Thalassaemia - Lecture Materials

Thalassaemia Recessively inherited Absence of synthesis of one of the 2 polypeptide chains (alpha or beta) which make the usual adult Hb (A2,B2) Causing anaemia and low MCHC Letter = chain affected à B thalassaemia = unable to make B chains Classification by genotype and phenotype (clinical severity) Alpha Thalassaemia Normal individuals have 2 copies the active Alpha globin gene on chromosome 16 = total of 4 copies HbBarts: Fetal Haemoglobin is a2/y2 = if a cannot be made at all then fetal Hb is y4 = non functional. Then the only functioning oxygen carrier is the protein haemoglobin Portland (switched off in early embryonic development) Profound anaemia à hypoxic damage to fetus à death HbH Excess of unpaired y chains in utero à formation of some y4 Definition Normal a+ thalassaemia heterozygous a+ thalassaemia homozygous ao thalassaemia heterozygous HbH disease Genotype a,a / a,a a,- / a,a HPLC Normal Normal a,- / a,- Normal a,a / -,- Normal a,- / -,- HbH a thalassaemia major -,- / -,- Hb Bart’s Phenotype and finding Normal Hb & MCHC Borderline low Hb & MCH, clinically asymptomatic Slightly anaemia. Low MCV and MCH. Clinically Asymptomatic Slightly anaemic, low MCH & MCV, clinically asymptomatic Anaemic, very low MCV and MCH, Splenomegaly, variable bone changes Severe non-immune intrauterine haemolytic anaemia. HbBarts hydrops fetalis, usually fatal HPLC = High performance liquid chromatography Beta Thalassaemia Normal individuals have 2 copies of B – one on each copy of Chr 11 There are 200+ different possible mutations to B gene Beta thalassaemia major usually become symptomatic at around 3 months of age Develop feeding problems and irritability Then massive hepatosplenomegaly (from haemolysis and extramedullary haematopoesis If untreated à growth failure, poor muscle development, short deviated legs, tendency to pathological fractures and frontal bossing with maxillary prominence due to bone marrow expansion Increased GI iron absorption can à iron overload à damage to liver and heart Without treatment life expectancy is 5-10 yrs (usually due to cardiac failure) Beta thalassaemia intermedia Maintain Hb above 7 (at the cost of intense marrow hyperplasia and splenomegaly Definition Normal Genotype B/B HPLC Normal B-thalassaemia trait B thalassamia intermedia -/B Hb A2 > 4% -/Bo or B+/B+ High HbF, variable B thalassaemia major -o/-o HbF > 90% (untransfused) Phenotype and clinical findings Normal HB, MCV & MCH, Asymptomatic Slightly anaemic, low MCV & MC, clinically asymptomatic Anaemia, very low MCV and MCH. Splenomegally, variable bone changes, variable transfusion dependency Severe haemolytic anaemia, very low MCV & MCH. Hepatosplenomegally, chronic transfusion dependence Testing Symptoms – can be from birth in alpha thal or from several months old in beta thal Microcytic hypochromic anaemia not responding to iron therapy (test ferritin or MCV to check compliance) Electrophoresis or chromatography Beta Thalassamia major = now / low Hb A AND high persistent Hb F Beta thalassaemia trait – Hb A slightly raised (>4%) HbH disease = about 20% y4 in neonatal period (cariable later in life) If mild anaemia (testing for mild alpha) then genetic Treatment If mild / carrier then DON’T iron supplement unless proven deficient (as can cause overload) Thalassamia intermedia / HbB – should be monitored closely. Transfusion occasionally required during periods of rapid growth / infection assoc aplastic crisis or pregnancy. Generally transfuse if Hb < 5.0, falling Hb with profound splenic enlargement, growth failure, poor school performance, decreased exercise tolerance, severe bone changes, pregnancy, infection or other specific complications including heart failure, hypertension, leg ulcers etc Thalassaemia Major – regular transfusion to Hb > 9.5, iron chelation to avoid overload, MDT care, hypersplenism, hydroxyurea, donor search for stem cell transplant