MEGALOBLASTIC ANEMIA - Anemia Thursday, February 12, 2004 ... PERNICIOUS ANEMIA ... 032406heme-Diugui

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Megaloblastic Anemia Thursday, February 12, 2004 9:00 am1MEGALOBLASTIC ANEMIAMARROW FAILURE Metabolically highly active, 2 to rapid cell turnover White cell life span 12-24 hours Platelet life span 7 days Red blood cell lifespan 120 days Any slowing of DNA production marrow failureMegaloblastic Anemia Thursday, February 12, 2004 9:00 am2MEGALOBLASTIC ANEMIA Hemoglobin production probably normal Defect in nuclear replication & division Affects all marrow elementsMEGALOBLASTIC ANEMIA Trademark cell: Oval macrocyte, (MCV > 100 fl) Hypersegmented neutrophils - 98% Pancytopenia, esp if anemia severe Reticulocytopenia LDH elevated (90%) Serum Fe normal or elevated Serum B12 or folate low Marrow classic megaloblastic changesMegaloblastic Anemia Thursday, February 12, 2004 9:00 am3Megaloblastic Anemia Thursday, February 12, 2004 9:00 am4Megaloblastic Anemia Thursday, February 12, 2004 9:00 am5FOLIC ACIDOHNNNNNHCONHCOCH2CH2CHCOOH(GLU)nPteridine PABA Glutamic AcidsH2N1234 5678910FOLIC ACIDOHNNHNNNHCONHCOCH2CH2CHCOOH(GLU)nH2N1234 5678910NHNHMegaloblastic Anemia Thursday, February 12, 2004 9:00 am6FOLIC ACIDOne Carbon Fragment FormsNHNHCH2N5,10 methylene THFThymidylatebiosynthesisNHNH2CH3N5 methyl THFTransportN NHNHNHCHHCON5,10-methenyl THFN10- formyl THFH2OPurine biosynthesisFOLATE ABSORPTIONMegaloblastic Anemia Thursday, February 12, 2004 9:00 am7FOLATE DEFICIENCYCauses Folate-poor diet Alcoholism Severe poverty Increased folate requirement Pregnancy Severe hemolytic anemia Severe Psoriasis Drug therapy Malabsorption Tropical sprueFOLATE DEFICIENCYManifestations Megaloblastic anemia Glossitis/stomatitis GI malabsorption 2 to impaired GI epithelium (rare)Megaloblastic Anemia Thursday, February 12, 2004 9:00 am8COBALAMIN (Vitamin B12)Functions Folate metabolism - Required for demethylation of methyl-THF Methylation of myelin Conversion of methylmalonyl CoAto succinyl CoACOBALAMINStructureCoNucleotide-groupsCN - Cyano; inactiveOH - Hydroxyl; inactiveMethyl - Folate metabolismAdenosyl - Mutase activityMegaloblastic Anemia Thursday, February 12, 2004 9:00 am9COBALAMIN REACTIONSNHNHCH3THFHomocysteine MethionineMethylCobalaminMethylmalonyl CoASuccinyl CoAAdenosylCobalaminGI ABSORPTION OF COBALAMINIFRCblR-CblR-CblRIF-CblIF-Cbl IF-Cbl TCIIIF CblTCII-Cbl TCII-CblCbl TCIIStomachDuodenumTerminal IleumTCI-CblMegaloblastic Anemia Thursday, February 12, 2004 9:00 am10COBALAMIN DEFICIENCYCauses Gastric Failure Pernicious Anemia Total gastrectomy Ileal Failure Regional enteritis (Crohn's disease) Ileal resection Tropical sprue Competing organisms Bacterial overgrowth (Blind loop) Diphyllobothrium latumPERNICIOUS ANEMIA Autoimmune destruction of parietal cells Antibodies vs. parietal cells, intrinsic factor Achlorhydria is universal Increased incidence of gastric cancer Increased incidence American blacks, northern Europeans Often associated with other immune diseases(eg Hashimoto's thyroiditis)Megaloblastic Anemia Thursday, February 12, 2004 9:00 am11COBALAMIN DEFICIENCYPeripheral Folate DepletionN5-methyl-THFN5-methyl-THF THF Conjugated folatesTHFCblHomocysteine MethionineCOBALAMIN DEFICIENCYPeripheral Manifestations Megaloblastic anemia - Indistinguishablefrom folate deficiency & due to intracellularfolate deficiency Stomatitis/glossitis GI Mucosa alterations Can correct all of the above with high dose folate;DON'T DO THIS!!!!!DON'T DO THIS!!!!!Megaloblastic Anemia Thursday, February 12, 2004 9:00 am12COBALAMIN DEFICIENCYManifestations-Central Both brain and spinal cord Brain: Dementia Psychological disturbances Spinal cord: Demyelinating disease Loss of posterior & lateral columns-hence name "Combined system disease" Neurologic disease stabilized with treatment,but usually not reversed Treatment with folate does nothing for neurologic diseaseSUBACUTE COMBINED DEGENERATIONMegaloblastic Anemia Thursday, February 12, 2004 9:00 am13COBALAMIN DEFICIENCYUsual Sequence of Events Serum homocysteine & methylmalonicacid rise Serum cobalamin falls MCV rises; neutrophil hypersegmentation MCV rises above normal Anemia SymptomsFOLATE/COBALAMINPropertiesP ro p e rty F o lic A c id C o b a la m inF o o d S o u rce A lm o s t a ll foo d s A n im a l p ro te in o n lyW ate r so lub le Y e s Y e sS ite o f ab so rp tion D u o d en um /Je ju n um Ile umM e ch o f a b so rp tion D e co n ju ga tion o fp o ly-G luU p ta ke o f IF -C b lco m p le xM e ta bo lic F u n c tion O n e C a rb o ntra n s fe rsU n kn o w nB o d y s to re s 4 -5 m o n th s 2 -1 2 ye a rsD ie ta ry d e fic ie n cy C o m m o n R a reD e fic ien cy s ta te sM e ga lo b la s tica n em iaY e s Y e sN e u ro lo g icd ise a seN o Y e sMegaloblastic Anemia Thursday, February 12, 2004 9:00 am14MEGALOBLASTIC ANEMIADiagnosis /Therapy Draw levels at first suspicion of problem,BEFORE ANY THERAPY Once levels drawn, begin treatment with both B12and folate Once levels are back, can stop the normal vitamin Transfusions to be avoided unless hemodynamic compromise is present, or patient having anginaMegaloblastic Anemia Thursday, February 12, 2004 9:00 am15MEGALOBLASTIC ANEMIAResponse to Therapy0 5 10 15 20 25 3035 40 45 50 55 6001020304050Retic (%), Hematocrit (%)DaysRetic (%) Hematocrit (%)SCHILLING TESTCause of Cobalamin Deficiency Part I Without IFPart II With IF Part III After Ab Pernicious Anemia Low Normal Not neededBacterial Overgrowth Low Low Normal Ileal dysfunction Low Low Low Megaloblastic Anemia Thursday, February 12, 2004 9:00 am16MEGALOBLASTIC ANEMIASSummary Deficiency in folate or B12 Macrocytic anemia; other cytopenias Slowly developing anemia, usually wellcompensated Response to therapy rapid and dramatic Treatment essential to avoid other complications Anemia is secondary to an underlying disease process

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