Prevalence of calcified carotid artery atheromas on panoramic images of individuals with primary hyperparathyroidism

Abstract

Objectives:

Primary hyperparathyroidism (PHPT), affecting 1% of the population, is associated with increased cardiovascular morbidity and mortality. The presence of calcified carotid artery plaque (CCAP) on panoramic images is a validated risk indicator of future adverse cardiovascular events. We hypothesized that military veterans aged 50 years or older diagnosed with PHPT by increased parathyroid hormone and calcium levels would frequently have CCAP on their images.

Methods:

We determined the prevalence rates of CCAP on the images of patients diagnosed with PHPT and evaluated their atherogenic risk profiles, including hypertension, dyslipidaemia, diabetes and obesity. Comparisons of atherogenic risk factors were made between subjects with and without observed CCAP on their panoramic images.

Results:

Of the 60 patients (86.7% males and 13.3% females, mean age 73.2 ± 11.3 years) with PHPT, 40% had atheromas. There were no significant differences between CCAP+ and CCAP− groups in gender or race (p > 0.05). The atherogenic profile (age, body mass index, hypertension, diabetes, hyperlipidaemia) in the CCAP+ and CCAP− groups was not significantly different (p > 0.05).

Conclusions:

Calcified carotid artery atheromas are often seen on the panoramic images of patients with PHPT. Thus, dentists must be uniquely vigilant for these lesions when evaluating these studies.

Introduction

Primary hyperparathyroidism (PHPT) develops when one or more of the four parathyroid glands becomes adenomatous/hyperplastic and secretes excess parathyroid hormone (PTH).¹ Elevated levels of PTH cause a corresponding increase in serum calcium levels as osteoclasts are activated and bone resorbed, renal tubular reabsorbtion of calcium is enhanced and intestinal calcium absorption is increased. The incidental finding of hypercalcaemia on routine screening blood chemistry analysis (with subsequent substantiation of elevated PTH) in “asymptomatic” middle aged/older males (≥50 years) and post-menopausal females (ratio 1:2) is how the disorder is most commonly (80–85%) diagnosed in Western Europe and North America.² Less often encountered are “symptomatic” patients exhibiting osteoporotic fractures, nephrolithiasis and giant cell “brown” tumours of bone including the jaws.

Atherosclerosis of the coronary and carotid arteries is the cause of an unexpectedly high rate of fatal and non-fatal myocardial infarction and ischaemic stroke in individuals with PHPT independent of age, gender and presence of overt symptoms, as reported by studies conducted in Scotland, Sweden, Germany, Israel and Denmark.^3–8 The single American epidemiological study assessing this issue among patients treated in Rochester, MN, could not confirm this fact.⁹ However, a recent clinical study executed in New York City, NY, demonstrated that a significant number of individuals with PHPT, exhibited on ultrasound, had carotid artery atherosclerotic plaques with a mean thickness well above the threshold associated with doubling of risk of myocardial infarction and ischaemic stroke.¹⁰ Atherosclerotic lesions, which contain calcium, in the bifurcation and/or in the proximal component of the internal carotid artery may be detected by panoramic imaging studies. An evaluation of >1500 consecutively obtained panoramic images from older (≥50 years) American military veterans (96% males) receiving routine dentistry identified 4.2% with calcified carotid artery plaque (CCAP).¹¹ The prognostic significance of CCAP on panoramic images is confirmed by a separate study of 46 multiethnic American male military veterans, which demonstrated that such lesions significantly heralded future adverse cardiovascular and cerebrovascular events.¹²

Given that there have not been any previously reported studies evaluating panoramic images for the presence of CCAP among individuals with PHPT we undertook this project. Its specific purpose was to determine the prevalence rate of CCAP among military veterans having a diagnosis of PHPT determined by an endocrinologist because of persistently elevated PTH (≥65 pg mL⁻¹) and serum calcium (≥10.4 mg dL⁻¹). The prevalence rate of CCAP in this cadre of patients was hypothesized to be greater than that previously reported in the general population. The specific aim of the project was to identify risk factors that distinguished between the subgroups of patients with and without CCAP on their panoramic images.

Materials and methods/patients

Study design and patient sample

To address these research questions, the investigators designed and implemented a retrospective study. The study was conducted in accordance with the Declaration of Helsinki guidelines. The study protocol was approved by the Institutional Review Board (Project Coordinating Center 2013-030328) of the Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, and the need for informed consent from each subject was waived given the retrospective nature of the project and its use of deidentified patient data. The medical centre's electronic medical records and dental digital image library were accessed, and the charts of all patients aged 50 or over having a panoramic imaging study between 1 January 2000 and 30 June 2012 and a concurrent diagnosis of PHPT were reviewed.

To be included as a case subject, the individual had to have: (1) a panoramic image which viewed, at a minimum, the area of interest, 2.5 cm inferior and 2.5 cm posterior to the cortical rim of the midpoint of the mandibular angle; (2) evidence of CCAP that was jointly determined by two dentists certified by the American Board of Oral and Maxillofacial Surgery using the American Academy of Oral and Maxillofacial Radiology-sponsored training packet for identification of carotid artery calcifications on panoramic radiographs.¹³ Consistent with these guidelines, heterogeneous radio-opacities in a verticolinear orientation adjacent to or inferior to the hyoid bone, epiglottis and cervical vertebrae at, above or below the intervertebral space C3–4 were diagnosed as CCAP after ruling out confounding radio-opacities that lie in close proximity to the vessel, such as a calcified triticeous cartilage or a superior cornu of calcified thyroid cartilage.¹⁴ To enhance interobserver reliability, cases in which the two clinicians differed regarding the presence of CCAP were excluded from the study. Also excluded from the study were individuals whose medical record identified a history of vitamin D deficiency and chronic renal disease. These criteria were invoked to obviate the confounding issue of secondary hyperparathyroidism.

Study variables and data source retrieval

The primary measure was the prevalence of calcified carotid artery atheromas on the panoramic images of the subjects with PHPT. Secondary variables recorded included age, body mass index (BMI), hypertension, dyslipidaemia and diabetes mellitus. The demographic data and determination of the presence of active comorbid illnesses (determined by the list of physician-prescribed medications) were derived from the subjects' medical records.

Data analysis

Data were recorded in a deidentified fashion, entered into a standardized electronic database and imported into PASW Statistics 18, release 18.0.02009 (IBM Corporation, Somers, NY) and SAS v. 9.1 (SAS Institute Inc., Cary, NC). Descriptive statistics included measures of central tendency and dispersion for age and BMI and frequency distributions for the categorical atherosclerotic risk factor variables. Fisher exact tests were utilized to compare distributions for nominal and ordinal variables between the CCAP+ and CCAP− groups, and t-tests were used to compare means between groups for age and BMI. Logistic regression was used to predict the extent of CCAP based upon atherogenic risk factors (BMI, hypertension, dyslipidaemia and diabetes mellitus) and age and race. The α-value for each statistical comparison was 0.05.

Results

The 60 subjects selected for hyperparathyroidism ranged in age from 50 to 97 years (mean 73.2 ± 11.3 years) and were predominantly males (86.7%: 52/60). The racial distribution of the sample was 40% (24/60) African–American and the remaining 60% (36/60) was Caucasian. Most of the subjects evidenced hypertension (93.3%; 56/60) and dyslipidaemia (85%; 51/60), and diabetes mellitus was seen in 38.3% (23/60). BMI ranged from 17.9 to 50.0 with a mean BMI of 27.5 (±6.1).

CCAP was identified on images (Figure 1) of 24 subjects (40%), 4 of whom were females. Although the sample of subjects with atheromas (CCAP+) were slightly older (mean difference in age, 4.4 years), no significant differences (p > 0.05) in age, gender and race were found compared with subjects without atheromas (CCAP−).

Figure 1.

Panoramic image of a patient's right maxillofacial complex, which has been cropped, digitally enhanced with the manufacturer's provided software and evidences calcified carotid artery plaque (arrows). Note the verticolinear orientation of the opacity that lies anterior to the cervical spine

Comparisons of atherogenic risk factors found high prevalence rates for both CCAP+ and CCAP− groups for hypertension, dyslipidaemia and diabetes, with no significant differences (p > 0.05) in these rates between groups (Table 1). The mean BMI was only slightly greater in the CCAP+ group (28.1) than in the CCAP− group (27.1) (p > 0.05). The logistic regression utilizing age, race, BMI, hypertension, diabetes and dyslipidaemia to predict CCAP+/− also did not find a statistically significant relationship (Wald χ² = 6.18, p = 0.403) and only accounted for 18% of the variability (r²).

Table 1.

Comparisons of atherogenic risk factors between subjects with (CCAP+) and without (CCAP−) images showing atheromas

Atherogenic risk factors	CCAP+ (N = 24)	CCAP− (N = 36)	p-value (t or Fisher exact)
Age (years)
Mean (SD)	75.8 (10.3)	71.4 (11.7)	0.14
BMI
Mean (SD)	28.1 (10.3)	27.1 (6.6)	0.55
Hypertension (%)	100.0	88.9	0.14
Diabetes (%)	37.5	38.9	1.00
Dyslipidaemia (%)	91.7	80.6	0.29

BMI, body mass index; CCAP, calcified carotid artery plaque.

Discussion

The 40% prevalence of CCAP on panoramic images far exceeds the 3.6% reported for a general population of individuals attending a dental school clinic and 4.2% for discharged male soldiers attending a Veterans Affairs outpatient dental clinic.^11,15 The atherogenic profile of the individuals with PHPT and CCAP showed high prevalence of classic risk factors but not significantly greater than individuals with PHPT and not having CCAP. The increased cardiovascular morbidity and mortalities associated with PHPT are believed to arise from the synergistic interplay between elevated levels of PTH and calcium and proatherogenic metabolic abnormalities [i.e. diabetes, dyslipidaemia (decreased levels of high-density lipoprotein cholesterol and increased levels of total triglycerides), elevated BMI] and hypertension, which are more common than in the general population.^8,16,17 It should also be noted that a number of other studies have demonstrated the direct and independent (of classic risk factors) effects of PTH and excess calcium on increased vascular risk^18–21 by facilitating hypertension through the renin–angiotensin system and impairing vessel wall function by adversely affecting the endothelial nitric oxide synthase system.^22–25

There were a few limitations in our project. Our analysis was limited by its study population (military veterans, almost exclusively male) and by the fact that it included only those individuals with a diagnosis of PHPT who also required a panoramic image necessitated by dental disease. The study's most significant weakness, however, given its retrospective nature, was that ultrasound studies were not used to confirm the presence of CCAP on the panoramic images, thus some calcifications other than those caused by carotid atheroma may have been included. Furthermore, in this study, we have demonstrated a direct association between a diagnosis of PHPT and CCAP on the panoramic images and have suggested that this indicates enhanced risk of future adverse cardiovascular outcomes; a direct link with incident cardiovascular disease remains to be established.

In conclusion, we demonstrated for the first time that the panoramic images of patients with PHPT often exhibit calcified carotid artery atheromas. Thus, dentists caring for these patients must be uniquely vigilant for the presence of these lesions because both the medical and the dental literature documents that carotid artery calcification, irrespective of the extent of stenosis, heralds future adverse cardiovascular events (myocardial infarction and stroke).^12,26