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Wu Chunmei Anemia due to Impaired Iron Metabolism.

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Presentation on theme: "Wu Chunmei Anemia due to Impaired Iron Metabolism."— Presentation transcript:

1 Wu Chunmei Anemia due to Impaired Iron Metabolism

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

3 Iron Metabolism

4 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: 50-55mg/Kg Female: 35-40mg/Kg 1ml blood=0.5mg Fe 1gHb=3.3mgFe 1mlRBC=1~2mgFe Amount and distribution:

5 Compartments iron content(mg) total body iron(TBI) Hb iron: % Tissue iron myoglobin % Labile iron pool % cytochromes 8 0.2% catalase peroxidase Storage (available) iron Ferritin % Haemosiderin 390 Transport iron 3 0.1% The iron is distributed in several forms:

6 Balance of iron metabolism Absorption ----excretion

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8 Absorption Transport of iron Utilization Affecting factors?

9 Fe 3+ in food combined Free Fe 3+ stomach reduced(VitC, GSH) gastric juice Fe 2+ Duodenum and upper jejunum Epithelial cells brush border apo-Ferritin + Fe 3+ Fe 2+ ferritin receptor reductase Fe 2+ Circulation Fe 2+ Tf + Fe 3+ Tf-Fe 3+ Storage inMMS Ferritin Haemosiderin In tissue: myoglobin heme-containing enzymes liver Iron cycle Normablasts Ret. marrow for Hb absorption Trans- port

10 transferrin Serum beta-globulin that binds and transports iron transferrin receptors Transport of iron

11 MMS Ferritin: Haemosiderin: Storage of iron apoferritin + Fe An iron-containing protein complex that is formed by a combination of ferric iron with the protein.(apoferritin) 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.

12 Iron utilized in normoblast Tf Fe 3+ Fe 2+ protophor phyrin + Fe 2+ Heme Heme+globin Hb Ferritin 80% sideroblasts Fe 3+ Tf-Fe 3+ 1/3 SA

13 Hb heme globin Fe 3+ Fe 2+ Hemosiderin ferritin apo-Ferritin Old RBC Storage iron in macrophages Normoblasts Hepatocytes Placental cells have more receptors Reutilization of Iron blood

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 C: Increased requirements --Early childhood and adolescence --Women during the reproductive years Causes of iron deficiency : A: Decreased iron intake --Poor diet --Impaired absorption B: 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)

16 --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 Pathogenesis of ID

17 Clinical Features 1. General symptom of anemia:Fatigue,weakness,or palpitations, headache 2. 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 examination Pallor Smooth red tongue, stomatitis Angular cheilitis Koilonychia(rare) Retinal hemorrhages/exudates(severe anemia) Accelerated retinopathy in diabetics Splenomegaly(occasionally)

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21 RBC↓,Hct ↓, Hb ↓ :male<120g/l, female<110g/l, pregnant women<100g/l, MCV<80gl, MCH<26g, MCHC<31% RDW ↑(>14%, earliest change ) morphology: anisocytosis, mild ovalocytosis, target cells, ring cells, elongated hypochromic elliptocytes (pencil cells), nucleated RBC, basophilic stippling RBC Ret normal or reduced Leukocyte normal or decreased Platelets increased or decreased Laboratory Findings 1.Blood : Hypochromic microcytic anemia

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23 IDA 早期血象:红细胞生成缺铁期,部分红细胞生理性中心浅染区轻度 扩大,临床上无贫血

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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 anemiahypercellularity anemia

26 Nucleated cells marked hypercellularity

27 IDA 骨髓象:中幼红细胞、晚幼红细胞增生为主,胞体较小,胞浆边缘不 规则呈锯齿状、胞浆偏蓝,呈 “ 幼浆老核 ” 现象。

28 HA IDA

29 ① Marrow stainable iron. Reference value: -extracellular iron (+~++) -intracellular iron (19%~44%) It is a direct and reliable index to reflect the level of storage iron. 3 The indexes of iron metaolism It decrease (<15%) , or absent in ID Sideroblasts decrease in IDE

30 IDA 骨髓铁染色:外铁阴性

31 IDA 骨髓铁染色:内铁阴性 正常:内铁阳性

32 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 30 µ g/l in chronic inflammation. It is a sensitive and reliable index to evaluate total body iron stores, but can be interfered by some conditions. Adult male:50~200µg/l; ② SF(serum ferritin)and EF(erythrocyte alkaline ferritin ) EF reference value: less sensitive than SF, <6.5µg/E in IDA

33 Measurements of iron stores Iron storesSF( µ g/l )Marrow iron stain(0-4+) 0<120 1~300mg12~ ~800mg20~ ~1000mg50~ ~2g150~3004+ Iron overload>500

34 ③ Serum iron concentration SI is a direct measure of the amount of iron bound to transferrin. Reference value: µ g/dl transporting iron, with a lot of affect factors Adult M:11.6~31.3µmol/l; F:9.0~30.4µmol/l(A:20µmol/l)

35 ④ TIBC: total iron binding capacity TIBC is a measure of the amount of iron that can be bound by transferrin. Reference value: 360~390 µ g/l TIBC:male:50~77µmol/l; female 54~77µmol/l Usually increased in ID. decreased in liver disease, malignant tumor, HA, chronic renal disease…

36 ⑤ TS (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.

37 UIBC SI TIBC

38 ⑥ sTfR(serum soluble transferrin receptor) : Reference value: 5~9 μg/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 suitable for large-scale screening of children, detecting both ID and lead poisoning.(why?) ⑦ FEP (Free Erythrocyte Protophorphyrin) and ZPP( protophorphyrin binds to zinc) FEP less sensitive than SF and EF.

40 Sensitivity of indexes of iron: Marrow stainable iron SF EF FEP TIBC TS SI sTfR

41 Diagnosis of IDA: ① +more than two of ② ~ ⑧ ① Hypochromic microcytic anemia(Hb male 14%, and morphologic changes) ② Identified causes associated with ID and significant clinical symptoms ③ SI µmol/L ④ TS<0.15 ⑤ Extracellular iron ( - ), sideroblasts <15% or absent ⑥ FEP>0.9 µmol/L(blood),or ZPP>0.96umol/L(blood), or FEP/Hb >4.5µg/gHb ⑦ SF<14µg/L; ⑧ Effective to therapy with iron

42 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 There are three stages of iron deficiency:

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 --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. manifestations

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

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47 Laboratory studies in three stages if iron deficiency IDIDEIDA hemoglobinNormal slight decreaseMarked decrease (microcytic/hypochromic) Iron stores<100mg(0-1+)00 SI (μg/dl)normal<6040 TIBC(μg/dl) >390>410 TS(%)20-30<15<10 SF((μg/l) ) <20<12 Percent sideroblasts 40-60<10 FEP(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 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 Classification:

51 1.underlying biochemical lesions Sideroblasts appear by a defect of pyridoxine metabolism or other intramitchondrial defect in heme synthesis. 2. anemia: ineffective erythropoiesis Pathogenesis: not clear

52 铁的利用与血红蛋白合成示意图 Fe 3+ Tf-Fe 3+ Tf Fe 3+ Fe 2+ protophor phyrin + Fe 2+ Heme Heme+globin Hb Ferritin 80% 骨髓:幼红细胞和网织红细胞血浆 TfR

53 Pathway of heme Biosynthesis UROI COPRO I UROgen I Gly Succinyl CoA ALAPBG 线粒体 Heme ⑤ Heme synthetase UROgen III COPROgenIII PROTO genIII PROTO 9 UROIII COPROIII Fe ① ALA synthetase pyridoxine Phosphate pyrindoxine ② Phosphate pyridoxine ③ ④ ⑥

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

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57 Anemias 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. Secondary anemia

58 --Sequestration of iron in the macrophages SI,TS decrease --reduce the secretion of EPO and impair its action in marrow Tf, sTfR,TIBC decrease --Shortened RBC life span (slightly hemolysis) Pathogenesis of ACD

59 Tf Fe 3+ Fe 2+ protophor phyrin + Fe 2+ Heme Heme+globin Hb Ferritin 80% Fe 3+ Tf-Fe 3+ ACD Reutilization of iron impaired Hypochromatic anemia

60 Hb heme globin Fe 3+ Fe 2+ Hemosiderin ferritin apo-Ferritin Macrophages Neutrophils Inflammatory cells growth factors-IL 1 Precursor cells Cytokines, such as IL 1, TNF,gamma interferon. SF, extracellular iron increase

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 Bone 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 Lab Findings

63 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? Questions:

64 Differential Diagnosis in Lab Lab test Thalassemia ACD IDA RBC low low low MCV low in 20-30% rarely to Tf N decrease increase SF N/Increased N/Increased low SI N to high low low HbA2,F,H usually present absent absent TIBC N/ low usually low usually high TS N to high > 15%, low low or N Extracelluiar iron N increase decrease Intracellular iron N decrease decrease

65 Case A female, complained of fatigue and headache for a few months since she had functional uterine bleeding and short of breath when climbing stairs The doctor found her face look pale. He ordered an CBC detection. The result is the follow. Ret is 2.5%

66 Result of CBC

67 外周血涂片染色

68 骨髓细胞学检查。

69 Questions: 1.Does the female has anemia? 2. Do you think which type anemia she has? Give your reasons. 3. Which tests do you need to confirm your advice. Do you image the results?


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