Moliterno_B12andIron 07.11.12

7/30/2019 Moliterno_B12andIron 07.11.12

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Anemia:

NutritionalDeficiencies

AlisonR.MoliternoMD

JHUSOM

July2012


2/44

A44yo socialworkerisreferredtoyouforanemia. Sheismarried,withteenagechildren,

andhasnohistoryofbleeding,andnomenorrhagia.Shehasbeentoldaslongasshecan

rememberthatshehaslowiron,becameanemicwithpregnanciesbutdidnotrequiretransfusions. Shehastakenoralironinfrequently,last morethanayearago.

LatelyshehasseenasleepspecialistandbeenfittedforCPAP,acardiologistfordyspnea

andisplanningtoseeapulmonologistbecauseofdyspnea andexerciseintolerance.ROS

wasnotedforanonrestricteddiet,anddramaticpagophagia.ExamisnotedforaBMIof

33,palemucousmembranes,asystolicejectionmurmur,spoonnails.ROSisremarkable

fordramaticpagophagia andpica.


3/44

low High 2012 2008

WBC 4500 11000 4000 5900

Hemoglobin 12 15 8.8 10.7

MCV 80 100 67 72

Platelets 150 350 422 281

Iron 50 170 18 24

Transferrin 200 400 426 381

TIBC 250 450 533 476

%sat 20 55 3 5

Ferrritin 13 150 10 4

Bloodcountsandironstudiesonour42yo femalearelistedbelow.

Howwouldyouproceedwithevaluatingandmanagingthispatient:

1) Nofurtherevaluation,treatorally

2) Treatorallyand/orintravenously

3) RefertoGIforEGD,colonoscopy

4) RefertoGIforEGD,smallbowelbiopsies,celiacserologies

5) Treatintravenously,recommendawheatfreediet


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Iron

Distribution

inMan

Hemoglobin

(2500mg) Myoglobin,

Enzymes(500mg)

Ferritin,Hemosiderin

(1000

mg)

Transferrin 4mg


5/44

Iron

Absorption Foodsources: 10 25mg/day

Absorbedinthebrushborderof

theduodenum

Mostdietaryironisnonheme

form,


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The

iron

cycle


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IronStorage

Ferritin

multisubunitprotein

primarilyintracellular

somein

plasma

Hemosiderin

insolubleformof

ferritin

visiblemicrosopically


8/44

Pathophysiologyof

Iron

Deficiency

Depletionof

iron

stores

Ironbecomesalimitingfactorinhemebiosynthesis

Hemedeficiencylimitshemoglobinassembly

Hemoglobindeficiencylimitsredcellproduction

Redcellsaresmall(microcytic,lowMCV)

Redcells

are

deficient

in

hemoglobin

(hypochromic,

lowMCH)


9/44

Iron

Losses Ironiscloselyconservedinhumans


10/44

RoutestoIronDeficiency

OccultorovertGIlosses,traumaticorsurgicallosses

Failuretomeetincreasedrequirements

Rapidgrowthininfancyandadolescence

Menstruation,pregnancy,delivery

Inadequatedietarysource

Dietlowinheme iron(vegans,impoverished)

Malabsorption

Gastrointestinaldiseaseorsurgery(gastricfailure,atrophic

gastritis,gastricbypass,H.pylori)

Duodenal/smallbowel

malabsorptive disease

Celiacdisease,lymphoma

Chronichemolysis

PNH,march

hemoglobinuria


11/44

SymptomsandsignsofIDA

Anemiasymptoms fatigue,feelingcold,dyspnea on

exertion,palpitations,tinnitus

Pica

cravingof

nonfood

substances

e.g.,ice,dirt,clay,laundrystarch,newspaper

Glossitis smoothtongue

Angularstomatitis

cracking

of

corners

of

mouth

Koilonychia thin,brittle,spoonshapedfingernails

Bluesclerae

Shortterm

memory

loss

Restlesslegs


12/44

SequentialChanges

in

IDA

NORMALDEPLETED

IRONSTORES

IRONDEFICIENCY

IRONDEFICIENCY

ANEMIA

FERRITIN

IRON SATURATION

MCV & Hb & Hct


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Peripheralblood

smear

in

IDA


14/44

Therapyof

Iron

Deficiency

Patienteducation RBC

transfusion

Oralironsalts(FeSO4)

Formalabsorbers(gastricbypass,celiacdisease,Barretts,

gastrectomy)or

chronic

bleeders

(menorrhagia,

angiodysplasia,

Chrohns)

Injectable ironpreparations(irondextran,ironsucrose)

DOMinfusion

center

Ascorbicacidincreasesoralironabsorption

Phytates (cerealgrains),tannins(tea)andantacidtherapyinhibit

oraliron

absorption


15/44

Responseto

Iron

Therapy

Peakreticulocyte count 7

10

d.

IncreasedHbandHct 14 21d.

NormalHbandHct 2months

Normalironstores 4 5months


16/44

ASH

SAP A30yo femalepresentswithirondeficiencyrefractorytoiron

supplementation.Shehasbeenamenorrheic forthepastyear,

andruns

30

miles

aweek.

She

denies

other

sources

of

blood

loss,anddeniesGIsymptomsofanysort.Sheisavegetarian.

HerBMIis18,ferritin isundetectable,andhemoglobinis11

gm/dl.Contributorstohercurrentclinicalpictureincludeall

ofthe

following

except:

A.femalesex

B.vegetariandiet

C.undiagnosed

celiac

disease

D.longdistancerunning

E Alloftheabove


17/44

A37yearoldpreviouslyhealthyAfricanAmericanmaleishospitalizedforanillness

characterizedbyhighfevers,incapacitatingpolyarthritis andrash. Hehadlaboratories

consistentwithmarkedinflammationincludinganerythrocytesedimentationrateofgreater

than100,

and

aCreactive

protein

of

greater

than

40.

In

addition

to

his

hemogram,

the

intern

sendsironstudiesandbasedonthoseresults,hemochromatosis genetesting:

Patient NormalRange

WBCCOUNT 36650 4500 11000

RBCCOUNT 3.00 4.50

5.90

HEMOGLOBIN 9.1 13.9 16.3

PACKEDCELLVOLUME 27.1 41.0 53.0

MCV 90.3 80.0 100.0

MCHEMOGLOBIN 30.3 26.0 34.0

MC

HGB

CONCENTRATION 33.6 31.0

37.0RBCDISTRIBUTIONWIDTH 12.9 11.5 14.5

PLATELETCOUNT 443 150 350

ABSRETICCOUNT 38.3 24.1 87.7

Serumiron 84 65170mcg/dL

Transferrin 136 200400

mg/dL

Totalironbindingcapacity 170 250450mg/dL

%Saturation 49 2055%

Ferritin 19,322 10300ng/mL

HFEgenotypeC282Y Wildtype


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Patientin

Hospital

Patientafter3monthsof

treatmentNORMALRANGE

WBCCOUNT 36650 9800 4500 11000

RBCCOUNT 3.00 4.45 4.50

5.90

HEMOGLOBIN 9.1 13.8 13.9 16.3

PACKEDCELLVOLUME 27.1 42.5 41.0 53.0

MEANCORPUSCULARVOLUME 90.3 95 80.0 100.0

MCHEMOGLOBIN 30.3 33.0 26.0 34.0

MCHGBCONCENTRATION 33.6 33.7 31.0 37.0

RBCDISTRIBUTION

WIDTH 12.9 12.0 11.5

14.5

PLATELETCOUNT 443 397 150 350

SERUMIRON 84 65 170mcg/dL

TRANSFERRIN 136 200 400mg/dL

TOTALIRONBINDINGCAPACITY 170 250 450mg/dL

%

SATURATION 49 20

55%FERRITIN 19,322 213 10 300ng/mL

Thepatientisgivenacourseofprednisoneandhisrash,arthritisandfeverresolve

withinweeks. Atafollowupclinicvisithisironstudiesandhemogram arerepeated. Did

thepatientsufferfromironoverload?Washemochromatosis genetestingindicated?


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Anemiaof

inflammation

IL6and

hepcidin

Hypoferremia

Impairedironabsorption

Impairediron

release


20/44

Hepcidinin

anemia

of

inflammation

TomasGanz,Blood2003;102:873


21/44

IDAvs.

Inflammation

Ferritin

IDA Inflammation

Serum Iron

TIBC

Both

?

?


22/44

A50yearoldAfricanAmericanfemalewasbroughttotheemergencydepartmentbyher

daughterbecauseoferraticbehavior,personalitychanges,shortnessofbreathandataxia. The

patientwasdismissedbyheremployerduetoerraticbehavior.Hermedicalhistorywas

remarkablefor

ahistory

of

hypothyroidism

diagnosed

many

years

ago,

but

otherwise

was

benign.

Physicalexaminationrevealedawellnourishedmiddleagedfemaleinnoacutedistress.The

patientwasirritableandwasvagueinansweringquestionsthroughouttheinterview. Her

neurologicexamwasnotedforintact cranialnervesIIXII.Hermusclestrengthwas5/5bilaterally

whentestedinthesupineposition.Shehadintactsensationtolighttouchandpinprick,though

markedlydiminishedproprioception. Shewasmarkedlyataxicandneededtosteadyherselfon

thewallforaddedsupport.

50YO

FEMALE

NORMALRANGE

WBCCOUNT 3120 4500 11000

RBCCOUNT 1.92 4.50

5.90

HEMOGLOBIN 7.8 13.9 16.3

PACKEDCELLVOLUME 22.7 41.0 53.0

MEANCORPUSCULAR

VOLUME

118.2 80.0 100.0

MCHEMOGLOBIN 40.6 26.0 34.0

MCHgb

CONCENTRATION 34.4 31.0

37.0

RBCDISTRIBUTIONWIDTH 20.0 11.5 14.5

PLATELETCOUNT 123 150 350

NUCLEATEDRBCNUMBER 20 0 12

RETICULOCYTE% 0.9 0.51.8

ABS

RETIC

COUNT 13.4 24.1

87.7


23/44

Milestonesin

Vitamin

Theory

and

Therapeutics

1907scurvyinguineapigs VitaminC1932

1912vitamin(e)

theory

postulated

1913growthfailureinrats VitaminA1937

1918ricketsinpuppies

1922therapeuticinsulinpreparationsderived

frombovinepancreas

1926

liver

feeding

to

pernicious

anemia

patients 1935liverasanironsource


24/44

Pernicious

Anemia

Megaloblastic anemia

Gastric atrophy

Neurologic degeneration


25/44

PerniciousAnemia

laboratory

exam

bloodsmearandbonemarrow

hemolysis (hyperbilirubinemia,LDH)

thrombocytopenia,leukopenia

elevatedgastric

pH


26/44

Studyof

Pernicious

Anemia

=B12 Identification

Responsestodailyliverfeedingsupportedthetheory

thatadeficiency

was

the

cause

of

PA.

Livercontainedanextrinsicfactorthatcouldnotbe

absorbedby

PA

patients

due

to

loss

of

an

intrinsic

factorintheirgastricsecretions

Identity

of

the

extrinsic

factor

crystallized

from

liver,

namedvitaminB12 in1948


27/44

VitaminB12

Cobalamin

CoenzymeB12


28/44

VitaminB12

synthesizedonlybymicroorganisms

dietarysources

include

liver,

glandular

tissue,

muscle,eggs,dairyproducts,seafood

bodystoresare25mg,withtheliverasthe

majorstorehouse

dailyneedsare25ug,0.1%ofthestores

B12excretedinbile,extensivereabsorptionvia

theenterohepatic

circulation


29/44

Absorption of B12 (Cbl) from food


30/44

CausesofB12 Deficiency

Common

Malabsorption dueto:

Salivaryglanddysfunction

Lossofgastricfunctionresultingin

intrinsicfactor

deficiency

and/or

loss

ofgastricacidsecretion

Autoimmunebasis

Atrophicgastritis

due

to

H.

pylori

Gastrectomy

Ageing

H2blockers

Pancreaticdisease

Terminalileumdisease

sprue,

inflammatory

bowel

disease


31/44

CausesofB12 Deficiency

raretonever Acquireddeficiencystates

Inadequateingestion

Vegans

Breastfedinfantsofvegans

BreastfedinfantsofB12

deficientmothers

Congenitaldeficiencystates

TranscobalaminIIdeficiency

ImerslundGrasbeck

syndrome

mutationofreceptorforIFB12


32/44

TCITCII

B12 B12

TCI

B12 TCII

B12

TCI

B12TCII

TCII

B12

TCII

B12

TCI

B12-analogue

B12-analogue

TCII

Measurement

of

serum

B12is

not

fool

proof

B12


33/44

TCITCI

B12 B12

TCI

TCI

B12

TCI

B12TCII

TCI

B12

TCII

B12

TCI

B12-analogue

TCII

SerumB12 falselynormal

intestinalbacterial

overgrowth,

liver

disease,

myeloid

disorde

B12-

analogue

B12-analogue

B12


34/44

TCITCII

B12 B12

TCI

B12

TCII

TCII

B12

TCII

B12

TCII

B12

B12

SerumB12

falselylowpregnancy,

lymphoid

disorders,

ageing,

racial

differences


35/44

100

1000

10000

100000

0 100 200 300 400

MMA90-318

B12 pg/ml

Sensitivity

of

methylmalonic acid

in

B12 deficiency


36/44

VitaminB12 mediates

2reactions

Methyltransfer

methylation ofhomocysteine togeneratemethionine

B12isacofactor,methyltetrahydrofolate suppliesthemethylgroup(substrate)

B12acceleratesthisreactionseveralthousandfold

Tetrahydrofolate requiredfor

thymine

and

purine

generation=crucialforrapidlydividingtissues

Hydrogentransfer

generationof

succinyl coA from

methylmalonyl coA

crucialformyelinmaintenance


37/44

ConvergenceofB12

andFolicacid

Cystathioninebeta synthase

Cysteine


38/44

Causesof

hyperhomocysteinemia

Cystathionine synthase

B12deficiency

Folate deficiency

Renaldisease

MTHFRgene

polymorphisms

Normalindividuals

>200mcmol/L

20241

1550

1720

815

412


39/44

FolicAcidOvercomesMethylfolate Trap

Cystathioninebeta synthase

Cysteine

Folic Acid

Dietary

Folates


40/44

Manyunanswered

questions

VariationinclinicalpresentationofB12deficiency

Anemiaand

neurologic

features

30%

Anemiawithoutneurologicsymptoms 50%

Predominantlyneurologicpresentationswithvery

mildanemiaornoanemia 20%

Basisofthisvariationinclinicalphenotype?

Dietary

methionine and

folate stores,

polymorphismsinenzymaticactivityhypothetical

claims

YouareinvolvedintwootherpatientswithB12deficiency.One,an8monthold


41/44

50YOFEMALE 8MONTHOLD 60YOMALE NORMALRANGE

WBCCOUNT 3120 2990 2620 4500 11000

RBCCOUNT 1.92 2.20 1.55 4.50 5.90

HEMOGLOBIN 7.8 6.0 5.6 13.9 16.3

PACKEDCELL

VOLUME

22.7 18.3 16.4 41.0

53.0

MEANCORPUSCULAR

VOLUME

118.2 83.0 106 80.0 100.0

MCHEMOGLOBIN 40.6 27.3 36.1 26.0 34.0

MCHgb

CONCENTRATION

34.4 32.0 34.1 31.0 37.0

RBCDISTRIBUTION

WIDTH20.0 28.3 20.0 11.5

14.5

PLATELETCOUNT 123 91 140 150 350

NUCLEATEDRBC

NUMBER

20 50 20 0 12

RETICULOCYTE% 0.9 0.7 0.7 0.51.8

ABSRETICCOUNT 13.4 16.9 10.4 24.1 87.7

SerumB12 72


42/44

Therapy

for

B12

malabsorption Identifyandcorrectmalabsorption

Celiacdisease,lymphoma,Crohns,H.pylori

Supplement

Oral ?Passivetransfertheory,requiresmonitorin

Parenteral foolproof

(doctors

and

patients),

inexpensive,effective,nevertoxic,preferredby

patients

Durationof

therapy

Dependentonclinicalscenario longtermmosto

thetime


43/44

Diseaseschange

Atrophicgastritis

Infectious

diseases

evolve H.pylori

Treatmentsevolve

H2blockers

Nutritionalstatus

evolves

Foodfortification,Nutritionallifestyle,Obesity,Wheatgenetically

modified

Populationschange

Agingof

the

world

RacialmakeupoftheUSpopulation genomicandculturalfactors

Diagnostictestingevolves

Forces

at

play

in

nutritional

anemias


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Moliterno_B12andIron 07.11.12

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