Clinical Oral Investigations

https://doi.org/10.1007/s00784-019-03102-9

ORIGINAL ARTICLE

Vitamin D and hematinic deficiencies in patients with recurrent

aphthous stomatitis
Suhail H. Al-Amad 1,2 & Hayder Hasan 3,4

Received: 19 June 2019 / Accepted: 26 September 2019

# Springer-Verlag GmbH Germany, part of Springer Nature 2019

Abstract
Objectives Recurrent aphthous stomatitis (RAS) represents a dysfunction in focal inflammatory processes. With the emerging
anti-inflammatory roles of vitamin D (VD), we wanted to investigate the association between the onset and severity of RAS and
serum VD level.
Methods Fifty-two RAS cases and sex and age-matched controls were screened for serum iron, B12, folic acid, VD and red cell
indices. Variables were compared using independent samples t test and chi square. Binary logistic regression was used to assess
the association between the severity of RAS and various hematinic deficiencies.
Results VD was deficient in 53% of the study population with no statistically significant difference between the RAS patients and
healthy controls (53.6 versus 51.5 nmol/l, respectively). In comparison with controls, RAS patients had lower means of iron (81.0
versus 89.3 μg/dl), vitamin B12 (368.5 versus 412.7 pg ml) and most of the red cell indices; however, these differences were not
statistically significant. No correlations were seen between RAS severity assessed by ulcer diameter, number of ulcers and their
frequency and hematinic deficiencies. However, logistic regression showed a significant association between the number of
ulcers (single or multiple) and VD deficiency (OR 4.978; 95% CI 1.204–20.576; p value = 0.027), adjusted for age, sex and other
hematinics.
Conclusions VD deficiency appears to have a role in aggravating RAS ulcerative episodes, but not their onset.
Clinical Relevance Multiple aphthous ulcers might represent a subcategory of RAS lesions in which VD deficiency plays a role in
aggravating the oral ulcerative condition.

Keywords Oral ulcer . Vitamin D . Vitamin B12 . Iron . Anemia . United Arab Emirates

Introduction ineffective in completely eradicating the disease and are mere-

Recurrent aphthous stomatitis (RAS) is a common oral muco-
sal disorder that is thought to represent a dysfunction of the
immune system [1, 2]. Available treatment regimens are
* Suhail H. Al-Amad
salamad@sharjah.ac.ae
1
Department of Oral and Craniofacial Health Sciences, College of
Dental Medicine, University of Sharjah, Sharjah United Arab
Emirates
2
Consultant Oral Medicine, University Hospital Sharjah, Sharjah
United Arab Emirates
3
Department of Clinical Nutrition and Dietetics, College of Health
Sciences, University of Sharjah, Sharjah United Arab Emirates
4
Research Institute of Medical and Health Sciences, University of
Sharjah, Sharjah United Arab Emirates
ly used to reduce the pain that is commonly associated with
RAS [1].
Several studies have focused on identifying local and sys-
temic factors that predispose the oral mucosa to the recurrent
aphthae. Those predisposing factors have been categorized
into hematinic deficiencies, disorders in the gastrointestinal
system and hypersensitivity to certain food additives. An as-
sociation has been observed between RAS and systemic dis-
orders, such as celiac disease and Crohn’s disease, inferring an
immune-dysfunction related to the body’s intolerance to var-
ious antigens [3]. Several studies have investigated the asso-
ciation between RAS and the deficiencies of B12, folic acid,
iron and zinc with some results suggesting an association
while others ruling it out [4–7].
There has been a growing interest in the roles of vitamin D
(VD), vitamin D receptors (VDR) and the enzymes involved
in the formation of the biologically active form of VD
[1,25(OH)2D] and their association with various human

diseases. VDRs have been detected in various tissues, sug-
gesting new roles of VD both at the physiological and patho-
logical level. Low VD levels have now been associated with
many conditions like obesity, hypertension, cardiovascular
diseases, diabetes mellitus, common cancers and autoimmune
diseases [8, 9]. An association between VD deficiency and
other forms of anemia has been reported in both healthy per-
sons and patients with chronic illnesses, such as end-stage
renal disease and heart failure [10–14].
Growing body of evidence suggests that VD and VDR are
directly involved in T-cell antigen receptor signaling, indicat-
ing their role in the anti-inflammation processes. Therefore,
defects in VD/VDR may be associated with the body’s normal
response to bacterial infections and inflammations [15].
An association between VD level and idiopathic oral mu-
cosal disorders, such as RAS, has the potential of improving
our understanding of the immunological steps that lead to the
development of aphthous ulcers. Recent studies have shown
conflicting results regarding an association between low VD
and RAS. Bahramian et al. and Oztekin and Oztekin found
that the mean serum VD level in patients with RAS was lower
than that of the controls [16, 17], while Krawiecka et al. found
that this difference was not statistically significant [18]. Stagi
et al., on the other hand, found that VD supplementation in
children with periodic fever, aphthous stomatitis, pharyngitis
and cervical adenitis (PFAPA) syndrome, who happened to
have reduced levels of VD, improved their clinical disease
[19].
In this research, we aimed at establishing possible relation-
ships between the occurrence and the severity of RAS and
various hematinic changes, specifically red cell indices, iron,
folic acid, vitamin B12 and vitamin D, using a cohort of pa-
tients from the United Arab Emirates (UAE).
Materials and methods
A case-control study was conducted at the Oral Medicine
clinic of the University Dental Hospital Sharjah, UAE, be-
tween October 2017 and March 2019. The cases were patients
who presented with aphthous ulcers at the time of recruitment
and who indicated that they have a history of recurrence of
similar ulcers. Controls were healthy patients who were at-
tending the Screening Clinic of the same hospital and who
indicated that they have never got oral ulcers. Controls were
progressively matched with each RAS case based on sex and
age (± 5 years). Inclusion criteria for both groups included an
age of more than 18 years and having lived in the UAE for
more than 5 years. Patients taking medications at the time of
recruitment and pregnant and lactating mothers were
excluded.
This research was designed and conducted in accordance
with the ethical standards of the 1964 Declaration of Helsinki
Clin Oral Invest
and its later amendments and was approved by the University
of Sharjah Research Ethics Committee (No. REC-16-09-24).
Consenting patients were asked to fill a questionnaire, which
consisted of demographic information. RAS severity was
assessed based on three criteria: number of ulcers in a single
episode, frequency of ulcerative episodes in a year and the
diameter of the ulcer or of the biggest ulcer in case of multiple
ulcers. The diameter was measured using a calibrated peri-
odontal probe.
Five milliliters of venous blood were drawn from cases and
controls. The following blood investigations were orders:
complete blood count using fully-automated CBC analyzer,
folic acid and vitamin B12 using electrochemiluminescence
assay (ECLA), serum iron using fully automated
colorometric/spectrophotometric assay and serum vitamin D
(25(OH)D) using electrochemiluminescence immunoassay.
All tests were performed in the same laboratory under the
same quality assurance standards.
Statistical Package for the Social Science (SPSS) Version
25.0 (IBM Corp. Released 2017; IBM SPSS Statistics for
Macintosh, Version 25.0. Armonk, NY) was used for statisti-
cal analyses. Demographics and blood test results were cate-
gorized and described using frequencies. Correlations be-
tween cases and controls were assessed using chi square test
for categorical variables, while independent samples t test was
used to assess the means of blood test results as continuous
variables. Finally, correlation between the hematinic status of
the cases and the three RAS severity criteria was assessed
using both chi square test and binary logistic regression. The
latter was used to produce odds ratios and 95% confidence
intervals for the association between the dependent variable
(number of ulcers) and hematinic status, adjusted for sex and
age and other hematinic deficiencies. p value was considered
significant if ≤ 0.05.
Results
Over a period of 18 months, 52 patients with RAS and 52 sex-
and age-matched controls were recruited in this study. Male-
to-female ratio was approximately 2:1 in both groups. The
mean age was 34 and 31 years for the cases and the controls,
respectively. Demographic variables did not show statistically
significant differences between the cases and the controls
(Table 1).
Overall, RAS patients had a lower mean of serum iron,
vitamin B12 and most of the red blood cell indices in compar-
ison with healthy controls. However, this difference was not
statistically significant nor was the difference between the two
groups when those variables were categorized into normal and
low categories (Tables 2 and 3). Table 3 shows the seroprev-
alence of various forms of anemias among the entire study
population. The most prevalent form of deficiency was that
Clin Oral Invest

Table 1 Sample demographics and correlations between RAS patients Table 3 Crosstabulation showing the relationship between the
and controls hematinic results between RAS patients and controls

Variable Total RAS Controls p value* Variable Value RAS Controls p value*
N (%) N (%) N (%) N (%) N (%)
Total = 52 Total = 52 Total = 104 Total = 52 Total = 52

Sex Hb Normal 82 (78) 39 (47.6) 43 (52.4) 0.337

Males 64 32 (50) 32 (50) 1.00 Low 22 (22) 13 (59.1) 9 (40.9)
Females 40 20 (50) 20 (50) Hct Normal 98 (94) 47 (48) 51 (52) 0.093
Low 6 (6) 5 (83.3) 1 (16.7)
Age (years)
MCV Normal 93 (89) 48 (51.6) 45 (48.4) 0.467
18–25 43 18 (41.9) 25 (58.1) 0.31
Low 11 (11) 4 (36.4) 7 (63.6)
26–35 30 17 (56.7) 13 (43.3)
MCH Normal 82 (79) 42 (51.2) 40 (48.8) 0.631
36–45 16 7 (43.8) 9 (56.3) Low 22 (21) 10 (45.5) 12 (54.5)
> 45 15 10 (66.7) 5 (33.3) MCHC Normal 103 (99) 51 (49.5) 52 (50.5) 0.315
Occupation Low 1 (1) 1 (100) 0 (0)
Student 38 21 (55.3) 17 (44.7) 0.62 RDW Normal 97 (93) 48 (49.5) 49 (50.5) 0.696
Office 47 23 (48.9) 24 (51.1) Low 7 (7) 4 (57.1) 3 (42.9)
Vocational 16 6 (37.5) 10 (62.5) Iron Normal 93 (89) 44 (47.3) 49 (52.7) 0.111
Low 11 (11) 8 (72.7) 3 (27.3)
Unemployed/Retired 3 2 (66.7) 1 (33.3)
Folic acid** Normal 93 (89) 49 (52.7) 44 (47.3) 0.111
Smoking High 11 (11) 3 (27.3) 8 (72.7)
Yes 17 11 (64.7) 6 (35.3) 0.18 Vitamin B12 Normal 88 (85) 44 (50) 44 (50) 1.000
No 87 41 (47.1) 46 (52.9) Low 16 (15) 8 (50) 8 (50)
History of allergies Vitamin D Normal 49 (47) 27 (55.1) 22 (44.9) 0.326
Yes 25 11 (44) 14 (56) 0.49 Low 55 (53) 25 (45.5) 30 (54.5)
No 79 41 (51.9) 38 (48.1)
Hb hemoglobin, Hct hematocrit, MCV mean corpuscular volume, MHC
mean corpuscular hemoglobin, MCHC mean corpuscular hemoglobin
*Based on chi square test
concentration, RDW red cell distribution width
*Based on chi square test
of VD reaching up to 53%. Iron and vitamin B12 deficiency **Values of folic acid were categorized into normal or high. There were
no reports of folic acid deficiency
were 11% and 15%, respectively. However, no statistically
significant difference was seen between cases and controls
in any of those deficiencies. binary logistic regression analysis showed a significant asso-
Associations between RAS severity and hematinic vari- ciation between the number of ulcers (single or multiple) and
ables did not show statistically significant differences between VD deficiency (OR 4.978; 95% CI 1.204–20.576; p = 0.027),
normal and abnormal hematinic values and the ulcer diameter, adjusted for sex, age, iron and vitamin B12 levels (Table 5),
number of ulcers and their frequency (Table 4). However, despite a correlation between VD with both iron (r = − 0.40; p
= 0.003) and vitamin B12 (r = 0.46; p = 0.001) (Table 6).
Table 2 Differences in the mean values between RAS patients and
controls

Variable RAS Control p value*

Mean (SD) Mean (SD)
Discussion

Hb (g/dl) 14.0 (1.6) 14.5 (1.6) 0.14 Recurrent aphthous stomatitis (RAS) is a common oral
Hct (%) 41.9 (4.1) 43.0 (4.4) 0.17 mucosal disorder that is thought to represent a dysfunction
MCV (fl) 84.0 (11.5) 85.1 (4.6) 0.51 of the immune system [1, 2]. RAS is clinically classified as
MCH (pg) 28.6 (1.8) 30.0 (9.8) 0.31 minor, major and herpetiform. This classification is mainly
MCHC (g/dl) 33.4 (0.9) 33.6 (0.8) 0.25 based on the clinical characteristics of the ulcer (i.e., the
RDW (%) 13.4 (0.9) 13.2 (0.9) 0.40 ulcer diameter, the number of ulcers in each episode and its
Iron (μg/dl) 81.0 (30.4) 89.3 (29.2) 0.16 duration) [1]. Attempts to correlate the occurrence of RAS
Folic acid (ng/dl) 11.3 (29.2) 11.2 (5.0) 0.93 with systemic factors, mainly hematinic deficiencies such
Vitamin B12 (pg/ml) 368.6 (208.8) 412.7 (192.2) 0.26 as vitamin B12, folic acid and iron, have not been conclu-
Vitamin D (nmol/l) 53.6 (24.6) 51.5 (26.9) 0.68 sive with some research observing an association while
others ruling it out [4–7].
 Clin Oral Invest

Table 4 Correlations between the hematinic status and the severity of RAS (measured by ulcer diameter, number of ulcers at the time of presentation
and frequency of ulcerative episodes)

Variable Ulcer diameter Number of ulcers during an episode Frequency of ulcers in a year

< 4mm ≥ 4mm p value* Single Multiple p value* ≤ 4 times > 4 times p value*
33 (63.5%) 19 (36.5%) 33 (63.5%) 19 (36.5%) 25 (48.1%) 27 (51.9%)

Hb Normal 24 (61.5) 15 (38.3) 0.746 24 (61.5) 15 (38.5) 0.746 19 (48.7) 20 (51.3) 0.873
Low 9 (69.2) 4 (30.8) 9 (69.2) 4 (30.8) 6 (46.2) 7 (53.8)
Hct Normal 28 (61.7) 19 (38.3) 0.641 29 (61.7) 18 (38.3) 0.641 22 (46.8) 25 (53.2) 0.662
Low 4 (80) 1 (20) 4 (80) 1 (20) 3 (60) 2 (40)
MCV Normal 31 (64.6) 17 (35.4) 0.617 30 (62.5) 18 (37.5) 0.618 24 (50) 24 (50) 0.611
Low 2 (50) 2 (50) 3 (75) 1 (25) 1 (25) 3 (75)
MCH Normal 27 (64.3) 15 (35.7) 0.800 26 (61.9) 16 (38.1) 0.729 22 (52.4) 20 (47.6) 0.296
Low 6 (60) 4 (40) 7 (70) 3 (30) 3 (30) 7 (70)
MCHC Normal 33 (64.7) 18 (35.3) 0.365 32 (62.7) 19 (37.3) 0.444 25 (49) 26 (51) 0.331
Low 0 (0) 1 (100) 1 (100) 0 (0) 0 (0) 1 (100)
RDW Normal 30 (62.5) 18 (37.5) 0.618 30 (62.5) 18 (37.5) 0.618 24 (50) 24 (50) 0.336
Low 3 (73) 1 (25) 3 (75) 1 (25) 1 (25) 3 (75)
Iron Normal 28 (63.6) 16 (36.4) 0.951 30 (68.2) 14 (31.8) 0.097 22 (50) 22 (50) 0.515
Low 5 (62.5) 3 (37.5) 3 (37.5) 5 (62.5) 3 (37.5) 5 (62.5)
Folic acid** Normal 30 (61.2) 19 (38.8) 0.176 31 (63.3) 18 (36.7) 0.905 24 (49) 25 (51) 0.599
High 3 (100) 0 (0) 2 (66.7) 1 (33.3) 1 (33.3) 2 (66.7)
Vitamin B12 Normal 27 (61.4) 17 (38.6) 0.461 26 (59.1) 18 (40.9) 0.125 23 (52.3) 21 (47.7) 0.156
Low 6 (75) 2 (25) 7 (87.5) 1 (12.5) 2 (25) 6 (75)
Vitamin D Normal 16 (59.3) 11 (40.7) 0.513 20 (74.1) 7 (25.9) 0.099 12 (44.4) 15 (55.6) 0.586
Low 17 (68) 8 (32) 13 (52) 12 (48) 13 (52) 12 (48)

Hb hemoglobin, Hct hematocrit, MCV mean corpuscular volume, MHC mean corpuscular hemoglobin, MCHC mean corpuscular hemoglobin concen-
tration, RDW red cell distribution width
*Based on chi square test
**Values of folic acid were categorized into normal or high. There were no reports of folic acid deficiency

In this study, we investigated red blood cell indices and the
hematinic status of vitamin B12, folic acid, iron and VD
among a cohort of active RAS patients and sex- and age-
matched healthy controls. Our exclusion criteria included
pregnant and lactating women in order to rule out possible
cases of deficiencies as a result of increased physiological
demands. Our results revealed a relatively high prevalence
of low hemoglobin (22%), vitamin B12 (15%), iron (11%)
and vitamin D (53%) in the overall study population, with
no statistically significant difference between RAS patients
and healthy controls.
Epidemiological studies on the prevalence of various forms
of anemia in the UAE are scarce. Miller et al. found that more
than one third of children in the UAE had low Hb levels [20],
while Sultan found that around 25% of female college stu-
dents were anemic with Hb levels less than 12.0 g/dl; the
majority of whom had microcytic anemia [21]. Our results
are similar to those of Sultan, considering that our sample
was based on adult population rather than children.
Fifteen percent (15%) of our sample had low levels of
vitamin B12. This is less than that reported in two neighboring
countries by Shams et al. who found low vitamin B12 in
25.8% of Iranian adults [22] and by al-Momen who reported
vitamin B12 deficiency in 43.5% of Saudi patients with sickle
cell disease [23]. No previous reports exist on the seropreva-
lence of B12 in the UAE.
The UAE is among the countries with the lowest levels of
VD despite yearlong sunshine. In a retrospective study that
involved a large sample of almost 61,000 patients of various
nationalities and age groups, Haq et al. found that more than
80% of the UAE population has low levels of VD [24], which
is higher than our finding of 53%. Our study sample consisted
of otherwise healthy RAS patients and matched healthy con-
trols, while the sample used by Haq et al. consisted of the
patients who had previously been screened for VD deficiency
following clinical signs and symptoms suggestive of such
deficiency, such as rickets, osteoporosis, osteopenia, hypocal-
cemia among others. The difference in the sampling method
could be the reason for the higher seroprevalence of VD defi-
ciency reported by Haq et al. [24].
A range of body tissues have receptors for VD suggesting
that this vitamin has an important role in regulating a variety
of metabolic and immune-mediated processes [8, 9]. Low VD
levels have now been associated with many conditions such as
obesity, hypertension, cardiovascular diseases, diabetes
mellitus, common cancers and autoimmune diseases [8, 9,
Clin Oral Invest

Table 5 Binary logistic regression analysis for the association between sex and age or the status of his/her other hematinic deficien-
the number of ulcers and independent variables
cies, even when a statistical correlation was seen between VD,
Variable Odds ratio 95% CI p value iron and vitamin B12. These findings infer that VD has no role
in the onset of aphthous ulcers but might have a significant
Upper Lower role in ameliorating their severity.
Age 0.992 0.94 1.046 0.758
Although the etiology of RAS is not entirely clear, there is
good evidence to support a dysfunction in the focal inflamma-
Sex Female/male* 0.642 0.166 2.48 0.52
tory response that is mediated by inflammatory cytokines,
Iron Low/normal* 5.252 0.877 31.449 0.069
such as TNF-a, IL-2, IL-6 and IL-8 [7, 26, 27]. Recently, the
Vitamin D Low/normal* 4.978 1.204 20.576 0.027
T helper17 lymphocytes were found to produce IL-17, which
Vitamin B12 Low/normal* 0.187 0.018 1.959 0.162
has the ability to recruit neutrophils and increase the produc-
*Reference category tion of IFN-g and IL-17 by epithelial cells. Interestingly, pa-
tients with RAS were found to have significantly higher serum
levels of IFN-g and IL-17 [28].
14, 25]. It is currently believed that VD is directly involved in VD, on the other hand, can modulate the function of the
T-cell antigen receptor signaling, and defects in VD and its immune system by regulating the inflammatory cytokines,
receptors might affect the body’s normal response to infec- such as IL-2, IL-6, IL-8, IL-17 and TNF-a [29].
tions and inflammations [15]. Accordingly, a reduced level of VD might result in a micro-
Recent studies have explored a possible relationship be- environment where those cytokines become dysregulated,
tween VD level and RAS. Both Bahramian et al. and resulting in an increased severity of RAS and hinder natural
Oztekin and Oztekin found that the mean serum VD in pa- healing of ulcerative lesions. The role VD has in regulating
tients with RAS was lower than that of the controls [16, 17], inflammatory cytokines can explain the clinical improvement
while Krawiecka et al. found that this difference was not sta- in oral aphthae when VD supplements were administered as a
tistically significant [18]. Stagi et al., on the other hand, found therapeutic intervention to children with PFAPA as reported
that VD supplementation in children with periodic fever, by Stagi et al. [19].
aphthous stomatitis, pharyngitis and cervical adenitis Our results add to the world literature partial data on the
(PFAPA) syndrome, who happened to have reduced levels seroprevalence of iron, vitamin B12, folic acid and VD among
of VD, improved their clinical disease [19]. the multinational communities of the UAE. We have shown
Our results showed that the mean value of the VD level was that, despite the relatively high prevalence of hematinic defi-
53.6 and 51.5 nmol/l for RAS and controls, respectively, ciency, there were no statistically significant relationships be-
which is not statistically different between the two groups (p tween those deficiencies and aphthous ulcers. Screening for
= 0.68). A similar outcome is seen when the values were hematinic deficiency in RAS patients appears therefore to be
categorized into normal and low (p = 0.32). This result indi- unjustifiable. Our study also shows that, although VD does
cates that the VD serum level does not have a role in the onset not appear to have a role in the etiology of RAS, its deficiency
of RAS, contrary to what has been previously reported [16, does make the ulcerative lesions more severe. It would there-
17]. fore be advisable to screen patients with severe RAS for VD
Nevertheless, binary logistic regression shows a significant deficiency and to correct this deficiency if found. Further stud-
association between VD deficiency and the number of ulcers ies at the molecular level are needed in order to determine the
in each episode (single versus multiple). Those with VD de- precise actions of VD in ameliorating RAS lesions and the
ficiency were approximately 5 times more likely to be getting potential therapeutic benefits of using VD as an anti-
multiple ulcers than a single ulcer during each episode (OR inflammatory agent.
4.97; 95% CI 1.20–20.57; p = 0.02), regardless of the person’s
Acknowledgments The authors thank Professor Manal Awad for her as-
Table 6 Pearson’s bivariate correlation between sex, age, iron, vitamin sistance in statistical analysis, Dr. Jihad Saadeh for his technical assis-
B12 and vitamin D tance in laboratory analysis and Dr. Manal Elbakai and Dr. Rand Rizq for
their assistance in recruiting cases and controls.
Sex (r) Age (r) Iron (r) Vitamin B12 (r)
Funding This research was funded by the University of Sharjah
Age − 0.056 – – – Competitive Research Grant (no. 16011001020-P).
Iron − 0.140 0.058 – –
Vitamin B12 0.325* − 0.132 − 0.337* – Compliance with ethical standards
Vitamin D − 0.007 − 0.030 − 0.402** 0.463**
Conflict of interest The authors declare that they have no conflict of
*p < 0.05; **p < 0.01 interest.

Ethical approval This research was reviewed and approved by the
University of Sharjah Research Ethics Committee (approval letter no.
REC-16-09-24). The said committee works in accordance with the ethical
standards of the 1964 Declaration of Helsinki and its later amendments.
Informed consent Informed consent was obtained from all individual
participants included in the study. The Participant Information Sheet and
the Informed Consent documents were reviewed and approved by the
University of Sharjah Research Ethics Committee.
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