Anemia: NutritionalDeficiencies

AlisonR.MoliternoMD JHUSOM July2012

A44yo socialworkerisreferredtoyouforanemia.Sheismarried,withteenagechildren, andhasnohistoryofbleeding,andnomenorrhagia.Shehasbeentoldaslongasshecan rememberthatshehaslowiron,becameanemicwithpregnanciesbutdidnotrequire transfusions.Shehastakenoralironinfrequently,lastmorethanayearago. LatelyshehasseenasleepspecialistandbeenfittedforCPAP,acardiologistfordyspnea andisplanningtoseeapulmonologistbecauseofdyspnea andexerciseintolerance.ROS wasnotedforanonrestricteddiet,anddramaticpagophagia.ExamisnotedforaBMIof 33,palemucousmembranes,asystolicejectionmurmur,spoonnails.ROSisremarkable fordramaticpagophagia andpica.

Bloodcountsandironstudiesonour42yo femalearelistedbelow. Howwouldyouproceedwithevaluatingandmanagingthispatient: 1) Nofurtherevaluation,treatorally 2) Treatorallyand/orintravenously 3) RefertoGIforEGD,colonoscopy 4) RefertoGIforEGD,smallbowelbiopsies,celiacserologies 5) Treatintravenously,recommendawheatfreediet

low WBC Hemoglobin MCV Platelets Iron Transferrin TIBC %sat Ferrritin 4500 12 80 150 50 200 250 20 13

High 11000 15 100 350 170 400 450 55 150

2012 4000 8.8 67 422 18 426 533 3 10

2008 5900 10.7 72 281 24 381 476 5 4

IronDistributioninMan
Transferrin 4mg

Hemoglobin (2500mg)

Myoglobin, Enzymes(500mg) Ferritin,Hemosiderin (1000mg)

IronAbsorption
Rice Spinach Foodsources:10 25mg/day Black beans Corn Absorbedinthebrushborderof Lettuce theduodenum Wheat Mostdietaryironisnonheme Soy beans Ferritin form,<5%bioavailability Veal liver <10%dietaryironisheme form, Fish muscle >25%bioavailability Hemoglobin Veal muscle
0 5 10

Non-heme iron

Heme iron
15 20 25

Iron Absorption (% of dose)

Theironcycle

IronStorage
Ferritin
multisubunitprotein primarilyintracellular someinplasma

Hemosiderin
insolubleformof ferritin visiblemicrosopically

PathophysiologyofIronDeficiency
Depletionofironstores Ironbecomesalimitingfactorinhemebiosynthesis Hemedeficiencylimitshemoglobinassembly Hemoglobindeficiencylimitsredcellproduction Redcellsaresmall(microcytic,lowMCV) Redcellsaredeficientinhemoglobin(hypochromic, lowMCH)

IronLosses
Ironiscloselyconservedinhumans <0.05%ofironislostperdaynormally Verysmallamountsinurine,bileandsweat Cellsshedfromskin,intestinalandurinarytracts Menstrualbloodloss Pregnancy,deliveryandlactation HumanshaveNO physiologicmeanstoexcreteexcessiron

RoutestoIronDeficiency
OccultorovertGIlosses,traumaticorsurgicallosses

Failuretomeetincreasedrequirements Rapidgrowthininfancyandadolescence Menstruation,pregnancy,delivery Inadequatedietarysource Dietlowinheme iron(vegans,impoverished) Malabsorption Gastrointestinaldiseaseorsurgery(gastricfailure,atrophic gastritis,gastricbypass,H.pylori) Duodenal/smallbowelmalabsorptive disease Celiacdisease,lymphoma Chronichemolysis PNH,marchhemoglobinuria

SymptomsandsignsofIDA
Anemiasymptoms fatigue,feelingcold,dyspnea on exertion,palpitations,tinnitus Pica cravingofnonfoodsubstances e.g.,ice,dirt,clay,laundrystarch,newspaper Glossitis smoothtongue Angularstomatitis crackingofcornersofmouth Koilonychia thin,brittle,spoonshapedfingernails Bluesclerae Shorttermmemoryloss Restlesslegs

SequentialChangesinIDA
NORMAL DEPLETED IRON STORES IRON DEFICIENCY IRON DEFICIENCY ANEMIA

FERRITIN IRON SATURATION MCV & Hb & Hct

PeripheralbloodsmearinIDA

TherapyofIronDeficiency
Patienteducation
RBCtransfusion Oralironsalts(FeSO4) Formalabsorbers(gastricbypass,celiacdisease,Barretts, gastrectomy)orchronicbleeders(menorrhagia,angiodysplasia, Chrohns) Injectable ironpreparations(irondextran,ironsucrose) DOMinfusioncenter Ascorbicacidincreasesoralironabsorption Phytates (cerealgrains),tannins(tea)andantacidtherapyinhibit oralironabsorption

ResponsetoIronTherapy
Peakreticulocyte count IncreasedHbandHct NormalHbandHct Normalironstores 7 10d. 14 21d. 2months 4 5months

ASHSAP
A30yo femalepresentswithirondeficiencyrefractorytoiron supplementation.Shehasbeenamenorrheic forthepastyear, andruns30milesaweek.Shedeniesothersourcesofblood loss,anddeniesGIsymptomsofanysort.Sheisavegetarian. HerBMIis18,ferritin isundetectable,andhemoglobinis11 gm/dl.Contributorstohercurrentclinicalpictureincludeall ofthefollowingexcept: A.femalesex B.vegetariandiet C.undiagnosedceliacdisease D.longdistancerunning E Alloftheabove

A37yearoldpreviouslyhealthyAfricanAmericanmaleishospitalizedforanillness characterizedbyhighfevers,incapacitatingpolyarthritis andrash.Hehadlaboratories consistentwithmarkedinflammationincludinganerythrocytesedimentationrateofgreater than100,andaCreactiveproteinofgreaterthan40.Inadditiontohishemogram,theintern sendsironstudiesandbasedonthoseresults,hemochromatosis genetesting: Patient WBCCOUNT RBCCOUNT HEMOGLOBIN PACKEDCELLVOLUME MCV MCHEMOGLOBIN MCHGBCONCENTRATION RBCDISTRIBUTIONWIDTH PLATELETCOUNT ABSRETICCOUNT Serumiron Transferrin Totalironbindingcapacity %Saturation Ferritin HFEgenotypeC282Y 36650 3.00 9.1 27.1 90.3 30.3 33.6 12.9 443 38.3 84 136 170 49 19,322 Wildtype NormalRange 4500 11000 4.50 5.90 13.9 16.3 41.0 53.0 80.0 100.0 26.0 34.0 31.0 37.0 11.5 14.5 150 350 24.1 87.7 65170mcg/dL 200400mg/dL 250450mg/dL 2055% 10300ng/mL

Thepatientisgivenacourseofprednisoneandhisrash,arthritisandfeverresolve withinweeks.Atafollowupclinicvisithisironstudiesandhemogram arerepeated. Did thepatientsufferfromironoverload?Washemochromatosis genetestingindicated?

WBCCOUNT RBCCOUNT HEMOGLOBIN PACKEDCELLVOLUME MEANCORPUSCULARVOLUME MCHEMOGLOBIN MCHGBCONCENTRATION RBCDISTRIBUTIONWIDTH PLATELETCOUNT SERUMIRON TRANSFERRIN TOTALIRONBINDINGCAPACITY %SATURATION FERRITIN

Patientin Hospital 36650 3.00 9.1 27.1 90.3 30.3 33.6 12.9 443 84 136 170 49 19,322

Patientafter3monthsof treatment 9800 4.45 13.8 42.5 95 33.0 33.7 12.0 397

NORMALRANGE 4500 11000 4.50 5.90 13.9 16.3 41.0 53.0 80.0 100.0 26.0 34.0 31.0 37.0 11.5 14.5 150 350 65 170mcg/dL 200 400mg/dL 250 450mg/dL 20 55% 10 300ng/mL

213

Anemiaofinflammation

IL6andhepcidin Hypoferremia Impairedironabsorption Impairedironrelease

Hepcidininanemiaofinflammation

TomasGanz,Blood 2003;102:873

IDAvs.Inflammation
IDA Ferritin Serum Iron TIBC Inflammation Both

? ?

A50yearoldAfricanAmericanfemalewasbroughttotheemergencydepartmentbyher daughterbecauseoferraticbehavior,personalitychanges,shortnessofbreathandataxia.The patientwasdismissedbyheremployerduetoerraticbehavior.Hermedicalhistorywas remarkableforahistoryofhypothyroidismdiagnosedmanyyearsago,butotherwisewasbenign. Physicalexaminationrevealedawellnourishedmiddleagedfemaleinnoacutedistress.The patientwasirritableandwasvagueinansweringquestionsthroughouttheinterview.Her neurologicexamwasnotedforintact cranialnervesIIXII.Hermusclestrengthwas5/5bilaterally whentestedinthesupineposition.Shehadintactsensationtolighttouchandpinprick,though markedlydiminishedproprioception. Shewasmarkedlyataxicandneededtosteadyherselfon thewallforaddedsupport. 50YO FEMALE 3120 1.92 7.8 22.7 118.2 40.6 34.4 20.0 123 20 0.9 13.4 NORMALRANGE 4500 11000 4.50 5.90 13.9 16.3 41.0 53.0 80.0 100.0 26.0 34.0 31.0 37.0 11.5 14.5 150 350 0 12 0.51.8 24.1 87.7

WBCCOUNT RBCCOUNT HEMOGLOBIN PACKEDCELLVOLUME MEANCORPUSCULAR VOLUME MCHEMOGLOBIN MCHgbCONCENTRATION RBCDISTRIBUTIONWIDTH PLATELETCOUNT NUCLEATEDRBCNUMBER RETICULOCYTE% ABSRETICCOUNT

MilestonesinVitaminTheoryandTherapeutics
1907scurvyinguineapigs VitaminC1932 1912vitamin(e)theorypostulated 1913growthfailureinrats VitaminA1937 1918ricketsinpuppies 1922therapeuticinsulinpreparationsderived

frombovinepancreas 1926liverfeedingtoperniciousanemiapatients 1935liverasanironsource

PerniciousAnemia

Megaloblastic anemia

Gastric atrophy Neurologic degeneration

PerniciousAnemia laboratoryexam
bloodsmearandbonemarrow

hemolysis(hyperbilirubinemia,LDH) thrombocytopenia,leukopenia elevatedgastricpH

StudyofPerniciousAnemia=B12 Identification
Responsestodailyliverfeedingsupportedthetheory thatadeficiencywasthecauseofPA. Livercontainedanextrinsicfactorthatcouldnotbe absorbedbyPApatientsduetolossofanintrinsic factorintheirgastricsecretions Identityoftheextrinsicfactorcrystallizedfromliver, namedvitaminB12in1948

VitaminB12 Cobalamin CoenzymeB12

VitaminB12
synthesizedonlybymicroorganisms dietarysourcesincludeliver,glandulartissue, muscle,eggs,dairyproducts,seafood bodystoresare25mg,withtheliverasthe majorstorehouse dailyneedsare25ug,0.1%ofthestores B12excretedinbile,extensivereabsorptionvia theenterohepaticcirculation

Absorption of B12 (Cbl) from food

CausesofB12 Deficiency

Common
Malabsorption dueto: Salivaryglanddysfunction Lossofgastricfunctionresultingin intrinsicfactordeficiencyand/orloss ofgastricacidsecretion Autoimmunebasis AtrophicgastritisduetoH.pylori Gastrectomy Ageing H2blockers Pancreaticdisease Terminalileumdisease sprue,inflammatoryboweldisease

CausesofB12 Deficiency raretonever

Acquireddeficiencystates Inadequateingestion Vegans Breastfedinfantsofvegans BreastfedinfantsofB12 deficientmothers Congenitaldeficiencystates TranscobalaminIIdeficiency ImerslundGrasbecksyndrome mutationofreceptorforIFB12

MeasurementofserumB12isnotfoolproof
B12 B12
TCI

B12
TCII

TCII

B12 B12
TCI
B12analogue

B12
TCII

B12
TCI

TCII

B12
TCII
B12analogue

TCI

TCII

SerumB12 falselynormal
intestinalbacterialovergrowth,liverdisease,myeloiddisorde B12 B12
TCI
B12analogue

B12
TCI

TCII

B12 B12
TCI
B12analogue

B12
TCII

TCI

TCI

B12
TCI

B12analogue

TCI

TCII

SerumB12 falselylow
pregnancy,lymphoiddisorders,ageing,racialdifferences B12 B12
TCI

B12
TCII

TCII

B12
TCI

B12
TCII

B12
TCII

B12
TCII

Sensitivityofmethylmalonic acidinB12 deficiency

100000

10000

MMA 90-318

1000

100 0 100 200 300 400

B12 pg/ml

VitaminB12 mediates2reactions
Methyltransfer
methylation ofhomocysteine togeneratemethionine

B12isacofactor,methyltetrahydrofolate suppliesthe methylgroup(substrate) B12acceleratesthisreactionseveralthousandfold Tetrahydrofolate requiredforthymineandpurine generation=crucialforrapidlydividingtissues Hydrogentransfer generationofsuccinyl coA frommethylmalonyl coA crucialformyelinmaintenance

ConvergenceofB12 andFolicacid

Cystathionine beta synthase

Cysteine

Causesofhyperhomocysteinemia
Cystathionine synthase B12deficiency Folate deficiency Renaldisease MTHFRgenepolymorphisms Normalindividuals >200mcmol/L 20241 1550 1720 815 412

FolicAcidOvercomesMethylfolate Trap
Folic Acid

Cystathionine beta synthase

Dietary Folates

Cysteine

Manyunansweredquestions
VariationinclinicalpresentationofB12deficiency Anemiaandneurologicfeatures 30% Anemiawithoutneurologicsymptoms 50% Predominantlyneurologicpresentationswithvery mildanemiaornoanemia 20% Basisofthisvariationinclinicalphenotype? Dietarymethionine andfolate stores, polymorphismsinenzymaticactivityhypothetical claims

YouareinvolvedintwootherpatientswithB12deficiency.One,an8monthold patient,presentedwithseveredevelopmentaldelay.Thethird,a60yearoldmale, presentedwithanemiaandnoneurologicsymptoms.Theirhemograms and laboratoriesarepresentedbelow. Whatfactorsmayaccountforthevariabilityintheir clinicalpresentations?

WBCCOUNT RBCCOUNT HEMOGLOBIN PACKEDCELLVOLUME MEANCORPUSCULAR VOLUME MCHEMOGLOBIN MCHgb CONCENTRATION RBCDISTRIBUTION WIDTH PLATELETCOUNT NUCLEATEDRBC NUMBER RETICULOCYTE% ABSRETICCOUNT SerumB12 Homocysteine Methylmalonicacid Ferritin 50YOFEMALE 3120 1.92 7.8 22.7 118.2 40.6 34.4 20.0 123 20 0.9 13.4 72 241 65,700 454 8MONTHOLD 2990 2.20 6.0 18.3 83.0 27.3 32.0 28.3 91 50 0.7 16.9 <45 Notmeasured Notmeasured 257 60YOMALE 2620 1.55 5.6 16.4 106 36.1 34.1 20.0 140 20 0.7 10.4 65 72.6 2,463 270 NORMALRANGE 4500 11000 4.50 5.90 13.9 16.3 41.0 53.0 80.0 100.0 26.0 34.0 31.0 37.0 11.5 14.5 150 350 0 12 0.51.8 24.1 87.7 200900pg/ml 4.012.0mcmol/L 90279nMol/L 10300ng/ml

TherapyforB12malabsorption
Identifyandcorrectmalabsorption Celiacdisease,lymphoma,Crohns,H.pylori Supplement Oral ?Passivetransfertheory,requiresmonitoring Parenteral foolproof(doctorsandpatients), inexpensive,effective,nevertoxic,preferredby patients Durationoftherapy Dependentonclinicalscenario longtermmostof thetime

Forcesatplayinnutritionalanemias
Diseaseschange Atrophicgastritis Infectiousdiseasesevolve H.pylori Treatmentsevolve H2blockers Nutritionalstatusevolves Foodfortification,Nutritionallifestyle,Obesity,Wheatgenetically modified Populationschange Agingoftheworld RacialmakeupoftheUSpopulation genomicandculturalfactors Diagnostictestingevolves