Riccardo Muscariello

Clinical Characteristics and Evolution of Giant Cell Tumor Occurring in Paget's Disease of Bone

Patients with Pagets bone disease (PDB) have an increased risk of developing giant cell tumor (GCT). This study was performed to evaluate the clinical characteristics and evolution of GCT complicating PDB and to compare these clinical characteristics to those observed in two large PDB cohorts, the PDB Italian Registry and the United Kingdoms Multi‐Centre Randomised Controlled Trial of Symptomatic Versus Intensive Bisphosphonate Therapy for Pagets Disease (PRISM) study. A systematic literature review identified 117 cases of PDB complicated by GCT (PDB‐GCT), which involved the skeletal sites affected by PDB (110 patients) or the extraskeletal tissues adjacent to affected bones (7 patients). In contrast to what previously reported for GCT patients without GCT patients (83.2%) were white and one‐fourth of them (24.8%) had multifocal GCTs. Compared to PDB patients without GCT, PDB‐GCT patients showed a higher male/female ratio (2.1 versus 1.2) and more severe disease (age at PDB onset 52.1 ± 12.1 versus 63.3 ± 10.6 years; number of affected sites 6.1 ± 2.9 versus 2.34 ± 1.6; prevalence of polyostotic PDB 93.3% versus 60.6%). The mortality rate of PDB‐GCT patients was higher than those occurring in GCT patients without PDB (about 50% versus 0% to 5% at 5 years) or in PDB patients without GCT (log rank = 29.002). Moreover, up to 98% of PDB‐GCT cases had elevated total alkaline phosphatase levels at neoplasm diagnosis, suggestive of active PDB. Importantly, PDB‐GCT patients from Southern Italy (45.6% of all GCT patients) showed a higher prevalence of multifocal GCT (51.7%) and of positive familial history for PDB (70.8%) and GCT (65.0%). Finally, indirect evidence suggests a decline in the incidence of GCT in PDB patients. The occurrence of GCT in PDB patients is associated with severe disease and reduced life expectancy of affected patients. The increased prevalence of familial diseases in PDB‐GCT patients from Southern Italy suggests a founder effect. The observed changes over time in the incidence of GCT in PDB patients could be related to improved clinical management and/or living conditions of patients.

Giant cell tumor occurring in familial Paget's disease of bone: Report of clinical characteristics and linkage analysis of a large pedigree

Neoplastic degeneration represents a rare but serious complication of Pagets disease of bone (PDB). Although osteosarcomas have been described in up to 1% of PDB cases, giant cell tumors are less frequent and mainly occur in patients with polyostotic disease. We recently characterized a large pedigree with 14 affected members of whom four developed giant cell tumors at pagetic sites. The high number of affected subjects across multiple generations allowed us to better characterize the clinical phenotype and look for possible susceptibility loci. Of interest, all the affected members had polyostotic PDB, but subjects developing giant cell tumors showed an increased disease severity with a reduced clinical response to bisphosphonate treatment and an increased prevalence of bone pain, deformities, and fractures. Together with an increased occurrence of common pagetic complications, affected patients of this pedigree also evidenced a fivefold higher prevalence of coronary artery disease with respect to either the unaffected family members or a comparative cohort of 150 unrelated PDB cases from the same geographical area. This association was further enhanced in the four cases with PDB and giant cell tumors, all of them developing coronary artery disease before 60 years of age. Despite the early onset and the severe phenotype, PDB patients from this pedigree were negative for the presence of SQSTM1 or TNFRSF11A mutations, previously associated with enhanced disease severity. Genome‐wide linkage analysis identified six possible candidate regions on chromosomes 1, 5, 6, 8, 10, and 20. Because the chromosome 8 and 10 loci were next to the TNFRSF11B and OPTN genes, we extended the genetic screening to these two genes, but we failed to identify any causative mutation at both the genomic and transcription level, suggesting that a different genetic defect is associated with PDB and potentially giant cell tumor of bone in this pedigree.

The melatonin receptor 1A (MTNR1A) gene is associated with recurrent and idiopathic calcium nephrolithiasis

BACKGROUND Experimental evidence indicate that melatonin regulates some renal tubular functions via specific melatonin receptors (MTNRs) located in the kidney of several avian and mammalian species, including humans. We hypothesized that single nucleotide polymorphisms (SNPs) in the melatonin receptor 1A gene (MTNR1A) might influence the risk of calcium nephrolithiasis. METHODS We performed a systematic analysis of the MTNR1A gene in 246 recurrent calcium stone formers (136 men, 110 women; mean age 40.2 ± 12.0 years; body mass index 25.8 ± 4.5 kg/m2) and 269 healthy controls comparable for age and gender without a history of nephrolithiasis. RESULTS Two SNPs in Intron 1 of MTNR1A were significantly associated with calcium nephrolithiasis: rs13140012 (P = 0.0004) and rs6553010 (P = 0.009). The haplotypes resulting from the two SNPs were also differently distributed between stone formers and controls, the haplotype A-T being more represented among stone formers (P = 0.00001) and the haplotype T-C being more common in healthy controls (P = 0.00001). Preliminary functional studies showed that the SNP rs13140012 could modify the binding sites for transcription factors. CONCLUSION The results of this case-control study indicate a strong association between allelic variants of MTNR1A and recurrent calcium nephrolithiasis.

Characteristic clinical and biochemical profile of recurrent calcium-oxalate nephrolithiasis in patients with metabolic syndrome

BACKGROUND Metabolic syndrome is a risk factor for nephrolithiasis. This study was performed to evaluate the clinical and biochemical profile of calcium-oxalate nephrolithiasis in stone formers with metabolic syndrome. METHODS A total of 526 recurrent stone formers, 184 of them with metabolic syndrome, and 214 controls were examined on a free diet and after a sodium-restricted diet (sodium intake < 100 mmol/24 h). RESULTS On free diet, stone formers with metabolic syndrome showed higher sodium excretion [mean (95% confidence interval), 196 (176-218) vs 160 (150-168) mmol/24 h; P < 0.01] and lower citrate excretion [2.23 (1.99-2.58) vs 2.84 (2.51-3.17) mmol/24 h; P < 0.01] compared to controls, whereas stone formers without metabolic syndrome showed higher calcium and oxalate excretion [5.43 (5.01-5.82) vs 3.58 (2.84-4.19) and 0.34 (0.32-0.36) vs 0.26 (0.20-0.31)m mmol/24 h for calcium and oxalate, respectively; P < 0.01] and lower citrate excretion [2.18 (1.98-2.38) vs 2.84 (2.51-3.17) mmol/24 h; P < 0.01] compared to controls. The ion activity product of urinary calcium-oxalate salts was similar between stone formers with and without metabolic syndrome [1.41 (1.31-1.59) vs 1.40 (1.35-1.45); P > 0.05]. After the test diet, this index was lower in diet-compliant stone formers with metabolic syndrome compared to diet-compliant stone formers without metabolic syndrome [1.15 (1.10-1.21) vs 1.39 (1.31-1.45); P < 0.01]. CONCLUSIONS The biochemical profiles and responses to the sodium-restricted diet were significantly different between stone formers with metabolic syndrome and those without. Dietary habits play a central role in the pathogenesis of nephrolithiasis in stone formers with metabolic syndrome.

Relationship between metabolic syndrome and multinodular non-toxic goiter in an inpatient population from a geographic area with moderate iodine deficiency.

Background: Obesity and insulin resistance predispose individuals to the development of both metabolic syndrome and non-toxic nodular thyroid diseases. Aim: The aim of this observational, cross-sectional study is to evaluate the relationship between metabolic syndrome and multinodular non-toxic goiter in an inpatient population from a geographic area with moderate iodine deficiency. Subjects and methods: We examined 1422 Caucasian euthyroid inpatients. Thyroid volume was determined by ultrasound of the neck. A fine-needle aspiration biopsy was performed to evaluate single thyroid nodules and dominant nodules ≥15 mm in euthyroid multinodular goiter. The diagnosis of metabolic syndrome was made according to the criteria of the American Heart Associaion/National Heart, Lung, and Blood Institute. Results: Of the sample, 277 patients had clinical evidence of multinodular non-toxic goiter, 461 met the criteria for the diagnosis of metabolic syndrome, and 132 were found to have both conditions. After adjusting for age, gender, body mass index, nicotinism, parity, alcohol intake, thyroid function, and metabolic syndrome-related pharmacological treatment, metabolic syndrome was found to be an independent risk factor for the occurrence of multinodular non-toxic goiter. The relationship between metabolic syndrome and multinodular non-toxic goiter was apparent in both men and women. Conclusions: In this study of euthyroid inpatients, we demonstrate that metabolic syndrome is an independent risk factor for the occurrence of multinodular non-toxic goiter in a geographic area with moderate iodine deficiency. We propose that patients meeting the criteria for metabolic syndrome should be screened for the presence of multinodular non-toxic goiter.

The changing profile of patients with calcium nephrolithiasis and the ascendancy of overweight and obesity: a comparison of two patient series observed 25 years apart

BACKGROUND Epidemiological data indicate an increasing incidence and prevalence of nephrolithiasis (NL) worldwide in the last few decades. METHODS The aim of this study was to compare the clinical and biochemical profiles of recurrent stone formers referred to a Kidney Stone Centre from March 1983 to June 1986 with the one featured by patients seen 25 years later in the same geographical area, Campania, southern Italy. RESULTS Idiopathic calcium stone formers made up the large majority of the patient population in both series. Those examined in 2008-11 showed higher age at the onset of NL, higher prevalence of overweight/obesity and higher urinary excretion of oxalate and phosphate compared with those seen in 1983-86. The differences in the urinary biochemical variables remained significant upon accounting for age, gender, creatinine clearance and body mass index (BMI), and were not observed in patients with primary hyperparathyroidism enrolled in the same periods. A greater prevalence of uric acid stone formers was also observed in the 2008-11 population. CONCLUSIONS The massive epidemics of overweight/obesity and the substantial modifications of dietary habits over the last few decades in most Western countries may be the factors underlying the changing clinical and biochemical profiles of patients with recurrent NL.

Prevalence of simple nodular goiter and Hashimoto's thyroiditis in current, previous, and never smokers in a geographical area with mild iodine deficiency.

Simple nodular goiter and Hashimotos thyroiditis are 2 frequent nonmalignant thyroid diseases. Tobacco smoking has detrimental effects on the endocrine system and in particular on thyroid function and morphology. The objective of this cross-sectional study, involving 1800 Caucasian adults from a geographical area with mild iodine deficiency, was to evaluate the relationship between tobacco smoking, smoking cessation, and the prevalence of simple nodular goiter and Hashimotos thyroiditis. Thyroid status was evaluated by ultrasonic exploration of the neck, measurement of FT3, FT4, TSH, antibodies against thyroid peroxidase and thyroglobulin, and urinary iodine excretion. The fine-needle aspiration biopsy of significant nodules was also performed. Smoking habits were evaluated by a specific questionnaire and the calculation of number of pack years. Both current and previous smokers showed an increased risk of simple nodular goiter compared to never smokers after adjustment for potential confounders and known goitrogen factors. Interestingly, the simple nodular goiter risk was similar for never smokers and for previous smokers declaring a time since cessation of smoking for more than 69 months. Smoking habit was not associated to an increased risk of Hashimotos thyroiditis.Smoking appears to be an independent risk factor for simple nodular goiter but not for Hashimotos thyroiditis in an area with mild iodine deficiency. A prolonged withdrawal of smoking dramatically reduces the risk of simple nodular goiter occurrence.

Evidence for epistatic interaction between VDR and SLC13A2 genes in the pathogenesis of hypocitraturia in recurrent calcium oxalate stone formers.

BackgroundGenetic factors play a key role in the pathogenesis of hypocitraturia, a common risk factor for nephrolithiasis. The Na+-dicarboxylate cotransporter NaDC1, encoded by the sodium-dicarboxylate cotransporter (SLC13A2) gene, is a major determinant of urinary citrate excretion and its biological functions are regulated also by the vitamin D/Vitamin D receptor (VDR) biological system. The aim of this case-control study was to evaluate the possible epistatic interaction between VDRrs731236and SLC13A2rs11567842 allelic variants in the pathogenesis of hypocitraturia.MethodsRecurrent calcium-oxalate stone formers (SF) with or without hypocitraturia and healthy controls (C) were genotyped. Gene–gene interactions were estimated by the 1.0 software package of multifactor dimensionality reduction (MDR).ResultsThe prevalence of VDRTT and SLC13A2GG genotypes was higher in hypocitraturic SF compared to C (odds ratio [OR] 3.24, 95 % confidence interval [CI] 1.38–7.60 for VDRTT vs. VDRtt and OR 4.06, 95 % CI 1.75–9.42 for SLC13A2GG vs. SLC13A2AA). MDR analysis indicated a significant interaction between VDRTT and SLC13A2GG in hypocitraturic SF compared to C [OR 3.81 (2.11–6.88)]. These data are compatible with an epistatic interaction between the VDRTT and SLC13A2GG genotypes with a significant impact on the magnitude of the effect (suppressive effect).ConclusionsThese results point to an epistatic interaction between the VDR and the SLC13A2 alleles in the pathogenesis of idiopathic hypocitraturia in calcium-oxalate SF.

Vitamin D and Cardiometabolic Disorders

Recent clinical and experimental studies suggest that vitamin D status could play a significant role in the pathogenesis of cardiometabolic disorders as well as in their clinical severity. In particular, low vitamin D levels appear to increase the risk of major cardiovascular events in apparently healthy individuals and to worsen the prognosis quoad vitam and quoad valetudinem following a cardiovascular event. The relevance of these observations is amplified by the high prevalence of vitamin D deficiency and insufficiency that affect over one billion individuals at all ages worldwide. Randomized controlled trials are currently underway in U.S., Europe and Oceania to demonstrate a cause-effect relationship by assessing the effects of vitamin D supplementation on various cardiovascular outcomes. Aim of this review is to point out the more recent advances in knowledge about the relationship between vitamin D status and the incidence, prevalence and pathogenesis of more common cardiometabolic disorders.

Characteristic Clinical and Biochemical Profile of Recurrent Calcium-Oxalate Nephrolithiasis in Patients with Metabolic Syndrome

Metabolic syndrome is a risk factor for nephrolithiasis. This study was performed to evaluate the clinical and biochemical profile of calcium-oxalate nephrolithiasis in stone formers with metabolic syndrome. A total of 526 recurrent stone formers, 184 of them with metabolic syndrome, and 214 controls were examined. Stone formers with metabolic syndrome showed higher sodium excretion [mean (95% confidence interval), 196 (176–218) vs 160 (150–168) mmol/24h; p<0.01] and lower citrate excretion [2.23 (1.99–2.58) vs 2.84 (2.51–3.17) mmol/24 h; p<0.01] compared to controls, whereas stone formers without metabolic syndrome showed higher calcium and oxalate excretion [5.43 (5.01–5.82) vs 3.58 (2.84–4.19) and 0.34 (0.32–0.36) vs 0.26 (0.20–0.31) mmol/24h for calcium and oxalate, respectively; p<0.01] and lower citrate excretion [2.18 (1.98–2.38) vs 2.84 (2.51–3.17) mmol/24 h; p<0.01] compared to controls. The biochemical profiles was significantly different between stone formers with metabolic syndrome and those without. Dietary habits play a central role in the pathogenesis of nephrolithiasis in stone formers with metabolic syndrome.