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MEGALOBLASTIC ANEMIA

MEGALOBLASTIC ANEMIA. MARROW FAILURE. Metabolically highly active, 2º 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 failure. MEGALOBLASTIC ANEMIA.

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MEGALOBLASTIC ANEMIA

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  1. MEGALOBLASTIC ANEMIA

  2. MARROW FAILURE • Metabolically highly active, 2º 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 failure

  3. MEGALOBLASTIC ANEMIA • Hemoglobin production probably normal • Defect in nuclear replication & division • Affects all marrow elements

  4. MEGALOBLASTIC 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 changes

  5. FOLIC ACID OH N N (GLU)n COCH2CH2CHCOOH N N H2N NH CONH Pteridine PABA Glutamic Acids

  6. FOLIC ACID OH HN N (GLU)n COCH2CH2CHCOOH N NH H2N NH CONH NH NH

  7. FOLIC ACIDOne Carbon Fragment Forms NH NH NH NH NH NH N5,10-methenyl THF CH2 CH CH3 N5,10 methylene THF N5 methyl THF Thymidylatebiosynthesis Transport H2O N10-formyl THF NH NH Purine biosynthesis HC O

  8. FOLATE ABSORPTION Folate-(Glu)n Folate-Glu Homocysteine Methionine N5-methyl THF-Glu N5-methylTHF-Glu N5-methylTHF-Glu THF-Glu Glu THF-(Glu)n 1-carbon metabolism

  9. DNA dUMP  dTMP DHFR FolicAcid 5,10-methylene THF DHF DHFR THF Methionine Methyl-Cbl 5-methyl THF Homocysteine THYMIDILATE SYNTHESIS

  10. FOLATE DEFICIENCYCauses • Folate-poor diet • Alcoholism • Severe poverty • Increased folate requirement • Pregnancy • Severe hemolytic anemia • Severe Psoriasis • Drug therapy • Malabsorption • Tropical sprue

  11. FOLATE DEFICIENCYManifestations • Megaloblastic anemia • Glossitis/stomatitis • GI malabsorption 2º to impaired GI epithelium (rare)

  12. COBALAMIN (Vitamin B12)Functions • Folate metabolism - Required for demethylation of methyl-THF • Degradation of certain fatty acids • Conversion of methylmalonyl CoAto succinyl CoA

  13. Co Nucleotide COBALAMINStructure -groupsCN - Cyano; inactiveOH - Hydroxyl; inactiveMethyl - Folate metabolismAdenosyl - Mutase activity

  14. COBALAMIN REACTIONS Methylmalonyl CoA Homocysteine Methionine MethylCobalamin AdenosylCobalamin THF NH NH CH3 Succinyl CoA

  15. Cbl R Stomach R-Cbl R-Cbl IF R TCII Cbl TCI-Cbl IF-Cbl Duodenum Cbl IF TCII-Cbl TCII-Cbl TCII IF-Cbl IF-Cbl Terminal Ileum GI ABSORPTION OF COBALAMIN

  16. COBALAMIN 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 latum

  17. PERNICIOUS 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)

  18. COBALAMIN DEFICIENCYPeripheral Folate Depletion N5-methyl-THF THF Cbl Conjugated folates N5-methyl-THF THF Homocysteine Methionine

  19. COBALAMIN 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!!!!!

  20. COBALAMIN 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 disease

  21. COBALAMIN DEFICIENCYUsual Sequence of Events • Serum homocysteine & methylmalonicacid rise • Serum cobalamin falls • MCV rises; neutrophil hypersegmentation • MCV rises above normal • Anemia • Symptoms

  22. FOLATE/COBALAMINProperties

  23. MEGALOBLASTIC ANEMIADiagnosis /Therapy • Draw levels at first suspicion of problem,BEFORE ANY THERAPY • Once levels drawn, begin treatment with both B12 and folate • Once levels are back, can stop the normal vitamin • Transfusions to be avoided unless hemodynamic compromise is present, or patient having angina

  24. MEGALOBLASTIC ANEMIAResponse to Therapy

  25. SCHILLING TEST

  26. MEGALOBLASTIC 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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