Clinical Endocrinology (2015) 83, 951–956
doi: 10.1111/cen.12666
ORIGINAL ARTICLE
Impaired endothelial function in patients with mild primary hyperparathyroidism improves after parathyroidectomy an†, Aysße Arduc߇, Narin Nasirog lu Imga†, Yasemin Tu € tu € ncu € §, Dilek Berker† Mazhar M. Tuna*, Bercßem A. Dog € ler¶ and Serdar Gu *Department of Metabolism, Medical Faculty of Endocrinology, Dicle University, Diyarbakir, †Department of Endocrinology and Metabolism, Ankara Numune Training and Research Hospital, Ankara, Turkey, ‡Diabetes, Endocrine and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Washington, DC, USA, §Department of Endocrinology and Metabolism, Haydarpasßa Numune Training and Research Hospital, Istanbul, and ¶Department of Metabolism, Medical Faculty of Endocrinology, Hitit University, C ß orum, Turkey
Summary Background Primary hyperparathyroidism (PHPT) is associated with cardiovascular morbidity; however, data on the reversibility of cardiovascular disease in mild primary hyperparathyroidism are conflicting. The aim of this study was to assess endothelial function in patients with mild PHPT before and after parathyroidectomy (Ptx). Methods We prospectively evaluated 53 patients with mild PHPT (Group 1; 45 women, eight men; aged 52 31 years) and 46 healthy control subjects (Group 2; 38 women, eight men; aged 46 95 years). Endothelial function was measured as flow-mediated dilation (FMD) and carotid intima-media thickness (CIMT) using Doppler ultrasonography. Patients with diabetes mellitus, coronary heart disease, impaired renal function, hyperthyroidism, hypothyroidism and a history of smoking were excluded from the study. Patients were studied at baseline and 6–12 months after the first evaluation. Results There were no differences with respect to age, gender and BMI between the two groups. Hypertension prevalence was three times higher in group 1 than in controls. % FMD was lower in group 1 than in group 2 (26 12 vs 148 96, P < 0001). CIMT was higher in patients with PHPT than controls (069 018 vs 061 012, P = 0045). This significance remained when hypertensive patients were excluded from the analysis. While FMD and CIMT improved significantly after Ptx, there were no differences in mild PHPT patients who followed without parathyroidectomy. Conclusion FMD and CIMT are impaired in patients with mild PHPT compared to controls and improved significantly after a successful Ptx. Ptx improves endothelial function in patients with mild PHPT that may lead to decreased cardiovascular morbidity and mortality. Correspondence: Mazhar M. Tuna, Dicle University Medical Faculty Endocrinology and Metabolism Division, Sur, Diyarbakır, Turkey. Tel.: +90 505 222 6556; E-mail: [email protected] © 2014 John Wiley & Sons Ltd
(Received 14 August 2014; returned for revision 3 October 2014; finally revised 6 October 2014; accepted 10 November 2014)
Introduction Primary hyperparathyroidism (PHPT) is a relatively common endocrine disorder, with prevalence estimates of 1–7 cases per 1000 adults.1,2 An increased mortality rate has been demonstrated in both unselected PHPT,3–5 and in mild PHPT.6 Despite the increased cardiovascular mortality in PHPT patients with moderate to severe hypercalcaemia, it is not known clearly whether such an increase exists in milder hypercalcaemia. However, diabetes mellitus, insulin resistance, hypertension and hyperlipidaemia, which are well-known atherosclerotic risk factors, are more prevalent in patients with mild PHPT.7 Flowmediated dilation (FMD) is a parameter used to assess endothelial function. It has been shown that impaired FMD is an early marker of atherosclerosis and is correlated with coronary endothelial dysfunction.8 Data regarding endothelial function in PHPT are conflicting and sparse in patients with mild disease.9–12 Due to its relatively higher prevalence and the lower rate of surgery for patients with mild PHPT, it is important to determine the impact of PHPT on the cardiovascular system. The aim of our study was to evaluate the endothelial function in patients with mild PHPT.
Material and methods Study design and patients We prospectively evaluated 53 patients with mild PHPT (group 1) and 46 healthy subjects (group 2) who were examined at Ankara Numune Training and Research Hospital between May 2012 and June 2013. We excluded patients with diabetes mellitus, coronary heart disease, impaired renal function, hyperthyroidism, hypothyroidism and a history of smoking. Height, 951
952 M. M. Tuna et al. weight, body mass index (BMI), and systolic and diastolic blood pressures were measured. Hypertension was defined as the presence of one of the following conditions: systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm/Hg, or a patient’s self-report of hypertension or antihypertensive medication use. All patients underwent a biochemical and hormonal examination and vascular imaging studies to determine endothelial function. Patients who met one or more 2009 National Institutes of Health Consensus Third International Workshop guidelines for parathyroidectomy (n = 35) underwent surgery. Twenty-two patients underwent surgery due to hypercalcaemia (1 mg/dl above the upper limit) and 13 due to osteoporosis. Patients who did not meet any surgical criteria (n = 14) or who declined the operation (n = 4) were followed up during the study period. The control subjects were evaluated only at baseline, but all patients with PHPT were called for re-examination. Of 35 patients, fifteen were excluded from the longitudinal analysis; 12 subjects were lost during follow-up; and three subject did not have FMD and CIMT measurements after surgery. Therefore, thirty-eight patients were re-examined for laboratory examination and vascular studies, after a mean follow-up time of 9 3 months (range 6–12 months). Laboratory analyses At baseline, venous blood samples were drawn after an overnight fast. Standard laboratory assays were used to determine fasting concentrations of serum creatinine, total cholesterol, triglycerides, LDL, HDL, glucose, albumin, total calcium and phosphate levels. A fasting blood sample was obtained for measuring uric acid, insulin, homocysteine and high sensitive CRP (hsCRP) levels. HsCRP (30 mg/l: high risk) was measured using a turbidimetric assay. Plasma intact (1–84) parathyroid hormone concentration was measured with chemiluminescent immunoassay with an Immulite 2000 (normal range: 12–65 ng/l). Plasma 25-OH vitamin D was measured by radioimmuneassay. Estimates of insulin resistance were calculated using the homoeostasis model assessment insulin resistance (HOMA-IR = basal insulin (mU/ml) 9 glucose (mg/dl)/405).13 Vascular imaging studies All studies were performed in fasting state, after at least 10 min at rest and in a quiet, temperature-controlled room. CIMT and FMD were measured using high-resolution B-mode Doppler ultrasonography by the same technician. Three measurements at three sites of the common carotid artery were averaged to assess mean CIMT. A standard protocol was used to assess FMD, according to guidelines.14 The brachial artery of the right arm was visualized longitudinally. Brachial artery diameter was determined in end-diastole. After three baseline measurements were obtained, a cuff was inflated to suprasystolic pressure (20– 50 mmHg above systolic arterial pressure) to produce ischaemia in the forearm. The cuff was deflated after three minutes, causing a reactive hyperaemia and shear stress stimulus that induced
the endothelium to release nitric oxide. After the deflation of the cuff, diameter measurements were obtained after one minute. FMD% was calculated using the formula: FMD (%) = (maximum diameter- baseline diameter)/baseline diameter 9 100. The intra-observer variabilities in our laboratory for repeated measurements of carotid IMT and FMD were identified. The two measurements for both carotid IMT and FMD were conducted by the same investigator to assess intra-observer variability in a pilot population. The mean biases for carotid IMT and FMD were found 0008 0082 (95% CI: 0090– 0074) and 0067 6590 (95% CI: 6523–6657), respectively. Ethical committee approval This study was approved by the local ethics committee of Ankara Numune Education and Research Hospital. Statistical analyses SPSS (Statistical Package for the Social Sciences, SPSS ver. 11.0 (Chicago, IL, USA)) for WINDOWS was used for statistical analyses of the data in this study. The Shapiro–Wilk test was used to test the normality of the continuous data. Normally distributed continuous data were presented as mean standard deviation; non-normally distributed continuous data were presented as median [minimum-maximum]; and categorical variables were presented as number of cases (percentage). Group comparisons were performed using Student’s t-test for normally distributed data and the Mann–Whitney U-test for non-normally distributed data. For those associations that were statistically significant, we tested several multiple regression models. Categorical variables were compared between groups using Pearson’s chi-square test. A P value
doi: 10.1111/cen.12666
ORIGINAL ARTICLE
Impaired endothelial function in patients with mild primary hyperparathyroidism improves after parathyroidectomy an†, Aysße Arduc߇, Narin Nasirog lu Imga†, Yasemin Tu € tu € ncu € §, Dilek Berker† Mazhar M. Tuna*, Bercßem A. Dog € ler¶ and Serdar Gu *Department of Metabolism, Medical Faculty of Endocrinology, Dicle University, Diyarbakir, †Department of Endocrinology and Metabolism, Ankara Numune Training and Research Hospital, Ankara, Turkey, ‡Diabetes, Endocrine and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Washington, DC, USA, §Department of Endocrinology and Metabolism, Haydarpasßa Numune Training and Research Hospital, Istanbul, and ¶Department of Metabolism, Medical Faculty of Endocrinology, Hitit University, C ß orum, Turkey
Summary Background Primary hyperparathyroidism (PHPT) is associated with cardiovascular morbidity; however, data on the reversibility of cardiovascular disease in mild primary hyperparathyroidism are conflicting. The aim of this study was to assess endothelial function in patients with mild PHPT before and after parathyroidectomy (Ptx). Methods We prospectively evaluated 53 patients with mild PHPT (Group 1; 45 women, eight men; aged 52 31 years) and 46 healthy control subjects (Group 2; 38 women, eight men; aged 46 95 years). Endothelial function was measured as flow-mediated dilation (FMD) and carotid intima-media thickness (CIMT) using Doppler ultrasonography. Patients with diabetes mellitus, coronary heart disease, impaired renal function, hyperthyroidism, hypothyroidism and a history of smoking were excluded from the study. Patients were studied at baseline and 6–12 months after the first evaluation. Results There were no differences with respect to age, gender and BMI between the two groups. Hypertension prevalence was three times higher in group 1 than in controls. % FMD was lower in group 1 than in group 2 (26 12 vs 148 96, P < 0001). CIMT was higher in patients with PHPT than controls (069 018 vs 061 012, P = 0045). This significance remained when hypertensive patients were excluded from the analysis. While FMD and CIMT improved significantly after Ptx, there were no differences in mild PHPT patients who followed without parathyroidectomy. Conclusion FMD and CIMT are impaired in patients with mild PHPT compared to controls and improved significantly after a successful Ptx. Ptx improves endothelial function in patients with mild PHPT that may lead to decreased cardiovascular morbidity and mortality. Correspondence: Mazhar M. Tuna, Dicle University Medical Faculty Endocrinology and Metabolism Division, Sur, Diyarbakır, Turkey. Tel.: +90 505 222 6556; E-mail: [email protected] © 2014 John Wiley & Sons Ltd
(Received 14 August 2014; returned for revision 3 October 2014; finally revised 6 October 2014; accepted 10 November 2014)
Introduction Primary hyperparathyroidism (PHPT) is a relatively common endocrine disorder, with prevalence estimates of 1–7 cases per 1000 adults.1,2 An increased mortality rate has been demonstrated in both unselected PHPT,3–5 and in mild PHPT.6 Despite the increased cardiovascular mortality in PHPT patients with moderate to severe hypercalcaemia, it is not known clearly whether such an increase exists in milder hypercalcaemia. However, diabetes mellitus, insulin resistance, hypertension and hyperlipidaemia, which are well-known atherosclerotic risk factors, are more prevalent in patients with mild PHPT.7 Flowmediated dilation (FMD) is a parameter used to assess endothelial function. It has been shown that impaired FMD is an early marker of atherosclerosis and is correlated with coronary endothelial dysfunction.8 Data regarding endothelial function in PHPT are conflicting and sparse in patients with mild disease.9–12 Due to its relatively higher prevalence and the lower rate of surgery for patients with mild PHPT, it is important to determine the impact of PHPT on the cardiovascular system. The aim of our study was to evaluate the endothelial function in patients with mild PHPT.
Material and methods Study design and patients We prospectively evaluated 53 patients with mild PHPT (group 1) and 46 healthy subjects (group 2) who were examined at Ankara Numune Training and Research Hospital between May 2012 and June 2013. We excluded patients with diabetes mellitus, coronary heart disease, impaired renal function, hyperthyroidism, hypothyroidism and a history of smoking. Height, 951
952 M. M. Tuna et al. weight, body mass index (BMI), and systolic and diastolic blood pressures were measured. Hypertension was defined as the presence of one of the following conditions: systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm/Hg, or a patient’s self-report of hypertension or antihypertensive medication use. All patients underwent a biochemical and hormonal examination and vascular imaging studies to determine endothelial function. Patients who met one or more 2009 National Institutes of Health Consensus Third International Workshop guidelines for parathyroidectomy (n = 35) underwent surgery. Twenty-two patients underwent surgery due to hypercalcaemia (1 mg/dl above the upper limit) and 13 due to osteoporosis. Patients who did not meet any surgical criteria (n = 14) or who declined the operation (n = 4) were followed up during the study period. The control subjects were evaluated only at baseline, but all patients with PHPT were called for re-examination. Of 35 patients, fifteen were excluded from the longitudinal analysis; 12 subjects were lost during follow-up; and three subject did not have FMD and CIMT measurements after surgery. Therefore, thirty-eight patients were re-examined for laboratory examination and vascular studies, after a mean follow-up time of 9 3 months (range 6–12 months). Laboratory analyses At baseline, venous blood samples were drawn after an overnight fast. Standard laboratory assays were used to determine fasting concentrations of serum creatinine, total cholesterol, triglycerides, LDL, HDL, glucose, albumin, total calcium and phosphate levels. A fasting blood sample was obtained for measuring uric acid, insulin, homocysteine and high sensitive CRP (hsCRP) levels. HsCRP (30 mg/l: high risk) was measured using a turbidimetric assay. Plasma intact (1–84) parathyroid hormone concentration was measured with chemiluminescent immunoassay with an Immulite 2000 (normal range: 12–65 ng/l). Plasma 25-OH vitamin D was measured by radioimmuneassay. Estimates of insulin resistance were calculated using the homoeostasis model assessment insulin resistance (HOMA-IR = basal insulin (mU/ml) 9 glucose (mg/dl)/405).13 Vascular imaging studies All studies were performed in fasting state, after at least 10 min at rest and in a quiet, temperature-controlled room. CIMT and FMD were measured using high-resolution B-mode Doppler ultrasonography by the same technician. Three measurements at three sites of the common carotid artery were averaged to assess mean CIMT. A standard protocol was used to assess FMD, according to guidelines.14 The brachial artery of the right arm was visualized longitudinally. Brachial artery diameter was determined in end-diastole. After three baseline measurements were obtained, a cuff was inflated to suprasystolic pressure (20– 50 mmHg above systolic arterial pressure) to produce ischaemia in the forearm. The cuff was deflated after three minutes, causing a reactive hyperaemia and shear stress stimulus that induced
the endothelium to release nitric oxide. After the deflation of the cuff, diameter measurements were obtained after one minute. FMD% was calculated using the formula: FMD (%) = (maximum diameter- baseline diameter)/baseline diameter 9 100. The intra-observer variabilities in our laboratory for repeated measurements of carotid IMT and FMD were identified. The two measurements for both carotid IMT and FMD were conducted by the same investigator to assess intra-observer variability in a pilot population. The mean biases for carotid IMT and FMD were found 0008 0082 (95% CI: 0090– 0074) and 0067 6590 (95% CI: 6523–6657), respectively. Ethical committee approval This study was approved by the local ethics committee of Ankara Numune Education and Research Hospital. Statistical analyses SPSS (Statistical Package for the Social Sciences, SPSS ver. 11.0 (Chicago, IL, USA)) for WINDOWS was used for statistical analyses of the data in this study. The Shapiro–Wilk test was used to test the normality of the continuous data. Normally distributed continuous data were presented as mean standard deviation; non-normally distributed continuous data were presented as median [minimum-maximum]; and categorical variables were presented as number of cases (percentage). Group comparisons were performed using Student’s t-test for normally distributed data and the Mann–Whitney U-test for non-normally distributed data. For those associations that were statistically significant, we tested several multiple regression models. Categorical variables were compared between groups using Pearson’s chi-square test. A P value
