Periodontitis and general health

Periodontal diseases are amongst the most common human chronic diseases and are responsible by a large amount for loss of teeth worldwide and poor oral health.

Today oral health promotion including control of periodontal inflammation is listed among primary prevention programmes of the WHO under the common risk factor initiative1.

The term gingivitis refers to a reversible marginal gingival inflammation triggered by dental plaque accumulation. Periodontitis (See section 1.04), on the contrary is an irreversible inflammation of the gingival tissue which, if left untreated, results in a progressive deepening of the gingival sulcus (pocket) leading to alveolar bone and eventually tooth loss2.

Prevalence reports on various forms of periodontitis confirm that at least 20% and up to 60% of the worldwide population suffer from some form of gingival inflammation3.

Bacterial challenge is an essential component in the causal pathway to gingivitis and periodontitis. However the dental biofilm is not sufficient to cause periodontal tissue destruction.

Indeed, over the last 40 years new evidence has identified a primary role of the body inflammatory response as responsible in causing tissue destruction. A variety of environmental, acquired and genetic factors can influence the inflammatory response to oral bacteria.

Recent evidence suggests that the effect of periodontitis might not be limited just to the oral cavity but it might have systemic consequences. Periodontitis has been associated not just with local tissue damage but also with a moderate systemic inflammatory response. Although the mechanisms behind this association remain unclear, periodontitis might represent one distant source of systemic inflammation. This can explain the observed increased risk of future cardiovascular diseases, impaired metabolic control in diabetes subjects, and adverse pregnancy outcomes observed in populations suffering from periodontitis.

1 http://www.who.int/oral_health/strategies/cont/en/
2 Williams RC: Periodontal disease. N Engl J Med 322:373-382, 1990
3 Dye BA: Global periodontal disease epidemiology. Periodontol 2000 58:10-25, 2012

It is more than a century that the idea of a possible connection between the mouth and the rest of the body first appeared in the medical literature.

The terms “oral sepsis” and “focal infection” first appeared at the beginning of last century and were extensively debated among dentists and physicians from 1912 to around 19501. Reports by individuals such as WD Miller, William Hunter, and Frank Billings noted that in their opinion many of the diseases of humans could be traced to specific foci of infection elsewhere in the body, such as the teeth and gums, the tonsils, or the sinuses.

The evidence supporting this theory was mainly based on case series2 and primitive animal experiments3. Nevertheless indiscriminate extractions became a common preventive strategy among dentists likewise tonsillectomy was among physicians.

With time and improvements in clinical research design and experiments, the focal infection theory collapsed, not at least because extractions of “infected” teeth proved not beneficial in treating serious systemic diseases (like rheumatism, arthritis or kidney diseases).

Then in 1989, with a series of intriguing reports from Finland, the current interest in the oral systemic connection was revamped. Dr Mattila observed in a case-control study that patients presenting with diagnosis of myocardial infarction were most likely to suffer from caries and severe periodontitis compared to a control group matched for age and gender4.

Since then, an increasing number of studies and experiments have been performed to improve our understanding on how periodontitis might affect distant parts of the body, and thus have an effect on overall health.

New evidence from animal experiments suggests a plethora of plausible mechanisms linking oral and systemic health including systemic inflammation, bacterial burden and autoimmunity. A lot of questions however remain unanswered including the role of common risk factors between oral and systemic diseases.

1 Reviewed in O'Reilly PG, Claffey NM: A history of oral sepsis as a cause of disease. Periodontol 2000 23:13-18, 2000
2 Hunter W: Oral Sepsis as a Cause of Disease. Br Med J 2:215-216, 1900
3 Billings F: Focal Infection as the Cause of General Disease. Bull N Y Acad Med 6:759-773, 1930
4 Mattila KJ, Nieminen MS, Valtonen VV, Rasi VP, Kesaniemi YA, Syrjala SL, Jungell PS, Isoluoma M, Hietaniemi K, Jokinen MJ: Association between dental health and acute myocardial infarction. BMJ 298:779-781, 1989
 

From ancient Greece with Hippocrates (400 BC) and Rome with Galen (166AD) the inter-relationship between the oral cavity and other illnesses was first reported.

It was only hundreds of years after that the debate about the oral systemic connection gained attention again. It was not a coincidence that this renewed interest collided with the modern advances in our understanding of microbes and infection (thanks to the work of Pasteur, Lister, and Koch).

In 1891 an American dentist, Miller published a classic article in the Dental Cosmos journal1 with the title “The Human Mouth as a Focus of Infection.” He reported over 100 cases of non-oral diseases which could be ascribed to a dental/oral origin.

Following Miller’s theory, in 1900 a senior English physician, William Hunter implicated poor oral hygiene and dental health as the cause of a variety of systemic diseases in a historical article published in the British Medical Journal with the title “Oral Sepsis as a Cause of Disease”2.

In 1911, Billings used the term “focal infection” to describe all sources of bacteria including teeth, tonsils, adenoids, and mastoids3. Six years later he published a retrospective survey reporting that 23% of patients were relieved of their arthritis and 46% improved their symptoms following removal of focal infections. In addition one of his associates (Rosenow) produced experimental evidence in support of this theory by inoculating bacteria obtained from patients with oral infections and reporting on distant infections4.

With the progresses in biomedical research over the following 20 years, the lack of substantial evidence and inconsistent data were soon identified and the focal infection theory started its decline. A number of physicians started to re-evaluate their approach and questioned the scientific basis of whole theory. In 1951, a review by Williams and Burket clearly stated that there was no scientific evidence to support the theory and the removal of infected foci5.

1 Miller WD. The human mouth as a focus of infection. Dental Cosmos 33:689–706, 1891
2 Hunter W: Oral Sepsis as a Cause of Disease. Br Med J 2:215-216, 1900
3 Billings F: Focal Infection as the Cause of General Disease. Bull N Y Acad Med 6:759-773, 1930
4 Rosenow EC: Studies on elective localization, J Dent Res 1:205-249, 1919
5 Williams NB, Burkett LW. Focal infection—a review. Philadelphia Med 46:1509, 1951
 

Periodontitis is a multi-factorial disease characterized by loss of the connective tissue attachment to the teeth and resorption of the alveolar bone1. The process is initiated by the accumulation of a dental plaque biofilm on the tooth surface near the gingival margin2.

Bacteria
Microbial plaque (supra and subgingival) is the crucial factor in the initiation of the gingival inflammation. Subgingival microbial plaque behaves as a biofilm or “highly organized community” which allows them to increase their virulence3. Socransky’s group demonstrated that some members of this bacterial community did not co-exist randomly but rather were closely associated in complexes when found in patients suffering from periodontitis4. Bacterial pathogens and their toxic products found within the gingival sulcus recruit a local inflammatory response.

Host response
Despite robust evidence on the role of bacterial biofilm in periodontitis, the host defense mechanisms drive the periodontal tissue destruction. This occurs as the result of excessive local production of destructive enzymes (matrix metalloproteinases) due to the increased inflammatory response5. Loss of connective tissue attachment results in the deepening of the gingival sulcus (periodontal pocket) which can progress up to the apex of the tooth rendering tooth loss inevitable. A peculiar local and systemic immune response typical of chronic inflammatory diseases is found in patients with periodontitis (including a local autoimmune reaction)6.

Management
Treatments for periodontitis aim to remove the supra and subgingival dental biofilm. Substantial improvement in gingival bleeding and reduction of the periodontal pocket depth occurs after successful hygiene therapy (from the patient and health professional). Anti-inflammatory and host-response modulators have also been added to conventional treatment to further improve the effects of periodontal therapy representing a further proof of the crucial role played by the body response to bacteria.

1 Williams RC: Periodontal disease. N Engl J Med 322:373-382, 1990
2 Page RC, Kornman KS. The pathogenesis of human periodontitis: an introduction. Periodontol 2000 14: 9-11, 1997
3 Costerton JW, Lewandowski Z, DeBeer D, Caldwell D, Korber D, James G. Biofilms, the customized microniche. J Bacteriol 176: 2137-42, 1994
4 Socransky SS, Haffajee AD, Cugini MA, Smith C, Kent RL, Jr. Microbial complexes in subgingival plaque. J Clin Periodontol 25: 134-44, 1998
5 Page RC, Offenbacher S, Schroeder HE, Seymour GJ, Kornman KS. Advances in the pathogenesis of periodontitis: summary of developments, clinical implications and future directions. Periodontol 2000 14: 216-48, 1997
6 Ebersole JL, Taubman MA, Smith DJ, Frey DE, Haffajee AD, Socransky SS. Human serum antibody responses to oral microorganisms. IV. Correlation with homologous infection. Oral Microbiol Immunol 2: 53-9, 1987
 

In health, the gingival sulcular epithelium along with innate immune molecules acts as a natural barrier system that inhibits and eliminates penetrating bacteria.

The inflamed and ulcerated epithelium found in periodontitis is vulnerable to bacteria and forms an easy port of entry. The estimated inflamed/ulcerated area found in a patient with generalized periodontitis amounts to 40cm2 (equivalent to the palm of the hand)1. An increased number of bacteria can then invade the gingival tissues and systemic circulation.

Bacteremia occur after irritation of inflamed gingiva upon tooth brushing, chewing, oral examination, and professional tooth cleaning. The microorganisms making through the blood circulation are efficiently neutralized by the immune systems within minutes (transient bacteremia) with no consequences.

Nevertheless bacteria and their virulence factors may stimulate distant sites (invade vascular tissues) and trigger a moderate systemic inflammatory response. Moreover, circulating bacterial products can trigger specific antibodies which in turn may further amplify the host inflammatory reaction.

1 Nesse W, Abbas F, van dP, I, Spijkervet FK, Dijkstra PU, Vissink A: Periodontal inflamed surface area: quantifying inflammatory burden. J Clin Periodontol 35:668-673, 2008

A series of studies have provided evidence that both acute and chronic infections of either viral or bacterial origin are linked to cardiovascular diseases or other common chronic diseases.

A plausible mechanism linking periodontitis to systemic diseases would include the possible negative role of bacteria originated from the oral cavity onto distant sites.

75% of patients suffering from periodontitis present with positive bacterial blood cultures following subgingival debridement1.

Several studies have reported the presence of bacterial DNA in samples from aortic and valvular lesions2. However, their mere existence does not necessarily prove that they have induced the lesions.

Elevated antibodies to bacteria involved with periodontitis are linked to increased risk of cardiovascular disease and diabetes. Periodontal bacteria induce a local immune response, which cross-reacts (molecular mimicry) with resident cells of the local blood vessels and trigger local and systemic inflammation.

Experiments performed in animal model of atherosclerosis confirmed a potential role of periodontal bacteria (i.e. Porphyromonas gingivalis) in accelerating the progression of vascular disease3.

1 Forner L, Larsen T, Kilian M, Holmstrup P: Incidence of bacteremia after chewing, tooth brushing and scaling in individuals with periodontal inflammation. J Clin Periodontol 33:401-407, 2006
2 Haraszthy VI, Zambon JJ, Trevisan M, Zeid M, Genco RJ: Identification of periodontal pathogens in atheromatous plaques. J Periodontol 71:1554-1560, 2000
3 Li L, Messas E, Batista EL, Jr., Levine RA, Amar S: Porphyromonas gingivalis infection accelerates the progression of atherosclerosis in a heterozygous apolipoprotein E-deficient murine model. Circulation 105: 2002
 

Pro-inflammatory molecules are significantly elevated within the gingival tissue during periodontitis1. In particular elevated concentrations of Interleukin(IL)-6, C-Reactive Protein (CRP) have been detected in the gingival fluid.

Patients with periodontitis also present consistently elevated systemic levels of CRP and IL-6 when compared with matched healthy populations. These findings corroborate the hypothesis that periodontitis triggers systemic inflammation (See below).

This chronic systemic inflammatory state could be due to: 1) the excess spill of locally produced inflammatory molecules at the gingival level, 2) due to the triggering of a distant hepatic host response (acute phase response) either by circulating bacteria or inflammatory molecules.

On average cases with periodontitis present with 1.56 mg/l more CRP than controls2. In the same systematic review, data originated from 6 clinical randomized studies demonstrated that effective periodontal treatment produced a significant reduction (on average of 0.50 mg/L) in CRP serum levels.  

Inflammation is the body’s response to an injury or infection. It usually involves swelling, redness, pain and heat at the local site.

Acute phase response (APR) includes a series of changes which occur when inflammation starts including changes in circulating proteins levels, behavioural, biochemical and nutritional changes3.

APR is the body’s rapid response to a variety of insults (i.e. trauma, infection, burn). It starts as a local increased production of molecules at the site of injury which eventually gain access to the circulation. Amplification of the local response is then obtained by the circulating inflammatory molecules targeting the liver which in turns produces a series of proteins (acute phase proteins, APP) capable of helping to contain or to clear the local insult4. 

APP are defined by their rapid increase during inflammation within 24-48 hours from the injury. C-Reactive protein (CRP) is the prototypic APP which rapidly increases following local injury.

A well-controlled APR has several protective roles: 1) preventing the spread of infectious agents and damage to nearby tissues,
2) clearing the damaged tissue and pathogens, and 3) assisting the body’s repair processes.

An uncontrolled inflammatory reaction can produce more damage than benefits. Indeed the role of chronic long-standing mild inflammation has gained interest due to its impact on the onset and progression of a number of chronic diseases such as atherosclerosis, diabetes and cancer.

Cardiovascular diseases (CVD). Inflammation is central component of the onset and progression of atherosclerosis. Circulating inflammatory molecules are predictive of future coronary heart and vascular diseases5.

Diabetes. Systemic inflammation is increased in people with diabetes due to a hyper-inflammatory status of all circulating inflammatory cells and those resident in the fat tissue6. Systemic inflammation reduces insulin sensitivity and negatively influence metabolic control in people with diabetes7.

Chronic kidney disease (CKD). Increased level of inflammatory molecules is found in people with kidney insufficiency and it is linked to faster progression of glomerular function decline8. In turn the increased inflammatory state found in people with CKD is also associated with increased progression of common inflammatory diseases (i.e. diabetes, CVD).

Osteoporosis. Inflammatory molecules modulate bone metabolism (formation and resorption). A systemic inflammatory state can shift the bone metabolism balance towards bone resorption and increase severity and progression of bone diseases including osteopenia and osteoporosis9.

Cognitive decline. Several studies have linked chronic inflammation in older adults to cognitive decline and dementia10. Higher levels of inflammatory molecules are predictive of future cognitive decline which are also associated with vascular changes similar to those responsible of complications in other common chronic diseases (i.e. diabetes, CVD).

Cancer. Several studies have established links between systemic inflammation and many types of cancer, including lymphoma, prostate, ovarian, pancreatic, colorectal and lung11. There are several mechanisms by which inflammation may contribute to carcinogenesis, including alterations in gene expression, DNA mutation, epigenetic alterations, promotion of tumor vascularization, and the expression of pro-inflammatory cytokines that have roles in cancer cell

1 Lamster IB, Novak MJ. Host mediators in gingival crevicular fluid: implications for the pathogenesis of periodontal disease. Crit Rev Oral Biol Med 3: 31-60, 1992
2 Paraskevas S, Huizinga JD, Loos BG: A systematic review and meta-analyses on C-reactive protein in relation to periodontitis. J Clin Periodontol 35: 2008
3 Baumann H, Gauldie J. The acute phase response. Immunol Today15: 74-80, 1994
4 Lawrence T, Willoughby DA, Gilroy DW: Anti-inflammatory lipid mediators and insights into the resolution of inflammation. Nat Rev Immunol 2:787-795, 2002
5 Nesse W, Abbas F, van dP, I, Spijkervet FK, Dijkstra PU, Vissink A: Periodontal inflamed surface area: quantifying inflammatory burden. J Clin Periodontol 35:668-673, 2008
6 Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, Di AE, Ingelsson E, Lawlor DA, Selvin E, Stampfer M, Stehouwer CD, Lewington S, Pennells L, Thompson A, Sattar N, White IR, Ray KK, Danesh J: Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 375:2215-2222, 2010
7 Kammoun HL, Kraakman MJ, Febbraio MA: Adipose tissue inflammation in glucose metabolism. Rev Endocr Metab Disord 15:31-44, 2014
8 Glorieux G, Cohen G, Jankowski J, Vanholder R: Platelet/Leukocyte activation, inflammation, and uremia. Semin Dial 22:423-427, 2009
9 Proff P, Romer P: The molecular mechanism behind bone remodelling: a review. Clin Oral Investig 13:355-362, 2009
10 Gorelick PB: Role of inflammation in cognitive impairment: results of observational epidemiological studies and clinical trials. Ann N Y Acad Sci 1207:155-162, 2010
11cAggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G: Inflammation and cancer: how hot is the link? Biochem Pharmacol 72:1605-1621, 2006
 

Periodontitis shares a series of common risk factors with a number of systemic diseases included in the oral-systemic connection (including cardiovascular diseases CVD, diabetes). These traditional factors represent and element of confounding. Indeed they could be responsible for the increased risk of systemic complications in patients with periodontitis rather than the gingival infectious/inflammatory response alone. For example periodontitis and CVD share in common risk factors including age, gender, socio-economic status, smoking, stress and metabolic factors.
Age: Age is an important risk factor associated with both periodontitis and CVD. Aging is a not-modifiable confounding factor in the link between periodontitis and CVD and therefore caution should be given when interpreting data from studies that did not account for age differences1.
Gender: Population studies have reported a gender effect in the association between periodontitis and risk for CVD2. However these findings have not been replicated by all investigators3.
Socioeconomic status: Although lower socioecononomic status (SES) has been associated with both higher prevalence of CVD and periodontitis4, most studies evaluating the relationship between SES and periodontitis in the context of CVD development have reported an attenuated association between these two factors.
Smoking: Cigarettes smoking does represent the most common and plausible confounding factor in the link between periodontitis and most chronic systemic disease. Large case–control studies have however demonstrated that the association between periodontitis and CVD persist in never smokers5. However the statistical adjustment and incomplete assessment of quantity of cigarettes smoking performed by many researchers is often not sufficient to confirm the doubts about the association between periodontitis and systemic diseases.
Metabolic factors: An association between obesity and CVD has been repeatedly demonstrated. The epidemic prevalence of increased body weight is driving the worldwide higher incidence of insulin resistance and diabetes and in turn could be responsible of the association between periodontitis and metabolic diseases. Many studies have linked periodontitis with individual and clustered alteration of serum levels of cholesterol, triglycerides and blood glucose6.
Stress: Stress has been historically associated with elevated risk for CVD. Similarly stress has been correlated with periodontitis severity and with poorer treatment outcomes7. Stress may therefore represent a risk factor for both CVD and periodontitis.

1 Genco RJ, Borgnakke WS: Risk factors for periodontal disease. Periodontol 2000 62:59-94, 2013
2 Desvarieux M, Schwahn C, Volzke H, Demmer RT, Ludemann J, Kessler C, Jacobs DR, Jr., John U, Kocher T: Gender differences in the relationship between periodontal disease, tooth loss, and atherosclerosis. Stroke 35: 2004
3 Andriankaja OM, Genco RJ, Dorn J, Dmochowski J, Hovey K, Falkner KL, Trevisan M: Periodontal disease and risk of myocardial infarction: the role of gender and smoking. Eur J Epidemiol 22:699-705, 2007
4 Borrell LN, Beck JD, Heiss G: Socioeconomic disadvantage and periodontal disease: the Dental Atherosclerosis Risk in Communities study. Am J Public Health 96:332-339, 2006
5 Holmlund A, Holm G, Lind L: Severity of periodontal disease and number of remaining teeth are related to the prevalence of myocardial infarction and hypertension in a study based on 4,254 subjects. J Periodontol 77:1173-1178, 2006
6 Reviewed in D'Aiuto F, Orlandi M, Gunsolley JC: Evidence that periodontal treatment improves biomarkers and CVD outcomes. J Clin Periodontol 40 Suppl 14:S85-105, 2013
7 Reviewed in Preeja C, Ambili R, Nisha KJ, Seba A, Archana V: Unveiling the role of stress in periodontal etiopathogenesis: an evidence-based review. J Investig Clin Dent 4:78-83, 2013
 

Atherosclerosis, with its consequent CVD, represents one of the leading causes of death in the industrialized world.

It is now recognized that atherosclerosis is a chronic inflammatory disease affecting the arterial wall. However the causes of arterial inflammation remain poorly understood1 and traditional CVD risk factors (i.e. age, gender, smoking, hypercholesterolemia, hypertension) do not explain a proportion of cardiovascular events.

The role of infections in causing atherosclerosis received increasing attention well over 20 years ago2. Numerous studies had shown an association between specific chronic infections and CVD. However, the lack of a clinical benefit reported following completion of numerous intervention trials using systemic antibiotics reduced the general enthusiasm about this hypothetical association3.

Since the first case-control report published in 1989 several investigations have repeatedly shown a consistent association between CVD (myocardial infarction, hospitalization, cardiac sudden death and peripheral vascular disease) and various measures of oral health4.

Some of these studies however have found either weak or no association at all5. The majority of systematic reviews on the topic indicated that periodontitis is consistently associated with a 15 to 20% increased risk of developing future CVD6. These associations were independent of traditional CVD risk factors.

After more than 30 years from the first reports on the association we are still debating on whether these associations are causal or casual in nature. Over the last 10 years the number of clinical intervention trials investigating the effect of periodontal therapy on traditional and novel CVD risk factors has exponentially increased. However there is still limited evidence on the effect of periodontal therapy on CVD hard outcomes (myocardial infarction or stroke).

The main finding reported to date after periodontal therapy is a substantial improvement of measures of endothelial function (which represents a surrogate marker of CVD)7.

The endothelium is a key regulator of blood vessel biology. The loss of normal endothelial function and integrity, called endothelial dysfunction, occurs in the early stage of the atherosclerosis and its progression. Endothelial dysfunction can predict adverse CVD events and long-term outcomes8. Flow-mediated dilatation (FMD) represents the most widely used non-invasive ultrasound method to assess endothelial function of the brachial artery9.

Several clinical periodontal studies demonstrated a positive effect of periodontal treatment on endothelial function (improvement).

One of the largest randomized trials included 120 patients suffering from periodontitis and who received randomly either an intensive course of subgingival instrumentation and locally delivered antimicrobials or scaling and polishing. Six months after periodontal therapy, patients in the intensive treatment group presented with the greatest improvement in periodontal health and endothelial function (2.0% improvement compared to controls) . However whether this finding would translate into a clinical benefit for the patients with periodontitis (i.e. lower future risk of CVD) is still unknown.

There is a need for large clinical studies to assess whether or not treating periodontitis can improve CVD in the general population.

1 Libby P: Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol 32:2045-2051, 2012
2 Leinonen M, Saikku P: Evidence for infectious agents in cardiovascular disease and atherosclerosis. Lancet Infect Dis 2:11-17, 2002
3 Cannon CP, Braunwald E, McCabe CH, Grayston JT, Muhlestein B, Giugliano RP, Cairns R, Skene AM: Antibiotic treatment of Chlamydia pneumoniae after acute coronary syndrome. N Engl J Med 352:1646-1654, 2005
4 Mattila KJ, Nieminen MS, Valtonen VV, Rasi VP, Kesaniemi YA, Syrjala SL, Jungell PS, Isoluoma M, Hietaniemi K, Jokinen MJ: Association between dental health and acute myocardial infarction. BMJ 298:779-781, 1989
5 Hujoel PP, Drangsholt M, Spiekerman C, DeRouen TA: Periodontitis-systemic disease associations in the presence of smoking--causal or coincidental? Periodontol 2000 30:51-60, 2002
6 Dietrich T, Sharma P, Walter C, Weston P, Beck J: The epidemiological evidence behind the association between periodontitis and incident atherosclerotic cardiovascular disease. J Clin Periodontol 40 Suppl 14:S70-S84, 2013
7 Reviewed in D'Aiuto F, Orlandi M, Gunsolley JC: Evidence that periodontal treatment improves biomarkers and CVD outcomes. J Periodontol 84:S85-S105, 2013
8 Schachinger V, Zeiher AM: Prognostic implications of endothelial dysfunction: does it mean anything? Coron Artery Dis 12:435-443, 2001
9 Donald AE, Charakida M, Cole TJ, Friberg P, Chowienczyk PJ, Millasseau SC, Deanfield JE, Halcox JP: Non-invasive assessment of endothelial function: which technique? J Am Coll Cardiol 48:1846-1850, 2006
 

Diabetes mellitus is the sixth leading cause of death in the world1. It is a chronic condition resulting from an imbalance of either production and/or utilization of insulin in the body. This could be the consequence of direct pancreatic damage and reduction of insulin secreting cells (diabetes type 1) or it could be due to the inability of the body to use insulin (type 2). Both mechanisms result in a chronic increase of blood glucose levels.

The oral cavity is affected by diabetes with a variety of prevalent complications including periodontitis, caries, dry mouth, candidiasis and burning mouth syndrome2.

Diabetes and periodontitis both affect millions of people worldwide and are often diagnosed in the same individuals. For several years though this relationship has been studied only in one direction (uncontrolled or poorly controlled diabetes increases risk of periodontitis).

People with diabetes have almost three times greater odds to suffer from periodontitis3. Further, a recent meta-analysis confirmed that diagnosis of diabetes was associated with poor periodontal conditions4.

Recent studies however have shown how periodontitis could in turn affect glycaemic control. In a longitudinal study of the Pima Indians in Arizona, one the of population with the highest risk of diabetes and periodontitis, initial diagnosis of severe periodontitis increased substantially the odds of poor glucose control at 2-years follow-up5.

A further study performed on the same population but over a longer follow-up (10 years) demonstrated that severe periodontitis was associated with an increased risk of diabetic complications (nephropathy) and mortality (mainly due to stroke and myocardial infarction)6.

It is widely recognized that chronic infections may produce endocrine-metabolic changes resulting in poorer glucose control and insulin resistance.

Further analyses on large prospective clinical trials suggested that diagnosis of severe periodontitis predicts the development of diabetes independently of other common risk factors.

A recent systematic review of all clinical intervention studies performed including patients with periodontitis and diabetes confirmed a reduction in plasma levels of glycated hemoglobin (HbA1C) of 0.36% following 3 months of periodontal therapy7.

The largest randomized trial published to date on the impact of periodontal treatment in people with type 2 diabetes was recently published. The trial results do not confirm the consistent beneficial effect of periodontal therapy on glucose control in people with diabetes. 514 participants were randomized to either scaling and root planing or no treatment and followed over 6 months8. Nonsurgical periodontal therapy did not improve glycemic control at the end of the study. A large wave of criticism accompanied this latest trial, mainly justified by the poor clinical periodontal improvement reported by the study investigators and coupled with persistent high levels of gingival inflammation and dental plaque in the test group. On this basis the results of the largest trial on the effects of periodontal therapy on glucose control in people with type 2 diabetes are inconclusive.

There is a need for large clinical studies to assess whether treating effectively and objectively periodontitis can improve glucose control in people with diabetes and affect their future risk of complications.

1 http://www.who.int/mediacentre/factsheets/fs310/en/
2 D'Aiuto, F; Massi-Benedetti, M; (2008) Oral health in people with diabetes: why should we care? Diabetes Voice , 53 (2) 33 - 36.
https://www.idf.org/sites/default/files/attachments/2008_2_D%20Aiuto_Massi%20Benedetti_EN.pdf
3 Preshaw PM, Alba AL, Herrera D, Jepsen S, Konstantinidis A, Makrilakis K, Taylor R: Periodontitis and diabetes: a two-way relationship. Diabetologia 55:21-31, 2012
4 Khader YS, Dauod AS, El Qaderi SS, Alkafajei A, Batayha WQ: Periodontal status of diabetics compared with nondiabetics: a meta-analysis. J Diabetes Complications 20:59-68, 2006
5 Taylor GW, Burt BA, Becker MP, Genco RJ, Shlossman M, Knowler WC, Pettitt DJ: Severe periodontitis and risk for poor glycemic control in patients with non-insulin-dependent diabetes mellitus. J Periodontol 67:1085-1093, 1996
6 Saremi A, Nelson RG, Tulloch-Reid M, Hanson RL, Sievers ML, Taylor GW, Shlossman M, Bennett PH, Genco R, Knowler WC: Periodontal disease and mortality in type 2 diabetes. Diabetes Care 28:27-32, 2005
7 Engebretson S, Kocher T: Evidence that periodontal treatment improves diabetes outcomes: a systematic review and meta-analysis. J Clin Periodontol 40 Suppl 14:S153-S163, 2013
8 Engebretson SP, Hyman LG, Michalowicz BS, Schoenfeld ER, Gelato MC, Hou W, Seaquist ER, Reddy MS, Lewis CE, Oates TW, Tripathy D, Katancik JA, Orlander PR, Paquette DW, Hanson NQ, Tsai MY: The effect of nonsurgical periodontal therapy on hemoglobin A1c levels in persons with type 2 diabetes and chronic periodontitis: a randomized clinical trial. JAMA 310:2523-2532, 2013
 

Pregnancy and more in general hormonal changes are closely linked to periodontal inflammation1. Pregnancy per se is not a risk factor for periodontitis but it only aggravates a pre-existing state of increased periodontal inflammation2.
Preterm low birth-weight (PLBW) delivery (before 37th week of gestation and < 2500g of weight) is one of the leading causes of neonatal death and other health problems including neuro-developmental disorders in many western countries. It is commonly caused by maternal young age, alcohol, drug and tobacco use and genetic predisposing factors3. However a large number of studies suggest that infections (mainly of the genitor-urinary tract) can account for a significant number of prematurities.
Many studies suggest a possible relationship between periodontitis and premature birth.
In one of the first case control studies looking at the association, maternal periodontal infection was associated with a significant increase in the risk (nearly 8 times) of PLBW delivery and intra-uterine growth restriction4.
Following this report several observational studies have reported on the association however with some inconsistencies. Indeed two large studies performed in the UK did not find such an association ascribing the previous reports mainly due to a strong association between PBLW in afro-americans5.
More recently, it has been suggested that periodontal infections may also cause other adverse pregnancy events such as pre-eclampsia, which commonly results in maternal hypertension, proteinuria and affects maternal mortality and morbidity.
In a large cohort of pregnant women, those who were diagnosed with periodontitis showed higher risk of pre-eclampsia independent of other recognized risk factors (maternal age, smoking etc)6.

Direct bacterial invasion of the feto-placental unit and an excessive production of pro-inflammatory mediators may affect gestational age and predispose to PBLW7.

Numerous small intervention trials on the effect of periodontal therapy on pregnancy outcomes have been reported to date. The majority of these studies confirmed a beneficial effect of treating periodontitis on gestational age and infant birth weight8.
However recent multicenter intervention trials including more than 1000 pregnant women, suggest that non-surgical periodontal therapy does not influence adverse pregnancy outcomes after all 9,10.
Despite the strong epidemiological association between periodontitis and adverse pregnancy outcomes these reports highlight the difficulty of researchers in attempting to provide answers on causality using clinical trials. The nature of the periodontal treatment provided, its timing during pregnancy and the control group chosen have been considered to be determining factors in planning future clinical trials to investigate the role of periodontitis on PBLW.

1 Glickman I: Periodontal disease. N Engl J Med 284:1071-1077, 1971
2 Taani DQ, Habashneh R, Hammad MM, Batieha A: The periodontal status of pregnant women and its relationship with socio-demographic and clinical variables. J Oral Rehabil 30:440-445, 2003
3 Voltolini C, Torricelli M, Conti N, Vellucci FL, Severi FM, Petraglia F: Understanding spontaneous preterm birth: from underlying mechanisms to predictive and preventive interventions. Reprod Sci 20:1274-1292, 2013
4 Offenbacher S, Katz V, Fertik G, Collins J, Boyd D, Maynor G, McKaig R, Beck J: Periodontal infection as a possible risk factor for preterm low birth weight. J Periodontol 67:1103-1113, 1996
5 Davenport ES, Williams CE, Sterne JA, Murad S, Sivapathasundram V, Curtis MA: Maternal periodontal disease and preterm low birthweight: case-control study. J Dent Res 81:313-318, 2002
6 Boggess KA, Lieff S, Murtha AP, Moss K, Beck J, Offenbacher S: Maternal periodontal disease is associated with an increased risk for preeclampsia. Obstet Gynecol 101:227-231, 2003
7 Madianos PN, Bobetsis YA, Offenbacher S: Adverse pregnancy outcomes (APOs) and periodontal disease: pathogenic mechanisms. J Periodontol 84:S170-S180, 2013
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