BETA THALASSEMIA
 
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BETA THALASSEMIA

 

DEFINITION:

A diverse group of microcytic hemolytic anemias characterized by the absence or decreased synthesis of the beta globin chain of hemoglobin.

EPIDEMIOLOGY:

  • incidence: ?
  • age of onset:
    • 2-4 years (Thal. Intermedia); 1st year of life (Thal. Major)
  • risk factors:
    • familial - autosomal recessive
      • chrom.#: 11p15.5
      • gene: beta-globin chain
    • certain ethnic groups:
      • Mediterranean, Near and Middle Eastern, Southeast Asia
      • type of mutation is usually specific to a given ethnic group
      • gene frequences range from 5-20%

PATHOGENESIS:

1. Background

  • 1. Normal Adult Hemoglobin (Hb)

    • Hb Chains %

    A a2b2 95.5

    A2 a2d2 2.5

    F a2g2 <2.0

  • 2. Embryogenesis
    • beta chain production is activated as early as the 8th week of gestation with the switch to adult hemoglobin completed between 3-4 months of age (thus Thal. Major will not present until after the 3-4 month of life)

    • 2. Genetic Defect

    • genetic defect -> abnormal or no synthesis of the beta-globin chain -> bone marrow fails to produce adequate RBC's and increased hemolysis of circulating RBC's -> anemia -> medullary hematopoiesis (bone marrow expansion with typical Beta-Thal. facies) and extramedullary hematopoiesis (hepatosplenomegaly, lymphadenopathy)
    • at least 91 point mutations and several deletional mutations have been identified within and around the beta-globin chain gene all affecting the expression of the beta-globin chain gene resulting in defects in activation, initiation, transcription, processing, splicing, cleavage, translation, and/or termination
    • types of expression:
    • 1. Beta+ - reduced beta-globin chain synthesis
    • 2. Betao - no beta-globin chain synthesis

    3. Types of Beta Thalassemia

  • 1. Heterozygous States
  • 1. Thal. Minima - silent beta-globin chain defect
  • 2. Thal. Minor - one normal beta-globin chain gene and one beta-thalassemia gene
  • 2. Homozygous States
  • 1. Thal. Intermedia - 2 beta-thalassemia genes (later-onset)
  • 2. Thal. Major - 2 beta-thalassemia genes (early-onset)

    • CLINICAL FEATURES:

    1. Heterozygote States

    1. Thalassemia Minima

    • asymptomatic

    2. Thalassemia Minor

    • majority asymptomatic and not anemic
    • women may become severely anemia during pregnancy
    • complications (in a minority):
      • bone changes
      • cholelithiasis
      • leg ulcers
      • splenomegaly

    2. Homozygous States

    1. Thalassemia Intermedia

    • 2-10% of Beta Thalassemics
    • symptomatic by 2-4 years of age (but CBC may show anemia during the first year of life)
    • moderate anemia
    • complications:
      • hepatosplenomegaly
      • growth failure
      • jaundice
      • thalassemic facies

    2. Thalassemia Major

    • also called Cooley anemia, Mediterranean anemia, or von Jaksch anemia
    • symptomatic by 12 months of age (often as early as 3 months)
    • severe anemia
    • complications:
    • 1. Craniofacial Features
      • onset within the first 6 months of life
      • represents medullary hematopoiesis
      • mandibular prominence - prominent malar
      • maxillary overbite eminences
      • depressed nasal bridge - frontal bossing
    • 2. Extramedullary Hematopoiesis
      • hepatomegaly/hepatosplenomegaly
      • peripheral lymphadenopathy
    • 3. Iron Overload (Hemosiderosis)
      • elevated GI absorption of iron due to chronic anemia results in:
      • hepatic fibrosis & cirrhosis (by age 5 years)
      • darkening of skin (iron-stimulated melanin production)
      • sideroblastic cardiomyopathy (arrhythmias, congestive heart failure, recurrent pericarditis)
      • endocrinopathies (diabetes mellitus, secondary hypopituitarism, hypoparathyroidism, hypothyroidism)
    • 4. Others
      • recurrent infections, overwhelming infections, septicemia
      • failure to thrive, growth retardation

    INVESTIGATIONS:

    1. CBC

    • normal Hb in the Heterozygote Forms
    • Hb > 70 g/L in Thal. Intermedia
    • Hb < 70 g/L in Thal. Major

    2. Blood Smear (RBC Morphology)

    • normal in Thal. Minima
    • microcytic hypochromic in all other forms
    • anisocytosis, poikilocytosis, target cells, ovalcytes, basophilic stippling, polychromasia, macrocytes, nucleated RBC's, precipitated alpha chain inclusions

    3. Hemoglobin Electrophoresis

    • diagnostic
    • pattern depends on the degree of beta-globin chain synthesis impairment and presence of other globin-chain defects
    • 1. Thalassemia Minima
      • elevated alpha/beta globin chain ratio
    • 2. Thalassemia Minor
      • decreased HbA
      • elevated HbA2 > 3.5% (normally 2.5%)
      • elevated HbF > 2.0 (normally < 2%)
    • 3. Homozygote States
    • 1. Beta+
      • decreased HbA
      • low, normal, or high HbA2
      • HbF is 10-90% of total hemoglobin
    • 2. Betao
      • absent HbA
      • elevated HbA2 and HbF (HbF may be 100% at birth)

    4. Serum

    • normal or low serum iron
    • normal transferrin (TIBC)
    • normal or elevated transaminases, bilirubin,
    • decreased haptoglobin, hemopexin

    5. Imaging Studies

  • 1. Skeletal X-Rays (Thal. Major)
    • "hair-on-end" pattern in the skull
    • thinning of the long bone cortices

    • MANAGEMENT:

    I. APPROACH

  • 1. Diagnosis
  • 2. Education
  • 3. Treatment Options
  • 4. Goals of Therapy
  • 5. Management Strategies
  • 1. Transfusion Therapy
  • 2. Chelation Therapy
  • 3. Splenectomy
  • 4. Bone Marrow Transplantation

    • 1. Diagnosis

  • 1. Clinical - hemolytic microcytic hypochronic anemia
  • 2. Laboratory - Hb electrophoresis, molecular characterization

    • 2. Education

    • definition, epidemiology, diagnostic criteria, prognosis, treatment options

    3. Treatment Options

  • 1. No Treatment
    • Heterozygote States
  • 2. Treatment
    • Homozygote States

    • 4. Goals of Therapy

    • to maintain a "physiologic" Hb level
    • prevent iron accumulation and promote iron excretion

    5. Management Strategies

    1. Transfusion Therapy

    • 6-8 cc/kg of PRBC's every 2-3 weeks
    • yearly requirement of <200 cc/kg/year of PRBC's
    • q2-3w interval decreases the yearly iron load by 20%
    • side effects:
      • urticaria, fever (use WBC-poor or washed PRBC's)
      • hepatitis B (immunize against Hepititis B)
      • hypersplenism, hemosiderosis

    2. Desferrioxamine (Chelation) Therapy

    • 20-60 mg/kg subcutaneously over 8 hours for a minimum of 5 days/week
    • goal is to achieve an iron balance in growing children and a negative iron balance in older or symptomatic patients
    • ascorbic acid supplementation to keep ascorbic acid levels normal (when iron chelation is optimal)
    • initiated between 4-5 years of age when serum ferritin is greater than 1000 ng/cc and transferrin is >50% saturated
    • Desferrioxamine toxicity:
      • local irritation - erythema, pruritis
      • neurotoxicity
        • visual impairment (cataracts, impaired colour vision, poor dark adaptation)
        • hearing impairment (high frequency sensorineuronal hearing loss)

    3. Splenectomy

    • indicated for hypersplenism:
      • due to regular transfusion therapy
      • occurs between 6-8 year of age
      • when PRBC requirements exceed 200-250 cc/kg/yr
    • risks:
      • post-splenectomy sepsis due to encapsulated organisms (S. pneumoniae, H. flu, N. meningitidis); risk is greater in those under 5 years of age
      • vaccinate against pneumococcus and H. flu prior to splenectomy
      • Penicillin (250 mg po bid) prophylaxis post splenectomy
      • aggressive infection control

    4. Bone Marrow Transplantation

    • used since 1982
    • risks:
      • mortality, chronic graft vs host disease

     

     

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