Vit B12 Defficiency

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clinical practice

T h e n e w e n g l a n d j o u r n a l o f medicine

n engl j med 368;2 nejm.org january 10, 2013 149

This Journal feature begins with a case vignette highlighting a common clinical problem.Evidence supporting various strategies is then presented, followed by a review of formal guidelines,

when they exist. The article ends with the author’s clinical recommendations.

An audio version

of this article isavailable atNEJM.org

Vitamin B12 Deficiency Sally P. Stabler, M.D.

From the University of Colorado Schoolof Medicine, Aurora. Address reprint re-quests to Dr. Stabler at the Division ofHematology, University of Colorado,Aurora, CO 80045, or at [email protected].

N Engl J Med 2013;368:149-60.

DOI: 10.1056/NEJMcp1113996Copyright © 2013 Massachusetts Medical Society.

A 57-year-old woman reports increasing symptoms of painful paresthesias in bothlegs for the past 18 months. Physical examination reveals impaired position senseand vibration sense. The serum vitamin B

12 level is 205 pg per milliliter (151.2 pmol

per liter), which is above the lower end of the laboratory reference range. The hemato-crit is 42%, with a mean corpuscular volume of 96 fl. The serum methylmalonic acidlevel is 3600 nmol per liter (normal level, <400), and the serum homocysteine level

49.1 µmol per liter (normal level, <14). How should this patient be further evaluatedand treated?

The Clinical Problem

The recognition and treatment of vitamin B12 deficiency is critical since it is a reversible cause of bone marrow failure and demyelinating nervous system disease.Vitamin B12 (cobalamin) is synthesized by microorganisms and detected in traceamounts mostly in foods of animal origin.1 Uptake in the gastrointestinal tractdepends on intrinsic factor, which is synthesized by the gastric parietal cells, andon the “cubam receptor” in the distal ileum.2 The most frequent cause of severe vitamin B

12

deficiency is a loss of intrinsic factor due to autoimmune atrophic gas-tritis,3 historically called “pernicious anemia,” even though many patients present with mainly neurologic manifestations.4,5

Pathophysiology of Vitamin B12 Deficiency

Vitamin B12 is a cofactor for only two enzymes: methionine synthase and L-methyl-malonyl–coenzyme A mutase6,7 (see Fig. 1 in the Supplementary Appendix, avail-able with the full text of this article at NEJM.org). The interaction between folateand B12 is responsible for the megaloblastic anemia seen in both vitamin deficien-cies. Dyssynchrony between the maturation of cytoplasm and that of nuclei leads tomacrocytosis, immature nuclei, and hypersegmentation in granulocytes6 in theperipheral blood (Fig. 1A). The hypercellular and dysplastic bone marrow can be

mistaken for signs of acute leukemia (Fig. 1B).10

The ineffective erythropoiesis re-sults in intramedullary hemolysis and release of lactate dehydrogenase, featuresthat are similar to those of microangiopathic hemolytic anemia.8 Clinical and labo-ratory f indings of megaloblastic anemia in the peripheral blood and bone marroware shown in Figure 2.

Vitamin B12 is necessary for the development and initial myelination of thecentral nervous system as well as for the maintenance of its normal function.Demyelination of the cervical and thoracic dorsal and lateral columns of the spinalcord, occasional demyelination of cranial and peripheral nerves, and demyelin-ation of white matter in the brain5 (i.e., “combined-systems disease” or “subacutecombined degeneration”) can occur with vitamin B12 deficiency (Fig. 2). Pathologi-

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n engl j med 368;2 nejm.org january 10, 2013150

cal analysis reveals a “spongy degeneration” dueto the loss of and swelling of myelin sheaths;this degeneration is visible on magnetic reso-nance imaging.11 For unclear reasons, the sever-ity of megaloblastic anemia is inversely corre-lated with the degree of neurologic dysfunction.4,5

Less common conditions associated with vi-tamin B12 deficiency include glossitis, malab-sorption, infertility, and thrombosis (includingthrombosis at unusual sites such as cerebral ve-nous sinus thrombosis).12,13 Thrombosis has beenattributed to the marked hyperhomocysteinemiaseen in severe cases of vitamin B12 deficiency.Patients occasionally have hyperpigmentation,

which clears with treatment.

6

Causes of Vitamin B12 Deficiency

Table 1 and Figure 3 list causes of vitamin B12 deficiency and recommended management. Per-nicious anemia is discussed below, since this isthe most common cause of severe vitamin B12 deficiency worldwide.

Dietary vitamin B12 deficiency in infants andchildren is also discussed because of the in-creasing recognition of severe abnormalities inexclusively breast-fed infants of mothers with

vitamin B12 deficiency.

Pernicious Anemia

Pernicious anemia1 is an autoimmune gastritisresulting from the destruction of gastric parietalcells and the associated lack of intrinsic factor tobind ingested vitamin B12. The immune responseis directed against the gastric H/K–ATPase, which accounts for associated achlorhydria.2,3 Other autoimmune disorders, especially thyroiddisease, type 1 diabetes mellitus, and vitiligo, are

also commonly associated with pernicious ane-mia. Whether the stomach pathogen Helicobacter

pylori plays a causative role in pernicious anemiais unclear.19 Autoimmune gastritis may causemalabsorption of iron, with clinical iron deficien-cy developing early in life and eventually progress-ing to malabsorption of vitamin B12.

20 The preva-lence of pernicious anemia ranges from 50 to4000 cases per 100,000 persons, depending onthe diagnostic criteria.1 All age groups are af-fected, but the median age range in large seriesis 70 to 80 years.21,22 Pernicious anemia is morecommon in persons of African or European an-cestry (4.3% and 4.0% prevalence among older

adults, respectively) than in those of Asian ances-try.1,21 Milder forms of atrophic gastritis withhypochlorhydria and an inability to release di-etary protein-bound vitamin B12 affect up to 20%of older adults.19,23,24

Dietary Deficiency in Infancy and Childhood

The infant of a mother with vitamin B12 defi-ciency may be born with the deficiency or it mayoccur if he or she is exclusively breast-fed,15,16 usually between 4 and 6 months of age. Typicalmanifestations of vitamin B12 deficiency in chil-

dren include failure of brain development andoverall growth and development, developmentalregression, hypotonia, feeding difficulties, leth-argy, tremors, hyperirritability, and coma (Fig.2).15,16 Brain imaging may reveal atrophy anddelayed myelination. Anemia may be present.Vitamin B12 replacement results in rapid im-provement in responsiveness, and many infantsrecover fully. However, the longer the period ofdeficiency, the more likely that there will bepermanent disabilities. Mothers of infants with

key Clinical points

vitamin b12

deficiency

• Vitamin B12

deficiency causes reversible megaloblastic anemia, demyelinating neurologic disease, or both.

• Autoimmune gastritis (pernicious anemia) is the most common cause of severe deficiency.

• Methodologic problems may compromise the sensitivity and specificity of current vitamin B12

assays.

• Measurement of methylmalonic acid, homocysteine, or both is used to confirm vitamin B12

deficiency in untreated patients;

an elevated level of methylmalonic acid is more sensitive and specific for the diagnosis.

• For patients with pernicious anemia or malabsorption, lifelong vitamin B12

therapy is indicated.

• High-dose oral vitamin B12

tablets (1000 to 2000 µg) taken daily are as effective as intramuscular monthly injections in

correcting blood and neurologic abnormalities.






clinical practice


vitamin B12 deficiency often have unrecognizedpernicious anemia, but alternatively, they mayhave a history of gastric bypass surgery, theshort-gut syndrome, or a long-term vegetarian or vegan diet.16 Tandem mass spectrometry, usedin neonatal screening programs in all 50 states,may detect nutritional B12 deficiency owing to

an increase in propionyl carnitine, but directmeasurement of methylmalonic acid has highersensitivity.25 Other causes of B12 deficiency inchildren, such as ileal resections, the Imerslund–Gräsbeck syndrome, inflammatory bowel disease,and pernicious anemia, are listed in Table 1.18

Str ategies and Evidence

Evaluation

Both the clinical recognition of vitamin B12 defi-ciency and confirmation of the diagnosis by

means of testing can be diff icult. An approach totesting is shown in Table 2.

The patient’s history may include symptomsof anemia, underlying disorders causing malab-sorption, and neurologic symptoms. The mostcommon neurologic symptoms are symmetricparesthesias or numbness and gait problems.4,5

The physical examination may reveal pallor, ede-ma, pigmentary changes in the skin, jaundice, orneurologic defects such as impaired vibrationsense, impaired position and cutaneous sensa-tion, ataxia, and weakness (Fig. 2).

Bone marrow biopsy and aspiration are notnecessary for the diagnosis of megaloblasticanemia and may be misleading in cases of severepancytopenia with hypercellularity, increasederythroblasts, and even cytogenetic abnormali-ties, confusing the diagnosis with acute leuke-mia.8-10 Imaging of the spinal cord is not indi-cated in patients with recognized vitamin B12

deficiency, but in cases of severe myelopathy thatare not initially recognized as the result of vita-min B12 deficiency, there is characteristic hyper-

intensity on T2-weighted imaging, described asan inverted V-shaped pattern in the cervical andthoracic spinal cord.11

Vitamin B12

Assay

The first test performed to confirm the diagnosisof vitamin B12 deficiency is generally measure-ment of the serum vitamin B12 level. Althoughan extremely low level (<100 pg per milliliter[<73.8 pmol per liter]) is usually associated withclinical deficiency, such low levels are infre-

quently observed. Both false negative and falsepositive values are common (occurring in up to50% of tests) with the use of the laboratory-reported lower limit of the normal range as acutoff point for def iciency.4,24,26 The high rate offalse negative and false positive results may be

A

B

Figure 1. Peripheral-Blood Cells and Bone MarrowSpecimen Obtained from a Patient with Vitamin B12

Deficiency.

In Panel A, a peripheral-blood smear shows oval macro-

cytes as well as fragmented, misshapen cells and an

immature megaloblastic nucleated red cell (arrow).

The variation in red-cell size and shape could lead to amisdiagnosis of microangiopathic hemolytic anemiainstead of megaloblastic anemia.8,9 The mean corpuscu-

lar volume was in the normal range, but an extremelyhigh red-cell distribution width suggested macrocytosis

combined with microcytic fragmented cells. In Panel B,a bone marrow aspirate shows megaloblastic features.

Large erythroblasts and other red-cell precursors arecharacterized by an open, immature nuclear chromatin

pattern. There is dyssynchrony between the maturationof cytoplasm and that of nuclei in later red-cell and

granulocyte precursors. A “giant” band is present. Sev-

eral red-cell precursors have dysplastic nuclei (arrows),with nuclear fragments (arrowhead) that are compati-

ble with cellular apoptosis and resulting intramedullaryhemolysis. (Photographs courtesy of John W. Ryder,

M.D., Department of Pathology, University of ColoradoSchool of Medicine.)








Brain

Altered mental status

Cognitive defects

“Megaloblastic madness”: depression,mania, irritability, paranoia,delusions, labilityOptic atrophy, anosmia, loss of taste,

glossitis

Infertility

Bone marrow

Hypercellular, increased erythroid precursors

Open, immature nuclear chromatin

Dyssynchrony between maturation of cytoplasm and nuclei

Giant bands, metamyelocytes

Karyorrhexis, dysplasia

Abnormal results on flow cytometry and cytogenetic analysis

Spinal cord

Myelopathy

Spongy degeneration

Paresthesias

Loss of proprioception: vibration,position, ataxic gait, limb weakness;

spasticity (hyperreflexia); positiveRomberg sign; Lhermitte’s sign;segmental cutaneous sensory level

Autonomic nervous system

Postural hypotension

Incontinence

Impotence

Peripheral nervous system

Cutaneous sensory loss

Hyporeflexia

Symmetric weakness

Paresthesias

Abnormalities in infants and children

Developmental delay or regression, permanent disability

Does not smile

Feeding difficulties

Hypotonia, lethargy, coma

Hyperirritability, convulsions, tremors,

myoclonusMicrocephaly

Choreoathetoid movements

Peripheral blood

Macrocytic red cells, macroovalocytes

Anisocytosis, fragmented forms

Hypersegmented neutrophils, 1% with

six lobes or 5% with 5 lobes

Leukopenia, possible immature white cells

Thrombocytopenia

Pancytopenia

Elevated lactate dehydrogenase level (extremes possible)

Elevated indirect bilirubin andaspartate aminotransferase levels

Decreased haptoglobin level

Elevated levels of methylmalonic acid, homocysteine, or both










clinical practice


absorption is no longer available. A potentialreplacement absorption test is under develop-ment wherein the increase in vitamin B12 satura-tion of holotranscobalamin is measured afterseveral days of oral B12 loading,39 but this re-quires further study.

Treatment of Vitamin B12 Deficiency

The daily requirement of vitamin B12 has been setat 2.4 µg,40,41 but higher amounts — 4 to 7 µgper day — which are common in persons who eatmeat or take a daily multivitamin, are associated with lower methylmalonic acid values.42 Healthyolder adults should consider taking supplementalcrystalline vitamin B12 as recommended by theFood and Nutrition Board.41 However, most pa-tients with clinical vitamin B12 deficiency havemalabsorption and will require parenteral or high-dose oral replacement. Adequate supplementa-

tion results in resolution of megaloblastic anemiaand resolution of or improvement in myelopathy.

Injected Vitamin B12

There are many recommended schedules for injections of vitamin B12 (called cyanocobalamin inthe United States and hydroxocobalamin in Eu-rope).6,23 About 10% of the injected dose (100 of1000 µg) is retained. Patients with severe abnor-malities should receive injections of 1000 µg atleast several times per week for 1 to 2 weeks,then weekly until clear improvement is shown,followed by monthly injections. Hematologic re-sponse is rapid, with an increase in the reticulo-cyte count in 1 week and correction of megalo-blastic anemia in 6 to 8 weeks. Patients withsevere anemia and cardiac symptoms should betreated with transfusion and diuretic agents, andelectrolytes should be monitored. Neurologicsymptoms may worsen transiently and then sub-side over weeks to months.5 The severity and du-ration of the neurologic abnormalities beforetreatment inf luence the eventual degree of recov-

ery.4,5

Treatment of pernicious anemia is lifelong.In patients in whom vitamin B12 supplementa-tion is discontinued after clinical recovery, neu-rologic symptoms recur within as short a periodas 6 months, and megaloblastic anemia recurs inseveral years.6

High-Dose Oral Treatment

High-dose oral treatment is effective and is increas-ingly popular. A study performed 45 years ago

C h i l d r e n

D i s e a s e s s i m i l a r t o t h o s e c a u s i n g m a l a b -

s o r p t i o n i n a d u l t s

1 0 0 µ g o f i n t r a m u s c u

l a r v i t a m i n B 1 2 m o n t h l y o r h i g h - d o s e o r a l

v i t a m i n B 1 2 d a i l y

i n y o u n g e r c h i l d r e n ; t r e a t m e n t a s p e r

a d u l t s i n o l d e r c h

i l d r e n

C o n f i r m p e r n i c i o u s a n e m i a o r c o n g e n i t a

l m a l a b s o r p t i o n

R e c r e a t i o n a l o r o c c u p a t i o n a l a b u s e o f n i t r o u s o x i d e §

I n t r a m u s c u l a r c y a n o c o b a l a m i n a t a d o s e o f 1 0 0 0 µ g a d m i n i s -

t e r e d o n t h e s a m e s c h e d u l e a s t h a t f o r p e r n i c i o u s a n e m i a

a b o v e a n d f o r l i f e

i f u n d e r l y i n g p e r n i c i o u s a n e m i a i s p r e s e n t

E v a l u a t e f o r v i t a m i n B 1 2 m a l a b s o r p t i o n ; p r o v i d e a d d i c t i o n c o u n -

s e l i n g

N i t r o u s o x i d e a n e s t h e s i a i n o c c u

l t p e r n i c i o u s a n e m i a 1 7

* I n t r a m u s c u l a r h y d r o x o c o b a l a m i n c a n b e s u b s t i t u t e d f o r i n t r a m u s c u l a r c y a

n o c o b a l a m i n , b u t d o c u m e n t t h e l o n g - t e r m

r e s p o n s e i f i t i s a d m i n i s t e r e d a t 3 - m o n t h i n t e r v a l s .

† E x p e r t s a r e n o t i n a g r e e m e n t a b

o u t t h e n e c e s s i t y o r f r e q u e n c y o f r o u t i n e u

p p e r e n d o s c o p y i n p a t i e n t s w i t h p e r n i c i o u s a n e m i a . H o w e v e r , s y m p t o m s s u g g e s t i v e

o f g a s t r i c c a r c i n o m a , u n -

e x p l a i n e d i r o n d e f i c i e n c y , a n d p

r o v e n g a s t r o i n t e s t i n a l b l o o d l o s s s h o u l d p r o m p t a f u l l i n v e s t i g a t i o n .

‡ C o n g e n i t a l m a l a b s o r p t i o n o f v i t

a m i n B 1 2 r e s u l t s f r o m m u t a t i o n s o f t h e i l e a l c u b a m r e c e p t o r , c u b i l i n , o r a m n i o n l e s s ( a s i n t h e I m e r s l u n d – G r ä s b e c k s y n d r o m e ) a n d f r o m m u t a t i o n s i n

g a s t r i c i n t r i n s i c f a c t o r . T h e s e s y

n d r o m e s a r e u s u a l l y m a n i f e s t e d i n i n f a n c y

a n d e a r l y c h i l d h o o d , a l t h o u g h s t u d i e s h a v e s h o w n a d e l a y i n o n s e t e v e n i n t o a d o l e s c

e n c e . 1

8

§ N i t r o u s o x i d e i n a c t i v a t e s t h e v i t a m i n B 1 2 – d e p e n d e n t e n z y m e m e t h i o n i n e s y n t h a s e a n d c a u s e s f o r m a t i o n o f v i t a m i n B 1 2 a n a l o g u e s a n d g r a d u a l t i s s u e d e p l e t i o n

o f v i t a m i n B 1 2 .








Figure 3. The Normal Mechanisms and Defects of Absorption of Vitamin B12.

The vitamin B12 (Cbl) released from food protein by peptic action is bound to haptocorrin (HC) in the stomach and

travels to the duodenum, where pancreatic proteases digest the HC, releasing Cbl to bind to intrinsic factor (IF).The IF-Cbl complex binds to a specific receptor in the distal ileum (the cubam receptor) and is internalized, eventu-

ally released from lysosomes, and transported into the blood. Both HC and transcobalamin (TC) bind Cbl in the cir-

culation, although the latter is the cellular delivery protein. Adapted from Stabler. 6










clinical practice


Canada. Epidemiologic studies show significantassociations between elevated homocysteine lev-els and vascular disease and thrombosis. How-ever, large randomized trials of combined high-dose vitamin B therapy in patients with vasculardisease have shown no reduction in vascularevents.49 Vitamin B12 status should be evaluated

in patients with hyperhomocysteinemia beforefolic acid treatment is initiated.

The potential role of mild vitamin B12 defi-ciency in cognitive decline with aging remainsuncertain. Epidemiologic studies indicate an in- verse association between vitamin B12 supplemen-tation and neurodegenerative disease, but resultsof randomized trials have been largely negative.50

Besides oral tablets, vitamin B is available insublingual preparations, oral sprays, nasal gelsor sprays, and transdermal patches. Data on theabsorption and efficacy of these alternative prep-

arations are lacking.

Guidelines

Nutritional guidelines for vitamin B12 intake arepublished by the Food and Nutrition Board,41 and nutritional guidelines for vegetarians arepublished by the American Dietetic Association.40 There are no recommendations from the Ameri-can Society of Hematology for the diagnosis andtreatment of vitamin B12 deficiency. The Ameri-can Academy of Neurology recommends mea-surements of vitamin B12, methylmalonic acid,and homocysteine in patients with symmetricpolyneuropathy.51 The American Society for Gas-trointestinal Endoscopy recommends a single

endoscopic evaluation at the diagnosis of perni-cious anemia.52

Conclusions

and R ecommendations

The patient in the vignette has neurologic abnor-

malities that are consistent with vitamin B12 de-ficiency. Since vitamin B12 levels may be abovethe lower end of the laboratory reference rangeeven in patients with clinical deficiency, methyl-malonic acid, total homocysteine, or both shouldbe measured to document vitamin B12 deficiencybefore treatment is initiated; the elevated levelsin this patient confirm the diagnosis. In the ab-sence of dietary restriction or a known cause ofmalabsorption, further evaluation is warranted— in particular, testing for pernicious anemia(anti–intrinsic factor antibodies). Either paren-

teral vitamin B12 treatment (8 to 10 loading injec-tions of 1000 µg each, followed by monthly1000-µg injections), or high-dose oral vitaminB12 treatment (1000 to 2000 µg daily) is an effec-tive therapy. I would review both options (includ-ing the possibility of self-injection at home) withthe patient. Effective vitamin replacement willcorrect blood counts in 2 months and correct orimprove neurologic signs and symptoms within6 months.

Dr. Stabler reports holding patents (assigned to the Universityof Colorado and Competitive Technologies) on the use of homo-

cysteine, methylmalonic acid, and other metabolites in the diag-nosis of vitamin B12 and folate deficiency, but no longer receiv-ing royalties for these patents. No other potential conflict ofinterest relevant to this article was reported.

Disclosure forms provided by the author are available with thefull text of this article at NEJM.org.

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Vit B12 Defficiency

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