Recurrent Aphthous Stomatitis As a Result of Zinc Deficiency

Recurrent Aphthous Stomatitis as a Result of Zinc Deficiency

Nelli Yıldırımyana / Öznur Özalpb / Samed Şatırc / Mehmet Ali Altayd / Alper Sindele

Purpose: The purpose of this study is to evaluate the results of patients, with a chief complaint of recurrent aphthous stomatitis (RAS), who were found to have zinc deficiency as the predisposing factor and received appropriate replacement therapy. Materials and Methods: A retrospective study was conducted using data from the medical records of patients with a chief complaint of RAS. Patients with potential ulcer-causing conditions were excluded. All patients were intra- orally examined to rule out trauma-associated aetiologies. Blood tests were ordered to measure total blood count, serum transferrin, ferritin, zinc, folic acid and vitamin B12 levels. Results: A total of 48 patients, 34 with zinc deficiency and 14 with both zinc and iron deficiencies, were included in this study. Patients received an initial three-monthly replacement treatment and blood tests for the certain defi- ciencies were repeated at the end of this time interval. Two patients with zinc deficiency reported no relief due to incorrect intake of tablets with milk. Following correct instructions, all patients reached normal serum mineral lev- els and reported no recurrences. All patients remained asymptomatic and their mineral levels were monitored in every 3 months to detect any abnormalities. Overall mean follow-up for this study was 12.06 months (range: 8–28 months, SD: ± 5.7). Conclusion: Zinc deficiency should be considered and investigated as part of the diagnostic process of RAS. A simple blood test may aid in correct diagnosis and complete resolution of this recurring condition rather than constant pre- scription of certain medicines to suppress the symptoms. Key words: diet, phytate, oral ulcers, recurrent aphthous stomatitis, zinc deficiency

Oral Health Prev Dent 2019; 17: 465–468. Submitted for publication: 19.02.2018; accepted for publication: 17.06.2018 doi: 10.3290/j.ohpd.a42736

he earliest use of the Greek term ‘aphthai’ is attributed a Research Assistant, Department of Oral and Maxillofacial Surgery, Akdeniz Tto Hippocrates (460–370 BC) and back in those times, University, Faculty of Dentistry, Antalya, Turkey. Helped design the study, data collection and analysis, wrote and proofread the final version of the manu- it was used to describe disorders of the mouth. Now, re- script. current aphthous stomatitis (RAS) is considered as the b Research Assistant, Department of Oral and Maxillofacial Surgery, Akdeniz most common oral mucosal disease in humans.21 RAS or University, Faculty of Dentistry, Antalya, Turkey. Helped data collection and recurrent aphthous ulceration is a painful condition com- analysis, wrote and proofread the final version of the manuscript. monly involving the oral non-keratinised mucosa, and is c Research Assistant, Department of Oral and Maxillofacial Radiology, Akdeniz University, Faculty of Dentistry, Antalya, Turkey. Assisted with data collection characterised by repeated occurrences of shallow and and analysis. round ulcerations.20 RAS is associated with trauma, d Assistant Professor, Department of Oral and Maxillofacial Surgery, Akdeniz stress, hormonal imbalances, several systemic diseases University, Faculty of Dentistry, Antalya, Turkey. Helped design the study and and certain vitamin or mineral deficiencies.8,20 However; proofread the final version of the manuscript. the true aetiopathology of RAS still remains uncertain. Due e Research Assistant, Department of Oral and Maxillofacial Surgery, Akdeniz University, Faculty of Dentistry, Antalya, Turkey. Helped design the study and to its multifactorial aetiology, physicians tend to treat RAS proofread the final version of the manuscript. with palliative measures aiming to decrease symptoms, to reduce the number and size of the ulcerations and to in- Correspondence: Nelli Yıldırımyan, Department of Oral and Maxillofacial Surgery, Akdeniz University, Dumlupinar Boulevard, Campus, 07058 Antalya, Turkey. Tel: crease ulcer-free periods, instead of searching for the true +90-535-748-6808; Fax: +90-242-310-6967; E-mail: [email protected] cause of these ulcerations.20

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Table 1 Normal reference values ences (SPSS) file for further examination. Descriptive statis- tics were recorded as numbers, percentages or mean ± Investigated parameter Reference value standard deviation. Differences between patients with zinc Transferrin 25–34 μmol/L deficiency and patients with both zinc and iron deficiencies were compared with Mann–Whitney U test for continuous Ferritin 34–562 pmol/L variables, depending on the normality of the data, and with Zinc 70–120 μg/dL the Fisher’s exact test for categorical variables, depending on the expected count of events in a 2 × 2 contingency table. Vitamin B9 (folic acid) 12.7–104 nmol/L The level of statistical significance was set at p < 0.05. All Vitamin B12 206–1300 pg/ml data were analysed statistically using the software IBM SPSS Statistics version 22 (IBM, Armonk, NY, USA). This retrospective study conforms to the values laid down in the Declaration of Helsinki and has been approved by the Clinical Researches Ethics Committee of the Akdeniz University with the approval number of 629/01.11.2017.

Deficiencies of iron and vitamins B9 (folic acid), B12 or D are well-associated with RAS.10,21 Zinc is also listed among RESULTS one of the minerals which may cause RAS in deficient cases; however it often gets omitted as one of the caus- Based on the aforementioned criteria, a total of 48 patients ative factors of RAS.5,14,15 Therefore the purpose of the were included in this study. Demographic details (age, gen- present study is to evaluate the results of patients, with a der, rate of recurrence) of the patients are presented on chief complaint of recurrent aphthous stomatitis, who were Table 2. Thirty-four of these patients presented with zinc found to have zinc deficiency as the predisposing factor and deficiency and the remaining 14 patients presented with received appropriate replacement therapy. both zinc and iron deficiencies. An initial three-monthly treatment regimen of daily 50 mg of zinc (Zinco, Berko Ilac, Istanbul) or 100 mg of ferrous fumarate (Femarat, Tri- MATERIALS AND METHODS pharma Ilac, Istanbul) according to the specific type of defi- ciency, was prescribed. Blood tests for the certain deficien- This retrospective study was conducted using the data ob- cies were repeated at the end of the medical treatment, tained from the medical records of patients, who attended along with a clinical examination to assess the rate of re- the Oral and Maxillofacial Surgery Clinic at Akdeniz Univer- currences. Two patients with zinc deficiency were found to sity School of Dentistry between June 2015 and February consume milk with their zinc tablets, which caused an inhi- 2017, with a chief complaint of recurrent aphthous stoma- bition of zinc absorption due its casein content.12 They re- titis. All patients had received a diagnosis of RAS according ported no relief in their symptoms, rates of recurrences, as to the criteria presented at the consensus conference be- well as no improvement in their serum zinc levels. Thus tween the American Academy of Oral Medicine and the Eu- these patients were prescribed with an additional 3-monthly ropean Association of Oral Medicine.20 regimen with correct instructions of intake with water only. Patients who had a medical record of ulcerative colitis, They reached normal serum zinc levels and reported no re- Crohn’s disease, Behçet’s disease, HIV or non-HIV immuno- currences following their second course of treatment. deficiencies, herpes simplex infection, oral cancer or pre- Patients with only zinc deficiency and with both zinc and sented with neutropenia were excluded from this study in iron deficiencies reported a mean yearly recurrence rate of order to isolate RAS as much as possible from other poten- 4.35 (± 3.05) and 7.93 (± 3.29), respectively. The differ- tial ulcer-causing conditions. All patients were intraorally ence between two groups reached a level of clinical statisti- examined to rule out trauma-associated aetiologies. cal significance (p = 0.000; Mann–Whitney U test). When Before any treatment measures were started with these both groups were analysed depending on their follow-up du- patients, a blood test was ordered to measure total blood ration, the statistical analyses failed to reach statistically count, serum transferrin, ferritin, zinc, folic acid and vitamin significant levels (p = 0.342; Mann–Whitney U test). Simi- B12 levels. Accepted normal values of these parameters larly, gender differences were not found to be statistically were listed on Table 1 in accordance with the Centers for significant between both groups (p = 0.522; chi-square test) Disease Control and Prevention and World Health Organiza- Replacement treatment was discontinued if normal tion.3,16,17,23 The initial and control (ie, following the initial serum mineral levels were achieved. All patients remained therapy) test results as well as the clinical examination asymptomatic and their mineral levels were monitored every notes from the control sessions were required in order to 3 months to detect any abnormalities. Overall, mean follow- include the data in the study. up for this study was calculated as 12.06 months (range: Patient records were collected according to the inclu- 8–28 months, SD: ± 5.7). sion/exclusion criteria. Data that met the inclusion criteria were analysed in a Statistical Package for the Social Sci-

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Table 2 Patient demographics

Mean rate of recurrence before treatment Deficiency Patients Mean age (years ± SD) (recurrence per year ± SD)

Zn 34 (11 M, 23 F) 37.62 (± 13.95) 4.35 (± 3.05)

Zn and Fe 14 (6 M, 8 F) 38.14 (± 14.42) 7.93 (± 3.29)

Total 48 (17 M, 31 F) 37.77 (± 13.94) 5.40 (± 3.50)

Zn; zinc, Fe; Iron, M; male, F; female, SD; standard deviation.

DISCUSSION tential ulcerative disorders and conditions, as well as any predisposing factors such as stress, trauma or certain food Recurrent aphthous stomatitis is an ulcerative condition of reactions (eg, cheese, tomatoes, lemon, peanuts, and oth- the oral mucosa which presents with recurring ovoid or ers) before choosing a management option for RAS.9,20,25 round painful inflammatory lesions. The earliest symptoms A complete blood cell count and hematinic laboratory of the ulcers are pain and localised burning, which precede tests for serum iron, zinc, folic acid and vitamin B12 can the actual lesions. The ulcers are surrounded with erythem- help physicians rule out certain conditions associated with atous and raised margins, and are covered with yellow-grey- RAS.1 Specific replacement therapies provide beneficial re- ish pseudomembrane.20 RAS clinically presents as minor or sults, especially in cases of hematinic deficiencies.15,24 major aphthae or as herpetiform ulcers. Almost three-quar- Zinc is the second most abundant trace element, follow- ter of the RAS patients experience minor aphthae, which ing iron, in the human body.4 Research shows that zinc is are defined as non-scarring ulcers smaller than 10 mm that the cofactor for more than 300 different enzymes function- heal within two weeks.6 Major aphthae account for 10–15% ing in cell replication, protein synthesis and repair systems. of RAS cases and have more severe symptoms. These ul- It has important roles in growth and development as well as cerations measure larger than 10 mm in size, take longer the immune response, neurological function and reproduc- than 2 weeks to heal and heal with scarring. Herpetiform tion. But in considering RAS, the most important function of ulcers are named after their resemblance to oral lesions zinc appears to be its involvement in the stabilisation of seen in herpes simplex infections.19 They constitute the cellular membranes.4,11 rarest form of RAS and present with multiple ulcerations Zinc absorption is negatively affected by the high phytate measuring less than 5 mm. Herpetiform ulcerations have content of foods because it forms an insoluble phytate-min- similar properties in scarring and duration to that of minor eral complex which interferes with the absorption of the aphthae.20 Recurrences in RAS may occur two to four times mineral.13 People who follow a diet which is rich in vegeta- a year or may persist continuously as newer lesions mani- bles and legumes are subjected to consume large amounts fest and older lesions heal.19 of phytate.22 Besides, low consumption of red meat, a rich Several systemic conditions may include similar oral source of zinc, also compromises serum levels of this min- symptoms, therefore mimic RAS. Among these are immune eral.7,13 Therefore dietary habits (like veganism, vegetarianism disturbances (ie, HIV or non-HIV immunodeficiencies), my- or Mediterranean diets) should also be remembered and elodysplastic syndromes, benign or cyclin neutropenia, gas- questioned when treating patients with RAS who present trointestinal diseases such as celiac, gluten-sensitive enter- with a zinc deficiency.13 opathies, Crohn’s or ulcerative colitis, Behçet’s disease, periodic fever-aphthae-pharyngitis-adenitis syndrome (PFAPA), and acute febrile neutrophilic dermatosis (Sweet’s CONCLUSION syndrome).5,20 There are several reports on drug-induced aphthous lesions as a result of nicorandil (an anti-anginal In the present study, a high rate of zinc deficiency (70.83%) medicine) and non-steroid anti-inflammatory drug usage.2 was found in patients with recurrent aphthae, followed by a Lastly, iron, zinc, vitamin B12 and folic acid deficiencies are moderate number of patients with both zinc and iron defi- also reported to be associated with RAS.14,20 ciencies. The high prevalence of zinc deficiency in patients The true aetiology of RAS is still debatable and there is with RAS may be attributed to the dietary habits of the re- no definitive treatment. Symptomatic treatments using top- gion (Antalya, Turkey) in which the study was conducted. ical, intralesional or systemic corticosteroids, azathioprine, Also, according to this study’s results, it may be concluded dapsone or other immunosuppressants, pentoxifylline or that patients with more than one deficiency (ie, both zinc thalidomide, mostly provide pain management but remain and iron) experience more recurrences compared to those ineffective in reducing the number of recurrences.18 There- with only zinc deficiency (7.93 [± 3.29] and 4.35 [± 3.05], fore it is the physician’s responsibility to rule out other po- respectively). However; further research is required to as-

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