Thalassemia Dr.Alireza Nikanfar Hematology and oncology research center of Tabriz University of...
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Transcript of Thalassemia Dr.Alireza Nikanfar Hematology and oncology research center of Tabriz University of...
ThalassemiaThalassemia
Dr.Alireza NikanfarDr.Alireza Nikanfar
Hematology and oncology research Hematology and oncology research center of Tabriz University of center of Tabriz University of Medical SciencesMedical Sciences
Hemoglobin Structure Hemoglobin Structure
tetramer of globin polypeptide chains: tetramer of globin polypeptide chains: a pair of a pair of αα -like chains 141 amino -like chains 141 amino acids long and a pair of acids long and a pair of ßß -like chains -like chains 146 amino acids long 146 amino acids long
The major adult hemoglobin, HbA, has The major adult hemoglobin, HbA, has the structure the structure αα2 2 ßß22. HbF (. HbF (αα22 γγ22) ) predominates during most of predominates during most of gestation, and HbA2 (gestation, and HbA2 (αα22δδ22) is a minor ) is a minor adult hemoglobin. adult hemoglobin.
Hemoglobin StructureHemoglobin Structure
Each globin chain enfolds a single Each globin chain enfolds a single heme moiety, consisting of a heme moiety, consisting of a protoporphyrin IX ring complexed protoporphyrin IX ring complexed with a single iron atom in the ferrous with a single iron atom in the ferrous state (Festate (Fe22+), +),
Each heme moiety can bind a single Each heme moiety can bind a single oxygen molecule; every molecule of oxygen molecule; every molecule of hemoglobin can thus transport up to hemoglobin can thus transport up to four oxygen molecules. four oxygen molecules.
Thalassemia Syndromes Thalassemia Syndromes
inherited disorders ofinherited disorders of αα- or - or ßß-globin -globin biosynthesis biosynthesis
The reduced supply of globin The reduced supply of globin diminishes production of hemoglobin diminishes production of hemoglobin tetramers, causing hypochromia and tetramers, causing hypochromia and microcytosis. microcytosis.
Unbalanced chain accumulation Unbalanced chain accumulation dominates the clinical phenotype dominates the clinical phenotype
αα-Thalassemia -Thalassemia Syndromes Syndromes
αα-thalassemia-2 trait, in which one of -thalassemia-2 trait, in which one of the four the four αα-globin loci is deleted -globin loci is deleted
αα -thalassemia-1 trait, with two deleted -thalassemia-1 trait, with two deleted lociloci
HbH disease, with three loci deleted HbH disease, with three loci deleted hydrops fetalis with Hb Bart's, with all hydrops fetalis with Hb Bart's, with all
four loci deleted four loci deleted
Nondeletion forms Nondeletion forms
αα-Thalassemia -Thalassemia SyndromesSyndromes
αα -Thalassemia-2 trait -Thalassemia-2 trait is an asymptomatic, is an asymptomatic, silent carrier state. silent carrier state.
αα -Thalassemia-1 trait-Thalassemia-1 trait resembles - resembles -thalassemia minor thalassemia minor
Heterozygosity for a deletion that removes Heterozygosity for a deletion that removes both genes from the same chromosome (both genes from the same chromosome (ciscis deletion) is common in Asians and deletion) is common in Asians and Mediterranean individuals, as is homozygosity Mediterranean individuals, as is homozygosity for -thalassemia-2 (for -thalassemia-2 (transtrans deletion). Both deletion). Both produce asymptomatic hypochromia and produce asymptomatic hypochromia and microcytosis. microcytosis.
αα-Thalassemia -Thalassemia SyndromesSyndromes
In In HbH diseaseHbH disease, HbA production is only 25 to , HbA production is only 25 to 30% of normal 30% of normal
In adults, unpaired chains accumulate and In adults, unpaired chains accumulate and are soluble enough to form are soluble enough to form ßß44 tetramers called tetramers called HbHHbH
Patients with HbH disease have thalassemia Patients with HbH disease have thalassemia intermedia characterized by moderately intermedia characterized by moderately severe hemolytic anemia but milder ineffective severe hemolytic anemia but milder ineffective erythropoiesis erythropoiesis
Survival into midadult life without transfusions Survival into midadult life without transfusions is common. is common.
αα-Thalassemia -Thalassemia SyndromesSyndromes
The homozygous state for the The homozygous state for the αα--thalassemia-1 thalassemia-1 ciscis deletion (hydrops fetalis) deletion (hydrops fetalis) causes total absence of causes total absence of αα-globin synthesis -globin synthesis
Excess Excess γγ globin forms tetramers called globin forms tetramers called Hb Hb Bart'sBart's ( (γγ44), which has an extraordinarily ), which has an extraordinarily high oxygen affinity high oxygen affinity
It delivers almost no OIt delivers almost no O22 to fetal tissues, to fetal tissues, causing tissue asphyxia, edema (hydrops causing tissue asphyxia, edema (hydrops fetalis), congestive heart failure, and fetalis), congestive heart failure, and death in utero. death in utero.
ßß -Thalassemia -Thalassemia Syndromes Syndromes
Mutations causing thalassemia can Mutations causing thalassemia can affect any step in the pathway of affect any step in the pathway of globin gene expression: globin gene expression:
Hypochromia and microcytosis Hypochromia and microcytosis In heterozygotes (In heterozygotes (ßß -thalassemia -thalassemia
trait), this is the only abnormality trait), this is the only abnormality seen; anemia is minimal. seen; anemia is minimal.
ßß -Thalassemia -Thalassemia SyndromesSyndromes
In homozygous states accumulation of highly In homozygous states accumulation of highly insoluble unpaired insoluble unpaired αα chains, which form toxic chains, which form toxic inclusion bodies that kill developing inclusion bodies that kill developing erythroblasts in the marrow ineffective erythroblasts in the marrow ineffective erythropoiesis erythropoiesis
The few surviving red cells bear a burden of The few surviving red cells bear a burden of inclusion bodies, detected in the spleen, inclusion bodies, detected in the spleen, shortening the red cell life span and producing shortening the red cell life span and producing severe hemolytic anemia. severe hemolytic anemia.
Erythroid hyperplasia can become exuberant Erythroid hyperplasia can become exuberant and produce extramedullary erythropoietic and produce extramedullary erythropoietic tissue in the liver and spleen tissue in the liver and spleen
ßß -Thalassemia -Thalassemia SyndromesSyndromes
Massive bone marrow expansion Massive bone marrow expansion deranges growth and development. deranges growth and development.
"chipmunk" facies "chipmunk" facies thinning and pathologic fracture of thinning and pathologic fracture of
long bones and vertebrae due to long bones and vertebrae due to cortical invasion by erythroid cortical invasion by erythroid elements, elements,
profound growth retardation profound growth retardation
ßß -Thalassemia -Thalassemia SyndromesSyndromes
Hemolytic anemia causes Hemolytic anemia causes hepatosplenomegaly, leg ulcers, hepatosplenomegaly, leg ulcers, gallstones, and high-output congestive gallstones, and high-output congestive heart failure. heart failure.
The conscription of caloric resources to The conscription of caloric resources to support erythropoiesis leads to inanition, support erythropoiesis leads to inanition, susceptibility to infection, endocrine susceptibility to infection, endocrine dysfunction, and, in the most severe dysfunction, and, in the most severe cases, death during the first decade of cases, death during the first decade of life. life.
ßß -Thalassemia -Thalassemia SyndromesSyndromes
Severity is highly variable Severity is highly variable Alleles associated with milder Alleles associated with milder
synthetic defects and coinheritance synthetic defects and coinheritance of of
αα-thalassemia trait reduce clinical -thalassemia trait reduce clinical severity severity
HbF persists to various degrees in HbF persists to various degrees in thalassemias. thalassemias.
ßß -Thalassemia -Thalassemia SyndromesSyndromes
ßß-thalassemia major-thalassemia major ßß-thalassemia intermedia-thalassemia intermedia can can
survive without transfusion survive without transfusion ßß-thalassemia minor-thalassemia minor and and ßß--
thalassemia traitthalassemia trait describe describe asymptomatic heterozygotes for asymptomatic heterozygotes for ßß thalassemia thalassemia
Diagnosis Diagnosis
The diagnosis of The diagnosis of ßß-thalassemia major is -thalassemia major is readily made during childhood on the readily made during childhood on the basis of severe anemia accompanied basis of severe anemia accompanied by hepatosplenomegaly; profound by hepatosplenomegaly; profound microcytosis; a characteristic blood microcytosis; a characteristic blood smear ; and elevated levels of HbF, smear ; and elevated levels of HbF, HbA2, or both. HbA2, or both.
Patients with Patients with ßß-thalassemia intermedia -thalassemia intermedia exhibit similar stigmata but can survive exhibit similar stigmata but can survive without chronic hypertransfusion. without chronic hypertransfusion.
DiagnosisDiagnosis
ßß-Thalassemia minor (i.e., -Thalassemia minor (i.e., ßß thalassemia thalassemia trait) usually presents as profound trait) usually presents as profound microcytosis and hypochromia with target microcytosis and hypochromia with target cells but only minimal or mild anemia cells but only minimal or mild anemia
The mean corpuscular volume is rarely >75 The mean corpuscular volume is rarely >75 fL; the hematocrit is rarely <30 to 33%. fL; the hematocrit is rarely <30 to 33%.
Hemoglobin electrophoresis classically Hemoglobin electrophoresis classically reveals an elevated HbA2 (3.5 to 7.5%), but reveals an elevated HbA2 (3.5 to 7.5%), but some forms are associated with normal some forms are associated with normal HbA2 and/or elevated HbF. HbA2 and/or elevated HbF.
DiagnosisDiagnosis
Persons with Persons with αα-thalassemia trait may -thalassemia trait may exhibit mild hypochromia and exhibit mild hypochromia and microcytosis, usually without anemia microcytosis, usually without anemia
HbA2 and HbF levels are normal. HbA2 and HbF levels are normal. HbH disease resembles HbH disease resembles ßß--
thalassemia intermedia, with the thalassemia intermedia, with the added complication that the HbH added complication that the HbH molecule behaves like a moderately molecule behaves like a moderately unstable hemoglobin. unstable hemoglobin.
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