Erythropoiesis RBC production Hemoglobin heme globin Heme a

Erythropoiesis

• RBC production • Hemoglobin = heme + globin • Heme = a porphyrin ring + an iron atom

Iron • Critical element of cell function • Free iron : highly toxic : free radical generation – Transferrin, ferritin, hemosiderin • 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 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 • Daily 0. 8 – 1% destruction • Fe turnover : 16 – 20 mg/day

Iron absorption • Absorption site : proximal small intestine • Fe 3+ (stomach)----- ferrireductase (brush border) ----- Fe 2+ --- DMT-1(memb. ) --- Gut cell(ferritin) ----ferroportin(memb) --3+-------- plalsma(transferrin) Fe • • (by hephaestin) DMT-1(divalent metal transporter-1) Ferroportin : negatively controlled by hepcidin Hepcidin : principal iron regulatory hormone Hephaestin : ferroxidase

Nutritional Iron • • • 6 mg/ 1, 000 calories Red meat : most efficient source of iron M : 6 mg – 15% absorption F : 11 mg – 12% 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 : Egg iron : Liver iron : Heme iron : 1/20 1/8 1/2 - 2/3

Increased iron requirement • • • Infant Children Adolescent Pregnancy : last trimesters : 5 -6 mg Increased erythropoiesis

Stages of iron deficiency • Negative iron balance : blood loss(10 -20 m. L/day), pregnancy, rapid growth spurt, inadequate dietary iron • Iron-deficient erythropoiesis : microcytic cells, hypochromic reticulocytes • Iron-deficiency anemia

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 • 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 RBC transfusion Oral iron therapy Parenteral iron therapy – Iron dextran – Sodium ferric gluconate – Iron sucrose – Ferric chloride

Amount of iron needed Ganzoni’s fomula : BW(kg) X 2. 3 X (15 – pt’s Hb, g/d. L) 500 or 1, 000 mg (for stores) +

Parenteral iron therapy • • Unable to tolerate oral iron Absorbtion defect Whose need are relatively acute Epo therapy • Iron dextran : severe side effect Sodium ferric gluconate Iron sucrose Ferric chloride

Iron prep. (본원) • Ferrous sulfate – Feroba-You : 256 mg (80 mg) / tab (SR) • Iron acetyl-transferrin hydroglycerin – Bolgre Soln : 2 m. L (40 mg) / 10 m. L • Iron protein succinylate – Hemo-Q : 800 mg (40 mg) / 15 m. L • Ferric chloride – Blutal : 197 mg (40 mg) / 10 m. L Amp

Anemia of Chronic Disorders • • • 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 def, hemolysis, sequestration. BM usually not helpful • DDx of IDA (serum ferritin? , serum transferrin receptor? )

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 – Long acting EPO