Beneficial effects of periodontal treatment on metabolic control of hypercholesterolemia.

Background: The authors aimed to evaluate whether local periodontal therapy may influence plasma lipid levels in patients with periodontitis.

Methods: Fifty patients (31 females and 19 males, age 36-66 yr) were randomly assigned to the treatment and control groups. Lipid profile and dental variables were measured at baseline and at the end of the study in both groups.

Results: In the third month, there was a significant decrease in total and low density lipoprotein (LDL) cholesterol levels of the treatment group compared with baseline values. Also, the reduction in bleeding on probing, pocket depth, attachment loss, plaque index and gingival index were statistically significant in the treatment group.

Conclusions: The present study indicates that periodontitis causes changes in total and LDL cholesterol levels and local periodontal treatment resulted in a significant decrease in these markers. These results suggest a potential effect of periodontitis-driven systemic inflammation on lipid metabolism.

Key Words: total cholesterol, LDL cholesterol, periodontitis, inflammation, cardiovascular disease 

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Inflammation plays an important role in atherothrombogen-esis and its clinical complications. (1,2) Acute systemic or local chronic infections seem to induce changes in the plasma concentration of cytokines and hormones, which result in alteration of the lipid metabolism. (3,4) Periodontitis is a chronic infection of the periodontium which is associated with predominantly anaerobic Gram negative bacteria present on the tooth surface as microbial biofilms. Recent studies have proven that periodontal disease can produce disorders in systemic health by changing the blood chemistry with a rise in inflammatory mediators, proteins and lipids in the serum. (5-7) Periodontitis is often associated with endotoxemia and mild systemic inflammatory reactions, and periodontal pathogens have been identified in early atherosclerotic lesions. (8-10) It has also been shown to be associated with increased levels of proatherogenic plasma lipoproteins; in particular, low-density lipoprotein (LDL) cholesterol, and triglycerides. (11-14) Several case control and cohort studies have indicated that patients with periodontitis have an increased risk of cardiovascular disease (CVD) compared with subjects with a healthy periodontium, even after adjustment for established cardiovascular risk factors. (15,16) It is well known that there is a causal relationship between serum lipid levels and cardiovascular disease and serum levels of proinflammatory cytokines. Periodontitis-induced changes in immune cell function may cause metabolic disregulation of lipid metabolism through a mechanism involving proinflammatory cytokines. (17,18)

Since hyperlipidemia is a causative factor for cardiovascular diseases and contributes to the high prevalence, mortality and morbidity of these diseases, we aimed to evaluate whether local periodontal therapy may influence plasma lipid levels in patients with periodontitis.

Subjects, Materials and Methods

Subjects

Patients and controls were recruited between September 1, 2004, and August 31, 2005 from subjects who attended our internal medicine outpatient clinic with hypercholesterolemia and periodontitis. Fifty patients (31 females and 19 males, age 36-66 yr, mean age 50.3 [+ or -] 6.7 yr) who had more than 3 pockets with a probing depth [greater than or equal to]4 mm participated in the study. Patients who had any dental treatment during the previous 6 months, any antibiotic or drug treatment for hypercholesterolemia during the past 3 months, a medical history of any systemic disease (ie, cancer, rheumatoid arthritis, pregnancy, diabetes mellitus or CVD) were not included in the study. Likewise, since it would not be ethical to leave the subjects who had elevated plasma lipid levels without any intervention throughout the study period, subjects who had trigliceride levels [greater than or equal to]200 mg/dL, HDL levels <35 mg/dL, and blood fasting glucose levels [greater than or equal to]126 mg/dL were also excluded from the study. Patients who met these criteria were randomly assigned to the treatment and control groups. Forty-three of the patients were nonsmokers and 7 were current smokers. In the treatment group, 10 males and 15 females (mean age 48.92 [+ or -] 5.6) and in the control group, 25 age- and sex-matched subjects (9 males and 16 females, mean age 51.76 [+ or -] 7.6) participated in this study.

The study protocol was approved by the local Ethics Committee-Institutional Board, and was carried out in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki as revised in 2000. The study was performed in a prospective cohort design. After being informed on the purpose of the study, the patients signed informed consent forms. All participants underwent a standardized interview performed by trained personnel. Their medical history, age at diagnosis of hypercholesterolemia, history of tobacco and alcohol use, current medications, sociodemographic characteristics and lifestyle habits were recorded. In addition, information on their oral system, tooth brushing habits, presence of oral prosthesis, former diagnosis or family history of periodontitis, tooth loss, gingival inflammation, and oral hygiene was also collected. The subjects were asked to maintain their usual diet and physical exercise.

Biochemical Measurements

Serial blood samples were collected before and 3 months following therapy. Venous blood samples were obtained for the measurement of plasma total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, very low-density lipoprotein (VLDL) cholesterol and triglyceride (TG) levels at baseline and at the end of the study, both in the treatment group and in the control group. The samples were obtained after a 12-hour fasting period from an antecubital vein. Plasma lipids were determined in the university hospital laboratory, using routine enzymatic methods. To identify subjects with pathologic values, the following cut off points were used according to the laboratory's recommendation: Total cholesterol >200 mg/dL, LDL cholesterol >130 mg/dL, HDL cholesterol <35 mg/dL, VLDL cholesterol >40 mg/dL, and triglycerides >200 mg/dL.

Dental Variables and Periodontal Treatment

All subjects were examined by the same dentist. The dental variables were assessed at six different sites around each tooth at baseline and at the end of the study in both the treatment group and the control group. For the periodontal assessment; plaque index (PI), gingival index (GI), probing pocket depth (PPD), attachment level (AL), and bleeding on probing (BOP) measurements were evaluated.

At the initial visit, the oral hygiene levels and dental variables were recorded. Instructions on oral hygiene, brushing technique and the use of dental floss were given to the patients in the treatment group and were recalled at weekly intervals. When optimum oral hygiene had been obtained, supragingival scaling and polishing, followed by quadrant root planing were commenced under a local anesthetic. During the treatment period, five patients underwent an open periodontal flap debridement operation. Systemic and periodontal evaluations were repeated after three months following the periodontal treatment and the dental variables detailed above. In the control group, biochemical and periodontal evaluations were repeated after three months without applying periodontal treatment.

Statistical Analysis

Statistical analyses were performed with SPSS statistical software package (version 10.0, SPSS; Chicago, IL). All data were on a patient basis and numerical data were expressed either as mean [+ or -] SD or as a percentage in the qualitative variables. The distribution of variables was analyzed with the Kolmogorov-Smirnov test. Subject characteristics were summarized using simple descriptive statistics. The difference between means of biochemical and dental parameters obtained before and after periodontal treatment of the same group were proved for significance using the Student t test for paired samples or the nonparametric Wilcoxon Signed Ranks Test. The differences between means of biochemical and dental parameters at baseline and at the end of the study of the two groups were analyzed using Student t test for independent samples or Mann-Whitney U test. Pearson correlation coefficient was used to describe correlations between dental and biochemical variables. P-values below 0.05 were considered to indicate significance.

Results

We did not observe significant differences in subject characteristics between the two groups at baseline (Table 1). Age- and sex-matching variables were similar in both groups. No significant difference was present between the treatment and control groups regarding the smoking status, duration of hypercholesterolemia, tooth brushing habits and the number of missing teeth. All subjects completed the trial and no adverse effects were reported in either group over the study period.

The summary of the lipid levels in test and control groups at baseline and at the end of the study are shown in Table 2. No statistical significance was observed in baseline lipid levels between the two groups. The trigliceride levels of the treatment group showed no difference in the third month; however, there was a significant elevation compared with baseline levels in the control group (P < 0.05). There was no significant difference in triglyceride levels between the two groups at the end of the study. Total cholesterol and LDL cholesterol levels decreased in the third month in both groups. The reduction in the treatment group was 12.7% in total cholesterol and 25.7% in LDL, and these results were statistically significant compared with baseline values. However, the reduction in total cholesterol was 3.9% and 2.5% in LDL in the control group, and these results showed no significance. There were also significant differences in total cholesterol and LDL levels between the two groups at the end of the study (Table 2).

Periodontal clinical parameters were significantly improved at follow-up assessments. The effects of the periodontal treatment on the dental variables are indicated in Table 3. At the end of the study, bleeding on probing, pocket depth and attachment loss were reduced by about 42%, 11% and 24.5% respectively in the treatment group; whereas 10%, 7%, 0% respectively in the control group. The reduction in the treatment group was statistically significant and there were significant differences in bleeding on probing and in the pocket depth between the two groups at the end of the study, but the difference in the attachment loss was not significant (Table 3).

Plaque index of the treatment group showed statistically significant reduction in the third month. In the control group, there was also a reduction, but the difference was not significant. At the end of the study, there was a significant difference in plaque index between the two groups. The gingival index was reduced significantly both in the treatment and in the control groups in the third month compared with baseline values and the difference between the two groups was statistically significant (Table 3).

There was a significant correlation between total cholesterol and bleeding on probing at baseline and this correlation was completely lost after periodontal treatment (Fig.). We also observed significant positive correlations for the differences between the baseline and end of study values of plaque index, gingival index, bleeding on probing and total cholesterol and LDL levels. In addition, a negative correlation was found between the differences of the probing pocket depth and triglyceride and VLDL levels (P < 0.05 and P < 0.01 respectively).

Discussion

Coronary heart disease has become a public health problem and major cause of death both in developed and developing countries. (19,20) As a significant risk factor for the development of coronary heart disease, there is a great concern about the blood lipid levels. Lipid markers such as total, HDL and LDL cholesterol have assumed considerable importance in the prediction of individual future risk for cardiovascular events. (21,22) Changes in concentrations of these markers have also been associated with acute and chronic infections, and in this respect, bacterial infections have been implicated as a possible risk factor in the etiology of coronary heart disease. (5,7,23,24) The present data suggest that periodontitis may trigger lipid level alterations, perhaps by eliciting an increased systemic inflammatory burden. Periodontitis is a chronic, inflammatory, destructive disease that affects the supporting tissues of the teeth, and is often associated with enhanced concentrations of proatherogenic plasma lipids, ie, total and LDL cholesterol as well as triglycerides. (13,14,25-27) The outcomes of our study support this overall conclusion. The data of the present study indicate that periodontitis causes changes in serum total and LDL cholesterol levels.

It has been suggested that changes in dietary behavior due to reduced chewing ability and increased intake of soft high-calorie food with larger amounts of carbohydrates and fat may underlie this relationship. Moreover, environmental variables such as eating and physical activity habits, and socioeconomic conditions can interfere with the study results, since they are confounders that are difficult to control. (28-30) Although the role of periodontitis-associated dietary behavior cannot be excluded, periodontitis itself was shown to be accompanied by a proatherogenic lipid profile. (13,25,31) A possible explanation for this finding could be that the inflammatory local production of cytokines such as IL-1 or TNFa leaking from the local inflammation into the circulation and its effect on other systemic mediators such as IL-6 might induce alteration of lipid metabolism and subsequently, an increase in plasma lipids. (17,32-36) Bacterial toxins such as lipopolysaccharide, [[beta].sub.2]-glycoprotein I, and modified phospholipids can also induce changes in cholesterol concentrations. (5,31,37,38)

The results of the present study show that local periodontal treatment resulted in a significant decrease in total and LDL cholesterol levels. Bleeding on probing is a sign of acute inflammation in the gingival tissue and there was a significant correlation between total cholesterol level and bleeding on probing at baseline which was completely lost after periodontal treatment. The disappearance of the correlation between baseline cholesterol level and bleeding on probing could be a result of the positive effect of periodontal infection treatment on lipid profile. (5,39) The significant reduction of gingival index in the control group at the end of the study can be attributed to the influence of the Hawthorne effect as an unintended consequence of research participation. (40) The reduction of total and LDL cholesterol after treatment suggests a potential effect of periodontitis-driven systemic inflammation on lipid metabolism. These findings are in concordance with a recent report by Pussinen et al who reported that periodontitis is associated with a reduction of the HDL cholesterol level and that periodontal therapy results in an increase in this antiatherogenic lipid fraction. (31) However, in another study conducted by D'Aiuto et al, lipid marker changes were insignificant between standard periodontal treatment and control groups, and some reductions of total and LDL cholesterol were present only in the intensive periodontal treatment group. (41)

There have been studies which reported that periodontal treatment is associated with the reduction of proatherogenic plasma lipid levels, ie, total and LDL cholesterol as well as triglycerides in patients with severe periodontitis. (5,41) However, to date, there have been no studies reporting the effect of periodontal treatment in hyperlipidemic subjects. In the present study, we evaluated for the first time the effect of local periodontal treatment on the lipid profiles of hyperlipidemic subjects who have moderate periodontitis at the same time. Because of the small number of patients examined, caution is warranted in generalizing these data to all patients affected by periodontitis. Further investigations are needed for further exploration of the relationship among periodontitis, periodontal therapy, and lipid metabolism. Larger studies and clinical intervention trials are necessary to better define the periodontitis subjects in whom local infection causes significant systemic inflammation, and whether these findings are true or confounded by other important factors like smoking, nutrition, socioeconomic status, or age.

The observation that cardiovascular risk factors might be influenced by periodontitis may have important clinical consequences. Periodontitis may increase the risk of future cardiovascular events due to proatherogenic effects (by increasing cholesterol levels) induced in affected individuals. For this reason, it has to be discussed in the context of the high prevalence of chronic periodontitis which has an effect in up to 40% in mild forms of the disease, and in 10% in more severe forms in the adult population. (42) We conclude that such data might eventually give rise to the adoption of infection control strategies for the purpose of reducing the impact of symptomatic cardiovascular disease.

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S. Gul Oz, MD, Ozlem Fentoglu, DDS, Alpaslan Kilicarslan, MD, Gulay Sain Guven, MD, Mine Durusu Tanriover, MD, Yasar Aykac, DDS, and Tumay Sozen, MD

From Hacettepe University Faculty of Medicine, Department of Internal Medicine, and Ankara University Faculty of Dentistry, Department of Periodontology, Ankara, Turkey.

Reprint requests to Dr. S. Gul Oz, Hacettepe University Faculty of Medicine, Department of Internal Medicine, Sihhiye, 06100 Ankara, Turkey. Email: [e-mail]

The authors have no commercial or proprietary interest in any drug, device, or equipment mentioned in this article.

The study protocol was approved by the local Ethics Committee-Institutional Board and was carried out in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki as revised in 2000.

Accepted October 31, 2006.

RELATED ARTICLE: Key Points

* Periodontitis is a chronic, inflammatory, destructive disease which is often associated with enhanced concentrations of proatherogenic plasma lipids.

* Patients with periodontitis have an increased risk of cardiovascular disease.

* Local periodontal treatment resulted in a significant decrease in total and LDL cholesterol levels.

Table 1. Characteristics of the study population

                            Treatment group      Control group
Characteristic              (n = 25)             (n = 25)

Male (%)                    40                   36
Female (%)                  60                   64
Age, yr (mean [+ or -] SD)  48.92 [+ or -] 5.6   51.76 [+ or -] 7.6
Smokers (n)                  3                    4
Duration of                  5.52 [+ or -] 2.64   4.80 [+ or -] 2.66
  hypercholesterolemia,
  yr (mean [+ or -] SD)
Tooth brushing (%)
  0 time/day                 4                   12
  1 time/day                64                   72
  2 times/day               24                   16
  3 times/day                8                    0
Missing teeth (mean         12.04 [+ or -] 7.1    9.8 [+ or -] 4.1
  [+ or -] SD)

Table 2. Levels of plasma lipids at baseline and at the end of the study
in treatment and control groups and differences between baseline and end
of the study values of plasma lipids (data are given as mean [+ or -]
SD)

                             Treatment group
             Baseline               End of study            P

TG mg/dL     181.28 [+ or -] 91.79  181.28 [+ or -] 141.89  NS
TC mg/dL     244.88 [+ or -] 21.22  213.60 [+ or -] 32.59   <0.001
LDL mg/ dL   155.22 [+ or -] 19.02  115.80 [+ or -] 37.07   <0.001
HDL mg/ dL    53.40 [+ or -] 10.04   52.74 [+ or -] 11.91   NS
VLDL mg/ dL   36.25 [+ or -] 18.35   37.05 [+ or -] 29.08   NS

                             Control group
             Baseline               End of study           P

TG mg/dL     175.88 [+ or -] 54.03  195.48 [+ or -] 73.82  0.04
TC mg/dL     237.28 [+ or -] 24.20  227.88 [+ or -] 30.37  NS
LDL mg/ dL   146.63 [+ or -] 14.82  142.95 [+ or -] 19.93  NS
HDL mg/ dL    53.86 [+ or -] 11.21   50.62 [+ or -] 9.90   0.02
VLDL mg/ dL   36.77 [+ or -] 12.07   38.29 [+ or -] 14.55  NS

             Difference between groups  P

TG mg/dL     19.60 [+ or -] 19.45       NS
TC mg/dL     21.88 [+ or -] 9.16        0.02
LDL mg/ dL   35.74 [+ or -] 9.30        <0.001
HDL mg/ dL   -2.58 [+ or -] 1.87        NS
VLDL mg/ dL   0.72 [+ or -] 4.01        NS

TG, triglycerides; TC, total cholesterol; LDL, low density lipoprotein;
HDL, high density lipoprotein; VLDL, very low density lipoprotein; NS,
not significant.

Table 3. Dental variables (mean [+ or -] SD) at baseline and at the end
of the study and differences between baseline and end of the study
values (mean [+ or -] SD) of dental variables

                           Treatment group
          Baseline            End of study        P

PI        1.87 [+ or -] 0.41  0.99 [+ or -] 0.46  <0.001
GI        1.39 [+ or -] 0.25  0.97 [+ or -] 0.42  <0.001
BOP       0.62 [+ or -] 0.20  0.36 [+ or -] 0.22  <0.001
PPD (mm)  3.38 [+ or -] 0.90  2.55 [+ or -] 0.52  <0.001
AL (mm)   2.65 [+ or -] 0.94  2.36 [+ or -] 0.79  <0.001

                           Control group
          Baseline            End of study        P

PI        1.82 [+ or -] 0.52  1.69 [+ or -] 0.57  NS
GI        1.53 [+ or -] 0.37  1.31 [+ or -] 0.30  <0.01
BOP       0.62 [+ or -] 0.18  0.56 [+ or -] 0.24  NS
PPD (mm)  2.75 [+ or -] 0.77  2.79 [+ or -] 0.66  NS
AL (mm)   2.37 [+ or -] 0.62  2.23 [+ or -] 0.59  NS

          Difference between groups  P

PI        0.74 [+ or -] 0.14         <0.001
GI        0.20 [+ or -] 0.10         <0.05
BOP       0.20 [+ or -] 0.06         <0.01
PPD (mm)  0.14 [+ or -] 0.10         NS
AL (mm)   0.85 [+ or -] 0.21         <0.001

PI, plaque index; GI, gingival index; PPD, probing pocket depth; AL,
attachment level; BOP, bleeding on probing; NS, not significant.