Although dentistry has long insisted on the concept of oral health as essential to general health, as a profession we are just beginning to realize the specific role that oral diseases can play in systemic disease. The past decade has seen a growing body of studies reporting that inflammation arising from oral infections, and, in particular, those associated with destructive periodontal diseases, need not be limited to the oral cavity, but can also have significant systemic effects.

To date, the majority of studies have focused on three systemic conditions: diabetes, atherosclerosis, and delivery of preterm, low birth-weight babies. For example, the presence of periodontitis has been associated with an increased incidence of type 2 diabestes mellitus, formerly termed adult onset diabetes. In addition, decreased glycemic control has been reported for diabetic patients who also have moderate to severe periodontitis. Increased incidence of atherosclerotic complications including myocardial infarction and stroke has been reported for individuals with destructive periodontal diseases, and pregnant women with periodontitis have been reported to be at increased risk to give birth to preterm, low birth-weight babies.

What Causes the Link?
While no single underlying mechanism has been found to explain the association between destructive periodontal disease and the systemic conditions mentioned above, intensive investigations are under way to determine if such a mechanism exists, and several working hypotheses have been put forward. One potential mechanism involves the direct seeding of oral bacteria or bacterial products into the blood with subsequent vascular dissemination to distant sites such as atheromatous plaques or fetal tissues. Another potential mechanism suggests that inflammatory cells, including polymorphonuclear leukocytes and monoctyes, assume a hyper-responsive phenotype as they pass through inflamed periodontal tissues. These same cells then exhibit increased destructive activity at distant inflammatory sites. Yet another study has suggested that the association between destructive periodontal diseases and systemic diseases may actually be due to failure to adequately control for confounding variables that would confer increased risk for both diseases, such as current or past cigarette smoking.

The NYUCD Research Focus
At NYUCD we are focusing on a fourth possible mechanism that may account for the systemic effects of periodontitis: the induction of an acute phase response by destructive periodontal diseases. The acute phase response is a general systemic response triggered by infection, trauma, or malignancy. A more primitive host response than cellular or humoral immunity, the acute phase response functions to facilitate the removal of the inciting agent, such as bacterial infection, and promote healing. Components of the acute phase response include fever, neutrophilia, altered serum lipids, decreased serum iron, increased serum glucose, and induction of acute phase proteins. Acute phase proteins are synthesized mainly by the liver under the regulations of pro-inflammatory cytokines, such as IL-1, IL-6, and TNF-a that are released locally by inflammatory cells recruited to sites of infection or inflammation. In humans, the major acute phase proteins are C-reactive protein (CRP), serum amyloid A, fibrinogen and haptoglobin, whose serum concentration increases with inflammation, and albumin and transferrin, whose concentration decreases with inflammation.

CRP values are routinely monitored in hospital settings as a marker of inflammatory status. Greatly elevated CRP values (greater than 100 mg/L) are indicative of acute bacterial infections. Recently, CRP values previously regarded as “high normal” (2-10 mg/L), which may possibly reflect an underlying inflammatory process, have been found to be a major risk factor for atherosclerotic complications, including heart attack and stroke. As a group, end stage renal disease (ESRD) patients on hemodialysis maintenance therapy suffer one of the highest rates of atherosclerotic complications known. A 25 percent mortality rate was reported nationally in 1998 with 50 percent of all deaths attributed to atherosclerotic complications.

At NYUCD we are focusing on a fourth possible mechanism that may account for the systemic effects of periodontitis: the induction of an acute phase response by destructive periodontal diseases.

In contrast to the general population, altered serum lipids, including cholesterol or LDL, are not predictive of atherosclerotic complications in ESRD populations; instead, elevated CRP is the single best predictor of all causes of death, including those arising from atherosclerotic complications. However, many ESRD patients exhibit elevated CRP values without clinically apparent sources of infection or inflammation. Since an analysis of the third National Health and Nutrition Survey (NHANES III) reported that subjects with destructive periodontal disease had higher CRP values than subjects who were periodontally healthy, we investigated whether destructive periodontal diseases could contribute to elevated CRP values for a subset of this population. Serum samples from 120 consecutive ESRD patients were analyzed for serum antibody levels to six periodontal pathogens as well as a battery of acute phase proteins.

Subjects with elevated CRP values (greater than 10 mg/ml) were found to have changes in serum components consistent with an acute phase response including decreased hemoglobin, iron, and albumin values. Elevated CRP values were also associated with elevated antibody levels to P. gingivalis but not to B. forsythus, A. actinomycetemcomitans serotypes a or b, C rectus or P. intermedia. These associations remained significant after adjustment for age, duration of dialysis, ethnic/racial group, smoking, and route of vascular access. Since elevated antibody to P. gingivalis had been associated with chronic adult periodontitis by our laboratory and others, this study suggests that an acute phase response including elevated CRP values was associated with destructive periodontal diseases for a subset of the ESRD population. It’s worth noting that a primary cause for renal disease in the U.S. is type 2 diabetes, and, recently, elevated CRP values have been identified as a risk factor for the development of type 2 diabetes.

ESRD Patient Responses and the General Population
Could destructive periodontal disease also induce an acute phase response in the general population? To address this possibility, we measured the serum concentration of several acute phase proteins in samples from an earlier risk assessment study that examines a group of clinical, demographic, immunologic, and microbiologic variables for destructive periodontal disease status and progression. Periodontally diseased subjects were found to have increased glucose, cholesterol and LDL, and decreased HDL and iron values when compared to periodontally healthy subjects. In addition, elevated CRP, glucose, and cholesterol values were found in subjects whose periodontal disease progressed, as evidenced by the loss of periodontal connective tissue attachment over the two-month study protocol. These results suggest that in the general as well as ESRD populations, destructive periodontal diseases are associated with changes in serum components that are consistent with an acute phase response, including the elevation of CRP values.

Additional prospective and interceptive studies will be required to determine whether the induction of an acute phase response is the mechanistic link between destructive periodontal diseases and systemic diseases. At present we are conducting a multicenter study to determine whether initial periodontal therapy, consisting of oral hygiene instruction, scaling, and root planing and the local application of antibiotics will increase diabetic control in type 2 diabetic subjects who also have moderate to severe chronic adult periodontitis. Our collaborators include the Eastman Dental Institute in London, the University of Connecticut Health Center, and the Washington, D.C., Veterans Administration Hospital. Outcome variables to be measured in this study include several markers of glycemic control, such as glycosylated hemoglobin, fructosamine, and fasting blood glucose, as well as serum antibody to subgingival species and acute phase proteins including CRP. The results of this multicenter study will suggest whether treatment of periodontal infections can decrease a systemic acute phase response and provide the foundation for larger interception studies in the future.