Low-grade inflammation, periodontitis and systemic health

The bidirectional relationship that exists between periodontitis and systemic diseases arises from the inflammatory nature of the conditions affecting the periodontium. The proposed mechanisms are different; the effects that mediators of inflammation can exert on distant organs are the same . From this stems the hypothesis that periodontitis may be involved in the induction and/or maintenance of a systemic state of low-grade inflammation (LGI).

The dissertation of Dr Iuorio is based on a scoping review of the literature. The review included studies that evaluate the correlation between low-grade inflammation (LGI), periodontitis and systemic diseases. Some of the included studies focused on diabetes and cardiovascular diseases, as well as other diseases and conditions such as obesity, cerebrovascular disease, endothelial dysfunction, chronic kidney disease, Alzheimer’s disease, Parkinson’s disease, and systemic lupus erythematosus.

Low-grade inflammation

The contribution of inflammation to systemic diseases has been extensively studied. Recently, the concept of low-grade inflammation (LGI) has been proposed. Chronic low-grade inflammation, as we can appreciate by the term itself, is characterised by a constant and moderate production of inflammatory factors, very close to the minimum threshold values. LGI is defined by slightly borderline values ​​of inflammatory biomarkers, such as C-reactive protein (CRP), fibrinogen, IL-6, but according to some authors also of white blood cells, platelets, molecules and adhesion proteins (E -selectins, ICAM-1, VCAM-1). However, this condition has not yet been uniquely defined, and the same scoping review on which the thesis is based has found different definitions and values. Concentrations of inflammatory markers such as PCR, albumin, and white blood cell counts can vary significantly during acute responses to infection, tissue damage, or systemic conditions, but these acute phase reagents or proteins have also have been suggested as potential markers of a persistent and more subtle systemic condition, which has indeed been defined as low-grade inflammation. Furthermore, we now have highly sensitive methods available to detect C-reactive protein and other markers, in order to identify the presence of low-grade inflammation that would not have been detected in the past. Speaking of values, several authors report CRP higher than 3 mg/L but lower than 10 mg/L as representative for LGI, but as already mentioned, different values ​​are proposed for different biomarkers.

A combined method for the assessment of low-grade inflammation has recently been suggested, based on plasma levels of CRP combined with cell markers (leukocyte count, platelet count, granulocyte/lymphocyte ratio). The use of this method in future trials could represent the beginning in defining this condition clearly. LGI is a recognised risk factor for some chronic diseases, and it has been hypothesised that there is a relationship between LGI and periodontitis: recent studies have shown that periodontitis can contribute to low-grade inflammatory conditions, but also that the condition itself can be a risk factor for periodontitis and contributing to its link with some systemic conditions and pathologies such as cardiovascular diseases (Barbaresko, Koch, Schulze, & Nöthlings, 2013; Cecoro, Annunziata, Iuorio, Nastri, & Guida, 2020; Danesh et al., 2000).

Low-grade inflammation and periodontitis:

Research in periodontology has recently focused on the potential contribution of chronic low-grade inflammation on the systemic inflammatory phenotype generation. Periodontitis has shown to be an independent factor contributing to systemic inflammation through the many studies showing periodontal patients with higher levels of inflammatory markers. Periodontitis is a chronic infectious disease, in which the effect and the pathogenesis are given by a continuous local inflammatory process, but also a disease in which the dissemination of inflammatory mediators from the local site can cause systemic inflammation and inflammatory processes in distant sites. Local infectious diseases like periodontitis can contribute to a so called “hyperinflammatory phenotype”, meaning genetic conditions and background predisposing to inflammation.

Systemic low-grade inflammation appears to be influenced by the type of oral microbiome, and in fact, higher levels of inflammatory markers are present in periodontal patients than in healthy subjects. Circulating levels of CRP are higher in patients suffering from periodontitis, with values ​​ranging between 2 and 10 mg/L, consistent with low-grade systemic inflammation (Moutsopoulos & Madianos, 2006). Furthermore, fibrinogen and white blood cell levels also appear to be directly related to probing depth (PPD) and clinical attachment level (CAL) (Gocke et al., 2014). Also, a study by Nibali et al. (Nibali et al., 2007) shows how the number of pathological periodontal pockets is directly related to an increase in white blood cells. The aim of the study was, in fact, to evaluate inflammatory and metabolic markers (leukocytes, lipids and glucose) in subjects with severe periodontitis compared to healthy subjects, and results showed that both types of markers were related to patient’s’ periodontal conditions. Patients with severe periodontitis had a low-grade inflammation, defined as an increased number of neutrophils and lymphocytes, and dysmetabolic state, assessed through HDL, LDL and glucose levels. Moreover, what emerged from this study is that there was a dose-dependent relationship.

Low-grade inflammation and systemic health:

The review on which the dissertation is based has included studies evaluating the link between LGI, periodontitis and systemic health. To date, in fact, low-grade inflammation is considered a risk factor for some cardiovascular, cerebrovascular and neurodegenerative diseases. From what emerges from the most significant studies, LGI is considered a risk factor for cardiovascular disease, endothelial dysfunction, diabetes and Alzheimer’s disease, and periodontitis, capable of increasing LGI through the increase of CRP and interleukins, can represent an indirect risk for these systemic pathologies. Similarly, it seems that low-grade inflammation is also linked to stroke and acute myocardial infarction, and reports how periodontal therapy could be involved in reducing the risk of these diseases through LGI. The paper by Kolb et al. (Kolb & Mandrup-Poulsen, 2010) specifically suggests that the main risk factors for type II diabetes (overnutrition, sleep deprivation, sedentary lifestyle) can induce low-grade inflammation, which can eventually lead to diabetes, in cases in which a genetic and/or epigenetic predisposition compromises the regulatory mechanisms of inflammation and metabolic stress. In the paper by Danesh et al. (Danesh et al., 2000), on the other hand, 4 markers of low-grade inflammation were measured: CRP, serum amyloid-A, leukocytes and albumin. The study shows that these values ​​are linked to one another and also to the risk of cardiovascular diseases. They may also be present without being linked to other risk factors for cardiovascular diseases, suggesting how LGI can also contribute to these diseases. LGI can be a risk factor for some systemic diseases, and concomitant diseases such as periodontitis, can contribute by inducing low-grade inflammation (Holmstrup et al., 2017; Pink et al., 2015).

Conclusions:

From the data of this scoping review, we perceive the possibility of a correlation between systemic diseases and periodontitis through LGI. Specific clinical trials are undoubtedly needed to support this relationship, as well as a more specific and exclusive definition of low-grade inflammation that establishes ranges and threshold values ​​of the inflammation markers involved. That is to say, observational clinical studies in which the levels of LGI markers and periodontal parameters are compared both in patients with periodontitis and in healthy subjects, with and without concomitant systemic diseases, would be necessary.

Literature and suggested reads:

Barbaresko, J., Koch, M., Schulze, M. B., & Nöthlings, U. (2013). Dietary pattern analysis and biomarkers of low-grade inflammation: A systematic literature review. Nutrition Reviews, 71(8), 511–527. https://doi.org/10.1111/nure.12035

Cecoro, G., Annunziata, M., Iuorio, M. T., Nastri, L., & Guida, L. (2020). Periodontitis, Low-Grade Inflammation and Systemic Health: A Scoping Review. Medicina, 56(6). https://doi.org/10.3390/medicina56060272

Danesh, J., Whincup, P., Walker, M., Lennon, L., Thomson, A., Appleby, P., Gallimore, J. R., & Pepys, M. B. (2000). Low grade inflammation and coronary heart disease: Prospective study and updated meta-analyses. BMJ (Clinical Research Ed.), 321(7255), 199–204. https://doi.org/10.1136/bmj.321.7255.199

Gocke, C., Holtfreter, B., Meisel, P., Grotevendt, A., Jablonowski, L., Nauck, M., Markus, M. R. P., & Kocher, T. (2014). Abdominal obesity modifies long-term associations between periodontitis and markers of systemic inflammation. Atherosclerosis, 235(2), 351–357. https://doi.org/10.1016/j.atherosclerosis.2014.05.926

Holmstrup, P., Damgaard, C., Olsen, I., Klinge, B., Flyvbjerg, A., Nielsen, C. H., & Hansen, P. R. (2017). Comorbidity of periodontal disease: Two sides of the same coin? An introduction for the clinician. Journal of Oral Microbiology, 9(1), 1332710. https://doi.org/10.1080/20002297.2017.1332710

Kolb, H., & Mandrup-Poulsen, T. (2010). The global diabetes epidemic as a consequence of lifestyle-induced low-grade inflammation. Diabetologia, 53(1), 10–20. https://doi.org/10.1007/s00125-009-1573-7