doi:10.1111/iej.
13030
Cholesterol crystals in periapical lesions of root
filled teeth
C. Plengwitthaya1, K. Dhanuthai2, S. Chantarangsu2 & C. Ratisoontorn1
1
Section of Endodontics, Department of Operative Dentistry, Chulalongkorn University; and 2Department of Oral Pathology,
Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
Abstract
Plengwitthaya C, Dhanuthai K, Chantarangsu S,
Ratisoontorn C. Cholesterol crystals in periapical lesions of
root filled teeth. International Endodontic Journal, 52, 484–
490, 2019.
Aim To determine the prevalence of cholesterol crys-
tals in periapical biopsies and to evaluate the correla-
tion between cholesterol crystals in periapical biopsies
and age, gender, location of the periapical lesion,
pathologic diagnosis and lesion size.
Methodology The biopsy report database (Faculty
of Dentistry, Chulalongkorn University, Bangkok,
Thailand) during 2005–2014 was reviewed. The
prevalence of cholesterol crystals in the periapical
lesions of root filled teeth was determined. Pathologi-
cal diagnosis, patients’ age, gender and the location
(maxilla or mandible) of the periapical lesion were
obtained from treatment records. The area of the
lesion from the periapical radiograph before surgery
was calculated using ImageJ software. Univariate and
multivariate logistic regression analyses were used to
Introduction
Periapical bone resorption, which can be seen as radi-
olucency in a radiograph, is an important sign of api-
cal periodontitis. Intraradicular infection is the major
cause of this condition (Kakehashi et al. 1965), and
root canal treatment aims to eradicate it. Subsequent
Correspondence: Chootima Ratisoontorn, Section of
Endodontics, Department of Operative Dentistry, Faculty of
Dentistry, Chulalongkorn University, 34 Henry-Dunant
Road, Bangkok 10330, Thailand (Tel.: 662-218-8795;
fax: 662-218-8794; e-mail: chootima@gmail.com).
484 International Endodontic Journal, 52, 484–490, 2019
determine the association between independent vari-
ables and the presence of cholesterol crystals.
Results The overall prevalence of cholesterol crystals
was 20.31%. The periapical biopsies >100 mm2 in size
on periapical films had a significantly greater preva-
lence of cholesterol crystals than those <100 mm2
(P = 0.005). The biopsies diagnosed as radicular cysts
had a significantly greater prevalence of cholesterol
crystals than the biopsies with other diagnoses
(P < 0.001). A pathological diagnosis of radicular cyst
was the variable with the strongest association with
the presence of cholesterol crystals (P < 0.001;
adjusted OR, 12.39).
Conclusions Presence of cholesterol crystals was
associated with periapical lesion diagnosed as a radic-
ular cyst and lesion >100 mm2 in area. Age, gender
and location of the lesion did not influence the pres-
ence of cholesterol crystals.
Keywords: age, cholesterol crystal, cyst, periapical
lesion, size.
Received 27 June 2018; accepted 15 October 2018
to treatment, new bone formation occurs, resulting in
the initial reduction of the lesion size and its eventual
healing (Seltzer et al. 1963, Storms 1969). On the
contrary, periapical lesions can persist or emerge as a
consequence of the inability to adequately control the
intraradicular infection. However, extraradicular
infection (Nair et al. 1990a), the presence of a foreign
body (Nair et al. 1990b), cyst (Nair et al. 1993) and
the formation of cholesterol crystal (Nair et al. 1998)
are also potential causes of post-treatment endodontic
disease, which need to be treated surgically.
Cholesterol is a steroid alcohol found in all tissue
types. It is the main component of cell membranes
and also a precursor of bile acids, steroid hormones
© 2018 International Endodontic Journal. Published by John Wiley & Sons Ltd

and vitamin D (Harvey & Champe 2005). Cholesterol
is absorbed in the small intestine (Carr & Jesch
2006), synthesized in the liver and transported to tis-
sues and organs through blood by binding to proteins
in the form of lipoprotein. Many dietary and genetic
factors regulate plasma cholesterol levels (Lecerf & de
Lorgeril 2011). A notorious cholesterol crystal-related
disease is atherosclerosis, an accumulation of choles-
terol in the blood vessel walls. Cholesterol crystal can
also be found in other tissues and causes inflamma-
tion of the organ, such as otitis media, or the choles-
terol granuloma in the thorax (Ross 1999).
Cholesterol crystals can be found in odontogenic
cysts, especially radicular cysts. The cystic fluid with
cholesterol crystals is gold- or straw-coloured clini-
cally (Browne 1971) and is crystalline diamond
(rhomboid) in shape when viewed under a micro-
scope. If a tissue with cholesterol crystal is stained
with H & E, needle-shaped clefts, also called choles-
terol clefts, are revealed. The prevalence of cholesterol
crystals was reported in the range of 18%–44% (Nair
et al. 1998) being higher in inflammatory odonto-
genic cysts and lower in non-inflammatory cysts such
as odontogenic keratocyst (keratocystic tumour). The
inflammatory process is likely to have an important
role in the formation of cholesterol crystal (Browne
1971). Cholesterol crystals are also surrounded by
multinucleated giant cells (Shear 1963). In
atherosclerosis, cholesterol deposition and crystalliza-
tion on inflammatory responses has been described
(Grebe & Latz 2013).
Recently, Slutzky-Goldberg et al. (2013) reported
the relationship between cholesterol crystals and age
in tissues from apical surgery cases. They reported
that elderly patients had a significantly greater preva-
lence of cholesterol crystals than adolescent patients.
However, factors such as gender, location of the peri-
apical lesion, pathologic diagnosis and lesion size
have not been evaluated for the correlation with the
prevalence of cholesterol crystals in periapical lesions.
Therefore, this study aimed to determine the preva-
lence of cholesterol crystals in periapical biopsies and
evaluate the correlation between cholesterol crystals
in periapical biopsies and age, gender, location of
the periapical lesion, pathologic diagnosis and lesion
size.
Materials and methods
In this retrospective study, the biopsy reports during
2005–2014 from the Department of Oral Pathology,
© 2018 International Endodontic Journal. Published by John Wiley & Sons Ltd
Plengwitthaya et al. Cholesterol crystals of root canal treated teeth
Chulalongkorn University were reviewed. The proto-
col was approved by the Human Research Ethics
Committee of the Faculty of Dentistry, Chulalongkorn
University. The periapical biopsies were obtained dur-
ing surgical retreatment of teeth with apical pathosis
at the Postgraduate Endodontic clinic and the Oral
and Maxillofacial Surgery clinic. Inclusion criteria
were as follows:
1. Teeth with history of previous root canal treat-
ment before periapical surgery.
2. Periapical radiographs (include the entire periapi-
cal lesion) taking before the periapical surgery
were available.
3. Periapical radiolucencies were observed on the
radiographs.
The pathological diagnosis was previously reported
by oral pathologists on duty at the time of surgery.
The formalin-fixed paraffin-embedded tissues were
stained with haematoxylin-eosin (H&E) and examined
under a light microscope at the magnifications from
409 to 2009. The pathological diagnosis was classi-
fied as follows:
1. Radicular cyst: Cavity partially or completely
lined by non-keratinized stratified squamous
epithelium with inflammatory cells in the centre
or lumen.
2. Periapical granuloma: Granulation lesion at the
apical area of the tooth infiltrated by lympho-
cytes, plasma cells and macrophages with well-
developed fibrous capsule.
3. Scar tissues: A dense, collagenous connective tis-
sue with wavy collagen fibres and a lack of
inflammatory cells.
4. Abscess: A collection of PMNs, pus cells and cell
debris in the tissue.
To determine the prevalence of cholesterol crystals,
one researcher (CP) examined the histopathological
sections for the presence of cholesterol clefts and
foamy cells. In paraffin sections processed for H&E
staining, the cholesterol was dissolved by the fat sol-
vents used in dehydration and infiltration, and
appeared as needle-shaped space (cholesterol clefts)
within the tissues. In case of doubt, CP consulted the
board-certified oral pathologist (KD). Foamy cells are
known to form by the unregulated uptake of oxidized
low-density lipoprotein (LDL), thus showing massive
lipid droplets in macrophage cytoplasm.
Variables including patients’ age, gender and the
location of the periapical lesion were searched from
treatment records. For the size of the lesion, the peri-
apical radiographs before surgery were obtained from
International Endodontic Journal, 52, 484–490, 2019 485
 Cholesterol crystals of root canal treated teeth Plengwitthaya et al.
treatment records and digitized with an optical scan-
ning process for digital files (JPEG) with 800 dpi reso-
lution. The images were transferred to the ImageJ
software (version 1.48v, National Institutes of Health,
Washington, DC, USA) for lesion area measurement.
Delineation was performed on the radiographic image
to exclude tooth structure, but include the area of
bone rarefaction.
Statistical analysis
Independent variables were included as follows: (i) age
(<60, ≥60); (ii) gender; (iii) location (maxilla, mand-
ible); (iv) area (<100, ≥100 mm2) and (v) pathological
diagnosis (cyst, others). The association between the
presence of cholesterol crystals and each independent
variable was calculated using the Pearson chi-square
test. Univariate and multivariate logistic regression
analyses were used to determine the degree of associa-
tion between independent variables and the presence
of cholesterol crystals. In the multivariate model, those
independent variables were included in the model
regardless of their significance in univariate model.
Crude and adjusted odds ratios (ORs) and correspond-
ing 95% confidence intervals (CIs) were calculated for
each independent variable. Statistical analyses were
performed using SPSS Statistics for Windows, version
19.0 (IBM, Armonk, NY, USA), and a P value <0.05
was considered statistically significant.
Results
From 401 periapical biopsies of apical surgery cases
in the database during 2005–2014, 128 biopsies
were included. The reasons for exclusion of cases
were unavailable periapical films (171 biopsies), teeth
were not previously root filled (85 biopsies) and large
lesions were not included fully in the periapical films
(19 biopsies). Amongst the 128 biopsies analysed, the
majority of biopsies were in the <60 years old age
group (116 of 128, 90.6%), female patients (73 of
128, 57.0%), located in the maxilla (111 of 128,
86.7%), <100 mm2 in size on periapical films (96 of
128, 75.0%) and were diagnosed as radicular cyst
(62 of 128, 48.4%) and periapical granuloma (62 of
128, 48.4%) (Table 1).
Cholesterol crystals were detected as needle-shaped
space in sections of periapical tissues. The overall
prevalence of cholesterol crystals was 20% (26 of
128). Foam cells were concertedly observed in sec-
tions with cholesterol crystals (Fig. 1).
486 International Endodontic Journal, 52, 484–490, 2019
Table 1 Case distribution according to pathological diag-
noses
Radicular Scar
Cyst Granuloma tissue Abscess
Maxilla 51 57 3 1
Mandible 11 5 0 0
Total 62 62 3 1
Bivariate associations between investigated vari-
ables and the presence or absence of cholesterol crys-
tals are presented in Table 2. The periapical biopsies
from lesions ≥100 mm2 on the periapical films or the
pathological diagnosis as radicular cyst were associ-
ated with significantly higher occurrence of choles-
terol crystals than the periapical biopsies from lesions
<100 mm2 or other diagnoses (P = 0.005 and
<0.001, respectively). The age <60, male gender and
mandibular location were associated with higher fre-
quency of cholesterol crystals, but the differences were
not significant.
Logistic regression analyses were performed to fur-
ther determine the degree of association between the
independent variables and the presence of cholesterol
crystals (Table 3). In the univariate analysis, the peri-
apical lesion size ≥100 mm2 and the pathological
diagnosis as radicular cyst significantly increased the
likelihood for the presence of cholesterol crystals, with
an OR of 3.51 (95% CI: 1.41–8.76) and 12.39 (95%
CI: 3.49–43.99), respectively. However, no significant
association was observed between age <60 or male
gender or mandibular location and the presence of
cholesterol crystals (P > 0.05). When the independent
variables were regressed multivariately, the
Figure 1 Photomicrograph showing radicular cyst with
cholesterol crystals and foam cells in the lumen. (Haema-
toxylin & eosin stain, original magnification 2009).
© 2018 International Endodontic Journal. Published by John Wiley & Sons Ltd
 Plengwitthaya et al. Cholesterol crystals of root canal treated teeth

Table 2 Bivariate associations between investigated variables et al. 2013). The limitation of the present study is
and the presence or absence of CC in periapical biopsies of that the whole lesion was not always available for
root canal treated teeth histopathological examination. As a result, the cases
Variables Total n CC n (%) No CC n (%) P-value* in which cholesterol crystals were not observed, may
actually contain cholesterol crystals in parts of the tis-
Age
<60 116 24 (20.7) 92 (79.3) 0.742
sue that were not examined. However, all cases were
≥60 12 2 (16.7) 10 (83.3) subject to the same criteria, examining the whole
Gender histopathological slides for the presence of cholesterol
Male 55 14 (25.5) 41 (74.5) 0.209 crystals. A highly significant prevalence of cholesterol
Female 73 12 (16.4) 61 (83.6)
deposit in periapical biopsies amongst elderly patients
Location
Upper 111 22 (19.8) 89 (80.2) 0.723
(>60 years old) has been reported (Slutzky-Goldberg
Lower 17 4 (23.5) 13 (76.5) et al. 2013). The authors reported that the prevalence
Size of cholesterol crystals was significantly higher in male
<100 mm2 96 14 (14.6) 82 (85.4) 0.005 biopsies than female biopsies in the elderly. However,
≥100 mm2 32 12 (37.5) 20 (62.5)
no correlation between age or gender and the preva-
Pathological diagnosis
Cyst 62 23 (37.1) 39 (62.9) <0.001
lence of cholesterol crystals was found in the present
Others 66 3 (4.5) 63 (95.5) study. One major contrast between the present study
and that of Slutzky-Goldberg et al. (2013) was the
*Association between the presence of CC and each indepen-
dent variable was analysed using the Pearson chi-square test. age groups. They grouped the specimens as elderly
A significant association (P < 0.05) was indicated in bold. (over 60 years old) and adolescent (13–21 years old),
whilst the present study compared <60 to ≥60 years
pathological diagnosis of radicular cyst remained sig- old. Besides the aforementioned age grouping, the dif-
nificant, with adjusted OR of 10.90 (95% CI: 2.81– ference in genetic backgrounds could also contribute
42.34). to the disagreement between the two studies.
The two variables that had an association with the
presence of cholesterol crystal in the persisting peri-
Discussion
apical lesion of the root filled teeth were the patholog-
Cholesterol crystals have been related to inflammatory ical diagnosis of radicular cyst and lesion size larger
diseases including chronic apical periodontitis (Grebe than 100 mm2. According to Grossman (1950), one
& Latz 2013). Accumulation of cholesterol crystals in of the preliminary clinical diagnostic signs of a peri-
the periapical area is one of the histopathological fea- radicular cysts is a periapical lesion greater than
tures of persistent chronic apical periodontitis and 200 mm2 (Grossman 1950). In addition, Natkin et al.
implicated as an aetiologic factor in non-resolving (1984) analysed the data of various studies and
chronic inflammation (Nair et al. 1998). In this study, related the radiographic lesion size to histology. They
the prevalence of cholesterol crystals in periapical reported that with a radiographic lesion area of
biopsies of root filled teeth that had undergone peri- 200 mm2 or larger, the prevalence of cysts was
apical surgery (20%) falls within the range of previ- almost 100%. In this study, the largest granuloma
ous studies that reported a range from 18% to 44% size was 199.32 mm2, and lesions larger than
(Sanchis et al. 1998, Nair 2006, Slutzky-Goldberg 200 mm2 were pathologically diagnosed as cysts in

Table 3 Crude and adjusted odds

Univariate logistic Multivariate logistic
ratios (OR) and 95% confidence inter-
regression regression
vals (CI) for the association between
independent variables and the presence Crude OR Adjusted OR
of CC in periapical biopsies of root filled Variables (95% CI) P-value (95% CI) P-value
teeth Age <60 1.30 (0.27–6.35) 0.742 1.31 (0.23–7.64) 0.764
Male 1.74 (0.73–4.13) 0.212 1.18 (0.45–.3.08) 0.739
Lower jaw 1.25 (0.37–4.19) 0.724 0.92 (0.24–3.56) 0.909
Size ≥100 mm2 3.51 (1.41–8.76) 0.007 1.28 (0.46–3.59) 0.641
Cyst 12.39 (3.49–43.99) <0.001 10.90 (2.81–42.34) 0.001

A significant association (P < 0.05) is indicated in bold.

© 2018 International Endodontic Journal. Published by John Wiley & Sons Ltd International Endodontic Journal, 52, 484–490, 2019 487
 Cholesterol crystals of root canal treated teeth Plengwitthaya et al.
agreement with previous reports. The biopsies were
grouped into <100 and >100 mm2 in size, and the
cholesterol crystals were more prevalent in the peri-
apical lesion of the larger lesions. In the past, choles-
terol crystals from cystic fluid were used for the
diagnosis of radicular cyst or other inflammatory
odontogenic cysts. However, in some radicular cysts,
cholesterol crystals cannot be detected from the cystic
fluid. Therefore, cholesterol crystals are no longer
used as a diagnostic aid for the diagnosis of radicular
cysts (Shear & Speight 2007). Recently, different
‘grayscale value’ readings of a CBCT image were pro-
posed for determining the presence of a cyst or a
granuloma; however, this method was reported to be
unreliable (Rosenberg et al. 2010), and surgical
biopsy and histopathological evaluation remain the
gold standard for the diagnosis of radicular cyst
(Trope et al. 1989, Simon et al. 2006).
How cholesterol crystals are generated in chronic
apical periodontitis has not been elucidated clearly. In
a study of 535 teeth with odontogenic cysts, and 402
with radicular cysts, cholesterol crystals were found
in lesions with hemosiderin pigment (Browne 1971);
hence, it is believed that cholesterol crystals are
derived from the cell membrane decomposition of ery-
throcytes. Cholesterol crystals evidently play an
important role in atherosclerosis. Cholesterol crystals
found in the pathologic intimal thickening (American
Heart Association Type III lesion), the earliest sign of
progressive lesion of atherosclerosis, were assumed to
be derived from dead and dying smooth muscle cells
(Sakakura et al. 2013). However, it has been reported
that endothelial cells were active in processing LDL
by taking up and metabolizing LDL. Ultimately, when
overburdened with intracellular cholesterol, it gener-
ated cholesterol crystals (Baumer et al. 2017). Physi-
cal factors including temperature, pH, cholesterol
hydration and saturation influenced rate and volume
of cholesterol crystallization (Vedre et al. 2009).
Whether the pathogenesis of chronic apical periodon-
titis with cholesterol crystals is a reflection of
atherosclerosis plaque formation remains to be
explored.
The role of cholesterol crystals in mediating chronic
apical periodontitis could be regarded as the inflam-
matory response against the crystalline material (Nair
et al. 1998) and the bone resorbing activity of the
cytokine (IL-1a) released from macrophages exposed
to crystalline cholesterol (Sj€ogren et al. 2002). Foam
cells were observed in the periapical lesions with
cholesterol crystals in this study as well as in previous
488 International Endodontic Journal, 52, 484–490, 2019
ones (Slutzky-Goldberg et al. 2013). Foam cells are a
hallmark of early-stage atherosclerotic lesions, gener-
ated in association with imbalance of cholesterol
influx, esterification and efflux (Yu et al. 2013). Crys-
talline cholesterol found in early atherosclerotic
lesions induces NLRP3 inflammasome activation driv-
ing atherosclerosis development and progression (Due-
well et al. 2010). Multimolecular protein complexes,
NLRP3 inflammasome, which regulate the activity of
caspase-1 and the maturation and release of inter-
leukin-1beta (IL-1b), can contribute to atherosclerosis.
Cholesterol-exposed macrophage also increases the
secretion of IL-1 and stimulates bone resorption by
ogren et al.
increasing the activity of the osteoclasts (Sj€
2002). Elevated asymmetrical dimethylarginine
(ADMA) plasma level is also implicated in endothelial
dysfunction and the pathogenesis and progression of
atherosclerosis (Notsu et al. 2015). Likewise, apical
periodontitis is also associated with increased serum
levels of inflammatory markers, C-reactive protein,
interleukin (IL)-1, IL-2, IL-6, IgA, IgG, IgM and
ADMA (Gomes et al. 2013). Due to the similar serum
inflammatory marker profile between apical periodon-
titis and atherosclerosis, patients with risk factors of
atherosclerosis, in particular smoking hypertensive
patients, were also found to have the increased preva-
lence of apical periodontitis and root canal treatment
(Segura-Egea et al. 2011). However, under the limita-
tions of this retrospective study, the association
between the risk factors of atherosclerotic cardiovas-
cular disease, such as tobacco exposure, hyperlipi-
daemia, hypertension, inactivity, overweight and
diabetes and the presence of cholesterol crystal in the
persisted periapical lesion of the root canal treated
teeth has not been examined.
The connection between low-grade inflammation of
apical periodontitis and early endothelial impairment,
a predictor for future development of cardiovascular
disease, has been demonstrated. Young adult patients
with apical periodontitis (age 20–40 years old) free
from periodontal disease, cardiovascular disease and
cardiovascular risk factors had reduced endothelial
flow reverse, suggesting the existence of an early
endothelial dysfunction (Cotti et al. 2011, Cotti &
Mercuro 2015). These patients with apical periodonti-
tis had significantly greater blood concentrations of
IL-1, IL-2, IL-6 and ADMA and a significant reduction
of endothelial flow reverse (Cotti & Mercuro 2015).
Relationship between the presence of cholesterol crys-
tal in persistent periapical lesions and cardiovascular
function remains to be clarified.
© 2018 International Endodontic Journal. Published by John Wiley & Sons Ltd

Conclusion
The presence of cholesterol crystals in periapical
lesions of root filled teeth was associated with radicu-
lar cysts and lesions >100 mm2 in area. Age, gender
and location of the lesion were not associated with
the presence of cholesterol crystals.
Conflict of interest
The authors have stated explicitly that there are no
conflict of interests in connection with this article.
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