Thalassemia

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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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