is commonly diagnosed by postoperative histopathological examination. In this study, we investigated whether preoperative inflammatory markers can be used as predictors of cancer in patients with primary hyperparathyroidism.

Design

This was a retrospective study.

Methods

Thirty-six cases of parathyroid carcinoma and 50 cases of parathyroid adenoma (PA) operated with the diagnosis of primary hyperparathyroidism and confirmed histopathologically at Ito Hospital were included in this study. Preoperative clinical characteristics and inflammatory markers (neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio (LMR)) were compared and their values in preoperative prediction were evaluated and analyzed.

Results

Preoperative intact-parathyroid hormone (P  = 0.0003), serum calcium (P  = 0.0048), and tumor diameter (P  = 0.0002) were significantly higher in parathyroid carcinoma than in PA. LMR showed a significant decrease in parathyroid carcinoma (P  = 0.0062). In multivariate analysis, LMR and tumor length diameter were independent predictors. In the receiver operating characteristics analysis, the cut-off values for LMR and tumor length diameter were 4.85 and 28.0 mm, respectively, for parathyroid cancer prediction. When the two extracted factors were stratified by the number of factors held, the predictive ability improved as the number of factors increased.

Conclusion

In the preoperative evaluation, a combination of tumor length diameter of more than 28 mm and LMR of less than 4.85 was considered to have a high probability of cancer.

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Shu-Meng Hu Department of Nephrology, West China Hospital, Sichuan University, Chengdu, Sichuan, China

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Yang-Juan Bai Department of Laboratory Medicine/Research Centre of Clinical Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China

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Ya-Mei Li Department of Laboratory Medicine/Research Centre of Clinical Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China

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Ye Tao Department of Nephrology, West China Hospital, Sichuan University, Chengdu, Sichuan, China

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Xian-Ding Wang Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China

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Tao Lin Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China

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Lan-Lan Wang Department of Laboratory Medicine/Research Centre of Clinical Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China

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Yun-Ying Shi Department of Nephrology, West China Hospital, Sichuan University, Chengdu, Sichuan, China

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Introduction

Tertiary hyperparathyroidism (THPT) and vitamin D deficiency are commonly seen in kidney transplant recipients, which may result in persistently elevated fibroblast growth factor 23 (FGF23) level after transplantation and decreased graft survival. The aim of this study is to evaluate the effect of vitamin D supplementation on THPT, FGF23-alpha Klotho (KLA) axis and cardiovascular complications after transplantation.

Materials and methods

Two hundred nine kidney transplant recipients were included and further divided into treated and untreated groups depending on whether they received vitamin D supplementation. We tracked the state of THPT, bone metabolism and FGF23–KLA axis within 12 months posttransplant and explored the predictors and risk factors for intact FGF23 levels, KLA levels, THPT and cardiovascular complications in recipients.

Results

Vitamin D supplementation significantly improved FGF23 resistance, THPT and high bone turnover status, preserved better graft function and prevented coronary calcification in the treated group compared to the untreated group at month 12. The absence of vitamin D supplementation was an independent risk factor for THPT and a predictor for intact FGF23 and KLA levels at month 12. Age and vitamin D deficiency were independent risk factors for coronary calcification in recipients at month 12.

Conclusion

Vitamin D supplementation effectively improved THPT, FGF23 resistance and bone metabolism, preserved graft function and prevented coronary calcification after transplantation.

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Julie Wulf Christensen Department of Nuclear Medicine, Herlev and Gentofte Hospital, Herlev, Denmark

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Karin Folmer Thøgersen Department of Nuclear Medicine, Herlev and Gentofte Hospital, Herlev, Denmark

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Lars Thorbjørn Jensen Department of Nuclear Medicine, Herlev and Gentofte Hospital, Herlev, Denmark

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Martin Krakauer Department of Nuclear Medicine, Herlev and Gentofte Hospital, Herlev, Denmark
Department of Clinical Physiology and Nuclear Medicine, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark

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Bent Kristensen Department of Nuclear Medicine, Herlev and Gentofte Hospital, Herlev, Denmark

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Finn Noe Bennedbæk Division of Endocrinology, Department of Medicine, Herlev and Gentofte Hospital, Herlev, Denmark

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Bo Zerahn Department of Nuclear Medicine, Herlev and Gentofte Hospital, Herlev, Denmark

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Objective

The extent of symptoms due to primary hyperparathyroidism (PHPT) depends on the population being studied. PHPT is mainly discovered incidentally through routine laboratory findings. Less is known about patient-experienced improvement following successful parathyroidectomy. The aim of our study was to assess the changes in the quality of life (QoL) after successful surgery using an SF-36 questionnaire.

Design

This is a prospective cohort study based on questionnaires.

Methods

Forty consecutive patients diagnosed with PHPT were prospectively administered an SF-36 questionnaire before and 6 months after successful parathyroidectomy. A subgroup of 18 patients answered the questionnaire at 1 and 3 months after surgery. Successful surgery was based on biochemistry and pathology reports as confirmed by an endocrinologist. Results of each SF-36 subcategory were compared to the results at baseline in order to detect changes in patient-reported QoL after successful surgery.

Results

There were significant improvements in six of eight SF-36 subcategories: vitality (P = 0.0001), physical functioning (P = 0.04), general health perception (P = 0.004), physical role functioning (P = 0.04), social role functioning (P = 0.004), and mental health perception (P = 0.0001). Changes appeared within a month after surgery with no further significant changes at later time points.

Conclusions

Parathyroidectomy significantly improves QoL as measured by a decrease in SF-36 scores as early as 1 month after successful parathyroidectomy. The SF-36 QoL questionnaire is suitable for monitoring changes in patient well-being after successful parathyroidectomy.

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Sara Lomelino Pinheiro Serviço de Endocrinologia, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal

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Ana Saramago Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal

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Branca Maria Cavaco Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal

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Carmo Martins Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal

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Valeriano Leite Serviço de Endocrinologia e Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal

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Tiago Nunes da Silva Serviço de Endocrinologia e Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal

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Nineteen cases of parathyroid carcinoma in patients with multiple endocrine neoplasia type 1 have been reported in the literature, of which 11 carry an inactivating germline mutation in the MEN1 gene. Somatic genetic abnormalities in these parathyroid carcinomas have never been detected. In this paper, we aimed to describe the clinical and molecular characterization of a parathyroid carcinoma identified in a patient with MEN1. A 60-year-old man was diagnosed with primary hyperparathyroidism during the postoperative period of lung carcinoid surgery. Serum calcium and parathyroid hormone levels were 15.0 mg/dL (8.4–10.2) and 472 pg/mL (12–65), respectively. The patient underwent parathyroid surgery, and histological findings were consistent with parathyroid carcinoma. Analysis of the MEN1 gene by next-generation sequencing (NGS) identified a novel germline heterozygous nonsense pathogenic variant (c.978C>A; p.(Tyr326*)), predicted to encode a truncated protein. Genetic analysis of the parathyroid carcinoma revealed a c.307del, p.(Leu103Cysfs*16) frameshift truncating somatic MEN1 variant in the MEN1 gene, which is consistent with MEN1 tumor-suppressor role, confirming its involvement in parathyroid carcinoma etiology. Genetic analysis of CDC73, GCM2, TP53, RB1, AKT1, MTOR, PIK3CA and CCND1 genes in the parathyroid carcinoma DNA did not detect any somatic mutations. To our knowledge, this is the first report of a PC case presenting both germline (first-hit) and somatic (second-hit) inactivation of the MEN1 gene.

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Julia Herteux Medical University of Graz, Auenbruggerplatz, Graz, Austria

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Simon Johannes Geiger Medical University of Graz, Auenbruggerplatz, Graz, Austria

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Christina Starchl Medical University of Graz, Auenbruggerplatz, Graz, Austria

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Johanna Windisch Medical University of Graz, Auenbruggerplatz, Graz, Austria

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Theresa Lerchl Medical University of Graz, Auenbruggerplatz, Graz, Austria

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Adelina Tmava-Berisha Medical University of Graz, Auenbruggerplatz, Graz, Austria

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Gerit Wünsch Medical University of Graz, Auenbruggerplatz, Graz, Austria

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Kathrin Eller Medical University of Graz, Auenbruggerplatz, Graz, Austria

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Astrid Fahrleitner-Pammer Medical University of Graz, Auenbruggerplatz, Graz, Austria

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Karin Amrein Medical University of Graz, Auenbruggerplatz, Graz, Austria

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Objective

Chronic hypoparathyroidism (HP) is associated with acute and chronic complications, especially those related to hypocalcemia. We aimed to analyze details on hospital admissions and the reported deaths in affected patients.

Design and methods

In a retrospective analysis, we reviewed the medical history of 198 patients diagnosed with chronic HP over a continuous period of up to 17 years at the Medical University Graz.

Results

The mean age in our mostly female cohort (70.2%) was 62.6 ± 18.7 years. The etiology was predominantly postsurgical (84.8%). About 87.4% of patients received standard medication (oral calcium/vitamin D), 15 patients (7.6%) used rhPTH1–84/Natpar® and 10 patients (4.5%) had no/unknown medication. Two hundred and nineteen emergency room (ER) visits and 627 hospitalizations were documented among 149 patients, and 49 patients (24.7%) did not record any hospital admissions. According to symptoms and decreased serum calcium levels, 12% of ER (n = 26) visits and 7% of hospitalizations (n = 44) were likely attributable to HP. A subgroup of 13 patients (6.5%) received kidney transplants prior to the HP diagnosis. In eight of these patients, parathyroidectomy for tertiary renal hyperparathyroidism was the cause of permanent HP. The mortality was 7.8% (n = 12), and the causes of death appeared to be unrelated to HP. Although the awareness for HP was low, calcium levels were documented in 71% (n = 447) of hospitalizations.

Conclusions

Acute symptoms directly related to HP did not represent the primary cause of ER visits. However, comorbidities (e.g. renal/cardiovascular diseases) associated with HP played a key role in hospitalizations and deaths.

Significance statement

Hypoparathyroidism (HP) is the most common complication after anterior neck surgery. Yet, it remains underdiagnosed as well as undertreated, and the burden of disease and long-term complications are usually underestimated. There are few detailed data on emergency room (ER) visits hospitalizations and death in patients with chronic HP, although acute symptoms due to hypo-/hypercalcemia are easily detectable. We show that HP is not the primary cause for presentation but that hypocalcemia is a typical laboratory finding (when ordered) and thus may contribute to subjective symptoms. Patients often present with renal/cardiovascular/oncologic illness for which HP is known to be a contributing factor. A small but very special group (n = 13, 6.5%) are patients after kidney transplantations who showed a high ER hospitalization rate. Surprisingly, HP was never the cause for their frequent hospitalizations but rather the result of chronic kidney disease. The most frequent cause for HP in these patients was parathyroidectomy due to tertiary hyperparathyroidism. The causes of death in 12 patients appeared to be unrelated to HP, but we found a high prevalence of chronic organ damages/comorbidities related to it in this group. Less than 25% documented HP correctly in the discharge letters, which indicates a high potential for improvement.

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