Diagnostic value of oral “beefy red” patch in vitamin B12 deficiency
Peiru Zhou,1 Hong Hua,1 Zhimin Yan,1 Liwu Zheng,2Xiaosong Liu1
1Department of Oral Medicine, Peking University School and Hospital of Stomatology, Beijing, China; 2Discipline of Oral Diagnosis and Polyclinics, Faculty of Dentistry, Prince Philip Dental Hospital, The University of Hong Kong, Hong Kong Special Administrative Region, China
Bakgrunn: Vitamin B12-mangel, som kan forårsake alvorlig nevropsykiatrisk skade, er vanlig hos eldre. De ikke-spesifikke kliniske egenskapene til B12-mangel og upålitelige serumparametere gjør diagnosen vanskelig. Vi har som mål å evaluere verdien av orale "biffete røde" flekker som en klinisk markør for B12-mangel.
Background: Vitamin B12 deficiency, which may cause serious neuropsychiatric damage, is common in the elderly. The non-specific clinical features of B12 deficiency and unreliable serum parameters make diagnosis difficult. We aimed to evaluate the value of oral "beefy red" patches as a clinical marker of B12 deficiency.
Metoder: En diagnostisk studie ble utført hos pasienter som klaget over oral ømhet, brennende følelse eller alvorlige gjentatte magesår. Pasientene gjennomgikk klinisk undersøkelse og laboratorieundersøkelser, inkludert fullstendig blodtall og estimering av serum B12, folat, jern og ferritinnivå. Oppløsning av kliniske tegn og symptomer etter 1 måneders B12 supplement ble ansett som den diagnostiske gullstandarden.
Methods: A diagnostic study was conducted in patients complaining of oral soreness, burning sensation, or severe recurrent oral ulcers. Patients underwent clinical examination and laboratory investigations, including complete blood count and estimation of serum B12, folate, iron, and ferritin levels. Resolution of clinical signs and symptoms after 1 month of B12 supplement was regarded as the diagnostic gold standard.
Resultater: Av 136 pasienter hadde 70 B12-mangel. Blant disse pasientene ble det observert "beefy red" -munnsår i 61, abnormalt gjennomsnittlig korpuskulært volum (MCV) ble observert i 30, og serumkobalaminnivåene <200 og <350 pg / mL ble observert i henholdsvis 59 og 67 tilfeller. Den "biffete" tungen hadde den høyeste diagnostiske verdien (Youden-indeksen 0,84) og påliteligheten (konsistens 91,9% [95% CI: 87,3% -96,5%]), etterfulgt av serumkobalaminnivåene og MCV. Kombinasjonen av "beefy red" -plaster med kobalamin <350 pg / ml viste bedre diagnostisk verdi enn kombinasjonen av "bøyd rød" lapp med kobolamin <200 pg / ml, med nøyaktighet på 0,81 mot 0,74 og pålitelighet på 90,4% (95% CI: 85,5% -95,4%) mot 86,8% (95% CI: 81,1% -92,5
.Results: Of 136 patients, 70 had B12 deficiency. Among these patients, the oral "beefy red" patch was observed in 61, abnormal mean corpuscular volume (MCV) was noted in 30, and serum cobalamin levels <200 and <350 pg/mL were seen in 59 and 67 cases, respectively. The "beefy red" patch demonstrated the highest diagnostic validity (Youden index 0.84) and reliability (consistency 91.9% [95% CI: 87.3%-96.5%]), followed by the serum cobalamin levels and MCV. The combination of "beefy red" patch with cobalamin <350 pg/mL exhibited better diagnostic value than the combination of "beefy red" patch with cobalamin <200 pg/mL, with accuracy of 0.81 vs 0.74 and reliability of 90.4% (95% CI: 85.5%-95.4%) vs 86.8% (95% CI: 81.1%-92.5%).
Conclusion: The combination of oral "beefy red" patch and serum cobalamin level <350 pg/mL appears to be useful for diagnosis of B12 deficiency.
Keywords: vitamin B12 deficiency, "beefy red" patch, oral manifestation, diagnosis
Vitamin B12 (cobalamin) is an important coenzyme for DNA synthesis and erythrocyte production and differentiation, and is essential for normal neurological function. B12 deficiency may lead to megaloblastic anemia, epithelial abnormalities in the digestive tract mucosa, and severe neuropsychiatric damage.1 Deficiency is common among the elderly, and the prevalence is known to increase with age. Cobalamin malabsorption is the primary cause of deficiency.2 About 10%-30% of the elderly3-5 and 30%-41.6% of sick and malnourished patients6,7 have low serum cobalamin levels. Patients with untreated clinical and subclinical B12 deficiency are at high risk of developing serious neurological disorders such as age-related brain atrophy and degeneration of the funiculi of the spinal cord. Patients with neurological impairment present with paresthesias, ataxia, and cognitive problems.8Furthermore, the risk of Alzheimer's disease is doubled in patients with hyperhomocysteinemia, which is partially attributable to low serum levels of cobalamin.9 Early disease recognition and treatment are therefore crucial for prevention of cobalamin deficiency-related central nervous system damage. However, the initial non-specific clinical features of cobalamin deficiency and the insidious progression of the condition make diagnosis difficult, particularly in elderly patients with multiple age-related disorders.10 Although abnormal laboratory results may provide important evidence for confirmation of the disease, the commonly used cutoff for diagnosis of B12 deficiency (serum cobalamin level of <200 pg/mL) has poor sensitivity.11-13 In Carmel and Agrawal's report, for example,
22%-35% of patients with B12 deficiency (mostly due to pernicious anemia) had normal serum cobalamin levels.12 In such cases, measurements of serum homocysteine (Hcy) and methylmalonic acid (MMA) - by-products of the cobalamin metabolic pathway - are currently recommended for confirming B12 deficiency. However, serum Hcy and MMA have low or questionable specificity; moreover, serum Hcy level is influenced by lifestyle factors (smoking and alcohol or coffee consumption).14,15 These tests are also expensive, and therefore it would be useful to have reliable clinical markers that could be used to identify patients who need further verification with Hcy or MMA determination.
A potentially useful clinical marker is oral mucosal change in B12 deficiency. The oral mucosa is composed of rapidly dividing cells, and is therefore susceptible to cobalamin deficiency-related disorders in DNA synthesis. The resulting changes in cell structure and the epithelial keratinization pattern16 precede some systemic symptoms.17 Hunter's glossitis, a well-known oral feature of B12 deficiency, presents as diffuse bright red patches ("beefy red" patches) initially and gradually progresses to atrophic glossitis.18 Lesions primarily occur on the dorsal and ventral surfaces and the margin of the tongue. The palatal, buccal, and labial mucosa may also be affected, with lesions presenting as areas of linear, band-like, or irregular erythema.16,19,20
Only a few studies have focused on the value of the oral "beefy red" patch as an indicator of B12 deficiency. In the present study, we aimed to assess the validity and reliability of the oral "beefy red" patch as a clinical marker of B12 deficiency.
A diagnostic study was consecutively conducted among 143 adult patients (≥18 years) with complaints of oral soreness, burning sensation, or persistent severe recurrent oral ulcers over the past 6 months who were recruited from among the outpatients visiting the Department of Oral Medicine, Peking University School and Hospital of Stomatology during 2012 and 2014. Individuals with a history of cancer (except those who had undergone gastrectomy for stomach cancer), gout, low serum potassium, or allergy to cyanocobalamin or cobalt were excluded.
All participants signed informed consent prior to inclusion in the study. The study protocol was approved by the Institutional Review Board of Peking University School and Hospital of Stomatology (PKUSSIRB-2012100409).
Detailed medical history was recorded, including main complaints, general health condition, past medical history, and family history. Oral evaluation was performed by two clinicians who were trained by the principal investigator (HH). The presence of the oral "beefy red" patch was the main sign assessed.
All participants underwent laboratory investigations at an assigned clinical biochemical laboratory; the tests included complete blood count and estimation of serum levels of cobalamin, folate, iron, and ferritin. To confirm oral candidiasis, microorganism examinations (smear or salivary culture for Candida) were also carried out among the patients with oral red lesions. Candida-positive patients were prescribed a topical antifungal agent (nystatin) for 1 month, after which they were reassessed. Those who had complete resolution of symptoms and signs were diagnosed as having oral candidiasis alone and were assigned to the control group. Otherwise, the patients were regarded as having non-oral candidiasis disease or oral candidiasis combined with other diseases. To determine the real B12 deficiency, all subjects enrolled except for those with oral candidiasis alone were administered cobalamin supplements for 1 month. The patients who had complete resolution of clinical signs and symptoms were diagnosed as having had B12 deficiency and were assigned to the case group. The other patients were assigned to the control group, and further examinations (biopsy, immunological tests, and trace elements examination, if necessary) were conducted for their definitive diagnosis (Figure 1).
In general, the daily requirement for cobalamin in adult is 2 μg. Most excessive cobalamin is stored in the liver with about 4,000-5,000 μg.21 According to the US Institute of Medicine, 100 μg of daily cobalamin supplement is recommended to those over 50 years of age to maintain cobalamin levels, and no tolerable upper intake levels of cobalamin is set.22 Therefore, following the above mentioned rules and based on the findings of previous study,19 the subjects were administered a daily intramuscular injection of 500 μg cyanocobalamin for 1 month. The oral condition of each case was reassessed at the 1-month follow-up. The normalization of both clinical signs and symptoms by cobalamin administration was regarded as the gold standard diagnostic criteria for B12 deficiency. Participants were advised to stop cobalamin supplements and consult their doctors immediately in case of side effects such as diarrhea or allergic symptoms such as hives or rash on any part of the body, swelling of the face, mouth or throat, shortness of breath, or wheezing.
Differential diagnosis of oral "beefy red" patch
The oral "beefy red" patch was evaluated and identified by two clinicians who were trained by the principal investigator (HH). The "beefy red" patch in B12 deficiency is often confused with other oral red lesions (Figure 2). Table 1 shows the differential diagnoses and the characteristic features of each condition.16,19,20,23,24
The sample size yielding a sensitivity of 80% and specificity of 80% was estimated, with a relative error (Δ) of 5%-10%. Based on the formula (N = Uα2 P (1 − P)/Δ2), 62-246 patients would be required for the case or control group, with an alpha value of 0.05. Parametric statistical tests were used to analyze the data. The independent samples t-test and the chi-squared test were used to analyze the differences between groups with regard to age and gender, respectively. Sensitivity, specificity, and consistency were used to describe the diagnostic value of the clinical and laboratory parameters. SPSS 17.0 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. P ≤ 0.05 was considered statistically significant.
A total of 143 patients were initially enrolled; however, 7 patients withdrew from the study due to personal reasons, and thus 136 patients were included in the final analysis. Of these 136 patients, 6 patients were diagnosed with oral candidiasis alone and were classified into the control group. The remaining 130 patients received cobalamin supplementation, as daily cobalamin supplement is recommended to those over 50 years of age and no tolerable upper intake levels of cobalamin is set by the US Institute of Medicine.22 None of the patients experienced any adverse effects due to the cobalamin supplementation. Among the 130 patients, 70 responded well to cobalamin supplement and were therefore identified as having B12 deficiency and classified into the case group. The other 60 patients did not respond to cobalamin supplementation and were assigned to the control group. Thus, there were a total of 66 patients in the control group. Burning mouth syndrome (50/66) was the major diagnosis in the control group, followed by oral candidiasis alone (6/66), recurrent aphthous stomatitis (4/66), and geographic tongue (4/66). Other 2 patients were unidentified, in which the "beefy red" patches continued in spite of cobalamin replacement