THALASSEMIA DEFINITION INHERITANCE BASICS 2014/03/04. THALASSA : GREEK WORD GREAT SEA First observed: MEDITTERANIAN SEA

Transcription

1 THALASSA : GREEK WORD GREAT SEA First observed: MEDITTERANIAN SEA THALASSEMIA Fareed Omar Paediatric Oncologist Steve Biko Academic Hospital University of Pretoria DEFINITION Thalassemia syndromes are a heterogeneous group of inherited anaemia characterised by reduced or absent synthesis of either Alpha or Beta globin chains of Hb A Most common single gene disorder BASICS Hb A:(2α/2β) chains forming a tetramer 97% of adult Hb Postnatal life Hb A replaces Hb F by 6 months Fetal Hb (Hb F): (2α/2γ) 1% of adult Hb 70-90% at term. Falls to 25% by 1 st month and progressively Hb A2: (2α/2δ) 1.5-3% of adult Hb Autosomal recessive Beta thal: point mutations on chromosome 11 Alpha thal: gene deletions on chromosome 16 INHERITANCE 1

2 CLASSIFICATION If α chain /absent: alpha thalassemia Will affect all 3 N Hb s : HbA(2α, 2β), HbA2 (2α, 2δ), HbF(2α, 2γ) HbH (β 4 ) (HbA) ; HbBart s (γ 4 ) (HbF) If β chain /absent: Beta thalassemia Only affect adult Hb(HbA) (2 α, 2β) β + thal: reducedsynthesis heterozygous β 0 thal: absentsynthesis homozygous CLASSIFICATION OF β THALASSEMIA CLASSIFICATION GENOTYPE CLINICAL SEVERITY β thal minor/trait β/β +, β/β 0 Silent βthalintermedia β + /β +, β + /β 0 Moderate βthalmajor β 0 /β 0 Severe NO.OF GENES PRESENT α-thalassemia GENOTYPE 4 genes αα/ αα Normal CLINICAL CLASSIFICATION 3 genes αα/ -α Silent carrier 2 genes -α/-α OR α thalassemia trait αα/ -- 1 gene -α/-- HbH Hemoglobin H Disease Second most severe form alpha thalassemia. Only one gene producing alpha chains (--/-a). Results in accumulation of excess unpaired gamma or beta chains. HbH (β 4 ) (HbA) 0 genes --/-- HbBarts/ Hydrops fetalis Hemoglobin H Disease Live normal life; however, infections, pregnancy, exposure to oxidative drugs may trigger hemolytic crisis. RBCs are microcytic, hypochromic with marked poikilocytosis. Numerous target cells. HbH vulnerable to oxidation. Gradually precipitate in vivo to form Heinz-like bodies of denatured hemoglobin. BART S HYDROPS FETALIS SYNDROME Most severe form. Incompatible with life. Have no functioning alpha chain genes (--/--). Baby born with hydrops fetalis (edema and ascites caused by accumulation serous fluid in fetal tissues as result of severe anemia) Hepato-splenomegaly Cardiomegaly 2

3 BART S HYDROPS FETALIS SYNDROME Hemoglobin Bart's has high oxygen affinity so cannot carry oxygen to tissues. Fetus dies in utero or shortly after birth. At birth, see severe hypochromic, microcytic anemia with numerous NRBCs. Pregnancies dangerous to mother. Increased risk of toxemia and severe postpartum hemorrhage. ALPHA THALASSEMIA Usually no treatment indicated 4 deletions incompatible with life 3 or fewer deletions have only mild anemia CLASSICAL SYNDROMES OF BETA THALASSEMIA Silent carrier state the mildest form of beta thalassemia. Beta thalassemia minor-heterozygous disorder resulting in mild hypochromic, microcytic hemolytic anemia. Beta thalassemia intermedia-severity lies between the minor and major. Beta thalassemia major-homozygous disorder resulting in severe transfusion-dependent hemolytic anemia. PATHOPHYSIOLOGY Since βchain synthesis reduced: Gamma (γ) and delta (δ) chains combine with normally produced alpha (α) chains. HbF (2α, 2γ) and HbA2 (2α, 2δ) Relative excess of αchains αtetramers form aggregates precipitate in red cells inclusion bodies premature destruction of maturing erythroblasts within the marrow (Ineffective erythropoiesis) or in the periphery (Haemolysis) destroyed in the spleen PATHOPHYSIOLOGY Anaemia results from lack of adequate HbA tissue hypoxia EPO production erythropoiesis in the marrow and sometimes extramedullary expansion of medullary cavity of various bones Liver & spleen enlarge extramedullary hematopoiesis 3

4 EFFECTS OF MARROW EXPANSION HEPATOMEGALY Pathological fractures due to cortical thinning Deformities of skull and face Sinus and middle ear infection due to ineffective drainage Folate deficiency Hypermatabolic state fever, wasting Increased absorption of iron from intestine Extra medullary erythropoeisis Iron released from breakdown of endogenous or transfused RBC s cannot be utilized for Hb synthesis -> hemosiderosis Hemochromatosis Infections -> transfusion related (Hep B, C, HIV) Chronic active hepatitis SPLENOMEGALY Extra medullary hematopoeisis Work hypertrophy due to constant hemolysis Hypersplenism (progressive splenomegaly) JAUNDICE Unconjugated hyperbilirubinemia haemolysis Hepatitis transfusion, hemochromatosis GB stones obstructive jaundice Cholangitis INFECTIONS - CAUSES Poor nutrition Increased iron in body Blockage of monocyte-macrophage system Hypersplenism leukopenia Infections associated with transfusions CLINICAL FEATURES (Thal Major) Infants: Age of presentation: 6-9mo (HbF replaced) Progressive pallor and jaundice Cardiac failure FTT, gross motor delay Feeding problems Bouts of fever and diarrhoea Hepato-splenomegaly 4

5 CLINICAL FEATURES (Thal Major) SKELETAL CHANGES Childhood: Growth retardation Severe anaemia cardiac dilatation Transfusion dependent Jaundice Changes in skeletal system Chipmunk facies(hemolytic facies): Frontal bossing, maxillary hypertrophy, depression of nasal bridge, malocclusion of teeth Paravertebral masses: Broad expansion of ribs at vertebral attachement Paraparesis Pathalogical fractures: Cortical thinning Increased porosity of long bones OTHERS Short stature premature fusion of epiphyses Delayed menarche Gall stones, leg ulcers Pericarditis Diabetes / cirrhosis Evidence of hypersplenism CLINICAL FEATURES (Thal intermedia) Moderate pallor (Hb usually >6g/dl) Anaemia worsens with pregnancy and infections (erythroid stress) Less transfusion dependent Skeletal changes present, progressive splenomegaly Growth retardation Longer survival than Thal major CLINICAL FEATURES (Thal minor) Usually ASYMPTOMATIC Mild pallor, no jaundice No growth retardation, no skeletal abnormalities, no splenomegaly MAY PRESENT AS IRON DEF ANAEMIA (Hypochromic microcytic anaemia) Unresponsive / refractory to Fe therapy Normal life expectancy 5

6 LAB DIAGNOSIS OF THALASSEMIA FBC WITH DIFFERENTIAL Need to start with patient's individual history and family history. Ethnic background important. Perform physical examination: Pallor indicating anemia. Jaundice indicating hemolysis. Splenomegaly due to pooling of abnormal cells. Skeletal deformity, especially in beta thalassemia major. Microcytic hypochromic pattern: Hb; HCT; MCV; N/ MCHC N/ RBC count (differentiate from iron def) N RDW (differentiate from iron def) Mild to moderate poikilocytosis In severe cases, target cells and elliptocytes. Polychromasia, basophilic stippling, and NRBCs Reticcount: HEMOGLOBIN ELECTROPHORESIS Haemoglobin Major Minor Normal HbF 10 98% Variable <1 % Hb A Absent 80 90% 97% Hb A2 Variable 5 10% (increased) 1 3% ROUTINE CHEMISTRY TESTS Indirect bilirubin in thal major and intermed Assessment of Fe status, TIBC, and ferritin level important in differentiating thalassemia from iron deficiency anemia. ThalMajor: HbF: 98% HbA2: 2% HbA: 0% OTHER SPECIAL PROCEDURES Globin Chain Testing -determines ratio of globin chains being produced. DNA Analysis -Determine specific defect at molecular DNA level. PRENATAL DIAGNOSIS β/αratio: <0.025 in fetalblood Thalmajor Chorionic villous biopsy at weeks Amniocentesis at wkgestation Analysis of fetaldna PCR to detect βglobin gene 6

7 Differential Diagnosis of Microcytic, Hypochromic Anemias RDW Serum Fe TIBC Serum Ferritin Iron deficiency Alpha thalassemia N N N N Beta thalassemia N N N N Anaemiaof chronic disease Sideroblastic anaemia N N TREATMENT Regular blood transfusions (BT) mainstay of care for Thalmajor (and many with Thal intermedia) Purpose of BT: 1) Improve anaemia 2) Suppress ineffective eryhropoiesis Regular BT prevent most of the serious growth, skeletal and neurological complications Lead poison N N N N TREATMENT BT intervals: 3-4 weeks Aim to maintain pre-transfusion Hb: 9 10g/dl If cardiac insufficiency: aim for higher Hb levels (10 12g/dl) and transfuse at slower rate Leucocyte depleted PRBC s IRON OVERLOAD Iron overload major cause of morbidity, organ injury and mortality 1 U of blood contains approximately 250mg iron Non-transfused patients also develop iron overload (intestinal absorption) ACCUMULATION OF IRON Deposition in pituitary endocrine disturbance short stature, delayed puberty, poor secondary sexual characteristics Hemochromatosis cirrhosis of liver Cardiomyopathy (cardiac hemosiderosis) cardiac failure, sterile pericarditis, arrythmias, heart block Deposition in pancreas diabetes mellitus ACCUMULATION OF IRON Lungs: restrictive lung defects Adrenal insufficiency Hypothyroidism, hypoparathyroidism Increased susceptibility to infections (iron favours bacterial growth) espyersinia infections 7

8 Monitor s-ferritin after BT every 3 months S-Ferritin >1000ng/ml need chelation S-Ferritin not accurate reflection of absolute iron status Liver iron concentration (LIC) liver biopsy to measure dry iron weight Need to measure cardiac iron concentration as well Annual cardiac assessment with ECG and U/S MRI T2 non invasive alternative to assess liver and cardiac status annually With effective chelation can live a normal life DESFERRIOXAMINE IV/SC infusion pump over 12 hrperiod 5-6 days / week Start when s-ferritin >1000ng/ml Dose: 30-60mg/kg/day Big problem: poor compliance in <5 yrs ADVERSE EFFECTS: Cardiotoxicity arrythmias Eyes cataracts Ears sensorimotor hearing loss Bone dysplasia growth retardation Rapid infusion histamine related reaction: hypotension, erythema, pruritis Infection, sepsis DEFERASIROX (Exjade): Oral preperation Not registered in under 2 yr Compliance much better ADVERSE EFFECTS: Mainly GE: abdpain, D&V Skin rash, headache, fever, cough SPLENECTOMY Deferred as long as possible at least till 5-6 years of age INDICATIONS: Massive splenomegaly causing mechanical discomfort Progressively increasing blood transfusion requirements (> ml kg/yr) Other oral: Deferiprone 8

9 STEM CELL TRANSPLANTATION No prospective randomized clinical trials can be designed for definitive answer Decision highly individualized Need to consider: Age; clinical status, donor availability, compliance, risk 90% O/S; 80% TFS STEM CELL TRANSPLANTATION PATIENTS SC SOURCE OS TFS REFERENCE 70 MSD/MRD 83% 73% Ghavamzadehet al MUD 79% 40% La Nasa et al CORD 100% 79% Locatelli et al HAPLO 93% 71% Sodani et.al THANK YOU 9