Association between primary hyperparathyroidism and cardiovascular outcomes: A systematic review and meta-analysis.

BACKGROUND: Excess parathyroid hormone (PTH) is associated with an increased risk of cardiovascular disease (CVD). PURPOSE: We aimed to evaluate the correlation between primary hyperparathyroidism (PHPT) and CVD or cardiovascular (CV) death. DATA SOURCES: Comprehensive searches of PubMed, Embase and ClinicalTrials.gov until May 20, 2023 with the following keywords: "primary hyperparathyroidism," "cardiovascular disease," and "mortality." STUDY SELECTIONS: Cohort studies and randomized controlled trials comparing PHPT patients to the general population and those who had received parathyroidectomy (PTX) to those who did not. DATA EXTRACTION: Three investigators independently extracted data and assessed study quality. DATA SYNTHESIS: Eleven cohort studies and one randomized controlled trial were identified, including 264,227 PHPT patients with or without PTX, and the average age reported in the studies was 62 years. PHPT was associated with a higher risk of total death (RR 1.39 [95 % confidence interval (CI) 1.23-1.57) and CV death (RR 1.61 [95 % CI 1.47-1.78]) than the general population. However, there was no significant difference in CVD risk between patients with PHPT and the general population (RR 1.73 [95 % CI 0.87-3.47]). When compared to patients without PTX, PTX had a lower risk of CV death (RR 0.75 [95 % CI 0.71-0.80]), total death (RR 0.64 [95 % CI 0.60-0.70]) and CVD (RR 0.92 [95 % CI 0.90-0.94]). LIMITATION: High heterogeneity among the included articles, and most of them were retrospective and older studies. CONCLUSIONS: PHPT was associated with higher risk of total death and CV death while PTX was associated with lower risk of total death, CV death, and CVD.

Parathyroidectomy for nephrolithiasis in primary hyperparathyroidism: Beneficial but not a panacea.

BACKGROUND: Nephrolithiasis is a classic indication for parathyroidectomy in primary hyperparathyroidism patients; however, the effects of parathyroidectomy on nephrolithiasis recurrence are not well studied. The aim was to determine effect of parathyroidectomy on time to first nephrolithiasis recurrence and recurrence rate per patient-years. METHODS: A retrospective cohort study of patients diagnosed with primary hyperparathyroidism and at least one episode of nephrolithiasis was performed. The patients were divided into observation, presurgery, and postsurgery groups. Endpoints were time to first recurrence of nephrolithiasis and average recurrence rate per patient-years. RESULTS: The cohort was comprised of 1,252 patients. In addition, 334 (27%) patients underwent parathyroidectomy and 918 (73%) were observed. The surgical and nonsurgical groups differed significantly in age, sex, Charlson, calcium, and primary hyperparathyroidism level. Overall recurrence rate was 31.3%. The 5-, 10-, and 15-year recurrence-free survival rates were 74.4%, 56.3%, 49.5%, respectively (presurgery), 82.4%, 70.9%, 62.8%, respectively (postsurgery; P < .0001), and 86.3%, 77.7%, and 70.6%, respectively (observation). The presurgery group had an increased risk of first recurrence compared with the observation group (hazard ratio 1.89; 95% confidence interval, 1.44-2.47). The average recurrence rates among all surgical patients who recurred were 1 event per 4.3 patient-years presurgery versus 1 event per 6.7 patient-years postsurgery (P = .0001). CONCLUSION: Recurrent nephrolithiasis is a significant problem in patients with primary hyperparathyroidism. Parathyroidectomy prolongs the time to first recurrence and decreases the number of re-recurrences over time but does not eliminate recurrences. Observation may also be a reasonable approach in selected patients.

Mortality after surgery for primary hyperparathyroidism: results from a nationwide cohort.

BACKGROUND: Contemporary patients with primary hyperparathyroidism are often diagnosed with mildly raised serum calcium levels. Previous studies have reported increased mortality in patients with primary hyperparathyroidism. This retrospective cohort study aimed to examine whether contemporary patients operated for primary hyperparathyroidism have higher mortality than the general population, and whether mortality in these patients is associated with serum calcium concentration, adenoma weight or multiglandular disease. METHODS: Patients from a Swedish national cohort consisting of patients registered in the Scandinavian Quality Register for Thyroid, Parathyroid, and Adrenal Surgery 2003-2013, were matched with population controls. The National Patient Register, the Swedish Cause of Death Register, and socioeconomic data were cross-linked. End of follow-up was 10 years after surgery, 31 December 2015, or emigration. Mortality was analysed by standardized mortality ratio, Kaplan-Meier survival estimates, and univariable and multivariable Cox regression. Multiple imputation by chained equations was performed on missing data. RESULTS: After exclusions, there were 5009 patients with primary hyperparathyroidism and 14 983 controls. Multivariable Cox regression analysis adjusted for age, sex, Charlson Co-morbidity Index, marital status, level of education, disposable income, and period of surgery showed lower mortality in patients than controls (hazard ratio (HR) 0.83, 95 per cent c.i. 0.75 to 0.92). In univariable Cox regression of mortality in patients, serum calcium concentration (mmoles per litre) was associated with mortality (HR 2.20, 1.53 to 3.16). This association remained in multivariable Cox regression after multiple imputation (HR 1.79, 1.19 to 2.70). CONCLUSION: Mortality was not increased in patients operated for primary hyperparathyroidism compared with controls in a contemporary setting. Preoperative serum calcium concentration might, however, influence survival.

Impact of parathyroidectomy on cardiovascular risk in primary hyperparathyroidism: A narrative review.

AIMS: Primary hyperparathyroidism (PHPT), one of the most frequent endocrine disorders, is not only associated with bone and kidney disorders but also with increased cardiovascular risk. This cardiovascular risk is not part of the indication for surgery owing to discordant evidence of the effects of parathyroidectomy (PTX), especially in mild PHPT which is the most common presentation of PHPT. This literature review focuses on the effects of PTX on the cardiovascular risk in PHPT. The MEDLINE database was searched via the PubMed interface, selecting relevant articles published after 1990 in English. DATA SYNTHESIS: In the most recent series, PTX appeared to have a positive impact on cardiovascular morbidity and mortality. Surgery improves arterial hypertension, markers of glucose homeostasis, vascular and cardiac remodeling and electrocardiographic impairments due to classical PHPT. However, the results of surgery on mild PHPT are conflicting. CONCLUSIONS: PTX seems to improve cardiovascular risk in patients presenting the classical form of PHPT. This improvement is correlated with preoperative serum calcium and/or PTH level, depending on the cardiovascular risk factor. However, many aspects of this improvement are not fully understood. Future studies should assess the effects of PTX on nocturnal hypertension, cardiac morphology and functions. The results for mild PHPT are conflicting owing to the limited size of the cohorts included in studies and the lack of randomized trials. Surgery is not currently recommended for patients presenting mild PHPT based on the cardiovascular risk and more studies are needed to better understand the interest of PTX on cardiovascular outcomes.

Predictors of Nephrolithiasis, Osteoporosis, and Mortality in Primary Hyperparathyroidism.

CONTEXT: Primary hyperparathyroidism (PHPT) has a prevalence of 0.86% and is associated with increased risk of nephrolithiasis and osteoporosis. PHPT may also be associated with increased risk of cardiovascular disease and mortality. OBJECTIVE: To identify risk factors for nephrolithiasis, osteoporosis, and mortality in PHPT. DESIGN: Retrospective cohort study. SETTING: University teaching hospital. PATIENTS: Presented with PHPT between 2006 and 2014 (n = 611). MAIN OUTCOME MEASURE: Assessment of nephrolithiasis, osteoporosis, and mortality. RESULTS: Of patients with PHPT, 13.9% had nephrolithiasis. Most had previously documented stone disease, and only 4.7% of asymptomatic patients who were screened for renal stones had calculi identified, not very dissimilar to the rate in the non-PHPT population. Younger age (P < 0.001) and male sex (P = 0.003) were the only independent predictors of nephrolithiasis. Of patients with dual-energy X-ray absorptiometry data, 48.4% had osteoporosis (223/461). Older age (P < 0.001), lower body mass index (P = 0.002), and lower creatinine (P = 0.006) were independently associated with a diagnosis of osteoporosis. Higher PTH was independently associated with lower z score at the hip (P = 0.009); otherwise, calcium and PTH were not associated with lower z scores. Mortality in PHPT was associated with older age (P < 0.008), social deprivation (P = 0.028), and adjusted calcium (P = 0.009) but not independently with PTH at diagnosis. CONCLUSIONS: Screening for nephrolithiasis has a low yield, particularly in lower risk patients. Osteoporosis is only minimally associated with biochemical indices of PHPT. Mortality is associated with higher calcium (and possibly vitamin D deficiency) but not PTH.

Morbidity in parathyroid surgery for renal disease is under reported: a comparison of outcomes with primary hyperparathyroidism.

Introduction Parathyroidectomy is considered to be a safe procedure with low morbidity. However, while this is true for primary hyperparathyroidism, whether it applies to tertiary disease is not so well documented. The aim of this study was to assess the morbidity of surgery for tertiary hyperparathyroidism compared with primary disease and to establish whether there are predictive factors for poor outcomes. Methods Data for patients subjected to parathyroidectomy during the period 2007-2015 were retrospectively analysed from a prospectively collected database. Patient age, sex, American Society of Anesthesiologists (ASA) score, renal status, extent of operation and indications for surgery were examined. The complication and mortality rate were compared and independent predictors of outcome were examined. Results A total of 1079 patients were scheduled for a parathyroidectomy during the study period of whom 158 for renal related hyperparathyroidism (renal group) and 921 for primary disease (non-renal group). There was a significantly higher complication rate in the renal parathyroid group, including a higher mortality (1.3% vs 0.1%, P = 0.011), overall complication rate (7.0% vs 2.3%, P = 0.001), surgery related complication rate (4.4% vs 1.7%, P = 0.03) and systemic complication rate (2.5% vs 0.4%, P = 0.005). In patients with ASA score ≤ 2 reoperative surgery (OR 9.25, 95% confidence interval, CI 1.41-60.75), male sex (OR 4.12, 95% CI 1.46-11.63) and renal impairment were (OR 5.86, 95% CI 1.65-20.78) were predictors of worse outcomes. In patients with ASA score ≥3 renal impairment, in addition to other variables, were not predictors of complications. Conclusions Parathyroidectomy in renal-related disease is associated with a significantly higher risk of morbidity and mortality compared with primary hyperparathyroidism.

Impact of "Tailored" Parathyroidectomy for Treatment of Primary Hyperparathyroidism in Patients with Multiple Endocrine Neoplasia Type 1.

BACKGROUND: Whether total parathyroidectomy (TPTX) or subtotal parathyroidectomy (SPTX) should be performed for primary hyperparathyroidism (PHPT) in patients with multiple endocrine neoplasia type 1 (MEN1) is controversial. At our institution, the parathyroidectomy strategy is based on the number of enlarged intraoperative parathyroid glands. We retrospectively analyzed our parathyroidectomy procedures. METHODS: Data of PHPT treatment in patients with MEN1 who underwent parathyroidectomy from 1982 to 2012 at our department were retrospectively collected. The data were grouped according to the surgical procedure: TPTX, SPTX, and less than SPTX (LPTX). TPTX or SPTX was selected based on the preoperative examination findings and number of enlarged intraoperative parathyroid glands. The outcomes were the disease-free survival (DFS) rate and postoperative calcium replacement rate based on Kaplan-Meier analysis for each type of surgical procedure. RESULTS: Forty-five patients were analyzed. The overall 5- and 10-year DFS was 91.7 and 55.8%, respectively. The 5- and 10-year DFS in each subgroup was 100.0 and 85.7% in the TPTX group, 89.4 and 57.3% in the SPTX group, and 91.6 and 57.3% in the LPTX group, respectively. The postoperative calcium replacement rate at 1 and 12 months was 91.7 and 58.3% in the TPTX group, 21.1 and 7.0% in the SPTX group, and 30.0 and 0.0% in the LPTX group, respectively. CONCLUSIONS: Although LPTX was not satisfactory as a standard procedure, both SPTX and TPTX are effective treatment methods for PHPT in patients with MEN1. The parathyroidectomy strategy should be based on intraoperative evaluation of the parathyroid glands.

Parathyroidectomy for the treatment of hyperparathyroidism: Thirty-day morbidity and mortality.

OBJECTIVES/HYPOTHESIS: Evaluate morbidity and mortality rates for patients with different levels of hyperparathyroidism (HPT) undergoing parathyroidectomy (PTX), specifically comparing primary hyperparathyroidism to secondary and tertiary hyperparathyroidism. Assess predictive factors of increased morbidity and mortality. STUDY DESIGN: Retrospective national database review. METHODS: Patients undergoing PTX, defined by Current Procedural Terminology codes 60500, 60502, 60505, for the treatment of HPT, were identified in the American College of Surgeons National Surgical Quality Improvement Program database between 2006 and 2014. Incidence of morbidity and mortality was calculated for primary, secondary, and tertiary HPT. A t test, analysis of variance, and χ2 analyses were used to assess preoperative characteristics among the three groups. RESULTS: A total of 21,267 patients were included in the analysis. There was an overall 7.2% morbidity and mortality rate, including 45 (0.21%) deaths, a 1.8% readmission rate, and a 1.9% reoperation rate, but morbidity and mortality rates were widely divergent when comparing primary to secondary and tertiary HPT. PTX resulted in a 4.9% morbidity and mortality rate for primary HPT (n = 14,500), 26.8% morbidity and mortality rate for secondary HPT (n = 1661), and 21.8% morbidity and mortality rate for tertiary HPT (n = 588). The primary reason for readmission was hypocalcemia (18.3%). Hematoma (7.2%) and postoperative hemorrhage (3.3%) were the two most common causes of reoperation. Elevated preoperative serum creatinine, alkaline phosphatase, and hypertension resulted in a higher rate of complications after PTX (P < .0001). CONCLUSIONS: Although surgery for primary HPT is an extremely common and safe procedure with minimal morbidity and mortality rates, PTX for secondary and tertiary HPT has significantly higher rates of morbidity and mortality, requiring special attention in the postoperative period. Predictive factors of poor outcomes include hypertension, elevated creatinine, and elevated alkaline phosphatase. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:528-533, 2018.

Declining Rates of Inpatient Parathyroidectomy for Primary Hyperparathyroidism in the US.

Parathyroidectomy is the only curative therapy for patients with primary hyperparathyroidism. However, the incidence, correlates and consequences of parathyroidectomy for primary hyperparathyroidism across the entire US population are unknown. We evaluated temporal trends in rates of inpatient parathyroidectomy for primary hyperparathyroidism, and associated in-hospital mortality, length of stay, and costs. We used the Healthcare Cost and Utilization Project Nationwide Inpatient Sample (NIS) from 2002-2011. Parathyroidectomies for primary hyperparathyroidism were identified using International Classification of Diseases, Ninth Revision codes. Unadjusted and age- and sex- adjusted rates of inpatient parathyroidectomy for primary hyperparathyroidism were derived from the NIS and the annual US Census. We estimated 109,583 parathyroidectomies for primary hyperparathyroidism between 2002 and 2011. More than half (55.4%) of patients were younger than age 65, and more than three-quarters (76.8%) were female. The overall rate of inpatient parathyroidectomy was 32.3 cases per million person-years. The adjusted rate decreased from 2004 (48.3 cases/million person-years) to 2007 (31.7 cases/million person-years) and was sustained thereafter. Although inpatient parathyroidectomy rates declined over time across all geographic regions, a steeper decline was observed in the South compared to other regions. Overall in-hospital mortality rates were 0.08%: 0.02% in patients younger than 65 years and 0.14% in patients 65 years and older. Inpatient parathyroidectomy rates for primary hyperparathyroidism have declined in recent years.

Hyperparathyroidism in octogenarians: A plea for ambulatory minimally invasive surgery under local anesthesia.

BACKGROUND: With the current aging of the world's population, diagnosis of primary hyperparathyroidism is being reported in increasingly older patients, with the associated functional symptomatology exacerbating the vicissitudes of age. This retrospective study was designed to establish functional improvements in older patients following parathyroid adenomectomy under local anesthesia as outpatient surgery. MATERIALS AND METHODS: Data were collected from 53 patients aged 80 years or older who underwent a minimally invasive parathyroid adenomectomy. All patients underwent a preoperative ultrasound, scintigraphy, and were monitored for the effectiveness of the procedure according to intra- and postdosage of parathyroid hormone (PTH) at 5min, 2h and 4h. RESULTS: Mean preoperative serum calcium level was 2.8mmol/L (112mg/L) and mean PTH was 180pg/ml. Thirty-eight patients were operated under local anesthesia using minimally invasive surgery and 18 patients were operated under general anesthesia. In 26 cases, the procedure was planned on an outpatient basis but could only be carried out in 21 patients. Fifty-one patients had normal serum calcium and PTH levels during the immediate postoperative period. Two patients were reoperated under general anesthesia, since immediate postoperative PTH did not return to normal. Four patients died due to reasons unrelated to hyperparathyroidism. Five patients were lost to follow-up six months to two years postsurgery. Of the 44 patients (83%) with long-term monitoring for PTH, none had recurrence of biological hyperparathyroidism. Excluding the three asymptomatic patients, 38 of the 41 symptomatic patients (93%) with long-term follow-up were considering themselves as "improved" or "strongly improved" after the intervention, notably with respect to fatigue, muscle and bone pain. Two patients (4.9%) reported no difference and one patient (2.4%) said her condition had worsened and regretted having undergone surgery. CONCLUSION: In patients 80 years or older, minimally invasive surgery as an outpatient under local anesthesia offered an excellent risk/benefit ratio given its many advantages: simplicity, speed, absence of general anesthesia, ease of monitoring, direct voice control intraoperatively, very low morbidity, effectiveness in treating primary hyperparathyroidism in more than 95% of first intention patients, and the possibility of immediate or delayed recovery in the event of multiglandular disease going unnoticed.

Mortality associated with primary hyperparathyroidism.

561 patients with primary hyperparathyroidism were followed between 1961 and 1994. Relative survival was compared to that of the Australian population studied during the same time interval. Mortality was significantly greater in the hyperparathyroid population (P<0.001). Mortality was not greater in the patients with serum calcium levels >3.00 mmol/L compared to those with a serum calcium levels <3.00 mmol/L. 113 patients did not have parathyroid surgery. Their relative survival was not significantly different from those who had surgery but their mean serum calcium and parathyroid hormone (PTH) levels were significantly lower than those who had surgery. A re-analysis of the 453 patients followed between 1972 and 2011 was carried out and a 20-year survival analysis made of those diagnosed between 1972 and 1981 and those diagnosed between 1982 and 1991. The latter group had significantly worse relative mortality than the former group (P<0.001) but was significantly older at the time of diagnosis (56.94 ± 14.83 vs 52.01 ± 13.58, P<0.001). The serum calcium and serum PTH levels were not significantly different between these two groups.

Long-term follow-up of patients with elevated serum calcium concentrations in Swedish primary care.

OBJECTIVE: To follow up patients with elevated calcium concentrations after 10 years. DESIGN: Longitudinal, using medical records, questionnaires, and clinical investigation. SETTING: Primary care in Tibro, Sweden, 2008-2010. SUBJECTS: 127 patents with elevated calcium concentrations and 254 patients with normal calcium concentrations from the local community, attending the health care centre. MAIN OUTCOME MEASURES: Diagnoses and mortality in patients with elevated calcium concentrations in 1995-2000, compared with patients with normal calcium concentrations and the background population. RESULTS: The proportion of patients for whom no underlying cause was detected decreased from 55% at baseline to 12% at follow-up. Primary hyperparathyroidism was most common in women, 23% at baseline and 36% at follow-up, and the cancer prevalence increased from 5% to 12% in patients with elevated calcium concentration. Mortality tended to be higher in men with elevated calcium concentrations compared with men with normal calcium concentrations, and was significantly higher than in the background population (SMR 2.3, 95% CI 1.3-3.8). Cancer mortality was significantly increased in men (p = 0.039). Low calcium concentrations were also associated with higher mortality (p = 0.004), compared with patients with normal calcium concentrations. CONCLUSION: This study underscores the importance of investigating patients with increased calcium concentrations suggesting that most of these patients--88% in our study--will turn out to have an underlying disease associated with hypercalcaemia during a 10-year follow-up period. Elevated calcium concentrations had a different disease pattern in men and women, with men showing increased cancer mortality in this study.

Multigland disease and slower decline in intraoperative PTH characterize mild primary hyperparathyroidism.

BACKGROUND: Many patients with primary hyperparathyroidism (PHPT) present with less severe biochemical parameters. The purpose of this study was to compare the presentation, operative findings, and outcomes of these patients with "mild" PHPT to patients with "overt" disease. METHODS: A retrospective review of a prospectively collected parathyroid database was performed to identify cases of PHPT undergoing an initial neck operation. Patients were classified as mild when either the preoperative calcium or PTH was within the normal limits. Comparisons were made with the Student's t test, Chi-squared test, or Wilcoxon rank-sum test where appropriate. Kaplan-Meier estimates were plotted for disease-free survival and compared by the log-rank test. RESULTS: Of the 1,429 patients who met inclusion criteria, 1,049 were classified as overt and 388 (27.1 %) were mild. Within the mild group, 122 (31.4 %) presented with normocalcemic PHPT and 266 (68.6 %) had a normal PTH. The two groups had similar demographics and renal function. Interestingly, the mild group had more than double the rate of kidney stones (3.1 vs. 1.3 %, p = 0.02). The mild group was less likely to localize on sestamibi scan (62.4 vs. 78.7 %, p < 0.01). Intraoperatively, more mild patients exhibited multigland disease (34.3 vs. 14.1 %, p < 0.01). When examining intraoperative PTH (IoPTH) kinetics where single adenomas were excised, the IoPTH fell at a rate of 6.9 pg/min in mild patients compared with 11.5 pg/min in the overt group (p < 0.01). Accordingly, 62.2 % of patients in the overt group and 53.3 % in the mild group were cured at 5 min postexcision (p < 0.01). There was no difference in the rates of persistence or recurrence between the groups, and disease-free survival estimates were identical (p = 0.27). CONCLUSIONS: Patients with mild PHPT were more likely to have multigland disease and a slower decline in IoPTH, but these patients can be successfully treated with surgery.

Epidemiology of primary hyperparathyroidism.

Primary hyperparathyroidism is the third most common endocrine disorder. The epidemiology of this disorder is increasingly well understood, but significant limitations still exist in our understanding of the mortality, hospitalizations, incidence, prevalence, and costs associated with this condition. These limitations are due to the small number of population-based epidemiologic studies that have evaluated this condition. Further studies will be required to fully characterize the epidemiology of primary hyperparathyroidism.

Multiple endocrine neoplasia type 1 in Japan: establishment and analysis of a multicentre database.

OBJECTIVE: Multiple endocrine neoplasia type 1 (MEN1) is less well recognized in Asian countries, including Japan, than in the West. The clinical features and optimal management of MEN1 have yet to be clarified in Japan. The aim of this study was to clarify the clinical features of Japanese patients with MEN1. DESIGN/PATIENTS: We established a MEN study group designated the 'MEN Consortium of Japan' in 2008, and asked physicians and surgeons to provide clinical and genetic information on patients they had treated. Of 680 registered patients, 560 were analysed. MEASUREMENTS: Clinical and genetic features of Japanese patients with MEN1 were examined. RESULTS: Primary hyperparathyroidism, gastroenteropancreatic neuroendocrine tumours (GEPNET), and pituitary tumours were seen in 94·4%, 58·6% and 49·6% of patients, respectively. The prevalence of insulinoma was higher in the Japanese than in the West (22%vs 10%). In addition, 37% of patients with thymic carcinoids were women, while most were men in western countries. The MEN1 mutation positive rate was 91·7% in familial cases and only 49·3% in sporadic cases. Eight novel mutations were identified. Despite the availability of genetic testing for MEN1, the application of genetic testing, especially presymptomatic diagnosis for at-risk family members appeared to be insufficient. CONCLUSIONS: We established the first extensive database for Asian patients with MEN1. Although the clinical features of Japanese patients were similar to those in western countries, there were several characteristic differences between them.

Should 'mild primary hyperparathyroidism' be reclassified as 'insidious': is it time to reconsider?

Primary hyperparathyroidism (PHPT) is a common incidental finding on routine biochemical testing, affecting around 1% of the population. The majority of individuals will be asymptomatic at diagnosis, with no evidence of end organ damage, and unless individuals aged <50 years at diagnosis, they are often considered to have 'mild' PHPT, as they do not meet published criteria for parathyroidectomy (PTX). However, there is increasing evidence that 'mild' PHPT is associated with adverse health outcomes. Long-term observational studies describing the natural history of 'mild' PHPT suggest that even though biochemistry may be relatively stable in the majority, bone mineral density (BMD) does decline after approximately 10 years of observation, whereas significant improvements in BMD are seen following PTX. Recent large European record linkage studies of 'mild PHPT' demonstrate significantly increased all-cause and cardiovascular mortality, similar to rates published for patients with PHPT who meet the NIH surgical criteria. 'Mild' PHPT was also associated with increased admissions for nonfatal cardiovascular disease, renal failure, renal stones, fractures, hypertension, psychiatric disease, cancer and diabetes, suggesting that 'insidious' PHPT may be a more appropriate description, or at least that the term 'mild' should be abandoned. Randomized controlled trials (RCTs) have begun to explore the benefits of PTX in this condition, demonstrating improvements in BMD and some psychiatric outcomes at approximately 2 years of follow-up. However, larger, adequately powered, long-term, RCTs will be required to determine whether PTX improves potential long-term morbidity and mortality in patients with PHPT who do not meet standard surgical criteria.

Cinacalcet as alternative treatment for primary hyperparathyroidism: achievements and prospects.

Primary hyperparathyroidism (pHPT), which most frequently occurs asymptomatically, is a common endocrine disease associated with increased morbidity and mortality. The newly introduced management guidelines as well as the recent availability of the first calcimimetic offer a highly promising therapeutic option for patients with pHPT. Cinacalcet, the first available calcimimetic, increases the sensitivity of the calcium-sensing receptor (CaR) to circulating serum calcium, thereby safely reducing serum calcium and PTH concentrations in patients with mild-to-moderate pHPT, intractable disease, and also parathyroid carcinoma. Cinacalcet has proved efficient in short- and long-term controls of hypercalcemia and, though bone mineral density was not improved, the available data point to cinacalcet as the treatment of choice in non-operable patients with pHPT. These results encompass a wide spectrum of disease severity. Results are pending as to whether cinacalcet decreases mortality and morbidity in pHPT, confirmation of which would conclusively recommend this drug as a valid alternative to surgery.

A record linkage study of outcomes in patients with mild primary hyperparathyroidism: the Parathyroid Epidemiology and Audit Research Study (PEARS).

CONTEXT: Primary hyperparathyroidism (PHPT) is a common endocrine disorder, but the majority of cases are perceived to be mild and remain untreated. OBJECTIVE: To determine the risk of mortality and morbidities in patients with mild PHPT. SETTING: Tayside, Scotland, 1997-2006. DESIGN: A historical, prospective, record-linkage, population-based, matched cohort study. PATIENTS: All patients with diagnosed but untreated, mild PHPT. METHOD AND OUTCOME MEASURES: Each patient with PHPT was matched with five population-based comparators, by age, gender and calendar year of PHPT diagnosis, selected from the general population. Primary outcomes were all-cause mortality, fatal and nonfatal cardiovascular disease (CVD). Secondary outcomes were cancer-related deaths and other hospital admitted morbidities, including cerebrovascular disease, fractures, hypertension, psychiatric disease, renal complications, cancer and diabetes. The risk was assessed using the Cox proportional hazards model, adjusting for confounding factors of pre-existing co-morbidities, previous prescription of bisphosphonates, socio-economic deprivation score and the probability of having a calcium check. RESULTS: Compared to the matched cohort, the risk of all cause mortality, fatal and nonfatal CVD was increased in patients with asymptomatic PHPT: adjusted hazard ratios (HR) 1·64 (95% CI: 1·43-1·87), 1·64 (95% CI: 1·32-2·04) and 2·48 (95% CI: 2·13-2·89), respectively. The risk was also increased in all secondary outcomes, with the risk of renal failure and renal stones being the highest, adjusted HRs being 13·83 (95% CI: 10·41-18·37) and 5·15 (95% CI: 2·69-9·83), respectively. CONCLUSIONS: Patients with mild PHPT had an increased risk of mortality, fatal and nonfatal CVD, and the risk of developing other co-morbidities was also increased.

Increased mortality and morbidity in mild primary hyperparathyroid patients. The Parathyroid Epidemiology and Audit Research Study (PEARS).

OBJECTIVE: To describe mortality and disease-specific morbidities in patients with mild primary hyperparathyroidism (PHPT). DESIGN: Retrospective population-based observational study. SETTING: Tayside, Scotland, from 1997 to 2006. PARTICIPANTS: Patients with mild PHPT were selected from a predefined PHPT cohort between 1997 and 2006. MAIN OUTCOME MEASURES: Standardised mortality ratios (SMRs) were examined for all-cause mortality, as well as cardiovascular and cancer mortality. Standardised morbidity ratios and standardised incidence ratios were also calculated for eleven observed co-morbidities. RESULTS: In total, there were 1683 (69.1% female) patients identified with mild PHPT in Tayside. Patients were found to have an increased risk of all-cause mortality and cardiovascular mortality (SMR-all cause 2.62, 95% CI 2.39-2.86; SMR-cardiovascular 2.68, 95% CI 2.34-3.05). Patients with mild PHPT had a significantly increased risk of developing cardiovascular and cerebrovascular disease, renal dysfunction and fractures compared to the age- and sex-adjusted general population. CONCLUSIONS: Mortality and morbidity were increased for patients with mild untreated PHPT, which is similar to more severe PHPT.