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Microglial dysfunction is one of the hallmarks and leading causes of common neurodegenerative diseases (NDD), including Alzheimer’s disease (AD) and Parkinson’s disease (PD). All these pathologies are characterized by aberrant aggregation of disease-causing proteins in the brain, which can directly activate microglia, trigger microglia-mediated neuroinflammation, and increase oxidative stress. Inhibition of glial activation may represent a therapeutic target to alleviate neurodegeneration. Recently, 3-iodothyronamine (T1AM), an endogenous derivative of thyroid hormone (TH) able to interact directly with a specific GPCR known as trace amine-associated receptor 1 (TAAR1), gained interest for its ability to promote neuroprotection in several models. Nevertheless, T1AM’s effects on microglial disfunction remain still elusive. In the present work we investigated whether T1AM could inhibit the inflammatory response of human HMC3 microglial cells to LPS/TNFα or β-amyloid peptide 25-35 (Aβ25-35) stimuli. The results of ELISA and qPCR assays revealed that T1AM was able to reduce microglia-mediate inflammatory response by inhibiting the release of proinflammatory factors, including IL-6, TNFα, NF-kB, MCP1 and MIP1, while promoting the release of anti-inflammatory mediators, such as IL-10. Notably, T1AM anti-inflammatory action in HMC3 cells resulted to be a TAAR1-mediated response, further increasing the relevance of the T1AM/TAAR1 system in the management of NDD.

Background and aims Fibroblast growth factor-23 (FGF23) has been associated with left ventricular (LV) hypertrophy, fibrosis, and heart failure (HF). We aimed to investigate the clinical correlates and prognostic value of intact FGF23 (iFGF23) in HF patients. Methods Patients with systolic HF (left ventricular ejection fraction – LVEF Results We enrolled 150 patients (82% males; median age 65 years). First, second, and third iFGF23 tertiles were 50.9 pg/mL. Patients in the upper iFGF23 tertile had lower LVEF (p=0.014), higher N-terminal pro-B-type natriuretic peptide (NT-proBNP, p=0.001), and lower peak VO2 (p Conclusions Circulating iFGF23 is associated with renal dysfunction, disease severity and outcome in systolic HF. Figure. Prognostic impact of FGF23 levels in patients with systolic heart failure (HF). In a cohort of HF patients with systolic dysfunction, higher iFGF23 levels (marker of increased cardiac fibrosis and hypertrophy) were associated with a more severe disease, as expressed by lower left ventricular systolic function, higher circulating levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), lower oxygen consumption at cardiopulmonary exercise test and worse renal function. Moreover, iFGF23 elevation identified patients at higher risk for all-cause and cardiac mortality, and HF hospitalization.

Background Fibroblast growth factor-23 (FGF23) has been associated to left ventricular (LV) hypertrophy and heart failure (HF) severity. We aimed to investigate clinical correlates and prognostic value of intact FGF23 (iFGF23) in HF patients.Methods Patients with systolic HF (left ventricular ejection fraction - LVEFResults We enrolled 150 patients (82% males; median age 65 years). First, second, and third iFGF23 tertiles were 50.9 pg/mL. Patients in the upper iFGF23 tertile had lower LVEF (p=0.014), higher NT-proBNP (p=0.001), and lower peak VO2 (pConclusions Circulating iFGF23 is associated with renal dysfunction, disease severity and outcome in systolic HF.

Context The pathogenesis of nephrolithiasis in primary hyperparathyroidism (PHPT) remains to be elucidated. The latest guidelines suggest parathyroidectomy in patients with asymptomatic PHPT with hypercalciuria (> 400 mg/d) and increased stone risk profile. Objective The objective of this work is to evaluate the association of urinary stone risk factors and nephrolithiasis in patients with asymptomatic sporadic PHPT and its clinical relevance. Design A total of 157 consecutive patients with sporadic asymptomatic PHPT were evaluated by measurement of serum and 24-hour urinary parameters and kidney ultrasound. Results Urinary parameters were tested in the univariate analysis as continuous and categorical variables. Only hypercalciuria and hypomagnesuria were significantly associated with nephrolithiasis in the univariate and multivariate analysis adjusted for age, sex, body mass index, estimated glomerular filtration rate, parathyroid hormone, 25-hydroxyvitamin D, serum calcium, and urine volume (odds ratio, OR 2.14 [1.10-4.56]; P = .04; OR 3.06 [1.26-7.43]; P = .013, respectively). Hypomagnesuria remained associated with nephrolithiasis in the multivariate analysis (OR 6.09 [1.57-23.5], P = .009) even when the analysis was limited to patients without concomitant hypercalciuria. The urinary calcium/magnesium (Ca/Mg) ratio was also associated with nephrolithiasis (univariate OR 1.62 [1.27-2.08]; P = .001 and multivariate analysis OR 1.74 [1.25-2.42], P = .001). Hypomagnesuria and urinary Ca/Mg ratio had a better, but rather low, positive predictive value compared with hypercalciuria. Conclusions Hypomagnesuria and urinary Ca/Mg ratio are each associated with silent nephrolithiasis and have potential clinical utility as risk factors, besides hypercalciuria, for kidney stones in asymptomatic PHPT patients. The other urinary indices that have been commonly thought to be associated with kidney stones in PHPT are not supported by our results.

Calcium homeostasis is maintained by the equilibrium among renal excretion, bone resorption, and intestinal absorption of calcium. Hypercalcaemia, which develops when the renal calcium overload exceeds its capacity to reabsorb calcium. Hyperparathyroidism is one of the most common causes of hypercalcaemia in free-living individuals, whereas hypercalcaemia of malignancy is the second cause of hypercalcaemia and the most common in hospitalized patients. The principal challenge in the evaluation of hypercalcaemia is distinguishing parathyroid hormone-related hypercalcaemia from other causes. Symptoms generally, but not always, correlate with the severity of hypercalcaemia and time course. The management of hypercalcaemia should be addressed at the underlying cause/mechanisms. When hypercalcaemia in moderate to severe the aim is also and most importantly directed to decrease hypercalcaemia, by increasing renal calcium excretion and decreasing bone resorption and intestinal calcium absorption. Severe hypercalcaemia represents an emergency and treatment is urgently required.

Objectives The aims of this paper were to evaluate the levels of Vitamin D (VitD) in patients with heart failure (HF), compared to a control group, to assess the effects of VitD on HF outcome and to compare VitD measurement between LIAISON immunoassay and HPLC-MS-MS methods in this population. Design and Methods We collected clinical, biochemical and outcome data from 247 patients with HF and in a subgroup of 151 patients, we measured VitD both with LIAISON and HPLC-MS-MS. Results HF patients had statistically lower 25OHD levels (45.2 ± 23.7 nmol/L vs 58.2 ± 24.0 nmol/L, P P P P = 0.02), confirmed in a multivariate adjusted analysis. Kaplan–Meier survival analyses showed that VitD insufficiency was associated with reduced survival in HF patients (log rank P = 0.017). There was a good agreement between LIAISON and HPLC-MS-MS (Cohen’s kappa coefficient 0.70), but the prevalence of VitD insufficiency was significantly higher with the former compared to the latter method (58.3%, n = 88 vs 55.6%, n = 84, P Conclusions 25OHD levels adequately measured by HPLC-MS-MS showed to be low in HF population and to be correlated with HF-related risk of death.

Context Pseudohypoparathyroidism (PHP) is a group of disorders characterized by hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone (PTH) levels as a result of end-organ resistance to PTH. Objective To describe a cohort of 26 patients with PHP followed in a single tertiary center. Methods Clinical, biochemical, radiological, and genetic analysis of the GNAS gene in 26 patients recruited since 2002. Results Ten patients harbored a GNAS mutation, 15 epigenetic abnormalities at the GNAS locus, and 1 did not show genetic or epigenetic abnormalities. According to clinical, biochemical, and genetic features, patients were classified as PHP1A, PHP1B, and pseudopseudohypoparathyroidism. Patients with PHP1A had an earlier diagnosis and more cases with family history, Albright hereditary osteodystrophy (AHO) features, hormonal resistance, and hypertension. Obesity was a common feature. No difference in biochemical values was present among PHP1A and PHP1B. Intracerebral calcification occurred in 72% of patients with no difference among PHP1A and PHP1B subgroups. No significant difference was observed between patients with and without intracerebral calcification for the time-weighted average values of total serum calcium, phosphate, calcium–phosphate product, and PTH fold increase. A borderline association between cerebral calcification and age at the time of diagnosis (P = .04) was found in the whole cohort of patients. No renal calcifications were found in the overall cohort. Conclusion Patients with PHP1A more frequently have AHO features as well as hypertension than patients with PHP1B. Patients with PHP presented a high rate of intracerebral calcification with no significant difference between subgroups. No increased risk of renal calcifications was also found in the entire cohort.

This article discusses rare causes of hypercalcemia. Hypercalcemia can rarely be associated with immobilization, genetic diseases in children such as Williams-Beuren syndrome, Hypophosphatasia, Jansen Metaphyseal Chondrodysplasia (JMC), cosmetic injection, milk-alkali syndrome (MAS), calcium sulfate beads administration, manganese intoxication, postacute kidney failure recovery, and Paget's disease.

ContextAtypical parathyroid adenomas (APAs) are neoplasms with uncertain malignant potential but lack unequivocal histological signs of malignancy.ObjectiveThis work aims to retrospectively evaluate the clinical and biochemical profiles of patients with APA, the outcome after parathyroidectomy (PTX), and the presence of CDC73 germline and somatic mutations.MethodsThis monocentric study was conducted on consecutive patients undergoing PTX for primary hyperparathyroidism (PHPT) between June 2000 and December 2020. Fifty-eight patients with a confirmed histopathological diagnosis of APA, and age- and sex-matched controls with parathyroid adenoma (PA) were also included.ResultsFifty-four patients had sporadic PHPT and 4 had familial isolated hyperparathyroidism (FIHP). Thirty-four patients (59%) had symptomatic disease. Serum calcium and parathyroid hormone (PTH) levels were significantly higher in symptomatic compared to asymptomatic patients (P = .048 and .008, respectively). FIHP patients were younger than their sporadic counterparts (30 ± 17 years vs 55 ± 13 years). APA patients had significantly higher serum calcium and PTH levels and lower 25-hydroxyvitamin D concentration, bone mineral density, and T score at one-third distal radius compared to those with PA. Four of 56 APA patients displayed a CDC73 germline mutation. No somatic CDC73 mutation was identified in 24 tumor specimens. The mean follow-up after surgery was 60 ± 56.4 months. All but 6 patients (90%), 5 with apparently sporadic PHPT and 1 with FIHP, were cured after surgery.ConclusionThe large majority of patients with APA, despite a moderate/severe phenotype, have a good prognosis. Germline CDC73 mutation–positive patients had a higher rate of persistent/recurrent disease. CDC73 gene alterations do not seem to have a relevant role in the tumorigenesis of sporadic APA.

Transthyretin (TTR), previously named prealbumin is a plasma protein secreted mainly by the liver and choroid plexus (CP) that is a carrier for thyroid hormones (THs) and retinol (vitamin A). The structure of TTR, with four monomers rich in β-chains in a globular tetrameric protein, accounts for the predisposition of the protein to aggregate in fibrils, leading to a rare and severe disease, namely transthyretin amyloidosis (ATTR). Much effort has been made and still is required to find new therapeutic compounds that can stabilize TTR (“kinetic stabilization”) and prevent the amyloid genetic process. Moreover, TTR is an interesting therapeutic target for neurodegenerative diseases due to its recognized neuroprotective properties in the cognitive impairment context and interestingly in Alzheimer’s disease (AD). Much evidence has been collected regarding the neuroprotective effects in AD, including through in vitro and in vivo studies as well as a wide range of clinical series. Despite this supported hypothesis of neuroprotection for TTR, the mechanisms are still not completely clear. The aim of this review is to highlight the most relevant findings on the neuroprotective role of TTR, and to summarize the recent progress on the development of TTR tetramer stabilizers.

The 4th International Workshop for the management of asymptomatic PHPT included, among the criteria for parathyroidectomy, the presence of hypercalciuria (dUCa> 400 mg/day) and increased biochemical stone risk profile. The aim of the present study was to evaluate the biochemical stone risk profile in 176 consecutive patients (143 females and 33 males) with asymptomatic PHPT. We recorded clinical and biochemical data, including 24 hours urinary measurements of the following parameters: volume and pH, creatinine, calcium, magnesium, sodium, potassium, ammonium, uric acid, oxalate, citrate, phosphate, inorganic sulphate and chloride and kidney ultrasound. In our cohort dUCa> 400mg/day showed a low sensitivity and positive predictive value (PPV) for nephrolithiasis with high specificity (46.2, 32.7, 73.0% respectively), while hypercalciuria by 4 mg/kg/bw (d-UCa>4mg/kg) had a high sensibility, with low PPV and specificity (79.5, 27.7, 40.1%) Daily hypomagnesuria (d-HypoMg), but not any other urinary parameter, was an independent predictor of nephrolithiasis in the univariate (OR 2.97 CI 1.27-7.09 P=0.014) and multivariate analyses adjusting for age, sex, BMI, and eGFR (OR 3.13 CI 1.17-8.42 P=0.02). d-HypoMg was relatively lower in the regression analysis with urinary calcium in patients with nephrolithiasis compared with those without. The mean ratio between (dUCa) and (dUMg) was higher in patients with nephrolithiasis compared with those without (4.6±2.0 vs 3.3±4.1; P In patients with hypercalciuria (>400 mg/24-hour) dUMg was positively correlated with dUCa in those without nephrolithiasis (r=0.50, β=0.2, P=0.002) but not in those with nephrolithiasis (r=0.05, β= 0.014; P=0.8). In patients without hypercalciuria we found that hypomagnesuria remained a predictor of nephrolithiasis using either 400 mg/die (P=0.002, OR 5.12 (1.84-14.24) or 4 mg/kg bw (P=0.014, OR 6.24 (1.45-26.8). Moreover, the OR for nephrolithiasis improved using the combination of d-HypoMg with d-UCa>4mg/kg (OR 8.12, CI 1.92-34.18, P=0.004), but not with dUCa> 400mg/day. The current urinary calcium threshold of >400 mg/24-hour has a low sensitivity in detecting nephrolithiasis; our data suggest that sensitivity, specificity and positive predictive value could be improved including dUMg, dUCa/dUMg ratio and the combination of d-HypoMg with d-UCa>4mg/kg in the stone risk evaluation.

Post-operative hypoparathyroidism (PoHypo) is the most common cause of hypoparathyroidism and it is the result of accidental parathyroid removal/injury during neck surgery. The lack of PTH alters calcium homeostasis and patients are at risk of renal complications, bone involvement, infections and psychiatric syndromes. Conventional therapy, that includes calcium supplements and activated vitamin D, does not restore the complete calcium homeostasis. From a neuropsychological point of view, patients complain with neurocognitive symptoms such as “brain fog”, impaired ability to focus, memory loss, depression. Poor quality of life (QoL), evaluated by non-specific questionnaires, has been demonstrated in these patients. The aim of this study is to evaluate the cognitive function by neuropsychological specific tests in patients with PoHypo and matched controls and their relationship with biochemical parameters. This is a prospective monocentric study; we enrolled outpatients who underwent total thyroidectomy for malignant cured disease, 34 with chronic (>6 months) PoHypo (mean age 50.7 ys) and 31 without PoHypo (mean age 49.9 ys). The two groups did not differ significantly in TSH; PoHypo group had a relatively controlled serum calcium adjusted for albumin (SAlbCa) levels in therapy (mean 8.8±0.1mg/dl, 4 patients with or < than 9 mg/dl) was performed in both patients groups. PoHypo patients with serum calcium levels 9mg/dl, either at the Trail-Making Test_A (scores:34.00 vs 21.05, p

Introduction: Conventional therapy of chronic post-operative hypoparathyroidism (PO-HypoPT) with calcium and activated vitamin D is suboptimal and associated with several complications, including impairment of the quality of life. Aim of this study was to compare clinical, biochemical and instrumental parameters in 120 patients who underwent total thyroidectomy for differentiated thyroid cancer, 60 with PO-HypoPT (Group A) treated with conventional therapy and 60 without (Group B), matched for age and sex, followed a tertiary referral center. Matherials and methods: An “ad hoc” CRF was used to collect epidemiological, clinical (symptoms, treatment) and biochemical data (total and ionized calcium, albumin, phosphate, magnesium, calcium/phosphate product, creatinine, 25-OH vitamin D, PTH, TSH, eGFR, 24-h urinary calcium and creatinine), and renal ultrasound. Results: The median duration of PO-HypoPT was 7 years (IQR 4-13). All patients of group A were treated with calcitriol (median 0.5 μg/daily; IQR 0.5-1.0), and 33/60 (55%) were also given calcium carbonate supplementation (median 1000 mg/daily; IQR 500-1000). Hypocalcemia related symptoms were more frequent in group A (27/60 - 45%) than in group B (1/60 - 1.7%) (p

Unfortunately, the 13th author name has been published incorrectly in the original publication.

Thyroid hormones (THs), namely T3 and T4, display many effects on cardiac function by interacting with their specific nuclear receptors (genomic effects) or with different targets (non-genomic effects). Moreover, new metabolites of THs have been characterized which may represent independent chemical messengers. Deiodination is responsible for the production of 3,5-diiodothyronine (3,5-T2), which has been detected in human blood and modulates mitochondrial function and lipid metabolism. Deamination and decarboxylation of THs lead to the production of thyroacetic acids, which are considered potential thyromimetic agents. Decarboxylation and deiodination yield a class of compounds known as thyronamines, particularly 3-iodothyronamine (T1AM). T1AM has shown functional effects on the central nervous system and on energy metabolism, possibly by interacting with a specific class of receptors (trace amine-associated receptors). In the heart, T1AM produces a negative inotropic and chronotropic effect and has been shown to have a cardioprotective action, which might be due to mitochondrial modulation.

Vitamin D is a steroid hormone classically involved in the calcium metabolism and bone homeostasis. Recently, new and interesting aspects of vitamin D metabolism has been elucidated, namely the special role of the skin, the metabolic control of liver hydroxylase CYP2R1, the specificity of 1α-hydroxylase in different tissues and cell types and the genomic, non-genomic and epigenomic effects of vitamin D receptor, which will be addressed in the present review. Moreover, in the last decades, several extraskeletal effects which can be attributed to vitamin D have been shown. These beneficial effects will be here summarized, focusing on the immune system and cardiovascular system.

Novel interest has arisen in recent years regarding bone, which is a very complex and dynamic tissue deputed to several functions ranging from mechanical and protective support to hematopoiesis and calcium homeostasis maintenance. In order to address these tasks, a very refined, continuous remodeling process needs to occur involving the coordinated action of different types of bone cells: osteoblasts (OBs), which have the capacity to produce newly formed bone, and osteoclasts (OCs), which can remove old bone. Bone remodeling is a highly regulated process that requires many hormones and messenger molecules, both at the systemic and the local level. The whole picture is still not fully understood, and the role of novel actors, such as the components of the endocannabinoids system (ECS), including endogenous cannabinoid ligands (ECs), cannabinoid receptors (CBRs), and the enzymes responsible for endogenous ligand synthesis and breakdown, is extremely intriguing. This article reviews the connection between the ECS and skeletal health, supporting the potential use of cannabinoid receptor ligands for the treatment of bone diseases associated with accelerated osteoclastic bone resorption, including osteoporosis and bone metastasis.

In March 2020, the infection COVID-19 spread as a pandemic emergence. Among multiple biological and environmental factors, hypovitaminosis D is a credible candidate. The aim of this study is to shed light on the pathogenic role of vitamin D deficiency in the susceptibility to SARS-CoV-2 and in the aggressive immune and inflammatory response by the host. We retrospectively analyzed the biochemical panel of immune system markers and the tandem mass spectrometry coupled to liquid chromatography (LC-MS-MS) measured vitamin D, in the serum samples of patients with SARS-CoV-2 studied in all aspects of clinical relevant parameters. RESULTS between 18th March and 20th April 2020 we enrolled 29 consecutive patients with COVID-19. They were 17 (58.6%) males and 12 (41.4) females, and the median age was 79 (69–88) years. Mean 25OHD was 17.3±2.1 ng/ml, with a median of 15.7 1 ng/ml (i.r. 6.7–25). Twenty-five patients (86.2%) had 25OHD levels

The latest guidelines of the 4th International Workshop on Asymptomatic Primary Hyperparathyroidism (aPHPT) reintroduced hypercalciuria (i.e. urinary calcium > 400 mg/day) as criterion for surgery. However, the value of hypercalciuria as a predictor of nephrolithiasis and the correct cut-off values still need to be confirmed. To evaluate the prevalence of silent kidney stones in a large series of patients with aPHPT and the sensibility, specificity and predictive value of different cut-off values of hypercalciuria in identifying patients with nephrolithiasis. One hundred seventy-six consecutive patients with aPHPT were evaluated at our Institution by serum and urinary parameters and kidney ultrasound. Silent nephrolithiasis was found in 38 (21.6%) patients. In the univariate and multivariate model, hypercalciuria was a predictor of nephrolithiasis using the criterion of 400 mg/24 h [(OR 2.30, (1.11–4.82) P = 0.025], 4 mg/kg/bw [OR 2.65, (1.14–6.25) P = 0.023], gender criterion [OR 2.79, (1.15–6.79) P = 0.023] and the cut-off value derived from the ROC analysis [(> 231 mg/24 h) OR 5.02 (1.68–14.97) P = 0.004]. Despite these several predictive criteria, however, hypercalciuria had a low positive predictive value (PPV), ranging from 27.4 to 32.7%. Hypercalciuria is a predictor of nephrolithiasis, but its PPV is low.

Familial isolated hyperparathyroidism (FIHP) is a rare inherited disease accounting for 1% of all cases of primary hyperparathyroidism (PHPT). It is genetically heterogeneous being associated with mutations in different genes, including MEN1, CDC73, CASR, and recently GCM2. The aim of the study was to further investigate the molecular pathogenesis in Italian FIHP kindreds. We used whole exome sequencing (WES) in the probands of seven unrelated FIHP kindreds. We carried out a separate family-based exome analysis in a large family characterized by the co-occurrence of PHPT with multiple tumors apparently unrelated to the disease. Selected variants were also screened in 18 additional FIHP kindreds. The clinical, biochemical, and pathological characteristics of the families were also investigated. Three different variants in GCM2 gene were found in two families, but only one (p.Tyr394Ser), already been shown to be pathogenic in vitro, segregated with the disease. Six probands carried seven heterozygous missense mutations segregating with the disease in the FAT3, PARK2, HDAC4, ITPR2 and TBCE genes. A genetic variant in the APC gene co-segregating with PHPT (p.Val530Ala) was detected in a family whose affected relatives had additional tumors, including colonic polyposis. We confirm the role of GCM2 germline mutations in the pathogenesis of FIHP, although at a lower rate than in the previous WES study. Further studies are needed to establish the prevalence and the role in the predisposition to FIHP of the novel variants in additional genes.

The field of thyroid hormone signaling has grown more complex in recent years. In particular, it has been suggested that some thyroid hormone derivatives, tentatively named "novel thyroid hormones" or "active thyroid hormone metabolites", may act as independent chemical messengers. They include 3,5-diiodothyronine (T2), 3-iodothyronamine (T1AM), and several iodothyroacetic acids, i.e., 3,5,3',5'-thyroacetic acid (TA4), 3,5,3'-thyroacetic acid (TA3), and 3-thyroacetic acid (TA1). We summarize the present knowledge on these compounds, namely their biosynthetic pathways, endogenous levels, molecular targets, and the functional effects elicited in experimental preparations or intact animals after exogenous administration. Their physiological and pathophysiological role is discussed, and potential therapeutic applications are outlined. The requirements needed to qualify these substances as chemical messengers must still be validated, although promising evidence has been collected. At present, the best candidate to the role of independent chemical messenger appears to be T1AM, and its most interesting effects concern metabolism and brain function. The responses elicited in experimental animals have suggested potential therapeutic applications. TA3 has an established role in thyroid hormone resistance syndromes, and is under investigation in Allen-Herndon-Dudley syndrome. Other potential targets are represented by obesity and dyslipidemia (for T2 and T1AM); dementia and degenerative brain disease (for T1AM and TA1); cancer (for T1AM and TA4). Another intriguing and unexplored question is the potential relevance of these metabolites in the clinical picture of hypothyroidism and in the response to replacement therapy.

Vitamin D is classically involved in maintaining bone and mineral health, but it has been shown to exert many extraskeletal functions, including pleiotropic effects on cardiovascular system. This review aims to summarize evidences in literature about vitamin D and cardiovascular outcome. Calcitriol or 1,25(OH)2D, the active hormone, binds to the specific nuclear receptor VDR, which is expressed in rat and human heart and vasculature and has effects on myocardiocytes, smooth cells, and endothelial cells. 25-Hydroxy-vitamin D (25OHD) represents the biomarker of vitamin D levels and reflects vitamin D status. There is consistent evidence that low serum 25OHD levels are associated with increased risk of cardiovascular diseases, including hypertension, coronary artery disease, ischemic heart disease, heart failure, stroke, and type 2 diabetes. Randomized-controlled trials and Mendelian randomization studies so far have not succeeded in proving a benefit of vitamin D supplementation. However, the latter investigations are affected by some methodological limitations, and therefore, it is still unclear if vitamin D deficiency has a causative role in cardiovascular diseases or is rather a marker of poor health in chronic disease.

3,5-diiodo-L-thyronine (3,5-T2) is an endogenous derivative of thyroid hormone with potential metabolic effects. It has been detected in human blood by immunological methods, but a reliable assay based on mass spectrometry (MS), which is now regarded as the gold standard in clinical chemistry, is not available yet. Therefore, we aimed at developing a novel ad-hoc optimized method to quantitate 3,5-T2 and its isomers by MS in human serum. Serum samples were obtained from 28 healthy subjects. Two ml of serum were deproteinized with acetonitrile and then subjected to an optimized solid phase extraction-based procedure. To lower background noise, the samples were furtherly cleaned by hexane washing and acetonitrile precipitation of residual proteins. 3,5-T2 and its isomers 3,3′-T2 and 3′,5′-T2 were then analyzed by HPLC coupled to tandem MS. Accuracy and precision for T2 assay were 88–104% and 95–97%, respectively. Recovery and matrix effect averaged 78% and +8%, respectively. 3,5-T2 was detected in all samples and its concentration averaged (mean ± SEM) 41 ± 5 pg/ml, i.e., 78 ± 9 pmol/l. In the same samples the concentration of 3,3′-T2 averaged 133±15 pg/ml, i.e., 253±29 pmol/l, while 3′,5′-T2 was not detected. 3,5-T2 concentration was significantly related to 3,3′-T2 concentration (r = 0.540, P < 0.01), while no significant correlation was observed with either T3 or T4 in a subset of patients in which these hormones were assayed. In conclusion, our method is able to quantify 3,5-T2 and 3,3′-T2 in human serum. Their concentrations lie in the subnanomolar range, and a significant correlation was detected between these two metabolites in healthy individuals.

PARAT, a new European Society of Endocrinology program, aims to identify unmet scientific and educational needs of parathyroid disorders, such as primary hyperparathyroidism (PHPT), including parathyroid cancer (PC), and hypoparathyroidism (HypoPT). The discussions and consensus statements from the first PARAT workshop (September 2018) are reviewed. PHPT has a high prevalence in Western communities, PHPT has a high prevalence in Western communities, yet evidence is sparse concerning the natural history and whether morbidity and long-term outcomes are related to hypercalcemia or plasma PTH concentrations, or both. Cardiovascular mortality and prevalence of low energy fractures are increased, whereas Quality of Life is decreased, although their reversibility by treatment of PHPT has not been convincingly demonstrated. PC is a rare cause of PHPT, with an increasing incidence, and international collaborative studies are required to advance knowledge of the genetic mechanisms, biomarkers for disease activity, and optimal treatments. For example, ~20% of PCs demonstrate high mutational burden, and identifying targetable DNA variations, gene amplifications and gene fusions may facilitate personalized care, such as different forms of immunotherapy or targeted therapy. HypoPT, a designated orphan disease, is associated with a high risk of symptoms and complications. Most cases are secondary to neck surgery. However, there is a need to better understand the relation between disease biomarkers and intellectual function, and to establish the role of PTH in target tissues, as these may facilitate the appropriate use of PTH substitution therapy. Management of parathyroid disorders is challenging, and PARAT has highlighted the need for international transdisciplinary scientific and educational studies in advancing in this field. peerReviewed

Individuals with a familial predisposition to the development of parathyroid tumors constitute a small minority of all patients with primary hyperparathyroidism (PHPT). These familial syndromes exhibit Mendelian inheritance patterns and the main causative genes in most families have been identified. They include multiple endocrine neoplasia (MEN; types 1, 2A, and 4), hyperparathyroidism-jaw tumor (HPT-JT) syndrome, familial isolated hyperparathyroidism, familial hypocalciuric hypercalcemia (FHH), and neonatal severe PHPT. Each MEN type is associated with the various combinations of specific tumors. MEN1 is characterized by the occurrence of parathyroid, enteropancreatic, and pituitary tumors; MEN2A is characterized by medullary thyroid carcinoma and pheochromocytoma, and MEN4 is characterized by a pathological spectrum similar to that of MEN1 in association with tumors of the adrenal, kidney, and reproductive organs. HPT-JT is characterized by PHPT, ossifying fibromas of maxillary bones, kidney disease, and uterine neoplasias. The prompt diagnosis of these diseases is of great importance for planning appropriate surveillance of the mutant carriers and correct surgical management. The search for mutation is also useful for the identification of the family members who do not carry the mutation and can avoid unnecessary biochemical and instrumental evaluations. Surgery remains the treatment of choice in all familial forms except FHH.