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J. Endocrinol. Invest. 35: 548-552, 2012DOI: 10.3275/7861

ABSTRACT. Objective: To investigate the prevalence of car-diovascular risk factors in patients with primary hyperpara-thyroidism (PHPT) and to determine if they are gender spe-cific. Methods: This was a retrospective case control study.Three hundred and sixty-three men and women with PHPTand 363 age-, sex-, and body mass index (BMI)-matched con-trols with benign goiter were included in the study. We doc-umented each patient’s laboratory results along with thepresence of any cardiovascular risk factors. Intra-operative-ly, the resected parathyroid adenomas were weighed andrecorded. The data are expressed as the number of patientsin each category and percentage of total patients in thatgroup and the mean±SD. Results: The prevalence of obesi-ty, hypertension, hyperlipidemia, Type 2 diabetes, and coro-nary artery disease (CAD) is higher in PHPT patients com-

pared to the general New Jersey population and age-, sex-,and BMI-matched goiter patients. Male PHPT patients tend-ed to be more obese and were found to have heavierparathyroid adenomas compared to female patients(p<0.05). Additionally, a higher percentage of male PHPTpatients were found to have higher rates of CAD (11.5%)and Type 2 diabetes (23.0%) compared to female patients(5.80% and 10.9%, respectively, p<0.05). Conclusions: Thereis a higher prevalence of metabolic disorders and CAD inPHPT patients. Male PHPT patients had larger parathyroidadenomas at the time of surgery and had a higher preva-lence of obesity, Type 2 diabetes and CAD compared to fe-male PHPT patients.(J. Endocrinol. Invest. 35: 548-552, 2012)©2012, Editrice Kurtis

INTRODUCTION

Primary hyperparathyroidism (PHPT) has become a com-monly recognized endocrine disease with the develop-ment of multichannel chemistry screening tests (1). Theclassical presentation of hyperparathyroidism has shift-ed from a symptomatic disorder of complaints charac-terized by “bones, stones, abdominal moans, andgroans” to an asymptomatic one in western countrieswith most patients now detected by routine biochemicalscreening or as part of an osteoporosis evaluation (2-4).With the majority of PHPT presenting as a more subtleand asymptomatic disorder, the appropriate manage-ment for patients with PHPT has become less defined.The controversy to determine the most appropriate man-agement for PHPT patients has led to debates regard-ing the natural history of the disease, especially theasymptomatic variant (5-9). Recent studies have sug-gested that even asymptomatic PHPT may not truly beasymptomatic and may be associated with higher rates ofother illnesses. Several authors have demonstrated anassociation between mild PHPT with obesity (10-13), in-sulin resistance (14), glucose intolerance, and a higherincidence of type 2 diabetes (14-16). Kamycheva et al.found a positive correlation between intact PTH (iPTH)levels and body weight in women (13). Epidemiological

studies suggest a greater risk of cardiovascular abnor-malities, cancer and an increased mortality among PHPTpatients (17). However, associations between PHPT andmetabolic disorders still remain controversial. Cardenas etal. does not confirm the association of PHPT with a high-er prevalence of Type 2 diabetes (18) while Werners et al.found that overall survival was not adversely affected inPHPT patients (19).There is minimal data comparing gender differences ofmetabolic disorders and cardiovascular disease in pa-tients with PHPT. We therefore sought to compare maleand female patients presenting with PHPT by evaluatingdifferences in obesity, hypertension (HTN), hyperlipi-demia, Type 2 diabetes, and coronary artery disease(CAD).

METHODS

From January 2003 to June 2010, 363 patients with PHPT (ICD9code 252.01) attended clinics of Divisions of Endocrinology andGeneral Surgery at Robert Wood Johnson Medical School. PH-PT was diagnosed by: 1) confirmed hypercalcemia (calcium>10.6 mg/dl) and elevated iPTH (>65 pg/ml); or confirmed hy-percalcemia (calcium >11.0 mg/dl) and non-suppressed iPTH(≥45 pg/ml); 2) a 24-h urine calcium level >100 mg/dl. All PHPTpatients were referred by primary care physician to Divisions ofEndocrinology and General Surgery for further evaluation andmanagement. Surgery was indicated for treatment according toNational Institutes of Health (NIH) guidelines (5, 6) or upon pa-tient’s request.A total of 363 age-, sex-, and weight-matched patients with be-nign thyroid nodule (ICD9 code of 240.0, 241.0 and 241.1) fromDivisions of Endocrinology and General Surgery and from thesame time periods were chosen as the control group. All goiter

Key-words: Cardiovascular disease, diabetes, hyperlipidemia, hyperparathyroidism,obesity.

Correspondence: X. Wang, MD, PhD, FACE, Division of Endocrinology, Metabolismand Nutrition, RWJMS-UMDNJ.

E-mail: wangx9@umdnj.edu

Accepted April 28, 2011.

First published online July 12, 2011.

Prevalence of cardiovascular risk factors in male and femalepatients with primary hyperparathyroidismD. Han1,2, S. Trooskin1, and X. Wang2

1Division of General Surgery, Deparment of Surgery; 2Division of Endocrinology, Departments of Medicine, Robert Wood JohnsonMedical School, New Brunswick, New Jersey, USA

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or thyroid nodule patients were referred by primary care physi-cian to Divisions of Endocrinology and General Surgery for fineneedle biopsies and management. Prevalence of metabolic dis-orders among the general New Jersey population was acquiredfrom the Centers for Disease Control database(www.cdc.gov/brfss. 2010) for comparison.Each patient’s chart was retrospectively reviewed and the fol-lowing data were documented: age, gender, body mass index(BMI), systolic and diastolic blood pressures (BP), fasting bloodglucose and lipid panel, calcium, 25 (OH) vitamin D [25(OH)vitD], iPTH, 24-h urine calcium levels, blood urine nitrogen (BUN)and creatinine (Cr). Patient comorbidities including HTN, hy-perlipidemia, diabetes, and CAD were also recorded. The di-agnostic criteria for each disease are as follows: HTN: BP>140/90or already on BP medications; Type 2 diabetes: fasting glucose>126 mg/dl or random glucose > 200 mg/dl or already on an-ti-diabetic medications; hyperlipidemia: total cholesterol >200 oralready on lipid-lowering medications; CAD: patient had docu-mented myocardial infarction, or cardiac catherization confirmedCAD with stent placement. All data were obtained before surge-ry or during the initial visit for patients who did not have surgery.The data are expressed as the number of patients in each cate-gory and percentage of total patients in that group and themean±SD. Relative gender differences were calculated as preva-lence of male/prevalence of female. Normally distributed mea-surements between groups were compared with Student t testand the prevalence rates between groups were compared withChi-Square tests for significance. Correlation coefficients wereused to assess relationship. A p value <0.05 was considered sig-nificant. All statistical analysis was conducted using OpenEpisoftware, version 2.3.1 (20). This study was approved by Institu-tional Review Board at Robert Wood Johnson Medical Schoolat New Brunswick, New Jersey.

RESULTS

A total of 363 patients (male 83 and female 280) with anaverage age of 56±10.9 yr were included in the presentstudy. Three hundred and thirty-four patients underwenta parathyroidectomy and 242 patients of this group werefound to have a single parathyroid adenoma with itsweight documented in grams. The mean iPTH was171±117 pg/ml, mean serum calcium was 11.0±0.76mg/dl, mean 24-h urine calcium was 381±270 mg andmean 25(OH)vitD level was 27.9±16.0 ng/ml. Eleven pa-tients with 24-h urine calcium levels close to 100 mg werefound to have low 25(OH)vitD levels. In that case, weused calcium/Cr clearance ratio >0.01 to exclude the di-agnosis of familial hypocalciuric hypercalcemia; 40.6% ofthe patients were obese with a mean BMI of 29.6±6.27kg/m2. More than half of the patients had past medicalhistories of HTN and hyperlipidemia (50.5% and 52.3%,respectively). Additionally, 13.5% of the patients hadbeen diagnosed with Type 2 diabetes and 6.95% withCAD. The prevalence of obesity, HTN, hyperlipidemia,Type 2 diabetes, and CAD among PHPT patients washigher compared to the New Jersey general population(Table 1). Since the prevalence of obesity, HTN, hyper-lipidemia, diabetes, and CAD of the general New Jerseypopulation might not be an ideal control group, we alsocompared PHPT patients with 363 age-, sex-, and BMI-matched benign goiter patients. The average age of the

363 goiter patients was found to be 56±10.4 yr and all ofthese patients had normal thyroid function tests with amean TSH level of 1.70±1.15 mIU/l and a mean free T4level of 1.22±0.21 ng/dl. There were no significant dif-ferences in terms of age or BMI between the two groupsof patients (p>0.05). However, PHPT patients were ob-served to have a higher prevalence in HTN, hyperlipi-demia, and CAD compared to goiter patients (p<0.05)(Table 2).When male PHPT patients were compared to female PH-PT patients, no significant differences were observed interms of age, serum iPTH, serum calcium, 24-h urine cal-cium, BUN/Cr and serum 25(OH)vitD levels (p>0.05)(Table 3). However, male patients tended to be moreoverweight (BMI 31.2±5.98 kg/m2 vs 29.1±6.30 kg/m2),had higher diastolic BP (81.3±9.15 mmHg vs 78.0±9.37mmHg), higher fasting glucose levels (107±22.9 mg/dlvs 99.4±21.5 mg/dl), higher triglyceride levels (176±127mg/dl vs 131±76.2 mg/dl) and lower HDL levels(45.0±14.6 mg/dl vs 58.2±16.0 mg/dl) (p<0.05). Fur-thermore, a higher percentage of male patients had doc-umented cases of kidney stones (30.3%), CAD (11.5%)and Type 2 diabetes (23.0%) compared to their femalecounterparts (19.3%, 5.80 %, and 10.9%, respectively,p<0.05) (Table 3). When male PHPT patients were com-pared with menopausal female PHPT patients (age >50yr), no significant differences were observed in terms ofthe prevalence of CAD and Type 2 diabetes (p>0.05)(Table 3).The weight of the surgically excised parathyroid adeno-ma was positively correlated with serum iPTH levels (r=0.415; p<0.001) and calcium levels (r=0.241; p<0.01).Additionally, those patients with adenoma weights ≥1 gwere found to have much higher iPTH and calcium levelscompared to patients with adenomas weighing <1 g

Table 1 - Prevalence of metabolic disorders in New Jersey generalpopulation and primary hyperparathyroidism (PHPT) patients.

Table 2 - Prevalence of metabolic disorders in primary hyper-parathyroidism (PHPT) patients and goiter patients.

PHPT patients Goiter patients

No. of patients 363 363Gender (M/F) 83/280 83/280Age (yr) 56±10.9 56±10.4BMI (kg/m2) 29.6±6.27 29.4±6.33Obesity% 40.6% 40.1%Hyperlipidemia% 52.3% 23.4%**Type 2 DM% 13.5% 18.5%CAD% 6.95% 3.58%*HTN% 50.5% 31.4%**

M: male; F: female; BMI: body mass index; DM: diabetes mellitus; CAD:coronary artery disease; HTN: hypertension. *<0.05; **<0.01.

Obesity HTN Hyperlipidemia DM CAD

NJ general population* 23.9% 28.1% 37.0% 8.7% 3.7%

PHPT patients 40.6% 50.5% 52.3% 13.5% 6.95%

*Centers for Disease Control and Prevention. Behavioral Risk FactorSurveillance System. www.cdc.gov/brfss (2010). HTN: hypertension; DM:diabetes mellitus; CAD: coronary artery disease.

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(p<0.05). It was also observed that male patients hadadenomas that weighed around 0.5 grams heavier thanthe adenomas found in female patients (1.40±1.53 g vs0.93±1.11 g, p<0.05) (Fig. 1).In regards to relative gender differences of cardiovascu-lar risk factors in the New Jersey general population,males were found to have a prevalence 6.85% greaterthan that of females in terms of obesity, 6.21% greaterin terms of HTN, 11.8% greater in terms of Type 2 dia-betes (Table 4). The relative gender differences of car-

diovascular risk factors in PHPT patients were found tobe much greater than those of the general population.Compared with female PHPT patients, male PHPT pa-tients had a prevalence 29.7% greater in terms of obesi-ty, 15.3% greater in terms of HTN, 52.6% greater in termsof Type 2 diabetes (Table 4). The relative gender differ-ence of CAD prevalence among PHPT patients wasgreater than that of the general population as well (49.6%vs 40.4%) (Table 4).

DISCUSSION

There have been substantial changes in our understand-ing of PHPT over the last few decades. While moderateand severe PHPT have remained mainly bone and min-eral disorders, accumulated data suggests that mild PH-PT may be associated with an increased risk for obesity,dyslipidemia, glucose intolerance, and diabetes (12-16).Reports have demonstrated slightly increased levels offasting insulin and homeostasis model assessment of in-sulin resistance in the asymptomatic PHPT group com-pared to a control group (14). Some epidemiologicalstudies have suggested a greater risk for cardiovascularproblems in PHPT patients (12-16). Compared with theprevalence of cardiovascular risk factors in the generalpopulation of New Jersey and age-, sex-, and BMI-matched goiter patients, our present study demonstratesthat among PHPT patients, there is a higher prevalenceof coronary cardiovascular diseases and metabolic dis-orders such as obesity, hyperlipidemia, HTN, and Type 2diabetes. Our results are thus consistent with the epi-demiological studies, which suggest a greater risk ofmetabolic disorders and cardiovascular disease amongpatients with PHPT (12-14).In the present study, we found that gender may play arole in increasing the risk for metabolic diseases in pa-tients with PHPT. This observation is consistent with thealready known fact that there is a higher cardiovascularrisk in males of the general population. However, ourstudy shows that the relative gender difference of car-diovascular risk factors among PHPT patients is muchhigher than that of the general population. This increasedgender disparity among PHPT patients may be closelyassociated with the higher BMI, fasting glucose, triglyc-erides levels and lower HDL levels observed in male PH-PT patients compared to female PHPT patients. The ac-

Table 4 - Prevalence of metabolic disorders between males andfemales in New Jersey general population and primary hyper-parathyroidism (PHPT) patients.

Table 3 - Comparison of metabolic characteristics between maleand female patients with primary hyperparathyroidism (PHPT).

Fig. 1 - Comparison of parathyroid adenoma weight betweenmale and female patients with primary hyperparathyroidism(1.40±1.53 g vs 0.93±1.11 g respectively; p<0.05).

Obesity HTN Hyperlipidemia DM CAD

NJ male* 24.8% 29.0% 40.1% 9.3% 4.7%NJ female* 23.1% 27.2% 34.3% 8.2% 2.8%Relative risk 6.85% 6.21% 14.5% 11.8% 40.4%Male PHPT patients 52.8% 57.4% 55.7% 23.0% 11.5%Female PHPT patients 37.1% 48.6% 51.4% 10.9% 5.8%Relative risk 29.7% 15.3% 7.72% 52.6% 49.6%

*Centers for Disease Control and Prevention. Behavioral Risk FactorSurveillance System. www.cdc.gov/brfss (2010). Relative risk is calculat-ed: [(Prevalence(M) – Prevalence(F))/Prevalence(M)] × 100%. HTN: hy-pertesion; DM: diabetes mellitus; CAD: coronary artery disease.

PHPT (Tot) Male Female Menopausalfemale

No. of patients 363 83 280 213

Age (yr) 56±10.9 56±11.6 56±10.7 61±6.21##

BMI 29.6±6.27 31.2±5.98 29.1±6.30* 29.2±6.22#

iPTH 171±117 188±117 166±117 162±99.2

25(OH)vitD 27.9±16.0 28.9±19.2 27.6±14.8 28.5±15.0

Serum calcium 11.0±0.76 11.1±0.72 10.9±0.77 11.0±0.77

24-h urine calcium (mg) 381±270 477±468 354±175 345±174

SBP (mmHg) 131±16.6 133±16.7 131±16.1 133±16.9

DBP (mmHg) 78.7±9.41 81.3±9.15 78.0±9.37* 78.2±9.69#

FBS (mg/dl) 101±22.0 107±22.9 99.4±21.5* 101±22.4

Total chol (mg/dl) 197±36.1 185±33.5 200±36.2* 203±34.7##

HDL (mg/dl) 55.0±16.6 45.0±14.6 58.2±16.0** 58.9±16.0##

TG (mg/dl) 142±92.6 176±127 131±76.2* 134±76.7#

LDL (mg/dl) 114±32.3 106±31.1 116±32.4 118±33.0#

BUN (mg/dl) 14.9±5.91 15.8±4.46 14.6±6.24 15.4±5.57

Cr (mg/dl) 0.94±0.67 1.07±0.20 0.91±0.75 0.88±0.28

Hyperlipidemia% 52.3% 55.7% 51.4% 57.4%

DM% 13.5% 23.0% 10.9%* 15.4%

CAD% 6.95% 11.5% 5.80%* 8.28%

HTN% 50.5% 57.4% 48.6% 56.2%

Osteoporosis% 26.1% 16.7% 28.9%* 35.5%##

Kidney stones% 21.8% 30.3% 19.3%* 17.2%#

*p<0.05: male vs female, **p<0.01: male vs female; #p<0.05: male vsmenopausal female, ##p<0.01: male vs menopausal female. BMI: body massindex; iPTH: intact PTH; 25(OH)vitD: 25(OH) vitamin D; SBP: systolic bloodpressure; DBP: diastolic blood pressure; FBS: fasting blood sugar; TG: triglyc-erides; BUN: blood urea nitrogen; Cr: creatinine; DM: diabetes mellitus;CAD: coronary artery disease; HTN: hypertension.

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tual mechanisms underlying the gender differences areunknown at the present time and deserve further inves-tigation. One possible explanation involves the role ofestrogen. Studies have reported that estrogens have pro-tective effects in PHPT patients by reducing the iPTH ef-fects of bone resorption and thus lowering the serum cal-cium by 0.5-1 mg/dl (21, 22).The chronic effects of elevated PTH levels on glucoseand lipid metabolism and its involvement in cardiovas-cular risk factors are unknown at present time. However,there is some laboratory data that does suggest a link.One study reports that PTH stimulates MCP-1 releasingin the osteoblast (23). Additionally, our recent studyshowed that MCP-1 levels tended to be higher in pa-tients with high PTH levels compared to patients withnormal PTH levels (24). This data suggests that higherPTH levels may be associated with the increase in circu-lating levels of inflammatory cytokines, like MCP-1.There are controversial issues regarding the appropriatemanagement of patients with asymptomatic or mild PH-PT. The recently revised NIH Consensus Conferenceguidelines are based on the age of patients, calcium lev-els, presence of bone disorders, and renal function (25).Our results suggest that gender should also be consid-ered when deciding the appropriate treatment optionsfor these patients due to the differences in metabolic pro-files. In addition, since males are less likely to have os-teoporosis and thus less likely to be referred for PHPTsurgery, a male patient who is referred by his primaryphysician for a surgical evaluation is likely to present withstrong indications for a surgical intervention. A parathy-roidectomy would be a one-time treatment with no needfor numerous follow-up visits or strict compliance withmedications, which are important factors to consider inmale patients since it has been shown that males are lesslikely to follow up medical treatment due to complianceissues (26). Our current study demonstrates that maleshave larger parathyroid adenomas at the time of diag-nosis. Since the adenoma weight was positively correlat-ed to serum iPTH and calcium levels, the adenomaweight might reflect the severity of disease (27). Thismight explain the higher prevalence of kidney stones,obesity, HTN, Type 2 diabetes, and CAD observed in ourmale patients.There has been debate over whether undergoing aparathyroidectomy, as opposed to medical observation,is the more appropriate course of action to take for mildPHPT patients (28-30). The fact that some reports haveshown improvements of cardiovascular risk factors afterparathyroidectomy (31, 32) suggests parathyroid opera-tion may be a very attractive option in male PHPT pa-tients who may hitherto have been considered asymp-tomatic.

LimitationsThis is a retrospective chart review study and thus avail-able data was limited in terms of accounting for all thepossible factors that may have played a role in the in-creased risk of cardiovascular disease seen in PHPT pa-tients. For example, data regarding family histories ofCAD and metabolic disorders or smoking histories of thepatients were not available. These factors are confound-

ing variables that may have altered our results. Addi-tionally, many patients were already on medications forHTN, hyperlipidemia or diabetes before visiting our clin-ic. Therefore, the documented BP, fasting glucose lev-els, and lipid panels might not accurately reflect the truelevels in PHPT patients. The possibility of selection biasmust also be addressed since all patients were referredby primary care physicians and thus more likely to pre-sent with advanced stages of the disease.

ConclusionThere is a higher prevalence of CAD and metabolic dis-orders in PHPT patients. Male PHPT patients had largerparathyroid adenomas at time of diagnosis. They alsohad a higher prevalence of kidney stones, Type 2 dia-betes and coronary cardiovascular disease. We thereforesuggest that gender should be one factor in addition toage, calcium level, bone mineral density, and renal func-tion when considering therapeutic options for patientswith mild PHPT.

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