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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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Background
The diagnosis of primary hyperparathyroidism (PHPT) remains a challenge because of increased asymptomatic PHPT or patients with normocalcaemic PHPT (NPHPT). In addition, some primary hospitals in China have no equipment to measure parathyroid hormone (PTH) levels. Therefore, an additional, simple, and inexpensive laboratory biochemical marker is urgently needed. The calcium/phosphate (Ca/P) ratio and chloride/phosphate (Cl/P) ratio have been proposed as suitable tools to diagnose PHPT in Europe; however, the Ca/P ratio has never been tested in China. We aimed to conduct a confirmatory study to explore the diagnostic performance of the Ca/P ratio for PHPT in China.
Methods
From January 2015 to December 2020, a total of 155 patients who underwent parathyroidectomy (143 PHPT patients and 12 NPHPT patients) and 153 controls were enrolled in this single-center , retrospective study. Serum calcium, phosphate, parathyroid hormone, 25-hydroxyvitamin vitamin D (25(OH) vitamin D), chloride, alanine transaminase (ALT), aspartate aminotransaminase (AST), estimated glomerular filtration rate (eGFR), and creatinine levels were recorded for all the study participants. Pairwise comparisons were made between groups, and the diagnostic performance of the Ca/P ratio was determined using receiver-operating characteristic (ROC) analysis.
Results
Patients with PHPT had a higher Ca/P ratio than controls (P < 0.001). A Ca/P ratio above 2.94 with a sensitivity of 95.5% and specificity of 98.7% can distinguish PHPT patients from healthy individuals. This index was positively correlated with the PTH level (r = 0.875, P < 0.001).
Conclusion
The Ca/P ratio is an ideal and inexpensive indicator for diagnosing PHPT in China when using a cut-off value of 2.94.
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Both in the United States and Europe, the number of minors who present at transgender healthcare services before the onset of puberty is rapidly expanding. Many of those who will have persistent gender dysphoria at the onset of puberty will pursue long-term puberty suppression before reaching the appropriate age to start using gender-affirming hormones. Exposure to pubertal sex steroids is thus significantly deferred in these individuals. Puberty is a critical period for bone development: increasing concentrations of estrogens and androgens (directly or after aromatization to estrogens) promote progressive bone growth and mineralization and induce sexually dimorphic skeletal changes. As a consequence, safety concerns regarding bone development and increased future fracture risk in transgender youth have been raised. We here review published data on bone development in transgender adolescents, focusing in particular on differences in age and pubertal stage at the start of puberty suppression, chosen strategy to block puberty progression, duration of puberty suppression, and the timing of re-evaluation after estradiol or testosterone administration. Results consistently indicate a negative impact of long-term puberty suppression on bone mineral density, especially at the lumbar spine, which is only partially restored after sex steroid administration. Trans girls are more vulnerable than trans boys for compromised bone health. Behavioral health measures that can promote bone mineralization, such as weight-bearing exercise and calcium and vitamin D supplementation, are strongly recommended in transgender youth, during the phase of puberty suppression and thereafter.
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Immune checkpoint inhibitors (ICIs) belong to a new group of anticancer drugs targeting T-cell proteins involved in the activation of immune response toward malignancies. Their introduction into clinical practice was a milestone in modern cancer treatment. However, the significant advantage of ICIs over conventional chemotherapy in terms of therapeutic efficacy is accompanied by new challenges related to specific side effects. ICI-induced immune system activation could lead to the loss of self-tolerance, presenting as autoimmune inflammation and dysfunction of various tissues and organs. Thus, the typical side effects of ICIs include immune-related adverse events (irAEs), among which endocrine irAEs, affecting numerous endocrine glands, have been commonly recognized. This review aimed to outline the current knowledge regarding ICI-induced endocrine disorders from a clinical perspective. We present updated information on the incidence and clinical development of ICI-induced endocrinopathies, including the most frequent thyroiditis and hypophysitis, the rarely observed insulin-dependent diabetes mellitus and primary adrenal insufficiency, and the recently described cases of hypoparathyroidism and lipodystrophy. Practical guidelines for monitoring, diagnosis, and treatment of ICI-related endocrine toxicities are also offered. Rising awareness of endocrine irAEs among oncologists, endocrinologists, and other health professionals caring for patients receiving ICIs could contribute to better safety and efficacy. As immunotherapy becomes widespread and approved for new types of malignancies, increased incidences of endocrine irAEs are expected in the future.
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Background
Despite mounting evidence linking both calcium and IGF1, there is a lack of studies investigating any association between circulating levels of IGF1 and serum calcium.
Methods
Serum calcium, IGF1, and IGF-binding protein 3 (IGFBP3) were measured for 5368 participants in NHANES III. We calculated multivariable-adjusted geometric means of serum concentrations of IGF1, IGFBP3, and IGF1/IGFBP3 by categories of calcium (lowest 5% (<1.16 mmol/l), mid 90%, and top 5% (≥1.31 mmol/l)). We also performed stratified analyses by sex, age, ethnicity, BMI, serum levels of vitamin D, and bone mineral density (BMD).
Results
Overall, we found that circulating calcium was positively associated with circulating levels of IGF1 and IGFBP3, but not their molar ratio (i.e., geometric mean of IGF1 by increasing calcium categories: 237.63, 246.51, and 264.22 ng/nl; P trend: 0.43; P first vs third category: 0.01). In particular, these associations were observed in women, people aged <60, non-Hispanic whites, those with vitamin D levels above the mean, and those with low BMD. In contrast, there was an inverse association with the molar ratio for those with BMI ≥30 kg/m2.
Conclusion
We found an overall positive association between circulating levels of IGF1 and IGFBP3 and serum calcium. However, stratification by potential effect-modifiers did not support all suggested hypotheses. Our findings provide more insight into the interplay between calcium and IGF1, which in the future can be investigated in larger observational studies allowing for additional stratifications based on a combination of the different effect-modifiers investigated here.
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Background
Despite significant improvement in imaging quality and advanced scientific knowledge, it may still sometimes be difficult to distinguish different parathyroid lesions. The aims of this prospective study were to evaluate parathyroid lesions with ultrasound elastography and to determine whether strain index can help to differentiate parathyroid lesions.
Methods
Patients with biochemically confirmed hyperparathyroidism and localised parathyroid lesions in ultrasonography were included. All patients underwent B-mode US and USE examination. Ultrasound elastography scores and strain index of lesions were determined. Strain index was defined as the ratio of strain of the thyroid parenchyma to the strain of the parathyroid lesion.
Results
Data of 245 lesions of 230 patients were analysed. Histopathologically, there were 202 (82.45%) parathyroid adenomas, 26 (10.61%) atypical parathyroid adenomas, and 17 (6.94%) cases of parathyroid hyperplasia. Median serum Ca was significantly higher in atypical parathyroid adenoma patients than parathyroid hyperplasia patients (P = 0.019) and median PTH was significantly higher in APA compared to PA patients (P < 0.001). In 221 (90.2%) of the parathyroid lesions, USE score was 1 or 2. The median SI of atypical parathyroid adenomas was significantly higher than parathyroid adenomas and hyperplasia lesions (1.5 (0.56–4.86), 1.01 (0.21–8.43) and 0.91 (0.26–2.02), respectively, P = 0.003).
Conclusion
Our study revealed that SI of parathyroid lesions as well as serum calcium, parathyroid hormone levels, and B-mode US features may help to predict the atypical parathyroid adenoma. Ultrasound elastography can be used to differentiate among parathyroid lesions and guide a surgical approach.
Department of Oncology–Pathology, Cancer Centre Karolinska, Department of Biosciences and Nutrition, Department of Molecular Medicine and Surgery, Department of Surgery #4, Karolinska Institutet, Stockholm, Sweden
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Department of Oncology–Pathology, Cancer Centre Karolinska, Department of Biosciences and Nutrition, Department of Molecular Medicine and Surgery, Department of Surgery #4, Karolinska Institutet, Stockholm, Sweden
Department of Oncology–Pathology, Cancer Centre Karolinska, Department of Biosciences and Nutrition, Department of Molecular Medicine and Surgery, Department of Surgery #4, Karolinska Institutet, Stockholm, Sweden
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Department of Oncology–Pathology, Cancer Centre Karolinska, Department of Biosciences and Nutrition, Department of Molecular Medicine and Surgery, Department of Surgery #4, Karolinska Institutet, Stockholm, Sweden
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Department of Oncology–Pathology, Cancer Centre Karolinska, Department of Biosciences and Nutrition, Department of Molecular Medicine and Surgery, Department of Surgery #4, Karolinska Institutet, Stockholm, Sweden
Department of Oncology–Pathology, Cancer Centre Karolinska, Department of Biosciences and Nutrition, Department of Molecular Medicine and Surgery, Department of Surgery #4, Karolinska Institutet, Stockholm, Sweden
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Department of Oncology–Pathology, Cancer Centre Karolinska, Department of Biosciences and Nutrition, Department of Molecular Medicine and Surgery, Department of Surgery #4, Karolinska Institutet, Stockholm, Sweden
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Department of Oncology–Pathology, Cancer Centre Karolinska, Department of Biosciences and Nutrition, Department of Molecular Medicine and Surgery, Department of Surgery #4, Karolinska Institutet, Stockholm, Sweden
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Department of Oncology–Pathology, Cancer Centre Karolinska, Department of Biosciences and Nutrition, Department of Molecular Medicine and Surgery, Department of Surgery #4, Karolinska Institutet, Stockholm, Sweden
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Primary hyperparathyroidism (PHPT) is a common endocrinopathy, frequently caused by a parathyroid adenoma, rarely by a parathyroid carcinoma that lacks effective oncological treatment. As the majority of cases are present in postmenopausal women, oestrogen signalling has been implicated in the tumourigenesis. Oestrogen receptor beta 1 (ERB1) and ERB2 have been recently identified in parathyroid adenomas, the former inducing genes coupled to tumour apoptosis. We applied immunohistochemistry and slide digitalisation to quantify nuclear ERB1 and ERB2 in 172 parathyroid adenomas, atypical adenomas and carcinomas, and ten normal parathyroid glands. All the normal parathyroid glands expressed ERB1 and ERB2. The majority of tumours expressed ERB1 (70.6%) at varying intensities, and ERB2 (96.5%) at strong intensities. Parathyroid carcinomas expressed ERB1 in three out of six cases and ERB2 in five out of six cases. The intensity of tumour nuclear ERB1 staining significantly correlated inversely with tumour weight (P=0.011), and patients whose tumours were classified as ERB1-negative had significantly greater tumour weight as well as higher serum calcium (P=0.002) and parathyroid hormone levels (P=0.003). Additionally, tumour nuclear ERB1 was not expressed differentially with respect to sex or age of the patient. Levels of tumour nuclear ERB2 did not correlate with clinical characteristics. In conclusion, decreased ERB1 immunoreactivity is associated with increased tumour weight in parathyroid adenomas. Given the previously reported correlation with tumour-suppressive signalling, selective oestrogen receptor modulation (SERMs) may play a role in the treatment of parathyroid carcinomas. Future studies of SERMs and oestrogen treatment in PHPT should consider tumour weight as a potential factor in pharmacological responsiveness.
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Objective:
Investigate the prevalence of vitamin D deficiency in an equatorial population through a large-sample study.
Methods:
Cross-sectional study with 30,224 healthy individuals from the North Region, in Brazil (Amazônia – state of Pará), who had 25-hydroxy-vitamin D (25(OH)D) and intact parathyroid hormone (PTH) serum levels measured by immunoassay method. Those with history of acute or chronic diseases were excluded. Abnormal levels of calcium, creatinine, glycemia and albumin were also exclusion criteria.
Results:
25(OH)D levels were 29.1 ± 8.2 ng/mL and values <12.7 ng/mL were equal to < −2 s.d. below average. Hypovitaminosis D was present in 10% of subjects according to the Institute of Medicine (values <20 ng/mL) and in 59%, in consonance with Endocrine Society (values 20–30 ng/mL as insufficiency and <20 ng/mL as deficiency) criteria. Individuals were divided according to four age brackets: children, adolescents, adults and elderly, and their 25(OH)D levels were: 33 ± 9; 28.5 ± 7.4; 28.3 ± 7.7; 29.3 ± 8.5 ng/mL, respectively. All groups differed in 25(OH)D, except adolescents vs adults. Regression model showed BMI, sex, living zone (urban or rural) and age as independent variables to 25(OH)D levels. Comparing subjects with vitamin D deficiency (<20 ng/mL) to those with vitamin D insufficiency (20–30 ng/mL), a difference between PTH levels in these two groups was observed (95.9 ± 24.7 pg/mL vs 44.2 ± 64.5 pg/mL; P < 0.01). Additionally, the most accurate predictive vitamin D level for subclinical hyperparathyroidism in ROC curve was 26 ng/mL.
Conclusion:
Our equatorial population showed low prevalence of vitamin D hypovitaminosis ranging with age bracket. The insufficient category by Endocrine Society was corroborated by our PTH data.
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Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Sweden
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Objective
Autoimmune polyendocrine syndrome type 1 (APS1) is a rare autosomal recessive disorder characterized by progressive organ-specific autoimmunity. There is scant information on APS1 in ethnic groups other than European Caucasians. We studied clinical aspects and autoimmune regulator (AIRE) gene mutations in a cohort of Indian APS1 patients.
Design
Twenty-three patients (19 families) from six referral centres in India, diagnosed between 1996 and 2016, were followed for [median (range)] 4 (0.2–19) years.
Methods
Clinical features, mortality, organ-specific autoantibodies and AIRE gene mutations were studied.
Results
Patients varied widely in their age of presentation [3.5 (0.1–17) years] and number of clinical manifestations [5 (2–11)]. Despite genetic heterogeneity, the frequencies of the major APS1 components (mucocutaneous candidiasis: 96%; hypoparathyroidism: 91%; primary adrenal insufficiency: 55%) were similar to reports in European series. In contrast, primary hypothyroidism (23%) occurred more frequently and at an early age, while kerato-conjunctivitis, urticarial rash and autoimmune hepatitis were uncommon (9% each). Six (26%) patients died at a young age [5.8 (3–23) years] due to septicaemia, hepatic failure and adrenal/hypocalcaemic crisis from non-compliance/unexplained cause. Interferon-α and/or interleukin-22 antibodies were elevated in all 19 patients tested, including an asymptomatic infant. Eleven AIRE mutations were detected, the most common being p.C322fsX372 (haplotype frequency 37%). Four mutations were novel, while six others were previously described in European Caucasians.
Conclusions
Indian APS1 patients exhibited considerable genetic heterogeneity and had highly variable clinical features. While the frequency of major manifestations was similar to that of European Caucasians, other features showed significant differences. A high mortality at a young age was observed.
The University of Warwick, Coventry, UK
Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
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Low serum 1,25-dihydroxyvitamin D (1,25(OH)2D) in end-stage renal disease (ESRD) is considered a consequence of elevated fibroblast growth factor 23 (FGF23) and concomitant reduced activity of renal 1α-hydroxylase (CYP27B1). Current ESRD treatment strategies to increase serum calcium and suppress secondary hyperparathyroidism involve supplementation with vitamin D analogues that circumvent 1α-hydroxylase. This overlooks the potential importance of 25-hydroxyvitamin D (25(OH)D) deficiency as a contributor to low serum 1,25(OH)2D. We investigated the effects of vitamin D (cholecalciferol) supplementation (40,000 IU for 12 weeks and maintenance dose of 20,000 IU fortnightly), on multiple serum vitamin D metabolites (25(OH)D, 1,25(OH)2D3 and 24,25(OH)2D3) in 55 haemodialysis patients. Baseline and 12 month data were compared using related-samples Wilcoxon signed rank test. All patients remained on active vitamin D analogues as part of routine ESRD care. 1,25(OH)2D3 levels were low at baseline (normal range: 60–120 pmol/L). Cholecalciferol supplementation normalised both serum 25(OH)D and 1,25(OH)2D3. Median serum 25(OH)D increased from 35.1 nmol/L (IQR: 23.0–47.5 nmol/L) to 119.9 nmol/L (IQR: 99.5–143.3 nmol/L) (P < 0.001). Median serum 1,25(OH)2D3 and 24,25(OH)2D3 increased from 48.3 pmol/L (IQR: 35.9–57.9 pmol/L) and 3.8 nmol/L (IQR: 2.3–6.0 nmol/L) to 96.2 pmol/L (IQR: 77.1–130.6 pmol/L) and 12.3 nmol/L (IQR: 9–16.4 nmol/L), respectively (P < 0.001). A non-significant reduction in daily active vitamin D analogue dose occurred, 0.94 µmcg at baseline to 0.77 µmcg at 12 months (P = 0.73). The ability to synthesise 1,25(OH)2D3 in ESRD is maintained but is substrate dependent, and serum 25(OH)D was a limiting factor at baseline. Therefore, 1,25(OH)2D3 deficiency in ESRD is partly a consequence of 25(OH)D deficiency, rather than solely due to reduced 1α-hydroxylase activity as suggested by current treatment strategies.
