Nejmcp1113996 Vitamin B12 Deficiency

8/22/2019 Nejmcp1113996 Vitamin B12 Deficiency

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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

ThisJournal 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 authors clinical recommendations.

An audio version

of this article isavailable atNEJM.org

Vitamin B12 DeficiencySally 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

12level 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,


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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 B12deficiency and recommended management. Per-nicious anemia is discussed below, since this isthe most common cause of severe vitamin B12deficiency 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/KATPase,which accounts for associated achlorhydria.2,3Other autoimmune disorders, especially thyroiddisease, type 1 diabetes mellitus, and vitiligo, are

also commonly associated with pernicious ane-mia. Whether the stomach pathogen Helicobacterpylori 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,15,16usually 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 g) taken daily are as effective as intramuscular monthly injections in

correcting blood and neurologic abnormalities.

The New England Journal of Medicine

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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 orvegan 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 ImerslundGrsbeck 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 patients 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 B12deficiency, 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 (


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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 erythroidprecursors

Open, immature nuclear chromatin

Dyssynchrony between maturation ofcytoplasm and nuclei

Giant bands, metamyelocytes

Karyorrhexis, dysplasia

Abnormal results on flow cytometryand cytogenetic analysis

Spinal cord

Myelopathy

Spongy degeneration

Paresthesias

Loss of proprioception: vibration,position, ataxic gait, limb weakness;spasticity (hyperreflexia); positiveRomberg sign; Lhermittes 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 whitecells

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





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due to the fact that only 20% of the total mea-sured vitamin B12 is on the cellular delivery pro-tein, transcobalamin; the remainder is bound tohaptocorrin, a protein of unknown function.27Most laboratories now perform automated assaysof vitamin B12 on platforms used for many other

analytes. There is often poor agreement whensamples are assayed by different laboratories orwith the use of different methods.31-34 Becauseintrinsic factor is used as the assay-binding pro-tein, antiintrinsic factor antibodies (which arecommon in pernicious anemia) must be removedchemically from the sample, which has proved tobe problematic in the automated assays.33,34 Re-cent studies show normal values34 or falsely highvalues33 of vitamin B12 in many patients with per-nicious anemia. New assays of holotranscobala-min (to measure the vitamin B

12saturation of

transcobalamin) provide a modest improvementin specificity over that provided by assays of totalserum vitamin B12, but they have not been clini-cally validated27-29 and are not yet available com-mercially in the United States.

Given the limitations of available assays, cli-nicians should not use a laboratorys reportedlower limit of the normal range to rule out thediagnosis of vitamin B12 deficiency in patientswith compatible clinical abnormalities. Cliniciansshould also recognize that vitamin B12 values are

frequently low in patients without other meta-bolic or clinical evidence of vitamin B12 deficiency(i.e., megaloblastic anemia or myelopathy).

Measurement of Serum Methylmalonic Acid

and Total Homocysteine

Measurement of methylmalonic acid, total ho-mocysteine, or both is useful in making the diag-nosis of vitamin B12 deficiency in patients whohave not received treatment.4,22,24,26,33,35,36 Thelevels of both methylmalonic acid and total ho-

mocysteine are markedly elevated in the vast ma-jority (>98%) of patients with clinical B12 defi-ciency (Fig. 4),7,22 including those who have onlyneurologic manifestations of deficiency (i.e., noanemia).4,22

Elevated levels of methylmalonic acid and totalhomocysteine decrease immediately after treat-

ment, and the levels can be remeasured to docu-ment adequate vitamin B12 replacement. Levels ofthese metabolites are normal in up to 50% ofpatients with low vitamin B12 levels who have nohematologic or neurologic response to replacementtherapy, indicating that the low values are falsepositive results.26 Given the limitations of vitaminB12 assays in confirming the diagnosis of B12deficiency,31,34 it may be prudent to measure meth-ylmalonic acid, total homocysteine, or both in pa-tients with compatible clinical findings or pro-vide empirical treatment with the use of defined

end points to document a clinical response.An elevated level of methylmalonic acid is rea-

sonably specific for vitamin B12 deficiency, and thelevel always decreases with vitamin B12 thera-py.24,36 Modest increases (to 300 to 700 nmol perliter) occur with renal failure.36,37 However,nearly all patients with megaloblastic anemia ormyelopathy have levels of methylmalonic acidthat are higher than 500 nmol per liter, and 86%have levels that are higher than 1000 nmol perliter (Fig. 3). The level of serum total homocys-teine is less specific, since it is also elevated infolate deficiency,22,35 classic homocystinuria, andrenal failure.

Tests to Determine the Cause of Vitamin B12

Deficiency

If the patient consumes sufficient amounts of vi-tamin B12 and has clinically confirmed B12 defi-ciency, then malabsorption must be present.Testing for pernicious anemia is described inTable 2. A positive test for antiintrinsic factor orantiparietal-cell antibodies is indicative of per-

nicious anemia; surveillance for autoimmunethyroid disease is reasonable in patients withpositive antibody tests. Chronic atrophic gastritiscan be diagnosed on the basis of an elevated fast-ing serum gastrin level and a low level of serumpepsinogen I.3,19 Some experts recommend en-doscopy to confirm gastritis and rule out gastriccarcinoid and other gastric cancers, since pa-tients with pernicious anemia are at increasedrisk for such cancers.3

The Schilling test of radioactive vitamin B12

Figure 2 (facing page). Clinical and Laboratory Findingsin Vitamin B12 Deficiency.

The spectrum of disease associated with vitamin B12deficiency is wide, from asymptomatic to life-threatening

pancytopenia or myelopathy. An increase in the mean

red-cell volume or distribution width or a mean volumethat is higher than expected for the patients age, pre-

sumed iron status (either high or low iron levels), andthe presence of thalassemia are important determinants

of macrocytosis, rather than an absolute value above thereference range. Cerebral symptoms are usually accom-

panied by paresthesias and signs of myelopathy orneuropathy.5





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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 g,40,41 but higher amounts 4 to 7 gper day which are common in persons who eatmeat or take a daily multivitamin, are associatedwith 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 in-jections of vitamin B12 (called cyanocobalamin inthe United States and hydroxocobalamin in Eu-rope).6,23 About 10% of the injected dose (100 of1000 g) is retained. Patients with severe abnor-malities should receive injections of 1000 g 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

Children

Diseasessimilartothosecausingmalab-

sorptioninadults

100gofintramuscu

larvitaminB12monthlyorhigh-doseoral

vitaminB12daily

inyoungerchildren;treatmentasper

adultsinolderch

ildren

Confirmperniciousanemiaorcongenita

lmalabsorption

Recreationaloroccupationalabuseofnitrousoxide

Intramuscularcyanocobalaminatadoseof1000gadminis-

teredonthesamescheduleasthatforperniciousanemia

aboveandforlife

ifunderlyingperniciousanemiaispresent

EvaluateforvitaminB12malabsorption;provideaddictioncoun-

seling

Nitrousoxideanesthesiainoccu

ltperniciousanemia17

*Intramuscularhydroxocobalamincanbesubstitutedforintramuscularcya

nocobalamin,butdocumentthelong-term

responseifitisadministeredat3-monthintervals.

Expertsarenotinagreementab

outthenecessityorfrequencyofroutineu

pperendoscopyinpatientswithperniciousanemia.However,symptomssuggestive

ofgastriccarcinoma,un-

explainedirondeficiency,andp

rovengastrointestinalbloodlossshouldpromptafullinvestigation.

Congenitalmalabsorptionofvit

aminB12resultsfrommutationsoftheilealcubamreceptor,cubilin,oramnionless(asintheImerslundGrsbecksyndrome)andfrommutationsin

gastricintrinsicfactor.Thesesy

ndromesareusuallymanifestedininfancy

andearlychildhood,althoughstudieshaveshownadelayinonsetevenintoadolesc

ence.1

8

NitrousoxideinactivatesthevitaminB12dependentenzymemethioninesynthaseandcausesformationofvitaminB12analoguesandgradualtissuedepletion

ofvitaminB12.





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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





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showed that 0.5 to 4% of radioactively labeledoral vitamin B12 can be absorbed by passive dif-fusion in both normal controls and patients withpernicious anemia.43 Thus, oral doses of 1000 gdeliver 5 to 40 g, even if taken with food.

A randomized trial that compared an oraldose of 2000 g daily with parenteral therapy

(seven injections of 1000 g of cyanocobalaminover a period of 1 month, followed by monthlyinjections) in patients with pernicious anemia,atrophic gastritis, or a history of ileal resectionshowed similar reductions in the mean corpus-cular volume and increases in the hematocrit at4 months in both groups.38 All participants(four in each group) with paresthesias, ataxia, ormemory loss had resolution or improved withtreatment. However, levels of methylmalonicacid after treatment were significantly lower

with daily oral treatment (169 nmol per liter, vs.265 nmol per liter with parenteral treatment)and vitamin B12 levels were significantly higher(1005 pg per milliliter vs. 325 pg per milliliter[741.5 vs. 239.8 pmol per liter]). A more recenttrial with a similar design involving a proprie-tary oral vitamin B12 preparation also revealed

significantly lower levels of methylmalonic acidin the oral-treatment group at the 3-month follow-up.30 In a randomized trial comparing oral withintramuscular vitamin B12 (1000-g doses, dailyfor 10 days, then weekly for 4 weeks, and month-ly thereafter), the two groups had similar im-provements in hematologic abnormalities andvitamin B12 levels at 90 days.

44 Case series ofpatients treated with oral vitamin B12 haveyielded variable results; elevated levels of meth-ylmalonic acid, homocysteine, or both were re-ported in about half of patients with malabsorp-

tion who were treated with twice-weekly oraldoses of 1000 g,45 whereas normal homocyste-ine levels were reported in patients treated with1500 g daily after gastrectomy.46 Data are lack-ing from long-term studies to assess whetheroral treatment is effective when doses are ad-ministered less frequently than daily. Studiesinvolving older adults, many of whom hadchronic atrophic gastritis, showed that 60% re-quired large oral doses (>500 g daily) to correctelevated levels of methylmalonic acid.47,48

Proponents of parenteral therapy state thatcompliance and monitoring are better in patientswho receive this form of therapy because theyhave frequent contact with health care providers,whereas proponents of oral therapy maintainthat compliance will be improved in patientswho receive oral therapy because of convenience,comfort, and decreased expense. High-dose vita-min B12 tablets (500 to 1500 g) are available inthe United States without a prescription. Self-administered injections are also easily taught,economical, and in my experience, effective. Pa-

tients should be informed of the pros and consof oral versus parenteral therapy, and regardlessof the form of treatment, those with perniciousanemia or malabsorption should be reminded ofthe need for lifelong replacement.

Area s of Uncertainty

Vitamin B12 deficiency is the major cause of hy-perhomocysteinemia in countries with folate-fortified food, such as the United States and

SerumM

ethylmalonicAcid

(nmol/liter)

300,000

100,000

10,000

5,000

1,000

500

50,000

100

10 50 1000 150 200 250 300 350 400 450

Serum Total Homocysteine (mol/liter)

Figure 4. Serum Methylmalonic Acid and Total Homocysteine Concentrationsin 491 Episodes of Vitamin B12 Deficiency.

The data shown have been combined from studies performed over a periodof 25 years.4,6,22,24,26,35,37,38 Most of the patients with clinically confirmed

vitamin B12 deficiency had documented pernicious anemia and a proven re-sponse to vitamin B12 therapy. Open circles indicate episodes in patients

with a hematocrit lower than 38%, and solid circles indicate episodes in

those with a hematocrit of 38% or higher. Patients without anemia hadneurologic manifestations of vitamin B12 deficiency and similar values of

methylmalonic acid and total homocysteine. The axis for serum methylmalo-nic acid is plotted on a log scale. The dashed lines indicate values that are

3 SD above the mean for healthy blood donors: 376 nmol per liter for meth-

ylmalonic acid and 21.3 mol per liter for total homocysteine. The level ofmethylmalonic acid was greater than 500 nmol per liter in 98% of the pa-tients and greater than 1000 nmol per liter in 86%. Adapted from Stabler.7





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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,41and nutritional guidelines for vegetarians arepublished by the American Dietetic Association.40There 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(antiintrinsic factor antibodies). Either paren-

teral vitamin B12 treatment (8 to 10 loading injec-tions of 1000 g each, followed by monthly1000-g injections), or high-dose oral vitaminB12 treatment (1000 to 2000 g 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 def iciency, 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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