Archives of Oral Biology 87 (2018) 180–190

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Archives of Oral Biology

journal homepage: www.elsevier.com/locate/archoralbio

Review

Association between developmental defects of enamel and celiac disease: A T

meta-analysis
Débora Souto-Souzaa, Maria Eliza da Consolação Soaresa, Vanessa Silva Rezendea,
⁎
Paulo César de Lacerda Dantasb, Endi Lanza Galvãoc, Saulo Gabriel Moreira Falcib,
a
Department of Pediatric Dentistry, Federal University of the Jequitinhonha and Mucuri Valleys, Diamantina, Minas Gerais, Brazil
b
Department of Oral and Maxillofacial Surgery, Federal University of the Jequitinhonha and Mucuri Valleys, Diamantina, Minas Gerais, Brazil
c
Clinical Research and Public Policy in Infectious and Parasitic Diseases, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Fiocruz, Belo Horizonte, Minas
Gerais, Brazil

A R T I C L E I N F O A B S T R A C T

Keywords: Objectives: Studies have observed the presence of extra-intestinal manifestations of celiac disease (CD), including
Celiac sprue involvement of the oral cavity, such that developmental defects of enamel (DDE) occur. Thus, the aim of this
Dental enamel review was to access the polled prevalence of DDE in individuals with CD, and to establish the strength of the
Enamel hypoplasia association between these two variables.
Epidemiology
Methods: To carry out the systematic review, four electronic databases and the Grey Literature were searched,
complemented by a manual search of reference lists within the selected articles. Two pairs of independent
reviewers selected the articles, and perform the data extractions and bias risk assessment Studies evaluating the
presence of DDE in individuals with CD as well as in healthy individuals and which performed the DDE diagnosis
by direct visualization of tooth enamel changes and the CD diagnosis were included. Meta-analyses were per-
formed using the software R.
Results: Of 557 studies, 45 were selected for review, encompassing 2840 patients. The prevalence of DDE in
people with CD was 50% (95% CI 0.44–0.57, I2 = 88%). In a general analysis, it was observed that patients with
CD had a significantly higher prevalence of enamel defects compared to healthy people (RR: 2.31, 95% CI:
1.71–3.12, I2 = 98%). Only developmental defects of enamel diagnosed using Aine’s method were associated
with the disease (RR: 3.30, 95% CI 2.39–4.56, I2 = 75%). In a sensitivity analysis involving the deciduous, mixed
and permanent dentitions, only individuals with deciduous dentition were observed to have association with the
disease (RR: 2.34, 95% CI 1.25–4.39, I2 = 39%).
Conclusions: Patients with enamel developmental defects should be screened for the possibility of their having
celiac disease.

1. Introduction
Celiac Disease (CD), an autoimmune disease present in genetically
predisposed individuals, is characterized by an inflammatory reaction
in the intestinal villi caused by the ingestion of foods containing gluten
(Schuppan, Esslinger, & Dieterich, 2003). Malabsorption of nutrients,
such as iron, calcium and fat-soluble vitamins is consequence of this
disease (Rashid et al., 2011). Epidemiological data show that CD is
common around the world, occurring at rates approaching 1% of the
population (Green & Cellier, 2007), and affecting not only Europeans,
but also the population of South Asia, South Africa, South America
(Cataldo & Montalvo, 2007). Until recently, CD has been considered a
rare disease in the United States, but studies have shown that CD may
affect as many as 3 million Americans (NIH Consensus Development
Conference on Celiac Disease, 2005), indicating that the disease may be
underestimated in North America (Fasano et al., 2003).
CD is one of the most significant causes of chronic malabsorption of
nutrients in children. Affected children may also report diarrhea, ab-
dominal pain and growth defects. Symptoms in adulthood include an-
emia, fatigue, weight loss, diarrhea, constipation, infertility, neurolo-
gical symptoms and osteoporosis (Sollid, 2000). Although the disease
may be hidden in the sense that it, present minimal symptoms, the
persistence of gluten in the diet, even in small amounts, has been as-
sociated with the presence of malignancy, mainly small intestine non-

⁎
Corresponding author at: Department of Oral and Maxillofacial Surgery, Federal University of the Jequitinhonha and Mucuri Valleys, 187 Street Rua da Glória, Centro, 39.100-000,
Diamantina City, Minas Gerais State, Brazil.
E-mail address: saulofalci@hotmail.com (S.G.M. Falci).

https://doi.org/10.1016/j.archoralbio.2017.12.025
Received 18 May 2017; Received in revised form 19 December 2017; Accepted 23 December 2017
0003-9969/ © 2017 Elsevier Ltd. All rights reserved.
D. Souto-Souza et al.
Hodgkin's lymphoma (Polanco, 2000). This shows the importance of
early diagnosis and appropriate treatment.
The presence of extra-intestinal manifestations, including involve-
ment of the oral cavity, such as dental enamel depigmentation and
hypoplasia can be found in CD patients and has already been reported
(Aine, Maki, Collin, & Keyrilainen, 1990; Acar et al., 2012; Amato et al.,
2017; El-Hodhod et al., 2012; Majorana et al., 2010; Ortega Paez et al.,
2008; Queiroz et al., 2017). Moreover, patients with CD may experience
a delay in tooth eruption (Pastore et al., 2008). These developmental
defects of enamel (DDE) in CD patients have been described by Aine
et al. (1990) as typical alterations, where the defects affect the teeth in
a symmetrical and chronological manner. According to Avsar and
Kalayci (2008), they are most commonly found in permanent dentition.
Studies have reported a higher prevalence of these defects in patients
with CD, ranging from 38% to 83% (Aguirre et al., 1997; Wierink et al.,
2007).
Majorana et al. (2010) conducted an investigation on the prevalence
of DDE in individuals with CD as compared to healthy individuals and
found that 46.4% of those suffering from the disease had enamel de-
fects, compared to 5.6% of the healthy group. Other, more recent,
comparative studies have confirmed this result (Cantekin, Arslan, &
Delikan, 2015; Dane & Gurbuz, 2016; de Carvalho et al., 2015). How-
ever, there are also studies in which the association was not found
(Procaccini et al., 2007; Shteyer et al., 2013)and the cause of the pos-
sible association remains controversial. Although no consensus has
been reached so far, studies suggest that hypocalcaemia, caused by the
malabsorption syndrome in the intestine (Nikiforuk & Fraser, 1981)
may be associated with the presence of DDE in patients with CD. In
recent years, although the pathogenesis of CD has not yet been fully
unraveled, it has become clear that immunological mechanisms
(Borrelli et al., 2013) and genetic factors (Mariani et al., 1994) may be
associated with the presence of DDE in patients with CD.
In 2008 and 2012, systematic reviews were carried out in order to
prove the existence of an association between CD and DDE, however
the evidence was not compiled in a meta-analysis (Giuca, Cei, Gigli, &
Gandini, 2010; Pastore et al., 2008). Consequently, even after the
publication of these studies, several further studies seeking to clarify
this association were performed (Cantekin et al., 2015; Dane & Gurbuz,
2016; de Carvalho et al., 2015; Majorana et al., 2010; Mina et al., 2012;
Ouda et al., 2010). Intestinal biopsy is the gold standard for the diag-
nosis of CD and, because it is a very invasive procedure, noninvasive
monitoring methods are being developed to select its indications
(Dewar, Pereira, & Ciclitira, 2004). In this sense, it has been observed
that the oral cavity is a direct and simple place to perform examina-
tions, that may facilitate the investigation of CD’s symptoms, since DDE
may be an indication for CD (Ortega Paez et al., 2008). Therefore, the
objective of this systematic review was to access the prevalence of DDE
in individuals with CD, and to establish the strength of the association
of these two variables.
2. Methods
The present systematic review was performed according to the
MOOSE Guidelines for Meta-Analyses and Systematic Reviews of
Observational Studies (Stroup et al., 2000) and was recorded in the
International Prospective Record of Systematic Reviews (PROSPERO
protocol CRD42017055414). The clinical question: “Does DDE affect
more individuals with CD than healthy individuals?” was formulated,
and the PECO strategy (Population, Exposure, Comparison, Outcome)
was: P- people who underwent dental evaluation; E- individuals af-
fected by CD; C- individuals without CD and O- presence of DDE.
Four electronic databases were searched with a cutoff in December
2017. There were: PubMed (www.pubmed.gov), Web of Sciences
(http://www.isiknowledge.com), Science Direct (www.sciencedirect.
com) and Virtual Health Library (Http://bvsalud.org/); all of which
place no restrictions on publication date and language. The search
181
Archives of Oral Biology 87 (2018) 180–190
strategies and the filters used are described in the Supplementary
Appendix. A manual search was also performed from the lists of re-
ferences in the included studies. Furthermore, the grey literature
(Google Scholar and Open Grey) was searched with a cutoff of November
2017.
Cross-sectional, case-control and cohort studies that evaluated the
presence of DDE in individuals with CD, as well as in healthy in-
dividuals, were included. The diagnosis of DDE was required to be
performed by oral clinical evaluation through the direct visualization of
tooth enamel changes. Exclusion criteria were: animal studies, case
reports, case series, laboratory studies and conference summaries.
The electronic search was performed by two pairs of independent
reviewers (pair 1: DSS and VSR, pair 2: PCLD and MECS), which were
calibrated using the Cohen Kappa Test (κ) according to the inclusion/
exclusion criteria using a sample of 20% of the studies recovered. After
the search, the article selected were inserted in the End Note® program
(End Note, Thomson Reuters, version x7) to exclude duplicates.
Subsequently, the evaluation of the titles and abstracts was performed
to screeng the papers according to the eligibility criteria for the full text
evaluation after which the studies for inclusion in the qualitative and
quantitative evaluations were determined.
Descriptive data of clinical or methodological factors such as loca-
tion, type of study, sample, age, DDE diagnosis, enamel defect type,
assessed dentition and DDE prevalence results, were extracted. In the
case of lost or confusing data, the researchers contacted the authors via
e-mail.
After selecting the papers, the scientific relevance of each was in-
dependently assessed by the same reviewers, and any divergence in the
evaluation was solved by consensus.
The evaluation of the quality of each of the studies’ was performed
using the Newcastle-Ottawa Scale (Wells et al., 2016) for the case-
control and cohort studies and the modified version was used for the
cross-sectional studies (Herzog et al., 2013), both of which evaluated
the methodological quality of the study through a system of scores/
stars. The risk of bias was evaluated for each of the studies in question
from the scale for all included studies taking consideration of three
main aspects: selection, comparability and exposure/outcome. When an
item was considered and described in the article, a score of one or two
stars indicated a low risk of bias for the item evaluated (Higgins &
Altman, 2012). The maximum score was nine stars.
The R software, version 3.2.2, was used to perform the meta-ana-
lysis with the “meta” and “metafor” packages activated. Heterogeneity
was assessed using the I2 test and was considered high when the I2
value was > 50%. The random effects model was considered for all
analyses since I2 was > 0. For all variables, the Relative Risk (RR) for
the presence of DDE in patients with CD compared to healthy patients
was calculated. For each analysis a Forest Plot was generated. Analyses
for the presence of publication bias were performed whenever the
number of studies reporting a particular variable of interest was greater
than 10. For the comparative meta-analyses, Egger's test was used,
while the Begg test was used for the prevalence. A possibility of pub-
lication bias was present when p < 0.05.
3. Results
The search identified a total of 557 articles which were transferred
to the End Note® program and the duplicates removed, leaving a total of
remaining 409 articles. The list provided to the program was analyzed
and articles were selected based on the titles and abstracts by two pairs
of independent reviewers (pair 1: DSS and VSR, pair 2: PCLD and
MECS), which were calibrated according to the criteria of inclusion/
exclusion, using a sample of 20% of the studies recovered. The agree-
ment between the reviewers was κ = 0.85 and κ = 0.86, respectively.
Any disagreement over the selection of studies was resolved by con-
sensus among the researchers.
A total of 76 articles were finally selected for full reading 45 of
D. Souto-Souza et al.
which met the eligibility criteria and were included in this systematic
review. −Forty studies, with a total of 2840 subjects with CD, were
included in the meta-analysis. Fig. 1 illustrates the entire process re-
lating to the screening of the articles.
Of the 45 studies included (Acar et al., 2012; Aguirre et al., 1997;
Aine, 1986; Aine et al., 1990; Amato et al., 2017; Andersson-Wenckert,
Blomquist, & Fredrikzon, 1984; Avsar & Kalayci, 2008; Bolgul et al.,
2009; Bucci et al., 2006; Campisi et al., 2007; Cantekin et al., 2015;
Cheng et al., 2010; Coloma, 2013; Costacurta et al., 2010; Cruz, 2016;
Dane & Gurbuz, 2016; de Carvalho et al., 2015; El-Hodhod et al., 2012;
Erriu et al., 2011; Erriu et al., 2013; Ertekin et al., 2012; Farmakis,
Puntis, & Toumba, 2005; Giammaria, Ciavarelli Macozzi, & Giammaria,
1996; Lahteenoja et al., 1998; Lopes, Barbieri, & Ando, 2001; Majorana
et al., 2010; Marcos, 2008; Mariani et al., 1994; Martelossi et al., 1996;
Mina, 2008; Mina et al., 2012; Orta et al., 2004; Ortega Paez et al.,
2008; Ouda et al., 2010; Petrecca, Giammaria, & Giammaria, 1994;
Prati, Santopadre, & Baroni, 1987; Priovolou, Vanderas, &
Papagiannoulis, 2004; ; Procaccini et al., 2007; Queiroz et al., 2017;
Rasmusson & Eriksson, 2001; Rea et al., 1997; Shteyer et al., 2013;
Sousa, 2012; Trotta et al., 2013; Wierink et al., 2007), one was con-
ducted in Africa, eight were conducted in Asia, eight in South America
and 28 in Europe. The oldest study included was carried out in 1987
and the most recent in 2017. Regarding the designs of the study, 39
articles were cross-sectional (of which 32 included a control group for
comparison), five studies were case control and one was a cohort study.
Table 1 summarizes the characteristics of these studies.
The largest sample of any study consisted of 610 participants
(Campisi et al., 2007) and the lowest sample had 18 participants
(Shteyer et al., 2013). The ages of the participants ranged from one year
(Majorana et al., 2010) to 86 years old (Lahteenoja et al., 1998). There
were variations among the dentitions evaluated, and not all texts were
clear regarding the results of each dentition in isolation.
Only six studies did not use Aine’s method for the diagnosis of DDE
182
Archives of Oral Biology 87 (2018) 180–190
Fig. 1. Flow chart of study selection.
(Andersson-Wenckert et al., 1984; Farmakis et al., 2005; Marcos, 2008;
Mariani et al., 1994; Ouda et al., 2010; Prati et al., 1987) and two did
not report the index used (Cantekin et al., 2015; Rasmusson & Eriksson,
2001). Andersson-Wenckert et al. (1984) used two classifications, those
according to Murray & Shaw, and Thylsrrup & Fejerskov. Farmakis
et al. (2005) used the DDE Index (Clarkson & O’Mullane, 1989) and El-
Hodhod et al. (2012) and Marcos (2008) used the modified DDE Index,
in accordance with FDI criteria (1992). Mariani et al. (1994) used the
index of the Oral Health Research Commission and Ouda et al. (2010)
used the International Classification of Diseases in Dentistry and Sto-
matology Index (ICDA-DA, WHO, 1978). Finally, Prati et al. (1987)
used a non-specific classification of DDE.
Five articles in the review were not included in the meta-analysis
(El-Hodhod et al., 2012; Giammaria et al., 1996; Lopes et al., 2001;
Mina, 2008; Mina et al., 2012), as it was determined that they did not
present complete data.
According to quality assessment, case control studies showed a risk
of bias score of 4 to 7 points from a total of 9 on the Newcastle Ottawa
Scale (Table 2). In this case, the domain most contemplated was “se-
lection” and the least was “comparability”, indicating that few studies
had adjusted their analysis according to the confounding factors. No
study had stated that the “Same method of ascertainment for cases and
controls” was used, indicating that there is no certainty that the control
group was free of celiac disease. In this context, El-Hodhod et al. (2012)
and Marcos (2008) reported a laboratory assessment of celiac disease
based on the quantitative determination of antitissue transglutaminase
IgA and IgG to define negative serology patients. The others performed
an assessment based on medical records or the self-reporting of patients
(Costacurta et al., 2010; Cruz, 2016; Orta et al., 2004).
Among the cross-sectional studies, none scored a total of 9 stars and
only three studies scored 8 stars. Fourteen studies scored a total of 3
stars, indicating very low-quality assessment. Lahteenoja et al. (1998)
determined their sample using a calculation method and the
 Table 1
Characteristics of the Studies Included in the Review.

Author, Year Country (n) Study design Sample Age (range years) Diagnosis DDE Type of DDE Dentition evaluated Prevalence DDE

Group CD Group Group CD Group Group CD n Group control

D. Souto-Souza et al.

control control (%) n (%)

Acar et al. (2012) Turkey (70) Cross- 35 35 6–19 6–19 Aine Grades I and II Permanent 14 (40) 0 (0)
sectional
Aguirre et al. (1997) Spain (189) Cross- 137 52 5–68 5–64 Aine and Unspecific DDE Grades 0–IV Non-specific Permanent 72 (52.5) 22 (43)
sectional defects
Aine (1986) Finland (226) Cross- 76 150 3–22 13–14 Aine Grades 0–IV Permanent 73 (96) 47 (31)
sectional
Aine et al. (1990) Finland (152) Cross- 40 112 19–67 19–67 Aine and Unspecific DDE Grades 0–IV Permanent 40 (100) 105 (94)
sectional
Amato et al. (2017) Italy (100) Cross- 49 51 NR NR Aine Grades 1 and 2 Permanent 7(14.3) 0(0)
sectional
Andersson-Wenckert Sweden (38) Cross- 19 19 6–20 6–20 Murray & Shaw; Hypoplasia and/or opacity of Permanent 14 (74) 13 (68)
et al. (1984) sectional Thylsrrup & Fejerskov enamel
Avsar and Kalayci Turkey (128) Cross- 64 64 6–15 6–15 Aine and Unspecific DDE Grades 0–IV Permanent 27 (42.2) 6 (9.4)
(2008) sectional
Bolgul et al. (2009) Turkey (192) Cross- 82 110 4–7 3–7 Aine and Unspecific DDE Grades 0–IV Deciduous,Permanent 59 (72) 6 (5.5)
sectional
Bucci et al. (2006) Italy (234) Cross- 70 159 NR NR Aine Grades 0–IV Non-specific Deciduous,Permanent 14 (20) 9 (5.6)
sectional defect
Campisi et al. (2007) Italy (610) Cross- 197 413 2–75 2–77 Aine Grades 0–IV Deciduous,Permanent 46 (23) 37 (9)
sectional
Cantekin et al. (2015) Turkey (50) Cross- 25 25 4–16 4–16 NR NR Deciduous,Permanent 12 (48) 4 (16)
sectional

183
Cheng et al. (2010) Colombia(136) Cross- 67 69 NR NR Aine Grades 0–IV Mixed, Permanent 34 (51) 21 (30)
sectional
Coloma (2013) Espanha (180) Cross- 100 80 8–32 12–34 Aine Grades 0–IV NR 53 (53) 34 (42.5)
sectional
Costacurta et al. (2010) Italy (600) Case-control 300 300 4–13 4–13 Aine Grades I–IV Deciduous, Mixed and 99 (33) 33 (11)
Permanent
Cruz (2016) Brazil (80) Case-control 40 40 5–34 5–34 Aine Grades 0–IV Deciduous, Mixed and 15 (37.5) 7 (17.5)
Permanent
Dane and Gurbuz Turkey (70) Cross- 35 35 5–15 5–15 Aine Grades 0–IV Non-specific NR 19 (54.3) 7 (20)
(2016) sectional defects
de Carvalho et al. Brazil (104) Cross- 52 52 2–15 2–15 Aine and Unspecific DDE Grades 0–IV Non-specific Deciduous,Permanent 32 (61.5) 11 (21.5)
(2015) sectional defects
El-Hodhod et al. (2012) Egypt (140) Case-Control 25 115 4–12 4–12 Aine; modified DDE Grades 0–IV Non-specific Deciduous,Permanent 25 (78.1)a 115 (13.9)b
Index defects
Erriu et al. (2011) Italy (98) Cross- 98 0 7–77 – Aine Grades 0–IV Permanent 28(28.6) –
sectional
Erriu et al. (2013) Italy (44) Cross- 44 0 6–16 – Aine Grades 0–IV Mixed, Permanent 17 (38.6) –
sectional
Ertekin et al. (2012) Turkey (101) Cross- 81 20 2.5–17 2.5–17 Aine Grades 0–IV Deciduous, Mixed and 43 (53.1) 5 (25)
sectional Permanent
Farmakis et al. (2005) England (38) Cross- 19 19 NR NR DDE Index Non-specific defects Deciduous,Mixed 18 (95.7) 9 (47.4)
sectional
Giammaria et al. Italy (339) Cross- NR NR 11–14 11–14 Aine Grades I–IV Mixed, Permanent NR NR
(1996) sectional
Lahteenoja et al. (1998) Finland (166) Cross- 136 30 3–86 NR Aine Grades III and IV Permanent 13 (10.1) NR
sectional
Lopes et al. (2001) Brazil (132) Cross- 49 83 1–18 1–16 Aine Grades 0–IV Deciduous, Permanent NR NR
sectional
(continued on next page)
Archives of Oral Biology 87 (2018) 180–190
 Table 1 (continued)

Author, Year Country (n) Study design Sample Age (range years) Diagnosis DDE Type of DDE Dentition evaluated Prevalence DDE

Group CD Group Group CD Group Group CD n Group control

control control (%) n (%)
D. Souto-Souza et al.

Majorana et al. (2010) Italy (250) Cross- 125 125 1–12 1–12 Aine Grades 0–IV Deciduous,Permanent 58 (46.4) 7 (5.6)
sectional
Marcos (2008) Brazil (200) Case-control 50 150 3–19 3–19 modified DDE Index Grades 0–4 Deciduous, Mixed and 49 (98) 140 (93.3)
Permanent
Mariani et al. (1994) Italy (271) Cross- 82 189 NR NR Oral Health Research Systematic Unspecific Deciduous,Permanent 58 (46.4) 7 (5.6)
sectional Commission
Martelossi et al. (1996) Italy (90) Cross- 90 0 7–58 – Aine Grades 0–IV Deciduous, Mixed and 48 (53) –
sectional Permanent
Mina (2008) Argentina (75) Cross- 52 23 4–12 4–12 Aine Grades 0–IV Deciduous,Permanent NR NR
sectional
Mina et al. (2012) Argentina(50) Cohort 25 25 4–12 4–12 Aine Grades 0–IV Deciduous, Permanent 8 (30) NR
Orta et al. (2004) Spain (293) Case-control 213 80 2–35 NR Aine Grade I–III NR 93 (43.7) 29 (36.3)
Ortega Paez et al. Spain (60) Cross- 30 30 NR NR Aine and Unspecific DDE Grades 0–IV Non-specific Deciduous 25 (83.3) 16 (53.3)
(2008) sectional defects
Ouda et al. (2010) Saudi Arabia Cross- 50 50 10–18 10–18 WHO ICD-DA Non-specific defects Deciduous,Permanent 18 (36) 3 (6)
(100) sectional
Petrecca et al. (1994) Italy (58) Cross- 29 29 8–18 8–18 Aine Grades 0–IV NR 22 (76) NR
sectional
Prati et al. (1987) Italy (25) Cross- 10 15 3–12 3–12 Non-specific Non-specific defects Deciduous,Permanent 3 (30) 0
sectional classification
Priovolou et al. (2004) Greece (18) Cross- 9 9 3–18 3–18 Aine Grades 0–IV Permanent 7 (83.3) 4 (50)
sectional
Procaccini et al. (2007) Italy (100) Cross- 50 50 3–18 3–18 Aine Grades 0–IV Deciduou, Permanent 13 (26) 8 (16)

184
sectional
Queiroz et al. (2017) Brazil Cross- 45 0 NR NR Aine Grades 0–IV Permanent 25(55.5) –
sectional
Rasmusson and Sweden (80) Cross- 40 40 7–25 7–25 NR Hypoplasia and Permanent 20 (50) 15 (38)
Eriksson (2001) sectional hypomineralization
Rea et al., (1997) Italy (150) Cross- 45 15 2–26 2–26 Aine Grades 0–IV Deciduous, Mixed and 11 (24.4) 5 (4.7)
sectional Permanent
Shteyer et al. (2013) Jerusalem (90) Cross- 60 30 1–18 1–18 Aine and Unspecific DDE Grades 0–IV Deciduous,Permanent 33 (55) 10 (33.3)
sectional
Sousa (2012) Portugal (28) Cross- 28 0 4–18 – Aine Grades 0–IV Deciduous, Mixed and 13 (46.4) –
sectional Permanent
Trotta et al., (2013) Italy (54) Cross- 54 0 NR – Aine Grades 0–IV Non-specific Permanent 54 (100) –
sectional defects
Wierink et al. (2007) Holland (81) Cross- 53 28 6–18 6–18 Aine and Unspecific DDE Grades 0–IV Non-specific Mixed, Permanent 29 (54.7) 5 (17.8)
sectional defects

Subtitle – DDE: developmental defects of enamel, CD: celiac disease, NR: Not reported.
a
Presence of celiac disease in patients with developmental defects of enamel.
b
Absence of celiac disease in patients with developmental defects of enamel.
Archives of Oral Biology 87 (2018) 180–190
D. Souto-Souza et al.
Table 2
Qualitative analysis of case-control studies (Newcastle Ottawa scale).
Author, Year Selection
Case Representativeness of Selection of Definition of
Definition the cases controls controls
Costacurta ★ ★ ★ ★
et al.
(2010)
Cruz (2016) ★ ★ ★ ★
El-Hodhod ★ ★ ★ –
et al.
(2012)
Orta (2004) ★ ★ ★ –
Marcos (2008) ★ ★ – –
Selection: 1) a – yes, with independent validation (1 star), b) yes, eg record linkage or based on self-reports, c) no description; 2) a – consecutive or obviously representative series of
cases (1 star), b – potential for selection biases or not stated; 3) a – community controls (1star), b – hospital controls, c – no description; 4) a – no history of gastrointestinal diseases
(endpoint) (1 star); b – no description of source. Comparability: 1) a – Study control for the most important factor (fluorosis) (1 star), b – the study control for any additional factor (1
star). Exposure: 1) a – diagnosis through biopsy (1 star), or b – structured interview where blind to case/control status (1 star), c – interview not blinded to case/control status, d – written
self-report or medical record only without diagnosis confirmation, e – no description; 2) a – yes (1 star), b – no; 3) a – same rate for both groups (1 star), b – non-respondents described, c –
rate different and no designation.
measurement of some studies were conducted by blind examiners
(Aguirre et al., 1997; Campisi et al., 2007; Cheng et al., 2010; de
Carvalho et al., 2015; Ortega Paez et al., 2008; Priovolou et al., 2004;
Shteyer et al., 2013; Trotta et al., 2013; Wierink et al., 2007). These
results can be found in Table 3. The study of Mina et al. (2012), the only
longitudinal study, may have suffered from bias, scoring only in the
definition, follow-up time and complete follow-up sub-items.
The pooled prevalence rate of DDE among the 2840 CD patients was
50% (95% CI 0.44–0.57, I2 = 88%) (Fig. 2). In an overall analysis, it
was observed that patients with CD had a significant association with
enamel defects (RR: 2,31, 95% CI 1.71–3.12, I2 = 98%), as seen in
Fig. 3. However, after a subgroup analysis, neither the permanent
dentition nor the mixed dentition of CD patients was found to be as-
sociated with DDE. Only the group of CD patients with deciduous
dentition had an association with DDE (RR: 2.34, 95% CI 1.25–4.39,
I2 = 39%) (Fig. 4). No significant association was found when the DDE
was diagnosed by non-specific methods (RR: 1.03, 95% CI 0.68–1.54,
I2 = 83%) (Fig. 5). Thus, only DDE diagnosed through Aine’s method
was significantly associated with the occurrence of CD (RR: 3.30, 95%
CI 2.39–4.56, I2 = 75%) (Fig. 6).
Publication bias was evident in the pooled prevalence meta-analysis
(p = 0.014) and in the meta-analysis concerning the relative risk of
DDE in CD (p > 0.001), as illustrated by the funnel plot for the studies
in the compilation (Fig. 6). Funnel plots for the studies in the compi-
lation where diagnosis for DDE was performed according to a non-
specific method (p = 0.931) or via Aine’s method (p = 0.097) were
relatively symmetrical, as observed in Fig. 7.
4. Discussion
The present study, involving a total of 2840 celiac patients, revealed
a DDE prevalence of 50% in this population, and was able to establish
with stronger evidence that CD is associated with developing these oral
disorders (RR: 2.31). Although nutritional, immunological and/or ge-
netic factors are considered to be the prerequisites for the occurrence
DDE (Maki et al., 1991; Mariani et al., 1994; Pastore et al., 2008), the
exact mechanism for this association with CD remains unclear.
In 1990, a hypothesis was formed such that DDE in patients with CD
may occur due to an intestinal malabsorption of nutrients such as cal-
cium, leading to dental enamel hypoplasia (Aine et al., 1990). Another
hypothesis is that CD shows an autoimmune response that can cause
changes in the enamel organ up to the seventh year of life, resulting in
defective enamel formation (Aine, 1986; Maki et al., 1991). Genetic
causes associated with human leukocyte antigen (HLA), and alleles DR3
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Archives of Oral Biology 87 (2018) 180–190
Comparability Exposure Total (9
points)
Based on design Ascertainment of Same method of Non-
or analysis exposure ascertainment for response
cases and controls rate
– ★ – ★ 6
★★ ★ – ★ 7
★ ★ – 5
– – – ★ 4
– ★ – ★ 4
and DQ2, have also been investigated in the context of enamel defects
in celiac patients (Ortega Paez et al., 2008; Pastore et al., 2008;
Procaccini et al., 2007; Wierink et al., 2007).
There is a growing concern regarding the increased incidence of CD
in the 21st century, as this disease is increasingly diagnosed in
asymptomatic individuals (Newnham, 2017). The earlier an individual's
CD is diagnosed, the earlier treatment can be initiated and the better
the prognosis (Aguirre et al., 1997). The definitive diagnosis of CD
should be performed by serological markers or by histological analysis
of duodenal biopsy (Husby et al., 2012). However, factors such as lack
of the clarification about the disease’ symptoms in the community,
socioeconomic factors and the availability of endoscopy services may
represent a challenge in the tracking of CD at a population level.
To address this issue, studies have reported on the development of
specific questionnaires to assist in the tracking of the disease (Ribes-
Koninckx et al., 2012; Rosén et al., 2014). However, a questionnaire
based on symptoms and associated pathologies such as nausea, lactose
intolerance, abdominal gas and others was found to be not sufficiently
sensitive for mass screening of CD (Rosén et al., 2014).
This systematic review presents a new perspective for a multi-
disciplinary approach to the disease, suggesting that patients with DDE
should be investigated for the possibility of CD. In this way, dentists can
actively contribute to the diagnosis of this enteropathy, especially in
cases of the disease where no symptoms occur.
Development defects of dental enamels are alterations that can
occur both in the formation of the enamel and in its maturation
(Weerheijm et al., 2003). Aine, in 1986, described DDE in patients with
CD as symmetrical and chronological, detectable in all quadrants of the
dentition, while non-symmetric enamel defects, similarly detectable in
different quadrants, were considered non-specific. Aine’s classification
is divided into degrees ranging from 0 to 4 (0 = no defect, 1 = enamel/
hypomineralization discolorations, 2 = slight structural defects/hypo-
plasia, 3 = evident structural defects/discoloration, and 4 = severe
structural defects/altered form) (Aine, 1986). The results of this review
reaffirm the utility of Aine’s method in the identification of dental DDE
in celiac patients, in preference to non-specific methods of DDE diag-
nosis.
According to Jälevik (2010), the prevalence of these enamel defects
in the general population ranges from 2.4% to 40.2%. More recently,
the prevalence of enamel defects in the infant population in India was
determined to range from 4.9% to 7.1% (Mittal et al., 2016). In a study
conducted in Brazil, 8.7% of enamel hypoplasia cases occurred in the
permanent dentition and 5.5% occurred in the deciduous dentition
(Hoffmann, de Sousa, & Cypriano, 2007). The lower prevalence of
D. Souto-Souza et al. Archives of Oral Biology 87 (2018) 180–190

Table 3
Qualitative analysis of cross-sectional studies (Newcastle Ottawa Modified).

Author, Year Selection Comparability Outcome Total (9

points)
Representativeness of the Sample size Ascertainment of Based on design and Assessment of Statistical test
sample exposure analysis outcome

Acar et al. (2012) ★ – ★★ – – ★ 4

Aguirre et al. (1997) ★ – ★★ – ★★ ★ 6
Aine (1986) ★ – ★★ – – – 3
Aine et al. (1990) ★ – ★★ – – – 3
Amato et al. (2017) – – ★★ ★ ★★ ★ 6
Andersson-Wenckert ★ – ★★ ★★ – ★ 6
et al. (1984)
Avsar and Kalayci ★ – ★★ – – ★ 4
(2008)
Bolgul et al. (2009) ★ – ★★ – – ★ 4
Bucci et al. (2006) – – ★★ ★ – ★ 4
Campisi et al. (2007) ★ – ★★ – ★★ ★ 6
Cantekin et al. (2015) – – ★★ ★ – ★ 4
Cheng et al. (2010) – – ★★ – ★★ ★ 5
Coloma (2013) ★ – ★★ – – ★ 4
Dane and Gurbuz (2016) – – ★★ ★ – ★ 4
de Carvalho et al. (2015) – – ★ ★★ ★★ ★ 6
Erriu et al. (2011) – – ★★ – – ★ 3
Erriu et al. (2013) – – ★★ – – ★ 3
Ertekin et al. (2012) – – ★★ – – ★ 3
Farmakis et al. (2005) – – ★★ – – ★ 3
Giammaria et al. (1996) – – ★★ – – – 2
Lahteenoja et al. (1998) ★ ★ ★★ – – ★ 5
Lopes et al. (2001) – – ★★ – – ★ 3
Majorana et al. (2010) – – ★★ – – ★ 3
Mariani et al. (1994) – – ★★ – – ★ 3
Martelossi et al. (1996) – – ★★ – – ★ 3
Mina (2008) – – ★★ – – ★ 3
Ortega Paez et al. (2008) ★ – ★★ ★ ★★ ★ 7
Ouda et al. (2010) – – ★★ – – ★ 3
Petrecca et al. (1994) – – ★★ – – – 2
Prati et al. (1987) – – ★★ – – ★ 3
Priovolou et al. (2004) ★ – ★★ ★★ ★★ ★ 8
Procaccini et al. (2007) ★ – ★★ – – ★ 4
Queiroz et al. (2017) – – ★ ★★ – ★ 4
Rasmusson and Eriksson ★ – ★★ ★ – – 4
(2001)
Rea et al. (1997) ★ – ★★ – – – 3
Shteyer et al. (2013) ★ – ★★ ★★ ★★ ★ 8
Sousa (2012) ★ – ★★ – – ★ 4
Trotta et al. (2013) ★ – ★★ – ★★ ★ 6
Wierink et al. (2007) ★ – ★★ ★★ ★★ ★ 8

Selection: (1) (a) truly representative of the average in the target population or (b) somewhat representative of the average in the target population (1 star), (c) selected group of users, (d)
no description; (2) (a) justified and satisfactory (1 star), (b) not justified; (3) (a) biopsy diagnosis (2 stars) (b) no description of the diagnosis method (1 star). Comparability: (1) (a) the
study controlled for the most important factor (fluorosis) (1 star), (b) the study controlled for any additional factor (1 star). Outcome: (1) (a) independent blind assessment for knowing
CD or (b) record linkage (2 stars), (c) no description; (2) (a) the statistical test used to analyze the data is clearly described and appropriate, and the measurement of the association is
present (1 star), (b) the statistical test is not appropriate, not described, or incomplete.

childhood enamel defects may increase the sensitivity for the detection
of cases associated with CD.
In the sensitivity analysis performed in this review, only the de-
ciduous dentition of patients with CD was found to be associated with
DDE, in contradiction to the Celiac Disease Guideline Committee of the
NASPGHAN, who reported that dental enamel defects involve espe-
cially the secondary (or permanent) dentition. Unfortunately, only two
studies included in this systematic review presented results that enabled
an evaluation of the association between mixed dentition and CD
(Cheng et al., 2010; Dane & Gurbuz, 2016). Thus, studies evaluating the
association of DDE with CD in the case of mixed dentition are still
necessary. Finally, considering permanent dentition, there were eleven
studies evaluating this aspect all of which gave similar results. There
was no evidence of publication bias regarding this analysis, suggesting
that this result is reliable.
Another systematic review on this topic has recently been published
(Nieri et al., 2017). This study registered enamel defects separately for
children (up to the age of 18 years) and adults, in addition to the
classification according to dentition. They are complementary analyses
and reinforce the association of CD with DDE in childhood. Apparently,
these two systematic reviews were conducted at the same time, con-
sidering the methodology steps. Despite the similarities, the present
study conducted the search strategy in different databases and included
more articles relating to variable enamel defects. Furthermore, the in-
clusion of the assessment of outcomes considering Aine’s method for
diagnosis of DDE was not previously considered.
Although it was not the objective of this systematic review, other
important oral alterations have been reported in the literature. In a
study conducted in 128 people with CD, 71 (55%) presented lesions of
the oral mucosa (such as strong erythema, lingual atrophy and ulcers),
against a 23% occurrences in the control group (Lahteenoja et al.,
1998). Other oral signs related to CD reported in the literature are
angular cheilitis, glossitis, depapillated tongue (Catassi et al., 1994) and
recurrent aphthous stomatitis (Nieri et al., 2017).
The American Society of Pediatric Gastroenterology, Hepatology
and Nutrition (Hill et al., 2005) and the European Society of Pediatric

186
D. Souto-Souza et al.
Gastroenterology, Hepatology and Nutrition (Husby et al., 2012) re-
commend that children with non-gastrointestinal symptoms of CD,
should be investigated for this disease. However, the wide variety of
clinical manifestations and conditions associated with CD, together
with the low level of awareness of the disease among health profes-
sionals make the diagnosis of this enteropathy challenging.
187
Archives of Oral Biology 87 (2018) 180–190
Fig. 2. Pooled prevalence rate (and 95% confidence
interval) of DDE in patients with CD.
A study conducted in North America showed positive results for
screening of patients with typical symptoms of CD conducted by pri-
mary care physicians (Catassi et al., 2007). In this context, it is highly
recommended that primary care dentists contribute to the screening of
this disease. This would have a great and positive impact on public
health, optimizing the use of different areas of health care.
Fig. 3. Relative risk of DDE in CD.
D. Souto-Souza et al. Archives of Oral Biology 87 (2018) 180–190

Fig. 4. Relative risk of DDE in CD, according denti-

tion type.

Fig. 5. Relative risk of DDE diagnosed by non-spe-

cific method, in CD.

Fig. 6. Relative risk of DDE diagnosed by the AINE's

method, in CD.

This review presents some strengths compared with previous re- no limit on the publication dates, covering a period of 30 years
views (Giuca et al., 2010; Pastore et al., 2008) such as its use of com- (1987–2017). On the other hand, some limitations were also present.
prehensive and systematic bibliographic research and meta-analysis to Most of the data came from cross-sectional studies; this type of study
compile the results. The databases searched were relatively large, with does not allow a cause and effect relationship to be established, making

188
D. Souto-Souza et al.
Fig. 7. Publication assessment for outcomes a) Funnel plot for pooled prevalence rate of DDE in patients with CD; b) Funnel plot for the compilation of relative risk of DDE in CD; c)
Funnel plot for the compilation of relative risk of DDE diagnosed by non-specific method, in CD; d) Funnel plot for the compilation of relative risk of DDE diagnosed by AINE's method, in
CD.
it impossible to define temporality patterns for the occurrence of the
event. Thus, new cohort studies, with newborns CD+ and CD-, must be
conducted, to determine the natural history of DDE. This type of study
design will help us to define the order of occurrence of these events.
In addition, there is high heterogeneity between studies concerning
age, ethnicity, different diagnosis methods and the quality of the stu-
dies. We conducted subgroup analyses intending to control for these
sources of heterogeneity and to evaluate the risk of bias using a vali-
dated tool. However, the quality of the included studies was generally
low, and publication bias was presented, suggesting that the results
should be interpreted with caution.
Nevertheless, due to the large number of studies included in this
review, it was possible to establish the association between DDE and
CD, especially in deciduous dentitions, which should be considered in
clinical practice. In this context, it is recommended that studies that
may lead to the validation of questionnaires for symptom screening,
used together with the dental evaluation standardized by Aine’s method
(Aine, 1986), should be carried out, in order to increase the sensitivity
of this means of tracking the disease.
5. Conclusion
This meta-analysis indicated a high prevalence of DDE among celiac
patients with a significant association of DDE with this population
when compared to healthy people. Only the enamel defects diagnosed
through the Aine’s method were associated with the disease. In addi-
tion, when considering the types of dentitions, only in patients with
deciduous dentition was there observed to be an associated of CD with
DDE.
Conflict of interest
The authors declare no conflicts of interest.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
189
Archives of Oral Biology 87 (2018) 180–190
Acknowledgements
Endi Lanza Galvão is currently receiving a grant from Research
Foundation of the State of Minas Gerais (FAPEMIG).
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the
online version, at https://doi.org/10.1016/j.archoralbio.2017.12.025.
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