Summary

The progression of deep carious lesions will eventually affect the pulp, causing irreversible pulpitis and pulp necrosis. Bacterial toxins reaching the periapical tissues induce immunologic reactions causing apical periodontitis. Several studies have highlighted the high prevalence of apical periodontitis, which affects 60% of individuals and 10% of teeth, with an increasing prevalence with age. The prevalence of root canal treatment, the elective treatment for teeth with irreversible pulpitis or apical periodontitis, is also high. It has been estimated that around 30–50% of individuals and 2%–9% of teeth have radiographic evidence of chronic persistent apical periodontitis with this figure approaching 30%–65% in root filled teeth. Apical periodontitis is not just a local phenomenon. In its non-balanced acute stage, spreading of the infection and the inflammatory process to nearby tissue compartments is possible and may result in severe, but fortunately rare, fatal inflammatory conditions. Numerous epidemiological studies have suggested the association between apical periodontitis or root canal treatment and systemic conditions such as diabetes, smoking habits, coronary heart disease, low bone mineral density in postmenopausal women, inflammatory bowel disease, chronic liver disease, and inherited coagulation disorders. Endodontic medicine studies the possible connection between endodontic infections and systemic health.

7.1 From Focal Infection Theory to Endodontic Medicine

The progression of a deep carious lesion will eventually affect the pulp, causing irreversible pulpitis and pulp necrosis. In due course, bacterial toxins and the products of necrotic pulp tissue will reach the periapical tissues via the apical foramen, accessory canals, or through exposed dentinal tubules, inducing a number of inflammatory and immunologic reactions resulting in apical periodontitis [1]. Thus, pulpitis and apical periodontitis have an immune-pathologic origin (Figure 7.1).

In accordance with the high frequency of carious lesions, apical periodontitis is a very frequent disease, ranging in prevalence from 34 to 61% of middle-age patients [2–6]. Likewise, root canal treatment is also very prevalent. Epidemiological studies have reported that 2–12% of adult teeth have been root filled [2–6]. The high prevalence of both apical periodontitis and root canal treatment has the potential to affect general health; equally, it is important to determine if systemic diseases can modify the course of periapical pathosis or affect the outcome of endodontic treatment [7].

7.1.1 The Discredited Focal Infection Theory

It is now more than 100 years since the possible participation of oral infections in systemic health was first raised. In the early 20th century, the theories of focal infection and elective localization implicated bacteria found in oral infections in systemic inflammatory conditions. In 1910, William Hunter highlighted the possible correlation of oral infections and oral sepsis with progressive kidney diseases, colitis, anaemia, gastritis, and many other conditions, igniting the fire of focal infection [8]. Billings replaced Hunter’s term ‘oral sepsis’ with ‘focal infection’, and presented case reports claiming that tonsillectomies and tooth extractions cured infections in distant organs [9]. Around the same time, Rosenow developed the principle of elective localization, which related periapical infection with the colonization of bacteria in particular organs, those for which the bacteria would have special affinity [10]. An American dentist, Weston Price, published results supporting the focal infection theory in relation to endodontically treated teeth suggesting the extraction of all pulpless teeth [11]. As a consequence, millions of tonsils and adenoids were removed whilst teeth were removed in an “orgy of extractions” [12, 13]. This stimulated the development of biological research in Endodontics, with the pathogenesis of apical periodontitis being a particular focus.

7.1.2 Endodontic Medicine: Interrelation Between Systemic and Endodontic Pathosis

Currently, the focal infection theory has been discredited by advances in Medicine and Dentistry [14]. However, since the mid-1990s, numerous epidemiological studies have reported an association between periodontal disease and several systemic diseases, such as diabetes mellitus [15, 16], coronary heart disease [17], and ischemic stroke [18]. Likewise, there is now a substantial body of evidence suggesting the existence of an association between endodontic disease and various systemic diseases [7, 19, 20]. The nature of the association between endodontic infection and systemic diseases does not only involve descriptive issues of science but also ethical matters of society. If apical periodontitis can cause diabetes or cardiovascular disease, it becomes a more critical public health concern and not only a scientific one [21]. Therefore, the findings on the relationship between periodontal or endodontic diseases and systemic health should not mean the resurgence of the focal infection theory [22]. On the contrary, the results of these epidemiological studies should be analysed critically to establish if the association described is causal or not [23].

Endodontic medicine highlights the biological and medical aspects of Endodontology [7], studying the systemic consequences of apical periodontitis and root canal treatment as well as the influence of systemic diseases on periapical inflammation, periapical repair, and root canal treatment outcome [7, 19]. The existence of bidirectional mechanisms connecting endodontic and systemic diseases supports a possible association between both conditions. However, an association does not always imply causation. To demonstrate a significant association, by itself, is not evidence that there is a cause–effect relationship [23]. In many cases, there is a statistical association between two variables without any of them directly affecting the other, establishing a non-causal relationship. On the contrary, there is a causal association between two variables, a risk factor and a disease, when it is shown that the factor really influences the development of the disease, affecting its frequency or intensity [24]. The list of causation criteria defined by Hill [24] (Table 7.1) attempted to assess whether there is real causality, providing epidemiologic evidence of the existence of causal relationship or not.

Key points

• The theories of focal infection and elective localization have been discredited.
• Endodontic medicine highlights the biological and medical aspects of Endodontics.
• The association between endodontic infection and systemic diseases involves ethical matters of society.
• The results of epidemiological studies should be critically analysed.
• An association does not always imply causation.

7.2 Pathways Linking Periapical Inflammatory Lesions to Systemic Health Status

Periapical tissues, including periodontal ligament, cementum, and alveolar bone, are exposed directly, without any protective epithelial barrier, to the toxins and antigens leaking from the infected/necrotic dental pulp [25] (Figure 7.1). This special circumstance converts the immune response (innate and acquired) of the periapical tissues into the only defensive mechanism to control further spread of the infection to other vital structures. The periapical defensive response, mediated by the immune system, induces an inflammatory reaction (acute or chronic), which is responsible for periapical bone destruction [26], manifested radiologically by the appearance of widening of the periodontal space, loss of the lamina dura, and eventually an obvious periapical radiolucency [1]. Microorganisms also cause direct damage to periapical tissues by secretion of enzymes, exotoxins, and metabolic end-products. Moreover, the interaction between the lipopolysaccharide (LPS) from anaerobic gram negative bacteria causing apical periodontitis, with Toll-like receptor 4 (TLR4) on host-periapical tissues, macrophages, and neutrophils activates the broad axis of innate immunity, up-regulating cytokines such as IL-1β, IL-6, IL-8, TNF-α, chemokines, and PGE₂ [27]. These pro-inflammatory cytokines play an important role in the stimulation of tissue damage and bone resorption [28]. Therefore, apical periodontitis is the tissue and immune response to root canal infection.

However, apical periodontitis is not only a local phenomenon with no effect on the rest of the body. There are three possible pathways linking periapical inflammatory lesions to systemic health status (Table 7.2; Figure 7.1).

7.2.1 The Spread of Endodontic Bacteria to Adjacent Tissues and Organs

The inflammatory responses may spread directly (per continuitatem) to neighbouring tissues, causing cervical-facial cellulitis and systemic involvement. This clinical scenario can be very serious, even fatal, if the appropriate treatment is not established [29].

Bacteraemia, with metastatic haematogenous spread of endodontic microbes to tissue surfaces of remote organs, such as the endocardium, endothelium, kidney, or a prosthetic joint, is another potential pathway linking endodontic infection and systemic health, especially in medically compromised patients with an immunodeficiency [30]. The intimate anatomical relationship of the periapical infection to the bloodstream, together with the absence of a barrier between the infected and necrotic root canal [31] and the highly vascularised granulomatous inflammatory tissue, increases the potential for developing bacteraemia [32]. Although scientific evidence has discredited the theory of focal infection, there is still no conclusive evidence on whether an infected root canal, or bacteria from extra-radicular biofilms in the periapical area, can act as an infectious focus that influences distant parts of the body [33]. The theoretical existence of this possibility is the basis for the European Society of Endodontology (ESE) recommendation to carry out antibiotic prophylaxis in endodontic treatments performed in patients at risk of infective endocarditis or in those with prosthetic joints.

Another possibility is that bacteria of endodontic origin invade and directly infect endothelial cells, contributing to atherosclerotic lesions. Human specimens of atheroma, obtained during carotid endarterectomy, have been reported to be positive for Tannerella forsythia or Porphyromonas gingivalis present within atherosclerotic plaques [34]. A recent meta-analysis has confirmed the presence of 23 oral bacterial species in atherosclerotic plaque samples (e.g. Campylobacter rectus, P. gingivalis, Porphyromonas endodontalis, Prevotella intermedia, and Prevotella nigrescens) implicated in endodontic lesions [35]. Nevertheless, it was unknown if these bacteria had either periodontal or endodontic origin.

7.2.2 Local Production of Soluble Regulatory Molecules that May Initiate or Sustain Inflammatory Events in Remote Tissues and Organs

Apical periodontitis could affect systemic health when molecules from endodontic bacteria or host compounds spread through the blood and reach remote areas of the body system [30].

The continuous passage of bacterial antigens, such as lipopolysaccharide (LPS) of gram-negative bacteria and lipotheicoic acid (LTA) from gram-positive bacteria, released from intracanal and/or extra-radicular biofilms into the bloodstream, could influence general health and modify the susceptibility of the host to certain diseases. These PAMPs stimulate the innate immune response, binding to their specific receptors in immune cells (LTA/TLR2, LPS/TLR4) and activating intracellular pathways, specifically the transcriptional factor NF-κβ, up-regulating pro-inflammatory cytokines and initiating or sustaining a pro-inflammatory systemic status [36, 37]. The pro-inflammatory cytokines IL-1, IL-6, and TNF-α stimulate the synthesis and liberation of acute phase proteins from the liver, such as CRP, and coagulation factors, such as fibrinogen, that could contribute to the injury of tissues remote from the endodontic lesion. Both fibrinogen and aggregated CRP favour athero-thrombotic events.

Likewise, molecular mimicry, a way in which autoimmunity can occur, could also be involved via immunologic cross-reactions between bacteria and human tissues or through sequence homology of bacterial proteins with human regulatory molecules [30]. The possible sequence homology between proteins of endodontic bacteria and host peptides causes the cross-activation of T or B cells. Then, an autoimmune response is generated that destroys the cells and tissues of the host associated with the protein with homologous sequence.

On the other hand, host compounds, such as pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α), chemokines, pro-atherogenic enzymes, immunoglobulins, transforming growth factors, acute phase proteins (serum amyloid A and CRP), PGE₂, thromboxane A2, and leukotrienes, accumulate in the areas of bone resorption around the root of teeth with apical periodontitis [26]. These inflammatory mediators and immune complexes can be released into the systemic circulation [38, 39], inducing or perpetuating an elevated chronic systemic inflammatory state [40, 41].

The cytokines released in periapical lesions can stimulate the production, recruitment, and activity of certain subpopulations of macrophages and T lymphocytes [30, 42]. This could play a role in the pathogenesis of systemic diseases associated with endodontic disease. TNF-α and IL-1 increase the binding of low-density lipoproteins (LDLs) to endothelium and smooth muscle, up-regulating the LDL receptor gene, so they could induce endothelial dysfunction and smooth muscle cell proliferation [43].

7.2.3 Extrinsic or Intrinsic Pathological Mechanisms Resulting or Contributing to Both Local and Systemic Inflammation

Endodontic pathosis and systemic diseases share risk factors and biological response mechanisms, both of which are subjected to genetic predisposition.

7.2.3.1 Common Patient-related and Environmental Risk Factors

Several environmental and patient-related factors, such as age, smoking, socioeconomic status, and lifestyle, are well-defined risk factors for certain systemic diseases and can also be risk factors for endodontic disease. For example, smoking is well known as a cardiovascular risk factor and, at the same time, is associated with a higher prevalence of apical periodontitis [7, 44].

7.2.3.2 Genetic Polymorphisms

Genetic polymorphisms result in altered gene expression and functional variations of the encoded molecules. Individuals with specific genotypes could be more susceptible to disease or could present an increase in disease severity. Polymorphisms of genes encoding for cytokines, enzymes, transcriptional factors, or other molecules implicated in immune and reparative responses, are associated with systemic diseases, such as cardiovascular disease or diabetes. On the other hand, the outcome of root canal treatment is related closely to the host immune and reparative responses. Consequently, the same genetic polymorphism that increases a predisposition to systemic diseases could, at the same time, increase susceptibility to apical periodontitis, or delay periapical repair, causing persistent apical periodontitis. For example, polymorphisms in the IL-1B gene are associated with apical periodontitis [45], but also with the risk of myocardial infarction or stroke [46]. Likewise, single nucleotide polymorphism in KCNK3, a gene known to be involved in increased susceptibility to hypertension, is also associated with apical periodontitis [47]. The existence of genetic polymorphisms involved, at the same time, in the aetiology of a systemic disease and apical periodontitis, could explain the association between both diseases observed in epidemiological studies.

Key points

• Apical periodontitis may spread to neighbouring tissues causing cervical-facial cellulitis and systemic involvement.
• Molecules from endodontic bacteria or host compounds could spread through the blood reaching remote areas of the body system.
• Molecular mimicry could be involved in the relationship between endodontics and systemic health.
• Inflammatory mediators can be released into the systemic circulation inducing a pro-inflammatory systemic status.
• Endodontic and systemic diseases share risk factors and biological response mechanisms, both subjected to genetic predisposition.

7.3 Endodontic Implications of Systemic Diseases – Systemic Factors Affecting Periapical Repair

Apical periodontitis is an immune-pathological reaction developed in the periapical tissues against pulpal antigens that manifests as an inflammatory reaction. Periapical inflammation is the first step of periapical healing, its objective being to neutralize the immunogen that stimulates the periapical immune response. However, as long as the pulpal infection persists, antigens will continue to pass to the periapical tissue and the repair process will not continue, and the inflammation becomes chronic [48]. Root canal treatment reduces the intracanal bacterial load, fills the root canal system, and prevents the passage of pulpal antigens to the periapical tissues, which allows the proliferative and maturation phases of the healing process to take place, thus promoting periapical tissue repair [49].

Nevertheless, some systemic conditions, such as cardiovascular disease, diabetes mellitus, tobacco smoking, hypertension, inherited coagulation disorders, and osteoporosis, can impair the nonspecific immune system and alter the periapical healing process of teeth following root canal treatment [7].

Pro-inflammatory status and impaired immune response associated with systemic diseases can affect the reparative response of the dental pulp and periapical healing, influencing the two main endodontic variables: the prevalence of apical periodontitis (AP) and the frequency of RCT [7, 50]. Innate immunity is the first line of defense against pathogens. Systemic conditions altering innate immunity cell functions, decreasing neutrophil phagocytosis or macrophage chemotaxis, result in an inflammatory state that impairs host cellular proliferation, delaying wound healing and preventing periapical repair. Likewise, systemic diseases in which there is an alteration in bone turnover, such as increased osteoclastic activity or osteoblast and fibroblast dysfunction, with increased bone resorption and altered collagen synthesis, could also prevent or delay periapical wound healing [51, 52]. Systemic diseases in which a stronger systemic inflammatory reaction is induced, with activation of NF-κβ in macrophages and increased cellular oxidant stress, can alter bone turnover and periapical wound healing [52]. These clinical situations are characterised by increased C-reactive protein levels in serum and the release of potentially tissue-destructive substances such as reactive oxygen species, collagenase, serine proteases, and up-regulation of pro-inflammatory cytokines (IL-1b, IL-6, IL-8, IL-10, TNF-α). This results in further progression of the periapical inflammation and impaired periapical healing. It is worth noting that alterations at the level of vascularization and oxygen supply could also affect periapical repair. Some systemic diseases or conditions, such as smoking, alter, morphologically and/or functionally, the microvasculature and so reduce blood flow and decrease the supply of nutrients and oxygen [7, 53].

Key points

• Periapical inflammation is the first step of periapical healing.
• Systemic diseases can impair the nonspecific immune system, altering the periapical healing process.
• Pro-inflammatory status and impaired immune response associated with systemic diseases can affect the reparative response of the dental pulp and periapical healing.
• Systemic diseases can alter bone turnover and fibroblast function, preventing or delaying periapical wound healing.
• Systemic diseases can alter the microvasculature reducing nutrients and oxygen supply to pulpal or periapical tissues.

7.4 Diabetes and Endodontics

Diabetes mellitus is a group of disorders affecting the metabolism of carbohydrates, lipids, and proteins, in which hyperglycaemia is a main feature [54]. These disorders are due to a deficiency in insulin secretion caused by pancreatic β-cell dysfunction and/or insulin resistance in liver and muscle. Diabetes is associated with devastating complications, such as retinopathy, nephropathy, neuropathy, vascular disease, and impaired wound healing. In diabetics, metabolic glycemic control is performed by determining the glycated haemoglobin (HbA1c) [54]. HbA1c levels less than or equal to 6.5% are the goal for optimal glycaemic control in diabetic patients.

7.4.1 Scientific Evidence on the Association Between Diabetes and Endodontics

In 1963, Bender et al. [55] suggested that uncontrolled or poorly controlled diabetes may be a risk factor for the development of large and debilitating periapical infections. Since then, many experimental and epidemiological studies have investigated the association between endodontics and diabetes with substantial scientific evidence accumulating [7, 23, 56].

Experimental studies in rats and mice [57–63] have concluded that diabetic animals are associated with:

• more pronounced pulp and periapical inflammation, with larger periapical lesions [57, 64],
• accelerated development and progression of apical periodontitis [65],
• inhibition of dentine bridge formation after direct pulp capping [58],
• diabetogenic status after induction of apical periodontitis [59, 66], and
• increased glycated haemoglobin levels after induction of apical periodontitis [65].

The scientific evidence also includes the clinical and epidemiological studies conducted in humans analysing the association between endodontic variables (prevalence of apical periodontitis and root canal treatment) and diabetes. The literature reveals delayed periapical healing in diabetic subjects, lower rate of repair associated with root filled teeth [55, 67, 68], slower reduction in the size of periapical lesions in poorly controlled diabetic patients [69], and greater percentage of persistent apical periodontitis in diabetics, compared to control subjects [70–76]. Some of the epidemiological studies have determined the strength of the association by calculating the odds ratio (OR) values, which are not constant and are not always significant (Table 7.3). However, the OR values calculated for the outcome of RCT in diabetics and control subjects, ranged from 1.3 to 5.3, indicate that the outcome of RCT could be considered moderately associated with the diabetic state. These studies have been analysed by systematic reviews and meta-analysis (Table 7.4, C and D), concluding that individuals with diabetes have significantly higher prevalence of root filled teeth (RFT) with radiolucent periapical lesions [77] and significantly higher prevalence of extracted RFT than healthy nondiabetic subjects [78, 79]. On the other hand, two studies have found a significant association amongst higher HbA1c levels and the prevalence of apical periodontitis [80], or the prevalence of RFT and RFT with apical periodontitis (AP) [81].

7.4.2 Biological Mechanisms Involved in the Association Between Diabetes and Endodontics

Several well-known biological mechanisms could explain the interrelation between diabetes and apical periodontitis [7]. The increased prevalence of persistent apical periodontitis found in diabetic patients could be explained by the impaired innate immunity, hyperglycaemia, and high serum levels of advanced glycation end products (AGEs), which are characteristic of the diabetic state (Figure 7.2, left; Figure 7.3). Genetic polymorphism can also explain the association found in epidemiological studies between the outcome of RCT and diabetes. It has been described as a gene associated both with persistent apical periodontitis [82] and type 2 diabetes [83]. On the other hand, there are biological mechanisms that can explain how periapical inflammation can influence diabetic metabolic control (Figure 7.2, right; Figure 7.4) [23]. Periapical chronic inflammation can induce or perpetuate an elevated chronic systemic inflammatory status, contributing to increased insulin resistance and poor glycaemic control, with increased HbA1c levels [7].