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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 7  |  Issue : 2  |  Page : 35-39

Relevance of hematological parameters in patients with recurrent aphthous stomatitis


Department of Stomatology, Oral Medicine Unit, Faculty of Dentistry, University of Granada, Granada, Spain

Date of Submission18-May-2019
Date of Decision03-Sep-2019
Date of Acceptance03-Sep-2019
Date of Web Publication22-Oct-2019

Correspondence Address:
Alberto Rodriguez-Archilla
Faculty of Dentistry, University of Granada, Colegio Maximo, s/n. Campus de Cartuja, Granada 18071
Spain
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/dmr.dmr_13_19

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  Abstract 


Background: Recurrent aphthous stomatitis (RAS) continues to be a very common ulcerative disease of the oral mucosa, affecting approximately 20% of the general population. Hematinic deficiencies have been considered as a possible triggering factor, being iron, Vitamin B12, or folic acid deficiencies two times more frequent in patients with RAS. Objective: The objective was to assess the hematological parameters as possible etiological factors of RAS. Materials and Methods: A PubMed search of articles on hematological parameters in RAS was conducted. From 93 articles published between 1954 and 2018 (64 with full-text availability), 45 were excluded for several reasons: studies without a control group (17), studies with no clinical data (12), and studies with nonusable data (16). Data were processed using the statistical software RevMan 5.3 (The Cochrane Collaboration, Oxford, UK). For continuous outcomes, the estimates of effects of an intervention were expressed as mean differences using the inverse variance method, and for dichotomous outcomes, the estimates of effects of an intervention were expressed as odds ratio (OR) using Mantel-Haenszel method, both with 95% confidence intervals. Results: Nineteen studies of hematological parameters on RAS were included in this meta-analysis. RAS patients had a significantly higher risk of presenting low levels, together with lower concentrations, of hemoglobin (OR: 17.30), iron (OR: 6.67), folic acid (OR: 4.98), Vitamin B12(OR: 3.99), ferritin (OR: 2.86), and higher levels of homocysteine (OR: 7.22). Conclusion: Hematological disturbances may be an etiological factor of RAS.

Keywords: Aphthous, folic acid, hemoglobin, iron, stomatitis, Vitamin B12


How to cite this article:
Rodriguez-Archilla A, Brykova M. Relevance of hematological parameters in patients with recurrent aphthous stomatitis. Dent Med Res 2019;7:35-9

How to cite this URL:
Rodriguez-Archilla A, Brykova M. Relevance of hematological parameters in patients with recurrent aphthous stomatitis. Dent Med Res [serial online] 2019 [cited 2019 Nov 12];7:35-9. Available from: http://www.dmrjournal.org/text.asp?2019/7/2/35/269666




  Introduction Top


Recurrent aphthous stomatitis (RAS) continues to be a very common ulcerative disease of the oral mucosa, affecting approximately 20% of the general population. Depending on the size of the lesions, three clinical forms of RAS have been described: minor aphthae (90% of cases), major aphthae (8%), and herpetiform ulcers (2%).[1] RAS is considered as a multifactorial process of unknown etiology, in which various triggering factors and an immunological disturbance are combined. Among its possible triggers are food allergy, oral mucosal trauma, hormonal changes, stress and anxiety, blood and/or nutritional deficiencies, family history, certain infectious agents, and various systemic diseases.[2]

Specifically, hematinic deficiencies (iron, Vitamin B12, or folic acid) are twice as frequent in individuals with RAS compared to the control population.[3] In adult patients prone to develop RAS episodes, the existence of an underlying systemic disease, a connective tissue disease, a hematinic deficiency, or an immunodeficiency must be suspected.[4] The aim of this study was to analyze the role of hematological parameters as possible etiological factors of RAS.


  Materials and Methods Top


A PubMed database search of articles on hematological parameters in RAS was made combining Medical Subjects Headings (MeSH) terms. The search terms were: “stomatitis, aphthous” (MeSH terms) AND (“iron” [MeSH terms] OR “folic acid” [MeSH terms] OR “Vitamin B12” [MeSH terms] OR “ferritins” [MeSH terms] OR “hemoglobins” [MeSH terms] OR “homocysteine” [MeSH terms]). The initial search found 93 articles published between 1954 and 2018. The two inclusion criteria were: (a) articles with full-text availability (n = 64) and (b) studies that included, at least, one control group without RAS (n = 47). The exclusion criteria were: (a) studies without clinical data (n = 12) and (b) studies with irrelevant or nonusable data (n = 16). After the application of these criteria, 19 articles were analyzed in this meta-analysis [Figure 1].
Figure 1: Study flow diagram

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Statistical analysis

The meta-analysis was performed with the RevMan 5.3 program (The Cochrane Collaboration, Oxford, UK). For dichotomous variables, the Mantel-Haenszel Chi-square odds ratio (OR) with 95% confidence interval (CI) was used. For continuous variables, the inverse of the variance for the mean difference (MD) with 95% CI was used. Heterogeneity was determined according to the Higgins statistic (I2). The random-effects model was applied in cases of high heterogeneity. P < 0.05 was considered statistically significant.


  Results Top


[Table 1] presents the main descriptive characteristics of the 19 studies considered in this meta-analysis.[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23] The different hematological parameters assessed in patients with RAS and controls are shown in [Table 2].
Table 1: Descriptive characteristics of included articles

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Table 2: Different hematological parameters in recurrent aphthous stomatitis patients and controls

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Regarding the iron, 11 studies[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15] compared the presence of low iron levels (<50 μg/dL) in RAS patients versus control subjects without the disease. RAS patients were 6.67 times more likely to have low iron levels, with highly significant statistical differences (OR = 6.67, 95% CI: 2.37–18.77, P < 0.001). Six studies[8],[11],[12], [13,[15],[16] analyzed the iron concentrations both in the RAS patients group and control group, observing lower iron concentrations of 11.75 μg/dL on average in RAS patients with respect to controls. After the statistical analysis, a highly significant association was observed (MD = −11.75, 95% CI: −15.76–−7.74, P < 0.001).

Fourteen studies[5],[6],[7],[8],[9],[11],[12],[13],[14],[15],[17],[18],[19],[20] examined the presence of low levels of Vitamin B12(<200 pg/mL) in patients with RAS with respect to controls subjects. RAS patients were 3.99-fold more likely to have low levels of Vitamin B12, with a highly significant statistical relationship (OR = 3.99, 95% CI: 2.43–6.53, P < 0.001). Another seven studies[8],[11],[12],[13],[15],[16],[21] examined Vitamin B12 concentrations in both groups, RAS patients and controls. Vitamin B12 concentrations in RAS patients were lower in 31.35 pg/mL on average compared to controls. Statistical analysis showed significant differences (MD = −31.35, 95% CI: −55.75–−6.94, P = 0.01).

Fourteen studies[5],[7],[8],[9],[11],[13],[14],[15],[17],[18],[19],[20],[22],[23] considered the low levels of folic acid (<6 ng/mL) in RAS patients and controls. Patients with RAS were 4.98 times more likely to present low levels of folic acid respect to controls, with a highly significant statistical association (OR = 4.98, 95% CI: 2.67–9.30. P < 0.001). Moreover, six studies[8],[11],[13],[15],[16],[21] compared folic acid concentrations in both groups, finding folic acid concentrations lower in 0.95 ng/mL on average in RAS patients. After the statistical analysis, a very significant relationship was found (MD = −0.95, 95% CI: −1.53–−0.38, P < 0.01).

Six studies[8],[12],[13],[15],[18],[19] assessed the low hemoglobin levels (<14 g/dL) in patients with RAS and controls without the disease. RAS patients were 17.30-fold more likely to have low hemoglobin levels, with very significant statistical differences (OR = 17.30, 95% CI: 2.27–131.79, P < 0.01). Respect to the mean hemoglobin concentrations in both study populations,[8],[13],[15],[16] RAS patients had lower hemoglobin concentrations in 0.85 g/dL on average compared to controls. The statistical analysis showed a highly significant relationship (MD = −0.85, 95% CI: −1.21–−0.49, P < 0.001).

Eight studies[7],[9],[11],[17],[18], [19,][20],[23] analyzed the levels of serum ferritin, finding lower levels (<15 ng/mL) in patients with RAS. These patients were 2.86 times more likely to have low ferritin levels than controls without the disease. The statistical association was highly significant (OR = 2.86, 95% CI: 1.97–4.14, P < 0.001). Three studies[11],[16],[23] investigated mean concentrations of serum ferritin in RAS patients and controls, although no statistically significant differences were found (MD = −14.57, 95% CI: −56.54–27.39, P = 0.50).

Finally, four studies[8],[13],[15],[21] investigated blood homocysteine in RAS patients versus controls. About 8.6% of RAS patients (61/708) and 1.3% of controls (13/970) had high homocysteine levels (>10.4 μmol/L). Patients with RAS were 7.22-fold more likely to have high homocysteine levels, with a highly significant statistical relationship (OR = 7.22, 95% CI: 3.90–13.38, P < 0.001). In contrast, when homocysteine concentrations were compared in both population groups, there were no statistically significant differences (MD = −0.02, 95% CI: −0.11–0.08, P = 0.74).


  Discussion Top


In the present meta-analysis on the possible influence of different hematological parameters on RAS, data from 19 studies were included.

In this study, RAS patients had 6.67 times more likely than controls to have low iron levels (<50 μg/dL) with statistically significant differences (P < 0.001). The 11 studies[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15] that considered this parameter also found low iron levels in RAS patients. Similarly, patients with RAS had significantly lower iron concentrations (11.75 μg/dL lower on average) compared to controls (P < 0.001). Of the six studies[8],[11],[12],[13],[15],[16] that analyzed these iron mean concentrations, only one of them[11] found lower iron concentrations in the controls, although without a significant relationship. Iron deficiency is responsible for anemia in which the decrease in the number of erythrocytes results in less oxygen transport to tissues, including the oral mucosa. This lack of oxygen affects the differentiation and maturation of the epithelial cells causing the atrophy of the oral mucosa. This atrophy increases tissue susceptibility favoring antigenic exposure and the development of a cytotoxic immunological response that could lead to RAS.[13]

With respect to Vitamin B12, in the present study, RAS patients had 3.99-fold more likely of having low levels of this vitamin compared to controls. After the statistical analysis, highly significant differences were found (P < 0.001). Thirteen studies[6],[7],[8],[9],[11], [12,[13],[14],[15],[17],[18],[19],[20] coincided in finding low Vitamin B12 levels (<200 pg/mL) in patients with RAS; meanwhile, a single study observed low levels in the controls.[5] Similarly, RAS patients had Vitamin B12 concentrations lower in 31.35 pg/mL on average in contrast to those in controls with a statistically significant relationship (P = 0.01). Only one of the seven studies[8],[11],[12],[13],[15],[16],[21] that evaluated these concentrations found higher Vitamin B12 concentrations in patients with RAS.[21] Vitamin B12 deficiency, either separately or in combination with other deficiencies of the Vitamin B complex, can be a possible precipitating factor for RAS. Vitamin B12 plays an important role in the synthesis of DNA and cell division of epithelial cells, and its deficiency may result in atrophy of the oral epithelium. In addition, according to some studies, replacement therapy with Vitamin B12 produces a clinical improvement in RAS patients, reducing the frequency, and severity of oral aphthous ulcers.[13]

The possible relationship between folic acid and RAS was also investigated. A greater number of RAS patients had low levels (<6 ng/mL) of folic acid, in line with findings of 14 studies.[5],[7],[8],[9],[11],[13],[14],[15],[17],[18],[19],[20],[22],[23] In fact, RAS patients were 4.98 times more likely than controls to have low levels of folic acid with a highly significant statistical association (P < 0.001).

Six studies[8],[11],[13],[15],[16],[21] also investigated folic acid concentrations in patients with RAS and in controls. Patients showed lower folic acid concentrations (0.95 ng/mL lower on average) compared to controls with very significant statistical differences (P = 0.001). Only one study[16] did not find lower folic acid concentrations in RAS patients, although these results could be conditioned by the characteristics of the population included in that study. Folic acid deficiency also induces oral mucosa atrophy and increases the inflammation, situations that favor the appearance of oral aphthae.[13] As in the case of Vitamin B12, folic acid replacement therapy has shown an improvement in patients with RAS.[18]

When analyzing hemoglobin, RAS patients had 17.30 times more likely of having low hemoglobin levels (<14 g/dL) compared with controls. After the statistical analysis, a very significant relationship was observed (P < 0.01). Six studies[8],[12],[13],[15],[18],[19] coincided in finding low levels of hemoglobin in RAS patients. Likewise, lower hemoglobin concentrations in 0.85 g/dL on average were found in patients with RAS, with a highly significant statistical association (P < 0.001) in consonance with the results of three studies.[8],[13],[15] The lack of hemoglobin reduces the capacity of the blood to transport oxygen to the oral tissues, inducing epithelial atrophy that increases the risk of developing RAS lesions.[13]

Of the eight studies[7],[9],[11],[17],[18],[19],[20],[23] that investigated the ferritin levels, all of them found low ferritin levels (<15 ng/mL) in RAS patients with respect to the control subjects. Patients with RAS were 2.86-fold more likely to have low ferritin levels, with a highly significant statistical relationship (P < 0.001). Nevertheless, when ferritin concentrations were analyzed both RAS patients and controls, no statistically significant differences were found (P = 0.50).

There is a direct relationship between iron and ferritin levels, the decrease of ferritin has the same biological effect on tissues as iron deficiency.[19] In RAS patients, it seems that other factors such as age or sex influence ferritin levels. Hence, serum ferritin deficiency is more common in young women with RAS.[17]

Finally, four studies[8],[13],[15],[21] assessed the possible influence of homocysteine on RAS. Patients with RAS had 7.22-fold more likely to have high homocysteine levels (>10.4 μmol/L) compared to controls, with a highly significant statistical association (P < 0.001). However, in the case of blood homocysteine concentrations, no statistically significant differences (P = 0.74) were observed between RAS patients and controls. The increase in blood homocysteine levels can cause oxidative cell stress and endothelial damage.[13] In patients with RAS, Vitamin B12 deficiency increases the levels of homocysteine that induces the thrombosis of the blood capillaries which supply the oral tissues, favoring the breakdown of the epithelial integrity, and the development of aphthous ulcers.[8]

The high heterogeneity of some studies considered in this meta-analysis and the methodological differences among the different studies could be a potential source of bias, compelling to interpret the findings with caution.


  Conclusion Top


In this meta-analysis, RAS patients were more likely to have significantly lower levels of hemoglobin (OR: 17.30 and MD: −0.85 g/dL), iron (OR: 6.67 and MD: −11.75 μg/dL), folic acid (OR: 4.98 and MD: −0.95 ng/mL), Vitamin B12(OR: 3.99 and MD: −31.35 pg/mL), and ferritin (OR: 2.86). In contrast, these patients had higher homocysteine values (OR: 7.22).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Rodríguez-Archilla A, Raissouni T. Clinical study of 200 patients with recurrent aphthous stomatitis. Gac Med Mex 2018;154:165-71.  Back to cited text no. 1
    
2.
Queiroz SI, Silva MV, Medeiros AM, Oliveira PT, Gurgel BC, Silveira ÉJ. Recurrent aphthous ulceration: An epidemiological study of etiological factors, treatment and differential diagnosis. An Bras Dermatol 2018;93:341-6.  Back to cited text no. 2
    
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Cui RZ, Bruce AJ, Rogers RS 3rd. Recurrent aphthous stomatitis. Clin Dermatol 2016;34:475-81.  Back to cited text no. 3
    
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Akintoye SO, Greenberg MS. Recurrent aphthous stomatitis. Dent Clin North Am 2014;58:281-97.  Back to cited text no. 4
    
5.
Barnadas MA, Remacha A, Condomines J, de Moragas JM. Hematologic deficiencies in patients with recurrent oral aphthae. Med Clin Barc 1997;109:85-7.  Back to cited text no. 5
    
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Challacombe SJ, Barkhan P, Lehner T. Haematological features and differentiation of recurrent oral ulceration. Br J Oral Surg 1977;15:37-48.  Back to cited text no. 6
    
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Compilato D, Carroccio A, Calvino F, Di Fede G, Campisi G. Haematological deficiencies in patients with recurrent aphthosis. J Eur Acad Dermatol Venereol 2010;24:667-73.  Back to cited text no. 7
    
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Lin HP, Wu YH, Wang YP, Wu YC, Chang JY, Sun A. Anemia and hematinic deficiencies in anti-gastric parietal cell antibody-positive or all autoantibodies-negative recurrent aphthous stomatitis patients. J Formos Med Assoc 2017;116:99-106.  Back to cited text no. 8
    
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Lopez-Jornet P, Camacho-Alonso F, Martos N. Hematological study of patients with aphthous stomatitis. Int J Dermatol 2014;53:159-63.  Back to cited text no. 9
    
10.
Olson JA, Feinberg I, Silverman S Jr., Abrams D, Greenspan JS. Serum Vitamin B12, folate, and iron levels in recurrent aphthous ulceration. Oral Surg Oral Med Oral Pathol 1982;54:517-20.  Back to cited text no. 10
    
11.
Piskin S, Sayan C, Durukan N, Senol M. Serum iron, ferritin, folic acid, and Vitamin B12 levels in recurrent aphthous stomatitis. J Eur Acad Dermatol Venereol 2002;16:66-7.  Back to cited text no. 11
    
12.
Ślebioda Z, Krawiecka E, Szponar E, Dorocka-Bobkowska B. Haematinic deficiencies and patient clinical profiles in Polish patients with recurrent aphthous stomatitis (RAS). J Oral Pathol Med 2018;47:531-7.  Back to cited text no. 12
    
13.
Sun A, Chen HM, Cheng SJ, Wang YP, Chang JY, Wu YC, et al. Significant association of deficiencies of hemoglobin, iron, Vitamin B12, and folic acid and high homocysteine level with recurrent aphthous stomatitis. J Oral Pathol Med 2015;44:300-5.  Back to cited text no. 13
    
14.
Wray D, Ferguson MM, Mason DK, Hutcheon AW, Dagg JH. Recurrent aphthae: Treatment with Vitamin B12, folic acid, and iron. Br Med J 1975;2:490-3.  Back to cited text no. 14
    
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Wu YC, Wu YH, Wang YP, Chang JY, Chen HM, Sun A. Hematinic deficiencies and anemia statuses in recurrent aphthous stomatitis patients with or without atrophic glossitis. J Formos Med Assoc 2016;115:1061-8.  Back to cited text no. 15
    
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Koybasi S, Parlak AH, Serin E, Yilmaz F, Serin D. Recurrent aphthous stomatitis: Investigation of possible etiologic factors. Am J Otolaryngol 2006;27:229-32.  Back to cited text no. 16
    
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Bao ZX, Shi J, Yang XW, Liu LX. Hematinic deficiencies in patients with recurrent aphthous stomatitis: Variations by gender and age. Med Oral Patol Oral Cir Bucal 2018;23:e161-e167.  Back to cited text no. 17
    
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Khan NF, Saeed M, Chaudhary S, Khan NF. Haematological parameters and recurrent aphthous stomatitis. J Coll Physicians Surg Pak 2013;23:124-7.  Back to cited text no. 19
    
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Porter SR, Scully C, Flint S. Hematologic status in recurrent aphthous stomatitis compared with other oral disease. Oral Surg Oral Med Oral Pathol 1988;66:41-4.  Back to cited text no. 20
    
21.
Gönül M, Gül U, Kilinç C, Cakmak SK, Soylu S, Kiliç A. Homocysteine levels in patients with Behçet's disease and patients with recurrent aphthous stomatitis. Clin Rheumatol 2009;28:1153-6.  Back to cited text no. 21
    
22.
Thongprasom K, Youngnak P, Aneksuk V. Hematologic abnormalities in recurrent oral ulceration. Southeast Asian J Trop Med Public Health 2002;33:872-7.  Back to cited text no. 22
    
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Challacombe SJ, Scully C, Keevil B, Lehner T. Serum ferritin in recurrent oral ulceration. J Oral Pathol 1983;12:290-9.  Back to cited text no. 23
    


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