Pathophysiology

The classic categorization of recurrent aphthous ulcer is division into 3 clinical forms: recurrent
aphthous ulcer minor, recurrent aphthous ulcer major, and herpetiform recurrent aphthous ulcer.
Recurrent aphthous ulcer affects the following nonkeratinized or poorly keratinized surfaces of
the oral mucosa:

Labial and buccal mucosa

Maxillary and mandibular sulci

Unattached gingiva

Soft palate

Tonsillar fauces

Floor of the mouth

Ventral surface of the tongue

Recurrent aphthous ulcer minor

Recurrent aphthous ulcer minor is the most common form, accounting for 80% of all cases.
Discrete, painful, shallow, recurrent ulcers smaller than 1 cm in diameter characterize this form.
At any time, one or more ulcers can be present. Lesions heal without scarring within 7-10 days.
The periodicity varies between individuals, with some having longer ulcer-free episodes and
some never being free from ulcers.

Recurrent aphthous ulcer major

Recurrent aphthous ulcer is formerly known as periadenitis mucosa necrotica recurrens. This
form is less common than the others and is characterized by oval ulcers greater than 1 cm in
diameter. In this relatively severe form, many major aphthae may be present simultaneously.
Ulcers are large and deep, may have irregular borders, and may coalesce. Upon healing, which
may take as long as 6 weeks, ulcers can leave scarring, and severe distortion of oral and
pharyngeal mucosa may occur.

Herpetiform recurrent aphthous ulcer

This least common form (5-10% of cases) has the smallest of the aphthae, commonly no larger
than 1 mm in diameter. The aphthae tend to occur in clusters that may consist of tens or hundreds

of minute ulcers. Clusters may be small and localized, or they may be distributed throughout the
soft mucosa of the oral cavity.
What causes aphthous stomatitis?

The exact cause of this disease is not known. However, there are many factors that are thought to
be involved with the development of canker sores, including:

Weakened immune system

Allergies to food such as coffee, chocolate, cheese, nuts, and citrus fruits

Stress

Viruses and bacteria

Trauma to the mouth

Poor nutrition

Certain medications

Aphthous stomatitis is usually first seen in children and adolescents from the ages of 10 to 19
years. For about one-third of the children affected, lesions continue to reappear for years after the
initial outbreak.
These ulcers are not contagious and cannot be spread from one child to another.

Effectiveness of Vitamin B12 in Treating Recurrent

Aphthous Stomatitis: A Randomized, Double-Blind,
Placebo-Controlled Trial
Abstract

Background: The frequency of recurrent aphthous stomatitis (RAS), the most common oral
mucosa lesions seen in primary care, is up to 25% in the general population. However, there has
been no optimal therapeutic approach. Our objective was to confirm our previous clinical
observation of the beneficial treatment of RAS with vitamin B12.
Methods: A randomized, double-blind, placebo-controlled trial was done using primary care
patients. A sublingual a dose of 1000 mcg of vitamin B12 was used in patients in the intervention
group for 6 months.

Results: In total, 58 patients suffering from RAS participated in the study: 31 were included in
the intervention group and 27 were included in control group. All parameters of RAS among
patients in the intervention group were recorded and compared with the control group. The
duration of outbreaks, the number of ulcers, and the level of pain were reduced significantly (P <
.05) at 5 and 6 months of treatment with vitamin B12, regardless of initial vitamin B12 levels in the
blood. During the last month of treatment a significant number of participants in the intervention
group reached no aphthous ulcers status (74.1% vs 32.0%; P < .01).
Conclusion: Vitamin B12 treatment, which is simple, inexpensive, and low-risk, seems to be
effective for patients suffering from RAS, regardless of the serum vitamin B12 level.
Discussion : Results of this double-blind, placebo-controlled study conducted with primary care
patients indicate that vitamin B12 treatment was associated with decreases in the level of pain, the
number of ulcers, and the duration of outbreaks among patients with RAS. This outcome did not
depend on initial level of vitamin B12.
How can we explain this phenomenon? The possibility of functional vitamin B12 deficiency
was not excluded because we did not check methylmalonic acid (MMA), homocysteine (HCY),
or holotranscobalamin II (holoTC). To increase specificity and sensitivity when diagnosing
vitamin B12 deficiency, the concept of measuring HCY, MMA, and holoTC (a subfraction of
vitamin B12) has aroused great interest. HoloTC, as a biologically active vitamin B12 fraction,
promotes uptake of its vitamin B12 by all cells.22 However, diagnostic algorithms using vitamin
B12, MMA, and HCY measurements are reflected in studies from some academic centers, and
their negative predictive values have not been established. Therefore, the identification and
measurement of functional vitamin B12 deficiency remains controversial.23 The recommended
cut off serum level for vitamin B12 deficiency is 250 pg/mL.24 The probability of functional
vitamin B12 deficiency decreases when the blood level of vitamin B12 is increased. Because the
vitamin B12 level was >250 pg/mL in 80.6% of participants in the intervention group, the
probability of functional vitamin B12 deficiency was low. Another explanation for the possible
effectiveness of vitamin B12 in treating RAS is that vitamin B12 has some unique but still
unrecognized functions.25
The response seemed delayed to about 4 months. One possible explanation of delayed response
was the low treatment dosage. According to our previous clinical observations, some patients
responded more rapidly (after 1 or 2 months) to injections of vitamin B12, which were of a higher
dose than the oral treatment.
Although statistical significance was found between the groups, we must interpret the results
carefully because of the small sample size. However, this was a prospective double-blind study
design and is consistent with our previous clinical observations.20 More than 74.1% of patients in

the intervention group were free from aphthous ulcers at the end of the treatment period
compared with 32% of patients in the control group.
Vitamin B12 seems to be an effective treatment for patients suffering from RAS regardless of
their serum vitamin B12 level. This treatment is simple and inexpensive and has no known
significant toxic effects.