Advertisement

Cyanocobalamin May be Beneficial in the Treatment of Recurrent Aphthous Ulcers Even When Vitamin B12 Levels Are Normal

      ABSTRACT

      Objective

      To evaluate the efficacy of cyanocobalamin treatment in patients having recurrent aphthous ulcers (RAUs) with normal or decreased serum vitamin B12 (cobalamin) levels.

      Methods

      Seventy-two patients with RAU were included in the study. In addition to serum cobalamin levels, hemanitic and biochemistrical parameters were measured. Patients with serum cobalamin levels <140 pg/mL were defined as the cobalamin deficient group (CDG) whereas patients with cobalamin levels ≥140 pg/mL were defined as the cobalamin normal group (CNG). The degree of aphthous ulcer healing was determined according to serum cobalamin levels at the first and sixth month after cyanocobalamin treatment protocol.

      Results

      Of the 72 participants, 37 were in the CDG whereas 35 were considered to have normal cobalamin levels. In the first admission the cobalamin levels were 215.8 ± 116.90 pg/mL in CNG and 107.43 ± 29.35 pg/mL in the CDG. The frequency of aphthous ulcers was defined numerically according to monthly occurrence of the lesions. The mean aphthous ulcer frequency in CNG group was 1.9 ± 0.7, whereas it was 2.4 ± 0.9 in the CDG. A significant increase in cobalamin levels was observed after cyanocobalamin treatment in both groups. A significant decrease in aphthous ulcer frequency was also concurrently observed. 96% of the patients showed good response to replacement treatment, 4% of the study population did not respond to the treatment.

      Conclusion

      Cyanocobalamin treatment maybe beneficial for patients with RAU even when serum cobalamin levels are normal. We suggest that higher serum cobalamin levels should be attained in patients with RAU for mucosal protection.

      KEY INDEXING TERMS

      Recurrent aphthous ulcers (RAUs), or canker sores, are among the most common (25%–30%) oral mucosal lesions that physicians and dentists observe.
      • Scully C.
      • Gorsky M.
      • Lozada-Nur F.
      The diagnosis and management of recurrent aphthous stomatitis: a consensus approach.
      RAU is a disorder of unknown etiology that causes clinically significant morbidity. One to several discrete, shallow, painful ulcers is visible on the unattached mucous membranes. Individual ulcers typically last for 1 to 2 weeks. Large ulcers may last several weeks to months.
      • Scully C.
      • Gorsky M.
      • Lozada-Nur F.
      The diagnosis and management of recurrent aphthous stomatitis: a consensus approach.
      • Shashy R.G.
      • Ridley M.B.
      Aphthous ulcers: a difficult clinical entity.
      RAUs are divided into 3 categories: minor, major, and herpetiform RAU. RAU minor is the most common form, accounting for 80% of all RAUs. This form is characterized by discrete, painful, shallow, recurrent ulcers measuring 3 mm to smaller than 1 cm in diameter. At any time, 1 to 5 ulcers can be present. RAU minor occurs on the labial and buccal mucosa and on the floor of the mouth. Lesions heal without scarring within 7 to 10 days. Major RAU is less common than the others and is characterized by oval ulcers 1 to 3 cm in diameter. In this relatively severe form, 1 to 10 major aphthae maybe present simultaneously. The ulcers are large and deep; they may coalesce, and they often have a raised and irregular border. On healing, which may take as long as 6 weeks, the ulcers leave extensive scarring, and severe distortion of oral and pharyngeal mucosa may occur. This form most commonly affects the lips, the soft palate, and the fauces. Herpetiform RAU, the least common form, has the smallest of the aphthae, measuring 1 to 3 mm in diameter. The aphthae tend to occur in clusters that may consist of tens or hundreds of minute ulcers. Clusters maybe small and localized, or they maybe distributed throughout the soft mucosa of the oral cavity.
      • Scully C.
      • Gorsky M.
      • Lozada-Nur F.
      The diagnosis and management of recurrent aphthous stomatitis: a consensus approach.
      • Shashy R.G.
      • Ridley M.B.
      Aphthous ulcers: a difficult clinical entity.
      Although the clinical characteristics of RAU are well defined, the precise etiology and the pathogenesis of RAU remain unclear. It is believed that several factors such as genetics, immune dysregulation, microbial infection, and hemanitic deficiency (iron, folic acid, and vitamin B12 (cobalamin), etc) have a role in the pathogenesis of RAU.
      • Scully C.
      • Gorsky M.
      • Lozada-Nur F.
      The diagnosis and management of recurrent aphthous stomatitis: a consensus approach.
      RAU is treated not only by symptomatic local and systemic medical treatments but also treated concerning etiology.
      • Burgess J.A.
      • Johnson B.D.
      • Sommers E.
      Pharmacological management of recurrent oral mucosal ulceration.
      Because of the difficulties in treatment of RAU, new treatment modalities are of great importance.
      • Shashy R.G.
      • Ridley M.B.
      Aphthous ulcers: a difficult clinical entity.
      There are a few studies with insufficient numbers of patients with RAU, reporting significant healing rates by cyanocobalamin replacement in case of cobalamin deficiency.
      • Porter S.
      • Flint S.
      • Scully C.
      • et al.
      Recurrent aphthous stomatitis: the efficacy of replacement therapy in patients with underlying hemanitic deficiencies.
      • Volkov I.
      • Rudoy I.
      • Abu-Rabia U.
      • et al.
      Case report: recurrent aphthous stomatitis responds to vitamin B12 treatment.
      • Juangbhanit C.
      • Nitidanhaprabhas P.
      • Sirimachan S.
      • et al.
      Vitamin B12 deficiency: report of a childhood case.
      • Wray D.
      • Ferguson M.M.
      • Mason D.K.
      • et al.
      Recurrent aphthae: treatment with vitamin B12, folic acid, and iron.
      We hypothesized that the frequency of aphthous ulcers maybe decreased in patients with RAU by increasing serum cobalamin levels. In this study, we investigated the efficacy of cyanocobalamin treatment in patients with RAU who have normal or low serum cobalamin levels.

      Materials and Methods

      Patients (n=72; 46 females, 26 males) with RAUs admitted to Dumlupinar University Hospital, Department of Internal Medicine and Dentistry between January 2006 and June 2006 were recruited. All patients provided informed consent and necessary ethical approval was obtained.
      After performing physical examination, serum cobalamin levels, hemoglobin, white blood cell, mean corpuscular volume, iron, total iron binding capacity, ferritin, folic acid, rheumatoid factor, and C-reactive protein levels were obtained. The criteria to create the study group were lack of any systemic, hemanitic deficiency that may cause RAU (except cobalamin deficiency) and presence of at least 1 recurrent minor oral aphthous ulcer each month. Pathergy test and antinuclear antibody tests were performed to rule out any possible coexisting systemic disease. Patients with generalized joint pain and bone and joint problems were examined by the Orthopedics Department and such patients were excluded. Patients with Behcet disease or gastrointestinal symptoms and immune deficiency were not included in the study.
      Patients with serum cobalamin levels lower than 140 pg/mL were defined as cobalamin deficient group (CDG) (n=37), whereas patients with higher levels were defined as cobalamin normal group (CNG) (n=35) (reference ranges: 140–820 pg/mL).
      • Nicoll C.D.
      Appendix: therapeutic drug monitoring and laboratory reference ranges.
      Cyanocobalamin was injected intramuscularly to all patients (1000 μg/d for initial 7 days then once a week for 1 month and finally once a month for 6 months). Serum cobalamin levels and degree of ulcer healing were observed at the first and sixth months.

      Statistical Methods

      The efficacy of cobalamin levels on healing of aphthous ulcers before replacement treatment and at the first and sixth months of treatment, was analyzed in 2 groups of patients by SPSS 11.00 Independent sample T test and Friedman 2-dimension variant analysis methods.

      Results

      Thirty-seven patients (51.3%, 19 females, 18 males) with serum cobalamin levels lower than 140 pg/mL were in the CDG whereas 35 (48.6%, 27 females, 8 males) were in CNG with cobalamin levels higher than 140 pg/mL.
      There was no statistically significant difference in levels of hemoglobin, mean corpuscular volume, white blood cell, iron, total iron binding capacity, ferritin, folic acid, and in smoking between 2 groups (P > 0.05) (Table 1). However significant differences in ages and platelet levels were obtained (P=0.005, 0.015, respectively).
      Table 1Study Population Characteristics
      B12 Levels
      <140>140P
      n37 (51.3%)35 (48.6%)None
      Age40.5 ± 15.637.1 ± 11.20.005
      Gender (Female/Male)19/18 127/8None
      Smoking12None
      Hb13.9 ± 1.714.2 ± 1.20.071
      MCV85.8 ± 6.984.2 ± 4.10.212
      WBC6227 ± 15596771 ± 17380.973
      Iron82.8 ± 21.890.6 ± 27.10.183
      TIBC262.0 ± 60.5292.5 ± 92.20.345
      Ferritin64.9 ± 18.267.2 ± 17.50.590
      Folic acid6.8 ± 3.16.6 ± 2.80.812
      Hb, hemoglobin; MCV, mean corpuscular volume; WBC, white blood cell; TIBC, total iron binding capacity.
      In the first admission, the cobalamin levels were 215.8 ± 116.90 (140–615) in the normal group and 107.43 ± 29.35 (35–139) in the deficient group (Table 2). The frequency of aphthous ulcers was defined numerically according to monthly occurrence of the lesions. The mean aphthous ulcer frequency in the CNG was 1.9 ± 0.7, whereas it was 2.4 ± 0.9 in the CDG (Table 2). Serum cobalamin levels and aphthous ulcer frequencies were recorded at the first and sixth months after intramuscular cyanocobalamin treatment (Table 2).
      Table 2Correlation Between Frequency of RAU (fRAU) and Serum Vitamin B12 Levels
      Groupsn0 mo1 mo6 moP
      VitB12<14037107.4 ± 29.3303.7 ± 151.9649.0 ± 139.4<0.001
      >14035215.8 ± 116.9384.0 ± 105.8795.0 ± 148.2<0.001
      fRAU<140372.4 ± 0.90.54 ± 0.640.18 ± 0.46<0.001
      >140351.8 ± 0.70.34 ± 0.530.20 ± 0.47<0.001
      The response to the treatment was categorized into 3 groups: (1) Complete recovery: healing of aphthous ulceration and no recurrence, (2) Partial recovery: decrease in frequency of recurrence of the aphthous lesion, and (3) No recovery: no healing of ulcers and no difference in frequency of recurrence. Complete recovery was obtained in 60 of 72 patients (83%) and partial recovery was obtained in 9 (12%) patients. Three (4%) patients had no recovery.

      Discussion

      The correlation between recurrent aphthous stomatitis and cobalamin deficiency has been the subject of several recent studies.
      • Wray D.
      • Ferguson M.M.
      • Hutcheon W.A.
      • et al.
      Nutritional deficiencies in recurrent aphthae.
      • Barnadas M.A.
      • Remacha A.
      • Condomines J.
      • et al.
      Hematologic deficiencies in patients with recurrent oral aphthae.
      • Weusten B.L.
      • van de Wiel A.
      Aphthous ulcers and vitamin B12 deficiency.
      • Piskin S.
      • Sayan C.
      • Durukan N.
      • et al.
      Serum iron, ferritin, folic acid, and vitamin B12 levels in recurrent aphthous stomatitis.
      • Koybasi S.
      • Parlak A.H.
      • Serin E.
      • et al.
      Recurrent aphthous stomatitis: investigation of possible etiologic factors.
      • Palopoli J.
      • Waxman J.
      Recurrent aphthous stomatitis and vitamin B12 deficiency.
      • Burgan S.Z.
      • Sawair F.A.
      • Amarin Z.O.
      Hematologic status in patients with recurrent aphthous stomatitis in Jordan.
      In some reports, it is stated that cobalamin deficiency might have an important role in the etiology of RAU.
      • Weusten B.L.
      • van de Wiel A.
      Aphthous ulcers and vitamin B12 deficiency.
      • Piskin S.
      • Sayan C.
      • Durukan N.
      • et al.
      Serum iron, ferritin, folic acid, and vitamin B12 levels in recurrent aphthous stomatitis.
      • Koybasi S.
      • Parlak A.H.
      • Serin E.
      • et al.
      Recurrent aphthous stomatitis: investigation of possible etiologic factors.
      • Palopoli J.
      • Waxman J.
      Recurrent aphthous stomatitis and vitamin B12 deficiency.
      Some others suggested that cobalamin levels might also be important in case of detecting the hemanitic disorders in patients with RAU.
      • Wray D.
      • Ferguson M.M.
      • Hutcheon W.A.
      • et al.
      Nutritional deficiencies in recurrent aphthae.
      • Barnadas M.A.
      • Remacha A.
      • Condomines J.
      • et al.
      Hematologic deficiencies in patients with recurrent oral aphthae.
      • Burgan S.Z.
      • Sawair F.A.
      • Amarin Z.O.
      Hematologic status in patients with recurrent aphthous stomatitis in Jordan.
      These studies suggest that there maybe a correlation between serum cobalamin levels and RAU.
      Cobalamin plays several important roles in cell physiology.
      • Wickramasinghe S.N.
      “Morphology, biology and biochemistry of cobalamin- and folate-deficient bone marrow cells.”.
      Cobalamin is the cofactor of methylmalonyl-CoA mutase enzyme, that has an important role in the extraction of energy from proteins and fats as well as a cofactor for the 5-methyltetrahydrofolate (THF)-homocysteine methyltransferase enzyme that catalyses the formation of 5,10-methylene-THF which takes part in DNA and thymine synthesis. The association between cobalamin deficiency and RAU maybe explained by cobalamin‘s role in DNA synthesis. Cell-mediated immunity is suppressed, and there are changes in the epithelium of the tongue and the buccal mucosa. These changes are analogous to those seen in the blood and bone marrow in cases of insufficient DNA synthesis. In our study, serum cobalamin levels were low in a great proportion of patients (51.3%) with RAU. These clinical and pathophysiological data suggests that cobalamin deficiency could be an etiologic factor in patients with RAU. Studies regarding cyanocobalamin replacement in case of cobalamin deficiency and RAU showed that a significant portion of patients showed good recovery with this treatment.
      • Porter S.
      • Flint S.
      • Scully C.
      • et al.
      Recurrent aphthous stomatitis: the efficacy of replacement therapy in patients with underlying hemanitic deficiencies.
      • Wray D.
      • Ferguson M.M.
      • Mason D.K.
      • et al.
      Recurrent aphthae: treatment with vitamin B12, folic acid, and iron.
      Volkov et al reported complete recovery after cyanocobalamin treatment of 3 patients with cobalamin deficiency.
      • Volkov I.
      • Rudoy I.
      • Abu-Rabia U.
      • et al.
      Case report: recurrent aphthous stomatitis responds to vitamin B12 treatment.
      Similarly, 66% to 100% recovery rates were reported by some other studies in which patients with RAU were treated by the same fashion.
      • Porter S.
      • Flint S.
      • Scully C.
      • et al.
      Recurrent aphthous stomatitis: the efficacy of replacement therapy in patients with underlying hemanitic deficiencies.
      • Volkov I.
      • Rudoy I.
      • Abu-Rabia U.
      • et al.
      Case report: recurrent aphthous stomatitis responds to vitamin B12 treatment.
      • Juangbhanit C.
      • Nitidanhaprabhas P.
      • Sirimachan S.
      • et al.
      Vitamin B12 deficiency: report of a childhood case.
      • Wray D.
      • Ferguson M.M.
      • Mason D.K.
      • et al.
      Recurrent aphthae: treatment with vitamin B12, folic acid, and iron.
      In our study, we applied the same cyanocobalamin treatment protocol to the cobalamin deficient and cobalamin normal patients with RAU. The serum cobalamin levels were between 510.9 and 943.2 pg/mL at the sixth month after initiation of treatment. Nearly all the patients of our study group recovered as a result of the treatment (n=69; 95.8%). However 3 (4%) of the patients had no recovery. These results suggest that cyanocobalamin replacement treatment, even without obtaining serum cobalamin levels, maybe an effective approach in management of RAU treatment. In addition, we also propose that maintaining the serum cobalamin levels after treatment of RAU maybe beneficial.
      The present study has some superiorities and differences from recent studies. We enrolled higher numbers of patients in the CDG. In addition, the treatment was applied not only to the CDG but also to CNG with good results. Additionally, we achieved complete recovery of both groups’ lesions with lack of recurrences and we could estimate the approximate serum cobalamin levels to prevent mucosal protection [healing of nearly all of the ulcers (96%) with >500 pg/mL] at the end of the sixth month.
      However, our study had some disadvantages such as not performing the Schilling test for pernicious anemia, endoscopic examination for atrophic gastritis, and other malabsorbtion syndromes. Besides, another limitation of the present study was that we did not use a placebo. However, despite these we suggest that the outcome of our study will significantly affect the future treatment protocols for aphthous ulcers.

      Conclusion

      Our study showed that cyanocobalamin treatment maybe beneficial for patients with RAU even when serum cobalamin levels are normal. We state that for mucosal protection, preventing recurrences and treatment of lesions, higher serum cobalamin levels (>500 pg/mL) should be achieved in patients with RAU. Clinicians and patients alike should keep in mind that cyanocobalamin treatment as an alternative therapy may have potential benefits.

      References

        • Scully C.
        • Gorsky M.
        • Lozada-Nur F.
        The diagnosis and management of recurrent aphthous stomatitis: a consensus approach.
        J Am Dent Assoc. 2003; 134: 200-207
        • Shashy R.G.
        • Ridley M.B.
        Aphthous ulcers: a difficult clinical entity.
        Am J Otolaryngol. 2000; 21: 389-393
        • Burgess J.A.
        • Johnson B.D.
        • Sommers E.
        Pharmacological management of recurrent oral mucosal ulceration.
        Drugs. 1990; 39: 54-65
        • Porter S.
        • Flint S.
        • Scully C.
        • et al.
        Recurrent aphthous stomatitis: the efficacy of replacement therapy in patients with underlying hemanitic deficiencies.
        Ann Dent. 1992; 51: 14-16
        • Volkov I.
        • Rudoy I.
        • Abu-Rabia U.
        • et al.
        Case report: recurrent aphthous stomatitis responds to vitamin B12 treatment.
        Can Fam Physician. 2005; 51: 844-845
        • Juangbhanit C.
        • Nitidanhaprabhas P.
        • Sirimachan S.
        • et al.
        Vitamin B12 deficiency: report of a childhood case.
        J Med Assoc Thai. 1991; 74: 348-354
        • Wray D.
        • Ferguson M.M.
        • Mason D.K.
        • et al.
        Recurrent aphthae: treatment with vitamin B12, folic acid, and iron.
        Br Med J. 1975; 2: 490-493
        • Nicoll C.D.
        Appendix: therapeutic drug monitoring and laboratory reference ranges.
        in: Tierney L.M. McPhee S.J. Papadakis M.A. Current medical diagnosis and treatment. Medical Publishing Division, Lange Medical Books/McGraw-Hill2004: 1714
        • Wray D.
        • Ferguson M.M.
        • Hutcheon W.A.
        • et al.
        Nutritional deficiencies in recurrent aphthae.
        J Oral Pathol. 1978; 7: 418-423
        • Barnadas M.A.
        • Remacha A.
        • Condomines J.
        • et al.
        Hematologic deficiencies in patients with recurrent oral aphthae.
        Med Clin (Barc). 1997; 109: 85-87
        • Weusten B.L.
        • van de Wiel A.
        Aphthous ulcers and vitamin B12 deficiency.
        Neth J Med. 1998; 53: 172-175
        • Piskin S.
        • Sayan C.
        • Durukan N.
        • et al.
        Serum iron, ferritin, folic acid, and vitamin B12 levels in recurrent aphthous stomatitis.
        J Eur Acad Dermatol Venereol. 2002; 16: 66-67
        • Koybasi S.
        • Parlak A.H.
        • Serin E.
        • et al.
        Recurrent aphthous stomatitis: investigation of possible etiologic factors.
        Am J Otolaryngol. 2006; 27: 229-232
        • Palopoli J.
        • Waxman J.
        Recurrent aphthous stomatitis and vitamin B12 deficiency.
        South Med J. 1990; 83: 475-477
        • Burgan S.Z.
        • Sawair F.A.
        • Amarin Z.O.
        Hematologic status in patients with recurrent aphthous stomatitis in Jordan.
        Saudi Med J. 2006; 27: 381-384
        • Wickramasinghe S.N.
        “Morphology, biology and biochemistry of cobalamin- and folate-deficient bone marrow cells.”.
        Baillieres Clin Haematol. 1995; 8: 441-459