Recurrent aphthous stomatitis and serum zinc levels


Recurrent aphthous stomatitis (RAS) (synonymous with recurrent aphthous ulcers) can affect up to 25% of the general population. It is classified as minor (>70% of cases; 1-5 ulcers mainly affecting non-keratinised mucosa <10mm in size), major (10% of cases; 1-10 ulcers >10mm in size and can affect keratinised mucosa) and herpetiform (10% of cases; 10-100 ulcers which converge, 2-3mm in size and can affect any mucosal surface) (Edgar et al. 2017). Minor RAS is the most common form (Dental Elf – 10th January 2013). There are several aetiological factors such as genetic predisposition, local trauma, stress (Dental Elf – 31st January 2012), systemic diseases, immunological disturbances and nutrient deficiencies (Chavan et al. 2012). Zinc is a micronutrient which has a role in cell growth/reproduction, collagen synthesis, regulating the immune system and wound healing.

This systematic review and meta-analysis aimed to assess the evidence on the potential association between zinc levels and occurrence of RAS.


The Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) were used to inform the methodology of this systematic review. The review included all observational studies that assessed the potential role of zinc deficiency in development of RAS. PubMed, Scopus, Web of Science, Google Scholar and China National Knowledge Infrastructure (CNKI) were the databases searched. The risk of bias was assessed using the Newcastle Ottawa Scale and publication bias using the funnel plot and Egger’s test.


  • 19 case-control studies were included.
  • 15 (of the 19) studies reported a significant association between low zinc levels and RAS.
  • The results of the pooled 19 studies revealed that zinc levels were significantly lower in RAS patients than in healthy controls, weighted difference in means = − 092 (95%CI; −26.695 to − 15.490), I2 = 95.375%, P < 0.001.
  • Subgroup analyses by geographical distribution (Chinese vs others) reported the results remained significant, although the relationship was more pronounced amongst the Chinese population.
  • Trial sequential analysis showed the cumulative Z curves crossed the conventional boundary and surpassed the required information size. Therefore, the conclusion is reliable and further trials are not needed.
  • There was no evidence of publication bias assessed through the Egger’s test (p=0.982).
  • 2 of the included studies were high quality, 14 moderate quality and 3 low quality.


The authors concluded:

(There is a)…significant association of low serum zinc and the risk of RAS…


This systematic review and meta-analysis showed a significant relationship between zinc levels and occurrence of RAS. The systematic review could have included searches of the grey literature that may have captured additional studies. The meta-analysis methodology was robust however the systematic review search strategy did not indicate the date range. However, the included studies were published between 1994 and 2019. This meta-analysis provides support for investigating zinc levels in patients with RAS.


Primary reference

Al-Maweri SA, Halboub E, Al-Sharani HM, Shamala A, Al-Kamel A, Al-Wesabi M, Albashari A, Al-Sharani A, Abdulrab S. Association between serum zinc levels and recurrent aphthous stomatitis: a meta-analysis with trial sequential analysis. Clin Oral Investig. 2021 Feb;25(2):407-415. doi: 10.1007/s00784-020-03704-8. Epub 2021 Jan 6. PMID: 33409687.

Other references

Chavan M, Jain H, Diwan N, Khedkar S, Shete A, Durkar S. Recurrent aphthous stomatitis: a review. J Oral Pathol Med. 2012 Sep;41(8):577-83. doi: 10.1111/j.1600-0714.2012.01134.x. Epub 2012 Mar 13. PMID: 22413800.

Edgar NR, Saleh D, Miller RA. Recurrent Aphthous Stomatitis: A Review. J Clin Aesthet Dermatol. 2017 Mar;10(3):26-36. Epub 2017 Mar 1. PMID: 28360966; PMCID: PMC5367879

Dental Elf – 31st January 2012

Stress associated with onset of recurrent mouth ulcers

Dental Elf – 10th January 2013

Study shows that berberine had a positive effect on recurrent aphthous ulceration




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