FRACP Haemolysis Nutritional Def2010.ppt

Nutritional deficiencies andHaemolytic AnaemiasIron Deficiency Iron absorptionzHeme ironNon-heme ironzEnhanced by gastric acid, ascorbate (vit C), breast milkzDecreased by bovine milk proteins, egg white,phytates, bran, calcium, zinc, leadzFRACP Lectures 2010Iron Deficiency Iron DeficiencyStages in development of iron deficiencyzzz Iron depletion: low ferritin; normal Hb and indices(MCV)Iron deficiency: low ferritin and indices; Hb normalIron deficiency anaemiaRisk factors:zIron DeficiencyNeonatal period and infancyz prematurityz fetomaternal haemorrhagez placenta praeviaz rupture of umbilical blood vesselsz twin-twin transfusionz cows milkz oesophagitisz Meckel’s diverticulumIron DeficiencyPrevalence of iron deficiency in Australian children Age (months)niron depletion%iron .81.1Risk factors:zzGIT diseasez Coeliac diseasez IBDz Cow’s milk enteropathyz Worm infestationBlood lossz Menstrualz Hereditary haemorrhagic telangiectasiaz Urinaryz Pulmonary1

Iron Deficiency Clinical consequences of iron deficiencyzzzzzzAnaemiaPoor growthExercise intoleranceEpithelial changesImmunityPicaIron Deficiency Iron DeficiencyClinical consequences of iron deficiencyz Neurological dysfunctionz Lower scores on Bayley Scale of infantdevelopmentz Changes irreversible at Hb 100 g/L even withtherapyz Impaired short term memory and reduced attentionspan in older childrenLaboratory evaluation of iron deficiencyzzIron DeficiencyzzzzIron studies:z Serum iron unreliablez diurnal variationz falls in acute illnessz Transferrinz Ferritinz acute phase reactantSoluble transferrin receptors (α erythroidactivity/inverse to iron availability), sTfr/Log ferritin ?more useful 1 ACD, 2 IDA or combinedBone marrow ironRBC Zinc protophorphyrin (elevated in both IDA/ACD)FBE:z Hbz MCV and MCHz RCCz RDWz PlateletsFilm:z elongated cells z target cells Iron Deficiency TherapyzzzUnderlying factorsIron supplementsz Oral iron: 4-6 mg/kg in 2-3 divided doses per dayz Adolescents 100-300 mg/dayz Ascorbic acidz Parenteral ironIron-fortified cereals/formulae after 6/12z Irons supps for exclusively breast fed infants after 6/122

Iron Deficiency Vitamin B12 DeficiencyCauses of poor response to oral ironzzzzzzznon-complianceongoing lossesinsufficient duration of treatmenthigh gastric pHinhibitors of iron absorptionz tannins, calciumz lead; aluminiumincorrect diagnosisz thalassaemiaz anaemia of chronic diseasez sideroblastic anaemiazzCobalamin essential coenzyme forz synthesis of methionine from homocysteinez Methylcobalaminz requires 5-methyl-THF)z S-adenosyl methionine is the principle methyldonor in numerous biological reactionsz conversion of methylmalonyl CoA to succinyl CoAz Adenosylcobalamintransported in plasma bound to transcobalamin IIcontained only in animal productsVitamin B12 Deficiency Risk factors for vitamin B12 deficiencyzMaternalB12 deficiencypernicious anaemiaz vegetarian dietz terminal ileal disease/gastric bypass/gastritiszNECzCrohn’s diseasezSmall bowel resectionzBlind loops/intestinal infectionszPancreatic insufficiencyzVitamin B12 DeficiencyzzzInborn errors of vitamin B12 transport and metabolismTransportz Transcobalamin I and II deficiency- ARz Intrinsic factor deficiency-Juvenile PAz Immerslund Grasbeck syndrome – abnormalitiy incubulin gene results in failure of absorption of B12in terminal ileum /- proteinuriaUtilisationz Methylmalonic aciduriasz Methylcobalamin deficiency- distinct phenotype andbiochemical abormalitiesz Other- drugs NO (-methionine synthetase),PPI,metforminVitamin B12 Deficiency Clinical manifestations:zzMegaloblastic anaemiaz macrocytic anaemia /leucopenia/thrombocytopeniaNeurologicalz posterior columnsz pyramidal tractsz peripheral neuropathyz depressionz dementia3

Vitamin B12 DeficiencyzVitamin B12 DeficiencyVitamin B12 deficiency in infancy:z period of normal development followed bydevelopmental delay or regressionz macrocytosis, anaemia and marrow changes maybe mild or absentz /- seizuresz may be irreversiblezLaboratory evaluation:zFBE and filmzzzzzbone marrowzzzzzzVitamin B12 DeficiencyzzzzzHolotranscobalamin “active B12”Has replaced serum B12 as investigation of choice atRCHEarliest marker of B12 deficiencyMore sensitive and specific than serum B12More sensitive than Hcy or MMAFolates widely distributed in foodszzzAdult dietz 1/3 from meats and fishz 1/3 from cereals and breadz 1/3 from fruit and vegetablesAdequate quantities in breast milk but may beinadequate in cow’s milkNo folate in goat’s milkhypercellular;left shiftmegaloblasts; nuclear:cytoplasmic dysynchronygiant metamyelocytesRaised LDH, homocysteine and methylmalonic acidLow serum B12 (except TCII deficiency)Holotranscobalamin level (measures B12/TCII)Vitamin B12 DeficiencyzFolate Deficiency oval macrocytesanaemia /- other cytopeniashypersegmented neutrophils /- teardrop cellsTherapy:z Cyanocobalamin 1000 μg IMz daily for 1 weekz weekly for 3 weeksz 3 monthly for maintenancez pernicious anaemia: oral B12 1000 μg/dz infants of B12 deficient mothers - maintenance notrequired once stores replete - monitor to excludeinborn error of metabolismFolate Deficiency Folates act in numerous single carbon reactionszz synthesis of methionine from homocysteinepurine and pyrimidine metabolismCirculates in plasma as 5-methyl5 methyl THFBody folate stores limited to several weekszacute folate deficiency may develop in hospitalisedpatients4

Folate Deficiency Risk factors for folate deficiencyzzzFolate Deficiency Poor absorptionz Coeliac disease; Crohn’sz Parasitic infestationsInadequate storesz maternal deficiencyz prematurityIncreased demandz pregnancyz haemolysis (thalassaemia; sickle cell disease,congenital haemolytic anaemias)Risk factors for folate deficiencyzFolate Deficiency Clinical associations:zzzzzmegaloblastic anaemiaanaemic crisis in chronic haemolysisneurologicalz depressionz dementiaz psychosiscardiovascular diseasemalignancyz GIT; cervicalFolate Deficiency Laboratory evaluation:zzzFolate Deficiency TherapyzzzzzExclude vitamin B12 deficiencyIncrease dietary folatefolate 100 μg/kg/daypreconception folate supplements for prevention NTDFefol/FGF inadequate in pregnant women withincreased folate requirementsDrugs/toxinsz Alcoholz Anticonvulsantsz Oral contraceptivesz Methotrexatez BactrimFBE , film and BM as for B12 deficiencyz NB acute folate deficiency not macrocyticRaised LDH, homocysteine but not methylmalonic acidFolate assayz serum folatez RCFFolate DeficiencyzInborn errors of folate metabolism and transportz MTHFR deficiencyz No megaloblastic anaemiaz Neurological abnormalities and developmentaldelayz Homocysteinuria and hypomethioninaemiaz Rx with folate, MTHF, B12, pyridoxine, carnitineand betainz Hereditary folate malabsorption- ARz megaloblastic anaemia, FTT and CNSabnormalitiesz may require parenteral folate5

Classification of HaemolysisFolate DeficiencyzInborn errors of folate metabolism and transportz Thermolabile variant of MTHF reductasez 10% population homozygous deficiencyz mild homocysteinaemiaz increased arterial thrombosisz ?venous thrombosisz no clinical expression in childhood PathologiczzClassification of Haemolysis MorphologiczzzzSpherocytic-spherocytes, acanthocytesOxidative-bite and blister cellsMicroangiopathic-fragmentsOther-spurr cells, bizarre pyknocytesIntrinsicz Abnormal haemoglobinsz Red cell enzyme deficienciesz Red cell membrane disordersExtrinsicz DICz Drug-inducedz Mechanicalz Immune-mediatedClassification of Haemolysis ClinicalzzzSick versus well childCongenital versus acquiredAssociated with other abnormalitiesz Coagulopathyz Thrombocytopeniaz Neurological abnormalitiesLaboratory evaluation ofHaemolysiszScreeningz FBE and filmz Reticulocyte countz Blood group and Ab screenz Coomb’s testz Biochemistryz bilirubinz LDHz (haptoglobin)Laboratory evaluation ofHaemolysiszFurther investigationsz Flow cytometry for eosin-5 maleimide stainingz Hb instabilityz Hb electrophoresisz RBC enzyme assaysz G-6-PDz Pyruvate kinasez Others6

Immune-mediated Haemolysis Primary AIHAzz Immune-mediated Haemolysis Warm - IgGCold - IgMzSecondary AIHAzzzzzzSystemic autoimmune disease eg SLEImmunodeficiencyInfectionsDrugsMalignancy esp lymphomaImmune-mediated Haemolysis Drug-associated AIHAzzzzzzInfectionsWarmz viral esp CMV; EBVColdz mycoplasmaz EBVz syphilis (Paroxysmal Cold Haemoglobinuria)Immune-mediated Haemolysis penicillinscephalosporinsalpha stigationszDCTzBlood filmzzzzzzzzImmune-mediated Haemolysis Therapy:zzzzzzUnderlying diseaseInfection-associated haemolysis usually self-limitingMinimise transfusionImmunosuppressionz More effective for IgG vs IgMz steroids; second line agentsz IVIGSplenectomy -curative in 60-80%Monoclonal anti-CD20 antibodyWarm - IgG and complementCold – complement onlypolychromasiaspherocytosis (warm Ab)agglutination (cold Ab)Haemophagocytosis (PCH)Donath-Landsteiner Ab for PCHSerologyImmune-mediated Haemolysis Therapy:zIgM mediated cold haemolysisz warm extremitiesz plasma exchangez monoclonal Ab to CD207

Red Cell Fragmentation Syndromes Endothelial Damagezzz zExtracorporeal circulation- ECMOCardiac malformations/prostheses- VADRed Cell Fragmentation Syndromes Haemolytic-uraemic Syndromezzzz Haemolytic-uraemic syndrome/TTPHaemangioma (Kasabach-Merritt syndrome)Autoimmune disorders eg.SLETraumazRed Cell Fragmentation Syndromeszzz Red cell fragmentation/haemolysis, low plts,renaldysfunction, neurological dysfunction, feverDeficiencies of Metalloprotinase (ADAMTS 13)- enzymeresponsible for breakdown of ULVWM, excess multimerscause intravascular fibrin xlinkage, fibrin strandsmechanical red cell destruction with thrombosisAcquired causes- infection (HIV/pneumo), drugs (quinine,chemotherapy,cyclosporin, ticlopidine/clopidogrel), postBMT, pregnancyInherited- deficiency of ADAMTS 13, AR, Rx prophylacticFFPAcute Rx: plasma exchange- cryodeplete FFP (removedULVWM)Significant mortality and morbidity- 50% fatalityCongenital Form- Upshaw Schulman syndromeT-activationNecrotising enterocolitisDrugs eg. Cyclosporin, chemotherapyHaemolytic Uraemic syndromezzInvestigationsz Microangiopathic haemolytic anaemiaz Thrombocytopeniaz Leucocytosisz Coags normal or only mildly abnormalz D-Dimers normal or only mildly increasedTreatmentz supportivez Plasma infusion or exchange for atypical HUS and TTPz Avoid platelet transfusionsRed Cell Membrane AbnormalitiesTTP (Thrombotic ThrombocytopenicPurpura) SepsisDeficiency of natural anticoagulants (Purpura fulminans)MalignancyRed Cell Fragmentation SyndromesAge 6 months-5 years in 90%Preceding diarrhoeal illnessz E coli 0157:H7z Shigellaz SalmonellaFamilial/relapsing formsAnaemia, thrombocytopenia and renal impairment /- fever andCNS disturbance Disseminated intravascular coagulation Hereditary SpherocytosiszzzzzzMechanismz deficiency of spectrin, ankyrin, band 3 or protein 4.2z Affects vertical stability of red cell membranez membrane blebs 2o to poor membrane attachmentz spherocytes formed in spleenIncreased Na flux across membraneActivation of K -Cl- cotransporterNeonatal jaundice or anaemiaHaemolysis, splenomegaly and anaemia75% AD, ?25% AR/spontaneous mutations8