Presentation on theme: "Anemia due to Impaired Iron Metabolism"— Presentation transcript:
1 Anemia due to Impaired Iron Metabolism Wu Chunmei
2 This group disorders are caused by impaired iron metabolism which include: (a) Iron deficiency anemia: deficiency of iron (b) Sideroblastic anemia:`impaired utilization of iron (c) Anemia of chronic disease: defective iron reutilization
4 Amount and distribution: The total body iron varies from 3 to 4 g, depending on the sex and weight of the individual It is greater in males than in females and it increases roughly in proportion to body weight. Male: mg/Kg Female: 35-40mg/Kg1ml blood=0.5mg Fe1gHb=3.3mgFe1mlRBC=1~2mgFe
5 The iron is distributed in several forms: Compartments iron content(mg) total body iron(TBI) Hb iron: % Tissue iron myoglobin % Labile iron pool % cytochromes % catalase peroxidase Storage (available) iron Ferritin % Haemosiderin Transport iron %
6 Absorption ----excretion Balance of iron metabolismAbsorption ----excretion
8 AbsorptionTransport of ironUtilizationAffecting factors?
9 absorption Iron cycle Duodenum and upper jejunum Free Fe 3+ stomach Fe 3+ in foodcombinedreceptor reductaseEpithelial cells brush borderapo-Ferritin + Fe Fe 2+ferritinFe 2+Free Fe stomachreduced(VitC, GSH) gastric juiceFe 2+Circulation Fe 2+Tf Fe 3+Tf-Fe 3+Trans-portliverIron cycleStorage inMMSFerritin HaemosiderinNormablastsRet.marrow for HbIn tissue:myoglobinheme-containing enzymes
10 Serum beta-globulin that binds and transports iron Transport of irontransferrinSerum beta-globulin that binds and transports irontransferrin receptors
11 MMS Storage of iron apoferritin + Fe An iron-containing protein complex that is formed by a combination of ferric iron with the protein.(apoferritin)Haemosiderin:insoluble storage iron, golden yellow or brown granules in unstained tissue; blue granules when stained with potassium ferrocyanide. It contains more iron than ferritin and aggregates into granules, microscopically visible in tissue and phagocytes.Storage of iron
12 Iron utilized in normoblast SAFe 3+protophorphyrin+Fe 2+HemeTf-Fe 3+Tf80%1/3Fe 3+Fe 2+FerritinHeme+globin HbsideroblastsIron utilized in normoblast
13 Storage iron in macrophages Old RBCbloodHemosiderinferritinapo-FerritinHbglobinhemeFe 3+Fe 2+NormoblastsHepatocytesPlacental cellshave more receptorsStorage iron in macrophagesReutilization of Iron
14 IRON DEFICIENCY ANEMIA (IDA) Iron deficiency is the state in which the content of iron in the body is less than normal. When the supply of iron to the marrow is insufficient for the requirements of Hb synthesis, IDA develops with varying degrees of microcytic hypochromic anemia.
15 Causes of iron deficiency : A: Decreased iron intake --Poor diet --Impaired absorptionB: Increase iron loss (1ml blood =0.5mgFe) --losses from gastrointestinal tract --Neoplasm --Peptic ulcer --Others (hookworm disease) --Menometrorrhagia --Losses from urine (PNH) --Losses from sputum (rare)C: Increased requirements --Early childhood and adolescence --Women during the reproductive years
16 Pathogenesis of ID--Lack of iron interferes with heme synthesis, which leads to reduced Hb synthesis and defective erythropoiesis.--There is decreased activity of iron-containing proteins.--Neurologic dysfunction may occur, with impaired intellectual performance, paresthesias, etc.--Gastric acid secretion is reduced, often irreversibly.--Atrophy of oral and gastrointestinal mucosa may occur
17 Clinical Features1. General symptom of anemia:Fatigue,weakness,or palpitations, headache2. Essential iron deficiency:--Children may have poor attention span, poor response to sensory stimuli, retarded developmental and behavioral achievement, irritability and retarded longitudinal growth.--Paresthesias and burning of tongue may occur.--Pica, craving to eat unusual substances such as clay,or ice, is a classic manifestation.
18 Physical examinationPallorSmooth red tongue, stomatitisAngular cheilitisKoilonychia(rare)Retinal hemorrhages/exudates(severe anemia)Accelerated retinopathy in diabeticsSplenomegaly(occasionally)
25 marrow usually hypercellularity with M/E ratio variable. morphology: erythroid hyperplasia and mainly late normoblasts, which may be small, with narrow rim of ragged cytoplasm and poor Hb formation (polychromatic) and densed nucleus(old nucleated young cytoplasm). Basophiloic stippling and Howell-Jolly body may present in normoblasts.The mature RBCs as in blood.2. Marrow: hypercellularity anemia
29 3 The indexes of iron metaolism ①Marrow stainable iron.Reference value:-extracellular iron (+~++)-intracellular iron (19%~44%)It is a direct and reliable index to reflect the level of storage iron.It decrease (<15%)，or absent in IDSideroblasts decrease in IDE
32 ② SF(serum ferritin)and EF(erythrocyte alkaline ferritin） SF Reference value:--< 10µg/l in IDA--10 ~ 20µg/l are presumptive, but not diagnostic.--May be elevated with concomitant inflammation diseases . IDA can be suspected in rheumatoid arthritis if SF is less than 60µg/l or less than 30µg/l in chronic inflammation.Adult male:50~200µg/l;It is a sensitive and reliable index to evaluate total body iron stores, but can be interfered by some conditions.EF reference value: less sensitive than SF, <6.5µg/E in IDA
33 Measurements of iron stores SF(µg/l )Marrow iron stain(0-4+)<121~300mg12~201+300~800mg20~502+800~1000mg50~1503+1~2g150~3004+Iron overload>500
34 ③Serum iron concentration SI is a direct measure of the amount of iron bound to transferrin.Reference value:50-150µg/dlAdult M:11.6~31.3µmol/l; F:9.0~30.4µmol/l(A:20µmol/l)transporting iron, with a lot of affect factors
35 Reference value: 360~390µg/l ④TIBC: total iron binding capacityTIBC is a measure of the amount of iron that can be bound by transferrin.Reference value: 360~390µg/lTIBC:male:50~77µmol/l; female 54~77µmol/lUsually increased in ID.decreased in liver disease, malignant tumor, HA, chronic renal disease…
36 ⑤TS (Transferrin Saturation): SI TS = ×100% , TIBC In normal condition, 1/3 transferrin binds to iron.Reference value: 20~50%. ( A:30%)15% or less in patients with IDA ; >50~60% resulting in iron loading.
38 ⑥sTfR(serum soluble transferrin receptor) : Reference value: 5~9μg/L(ELISA)sTfR level increase in IDE, IDA (when iron store are exhausted)sTfR level also increase in other disease with ineffective or effective erythroid precursor proliferation
39 --usually increased in ID --Very sensitive for diagnosis of ID and ⑦ FEP (Free Erythrocyte Protophorphyrin) and ZPP( protophorphyrin binds to zinc)--usually increased in ID--Very sensitive for diagnosis of ID andsuitable for large-scale screening of children ,detecting both ID and lead poisoning.(why?)FEP less sensitive than SF and EF.
40 Sensitivity of indexes of iron: SFMarrow stainable ironEFsTfRFEPTIBCTSSI
41 Diagnosis of IDA: ①+more than two of ②~⑧ ①Hypochromic microcytic anemia(Hb male < 120 g/l , female<110g/l, pregnant women<100g/l, MCV < 80fl, MCH<26g, MCHC < 31% , RDW > 14% , and morphologic changes)② Identified causes associated with ID and significant clinical symptoms③ SI <10.7µmol/L,and TIBC>64.44 µmol/L④TS<0.15⑤ Extracellular iron (－), sideroblasts <15% or absent⑥ FEP>0.9 µmol/L(blood) ,or ZPP>0.96umol/L(blood), or FEP/Hb >4.5µg/gHb⑦ SF<14µg/L; ⑧ Effective to therapy with iron
42 There are three stages of iron deficiency: 1. Iron depletion (ID): It is the earliest stage of iron deficiency. In which storage iron is decreased or absent but serum iron concentration and blood Hb levels are normal Extracellular iron is decreased or absent ---SF concentration falls
43 2.Iron deficiency erythropoiesis (IDE): It is a somewhat more advanced stage of iron deficiency. In which deficit of the functional iron compartment is associated with the development of iron deficiency erythropoiesis It is characterized by decreased or absent storage iron, usually low SI and transferrin saturation, without frank anemia.
44 manifestations--Extracellular iron is absent --Intracellular iron is decreased --Serum soluble transferrin receptor(sTfR) is increased. --TIBC is increased --Serum iron level falls --Transferrin saturation falls --An increase in the RDW --generally asymptoms.
45 3.Iron deficiency anemia (IDA): It is a most advanced stage of iron deficiency. It is characterized by decreased or absent iron stores, low SI , low transferrin saturation and low Hb or hematocrit value. Besides the above characteristics, there are: --red cell count decrease --Many symptoms
47 Laboratory studies in three stages if iron deficiency IDIDEIDAhemoglobinNormalslight decreaseMarked decrease (microcytic/hypochromic)Iron stores<100mg(0-1+)SI (μg/dl)normal<6040TIBC(μg/dl)>390>410TS(%)20-30<15<10SF((μg/l))<20<12Percent sideroblasts40-60FEP(μg/dlRBC)30>100>200
48 Diagnosis process of-Anemia?-Microcytic hypochromic anemia?-IDA?(measurements of iron metabolism)-The cause of IDA!
49 Sideroblastic Anemias (SA) The sideroblastic anemias are a heterogeneous group of disordes that have as common features the presence of large number of ringed sideroblasts in the marrow, ineffective erythropoiesis, increased levels of tissue iron and varying proportions of hypochronic erythrocytes in the blood.
50 Classification:hereditary: x chromosome-linked ,partially recessive inheritance, males are anemic and females are carriers autosomally-linked, or mitochondria entities acquired : primary: neoplasia (MDS-RAS) secondary: drugs, toxin, alcohol, or coincident to neoplastic or inflammatory disease
51 Pathogenesis: not clear 1.underlying biochemical lesionsSideroblasts appear by a defect of pyridoxine metabolism or other intramitchondrial defect in heme synthesis.2. anemia: ineffective erythropoiesis
52 Fe 3+ Tf 80% TfR 铁的利用与血红蛋白合成示意图 血浆 骨髓：幼红细胞和网织红细胞 Tf-Fe 3+ Fe 3+ Fe 2+ protophorphyrin+HemeHeme+globin HbFerritin80%TfTfR铁的利用与血红蛋白合成示意图
54 Lab Findings--Hypochromic and micro- or normocytic anemia--Marked anisocytosis and poikilocytosis--Normal or elevated SI levels--Erythroid hyperplasia of the BM--Increased siderablasts in BM, ringed sideroblasts--Increased iron stores--Normal or slightly reduced red cell survival time--Hemosiderosis and/or hemochromatosis[Others] Refractory to therapy with iron
57 Anemias of Chronic Disorders(ACD) Secondary anemiaAnemias of Chronic Disorders(ACD)Anemias of chronic disorders are present in chronic infections, inflammatory diseases and neoplastic diseases .It is a common anemia, probably second in incidence to iron deficiency anemia.
58 Pathogenesis of ACD--Sequestration of iron in the macrophagesSI ,TS decrease--reduce the secretion of EPO and impair itsaction in marrow Tf, sTfR ,TIBC decrease--Shortened RBC life span (slightly hemolysis)
59 80% Tf Tf-Fe 3+ Fe 3+ Fe 2+ Fe 3+ Heme+globin Hb ACD protophorphyrin+Fe 2+HemeTf-Fe 3+80%Fe 3+Fe 2+FerritinFe 3+TfHeme+globin HbACDReutilization of iron impairedHypochromatic anemia
60 Hb Macrophages Neutrophils SF, extracellular iron increase globin heme Hemosiderinferritinapo-FerritinHbglobinhemeFe 3+Fe 2+MacrophagesNeutrophilsInflammatory cellsgrowth factors-IL 1Precursor cellsCytokines, such as IL 1 , TNF ,gamma interferon.
61 Clinical Features--Signs common to all anemias.--Signs specific to the underlying disease.--Showing no improvement with iron therapy and only improving with correction of the primary disorders.
62 Lab FindingsBone marrow--No distinctive abnormality--Iron stains shows increased stainable iron in the macrophages despite a decrease in sideroblasts.Other Test--SI decrease, Tf decrease--SF is normal or increased--TIBC is normal to decreased--TS is usually decreased
63 Questions:1.Describe the characteristics of three stages of iron deficiency.2. Describe the causes of iron deficiency.3. How to diagnose ID? IDE? IDA?4. What is IDA? Sideroblast? Ring sideroblast?5. What is ferritin? Tf ? TIBC? SI?6.How to differentiate hypochromatic microcytic anemias in Lab?
64 Lab test Thalassemia ACD IDA RBC low low low Differential Diagnosis in LabLab test Thalassemia ACD IDARBC low low lowMCV low in 20-30% rarely to 60-70Tf N decrease increaseSF N/Increased N/Increased lowSI N to high low lowHbA2,F,H usually present absent absentTIBC N/ low usually low usually highTS N to high > 15%, low low or NExtracelluiar iron N increase decreaseIntracellular iron N decrease decrease
65 CaseA female, complained of fatigue and headache for a few months since she had functional uterine bleeding and short of breath when climbing stairsThe doctor found her face look pale. He ordered an CBC detection. The result is the follow.Ret is 2.5%