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Objectives: There is relatively scarce data regarding the association between primary hyperparathyroidism (PHPT) and incident diabetes in large population-based longitudinal studies. We aimed to evaluate the risk of incident diabetes in individuals with and without PHPT and investigate the association between serum calcium concentrations and the risk of incident diabetes in patients with PHPT., Methods: We included 2749 PHPT patients and 13,745 age, sex and index year matched non-PHPT individuals during 2000-2019. We used Cox regression models to compare the risk of incident diabetes in individuals with and without PHPT, and the risk of incident diabetes in PHPT patients with serum calcium concentration above and below the median value. The association between serum calcium concentrations and the risk of incident diabetes was examined by restricted cubic spline analyses in patients with PHPT., Results: During a median follow-up time of 5.17 years (IQR 2.17, 9.58), 433 patients (15.75%) with PHPT and 2110 individuals (15.35%) without PHPT developed diabetes, respectively. Patients with PHPT had a higher incidence rate of diabetes compared to non-PHPT individuals (27.60 [95% CI 25.00, 30.30] vs. 23.90 [95% CI 22.80, 24.90] per 1000 person-years, log-rank test p = .007]. Crude Cox regression model showed PHPT was associated with a 15% higher risk of incident diabetes (HR 1.15, 95%CI 1.04, 1.28). In patients with PHPT, a 44% higher risk of incident diabetes was found in patients with serum calcium concentrations above the median value (2.63 mmol/L), compared to those below the median value (HR 1.44, 95%CI 1.08, 1.90). Restricted cubic spline analyses confirmed a positive linear association between serum calcium concentrations and the risk of incident diabetes in those with PHPT (p-value for nonlinear = .751) CONCLUSIONS: Patients with PHPT had a higher risk of incident diabetes compared to non-PHPT individuals. A positive linear association was found between serum calcium concentrations and the risk of incident diabetes in patients with PHPT., (© 2024 The Author(s). Clinical Endocrinology published by John Wiley & Sons Ltd.)

Objective: Kidney involvement is a common complication in primary hyperparathyroidism (PHPT). No study so far has assessed the prevalence of kidney injury developing before the reduction in glomerular filtration rate (GFR) in PHPT. The study was aimed at establishing the potential role of biomarkers of kidney injury in detecting subtle renal damage in patients with PHPT., Design: Cross-sectional study., Patients: A total of 69 postmenopausal patients with PHPT and 41 healthy age- and sex-matched subjects were studied. Exclusion criteria were as follows: GFR < 30 mL/min, chronic inflammatory disease, nephrotic syndrome, infection, malignancy, heart failure, recent exposure to iodinated contrast media or nonsteroidal anti-inflammatory drugs., Measurements: We measured a panel of sensitive biomarkers of kidney injury in PHPT vs controls., Results: Mean FGF23 and Klotho were higher in PHPT (72 ± 48 and 811 ± 366 pg/mL, respectively) than controls (53 ± 23.5 and 668.6 ± 17; P < .02 and P < .05). Urine KIM-1/uCr was significantly higher in PHPT (1.4 -6  ± 1.3 -6 ) than controls (9.2 -7  ± 7 -7 ; P < .05); this was particularly evident in the CrCl 60-89 mL/min category (1.3 6  ± 9 7 vs 8.2 -7  ± 3.6 -7 ; P < .02). Mean values of urine NGAL/uCr were higher in PHPT with (n = 28) compared to those without kidney stones (n = 35; 1.8 -5  ± 1.4 -5 and 1 -5  ± 8 -6 ; P < .0001). We found significant positive associations between urine NGAL/uCr and Ca (R = .292, P < .02) and urine KIM1/uCr and PTH (R = .329, P < .01)., Conclusions: We propose the utilization of these molecules, particularly urine KIM-1/uCr and urine NGAL/uCr ratios for the assessment of subtle kidney injury in patients with PHPT. These molecules are elevated in tubular necrosis and have potential role in the development of kidney damage in PHPT, according to the severity of the disease., (© 2019 John Wiley & Sons Ltd.)

Objective: The effects of thiazide medication in patients with primary hyperparathyroidism (PHPT) have so far not been elucidated. The aim of this study was to analyse the extent to which the administration of thiazides may influence biochemical parameters and therefore the diagnosis of PHPT in a large cohort of patients., Design and Patients: The biochemical parameters of 1066 patients with PHPT were analysed, and drug history was documented. Calcium (Ca)/creatinine clearance ratio (CCCR) was calculated. The results of patients given thiazides (n = 170) and those not given thiazides (n = 896) were analysed and compared., Measurements: Twenty-four-hour urinary calcium excretion (24hU), albumin-corrected serum calcium, PTH, creatinine, 1,25OH- and 25OH-vitamin D were measured, and CCCR was calculated., Results: 24hUC a and CCCR were significantly lower in patients on thiazides (P = 0·02 and P = 0·0068, resp.), and serum creatinine was significantly higher in those subjects (P < 0·0001). Serum Ca levels only proved different in an analysis of covariance among patients younger than 60 years (P = 0·003). Nevertheless, PTH was not different in both groups (P = 0·917)., Conclusions: According to recently published guidelines, 24hUCa measurement is necessary to give indication for surgery in asymptomatic patients and to distinguish between PHPT and familial hypocalciuric hypercalcaemia [FHH]. Thiazides significantly decrease 24hUC a , yet neither increase serum Ca nor influence PTH levels in patients with PHPT. However, discontinuing thiazides is crucial for a correct CCCR calculation to pre-operatively rule out FHH. As a consequence, the withdrawal of thiazide medication must be recommended for the diagnosis of PHPT prior to surgery., (© 2016 John Wiley & Sons Ltd.)

Background: Primary hyperparathyroidism (PHPT) is associated with cardiovascular morbidity; however, data on the reversibility of cardiovascular disease in mild primary hyperparathyroidism are conflicting. The aim of this study was to assess endothelial function in patients with mild PHPT before and after parathyroidectomy (Ptx)., Methods: We prospectively evaluated 53 patients with mild PHPT (Group 1; 45 women, eight men; aged 52 ± 3·1 years) and 46 healthy control subjects (Group 2; 38 women, eight men; aged 46 ± 9·5 years). Endothelial function was measured as flow-mediated dilation (FMD) and carotid intima-media thickness (CIMT) using Doppler ultrasonography. Patients with diabetes mellitus, coronary heart disease, impaired renal function, hyperthyroidism, hypothyroidism and a history of smoking were excluded from the study. Patients were studied at baseline and 6-12 months after the first evaluation., Results: There were no differences with respect to age, gender and BMI between the two groups. Hypertension prevalence was three times higher in group 1 than in controls. % FMD was lower in group 1 than in group 2 (2·6 ± 1·2 vs 14·8 ± 9·6, P < 0·001). CIMT was higher in patients with PHPT than controls (0·69 ± 0·18 vs 0·61 ± 0·12, P = 0·045). This significance remained when hypertensive patients were excluded from the analysis. While FMD and CIMT improved significantly after Ptx, there were no differences in mild PHPT patients who followed without parathyroidectomy., Conclusion: FMD and CIMT are impaired in patients with mild PHPT compared to controls and improved significantly after a successful Ptx. Ptx improves endothelial function in patients with mild PHPT that may lead to decreased cardiovascular morbidity and mortality., (© 2014 John Wiley & Sons Ltd.)

Objective: A calcium load to suppress parathyroid hormone (PTH) secretion can help to perform the diagnosis in some case of primary hyperparathyroidism (PHPT) with atypical presentation. A similar test with calcimimetic, which avoids hypercalcaemia, would be of interest. Our proof of concept study was conducted to compare firstly the results of a single-dose cinacalcet testing with those of the standardized short-time calcium load in healthy control (HC) and secondly the results of the single-dose cinacalcet testing in HC and in PHPT., Methods: Twelve HCs received in a random order, at a 2-week interval, either 0·33 mmol/kg calcium gluconate intravenously for 3 h, or a single oral dose of 30 mg or 60 mg cinacalcet. Twelve PHPTs received 30 mg cinacalcet and twelve other PHPTs 60 mg cinacalcet orally. Calcaemia and serum PTH levels were measured basally and then hourly for 6 h., Results: In HC, plasma calcium did not significantly change after cinacalcet intake, whereas calcaemia rose up to 3·47 ± 0·05 mmol/l (mean ± SEM) at the end of the calcium load. PTH dropped from basal level to a similar extend (≥80%) with 60 mg cinacalcet and calcium load, whereas the decrease was significantly lesser (P < 0·01) with 30 mg cinacalcet. In PHPT, serum PTH levels dropped by 44·8 ± 6·9% and 58·2 ± 5·3% 1 h after the respective intake of 30 and 60 mg cinacalcet. One hour after the oral intake of 60 mg cinacalcet, serum PTH levels were <8 ng/l in HC and ≥8 ng/l in PHPT., Conclusion: Sixty milligrams of cinacalcet provides similar results as the standardized calcium load test; PHPT patients have a lower response to 60 mg cinacalcet than HC., (© 2015 John Wiley & Sons Ltd.)

Context: PTH is an essential regulator of mineral metabolism; PTH hypersecretion may result in hyperparathyroidism including normocalcaemic, primary and secondary hyperparathyroidism., Objective: To examine the characteristics of participants with hyperparathyroid states and the relationship to bone mineral density (BMD)., Design and Participants: A cross-sectional study of 1872 community-dwelling men and women aged 35+ years (mostly Caucasian) with available serum PTH from Year 10 Canadian Multicentre Osteoporosis Study follow-up (2005-07). PTH was determined using a second-generation chemiluminescence immunoassay., Outcome Measures: L1-L4, femoral neck and total hip BMD., Results: We established a PTH reference range (2·7-10·2 pmol/l) based on healthy participants (i.e. normal serum calcium, serum 25-hydroxyvitamin D, kidney function and body mass index, who were nonusers of antiresorptives, glucocorticoids and diuretics and not diagnosed with diabetes or thyroid disease). Participants with PTH levels in the upper reference range (5·6-10·2 pmol/l), representing a prevalence of 10·7%, had lower femoral neck and total hip BMD, by 0·030 g/cm(2) [95% confidence interval: 0·009; 0·051] and 0·025 g/cm(2) (0·001; 0·049), respectively, than those with levels 2·7-5·6 pmol/l. Participants with normocalcaemic and secondary hyperparathyroidism also had lower total hip BMD than those with levels 2·7-5·6 pmol/l, and CaMos prevalences of normocalcaemic, primary and secondary hyperparathyroidism were 3·3%, 1·4% and 5·2%, respectively., Conclusion: We found reduced BMD in participants with accepted hyperparathyroid states but also a notable proportion of other participants that might benefit from having lower PTH levels., (© 2014 John Wiley & Sons Ltd.)

Context: The safety of vitamin D replacement in subjects with primary hyperparathyroidism (PHPT) and coexistent vitamin D deficiency is not well established., Objective: To evaluate the safety of vitamin D replacement in PHPT., Data Source: Data were searched from Medline, EMBASE, Cochrane CENTRAL and abstracts form annual scientific meetings of various international bone and mineral societies., Study Selection: Studies examining the effect of preoperative vitamin D replacement in patients with PHPT and coexisting vitamin D deficiency, irrespective of year and language of the publication were included in the present meta-analysis., Data Extraction: Data were extracted from text of the included publications or abstract of conferences., Data Synthesis: Ten studies enrolling 340 subjects with PHPT were analysed in this meta-analysis. After vitamin D replacement, there was significant increase in 25(OH) D levels by 55·3 nmol/l (95% CI 33·3-77·3), reduction in serum parathyroid hormone levels by 3·5 pmol/l (5·8 to -1·2) without change in serum calcium (-0·08 mmol/l, -0·2 to +0·03) and urinary calcium levels (0·72 mmol/24 h, P = 0·2) compared to baseline., Conclusion: Vitamin D replacement in subjects with PHPT and coexistent vitamin D deficiency increase 25 (OH) D and reduce serum PTH significantly without causing hypercalcaemia and hypercalciuria. The finding of the study needs to be confirmed by a large randomized trial in patient with PHPT and coexistent vitamin D deficiency., (© 2014 John Wiley & Sons Ltd.)

Background: Vitamin D deficiency (VDD) is common in patients with primary hyperparathyroidism (pHPT), and this could affect the clinical expression of the disease. However, few North American or North European studies have addressed this issue, showing vitamin D repletion in only about one-third of the patients., Subjects and Methods: Vitamin D status was evaluated both in an observational study in a series of 206 consecutive patients with pHPT at diagnosis and in a case-control analysis with 113 age- and sex-matched healthy blood donors. Vitamin D status was assessed by measuring plasma 25-hydroxy-vitamin D (25OHD) levels and was defined as VDD or severe VDD if 25OHD was <20 ng/ml (<50 nm) and <10 ng/ml (<25 nm), respectively., Results: No seasonal variability was observed in 25OHD levels. VDD was observed in 75 of 206 patients (36·4%). The VDD was severe in 24 of 75 patients (11·7%). There was no difference in prevalence of VDD between men and women nor between asymptomatic and 'bone and stone' symptomatic patients. 25OHD levels was negatively correlated with parathyroid hormone, ionized calcium, and bone turnover markers, and positively correlated with phosphate. 25OHD levels were also positively correlated with bone mineral density at all sites measured. In the case-control study, the overall prevalence of VDD and severe VDD was higher in patients with pHPT compared with controls (33·6% vs 10·6%, P < 0·0001, and 8·8% vs 1·8%, P = 0·0337, respectively)., Conclusions: Our study shows that VDD occurs in about one-third of patients with pHPT resident in a Southern European area, a lower figure than previously reported. Moreover, VDD is related to a more severe bone disease, and its prevalence is higher in patients with pHPT than in healthy matched subjects., (© 2013 John Wiley & Sons Ltd.)

Objective: This study aims to identify the best biochemical risk factors alongside other factors for predicting adverse outcomes seen in untreated primary hyperparathyroidism (PHPT)., Design: Population-based cohort study, 1997-2006., Setting: Tayside, Scotland, UK., Patients: Patients with untreated diagnosed PHPT. OUTCOME MEASURES AND METHODS: Outcomes considered were all-cause mortality, fatal and nonfatal cardiovascular disease (CVD). Models were derived using survival analysis. Potential biochemical predictors tested were baseline serum calcium, parathyroid hormone (PTH), creatinine and alkaline phosphatase (ALP), and other covariates considered were gender, age at diagnosis, deprivation, previous comorbidities and bisphosphonates usage., Results: From 1997 to 2006, 2097 patients (mean age, 68·4 years; 69·9% women) with untreated PHPT were identified with a total follow-up of 7338 person years, in the population of Tayside, Scotland. The median baseline calcium was 2·61 mm, and PTH was 7·2 pm. PTH was the only statistically significant risk factor in all outcomes observed adjusting for other covariates. Serum creatinine and ALP predicted mortality outcomes in the short term (≤3 years), but not long term. Calcium was associated with increased risk of all-cause mortality in the short term but had no significant impact on other outcomes., Conclusion: Baseline PTH, rather than calcium, best predicts long-term outcomes in untreated PHPT., (© 2013 John Wiley & Sons Ltd.)

Objective: 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., (© 2012 John Wiley & Sons Ltd.)

Background and Objective: Intra-operative parathyroid hormone (IOPTH) kinetics and therefore the efficacy of IOPTH utilization as a predictor of cure are likely to be affected by baseline IOPTH levels, vitamin D deficiency and parathyroid weight., Patients and Methods: Consecutive subjects with primary hyperparathyroidism (PHPT, n = 51) undergoing parathyroidectomy with IOPTH monitoring were studied prospectively during the period October 2009-November 2011. Samples were collected pre-incision, pre-excision and post-excision (5, 10, 15 min). Iterative analysis of IOPTH kinetics and half-life calculation was carried out in subgroups. Nonparametric testing was used for group statistics., Results: Hypovitaminosis D (25(OH)D3 < 50 nm) was present in 39 (76%), serum PTH > 1000 ng/l in 23 (45%), and giant parathyroid adenoma (weight > 3000 mg) in 23 (45%). The percentage drop at 10 min was significantly higher in large adenomas (weight > 3000 mg). Miami and 5 min criteria showed the highest negative predictive value and maximum accuracy. The average percentage IOPTH drop observed at 5 min post-excision was 79.8%. Kinetic analysis showed a mean half-life of PTH of 2.57 ± 0.27 min (range: 0.07-11.55)., Conclusion: IOPTH monitoring is reliable even in patients with extremely high baseline IOPTH value, with a greater percentage drop at 5 and 10 min post-excision. In patients with high baseline IOPTH, a 50% decay in PTH value at 5 min may be indicative of cure, obviating the need for 10 and 15 min samples. IOPTH kinetics are altered by adenoma weight but not affected by vitamin D status or baseline IOPTH levels., (© 2012 John Wiley & Sons Ltd.)

Background: Despite NIH clinical recommendations, many clinicians are reluctant to replace vitamin D in patients with hypercalcaemia with primary hyperparathyroidism (PHP) due to concerns over aggravating hypercalcaemia. Furthermore, the optimum level of vitamin D replacement in PHP remains unclear., Methods: We performed a large retrospective study to determine whether a relationship exists between serum 25-hydroxyvitamin D levels, calcium and other important biochemical markers in patients with PHP. Serum, plasma and urinary biochemical measurements were collected from 251 patients with hypercalcaemia diagnosed with PHP., Results: When examining overall mean circulating levels during clinical follow-up, serum 25-hydroxyvitamin D correlated highly significantly with plasma parathyroid hormone (PTH) (r = -0.23, P = 0.0003) and serum phosphate (r = 0.16, P = 0.0119). No significant relationship was observed between serum calcium and 25-hydroxyvitamin D (r = 0.002, P = 0.98). Mean plasma PTH during clinical follow-up was 51% lower in patients with serum 25-hydroxyvitamin D > 60 nm when compared with patients who had 25-hydroxyvitamin D < 20 nm (P < 0.01)., Conclusions: Patients with PHP who have 25-hydroxyvitamin D levels > 60 nm have significantly reduced PTH hypersecretion when compared with patients with deficient vitamin D levels, without exhibiting worse hypercalcaemia., (© 2012 John Wiley & Sons Ltd.)

BACKGROUND, OBJECTIVE: An international consensus conference underlined the importance of defining upper parathyroid hormone (PTH) reference values based on 25-OH-vitamin D [25(OH)D] to diagnose mild primary hyperparathyroidism. We determined the importance of this factor in a Belgian population., Design, Patients, Methods: Intact PTH and 25(OH)D were measured in 261 healthy controls (18-65 years, winter/summer). They were classified as 25(OH)D replete (50-153 nmol/l; n = 129) or deplete (8-50 nmol/l; n = 132). PTH was determined in 49 patients with surgically proven primary hyperparathyroidism. PTH thresholds for 95% specificities and corresponding sensitivities were computed from both 25(OH)D replete and deplete receiver operating characteristic (ROC) curves. The 95% bivariate reference ellipses, relating PTH to calcium for 25(OH)D replete and deplete controls, were compared to the PTH/calcium pairs of patients with primary hyperparathyroidism., Results: Parathyroid hormone correlated with 25(OH)D (r = -0.3232; P < 0.0001). PTH normative values were 20% lower in 25(OH)D replete than deplete controls (P < 0.0001). PTH thresholds, providing 95% specificities for primary hyperparathyroidism diagnosis, were 7.6 pmol/l and 5.8 pmol/l, using ROC curves derived from 25(OH)D deplete or replete controls, respectively. Corresponding sensitivities were of 56%vs 88%, respectively (P < 0.05). The 95% PTH/calcium bivariate reference ellipses for?deplete and replete 25(OH)D controls differed, but the PTH/calcium pairs of patients with primary hyperparathyroidism did not overlap these ellipses., Conclusion: For a given specificity, primary hyperparathyroidism diagnostic parathyroid hormone thresholds were lower and sensitivities higher using ROC curves, derived from 25(OH)D replete vs deplete controls. The 25(OH)D status does not affect the efficiency of primary hyperparathyroidism diagnosis, using bivariate PTH/calcium reference density ellipses., (© 2012 Blackwell Publishing Ltd.)

Context: The cardiovascular (CV) risk profile is worsened in primary hyperparathyroidism (PHPT), and CV mortality is related to serum calcium levels. It is unknown whether CV mortality is increased in the most common form of PHPT and whether the increased CV risk is reversible after surgery., Objective: To investigate reversibility of echocardiographic variables in patients with mild PHPT who were randomized to observation without surgery or operation, and followed for 2 years., Design/setting/patients: Forty-nine patients (mean age 63 ± 7 years, 8 men) who had performed the 2-year visit in a randomized study on mild PHPT (serum calcium at baseline 2·65 ± 0·09 mm) (observation) vs 2·67 ± 0·06 mm (surgery) and where echocardiography had been performed, participated in the study., Results: Calcium and parathyroid hormone (PTH) levels were normalized following surgery and were stable in the observation group. PTH levels at baseline were highly correlated with ventricular mass. Detailed echocardiography revealed a minor and borderline significant treatment effect of surgery on left ventricular mass index (LVMI) compared to observation (P = 0·066) and a significant 11% reduction in diastolic dimension of the interventricular septum (IVSd-mean) in the surgery group (P<0·01), with no alterations in the observation group., Conclusions: Based on detailed echocardiographic measures over a 2-year observation period, we found only minor differences between the two groups. However, the potential treatment effect on LVMI and the within-group differences in IVSd-mean suggest that longer follow-up may yield larger and clinically important differences., (© 2011 Blackwell Publishing Ltd.)

Objective: Low plasma 25-hydroxyvitaminD (25OHD) levels, reduced muscle strength and increased body mass index (BMI) are well-known characteristics of primary hyperparathyroidism (PHPT). Mechanisms for low 25OHD levels, increased BMI and potential changes after parathyroidectomy are unknown. Muscle strength is reported to increase following surgical cure, but whether the improvement corresponds to healthy controls' performances remains largely unknown., Patients: We studied 51 patients with former PHPT [mean age 61(36-77) years] successfully treated by surgery [mean time since operation 7·4(5-15) years] and 51 sex- and age-matched controls., Measurements: Physical performance include "repeated chair stand" (RCS), "timed up and go" (TUG), muscle strength [hand grip, elbow flexion/extension and knee flexion/extension (60°/90°)], postural stability, biochemistry and anthropometric indices., Results: Forty-one cases had pathologically verified adenoma, three had hyperplasia and three had uncertain diagnosis whereas four had missing data. Dietary calcium intake, vitamin D supplementation and biochemistry including PTH and 25OHD levels did not differ between groups. Former patients had significantly higher BMI (28·8 ± 6·0 kg/m²) than controls (26·0 ± 4·7kg/m²). Muscle pain was more frequently reported by cases than controls, and cases performed RCS slower than controls (P = 0·02). Furthermore, female cases had lower muscle strength in knee flexion 60° (P = 0·02) and 90° (P = 0·05). Former patients no longer differed from controls after adjustment for BMI., Conclusion: Following cure, 25OHD levels are normalized suggesting 25OHD insufficiency is not a constitutional characteristics in patients with PHPT. Increased BMI seems to be sustained. Whether this is caused by decreased muscle strength or reduced muscular performance causes adiposity needs further investigations., (© 2010 Blackwell Publishing Ltd.)

Objectives: Bone metabolism is only superficially described in familiar hypocalciuric hypercalcaemia (FHH). We describe and compare biochemical and osteodensitometric variables in FHH and primary hyperparathyroidism (PHPT) and assess whether they can improve the diagnostic discrimination between the groups., Design: Cross-sectional., Patients: Sixty-six FHH patients with known calcium-sensing receptor (CASR) gene mutations and 147 PHPT patients., Measurements: We determined calcium, creatinine, phosphate, magnesium, parathyroid hormone (PTH), 25OHD, 1,25(OH)(2) D and alkaline phosphatase (AP) in plasma, NTx/creatinine ratio in urine and calculated the calcium/creatinine clearance ratio (CCCR). We performed dual energy X-ray absorptiometry at the lumbar spine, hip, forearm and whole body., Results: When compared with normal controls, the FHH patients had increased levels of PTH and AP with normal U-NTx and regional Z-scores. Increased phenotypic expression of CASR mutations in terms of hypercalcaemia was associated with higher lumbar spine bone mineral density, but not with bone markers. FHH were younger and leaner than the PHPT patients. They had comparable plasma Ca(2+) and 25OHD, but lower levels of PTH, 1,25(OH)(2) D, AP and U-NTx. They had higher Z-scores in the hip and in the forearm. We achieved the best discrimination between groups by multiplying CCCR with AP, 1,25(OH)(2) D and PTH, but the difference between the area under the curves by receiver operating characteristic analysis remained insignificant., Conclusion: Familiar hypocalciuric hypercalcaemia is associated with increased PTH and AP compared to normal controls, but not with bone loss irrespective of the severity of the CASR mutations. A multiplicative model including CCCR, AP, 1,25(OH)(2) D and PTH insignificantly improved the power of the CCCR to differentiate between FHH and PHPT. However, we still recommend CASR gene analysis in patients with a CCCR <0.020., (© 2009 Blackwell Publishing Ltd.)

Objective: To determine the relationship between anaemia and myelofibrosis in patients with symptomatic primary hyperparathyroidism (PHPT) and to assess the effect of curative parathyroidectomy on anaemia and marrow fibrosis., Design and Methods: In this prospective follow-up study of 28 consecutive patients with symptomatic PHPT from January 2005 to June 2006, 15 patients were diagnosed with anaemia (haemoglobin < 130 g/l in males and < 120 g/l in females), eight (53%) of whom were finally recruited for the study. Complete blood cell count, serum calcium, phosphorus, alkaline phosphatase, intact PTH and 25-hydroxyvitamin D and bone marrow examination were performed both before and after parathyroidectomy in all (n = 8) patients, but bone marrow examination after surgery was performed only in those who had marrow fibrosis at baseline (n = 6)., Results: Anaemia was observed in 15 (53.3%) of the 28 patients with symptomatic PHPT. Normocytic normochromic anaemia that is characteristic of PHPT was found in 14 (50%) patients. Eight of the 15 patients with anaemia had a bone marrow examination and marrow fibrosis was observed in six (75%). Both anaemia and marrow fibrosis improved after successful parathyroidectomy, but improvement in anaemia was significant (P = 0.02) only in those with marrow fibrosis at baseline. Marrow fibrosis did not correlate with duration of the disease (P = 0.17), degree of hypercalcaemia (P = 0.53) or serum levels of intact PTH (P = 0.60)., Conclusions: Anaemia is common in patients with symptomatic PHPT, and was associated with marrow fibrosis in the majority of the patients who underwent bone biopsy. Both anaemia and marrow fibrosis improved after curative parathyroidectomy, but improvement in anaemia was noticeable only in those who had marrow fibrosis at presentation.

Background: Primary hyperparathyroidism (PHP) is caused by parathyroid adenomas or hyperplasia, and occasionally by parathyroid carcinoma. Recently a high third generation/second generation PTH ratio has been observed in some patients with parathyroid carcinoma., Patients and Methods: We report the case of a 60-year old woman who was presented a fourth episode of PTH-related hypercalcaemia due to a parathyroid carcinoma. Serum PTH levels were measured using a second generation assay and a third generation assay before, 4 and 7 months after the fourth surgery. Then, PTH levels were measured in 294 osteoporotic normocalcaemic patients as well as in 30 consecutive PHP patients., Results: Before surgery of the patient with parathyroid carcinoma, second generation PTH was 229 pg/ml, third generation PTH was 675 pg/ml and third generation/second generation PTH ratio was 2.95. Four and 7 months after surgery the third generation/second generation PTH ratio was 0.70 and 0.66, respectively. All osteoporotic patients had a normal third generation/second generation PTH ratio (0.585 +/- 0.118) whereas only one patient (3.3%) with PHP had a third generation/second generation PTH ratio > 1 (1.54)., Conclusion: A high third generation/second generation PTH ratio could be observed in patients with parathyroid carcinoma, is uncommon in benign PHP and is absent in osteoporotic patients without PHP. Therefore, PTH level can be measured using second and third generation assays in some PHP patients, and a specific surgical protocol for possible parathyroid carcinoma could be discussed in patients with a high third generation/second generation PTH ratio.

Background: Impaired GH secretion is a common finding in patients with primary hyperparathyroidism (PHP). Ghrelin displays strong GH-releasing action, mainly at the hypothalamic level., Objective: To evaluate secretory response of GH to ghrelin in PHP patients., Patients: Fifteen patients [11 women/4 men, mean age 54 years, range 32-70 years, body mass index (BMI) 25.0 +/- 0.7 kg/m(2)] affected with PHP due to single parathyroid adenoma and 35 normal age-matched subjects (23 women/12 men, mean age 58 years, range 35-68 years, BMI 24.1 +/- 1.1 kg/m(2))., Methods: A measure of 1 microg/kg body weight i.v. acylated ghrelin or 1 microg/kg body weight i.v. GH releasing hormone (GHRH) followed by 0.5 g/kg body weight i.v. arginine (ARG) hydrochloride were administered to all subjects on alternate days in order to evaluate GH response., Results: Mean serum GH peak after GHRH + ARG was 32.6 +/- 7.8 and 17.4 +/- 4.0 microg/l, in controls and PHP patients, respectively (P < 0.05). Mean serum GH peak after ghrelin was 70.4 +/- 31.5 and 16.8 +/- 1.9 microg/l, in controls and PHP patients, respectively, (P < 0.001). Using ROC curves, a serum GH peak > 22 microg/l after ghrelin stimulation might be considered as a cut-off value for identifying normal subjects. Ten (67%) PHP patients have impaired GH response to GHRH + ARG and 13 (87%) to ghrelin. Serum GH peak after ghrelin or GHRH + ARG was unrelated to serum IGF-1, PTH or ionized calcium concentrations., Conclusions: The present data confirm that GH secretion is impaired in PHP patients using the potent GH secretagogue ghrelin and suggest that impaired GH secretion is likely due to a deleterious effect of hypercalcaemia at the hypothalamic level in PHP patients.

Background: Primary hyperparathyroidism (PHPT) is associated with reduced bone mineral density (BMD) mainly at sites rich in cortical bone. However, successful parathyroidectomy causes an increase in BMD especially at sites rich in trabecular bone. Plasma 25-hydroxyvitamin D (25OHD) levels are typically reduced and plasma 1,25-dihydroxyvitamin D [1,25(OH)(2)D] slightly increased in PHPT. These variations in vitamin D metabolites may influence variations in BMD and fracture risk., Aim: To investigate relations between preoperative vitamin D metabolites and skeletal consequences in patients with untreated PHPT and to appraise the influence of preoperative vitamin D metabolites on postoperative changes in BMD. Design Cross-sectional and cohort study., Materials: Two hundred and forty-six consecutive Caucasian PHPT patients aged 19-91 years. (median 63, 87% females)., Results: BMD was reduced at the femoral neck (P < 0.001) and forearm (P < 0.001), but normal at the lumbar spine (P = 0.11). Levels of biochemical bone markers were associated with high plasma PTH, high plasma 1,25(OH)(2)D and low plasma levels of 25OHD. Moreover, low plasma 25OHD was associated with low levels of BMD at the femoral neck (r(p) = 0.23), the forearm (r(p) = 0.19) and the whole body (r(p) = 0.30), whereas plasma 1,25(OH)(2)D was inversely associated with BMD at all regional sites and the whole body. Plasma PTH only showed an inverse association with BMD at the forearm (r(p) = -0.21). No association was observed between biochemical variables and prevalent spinal fractures, all peripheral fractures or osteoporotic peripheral fractures. The annual increase in spinal BMD after surgery was positively associated with preoperative plasma PTH (r(p) = 0.40), whereas the annual increase in whole body BMD was inversely associated with plasma 25OHD (r(p) = -0.32). No change in BMD at the femoral neck and forearm was observed 1 year after surgery., Conclusion: Low vitamin D status and high plasma 1,25(OH)(2)D are associated with increased bone turnover and decreased BMD in patients with PHPT.

Background: Primary hyperparathyroidism (PHPT) is characterized by elevated plasma levels of PTH and calcium with reduced plasma phosphate. Physiologically, renal 1alpha,25-dihydroxyvitamin D [1,25(OH)(2)D] production is stimulated by PTH and phosphate deprivation, and inhibited by 1,25(OH)(2)D itself and calcium., Aim: To investigate relations between circulating levels of 1,25(OH)(2)D, 25-dihydroxyvitamin D (25OHD), PTH, calcium, phosphate, renal function and skeletal complications in patients with PHPT., Design: Cross-sectional study., Material: Two hundred and fifty-two consecutive hypercalcaemic Caucasian patients aged 24-91 (median 65.9) years (85.3% females) with PHPT., Results: In patients with PHPT, plasma 1,25(OH)(2)D was increased by 27%[107 (9-250) pmol/l, median (range)] compared to controls [84 (18-172) pmol/l, P < 0.001]. In univariate models, plasma 1,25(OH)(2)D depended inversely on age (r = -0.23, P < 0.001) and plasma phosphate (r = -0.23, P < 0.001) and positively on plasma calcium (r = 0.14, P < 0.05), plasma 25OHD (r = 0,15, P < 0.05) and creatinine clearance rate (r = 0.32, P < 0.001). In the final multiple regression model, plasma 1,25(OH)(2)D depended positively on renal function (r(p) = 0.43, P < 0.001) and female sex (r(p) = 0.15, P < 0.05) but inversely on body mass index (BMI; r(p) = -0.23, P < 0.005) and plasma phosphate (r(p) = -0.18, P < 0.05). Plasma 1,25(OH)(2)D correlated positively with renal calcium excretion and inversely with lumbar spine bone mineral density (BMD) but was not associated with risk of fractures or renal stones., Conclusion: Patients with PHPT have elevated plasma 1,25(OH)(2)D levels but, to a large extent, individual values overlap controls. The increase in plasma 1,25(OH)(2)D depends on renal function, hypophosphataemia and the female sex and is attenuated by high BMI. High plasma 1,25(OH)(2)D is associated with higher plasma calcium levels.

Objective: Primary hyperparathyroidism (PHPT) is associated with heart disease. The aims of the present study were to evaluate how cardiac function and secretion of N-terminal pro-B-type natriuretic peptide (NT-proBNP) correlate in patients with mild PHPT, and how the plasma level of NT-proBNP is influenced by cure of the parathyroid disease., Design and Patients: Forty-two patients with PHPT without symptoms of heart disease were examined before and 1 year after curative parathyroidectomy., Measurements: Plasma or serum concentrations of NT-proBNP, calcium, PTH, creatinine, oestradiol, testosterone and SHBG were measured. Cardiac function was evaluated by equilibrium radionuclide angiography (ERNA)., Results: At baseline, NT-proBNP levels correlated negatively with systolic function [left ventricular ejection fraction (LVEF), P < 0.001]. Twelve per cent of the patients had NT-proBNP levels above normal reference values preoperatively. One year postoperatively, the corresponding proportion was 21%. The mean plasma concentration of NT-proBNP increased after parathyroidectomy (P < 0.01) in parallel with a dip in diastolic function (peak filling rate, P < 0.05) and a falling trend in systolic function (LVEF, P = 0.08). The postoperative percentage changes in circulating NT-proBNP and total oestradiol correlated positively (P < 0.05)., Conclusions: Patients with mild PHPT and normal renal function may have high levels of circulating NT-proBNP despite the absence of symptomatic heart disease. Cure of the parathyroid disease is followed by a further increase in NT-proBNP secretion in parallel with ERNA measures, indicating subclinical changes in heart function. These results are in line with data indicating an association between PHPT and increased risk of premature death.

Background: GH and IGFBP-1 both play a role in glucose homeostasis., Objective: To assess the GH and IGFBP-1 responses to an oral glucose load and their relationship with glucose homeostasis in patients with primary hyperparathyroidism., Design: A cross-sectional study with a control group followed by a longitudinal study after parathyroidectomy., Patients and Methods: We studied 15 patients with primary hyperparathyroidism (eight women, aged 59.6 +/- 2.2 years) and nine healthy normocalcaemic controls. All subjects were ambulatory and were studied as outpatients. Glucose, insulin, GH and IGFBP-1 were measured during an oral glucose (75 g) tolerance test (OGTT)., Results: Patients with hyperparathyroidism showed similar glucose responses to OGTT to those found in controls. Insulin responses were higher in patients (peak insulin 96.33 +/- 9.71 mU/l) in relation to values found in controls (58.11 +/- 9.03 mU/l; P < 0.01). Suppression of GH levels after OGTT was more marked in patients [nadir 0.03 (0.02-0.05) microg/l] than in normocalcaemic subjects [nadir GH 0.12 (0.08-0.42) microg/l; P = 0.002]. However, baseline IGFBP-1 concentration and its decrease after glucose load were similar in patients and controls. Normalization of calcium levels after parathyroidectomy was not followed by any significant changes in glucose, insulin and GH responses to OGTT. The minimum concentration of IGFBP-1 and the area under the curve (AUC) of IGFBP-1 after OGTT were higher after parathyroidectomy (3.34 +/- 0.69 microg/l and 8.94 +/- 1.72 microg x h/l, respectively) than at diagnosis (2.19 +/- 0.42 microg/l and 6.74 +/- 1.28 microg x h/l, respectively; P < 0.05). No correlation was found between PTH, calcium and phosphorus concentrations and GH and IGFBP-1 values in patients before or after normalization of calcium metabolism., Conclusion: GH and IGFBP-1 do not seem to be directly involved in the hyperparathyroidism-associated changes in carbohydrate metabolism. The postoperative changes in the depression of IGFBP-1 after OGTT remain to be elucidated.

Objective: Increased risk of cardiovascular disease has been reported in patients with primary hyperparathyroidism (PHPT). The aim of this study was to evaluate novel plasma risk markers of cardiovascular disease in patients with PHPT., Design: PHPT patients were evaluated with a control group. Patients who underwent parathyroidectomy were re-evaluated after 7 and 18 months., Patients: Forty-five PHPT patients and 40 matched controls participated. Seventeen patients underwent parathyroidectomy., Measurements: Plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (CRP), interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-alpha), lipids and blood pressure were measured. In 27 patients a bicycle exercise test and radionuclide angiography were performed, and repeated in those who underwent parathyroidectomy., Results: Plasma NT-proBNP, CRP and TNF-alpha, but not IL-6, were higher in patients with PHPT than in controls (P < 0.01 and P = 0.17, respectively). In patients with PHPT, NT-proBNP correlated with systolic blood pressure, left ventricular end-diastolic volume, and peak oxygen uptake (all P < 0.01). Log CRP correlated with systolic and diastolic blood pressure (both P < 0.05) and log IL-6 (P < 0.01). No significant correlations were observed between PTH or calcium and risk markers of cardiovascular disease. No decrease in NT-proBNP, markers of inflammation or blood pressure was observed after parathyroidectomy., Conclusions: Our data suggest that hypertension or other factors, rather than plasma calcium or PTH, could explain the increased levels of the inflammatory markers and NT-proBNP in PHPT. We therefore suggest that aggressive treatment of hypertension should be initiated in patients with PHPT to try to reduce the increased cardiovascular mortality described in PHPT. Further prospective studies are needed to validate the suggestion that increased levels of NT-proBNP and inflammatory markers also represent strong prognostic markers of cardiovascular disease in patients with PHPT.

Background: Primary hyperparathyroidism (PHPT) and vitamin D insufficiency are common conditions that can occur in combination. However, low plasma 25-hydroxyvitamin D (25OHD) may also enhance the risk of PHPT or modify disease severity., Aim: To compare the risk of vitamin D insufficiency and deficiency stratified by age, sex and season between PHPT patients and controls and to assess associations between plasma 25OHD and adenoma weight, biochemical variables, bone mineral density (BMD) and clinical complications., Design: Cross-sectional study., Material: A total of 289 consecutive Caucasian patients with PHPT aged 65.9 (24-92) years, 289 sex-, age- and season-matched normocalcaemic controls and 187 healthy adult blood donors. PHPT diagnosis was confirmed in 214 by neck exploration., Results: Vitamin D insufficiency (plasma 25OHD < 50 nmol/l) was observed in 81% of PHPT patients compared with 60% of sex- and age-matched controls (P < 0.001) and 35% of blood donors (P < 0.001). During summer, 77%vs. 53% (P < 0.001) and 4% (P < 0.001), respectively, had vitamin D insufficiency. Average plasma 25OHD was 41 (range 9-87) nmol/l among 27 PHPT patients compared with 87 (21-173) nmol/l (P < 0.001) among aged-matched blood donors. During winter, 86%vs. 66% (P < 0.001) and 71% (P < 0.05), respectively, had vitamin D insufficiency. Vitamin D deficiency (plasma 25OHD < 25 nmol/l) was observed in 33% of PHPT patients compared with 20% of age- and sex-matched controls (P < 0.001) and 13% of blood donors (P < 0.001). Both PHPT patients and controls showed seasonal variations in 25OHD related to the average number of sun hours, but values were lower in PHPT patients at all calendar months. In PHPT patients low plasma 25OHD was associated with higher plasma levels of calcium, PTH and alkaline phosphatase and with lower renal calcium excretion, femoral neck and forearm BMD. No association was found between plasma 25OHD and adenoma weight (total or divided into tertiles). There was a trend towards increased risk of osteoporotic fractures (P < 0.08) with low plasma 25OHD., Conclusion: Vitamin D insufficiency and deficiency are common findings in PHPT and occur more often than in a sex- and age-matched control group referred from general practice and in normal blood donors irrespective of season. Low plasma 25OHD levels are associated with an aggravated clinical presentation of PHPT but do not affect adenoma size.