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Objective: Dyslipidemia, hypertension, diabetes mellitus and also primary hyperparathyroidism (pHPT) are associated with an increased risk of cardiovascular diseases. Metabolic abnormalities in mild pHPT have been reported, but never in cases with normal calcium and high parathyroid hormone (PTH) levels, i.e. suffering from 'normocalcemic pHPT'. Our aim was to explore the occurrence of these metabolic abnormalities in individuals with normocalcemic pHPT identified in a population-based screening, and the effects of parathyroidectomy vs conservative treatment on metabolic variables., Design and Methods: A population-based screening of 5202 post-menopausal women identified 30 patients with normal calcium, inappropriately high PTH and normal creatinine. A 5-year follow-up included 15 parathyroidectomized (PTx) and nine conservatively followed cases, in a non-randomized setting, together with age-matched controls. Biochemical variables and body mass index (BMI) were investigated., Results: At study entry, cases had higher calcium, PTH, glucose, low-density lipoprotein (LDL)/high-density lipoprotein (HDL)-cholesterol, very low-density lipoprotein (VLDL)-cholesterol, total triglycerides, and BMI compared to controls (P = < 0.0001-0.035). The cases had a lower HDL-cholesterol value (P = 0.013) and one third of the cases had hypertriglyceridemia. During follow-up, the PTx cases decreased in calcium, PTH, LDL/HDL-cholesterol, total and LDL-cholesterol (P = 0.0076-0.022). Investigated biochemical variables remained adverse in conservatively followed cases during follow-up except a decreased LDL-cholesterol value. All surgically treated patients had parathyroid adenoma., Conclusions: Cases with normocalcemic pHPT have increased proatherogenic lipoprotein levels, BMI and glucose levels compared to age-matched controls. Parathyroidectomy has positive effects on some of these variables and reverses them to the same level as the controls, while conservative treatment fails to normalize the investigated metabolic variables.

Objectives: Patients with mild primary hyperparathyroidism (pHPT) often appear asymptomatic, and have previously been regarded as not requiring treatment. However, increased cardiovascular morbidity and dyslipidaemia have also been recognized in mild pHPT, which also seem to be normalized after parathyroidectomy. The present study explores whether postmenopausal women with mild pHPT have decreased bone mineral density (BMD) compared with age-matched healthy controls, and the effects on BMD of parathyroidectomy., Design, Subjects and Intervention: A population-based health screening of 5202 postmenopausal women identified 87 overtly asymptomatic patients with mild pHPT as well as age-matched healthy controls. A 5-year follow-up included 49 cases who had undergone parathyroidectomy. BMD was measured with DXA at the femoral neck, the lumbar spine and the total body., Results: At study entry, BMD was 5-6% lower in the lumbar spine (L2-L4) and femoral neck in cases compared with matched controls. After the 5-year follow-up, BMD increased in L2-L4 by 2.9% (P = 0.002) in the parathyroidectomized cases and remained stable in the femoral neck. However, femoral neck BMD increased 4.1% (P = 0.013) for cases <67 years old (50% of the cohort)., Conclusion: In accordance with recent NIH guidelines for pHPT treatment, the level of BMD per se in the investigated group of patients justifies parathyroidectomy in almost half of the cases with mild pHPT. Surgery could be expected to increase BMD in L2-L4 to the level of the controls, to increase femoral neck BMD in patients <67 years of age and to preserve femoral neck BMD in the elderly population.

Background: Primary hyperparathyroidism (pHPT) has been associated with premature death in cardiovascular diseases. Short-term prospects for normalization of cardiovascular derangements have been described after parathyroidectomy. This study explores long-term effects of parathyroidectomy on cardiovascular functions in pHPT., Methods: Thirty consecutive patients with pHPT were reexamined 1 and 5 years after parathyroidectomy, together with 30 matched controls, with echocardiography and a bicycle exercise test., Results: Serum calcium was normal in all patients and control subjects at follow-up. The maximal blood pressure during the exercise was higher before parathyroidectomy (median 223 [range, 200-268] mm Hg vs 202 [165-277] mm Hg, P < .05) but not 5 years after (230 [155-270] mm Hg vs 219 [165-252] mm Hg. The ST-segment depression diminished from -1.4 (-8.3-0) to -0.8 (-3.3-0) mm 1 year after parathyroidectomy and further to -0.1 (-3.3-0.0) mm after 5 years but was unchanged in the control group. The number of ventricular extrasystolic beats at exercise testing in the pHPT group before parathyroidectomy was higher than in the control group (1 [0-340] vs 0 [0-3]). The isovolemic relaxation time at rest was prolonged before parathyroidectomy (mean 100 +/- 17 ms [SD] vs 89 +/- 14 ms, P < .05)., Conclusion: Parathyroidectomy can induce long-lasting improvement in regulation of blood pressure, left ventricular diastolic function, cardiac irritability (ventricular extrasystolic beats), and other signs of myocardial ischemia, with potential implications for the postoperative life expectancy of patients with pHPT who have undergone parathyroidectomy.

Background: The risk of dying from primary hyperparathyroidism (pHPT) is controversial and has been explored mainly in single parathyroid gland disease. The present study investigates mortality in pHPT due to multiple parathyroid gland disease., Methods: We used the nationwide Swedish In-patient Register and Cause-of-Death Registry to compare the mortality in 3485 Swedish patients subjected to parathyroidectomy during 1964 to 1999 with that of the Swedish population (standardized for age, gender, and calendar year). The patient cohort includes 36,596 person years., Results: Increased risk of death beyond the first postoperative year (standardized mortality ratio, 1.4; 95% CI, 1.37-1.52) was found in both sexes and for all age intervals below 80 years. The increased risk persisted more than 15 years postoperatively and related to cardiovascular diseases, diabetes mellitus, urogenital diseases, and malignant disorders. The increased risk of dying in cardiovascular diseases normalized during 1990 to 1999., Conclusions: pHPT caused by multiple parathyroid gland enlargement is associated with an excessive mortality similar to pHPT of single parathyroid adenoma. The findings substantiate that modern modes of surgical treatment for pHPT normalize the risk of dying from cardiovascular complications and that the hyperpararthyroid state per se is the possible cause of the premature death.

Background: Primary hyperparathyroidism has been associated with premature death in cardiovascular diseases, but reversibility and background mechanisms are uncertain. This study investigates autonomic nervous function in hyperparathyroidism because disturbances in this respect have been related to increased cardiovascular morbidity., Methods: Twenty-one consecutive patients with hyperparathyroidism and 23 matched control subjects without interfering medication underwent electrocardiographic recordings and ambulatory blood pressure (ABP) determination during a 24-hour period. Patients were re-examined at normocalcemia 1 year after parathyroidectomy. Heart rate variability was analyzed in subjects with sinus rhythm and normal atrioventricular conduction; time domain measures were calculated from the RR-intervals, and frequency domain variables were obtained with an autoregressive algorithm, which expressed power distribution (high, low, or very low frequency)., Results: Nocturnal increase in low frequency was blunted in cases versus control subjects (103+/-128 m(2) vs 430+/-171 m(2); P=.03). Very low frequency at nighttime correlated inversely with serum parathormone (r=-0.33; P<.05) and increased postoperatively (P=.03). ABP was higher both at daytime and nighttime (P<.05) in patients and remained unchanged after surgery. Systolic ABP correlated with the parathormone (r=0.47; P<.01)., Conclusion: Results suggest altered circadian autonomic function in hyperparathyroidism that can improve after parathyroidectomy. Despite elevated blood pressure, ABP shows retained diurnal rhythm, which indicates different pathophysiologic mechanisms behind the 2 predictors of cardiovascular death in hyperparathyroidism.

Primary hyperparathyroidism (HPT) is a common endocrine disease, in most cases without obvious symptoms of hypercalcemia and parathyroid hormone excess. The only curative treatment outside clinical trials is parathyroidectomy. Many patients are undiagnosed and left untreated, and the indications for curative treatment are still controversial. In 1990, NIH presented recommendations on the management of asymptomatic HPT, which was defined as HPT without symptoms and signs of renal or bone disease. Since then many studies have shed new light on mainly the cardiovascular complications and increased mortality of the disease, and the 1990 recommendations have been questioned. A workshop in 2002 revised the recommendations for handling of asymptomatic HPT in the United States. These recommendations are discussed from a Swedish perspective together with recent data on mortality in a large Swedish HPT cohort.

Primary hyperparathyroidism (PHPT) in developing countries is characterized by severe skeletal and renal complications and apparent mortality. This is in contrast with the Western hemisphere where research interests, rather than characteristics of PHPT, seem to differ between regions. In Europe, the "nontraditional" aspects of mild-to-moderate PHPT have attracted particular attention. These symptoms and signs include risk factors for cardiovascular disease such as hypertension, phenotype IV lipoproteinemia, insulin resistance, cardiac and vascular dysfunction, and morbidity in cardiovascular diseases. Mortality in cardiovascular diseases has been found to be increased in studies that include over 6500 European patients; this risk could not be verified in North American patients. By use of the nationwide Cancer Registry and Causes-of-Death Registry, mortality was analyzed in 10,995 Swedish patients (> 20 years of age) subjected to extirpation of single parathyroid adenoma of PHPT during 1958-1997. The Swedish population standardized for age, sex, and calendar year was used as control. The first postoperative year was excluded from the analysis. In total, the study included 102,515 observed person-years in the patients. Results verify an increased risk of dying after operation for PHPT (standard mortality ratio, 1.2; 95% CI, 1.19-1.27). The increased risk persisted far beyond 15 years postoperatively and occurred in both sexes and in all investigated age groups. Principal causes of excess mortality were cardiovascular diseases, diabetes mellitus, and urogenital diseases in all age groups. However, in patients operated on between 1985 and 1997 (n = 6386), overall mortality did not differ from that of the normal population, although there was maintained excess death in stroke, diabetes mellitus, and urogenital diseases. These findings infer that modern paradigms of surgical treatment normalize the risk of dying from PHPT. This improvement may be a late consequence of liberalized calcium screenings that were introduced about 30 years ago and indicate that operation at early disease stages may offer a survival advantage. An association between diabetes mellitus and PHPT is substantiated.

Background: Sporadic primary hyperparathyroidism (pHPT) occurs separately and in several hereditary disorders including multiple endocrine neoplasia type 1. Irradiation to the neck, female gender, and age are well-identified risk factors that predispose to pHPT. The multiple endocrine neoplasia type 1 gene is the most commonly deranged gene in parathyroid adenomas and contains several polymorphisms including D418D with a prevalence of roughly 50%., Methods: We genotyped 162 pHPT patients and control participants to evaluate if the D418D polymorphism is related to development of pHPT. One hundred fourteen of the pHPT patients and control participants were recruited from a health screening and were subjected to measurement of bone mineral density (BMD) at the lumbar spine, femoral neck, and total body., Results: The prevalence of each genotype (ie, MM, Mm, and mm) was for all pHPT patients: 62%, 29%, and 9%; and for all control participants: 32%, 43%, and 25% (P <.0004). For the screening-detected pHPT patients and control participants, the genotype distribution for MM, Mm, and mm was 60%, 30%, and 10%; and 31%, 44%, and 25%, respectively (P =.009). In the screening-recruited control participants, but not in pHPT patients, the MM genotype was also associated with higher total body BMD (P =.01) and BMD at the femoral neck (P =.02), whereas it failed to be significant for BMD at the lumbar spine (P =.08)., Conclusions: We report that the MM genotype was overrepresented in pHPT patients compared with control participants, suggesting a novel marker for pHPT. Furthermore, the MM genotype was associated with higher BMD at the femoral neck and in the total body in the screening-recruited control participants.

Population-based screening showed 2.1% prevalence of primary hyperparathyroidism (pHPT) in postmenopausal women. Individuals with total serum (s)-calcium levels of 2.55 mmol/L or more at screening were diagnosed with pHPT when subsequent analysis supported inappropriately elevated intact parathormone (PTH) levels in relation to even normal s-calcium levels. The arbitrary diagnostic criteria were validated by parathyroidectomy. Herein we reinvestigated biochemical signs of pHPT in women not diagnosed with pHPT due to s-calcium 2.50 to 2.54 mmol/L (group A, n = 160) at screening or due to appropriate PTH levels on two occasions after screening (group B, n = 70). Altogether, 99 women in group A and 47 in group B underwent reinvestigation 8.8 years after screening when they were 65 to 84 years old. The s-calcium levels averaged 2.56 mmol/L and had increased in group A (mean 0.04 mmol/L) and decreased in group B (mean 0.05 mmol/L). A total of 48 and 18 females (48%, 38%), respectively, met the previously validated criteria of pHPT. Altogether 21% of them were hypercalcemic (range 2.60-3.12 mmol/L). Subgroup analysis showed that PTH had not increased with time (n = 47) and that atherogenic blood lipids, but not glucose levels, were similar in pHPT patients and matched controls (n = 37). Assuming the existence of pHPT already at screening, the prevalence of pHPT could be adjusted to 3.4%. Even the most liberal diagnostic criteria utilized at pHPT screening seemed to underdiagnose the disease by inefficient cutoff limits for s-calcium and PTH. Because one-fifth of the women with pHPT progressed to hypercalcemia, long-term follow-up is advocated for those with s-calcium in the upper normal range.

Background: Familial primary hyperparathyroidism is associated with tumor-susceptibility syndromes, which are unrelated to mutations in the calcium receptor gene. This study describes parathyroidectomy in a kindred with hypercalcemia due to a heterozygous point mutation in the calcium receptor gene., Methods: Seventeen family members were studied, and postoperative follow-up averaged 5.1 years., Results: Radical parathyroid resection with total parathyroid remnants of 10 to 20 mg or total parathyroidectomy with autotransplantation normalized the serum calcium and parathyroid hormone values in 12 family members. Persistent hypercalcemia was noted in 3 of 5 patients subjected to less radical procedures. Diffuse to nodular hyperplasia and microscopic findings, interpreted incorrectly as a single adenoma, were found. Weight of the parathyroid tissue increased with the age of the patients (P <.05), and almost one third of them (29%) had 1 to 3 atypically located glands. There were no patients with recurrent hypercalcemia during follow-up., Conclusions: The heterozygous inactivating mutation of the calcium receptor gene of this family is accompanied by mild increases in parathyroid gland x weight and diffuse parathyroid hyperplasia with possibly secondary genetic events causing nodule formation. Radical parathyroid resection is advocated in this hypercalcemic disorder, which may represent an intermediary stage between primary hyperparathyroidism and familial hypocalciuric hypercalcemia.

Objective: Postmenopausal women are at increased risk of primary hyperparathyroidism (pHPT). Secondary dyslipidaemia in pHPT has attracted little attention, although morbidity and mortality associated with cardiovascular diseases have been reported to be increased in these patients., Design: A population-based screening programme was used to recruit postmenopausal women with mild, asymptomatic pHPT (mean serum calcium 2.57 +/- 0.12 mmol/l) and matched controls. MEASUREMENTS AND PATIENTS: Serum lipids, lipoprotein fractions and influences of treatment for the parathyroid disease were studied in 87 case-control pairs (mean age 67 years), 69 of whom completed a 5-year follow-up period., Results: pHPT was characterized by decreased serum high-density lipoprotein (HDL)-cholesterol, increased total triglycerides, very-low-density lipoprotein (VLDL)-triglycerides and VLDL-cholesterol levels and an elevated atherogenic index. The differences were more pronounced in the cases with serum parathyroid hormone levels in the normal range and were inversely correlated to the serum parathyroid hormone level. Parathyroidectomy, with or without additive hormone replacement therapy, normalized the dyslipidaemia. Five-year surveillance of pHPT without treatment was associated with a maintained increase in total triglycerides and the atherogenic index and a decrease in HDL-cholesterol levels., Conclusion: Proatherosclerotic dyslipidaemia characterizes mild pHPT and is effectively reversed by parathyroidectomy. As dyslipidaemia might contribute to the increased risk of cardiovascular diseases and death observed in pHPT, the findings favour operative intervention rather than conservative surveillance in mild, asymptomatic pHPT in postmenopausal females.

Objective: Parathyroid adenomas frequently harbour deletions of genomic DNA at chromosome regions 1p, 6q and 11q. In this study we related clinical characteristics in 56 patients with primary hyperparathyroidism (pHPT) to loss of heterozygosity (LOH) in these chromosome regions., Design: LOH analysis was performed on 56 sporadic parathyroid tumours using a total of 18 microsatellite markers for chromosome regions 1p, 6q and 11q. LOH was identified, for either radioactive or fluorescent labelled markers, as total absence or reduction of > or = 50% of the signal intensity of an allele in the tumour DNA vs. constitutional DNA., Patients: Twenty-one of the patients were recruited by a population-based screening for pHPT and the remaining pHPT patients were gathered from routine clinical practice., Results: In total, 27%, 23% and 23% of the tumours showed LOH at 1p, 6q and 11q, respectively. LOH at both 1p and 11q was more common in the screening-detected pHPT patients compared to those recruited from clinical practice (38% vs. 20%; P = 0.02 and 43% vs. 11%; P = 0.001, respectively), while allelic loss at 6q was more prevalent in the latter group (11% vs. 31%; P = 0.001). No apparent relationships between LOH at 1p, 6q, and 11q and clinical characteristics, such as glandular weight, serum levels of PTH or calcium, were demonstrated. Moreover, additional LOH analysis of chromosome 1p suggested a putative parathyroid tumour suppressor gene(s) in the region between markers DS214 and D1S503, spanning approximately 6 cM., Conclusion: A high frequency of LOH at 1p and 11q in tumours of screening-detected pHPT patients is intriguing, and may suggest that inactivation of known (the MEN1 gene) and putative tumour suppressor genes at these chromosomal regions is associated with a more benign disease.

Background: The natural history of mild hyperparathyroidism is incompletely clarified., Methods: Consistent hypercalcemia was found in 172 patients (aged 28-86 years) participating in population-based screenings in both 1969 and 1971. Mortality until 1994 was compared with 344 matched, normocalcemic controls from the study population. Altogether, 55 case-control pairs underwent biochemical analysis in 1992, whereas 86 patients had died, 8 were lost to follow-up, and 23 had undergone parathyroid operation., Results: Mortality was higher (P = .015) in patients younger than 70 years. Cardiovascular diseases were over-represented causes of death. The hazard ratio for hypercalcemia as an independent cause of cardiovascular mortality was 1.72 (95% CI, 1.24-2.37; P < .001). The initially mild hypercalcemia in patients (2.67 +/- 0.07 mmol/L) decreased over time (P = .0001), whereas the serum calcium value remained constant in the controls. Serum calcium and serum parathyroid hormone values in patients were higher than controls at the follow-up (P < .0001, .01, respectively). All but 17 patients were normocalcemic in 1992, and only 2 (1.4%) developed a serum calcium value higher than 3 mmol/L., Conclusions: Mild hypercalcemia in patients followed up for more than 2 decades is accompanied by premature cardiovascular death despite trends to spontaneous resolution. The principal cause of hypercalcemia probably is primary hyperparathyroidism, but mechanisms contributing to its regression over time are speculative.

Objectives: The cell cycle regulator cyclin D1 plays an important role in parathyroid tumourigenesis. The NciI polymorphism in exon 4 has recently been associated with early onset of hereditary nonpolyposis colorectal cancer and is a prognostic indicator of nonsmall cell lung cancer and squamous cell carcinomas. Furthermore, a limited study of 28 primary hyperparathyroidism (pHPT) patients displayed a tendency of NciI influence on HPT development. We hypothesized that the NciI polymorphism may relate to a risk of developing pHPT., Design, Setting and Subjects: We genotyped 182 patients with sporadic pHPT and matched controls for the cyclin D1 polymorphism. A total of 88 pHPT patients and controls were recruited via a health-screening., Results: The frequency distribution of the NciI genotypes NN, Ni, and ii were in pHPT patients and controls 22, 44 and 34%, and 26, 49 and 25%, respectively. The calculated allele frequencies were A = 0.56; G = 0.44 in cases and A = 0.49; G = 0.51 in controls. The frequency distributions did not differ comparing cases and controls when subgrouped after age and menopausal status. The NciI genotypes were not significantly associated with age of the individuals, serum (s)-calcium, s-parathyroid hormone (PTH), bone mineral density (BMD) or parathyroid tumour weight in any of the groups of pHPT patients or controls., Conclusions: No significant differences in distribution of the genotypes could be detected between the groups, suggesting that the polymorphism has minor or no pathogenic importance in the development of pHPT. Our results suggest that determination of the NciI polymorphism in the cyclin D1 gene is not a clinically useful tool for prediction of pHPT.

Background: The features of primary hyperparathyroidism (PHPT) in developing countries have rarely been examined. This study explored the clinical characteristics of PHPT in India with the hypothesis that this may improve understanding of the pathogenesis of the disease worldwide., Methods: Consecutive patients with PHPT (24 women, five men) were examined prospectively before and after parathyroidectomy., Results: All patients had osteitis fibrosa cystica with a median symptom duration of 2.5 (range 1-26) years. Single or multiple fragility fractures were present in 14 patients (eight were bedridden); 20 had brown tumours. Mean preoperative serum calcium was 3.1 mmol/l, while mean serum intact parathyroid hormone (iPTH) and total alkaline phosphatase (ALP) levels were 17-fold and 12-fold higher than normal respectively. Nine patients had overt renal damage, mainly nephrocalcinosis. Parathyroidectomy invariably resulted in severe hypocalcaemia, necessitating long-term vitamin D treatment. The mean parathyroid gland weight was 8.6 (range 2.0-36.6) g and features of carcinoma were found in four patients. Serum calcidiol level correlated inversely (P < 0.05) with serum iPTH and ALP, and parathyroid gland weight., Conclusion: PHPT in Indians is a severe, symptomatic disorder with skeletal, muscular and renal manifestations at a young age. The presence of this severe variant of PHPT in vitamin D-sufficient Indians, and the lack of skeletal disease in other vitamin D-deficient populations, raises the possibility of additional pathogenetic factors.

Background: Nontraditional manifestations of primary hyperparathyroidism (HPT) are controversial and may include morbidity, mortality, and risk factors for cardiovascular diseases. This study evaluates cardiovascular functions at rest and during exercise in HPT., Method: Thirty patients with HPT (mean serum calcium, 2.97 +/- 0.24 mmol/L) and 30 control people with normocalcemia, matched for age and sex, underwent symptom-limited exercise testing and echocardiography before and 13 months (mean) after having a parathyroidectomy., Results: Despite similar maximal workload and blood pressures at rest in patients and healthy controls, HPT associated with higher systolic blood pressure during exercise (P =.03) and increased number of ventricular extrasystolic beats (P =.04). There was also an operatively reversible increase in ST-segment depression during exercise. Echocardiography showed an increased left ventricular (LV) isovolemic relaxation time (P =.02) and mitral deceleration time (P =.08), which indicate an LV diastolic dysfunction that could be partially reversed by operation. LV systolic function (ejection fraction and shortening fraction) tended to be elevated in HPT (P =.07 and.06, respectively) and diminished after parathyroidectomy. There was a trend toward higher LV mass, especially among the men with HPT (P =.06), which was unchanged postoperatively., Conclusions: HPT couples to reversible signs of myocardial ischemia and LV dysfunctions with a possible increased risk of life-threatening arrhythmia.

Vitamin D, via its receptor (VDR), inhibits the hormone secretion and proliferation of parathyroid cells. Vitamin D deficiency and reduced parathyroid VDR expression has been associated with development of hyperparathyroidism (HPT) secondary to uremia. VDR polymorphisms may influence VDR messenger RNA (mRNA) levels and have been coupled to an increased risk of parathyroid adenoma of primary HPT. VDR mRNA relative to glyceraldehyde-3-phosphate dehydrogenase mRNA levels were determined by RNase protection assay in 42 single parathyroid adenomas of patients with primary HPT, 23 hyperplastic glands of eight patients with uremic HPT, and 15 normal human parathyroid glands. The adenomas and hyperplasias demonstrated similar VDR mRNA levels, which were reduced (42 +/- 2.8% and 44 +/- 4.0%) compared with the normal glands (P < 0.0001). Comparison of parathyroid adenoma with a normal-sized parathyroid gland of the same individual (n = 3 pairs) showed a 20-58% reduction in the tumor. Nodularly enlarged glands represent a more advanced form of secondary HPT and showed greater reduction in the VDR mRNA levels than the diffusely enlarged glands (P < 0.005). The reduced VDR expression is likely to impair the 1,25(OH)2D3-mediated control of parathyroid functions, and to be of importance for the pathogenesis of not only uremic but also primary HPT. Circulating factors like calcium, PTH, and 1,25(OH)2D3 seem to be less likely candidates mediating the decreased VDR gene expression in HPT.

Background: Primary hyperparathyroidism (HPT) is accompanied by hypertension and a cardiovascular mortality. Impaired endothelium-dependent vasodilatation (EDV) occurs in hypertension but has not been fully investigated in HPT despite the vasoactive influences of parathyroid hormone., Methods: Twenty-five HPT patients and 25 normocalcemic control subjects, matched for age and gender, underwent forearm venous occlusion plethysmography. EDV and endothelium-independent vasodilatation (EIDV) were evaluated during local infusion of metacholine (2 and 4 micrograms/min) and nitroprusside (5 and 10 micrograms/min), respectively. The endothelial function index was calculated as the ratio of forearm blood flows during the high doses of metacholine and nitroprusside. Ambulatory 24-hour blood pressures and thickness of the intima-media complex of the carotid arteries were also measured; the latter is considered an early marker of atherosclerosis., Results: Endothelial function index was lower in the HPT patients compared with control subjects (1.01 +/- 0.26 vs 1.27 +/- 0.31, P = .003). Reinvestigation 10 months after parathyroidectomy showed normalization of the index (1.31 +/- 0.39, P = .01) due to a numeric increase in EDV and decrease in EIDV. The carotid intima-media thickness and blood pressure were similar in the groups and unaltered postoperatively., Conclusions: Endothelial vasodilatory dysfunction is another indicator of the vascular disturbance of HPT and can be normalized by parathyroidectomy.

Vitamin D regulates parathyroid cell proliferation and secretion of PTH. Increased prevalence of the polymorphic vitamin D receptor (VDR) alleles b, a, and T has been reported in sporadic primary hyperparathyroidism (PHPT), suggesting that these genetic variants may predispose to the disease. Recently, another polymorphism in the VDR gene was related to bone mineral density, and this VDR-FokI polymorphism causes different lengths of the VDR, implying possible functional consequences. The VDR-FokI polymorphism was studied in 182 postmenopausal women with sporadic PHPT and in matched controls. No significant differences in distribution of the VDR-FokI genotypes could be detected between the groups, although there was a tendency toward overrepresentation of the F allele in the PHPT patients (P = 0.05). There were no significant associations with age, serum calcium, serum PTH, bone mineral density, or parathyroid tumor weight. The VDR genotypes were unrelated to VDR and PTH messenger ribonucleic acid levels in the parathyroid adenomas of 42 PHPT patients. In 23 PHPT patients, the Ca2+-PTH set-points were determined in vivo and were unrelated to the VDR alleles. We suggest that the VDR-FokI polymorphism has at most a minor pathogenic importance in the development of PHPT.

Background: Operation and reoperation for hyperparathyroidism in multiple endocrine neoplasia type 1 (MEN 1) is controversial regarding surgical strategy, preoperative localization, and biochemical indexes of recurrence., Methods: Fifty patients with MEN 1 with hyperparathyroidism were followed up 2 to 27 years after subtotal (SPX; n = 35) or total parathyroidectomy with forearm autografiing (TPX; n = 15), including 24 who underwent 28 reoperations because of persistent or recurrent hyperparathyroidism., Results: Persistent or recurrent hyperparathyroidism was seen in 66% and 20% of patients after SPX involving extirpation of at least 3 glands and TPX, respectively, and 100% after single-gland excision as a primary procedure. After reoperation, hypercalcemia was reversed in 33% of patients by SPX and 61% by intended TPX procedures. All patients received vitamin D substitution after TPX, but restricted thyroid function allowed withdrawal in all but 10 patients (36%). Intact serum parathyroid hormone levels in nongrafted and grafted arms rose with time, but only exceptional ratios localized graft recurrence. Localization of recurrent hyperparathyroidism was achieved with 11C-labeled methionine positron emission tomography., Conclusion: MEN 1 hyperparathyroidism has a high risk of recurrence, and operation may include primarily SPX of at least 3 glands or TPX, although the latter includes a higher risk of long-term hypoparathyroidism. Reoperation should involve TPX with recognition of the enhanced recurrence rate in individuals with postoperative hyperparathyroidism.

Background: Symptoms, signs, and treatment of mild primary hyperparathyroidism (HPT) are controversial., Methods: One hundred two patients with HPT and matched controls were recruited from 5202 females attending population-based mammography screening at age 55 to 75 years. Patients' total serum calcium averaged 10.40 +/- 0.564 mg/dL and intact serum parathyroid hormone 58 +/- 33 ng/L. All patients lacked knowledge of their disease. Questions revealed traditional symptoms of HPT in 24% of cases and 43% of controls (P = .01). All individuals underwent the same biochemical analyses, bone mass determination, and questionnaires on symptoms, illnesses, medications, and background variables., Results: Patients with HPT had more psychic complaints (P = .03 to .007) of lassitude, fatigue, irritability, and lack of sexual and emotional interests. They had lower bone density in total body, spine, and hip (P = .008 to .0004) and higher serum alkaline phosphatase, cholesterol (very-low-density lipoprotein), triglycerides (total, very-low-density lipoprotein), glucose, urate, and hemoglobin values (P = .02 to .0001). Patients visited physicians more often (P = .008) and had more antihypertensive therapy (P = .02)., Conclusions: Mild, "asymptomatic" HPT in patients unaware of their disorder displays significant psychic symptoms, bone loss, and risk factors of cardiovascular disease.

Objective: To analyse sick leave in women at risk of primary hyperparathyroidism before its diagnosis., Design: Case-control study nested within a screened cohort of postmenopausal women. Cases were women with hyperparathyroidism without prior knowledge of their disease and no traditional symptoms or complications. Controls were women from the screened population without hyperparathyroidism., Setting: Population based screening within a Swedish community., Subject: 48 case-control pairs of women aged 55-70 years., Main Outcome Measure: Sick leave during the 5 years before diagnosis., Results: Total duration of sickness benefits was longer in the cases than controls, and this discrepancy included sick leave on full time or half time and for periods of longer than a week. Cases had an increased risk of sick leave more than half of the investigated time compared with controls (odds ratio 12). Doctors' certificates showed that the overrepresented sick leave in the cases related mainly to cardiovascular diseases., Conclusion: Asymptomatic mild primary hyperparathyroidism in postmenopausal women is accompanied by a previously unrecognised morbidity, which has consequences for clinical management of the disorder and its impact on the health economy.

Background: Autoimmune diseases are characterized by induced parenchymal expression of major histocompatibility complex (MHC) class II antigens and circulating autoantibodies directed toward surface structures on the target cells. MHC class II expressions can be modified by viral infections of potential pathogenic importance in autoimmune reactions. Primary hyperparathyroidism exhibits incompletely clarified cause., Methods: With cryosections, human parathyroid glands were stained with monoclonal antibodies to MHC class II antigens according to a peroxidase-antiperoxidase technique. Human parathyroid adenoma tissue transplanted to nude mice and rat parathyroid glands was tested with serum from patients with hyperparathyroidism and control subjects., Results: Induced MHC class II expression was demonstrated on parathyroid parenchymal cells in 13 of 54 adenomatous and eight of 23 hyperplastic glands of patients with primary hyperparathyroidism. This reactivity was absent in 12 normal glands, nine normal-sized glands associated with the adenomas, and 17 enlarged glands of patients with hyperparathyroidism caused by uremia. Staining of parathyroid tissue was found with serum from 27 of 38 patients with primary hyperparathyroidism, whereas this reactivity was absent on rat thyroid and pancreatic tissue, as well as with control sera., Conclusion: The concurrent induction of MHC class II antigen expression and c circulating antiparathyroid autoantibodies in 16 or 38 patients with primary hyperparathyroidism suggests hitherto unrecognized immunologic involvement in this disease.

Biochemical signs and severity of symptoms of primary hyperparathyroidism (pHPT) differ among patients, and little is known of any coupling of clinical characteristics of nonfamilial pHPT to genetic abnormalities in the parathyroid tumors. Mutations in the recently identified MEN1 gene at chromosome 11q13 have been found in parathyroid tumors of nonfamilial pHPT. Using microsatellite analysis for loss of heterozygosity (LOH) at 11q13 and DNA sequencing of coding exons, the MEN1 gene was studied in 49 parathyroid lesions of patients with divergent symptoms, operative findings, histopathological diagnosis, and biochemical signs of nonfamilial pHPT. Allelic loss at 11q13 was detected in 13 tumors, and 6 of them demonstrated previously unrecognized somatic missense and frameshift deletion mutations of the MEN1 gene. Many of the detected mutations would most likely result in a nonfunctional menin protein, consistent with a tumor suppressor mechanism. Clinical and biochemical characteristics of HPT were apparently unrelated to the presence or absence of LOH and the MEN1 gene mutations. However, the demonstration of LOH at 11q13 and MEN1 gene mutations in small parathyroid adenomas of patients with slight hypercalcemia and normal serum PTH levels suggest that altered MEN1 gene function may also be important for the development of mild sporadic pHPT.

Double parathyroid adenoma (DA) has been suggested to be a clinically distinct entity of primary hyperparathyroidism (HPT). Altogether 659 patients with sporadic primary HPT were analyzed retrospectively by evaluating consecutive primary operations for more than three decades. Patients with postoperatively persistent HPT and those with incomplete medical, operative, or histologic records were disregarded. The mean age (+/- SD) at surgery was 60.9 +/- 12.7 years; 78% of the patients were female; and the duration of postoperative follow-up averaged 7.8 +/- 7.2 years. DA, defined as two enlarged parathyroid glands, was found in 77 patients (12%). Enlargement of a single gland (SA) or three or more glands (MA) occurred in 80% and 8%, respectively. DAs were bilateral in 72% of patients, and the weight of the two glands differed by 317 +/- 407 mg. The three histologic subgroups of patients exhibited no significant discrepancy with respect to age, classic symptoms of HPT, proportion of overtly asymptomatic individuals, or parathyroid tissue weight. A lower female predominance and extent of hypercalcemia and higher preoperative serum creatinine level occurred with DA and MA compared to SA. SA and DA differed from MA with respect to variably strong trends to lower postoperative incidences of recurrent HPT and hypoparathyroidism. DA seems to comprise an underrated histologic cause of HPT, which is eligible for a conservative operative approach. Clinical characteristics consistent with a distinct entity of sporadic primary HPT were not seen.

Calcitriol, via its receptor (VDR), inhibits parathyroid hormone (PTH) secretion and cell proliferation. Physically linked polymorphic VDR alleles denoted b,a, and T, comprise a novel risk factor for postmenopausal primary hyperparathyroidism (pHPT) by their presumed coupling to reduced VDR expression. This study examines VDR gene polymorphisms, parathyroid calcium-regulated cytoplasmic calcium concentrations ([Ca2+]i) and parathyroid expression of a calcium sensor protein (CAS/gp330). Genomic DNA was obtained from 66 postmenopausal women with pHPT and 66 age-matched female controls. Polymorphic VDR alleles were detected after polymerase chain reaction (PCR) and restriction digestion. Cryosections of pathologic parathyroid glands from 41 of the patients were immunostained with a monoclonal anti-CAS/gp330 antibody. Homozygosity for the VDR alleles b, a, and T was overrepresented in pHPT (p < 0.01-0.05) but did not couple to ED50 for calcium-regulated [Ca2+]i. The enlarged parathyroid glands possessed heterogeneous down-regulation of CAS/gp330. This down-regulation was the least conspicuous in the BBgenotype, and these few patients generally had larger parathyroid lesions (p < 0. 05). The VDR haplotype baTis a risk factor for pHPT possibly by hampering the regulatory actions of calcitriol. In contrast the BAt haplotype seems to be underrepresented in pHPT and to couple to larger parathyroid lesions as well as less deranged CAS/gp330 expression and parathyroid cell function. HPT in these individuals may relate to genetic events principally altering the regulation of cell proliferation, rather than calcium sensing of the parathyroid cells.

Background: Estrogen and its receptor play a key role in calcium homeostasis, with implications in both the development and treatment of primary hyperparathyroidism., Methods: Leukocyte DNA was isolated from 101 postmenopausal female patients with primary hyperparathyroidism and age-matched female control subjects (n = 101). Polymorphic estrogen receptor alleles denoted P/p and X/x were detected by polymerase chain reaction and restriction digestion with Pvu II and Xba 1, Results: Allelic prevalences were similar in the patients and control subjects. In contrast to normocalcemic control subjects, patients with primary hyperthyroidism homozygous for alleles P and X displayed less elevated serum calcium concentrations (mean, 2.63 and 2.66 mmol/L) versus those with Pp and pp (2.72 mmol/L; p < 0.01) and Xx and xx (2.71; p < 0.05), respectively, as well as trends for higher intact serum parathyroid hormone values (p = 0.09). The PP genotype was accompanied by lower bone mineral density in the lumbar spine (p < 0.05)., Conclusions: Estrogen receptor gene polymorphisms are presumably not directly involved in the parathyroid tumorigenesis. However, they seem to interact with the extent of biochemical derangements of primary hyperthyroidism by possible influences on both the peripheral action of parathyroid hormone and calcium regulation of its secretion.

Calcitriol acts via its receptor (VDR) and inhibits PTH secretion and parathyroid cell proliferation. Increased prevalence of the polymorphic VDR alleles b, a, and T has been demonstrated in sporadic primary hyperparathyroidism. Sixty-two patients with primary hyperparathyroidism due to parathyroid adenoma (mean age, 69.5 +/- 1.4 yr) were genotyped for these VDR polymorphisms. Dispersed cells of the adenomas were exposed to increasing concentrations of extracellular Ca2+ and analyzed for PTH release and cytoplasmic Ca2+ concentrations. Ca2+-mediated PTH inhibition exhibited higher ED50 and less suppression in the cells of patients who were homozygous for the b, a, and T alleles (P < 0.05-0.10). When analyzing haplotypes, the patients with baT demonstrated a ED50 of 1.81 +/- 0.15 vs. 1.29 +/- 0.10 for BAt (P < 0.05). As VDR alleles were unrelated to parathyroid intracellular Ca2+, influences of polymorphic VDR alleles on PTH secretion seem to involve mechanisms other than the Ca2+-sensing protein of the parathyroid cell surface.

Polymorphisms in the vitamin D receptor (VDR) gene have been hypothezised to interfere with VDR expression. VDR alleles (Bb, Aa and Tt) were examined in 254 Caucasian patients with sporadic primary hyperparathyroidism (spHPT, n = 206), HPT of multiple endocrine neoplasia type 1 (MEN-1; n = 17), and HPT of uremia (n = 31). In comparison to age- and sex-matched controls, the b, a and T alleles were overrepresented in 100 menopausal females with spHPT (p = 0.006-0.0004), equivalent to an odds ratio of 2.6-3.4 for spHPT in homozygotes for the b, a and, T alleles. The association between VDR genotypes and spHPT was restricted to female patients and those with parathyroid adenoma (p = 0.0006-0.0001), whereas HPT of MEN 1 and uremia seemed unrelated to the VDR polymorphisms (p = 0.26-0.96). The results suggest that the VDR alleles b, a, and T are novel risk factors in the essentially uncharacterized pathogenesis of spHPT.

Ca(2+)-induced changes in the cytoplasmic Ca2+ concentration ([Ca2+]i) were studied in bovine and normal and pathological human parathyroid cells using digital image analysis of fura-2-loaded cells. When raising external Ca2+ from 0.5 to 3.0 mmol L-1, about 95% of all cells reacted rapidly and simultaneously with sustained elevation of [Ca2+]i. In approximately two out of three bovine parathyroid cells, normal human cells and cells from most patients with hyperparathyroidism (HPT) the sustained phase was preceded by an overshooting [Ca2+]i transient. The proportion of cells, with such a transient was decreased in cells from severe cases of uraemic parathyroid hyperplasia only. However, pathological human cells from adenomas and normal-sized glands associated with adenomas, as well as cells from primary and uraemic hyperplasias, had lower peak and sustained levels than normal human and bovine cells. The results indicate that both normal and pathological parathyroid cells exhibit heterogeneity in their [Ca2+]i responses to elevation of external Ca2+. The Ca(2+)-induced [Ca2+]i transients and the sustained elevations are attenuated in pathological human parathyroid cells. However, the presence of the overshooting transient represents physiological variability rather than being a consequence of the pathophysiology associated with HPT.

Unlabelled: The study was designed to characterize L-[methyl-11 C]methionine accumulation in abnormal parathyroid tissues of hyperparathyroidism (HPT)., Methods: Thirty-four patients with primary (n = 32) or secondary HPT were investigated with PET before primary or reoperative (n = 25) parathyroid surgery. Parathyroid 11C-methionine accumulation was analyzed for integrated uptake values in defined tissue volumes standardized for the injected dose and body weight (SUV), four contiguous pixels of maximal accumulation (SUVhs), SUV multiplied by area of region of interest (SUVr) and by the excised tissue weight (SUVw). Transport rate constants (slope, slopehs) were calculated according to Patlak's formula using plasma 11C activity corrected for 11C-methionine metabolites., Results: True-positive localization was achieved in 85% of patients in whom 81% of the excised parathyroid lesions were visualized; no false-positive results were obtained. Corresponding proportions were 59% and 57% for CT and 55% and 52% for ultrasound, respectively. In the true-positive cases, parathyroid SUV, SUVhs and transport rate constants were consistently higher (p < 0.01) than in the thyroid, pharynx-esophagus, neck muscle and apical lung. Parathyroid SUV, SUVhs and SUVr increased with intact serum parathyroid hormone and calcium values (p = 0.0001-0.031), and weight of the excised tissue correlated with SUV and SUVhs (p = 0.024, 0.044). Parathyroid SUVhs varied strongly with the transport rate constants (p = 0.0008), and SUVr as well as s-calcium values differed significantly between parathyroid adenomas (n = 11), chief cell hyperplasias (n = 13), inadvertent implants (n = 3) and parathyroid cancers (n = 3)., Conclusion: Carbon-11-methionine PET has potential application in preoperative localization and metabolic characterization of abnormal parathyroid tissues in human HPT.

Parathyroid tissue from 57 women (mean age 65.5 years) with sporadic primary hyperparathyroidism (HPT) was analyzed mainly to clarify its characteristics versus tissue from those with normocalcemia. Patients were recruited by population-based health screening of menopausal women. Analysis of three or four total serum calcium values showed normocalcemia in 16 patients (mean 2.53 mmol/L); 20 and 21 of the women were consistently (mean 2.82 mmol/L) or intermittently (mean 2.59 mmol/L) hypercalcemic, respectively. Parathyroid operation demonstrated a single adenoma in 81% of the individuals, and these lesions were most prevalent and commonly dominated by oxyphil parathyroid cells in the persistently hypercalcemic patients. Chief cell hyperplasia (two or three abnormal glands) of the nodular type was found more often in the normocalcemic patients. Total glandular weight was the smallest (mean 270 mg) among the normocalcemic women and contributed to delicate decisions with regard to the extent of resection. Immunostaining of cryosections with a monoclonal antibody recognizing a putative Ca2+ sensor demonstrated variably heterogeneous down-regulation of the recognized glycoprotein in the pathologic parathyroid glands from all the individuals. Dose-response relations for PTH release and the cytoplasmic Ca2+ concentration ([Ca2+]i) were determined in Ca2+ 0.5-3.0 mmol/L by examining dispersed cells with radioimmunoassay and microfluorometry after fura-2 loading, respectively. ED50 for PTH release and [Ca2+]i and the [Ca2+]i concentrations at Ca2+ 3.0 mmol/L were the least deranged in cells from pathologic glands of the normocalcemic patients. The findings substantiate that the abnormal parathyroid tissue of normocalcemic HPT principally is characterized by the same, albeit less extensive, morphologic and functional derangements, which consistently have been demonstrated in patients with HPT accompanied by hypercalcemia and detected clinically.

Background: Hyperparathyroidism affects most patients with multiple endocrine neoplasia type 1 (MEN 1). This study investigates expression of the candidate MEN1 gene phospholipase C beta 3 (PLC beta 3) and expression and function of a putative calcium sensing protein (CAS) in hyperparathyroidism of MEN 1., Methods: In 31 parathyroid glands from 17 patients with MEN 1, CAS distribution was studied immunohistochemically and parallel sections were explored for PLC beta 3 mRNA expression by in situ hybridization. Enzymatically dispersed parathyroid cells were analyzed for cytoplasmic calcium concentrations [Ca2+]i and parathyroid hormone (PTH) release., Results: All glands exhibited a heterogeneously reduced CAS immunoreactivity, especially meager in nodularly assembled parathyroid cells. Calcium regulated [Ca2+]i and PTH release tended to be more deranged in the glands possessing the lowest immunostaining. Parathyroid PLC beta 3 invariably was homogeneously expressed, and this included even MEN 1 patients with reduced PLC beta 3 expression in endocrine pancreatic tumors., Conclusions: The findings support variable calcium insensitivity of [Ca2+]i and PTH release in hyperparathyroidism of MEN 1, apparently coupled to heterogeneously reduced CAS expression. For clarification of the role of PLC beta 3 in MEN 1 parathyroid tumorigenesis further study of this protein is required.

Background: Normal and abnormal human parathyroid tissue express the T-lymphocyte protein CD4, and parathyroid and lymphocyte cells show similarities with respect to mechanisms of calcium permeability and regulation of the cytoplasmic calcium concentration., Methods: Anti-Leu4, a monoclonal antibody recognizing the T-lymphocyte glycoprotein complex CD3, is used to immunohistochemically stain normal and abnormal human parathyroid cells and to explore influences on the parathyroid hormone (PTH) secretion of enzymatically dispersed parathyroid cells., Results: Parathyroid glands of patients with different forms of hyperparathyroidism displayed variable expression of the anti-CD3 reactive complex. The stainings correlated both positively and inversely to immunoreactivity for a previously defined calcium sensor, the decreased expression of which may constitute a molecular basis for hyperparathyroidism. Incubation of parathyroid cells with the anti-Leu4 antibody inhibited PTH secretion and reduced its sensitivity to external calcium without influence on parathyroid cytoplasmic calcium concentration., Conclusions: The results suggest that the human parathyroid cells express a CD3-like molecule with the ability to interact in PTH release.

Vitamin D and parathyroid hormone (PTH) constitute the main regulators of systemic calcium homeostasis. As well as its calcaemic effects, active vitamin D3(1,25(OH)2D3) has a direct regulatory role on parathyroid cells. Active vitamin D3 acts via its receptor (VDR), and binding of the ligand-receptor complex to specific promoter regions of the PTH gene inhibits transcription. Active vitamin D3 constitutes a principal regulator of parathyroid cell growth, and polymorphism in the VDR gene has recently been related to bone mineral density and suggested as predisposing to osteoporosis. Impaired effects of active vitamin D3 may contribute to the relatively enhanced secretion and cell proliferation seen in hyperparathyroidism (HPT). Indeed, VDR dysfunction, of essentially unknown character, has been demonstrated in the pathological parathyroid tissue of primary HPT as well as HPT secondary to uraemia. Consistent with the essential role of active vitamin D3 in parathyroid regulation, the VDR gene polymorphism was studied in 90 postmenopausal women with primary hyperparathyroidism. The VDR genotype bb was found in 60.0% of HPT patients and in 33.3% of the postmenopausal female controls (P < 0.001). As the b allele has been linked to decreased transcriptional activity or messenger RNA stability, reduced VDR expression may impede regulatory actions of vitamin D and may contribute to parathyroid tumorigenesis in these patients.

Parathyroid cells from patients with hyperparathyroidism were first cultured in a growth cocktail supplemented version of Dulbecco's MEM/F12 medium and then used for measurements of the cytoplasmic Ca2+ concentration ([Ca2+]i). Elevation of extracellular Ca2+ from 0.5 to 1.5-3 mM often triggered rhythmic oscillations of [Ca2+]i. Whereas the amplitude of the oscillations remained constant their frequency (0.4-2.6 /min) increased with the Ca2+ concentration and there was sometimes transformation into sustained increase of [Ca2+]i at the highest extracellular Ca2+ concentration. The oscillations were abolished by the inorganic Ca2+ channel blocker Ce3+ and by K+ depolarisation, which lowered [Ca2+]i, as well as by thapsigargin, an inhibitor of the intracellular Ca(2+)-pumping ATPase. The data indicate that extracellular Ca2+ can trigger [Ca2+]i oscillations in parathyroid cells, dependent on mobilisation of the ion from intracellular Ca2+ stores and on influx through non-voltage dependent channels.

Background: Gallium nitrate and the bisphosphonates pamidronate and its dimethylated derivative comprise antihypercalcemic drugs with actions on bone. This study examines the in vitro effects of these compounds on human parathyroid cells., Methods: Parathyroid hormone (PTH) release and the concentration of cytoplasmic calcium ion (Ca2+) of dispersed cells from parathyroid glands of 27 patients with sporadic primary or uremic hyperparathyroidism was measured., Results: In 1.25 mmol/L external Ca2+, 200 mumol/L gallium nitrate inhibited PTH release from preparations of primary and uremic hyperparathyroidism by 14% and 22%, respectively. Similar reductions were evident also in 0.5 and 3.0 mmol/L Ca2+. The gallium nitrate-induced suppression of PTH release was dose dependent in the 2 to 200 mumol/L range. Cytoplasmic Ca2+ concentration displayed a biphasic rise on elevation of external Ca2+ and remained unaffected by gallium nitrate. None of the bisphosphonates altered PTH release of pathologic human or normal bovine parathyroid cells., Conclusions: The results support clinical usefulness of gallium nitrate through its dual actions on bone and the parathyroid. The findings substantiate that gallium may reduce PTH release by stabilization of the plasma membrane rather than by interference with the surface cation receptor mediating Ca2+ regulation of the secretion.

Background: Positron emission tomography (PET) has not been evaluated for preoperative localization and functional characterization of the parathyroid tissue in hyperparathyroidism., Methods: Images of the neck and upper mediastinum of 23 patients with hyperparathyroidism were obtained by PET after intravenous administration of 400 to 800 MBq L-[methyl-11C]-methionine. The investigation was repeated in six patients after Na2-ethylenediamine tetraacetic acid infusion, whereby stable 65% to 157% rise in intact serum parathyroid hormone values was attained., Results: Parathyroid surgical procedure revealed single (21 patients) or two enlarged parathyroid glands (two patients) that were characterized as chief cell adenoma (n = 13), hyperplasia (n = 10), or carcinoma (n = 2) and weighed 80 to 6000 mg. Twenty (80%) of these glands were localized by PET. The remaining examinations (20%) were false negative and mainly encompassed small parathyroids in juxtathyroid position. Among 15 patients undergoing parathyroid reoperation true-positive localizations were obtained for 87% of the glands. The images displayed lower tracer uptake in residual thyroid lobes (n = 40), esophagus, and cervical vertebrae. Na2-ethylenediamine tetraacetic acid infusion failed to enhance parathyroid uptake values. Ultrasonography, computed tomography, technetium-thallium scintigraphy, and venous sampling revealed 25% to 53% of the pathologic parathyroid tissues of the patients undergoing reoperation and was largely complementary to PET., Conclusions: The results suggest that PET may provide novel possibilities for the imaging of pathologic parathyroid glands in hyperparathyroidism.

Retrospective analysis has been performed on 108 consecutive patients operated for primary hyperparathyroidism (HPT) at 75 to 85 years of age (mean 79 years). The preoperative serum calcium value averaged 2.99 mM, and six patients had hypercalcemic crisis. Psychic disturbances were seen in 60 patients (56%), 40% of whom demonstrated dementia. Skeletal and muscular complaints were registered in 29% and 19%, respectively, and only 6% were overtly asymptomatic. Cardiovascular diseases were presented by 69% of the patients, 13% had diabetes mellitus, and 26% were institutionalized prior to surgery. Bilateral neck exploration disclosed a single adenoma in 69%, which was of the oxyphil cell type in 13%, and water-clear (n = 3) or chief cell hyperplasia in 27%. The total glandular weight averaged 1085 mg. Altogether 72 patients operated on after 1980 demonstrated a perioperative (30-day) mortality of 1.4%; the corresponding morbidity of 8.7% mainly included infections as well as a vocal cord paralysis in one patient and two incisional hematomas. Analysis for mean 3.1 years postoperatively displayed reversal of hypercalcemia in 95% of the patients; 2.8% of those operated after 1980 had persistent disease. Symptoms seemed to be alleviated in 62%, with a similar rate attained in patients with dementia. Altogether 60 patients died from mainly cardiovascular diseases mean 4.2 years after the operation. Those succumbing the first postoperative year (n = 21) showed overrepresentation of cardiac diseases and diabetes mellitus. The results demonstrate prevalent psychic disturbances, oxyphil adenomas, and multiglandular parathyroid disease in elderly patients with primary HPT and favor rather liberal application of parathyroid surgery among these individuals.

Primary hyperparathyroidism (HPT) is a disease caused by an abnormal cytosolic regulation of calcium concentration [Ca++]i leading to an increased secretion of parathyroid hormone and thereby increased levels of extracellular calcium. It is well known that the QT-interval measured at electrocardiography (ECG) is shortened in HPT subjects. Whether this is due to an abnormal intracellular handling of calcium also in the heart or to the raised extracellular calcium levels is not known. In order to study the extent to which the deranged extra- and intracellular levels of calcium in HPT patients were related to ECG characteristics, [Ca++]i was determined in vitro by microfluorometry in surgery-removed parathyroid cells at extracellular calcium concentrations of 0.5 mM and 30.0 mM and ECG was recorded preoperatively in 42 HPT patients and in 15 subjects operated on for atoxic goitre. Serum calcium and plasma-ionized calcium also were measured preoperatively. The QT-interval and ST-segment duration were both shortened in the HPT patients compared to controls (P < 0.001). [Ca++]i at 3.0 mM extracellular calcium divided by that at 0.5 mM was correlated to the QT-interval, when measured at the onset of the T-wave (QoT, r = 0.39, P < 0.03) and early diastolic phase (end of T-wave to onset of p-wave, r = -0.34, P = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Background: This study investigates 410 persons (median age, 67 years) who underwent parathyroid operation for sporadic primary hyperparathyroidism 6 to 32 years (mean, 14.2 years) before 1991., Methods: Patient records and operative specimens were scrutinized, the patients answered a questionnaire, and fasting serum samples were analyzed for calcium, albumin, creatinine, and intact parathyroid hormone (PTH) values., Results: After primary parathyroid operations were performed with a conservative surgical approach, persistent and recurrent hypercalcemia were noticed in 3.7% and 1.7% of patients, respectively, whereas 4.7% of patients required vitamin D substitution or had essentially mild hypocalcemia. The PTH values were generally increased in patients with postoperative hyperparathyroidism, low in those with vitamin D substitution, and normal to elevated in the patients with hypocalcemia and in those with postoperative normocalcemia. The mean serum creatinine concentration was just below the upper reference range and correlated strongly with serum PTH value. No significant differences in serum PTH values were present between the normocalcemic patients and matched control patients after operation (n = 107), but the patients who underwent operation exhibited greater variation in the PTH concentration., Conclusions: The results substantiate the efficacy of parathyroid operation in sporadic primary hyperparathyroidism. Biochemical derangements compatible with secondary hyperparathyroidism may evolve during long-term follow-up and contribute to decreases in serum calcium values and increases in serum PTH values of these patients.

Analysis of 14 patients with primary hyperparathyroidism (HPT) prior to and during the first year after parathyroid surgery disclosed that the operation was associated with rapid reductions of intact serum parathyroid hormone (PTH) and total serum and ionized plasma calcium values. A decreased urinary calcium excretion, a gradual elevation of renal calcium reabsorption, a transient reduction of serum calcitriol, and a late increase in 25-hydroxycholecalciferol values were also noted. Dynamic tests of parathyroid function by EDTA infusion and an oral calcium load revealed a sigmoidal relationship between serum PTH and calcium levels, and that parathyroid surgery induced considerable changes in both the position and slope of the dose-response curve. It was also apparent that PTH release was submaximally stimulated event at periods of hypocalcemia. The findings substantiate that adjustments of PTH release to acute alterations of serum calcium occur along the prevailing dose-response relationship, while stimuli being maintained for longer periods of time induce compensatory shifts in the position and slope of this curve. It is further suggested that unknown factors with PTH-like function may participate in the calcium regulation after surgery for primary HPT.

Hypercalcemia was corrected in 62 (90%) of 69 patients after re-operation for primary hyperparathyroidism during a mean follow-up of 6.3 years. Failed primary exploration was mainly due to inadequate visualization of the pathological parathyroid glands, often in association with misleading or absent peroperative histology. Other causes included seeding of parathyroid adenoma tissue, truly recurrent adenomas, and recurrent hyperplasia, especially in patients with multiple endocrine neoplasia type 1. A considerable number of parathyroid glands missed at the primary operations were subsequently found in essentially normal positions. Ectopic superior glands were most frequently positioned para-esophageally or retro-esophageally, while abnormally placed inferior glands were generally situated within or close to the thymus. Glands in 3 patients were dissected from around the large vessels in the mediastinum. Concomitant thyroid procedures during the primary operation yielded few abnormal parathyroids and made the re-exploration considerably more difficult. We suggest a semilateral approach and caudal identification of the recurrent laryngeal nerve to reduce the hazards of difficult parathyroid re-operations. Mediastinal exploration may require total removal of the thymus and careful dissection of the middle mediastinum.

Forty-two patients with primary hyperparathyroidism (HPT) of multiple endocrine neoplasia type 1 (MEN-1) were evaluated a mean of 8.9 years after subtotal parathyroid resection (SPX, n = 34) or total parathyroidectomy with autotransplantation to the forearm (TPX, n = 23). TPX as the primary operation revealed asymmetric and mainly nodular enlargement of the parathyroid glands with the presence of at least one normal-size gland in half of the individuals. TPX and SPX were accompanied by resolution of the hypercalcemia in 78% and 38% of the patients. Persistent and recurrent HPT occurred in 22% and 61% of the patients, while hypoparathyroidism requiring oral supplements occurred in 30% and 12% of the patients, respectively. Intact serum parathyroid hormone (PTH) in the arm of parathyroid autograft was high in the normocalcemic patients, somewhat lower in the patients with recurrent HPT, and normal to very low in the hypoparathyroid patients. Ratios of intact PTH between the grafted and non-grafted arms varied from 1 to 56.3, with average of 28.1 in the normocalcemic individuals, 8.2 in the patients with recurrent HPT, and 3.3 in those requiring supplements to maintain normocalcemia. These findings substantiate an 80% to 92% reversal of hypercalcemia during long-term follow-up of MEN-1 patients undergoing total parathyroidectomy or subtotal resection of 3-4 parathyroid glands as primary operative procedures and demonstrate the usefulness of intact serum PTH for functional evaluation of parathyroid autografts.

Primary hyperparathyroidism (HPT) is a common disorder that mainly afflicts elderly women. It can be diagnosed in at least 1% of all postmenopausal females and autopsy studies indicate an even higher frequency. Although the widespread use of automated serum calcium analyses has increased the awareness of HPT, only 10% of all cases seem to be identified. The diagnosis relies on the demonstration of an inappropriately elevated serum concentration of parathyroid hormone (PTH) relative to the serum calcium value, which need not be markedly raised. Measurements of intact PTH with immunometric methods have considerably improved the diagnostic precision but it is still difficult to evaluate patients with only marginal hypercalcemia. Few patients with diagnosed HPT are completely without symptoms. Symptoms commonly encountered are psychiatric and neuromuscular disturbances. Subclinical bone disease might be relevant but there is insufficient information about its importance in otherwise asymptomatic individuals. Various cardiovascular risk factors appear more commonly in patients with HPT and untreated disease is associated with an increased risk of premature death.