Evaluating Red Patches and Burning Mouth Symptoms as Oral Biomarkers in Cobalamin Deficiency: A Comparative Study

Abstract

Background

Vitamin B12 (cobalamin) deficiency can manifest through various nonspecific oral symptoms. Early diagnosis is crucial but challenging due to subtle and progressive clinical features. Laboratory investigations like serum cobalamin levels and mean corpuscular volume (MCV) are used but have limitations.

Purpose

To assess the reliability of red patches and burning mouth symptoms as oral biomarkers for clinical and subclinical vitamin B12 deficiency, and correlate them with serum cobalamin and MCV values.

Methods

A sequential diagnostic analysis was conducted on 120 adult subjects (aged 18-45), divided into a control group consisting of asymptomatic subjects with subclinical cobalamin deficiency and a study group with symptomatic subjects with clinical cobalamin deficiency . Oral examinations and laboratory tests for MCV and serum cobalamin levels were performed. Statistical analyses included descriptive statistics, t-tests, and logistic regression.

Results

Significant differences were found in MCV and cobalamin levels between study and control groups (P < .001). The presence of red patches and burning mouth symptoms strongly correlated with variations in MCV and cobalamin levels. Logistic regression analysis showed high accuracy (98.3%) in distinguishing between groups based on these markers.

Conclusion

Oral red patches and burning mouth symptoms, in conjunction with MCV and cobalamin levels, can serve as reliable indicators for identifying clinical cobalamin deficiency. This underscores the importance of monitoring these oral indicators during initial clinical examinations for early detection and management of vitamin B12 deficiency.

Plain Language Summary Title: Oral Biomarkers in Cobalamin Deficiency: A Comparative Study

Plain Language Summary

Why was the study done?

The study was done to find out if oral symptoms like red patches in the mouth and burning sensations could serve as early warning signs (biomarkers) of vitamin B12 (cobalamin) deficiency. Diagnosing this deficiency early is difficult because the symptoms are often mild and nonspecific. Although lab tests like serum cobalamin and MCV are used, they have limitations. Therefore, the researchers wanted to determine whether these common oral signs could reliably indicate B12 deficiency, especially in settings where lab testing may be delayed or unavailable.

What did the researchers do?

The researchers examined 120 adults, dividing them into symptomatic and asymptomatic groups based on oral signs of vitamin B12 deficiency. They conducted oral examinations and measured serum cobalamin and MCV levels. Statistical analyses were used to compare groups and assess whether oral symptoms could reliably indicate B12 deficiency.

What did the researchers find?

The study found that people in the study group had significantly lower B12 levels and higher MCV values compared to the control group. These laboratory differences were strongly linked to the presence of oral red patches and burning sensations. Logistic regression analysis showed that cobalamin levels were a significant predictor of B12 deficiency. The overall model was highly accurate (98.3%), meaning it could correctly identify who had the deficiency in most cases.

What do the findings mean?

The findings indicate that oral red patches and burning mouth symptoms, when observed in conjunction with high MCV and low cobalamin levels, can be considered strong clinical indicators of vitamin B12 deficiency. These signs can help dentists identify and treat B12 deficiency earlier, especially before more serious symptoms appear. This is particularly useful in situations where lab testing is delayed, costly, or unavailable, making these oral symptoms valuable tools for early diagnosis and management.

Keywords

Vitamin B12 deficiency burning mouth erythema erythrocyte indices biomarkers

Introduction

Vitamins are organic compounds essential for various physiological functions and overall well-being. They are classified into two main groups: fat-soluble vitamins, which are stored in body fat; and water-soluble vitamins, which are rapidly eliminated from the system, are difficult to store, and must be consumed regularly to avoid deficiency.¹ Among the water-soluble vitamins, the B complex consists of eight distinct vitamins: B1 (Thiamine), B2 (Riboflavin), B3 (Niacin), B5 (Pantothenic acid), B6 (Pyridoxine), B7 (Biotin), B9 (Folate), and B12 (Cobalamin). These vitamins are grouped not by their chemical structure but by their solubility in water and their crucial roles as coenzymes in cellular processes.²

Deficiencies in B vitamins are linked to various neurological disorders and other pathological conditions.³ Specifically, a deficiency in Vitamin B12 can manifest through several nonspecific oral symptoms, including glossodynia, recurrent ulcers, lingual paraesthesia, burning sensations, pruritus, dysgeusia, intolerance to dental prostheses, xerostomia, stomatitis, and cheilitis.⁴

Vitamin B12 deficiency is characterized by a triad of symptoms: megaloblastic anaemia, glossitis, and neuropsychiatric disorders.⁵ The primary cause of this deficiency is malabsorption of cobalamin, which tends to increase with advancing age.⁶ Additionally, patients with hyperhomocysteinemia, a condition commonly associated with low serum cobalamin levels, have a twofold increased risk of developing Alzheimer's disease.⁷ Therefore, the early diagnosis and prevention of B12 deficiency-related central nervous system damage are crucial. However, diagnosing this condition is arduous due to its subtle and progressive nature and the nonspecific early clinical features.⁸

Even though the laboratory investigation confirms the condition, the generally employed threshold for diagnosing B12 deficiency, which is a serum cobalamin level below 200 pg/ml, has poor sensitivity. In such scenarios, serum levels of homocysteine, and methylmalonic acid (metabolites of cobalamin) are advisable for confirming cobalamin deficiency. However, this investigation has shown questionable specificity due to the impact on their serum levels of lifestyle factors such as smoking, alcohol, or coffee consumption.^9,10 Additionally, these investigations are not cost effective. Furthermore, an increased mean corpuscular volume (MCV) has been strongly linked to being associated with vitamin B12 deficiency, especially in the presence of anaemia.¹¹ Hence, it is more pragmatic to correlate reliable clinical features of B12 deficiency with specific investigations like serum cobalamin and MCV rather than relying on a single test for early diagnosis and management.

A particularly conspicuous clinical feature is the presence of mucosal changes in the oral cavity, along with a burning sensation. Cobalamin deficiency disrupts the process of DNA synthesis, thus impacting the rapidly dividing cells of the oral mucosa. A prominent clinical hallmark of B12 deficiency is “Hunter's glossitis,” which initially presents as diffuse bright red patches, known as “beefy red patches,” and eventually progresses to atrophic glossitis.¹² There seems to be a dearth of studies correlating laboratory investigations with reliable clinical features. Hence, the objective of the present study is to assess the reliability of red patches and burning mouth symptoms as oral biomarkers and correlate them with serum cobalamin and MCV values in subjects with clinical and subclinical vitamin B12 deficiency.

Methods

Sample Selection and Size

A sequential diagnostic analysis was carried out on 120 adult subjects (aged 18-45), who were selected purposive sampling and allocated into two groups, control group with subclinical cobalamin deficiency (220 - 400 pg/mL) and a study group with subjects who had a clinical presence of diffuse reddish areas anywhere in the oral cavity (Figure 1) and burning sensations at the time of reporting, following laboratory confirmed cobalamin deficiency (less than 400 pg/mL). These study subjects were selected from an intake of outpatients visiting the Department of Oral Medicine and Radiology across 2021 and 2024 and control group subjects were selected from the records archived at the in-house diagnostic centre. Patients with other oral lesions due to infections or tobacco or drug habits, a history of gastrectomy for stomach cancer, gout, low levels of serum potassium, or allergies to cyanocobalamin or cobalt were excluded from participating in the study. Before being included in the study, all participants provided their informed consent by signing an agreement. The study protocol received approval from the Institutional Ethical Review Board in a single-center setting with number 44/2023.

Figure 1.

Shows Patients Included in the Study Exhibiting Diffuse Erythematous Patches Involving the Buccal Mucosa [A] and the Ventral Surface of the Tongue [B].

Methodology

A comprehensive medical history was documented, encompassing the primary concerns, overall health status, previous medical conditions, and familial medical background. The careful oral examination for both the control and study groups was conducted by the principal investigator. The main clinical feature evaluated was the physical presence of the oral red patch and the presence of a burning mouth sensations. All subjects received laboratory investigations at an in-house clinical biochemical laboratory immediately after the examination. The tests conducted included the measurement of MCV and the calculation of serum levels of cobalamin.

Statistical Analysis

Descriptive statistics for covariates such as age and sex based on the prevalence of the dependent variables such as red patch and the presence of burning mouth sensation were evaluated for both control and study groups. Unequal variance was noted in the data while performing Brown Forsythe's test; hence, the Welch's t test was carried out to analyse the significance of cobalamin and MCV in the presence of a burning mouth sensation and a red patch. Logistic regression along with performance assumptions were carried out as this was a laboratory diagnostic investigation. The statistical tests were carried out using SPSS version 22. A P-value of less than .05 was considered significant.

Results

The mean age of the population included in the study was 35.7 ± 6.87 and 37.2 ± 6.82 for females and males, respectively. The descriptive statistics on all dependent variables based on the control and study group are illustrated in Table 1.

Table 1.

Descriptive Results Among Study and Control Group.

Parameters	Group	Mean	Std. Deviation	Minimum	Maximum	P
MCV (in fl)	Study	109.200	8.161	84.000	119.000	<.001
MCV (in fl)	control	88.867	4.115	81.000	96.000	<.001
Cobalamin (pg/mL)	Study	183.267	33.505	133.000	379.000	<.001
Cobalamin (pg/mL)	control	391.300	145.942	178.000	660.000	<.001

Abbreviation: MCV, mean corpuscular volume.

Table 1 also presents the results of an independent t-test comparing two groups: a study group and a control group. For MCV, the study group had a significantly higher mean (109.200 ± 8.161) compared to the control group (88.867 ± 4.115), with a P-value of less than .001, indicating strong statistical significance. The coefficient of variation was 0.075 for the study group and 0.046 for the control group. For cobalamin levels, the study group had a lower mean (183.267 ± 33.505) compared to the control group (391.300 ± 145.942), with a P-value also less than .001, indicating a significant difference between the groups. The coefficient of variation was 0.183 for the study group and 0.373 for the control group. Overall, the data suggest significant differences between the study and control groups for both MCV and cobalamin levels (Figure 2).

Figure 2.

Comparison of MCV and Cobalamin Values Among Control and Study. Abbreviation: MCV, mean corpuscular volume.

Table 2 presents the results of independent samples t-tests comparing characteristic features (evident red patch and presence of burning mouth symptoms) for two variables: MCV (mean corpuscular volume in fl) and cobalamin (vitamin B12 levels in pg/mL). The tests show significant differences for all comparisons, with P-values less than .001 in every case, indicating strong statistical significance. For the evident red patch, the t-values for MCV and cobalamin are −7.549 (df = 104.070) and 9.914 (df = 63.512), respectively. For the presence of a burning mouth symptoms, the t-values are −17.062 (df = 111.673) for MCV and 10.696 (df = 66.142) for cobalamin. These results indicate that there are statistically significant differences in both MCV and cobalamin levels between groups characterised by the presence of an evident red patch and those with a burning mouth symptom (Figure 3).

Figure 3.

Comparison of MCV and Cobalamin to the Characteristic Clinical Features. Abbreviation: MCV, mean corpuscular volume.

Table 2.

Comparing the Characteristic Clinical Features Between Study and Control Groups.

		t	df	P
Evident Red Patch	MCV (in fl)	−7.549	104.070	<.001
Evident Red Patch	Cobalamin (pg/mL)	9.914	63.512	<.001
Presence of Burning Mouth	MCV (in fl)	−17.062	111.673	<.001
Presence of Burning Mouth	Cobalamin (pg/mL)	10.696	66.142	<.001
Presence of Both	MCV (in fl)	−14.464	109.798	<.001
Presence of Both	Cobalamin (pg/mL)	9.314	81.210	<.001

Abbreviation: MCV, mean corpuscular volume.

The logistic regression analysis between the study and control group indicates a significant improvement in model fit from the null model (H₀) to the fitted model (H₁), as evidenced by the deviance reduction from 166.355 to 18.012 and the highly significant chi-square test (χ² = 148.343, P < .001). This suggests the predictors used in the model contribute meaningfully to distinguishing between the groups. The McFadden R² value of 0.892, along with high values for Nagelkerke R² (0.946), Tjur R² (0.926), and Cox & Snell R² (0.710), indicates a strong overall model fit.

Among the predictors, Cobalamin (pg/mL) is statistically significant (P = .043), with an estimate of 0.012, suggesting that higher cobalamin levels increase the likelihood of being in the study group. MCV (in fl) is marginally significant (P = .052) with a negative estimate, indicating that higher MCV values slightly decrease the likelihood of being in the study group. The variables “Evident Red Patch” and “Presence of Burning Mouth sensation” were not significant, suggesting these factors do not significantly contribute to differentiating between the study and control groups in this analysis. The intercept is not significant either, indicating no substantial baseline log-odds difference when all predictors are at zero (Table 3). However, the logistic regression model demonstrates excellent performance, with an overall accuracy of 98.3%, indicating it correctly classifies the vast majority of cases. The sensitivity of 1.000 shows that the model perfectly identifies all true positives, meaning it successfully detects all individuals in the study group. The specificity of 0.967 indicates a high ability to correctly identify true negatives, or individuals in the control group, further reinforcing the model's robustness as indicated by the significant predictors and high R² values.

Table 3.

Logistic Regression Analysis Between the Study and Control Group.

	Estimate	Standard Error	z	Wald Statistic	df	P
(Intercept)	14.938	8.383	1.782	3.175	1	.075
MCV (in fl)	−0.182	0.093	−1.945	3.784	1	.052
Cobalamin (pg/mL)	0.012	0.006	2.021	4.086	1	.043
Evident Red Patch (Yes)	2.552	2.043	1.249	1.561	1	.212
Presence of Burning mouth (Yes)	−21.045	3644.218	−0.006	3.335 × 10⁻⁵	1	.995

Abbreviation: MCV, mean corpuscular volume.

Discussion

Vitamin B12, also known as cobalamin, is essential for numerous critical physiological processes, underscoring its significance in maintaining overall health. This water-soluble vitamin is crucial for the synthesis of red blood cells, which are imperative for oxygen transport throughout the body, thereby preventing anaemia and associated fatigue.¹³ Furthermore, cobalamin is vital for maintaining the integrity of the nervous system, as it plays a key role in the synthesis of the myelin sheath that insulates nerve fibres, thereby ensuring efficient transmission of nerve signals.¹ Vitamin B12 is also essential for DNA synthesis and cellular energy metabolism, significantly impacting overall cellular function and energy levels.¹⁴ A deficiency in vitamin B12 can lead to severe neurological and haematological conditions, such as pernicious anaemia, which is characterised by the presence of abnormally large and dysfunctional erythrocytes, as well as neurodegenerative disorders that may result in cognitive impairments and neuropathy.¹⁵ Given that vitamin B12 is predominantly obtained from animal-derived foods, individuals following vegetarian or vegan diets are at an increased risk of deficiency and may require supplementation. Thus, maintaining adequate levels of vitamin B12 is critical for sustaining energy, cognitive function, and overall metabolic health.

The relationship between cobalamin (vitamin B12) and MCV is significant in the diagnosis and understanding of macrocytic anaemias.¹⁶ Elevated MCV, which denotes larger-than-normal red blood cells, is a hallmark of cobalamin deficiency.¹¹ This condition, termed macrocytosis, arises due to impaired DNA synthesis essential for cell division, resulting in fewer but larger red blood cells.¹⁷ An elevated MCV serves as a critical diagnostic marker, necessitating further testing for vitamin B12 levels and associated metabolites such as homocysteine and methylmalonic acid (MMA).¹⁸ Although other conditions, including folate deficiency, alcoholism, liver disease, and certain medications, can also result in elevated MCV, the identification and treatment of cobalamin deficiency generally involve vitamin B12 supplementation.¹⁹ In light of this, the present study aimed to evaluate MCV and cobalamin levels in subjects who exhibited characteristic oral manifestations of cobalamin deficiency for its reliability as a potential oral biomarker.

The red patch associated with vitamin B12 deficiency is known as the “beefy red” patch. This patch is a common oral manifestation of vitamin B12 deficiency and is characterised by diffuse and bright erythema on the oral mucosa, often presenting as linear, band-like, or irregular shapes.^4,8,20 The “beefy red” patch is considered a useful clinical marker for diagnosing vitamin B12 deficiency, particularly when combined with serum cobalamin levels below 350 pg/mL.⁸ A study conducted by Zhou et al,⁸ found that the “beefy red” patch demonstrated the highest diagnostic validity (Youden index of 0.84) and reliability (consistency of 91.9%) among the clinical markers evaluated, including serum cobalamin levels and MCV, which supports the current study, which showed an accuracy of 98.3% inclusive of ethic differences among the study population.

It is important to consider various factors that contribute to oral symptoms such as burning sensations and the appearance of oral red patches. Besides nutrient deficiency, these symptoms are often associated with local factors including the sharp edges of restorations, corrosion changes of dental metals, and chronic mechanical trauma.^21,22 Several studies have investigated the correlation between cobalamin deficiency, increased MCV, and associated burning mouth presentations. While the association between cobalamin deficiency and burning sensations has been questioned, studies consistently show that vitamin B12 deficiency is a common finding in patients who report these symptoms.^23–25 Additionally, these studies have highlighted the importance of MCV in diagnosing cobalamin deficiency. The present study found a highly significant correlation between increased MCV and the presence of oral red patches and burning sensations in the study group, which was not observed in the control group.^26–28 For instance, one study demonstrated a significant increase in MCV in patients with burning sensations and vitamin B12 deficiency, suggesting a strong correlation between these conditions.²⁴ Conversely, another study found that patients with burning sensations and microcytosis (MCV < 80 fL) exhibited higher frequencies of anaemia, haematinic deficiencies, hyperhomocysteinemia, and gastric parietal cell antibody positivity compared to those without microcytosis.²⁹ These findings collectively suggest that both local factors and systemic conditions like cobalamin deficiency, as indicated by increased MCV, may contribute to visible changes in the oral mucosa (such as atrophy), which can subsequently lead to burning sensations. Further research is needed to fully elucidate the interplay between these factors and to develop comprehensive diagnostic and treatment approaches.

In the context of treating cobalamin deficiency, the choice between parenteral and oral administration routes is pivotal. Although oral therapy has demonstrated efficacy in certain cases, parenteral administration remains the more efficacious and widely accepted approach.³⁰ Parenteral therapy ensures that cobalamin is directly delivered into the bloodstream, circumventing potential barriers to absorption and providing prompt and reliable correction of deficiency symptoms. This method is particularly crucial for patients with impaired gastrointestinal function or those unable to effectively absorb cobalamin via the oral route.³¹ Furthermore, parenteral therapy is often more effective in severe cases of deficiency, where rapid correction is essential to prevent irreversible damage. Consequently, parenteral therapy is frequently the preferred choice for hospitalised patients, individuals with severe neurological involvement, or those who are unable to take medication orally.³²

Integrating these insights, it becomes evident that a comprehensive approach to diagnosing and treating cobalamin deficiency is essential. The present study gives significant evidence that oral red patches and the presence of burning mouth sensations can serve as potential oral biomarkers in recognising severe to complex clinical cobalamin deficiency, which warrants supplementation by choosing the appropriate route of administration for cobalamin, thus significantly impacting patient treatment outcomes.

Limitations of the Study

While the study provides valuable insights into the potential use of oral biomarkers for diagnosing vitamin B12 deficiency, there are several limitations that should be considered. The relatively small sample size of 60 adult subjects aged 18-45 years from a single centre may limit the generalizability of the findings to other populations or settings. The observational design of the study cannot establish a causal relationship between the oral biomarkers and vitamin B12 deficiency, and randomised controlled trials would be needed to confirm the diagnostic value of these markers. The study focused on a limited set of oral biomarkers (red patches and burning mouth symptoms) and did not include long-term follow-up to assess the impact of vitamin B12 supplementation on these markers and overall health outcomes. Confounding factors, such as diet, medication use, or underlying health conditions, may not have been fully accounted for in the study. Addressing these limitations through larger sample sizes, randomised controlled trials, exploration of additional oral biomarkers, long-term follow-up assessments, and comprehensive consideration of confounding factors would strengthen the evidence base for using oral markers in diagnosing and managing clinical cobalamin deficiency.

Conclusion

This observational comparative study identified significant differences in MCV and cobalamin levels between the study and control groups. The study group exhibited higher MCV and lower cobalamin levels, suggesting these biomarkers indicate cobalamin deficiency. Oral symptoms like red patches and burning mouth sensations correlated strongly with MCV and cobalamin variations. Statistical analyses, including independent t-tests and model comparisons, showed substantial differences (P-values <.001), highlighting the findings’ robustness. High goodness-of-fit measures reinforce MCV and cobalamin levels as reliable diagnostic markers, and oral symptoms as potential indicators for early detection and management of cobalamin deficiency.

Footnotes

ORCID iD

Vidya Gowdappa Doddawad

Ethics Approval and Consent to Participate

The present study was taken institutional approval was taken priorly from the Institutional Ethical Committee. (JSSDCH IEC protocol number: 44/2023).

Consent for Publication

The authors certify that they have obtained all appropriate patient consent forms.

Author Contributions

VSC, NS, SPS: Conceptualization, Methodology, Investigation, Literature search, Original draft Writing.

KP, SCJ, VGD: Conceptualization, Writing – Review & editing, Supervision

All the authors have agreed to publish this manuscript.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Availability of Data and Materials

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

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