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Anemias. Body Contents of Iron. Structure of Hemoglobin. The Heme Group. Iron Absorption. Ferritin – a large protein for iron storage Hemosiderin – aggregated ferritin Iron storage sites: hepatocytes reticuloendothelial system muscle (minor)
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Iron Absorption • Ferritin – a large protein for iron storage • Hemosiderin – aggregated ferritin • Iron storage sites: hepatocytes reticuloendothelial system muscle (minor) • Iron absorption – duodenum and jejunum Ferrous (Fe2+) >>> Ferric (Fe3+) • Transferrin – iron transport
Iron Deficiency • Dietary intake of iron not adequate to meet normal requirements • Conditions producing an increased requirements of iron because of iron loss • Interference of iron absorption
Therapy for Iron Deficiency • Oral therapy Drug of Choice – ferrous sulfate administered under fasting Side effects – heart burn, nausea, upper gastric discomfort, constipation, diarrhea antidote – deferoxamine • Parenteral therapy Drug – iron dextran injection, im or iv Side effects – im: long tern discomfort, local discoloration of skin, malignant changes iv: serious anaphylactic reactions
Vitamin B12 Absorption • Release from food • Binds to intrinsic factor • Absorbed through ileum • Transport to blood • Binds transcobalamin II • Target tissue (bone marrow, liver)
Vitamin B12 Deficiency • Gastric achlorhydria and decreased intrinsic factor due to gastric atrophy and gastric surgery • Panacreatic disorders • Antibodies to intrinsic factor/vitamin B12 complex • Bacterial overgrowth and intestinal parasites prevent vitamin B12 from reaching the ileum • Damaged ileal mucosa • Congenital defects in transcobalamin II
Vitamin B12 Therapy • Oral preparations to supplement deficient diet to prevent vitamin B12 deficiency • Cyanocobalamin injection given by intramuscular and subcutaneous routes, never intravenously
Folate Absorption • Release from food • Hydrolyzed, reduced and methylated • Absorbed through duodenum and jejunum • Transport to blood – folate binding protein • Target tissues • Liver to bile reabsorption (enterohepatic cycle)
Folate Deficiency • Malnutrition • Acute and chronic alcoholism • Defect in folate enterohepatic cycle • Small intestinal diseases • Defects in folate binding protein • Vitamin B12 deficiency
Folate Therapy • Oral preparations Folic acid – drug of choice • Folic acid injection Problems with absorption • Do NOT use folic acid to treat vitamin B12 deficiency
Hematopoietic and LymphopoieticGrowth Factors • Glycoproteins produced by marrow cells and peripheral tissues • Active at low concentrations • Act on more than one committed stem cells • Synergism • Networking • Act on several points during cell proliferation and differentiation
Erythropoietin • Stimulates proliferation, maturation and hemoglobin formation by CFU-E • Stimulates the release of reticulocytes • Acts synergistically with IL-3 and GM-CSF • A glycoprotein (34 kDa) • Binds to the erythropoietin receptor and activates signal transduction processes • Produced primarily by the kidney • Deficiency in anephric patients
Erythropoietin Therapy • Recombinant erythropoietin (epoetin alpha) • Administered parenterally; half-life ~10 h • 50-100 units/kg; 3 times weekly for patients with chronic renal failure • Titrate dosage by hematocrit measurements • No significant allergic reactions • Mild adverse effects – lower dosage • Iron, vitamin B12/folate deficiency
Myeloid Growth Factors(Colony-stimulating Factors) • Glycoproteins that stimulate the proliferation of one or more myeloid cell lines • Recombinant GM-CSF, G-CSF, IL-3, M-CSF (CSF-1), SCF, thrombopoietin are available • GM-CSF and G-CSF are used for treatments of neutropenia • Administered subcutaneously or intravenously • Short half-life • Adverse effects – bone pain, malaise, flulike symptoms, more seriously vessel defects
Sickle Cell Anemia • Hemoglobin HbA (adult) – α2β2 HbF (fetal) – α2γ2 • Sickle Cell Hemoglobin – a single E6V mutation in the β chain HbA (adult) – α2β2s
Defects of Sickled Erythrocytes • More rigid and adhesive – lodged in micro-vasculatures resulting in vascular occlusion • Microinfarction – kidney, impaired its ability to concentrate urine and produce erythropoietin • Altered ability to activate complement and defective granulocyte function - infections • Splenic sequestration of sickled erythrocytes results in hemolytic anemia and splenomegaly
Treatments of Sickle Cell Disease • Gene therapy • Prevention of infections - penicillin in children • Supportive managements of vaso-occlusive crises – pain killers, chronic heparin therapy • Hydroxyurea increases HbF levels to 15-20%, reducing frequency of vaso-occlusive crises • Prophylactic use, not for treatments of crises • Cytotoxic, side effects include GI effects (nausea, vomiting, diarrhea), dermatologic effect (macular papular rash, pruritus) and risk of secondary neoplasm (leukemia) with prolonged use • Hydroxyurea + Erythropoietin therapy?