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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.

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

Thyroid hormones (THs) elicit significant effects on numerous physiological processes, such as growth, development, and metabolism. A lack of thyroid hormones is not compatible with normal health. Most THs effects are mediated by two different thyroid hormone receptor (TR) isoforms, namely TRα and TRβ, with the TRβ isoform known to be responsible for the main beneficial effects of TH on liver. In brain, despite the crucial role of TRα isoform in neuronal development, TRβ has been proposed to play a role in the remyelination processes. Consequently, over the past two decades, much effort has been applied in developing thyroid hormone analogs capable of uncoupling beneficial actions on liver (triglyceride and cholesterol lowering) and central nervous system (CNS) (oligodendrocyte proliferation) from deleterious effects on the heart, muscle and bone. Sobetirome (GC-1) and subsequently Eprotirome (KB2115) were the first examples of TRβ selective thyromimetics, with Sobetirome differing from the structure of thyronines because of the absence of halogens, biaryl ether oxygen, and amino-acidic side chain. Even though both thyromimetics showed encouraging actions against hypercholesterolemia, non-alcoholic steatohepatitis (NASH) and in the stimulation of hepatocytes proliferation, they were stopped after Phase 1 and Phase 2–3 clinical trials, respectively. In recent years, advances in molecular and structural biology have facilitated the design of new selective thyroid hormone mimetics that exhibit TR isoform-selective binding, and/or liver- and tissue-selective uptake, with Resmetirom (MGL-3196) and Hep-Direct prodrug VK2809 (MB07811) probably representing two of the most promising lipid lowering agents, currently under phase 2–3 clinical trials. More recently the application of a comprehensive panel of ADME-Toxicity assays enabled the selection of novel thyromimetic IS25 and its prodrug TG68, as very powerful lipid lowering agents both in vitro and in vivo. In addition to dyslipidemia and other liver pathologies, THs analogs could also be of value for the treatment of neurodegenerative diseases, such as multiple sclerosis (MS). Sob-AM2, a CNS- selective prodrug of Sobetirome has been shown to promote significant myelin repair in the brain and spinal cord of mouse demyelinating models and it is rapidly moving into clinical trials in humans. Taken together all these findings support the great potential of selective thyromimetics in targeting a large variety of human pathologies characterized by altered metabolism and/or cellular differentiation.

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

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.

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.

The purpose of this chapter is to discuss the options available for patients with primary hyperparathyrodism (PHPT) not undergoing parathyroidectomy (PTx). Adequate hydration should be recommended in all patients. Calcium intake should not be restricted and vitamin D deficiency should be corrected aiming at a serum concentration of 25OHD of >20 ng/mL or even higher (>30 ng/mL according to some opinion leaders). Pharmacologic therapy is not an alternative to PTx and could be considered in patients who meet the surgical criteria but unwilling to undergo PTx, as well as in patients with an increased risk of surgery or failed surgery. Targeted therapy includes antiresorptive drugs for skeletal protection and cinacalcet for lowering serum calcium. Combined therapy can be an option when appropriate. Pregnant women should be treated conservatively (hydration) and surgery, if needed, performed in the second trimester of pregnancy. Severe hypercalcemia is a life-threatening condition and requires immediate intensive treatment.

Purpose: Evaluation of the phenotype of primary hyperparathyroidism (PHPT), adherence to International Guidelines for parathyroidectomy (PTx), and rate of surgical cure. Method: From January 2014–January 2016, we performed a prospective, multicenter study in patients with newly diagnosed PHPT. Biochemical and instrumental data were collected at baseline and during 1-year follow-up. Results: Over the first year we enrolled 604 patients (age 61 ± 14years), mostly women (83%), referred for further evaluation and treatment advice. Five hundred sixty-six patients had sporadic PHPT (93.7%, age 63 ± 13 years), the remaining 38 (6.3%, age 41 ± 17 years) had familial PHPT. The majority of patients (59%) were asymptomatic. Surgery was advised in 281 (46.5%). Follow-up data were available in 345 patients. Eighty-seven of 158 (55.1%) symptomatic patients underwent PTx. Sixty-five (53.7%) of 121 asymptomatic patients with at least one criterion for surgery underwent PTx and 56 (46.3%) were followed without surgery. Negative parathyroid imaging studies predicted a conservative approach [symptomatic PHPT: OR 18.0 (95% CI 4.2–81.0) P < 0.001; asymptomatic PHPT: OR 10.8, (95% CI 3.1–37.15) P < 0.001). PTx was also performed in 16 of 66 (25.7%) asymptomatic patients without surgical criteria. Young age, serum calcium concentration, 24h urinary calcium, positive parathyroid imaging (either ultrasound or MIBI scan positive in 75% vs. 16.7%, P = 0.001) were predictors of parathyroid surgery. Almost all (94%) of patients were cured by PTx. Conclusions: Italian endocrinologists do not follow guidelines for the management of PHPT. Negative parathyroid imaging studies are strong predictors of a non-surgical approach. PTx is successful in almost all patients.

L’iperparatiroidismo primario asintomatico (IPA) e la forma piu frequente di IP e sono oggi disponibili nuove linee guida. L’IPA sembra essere stabile per lungo tempo, ma non indefinitamente, e la paratiroidectomia (PTx) determina un sicuro miglioramento. Nelle nuove indicazioni alla PTx ci sono la valutazione delle fratture con l’imaging e del rischio litogeno. La terapia medica comprende la correzione dell’ipovitaminosi D, i bisfosfonati e il cinacalcet.

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.

The aim of this study was to carry out genetic screening of the MEN1, CDKN1B and AIP genes, both by direct sequencing of the coding region and multiplex ligation-dependent probe amplification (MLPA) assay in the largest monocentric series of Italian patients with Multiple Endocrine Neoplasia type 1 syndrome (MEN1) and Familial Isolated Hyperparathyroidism (FIHP). The study also aimed to describe and compare the clinical features of MEN1 mutation-negative and mutation-positive patients during long-term follow-up and to correlate the specific types and locations of MEN1 gene mutations with onset and aggressiveness of the main MEN1 manifestations. A total of 69 index cases followed at the Endocrinology Unit in Pisa over a period of 19 years, including 54 MEN1 and 15 FIHP kindreds were enrolled. Seven index cases with MEN1 but MEN1 mutation-negative, followed at the University Hospital of Cagliari, were also investigated. FIHP were also tested for CDC73 and CaSR gene alterations. MEN1 germline mutations were identified in 90% of the index cases of familial MEN1 (F-MEN1) and in 23% of sporadic cases (S-MEN1). MEN1 and CDC73 mutations accounted for 13% and 7% of the FIHP cohort, respectively. A CDKN1B mutation was identified in one F-MEN1. Two AIP variants of unknown significance were detected in two MEN1-negative S-MEN1. A MEN1 positive test best predicted the onset of all three major MEN1-related manifestations or parathyroid and gastro-entero-pancreatic tumors during follow-up. A comparison between the clinical characteristics of F and S-MEN1 showed a higher prevalence of a single parathyroid disease and pituitary tumors in sporadic compared to familial MEN1 patients. No significant correlation was found between the type and location of MEN1 mutations and the clinical phenotype. Since all MEN1 mutation-positive sporadic patients had a phenotype resembling that of familial MEN1 (multiglandular parathyroid hyperplasia, a prevalence of gastro-entero-pancreatic tumors and/or the classic triad) we might hypothesize that a subset of the sporadic MEN1 mutation-negative patients could represent an incidental coexistence of sporadic primary hyperparathyroidism and pituitary tumors or a MEN1 phenocopy, in our cohort, as in most cases described in the literature.

Juvenile primary hyperparathyroidism is uncommon and more symptomatic than the adult counterpart. The aim of this prospective monocentric study, conducted in a tertiary referral center, was to evaluate the clinical, biochemical, and densitometric data, and the outcome of a series of patients with juvenile primary hyperparathyroidism. The study group included 154 patients with sporadic and familial juvenile primary hyperparathyroidism, aged ≤40 years. Relative frequency of sporadic and familial forms, comparison of the clinical and biochemical characteristics, rate of cure after parathyroidectomy and the outcome of patients not undergoing surgery were evaluated. Familial cases (n = 42) were younger, less frequently females, and had milder disease compared to sporadic cases (n = 112). No difference was observed in biochemical and densitometric parameters. Among patients undergoing parathyroidectomy (n = 116), familial cases had a higher rate of multigland disease and a higher persistence/relapse rate compared to sporadic cases (73 vs. 3.6% and 48.1 vs. 5.7%, respectively). Patients who did not undergo parathyroidectomy had stable clinical, biochemical, and densitometric parameters during follow-up (median 27 months). Using the cut-off age of 25 years, there was no difference in clinical, biochemical and densitometric parameters between younger and older patients, with the exception of parathyroid hormone and phosphate, which were significantly lower and higher, respectively, in patients

Chronic heart failure is a major cause of morbidity and mortality, but its prognosis remains poor. Vitamin D hormone has many extra-skeletal functions including a positive impact on the cardiovascular system, and has been proposed for mortality risk evaluation in heart failure patients. The aim of the present study was to evaluate vitamin D status in heart failure patients, measured by high performance liquid chromatography coupled with mass spectrometry and to correlate serum 25 hydroxy-vitamin D (25OHD) levels with functional (peak VO2%) and mortality (Metabolic Exercise Cardiac Kidney Index) heart failure parameters. We enrolled 261 consecutive patients diagnosed with heart failure; all patients underwent a comprehensive clinical and biochemical characterization, and serum 25OHD levels were measured by high performance liquid chromatography coupled with mass spectrometry. Cardiopulmonary test parameters and Metabolic Exercise Cardiac Kidney Index of mortality risk were measured in all patients. Serum 25OHD levels ranged between 2 and 45 ng/ml (mean 17 ± 9 ng/ml); most patients (87%) showed hypovitaminosis D, and 25% showed severe vitamin D deficiency (serum 25OHD 10 ng/ml. Patients with peak VO2% 50%. There was a significant, positive correlation (r = 0.16, p = 0.008) between 25OHD levels and peak VO2%, and an inverse correlation with Metabolic Exercise Cardiac Kidney Index (r = −0.21, p

MEN1 is the main gene responsible for tumorigenesis of syndromic and sporadic primary hyperparathyroidism (PHPT). Germline mutations of the CDKN1B/p27Kip gene have been associated with multiple endocrine tumors in rats and humans. To evaluate the involvement of the CDKN1B gene and its relationship with MEN1 in sporadic PHPT, we carried out sequencing and loss of heterozygosity analyses of the CDKN1B gene in 147 sporadic parathyroid adenomas. p27 immunohistochemistry and genetic screening of the MEN1 gene were performed in 50 cases. Three germline CDKN1B variants (c.-80C>T, c.-29_-26delAGAG, c.397C>A) were identified in 3/147 patients. Reduction of CDKN1B gene transcription rate was demonstrated in vitro for the novel c.-80C>T and the c.-29_-26delAGAG variants. Loss of p27 expression was detected in the tumor carrying the c.-29_-26delAGAG variant. Two tumors carrying the CDKN1B variants also harbored a MEN1 mutation. Fifty-four percent of 50 CDKN1B mutation-negative tumors had a reduction of p27 nuclear staining. Somatic MEN1 mutations, identified in 15/50 samples, significantly segregated in tumors negative for nuclear and cytoplasmic p27 staining. The germline nature of the CDKN1B mutations suggests that they might predispose to PHPT. The lack of somatic CDKN1B mutations in our samples points to a rare involvement in parathyroid adenomas, despite the frequent loss of nuclear p27 expression. MEN1 biallelic inactivation seems to be directly related to down-regulation of p27 expression through the inhibition of CDKN1B gene transcription.

The molecular pathogenesis of primary hyperparathyroidism is still largely unknown. The aryl hydrocarbon receptor interacting protein (AIP) gene has a major role in the pathogenesis of familial isolated pituitary adenoma.We evaluated the involvement of the AIP gene in sporadic parathyroid adenomas.We performed direct sequencing and multiplex ligation-dependent probe amplification analyses of the AIP gene in a large series of sporadic parathyroid adenomas. Loss of heterozygosity (LOH) at the AIP locus was studied, and aryl hydrocarbon receptor interacting protein immunostaining was also performed. In addition, alterations in the MEN1 gene were studied.A somatic AIP mutation, substitution of arginine with glutamine at codon 304 (R304Q), was identified in 2 of 132 tumors. The mutation was germline in both cases despite the nonfamilial presentation. Heterozygous AIP large deletions were detected in 29 cases including 1 of the 2 mutated tumors, confirming a biallelic inactivation of the AIP gene. The AIP-mutated tumor with LOH showed decreased AIP immunostaining compared with normal parathyroid. LOH at the MEN1 locus, which often shared LOH at the AIP locus, was found in one third of tumors. Somatic MEN1 mutations were found in the 1 of the 2 AIP-mutated tumors and in 22 parathyroid adenomas. In addition, multiplex ligation-dependent probe amplification analysis revealed 1 large deletion of the MEN1 gene in 1 patient.The AIP gene is rarely involved in parathyroid adenomas, but the germline nature of the mutations suggests that it might predispose to primary hyperparathyroidism. MEN1 gene alterations occur in a substantial proportion of sporadic parathyroid adenomas.

SummaryObjective To report the Italian experience on cinacalcet use following its approval by the European Medical Agency (EMA) to control hypercalcaemia in patients with primary hyperparathyroidism (PHPT). Design Retrospective data collection from 100 patients with sporadic (sPHPT) and 35 with familial PHPT (fPHPT) followed in eight Italian centres between October 2008 and March 2011. Measurements Albumin-adjusted serum calcium, PTH, 25OHD, daily cinacalcet dose and adverse events were recorded during the follow-up (1–46 months). Results Baseline serum calcium was 2·90 ± 0·27 nmol/l in sPHPT and 2·75 ± 0·17 nmol/l in fPHPT patients (P = 0·007). The cinacalcet EMA labelling was met in 53% sPHPT and 26% fPHPT patients. High surgical risk (34%), negative preoperative imaging (19%), control of hypercalcaemia before parathyroidectomy (PTx) (24%), and refusal of PTx (19%) accounted for cinacalcet prescription in 96% of sPHPT patients. Conversely, initial treatment (34%), persistent/relapsing PHPT after surgery (31%), and refusal of PTx (14%) were the indications in 79% fPHPT patients. Cinacalcet was started at 30 mg/daily in 64% of sPHPT and 91% of fPHPT and increased until normocalcaemia was reached or side effects occurred. The final daily dose ranged between 15 and 120 mg. The majority of patients (65% of sPHPT and 80% of fPHPT) become normocalcaemic. Treatment was withdrawn in six patients because of side effects. Conclusions There is a wide heterogeneity in the prescription of cinacalcet in PHPT patients in Italy and the EMA labelling is not always followed, particularly in fPHPT patients. Cinacalcet effectively reduces serum calcium in patients with either sPHPT or fPHPT.

It has been known for a long time that changes in cardiac function are a major component of the clinical presentation of thyroid disease. Increased heart rate and hyperdynamic circulation are hallmarks of hyperthyroidism, while bradycardia and decreased contractility characterize hypothyroidism. Recent findings have provided novel insights in the physiology and pathophysiology of heart regulation by thyroid hormones. In this review, we summarize the present knowledge on thyroxine (T4) transport and metabolism and on the biochemical pathways leading to genomic and non-genomic effects produced by 3,5,3'-triiodothyronine (T3) and by its active metabolites, particularly 3,5-diiodothyronine (T2) and 3-iodothyronamine (T1AM). On this basis, specific issues of special interest for cardiology are discussed, namely (1) relevance of the regulation of proteins involved in the control of calcium homeostasis and in pacemaker cell activity, due to non-genomic as well as to classical genomic effects; (2) stimulation of fatty acid oxidation by T2 and T1AM, the latter also causing a negative inotropic and chronotropic action at micromolar concentrations; (3) induction of D3 deiodinase in heart failure, potentially causing selective cardiac hypothyroidism, whose clinical implications are still controversial; and (4) cardioprotective effect of T1AM, possibly occurring at physiological concentrations, and relevance of T3 and of thyroid hormone receptor α1 in post-infarction repair.

We investigated the prevalence of normocalcemic primary hyperparathyroidism (NPHPT) in the adult population living in a village in Southern Italy. All residents in 2010 (n=2045) were invited by calls and 1046 individuals accepted to participate. Medical history, calcium intake, calcium, albumin, creatinine, parathyroid hormone (PTH) and 25OHD were evaluated. NPHPT was defined by normal albumin-adjusted serum calcium, elevated plasma PTH, and exclusion of common causes of secondary hyperparathyroidism (SHPT) (serum 25OHD 2 and thiazide diuretics use), overt gastrointestinal and metabolic bone diseases. Complete data were available for 685 of 1046 subjects. Twenty subjects did not meet the inclusion criteria and 341 could not be evaluated because of thawing of plasma samples. Classical PHPT was diagnosed in four women (0.58%). For diagnosing NPHPT the upper normal limit of PTH was established in the sample of the population (n=100) who had 25OHD ≥30 ng/ml and eGFR ≥60 ml/min per 1.73 m2 and was set at the mean+3s.d. Three males (0.44%) met the diagnostic criteria of NPHPT. These subjects were younger and with lower BMI than those with classical PHPT. Our data suggest, in line with previous studies, that NPHPT might be a distinct clinical entity, being either an early phenotype of asymptomatic PHPT or a distinct variant of it. However, we cannot exclude that NPHPT might also represent an early phase of non-classical SHPT, since other variables, in addition to those currently taken into account for the diagnosis of NPHPT, might cumulate in a normocalcemic subject to increase PTH secretion.