内科IDA-AA-陈春燕-12-17 课件

1、IRON DEFICIENCY ANEMIA(IDA)仅限学术交流山东大学齐鲁医院 陈春燕 教授IDA IS THE MOST PREVALENT ANEMIA THROUGHOUT THE WORLD !EpidemiologyIDA Infants:incorrectfeedingPregnant womanTeenagers rapid growthCASE REPORTA 36-year-old woman presented with general malaise for the past 3 months. History revealed heavy periods for t

2、he past year.PE a pale well-nourished lady and chest, heart and abdoman exam are nothing remarkable. Lab Findings CBC Hb 78 g/L, MCV 69 fl, normal renal and liver function, normal urinalysis and fecal routine. QUESTIONS1. What is your preliminary impression of the patient ?2. What lab tests should b

3、e ordered next to confirm the diagnosis? 3. Do you think a bone marrow test is needed? 4. Which is the most useful test( or tests) for the diagnosis in this patient?5. After diagnosis how do you plan to treat the patient?HemoglobinHemoglobin protein 4 polypeptides2 chains and 2 chainsEach chain cont

4、ains a single molecule of heme, an iron-containing pigmentThe iron ion in heme is able to reversibly bind an oxygen molecule.Meaning, O2 can bind to Hb at the lungs and then be released at the tissuesNote the 2 chains and 2 chains. Notice how each has an associated heme molecule with an iron atom.ME

5、TABOLISM OF IRON Source and absorption - Dietary iron (main source,10-15 mg/d) - 10% dietary iron absorbed by the body - Only Fe+2 and heme iron can be absorbed - Absorbed from the duodenum and upper jejunum. - Promotion and inhibition of iron absorption Vitamin C increases absorption by reducing di

6、etary ferric to ferrous iron. Caffeine, cheese, cereal and tea decrease absorption. IRON ABSORPTION Fe3+hemeDcytbDMT1HCP1HOxyIREG1hephaestinFe3+-TFFe2+HepcidinHOxy=heme oxygenase （血红素氧化酶） IREG1（膜铁转运蛋白1）hephaestin （膜结合铁氧化酶）TF=transferrin（运铁蛋白）Hepcidin （铁调素）Dcytb=duodenal cytochrome b （铁还原酶，十二指肠细胞色素b）

7、DMT1=divalent metal ion transporter-1 （二价金属离子转运蛋白1）HCP1=heme carrier protein1 （亚铁血红素携带蛋白1）Fe2+hemeFe2+IRON HOMOESTASISIREG1（膜铁转运蛋白） ； TF=transferrin （运铁蛋白）；TfR=transferrin receptor（运铁蛋白受体）FerritinSideroblastIREG1（膜铁转运蛋白） Transmembrane iron transporter Exports Fe into blood from gut,liver and macroph

8、age Regulates plasma Fe level to keep transferrin 35% saturated Cornerstone of the internal iron circuit Hepcidin Peptide(25AA) made primarily in liver Negative regulator of Fe release from gut,liver and macrophage Synthesis induced by increased Fe storage and inflammation Synthesis suppressed by Fe

9、 deficiency and hypoxemiaADVANCES IN IRON METABOLISMMETABOLISM OF IRON Transportation of iron - Transferrin (transportor of iron) - total iron-binding capacity （TIBC） - Sideroblast (intracellular iron)TfR depend pathwaySideroblastMETABOLISM OF IRON Distribution and storage of iron - Iron in all tiss

10、ues of the body - Male female (50 mg/kg vs 35 mg/kg) - Hb 65%, myoglobin 6%, storage 25% Ferritin Hemosiderin - iron enzymes hemosiderin in macrophages of alveolus Recycling and excretion of ironDaily requirement 20-25 mg ( from RBC) 1.0-1.5 mg/d from absorbed iron Very conservative in excretion: bo

11、dy cells male 0.5-1.0mg/d,female 1.0-1.5mg/dMETABOLISM OF IRON ETIOLOGY AND PATHOGENESISDYNAMIC BALANCE BTW ABSORPTION AND EXCRETION (IRON HOMEOESTASIS).NEGATIVE BALANCE RESULTS IN IRON DIFICIENCY.ETIOLOGY AND PATHOGENESIS Inadequate intake and increased requirement - Dietary allowance (M 5-10mg, F

12、7-20mg/d) - Rapid growth in childhood - Incorrect feeding (non-breast feeding) - Menorrhea loss - Pregnancy - LactationETIOLOGY AND PATHOGENESIS Disturbance in iron absorption - Dietary contents( animal or plant) - Gastrointestinal factors - Medication ETIOLOGY AND PATHOGENESIS Excessive loss of iro

13、n - Chronic loss of blood ( commonest )： Menorrhea loss， Gastrointestinal factors - Increased excretion from urine ( intravascular hemolysis ) - Copper deficiency - HemodialysisIntakeRequirement iron absorptionloss of ironDietary allowance Dietary contentsChronic loss of blood Rapid growth in childh

14、oodGastrointestinal factorsIncreased excretion from urine Incorrect feeding Medication:Aspirin/NSAID useCopper deficiencyMenorrhea lossHemodialysisPregnancy LactationETIOLOGY AND PATHOGENESISCLINICAL MANIFESTATIONIDA IS A SIGN OF MANY DISEASES.ITS MANIFESTIONS CONSIST OF TWO PARTS CLINICAL PICTURES

15、OF ANEMIA UNDERLYING DISORDERCLINICAL MANIFESTATIONCLINICAL MANIFESTATION General picture ( non-specific ) - Pallor - Fatigue, malaise - Headache, lightheadedness - Tinnitus（ringing noise） CLINICAL MANIFESTATION Skin and mucosa - Thin or flat nail (spoon-like) - Atrophy of lingual papilla - Smooth t

16、ongue - Glossitis (uncommon)CLINICAL MANIFESTATION Systemic manifestations - Cardiovascular and pulmonary ( palpitation, dyspnea) - Alimentary (anorexia, loose stool, constipation,pica, gastritis) - Increased susceptibility to bacterial infectionsLABORATORY FINDINGS Morphology Blood film - Microcyti

17、c hypochromic anemia - Enlarged central pallor of RBC - Normal WBC - Normal platelet (increased in some)Normal Blood Smear Blood Smear of IDAan increased zone of central pallor. This is indicative of a hypochromic (less hemoglobin in each RBC) microcytic (smaller size of each RBC) anemia. They have

18、a zone of central pallor (about 1/3 the size of the RBC).HISTOGRAM of MCVUpper: Normal MCVLower: IDA MCVLABORATORY FINDINGS Morphology Bone marrow Hypercellular Mild or moderate erythroid hyperplasia Normal megakeryopoiesis and granulopoiesis Decreased or absence of iron stain骨髓外铁染色骨髓内铁染色LABORATORY

19、FINDINGS Biochemistry Iron metabolism - Serum iron 64.44 mol/L ( 3600 g/L ) - Transferrin saturation 15% - Ferritin 14 g/L- storage of iron Erythropoiesis in iron deficiency - Increased free RBC protoporphyrin - Increased RBC free protoporphyrin/Hb ratioDIAGNOSIS OF IDA Microcytic hypochromic anemia

20、 (MCV 75fl) History of negative iron balance and clinical manifestations of anemia Serum iron 64.44 mol/L (3600 g/L) Transferrin saturation 0.15 Marrow iron extracellular (-) Intra 0.9umol/L or FEP/Hb4.5ug/gHb Serum ferritin 15% - Increased serum iron and ferritin Ringed sideroblastsDIAGNOSIS AND DI

21、FFERENTIALKeys to Diagnosis History of negative iron balance (reliability?) Microcytic anemia (MCV 75fl) Serum ferritin 14 g/L Marrow iron extracellular (-) Intra 15% (only indicated) IDA in men and post-menopausal women Justifies GI exam or referral to GI doctor Medication, such as NSAIDs, stopped

22、if possible TREATMENT Causal treatment ( most important )Iron supplement TREATMENT Oral iron supplement - Fe+2 : ferrous sulphate - 100 mg b.i.d 1hr before meal Increased retic 7-10 days Increased Hb 2 weeks Restore Hb level 1-2 months - 3 months to restore iron reserve ! Side effects Nausea Gastric

23、 discomfort Constipation Diarrhea Heartburn abdominal cramps Good idea to start patients on small doses and increase gradually. TREATMENT Parenteral iron substitution iron dextran,iron sucrose,etc.indication - Poor telerance for oral iron (nausea,diarrhea) - disorder of gastrointestinal tract - bad

24、absorption - negative belance of iron (hemodialysis) administration - 50-100 mg daily - Iv route, lethal anaphylaxis, avoided whenever possible - Im route much safer Total dose(mg)=N Hb-P Hb (g/L)BW(kg) 0.24+(500-1000) mg An abbreviated flow chart of the treatment of IDAOral iron toleratednoabnormal

25、Consider further investigation ;Blood transfusion if anaemia is severe.normalContinue iron for another 3-6 monthCheck FBC monthlyOral iron IDATreat cause if possibleConsider parenteral iron Recheck FBC every 3month;After a further year giving a further iron as necessaryNormal FBC maiteinednoNo furth

26、er action unless further symptonsyesTREATMENT Blood transfusion is not indicated except for life-threatening anemia because of quick recovery of anemia after iron therapy!ADVANCES IN THERAPHYOral iron therapy is the most widely prescribed treatment for IDA.issues prevent oral iron supplementationdif

27、ficulties of ingesting of the tabletside effectscompliancebowel disease gastrointestinal disturbances colicky pain, nausea, vomiting, diarrhoea, and/or constipationthe effectiveness of oral iron is largely compromised IV ironNow: type II and III iron better tolerated rapid repletion of iron stores。

28、past： undesirable sometimes serious side effects limited in use IV iron :an effective, rapid, and safe treatment option. avoid or reduce the demand for blood transfusions; effective rapid repletion of iron storesPROPHYLAXISPopulation prone to iron deficiency Women (menses, pregnancy,lactation) Child

29、 (rapid growth)Measures Treat the underlying diseases Increase iron in-take (iron-rich food)Reduce iron depletors (coffee,tea etc.)Answer to that caseQ. What is your preliminary impression of the patient ?A. IDA should be in consideration.Q. What lab tests should be ordered next to confirm a Dx? A.

30、Serum iron, ferrritinQ. Do you think a bone marrow test is needed ? A. No !Q. Which is the most useful test( tests) for the Dx in this patient ?A. CBC, ferritinQ. After diagnosis how do you plan to treat the patient ?A. Oral iron preparationsMedicolegal Pitfalls Failure to investigate the etiology o

31、f IDA causing a delayed or missed diagnosis of neoplasm Giving iron to patients who have a microcytic iron-overloading disorder (eg, thalassemia, sideroblastic anemia) Failure to promptly and adequately treat a patient with IDA who is symptomatic with a comorbid condition such as coronary artery dis

32、ease Anaphylaxis caused by the use of parenteral iron therapy in patients who should be treated with oral ironQUESTIONS What is iron deficiency anemia? How is iron absorbed? What kind of food is rich in iron ? What are the morphological features of IDA? Which preparation do you prefer to use to trea

33、t IDA, oral or injection agent? How to prevent the pregnant from iron deficiency? APLASTIC ANEMIA（AA）山东大学 齐鲁医院 血液科 陈春燕 教授CASE REPORTA 40-year-old male teacher complained of progressive Lassitude worsening in the past 3 months . Easy bruising was noted in recent days and urged him to seek medical car

34、e. History-taking No history of exposure to suspicious chemicals or medication.PE A pallor man with otherwise normal PE except for scattered skin ecchymosis on both lower extremities. Lab Findings CBC WBC 2.1 109/L with ANC 1.1 109/L, Hb 72 g/L, Plt 32 109/L and Rc 0.005. Questions1. What lab tests

35、would you intend to order for a diagnosis?2. What do you think about the differential diagnosis?3. Is a marrow examination is necessary for the diagnosis? 4. After diagnosis what is the treatment plan for this patient? DEFINITION OF AAAPLASTIC ANEMIA IS A MARROW FAILURE SYNDROME CHARACTERIZED BY PAN

36、CYTOPENIARESULTING IN ANEMIA, PREDISPOSITION TO INFECTION AND BLEEDING TENDENCYIncidence Rare. 4-7 people/million/year in ChinaDefinition of severity of aplastic anaemiaSevere AA BM cellularity 25%, or 25-50% with30% residual haemopoietic cells 2/3 of the following:1. neutrophils 0.5 x 109/l2. plate

37、lets 20 x 109/l3. reticulocytes 20 x 109/lVery severe AAAs for severe AA but neutrophils 0.2 x109/lNon-severe AAPatients not fulfilling the criteria for severeor very severe aplastic anaemiaETIOLOGY AND PATHOGENESISMost cases of aplastic anemia are idiopathic and there is no history of exposure to s

38、ubstances known to be causative agents of the diseaseETIOLOGY AND PATHOGENESIS Causes Chemical factors - Benzene and derivatives (important) - Antineoplastic agents (often transient) - Toxic substances - Medication other than antineoplastics (idiocrasy)Drugs associated with AAAntibiotics氯霉素、磺胺类、复方新诺

39、明、利奈唑胺Anti-inflammatory青霉胺、保泰松、消炎痛，双氯芬酸，萘普生，吡罗昔康，柳氮磺胺吡啶Anti-convulsants苯妥英钠、卡马西平Anti-thyroids卡比马唑#、硫脲嘧啶Anti-depressants度硫平、吩噻嗪类Anti-diabetics氯磺丙脲、甲苯磺丁脲Anti-malarials氯喹Others甲苯咪唑、噻嗪类、别嘌呤醇ETIOLOGY AND PATHOGENESISCauses Physical factor - Ionizing irradiation (accidental exposure ) - Therapeutic (rare)

40、 - Occupational exposureETIOLOGY AND PATHOGENESIS Causes Biological factors - Viruses (most relevant) - Hepatitis B and C - HIV - Parvovirus B-19 - EBVETIOLOGY AND PATHOGENESISHepatitis Associated Aplastic Anemia Incidence 6 mon. - Other androgens Cyclosporin A Cytokines (growth factors) - Erythropo

41、itin - G-CSF or GM-CSF - Thrombopoitin - Interleukins (IL-11) Miscellaneous - Chinese traditional medicine - Agents supposed to improve microenvironmentTreatment of Non-SAATREATMENTTreatment of SAA Allogeneic stem cell transplantation Immunosuppressive therapy - Indicated in SAA or VSAA- Age40 ys, h

42、aving a HLA identical donor- Non-myeloablative conditioning suitable- Rejection rate 5 - 10%，GVHD25 - 40% - Avoidance of transfusion before transplantation- Other stem cell sources: cord blood, non-related donor- Long-term survival 80 %- Indicated in SAA or VSAA (50-70%)- ATG or ALG 50%- Cyclosporin

43、 A ( same as non-SAA) 50%- Combination (intensive immunosuppression) 70-80%- Other immunosuppressive agents Treatment of SAA Immunosuppressive therapy secondary complications occurRisk of clonal disorders such as MDS/AML, PNHSolid tumorsCsA-induced renal failure, hypertension, infectionTREATMENTQUES

44、TIONS What is the nature of AA? What are the main causes of AA? What role does the immune system play in the happening of AA? Try to describe the difference btw non-SAA and SAA. What are the marrow features of of AA? Why are androgens used to treat AA? What are the treatment principles of SAA?Answer

45、 to that caseQ. What lab tests would you intend to order for a diagnosis?A. BM aspiration and biopsy (essential to diagnosis of AA)Q. What do you think about the differential diagnosis?A. All possible causes of pancytopeniaQ. Is a marrow examination is necessary for the diagnosis?A. Yes, BM examination is necessary for pancytopenia Q. After diagnosis what is the treatment plan for the patient? A. Treatment of AA depends on classification of AAMedicolegal Pitfalls Failure to correctly dia