Erythropoiesis RBC cell without nucleus Hb in cytoplsm
Erythropoiesis
• RBC : cell without nucleus, Hb in cytoplsm • Hemoglobin(Hb) = heme + globin • Heme = a porphyrin ring + an iron atom
Iron Critical element of cell function Free iron : highly toxic : free radical generation Transporting and storage iron Transferrin Ferritin, hemosiderin Functioning Iron Carry O 2 : hemoglobin, myoglobin Iron containing enzyme : cytochrome system in mitochodria Iron deficiency : Decreased Hb synthesis : anemia, hypoxia Impaired cell function : electron transport, energy Iron overload : Hemochromatosis
Iron cycle Gain : absorption – diet, medicine Loss : the loss of epithelial cells from the skin, gut, and genitourinary tract and blood loss (via GI bleeding, menses, or other forms of bleeding) Male : 1 mg/d Female : 1. 4 mg/d Fe in RBC : 1 mg/m. L ----- 2, 000 mg/2 L(60 kg) RBC destruction : daily 0. 8 – 1% ---- 20 m. L/d Fe turnover : 16 – 20 mg/day (diet : 1 mg/day)
Iron content of the body Total : 3 -4 g Hb in circulating RBC and developing erythroblast : 2. 5 g Iron-containing proteins (myoglobulin, cytochrome, catalase) : 400 mg Storage iron in liver, spleen, BM (ferritin, hemosiderin) : 1 g
Iron absorption and transport Absorption site : proximal small intestine Fe 3+ (stomach)----- ferrireductase (brush border) ------ Fe 2+ --- DMT 1(memb. ) --- Gut cell(ferritin) -----ferroportin(memb) ------ plalsma Fe 3+ (by hephaestin) (transferrin) ----- BM, Liver (ferritin) hepcidin DMT-1(divalent metal transporter-1) Ferroportin : negatively controlled by hepcidin Hepcidin : principal iron regulatory hormone (LEAP-1), acute phase reactant Hephaestin : ferroxidase (homology to the ceruloplasmin) Transferrin, Tf. R Ferritin : acute phase reactant Hemosiderin :
Major exporter of iron : From mother to fetus From enterocyte to circulation From damaged RBC to circulation
Nutritional Iron 6 mg/ 1, 000 calories 5 -10% of total food iron Inorganic iron, heme iron Red meat : most efficient source of iron Iron deficiency : meat-containing diet iron : 20% absorption Vegetarian diet iron : 5 – 10% Phytates and phosphates reduce absorption
Food iron absorption Compare to ferrous sulfate : 1. 0 Iron in vegetables : 1/20 Egg iron : 1/8 Liver iron : 1/2 Heme iron : 1/2 - 2/3
Increased iron requirement Infant Children Adolescent Pregnancy : last trimesters : 5 -6 mg/day 1, 000 mg each for pregnancy, delivery, and nurshing Increased erythropoiesis :
Iron deficiency Absolute iron deficiency : absent iron store Functional iron deficiency : insufficient availability Anemia of inflammation Treatment with ESA Stage Negative iron balance : iron store decrease Iron-deficient erythropoiesis : Iron-deficiency anemia : microcytic/hypochromic
Iron deficiency anemia One of the most prevalent forms of malnutrition Globally 50% of anemia 841, 000 deaths annually Africa and part of Asia : 71% North America : 1. 4%
Absolute iron deficiency Dietary (growth/development) Women’s health Pregnancy/breast feeding Menstrual blood losses Chronic blood loss Blood donation Nonsteroidal anti-inflammatory drugs (NSAIDs) Gastrointestinal neoplasms Gastrointestinal parasites (developing countries) Decreased iron absorption Celiac disease Helicobacter pylori infection Autoimmune atrophic gastritis Functional iron deficiency ESA therapy
Iron-sequestration syndromes Anemia of chronic disease/inflammation Autoimmune diseases Infections Malignancies Chronic kidney disease Hepcidin-producing adenomas Iron refractory iron deficiency anemia (IRIDA) Copper deficiency Molecular defects in iron transport, recycling, and utilization Divalent metal transporter 1 (DMT 1) mutations Hypotransferrinemia Ferroportin disease Aceruloplasminemia Hereditary sideroblastic anemias (ALAS 2 mutations) Heme oxygenase deficiency
Clinical presentation of IDA Signs of anemia : depends on severity and chronicity of anemia Fatigue Pallor Reduced exercise capacity Pica and pagophagia Restless leg syndrome Cheilosis (구순증, 구각미란) Koilonychia (숟가락손톱)
Laboratory iron studies Serum iron(SI) / Total iron-binding capacity(TIBC) : 50 -150/300 -360 µg/d. L Serum ferritin : < 15 µg/L Bone Marrow iron stores : stainable iron, sideroblast, ringed sideroblast (MDS) Red cell protoporhyrin levels : > 100 µg/d. L Soluble transferrin receptor (s. Tf. R) : 4 -9 µg/L (N) Percent hypochromic red cell (% Hypo) Hepcidin
Differential Diagnosis Hypochromic microcytic anemia Thalassemia Anemia of chronic inflammation MDS (sideroblastic anemia)
Treatment of IDA Diet : heme iron Oral iron therapy Parenteral iron therapy Iron dextran Sodium ferric gluconate Iron sucrose Ferric chloride RBC transfusion
Amount of iron needed Ganzoni’s fomula : Amount of iron needed (mg) = BW(kg) X 2. 3 X (15 – pt’s Hb, g/d. L) 500 or 1, 000 (for stores) +
Parenteral iron therapy Unable to tolerate oral iron Absorption defect Whose need are relatively acute Epo therapy Iron dextran : severe side effect Ferric gluconate Iron sucrose Ferumoxytol Ferric chloride
Iron prep. (본원) Ferrous sulfate Iron acetyl-transferrin hydroglycerin Bolgre Soln : 2 m. L (40 mg) / 10 m. L Iron protein succinylate Feroba-You : 256 mg (80 mg) / tab (SR) Hemo-Q : 800 mg (40 mg) / 15 m. L Ferric chloride Blutal : 197 mg (40 mg) / 10 m. L Amp
Anemia of Chronic Diseases (ACD) Anemia of Chronic Inflammation Anemia of Uremia Anemia due to Endocrine Failure Anemia of Liver Disease Anemia of Protein Deprivation
진 단 Unequivocal diagnosis is often difficult Diagnosis of exclusion (infiltration by tumor, fibrosis, or infection, MDS) Dx with reticulocyte, Fe, TIBC, serum ferritin, in systemic illness R/O nutritional deficiency, hemolysis, sequestration. BM usually not helpful DDx of IDA (serum ferritin? , serum transferrin receptor? )
Pathogenesis Hepcidin : Acute phase reactant Negative regulator of iron Internalization and degradation of ferroportin TNF-alpha : RA treatmenet (anti-TNF Ab) IL-6 : tocilizumab (anti-IL-6 R) IL-1 beta Interferon gamma Acute variant of ACD : surgery, trauma, MI, sepsis
Anemia of Hypometabolism: 산소요구량 감소에 의한 적혈구조혈 감소 Anemia due to Endocrine Failure hypothyroidism, Addison'sdisease, hypogonadism, panhypopituitarism, hyperparathyroidism Addison'sdisease 치료시 plama volume 감소가 교정되면서 잠시 혈색소치는 감소하기도 한다. Anemia of Liver Disease Cholesterol 증가: Burrcell, stomatocyte RBC 수명 단축, 골수 보상 활동 저하 alcohol: 골수에 독성, 엽산결핍, 철결핍(위장관 출혈, 식이 부족) Anemia of Protein Deprivation: volume depletion으로 masking 가능 치료: 수혈: 증상에 따라 결정. CV or pulm disease, elderly , risk of transfusion Erythropoietin(EPO) w/o iron: 4 -6주에 Hb 10 -12 g/d. L 도달. Decreased response: infection, iron del[etion, Al toxicity, hyperparathyroidism
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