Primary Hyperparathyroidism Subjects Research Articles

Bone Quality as Measured by Trabecular Bone Score in Normocalcemic Primary Hyperparathyroidism

ObjectiveThe impact of normocalcemic hyperparathyroidism (NHPT) on bone quality remains largely unexplored. We aimed to investigate the usefulness of trabecular bone score (TBS) assessment in NHPT and the accuracy of TBS in predicting vertebral fractures (VFs) in NHPT. MethodsIn this multicentric cross-sectional study, we assessed the TBS in 47 subjects with NHPT, 41 with primary hyperparathyroidism (PHPT), and 39 age- and sex-matched control subjects. ResultsTBS values did not differ among the 3 groups. The prevalence of low TBS (TBS < 1.2) was 23.4% in NHPT, 26.8% in PHPT, and 15.4% in controls, without statistically significant differences between groups. However, we found a lower lumbar spine Z-score adjusted for TBS (LS Z-score∗TBS) in PHPT participants when compared with controls (-0.48 ± 1.06 vs 0.07 ± 0.93, P = .017). In NHPT group, LS Z-score∗TBS did not detect patients with overall VFs (threshold, -0.15; area under the curve, 0.45; 95% CI, 0.253-0.648; accuracy, 55.3%). Instead, it was useful for moderate-severe VFs (threshold, 0.55; area under the curve, 0.81; 95% CI, 0.62-0.996; accuracy, 83%). In PHPT subjects also, TBS did not predict VFs. ConclusionIn NHPT, TBS is not reduced. When adjusted for TBS, the LS Z-score might predict moderate-to-severe VFs.

Serum Klotho levels in primary hyperparathyroidism patients before and after parathyroidectomy.

To investigate Klotho level and its association with biochemical indices of primary hyperparathyroidism (PHPT). Fifty PHPT patients and fifty-two age- and body mass index-(BMI) matched healthy control subjects were recruited. In addition, twenty-five PHPT patients underwent parathyroidectomy (PTX) and had 4-month follow-up visits. Intact parathyroid hormone (iPTH), 25-hydroxyvitamin D [25(OH)D], calcium, albumin, corrected calcium, and Klotho levels were determined. There was no significant difference in age and BMI between PHPT subjects and controls (p > 0.05). PHPT patients had Klotho levels (15.4 ± 1.2 ng/mL) about 23% higher compared with those of the controls (11.9 ± 0.8 ng/mL), but this difference was not significant (p = 0.063). However, postmenopausal PHPT patients had 45% higher Klotho levels (17.6 ± 1.5 ng/ml) compared with postmenopausal controls (12.1 ± 0.9 ng/mL, p = 0.008). For postmenopausal subjects, Klotho levels had positive correlation with levels of iPTH (r = 0.25, p = 0.026) and corrected calcium (r = 0.34, p = 0.003), but negative correlation with 25(OH)D (r = -0.23, p = 0.042). After PTX, levels of iPTH and corrected calcium decreased and 25(OH)D levels increased to normal range (p < 0.001). However, there was no significant change in Klotho levels after a 4-month follow-up. Serum Klotho levels are higher in postmenopausal PHPT patients than in healthy postmenopausal control subjects. The etiology of elevated Klotho level and its clinical significance requires further investigation.

The influence of gender on clinical manifestations of primary hyperparathyroidism

To explore the impact of gender on presentation of primary hyperparathyroidism (PHPT), clinical data of 150 histopathologically proven PHPT patients were collected and retrospectively analyzed. Most of the patients (72.0%) were parathyroid adenoma (PA), and 9.3% of them were parathyroid carcinoma (PC). In PA patients, albumin-corrected serum calcium levels (TASC) were lower in women than in men [ (2.84±0.28) mmol/L vs. (3.03±0.34) mmol/L, P=0.006]. In all PHPT subjects, serum urea nitrogen, creatinine, uric acid levels were lower in women than in men. Bone pain was more frequent in women over 50 years old than in men (52.33% vs.29.17%, P=0.045). The incidence of PC was higher in men than in women (20.59% vs. 6.03%, P=0.010). In conclusion, there are gender differences in the clinical presentation of PHPT. TASC was high in men with PA compared to women with PA. Bone pain was more common in the woman patients over 50 years old, and PC was more common in men.

Evaluation of Bone Mineral Density in Subjects with Primary Hyperparathyroidism by Dual Energy X-Ray Absorptiometry

&lt;p&gt;&lt;strong&gt;&lt;em&gt;Objective:&lt;/em&gt;&lt;/strong&gt;&lt;strong&gt; &lt;/strong&gt;Bone loss is a major complication of primary hyperparathyroidism (PHPT), and the extent of bone loss is an important factor for parathyroidectomy. Studies focused on this issue of bone loss in subjects with PHPT are quite rare in our country. This study will help the physicians to take proper action by giving an exact reflection of bone condition in subjects with PHPT. The purpose of this study was to evaluate the bone condition by measuring Bone Mineral Density (BMD), in subjects with PHPT using Dual Energy X-ray Absorptiometry (DEXA) and compare these findings with individuals without PHPT.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;&lt;em&gt;Patients and Methods:&lt;/em&gt;&lt;/strong&gt;&lt;strong&gt; &lt;/strong&gt;It was an analytic cross sectional study (group comparison) carried out at National Institute of Nuclear Medicine and Allied Sciences (NINMAS) BSMMU campus, Dhaka from July 2015-December 2016. Subjects of PHPT diagnosed by biochemical evaluation (increased serum calcium and parathyroid hormone concentrations), between age ranges 15-45 years were selected as group-A. Individuals without biochemical evidence of PHPT or other major illness causing bone loss were selected as comparison group or as group-B. The subjects underwent BMD test by DEXA at lumbar spines from L1-L4 vertebra and the left femoral neck using Norland XR-46 densitometer. BMD was classified according to WHO criteria. Data presented on categorical form were analyzed using chi-squared test. While the data presented on continuous scale were analyzed using student’s t-test. In each analysis, level of significance was 5% and P value &amp;lt;0.05 was considered significant. Data were processed and analyzed with the help of computer software SPSS, version 20.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;&lt;em&gt;Results:&lt;/em&gt;&lt;/strong&gt;&lt;strong&gt; &lt;/strong&gt;Total number of 90 subjects were selected for this study, 45 subjects with PHPT were in group-A and equal number of subjects without PHPT were in group-B. The findings derived from data analysis showed, a significantly more male participants in group-A. The mean age of group-A and group-B was 37.24 ± 8.03 years and 38.20 ± 5.74 years respectively. Mean BMI of group-A was 25.10 ± 4.35 kg/m&lt;sup&gt;2 &lt;/sup&gt;in compare to 29.43 ± 5.17 kg/m&lt;sup&gt;2&lt;/sup&gt; in group-B. Higher BMI was noted in both groups. PHPT subjects with high BMI had low BMD. BMD expressed in absolute value (gm/cm&lt;sup&gt;2&lt;/sup&gt;) and T score. BMD was significantly low in group-A (with PHPT) than in group-B (without PHPT), (p&amp;lt;0.0001). In group-A, prevalence of low BMD was 62.2% (osteopenia 37.8% and osteoporosis 24.4%) at lumbar spine and 84.5% (osteopenia 35.6% and osteoporosis 48.9%) at femoral neck. PHPT subjects had significant difference in both T score and BMD between lumbar spine and femoral neck.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;&lt;em&gt;Conclusion:&lt;/em&gt;&lt;/strong&gt;&lt;strong&gt; &lt;/strong&gt;Primary hyperparathyroidism (PHPT) is shown to be associated with significantly reduced BMD especially at femoral neck. Thus, an increased fracture risk should consider if it is left untreated.&lt;/p&gt;&lt;p&gt;Bangladesh J. Nuclear Med. 20(2): 129-135, July 2017&lt;/p&gt;

Analysis of the influence of the T393C polymorphism of the GNAS gene on the clinical expression of primary hyperparathyroidism

BackgroundThe receptor of parathyroid hormone and parathyroid hormone-related-protein (PTH/PTHrp) is located in the cell membrane of target tissues – kidney and osteoblasts. It is a G protein-coupled-receptor whose Gsα subunit is encoded by the GNAS gene. Our aim was to study whether the single nucleotide polymorphism (SNP) T393C of the GNAS gene is associated with renal stones, bone mineral density (BMD), or bone remodelling markers in primary hyperparathyroidism (PHPT). MethodsAn analysis was made of clinical and biochemical parameters and densitometric values in three areas and their relationship with the T393C SNP of the GNAS gene in 261 patients with primary hyperparathyroidism and in 328 healthy controls. Genotyping was performed using the Custom Taqman® SNP Genotyping assay. ResultsThe genotype frequencies of GNAS T/C 393 were similar in the control and PHPT groups. No association was found between genotypes and clinical expression of PHPT (renal stones and bone fractures). A nonstatistically significant trend was seen to lower BMD in the lumbar spine, femoral neck, and total hip in both PHPT and control C homozygote subjects. ConclusionGenetic susceptibility to PHPT related to the GNAS T393C polymorphism or a major influence in its development and clinical expression were found. A C allele-related susceptibility to lower BMD in trabecular bone in both PHPT and control subjects is not sufficient to suggest a more severe clinical expression of PHPT. This trend may be considered as a basis for further studies with larger sample sizes and complementary functional evaluation.

Analysis of the influence of the T393C polymorphism of the GNAS gene on the clinical expression of primary hyperparathyroidism

BackgroundThe receptor of parathyroid hormone and parathyroid hormone-related-protein (PTH/PTHrp) is located in the cell membrane of target tissues – kidney and osteoblasts. It is a G protein-coupled-receptor whose Gsα subunit is encoded by the GNAS gene. Our aim was to study whether the single nucleotide polymorphism (SNP) T393C of the GNAS gene is associated with renal stones, bone mineral density (BMD), or bone remodelling markers in primary hyperparathyroidism (PHPT). MethodsAn analysis was made of clinical and biochemical parameters and densitometric values in three areas and their relationship with the T393C SNP of the GNAS gene in 261 patients with primary hyperparathyroidism and in 328 healthy controls. Genotyping was performed using the Custom Taqman® SNP Genotyping assay. ResultsThe genotype frequencies of GNAS T/C 393 were similar in the control and PHPT groups. No association was found between genotypes and clinical expression of PHPT (renal stones and bone fractures). A nonstatistically significant trend was seen to lower BMD in the lumbar spine, femoral neck, and total hip in both PHPT and control C homozygote subjects. ConclusionGenetic susceptibility to PHPT related to the GNAS T393C polymorphism or a major influence in its development and clinical expression were found. A C allele-related susceptibility to lower BMD in trabecular bone in both PHPT and control subjects is not sufficient to suggest a more severe clinical expression of PHPT. This trend may be considered as a basis for further studies with larger sample sizes and complementary functional evaluation.

Secular trends in the incidence of primary hyperparathyroidism over five decades (1965–2010)

Introduction of automated serum calcium measurements in the 1970s resulted in a sharp rise in primary hyperparathyroidism (PHPT) incidence. However, recent investigations suggest a significant rise in PHPT incidence for unclear reasons. Our objective was to update our population-based secular trends in PHPT incidence, to determine if there has been a significant rise in PHPT incidence as suggested by others, and, if possible, to identify changes in clinical practice that might be responsible. Rochester, Minnesota, residents who met the criteria for PHPT from 2002 through 2010 were identified through the medical records-linkage system of the Rochester Epidemiology Project and added to the historical cohort beginning in 1965. Incidence rates were adjusted to the 2010 US white population. Altogether, 1142 Rochester residents have been diagnosed with PHPT since 1965, including 341 in 2002–2010. Over time, two periods of increased PHPT incidence occurred, one beginning in 1974 (121.7 per 100,000person-years) and a second peak (86.2 per 100,000person-years) starting in 1998. The median age of PHPT subjects has increased significantly from 55years in 1985–1997 to 60years of age in 1998–2010 and more patients (36%) had a parathyroidectomy in 1998–2010. Although serum calcium measurement has declined since 1996, there was a progressive increase in parathyroid hormone testing between 1994 and 2008. There was also a rise in orders for bone mineral density measurements in women since 1998, which peaked in 2003–2004. A second sharp rise in PHPT incidence occurred in our community in 1998, simultaneously with the introduction of national osteoporosis screening guidelines, Medicare coverage for bone density measurement, and new medications for the treatment of osteoporosis. Case ascertainment bias from targeted PHPT screening in patients being evaluated for osteoporosis is the most likely explanation.

Glucose intolerance and primary hyperparathyroidism: an unresolved relationship

Primary hyperparathyroidism (PHPT) can be characterized as either symptomatic or asymptomatic, or, most recently, as normocalcemic. In the current issue of the journal, Cakir et al. report that insulin resistance and glucose intolerance is not an aspect of normocalcemic PHPT. However, both the current study as well as the literature are compromised by the lack of appropriate classification of normocalcemic PHPT subjects. Rigorously characterized cohorts are necessary to determine whether glucose intolerance is in fact present in normocalcemic PHPT.

Acute Pancreatitis in Primary Hyperparathyroidism: A Population-Based Study

The association between acute pancreatitis and primary hyperparathyroidism (PHPT) is controversial. The aim of the study was to address the incidence and disease characteristics of acute pancreatitis in PHPT from a large inception cohort of community residents. Patients with acute pancreatitis were identified in an Olmsted County, Minnesota, cohort of PHPT subjects diagnosed from 1965-2001 and compared to matched control subjects. The estimated rate of developing acute pancreatitis was calculated by person-years method. Cox models assessed the effect of PHPT disease status on the development of acute pancreatitis. Of 684 patients with PHPT, 10 patients (1.5%) developed acute pancreatitis, compared to 32 of 1364 control patients (2.3%). The estimated rate of development of acute pancreatitis in PHPT was 114 per 100,000 person-years, compared to 140 per 100,000 person-years in control subjects (P = 0.56). The estimated hazard ratio of acute pancreatitis for PHPT relative to the control subjects was 0.84 (P = 0.89). The majority of subjects with PHPT and acute pancreatitis were women (n = 7), and the mean age was 70.6 yr at the time of acute pancreatitis. PHPT was present an average of 137 months before the development of acute pancreatitis, and contributing causes for acute pancreatitis were in identified in four patients. Maximal serum calcium levels in PHPT were not significantly associated with the development of acute pancreatitis. Acute pancreatitis was not increased in community patients with PHPT, and therefore, there does not appear to be a causal relationship between PHPT and acute pancreatitis.

Human chorionic gonadotropin measurements in parathyroid carcinoma

Preoperatively, it is difficult to differentiate between parathyroid cancer (PtCa) and severe primary hyperparathyroidism (PHPT) due to a benign tumor. Human chorionic gonadotropin (hCG) is a tumor marker in trophoblastic and nontrophoblastic cancers and hyperglycosylated hCG is increased in hCG-secreting malignancies. We investigated whether hCG can distinguish PtCa cancer from benign disease and add prognostic information. Observational study. Measurement of urinary hCG (total and malignant isoforms) and serum malignant hCG in 8 subjects with PtCa and in 18 subjects with PHPT (measurement of urine in ten and serum in eight). Total urinary hCG was normal in the benign PHPT control subjects (range: 0-17 fmol/mg Cr; nl<50). In the PtCa subjects, three had normal total urinary hCG levels and survived complication free for at least 2 years; three had persistently elevated total urinary hCG levels (range: 217-1986 fmol/mg Cr) and sustained hip fracture (n=3) and died (n=2) within 3 and 6 months respectively; two had a rise in total urinary hCG and had hip fracture (n=1) and died (n=2) within 4 and 10 months respectively. Elevated urinary hCG was of the malignant hyperglycosylated isoform. Serum malignant hyperglycosylated hCG values in all of the cancer patients exceeded the maximal serum malignant hCG level of the PHPT subjects with benign disease (3.77 pmol/l). hCG, especially its hyperglycosylated isoform, might add diagnostic and prognostic information in PtCa. Further studies would help to elucidate the role of hCG as a potential tumor marker in this disease.

Bone Quality determined by Fourier Transform Infrared Imaging Analysis in Mild Primary Hyperparathyroidism

Mild primary hyperparathyroidism (PHPT) is characterized by asymptomatic hypercalcemia, most commonly in the absence of classical signs and symptoms. Hence, there is need to characterize this disorder with particular attention to the skeleton. We determined the ratio of pyridinium and dehydrodihydroxylysinonorleucine collagen cross-links in 46 iliac crest bone biopsies from patients with PHPT (14 men, aged 28-68 yr; 32 women, aged 26-74 yr) by Fourier transform infrared imaging. The results were compared with previously reported collagen cross-links ratio determined in iliac crest biopsies from normal subjects. PHPT patients exhibited significantly lower pyridinium to dehydrodihydroxylysinonorleucine collagen cross-links ratio, compared with normal controls. Parathyroidectomy restored values to those comparable with normal controls. Moreover, the differences among PHPT subjects were gender dependent, with female PHPT patients having a statistically significant lower ratio, compared with either male PHPT patients or normal controls. Comparison of the obtained outcomes with histomorphometry showed that the collagen cross-link ratio was strongly correlated with rate of bone formation, and mineralizing surface, in individual patients. This ratio was also correlated with bone mineralization density distribution parameters obtained in the same patients. The strongest correlations were with bone mineralization density distribution variables reflecting heterogeneity of mineralization and primary mineralization parameters. The results are consistent with the high turnover state manifested in PHPT patients. Reduced collagen cross-link ratio in patients with PHPT would be expected to reduce the stiffness of bone tissue. These observations provide a more complete assessment of bone material properties in this disorder.

A Slight Decrease in Renal Function Further Impairs Bone Mineral Density in Primary Hyperparathyroidism

The impairment of renal function can affect the clinical presentation of primary hyperparathyroidism (PHPT), increasing cardiovascular morbidity, fracture rate, and the risk of mortality. The aim of the study was to assess the differences in bone status in a series of consecutive patients affected by PHPT without overt renal failure at diagnosis grouped according to creatinine clearance (Ccr). A total of 161 consecutive patients with PHPT were studied. They were divided into two groups based on Ccr. Group A had Ccr 70 ml/min or less (n = 49), and group B had Ccr greater than 70 ml/min (n = 112). PTH, total and ionized serum calcium; urinary calcium and phosphate; serum 25-hydroxyvitamin D3; serum and urinary bone markers; lumbar, forearm, and femoral bone mineral density (BMD) were evaluated. Patients in group A were older than those in group B (P < 0.0001). PTH levels did not differ in the two groups, whereas both urinary calcium and phosphorus were lower in group A than group B (P < 0.01). Lower BMD was evident in group A at lumbar spine (P < 0.002), forearm (P < 0.0001), and femur (P < 0.01). In asymptomatic PHPT, those with Ccr 70 ml/min or less had lower forearm BMD than patients with higher Ccr (P < 0.00001). When adjusting for age and body mass index in PHPT, BMD at each site persisted being lower (P < 0.05) in group A than group B. In all PHPT subjects, Ccr (beta = 0.29, P < 0.0005), age (beta = -0.27, P < 0.00001), and PTH levels (beta = -0.27, P < 0.0005) were all independently associated with forearm BMD. In PHPT a slight decrease in renal function is associated with more severe BMD decrease, independent of age, body mass index, and PTH levels. This association is also present in asymptomatic PHPT and strengthens the National Institutes of Health recommendations for surgery in patients with mild PHPT.

Increased intima-media thickness of the carotid artery wall, normal blood pressure profile and normal left ventricular mass in subjects with primary hyperparathyroidism.

Despite the increasing evidence that primary hyperparathyroidism (PHPT) contributes to greater risk of cardiovascular morbidity and mortality, its exact role in the development of cardiovascular changes and its clinical significance are still controversial. Given the multiple influence of PHPT on the cardiovascular system, this study aimed to assess the effects of PHPT on blood pressure profile, and on features of the heart and arterial vessels in normotensive symptomless patients. Twenty patients (8 males and 12 females) with a median age of 51.5 years (range 44 to 65 years) were evaluated and the results were compared with those of 20 controls matched for age, gender and body mass index. Patients' parathyroid hormone levels ranged from 172 to 454 pg/ml and Ca levels ranged from 11.4 to 13.5 mg/dl. Fasting levels of glucose, insulin, total and high density lipoprotein cholesterol and triglycerides were within the normal range in all subjects recruited. Twenty-four-hour blood pressure profile, left ventricle (LV) dimension and carotid artery anatomy were investigated, the latter two by ultrasonography. No difference was found between the patients and controls in blood pressure profile, when the following parameters were considered: supine systolic/diastolic pressure, average 24-h systolic, diastolic and mean arterial pressure, day-time mean arterial pressure and fall in nocturnal blood pressure (-17% and -18% respectively). Heart rate and all parameters of LV mass were similar in patients and controls. The only alteration found in patients was in significantly greater carotid intimal-medial thickness (IMT) (P<0.001). Atherosclerotic plaques were more frequent in patients than in controls, with a difference reaching a trend (40% vs 10%, chi(2)=4.8; P=0.091). Considering that the carotid IMT is considered to be a marker of systemic atherosclerosis, our finding suggests early atherosclerotic changes in PHPT. No correlation was found between the severity and cardiovascular manifestation of PHPT. Vascular changes may occur due to a combination of structural and functional impairments in PHPT patients, likely as a result of altered calcium metabolism and impaired equilibrium of other factors regulating vascular function. Both extent and duration of PHPT can play a relative role in the development of cardiovascular complications. Considering that PHPT is now recognized as a quite common and often symptomless endocrine disorder, the evidence of cardiovascular manifestation in normotensive patients, found by this morphological study, suggests a possible implication for the management of such patients. In this light, screening for abnormalities in cardiovascular system function should be recommended in all PHPT subjects.

Differential effects of primary hyperparathyroidism on ultrasound properties of bone.

Primary hyperparathyroidism (PHPT) may result in greater cortical than trabecular bone loss. Ultrasound is able to predict osteoporotic fracture risk independent of densitometric measurements, but little is known about the changes in ultrasound variables with PHPT. The aim of our study was to examine the effect of PHPT on ultrasound variables and bone density measurements at cortical (hand) and trabecular (lumbar spine and heel) sites, and to evaluate their reversibility following surgical treatment. We recruited 25 postmenopausal women diagnosed with PHPT ages 51-76 years (mean 62 years) and 95 postmenopausal controls ages 57-80 years (mean 67 years). Measurements were made at baseline and 1 year. Speed of sound (SOS) and broadband ultrasound attenuation (BUA) of the heel were measured using the Lunar Achilles (LA+) and McCue CUBA Clinical (CC). Amplitude-dependent speed of sound (AD-SoS) and ultrasound bone profile index (UBPI) of the fingers were measured using the IGEA DBM Sonic. Bone mineral density (BMD) of the hand and lumbar spine (LS) were measured by dual-energy X-ray absorptiometry (DXA). At baseline, hand BMD, LS BMD and heel BUA were significantly lower and finger UBPI significantly higher in the PHPT patients compared with controls ( p<0.001). There were no differences in Stiffness Index, heel SOS or finger AD-SoS between control and PHPT subjects. At 1 year postoperatively, there was a mean (+/-SD) increase in LS and hand BMD of 3+/-1% ( p<0.01). BUA at the heel increased (11+/-5%, p<0.001), and UBPI of the fingers decreased (17+/-7%, p<0.001) probably reflecting different modes of attenuation in trabecular (scattering) and cortical (absorption) bone. Stiffness Index, SOS of the heel and AD-SoS of the fingers did not change. BUA, UBPI and BMD returned towards normal postmenopausal values following surgery. There were no changes in BMD or QUS variables at 1 year in the control group. Quantitative ultrasound (QUS) measurements provide different information about bone structure than densitometric measurements and cannot be regarded as simply reflecting bone density. With further research the combined use of BMD and QUS could improve the assessment of skeletal status in patients with PHPT before and after surgery.

Impaired glucose tolerance and insulin insensitivity in primary hyperparathyroidism

A high prevalence of diabetes mellitus has been shown in patients with primary hyperparathyroidism (PHPT). However, it is unclear whether this is related to the metabolic abnormalities in PHPT or to the presence of other risk factors for glucose intolerance in these patients. The aim of our study was to determine whether glucose intolerance and insulin insensitivity occur in subjects with PHPT who do not have other risk factors for diabetes mellitus. Cross-sectional study of glucose metabolism in PHPT patients without other risk factors for diabetes mellitus, compared to age and body mass index (BMI) matched healthy subjects. Nineteen non-obese, non-diabetic, normotensive patients with PHPT and 11 age and BMI matched healthy subjects. The continuous infusion of glucose test was used to assess glucose tolerance. Plasma glucose and insulin were measured during a 1-hour continuous infusion of glucose (5 mg/kg ideal body weight/min); insulin sensitivity and beta-cell function were derived from the glucose and insulin data by mathematical modelling. Fasting serum concentrations of parathyroid hormone, ionized calcium and 1,25-dihydroxyvitamin D (1,25(OH)2D) were measured in all subjects. PHPT patients attained higher plasma glucose levels at the end of the glucose infusion (median 9.0 (interquartile range 8.1-9.8) mmol/l) than did controls (7.9 (7.1-8.9) mmol/l, P < 0.05), and 8 (42%) PHPT patients had impaired glucose tolerance. Insulin sensitivity was lower in PHPT (60.3% (49.8-85.4)) than in controls (113.7% (89.3-149.2), P < 0.001); beta-cell function was not different in PHPT subjects. PHPT subjects with impaired glucose tolerance had reduced beta-cell function compared to PHPT subjects with normal glucose tolerance (89.9% (70.5-106.4) vs 120% (98.8-156.6) respectively, P < 0.05). No significant correlations were found between insulin sensitivity and PTH (rs = -0.21), 1,25(OH)2D (rs = -0.14), ionized calcium (rs = -0.11) and inorganic phosphate (rs = 0.34). Beta-cell function did not correlate with PTH (rs = 0.15), 1,25(OH)2D (rs = 0.04), ionized calcium (rs = 0.23) or inorganic phosphate (rs = -0.35). Insulin insensitivity is present in PHPT even in the absence of hypertension and obesity, and may be the cause of glucose intolerance and diabetes. PHPT subjects with reduced beta-cell function are more likely to develop glucose intolerance.

Hypercalciuria in Parathyroid Disorders: Effect of Dietary Sodium Control

Moderate dietary Na restriction (80 mmol/d for 7 days) during constant Ca intake can reduce high urinary Ca excretion to normal levels in idiopathic hypercalciuria (IH). A similar protocol was used to test its effect in primary hyperparathyroidism (PHPT) and also in hypoparathyroid subjects (HOPT) during treatment with dihydrotachysterol (DHT). Nine subjects with PHPT, 10 with HOPT, and one with pseudo-HOPT were evaluated after Na-restricted (80 mmol/d) and Na-supplemented (200 mmol/d) diets for 7 days each with dietary Ca constant. Na restriction resulted in a decrease in mean urinary 24-hour Ca excretion in PHPT subjects (10.6 v 7.6 mmol/d [424 v 304 mg], P less than 0.0001) and in one pseudo-HOPT subject, similar to the pattern seen previously in IH subjects. In contrast, Na restriction was not accompanied by significant change in Ca excretion in HOPT. There was no change in serum immunoreactive PTH (iPTH) or 1,25(OH)2 vitamin D levels in either group when Na intake was altered. Thus, the presence of parathyroid hormone (PTH) is necessary for sodium-related alterations in urinary Ca to occur. The effect of PTH appears to be "permissive" rather than "active." Dietary Na restriction may have a role in the management of hypercalciuria in mild PHPT cases when parathyroidectomy is contraindicated.

The Pathogenesis of Idiopathic Hypercalciuria: Evidence for Renal Tubular Calcium Leak

A standard oral calcium loading test has been employed in a group of idiopathic hypercalciuria (IH) subjects and in a group of marginally hypercalcaemic subjects with primary hyperparathyroidism (PHPT) in whom the diagnosis was revealed by careful combined measurements of serum ionized calcium and immuno-reactive parathyroid hormone (iPTH). Initial values for serum ionized calcium and creatinine clearance were similar in IH and in a control group of normal subjects, whereas iPTH levels were normal or low. Following oral loading, serum ionized calcium rose to similar levels in both IH and control subjects, with no suggestion of relative hypercalcaemia due to a postulated intestinal hyperabsorption in the IH group. A renal tubular calcium 'leak' was however clearly evident in the IH group, in both the fasting and post-absorptive phase. In the marginally hypercalcaemic PHPT subjects on the other hand, a relative post-absorptive hypercalcaemia was clearly apparent, as well as a gross renal tubular calcium leakage. Thus careful preliminary separation of masked PHPT from IH subjects is an essential step before evaluation of response to oral calcium challenge in stone-forming subjects. When this is done, no evidence of a relative post-absorptive hypercalcaemia can be seen in the residual IH group, and hypercalciuria appears to be 'renal' rather than 'absorptive' in origin.