Keywords
sickle cell disease - computed tomography - bone changes
Introduction
Sickle cell disease (SCD) is a hematologic disease in which a genetic alteration in
the formation of hemoglobin (Hb) determines the formation of Hb S, instead of normal
Hb A. When in homozygosis (Hb SS), the disease is called sickle cell anemia (SCA),
with more evident signs and symptoms. The presence of one Hb S and Hb A determines
the sickle cell trait (SCT), when the person does not have the disease, but can transmit
it to their descendants; and the presence of Hb S with other Hb alterations (C or
D) determines other forms of SCD, generally with milder symptoms.[1]
[2]
Altered Hb is less flexible and adheres to the endothelium, causing vaso-occlusion
of the microcirculation, restricting blood flow to multiple organs and systems.[3] The accumulation of these cells is responsible for vaso-occlusion that can cause
ischemia, infarcts, and tissue damage. These pathophysiological events determine most
of the signs and symptoms of people with toms of people with SCD: painful crises,
high susceptibility to infections and bone necrosis, osteopenia, osteoporosis, hemolytic
crises, lower limb ulcers, splenic sequestration, priapism, strokes and chronic processes
impairment of multiples organs or systems.[4]
[5]
[6]
Commonly referred to as vaso-occlusive crises, these episodes can occur from infancy
to old age, although they increase in frequency throughout childhood, with a peak
in the mid-20s.[7]
The morphological change of the red blood cells (RBCs) promotes their early hemolysis
and thus the bone marrow, especially that of longer bones, increases the production
of new RBCs to try to compensate for the anemia and this leads to a bone marrow expansion.
This may explain the skeletal changes related to the disease, such as maxillary protrusion,
with elongation and rotation of the mandible, determining a class II profile.[8] Additionally, subjective changes in the bone density of the maxillomandibular complex
are also reported, such as increased medullary spaces, accentuated bone trabeculation,
and denser or more porous areas.[9]
[10]
[11]
Although the signs of the disease manifest early in the life of the affected person,
there are many situations in which the diagnosis of SCD occurs late, contributing
to the morbidity of the disease and decreased quality of life of the patient. Thus,
clinical or imaging signs are important to help triage suspected patients and indicate
tests to confirm the diagnosis.
Despite studies evaluating facial anatomical skeletal changes are found,[8] there are few that have objectively evaluated the bone microarchitecture in people
with SCD. The aim of this study is to characterize the microarchitecture of the mandibular
bone of people with SCD on computed tomography (CT) examination.
Materials and Methods
The sample consisted of CT scans of the mandible of people with SCD being treated
at University Hospital Professor Edgard Santos (Federal University of Bahia, Salvador,
BA, Brazil) from 2014 to 2019, which constituted the test group; and CT scans of the
mandible of people without SCD or SCT, matched for sex and age (+2 years), which constituted
the control group. CT scans were performed on clinical indication, as part of routine
care, with no unnecessary patient exposure to X-rays.
Inclusion criteria were diagnosis of SCD (for the test group), diagnosed by hemoglobin
electrophoresis (Hb SS genotype, Hb SC genotype, and β-thalassemia genotype), 18 years
or older at the time of CT scanning, CT scans obtained with thin reformatting (no
more than 0.5 mm thick), with a bone window, including the entire mandible. Exclusion
criteria were presence of bone lesions, fractures, deformities or previous surgery
in the mandible, or diseases that affected bone metabolism, or metallic artifacts
that hindered the correct evaluation of the images.
The selected scans were archived in electronic media in DICOM (Digital Imaging and
Communications in Medicine) format and opened in the software RadiAnt DICOM Viewer
(v. 5.01) for exportation of the sequence of bone window sections comprising the area
of interest of this study.
Then this sequence was opened in the MeVisLab software, in which the multiple files
were grouped into a single file, which was then converted into figure files with extension
bmp, in grayscale with eight bits by DicomToCTAn Converter (Medical Imaging Researcher
Center, Leuven, Belgium).
Then, in the DataViewer software, the images were aligned and cropped, selecting the
region of interest that were located on the body of both sides of each mandible, and
saved again. After this step, the images were opened in CTAnalyser software (v. 1.11.10.0,
Skyscan, Konitch, Belgium). The volume of interest (VOI) of each exam was standardized,
extending from 1 mm before the last image of the mental foramen to 1 mm after this
landmark. After establishing the VOI, the images from each side of the mandible were
binarized by applying an automatic threshold (the bony structures were shown in red
and the medullary spaces in green). Filters provided by the CTAnalyser software itself
(v. 1.11.10.0, Skyscan, Konitch, Belgium) were applied for better visualization of
the bone trabeculae, and then the selection of the area to be analyzed was performed.
The following parameters of the bone microarchitecture were automatically calculated
by the CTAnalyser software: thickness of the bone trabeculae (Tb.Th), separation of
the bone trabeculae (Tb.Sp), number of bone trabeculae (Tb.N), number of closed pores
(Po-C.N), frequency of open porosity, frequency of total porosity (Po-tot), and connectivity
(Conn).
After the analysis, the mean of the two measured values of each parameter, corresponding
to the two sides of each mandible, was calculated for statistical analysis. A single
examiner performed all measurements. The evaluations were performed on a single computer
(Pentium (R), 3.40GHz and 2.25GB RAM), with Windows XP (Microsoft Corporation, Washington,
United States) operating system, GeForce 6200 TurboCachel (NVIDIA, California, United
States) video card, on a 20.1-inch (51 cm), SuperVGA (1024 × 768 pixels), 32-bit FlexScanS2000
SlimEdge (Eizo Nanao Corporation, Ishikawa, Japan) monitor.
Data were tabulated in specific Microsoft Excel spreadsheets. The sociodemographic
variables (gender and age) were subjected to descriptive analysis by calculating means
and standard deviations. Bone microstructure descriptors were compared using Student's
t-test for paired samples. A 5% error probability was adopted for all analyses.
Results
The sample consisted of 57 CT scans of people with SCD and 57 of people without bone
changes, matched by age and sex. Thus, the mean age of the two groups was 37 years,
with 28 men (49.1%) and 29 women (50.1%) in each group ([Table 1]).
Table 1
Characterization of the sample groups regarding the age and sex of the patients
|
Test group
|
Control group
|
p-Value
|
|
Mean age (min–max age)
|
37,1 (18–59)
|
37.2 (18–59)
|
0.57
|
|
18 to 30 years (n [%])
|
18 (31.6%)
|
–
|
|
31 to 40 years (n [%])
|
22 (38.6%)
|
–
|
|
41 to 50 years (n [%])
|
7 (12.3%)
|
–
|
|
51 to 59 years (n [%])
|
10 (17.5%)
|
–
|
|
Female (n [%])
|
29 (50.1%)
|
–
|
|
Male (n [%])
|
28 (49.1%)
|
–
|
Abbreviations: Min, minimum; max, maximum.
Of the total number of scans, 19 (33.3%) were obtained in cone-beam CT equipment (with
isotropic voxel of 0.4 mm, 37 mA, and 120 kV) and the others (66.7%) were obtained
in 64-channel multidetector CT equipment (0.5 × 0.3 mm, 150 mA and 120 kV).
To evaluate bone microarchitecture, the values of seven different mandibular bone
pattern descriptors were compared. Three descriptors evaluated the configuration of
trabecular bone (thickness of trabeculae, separation of bone trabeculae, and number
of trabeculae), of which the last two showed significant difference between the groups
evaluated. Bone porosity was estimated by three descriptors (number of closed pores,
frequency of open porosity, and total porosity), and significant difference was observed
between the groups for all three descriptors. The connection between the bone trabeculae
was evaluated by connectivity. These results are shown in [Table 2].
Table 2
Descriptors of the mandibular bone pattern of the evaluated groups
|
Test group—mean (SD)
|
Control group—mean (SD)
|
p-Value
|
|
Trabeculae thickness (Tb.Th)
|
3.45 (1.0)
|
3.22 (0.8)
|
0.20
|
|
Separation of trabeculae (Tb.Sp)
|
4.00 (1.2)
|
3.08 (1.2)
|
<0.0001[a]
|
|
Number of trabeculae (Tb.N)
|
0.89 (0.8)
|
13.16 (10.2)
|
0.01[a]
|
|
Number of closed pores (Po-C. N)
|
44.4 (58.3)
|
129.5 (184.7)
|
0.0026[a]
|
|
Frequency of open porosity (Po-O)
|
57.5 (11.3)
|
47.5 (13.3)
|
<0.0001[a]
|
|
Frequency of total porosity (Po-tot)
|
57.5 (11.3)
|
47.6 (13.2)
|
<0.0001[a]
|
|
Connectivity (Conn)
|
633.3 (919.3)
|
880.9 (1291.1)
|
0.24
|
Abbreviation: SD, standard deviation.
a Significant difference.
Discussion
Some studies using radiomorphometric parameters in two-dimensional images or in animal
models have already been performed.[10]
[12]
[13]
[14] In our study, we observed a smaller number of bone trabeculae and a greater spacing
between trabeculae in the group of people with SCD. These findings were observed in
the study by Green et al[15], with micro-CT in rats, the connectivity density showed a reduction in up to 80%
when compared with the group without SCD. In this study, the authors found a reduction
in the volume occupied by mineralized tissue in older animals with SCD. Thinner trabeculae
with greater spacing between them and a smaller number of trabeculae were also found
in animals with the disease.
Similarly, in the study by de Carvalho et al,[11] an increase in medullary spaces was observed in 67% of individuals with SCD on periapical
radiographs, as well as in the study by Neves et al[16] who analyzed panoramic radiographs of individuals with SCD. In the study by Demirbas
et al[10] panoramic radiographs were evaluated and in 67% of the patients with SCD, the quality
of the mandibular bone tissue significantly deteriorated, trabecular bone density
decreased, and the medullary spaces were enlarged and became locular. These authors
also described a “ladder” trabecular pattern in 28% of the subjects analyzed, as well
as thinning of the mandibular cortex in 22%.
When analyzing bone porosity, in our study a significant reduction in closed pores
was observed, as well as an increase in open and closed porosity in people with SCD.
Zlataric and Celebić[17] conducted a study using bone densitometry and panoramic radiographs, and found that
individuals with low bone density values in the mandible had a much more porous cortical
bone at the lower mandibular border.
In our study, no significant difference in bone connectivity was observed, although
it was lower in people with SCD. In a study by Green et al [15] in which they analyzed micro-CT in rats, the connectivity density showed a reduction
in up to 80% when compared with the group without SCD.
The imaging findings discussed here can be visualized on imaging scans as less dense
and therefore more radiolucent tissue, with fewer radiopaque lines corresponding to
the bone trabeculae. This can be explained in people with SCD by the higher medullary
activity to contribute to increased hematopoiesis and compensate for the anemia that
characterizes the disease.
This bone tissue configuration, although not unique to SCD, should be a warning sign
for the underlying presence of diseases that may affect bone tissue metabolism.
Thus, this study proves the presence of mandibular bone changes in people with SCD,
which may suggest the presence of this disease in people still undiagnosed and contribute
to the screening of the disease.
Conclusion
This study showed that the mandibular bone of people with SCD has lower bone density
and more widely spaced trabeculae, which may contribute to the screening of people
who have not been diagnosed with SCD or allow monitoring of the disease. This work
is also important because knowing the mandibular bone microstructure of people with
SCD impacts on dental therapeutical decisions, since we know that bone quality impacts
directly in success in some procedures as surgeries and dental implants.
