Review Article

Oral manifestations of sickle cell disease and its effects on dental and periodontal health: A systematic review

Introduction

Sickle cell anemia is one of the world’s most common monogenic disorders.¹ It is caused by a mutation in the beta-globin gene’s sixth codon, which leads to the synthesis of an abnormal hemoglobin called hemoglobin S (HbS).² The mutation can be heterozygous (Hb AS), homozygous (Hb SS), or combined with other hemoglobin defects, such as the -globin gene (Hb SThal), to cause sickle cell trait (SCT) and beta-thalassemia (T). Mutant hemoglobin results in sickle-shaped erythrocytes in hypoxic conditions, causing blood vessel obstruction and tissue necrosis.^1,3

According to the World Health Organization (WHO), around 5% of the world’s population carries a gene causing a hemoglobin anomaly, and around 50 million people are affected, with severe forms predominating in equatorial Africa (15%–30%).^3-5 Due to the global migration of populations, sickle cell disease has become a public health issue.

The disease is characterized by hemolytic anemia, vaso-occlusive phenomena, and susceptibility to infection, with frequent acute or chronic complications.¹ These include pain, cerebral complications, heart failure, severe infections such as sepsis, osteomyelitis, and vaso-occlusive crises.^1-6

Some oral manifestations of sickle cell disease have been described, including increased levels of biofilm, aseptic pulpal necrosis, decreased salivary flow, paleness of the oral mucosa, delayed tooth eruption, enamel hypoplasia, and oral neuropathies.^7-11 Dental caries and periodontal disease can be a source of infection in sickle cell crises.^8,11 Gingival bleeding and biofilm have been noted in sickle cell patients with decreased salivary flow.¹² de Carvalho et al¹³ reported that SCT is associated with gingivitis and periodontitis. Mahmoud et al¹⁴ observed a significantly higher prevalence of inflammatory periodontium in children with sickle cell disease compared with controls without sickle cell disease. However, other studies have reported no oral manifestations in patients with sickle cell disease.^10,15 There is no consensus on the oral manifestations of sickle cell disease and its effects on dental and periodontal health. A synthesis of current data on the dental and periodontal manifestations of sickle cell disease is needed to establish a prevention and management policy. The present study was undertaken to identify the oral manifestations of sickle cell disease and its effects on dental and periodontal health.

Methods

This systematic review was conducted according to PRISMA statement guidelines.¹⁶ The research question was: “What are the dental and periodontal manifestations of sickle cell disease?” This question has been articulated as follows (P ₌ population; E ₌ exposure; O ₌ outcome):

• Population: sickle cell patients

• Exposure: oral manifestations of sickle cell disease

• Outcome: effects of oral manifestations on dental and periodontal health

Search strategy and identification of relevant studies

An article search was carried out using Pubmed, Embase, and the African Index Medicus. “anemia, sickle cell,” “sickle cell disease,” “hemoglobin SC disease,” “oral diseases,” “periodontal diseases,” “dental health,” “dental caries,” “dental pulp disease,” and “dental abnormality” were the MeSH designations and keywords used. The Boolean operators “AND” and “OR” were used to combine these words. Over one month, a manual search was also conducted in the journals of Periodontology and Oral Implantology, the International Journal of the African College of Odontology and Maxillofacial Surgery, and the Journal of Tropical Odontology.

Inclusion and exclusion criteria

This systematic review included research published in both English and French from 2000 to 2022. The included articles were case–control studies, cohort studies, cross-sectional studies, and case reports. Expert letters, opinions, animal research papers, systematic reviews, and experimental studies were excluded.

Study selection

After implementing the search strategy, the results were fed into the Rayyan program (Rayyan.ai). After removing duplicates, two independent reviewers examined all the collected studies for inclusion. During this phase, articles with irrelevant titles or abstracts were excluded, and the full texts of the selected articles were examined. Two separate reviewers subsequently assessed the full texts to determine their final inclusion. Discrepancies were handled by a third reviewer after anonymity was removed (Rayyan).

Quality assessment of studies

Two independent reviewers assessed the quality of the included studies. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of cohort and case–control studies. This scale takes into account selection, comparison, and exposure. These three key areas were used to provide a maximum of 9 points to the quality of cohort and case–control studies. Cross-sectional studies were graded using the modified NOS, which assigns a maximum of 10 stars to three areas (selection, comparability, and results). To evaluate the quality of case reports, the 2013 CARE Guideline was used. The introduction, discussion, and conclusion are all rated on this scale. These three key areas were used to assign a maximum of 9 points to case reports and case series.

Data extraction

FEB and AMD extracted the data. The parameters collected from each study were the identity of the first author, year of publication, country of study, type of study, sample size, mean age, means of diagnosis of sickle cell disease, oral manifestations studied, and the main results.

Results

Study selection

Figure 1 depicts the flowchart of the study selection process. PubMed, Embase, African Index Medicus, and grey literature yielded 308, 592, 61, and 1 article, respectively. We reviewed 35 full-text articles; however, 4 full-text articles were not retrieved, and data extraction was not possible for 5 articles. In the end, we included 26 studies in the systematic review.

Close

Figure 1.

PRISMA chart of the manuscript selection process

Figure 1.

PRISMA chart of the manuscript selection process

Characteristics of the included studies

Table 1 summarizes the key features of the included research. The articles chosen were published between 2001 and 2022 and included 13 case–control studies, 4 cohort studies, 7 cross-sectional studies, and 2 case reports. Most studies used electrophoresis to diagnose sickle cell disease, whereas others used medical history or medical records, high-performance liquid chromatography, genetics, and molecular biology. Cold heat test, gingival index, sulcular bleeding index, plaque index (PI), periodontal probing depth (PPD), clinical attachment loss (CAL), bleeding on probing (BOP), community periodontal index (CPI), and decayed, missing or filled teeth index (DMFT) were used to define oral manifestations. Most studies included in the review reported oral symptoms of sickle cell disease. Only two studies showed no link between sickle cell disease and the outlined oral symptoms. Several oral signs of sickle cell disease were recorded, with periodontal manifestations predominating in 10 of the 26 included studies.

Quality assessment

Tables 2, 3, 4, and 5 summarize the quality assessment of the included studies. Cohort studies had scores ranging from 7 to 8 (good quality) out of 9 (Table 2). Of 13 case–control studies, only one had a score of 4/9; all the others had scores ≥ 6/9, ranging from 6 (average quality) to 9 (good quality, Table 3). As for the cross-sectional studies, their scores ranged from 5 to 9 out of 10, i.e., from moderate risk of bias (5) to low risk of bias (9, Table 4). The evaluation of case reports resulted in scores ≥ 5/9 (Table 5).

Discussion

This systematic review only included studies written in French or English. Case reports or case series could weaken the level of evidence of the association found, as these are not ideal for testing evidence of association. The same applies to cross-sectional studies. However, they make it possible to identify factors without being able to rule on their causal role or to specify whether they predate or post-date the events. Nonetheless, most studies have attempted to control for cofactors, allowing associations to be confirmed. The indices used to define the presence of periodontal inflammation and dental caries varied from one study to another, making comparability difficult. This is also true for the multiple techniques used to diagnose sickle cell disease.

In our review, 57.60% of the studies had a low risk of bias, 38.46% had a medium risk of bias, and 3.84% had a high risk of bias. The high risk of bias might be explained primarily by mistake in heading one of the assessment tools, which refers to the selection process and includes items such as case definition, case representativeness, control selection, and control definition. The high rate of studies with a low risk of bias could be explained by the studies’ methodological rigor.

Ten of the 26 studies evaluated sickle cell disease’s periodontal symptoms. Six studies found a link between sickle cell disease and periodontal disease (PD), with PD identified simultaneously and under the same conditions as other oral diseases.^{12,13,23,27,33,37} Four studies focused only on periodontal symptoms and found a link to sickle cell disease.^13,14,20,25This systematic review showed a predominance of periodontal disease in patients with sickle cell disease. However, this conclusion must be qualified because of the heterogeneity of the periodontal indices used. Indeed, periodontal disease has been defined in different ways: PI, gingival index, sulcular bleeding index, CPI, pocket depth, clinical loss of attachment, and serum cytokine levels. Some studies have found a positive association between sickle cell disease and gingival index but not between sickle cell disease and PI.¹⁴ On the other hand, de Carvalho et al¹³ found no association between periodontal parameters and sickle cell disease but reported that SCT was associated with gingivitis and periodontitis. Furthermore, some studies did not dissociate gingivitis and periodontitis in PD.^15,23,27,37However, others identified a positive association between sickle cell disease and gingivitis but not with periodontitis.^12,25 These authors attributed gingival hypertrophy to repeat episodes of hemorrhage and tissue repair (blood extravasation) on the one hand and elevated levels of cytokines (interleukin-6, TNF-α) and salivary nitric oxide in sickle cell disease patients on the other, which may promote PD.^17,37 In addition, patients with sickle cell disease often have an increased inflammatory response that can intensify the gingival response to a minimal amount of biofilm, putting them at increased risk of developing PD.⁸ Other factors that may influence the occurrence of PD, such as social status, severity of sickle cell disease, and level of oral hygiene, need to be considered; however, this was not the case in the studies included in this systematic review.^38,39

Seven studies evaluated dental caries as an oral manifestation of sickle cell disease. A positive association was reported in all but one study, although the mean number of decayed teeth was significantly higher in subjects with sickle cell disease.²⁷ Laurence et al.¹⁰ reported that sickle cell patients had more decayed tooth surfaces than healthy subjects, with a statistically significant difference (P < 0.005) after adjustment for age and sex. Carvalho et al³⁵ showed that sickle cell pain attacks were positively associated with dental caries. In contrast, Yue et al,⁴⁰ in their meta-analysis including 9 studies on the association between sickle cell disease and dental caries, indicated that the DMFT and decayed, missing, and filled surface (DMFS) index scores were not significantly different between sickle cell disease patients and healthy participants. They concluded that sickle cell patients did not suffer from more severe forms of dental caries than healthy people.

Sickle cell disease is a risk factor for pulpal necrosis in clinically intact teeth, which can be explained on the one hand by vaso-occlusive crises in sickle cell disease, which lead to ischaemic necrosis of pulp tissue even in the absence of other risk factors and on the other hand by the vulnerability of the dental nerve when it passes through a narrow bone canal in sickle cell disease.^18,24,28

A positive association between sickle cell disease and delayed tooth eruption has been reported.^31,36 This condition may be associated with the same factors that determine somatic growth retardation in sickle cell disease.

In a cross-sectional study, Lopes et al³¹ showed that enamel defect was common in sickle cell patients and increased with age. The most common enamel defect was found to be diffuse enamel opacity. Pathological and/or medical disorders such as changes in oxygen saturation, antibiotics, infection, excessive fluoride exposure, and malnutrition might all lead to these symptoms.

Oredugba¹⁹ documented hypodontia in an adolescent with SC sickle cell disease, suggesting a genetic link between the two diseases, though this has not been validated in the literature. Similarly, hypotaurodontism has been linked to hereditary disorders and is thought to be associated with sickle cell disease.³⁰

Licciardello et al²¹observed increased posterior rotation of the mandible and prominence of the maxillary incisors in patients with sickle cell disease, suggesting craniofacial growth anomalies associated with the disease.

Despite the absence of a significant association, Souza et al³⁴ reported a high prevalence of pulpal calcification and external root resorption in sickle cell patients. Pulpal calcification can be due to an accumulation of sickle cells, leading to thrombosis of the blood vessels that supply the afflicted area. External resorption is possibly related to the propensity for infection in sickle cell disease, promoting the inflammatory mechanisms associated with dental tissue damage.³⁴

This systematic review is marked by the heterogeneity of the means of diagnosis of sickle cell disease observed even within four studies that used two different means of diagnosis for the same population.^10,22,26,32 However, for the same population, it is desirable to use a single diagnostic method for all participants to obtain reliable results. Seven studies diagnosed sickle cell disease based on medical history, with a high risk of bias, which could influence the reliability of the associations mentioned.^{15,17,29,36,37,41,42} Sickle cell disease was diagnosed in 1/3 of the studies included based on patients’ medical records, and the methods used were not specified in these studies. Electrophoresis was used in nine studies, demonstrating the reliability of the diagnosis of sickle cell disease and, consequently, the association evoked.

Conclusion

This study reported oral manifestations of sickle cell disease, with a predominance of its effects on periodontal health. Given the limitations of this study, the various reported dental and periodontal manifestations of sickle cell disease should be taken with caution. Studies using the same periodontal indices (PI, BOP, PPD, CAL, and alveolar bone loss) and the same diagnostic tools for sickle cell disease are needed to clarify the association between sickle cell disease and oral symptoms, particularly periodontal.

Competing Interests

The authors declare that they have no financial and non-financial competing interests concerning the publication of their work during submission.

Consent for Publication

Not applicable.

Data Availability Statement

The authors confirm that the data supporting the findings of this study are available within the article.

Ethical Approval

Not applicable.

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