Oral manifestations and management of sickle cell disease: a literature review : IJS Global Health

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Oral manifestations and management of sickle cell disease: a literature review

Soualem, Hajar Dmda,*; Mainassara, Samirb; Beenjelloun, Lailab; Chbicheb, Salihab

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International Journal of Surgery: Global Health 5(6):p e84, November 2022. | DOI: 10.1097/GH9.0000000000000084
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Abstract

Sickle cell disease (SCD) is commonly used to describe a group of disorders characterized by the production of abnormal hemoglobin S (HBS). These entities include SCD HbSS (homozygous) and SCD HbAS (heterozygous).

There are 2 forms: minor and major.

For minor sickle cell syndrome, or heterozygous form, HbA (normal allele)/HbS (mutated allele), the patient is said to be only a carrier of the sickle cell trait and in this case, there are no symptoms.

For major sickle cell syndrome (MDS), the S/S form, or homozygous, is the most common. The allelic combinations are the cause of major sickle cell symptoms1.

It is the most common single gene disorder and the commonest hemoglobinopathy found with high prevalence in many populations across the world. The Oral Management of SCD requires special consideration for 3 main reasons. Firstly, dental and oral tissues are affected by the blood disorder resulting in several orofacial abnormalities. Secondly, living with a hemoglobinopathy and coping with its associated serious consequences may result in individuals neglecting their oral health care. Finally, the treatment of these oral complications must be adapted to the systemic condition and special needs of these individuals, in order not to exacerbate or deteriorate their general health2.

While systemic complications are well documented, oral complications are less so. The aim of this article is to highlight recent advances on clinical outcomes of oral manifestations of SCD and to provide evidence of the effectiveness of existing recommendations in the literature for oral management in people with SCD.

Epidemiology

SCD has a worldwide distribution. It is estimated that 300,000 infants are born annually with SCD, most in sub-Saharan Africa3,4. In the United States, 1 in 2500 live births are afflicted with SCD5 and it is estimated that 100,000 patients with SCD live in the United States5. However, patients living in high-income countries account for only 10% of the world’s SCD population6.

The African continent, in particular, bears the burden of SCD, where the United Nations estimates that 12–15 million of the world’s 25 million SCD patients live7. Childhood mortality among SCD patients is highest between 6 months and 3 years of age6,9, and it is estimated that 75% of all babies born with SCD are born in Africa where the mortality rate for children under 5 is estimated to exceed 50%6.

Mediterranean, Middle Eastern, and East Indian persons may also be at risk2. In Morocco, SCD affects several thousands of people. According to several studies the Rabat Salé Kenitra area is the most affected region in Morocco2.

SCD may have been considered a public health priority by all health decision-making bodies in the world for the past 10 years, but it has been left out because it is considered expensive and incurable. Priority has been given to financing the fight against infectious diseases that provide high mortality, but curable diseases such as malaria9.

Pathophysiology of SCD

Sickle cell anemia (SCA) is an inherited multisystem disease caused by a defect in chromosome10. The sickle mutation itself is the result of a single base change (GAT→ GTT) in the sixth codon of exon 1 of the β-globin gene on short arm of chromosome 1110. This change, in turn, results in replacement of the normal glutamic acid with valine at position 6 oftheβ-globin chain and the formation of sickle Hb. SCA is the homozygous state, where the sickle gene is inherited from both parents. If only one of the pair of chromosomes is affected then sickle-cell trait develops,while SCA reflects the involvement of both chromosomes1.

This is how we differentiate the minor sickle cell syndrome carrying only the sickle cell trait and the MDS which are the actual sickle cell subjects. These MDS generally presents the most important clinical picture. This requires the practitioner to monitor the blood count of major sickle cell subject1.

In SCD, amino acid substitution causes HbS to polymerase intracellularly when deoxygenated, thus changing the biconcave discoid shape of red blood cells (RBCs) to sickle shapes. This sickle hemoglobin causes: hemolytic anemia and hyperbilirubinemiadue to the increased RBC destruction, It also predispose to bacterial infections, and painful vaso-occlusive crises due to the obstruction of blood flow2.

Oral manifestations

Effects on the oral mucosa

There are different oral manifestations of SCD; however, most are not specific to the disease but also can be seen in other haemoglobinopathies. One of the most common manifestations of SCD in the oral cavity is a consequence of the chronic hemolytic anemia. This can present in the oral cavity as pallor and jaundice of the mucous membrane. Although most patients will show a generalized paleness of all the mucosa in the oral cavity, some sites are most noticeable than others which are the gingiva (Fig. 1) and the buccal and labial mucosa11,12.

F1
Figure 1:
Paleness of all the mucosa in the oral cavity, more noticeable in some site than the others, particularly in the gingival site.

Numb chin syndrome (NCS) (mental nerve neuropathy)

NCS, also called mental nerve neuropathy, is a sensory neuropathy characterized by numbness involving the distribution of the mental nerve. Odontogenic etiologies of NCS include jaw osteomyelitis, facial trauma, and dental anesthesia, whereas systemic conditions such as SCD, have also been associated with the development of NCS. The first to describe mental nerve neuropathy as a result of SCD was Konotey-Ahulu in 198013,14. He found that 4% of patients had moderate to severe pain in the mandible during a sickle cell crisis, with many developing burning sensations and numbness in the lower lip along the path of the mental nerve and that recovery of sensation could take months. In some instances, teeth may also exhibit loss of sensation (in case of otherbranches of the inferior alveolar nerve are involved) and patients may bite their lip unintentionally causing painless ulcers1,15.

Sickle cell crisis causes a painful mental neuropathy due to vaso-occlusive disease particularly in the mandible because of its relatively low blood flow as compared with other bones16. A vaso-occlusive crisis in the mandible may cause permanent neuropathies affecting the inferior alveolar nerve that may cause persistent anesthesia for up to 24 months, in absence of treatment11,14,17.

Symptoms are usually: unilateral but up to a third may have bilateral symptoms. Reversible anesthesiaor not of a group of teeth innervated by the mental nerve (premolars and incisors). Therefore it can cause painless ulcers due to involuntary repeated bites of the lip12,14.

Dental pathologies

An association between SCD and pulp necrosis on clinically healthy teeth has been reported18. The presence of healthy necrotic teeth is 8.25 times higher in a patient with SCD compared with a nonsickle cell patient, because of vascular occlusions of the pulpal microcirculation. Painful dental episodes in the past have been reported in the past. However, this feature is not essential and there are many cases of pulpal necrosis without any painful history19,20.

Alveolar bone manifestations

Sickle cells have a limited lifespan in the circulation (5–15 vs. 120 d)2. By the end of their life, the red cells are phagocytosed by macrophages. This causes an increase in the viscosity of the blood. The hemoconcentration is the origin of a blood stasis.

Ischemia very often affects the long bones, vertebrae, and the sternum. The bones of the face and maxilla are less affected. An incidence of 3%–5%2 of osteonecrosis in MDS is raised in the mandible, particularly the posterior regions. This is explained by a single homolateral vascularization throught the inferior alveolar artery and the periosteal vascularization. The effect on alveolar bone comes down to irradiating bone pain, without any dental origin. A bone necrosis can be observed by radiologic examination17.

Periodontal disease

The effects of SCA on gum tissue and periodontium are unconclusive as studies are controversial on this subject11,22. Some authors states that in subjects with major SCD we are seeing an increase in the release rates of proinflammatory cytokines11,23. There is a stimulation of destructive enzymes collagenases and metalloproteinases activities in periodontal tissues which predispose sickle cell subjects to periodontal disease.

Radiographic manifestations

Dental radiographs of patients with SCD, may show enlarged medullary spaces and decreased number of trabeculations. As a result, the bone appears more radiolucent. The trabeculae between the teeth in patients with SCD may present as prominent horizontal rows, giving a “stepladder” appearance13 (Fig. 2).

F2
Figure 2:
The trabeculae between the teeth in patients with major sickle cell disease may present as prominent horizontal rows, giving a “stepladder” appearance. The arrow indicates Localisation of the mucosal paleness.

This is due to a persistent proliferation of erythrocytes in the marrow24, to compensate the destruction of erythrocytes. This causes the widening medullary spaces, creating abnormal trabecular spacings.

Osteomyelitis is an inflammatory condition of the bone, beginning in the medullar cavity and extending to involve the periosteum of the affected area. It is more common in the long bones. Osteomyelitis of the jaws secondary to SCD is rare; however, when it occurs, the mandible is the most commonly affected facial bone because of its relatively poor blood supply11,25.

In case of osteomyelitis, intra-oral examination, can show swelling of the maxilla,or the mandible with suppuration and the exposure of bone. Radiologic examination can reveal a large bone sequestration.

Osteomyelitis may:

  • Have an iatrogenic origin following a dental extraction or surgical procedure.
  • Appear secondary to bone infarction. It is a bone infection whose pathogens are most often of hematogenous origin. The germs are transmitted by blood and are often of digestive origin (cholecystitis or gastroenteritis)26.

It is often very difficult to differentiate early bone infarction from osteomyelitis. However, the treatment is the same and consists of an adapted, long-term antibiotic therapy associated with surgical drainage.

Management of SCD in oral surgery

Because there are insufficient studies and controversies between the different recommendations for oral managementof SCD patients, clinicians need to use their clinical judgement and refer to lower-level evidence (eg, observational studies, case reports, expert opinion) for selecting the best and most suitable form of intervention for treating the dental complications in these patients2. This article has been undertaken to summarize the recommendations for oral management in people with SCD.

Dental routine care can be provided, but several recommendations should, be a priority to avoid hemorrhagic and infectious complications2,27,28. The French recommendations for adult sickle cell patients call for an annual consultation to ensure that a dental examination and the necessary care are performed each year29. Neither the UK National Institute for Health and Care Excellence (NICE) nor the National Institutes of Health in the United States provides guidelines for dental care in sickle cell patients.

Caution for the risk of hemorrhage

Preoperative

The blood formula count (BFS) will be systematic before any oral surgery in patients with SCD. The biological examinations are then used to monitor the basal state: blood count and reticulocytes1. The interpretation of CBC in patients with SCD should take into account the change in references compared with the healthy subject1 (Table 1). The hemorrhagic risk is evaluated thanks to the preoperative assessment with the thrombocythemia (Table 1) and the rate of prothrombin (Table 2).

Table 1 - Proposal of preoperative CBC for the major sickle cell patient30.
Red blood cells (g/L) Platelets (103/mm) Leukocytes (/mm3) Recticulocytes (103/mm)
Healthy patient 12–16 150–400 4000–10,000 50–100
MDS 7–9 250–400 800–20,000 200–600
Clinical interest If RBc value <7, all surgery must be done in a hospital environment In case of decrease in platelets suspect hepatic involvement Sickle cell disease is a disease One of the markers is hyperleukocytosis A decrease in leukocytes should be alarming about bone marrow necrosis Chronic hemolysis induces a strong bone marrow regeneration to compensate for anemia, which leads to an increase in the number of reticulocytes A value <200 is a sign of bone marrow necrosis, which will lead to Thrombocytopenia
MDS indicates major sickle cell syndrome; TCA, Cephaline activated level; TP, Prothrombine.

Table 2 - Proposed prothrombin rate of a major sickle cell patient.
Hepatic check Healthy patient MSD Clinical interest
Rate of prothrombin (%) 100 >60 If for MSD 60 <TP <30 exploration of TCA and coagulation factors because the risk of hemorrhage is increased
MDS indicates major sickle cell syndrome; TCA, Cephaline activated level; TP, Prothrombine.

Perioperative

A periosteal flap is not recommended because local vascular rupture increases the risk of flap necrosis.

For MDS hemostasis is done using the most airtight sutures possible (Fig. 3)11. A collagen hemostatic sponge that is not very irritating to the bone such as Pangen can be added, allowing the formation of the blood clot and therefore perfect healing as quickly as possible (Fig. 3)28. The use of biological glues for coaptation of the banks and stability of the clot. In case of resumption of bleeding, hemostasis will be obtained by direct compression using a gaze or a thermoformed splint11.

F3
Figure 3:
Intraoral view showing the extraction site, sutured hermetically with simple O-shaped sutures to minimize the risk of tearing of the edges.

Caution for the risk of infection

The French recommendations for adult sickle cell patients call for an annual consultation to ensure that a dental examination and the necessary care are performed each year31. In SCD, splenic function is reduced in people with SCD, thus reducing their immunity especially against encapsulated bacteria and increasing their susceptibility to infection2. Thus, the prevention of infection by antibiotic prophylaxisis a priority in oral SCD management11. Antibiotic prophylaxis is prescribed for periodontal, periapical, and oral mucosal surgery. MDS and sickle cell patients have functional asplenia or have undergone splenectomy must receive antibiotic prophylaxis2.

According to ANSM, the protocol is: 2 g of Amoxicillin/if allergy 500 mg Azithromycin 1 hour before the procedure24. In cases of osteomyelitis in the mandibular region, various treatments can be considered: curetage, debridement, corticotomy or partial bone resection. Appropriate, long-term antibiotic coverage and follow-up are indicated6,7.

SCD and anesthesia6,27

Locoregional anesthesia is possible and preferable to general anesthesia. The use of vasoconstrictors is also possible. On the other hand, it is preferable to obtain deep local anesthesia to avoid situations of stress which may be responsible for subsequent occlusive vascular pain. If general anesthesia is unavoidable, some precautions should be considered. Anemia must be corrected preoperatively (Hg >10 g/dL). General anesthesia should allow all oral care in one session to avoid reintervention6,27.

The management of sickle cell patients largely relates, also to the management of their anxiety before surgery under local or general anesthesia. Sedative premedication can be used. The molecules used must not cause respiratory depression. We therefore favor hydroxyzine (Atarax) at 1 mg/kg. Yet the prescription must be carried out in collaboration with the attending physician. Indeed, hydroxyzine is contraindicated in QT-long syndrome which is slightly increased in about 15% of patients with SCA14.

Pain management and SCD

Pain management is difficult because patients with MDS are already dependent to analgesics2. In the management of postoperative pain, certain medications should be taken with caution. Steroidal anti-inflammatory drugs are contraindicated because of the risk of triggering serious pathologies31 (eg, hyperalgic or acute chest syndrome).

The combination of paracetamol and codeine is the best analgesic solution for these patients12,14. The use of morphine and derivative analgesics is also possible (buprenorphine, fentanyl, hydromorphone, nalbuphine, oxycodone, and pethidine). These central analgesics are reserved for intense pain that often requires hospitalization. The use of morphine at home is contraindicated as there is a risk of overdose and death.

Because of the association of slowing the blood circulation and vasoconstriction due to the cold. The use of an ice pack (cold) is contraindicated postoperatively because this would increase the chances of occurrence of a phlebitis14.

Future prospects

With the advent of implantology and its success with the general population, the prospects for the future would be a democratization of this advanced oral surgery technique in subjects at risk of osteonecrosis in particular. Increased risk of osteomyelitis in MDS is essential when approaching implantology. Indeed, the establishment of intraosseous implants is an etiological factor of osteomyelitis and the presence of implants on a site of medullary infection decreases the prognosis of healing. For these 2 reasons, implant placement in these patients would be inadvisable even if, to our knowledge, no article or recommendation suggests it.

This on the one hand, the realization of epidemiological study in the future would enrich the literature on this subject, indeed the subjects with SCD represent a large community of patients at multiple risks, which should be taken into consideration like the patients with heart disease or on bisphosphonate. This will result in the establishment of clear and precise recommendations serving as a roadmap for their care in oral surgery.

The biological mechanisms of SCA and its genetic etiology make it possible to understand the complications linked to this pathology. Knowledge of these complications is essential because they will have direct or indirect consequences on oral health, on the diagnosis of oral lesions and on the management of patients with MDS.

Indeed, the follow-up and most of the surgical acts can be carried out in outpatient consultation at the dentist, with a good knowledge of the pathology and treatment recommendations. It is therefore necessary to make dental surgeons and specialists in oral surgery aware of the specificities diagnosis and treatment of SCD2.

Conclusion

SCD is an autosomal recessive hematological disorder that results in defective RBCs. These RBCs become sickled in shape, have a shortened lifespan leading to vascular occlusion and ischemia resulting in damaging effect on many organs throughout the body. There are numerous oral manifestations of SCD, although some may not be specific to SCD, it is important to recognize these clinical presentations and have a good understanding of the disease process to help in management of SCD from an oral health care perspective. The oral care of sickle cell patients requires specific precautions such as good management of local anesthetics, rigorous anti-infective prophylaxis as well as controlled prescription of analgesics.

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Conflicts of interest disclosure

The authors declare that they have no financial conflict of interest with regard to the content of this report.

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Keywords:

Oral manifestations; pain management; infectious risk; hemorrhag risk

Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of IJS Publishing Group Ltd.