Aphthous ulcer pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Mehrsefat, M.D. [2], José Eduardo Riceto Loyola Junior, M.D.[3]


The exact pathophysiology of aphthous ulcer is not fully understood. The pathogenesis of recurrent aphthous ulcer is varies based on underlying medical conditions. It is thought that aphthous ulcer is the result of ​the cross reactivity theory between microbial antigens and mitrocondrial heat shock protein, dysembryoplastic theory, histopathogenesis of glandular cells in myxoma or the thrombotic theory​. Predisposing factors implicated so far in the development of aphthous ulcers are: trauma, smoking cessation, stress, hormonal disorders and food hypersensitivities.



The exact pathophysiology of aphthous ulcers is not fully understood. It is thought that the pathogenesis of recurrent aphthous ulcer is varies based on underlying medical conditions and environmental exposures. Predisposing factors implicated so far in the development of aphthous ulcers are: trauma, smoking cessation, stress, hormonal disorders and food hypersensitivities.



  • Despite the fact that many patients report having oral ulcers before stressful moments such as exams or job interviews, there is a lack of evidence to support that stress can be indeed a predisposing factor.[4]


  • There seems to exist a negative correlation between oral ulcers and smoking, with oral ulcers appearing after smoking cessation.[5] Another evidence of this negative correlation is the fact that nicotine tablets seem to control the surgeance of ulcers.[6]

Hormonal Disorders

Microbial Factors

Abnormal Immunologic Response

Abnormal immunological responds also considered as a viable theory in pathogenesis of aphthous stomatitis.

  • The exact pathogenesis of recurrent aphthous ulcer in patients with abnormal immunologic responds is not fully understood. It is thought abnormality in immunologic response may result in aphthous ulcer by following mechanisms:[12][13]
    • Deposition of immune complexes within the oral epithelium;
    • Elevated level of salivary immunoglobulin A ;
    • Alteration of the CD4/CD8 ratio ;
    • Increased levels of several cytokines such as interleukin-2, interferon-g, and [[tumor necrosis factor-a|tumor necrosis factor-a (TNF-a)];
    • Infiltration of the mucosal tissue by lymphocytes is theorized to be associated to a keratinocyte-associated antigen that has not been identified. The production of TNF-a results in keratinocyte death by mediating endothelial cell adhesion and neutrophil chemotaxis.[14]

Behcet’s syndrome

  • It is though that recurrent aphthous ulcer in Behcet syndrome may be caused by abnormal inflammatory response in patients. Abnormal Inflammatory respond in patient with behcet syndrome is mediated by T lymphocytes and plasma cells.[15]

HIV infected individuals

  • The exact pathogenesis of aphthous ulcer in HIV is remain unclear. Aphthous ulceration may occasionally arise in HIV disease as a initial finding. However, it can be a common finding in AIDS patients with CD4+ lymphocyte counts below 100cells/mm3.[16][17]

Crohn’s disease

  • The exact pathogenesis of aphthous ulcer in Crohn’s disease is not fully understood. It is though aphthous ulcer in patients with Crohn’s disease is a result of inflammation of salivary glands.[18]

Celiac disease

  • There is a commonly held belief that another cause of aphthous ulcers is gluten intolerance (Celiac disease), whereby consumption of wheat, rye, barley and sometimes oats can result in chronic mouth ulcers. However, two small studies of patients with celiac disease have demonstrated no link between the disease and aphthous ulcers.[19][20] If patients with aphthous ulcers do happen to have gluten intolerance, they may experience benefit in eliminating breads, pastas, cakes, pies, scones, biscuits, beers and so on from their diet and substituting gluten-free varieties where available.[19]

Associated conditions


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  2. Herlofson BB, Barkvoll P (1994). "Sodium lauryl sulfate and recurrent aphthous ulcers. A preliminary study". Acta Odontol Scand. 52 (5): 257–9. PMID 7825393.
  3. Wray D, Ferguson MM, Hutcheon WA, Dagg JH (1978). "Nutritional deficiencies in recurrent aphthae". J Oral Pathol. 7 (6): 418–23. PMID 105102 PMID 105102 Check |pmid= value (help).
  4. Pedersen A (1989). "Psychologic stress and recurrent aphthous ulceration". J Oral Pathol Med. 18 (2): 119–22. doi:10.1111/j.1600-0714.1989.tb00747.x. PMID 2746521.
  6. Bittoun R (1991). "Recurrent aphthous ulcers and nicotine". Med J Aust. 154 (7): 471–2. PMID 2005845.
  7. Ferguson MM, McKay Hart D, Lindsay R, Stephen KW (1978). "Progeston therapy for menstrually related aphthae". Int J Oral Surg. 7 (5): 463–70. doi:10.1016/s0300-9785(78)80038-6. PMID 102602.
  8. Ferguson MM, Carter J, Boyle P (1984). "An epidemiological study of factors associated with recurrent aphthae in women". J Oral Med. 39 (4): 212–7. PMID 6594461.
  9. Lindemann RA, Riviere GR, Sapp JP. Serum antibody responses to indigenous oral mucosal antigens and selected laboratory-maintained bacteria in recurrent aphthous ulceration. Oral Surg Oral Med Oral Pathol 1985;59:585.
  10. Leimola-Virtanen R, Happonen RP, Syrjanen S. Cytomegalovirus (CMV) and Hel- icobacter pylori (HP) found in oral mucosal ulcers. J Oral Pathol Med 1995;24: 14–7.
  11. Pedersen A, Hornsleth A. Recurrent aphthous ulceration: a possible clinical mani- festation of reaction of varicella zoster of cytomegalovirus infection. J Oral Pathol Med 1993;22:64–8.
  12. Pekiner FN, Aytugar E, Demirel GY, et al. Interleukin-2, interleukin-6 and T reg- ulatory cells in peripheral blood of patients with Behcet’s disease and recurrent aphthous ulcerations. J Oral Pathol Med 2012;41(1):73–9.
  13. Hasan A, Shinnick T, Mizushima Y, et al. Defining a T-cell epitope within HSP 65 in recurrent aphthous stomatitis. Clin Exp Immunol 2002;128(2):318–25.
  14. Natah SS, Häyrinen-Immonen R, Hietanen J, Malmström M, Konttinen YT (2000). "Immunolocalization of tumor necrosis factor-alpha expressing cells in recurrent aphthous ulcer lesions (RAU)". J Oral Pathol Med. 29 (1): 19–25. doi:10.1034/j.1600-0714.2000.290104.x. PMID 10678712.
  15. Klein P, Weinberger A, Altmann VJ, et al. Prevalence of Behcet syndrome among adult patients consulting three major clinics in a Druze town in Israel. Clin Rheu- matol 2010;29(10):1163–6.
  16. Di Alberti L, Porter SR, Speight P, et al. Detection of human herpesvirus-8 DNA in oral ulcer tissues of HIV infected individuals. Oral Dis 1997;3(Suppl 1):S133–4.
  17. Ramos-Gomez FJ, Flaitz C, Catapano P, Murray P, Milnes AR, Dorenbaum A. Classification, diagnostic criteria, and treatment recommendations for orofacial manifestations in HIV-infected pediatric patients. Collaborative Workgroup on Oral Manifestations of Pediatric HIV Infection. J Clin Pediatr Dent 1999; 23: 85–96.
  18. Schnitt SJ, Antonioli DA, Jaffe B, Peppercorn MA. Granulomatous inflammation of minor salivary gland ducts: a new oral manifestation of Crohn’s disease. Hum Pathol 1987; 18: 405–7.
  19. 19.0 19.1 Bucci P, Carile F, Sangianantoni A, D'Angio F, Santarelli A, Lo Muzio L. (2006). "Oral aphthous ulcers and dental enamel defects in children with celiac disease". Acta Paediatrica. 95 (2): 203–7. PMID 16449028.
  20. Sedghizadeh PP, Shuler CF, Allen CM, Beck FM, Kalmar JR. (2002). "Celiac disease and recurrent aphthous stomatitis: a report and review of the literature". Oral Surgery Oral Medicine Oral Pathology Oral Radiology & Endodontics. 94 (4): 474–8. PMID 12374923.

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