Purpose and Goal: CNEP #2010

  • Learn about the two main types of hemoglobin disorders.
  • Understand the effects of hemoglobin disorders on the neonate.

None of the planners, faculty or content specialists has any conflict of interest or will be presenting any off-label product use. This presentation has no commercial support or sponsorship, nor is it co-sponsored.

Requirements for successful completion:

  • Successfully complete the post-test
  • Complete the evaluation form

Date

  • June 2015 – June 2017

Learning Objectives

  • Describe the genetic transmission of hemoglobin disorders.
  • Describe the methods used to diagnose hemoglobin disorders.
  • Identify at least 2 approaches for the treatment of hemoglobin disorders.

Introduction

  • Hemoglobin disorders are also called hemoglobinopathies
  • Hemoglobinopathies are inherited disorders of hemoglobin
  • Many forms of inherited disorders may be seen worldwide
  • They are a common cause of hemolytic anemia in the neonate

Hemoglobin Disorders

  • Hemoglobinopathies are the result of globin gene mutations
  • They are inherited via autosomal recessive transmission
  • There are 2 main types of hemoglobinopathies
    • Decreased or absent production of globin genes
      • These are known as thalassemias
      • They are known as either alpha or beta
    • Structural abnormalities of globin genes
      • These result from amino acid substitutions
      • There is generally single amino acid involvement
  • Most common hemoglobinopathies
    • Alpha-Thalassemia
      • Hemoglobin H Disease
      • Hemoglobin H - Constant Spring Disease
      • Hemoglobin Bart Hydrops Fetalis
    • Beta-Thalassemia
      • Cooley Anemia
    • Other Hemoglobinopathies
      • Hemoglobin S Disease
      • Hemoglobin C Disease
      • Hemoglobin E Disease

Autosomal Recessive Transmission

  • There are several modes of genetic inheritance
    • Single gene or Mendelian
    • Multifactorial
    • Mitochondrial
  • Genetic conditions that are caused by single gene mutations follow predictable patterns of inheritance
  • There are 4 types of single gene inheritance
    • Autosomal
    • X-linked
    • Dominant
    • Recessive
  • Autosomal recessive disorders
    • Infants will inherit 2 copies of a defective gene
    • Both parents will generally be unaffected
    • Both parents will carry a single defective gene
    • Both parents will be considered carriers
    • Disorders are not typically seen in every generation

Hemoglobin Expression

  • Hemoglobin is composed of 4 globulins
    • 2 alpha-like globulins
    • 2 beta-like globulins
  • Alpha globulins are located on chromosome 16
    • There are 2 alpha-like globulins
    • There are 4 alpha-like genes
  • Beta globulins are located on chromosome 11
    • There are only 2 beta-like globulins
  • In the fetus, globulin switching occurs at fixed times
    • Alpha globulins begin to increase at 8 weeks
      • These form Hemoglobin F
      • They are present until birth
    • Beta globulins begin to increase close to term
      • These form Hemoglobin A
      • They are present after 40 weeks
  • At approximately 1 year of age:
    • Infants will have very few alpha globulins
      • Hemoglobin F or Fetal Hemoglobin
    • Infants will have predominately beta globulins
      • Hemoglobin A or Adult Hemoglobin
  • Switching occurs at term so preterm infants lack alpha globulins

Thalassemias

  • There are two main types of thalassemias
  • They are typed by the specific defective globulin
  • Alpha-Thalassemia
    • Results from mutations of alpha globulin genes
    • More than 15 mutations have been identified
    • Begins in utero and affects the fetus and neonate
    • There are 4 globulin genes on each chromosome
      • 1 defective gene → Alpha-Thalassemia carrier
      • 2 defective genes → Alpha-Thalassemia trait
      • 3 defective genes → Hemoglobin H Disease
      • 4 defective genes → Hemoglobin Bart Hydrops Fetalis
  • Beta-Thalassemia
    • Results from mutations of beta globulin genes
    • More than 200 mutations have been identified
    • Begins at term gestation and affects older infants
    • There are 2 globulin genes on each chromosome
      • 1 defective gene → Beta-Thalassemia trait
      • 2 defective genes → Beta-Thalassemia Disease

Other Hemoglobinopathies

  • Hemoglobin S
    • Also known as Sickle Cell Disease
    • Results from mutations of beta globulin gene
      • Amino acid sequence mutation
      • Valine is replaced by glutamic acid
    • Beta globulin expression begins close to term
    • Sickle Cell Disease tends to affect older infants
  • Hemoglobin C
    • Results from mutations of beta globulin genes
    • Beta globulin expression begins close to term
    • Hemoglobin C Disease tends to affect older infants
  • Hemoglobin E
    • Results from mutations of beta globulin genes
    • Beta globulin expression begins close to term
    • Hemoglobulin E Disease tends to affect older infants

Most Common Geographic Distribution

  • Alpha-Thalassemias
    • Most common in Asia
    • Up to 40% of the population
      • China
      • Southeast Asia
    • Also common in the Mediterranean
      • Turkey
      • Greece
      • Italy
    • Also common in Africa
  • Beta-Thalassemia
    • Most common in Asia
    • Also common in:
      • Southeast Asia
      • India
      • The Middle East
  • Hemoglobin S
    • Most common hemoglobinopathy in the US
      • Also known as Sickle Cell Disease
      • Also known as Sickle Cell Anemia
    • Most common among descendants from:
      • Africa
      • Central America
      • South America
      • The Middle East
      • India
      • Mediterranean countries
        • Turkey
        • Greece
        • Italy
    • Overall, 90,000 – 100,000 are affected
      • 1:500 African- American births
      • 1:36,000 Hispanic-American births
  • Hemoglobin C
    • Most common in West Africa
  • Hemoglobin E
    • Most common in Asia
  • There is increasing migration across the world
    • Migration from areas of high incidence has changed
    • For example, in the last 30 years:
      • 2000% increase in Asian immigration to the US
      • Alpha-Thalassemia is now common in California

Clinical Manifestations and Presentation

  • Globin gene mutations compromise hemoglobin stability
    • Instability → poor oxygen delivery
    • Poor oxygen delivery → hypoxia
    • Hypoxia → Hemolysis
    • Hemolysis → Chronic anemia
  • In general, variable gene mutations → variable presentations
    • Infants may be asymptomatic
    • Infants may develop severe symptoms
  • Alpha-Thalassemia
    • Alpha carriers have no clinical manifestations
    • Infants with alpha traits have mild anemia
      • They are clinically well
      • They have normal growth
      • They have normal development
    • Infants with Hemoglobin H Disease
      • Have varying degrees of hemolytic anemia
      • They may start out clinically well
      • They may require RBC transfusions
    • Infants with Hemoglobin H – Constant Spring Disease
      • Have more severe hemolytic anemia
      • They require frequent RBC transfusions
    • Infants with Hemoglobin Bart Hydrop Fetalis
      • Most fetuses die in utero
      • Neonates have significant hypoxia
      • Neonates have significant anemia
      • Hypoxia and anemia lead to:
        • Edema
        • Ascites
        • Heart failure
        • Pleural effusions
        • Pericardial effusions
        • Massive organomegaly
  • Beta-Thalassemia
    • Infants with beta traits have mild anemia
    • Infants with beta thalassemia disease
      • Have varying degrees of manifestations
      • Do not tend to become sick until 6 months
      • Are generally RBC transfusion dependent
    • The effects of beta-thalassemia are multifactorial
      • Severe RBC destruction
        • Severe hemolytic anemia
      • Ineffective RBC production
      • Hepatosplenomegaly
        • Caused by RBC destruction
        • A splenectomy is usually required
        • Immunity is severely decreased
        • Eventual liver cirrhosis develops
    • Skeletal abnormalities
      • “Chipmunk facies”
      • Poor overall growth
        • Short stature
      • Delayed skeletal maturation
        • Skull
        • Sternum
        • Ribs
    • Hyperbilirubinemia
      • From chronic liver damage
    • Gallstone formation
      • From biliary tract inflammation
    • Heart failure
    • Chronic pain
    • Developmental delays

Diagnosis of Hemoglobinopathies

  • Most neonates, infants and adults are asymptomatic
  • They may be diagnosed by the presence of mild anemia
  • Even neonates with severe beta-thalassemia may be well
    • Symptoms may not appear until close to 6 months
  • Laboratory diagnostic studies
    • Anemia is diagnosed by a CBC with reticulocyte count
      • Hemoglobin levels may be as low as 3-4 g/dL
      • Hematocrit levels will be low (usually > 30%)
      • Abnormal RBC shapes may be present
      • WBC counts may be significantly high
      • Platelet counts are generally normal
    • Reticulocyte counts may be beneficial
      • Retic counts may be significantly low
    • Iron studies may be beneficial
      • All thalassemias result in increased iron absorption
      • This leads to iron overload → elevated iron levels
    • Bilirubin levels may be beneficial
      • Indirect bilirubin levels may be elevated
    • Vitamin and mineral levels may be beneficial
      • Folic acid levels may be decreased
      • Zinc levels may be decreased
      • Vitamin C levels may be decreased
      • Vitamin E levels may be decreased
    • Bone marrow examination may be beneficial
      • Abnormal RBC shapes may be present
      • Abnormal levels of Hemoglobin A may be present
    • The diagnosis of hemoglobinopathies will be made by 6 months
      • Clinical presentation will be notable
      • Hemolytic anemia will be present in lab studies
      • Hemoglobin electrophoresis is confirmatory
    • Differential diagnosis
      • Iron deficiency anemia
        • Iron levels will be decreased
      • Anemia of inflammation
        • Iron levels will be decreased
        • Infection or inflammation will be present

Prenatal Screening and Diagnosis

  • Prenatal screening provides opportunities for:
    • Identification of asymptomatic parents
    • Genetic counseling for families at risk
  • Prenatal screening studies
    • A CBC with RBC indices is the Gold Standard
    • Maternal hemoglobin analysis can be beneficial
      • High-performance liquid chromatography
      • Isoelectric focusing
      • Hemoglobin electrophoresis
    • If the mother tests positive, then the father should be tested
    • If the father is not available, then the fetus should be tested
  • Prenatal screening has been recommended for all parents
    • Universal screening identifies more parents at risk
    • Currently, the American College of Obstetrics and Gynecology (ACOG) recommends screening parents:
      • Of African descent
      • Of Southeast Asian descent
      • Of Mediterranean descent
    • All positive screen parents should be offered diagnosis
  • Prenatal diagnosis is offered when the fetus is at risk
    • It allows parents to make reproductive choices
    • It allows for close monitoring for hydrops fetalis
    • It allows for intrauterine intervention
      • Fetal RBC transfusions may be beneficial
    • Studies estimate 50-70% of parents’ consent to testing
    • DNA-based testing for gene mutations is required
      • Chorionic villus sampling (10-12 weeks)
      • Amniocentesis (after 15 weeks)
      • Non-invasive techniques are being developed
    • All positive test parents should be offered counseling

Neonatal Screening

  • The Newborn Screening Program
    • Is a public health program
    • Is state mandated testing
    • Screens all US born newborns
  • Not all 50 states test for hemoglobinopathies
  • WA state screens for several hemoglobinopathies
    • Alpha-Thalassemia (Barts)
    • Beta-Thalassemia
    • Hemoglobin C Disease
    • Hemoglobin D Disease
    • Hemoglobin E Disease
    • Hemoglobin S Disease
    • Sickle Cell Diseases
  • The incidence of hemoglobinopathies in WA is 1:10,000
  • Several techniques are used to screen blood samples
    • Gel electrophoresis
    • Isoelectric focusing
    • High-performance liquid chromatography
    • Citrate agar electrophoresis
  • Early identification promotes early treatment
  • Early treatment promotes improved outcomes
    • Without early treatment:
      • Infants may develop severe infections
      • Infants face possible death by 2-3 months

Management of Hemoglobinopathies

  • Once a diagnosis is made, treatment should begin
  • Antibiotic prophylaxis
    • To prevent infections
    • To support immune function
  • Serial monitoring of CBCs, RBC indices, retic counts
    • At 2-3 months
    • At 9-12 months
    • At least once a year
  • If RBC indices are abnormal
    • Obtain iron studies
    • Iron overload is common
      • Therapeutic iron is not recommended
    • If evidence of iron-deficiency
      • Iron supplements can be considered
      • Treat cautiously for 3-6 months
      • Repeat CBC and RBC indices
    • If no evidence of iron-deficiency
      • Obtain hemoglobin electrophoresis
  • Serial examinations for splenomegaly
    • A splenectomy many be required
  • Serial RBC transfusions may be required
    • During periods of stress
    • During periods of infection
      • Especially parvovirus
    • Iron chelation therapy may be required
      • Iron may be absorbed from transfused RBCs
  • Folic acid supplements are recommended
  • Bone marrow transplantation is controversial
  • A Pediatric Hematology consult is always recommended
  • Parent counseling and education is critical
    • To provide the natural history of the disease
    • To learn to recognize signs and symptoms
    • To learn to treat symptoms to avoid crises

Summary

  • Hemoglobin Disorders occur worldwide
  • They are a common cause of chronic hemolytic anemia
  • They may not be commonly seen in the NICU
    • Abnormal newborn screen results are common
    • All NICU parents require education and support
    • Anticipatory guidance for post-NICU care is critical
  • Early recognition and treatment improves infant outcomes

References

  1. Nguyen, T. 2015. Hemoglobinopathies in the Neonate. NeoReviews, 16 (5), p. e278-e286.
  2. Schrier, S.L. 2014. Introduction to Hemoglobin Mutations. Up-To-Date.
  3. Benz, E.J. 2015. Clinical Manifestations and Diagnosis of the Thalassemias. Up-To-Date.
  4. Schrier, S.L. 2015. Pathophysiology of Alpha-Thalassemia. Up-To-Date.
  5. Kutlar, A. & Kutlar, F. 2013. Laboratory Diagnosis of the Hemoglobinopathies. Up-To-Date.
  6. Yates, A.M. 2015. Prenatal Screening and Testing for Hemoglobinopathy. Up-To-Date.

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