endodontic medicine: connections between apical ... · endodontic medicine: connections between...

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.



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



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



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



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.



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



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.


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.



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.



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



(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.



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.


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.

References

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