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J Am Dent Assoc, Vol 133, No 11, 1516-1523.
© 2002 American Dental Association
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DENTISTRY & MEDICINE

The prevalence of calcified carotid artery atheromas on the panoramic radiographs of patients with type 2 diabetes mellitus



ARTHUR H. FRIEDLANDER, D.D.S., NEAL R. GARRETT, Ph.D. and DEAN C. NORMAN, M.D.


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Background. People with type 2 diabetes mellitus are disproportionately at risk of experiencing stroke, because hyperglycemia and other risk factors associated with diabetes accelerate development of cervical carotid artery atheromas. Removal of these atheromas may reduce the incidence of stroke. The authors conducted a study to ascertain if those treated without insulin (noninsulin-treated, or NIT) would have a lower prevalence of atheromas on their radiographs and a lower prevalence of risk factors than those treated with insulin (insulin-treated, or IT).

Methods. The authors evaluated the panoramic radiographs and medical records of 46 neurologically asymptomatic men (n = 34) and women (n = 12) (age range 62–77 years, mean age 68.5 years) with type 2 diabetes. They used Fisher exact test to perform a statistical comparison of the prevalence of atherogenic atheromas and risk factors between groups.

Results. The radiographs showed that 24 percent of the NIT patients and 36 percent of the IT patients had atheromas; this difference was not statistically significant (P = .52). The groups had similar risk factors—that is, high levels of glycosylated hemoglobin A, or HbA1c; smoking; hypertension; and obesity (P > .05). When compared with the 4 percent atheroma prevalence rate among healthy people of similar age, the rates were significantly higher in both the NIT (P = .02) and IT (P = .0006) patients.

Conclusion. These results demonstrate that people with type 2 diabetes, irrespective of treatment modality, have high rates of atheromas as visualized on their panoramic radiographs.

Clinical Implications. Dentists treating patients with type 2 diabetes mellitus must review their panoramic radiographs carefully for evidence of atheroma formation. Patients with atheromatous lesions must be referred to their physicians for further evaluation and treatment, because the modification of atherogenic risk factors and the surgical removal of atheromas in certain people have been shown to reduce the likelihood of stroke.

Type 2 diabetes mellitus—previously known as noninsulin-dependent diabetes or adult-onset diabetes—is a disorder of abnormal metabolism of carbohydrates, fats and proteins that arises from a combination of resistance to insulin’s action and insufficient secretion of additional insulin to compensate for this resistance. The resultant hyperglycemia and other risk factors associated with the disease cause premature atherosclerosis of the cervical portion of the carotid artery and markedly increase the incidence of ischemic stroke.1,2 Approximately 15 million U.S. adults have type 2 diabetes.3 Its prevalence increases with age; nearly one in five people in the United States older than 65 years of age have the disorder.

Dentists treating patients with type 2 diabetes mellitus must review their panoramic radiographs carefully for evidence of atheroma formation.

A previously published study demonstrated that patients with type 2 diabetes treated with insulin had a high prevalence of calcified carotid artery atheromas visible on panoramic radiographs.4 Moreover, their medical histories were heavily laden with atherogenic risk factors.4 However, the vast majority of people with type 2 diabetes mellitus have a milder form of the disease that is managed without insulin. These patients receive diet and exercise counseling with or without oral hypoglycemic medication. Thus, we undertook this study to determine if the prevalence of atheromas is less in patients whose diabetes is noninsulin-treated, or NIT, compared with patients whose diabetes is insulin-treated, or IT.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
The data for this study were derived from a randomized clinical trial evaluating the efficacy of implant-retained mandibular dentures for edentulous people with type 2 diabetes.5 The study was reviewed and approved by the Veterans Affairs Greater Los Angeles Healthcare System’s and the University of California Los Angeles’ human studies review boards, and each subject in the project signed a detailed informed consent form. We used the following inclusion criteria for the patients selected from the parent study:

– a diagnosis of type 2 diabetes mellitus based on an initial fasting plasma glucose level of 140 milligrams/deciliter or higher and/or plasma glucose level of 200 mg/dL at two hours after oral glucose challenge, in accordance with criteria established by the National Diabetes Data Group6 in 1979;
– an age of 62 years or older;
– a conventional panoramic radiograph visualizing the area 2.5 centimeters posterior and 2.5 cm inferior to the cortical rim of the midpoint of the mandibular angle.

The subjects were treated by Veterans Affairs physicians and private physicians for their diabetes by one of three methods: following a physician-prescribed diet to manage the diabetes, following a physician-prescribed diet to manage the diabetes and taking an oral hypoglycemic medication, or following a physician-prescribed diet to manage the diabetes and self-administering insulin.

All patients included in the parent study were required to be cleared for dental implant surgery, leading to exclusionary criteria that included poor metabolic control of the diabetes, as evidenced by a glycosylated hemoglobin A, or HbA1c, level greater than 13 percent; renal disease as evidenced by a creatinine level more than 1.7 mg/dL; and advanced cerebrovascular or cardiovascular disease, as evidenced by transient ischemic attacks, stroke or myocardial infarct. In addition, we excluded from the study any patients whose radiographs were of poor quality (owing to incorrect patient positioning, overexposure or underexposure, and processing errors). Application of these criteria resulted in a study population of 46 people.

We took radiographs of all patients using a standard dental panoramic radiographic system. The system was operated at 15 to 16 milliamps and a peak kilovoltage of between 64 and 73, depending on the subject’s jaw size. We processed the exposed radiographs (Kodak T-Mat G panoramic film, PAN/TMG/RA-15, 14.8 x 29.8 cm with Intensifying Screen Kodak Lanex Medium, Eastman Kodak, Rochester, N.Y.) according to the manufacturer’s directions using an automatic developer (A/T 2000, Air Techniques Inc., Hicksville, N.Y.).

We divided the study sample into two groups, 21 patients treated without insulin (the NIT group) and 25 patients treated with insulin (the IT group). We reviewed the dental and medical records of the NIT and IT groups for factors related to both diabetes and atherosclerosis. Specifically noted were hypertension as determined by self-report of physician-diagnosed hypertension; current use of an antihypertension medication; or a systolic blood pressure of more than 150 millimeters of mercury or a diastolic blood pressure of more than 90 mm Hg or both; and body mass index, or BMI (calculated as weight in kilograms divided by the square of the height in meters), with patients categorized as normal (BMI, 18.5–24.9), overweight (BMI, 25–30) or obese (BMI ≥ 30); and number of pack-years smoking history.7 Also noted were HbA1c level (percentage of HbA1c, reference range 4.8–5.9 percent) and methods used to control diabetes.

One of the authors (A.H.F.) performed all radiographic interpretations. In subdued ambient light using transmitted light from a standard viewing box and a rheostat-controlled 75-watt bulb ("hot" light), he examined the radiographs for the presence of a calcified carotid artery atheroma. To evaluate within-rater reliability, he examined a series of 104 panoramic radiographs, randomly selected from our diabetic study and from those of edentulous people of similar ages, at two sessions held more than two weeks apart in a blinded presentation. A {kappa} statistic of 0.86 (P < .0001) indicated high agreement between the two separate ratings of the same radiographs.

We conducted data analysis that consisted of using Fisher exact test to compare the prevalence rates of atheroma formation and atherogenic risk factors between the NIT and IT groups. Additionally, we performed mean comparisons (t tests) to determine which risk factors, if any, distinguished between people with diabetes who were treated without or with insulin and those who had or did not have atheroma formation.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
Comparison of NIT and IT groups. Table 1Go presents general comparisons between the NIT and IT groups. The 21 NIT patients had a mean (± standard deviation, or SD) age of 68.0 ± 4.5 years (range 62–77), which was not significantly different (P < .05) than the mean (± SD) age of 68.9 ± 3.7 years (range 62–76) for the IT group. In the NIT group, four patients were treated for their diabetes by diet alone, and 17 patients received dietary counseling and oral hypoglycemic agents.


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  		TABLE 1 COMPARISONS OF PATIENTS WITH NIT* DIABETES MELLITUS AND PATIENTS WITH IT{dagger} DIABETES MELLITUS.

 
Atheromas and risk factors. Panoramic radiographs showing calcified carotid artery disease were identified for five patients (24 percent) in the NIT group and for nine patients (36 percent) in the IT group. The prevalence of carotid artery calcifications was 13 percent less in the NIT group than in the IT group, but this difference was not statistically significant, as measured by the Fisher exact test, P = .52 (Table 1Go). Hypertension was reported in 61.9 percent of the NIT patients and 60.0 percent of the IT patients. Only 19 percent of the NIT group and 12 percent of the IT group were categorized as having a normal BMI. About one-third of both the NIT (38.1 percent) and IT (32 percent) groups were classified as obese. Both groups had similar smoking prevalence, with 57.1 percent of the NIT group and 56.0 percent of the IT group classified as smokers. The mean (± SD) number of pack-years for the smokers was 68.2 ± 57.4 years in the NIT group and 61.8 ± 41.9 years in the IT group. Mean HbA1c levels were slightly lower in the NIT patients (mean HbA1c level [± SD] of 8.61 ± 2.06 percent) than in the IT patients (mean HbA1c level of 9.44 ± 1.58 percent), but this difference was not statistically significant (P = .13).

Comparison of NIT and IT patients with atheromas. We saw no significant differences (P > .05) in people who had radiographs positive for atheromas between the NIT and IT groups for age, hypertension, BMI, smoking prevalence, number of pack-years smoked or HbA1c levels. The people with atheromas on their radiographs had similar mean ages in both the NIT (|x| [± SD] = 67.8 ± 7.5 years, range 62–77 years) and IT (|x| = 66.6 ± 3.8 years, range 65–75 years) groups (Table 2Go). In the NIT group, 60 percent of the patients with radiographically visible atheromas had hypertension, as opposed to 66.7 percent in the IT group. A slightly smaller percentage of these patients in the NIT group (60 percent) than in the IT group (89 percent) was overweight or obese. Prevalence of smoking in these patients with atheroma-positive radiographs was 40.0 percent in NIT patients and 44.4 percent in IT patients. Average number of pack-years smoked was lower in the NIT group (12.2 years) compared with those in the IT group (19.5 years). HbA1c levels among patients with atheroma-positive radiographs also were slightly lower in the NIT group (8.1 percent) than in the IT group (9.3 percent).


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  		TABLE 2 COMPARISONS OF PATIENTS WITH NIT* DIABETES AND PATIENTS WITH IT{dagger} DIABETES WITH ATHEROMAS.

 
Comparisons of patients with and without atheromas. Patients identified with atheromas on their radiographs (designated "A+") were not significantly different (P > .05) from those without atheromas (designated "A–") for measures of hypertension, BMI, smoking or HbA1c (Table 3Go). Hypertension prevalence was similar among those with (64.3 percent) and without (59.4 percent) atheromas. A slightly higher percentage of the A-patients (87.5 percent) were overweight or obese than of the A+ patients (78.5 percent). Similarly, the percentage of smokers was greater in the A- group (62.5 percent) than in the A+ group (42.9 percent). Mean number of pack-years smoked also was greater in the A- group (70.3) than in the A- group (43.4). HbA1c levels were similar in the A+ (mean = 8.9 percent) and the A– (mean = 9.1 percent) patients.


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  		TABLE 3 COMPARISONS OF PATIENTS WITH AND WITHOUT ATHEROMAS.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
People controlling their type 2 diabetes with diet alone or with a hypoglycemic agent had slightly lower prevalence (24 percent) of calcified carotid artery atheromas visible on their panoramic radiographs than did those treated by diet and insulin (36 percent). When compared with the 4 percent prevalence rate of radiographically visible atheromas in a nondiabetic group of similar age range, the prevalence rates were significantly higher in both the NIT (P = .02) and the IT (P = .0006) patients.8 The NIT and IT patients with diabetes in this study had similar high prevalence of smoking (56 percent), hypertension (61 percent) and obesity (35 percent), as well as similar levels of HbA1c, which may explain the lack of differences in atheroma rates between the two groups.

The carotid atheromas seen in both populations had a similar morphological appearance (Figures 1Go and 2Go). The atheromas varied from single to multiple discrete radiopaque calcifications. They were located within the soft tissues of the neck, 1.5 to 2.5 cm inferior-posterior to the cortical rim of the midpoint of the angle of the mandible. Their appearances and locations differentiated them from anatomical entities (stylomandibular and stylohyoid ligaments, hyoid bone, epiglottis) and pathological entities (sialoliths, phleboliths, calcified lymph nodes) that variably appear contiguous to this region.8 In view of the valuable diagnostic information in the triangle of soft tissue beneath the mandibular angle, manufacturers of panoramic systems have been encouraged by Farman and colleagues9 to reposition lettering for patient identification and for indication of the left vs. the right side so as not to hide details of carotid calcifications.



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  		Figure 1. A portion of a standard panoramic radiograph that was scanned and digitized to enhance the reader’s visualization of an atherosclerotic lesion in the left neck (arrows). The patient had type 2 diabetes mellitus and was being treated with oral hypoglycemic agents.

 


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  		Figure 2. A portion of a standard panoramic radiograph that was scanned and digitized to enhance the reader’s visualization of an atherosclerotic lesion in the left neck (arrows). The patient had type 2 diabetes mellitus and was being treated with insulin.

 
Type 2 diabetes mellitus is a disease complex with both metabolic and vascular components that accelerate the development of atherosclerotic lesions at the bifurcation of the common carotid artery and double or triple the risk of ischemic stroke.11–23 Type 2 diabetes typically appears after age 40 years and often is associated with the excessive ingestion of a high-caloric diet and reduced physical activity, the combination of which results in central/abdominal obesity. Obese people require more insulin (a condition known as hyperinsulinemia) to maintain appropriate blood glucose levels because of a decrease in insulin receptor number and function. Strained by this high demand for additional insulin, the pancreatic ß cells eventually falter, producing an insulin that is deficient in quantity and quality. This results in skeletal muscles’ cells being less able to take up circulating free fatty acids and glucose produced during the digestive process (a condition called "insulin resistance"). These free fatty acids, as well as those drained by the portal vein from visceral adipose tissue, are delivered to the liver. The liver responds by increasing its production of small, very low-density lipoproteins, or VLDLs, and low-density lipoproteins, or LDLs. The elevated levels of serum VLDLs, LDLs and glucose induce circulating monocytes to pass through the carotid vessel’s intact endothelial layer at gap junctions. The monocytes lodge in the intimal wall, where they mature into macrophages. The VLDLs and LDLs also enter the arterial wall and are oxidized because of the hyperglycemic environment.23–27 The process is magnified in people who have hypertension or who smoke, because both entities damage the endothelium and increase its permeability.28–31 The vast majority of the oxidized lipoproteins then are engulfed by the vascular wall macrophages. This process stimulates the macrophage to esterify the lipoproteins, transforming itself into a foam cell. In a mechanism less well-defined, oxidized lipoproteins also are taken up by vascular wall smooth muscle cells, which then also undergo transformation into foam cells. This accumulation of foam cells constitutes the major component of the fatty streak that ultimately becomes the atheromatous plaque.32–46 Calcium salts taken up by the lesion during the maturation process correspond to radiopacities seen on the panoramic radiographs.

Most (85 percent) strokes experienced by people with type 2 diabetes mellitus are of an ischemic nature, and two-thirds of these arise in association with the development of an atherosclerotic lesion in the region of the carotid bifurcation. The hemodynamic force of the blood passing through the atheroma-narrowed lumen disrupts the endothelium overlying the plaque and produces an ulcer that acts as the nidus for a mural thrombus. The thrombus—consisting of platelets, fibrin and cholesterol—sheds emboli that plug the small intracranial arteries that arise from the middle cerebral artery, a direct continuation of the internal carotid artery. Prolonged blockage causes cerebral infarction, the classic manifestations of a completed stroke (long-term or permanent hemiplegia or aphasia) or death.47,48

A dentist caring for a patient with a suspected atheroma on his or her radiographs should show the patient the lesion, as well as its relationship to the course of the common and internal carotid arteries and angle of the mandible.9 Such a patient also should be informed that these lesions often are markers of generalized atherosclerosis and may be associated with a future cerebrovascular accident and/or myocardial infarct.49–51 Furthermore, the patient should be given a copy of a written consultation directed to his or her primary care physician that describes the radiographic findings and suggests obtaining an ultrasound study to confirm the presence and extent of disease.52 This protocol is consistent with a dentist’s professional responsibilities to diagnose oral manifestations of systemic disease and to counsel patients properly about the importance of arranging for and following through with the consultation.53

The initial therapeutic regimen for patients with type 2 diabetes includes a diet that limits calories and saturated fats, as well as exercise, which increases energy expenditure and high-density lipoprotein, or HDL, cholesterol. In obese patients, the loss of 10 to 12 pounds usually leads to diminished insulin resistance, diminished gluconeogenesis and improved glucose-stimulated insulin secretion. This results in a rapid decline in blood glucose levels and relative normalization of the lipid profile and blood pressure.54 If diet and exercise fail, the physician may choose a medication from one of the four classes of oral antidiabetic agents. The sulfonylurea drugs (for example, tolbutamide, glyburide and glipizide) initially increase the quantity of insulin secreted in response to a given glucose concentration and, with prolonged use, increase insulin receptor density and biguanides (for example, metformin) reduce hepatic glucose production. The thiazolidinediones (for example, pioglitazone and rosiglitazone) reduce insulin resistance, and the {alpha}-glucosidase drugs (for example, acarbose and miglitol) delay the intestinal absorption of carbohydrates such as starch, sucrose and maltose. Concurrently, patients are prescribed statin medications, which block the liver’s production of VLDLs and LDLs by 25 to 70 percent. Failure to achieve desired therapeutic goals with diet and exercise or with oral agents usually signifies ß-cell failure and the need for exogenous insulin.


   CONCLUSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
The results of our study demonstrate that dentists can detect carotid atheromas and risk factors associated with diabetes-induced or -accelerated atherosclerosis and stroke during a comprehensive examination. However, in recognition of the study’s limited sample size, we are now recruiting patients for a larger prospective study. In 1995, the National Institutes of Health confirmed that the finding of advanced subclinical atherosclerosis (that is, increased vascular wall intima-media thickness, calcification or both) by noninvasive testing (by means of various imaging modalities) is helpful in identifying older people at high risk of experiencing future cardiovascular events.55 Dentists are in a unique position to use the noninvasive tool of panoramic radiography to identify those at risk of developing cardiovascular disease. Thus, the identification of an atheroma on the radiograph of a person with diabetes mellitus mandates that the patient be referred to a physician for confirmation of the presence and extent of atheromatous disease, control of risk factors and possibly the surgical removal of the carotid atheroma. Research shows that these measures reduce the incidence of both fatal and nonfatal ischemic stroke.56–58



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  		Dr. Friedlander is associate chief of staff and director of graduate medical education, Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles; director of quality assurance, Hospital Dental Service, University of California Los Angeles Medical Center; and professor in-residence, Oral and Maxillofacial Surgery, School of Dentistry, University of California Los Angeles. Address reprint requests to Dr. Friedlander at VA Greater Los Angeles Healthcare System, 11301 Wilshire Blvd., Los Angeles, Calif. 90073, e-mail "arthur.friedlander{at}med.va.gov".

 


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  		Dr. Garrett is an associate professor of advanced prosthodontics, biomaterials and hospital dentistry and director, Weintraub Center for Reconstructive Biotechnology, School of Dentistry, University of California, Los Angeles; and the director, Oral Biology Research Laboratory, Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles.

 


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  		Dr. Norman is chief of staff, Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles; and professor of medicine, School of Medicine, University of California Los Angeles.

 


   FOOTNOTES
 

The U.S. Department of Veterans Affairs Medical Research Fund funded the study described here and National Institute of Dental and Craniofacial Research grant DE 09085.


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 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
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