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1
THALASSEMIA
HEMATO-ONCOLOGY DIVISIONPEDIATRIC DEPARTEMENT
MEDICAL SCHOOL UNIVERSITY OF NORTH SUMATERA
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HEMOGLOBINOPATHIES
CLASSIFIED INTO TWO MAJOR GROUPS
1. THALASSEMIAS Quantitative deficiencies in the
production of globin chains
2. HEMOGLOBINS DISORDER Structural abnormalities of globin chains
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CLASSIFICATION OF THE COMMON THALASSEMIAS AND RELATED DISORDERS
-Thalassemia+ o
- Thalassemia i
+ Hb Lepore thalassemia ()o (Aγ)o
εγ- Thalassemia(εγ)o
- Thalassemia-or- Thalassemia associated with -chain variants
Hb S -ThalassemiaHb E -Thalassemiamany others
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CLASSIFICATION OF THE COMMON THALASSEMIAS AND RELATED DISORDERS
-Thalassemia+ (deletion)+ (non-deletion)
o
Hereditary persistence of HbFDeletionNon-deletion A γ+ G γ+
Unlike to -globin gene cluster
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3 - THALASSEMIA
DIAGNOSE : African, Mediteranian, Middle Eastern, Chinese, or Southeast Asian ancestry Microcytic, hypochromic anemia of variable severity
Hemoglobin Bart’s detected by neonatal screening
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PATOPHYSIOLOGY
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USUALGENOTYP
ES
- GENE
NUMBER
CLINICAL FEATURE
S
HEMOGLOBIN ELECTROPHORESIS
BIRTH > 6 MO
/ 4 NORMAL NORMAL NORMAL
- / 3 SILENT CARRIER 0 – 3% Hb Bart’s NORMAL
-- / or- / -
2 - THAL TRAIT 2 – 10% Hb Bart’s NORMAL
-- / - 1 Hb H DISEASE
15 – 30% Hb Bart’s
Hb H PRESENT
-- / -- 0FETAL
HYDROPS
> 75% Hb Bart,s -
Table 1. The - thalassemias
11Thalassemia _alpha
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TREATMENT -thalassemia trait require no treatment
• Hb H disease should receive folic acid avoid the same oxidant drugs• Transfusions may be required• Splenectomy• Genetic counseling and prenatal diagnosis
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-THALASSEMIA
Essentials of diagnosis & typical features
-thalassemia minor- mild hypochromic microcytic anemia Haemoglobi 90-110g/l Mean cell volume 50-70 fl
mean corpuscular haemoglobin 20-22 pq- no clinical features, patient asymptomatic- often diagnosed on routine blood count- raised Hb A2 level
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-Thalassemia major :• severe anemia• Blood film - pronounced variation in red cell size and shape - pale (hypochromic) red cells - target cells - basophillic stippling - nucleated red cells - moderately raised reticulocyte count• infants are well at birth but develop anemia in first few months of life when switch occurs from γ to globin chains • progressive splenomegaly; iron loading; proneness to infection
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SCREENING
Peripheral blood stain Mean corpuscular volume (MCV) value
and MCH value Mentzer index RDW index Hb-electroforese
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PRENATAL DIAGNOSIS
If mother suffered thalassemia DNA analysis by CVS (chorion vilus
sampling) at 9-12th week of gestation PCR rapid detection of mutation
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Thalassemia_beta
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Thalassemia minor
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Thalassemia major
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thalassemia Hb elektroforese
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TREATMENT• red cell transfusion : PRC, neocyte • infective complication - viral hepatitis - Yersinia infection• splenectomy• chelation theraphy : desferrioxamine if serum ferritin 1500 g or got transfusion 10-20 x Dose of desferrioxamine :20-40 mg/kgBW for children
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INFECTIONS IN THALASSAEMIA MAJOR
The second commonest cause of death in thalassaemia major The reasons for infection are :
Transmission by blood transfusion Altered host immunity due to :
Hypersplenisme Iron overload and chelation therapy
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HEPATITIS C VIRUS
RNA virus was first characterized in 1989 Antibodies after infection are strain specific Preventive : careful selection of voluntary donors and
blood donor screening
The severity of hep.C greater because of: Concomitant iron overload Other concurrent viral infections ( HBV, HIV )
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COMPLICATIONS OF INFECTION Acute infection Chronic infection Cirrhosis End-stage liver disease Hepatocellular carcinoma (HCC) Non hepatic manifestations : arthritis, keratoconjunctivitis
sicca, lichen planus, glomerulonephritis, and vasculitis. Essential mixed cryoglobulinemia (EMC) Porphyria cutanea tarda
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DIAGNOSIS AND MONITORING Antibody Testing
HCV – RNA Detected by PCR Moct reliable indicator of viral activity Precedes sALT elevation in acute or recurrent cases by
2-10 weeks Anti HCV
Detected by RIBA Liver biopsy
Determined of the extend of liver disease Assesment liver tissue iron load Monitoring progression and response to antiviral virus
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TREATMENT
Selection of patients for therapy Confirmed presence of HCV-RNA Moderate to high sALT level Abnormal liver histology
Presence of persistent HCV RNA sufficient to consider treatment
Response to treatment Biochemical (sALT) Virological (HCV-RNA) The timing of the above response
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Treatment regiment : Interferone Dose: 3 MU sc or IM , 3 times daily Duration : 12 – 24 months Side effect : flu like symptoms, insomnia, cognitive
and mood changes, neutropenia, thrombocytopenia, hypothyroidism, heart failure
Monitoring side effect : thyroid function, blood counts
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RE-TREATMENT if non response, relaps, partial response, and
breakthrough patient
Re-treatment options : Recombinant interferon with Ribavirin for 6 months The same drug with longer periode (12-24 months),
or higher dose for 6-12 months A different interferon Side effect : haemolysis in thalassaemia patients
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Management of liver disease is important for : Children Cirrhosis Immunosuppresed patients Pregnancy Acute hepatitis C
PREVENTION No vaccine or immunoglobulin Safe sexual practices Avoiding sharing toothbrushes, razors, eating utensils.
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HEPATITIS B VIRUS
In thalassaemia major : HBsAg positive varies from <1% to >20%, and past infection rates range from <10-70%
HBV marker : Acute : HBsAg (4-5 mo), HBeAg (1-3 mo) Chronic : HBsAg, anti - HBc Previous infection or vaccination : antibody for HBsAg,
with anti HBc (prev. inf), or without anti HBc(vaccination)
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Natural history : Acute hepatitis : incubation periode 4-20 weeks Progression to chronic hepatitis B : 5-10% in healthy
adults, and 90% in neonates Cirrhosis : 1-2,2 % per year Hepatocellular carcinoma
PREVENTION Hep B Vaccine: 3 times (at 0, 1 and 6 mo), and booster Hep B vaccine and HBIg to neonates delivery by a carrier
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TREATMENT Lamivudin (3 TC) Recombinant α-interferon
HUMAN IMMUNODEFICIENCY VIRUS (HIV)
• Prevalence in thalassaemia : <1% - > 20%• Management :
•Antiretroviral therapy•Erythropoetin•Caution for drug that can exacerbate neutropenia•Control of iron overload•splenectomy
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CYTOMEGALOVIRUS Treatment : Bone Marrow Transplantation Leucoreduction of blood product
PARVOVIRUS B 19 May cause transient aplastic crisis Characterized by :
A fall in Hb 2 g/dl or more Reticulocytes < 0,2% Absence of red blood precursors in the bone marrow B 19 DNA viraemia reach up to 1014 virious/ml Transient drop lymphocytes, neutrophils, platelet
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Treatment : Blood transfusion : acute B19 crises Immunoglobulin administrations : chronics illness
MALARIA AND CHAGAS DISEASE Plasmodium sp and Trypanosoma cruzii remain viable
in refrigerator blood components at least 2 weeks Prevent transmission through blood product.
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IRON ASSOCIATED INFECTION Bacterial Infections : Yersinia anterocolica, Klebsiella sp,
E. colli, Strept. Pneumonia, Pseudomonas aeroginosa, Listeria monocytogenes
YERSINIA ENTEROCOLITICA Lives in an iron rich environment Transmitted by : ingested of contaminated food, meat,
water. Mortality rate among recipient > 50%
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Clinical manifestations : Severe in thalassaemia Fever, abvdominal pain, diarrhoea, or vomiting Athralgia, skin rashes Complications : abdominal abscess, nephritis, splenic
abscess
Laboratory diagnosis Culture from stool, blood, samples of affected tissue (e.g.
gut, lymph node) Serial IgG titres
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TREATMENT Stop iron chelation therapy immediately Obtain suitable laboratory samples Antibiotic treatment
Ciprofloxacin Gentamycin Chloramphenicol Trimethoprim-sulfomethoxazole
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Table 1. Clinical and laboratory evaluation checklist
Monthly• CBC
Every 3 months• serum feritin• clinical chemistry
• glucose • urate• creatinine• iron• TIBC• alk. Phosphatase• γ- GT• ALT/GPT• AST/GOT• LDH
Every 6 months• cardiac evaluations
• cardiac echo • EKG• heart chamber dimensions• systolic function• diastolic function• Fractional shortening
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Table 1. Clinical and laboratory evaluation checklist
Yearly • Virology
• Hep C panel ( anti- HCV, anti-HCV RIBA )• Hep B panel (HBsAg, anti HBs, anti HBc Ig)• anti HIV 1+ 2
• liver biopsi
• endocrine function evaluation
• free T4 and TSH • parathyroid hormone• FSH
• LH• testosterone• estradiol• DHEA-S• fasting a.m. cortisol• OGTT• bone age and density• zinc, cooper, selenium, Vit C, vit E
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Table 1. Clinical and laboratory evaluation checklist
Yearly • complete physical exam• opthalmology examination• audiology examination
As Indicated• 24 hour Holter monitor• Cardiac stress test ( EST)• anti HBc Ig M• anti HBe• HBeAg• anti HDV• HCV - RNA
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INSERTION OFDESFEROXAMINE
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post splenectomy
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