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7/30/2019 Moliterno_B12andIron 07.11.12
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Anemia:
NutritionalDeficiencies
AlisonR.MoliternoMD
JHUSOM
July2012
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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.
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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
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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
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Pathophysiologyof
Iron
Deficiency
Depletionof
iron
stores
Ironbecomesalimitingfactorinhemebiosynthesis
Hemedeficiencylimitshemoglobinassembly
Hemoglobindeficiencylimitsredcellproduction
Redcellsaresmall(microcytic,lowMCV)
Redcells
are
deficient
in
hemoglobin
(hypochromic,
lowMCH)
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Iron
Losses Ironiscloselyconservedinhumans
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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
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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
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SequentialChanges
in
IDA
NORMALDEPLETED
IRONSTORES
IRONDEFICIENCY
IRONDEFICIENCY
ANEMIA
FERRITIN
IRON SATURATION
MCV & Hb & Hct
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Peripheralblood
smear
in
IDA
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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
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Responseto
Iron
Therapy
Peakreticulocyte count 7
10
d.
IncreasedHbandHct 14 21d.
NormalHbandHct 2months
Normalironstores 4 5months
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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
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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
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Hepcidinin
anemia
of
inflammation
TomasGanz,Blood2003;102:873
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IDAvs.
Inflammation
Ferritin
IDA Inflammation
Serum Iron
TIBC
Both
?
?
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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
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Milestonesin
Vitamin
Theory
and
Therapeutics
1907scurvyinguineapigs VitaminC1932
1912vitamin(e)
theory
postulated
1913growthfailureinrats VitaminA1937
1918ricketsinpuppies
1922therapeuticinsulinpreparationsderived
frombovinepancreas
1926
liver
feeding
to
pernicious
anemia
patients 1935liverasanironsource
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Pernicious
Anemia
Megaloblastic anemia
Gastric atrophy
Neurologic degeneration
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PerniciousAnemia
laboratory
exam
bloodsmearandbonemarrow
hemolysis (hyperbilirubinemia,LDH)
thrombocytopenia,leukopenia
elevatedgastric
pH
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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
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VitaminB12
Cobalamin
CoenzymeB12
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VitaminB12
synthesizedonlybymicroorganisms
dietarysources
include
liver,
glandular
tissue,
muscle,eggs,dairyproducts,seafood
bodystoresare25mg,withtheliverasthe
majorstorehouse
dailyneedsare25ug,0.1%ofthestores
B12excretedinbile,extensivereabsorptionvia
theenterohepatic
circulation
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Absorption of B12 (Cbl) from food
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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
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CausesofB12 Deficiency
raretonever Acquireddeficiencystates
Inadequateingestion
Vegans
Breastfedinfantsofvegans
BreastfedinfantsofB12
deficientmothers
Congenitaldeficiencystates
TranscobalaminIIdeficiency
ImerslundGrasbeck
syndrome
mutationofreceptorforIFB12
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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
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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
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TCITCII
B12 B12
TCI
B12
TCII
TCII
B12
TCII
B12
TCII
B12
B12
SerumB12
falselylowpregnancy,
lymphoid
disorders,
ageing,
racial
differences
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100
1000
10000
100000
0 100 200 300 400
MMA90-318
B12 pg/ml
Sensitivity
of
methylmalonic acid
in
B12 deficiency
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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
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ConvergenceofB12
andFolicacid
Cystathioninebeta synthase
Cysteine
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Causesof
hyperhomocysteinemia
Cystathionine synthase
B12deficiency
Folate deficiency
Renaldisease
MTHFRgene
polymorphisms
Normalindividuals
>200mcmol/L
20241
1550
1720
815
412
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FolicAcidOvercomesMethylfolate Trap
Cystathioninebeta synthase
Cysteine
Folic Acid
Dietary
Folates
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Manyunanswered
questions
VariationinclinicalpresentationofB12deficiency
Anemiaand
neurologic
features
30%
Anemiawithoutneurologicsymptoms 50%
Predominantlyneurologicpresentationswithvery
mildanemiaornoanemia 20%
Basisofthisvariationinclinicalphenotype?
Dietary
methionine and
folate stores,
polymorphismsinenzymaticactivityhypothetical
claims
YouareinvolvedintwootherpatientswithB12deficiency.One,an8monthold
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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
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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
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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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