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MEGALOBLASTIC ANEMIAS

MEGALOBLASTIC ANEMIAS. MA. Definition.

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MEGALOBLASTIC ANEMIAS

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  1. MEGALOBLASTIC ANEMIAS MA

  2. Definition Megaloblastic anemias are disorders caused by impaired DNA synthesis due to the substances of DNA synthesis deficiency, such as folic acid and Vit B12,etc. It ischaracterized by the presence of megaloblastic cellsin the bone marrow and macrocytic anemia.

  3. Classification of MA 1.Vitamin B12 deficiency 2.Folate deficiency 3.Penicious anemia

  4. REVIEW The important role of folate and Vitamin B12 playing in the pathways of deoxynucleotide and DNA synthesis:

  5. thymidylate synthetase (N5,N10-methylene FH4) Ribonucleotide dUMP dTMP dTTP UTP(UR PPP ) → dUTP(UdRPPP) CTP(CR PPP) → dCTP(CdR PPP) ATP(AR PPP ) → dATP(AdR PPP) GTP(GR PPP) → dGTP(GdR PPP) reductase pyrimidine synthesis D NA purine synthesis

  6. 1. De novo synthesis of purine: N10-formyl FH4 FH4 C N N C C C C N N 7 1 8 2

  7. 2 . Thymidylate synthesis thymidylate synthetase d TMP d UMP N5,N10-methylene FH4 FH2 Glycine FH2 reductase Serine FH4

  8. ATP FH4 methionine PPi+Pi N5-methyl FH4 S-adenosyl methionine homocysteine RH adenosyl R-CH3 H2O S-adenosyl homocysteine N5-methyl FH4 methyltransferase (Vit B12) 3. Methionion synthesis Trap

  9. dUTP 合成异常DNA 巨幼变细胞 dTTP DNA正常合成 dTMP dUMP 亚甲基四氢叶酸 二氢叶酸 叶酸缺乏 二氢叶酸还原酶 四氢叶酸 甲硫蛋氨酸 Vit B12缺乏 高半胱氨酸 5-甲基四氢叶酸 叶酸和Vit B12缺乏对DNA合成的影响

  10. Methionine Homocysteine purine and pyrimidine synthesis Serine B6 glycine Thymidylate DNA Deoxyuridylate Diet Methyltetrahydrofolate Tetrahydrofolate Dihydrofolate N5,N10-methylene FH4 VitaminB12 methylB12 CH3

  11. Ineffective erythropoiesis Megaloblastic Anemias Morphologically and functionally change Megaloblastic cells Defective DNA synthesis Different disorders Deficiency of folate and Vit B12,etc. Non-deficiency Pathogenesis of MgAEtiology of MgA

  12. Food folate (daily needs 200μg) Folate stores (5-20mg) TFH- 多谷氨酸盐 多聚谷氨酸叶酸 liver Enterohepatic cycle Excretion urine blood γ-谷氨酰胺羧基肽酶 FBP 叶酸结合蛋白 单谷氨酸叶酸 甲基//四氢叶酸 tissue +Vit B12 蛋氨酸循环 DNA 合成 叶酸的吸收、利用、贮存和排泄

  13. 绿叶蔬菜、柠檬、香蕉、瓜类、香菇、酵母及动物内脏（尤其是肝脏）等都含大量叶酸。绿叶蔬菜、柠檬、香蕉、瓜类、香菇、酵母及动物内脏（尤其是肝脏）等都含大量叶酸。

  14. 1.The causes of folic acid deficiency I inadequate intake(diet) II intestinal malabsorption III increased demand IV inability to utilize folate due to action of folate antagonists

  15. Vit B12 stores (4 ～5mg) liver TcII-B12 Vit B12 +甲基叶酸 释放内因子 蛋氨酸循环 Food Vit B12 (daily needs 2 ～ 5μg) Vit B12 –R蛋白 Enterohepatic cycle IF Vit B12 –IF blood tissue Excretion urine faeces tear saliva milk Vit B12的吸收、利用、贮存和排泄

  16. 动物的肝、肾、肉类、禽蛋、乳类和海洋生物等B12含量较多。动物的肝、肾、肉类、禽蛋、乳类和海洋生物等B12含量较多。

  17. 2. The causes of Vitamin B12 deficiency I. inadequate intake II.intestinal malabsorption III. vitamin B12 destruction IV. congenital defects

  18. How to diagnose the megaloblastic anemia Clinical Features LaboratoryFeatures

  19. Clinical Features • 1. Common manifestations • Anemia develops slowly, severe anemia with • weakness, palpitation, fatigue, light-headedness, • and shortness of breath. • Slight jaundice • Glossitis 2. Different features caused by different disorders

  20. Vit B12 deficiency: • peripheral neuropathy and subacute combined degeneration of the spinal cord with nervous system symptomssuch as numbness and tingling of the extremities, loss of position sense, muscle weakness and decreased tendon reflexes. • Folate deficiency : • not produce nervous system manifestations. • Pernicious anemia • abdominal pain, diarrhea, nausea, and vomiting • nervous system symptoms.

  21. 腺苷钴胺 ATP+VitB12 adenosylcobalamin Methylmalonyl CoA Succinyl CoA 甲基丙二酰辅酶A 琥珀酰辅酶A 合成神经鞘磷脂 代谢产物堆积，血、尿可测

  22. Laboratory Features • Blood • macrocytic anemia, with MCV↑(100~150fl or more). • But coexisting IDA, Thalassemia trait, or inflammation may prevent macrocytosis. • Erythrocytes show marked anisocytosis and poikilocytosis, with many oval macrocytes and in severe cases, basophilic stippling, Howell-Jolly bodies, and Cabot rings • Megaloblastic normoblasts may be seen. • Ret count is low.

  23. Leukopenia and thrombocytopenia are frequently present. • “Hypersegmented neutrophils” (more than five lobes) are an early sign of megaloblastosis. • --Platelets:smaller and vary more widely in size.(PDW increase)

  24. Bone Marrow: • --Moderate or marked hypercellularity. • -- M/E ratio ↓ • --Erythroid hyperplasia with striking megaloblasts (more than 10%). Promegaloblasts and early megalonormoblasts increase with mitotic figures abundant in severe cases. • basophilic stippling, Howell-Jolly bodies, and Cabot rings may be seen.

  25. The characteristics of megaloblasts: 1. Cells and nuclei are larger in size and the chromatin is more looser. 2. Marked nuclear-cytoplasmic asynchrony. The development of the nucleus is behind that of cytoplasm, called “young nucleus and old cytoplasm”

  26. Pathogenesis of MgA Impaired synthesis of one or more deoxyribonucleotides DNA replication and cell division are blocked,while synthesis of cytoplasm(RNA and protein) proceeds normally. Chramatin is looser RNA/DNA ratio rises and cytoplasm is basophilic Cells are larger in size

  27. megalopronormoblast pronormoblast

  28. Polychromatic megalonormoblast Early normablast

  29. Normoblasts and megalonormoblast

  30. Orthochromatic normoblast

  31. Megaloblastic changes 核畸形、多核、核碎裂的巨幼红细胞

  32. Howell-Jolley bodies Basophilic stippling normoblast

  33. Myeloid megaloblastic changes The megaloblastic myeloid cells may be larger in size, deforming nucleus with looser chromatin; specific granules reduce and vacuoles appear in cytoplasm. Hpersegmented neutrophils (also be seen in the peripheral blood) and giant metamyelocytes and bands present.

  34. Megakaryocytic megaloblastic changes Megakaryocytes are usually present either in normal or slightly increased numbers, but occasionally they are decreased in number, some are atypical and have a deeply basophilic agranular cytoplasm or hypersegmented nucleus.

  35. Tests for determining the causes of MA --Serum vitB12 (RIA <74~103 pmol/L) --Urinary excretion of methylmalonic acid --Serum folate assay( <6.91nmol/L or <3 ng /ml) --The red cell folate assay (RIA)< 227 nmol/L --Folic acid therapy test --Intrinsic factor and its antibody

  36. 【Diagnosis】 Two steps: 1.To establish the anemia is of MA 2.To determine the cause of the anemia. Diagnosis of typical MA: --Macrocytic—normochromic anemia --Megaloblastic haemopoiesis of erythroid. --Myeloid and megakaryocytic series are involved also.

  37. When MA is atypical, how to diagnose it? Clinical features: history, signs, and specific tests Myeloid megaloblastic changes

  38. Why myeloid megaloblastic changes take an important role --Minimal anemia or no anemia, erythroid changes have not appeared when the myeloid megaloblastic changes present. --Dimorphic anemia(MA +IDA), the blood will show a small number of oval macrocytes and almost always neutrophil hypersegmentation ; the marrow usually show intermmidiate megaloblasts and giant stab forms.

  39. --After treatment, the myeloid changes still present when erythroid megaloblasts disappear. --If MgA with hypocellularity when pregnancy, megaloblastic normoblasts and megakaryocytes are seldom seen, megaloblastic changes in myeloid are distinctive.

  40. Questions: 1. What are the characteristics of megaloblastic cells? 2. Why myeloid megaloblastic changes sometimes take an important role in the diagnosis of MA? 3. What are the common cause of MA? 4. How to diagnose MA caused by folic acid deficiency, Vit B12 deficiency,or pernicious anemia?

  41. ANEMIA REVIEW

  42. 贫 血 急性失血性贫血 慢性失血性贫血 微血管病性溶血性贫血 化学、物理、生物因素致溶血 脾功能亢进 阵发性睡眠性血红蛋白尿症 遗传性椭圆红细胞增多症等 遗传性球形红细胞增多症 葡萄糖6磷酸脱氢酶缺乏症 丙酮酸激酶缺乏症等 珠蛋白生成障碍性贫血 异常血红蛋白病 不稳定血红蛋白病 肾病、肝病、感染性疾病、 内分泌疾病等 缺铁性贫血 铁粒幼细胞性贫血等 白血病、骨髓瘤、癌转移、 骨髓纤维化等 再障，纯红再障等 骨髓增生异常综合征等 红细胞生成减少 红细胞破坏过多 红细胞丢失增加 红细胞 内在缺陷 外在异常 骨髓造血功能障碍 造血物质缺乏或利用障碍 膜异常 酶异常 Hb异常 免疫因素 非免疫因素 干细胞增殖分化障碍 骨髓被异常组织侵害 骨髓造血功能低下 铁缺乏和铁利用障碍 维生素B12或叶酸缺乏 各种原因致免疫性 溶血性贫血 巨幼细胞贫血等 贫血的病因及发病机制分类

  43. Anemia: weakness,fatigue, listlessness,palpitation, pallor jaundice, splenomegaly MCV increase normal decrease MCH MA IDA,SA,Thala MCHC infection decrease ret increase acute loss blood hypopoiesis HA (Coomb’s) decrease PL normal IHA infection extracellular defect intra- WBC chronic renal disease osmotic fragility decrease increase increase normal decrease AA,MF AM HS,HE, G-6PD, PK Thala PNH (ham’s) abnormalHb

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