Oral Manifestations of Vitamin B 12 Deficiency:

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Oral Manifestations of Vitamin B 12 Deficiency:

A Case Report

Hélder Antônio Rebelo Pontes, DDS, MSc, PhD; Nicolau Conte Neto, DDS;

Karen Bechara Ferreira, DDS; Felipe Paiva Fonseca; Gizelle Monteiro Vallinoto;

Flávia Sirotheau Corrêa Pontes, DDS, MSc, PhD;

Décio dos Santos Pinto Jr, DDS, MSc, PhD

ABSTRACT

Megaloblastic anemias are a subgroup of macrocytic anemias, in which distinctive morphologic abnormalities occur in red cell precursors in bone marrow, namely megalo- blastic erythropoiesis. Of the many causes of megaloblastic anemia, the most common are disorders resulting from cobalamin or folate deficiency. The clinical symptoms are weakness, fatigue, shortness of breath and neurologic abnormalities. The presence of oral signs and symptoms, including glossitis, angular cheilitis, recurrent oral ulcer, oral candidiasis, diffuse erythematous mucositis and pale oral mucosa offer the dentist an opportunity to participate in the diagnosis of this condition. Early diagnosis is important to prevent neurologic signs, which could be irreversible. The aim of this paper is to describe the oral changes in a patient with megaloblastic anemia caused by a dietary deficiency of cobalamin.

M

egaloblastic anemias are a subgroup of macrocytic anemias caused by im- paired DNA synthesis that results in macrocytic red blood cells, abnormalities in leukocytes and platelets and epithelial changes, particularly in the rapidly dividing epithelial cells of the mouth and gastrointes- tinal tract. The most common causes of mega- loblastic anemias are cobalamin (vitamin B12) and folate (vitamin B9) deficiency.1-3

Clinically, megaloblastic anemia progresses slowly, and symptoms include weakness, fa- tigue, shortness of breath and neurologic abnormalities. Oral signs and symptoms, in- cluding glossitis, angular cheilitis, recurrent oral ulcer, oral candidiasis, diffuse erythema- tous mucositis and pale oral mucosa,4,5 offer

the dentist an opportunity to participate in the diagnosis of this condition.

The objective of this paper is to report a case of megaloblastic anemia in which oral manifestations were significant and to review the literature regarding symptoms, diagnostic methods and treatment.

Case Report

In March 2005, a 41-year-old woman was referred by her general dentist to the surgery and buccal pathology service at João de Barros Barreto University Hospital. Her chief com- plaint was difficulty in eating certain types of food (mainly banana and tomato) because of a burning sensation and the presence of red stains on the inside of her cheeks and on her tongue.

Mr. Fonseca

Email: felipepfonseca@

hotmail.com

For citation purposes, the electronic version is the definitive version of this article: www.cda-adc.ca/jcda/vol-75/issue-7/533.html

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She had been a strict vegetarian for 2.5 years and had not consumed milk, cheese, fish, meat or eggs during that time. She was not taking any medication. The current symp- toms had been present for more than a year. Her past medical and dental histories were non-contributory and she reported no history of allergy.

During clinical evaluation, pale- ness and dry lips were detected. The patient also displayed a disturbance of taste (she was unable to sense the flavour of a variety of fruits and vegetables), fatigue after simple daily activities, paresthesia of the ana- tomic structures innervated by the mandibular division of the trigem- inal nerve on her left side, disturb- ance of memory and slowing mental faculty, characterized by forgetting recent facts, dates, appointments and difficulty in answering simple questions, respectively.

Oral examination revealed pale oral mucosa, glossitis with papillary atrophy and multiple areas of painful erythema on the dorsal surface and lateral borders of the tongue and buccal mucosa (Figs. 1a and 1b). The

mucosa covering the lesions appeared atrophic, but no frank ulceration was evident (Figs. 1c and 1d).

Hematologic tests were done (Table 1). Neutrophil nuclei were hypersegmented, with more than 5 lobes.

Anti-intrinsic factor antibodies were not detected, there- fore it was not necessary to perform the Schilling test.

A diagnosis of megaloblastic anemia was made based on the high levels of mean corpuscule volume and red cell distribution width, neutrophil hypersegmentation and cobalamin deficiency, and the patient was referred to a centre for hemotherapy and hematology. Treatment comprised parenteral doses of cobalamin (1,000 mg/week hydroxocobalamin administered intramuscularly over 30 days) and 1 mg of folic acid daily for 30 days. Blood cell counts were repeated monthly. The patient was asked to modify her diet and to add beef liver daily. She re- turned weekly to the surgery and buccal pathology ser- vice for evaluation of her oral lesions, which began to diminish during the first week of therapy. After 14 days of treatment, the lesions had completely disappeared, as had all other symptoms (Figs. 2a–2d).

Discussion

Vitamin B12 is found only in bacteria, eggs and foods of animal origin. It does not occur in vegetables and

fruit. The average daily requirement for cobalamin in adults is 1–2 µg.6 Most cobalamin in food is bound to proteins and released when the protein is subjected to acid-peptic digestion in the stomach. The released cobal- amin rapidly attaches to a cobalamin-binding protein, R-binder, present in saliva and gastric juice. The R-binder in the R-binder complex is broken down in the alkaline environment of the jejunum by pancreatic trypsin and the Table 1 Comparison of patient’s hematologic test results

with normal values Test

Normal range (female)

Patient’s values RBC count (cells/µL) 3.90–5.03 1.63 Hemoglobin (g/dL) 12.0–15.5 7.2

MCV (fL) 80–100 144

Hematocrit (%) 36–45 23.4

RDW (%) 13±1.5 25

Serum folate (ng/mL) 3–16 7.73

Serum cobalamin (pmol/L) 118–716 71.8

MCV = mean corpuscular volume; RBC = red blood cell; RDW = red cell distribution width.

Figure 1a: Papillary atrophy and ery- thema involving the lateral border of the tongue before treatment.

Figure 1b: Erythema involving the mucosa of the cheek and the anterior portion of the tongue.

Figure 1d: Erythema involving the mucosa of the right cheek.

Figure 1c: Well-circumscribed ery- thematous macules seen on the lat- eral border of the tongue.

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released cobalamin binds to intrinsic factor produced by gastric parietal cells in the duodenum and is trans- ported to the distal ileum, where specific receptors bind the B12-intrinsic factor complex resulting in B12 absorp- tion. This attachment is calcium dependent, the calcium being provided by the pancreas. In the absence of intrinsic factor, cobalamin is absorbed only very inefficiently by passive diffusion. Most cobalamin is stored in the liver (about 4–5 mg). Megaloblastic anemia occurs when the body’s cobalamin stores fall below 0.1 mg.1,3,6-8

Macrocytosis due to cobalamin or folate deficiency is a direct result of ineffective or dysplastic erythropoiesis.

These vitamins are the most important cofactors neces- sary for normal maturation of all cells and cobalamin is necessary for DNA synthesis, as its deficiency pre- vents cell division in the marrow.4,9 When either of these factors is deficient, red blood cells (RBCs) become large erythroblasts with nuclear or cytoplasmic asynchrony (poikilocytosis), a characteristic of all megaloblastic anemias.4,10

Dentists’ involvement in the diagnosis of this condi- tion is based on changes in oral mucous membranes, which have been reported in 50%–60% of all patients with megaloblastic anemia.3,11 These oral changes may occur in the absence of symptomatic anemia or macrocytosis,

as they may precede many systemic indicators of B12 deficiency.4,12,13 Thus, the general dentist, who is cognizant of normal blood values and can in- terpret anomalies, may order specific blood tests before the patient is re- ferred to a hematologist. However, patients must be referred to a hemato- logic centre for adequate treatment.

A wide range of oral signs and symptoms may appear in anemic pa- tients as a result of basic changes in the metabolism of oral epithelial cells.

These changes give rise to abnormal- ities in cell structure and the keratin- ization pattern of the oral epithelium leading to a “beefy” red and inflamed tongue with erythematous macular lesions on the dorsal and border sur- faces because of marked epithelial atrophy and reduced thickness of the epithelial layer. In the case described above, for example, erythematous macules occurred on the surface of the patient’s cheek mucosa and tongue.

In addition, soreness of the tongue and generalized ulceration, as well as reduced taste sensitivity, generalized sore mouth or burning mouth are usually reported in the literature and were also present in the current case.3,11 Although candi- diasis and angular cheilitis are common oral complaints of patients with megaloblastic anemia, these problems were not observed in our patient. The differential diag- nosis of patients with these signs and symptoms includes iron deficiency, diabetes, allergy, autoimmune disease, physical and chemical injury, atrophic candidiasis and anemia of chronic disease.4,11,14

Megaloblastic anemia develops slowly and takes 2–

5 years to develop, as the body stores relatively large amounts of vitamin B12 in comparison with daily require- ments.4,8 This timeframe is consistent with our clinical case, as the patient reported that she had been a strict vegetarian for more than 2 years.

Although vitamin B12 deficiency is almost always as- sociated with people who are strict vegetarians, the con- dition also results from malabsorption of the vitamin, which can occur secondary to inadequate gastric produc- tion or defective functioning of intrinsic factor. Other conditions that can lead to vitamin B12 deficiency in- clude gastrectomy, bacterial overgrowth in the small intestine, diverticulitis, celiac disease, Crohn’s disease, alcoholism, HIV and medications such as neomycin and colchicine. In addition, malabsorption of dietary protein- bound vitamin B12 has been associated with the use of

Figure 2a: Dramatic resolution of ery- thema and all pathologic symptoms after 1 week of treatment with parenteral doses of cobalamin and folic acid.

Figure 2b: Absence of papillary atrophy and erythema previously seen on the lateral border of the tongue.

Figure 2d: Complete tissue regeneration on the tongue after treatment.

Figure 2c: Tissue regeneration on the mucosa of the cheek appeared complete after 2 weeks of treatment.

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H2-receptor antagonists and long-term use of proton- pump inhibitors, such as omeprazole, normally prescribed for gastroesophageal reflux disease. Malabsorption of dietary vitamin B12 is thought to be a result of its im- paired release from food protein, which requires gastric acid and pepsin as the initial step in the absorption pro- cess. Thus, according to some reports15-18 prolonged use of H2-receptor antagonists or proton-pump inhibitors could contribute to the development of vitamin B12 deficiency.

Patients taking these medications for extended periods, particularly >4 years, should be monitored for vitamin B12 status.

Careful investigation of clinical history and clinical examination are very helpful in determining the cause of megaloblastic anemia. In fact, the patient’s history often immediately reveals the cause. Mean corpuscular volume, RBC, hemoglobin level, blood film and levels of serum folate, red cell folate and serum B12 are the primary investigations. Also of use are tests for serum/plasma methylmalonic acid and plasma total homocysteine, which are both substrates of cobalamin, and serum holo- transcobalamin II, a metabolically active protein that transports cobalamin to cell membrane receptors. An increase in the levels of these metabolites usually pre- cedes the development of hematologic abnormalities and, thus, can signal this disorder in the absence of hema- tologic abnormalities.1,4,9,13,19,20 Definitive diagnosis of pernicious anemia, however, is made using the Schilling test to investigate intrinsic factor.4,11

When serum cobalamin levels are assessed, folate levels must be assayed at the same time to explore the possibility that the primary deficiency may be of folate rather than cobalamin.1 However, serum folate levels tend to be increased in patients with cobalamin deficiency, presumably because of impairment of the methionine synthase pathway and accumulation of methyltetrahydrofolate, the principal form of folate in serum. On the other hand, low RBC folate levels are seen in patients with cobalamin deficiency. Approximately 60% of patients with pernicious anemia have low RBC folate levels, presumably because cobalamin is neces- sary for normal transfer of methyltetrahydrofolate from plasma to RBCs.9 In our patient, RBC folate level was not investigated. In this situation, Aslinia and colleagues9 recommend that patients receiving treatment for cobal- amin deficiency should also receive folate supplementa- tion at the rate of 400 µg/day to 1 mg/day. Thus, folate was administered to our patient.

Cobalamin deficiency is usually treated by parenteral administration of cyanocobalamin (intramuscularly or subcutaneously, 1000 μg/week for 1 month and monthly thereafter) or hydroxocobalamin in the same dose every 1–3 months intramuscularly. Intramuscular adminis- tration has been used for years and, in the current case, this method was chosen because of the patient’s cognitive

and neurologic impairment. However, sublingual and oral administration of cobalamin are equally effective.9,20 Liver is recommended as a dietary supplement because beef liver contains about 110 µg of cobalamin and about 140 µg of folate per 100 g.6 An optimal response to thera- peutic doses of cobalamin confirms the diagnosis of co- balamin deficiency. A suboptimal response may indicate that the initial diagnosis was wrong, but is more often a result of coexisting iron deficiency, infection, chronic inflammatory disorder, renal failure or the use of drugs such as cotrimoxazole (combination of trimethoprim and sulfamethoxazole, a sulfa drug).1

In conclusion, megaloblastic anemia has a com- plex pathogenesis. As oral lesions are among the most common initial symptoms,11 the dentist, who is often consulted first, has a prime opportunity and respon- sibility to contribute to diagnosis. a

THE AUTHORS

Dr. H. Pontes is a professor of oral and maxillofacial pathology at the Dental School of the Federal University of Pará and oral pathologist in the surgery and oral pathology service, João de Barros Barreto University Hospital, Pará, Brazil.

Dr. Neto is an oral and maxillofacial surgeon in Araraquara, Brazil.

Dr. Ferreira is an oral and maxillofacial surgeon in the surgery and oral pathology service, João de Barros Barreto University Hospital, Federal University of Pará, Brazil.

Mr. Fonseca is an undergraduate student at the Dental School of the Federal University of Pará, Brazil.

Ms. Vallinoto is an undergraduate student at the Dental School of the Federal University of Pará, Brazil.

Dr. F. Pontes is a professor of oral and maxillofacial pathology at the Dental School of the Federal University of Pará and an oral pathologist in the surgery and oral pathology service, João de Barros Barreto University Hospital, Pará, Brazil.

Dr. Pinto is a professor in the department of oral pathology, Dental School, University of São Paulo, Brazil.

Correspondence to: Dr. Felipe Paiva Fonseca, 725 José Pio Street, Apt 504, 66050240 Umarizal, Belém, Pará, Brazil.

The authors have no declared financial interests.

This article has been peer reviewed.

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