deficitul de vitamina b12

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J Dent Sci 2006Vol 1No 1 23

Received: November 6, 2005ccepted: January 20, 2006

Reprint requests to: Dr. Shin-Yu Lu,Department of Dentistry, Chang GungMemorial Hospital, 123, Da Pi Road, Niaosung,Kaohsiung, Taiwan 83301, ROC.

Initial diagnosis of vitamin B12deficiency by sore mouth

and assessment of the red blood cell distribution width,mean corpuscular volume, and hemoglobin level

a preliminary study

SHIN-YU LU1 MING-CHUNG WANG

2

1Department of Oral Medicine and Oral Diagnosis, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung

University College of Medicine, Kaohsiung, Taiwan, ROC.2Department of Hematology-Oncology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University

College of Medicine, Kaohsiung, Taiwan, ROC.

The oral manifestations of glossodynia, glossitis, and stomatitis in vitamin B12deficiency have long

been recognized. These oral changes may occur in the preanemic stage. The aim of this paper was to

study the red blood cell distribution width (RDW), mean corpuscular volume (MCV), and hemoglobin

(Hb) level in 34 patients with a wide range of oral symptoms and signs as the initial manifestations of

vitamin B12deficiency. Of the 34 patients, 29 were normal to mildly anemic, and 5 were moderately to

severely anemic; none had generalized symptoms sufficient to arouse suspicion of micronutrient

deficiency or anemia before they visited the Oral Medicine Clinic. Nine (26.4%) of the 34 patients had

normal RDWs and 8 (88.9%) of these 9 patients also had normal MCVs. Overall, 13 (38.2%) of the 34

patients had normal MCVs and 3 (8.8%) had low MCVs. Our findings indicate that the classic

presentation of macrocytic heterogeneous anemia in vitamin B12deficiency does not hold true in a large

proportion of cases, and the increase of RDW is not necessarily the earliest indicator of vitamin B12

deficiency. Therefore, a diagnosis of vitamin B12 deficiency should be considered even in patients withnormal Hb levels and low or normal MCVs. Nevertheless, the combined increase in the RDW and MCV

in patients with a sore mouth is still a useful indicator of possible vitamin B 12deficiency after folate

deficiency and chronic diseases have been ruled out. J Dent Sci, 1(1)23-31, 2006

Key words:sore mouth, red blood cell distribution width, mean corpuscular volume, vitamin B12deficiency,

pernicious anemia.

Glossitis and glossodynia are classic symptomsof vitamin B12 deficiency

1. It is important forclinicians to be aware of these symptoms in

conjunction with other oral signs such as erythematouspatches, angular cheilitis, recurrent oral ulcers, oralcandidiasis, and a burning mouth. Hematologicalchanges in vitamin B12 deficiency and pernicious

anemia (PA) can aid clinicians in making a correctdiagnosis and in preventing serious neurologicalcomplications. A deficiency of vitamin B12 rarely

results from a lack of animal protein in the diet butcommonly from malabsorption. Inadequate B12absorption often originates from a deficiency ofintestinal cobalamin transport proteins or impairedsynthesis of an intrinsic factor due to severegastrointestinal diseases, a gastrectomy, or PA. Theintrinsic factor is a glycoprotein secreted by gastricparietal cells, and is necessary for the absorption ofvitamin B12in the distal ileum. Despite many causes,PA is now believed to be the most common cause ofvitamin B12 deficiency. A recent population survey


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S.Y. Lu and M.C. Wang.

J Dent Sci 2006Vol 1No 124

revealed that 1.9% of people over 60 years old haveundiagnosed PA2-4. Although the disease is silent

until the last phase, a wide spectrum of oral,gastrointestinal, hematological, and neuropsychiatricmanifestations can be predicted many years beforeanemia develops5-7. However, dental practitioners andmedical doctors often ignore the oral manifestationsand changes in the red blood cell distribution width(RDW) and mean corpuscular volume (MCV) untilthe hemoglobin level is very low.

The usefulness of RDW, an index of red bloodcell heterogeneity in the classification and workup ofmicrocytic anemia from iron deficiency has been welldocumented8-13. Its usefulness in macrocytic anemia

due to vitamin B12deficiency is less clear. Accordingto some surveys, all patients with vitamin B12deficiency have an increased RDW and can thus bedifferentiated from macrocytic anemias with normalRDWs, such as aplastic anemia13-16. It has also beensuggested that the increase in the RDW precedesthe increase in MCV in megaloblastic anemia andcan therefore serve as a sensitive index of earlydeficiency13-15. However, such claims did notcorrespond with our findings and preliminaryobservations and led us to believe that this was notalways the case. This retrospective study providesadditional evidence on this subject.

MATERIAL AND METHODS

Thirty four patients (19 males and 15 females,aged 42~76 years) with vitamin B12 deficiency and asore mouth for a wide range of durations from severalmonths to years were included in the study. Theirdata were collected from the files of the Departmentof Oral Medicine and Oral Diagnosis of Chang GungMemorial Hospital, Kaohsiung Medical Center fromJanuary 1992 to February 2005. Three patients hadcombined iron deficiency and 1 had coexistentthalassemia minor. All patients with a low serumvitamin B12 level or a combined low iron levelbelow the laboratory minimum were referred tohematologists for further evaluation and treatment. Afull medical history including diet, medication,previous operations, and previous care for sore mouthwas recorded. Patients were asked whether they hadhad any generalized symptoms and signs of anemiaincluding weakness, tiredness, exertional dyspnea,pallor, tachycardia, and postural hypotension. The

neuropathic manifestations of vitamin B12deficiencyincluding paresthesias of the extremities, disturbance

of gait, motor impairment, loss of position orvibration sense, disturbance of taste and smell,disturbance of memory and emotion, forgetfulness,mental slowing, depression, irritability, paranoia, andhallucinations were also screened and recorded.

The oral complaints and the presence ofstomatitis and angular cheilitis suggestive ofnutritional deficiency were recorded. Microbiologicalsamples were taken when clinically indicated. Allpatients underwent hematological investigationsconsisting of complete blood counts (CBCs) andserum vitamin B12 and folate levels. The serum

ferritin, iron, and transferrin levels and the totaliron-binding capacity (TIBC) were also measuredwhen normocytic or microcytic anemia existed. Thereported automated blood counts included hemoglobin(Hb), hematocrit (Hct), MCV, and RDW measured asthe mean standard deviation (SD). The antibodyto the parietal cell antigen, antinuclear antibody(ANA), and antithyroid antibodies were checkedwhen B12 deficiency was confirmed. An endoscopicexamination of the stomach was suggested but wasnot mandatory. One of our patients had been botheredby severe glossodynia for 8 months. He had visitedmany physicians for treatment but in vain. A bone

marrow biopsy from this patient after the CBC studyrevealed heterogeneous macrocytosis, and the Hblevel of this patient decreased from 13.5 to 10.2 g/dlwithin 1 month.

The minimum requirement for a diagnosis of PAincluded a low serum vitamin B12level accompaniedby 1 or more of the following: the presence of aparietal cell antibody in the blood, macro-ovalocytosisin a peripheral smear with hypersegmentedpolymorphonuclear leukocytes (at least 1 neutrophilwith 6 or more lobes or 5% of neutrophils with 5lobes), megaloblastic change in the bone marrow, and

a dramatic response to the replacement of vitaminB126,7.

Laboratory normal ranges were as follows: Hbof 12 g/dl for females and 13.5 g/dl for males, aMCV of 80~100 fl, RWD-SD of 40~45 fl, an RBCcount of (4~5.2) 10

6/m, serum folate of >2.5

ng/ml, serum vitamin B12 of 160~970 pg/ml, serumiron of 50~160 UG% for males and 40~150 UG% forfemales, TIBC of 250~400 UG%, and serum ferritinof 102 (21~453) ng/ml for males, 28 (6~142) ng/mlfor females younger than 50 years, and 94 (16~412)


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Vitamin B12deficiency


for females older than 50 years.The degree of anemia was scaled by the Hb

level as mild (Hb 10 g/dl to normal limits), moderate(Hb 8.0~10.0 g/dl), severe (Hb 6.5~7.9 g/dl), andlife-threatening anemia (Hb of


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Figure 1.Various sore tongues related to vitamin B12deficiency. (A) Typical beefy red tongue in a 58-year-old woman with advanced

vitamin B12 deficiency but normal hemoglobin (Hb), high red blood cell distribution width (RDW), and high mean corpuscle volume

(MCV) before therapy and (B) complete regeneration of the tongue mucosa 1 month after vitamin B12 replacement. (C) Moderate

papillary atrophy and lobulation of the tongue in a 50-year-old man with mild anemia, a high RWD, and high MCV. (D) Erythematous

glossitis along the tongue border and a chronic ulcer at the center of the tongue in a 45-year-old man with moderate anemia, a high

RDW, and high MCV. (E) Multiple recurrent aphthous ulcers on the ventral surface of the tongue but no change of the dorsal surface of

the tongue in a 53-year-old man with mild anemia, a normal RDW, and normal MCV. (F) Moderate papillary atrophy and lobulation of

the tongue with pseudomembranous candidiasis and angular cheilitis in a 47-year-old woman with severe anemia, a high RDW, and

high MCV.


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thalassemia minor. Two patients were moderatelyanemic, consisting of 1 with heterogeneousmacrocytosis and the other with heterogeneousmicrocytosis. Three patients were severely anemic,consisting of 1 with heterogeneous microcytosis andthe other 2 with heterogeneous macrocytosis. Nine

(26.4%) of the 34 patients had normal RDWs; 8(88.9%) of those 9 patients with normal RDWs alsohad normal MCVs. Overall, 13 (38.2%) of 34patients had normal MCVs, and 3 (8.8%) of 34patients had low MCVs. Eight of the 34 patients alsorevealed mild leucopenia.

Analysis of autoantibodies and possible etiology

Twenty-five of the 34 patients had anti-parietalcell antibodies. Nine of the 25 patients underwent anendoscopic examination of the stomach and wereconfirmed to have diffuse erosive or atrophic gastritis.Of the 5 patients without anti-parietal cell antibodies,3 had been strict vegetarians for many years and 2had had a subtotal gastrectomy due to gastric cancerand severe gastric bleeding 6~10 years ago. Elevenpatients were found to have ANA and 13 patients hadantithyroid antibodies.

Analysis of peripheral blood smears and bonemarrow biopsies

The histology of a bone marrow biopsy from theposterior iliac crest of 1 patient was consistent withthat of megaloblastic anemia, which showedmegaloblastic changes of the hematopoietic elements,erythroid hyperplasia, and hypersegmentation of theneutrophils. The peripheral smear was characterized

by macro-ovalocytosis, anisocytosis, and hyper-segmented neutrophils that were compatible withmegaloblastic anemia (Figure 2).

DISCUSSION

This study found that a significant proportion ofpatients with vitamin B12 deficiency had normalRDWs and MCVs. Of the 34 patients with vitaminB12deficiency, 26.4% had normal RDWs and 38.2%had normal MCVs. Only 18 (60%) of 30 patientswith pure vitamin B12 deficiency showed typicalheterogeneous macrocytosis. These findings areinconsistent with previous findings13-15 that de-monstrated elevations of both the RDW and MCVin patients with vitamin B12deficiency. However, ourfindings are consistent with those of Saxena17 andCarmel18, which showed a normal RDW in 27% ofuntreated PA patients and a normal MCV in 35% ofuntreated PA patients. It is obvious that a normalRDW or MCV or both can be seen at any stage ofdevelopment of PA and vitamin B12 deficiency.

Table 2.Classification of 34 patients with vitamin B12 deficiency based on hemoglobin (Hb; g/dl) level, mean corpuscular volume (MCV, fl),

and red blood cell distribution width (RDW)

No.of

casesNormal

Mild anemiaHb 10.0 to

normal

Moderateanemia

Hb 8.0~10.0

Severeanemia

Hb 6.5~7.9

Life-threateninganemia

Hb < 6.5

RDW normal, MCV lowHomogenous microcytosis

1 1 (TA)

RDW high, MCV lowHeterogeneous microcytosis

2 1 (IDA) 1 (IDA)

RDW and MCV normalHomogenous normocytosis

8 2 1 (IDA)+5

RDW high, MCV normalHeterogeneous normocytosis

5 5

RWD high, MCV highHeterogenous macrocytosis

18*(60%)

3 12 1 2

Total No. of cases 34 5 24 2 3 0

TA, thalassemia minor; IDA: iron deficiency anemia.* The typical heterogeneous macrocytosis in pure vitamin B12deficiency was found in 60% (18 out of 30 patients, 34 cases minus 3 IDA and 1 TA) ofpatients.


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Therefore, a high RDW is not necessarily the earliestfeature of cobalamin deficiency. Furthermore,combined iron deficiency and thalassemia minormight occur in conjunction with vitamin B12deficiency when patients also have normocytosis ormicrocytosis. This may represent a balance orimbalance between potential microcytosis as a result

of iron deficiency or thalassemia and potentialmacrocytosis resulting from a folate or vitamin B12deficiency12,19. An increase in the MCV to 100~150 flin patients with vitamin B12 deficiency or PA oftenprecedes the actual anemia by several years. The Hblevel in patients with vitamin B12deficiency often hasa biphasic course of change that begins to decreasewhen serum cobalamin is very low17. Consequently,patients with PA or vitamin B12 deficiency at thedegree between severe and life-threatening anemiaare seldom found in the dental clinic. In this study,

vitamin B12 deficiency was found to exist in theabsence of notable red cell changes; in this situation,the change in the oral mucosa was a relativelyimportant diagnostic indicator, and a further checkupof serum cobalamin and iron levels was thussuggested.

This study clearly demonstrates that a diagnosis

of vitamin B12 deficiency, PA, and iron deficiencyanemia by oral changes can be established before thedevelopment of generalized symptoms and signs ofanemia. Two patients showed the typical beefy redtongue and glossodynia but presented with a normalHb level in one and mild anemia in the other. Thus,the symptom of a sore mouth appeared to have littleto do with the degree of anemia. Vitamin B12 andfolate are the 2 most important cofactors necessaryfor DNA synthesis. Deficiency of these 2 cofactorscauses macrocytic changes of RBCs, abnormalities of

Figure 2.A 50-year-old man with advanced vitamin B12deficiency and pernicious anemia, but the CBC study

revealed mildly anemic heterogeneous macrocytosis. (A) Hypersegmented neutrophils in the peripheral smear

(Lius stain, 330). (B) Bone marrow biopsy revealed megaloblastoid changes of the hematopoietic elements,

erythroid hyperplasia, and hypersegmentation of neutrophils (H&E stain, 66). (C) Bone marrow smear

showing erythroid hyperplasia with megaloblastic change and dysplasia, a few of the giant band form, and

hypersegmented neutrophils (Lius stain, 132).


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leukocytes and platelets, and epithelial changes,particularly in the rapidly dividing epithelial cells of

the mouth and gastrointestinal tract. Glossitis andglossodynia are the 2 most classic oral symptoms inpatients with vitamin B12 deficiency. The tongue canbe normal or inflamed1,20. The inflamed tongue cancause discomfort at the levels of pain, soreness, and aburning sensation to intense paresthesia. Examples ofthe clinic features of an inflamed tongue are shown infigure 1. Even the classic beefy red tongue (Figure1A) can turn out to be a normal tongue (Figure 1B)after replacement treatment. The gradual loss offiliform papillae may lead to a smooth bald tonguewith lobulation (Figure 1C). Some small erythe-

matous ulcers may occur on the dorsal surfaceand lateral borders of the tongue (Figure 1D). A lossor distortion of taste is often reported. Oralcandidiasis is rarely found in patients with pure B12deficiency (Figure 1F) but may occur in patients withanemia of any cause1. An iron deficiency contributesto impaired cellular immunity, deficient bactericidalactivity of polymorphonuclear leukocytes, aninadequate antibody response, and epithelialabnormalities that may cause a high prevalence oforal candidiasis, angular cheilitis, and atrophicglossitis in patients with iron deficiency anemia. Theimmunocompromised condition in chronic anemia

may induce many oral changes21. Because of theoverlap of oral manifestations in patients with anemiadue to different causes, the top priority of adiagnostic approach to anemic individuals relies on adetailed medical evaluation of a patients history,definition of the anatomy of the patients complaints,and a good grasp of basic pathophysiology of theanemia. The results of this study further illustrate theimportance of a full blood screen, including serumB12, folate, and iron levels in patients with a widerange of mouth soreness when no other obviouscauses can be found1,20-24. This even applies to patients

with an apparently normal peripheral blood smear.Vitamin B12 deficiency may cause symmetricalneuropathies including peripheral neuritis andsubacute combined degeneration of the spinal cordand cerebrum that cannot be seen in folatedeficiency4,7. These lesions progress from de-myelination to axonal degeneration and eventualneuronal death. The most frequent manifestations ofperipheral neuropathies are paresthesia and numbness.The features of subacute combined degeneration ofthe spinal cord are limb weakness, spasticity, sensory

ataxia, and loss of vibration and position senses.Cerebral manifestations range from mild personality

defects and memory loss to frank psychosis(megaloblastic madness). Therefore, vitamin B12deficiency should be considered in the initial workupof patients with dementia and psychiatric disorders5,which are serious complications, because they cannotbe reversed after replacement therapy with vitaminB12

5,7. Hematological and neuropsychiatric mani-festations can occur simultaneously, in sequence,or independently, but they tend to occur in the latestage of vitamin B12deficiency. Neuropsychologicalproblems without anemia have been reported in14%~30% of PA patients7,17. In this study, patients

with the most severe neurological manifestationsoften had only mild hematological disease. Mostneurologic features in 11 of the 34 patients wereproven to be reversible; they rapidly improved withreplacement therapy except in 3 patients whocomplained of residual mild paresthesia of the feetand impaired memory.

There are several controversies in studies ofvitamin B12deficiency and PA. Chanarin stated that adiagnosis of PA requires the presence of bothmegaloblastic hemopoiesis and vitamin B12 de-ficiency as well as a lack of the gastric intrinsicfactor16. To confirm the first condition generally

requires bone marrow aspiration, the second issatisfied by a low serum B12level, and the third by astudy of B12 absorption with or without the intrinsicfactor. The Schilling test is normally chosen tohelp differentiate PA from primary intestinalmalabsorptive disorders. Thirty-three of the 34patients in this study did not undergo a bone marrowexamination; therefore, they did not meet with theminimum criteria for a diagnosis of PA. Someinvestigators suggested that serum methylmalonicacid (MMA) and plasma homocysteine tests areeffective in the diagnostic workup of suspected

cobalamin deficiency24-27

. Vitamin B12 cofactoractivity is required to convert methylmalonylcoenzyme A to succinyl coenzyme A. A normalMMA level makes the diagnosis of vitamin B12deficiency extremely unlikely26,28. However, anincreased MMA level is not specific to vitamin B12deficiency and can be falsely elevated in renalinsufficiency and is prevalent with advanced age27-29.Plasma homocysteine, whose main determinant is thefolate status, is a much less specific test for PA. Likethe Schilling test, MMA and homocysteine have not


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been validated as routine clinical tests of cobalamindeficiency28, especially in the phase of increasedfolate fortification27-29, and are not routinely availablein most laboratories including ours. Table 3summarizes several conditions and mechanisms thataffect malabsorption of vitamin B12 and should beconsidered during screening of a patients history4,6,30.

In this study, some patients suffered fromatrophic gastritis; 1 patient had megaloblastichemopoiesis and was subsequently confirmed as

having PA. From a purely practical point of view, thetherapeutic response with complete resolution ofclinical signs and symptoms in all of our patientsvalidates not only the diagnosis, but also thetreatment, which is rather safe and inexpensive.Whether or not these patients can be labeled assuffering from PA may be more of academic interestthan a clinical necessity.

In this study, most instances of B12 deficiencywere caused by cobalamin malabsorption. Parenteralsupplementation with large doses of hydro-xocobalamin (1000 g) by deep subcutaneousor intramuscular routes was given daily for 1~2weeks to replenish stores, followed by monthlyinjections (100~1000 g) for life. Three vegetarianswere given oral therapy with daily cyanocobalamin(250~500 g) for life. Three patients with irondeficiency were also given iron replacement. Aftertherapy began, it led to a rapid and dramatic relief oforal symptoms within 48 hours and subjectivelyincreased a sense of well-being and improvedappetite within days. The smooth tongue recoveredwith complete repapillation by 3~4 weeks (Figure

1B). All the oral symptoms and signs resolved within4~6 weeks and responded more rapidly than did theperipheral blood. Overall, correction of the Hb level,MCV, and RDW often took several weeks to monthsexcept for the case coexisting with thalassemia minor.In most patients, the high RDW and/or high MCVshowed a steady fall after therapy, while in a fewpatients the RDW showed a transient rise followedby a progressive drop. All patients maintainedsatisfactory serum vitamin B12 levels. Overall,

compliance and acceptability were excellent.Because the underlying cause of the cobalamin

deficiency cannot usually be corrected, therapy isgenerally life-long, and the patient must emphaticallybe informed that the therapy should never be stopped.The clinical response to initial therapy is oftendramatic. In patients with PA and those who haveundergone a gastrectomy, vitamin B12must be givenin large amounts (preferably >1000 g daily as anintramuscular injection). However, in vegan patients,oral vitamin B12 in smaller doses can provide aneffective alternative to intramuscular injections.Therefore, we can give a choice to those patientswithout absorption disorders and reduce costs inprimary care. Coexistent iron deficiency can limit thespeed and completeness of recovery and should betreated with iron replacement. Our observations canadd to doctors awareness that the classic presentationof macrocytic heterogeneous anemia in vitamin B12deficiency does not hold true, and the importance oforal changes appears before the modification in thesystemic markers of nutritional deficiency.

Table 3.Etiologies of vitamin B12 deficiency

State Cause

Dietary defect (lack of animal protein) Vegetarianism

Failure to digest food protein Decreased gastric acid

Absence of intrinsic factor Pernicious anemia, a gastrectomy, atrophic gastritis, ingestion of corrosive agents

Failure to digest R protein Pancreatic diseases

Inadequate absorption Ileal resection, regional ileitis, steatorrhea, sprue, abdominal x-ray therapy

Ileal mucosal or receptor defect Certain drugs

Other malabsorption syndromes HIV infection, multiple sclerosis

Congenital disease Transcobalamin deficiency

Altered intestinal utilization Bacterial growth, fish tapeworm

Increased requirements Pregnancy


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deficitul de vitamina b12

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