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Received: 26 March 2019    Revised: 14 June 2019    Accepted: 18 July 2019

DOI: 10.1111/jcpe.13172

CLINICAL PERIODONTOLOGY

Periodontitis in individuals with liver cirrhosis: A case–control

study

Fernando Oliveira Costa1  | Eugênio José Pereira Lages2 | Elizabeth Maria Bastos Lages1 |

Luís Otávio Miranda Cota1

1
Department of Periodontology, School
of Dentistry, Federal University of Minas Abstract
Gerais, Belo Horizonte, Minas Gerais, Brazil Aim: The aim of this study was to evaluate the association between liver cirrhosis and
2
Department of Dental Clinics, Oral
periodontitis.
Pathology, and Oral Surgery, School of
Dentistry, Federal University of Minas Methods: This case–control study included 294 individuals, 98 cases with liver cir‐
Gerais, Belo Horizonte, Minas Gerais, Brazil
rhosis and 196 controls. A full‐mouth periodontal examination was performed and
Correspondence plaque index, probing depth, clinical attachment level and bleeding on probing were
Fernando Oliveira Costa, School of
recorded. The association of risk variables with periodontitis was tested through uni‐
Dentistry, Department of Periodontology,
Federal University of Minas Gerais, Do variate analysis and multivariate logistic regression, stratified by alcohol status.
Contorno Avenue, 4849 Pampulha, Zip Code
Results: A high prevalence of periodontitis was observed among cases (62.2%)
30110‐031 Belo Horizonte, Minas Gerais,
Brazil. when compared to controls (41.8%). Individuals with cirrhosis presented a chance ~2
Email: focperio@uol.com.br
higher of having periodontitis than controls (OR = 2.28; 95% CI 1.39–3.78; p < .001).
Funding information Significant variables associated with periodontitis in the final logistic models were
This study was supported by grants from
the National Council of Scientific and as follows: (a) no/occasional alcohol use model—number of teeth up 14, age ≥45–
Technological Development—CNPq, Brazil 55 years, male sex and smoking; (b) moderate and intensive alcohol use models—cir‐
(grants #303447/2016‐8).
rhosis, number of teeth up 14, age ≥45–55 years, male sex and smoking.
Conclusions: An important risk association between liver cirrhosis and periodontitis
was observed. Additionally, the intensive alcohol use significantly increased the risk
for periodontitis.

KEYWORDS
cirrhosis, periodontal disease, periodontitis

1 |  I NTRO D U C TI O N
Periodontitis is an infectious inflammatory condition that causes de‐
struction of dental supporting structures (Kinane & Bartold, 2007).
Considering its complex pathogenesis, the susceptibility to peri‐
odontitis is related to disorders of the polymicrobial synergism that
results in dysbiosis (Mendes, Cota, Costa, Oliveira, & Costa, 2019;
Shaikh, Patil, Pangam, & Rathod, 2018).
Studies have indicated an association between periodontitis
and various systemic diseases, although with many conflicting re‐
sults (Bartold & Marriot, 2017). Probable explanations for these
associations may include oral hygiene neglect, shared risk factors
and chronic inflammatory processes (Almeida, Fagundes, Maia, &
Lima, 2018; Bartold & Marriot, 2017; Sanz et al., 2018). The exis‐
tence of periodontitis may affect the individual's immunity, which
can result in systemic infections due to the contribution of peri‐
odontitis to an increase in the global load of systemic inflamma‐
tion (Almeida et al., 2018; Grønkjær, 2015; Sanz et al., 2018). In
a systematic review, Grønkjær (2015) demonstrated that several
observational studies on the association between cirrhosis and
periodontitis are reported in the literature. However, the majority
of these studies present small samples and little robust definitions
of periodontitis, leading to conflicting results that need further
clarification.

J Clin Periodontol. 2019;46:991–998. wileyonlinelibrary.com/journal/jcpe   © 2019 John Wiley & Sons A/S. |  991
Published by John Wiley & Sons Ltd
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992       COSTA et al.
Cirrhosis is a condition in which a liver injury activates hepatic
stellate cells, leading to chronic inflammation and nodular fibrogen‐
esis (Di Profio et al., 2018). It is most commonly caused by alco‐
hol consumption, hepatitis (B and C) and non‐alcoholic fatty liver
disease (Angeli et al., 2018; Harris, Harman, Card, Aithal, & Guha,
2017). Typically, the consumption of more than two or three alco‐
holic drinks per day over a number of years is required for alcoholic
cirrhosis to occur. Non‐alcoholic fatty liver disease has a number
of causes, including overweight, autoimmune hepatitis diabetes,
high blood fat levels and high blood pressure (Angeli et al., 2018).
Cirrhosis diagnosis is based on blood testing, medical imaging and
liver biopsy. Cirrhotic individuals present impairment of innate and
adaptive immune responses that are associated with greater sus‐
ceptibility to systemic infections, such as bacteraemia and sponta‐
neous bacterial peritonitis (Angeli et al., 2018; Di Profio et al., 2018).
Some studies have addressed the relationship between periodon‐
tal disease and liver cirrhosis (Grønkjær, 2015). While studies re‐
ported a higher rate of periodontitis among cirrhotic individuals when
compared to controls (Åberg, Helenius‐Hietala, Meurman, & Isoniemi,
2014; Alazawi et al., 2017; Di Profio et al., 2018; Grønkjær,et al., 2018;
Jaiswal, Deo, Bhongade, & Jaiswal, 2011; Lins et al., 2011; Oettinger‐
Barak et al., 2001; Raghava, Shivananda, Mundinamane, Boloor, &
Thomas, 2013), others failed to indorse this finding (Guggenheimer,
Eghtesad, Close, Shay, & Fung, 2007; Movin, 1981; Novacek et al.,
1995). Additionally, other cirrhotic outcomes have been linked to
periodontitis and include the progression of liver disease, accelerated
Model for End‐Stage Liver Disease (MELD) scores (Åberg et al., 2014)
and the presence of systemic infections (Lins et al., 2011). Thus, ad‐
ditional conflicting data have been reported in the literature and they
have shown some controversial results and limitations.
Therefore, the aim of this case–control study was to evaluate the
association between liver cirrhosis and periodontitis, as well as the
influence of different risk factors on this association.
2 |  M ATE R I A L S A N D M E TH O DS
2.1 | Study sample and sampling strategy
Sample size calculation for the present case–control study was
based on an expected prevalence of periodontitis of 30% among
cirrhotic individuals compared to 15% among non‐liver disease
control ones (mean values from Grønkjær, 2015). Calculation was
carried out using the Fleiss method through the OpenEpi software
(Open Source Epidemiologic Statistics for Public Health, version
3.01, Boston, USA). Based on a significance level of 0.05, 80% study
power, and a case–control ratio of 1:2, a number of ~88 cases and
~175 controls were determined to be necessary.
Initial study sample comprised 380 individuals examined from
June/2008 to March/2015. All case individuals were selected
among 1,420 subjects from a single medical/dental waiting list
for health care in general practice at three Health Public Centres
from the west region of the city of Belo Horizonte, Brazil [database
from Lages et al. (2012) and Lages et al. (2015)]. Eligible individuals
Clinical Relevance
Scientific rationale for the study: The association between
immune‐mediated inflammatory diseases and periodontitis
has been widely studied and recognized each more over
the past few years. However, the relationship between
liver cirrhosis and periodontitis remains controversial.
Principal findings: A high prevalence of periodontitis was
observed in individuals with cirrhosis when compared to
controls; these individuals presented a chance of 2 up to
~3 times higher of having periodontitis.
Practical implications: Cirrhosis, as well the intensive alco‐
hol use, should be considered as a potential risk variable
for periodontitis.
for the case group initially comprised a convenience sample of 98
male and female adults, from 35 to 55 years of age, with an estab‐
lished diagnosis of liver cirrhosis based on either liver biopsy and/
or clinical, biochemical and ultrasonic findings. Eligible individuals
for the control group initially comprised 282 adults without liver
diseases that underwent the same data collection procedures,
from two previous cross‐sectional studies [databases from Lages
et al. (2012) and Cunha et al. (2019)]. Individuals from the control
group were examined at the same Health Public Centres and two
University Hospitals and presented the same socioeconomic pro‐
file of the case group.
After applying the exclusion criteria (age < 35 and >55 years,
use of systemic and topical antibiotic treatment within 3 months
prior to the start of the study; subgingival instrumentation within
12 months prior to the start of the study, and absence of complete
data of interest), a randomization process for the selection of con‐
trols were performed: for each two eligible controls, two envelopes
with “included” or “not included” were drawn until reaching the
proportion of two controls for each case. Therefore, the final sam‐
ple comprised of 98 cases and 196 controls. In attempt to reduce
variation resulting from a broad age range (Costa et al., 2009), the
present study focused on a main age group of 35–55 years.
The Research Ethics Committee from the Federal University of
Minas Gerais approved the study (protocol #0094.0.203.000‐10
and #CAAE30592413300005149). All procedures were in accor‐
dance with the ethical standards from 1964 Helsinki declaration and
its later amendments or comparable ethical standards. Written‐in‐
formed consent was obtained from all participants included in the
study.
2.2 | Sample characterization
Sample characteristics were determined through sex, age, number
of present teeth present, alcohol consumption, smoking (Tomar &
Asma, 2000), diabetes (American Diabetes Association, 2015), body
mass index (BMI), family income and last dental check‐up.
COSTA et al.
Alcohol consumption was stratified according to both: (a) CAGE
(Cut down, Annoyed, Guilty, Eye‐opener) questionnaire—made of
four questions, having scores ≥2 indicating alcohol dependence
(Masur & Monteiro, 1983; MayfieldMcleod & Hall, 1974); (b) AUDIT
(Alcohol Use Disorders Identification Test) questionnaire—made
of 10 questions, having scores >8 indicating alcohol use problems
(Saunders, Aasland, Babor, Fuente, & Grant, 1993). Therefore, par‐
ticipants were categorized into three groups: (a) none or occasional
alcohol use—never used or frequency of use less than monthly
(AUDIT and CAGE scores = 0); (b) moderate alcohol use—frequency
of use 2–4 times a month (AUDIT score ≤ 8 and CAGE score = 0);
(c) intense alcohol use—frequency of use ≥3 times a week (AUDIT
score > 8 and CAGE score ≥ 1).
2.3 | Periodontal clinical examination
Probing depth (PD), clinical attachment level (CAL), plaque index
(Turesky, Gimore, & Glickman, 1970) and bleeding on probing
(BOP) were evaluated through manual circumferential periodontal
probing (PCPUNC Hu‐Friedy®), recording the highest values for
each mesio‐buccal, buccal, disto‐buccal, mesio‐lingual, lingual and
disto‐lingual sites. The full‐mouth periodontal clinical examination
was performed by three trained experts in periodontics (F.O.C.,
F.A.C, and E.J.P.L).
2.4 | Intra‐ and inter‐examiners agreements
A pilot study comprising 12 individuals was performed in order to
determine intra‐ and inter‐examiner agreements for PD and CAL.
Analyses retrieved Kappa values for PD and CAL higher than 0.89
and intra‐class correlation coefficient higher than 0.90.
2.5 | Periodontitis definition and prevalence
The present study included individuals with moderate, severe or
advanced periodontitis [stage II, III and IV, respectively (Tonetti,
Greenwell, & Kornman, 2018)]. In relation the severity and com‐
plexity of management: (a) stage II (moderate periodontitis)—
established periodontitis with characteristic damages to tooth
support including inter‐dental CAL 3–4 mm, maximum PD ≤ 5 mm,
radiographic bone loss at the coronal third between 15–33%,
and no tooth loss due to periodontitis); (b) stage III (severe peri‐
odontitis)—at least inter‐dental CAL) ≥5  mm, radiographic bone
loss extending to mild‐third of the root; and tooth loss due to
periodontitis; (c) stage IV (advanced periodontitis)—inter‐dental
CAL ≥ 5 mm and presence of deep periodontal lesions that extend
to the apical portion of the root, and/or history of multiple tooth
loss. In relation to the extension, localized forms present <30%
of teeth involved and generalized forms present ≥30% of teeth
involved (Tonetti et al., 2018). Total periodontitis (periodontitis
case) was defined by the sum of moderate, severe and advanced
periodontitis stages.
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      993
2.6 | Model of end‐stage liver disease scores
The model for end‐stage liver disease (MELD) score (Kamath,
Wiesner, & Malinchoc, 2001), initially developed to predict survival
following transjugular intra‐hepatic portosystemic shunt, was sub‐
sequently found to be an accurate predictor of mortality among pa‐
tients with end‐stage liver disease. Since 2002, MELD score using
3 objective variables (serum bilirubin, serum creatinine and insti‐
tutional normalized ratio) has been used worldwide for listing and
transplanting patients with end‐stage liver disease allowing trans‐
planting sicker patients first irrespective of the wait time on the list.
MELD score is calculated using serum bilirubin, serum creatinine
and International Normalized Ratio (INR) by the formula 9.57 × loge
(creatinine) + 3.78 × loge (total bilirubin) + 11.2 × loge (INR) + 6.43.
In the interpretation of the MELD score in hospitalized patients, the
mortality in 3 months is as follows: 40 or more: 100%; 30–39:83%;
20–29:76%; 10–19:27%; and <10:4% mortality (Singal & Kamath,
2013). The score can be calculated using online website www.md‐
calc.com/meld-score-model-end-stage-liver-disea​se-12-older​.
2.7 | Statistical analysis
The statistical analysis included a descriptive characterization of
the sample, a univariate analysis and a multivariate logistic regres‐
sion. Study groups were initially compared in relation to the follow‐
ing variables: sex, age, family income, BMI, diabetes, smoking, last
dental check‐up and alcohol consumption through the chi‐square and
Mann–Whitney tests, when appropriate. In relation to periodontal pa‐
rameters (PI, BOP, PD, CAL), the values per individual were obtained
by the sum of the measures of all periodontal sites and expressed
as averages and/or percentages. In relation to the gradient effect, p
trend tests were performed using the chi‐square test for categorical
variables and the Spearman correlation for numerical variables.
Distribution of independent variables by periodontitis stage,
crude odds ratio (OR) and their 95% confidence intervals (CI) was
calculated. The effect of variables of interest in the presence of peri‐
odontitis was evaluated through multivariate logistic regression. To
evaluate the interaction effect of cirrhosis and alcohol consumption
as well as to avoid the effect of alcohol consumption as a confound‐
ing factor, three distinct logistic regression models stratified by al‐
cohol status (no/occasional use, moderate use and intensive alcohol
use) were created. Variables presenting a p‐value < .25 in the bivar‐
iate analysis were then included in each multivariate model for peri‐
odontitis [non‐cases (0) and cases (1)] and manually removed (step
by step) until the log‐likelihood ratio test indicated that no variable
should be removed. All variables included in the final multivariate
models were determined to be independent through the assessment
of their co‐linearity. The quality of the models was determined by
measures of sensitivity, specificity, area under the ROC (Receiver
Operating Characteristic) curve, R2 (Nagelkerke) and the Hosmer–
Lemeshow test. All analyses were performed using the statistical
software R.
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994       COSTA et al.

TA B L E 1   Association between
Controls
cirrhosis and variables of interest
Variables Cases (n = 98) (n = 196) Crude OR (95%CI) p* 

Age
≥35–45 18 (18.4%) 65 (33.4%) 1.0  
>45–55 80 (81.6%) 131 (66.4%) 2.20 (1.22–4.05) .003
Sex
Female 10 (10.2%) 60 (30.7%) 1.0  
Male 88 (89.8%) 136 (43.9%) 3.86 (1.92–8.34) <.001
BMI
≤25 kg/m2 28 (28.8%) 46 (23.5%) 1.0  
2
>25 kg/m 70 (71.2%) 150 (76.5%) 0.76 (0.44–1.39) .173
Smoking
No 31 (35.2%) 134 (68.4%) 1.0  
Yes 67 (64.8%) 62 (31.6%) 4.64 (2.76–7.89) <.001
Alcohol use
No/Former use 12 (12.2%) 57 (29.1%) 1.0  
Current use 86 (87.8%) 139 (70.9%) 2.92 (1.51–5.98) <.001
Diabetes
No 85 (86.8%) 174 (88.8%) 1.0  
Yes 13 (13.2%) 22 (11.2%) 1.20 (0.56–2.51) .304
Family income
Up to 2 BMW 54 (563%) 104 (53.8%) 1.0  
>2–4 BMW 44 (43.7%) 92 (47.2%) (0.66–1.77) .371
Last dental check‐up
<2 years 28 (28.4%) 30 (15.3%) 1.0  
>2 years 70 (71.6%) 166 (84.7%) 0.45 (0.25–0.81) .004

Note: BMI, body mass index; BMW, Brazilian minimum wage (equivalent to U$320).
*Chi‐square test.

3 |   R E S U LT S times in multivariate analysis (OR = 2.99; 95% CI 1.37–4.27; p = .001;

Sample comprised 294 individuals, being 224 men and 70 women,
mean age of 47.12 (±5.15) years in the control group and 49.3 (±6.9)
years in the case group. The following causes of cirrhosis were re‐
ported: alcohol use (72%), autoimmune cholestatic (17%), crypto‐
genic (10%), viral B and C hepatitis (3%), unknown (5%). Individuals
with cirrhosis had a MELD mean score of 12 (8–14 interquartile
range), which was not associated with the severity of periodontitis.
The mean alcohol use time in control and cases was 26.4 years (±9.7)
and 34.5 years (±10.4), respectively (p < .001). With respect to the
variables of interest, individuals with cirrhosis showed significantly
higher proportions of individuals with age ≥45  years (p = .003),
smoking (p < .001), alcohol use (p < .001) and lower number of dental
visits (p = .004). Other variables showed no significant differences
between the groups (Table 1).
A high prevalence of total periodontitis (stage II + III + IV) was
observed in the case group (62.2%) when compared to the control
group (41.8%). Individuals with cirrhosis presented a chance ~2 times
higher of having periodontitis than controls in the univariate anal‐
ysis (OR = 2.28; 95% CI 1.39–3.78; p < .001; Table 2) and up to ~3
Table 3). Additionally, stage and extension of periodontitis were as‐
sociated with cirrhosis (Table 2).
In relation periodontal clinical parameters, individuals with cir‐
rhosis presented with significantly worse parameters than individ‐
uals without cirrhosis, that is, smaller number of teeth, higher mean
PI, higher mean number of sites with BOP, PD and CAL, higher per‐
centage of sites with PD 4–6 mm and PD ≥ 6mm, higher percentage
of sites with CAL ≥ 3mm and CAL ≥ 5mm (Table 2).
Table 3 shows 3 final logistic regression models stratified by al‐
cohol status with significant variables and adjusted OR estimates
for total periodontitis: (a) Model 1 (no/occasional alcohol use)—
number of teeth up 14, age >45–55 years, male sex and smoking;
(b) Model 2 (moderate alcohol use) and Model 3 (intensive alcohol
use)—cirrhosis, number of teeth up 14, age >45–55 years, male sex
and smoking (Table 3). Moreover, an adjusted OR of 2.03 (95% CI
1.31–3.82; p = .001) for cirrhosis in the association with periodontitis
was demonstrated, independently from the alcohol use status (data
no show).
Despite the persistence of the same variables in the final models
2 and 3 (moderate and intensive alcohol use, respectively), it was
COSTA et al. |
      995

TA B L E 2   Periodontal clinical
Controls Crude OR (95%
parameters of the individuals in the
Variables Cases (n = 98) (n = 196) CI) p
sample
Total periodontitis (Stage II + III + IV)
No 37 (37.8%) 114 (58.2%) –  
Yes 61 (62.2%) 82 (41.8%) 2.28 (1.39 to 3.78) <.001* 
Stage of periodontitis*** 
Moderate (stage II) 40 (65.6%) 50 (61.0%) 2.45 (1.40–4.31) <.001* 
Severe and advanced 21 (34.4%) 32 (39.0%) 2.01 (1.02–3.92) .020* 
(stage III or IV)
Extension of periodontitis total*** 
Localized (<30% of 41 (71.4%) 61 (75.5%) 2.06 (1.19–3.57) .004*
teeth involved)
Generalized (≥30% of 17 (28.6%) 20 (24.5%) 2.60 (1.22–5.31) .006* 
teeth involved)
Number of teeth (%)
Up 14 37 (37.8%) 34 (17.2%) 3.03 (1.63 to 5.69) <.001* 
14–20 30 (30.6%) 75 (38.4%) 1.12 (0.61 to 2.03) .351* 
>20 31 (31.6%) 87 (44.4%) 1.0  
Plaque index 2.58 ± 0.69 1.59 ± 0.76 – <.001** 
BOP (%) 53.2 ± 32.1 44.5 ± 30.9 – .027** 
PD (mm) 2.9 ± 1.9 2.4 ± 1.2 – <.001**
CAL (mm) 4.9 ± 1.9 4.1 ± 1.6 – .044** 
% sites with BOP 23.6 ± 17.2 19.2 ± 18.3 – .045**
% sites with PD < 4MM 81.8 ± 19.0 82.0 ± 14.9 – .004** 
% sites with 4−6MM 14.9 ± 7.6 10.2 ± 5.6 – <.001** 
% sites PD > 6MM 3.9 ± 1.7 2.1 ± 1.2 – <.001** 
% sites with CAL < 4MM 31.6 ± 8.4 30.2 ± 6.4 – <.001** 
% sites with CAL ≥ 5MM 20.7 ± 22.6 18.6 ± 19.3 – .065** 

Note: BOP, bleeding on probing; PD, probing depth; CAL, clinical attachment level; mean ± SD,
(median). Significant p‐values are shown in bold.
*Chi‐square test.
**Mann–Whitney Test
***Reference: no periodontitis.

observed higher OR estimate for periodontitis with the increased
alcohol exposure gradient (Table 3). BMI, diabetes, family income <2
BMS and last dental check‐up not significantly associated with peri‐
odontitis in the multivariate regression models.
4 | D I S CU S S I O N
The relationship between periodontal diseases and systemic con‐
ditions with different inflammatory profiles has been studied and
there is emerging evidence that some conditions such as diabetes,
obesity, cardiovascular disease and rheumatoid arthritis may influ‐
ence the presence and severity of periodontitis (Almeida et al., 2018;
Bartold & Marriot, 2017; Sanz et al., 2018).
In this scenario, periodontitis, as well as cirrhosis, is influenced
by different components of the host immune system. Common
inflammatory mediators have been previously described in both
conditions (Di Profio et al., 2018; Grønkjær, 2015). The biological
plausibility for the association between periodontitis and cirrho‐
sis have been explained by the following mechanisms reported by
Di Profio et al. (2018): (a) cirrhosis leads to several abnormalities
in innate and adaptive immune response, such as impaired neu‐
trophil function; (b) efficiencies of the complement system; (c)
reduction in the number and function of monocytes; (d) reduced
number and dysfunction of T and B lymphocytes; (e) dysfunction
of natural killer cells. Furthermore, cirrhosis is associated with en‐
hanced pro‐inflammatory response and upregulated expression of
cell activation markers. It could be speculated that the immune
response impairment, which is associated with greater suscepti‐
bility for systemic infections, may also play a role in determining
an increased risk for periodontitis. However, there are no studies
validating this biological plausibility. Therefore, these hypothetical
arguments were pointed out as a possible explanation for asso‐
ciation between periodontitis (exposure) and cirrhosis (outcome).
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996       COSTA et al.

TA B L E 3   Final logistic regression models for total periodontitis by alcohol use status

Model 1 Model 2 Model 3

No/occasional alcohol use (n = 69) Moderate alcohol use (n = 145) Intensive alcohol use (n = 80)

Variables OR 95% CI p OR 95% CI p OR 95% CI p

Cirrhosis 0.36 0.33–1.14 .443 1.99 1.17–2.78 .029 2.99 1.37–4.27 .001
Number of teeth up 1.81 1.09–2.03 .002 2.27 1.18–3.92 .001 3.21 1.62–4.47 <.001
to 14
Age > 45–55 years 1.39 0.86–1.99 .037 1.92 1.09–2.76 .001 2.77 1.33–3.19 .001
Sex (male) 1.85 0.96–2.05 .003 1.96 1.28–2.68 .001 3.45 1.12–4.03 .001
Smoking 3.04 1.16–3.98 <.001 4.26 2.91–6.17 <.001 6.98 2.96–11.03 <.001
2
Note: Dependent variable: total periodontitis (Stage II + III + IV); Hosmer–Lemeshow test (p = 0.045); Pseudo R : 40.2; area under the Receiver
Operating Curve (ROC) for the models: model 1—0.725; model 2—0.767; model 3—0.711.

Furthermore, it is clear that in an observational study the direction
of association cannot be clearly established. Thus, future studies
focusing especially on the biological mechanisms, strength and
direction of the association between cirrhosis and periodontitis
should be conducted.
In the present study, it was observed that individuals with cirrho‐
sis presented with significantly worse periodontal clinical parameters
than individuals without cirrhosis. Thus, a high prevalence of peri‐
odontitis was observed among cases (62.2%) when compared to con‐
trols (41.8%). In addition, individuals with cirrhosis presented a chance
approximately 2 to up ~3 times higher of having periodontitis than
controls in the multivariate analysis. Moreover, the severity and ex‐
tension of periodontitis were associated with cirrhosis. These findings
are similar with other studies conducted in the Brazilian population
(Di Profio et al., 2018; Lins et al., 2011). Grønkjær (2015) in a previous
systematic review reported a prevalence of periodontitis varying from
25% to 68% with different criteria to its definition. Additionally, par‐
ticipants with cirrhosis and with no or occasional alcohol use did not
present a higher chance of having periodontitis than controls.
A positive association between cirrhosis and periodontitis was
initially reported by Sandler and Stahl (1960). Further, observational
studies have confirmed these findings (Aberg et al., 2014; Alazawi et
al., 2017; Di Profio et al., 2018; Jaiswa et al., 2011; Lins et al., 2011;
Oettinger‐Barak et al., 2001; Raghava et al., 2013). However, other
studies failed to report this association (Guggenheime et al., 2007;
Movin, 1981; Novacek et al., 1995). Frequent potential biases can be
observed in several studies such as the use of retrospective data ob‐
tained from medical records, indexes or radiograph exams for char‐
acterizing periodontitis, small samples, self‐reported information on
periodontal and cirrhosis conditions.
Alcohol is an established risk factor for cirrhosis. In patients with
concomitant liver diseases, a synergistic effect on fibrosis progres‐
sion and high consumption of alcohol is evident (Angeli et al., 2018;
Hagström, 2017). To evaluate the interaction effect of cirrhosis
and alcohol consumption, as well as to avoid the effect of alcohol
consumption as confounding factor, three distinct models logistic
regression stratified by alcohol status (no/occasional use, moderate
use, and intensive alcohol use) were performed. The final multivari‐
ate model for periodontitis in no/occasional alcohol use individuals
showed that up to 14 teeth and smoking were associated with peri‐
odontitis. On the hand, the final multivariate models for periodon‐
titis in moderate and intensive alcohol use individuals revealed that
cirrhosis, number of teeth up to 14, age >45 years, male sex, and
smoking remained significantly associated with periodontitis.
Tooth loss is considered the final outcome of oral diseases that
affect periodontal and dental tissues. It strongly impacts the oral
health‐related quality of life. In this present study, individuals with
cirrhosis presented significantly lower number of teeth than con‐
trols. Similar results were reported in previous studies (Costa et al.,
2014; Guggenheimer et al., 2007; Lins et al., 2011). Age (≥45 years
old) was retained in the final multivariate model, showing a poten‐
tial cumulative effect of time in clinical AL. Thus, several studies
have shown an association between older age and AL (Demmer &
Papapanou, 2010; Costa et al., 2012; Costa et al., 2014).
In general, the majority of evidence indicates that smokers are at
increased risk for the presence of unresponsive periodontal pockets
and further periodontal breakdown. Moreover, two‐ to sevenfold
higher risk for periodontitis were reported in current smokers when
compared to former/non‐smokers (Al Harthi et al., 2019; Nociti,
Casati, & Duarte, 2015; Ryder, Couch, & Chaffee, 2018).
Some limitations must be attributed to the present study though.
The convenience sample may have some impacts on the external va‐
lidity of the results, and the case–control design does not detect any
temporal influence among cirrhosis and periodontitis. Other issue is
that case–control studies are susceptible to selection bias, as both
the exposure and disease/outcome have occurred by the time the
patient is recruited into the study. However, our sample was re‐
cruited of the same Health Public Centres and University Hospital
with homogeneous risk variables. In addition, the prevalence of cir‐
rhosis is determined to be low at around 2–4% (Harris et al., 2017),
representing difficulties towards obtaining large samples. Studies
comprising larger samples and prospective designs, including micro‐
biological and immunological analysis, would be of paramount im‐
portance to provide more precise conclusions on periodontal status
of individuals with liver cirrhosis.
Our results are an important starting point to further studies
with intervention designs, as well as higher methodological rigour, so
as the direction and causality of this association can be consolidated.
COSTA et al. |
      997

5 | CO N C LU S I O N S Di Profio, B., Inoue, G., Marui, V. C., de França, B. N., Romito, G. A.,
Ortega, K. L., … Pannuti, C. M. (2018). Periodontal status of liver
transplant candidates and healthy controls. Journal of Periodontology,
Overall, the present study demonstrated an important risk associa‐
89, 1383–1389. https​://doi.org/10.1002/JPER.17-0710
tion between liver cirrhosis and periodontitis. Additionally, the in‐ Grønkjær, L. L. (2015). Periodontal disease and liver cirrhosis: A system‐
tensive alcohol use strongly increased the risk for periodontitis. atic review. SAGE Open Medical, 3, 2050312115601122. https​://doi.
org/10.1177/20503​12115​601122
Grønkjær, L. L., Holmstrup, P., Schou, S., Kongstad, J., Jepsen, P., &
C O N FL I C T O F I N T E R E S T Vilstrup, H. (2018). Periodontitis in patients with cirrhosis: A cross‐
sectional study. BMC Oral Health, 18, 22. https​://doi.org/10.1186/
The authors declare that there are no conflicts of interest. s12903-018-0487-5
Guggenheimer, J., Eghtesad, B., Close, J. M., Shay, C., & Fung, J. J.
(2007). Dental health status of liver transplant candidates. Liver
Transplantation, 13, 280–286. https​://doi.org/10.1002/lt.21038​
ORCID
Hagström, H. (2017). (2017) Alcohol, smoking and the liver disease pa‐
tient. Best Practice Research Clinical Gastroenterol, 31(5), 537–543.
Fernando Oliveira Costa  https://orcid.org/0000-0002-7687-1238
https​://doi.org/10.1016/j.bpg.2017.09.003
Luís Otávio Miranda Cota  https://orcid.org/0000-0003-1517-5842 Harris, R., Harman, D. J., Card, T. R., Aithal, G. P., & Guha, I. N. (2017).
Prevalence of clinically significant liver disease within the general
population, as defined by non‐invasive markers of liver fibrosis: A sys‐
tematic review. Lancet Gastroenterology and Hepatology, 2, 288–297.
REFERENCES
Jaiswal, G., Deo, V., Bhongade, M., & Jaiswal, S. (2011). Serum alkaline
phosphatase: A potential marker in the progression of periodontal
Åberg, F., Helenius‐Hietala, J., Meurman, J., & Isoniemi, H. (2014).
disease in cirrhosis patients. Quintessence International, 42, 345–348.
Association between dental infections and the clinical course of
Kamath, P. S., Wiesner, R. H., & Malinchoc, M. (2001). A model to pre‐
chronic liver disease. Hepatology Research, 44, 349–353. https​://doi.
dict survival in patients with end‐stage liver disease. Hepatology, 33,
org/10.1111/hepr.12126​
464–470.
Al Harthi, S. S. Y., Natto, Z. S., Midle, J. B., Gyurko, R., O'Neill, R., &
Kinane, D. F., & Bartold, P. M. (2007). Clinical relevance of the host re‐
Steffensen, B. (2019). Association between time since quitting smok‐
sponses of periodontitis. Periodontology 2000, 43, 278–279. https​://
ing and periodontitis in former smokers in the National Health and
doi.org/10.1111/j.1600-0757.2006.00169.x
Nutrition Examination Surveys (NHANES) 2009 to 2012. Journal of
Lages, E. J. P., Costa, F. O., Cortelli, S. C., Cortelli, J. R., Cota, L. O. M.,
Periodontology, 90, 16–25. https​://doi.org/10.1002/JPER.18-0183
Cyrino, R. M., … Gomez, R. S. (2015). Alcohol consumption and peri‐
Alazawi, W., Bernabe, E., Tai, D., Janicki, T., Kemos, P., Samsuddin, S., …
odontitis: Quantification of periodontal pathogens and cytokines.
Turner, W. (2017). Periodontitis is associated with significant hepatic
Journal of Periodontolology, 86, 1058–1068. https​://doi.org/10.1902/
fibrosis in patients with non‐alcoholic fatty liver disease. PLoS ONE,
jop.2015.150087
8(12), e0185902. https​://doi.org/10.1371/journ​al.pone.0185902
Lages, E. J. P., Costa, F. O., Lages, E. M. B., Cota, L. O. M., Cortelli, S.
Almeida, A. P. C. P. S. C., Fagundes, N. C. F., Maia, L. C., & Lima, R. R.
C., Nobre‐Franco, G. C., … Cortelli, J. R. (2012). Risk variables in the
(2018). Is there an association between periodontitis and atheroscle‐
association between frequency of alcohol consumption and peri‐
rosis in adults? A systematic review. Current Vascular Pharmacology,
odontitis. Journal of Clinical Periodontology, 39, 115–122. https​://doi.
16, 569–582.
org/10.1111/j.1600-051X.2011.01809.x
American Diabetes Association (2015). Classification and diagnosis of
Lins, L., Bittencourt, P. L., Evangelista, M. A., Lins, R., Codes, L.,
diabetes mellitus. Diabetes Care, 38, S8–S16.
Cavalcanti, A. R., … Bastos, J. (2011). Oral health profile of cirrhotic
Angeli, P., Bernardi, M., Villanueva, C., Francoz, C., Mookerjee, R. P.,
patients awaiting liver transplantation in the Brazilian Northeast.
Trebicka, J., … Gines, P. (2018). EASL clinical practice guidelines
Transplantation Procedures, 43, 1319–1321. https​://doi.org/10.1016/j.
for the management of patients with decompensated cirrhosis.
trans​proce​ed.2011.03.063
European Association for the study of the liver. Journal of Hepatology,
Masur, J., & Monteiro, M. G. (1983). Validation of the "CAGE" alcohol‐
69, 406–460. https​://doi.org/10.1016/j.jhep.2018.03.024
ism screening test in a Brazilian psychiatric inpatient hospital setting.
Bartold, M., & Marriot, P. P. (2017). The future of periodontal‐systemic
Brazilian Journal of Medical Biology Research, 16, 215–218.
associations: Raising the standards. Current Oral Health Reports, 4,
Mayfield, D., Mcleod, G., & Hall, P. (1974). The CAGE questionnaire:
258–262. https​://doi.org/10.1007/s40496-017-0150-2
Validation of a new alcoholism screening instrument. American
Costa, F. O., Guimarães, A. N., Cota, L. O. M., Pataro, A. L., Segundo, T. K.,
Journal of Psychiatry, 131, 1121–1123.
Cortelli, S. C., & Costa, J. E. (2009). Impact of different periodontitis
Mendes, V. S., Cota, L. O. M., Costa, A. A., Oliveira, A. M. S. D., &
case definitions on periodontal research. Journal of Oral Science, 51,
Costa, F. O. (2019). Periodontitis as another comorbidity associated
199–206. https​://doi.org/10.2334/josnu​sd.51.199
with psoriasis: A case‐control study. Journal of Periodontology, 90,
Costa, F. O., Lages, E. J. P., Cota, L. O. M., Lorentz, T. C. M., Soares, R. V., &
358–366.
Cortelli, J. R. (2014). Tooth loss in individuals under periodontal main‐
Movin, S. (1981). Relationship between periodontal disease and cirrhosis
tenance therapy: 5‐year prospective study. Journal of Periodontal
of the liver in humans. Journal of Clinical Periodontology, 4, 450–458.
Research, 49, 121–128. https​://doi.org/10.1111/jre.12087​
https​://doi.org/10.1111/j.1600-051X.1981.tb008​94.x
Cunha, F. A., Cota, L. O. M., Cortelli, S. C., Miranda, T. B., Neves, F. S.,
Nociti, F. H. Jr, Casati, M. Z., & Duarte, P. M. (2015). Current perspective
Cortelli, J. R., & Costa, F. O. (2019). Periodontal condition and levels
of the impact of smoking on the progression and treatment of peri‐
of bacteria associated with periodontitis in individuals with bipo‐
odontitis. Periodontology, 67, 187–210.
lar affective disorders: A case‐control study. Journal of Periodontal
Novacek, G., Plachetzky, U., Pötzi, R., Lentner, S., Slavicek, R., Gangl, A.,
Research, 1, 63–72. https​://doi.org/10.1111/jre.12605​
& Ferenci, P. (1995). Dental and periodontal disease in patients with
Demmer, R. T., & Papapanou, P. N. (2010). Epidemiologic patterns of
cirrhosis – role of etiology of liver disease. Journal of Hepatology, 22,
chronic and aggressive periodontitis. Periodontol, 53, 28–44. https​://
576–582. https​://doi.org/10.1016/0168-8278(95)80453-6
doi.org/10.1111/j.1600-0757.2009.00326.x
 |
998       COSTA et al.
Oettinger‐Barak, O., Barak, S., Machtei, E. E., Ardekian, L., Baruch, Y.,
& Peled, M. (2001). Periodontal changes in liver cirrhosis and post‐
transplantation patients I: Clinical findings. Journal of Periodontology,
72, 1236–1240. https​://doi.org/10.1902/jop.2000.72.9.1236
Raghava, K. V., Shivananda, H., Mundinamane, D., Boloor, V., & Thomas, B.
(2013). Evaluation of periodontal status in alcoholic liver cirrhosis pa‐
tients: A comparative study. Journal of Contemporary Dental Practice,
14, 179–182. https​://doi.org/10.5005/jp-journ​als-10024-1296
Ryder, M. I., Couch, E. T., & Chaffee, B. W. (2018). Personalized peri‐
odontal treatment for the tobacco‐ and alcohol‐using patient.
Periodontology, 78, 30–46. https​://doi.org/10.1111/prd.12229​
Sandler, H. C., & Stahl, S. S. (1960). Prevalence of periodontal disease in
a hospitalized population. Journal of Dental Research, 39, 439–449.
https​://doi.org/10.1177/00220​3 4560​03900​3 0401​
Sanz, M., Ceriello, A., Buysschaert, M., Chapple, I., Demmer, R. T.,
Graziani, F., … Vegh, D. (2018). Scientific evidence on the links be‐
tween periodontal diseases and diabetes: Consensus report and
guidelines of the joint workshop on periodontal diseases and dia‐
betes by the International Diabetes Federation and the European
Federation of Periodontology. Journal of Clinical Periodontology, 45,
138–149. https​://doi.org/10.1111/jcpe.12808​
Saunders, J. B., Aasland, O. G., Babor, T. F., De la Fuente, J. R., & Grant,
M. (1993). Development of the alcohol use disorders identification
test (AUDIT): WHO Collaborative project on early detection of per‐
sons with harmful alcohol consumption–II. Addiction, 88, 791–804.
https​://doi.org/10.1111/j.1360-0443.1993.tb020​93.x
Shaikh, H. F. M., Patil, S. H., Pangam, T. S., & Rathod, K. V. (2018).
Polymicrobial synergy and dysbiosis: An overview. Journal of Indian
Society of Periodontology, 22, 101–106.
Singal, A. K., & Kamath, P. (2013). Model for end‐stage liver disease.
Journal of Clinical Experimental Hepatology, 3, 50–60. https​ ://doi.
org/10.1016/j.jceh.2012.11.002
Tomar, S. L., & Asma, S. (2000). Smoking‐attributable periodontitis in
the United States, findings from NHANES III. National Health and
Nutrition Examination Survey. Journal of Periodontology, 71, 743–751.
https​://doi.org/10.1902/jop.2000.71.5.743
Tonetti, M. S., Greenwell, H., & Kornman, K. S. (2018). Staging and
grading of periodontitis: Framework and proposal of a new clas‐
sification and case definition. Journal of Clinical Periodontology, 45,
S149–S161.
Turesky, S., Gimore, N. D., & Glickman, I. (1970). Reduced plaque
formation by the chloromethyl analogue of victamine C. Journal
of Periodontology, 41, 41–43. https​ ://doi.org/10.1902/jop.1970.
41.41.41
How to cite this article: Costa FO, Lages EJP, Lages EMB,
Cota LOM. Periodontitis in individuals with liver cirrhosis: A
case–control study. J Clin Periodontol. 2019;46:991–998.
https​://doi.org/10.1111/jcpe.13172​