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Recurrent aphthous stomatitis (RAS) is one of the most common oral mucosa lesions

seen in primary care. The most treatments given to patients suffering from RAS achieve

“short term” therapeutic goals, such as alleviation of pain, reduction of ulcer duration, and

recovery of normal oral function. Just a few reported treatments have achieved “long term”

therapeutic goals, such as reduction of the frequency and severity of RAS and maintenance of

remission Although the precise role of vitamin B12 deficiency in the pathogenesis of RAS is

unclear, suppression of cell-mediated immunity and changes in the cells of the tongue and

buccal mucosa have been reported [51,52]. We have reported previously the successful

treatment of three RAS patients with intramuscular vitamin B12 injections [53]. According to

our own clinical experience of 5 years, treatment with vitamin B12 achieves “long term”

therapeutic goals and can be effective for patients suffering from RAS, regardless of their

serum vitamin B12 level. We have begun randomized, double placebo controlled clinical

trials, which should confirm this observation.

POTENTIAL ROLE AND USES OF VITAMIN

B12 IN PREVIOUSLY UNCOMMON AREAS

A possible correlation between vitamin B12 and problems of fertility, which indicates

vitamin B12 deficiency as one of causes of recurrent abortions and the use of vitamin B12 in

initial treatments in order to prevent these conditions, has been under debate for long time

[54,55,56]. In a statistical metaanalysis performed on five studies in which serum B12 was

The Role and Status of Vitamin B12: Need for Clinical Reevaluation and Change 183

assayed in women suffering from early recurrent abortions (ERA), a significant relationship

was found between ERA and vitamin B12 deficiency [57]. No difference was noticed between

cases and controls for folate. Then vitamin B12 study should be done in ERA women whether

or not hematological or neurological abnormalities are present.

Osteoporosis is a widespread problem, which frequently has devastating health

consequences because of its association with fragility fractures. The total number of fractures,

and hence the cost to society, will increase dramatically over the next 50 years as a result of

demographic changes in the number of elderly people. Thus, prevention of osteoporosis by

identifying risk factors or risk indicators, as well as the development of new treatment

strategies, is a major health issue. Recent data suggest that vitamin B12 affects bone

metabolism, bone quality and fracture risk in humans [58]. Strokes increase the risk of

subsequent hip fracture by 2 to 4 times. Hyperhomocysteinemia is a risk factor for both

ischemic stroke and osteoporotic fractures in elderly men and women. In a population with a

high baseline fracture risk, combined treatment with folate and vitamin B12 has been shown

to be safe and effective in reducing the risk of a hip fracture in elderly patients following

stroke [59]. The relationship of Hcy and vitamin B12 with bone turnover markers, broadband

ultrasound attenuation (BUA), and fracture incidence in healthy elderly people was studied

by a few researchers, who found that high homocysteine and low vitamin B12 concentrations

were significantly associated with low BUA, high markers of bone turnover, and increased

fracture risk [60]. A preventive vitamin B12 supplementation for healthy people with

mandatory risk factors for osteoporosis and a treatment with vitamin B12 of patients suffering

from osteoporosis could be a promising treatment for this serious problem. Controlled

clinical trials should be conducted to confirm the safety and effectiveness of vitamin B12

therapy for osteoporosis.

Cobalamin carrier proteins,the transcobalamins (TC), are elevated during trauma,

infections and chronic inflammatory conditions. This remains un-explained. It is proposed

that such TC elevations signal a need for cobalamin central to the resolution of inflammation

[61]. Vitamin B12 is an effective scavenger of nitric oxide (NO) [62]. Septic shock has an

extremely high mortality rate, with approximately 200,000 people dying from sepsis annually

in the U.S. The high mortality results in part from severe hypotension secondary to high

serum NO concentrations. Reducing NO levels should be beneficial in sepsis; a possible

approach in reducing NO levels in sepsis is the use an NO scavenger, which would leave

sufficient free NO for normal physiological functions. Animal and human clinical data

suggests that high dose cobalamin may prove a promising approach to systemic inflammatory

response syndrome (SIRS), sepsis, septic and traumatic shock.

Drugs which directly counteract nitric oxide, such as endothelial receptor blockers, NOsynthase inhibitors, and NO-scavengers, not only may be effective in the acute treatment of

migraine, but also are likely to be effective in migraine prophylaxis. The first prospective,

open study indicated that intranasal hydroxocobalamin may have a prophylactic effect in

migraine [63].

A number of studies have demonstrated that cobalamin is important in maintaining

differentiation, proliferation, and metabolic status of cells. NO can cause both apoptosis and

necrosis, making it a good candidate for antitumor therapy. Initially, vitamin B12 was

proposed for use as a scavenger and cytoprotective agent to bind and inactivate NO. The use

184 Ilia Volkov, Inna Rudoy and Yan Press

of vitamin B12 as a carrier to deliver nitric oxide into tumor cells is novel. In one

investigational study was shown that complex NO-cobalamin inhibited tumor growth in vivo

and in vitro by activating the extrinsic apoptotic pathway [64].

STRATEGY FOR PREVENTION AND

TREATMENT OF VITAMIN B12 DEFICIENCY

The question regarding which patients require tests for B12 level continues to be

discussed [65]. It is not always easy to decide whether a patient suffers from vitamin B12

deficiency or not. For initial screening, measurement of serum vitamin B12 levels may suffice.

However, the test for B12 has several pitfalls [66]. Most laboratories set normal limits at 200

to 900 pg/mL, but sensitivity and specificity vary greatly, depending on the method used.

False negatives (ie, elevated levels in the presence of deficiency) can occur in true deficiency,

active liver disease, lymphoma, autoimmune disease, and myeloproliferative disorders. False

positives (i.e., low levels in the absence of deficiency) can occur in folate deficiency,

pregnancy, multiple myeloma, and excessive vitamin C intake. The measurements are quite

accurate for serum vitamin B12 levels below 100 pg/mL, but they discriminate poorly when

vitamin B12 levels are between 100 and 400 pg/mL. When values fall in this range, levels of

serum or urine MMA and homocysteine should be measured. If MMA levels are elevated,

treatment should be initiated. If homocysteine levels are elevated, other causes of the

elevation (e.g., coexisting folate deficiency) should be ruled out. However, serum MMA and

homocysteine tests are expensive, and almost certainly these investigations are not feasible in

most clinics around the world.

After the diagnosis of vitamin B12 deficiency has been established, treatment may

commence or additional tests may be done to elucidate the causes of the deficiency. Planning

the strategy for treatment involves decisions concerning dosage, means, and form of vitamin

B12 to be employed, as well as determining need for continuous follow up [67]. Today,

physicians have a choice of several inexpensive treatments that are easy to administer and

have no known side effects. Treatment should be individualized according to patient and

healthcare provider preferences. Different forms of vitamin B12 can be used, including

cyano,- hydroxyl,- and methylcobalamin. Cyanocobalamin is the only form available in the

USA. Hydroxycobalamin may have advantages due to a slower metabolism. The co-enzyme

form, methylcobalamin, is the preferred form in Japan. In most countries vitamin B12 is still

given by intramuscular injection in the form of cyanocobalamin or hydroxycobalamin. As

mentioned, practices concerning both dose and administration vary considerably.

Traditionally, vitamin B12 deficiency has been corrected by parenteral administration of the

vitamin. Intramuscular injections are safe, but may cause local discomfort. Injections are

inconvenient and more expensive due to the need for the patient to visit the doctor in the

clinic or for the provider to see the patient at home. An alternative to parenteral therapy,

lately approved by the FDA, is intranasal administration of cyanocobalamin. In Europe,

intranasal hydroxocobalamin has been widely used for years. The intranasal administration of

500 micrograms of cyanocobalamin weekly attains blood levels that are comparable to those

found with intramuscular injections. A positive clinical experience of many years in several

The Role and Status of Vitamin B12: Need for Clinical Reevaluation and Change 185

countries [68] and current results of some studies [69], which investigated the effectiveness,

safety, and acceptability of oral vitamin B12, suggest that vitamin B12 deficiency may be

treated with oral dose vitamin B12 as effectively as that with injections of vitamin B12. The

evidence derived from limited studies [70] suggests that 2000 mcg doses of oral vitamin B12

daily and 1000 mcg doses initially daily and thereafter weekly and then monthly may be as

effective as intramuscular administration in obtaining short term hematological and

neurological responses in vitamin B12 deficient patients. Oral high dose vitamin B12 is

appropriate for both the replacement therapy in patients with vitamin B12 deficiency and for

maintenance treatment. Most likely oral vitamin B12 can provide an effective alternative to

intramuscular injections. Using different doses of vitamin B12 (from a few micrograms to

dozens of milligrams) is becoming more and more wide spread [30,71]. Because

approximately 1% of orally ingested B12 is absorbed via simple diffusion from the intestine

(independently of intrinsic factor), oral replacement with high doses of vitamin B12 is both

effective and safe, regardless of the etiology of vitamin B12 deficiency. Thus, in pernicious

anemia, vitamin B12 must be given in large amounts (preferably >1,000 micrograms a day).

However, in vegan patients or patients with food-cobalamin malabsorption syndrome and low

gastric acidity, oral B12 may be effective in smaller doses.

We conducted a comprehensive MEDLINE search using combinations of the following

keywords: vitamin B12, vitamin B12 deficiency, treatment with vitamin B12, cobalamin, doses

of cyanocobalamin, hydroxycobalamin, methylcobalamin, We did not find any reference

relating to explanation how a widespread dose regimen of cobalamin for treatment of

different conditions was done. As a result, we concluded that dosage was chose empirically

without solid scientific basis, and today overwhelming majority of practitioners continue to

treat their patients with dosages that were established decades ago, despite new research data

and possibilities provided by modern medicine. For example, cobalamin resistance may occur

in diabetes, renal insufficiency and advanced age, leading to functional cobalamin deficiency,

thus, requiring higher doses. In our opinion, perhaps negative results of some studies or

ineffective treatment of several conditions with vitamin B12 may be explained by insufficient

dose of cobalamin.

NECESSITY OF NEW APPROACH TO

THE PROBLEM OF VITAMIN B12

We know that not only ill individuals with special problems and vegetarians can suffer

from vitamin B12 deficiency, but also patients with low meat intake. There are many articles

indicating the increasing prevalence of low Vitamin B12 level in different segments of general

population [72,73,74,75,76,77]. In the past decade we have also become aware that vitamin

B12 deficiency occurs commonly in industrial countries at different levels of economic and

social status. A high prevalence of symptomatic vitamin B12 deficiency was discovered in a

pre-urban Bedouin area in Southern Israel due to low intake of animal products [72]. Dietary

vitamin B12 deficiency is a severe problem in India, Mexico, Central and South America [73]

and selected areas in Africa [74]. For example, at least 40% of the population in Central and

South America has deficient or marginal plasma vitamin B12 concentrations in almost all

186 Ilia Volkov, Inna Rudoy and Yan Press

areas and in all age groups [75]. As a rule, it appears to be prevalent in 30-40% of those in

the lower socioeconomic levels. Our clinic serves middle to upper-middle class population,

and, according to preliminary data received in our study, frequency of deficient or marginal

vitamin B12 level (<250pg/ml) was about 35%. We cannot extrapolate our finding to general

population in this area, because the study population is a selected sample, but we suppose

that a prevalence of low level of vitamin B12 in the overall population may be similar. Today

there is a tendency in modern society to change habits, for example cessation of smoking,

"fighting" with overweight, accentuating physical exercise, adopting correct eating habits.

We have come to the conclusion that as a result of media information disseminating the

relationship between meat, cholesterol and cardiovascular diseases, consumption of meat,

particularly beef, has decreased. We suppose that the decrease of level of vitamin B12 in the

population with higher educational level is caused by a premeditated decrease in

consumption of animal products. Also in modern society there is a tendency for ideological

motives, particularly among the younger generation, to be vegans. Changes in life style

among segments of the population with high socioeconomic level, on one hand, and the

existence of poverty, on the other, are two main factors in the decreasing consumption of

animal products (particularly red meat). This causes a decrease in the level of vitamin B12 in

general population, and as a consequence, this will increase pathology due to vitamin B12

deficiency (such as neurological and hematological disorders). As mentioned, vitamin B12

deficiency has various and serious health effects. In lieu of these possible developments and

in order to prevent serious health problems, Vitamin B12 routine fortification should be

seriously considered and discussed.

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