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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-2825
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 11 4260-4263
Copyright © 2006 by The Endocrine Society

Changes in Insulin Sensitivity and Glucose and Bone Metabolism over Time in Patients with Asymptomatic Primary Hyperparathyroidism

Semra Ayturk, Alptekin Gursoy, Neslihan Bascil Tutuncu, Derun Taner Ertugrul and Nilgun Guvener Demirag

Baskent University Faculty of Medicine, Department of Endocrinology and Metabolism, 06490 Ankara, Turkey

Address all correspondence and requests for reprints to: Alptekin Gursoy, M.D., Baskent University Faculty of Medicine, Department of Endocrinology and Metabolism, 5 cadde no. 48, 06490 Bahcelievler, Ankara, Turkey. E-mail: alptekingursoy{at}hotmail.com.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Objective: The clinical profile of asymptomatic primary hyperparathyroidism (PHPT) has shifted from a symptomatic disorder toward a more subtle, asymptomatic state. The lack of knowledge about the natural course of asymptomatic PHPT contributes to the controversy regarding the optimal management of these patients. The aim of this study is to evaluate the natural course of calcium and glucose metabolism abnormalities, insulin sensitivity, and bone mineral density (BMD) in subjects with asymptomatic PHPT over 18 months.

Design: The study was designed as a prospective observational examination of asymptomatic PHPT patients at baseline and at 6-month intervals for 18 months.

Methods: Our study examined 61 patients with asymptomatic PHPT and 80 healthy control subjects matched for age, sex, and body mass index. We evaluated calcium metabolism, glucose metabolism by oral glucose tolerance test, insulin sensitivity by homeostasis model assessment index, and BMD by dual-energy x-ray absorptiometry at distal radius, lumbar spine, and femur.

Results: Although in asymptomatic PHPT patients, homeostasis model assessment index at baseline was slightly higher than in controls (3.0 ± 2.2 vs. 2.2 ± 1.3; P = 0.035), the prevalence of preexisting diabetes mellitus (13.1 vs. 11.3%), undiagnosed impaired fasting glucose (34.4 vs. 30%), impaired glucose tolerance (13.1 vs. 18.8%), and newly diagnosed diabetes mellitus (4.9% vs. 2.5%) was similar. Baseline BMDs (g/cm2) at all three sites were not different between two groups. Six-month interval measurements showed no change in calcium metabolism parameters including serum calcium, phosphorus, 25-hydroxyvitamin D, and 24-h calcium excretion. No significant longitudinal adverse changes were noted in glucose metabolism, insulin sensitivity, or BMD at any site over the 18-month observation period.

Conclusions: Our follow-up of patients with asymptomatic PHPT revealed no progression of calcium and glucose metabolism abnormalities, insulin sensitivity, and loss of BMD during the 18-month study period.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
PRIMARY HYPERPARATHYROIDISM (PHPT) is being diagnosed more frequently with the development of screening tests and is a relatively common endocrine disease. Over the years, widespread screening has gradually led to higher rates of diagnosis of asymptomatic PHPT and thus earlier diagnosis of this condition. Moreover, serum calcium and PTH levels at the time of diagnosis were usually lower in asymptomatic than symptomatic subjects (1). The changing spectrum at diagnosis also increased awareness of a new variant of asymptomatic PHPT, named normocalcemic PHPT, in which the patients develop high PTH levels but have normal serum calcium (2). These patients could be regarded as being at the earliest stage of the disease.

Symptomatic, classic PHPT is well known to be associated with cardiovascular morbidity and mortality, attributed mostly to increased prevalence of hypertension, insulin resistance (IR), and dyslipidemia (3, 4, 5, 6, 7). In addition, studies showed increased prevalence of IR and diabetes mellitus (DM) in patients with PHPT (8, 9, 10, 11, 12). Moreover, limited data suggest that patients with asymptomatic PHPT may also demonstrate impaired glucose metabolism (12). If American Diabetes Association 2005 diagnostic criteria were applied to these results, the prevalence of impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and DM would be more pronounced (13).

Changing the pattern of PHPT diagnosis into a more subtle asymptomatic disorder in the vast majority of cases has brought considerable controversy to the appropriate management of these patients (14). The management dilemma is caused in part by ongoing debate about the natural course of PHPT, especially the asymptomatic variant. This study aimed to investigate the changes in calcium metabolism, insulin sensitivity, glucose metabolism abnormalities, and bone mineral density (BMD) in asymptomatic PHPT patients during an 18-month follow-up period.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
This prospective study was conducted at an endocrinology outpatient clinic. The Baskent University Ethics Committee for Human Studies approved the protocol. All participants provided informed consent.

Patients

Sixty-four consecutive patients with asymptomatic PHPT were recruited for the study. Patients were diagnosed with asymptomatic PHPT if their serum calcium concentrations were near the upper limit of normal level and/or higher than the normal level and if they had concomitant inappropriately raised serum intact PTH levels. Eighty-five control subjects were selected from patients attending the clinic for check-up purposes whose age, sex, and body mass index (BMI) were matched to the asymptomatic PHPT patients.

The diagnosis of normocalcemic PHPT was confirmed if at least three measurements showed no hypercalcemia and if all apparent causes of secondary hyperparathyroidism had been ruled out.

Individuals with conditions that could cause hypercalcemia and/or increased PTH (e.g. chronic renal and hepatic failure, abnormal thyroid function tests, vitamin D deficiency, secondary or tertiary hyperparathyroidism, and treatment with lithium) were excluded from the study.

Individuals who had a condition that could affect glucose tolerance and insulin sensitivity (e.g. those with chronic renal failure, chronic hepatic failure, or abnormal thyroid function tests) were excluded from the study. Treatments such as oral contraceptives, thiazide and loop diuretics, lithium, phenytoin, glucocorticoids, and psychotropic drugs that could affect glucose metabolism or serum and urine calcium concentrations were not given to patients during the study. Those with missing data because of noncompliance with the follow-up protocol (dropouts, n = 5 in the control group and n = 3 in the PHPT group) were not included in the statistical analysis.

Patients were questioned about the presence of nephrolithiasis, fractures, smoking, and alcohol consumption, which are known to affect calcium and glucose metabolism. They were also questioned about the family history of nephrolithiasis and DM.

Patients and control subjects who had no previous history of DM underwent the oral glucose tolerance test (OGTT). Glucose metabolism was evaluated by measurements of plasma venous blood glucose at 0, 30, 60, 90, and 120 min. Subjects followed an unrestricted diet for at least 3 d before taking the OGTT (75 g glucose). Patients were diagnosed with IFG, IGT, and DM using the American Diabetes Association 2005 criteria (13). IR was calculated by the homeostasis model assessment (HOMA) system described by Matthews et al. (15), using the following formula: [fasting plasma insulin (µIU/ml) x fasting plasma glucose (mmol/liter)] ÷ 22.5.

After initial assessment, follow-up visits were scheduled at 6-month intervals to monitor calcium metabolism, insulin sensitivity, glucose metabolism abnormalities, and BMD. At each follow-up visit, subjects were examined by OGTT, fasting serum insulin, PTH, 25-hydroxyvitamin D, calcium, phosphorus, and 24-h urinary calcium excretions. Patients diagnosed with DM were not further tested by OGTT throughout the study. Their BMD measurements were also taken. Bone density was assessed by dual-energy x-ray absorptiometry on a Hologic Elite QDR 4500 instrument (Bedford, MA). BMD measurements are given as grams per square centimeter.

Serum analysis

Plasma intact PTH level was measured with a solid-phase, two-site chemiluminescent, enzyme-labeled immunometric assay (Immulite Intact PTH; Diagnostic Products Corp., Los Angeles, CA). The upper limit of normal PTH levels was 72 pg/ml. Serum insulin levels were measured by the same technique and equipment. Vitamin D levels were assessed chromatographically by HPLC. Serum total calcium, phosphorus, and 24-h urinary calcium levels were measured by calorimetric methods. Plasma venous glucose was measured with the Hitachi Modular System (Roche Diagnostic GmbH, Roche Molecular Biochemicals, Mannheim, Germany) using the hexokinase method.

Statistical methods

All continuous data are expressed as mean ± SD. Data analysis was conducted using the Statistical Package for the Social Sciences (SPSS for Windows version 11.0; SPSS Inc., Chicago, IL). P values < 0.05 were considered statistically significant. Continuous, normally distributed variables were compared between the patient group and controls with the Student’s t test. Repeated-measures ANOVA, ANOVA, Mann-Whitney U test and {chi}2 test were performed accordingly. Tukey test was performed as a post hoc test for group comparisons after ANOVA.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Demographic, clinical, and laboratory characteristics of 61 asymptomatic PHPT patients and 80 control subjects included in the final analysis are shown in Table 1Go. Twenty asymptomatic PHPT patients (32.8%) were consistently normocalcemic, and 41 (67.2%) had persistent hypercalcemia at initial diagnosis. There were no differences between the demographic features of asymptomatic PHPT patients and the control group, except for a higher rate of family history of DM in the control group (P = 0.03).


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  		TABLE 1. Clinical features of the patients and controls

 
Calcium metabolism

The initial laboratory assessments of the studied subjects are shown in Table 2Go. During follow-up, parameters related to calcium metabolism remained significantly different between the two groups, whereas a significant increase in PTH levels was noted only in the PHPT group (Table 2Go).


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  		TABLE 2. Comparisons of patients’ values at baseline and 18 months

 
Insulin sensitivity and glucose metabolism

As shown in Table 3Go, the HOMA index was slightly higher in asymptomatic PHPT patients than in controls, both at baseline (3.0 ± 2.2 vs. 2.2 ± 1.3, P = 0.04) and 18 months later (2.9 ± 2.3 vs. 2.1 ± 1.3, P = 0.04). Glucose levels at OGTT were similar between the asymptomatic PHPT patients and the control group, both initially and at the 18-month follow-up examination. Moreover, the prevalence of preexisting DM (13.1 vs. 11.3%) and undiagnosed IFG (34.4 vs. 30%), IGT (13.1 vs. 18.8%), and DM (4.9 vs. 2.5%) was similar.


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  		TABLE 3. Glucose metabolism abnormalities and insulin sensitivity at baseline and at the end of 18 months of follow-up

 
At the end of the 18-month follow-up period, there were no significant differences in terms of the newly diagnosed cases of DM (n = 1 vs. n = 2), IFG (n = 4 vs. n = 3), or IGT (n = 0 vs. n = 1) either within each group or between the two groups (patient vs. control).

Measurements of BMD

Baseline BMDs at all three sites were not different between the two groups. When BMD measurements performed at baseline and during the 18-month period were compared, no changes in lumbar vertebrae, femoral neck and trochanter, and distal radius were observed in the PHPT group.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Although asymptomatic PHPT is frequently found in the population, the natural course of the disease, especially glucose metabolism, is still not well understood. Long-term prospective studies examining the development of IR, IFG, IGT, and DM in PHPT patients are lacking. In their cross-sectional study, Procopio et al. (12) found significantly increased IR, IGT, and DM prevalence rates in both symptomatic and asymptomatic PHPT patients compared with the control group, whereas they did not find any differences between asymptomatic and symptomatic PHPT patients.

In the present study, we studied glucose homeostasis in 61 patients with asymptomatic PHPT and 80 healthy individuals at 6-month intervals for 18 months. Although the groups had similar demographic, clinical, and laboratory features, we noticed slightly increased levels of fasting insulin and HOMA-IR in the asymptomatic PHPT group compared with the control group at the initial evaluation. Although the fasting insulin and IR status did not differ during the 18-month period in each group, differences among the groups in these parameters still persisted at the end of the study. That is, in the present study, patients with asymptomatic PHPT were more insulin resistant than the control group but did not reveal any progression of this insulin resistance status in 18-month period.

Serum calcium has long been known to have an important effect on insulin secretion in parathyroid disorders (16). Increased IR appears to result from the elevated intracellular free calcium concentrations in PHPT patients (17). Some studies have shown that patients with PHPT have long-term IR and have a risk for further DM development (10, 17). Likewise Kautzky-Willer et al. (11) have shown improvement in glucose metabolism after parathyroidectomy.

In one study, mean serum calcium and PTH levels remained constant over a 10-yr period in asymptomatic PHPT patients without surgical intervention. Mean bone mass, as measured by dual-energy x-ray absorptiometry, remained stable, and calciuria did not worsen in most of the patients. However, in approximately 27% of the patients, evidence of progressive disease, increases in hypercalcemia and hypercalciuria, and a decrease in bone mass were observed. The age of the subject appears to be the only valid predictor of disease progression, because the probability of progression is approximately three times higher in young patients (<50 yr of age) (18).

We examined calcium metabolism changes over time. We observed only a slight increase in serum PTH levels in the asymptomatic PHPT group during the 18-month follow-up period. None of the patients with normocalcemic PHPT developed hypercalcemia. No significant changes in the serum calcium and phosphorous levels, or in the 24-h urinary calcium excretions, were observed over time in both the normocalcemic and the hypercalcemic patients at baseline. We also found no deterioration of BMD at the lumbar vertebrae, femoral neck, trochanter, and distal radius in the asymptomatic PHPT group. Our observation may form the basis for rethinking the recommendations stated in the National Institutes of Health 2002 guidelines for asymptomatic patients with PHPT, which proposes twice-yearly monitoring of the serum calcium concentration, annual measurements of bone mass at all three sites (lumbar spine, hip, and forearm), and serum creatinine monitoring on a yearly basis (19). Performing serum calcium and BMD measurements at longer intervals may provide a more accurate management strategy in asymptomatic PHPT. Long-term, broad research is necessary to determine the metabolic changes in asymptomatic PHPT patients and to form a consensus for how to follow and treat these patients.

Major limitations of the present study are the short period of follow-up time and the high frequency of family history of diabetes in the healthy controls. A longer duration of time may be needed for the observation of any possible derangements in glucose metabolism in patients with PHPT. Similarly, healthy people with genetic susceptibility to diabetes may have confounded the results when compared with the genetically unsusceptible individuals in the PHPT group. Although the healthy control group was recruited randomly, their family history of diabetes was more frequent than the PHPT group. One study found that occurrence of diabetes was high among relatives of patients with PHPT (8). Previous studies have found that subjects with PHPT have increased BMI (20). However, in our study, patients and controls were apparently matched for BMI. This finding may explain the increased family history of DM in the control group and the finding of no major differences in metabolic parameters between the two groups, because a higher prevalence of glucose metabolism abnormalities was noted in the first-degree relatives of subjects with increased BMI (21). This may obviously mask a possible significant difference among groups regarding glucose homeostasis (with the exception of baseline HOMA-IR). Thus, this study forms the basis for future studies regarding the metabolic consequences of PHPT in larger groups of patients followed for longer periods of time.

Our data indicate that calcium metabolism abnormalities in asymptomatic PHPT patients are not progressive over the 18-month follow-up period. Similarly, no new glucose metabolism abnormalities developed in these patients during this time period. These factors might be considered when selecting an appropriate management plan for asymptomatic PHPT patients. Our data further support previous recommendations regarding conservative follow-up of asymptomatic PHPT patients. Although our data revealed no progression of calcium and glucose metabolism abnormalities, deterioration of insulin sensitivity, or loss of BMD during 18 months of follow-up, long-term follow-up studies would help to identify the optimal management strategy in asymptomatic PHPT patients.


   Footnotes
 
First Published Online August 8, 2006

Abbreviations: BMD, Bone mineral density; BMI, body mass index; DM, diabetes mellitus; HOMA, homeostasis model assessment; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; IR, insulin resistance; OGTT, oral glucose tolerance test; PHPT, primary hyperparathyroidism.

Received December 27, 2005.

Accepted August 2, 2006.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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  8. Taylor WH 1991 The prevalence of diabetes mellitus in patients with primary hyperparathyroidism and among their relatives. Diabet Med 8:683–687[Medline]
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  11. Kautzky-Willer A, Pacini G, Niederle B, Schernthaner G, Prager R 1992 Insulin secretion, insulin sensitivity and hepatic insulin extraction in primary hyperparathyroidism before and after surgery. Clin Endocrinol (Oxf) 37:147–155[Medline]
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