Endodontic medicine: connections between apicalperiodontitis and systemic diseases
J. J. Segura-Egea1, J. Mart�ın-Gonz�alez1 & L. Castellanos-Cosano2
1Endodontic Section, Department of Stomatology, School of Dentistry, University of Sevilla, Sevilla; and 2Special Care Dentistry
Section, Department of Stomatology, School of Dentistry, University of Sevilla, Sevilla, Spain
Abstract
Segura-Egea JJ, Mart�ın-Gonz�alez J, Castellanos-
Cosano L. Endodontic medicine: connections between
apical periodontitis and systemic diseases. International
Endodontic Journal, 48, 933–951, 2015.
The prevalence of apical periodontitis (AP) in Europe
has been reported to affect 61% of individuals and
14% of teeth, and increase with age. Likewise, the
prevalence of root canal treatment (RCT) in Europe is
estimated to be around 30–50% of individuals and
2–9% of teeth with radiographic evidence of chronic
persistent AP in 30–65% of root filled teeth (RFT). AP
is not only a local phenomenon and for some time
the medical and dental scientific community have
analysed the possible connection between apical peri-
odontits and systemic health. Endodontic medicine
has developed, with increasing numbers of reports
describing the association between periapical inflam-
mation and systemic diseases. The results of studies
carried out both in animal models and humans are
not conclusive, but suggest an association between
endodontic variables, that is AP and RCT, and
diabetes mellitus (DM), tobacco smoking, coronary
heart disease and other systemic diseases. Several
studies have reported a higher prevalence of periapi-
cal lesions, delayed periapical repair, greater size of
osteolityc lesions, greater likelihood of asymptomatic
infections and poorer prognosis for RFT in diabetic
patients. On the other hand, recent studies have
found that a poorer periapical status correlates with
higher HbA1c levels and poor glycaemic control in
type 2 diabetic patients. However, there is no scien-
tific evidence supporting a causal effect of periapical
inflammation on diabetes metabolic control. The pos-
sible association between smoking habits and
endodontic infection has also been investigated, with
controversial results. The aim of this paper was to
review the literature on the association between
endodontic variables and systemic health (especially
DM and smoking habits).
Keywords: diabetes mellitus, immune response,
oral health, periapical inflammation, persistent apical
periodontitis, root canal treatment, tobacco smoking.
Received 7 January 2015; accepted 5 July 2015
Introduction
Endodontology includes pulp and periapical biology
and pathology. Clinically, however, endodontics is
perceived as treatment of the root canal with files and
the placement of a root filling, or treatment by surgi-
cal endodontics. Whilst the initial diagnoses and the
difficulties associated with treatment may be related
to the state of the pulp, the ultimate biological aim of
this treatment is no longer the preservation of the
pulp, but the prevention and elimination of infection
in the root canal system to prevent or cure apical
periodontitis (AP) (Ørstavik & Pitt Ford 2007).
Apical periodontitis, an inflammatory process
around the apex of a root, is primarily a sequel to
microbial infection of the pulp space. The infectious
aetiology of AP and the main role of microbial factors
in the initiation, development and persistence of the
condition have been widely documented with the
result it can be considered as a disease of bacte-
rial infection (Siqueira & Roc�as 2014). AP may,
Correspondence: Juan J. Segura-Egea, Facultad de Odon-
tolog�ıa, Universidad de Sevilla, C/Avicena s/n, 41009-Sevilla,
Spain (e-mail: [email protected]).
International Endodontic Journal, 48, 933–951, 2015© 2015 International Endodontic Journal. Published by John Wiley & Sons Ltd
doi:10.1111/iej.12507
933
consequently, be viewed as a tissue response to pulp
infection from dental caries, trauma, attrition from
mastication and abrasion from the use of teeth as
tools for survival (Ørstavik & Pitt Ford 2007).
Apical periodontitis is a remarkably prevalent con-
dition (Figdor 2002). In Europe, the prevalence of AP
is as high as 34–61% of individuals and 2.8–4.2% of
the teeth (Jim�enez-Pinz�on et al. 2004, L�opez-L�opez
et al. 2012a) and increases with age (Eriksen 1998).
Root canal treatment (RCT) is the elective treatment
for teeth with AP. Nevertheless, complete healing of
bone or reduction in the size of apical radiolucencies
does not occur in all root filled teeth (RFT). Such
cases of nonresolving periapical radiolucencies are
also referred to as endodontic failures (Nair 2006).
Radiolucent periapical lesions (PLs) persist when
treatment procedures have not reached a satisfactory
standard for the control and elimination of infection.
Inadequate aseptic control, poor access cavity design,
missed canals, insufficient instrumentation and leak-
ing temporary or permanent restorations are common
problems that may lead to persistent AP (Sundqvist &
Figdor 1998). In Europe, the prevalence of endodontic
treatment is estimated around 41–59% of individuals
and 2–6.4% of teeth, with radiographic evidence of
persistent chronic AP in 24–65% of RFT (Jim�enez-
Pinz�on et al. 2004, L�opez-L�opez et al. 2012a).
Endodontic medicine
Even though periapical infections cause a number of
local tissue responses with the purpose of limiting the
spread of the infectious elements, AP may not exclu-
sively be a local phenomenon. The interaction
between the lipopolysaccharide (LPS) from anaerobic
gram-negative bacteria causing AP with Toll-like
receptor 4 (TLR4) on macrophages and neutrophils
activates the broad axis of innate immunity, up-regu-
lating pro-inflammatory cytokines such as IL-1b, IL-6,IL-8, TNF-a and prostaglandin E2 (PGE2) (Roc�as et al.2014). These cytokines may be released into the sys-
temic circulation (Doyle et al. 2007) inducing or per-
petuating an elevated chronic systemic inflammatory
status (Caplan et al. 2006).
Although there is no conclusive scientific evidence
indicating that an infected root canal may act as a focus
of infection to distant body sites (except for systemically
compromised patients), the opposite has not been pro-
ven either, that is, there is no clear evidence showing
that endodontic infections are an isolated event with no
effect on the rest of the body (Siqueira 2011).
It is well known that, in its nonbalanced acute stage,
spreading of infection and the inflammatory process to
nearby tissue compartments is possible and may bring
about severe, but fortunately rare, fatal inflammatory
conditions. Moreover, considering the increasing
awareness of a potential relationship between persis-
tent, inflammatory disorders of the oral cavity and dis-
ease conditions in other organs of the body, acute and
chronic manifestations of AP may also be implicated
(Marton 2004, Marton & Bergenholtz 2004).
Siqueira & Roc�as (2014) cite how primary and
post-treatment AP can influence an individual’s over-
all health and remains a question to be answered in
endodontic microbiology. The possible connection
between chronic oral inflammatory processes of infec-
tious origin, that is chronic AP and periodontal dis-
ease (PD), and systemic health is, nowadays, one of
the most interesting aspects faced by the medical and
dental scientific community. A question has risen:
whether direct cell-to-cell interactions between peri-
odontal or endodontic bacteria and host cells as well
as between different human cells or autocrine and
paracrine loops of stimulations may influence the
function of remote tissues and organs resulting in the
pathogenesis or contributing to the pathomechanism
of systemic diseases (Marton 2004).
In the two last decades, ‘periodontal medicine’ has
developed as a distinct area that focuses on the rela-
tionship between PD and systemic diseases (Seymour
2009). Several epidemiological studies have found
associations between systemic health and PD. Thus,
PD has been associated with diabetes mellitus (DM)
(Katz 2001, Soskolne & Klinger 2001), coronary
heart disease (CHD) and acute myocardial infarction
(AMI) (Beck et al. 1996, Janket et al. 2003, D€orfer
et al. 2004, Grau et al. 2004), preterm-low birth-
weight (Jeffcoat et al. 2003, Mar�ın et al. 2005), respi-
ratory diseases (Scannapieco et al. 2003), osteoporosis
in post-menopause women (Bull�on et al. 2005), meta-
bolic syndrome (Shrestha et al. 2015) and early loss
of memory and capacity for calculation (Noble et al.
2009). The evidence of the association between PD
and systemic diseases has focused attention on the
diagnosis and treatment of PD, improving, conse-
quently, the patient’s oral and systemic health.
Chronic periodontal and endodontic inflammatory
processes have three important similarities (Segura-
Egea et al. 2012):
1. Both are chronic infections of the oral cavity;
2. Both are polymicrobial infections sharing a com-
mon microbiota with a predominance of Gram-
Endodontic medicine Segura-Egea et al.
© 2015 International Endodontic Journal. Published by John Wiley & Sons LtdInternational Endodontic Journal, 48, 933–951, 2015934
negative anaerobic bacteria (Siqueira & Roc�as2014); and
3. Elevated cytokine levels may be released systemi-
cally from acute and chronic manifestations of
both disease processes, for example increased con-
centrations of inflammatory mediators have been
detected both in the gingival crevicular fluid of
subjects with PD and in the periapical tissues of
endodontically involved teeth (Caplan 2004,
Caplan et al. 2006).
Likewise, one might assume that AP is associated
with the same systemic disorders that are associated
with PD (JOE Editorial Board 2008, Segura-Egea et al.
2012). Therefore, ‘endodontic medicine’ should be
developed following the same path as ‘periodontal med-
icine’: evaluating the association between endodontic
and systemic diseases. However, the influence that
chronic periapical processes could produce on highly
prevalent systemic diseases, such as diabetes and CHD
has been poorly studied. The lack of scientific studies
on this topic might be masking the potential risk of
retaining teeth with chronic AP and the real impor-
tance and health advantages of endodontic treatments
to patients, doctors and dentists (Segura-Egea et al.
2012).
On the other hand, the impact of systemic diseases
and some general habits, such as smoking, on pulp
and periapical health also needs to be further investi-
gated (Walter et al. 2012a). Strindberg (1956), in his
classic study, did not find the general health status of
the patient as a significant factor affecting periapical
health. However, Marending et al. (2005) reported
that the integrity of the nonspecific immune system
was a significant predictor for endodontic initial treat-
ment and retreatment outcome (P = 0.05). Ng et al.
(2008) also demonstrated the impact that an
impaired nonspecific immune system had on the heal-
ing of periapical tissues. Thus, pro-inflammatory sta-
tus 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
AP and the frequency of RCT.
Association between endodontics and
diabetes mellitus
Diabetes mellitus is a clinically and genetically hetero-
geneous group of disorders affecting the metabolism of
carbohydrates, lipids and proteins, in which hypergly-
caemia is a main feature (Expert Committee on the
Diagnosis and Classification of Diabetes Mellitus
2000). These disorders are due to a deficiency in insu-
lin secretion caused by pancreatic b-cell dysfunctionand/or insulin resistance in liver and muscle (Mealey
& Oates 2006). Diabetes affects more than 9% of the
adult population, and its high morbidity and mortality
amongst affected individuals has a substantial impact
on national healthcare systems (Mealey & Oates
2006). Aged-adjusted and country-adjusted preva-
lence of Type 2 diabetes mellitus (T2DM) in 11 Euro-
pean countries in 2004 was 10.2% in men and 8.5%
in women (Espelt et al. 2013).
Glycated haemoglobin (HbA1c) has been used as a
‘gold standard’ for mean glycaemia and as a measure
of risk for the development of DM complications
(Expert Committee on the Diagnosis and Classification
of Diabetes Mellitus 2000). The American Association
of Clinical Endocrinologists (AACE) considers HbA1c
levels ≤6.5% as a goal for optimal glycaemic control
in diabetic patients (Gionfriddo et al. 2014).
Type 1 diabetes results from cellular-mediated
autoimmune destruction of pancreatic b-cells, which
usually leads to total loss of insulin secretion; in con-
trast, type 2 diabetes is caused by resistance to insulin
combined with a failure to produce enough additional
insulin to compensate for the resistance (Mealey &
Oates 2006). T2DM is characterized by hypergly-
caemia in the context of insulin resistance and b-celldysfunction (Montane et al. 2014). The aetiology of
T2DM is multifactorial, involving a complex interplay
between genetic, epigenetic and environmental factors
(Jiang et al. 2013). T2DM is frequently linked to obe-
sity, which contributes to insulin resistance through
elevation of circulating levels of free fatty acids,
derived from the adipocytes, which inhibit glucose
uptake, glycogen synthesis and glycolysis (Oakes et al.
1997). However, in one-third of obese individuals,
b-cell mass is reduced by a marked increase in b-cellapoptosis, which results in inadequate production of
insulin (Tunes et al. 2010). Many studies have shown
that inflammation plays a very important role in the
pathogenesis of T2DM. Inflammatory mechanisms
and cytokine production activated by stress via the
inflammasome may further alter the normal structure
of b-cells by inducing pancreatic islet cell apoptosis
(Montane et al. 2014).
Diabetes mellitus and oral health
Diabetes mellitus induces changes to immune cell
function, up-regulating pro-inflammatory cytokines
Segura-Egea et al. Endodontic medicine
International Endodontic Journal, 48, 933–951, 2015© 2015 International Endodontic Journal. Published by John Wiley & Sons Ltd 935
from monocytes/polymorphonuclear leucocytes and
down-regulating growth factors from macrophages,
predisposing to chronic inflammation, progressive tis-
sue breakdown and diminished tissue repair capacity
(Iacopino 2001). This immune phenotype leads to the
oral complications of DM, including xerostomia,
delayed wound healing of oral mucosa, candidiasis,
increased incidence and severity of caries, pulp-peri-
apical infections, PD and dry mouth syndrome (Little
et al. 1997). Moreover, evidence has consistently indi-
cated that DM is a risk factor for increased severity of
PD, both gingivitis and periodontitis (Salvi et al.
2008). One of the chronic complications of DM,
microangiopathy, would lead to decreased blood flow
and thus the input of nutrients and oxygen to the
periodontal tissues, facilitating progression of PD, loss
of support, increasing periodontal pockets, mobility
and a poorer response to periodontal treatment
(Thomson et al. 2004). Poor control of DM and
hyperglycaemia will further diminish the immune
response, with decreased leucocyte function and delay
of wound healing, and are associated with aggressive
forms of PD (Delamaire et al. 1997, Iacopino 2001,
Salvi et al. 2008).
Conversely, PD may be a risk factor for worsening
glycaemic control amongst patients with diabetes and
may increase the risk of diabetic complications (Katz
2001). PD may initiate or propagate insulin resis-
tance in a manner similar to that of obesity, by
enhancing activation of the overall systemic immune
response initiated by cytokines (Mealey & Oates 2006,
Allen et al. 2009). The destruction of the alveolar
bone and periodontal ligament, leads to a pathogenic
and inflammatory reactions that continues to sys-
temic level, due to the large amount of surface epithe-
lium of the periodontal pockets that allows, through
three possible mechanisms, the passage of bacteria
and their products to the body (Mealey & Koekkevold
2004):
1. Bacteraemia: microorganisms enter the blood-
stream, aren’t removed and spread;
2. Metastatic damage: caused by endotoxin release
and LPSs which are lethal to cells; and
3. Metastatic inflammation: caused by antigen-anti-
body reactions and release of chemical mediators.
The continuous passage of bacterial LPS of gram-
negative bacteria from biofilms, and proinflammatory
cytokines into the bloodstream, would be the basis of
the influence of the PD at the level of general health
and susceptibility to certain diseases. Furthermore, in
the case of DM, the PD becomes a risk factor for the
synthesis of advanced glycation end products (AGEs),
that bind to membrane receptors on phagocytic cells
and overregulate the functions of pro-inflammatory
chemical mediators that maintain a chronic hypergly-
caemia, as occurs in diabetes (Saremi et al. 2005). In
fact, some studies describe the improvement of dia-
betes with the treatment of PD, with decreased serum
levels of TNF-alpha, fibrinogen, HbA1c, and hs-CRP
(C-reactive protein of high sensitivity) (Katagiri et al.
2009, Correa et al. 2010). However, the literature is
insufficient and inconclusive to clearly support peri-
odontal treatment as a means to improve serum
HbA1c levels in patients with DM (Mauri-Obradorset al. 2014).
Diabetes mellitus and apical periodontitis: animal
studies
As far as studies in animal models are concerned,
Kohsaka et al. (1996) studied histologically and histo-
metrically changes in pulpal and periapical tissues
after pulpal exposure in streptozotocin-induced dia-
betic rats. In experimental rats, inflammation in the
apical periodontal ligament and root resorption and
alveolar bone resorption were more severe than in
control rats. Diabetic rats had larger PLs. Fouad et al.
(2002) induced PLs in first molars of female nonobese
diabetic (NOD) mice by inoculating a mixture of aero-
bic and facultative anaerobic bacteria. Then, they
measured periapical lesion size histomorphometrically,
observing more pronounced periapical inflammation
and larger PLs in diabetic rats compared with con-
trols. Iwama et al. (2003) studied the development of
periradicular lesions 4 weeks after exposure of the
pulp in GK rats with spontaneous noninsulin-depen-
dent DM and control Wistar rats. Histologic analysis
demonstrated that hyperglycaemic diabetic rats had
greater bone resorption and larger periradicular
lesions than control rats. Garber et al. (2009) studied
the effect of hyperglycaemia on pulp healing in
exposed rat pulps capped with mineral trioxide aggre-
gate. They found an inverse association between den-
tine bridge formation and inflammatory cell
infiltration: dentine bridge formation was inhibited in
diabetic rats and more inflammation was observed in
these pulps. Bain et al. (2009) described the develop-
ment of insulin resistance in pregnant rats with
induced periapical abscesses. Endodontically affected
pregnant rats had increased interleukins and serum
TNFa levels, together with significant increases in
blood glucose and serum insulin concentrations.
Endodontic medicine Segura-Egea et al.
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Kodama et al. (2011) conducted an experimental
study to determine whether diabetes induces or
enhances PD or dental caries and AP. They used a
strain of rat that develops spontaneous diabetes after
10 months of age. Their results revealed that the inci-
dence and severity of both molar caries and alveolar
bone resorption were much higher in rats with
chronic diabetes. Liu et al. (2012) reported that met-
formin, one of the antihyperglycaemic agents com-
monly used for the treatment of type 2 diabetes,
decreases periapical bone loss area after pulp exposure
in Wistar rats through lowering the RANKL/osteopro-
tegerin (OPG) ratio, reducing the number of osteo-
clasts and bone resorption areas. Wolle et al. (2013)
evaluated the development of PLs in a rat model of
type 2 diabetes and assessed the potential actions of
the antioxidant agent tempol. Neither radiographic
nor histologic analysis revealed any significant differ-
ence between controls and type 2 diabetic rats. In dia-
betic rats, AP was refractory to tempol treatment.
Recently, Astolphi et al. (2013) evaluated the effect
of PLs on insulin signalling and insulin sensitivity in
rats, reporting that PLs caused alterations to both
insulin signalling and insulin sensitivity, with insulin
resistance, probably because of elevation of plasmatic
TNFa. The same group carried out an experimental
study on Wistar rats using the model of streptozo-
tocin-induced diabetes. AP was induced by pulp expo-
sure to the oral environment and PD was induced by
periodontal ligature. Cintra & da Silva Facundo
(2013) reported changes in the lipid profile in dia-
betic rats with pulpitis, concluding that the presence
of oral infections and diabetes is associated to
changes in tryglyceride levels. In another report Cin-
tra et al. (2014a) investigated AP and PD for their
effects on both blood glucose concentrations and gly-
cosylated haemoglobin levels (HbA1c). Results
showed that inflammatory infiltrate and alveolar
bone resorption were more severe in diabetic rats.
They concluded that oral infections affect glycaemic
conditions in diabetic rats and increase HbA1c levels
in normoglycaemic and diabetic rats. In a third
paper, Cintra et al. (2014b) reported that the combi-
nation of AP and PD increased serum IL-17 levels in
DM and normoglycaemic rats, and increased neu-
trophil levels in DM rats. They found that diabetes
increased neutrophil levels and bone resorption in
rats. Interleukin-17 (IL-17) is a proinflammatory
cytokine that mediates multiple chronic inflammatory
responses, including angiogenesis, recruitment of
inflammatory cells, and induction of proinflammatory
mediators by endothelial and epithelial tissues
(Ouyang et al. 2008, Queiroz-Junior et al. 2010). In
the more recent report (Cintra & da Silva Facundo
2014c), the authors investigated the relationship
between blood profile and histologic findings in both
AP and PD associated with diabetes in Wistar rats.
They concluded that diabetes accelerated the develop-
ment and progression of AP and PD and caused an
increase in average erythrocyte volume as well as
leucocyte and neutrophil counts. Both oral infections
increase the total number of leucocytes, the number
of neutrophils and lymphocytes, and blood glucose
concentrations in DM rats.
Diabetes mellitus and endodontics: human studies
Several clinical and epidemiological studies carried
out in humans have analysed the association between
endodontic variables and DM. The main endodontic
variables analysed in these studies are as follows:
1. The prevalence of AP;
2. The prevalence of RCT; and
3. The outcome of RCT, assessed as the percentage
of RFT with or without PLs, or as the prevalence
of tooth extraction after nonsurgical RCT
(NSRCT). In diabetic patients, the variables usu-
ally assessed are blood glucose and glycated hae-
moglobin levels.
Diabetes mellitus and the prevalence of apical periodontitis
Is there an association between the prevalence of AP
and DM? The first human studies (Bender et al. 1963)
highlighted the substantial proportion of diabetics
amongst patients with odontogenic infections. Bender
& Bender (2003) found a high rate of asymptomatic
tooth infections in diabetics exhibiting poor glycaemia
levels of an unclear cause concluding that ‘clinical
and radiographic studies by other investigators have
shown that there is a greater prevalence of PLs in
diabetics than in nondiabetics’. Certainly, numerous
epidemiological studies have compared the prevalence
of AP in diabetic and nondiabetic patients. Thus, Falk
et al. (1989) carried out a clinical and radiographic
study analysing the prevalence of PLs in type 1 dia-
betic patients. They recorded the number of teeth,
carious lesions, RFT and PLs in ninety-four long dura-
tion diabetics, 86 short duration diabetics and 86
nondiabetic patients. There were no significant differ-
ences between long and short duration diabetics and
nondiabetics in the mean number of teeth with PLs,
but, amongst the diabetics, there was a group of
Segura-Egea et al. Endodontic medicine
International Endodontic Journal, 48, 933–951, 2015© 2015 International Endodontic Journal. Published by John Wiley & Sons Ltd 937
individuals who had more PLs than controls, and the
extension of PLs was greater in long duration diabet-
ics. Ueta et al. (1993) focused their study in the
prevalence of DM mellitus in patients with
odontogenic infections, finding a disproportionately
high percentage of severe clinical infections, both
pulp-periapical and periodontal, in diabetic patients.
Amongst 21 severe odontogenic infections, DM was
detected in five cases, concluding that diabetes is a
predisposing condition for odontogenic infec-
tions. Britto et al. (2003) studied the prevalence of
PLs in patients with and without diabetes, finding one
or more teeth with AP in 97% and 87% of diabetic
patients and control subjects, respectively, concluding
that there was no significant association between AP
and diabetes. On the contrary, in a cross-sectional
study carried out by Segura-Egea et al. (2005), the
prevalence of AP was determined using periapical
radiographs and the periapical index (PAI) (Ørstavik
et al. 1986), in patients with and without type 2 DM.
Results demonstrated that AP in one or more teeth
was significantly more frequent in diabetic patients
(81%) compared to healthy control patients (58%)
(OR = 3.2; P < 0.05); moreover, the percentage of
teeth with AP was significantly higher in diabetics
(7%) compared to controls (4%) (OR = 1.8;
P < 0.01). In another cross-sectional study carried
out by the same group in Spain (L�opez-L�opez et al.
2011), this time including only well-controlled dia-
betic patients as assessed by glycated haemoglobin
levels, the results revealed that the frequency of radio-
graphic signs of AP in at least one tooth was signifi-
cantly higher in diabetic patients (74%) compared to
controls (42%). Multivariate logistic regression analy-
sis concluded that the likelihood of having AP was
almost four times higher in diabetic patients com-
pared to nondiabetic subjects (OR = 3.9; P < 0.01).
Another cross-sectional study carried out in an adult
Brazilian population (Marotta et al. 2012) using full-
mouth radiographs and Strindberg’s criteria for the
diagnostic of AP (Strindberg 1956), also found that
AP was significantly more common in teeth from dia-
betic individuals (15%) than in nondiabetic controls
(12%) (P = 0.05). The significance was mostly
because of the prevalence of AP in untreated teeth:
the frequency of AP lesions in untreated teeth was
significantly higher in the teeth from type 2 diabetics
(10%) compared to (7%) (P = 0.03).
The results of studies conducted so far are incon-
clusive, but suggest an association between DM and a
higher prevalence of AP, odontogenic infections and
greater size of PLs. Longitudinal studies are needed to
further investigate this topic.
Diabetes mellitus and the prevalence of root canal
treatment
The second question is whether there is an associa-
tion between the prevalence of RCT, and DM. Falk
et al. (1989) found no significant differences between
long and short duration diabetics and nondiabetics in
the mean number of RFT. Women with long diabetes
duration, however, exhibited more RFT with PLs than
women with short diabetes duration and women
without diabetes. In the cross-sectional study carried
out by Segura-Egea et al. (2005) in a sample of the
Spanish population, no significant association
between diabetes and prevalence of RFT was found
(OR = 0.56; P = 0.25). The same percentage of RFT
(2%) was found both in diabetic and control subjects.
Marotta et al. (2012) also found no association
between well-controlled diabetic status and the preva-
lence of RFT (P = 0.25). However, in another cross-
sectional study also carried out in Spain (L�opez-L�opez
et al. 2011) comparing the endodontic status of well-
controlled diabetic patients (HbA1c = 6.6 � 0.6) and
control subject without DM, the percentage of sub-
jects with at least one root filled tooth (RFT) was sig-
nificantly higher in diabetics (70%) compared to
controls (50%). Multivariate logistic regression analy-
sis concluded that the likelihood of having at least
one RFT was twice in diabetic patients compared to
nondiabetic subjects (OR = 2.3; P < 0.05). It can also
be concluded that there is inconclusive evidence
about the association of diabetes with a higher preva-
lence of RCT.
Diabetes mellitus and the outcome of root canal treatment
The third question to be formulated is whether there
is an association between DM and the outcome of
RCT. This possible relationship can be investigated by
analysing two variables: the prevalence of RFT with
AP and the prevalence of tooth extraction after
NSRCT.
In relation to the prevalence of RFT with AP, Falk
et al. (1989) found a higher frequency of RFT with
PLs in long duration diabetics compared to non-dia-
betic patients. Fouad & Burleson (2003) investigated
endodontic treatment outcome data in 140 patients,
73 with DM, finding that patients with diabetes had a
reduced likelihood of success (assessed clinically and
radiographically) following RCT in cases with preoper-
ative periradicular lesions and increased flare-ups
Endodontic medicine Segura-Egea et al.
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during treatment. In a retrospective cohort study
(Britto et al. 2003), using a full-mouth series of peri-
apical radiographs and panoramic radiographs and
assessing the periapical status with the Strindberg’s
criteria (Strindberg 1956), no significant difference
between controls (44.2%) and diabetics (46.4%) in
the percentage of RFT with AP (P > 0.05) was found.
However, men with type 2 DM who had RFT were
more likely to have residual lesions. Similar results
were found in two studies comparing well-controlled
diabetic patients and control subjects, one using
panoramic digital radiographs (L�opez-L�opez et al.
2011) and the other using full-mouth periapical
radiographs and panoramic radiographs (Marotta
et al. 2012), which found 24% and 38% of RFT with
radiolucent PLs in the control group, respectively,
and 46% of RFT with AP in the diabetic group
(P > 0.05). In the study of Segura-Egea et al. (2005),
carried out using periapical radiographs and without
taking into account the metabolic control of diabetic
patients, 83% of RFT had radiographic signs of AP in
the diabetic group, whereas only 69% had PLs in the
control group; however, these differences were not
significant (OR = 3.3; P > 0.05). Recently, Ferreira
et al. (2014) compared the success rate of RFT,
assessed radiographically and clinically, in two groups
of 23 patients, one healthy controls and the other
diabetics, and found no significant differences between
the groups when using the PAI (P > 0.05).
Although it could be concluded that there is no evi-
dence indicating that diabetes is associated with a
higher prevalence of RFT with AP, when all the data
of these six epidemiological studies analysing this
topic are pooled (including 1076 RFT), the result
became statistically significant (Table 1; OR = 1.7;
C.I. 95% = 1.3–2.2; P = 0.0003).
On the other hand, it must be taken into account
that some of the periapical radiolucencies associated
with RFT and identified as AP in the cited epidemio-
logical studies, probably represent healing lesions,
particularly if the time elapsed since treatment was
<2 years (Dugas et al. 2003). Indeed, this is a recog-
nized limitation of cross-sectional studies (Jim�enez-
Pinz�on et al. 2004).
To evaluate the association between the prevalence
of RFT extraction and DM, Mindiola et al. (2006) car-
ried out an epidemiological study on a regional popu-
lation of Native Americans, identifying factors
affecting the retention of RFT. The results suggested
that diabetes contributed to decreased retention of
RFT (P < 0.01). Doyle et al. (2007), in a retrospective
study analysing 196 root filled treated teeth, evalu-
ated whether DM was associated with the outcome of
patients undergoing NSRCT. Results showed that the
treatments undertaken in diabetics were more likely
to fail, revealing a borderline significant association
(P = 0.063) between DM and RFT extraction.
Another epidemiological study carried out by Wang
et al. (2011) analysing 49 334 RFT, 4358 in diabetic
patients, found that DM was a significant risk factor
for tooth extraction after RCT (OR = 1.8; P < 0.01),
concluding that DM contributes to decreased reten-
tion of RFT. Ng et al. (2011) carried out a prospective
study involving 1600 RFT. The multiple Cox regres-
sion model concluded that diabetic patients were asso-
ciated with threefold more RFT loss than healthy
counterparts (Hazard ratio = 3.2–3.4; P < 0.01).
In conclusion, there is scientific evidence to demon-
strate a poorer prognosis for RFT in diabetics. Thus,
diabetic patients have delayed periapical repair and
greater likelihood of RFT loss.
Metabolic control of diabetes mellitus and apical
periodontitis
Finally, only a few studies have analysed the relation-
ship between metabolic control of DM and endodontic
variables. In a pioneer study, Bender et al. (1963)
argued that the lack of control in DM could delay
healing of PLs and increase their size, despite having
received endodontic treatment. On the contrary, in
well-controlled diabetic patients PLs healed as readily
as in nondiabetics. Cheraskin & Ringsdorf (1968)
studied the radiographic healing of periradicular
Table 1 Prevalence of root filled teeth (RFT) with apical
periodontitis (AP) in diabetic patients and control subjects:
summary of studies and pooled data
Authors (year)
Controls Diabetics
P
RFT-AP/
Total RFT (%)
RFT-AP/
Total RFT (%)
Falk et al. (1989) – – >0.05
Fouad &
Burleson (2003)
224/467 (48) 63/73 (86) >0.05
Britto et al. (2003) 19/43 (44) 26/56 (46) >0.05
Segura-Egea
et al. (2005)
12/20 (60) 10/12 (83) >0.05
L�opez-L�opez
et al. (2011)
6/25 (24) 16/35 (46) >0.05
Marotta et al.
(2012)
78/206 (38) 39/85 (46) >0.05
Ferreira et al.
(2014)
3/23 (13) 10/31 (32) >0.05
Total 343/784 (43.8) 164/292 (56.2) 0.0003
Segura-Egea et al. Endodontic medicine
International Endodontic Journal, 48, 933–951, 2015© 2015 International Endodontic Journal. Published by John Wiley & Sons Ltd 939
lesions after RCT in 12 patients with low-plasma glu-
cose and 13 patients with high-plasma glucose, find-
ing a lower reduction of the PLs in patients with high
glucose levels (48% reduction) compared to low glu-
cose group (74% reduction). Recently, S�anchez-
Dom�ınguez et al. (2015) carried out a cross-sectional
study on 83 diabetic patients using orthopantomo-
graphs and PAI. They assessed the metabolic control
of DM measuring glycated haemoglobin levels and
classifying diabetic patients as well-controlled
(HbA1c < 6.5%) or poor-controlled (HbA1c > 6.5%).
Results revealed that periapical status correlated sig-
nificantly with glycated haemoglobin levels. Multivari-
ate logistic regression analysis demonstrated a
significant association between periapical status of
RFT and HbA1c levels (P < 0.05).
Overall, the results are inconclusive, although some
studies suggest that chronic periapical disease may
contribute to diabetic metabolic dyscontrol. Once
more, further prospective studies are needed.
Biological mechanisms linking periapical status
and diabetes mellitus
To validate a relationship between diabetes and AP,
biologically plausible mechanisms must be evident to
explain the pathobiology of the interactions. In dia-
betics, there are three main alterations: impaired
innate immunity, hyperglycaemia and the formation
of irreversibly glycated-proteins forming AGEs (Fig. 1).
Innate immunity is the first line of defence against
pathogens. In DM the function of innate immunity
cells is altered. Neutrophil phagocytosis is decreases
and macrophages are up-regulated, with increased
production of proinflammatory cytokines (Lima et al.
2013). However, high glucose levels can inhibit
Figure 1 Biological mechanisms by which diabetes mellitus (DM) can influence periapical status. There are three main biologi-
cal mechanisms in DM (DM): impaired innate immunity, hyperglycaemia and the formation of irreversibly glycated-proteins
forming advanced glycation end products (AGEs). The function of innate immunity cells is altered; neutrophil phagocytosis is
decreased, and macrophages are up-regulated, with increased production of pro-inflammatory cytokines. On the other hand,
the advanced glycated end products that hyperglycaemia provokes, bind to collagen leading to alterations in bone metabolism,
reducing bone formation and osteoblastic differentiation. Moreover, AGEs interact with specific receptors in macrophages acti-
vating NF-jb, increasing cellular oxidant stress and up-regulating pro-inflammatory cytokines. Finally, the hyperglycaemic sta-
tus provokes apoptosis of osteoblasts and fibroblasts, inhibition of collagen production and inhibition of osteoblastic cell
proliferation and differentiation. Thus, as a result DM predisposes to chronic inflammation, diminishes tissue repair capacity,
and causes a greater susceptibility to infections and delays wound healing. In inflamed periapical tissues of root filled teeth
(RFT), DM compromises the immune response aggravating periapical chronic inflammation and impairing bone turnover and
wound healing, increasing the prevalence of persistent apical periodontitis.
Endodontic medicine Segura-Egea et al.
© 2015 International Endodontic Journal. Published by John Wiley & Sons LtdInternational Endodontic Journal, 48, 933–951, 2015940
macrophage function resulting in an inflammatory
state that impairs host cellular proliferation, delaying
wound healing of dental pulp and periapical tissues
(Garber et al. 2009).
Secondly, it has been stated that hyperglycaemia
causes structural alterations in dental pulp and peri-
apical tissues by the impairing collateral circulation
(Bender & Bender 2003, Lima et al. 2013). Moreover,
a reduction in IL-4 and OPG (Duarte et al. 2012) and
an up-regulation in IL-1b, IL-6, IL-8, IL-10, TNF-aand receptor activator of nuclear factor kappa B
ligand (RANKL) (Lima et al. 2013, Garc�Ia-Hernandez
et al. 2012) in the inflammatory response in hyper-
glycaemic conditions has been described. Additionally,
hyperglycaemia up-regulates the activity of differenti-
ated osteoclast cells, and it has been proposed that
could increase bone resorption (Dienelt & zur Nieden
2011).
A third possible mechanism linking DM and peri-
apical status could be AGEs. AGEs are synthesized via
the nonenzymaticglycation and oxidation of proteins,
lipids and nucleic acids during chronic hypergly-
caemia. AGEs interact with specific receptors in
macrophages (RAGE) activating nuclear factor-kappa
beta (NF-jb), increasing cellular oxidant stress and
up-regulating pro-inflammatory cytokines (Cai et al.
2012). The formation of irreversible AGEs in DM
compromises the tissues and alters the constitution of
the extracellular matrix (ECM) components. As peri-
apical tissues contain ECM targeted by AGE, DM
could have severe implications in subjects with AP
(Gurav 2013). AGEs bind to collagen leading to alter-
ations in bone metabolism, reducing bone formation
and osteoblastic cell proliferation and differentiation
(Tanaka et al. 2013). A linear correlation between
the expression of RAGE and NF-jb has been demon-
strated in human inflamed periradicular tissues (Crab-
tree et al. 2008). The co-expression of RAGE and AGE
by endothelial cells in human periapical granulomas
has been demonstrated, suggesting that the engage-
ment of RAGE and AGE may trigger cellular activa-
tion mediating periapical tissue injury (Takeichi et al.
2011). Recently, it has been reported that AGEs bind
to its receptor in periodontal ligament fibroblasts pro-
voking apoptosis and inhibition of collagen production
(Li et al. 2014). Therefore, AGEs could impair periapi-
cal repair after RCT.
Thus, as a result, diabetes predisposes to chronic
inflammation, diminishes tissue repair capacity,
causes a greater susceptibility to infections and
delayed wound healing. In inflamed periapical tissues
of RFT, DM can compromise immune response aggra-
vating periapical inflammation and impairing bone
turnover and wound healing, increasing the preva-
lence of persistent AP.
On the other hand, the mechanisms by which peri-
apical status could affect the glycaemic control in dia-
betic patients (Fig. 2) can be hypothesised. Type 2
diabetes is a manifestation of the host’s inflammatory
response, because an ongoing cytokine-induced acute-
phase response (a low-grade inflammation that occurs
through activation of the innate immune system) is
closely involved in the pathogenesis of this disease
(Santos Tunes et al. 2010). Similarly, the mechanisms
of the host-mediated response in AP involve activa-
tion of the broad axis of innate immunity, specifically
by up-regulation of pro-inflammatory cytokines from
monocytes and polymorphonuclear leucocytes. There-
fore, periapical chronic inflammation could induce or
perpetuate an elevated chronic systemic inflammatory
status, contributing to increased insulin resistance
and poor glycaemic control (Montoya-Carralero et al.
2010, Segura-Egea et al. 2012). The action of
inflammatory mediators released in periapical inflam-
mation could be associated with the development of
insulin resistance, which is influenced by genetically
modified environmental factors, including decreased
physical activity, poor nutrition, obesity and infection
(Pickup 2004, Segura-Egea et al. 2012, 2013, 2014).
The LPS from anaerobic gram-negative bacteria caus-
ing AP binds to their specific receptors in immune
cells (TLRs) and activates intracellular pathways,
specifically the NF-Kb on macrophages up-regulating
pro-inflammatory cytokines, such as IL-1b, IL-6, IL-8,tumour necrosis factor alpha (TNF-a) and PGE2, con-
tributing to the pro-inflammatory systemic status of
diabetics (Pickup 2004, Segura-Egea et al. 2014).
These locally produced cytokines move into the sys-
temic circulation (Doyle et al. 2007), where they can
interact with the free fatty acids and AGEs, character-
istic of type 2 DM (Cai et al. 2012). The activation of
these inflammatory pathways in immune cells (mono-
cytes or macrophages), endothelium cells, adipocytes,
hepatocytes and muscle cells enhances the activation
of the overall systemic immune response initiated by
cytokines (Mealey & Oates 2006, Allen et al. 2009)
and could promote an increase in the overall insulin
resistance, altering the metabolic control in patients
with both DM and chronic AP (Segura-Egea et al.
2012, Hu et al. 2015). Recently, it has been reported
that, under diabetic pulp conditions, AGEs increase
mRNA expression of IL-1b in dental pulp cells
Segura-Egea et al. Endodontic medicine
International Endodontic Journal, 48, 933–951, 2015© 2015 International Endodontic Journal. Published by John Wiley & Sons Ltd 941
through the RAGE-MAPK signalling pathway (Naka-
jima et al. 2015).
Conclusion
The results of the studies conducted so far are not
conclusive, but suggest an association between DM
an AP. There is evidence associating DM with a
higher prevalence of AP, greater size of periapical
osteolytic lesions, greater likelihood of asymptomatic
periapical infections and delay/arrest of periapical
repair. The prognosis for RFT is worse in diabetics,
with a higher rate of RCT failure with increased
prevalence of persistent chronic AP. On the other
hand, there are data suggesting that chronic periapi-
cal disease may contribute to diabetic metabolic
dyscontrol. However, prospective epidemiological
studies are needed to better understand the relation-
ship between DM and periapical inflammation. As dia-
betes is the third most prevalent condition in
medically compromised patients seeking dental treat-
ment (Dhanuthai et al. 2009), dentists should be
aware of the possible relationship between endodontic
infections and DM and take it into account when
treating patients.
Association between endodontics and
smoking habits
Tobacco consumption is a global pandemic, wide-
spread in Europe, killing half of all lifetime users. In
2011, six million people died as a result of tobacco
use, and by the year 2030 eight million people are
expected to die annually (Eriksen et al. 2012).
According to the WHO study Health Behaviour in
School-aged Children (HBSC), approximately 18% of
15-year-old adolescents smoke cigarettes at least once
a week (Currie et al. 2012). A recent study carried
out in Sweden has found that smoking prevalence
increased from 3% amongst 12–13 year olds to 25%
Figure 2 Mechanisms by which periapical status could affect the glycaemic control in diabetic patients. Chronic periapical
inflammation involves activation of the broad axis of innate immunity. The lipopolysaccharide from anaerobic gram-negative
bacteria causing apical periodontitis (AP) bind to their specific receptors in immune cells (TLRs) and activates intracellular
pathways, specifically the transcriptional factor NF-jb, up-regulating pro-inflammatory cytokines, contributing to the pro-in-
flammatory systemic status of diabetics. The activation of these inflammatory pathways in immune cells, endothelium cells,
adipocytes, pancreas, hepatocytes and muscle cells could promote an increase in the overall insulin resistance, altering the
metabolic control in patients with both type 2 diabetes mellitus and chronic AP. In diabetic patients, the advanced glycation
end products also bind to its receptor (RAGE) in macrophages and also activate NF-jb, closing the vicious circle.
Endodontic medicine Segura-Egea et al.
© 2015 International Endodontic Journal. Published by John Wiley & Sons LtdInternational Endodontic Journal, 48, 933–951, 2015942
amongst 17–18 year olds (Joffer et al. 2014).
Amongst all adults, this percentage is around 27%
(Włodarczyk et al. 2013). In Europe, tobacco smoking
causes approximately 1.6 million premature deaths
and 13 million Europeans currently suffer from
tobacco related diseases (Zato�nski et al. 2012).
Amongst the elderly, the overall smoking prevalence
in 17 European countries was 11.5%, with smoking
habits being of a higher prevalence in eastern/central
Europe for men (20.3%) and in northern Europe for
women (13.1%) (Lugo et al. 2013).
Smoking habits and oral health
It is already known that tobacco use is a well-estab-
lished risk factor for systemic and oral health (War-
nakulasuriya et al. 2010, Huttunen et al. 2011,
Walter et al. 2012a). The results of several studies
suggest that smoking increases the risk of caries
(Sgan-Cohen et al. 2000, Fure 2004), and cigarette
smoking, even passive smoking, has been identified
as a strong environmental risk factor for PDs (War-
nakulasuriya et al. 2010, Walter et al. 2012b). The
harmful effects of tobacco smoking on periodontal
bone have been demonstrated in several cross-sec-
tional and longitudinal studies (Krall et al. 1999,
Bergstr€om et al. 2000). Smokers have a diminished
response to periodontal therapy and have approxi-
mately half as much improvement in probing depths
and clinical attachment levels following nonsurgical
and various surgical modalities of therapy (Johnson
& Hill 2004).
Smoking has major effects on the host response to
infections and has a long-term chronic effect on many
important aspects of the inflammatory and both cell-
mediated immunity and humoral immunity (Palmer
et al. 2005). Smoking induces a significant systemic
neutrophilia and protease release from neutrophils,
and suppression of neutrophil cell spreading,
chemokinesis, chemotaxis and phagocytosis (Palmer
et al. 2005, Ryder 2007). Research on gingival
crevicular fluid has demonstrated that there are lower
levels of cytokines, enzymes and possibly polymor-
phonuclear cells in smokers (Palmer et al. 2005).
Smoking habits and apical periodontitis
On this basis, it can be assumed that smoking might
be a risk factor for AP, exerting a negative influence
on the apical periodontium of endodontically compro-
mised teeth, facilitating the extension of the process of
periapical bone destruction and/or interfering with
healing and repair events following endodontic treat-
ment. Consequently, an increased number and/or size
of PLs would be expected in smokers. The literature
demonstrates conflicting evidence relating smoking
with endodontic disease and prognosis, as well as to
whether smoking increases the prevalence of AP
(Duncan & Pitt Ford 2006).
Studies finding no association between smoking and
endodontic variables
Amongst the investigations carried out to study the
relation between smoking and AP, those finding no
association between tobacco smoking and AP will be
discussed first. Bergstr€om et al. (2004) analysed AP in
terms of radiographically detectable and measurable
destructive changes of periapical bone. Using periapi-
cal radiographs, they compared the prevalence of PLs
in 81 smokers, 63 former smokers and 103 nonsmok-
ers, finding that 56%, 57% and 46%, respectively,
had at least one tooth with AP, concluding that
smoking was not significantly associated with apical
AP (P > 0.05). The prevalence of RFT was also inves-
tigated, with 45% of nonsmokers having at least one
RFT, compared to 68% of smokers and 67% of former
smokers (P > 0.05). Finally, the prevalence of RFT
with radiolucent PLs was also determined, with no
association detected between periapical status of RFT
and smoking habits (P > 0.05).
Marending et al. (2005) analysed the influence of
smoking on RCT outcome. They carried out a follow-
up study including 66 patients who had undergone
RCT, followed 46 � 12 months, and using the PAI
(Ørstavik et al. 1986) to assess periapical status. No
association between smoking and periapical status of
RFT was found (OR = 0.80; P = 0.85). Frisk & Hake-
berg (2006), in a cross-sectional study including 981
women, 191 smokers and 653 nonsmokers, and
using orthopantomograms to assess periapical status,
also found no significant association between AP and
smoking (OR = 1.35; P > 0.05). Tour�e et al. (2011)
analysed the factors related to extraction of 119 RFT,
finding no significant differences between smokers
and nonsmokers. In another cross-sectional study,
Rodriguez et al. (2013) also found no significant rela-
tionship between smoking habits and AP. Using peri-
apical radiographs and the PAI score system
(Ørstavik et al. 1986), they evaluated the periapical
status of 66 smokers, 28 former smokers and 67
nonsmokers, concluding that smoking status did not
predict AP.
Segura-Egea et al. Endodontic medicine
International Endodontic Journal, 48, 933–951, 2015© 2015 International Endodontic Journal. Published by John Wiley & Sons Ltd 943
Studies finding association between smoking and
endodontic variables
Although five epidemiological studies have found no
significant association between tobacco smoking and
endodontic variables, there are nine studies whose
results suggest that this association exists. Alekseju-
niene et al. (2000), in a cross-sectional study, were
the first to identify smoking as a risk indicator for AP
in an adult Lithuanian population. In a cross-sec-
tional study, they analysed radiographically, using
orthopantomograms and the PAI score system (Ørsta-
vik et al. 1986), the periapical status of 147 patients,
concluding that smoking and AP were significantly
associated (P < 0.05). Kirkevang & Wenzel (2003)
published a cross-sectional study, carried out on 613
patients and using periapical radiographs and the PAI
system (Ørstavik et al. 1986), reported that smoking
was associated statistically with AP (OR = 1.64;
P = 0.05). Krall et al. (2006) carried out a longitudi-
nal study with 2–28 years follow-up, including 811
dentate male participants. Radiographic evaluation
demonstrated a dose response relationship between
cigarette smoking and the frequency of RCT. The risk
amongst cigarette smokers increased with greater
number of years of exposure and decreased with
length of abstinence. Compared with never smokers,
current cigarette smokers were 1.7 times as likely to
have RFT (P < 0.001). In a retrospective study (Doyle
et al. 2007), assessed clinically and radiographically
the outcome of 196 nonsurgically treated RFT, and
reported that RCT in smokers had fewer successes
and more failures than in nonsmoker patients
(P < 0.05). The same year, Kirkevang et al. (2007)
analysed individual and tooth specific factors associ-
ated with the incidence or the persistence of AP in a
general population, concluding that smoking was a
significant risk factor when assessed separately
(OR = 1.9; P < 0.05). Ojima et al. (2013) studied the
characteristics of dental care of 2835 current smokers
and 6850 nonsmokers finding that caries/endodontic
treatment were significantly more frequent in smokers
compared to nonsmokers (47.1% vs. 43.6%,
P = 0.002).
The group at the University of Sevilla has carried
out three epidemiological studies. First, they carried
out a cross-sectional study (Segura-Egea et al. 2008)
analysing periapical radiographs and using the PAI
score system (Ørstavik et al. 1986) to determine the
prevalence of radiographic periapical radiolucencies in
71 nonsmokers and 109 smokers. This study sup-
ported the concept that smoking is associated with an
increase in the prevalence of AP, being a risk factor
for AP (OR = 4.2; P < 0.01) and enhancing the
occurrence of RCT (OR = 2.0; P < 0.05). In the mul-
tivariate logistic regression analysis, with AP as
dependent variable and adjusting for age, gender,
number of teeth and endodontic status, smoking
remained significantly associated with periapical sta-
tus (OR = 4.4; P < 0.01). However, there was no
association between smoking and the prevalence of
RFT with AP (P > 0.05). In another cross-sectional
study (Segura-Egea et al. 2011), carried out in a sam-
ple of 100 hypertensive subjects, 50 smokers and 50
nonsmokers, the percentages of patients with AP in
one or more teeth or with at least one RFT were sig-
nificantly higher amongst smokers (P < 0.05).
Finally, in a case–control study (L�opez-L�opez et al.
2012b) including 79 smoker and 79 nonsmokers,
age- and sex-matched, tobacco smoking was strongly
associated with the presence of radiographically diag-
nosed PLs. Amongst the smokers, 75% had a history
of smoking, whereas in the control group only 13%
had been smokers (OR = 20.4; P = 0.0000). After
multivariate logistic regression analysis adjusting for
covariates (age, gender, number of teeth, RFT, RFT
with a technically unsatisfactory root filling and dia-
betes), a strong association was observed between the
presence of at least one radiographically detectable
periapical lesion and history of smoking (OR = 32.4;
P = 0.0000), concluding that smoking significantly
predicts AP.
Biological mechanisms linking periapical status
and smoking
Although the effects of smoking on the wound heal-
ing process are well recognized in clinical dental prac-
tice (Scabbia et al. 2001), the particular mechanisms
implicated are not well known. However, several bio-
logical mechanisms that could explain, at least in
part, the relationship between endodontic variables
and tobacco smoking can be suggested (Fig. 3). First,
smoking affects the microvasculature, both the mor-
phological and functional aspects of the microcircula-
tion, decreasing the oxygen supply to the blood and
causing endothelial cell injury because of free radicals
(Lehr 2000, Freiman et al. 2004). It can be hypothe-
sized that inflamed periapical tissues in smokers could
experience restrictions in nutrients and oxygen
supply.
Secondly, tobacco smoking has been shown to
cause delay fibroblast migration to the wound area
Endodontic medicine Segura-Egea et al.
© 2015 International Endodontic Journal. Published by John Wiley & Sons LtdInternational Endodontic Journal, 48, 933–951, 2015944
(Wong et al. 2004) and fibroblast dysfunction, with
altered collagen synthesis and impaired tissue repair
(Raulin et al. 1988). Smokers have an increased
RANKL⁄osteoprotegerin ratio in saliva and in serum,
mainly because of decreased levels of osteoprotegerin
(Johannsen et al. 2014), with bone loss exacerbation
(Lindquist et al. 1996).
Thirdly, tobacco smoking alters the innate and
acquired immune responses, suppressing the functions
of polymorphonuclear leucocytes, macrophages, T-cell
lymphocytes, decreasing leucocyte chemotaxis and
reducing the levels of antibodies (Kinane & Chestnutt
2000, Johnson & Hill 2004, Palmer et al. 2005,
Ryder 2007, Johannsen et al. 2014).
Fourthly, smoking induces a stronger systemic
inflammatory reaction, increasing C-reactive protein
levels in serum and the release of potentially tissue-
destructive substances such as reactive oxygen spe-
cies, collagenase, serine proteases and the pro-inflam-
matory cytokines IL-1b and TNFa (Barbieri et al.
2011, Johannsen et al. 2014).
Finally, a local and direct pro-inflammatory effect
of smoking on periapical tissues has been demon-
strated. In periapical granulomas removed from 46
patients, the endogenous synthesis of eicosanoids and
isoprostanes, the conversion rate of (14)C labelled
arachidonic acid and lipoxygenases (LOX) products
was analysed. Results demonstrate that in smokers
with granuloma due to AP, the products of lipid
peroxidation as 8-iso-PGF(2a) and products of the
LOX-pathway were increased at the expense of
cyclooxygenase products (Eder et al. 2012). Any one
of these pathophysiologic pathways can potentially
affect the health of the tooth pulp and periradicular
bone, resulting in a higher frequency of radiographic
PLs in smokers than in nonsmokers (L�opez-L�opez
et al. 2012b).
Conclusions
The possible association between endodontic vari-
ables and smoking is controversial. There are several
epidemiological studies where no association was
found (Bergstr€om et al. 2004, Marending et al.
2005, Frisk & Hakeberg 2006, Tour�e et al. 2011,
Rodriguez et al. 2013). On the contrary, other stud-
ies support the concept that smoking is associated
with an increase in the prevalence of AP (Alekseju-
niene et al. 2000, Kirkevang & Wenzel 2003, Kirke-
vang et al. 2007, Segura-Egea et al. 2008, 2011,
L�opez-L�opez et al. 2011), being able to act as a risk
factor for AP. Moreover, four epidemiological studies
Figure 3 Mechanisms by which tobacco smoking could affect the periapical status. Tobacco smoking: (i) decreases the oxy-
gen supply to the blood and causes endothelial cell injury because of free radicals; (ii) exacerbates bone loss and alters colla-
gen synthesis by fibroblasts, impairing tissue repair; (iii) alters the immune response by suppressing the functions of
polymorphonuclear leucocytes, macrophages, T-cell lymphocytes and reducing the levels of antibodies; (iv) induces a stron-
ger chronic systemic inflammatory response; and (v) enhances eicosanoids- and isoprostanes-metabolites synthesis in periapi-
cal granulomas.
Segura-Egea et al. Endodontic medicine
International Endodontic Journal, 48, 933–951, 2015© 2015 International Endodontic Journal. Published by John Wiley & Sons Ltd 945
have found that smoking increases the occurrence of
endodontic treatment (Krall et al. 2006, Segura-Egea
et al. 2008, 2011, Ojima et al. 2013). Finally, two
reports concluded that endodontic treatment in
smokers had fewer successes (Doyle et al. 2007) and
a higher incidence of persistent AP (Kirkevang et al.
2007) compared to nonsmokers. Taking into
account that most of these studies are cross-sectional
and that confounding factors cannot be ruled out,
further longitudinal studies are required to make
firm conclusions.
Association between endodontics and
other systemic diseases
In this paper, the scientific evidence on the associa-
tion between endodontic variables and two main sys-
temic conditions, diabetes and smoking habits, has
been discussed. In another paper in this issue, the
potential association between CHD and endodontics
has been discussed (Cotti & Mercuro 2015). Further-
more, there are several recent investigations studying
the possible relationship of other general diseases with
AP and RCT.
Hypertension
The possible connection between hypertension and
endodontic variables has been analysed. A cross-sec-
tional study carried out in Spain to determine the
prevalence of AP and RCT in hypertensive patients
and control subjects concluded that no association
existed between hypertension and endodontic vari-
ables (Segura-Egea et al. 2010). However, Mindiola
et al. (2006) and Wang et al. (2011) reported an
increased loss of RFT in hypertensive patients.
Osteoporosis
A cross-sectional study was conducted to determine
the prevalence of AP and RCT in post-menopausal
women with osteoporosis (L�opez-L�opez et al. 2013).
Bone mineral density (BMD) of 75 post-menopausal
women was measured using dual-energy X-ray
absorptiometry. Three BMD groups were established
(27 healthy bone group, 36 osteopenics and 12 osteo-
porotics), and periapical and endodontic status were
assessed using digital panoramic radiographs and the
PAI system (Ørstavik et al. 1986). The results demon-
strated that the prevalence of AP was marginally
associated with BMD (OR = 1.9; P = 0.05).
Inherited coagulation disorders
A cross-sectional study investigated the prevalence of
endodontic variables in 58 patients with inherited
coagulation disorders, such as haemophilia A or B, or
von Willebrand disease, compared to 58 healthy con-
trols (Castellanos-Cosano et al. 2013a). Results
revealed that patients with inherited coagulation dis-
orders had significantly more teeth with AP (2.2;
P = 0.038) and more RFT with AP (OR = 4.00;
P = 0.016), but fewer RFT (OR = 0.28; P = 0.0008).
Chronic liver disease
The prevalence of AP and RCT in a group of 42
patients with chronic liver disease, candidates for liver
transplant, compared to 42 healthy controls, has
been also studied (Castellanos-Cosano et al. 2013b).
Results revealed a higher prevalence of AP (P = 0.03)
and RCT (P = 0.01) in these patients, compared to
healthy controls.
Conclusions
General diseases, such as hypertension, osteoporosis,
chronic liver disease or inherited coagulation disor-
ders, are systemic conditions with important alter-
ations in wound healing and are associated with
impaired innate immune responses. Amongst other
biological mechanisms, this could be the main factor
implicated in the possible connection between these
systemic diseases and endodontic variables. Develop-
ing a thorough investigation on the possible associa-
tion of periapical disease and endodontic treatment
with systemic health status and systemic diseases of
high prevalence, morbidity and mortality, such as DM
or smoking habits, should be a priority of endodontic
research. Such findings will surely have important
implications in terms of the therapeutic approaches in
these patients.
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