Topic 5.2 Sideroblastic Anemia PDF

MTH65-213 Hematology I Microcytic anemia II : Sideroblastic anemia and Iron overload Asst. Prof. Dr. Wilawan Asst. Prof. Dr. Orawan Assoc. Prof. Dr. Manit Palachum, FHEA Sarakul, SFHEA Nuinoon, F...

MTH65-213 Hematology I Microcytic anemia II : Sideroblastic anemia and Iron overload Asst. Prof. Dr. Wilawan Asst. Prof. Dr. Orawan Assoc. Prof. Dr. Manit Palachum, FHEA Sarakul, SFHEA Nuinoon, FHEA Lecturer in Medical Technology Program Lecturer in Medical Technology Program Lecturer in Medical Technology Program School of Allied Health Sciences School of Allied Health Sciences School of Allied Health Sciences Walailak University Walailak University Walailak University Nakhon Si Thammarat, THAILAND Nakhon Si Thammarat, THAILAND Nakhon Si Thammarat, THAILAND Academic Building 7, room 145 Academic Building 7, room 255 Academic Building 7, room 203 E-mail address: [email protected] E-mail address: [email protected] E-mail address: [email protected] Intra-phone 72690 Intra-phone 72622 Intra-phone 72629 2  Learning Objectives 1. To describe the causes and pathology of sideroblastic anemia and iron overload 2. To describe the laboratory tests for sideroblastic anemia and iron overload diagnosis 3 Sideroblastic anemia 4  Classification and Diagnosis of Anemia Microcytic Anemia anemid Microcystic MCV *** *** 55  Sideroblastic anemia Sideroblastic anemias (SA) are a heterogeneous group of disorders characterized by pathologic iron accumulation in the mitochondria of erythroid precursors. – Abnormal, iron-laden mitochondria encircle nuclei “ringed sideroblasts” เห กเก Sideroblastic anemias (SA) เป็นกลุ่ มของความผิ ดปกติ ท่ี แตกต่ างกันซึ่ งมี ลักษณะเป็นการสะสมของธาตุ เหล็ กทางพยาธิ วิทยาในไมโตคอนเดรี ยของสาร ตั้งต้นของเม็ ดเลื อดแดง - ไมโตคอนเดรี ยที่ มีธาตุ เหล็ กผิ ดปกติ ล้อมรอบนิ วเคลี ยส "ไซเดโรบลาสต์ วงแหวน" A common feature of sideroblastic anemias: ลักษณะทั่ วไปของภาวะโลหิ ตจางไซด์โรบลาสต์: 1) ซิ เดโรบลาสต์ทางพยาธิ วิทยาจํานวนมากในไขกระดู ก 1) Large numbers of pathologic sideroblasts in the marrow 2) การสร้างเม็ ดเลื อดแดงที่ ไม่ มีประสิ ทธิ ภาพ ครนดทส้าง FL k 3) เพิ่ มระดับธาตุ เหล็ กในเนื ้อเยื่ อ 2) Ineffective erythropoiesis ·ค. สามารถ การส าง RBC- 4) สัดส่ วนที่ แตกต่ างกันของเม็ ดเลื อดแดงไฮโปโครมิ กในเลื อด 3) Increased levels of tissue iron 4) Varying proportions of hypochromic erythrocytes in the blood ↑ RBC ด 66 สี ล็ ร้ ติ  Ring sideroblast Ring sideroblasts are defined as erythroid precursors containing deposits of non-heme iron in mitochondria forming a ring-like distribution around the nucleus. The iron-formed ring covers at least one-third of the nucleus rim. Normal marrow stained with Prussian blue. Sideroblastic anemia Note the florid increase in Prussian blue– staining granules (ringed sideroblast) in the erythroblasts, most with circumnuclear locations. 77  Etiology of Sideroblastic Anemias เห ก งเคราะ heme ไ %เอา Defective heme synthesis includes impaired synthesis of heme, impaired iron-sulfur (Fe-S) cluster assembly and transport, or impaired synthesis of mitochondrial and cytosolic proteins essential for heme synthesis leading to deposition of iron granules in mitochondria. 88 Congenital sideroblastic anemia: Advances in gene mutations and pathophysiology, Gene, Volume 668, 2018, Pages 182-189, ห์ สั ล็  Heme Synthesis Heme synthesis pathway: 1 https://youtu.be/3PgQOaiTMCs * * enz. ุมก. ค งเครา home & 2 * * 3 4 5 6 7 # 8 9 สั  Sideroblastic anemia Causes of sideroblastic anemia: 1. Congenital defect: sex-linked recessive due to an abnormal δ-aminolevulinate synthase enzyme (ALAS2) >> RBC morphology >> hypochromic microcytic or dimorphic 2. Acquired defect: -Myelodysplastic syndromes (MDS), Malignant marrow disorders, polycythemia vera, myeloma -Drugs: isoniazid (INH), chloramphenicol -Toxin: alcohol, chronic lead poisoning >> RBC morphology >> hypochromic with vary in size depend on causes ↳ม า ่ใ เหล แต ใช 10 ล้ มี  Congenital sideroblastic anemia 1. Congenital sideroblastic anemia (CSA) is rare. – X-linked sideroblastic anemia (XLSA) (~40%) · G ALAS2 – Autosomal recessive (ARCSA) (~35–40%) – Mitochondrial DNA point mutations or large deletions (~20%) **The CSA is further classified as syndromic ** or non-syndromic. * Congenital sideroblastic anemia: Advances in gene mutations and pathophysiology, Gene, Volume 668, 2018, Pages 182-189, 11  X-linked sideroblastic anemias (XLSAs) X-linked recessive inheritance ALAS2 gene mutation The most common form is caused Impaired iron utilization by mutation of the erythroid- specific 𝛿𝛿-aminolevulinic acid Defective heme synthesis - น ดปก ใ synthase gene (ALAS2). เห > Low activity of ALAS2 in erythroid Decreased Hb Iron accumulation synthesis & deposition cells. Ineffective Ringed XLSA is characterized by mild erythropoiesis sideroblasts ส า ง RBC ไ ไ Anemia ม อน mitochondr hypochromic, microcytic เห กสะส sideroblastic anemia in Increased iron absorption combination with systemic iron overload. Systemic iron overload 12 12 ติ ล็ ม่ ร้ ช้ ผิ ยื ร้ ล็  Acquired sideroblastic anemia 2. Acquired sideroblastic anemia is more common. – Primary acquired clonal sideroblastic anemia Myelodysplastic syndrome with ring sideroblasts (MDS-RS) – Secondary acquired sideroblastic anemia/ Drug- and Toxin-induced sideroblastic anemia ษา ณโ ยา ก โ Drugs such as Isoniazid (INH), chloramphenicol, or linezolid ! ตะ1 Toxins such as Heavy metal poisoning (Lead, Arsenic), Overdose (Zinc), Deficiency (Copper), Vitamin B6 deficiency, Alcohol 13 13 รั วั  Lead poisoning (ALAS1/2) Lead poisoning (plumbism) Acquired condition leading to (ALAD) - sideroblastic anemia. (PBGD) Lead (Pb2+) ไปได้ Passes through the blood (URO3S) Bone marrow ยอดก าเ ท ลา (UROD) Pb2+ Accumulate in the mitochondria of normoblast (CPO) Inhibit enzymes involving Heme synthesis; 𝛿𝛿- (PPO) aminolevulinic acid dehydratase (ALAD) and ferrochelatase (FECH). (FECH) - ร 14 14 ทุ ำ  Lead poisoning and anemia Lead interferes several steps of heme synthesis – Inhibit the conversion of aminolevulinic acid to porphobilinogen >>>accumulation of aminolevulinic acid สะส – Interfere the incorporation of iron into protoporphyrin IX by ferrochelatase >>> accumulate of iron and protoporphyrin IX สะสม Accumulation of 𝛿𝛿-aminolevulinic acid (𝛿𝛿-ALA) Accumulate of iron and protoporphyrin IX http://www.namrata.co/answe20r- clinical-problem-lead-poisoning/ 15 Lead poisoning Routes of exposure to lead include contaminated air, water, soil, food, and consumer products. Acute intoxication; neurological symptoms (paresis and muscle contractions), digestive symptoms (nausea, vomiting, abdominal pain, and constipation). Chronic lead intoxication; renal impairment, neuropsychiatric disorders, and specific skin changes (Burton lines & plumbemic skin) Anemia occurs in both acute and chronic forms. 16 16  Lead poisoning and anemia Anemia in leadpoisoning: -Hypochromic RBC, Hemolytic anemia -basophilic stippling cause by lead interfering the breakdown of ribosomal RNA >> ribosome aggregated in RBC http://www.medical-labs.net/basophilic-stippling-142/ 17  Alcoholism Alcohol interferes with some (ALAS2) - enzymes of hemoglobin synthesis including: (ALAD) inhibition of activity of ALAS2 inhibition of activity of (PBGD) uroporphyrinogen decarboxylase (UROD) and ferrochelatase (FECH) งเคราะห ์D (URO3S) Alcohol direct effect on folate (UROD) - metabolism, absorption, storage and release. ↑ block เพ (CPO) (PPO) (FECH) - 18 18 สั  Sideroblastic anemia Characteristic of sideroblastic anemia: 1.Increase in total body iron ↑ 2.Presence of ringed sideroblasts inbone marrow 3.Chronic hypochromic anemia 7 RBC ซ 4.Ineffective erythropoiesis=ส าง RBC ไ Hemoglobin 5.Increase serum iron and serumferritin เห กสะสม : 19 ม่ ล็ ร้  Sideroblastic anemia Laboratory features *Anemia usually moderate to severe *Dimorphic picture of normochromic and hypochromic cell ↳ ด *Mild macrocytosis is found in some patient, especially in acquired types (MDS, Alcoholism) *Pappenheimer bodies in erythrocytes (Pappenheimer bodies are abnormal granules of iron found inside red blood cells. When cells are stained with Giemsa or Wright stain, they appear as blue-purple granules adjacent to the cell membrane. Prussian blue stain can be used to demonstrate the presence of iron.) *Normal or increase platelet *Ringed sideroblasts in bone marrow 20 สิ่ ตั  Sideroblastic Anemia: Peripheral smear (A) Hypochromic, microcytic (A & B) The dimorphic population of RBCs (C) Pappenheimer bodies ลเห -แกร ไ ใน R ก เ จอ BC ต (D) Ringed sideroblasts in bone marrow (Prussian blue staining) 21 21 ด้ นู ล็  Sideroblastic Anemia: Treatment Management of sideroblastic anemia depends on severity – For congenital sideroblastic anemia such as X-linked sideroblastic anemia, oral pyridoxine or blood transfusion +/- iron chelation or phlebotomy in case of normal Hb level – For secondary acquired sideroblastic anemia caused by known drugs or toxins, such drugs or toxins should be discontinued and avoided. Since it is acquired, anemia will improve after the removal of the drug. – Salt of ethylenediamine tetraacetic acid (salt of EDTA) for lead chelating >> excreted in the urine 22 22 Iron overload 23  Iron Overload Iron overload is an increase in the amount of body iron resulting from a sustained expansion of iron supply beyond iron requirements. ใช้ไ ไ หมด > สะสม 3 เ น ษ อตรง When the accumulation overwhelms the cellular capacity for safe storage, potentially lethal tissue damage is the result. The toxic manifestations of iron overload vary with the precise pathogenic defect responsible but are dependent on the amount of excess iron, rate of iron accumulation, cellular pattern of deposition, and presence of complicating factors such as hepatitis or drug or alcohol use. 24 24 ม่ ป็ พิ ต่ ที  Classification of Iron Overload Excess accumulation of iron results from body’s rate of iron acquisition exceeds the rate of loss Main types of iron overload 1.Hereditary: Hepcidin deficiency of genetic origin (Hemochromatosis) >Type 1 hemochromatosis mutation of HFE gene (Cys282Tyr (C282Y)) , which controls the amount of iron absorbed from food (autosomal recessive) >Type 2A hemochromatosis (juvenile hemochromatosis) mutations in the hemojuvelin (HJV) gene >Type 2B hemochromatosis mutations in the hepcidin gene (HAMP) >Type 3 hemochromatosis mutations in the transferrin receptor 2 (TFR2) gene >Type 4 hemochromatosis mutations in the ferroportin gene (SLC40A1) 25  Hemochromatosis ไม A genetic defect in the regulation of hepcidin production- - งเคราะะ ดปก An inappropriately elevated iron absorption at any level of body iron - A chronic progressive increase in body iron stores along with enhanced release of iron from reticuloendothelial macrophages. Iron overload Neil D. Theise.Liver and Gallbladder. In:Robbins ↑ and Cotrans Pathologic Basis of Disease. 9th ว ไไ ม คน b edition. 26 ผิ มี สั่ ห์ ม่ สั  Classification of Iron Overload 2. Acquired iron overload Iron overload by acquired hepcidin deficiency: dyserythropoiesis-related iron overload In thalassemia, either thalassemia major before any transfusion, or thalassemia intermedia (which do not require transfusions) In myelodysplastic syndromes which can develop iron overload independently of any transfusions Several medullary factors are involved in dyserythropoiesis, such as GDF15 (growth and differentiation factor 15), TWSG1 (twisted gastrula- tion modulation factor 1), and erythroferrone (ERFE), generating hypohepcidinemia. Iron overload by excessive parenteral entry of iron Transfusional iron overload Iron overload due to excessive supplementation of parenteral iron such as overdose of intravenous ferric hydroxide-sucrose (Venofer® ) or ferric carboxymaltose, especially in chronic renal failure with hemodialysis 27 27  Iron overload เห ินแ กเก วไปไ ↓ ไป สะสม ↓ organ ดปก https://slideplayer.com/slide/5706137/ 28 ล้ ล็ ผิ  Hemochromatosis The common phenotype The combination of hypersideremia Increased transferrin saturation Parenchymal type of iron excess (in the first place the hepatocytes) 29 29  Iron overload & IDA & ACD * Test Iron Normal Iron Iron deficiency IDA ACD ACD+ overload depletion erythropoiesis IDA Serum iron (µmol/L) H 10-30 N L L L L # Serum ferritin (µg/L) H ≥100 L L L N/H N/L Transferrin saturation H 20-50 N L L L L (%) TIBC L 300-360 N N H L N/L Hb (µg/dL) N ≥12 N N L L L Anemia No No Yes N: normal; H: high; L: low ที่มา: (จํานงค นพรัตน, 2562, น. 9) 30  References 1.Hoffbrand AV. , Moww PAH. Essential hematology. 6th ed. 2011 2.Mckenzie SB. Clinical labolatory hematology. New Jersey: Pearson education, 2004. 3.Rodax BF. Hematology: Clinical principles and applications. 3rd ed. China: W.B. Saunders company, 2007. 4.Turgeon ML. Clinical hematology: theory and procedures. 4th ed. Baltimore : 5.Lippincott Williams & Wilkins, 2005. 31