Purpose and Goal: CNEP #5114

  • Learn about glucose-6-phosphate dehydrogenase deficiency.
  • Understand the effects of G6PD deficiency 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

  • July 2015 – July 2017

Learning Objectives

  • Describe the genetic transmission of G6PD deficiency.
  • Describe the methods used to diagnose G6PD deficiency.
  • Identify at least 2 approaches for the treatment of G6PD deficiency.

Introduction

  • Glucose-6-phosphate dehydrogenase deficiency
    • Is also known as G6PD Deficiency Disorder
    • Is the most common inherited enzyme deficiency
  • Once rare in the US, it is becoming more common
  • The most severe manifestation is hyperbilirubinemia
  • Screening for G6PD is important for improving outcomes

Glucose-6-Phosphate Dehydrogenase Deficiency

  • G6PD deficiency is a disorder of red blood cells
  • It affects 200-400 million people worldwide
  • It places 4.5 million infants at risk for severe jaundice
  • G6PD is most common in:
    • Asia
    • Africa
    • The Middle East
    • The Mediterranean
  • It is becoming more common in the West
    • Due to extensive intermarriage
    • Due to extensive population migration
  • It affects 4 - 7% of the population in the US
    • Black males are most commonly affected
      • Up to 10% of all black males
  • G6PD is a protein in red blood cells (RBCs)
  • When the G6PD protein is missing:
    • Important enzymatic pathways are inhibited
    • RBCs are not protected from damage
    • RBCs are destroyed due to oxidative stress
  • Many affected people are asymptomatic
    • Many have episodic anemia
    • A few have chronic hemolytic anemia
  • The most severe manifestations are preventable
    • Severe hyperbilirubinemia
    • Bilirubin encephalopathy
    • Kernicterus

X-Linked Inheritance

  • G6PD deficiency is an X-linked disorder
    • It is genetically inherited
    • The affected gene is located on Xq28
    • It has more than 400 variants
  • There are 4 types of genetic inheritance
    • Autosomal
    • X-linked
    • Dominant
    • Recessive
  • X-linked inherited disorders
    • Are passed from mother to infant
    • They primarily affect male infants
    • Female infants can be mildly affected
      • If they inherit one abnormal gene
      • If they inherit one normal gene
    • Female infants can be severely affected
      • If they inherit one abnormal gene
        • From the mother who is a carrier
      • If they inherit one abnormal gene
        • From the father who is affected

Classification of G6PD Deficiency

  • Class I G6PD deficiency
    • Severe enzyme deficiency
    • Chronic hemolytic anemia
  • Class II G6PD deficiency
    • Also known as G6PD Mediterranean
    • Severe enzyme deficiency
      • Less than 10% of normal
    • Intermittent episode of hemolysis
      • Associated with infection
      • Associated with drugs
      • Associated with chemicals
  • Class III G6PD deficiency
    • Also known as G6PD A-
    • Moderate enzyme deficiency
      • 10 - 60% of normal
    • Intermittent episode of hemolysis
      • Associated with infection
      • Associated with drugs
      • Associated with chemicals
  • Class IV G6PD deficiency
    • No enzyme deficiency or hemolysis
  • Class V G6PD deficiency
    • Increased enzyme activity

Pathophysiology of G6PD Deficiency

  • G6PD is an enzyme that metabolizes carbohydrates into energy
  • It also catalyzes the initial step in RBC protection
  • It promotes formation of a protective barrier against RBC injury
    • Oxidants are formed in RBCs via hemoglobin and oxygen
    • G6PD protects against the build-up of harmful oxidants
  • Without G6PD protection, RBCs are easily destroyed
  • Infants who have G6PD deficiency
    • Have a higher incidence of RBC destruction
    • Have a higher incidence of neonatal jaundice
  • Generally develop jaundice by day 2-3
  • Have a lower incidence of hemolytic anemia
    • Especially in comparison with
      • Rh– related jaundice
      • ABO isoimmunization jaundice

Clinical Manifestations and Presentation

  • Clinical presentations are related to gene expression
  • There are four forms of expression
    • Acute hemolytic anemia
    • Favism
    • Congenital hemolytic anemia
    • Neonatal hyperbilirubinemia
  • Acute hemolytic anemia
    • Almost all individuals with G6PD are asymptomatic
    • They do not have anemia or hemolysis
    • Sudden onset hemolysis can be triggered by:
      • Infection
        • Parvovirus
        • Salmonella
        • Escherichia coli
        • Beta hemolytic streptococci
        • Rickettsiae
        • Viral hepatitis
      • Exposure to drugs
        • Aspirin or Ibuprofen to treat pain
        • Primaquine used to treat malaria
        • Sulfa antibiotics used to treat infection
      • Exposure to chemicals
        • Mothballs
        • Aniline dyes
        • Henna compounds
      • Certain foods can also trigger hemolysis
        • Soy products
        • Red wines
        • Legumes
        • Blueberries
        • Bitter melon
        • Sulfites
        • Menthol
        • Tonic water
      • Diabetic ketoacidosis can also trigger hemolysis
    • Triggers increase the build-up of harmful oxidants
    • Hemolysis is seen 5 – 7 days after being triggered
    • Symptoms of hemolysis include:
      • Pallor
      • Jaundice
      • Lethargy
      • Dark colored urine
      • Back or abdominal pain
  • Favism
    • Occurs primarily in children 1 – 5 years old
    • Can be fatal if severe hemolysis is not treated
    • Results from ingestion of raw fava beans
      • Can also result from cooked fava beans
      • Can also be transferred via breastmilk
    • Favism is seen 5 – 24 hours after fava bean ingestion
      • Headache
      • Nausea
      • Back pain
      • Chills
      • Fever
      • Jaundice
      • Hemolysis
  • Congenital nonspherocytic hemolytic anemia
    • Occurs in Class I G6PD deficiency
    • Severe G6PD deficiency → lifelong hemolysis
    • Anemia and jaundice occur in the neonatal period
    • The degree of hyperbilirubinemia → exchange transfusion
    • After infancy, mild-moderate anemia persists
    • Hemolysis can be exaggerated by exposure to:
      • Drugs
      • Chemicals
      • Fava beans
  • Neonatal hyperbilirubinemia
    • Jaundice is a common clinical diagnosis in neonates
    • Prolonged jaundice may be related to G6PD deficiency
    • G6PD related jaundice differs from hemolytic jaundice
      • It is rarely present at birth and occurs day 2 – 3
      • There is more jaundice and less anemia
      • The anemia is mild and rarely severe
    • The severity of G6PD jaundice can be profound
    • > 20% of readmissions for jaundice is associated with G6PD
    • > 30% of kernicterus is associated with G6PD

Diagnosis of G6PD Deficiency

  • G6PD should be considered in any neonate:
    • With unexplained jaundice
    • With nonimmune hemolytic anemia
  • Newborn metabolic screening
    • Only 2 states test for G6PD
    • WA state does not test for G6PD
  • Clinical laboratory testing
    • Peripheral blood smear analysis
    • Evaluation of RBCs for decreased enzyme activity
      • Bite or blister cells
        • Abnormal RBC membranes
      • Heinz bodies
        • Brilliant blue stained globin
    • Florescent spot testing
      • Simple, reliable, sensitive
  • False-negative results may occur following hemolysis
    • Retesting at a later date may be indicated
  • Prenatal screening tests have not been developed

Management and Treatment of G6PD Deficiency

  • Treatment is dependent on the classification
  • Neonatal jaundice should be aggressively treated
    • Intensive phototherapy
    • Exchange transfusion
    • Prophylactic phenobarbital
  • Intermittent and chronic hemolysis can lead to:
    • Cognitive deficits
    • Liver damage
    • Heart damage
    • Kidney failure
    • Iron toxicity
  • All affected individuals should avoid exposure to:
    • Known trigger drugs
    • Known trigger chemicals
    • Known trigger foods
  • Vitamin E supplements may be beneficial
  • Folic acid supplements may be beneficial
  • RBC transfusions may be indicated
  • A splenectomy has not been shown to be helpful

Summary

  • G6PD deficiency is becoming more prevalent in the US
  • It is a common cause of intermittent hemolytic anemia
  • It places infants at risk for poor neurodevelopmental outcomes
  • G6PD may not be commonly seen in the NICU
    • But all infants at risk need to be identified
    • All at risk families need education and support
    • Anticipatory guidance for post-NICU care is important
  • Early recognition and treatment improves infant outcomes

References

  1. Ridky, J. 2015. Glucose-6-Phosphate Dehydrogenase Deficiency: An Increasing Concern. Neonatal Network, 34 (6), p. 365-367.
  2. Glader. B. 2015. Genetics and Pathophysiology of Glucose-6-Phosphate Dehydrogenase Deficiency. Up-To-Date.
  3. Glader, B. 2015. Clinical Manifestations of Glucose-6-Phosphate Dehydrogenase Deficiency. Up-To-Date.
  4. Glader, B. 2014. Diagnosis and Treatment of Glucose-6-Phosphate Dehydrogenase Deficiency. Up-To-Date.
  5. Patient Information: Glucose-6-Phosphate Dehydrogenase Deficiency (The Basics). Up-To-Date.

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