Overview
Definition:
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive genetic disorder characterized by a deficiency in the enzyme G6PD
This enzyme is crucial for the pentose phosphate pathway in red blood cells, which protects them from oxidative stress by producing NADPH
Without sufficient G6PD, red blood cells are susceptible to hemolysis when exposed to oxidative triggers.
Epidemiology:
G6PD deficiency is the most common human enzyme defect, affecting an estimated 400 million people worldwide
It is particularly prevalent in populations from malaria-endemic regions, including parts of Africa, Asia, the Mediterranean, and the Middle East
In India, its prevalence varies significantly by region, with higher rates observed in certain communities
Neonatal jaundice is a common manifestation in newborns with G6PD deficiency, especially in genetically predisposed populations.
Clinical Significance:
G6PD deficiency is clinically significant due to the risk of acute hemolytic anemia triggered by certain drugs, foods, and infections
In neonates, it is a leading cause of severe, unconjugated hyperbilirubinemia and kernicterus
Understanding its triggers and management is vital for preventing life-threatening complications and is a frequent topic in DNB and NEET SS pediatrics examinations.
Neonatal Jaundice
Introduction:
Neonatal jaundice is a common condition, but severe hyperbilirubinemia in G6PD deficient neonates poses a significant risk
This deficiency impairs the red blood cell's ability to handle oxidative stress, leading to premature destruction (hemolysis).
Pathophysiology:
In neonates, the liver's bilirubin conjugation capacity is immature
In G6PD deficient infants, oxidative stress from various sources can trigger rapid hemolysis, overwhelming the already limited conjugation pathway
This leads to a rapid rise in unconjugated bilirubin, potentially exceeding safe levels.
Triggers In Neonates:
Triggers in neonates are often less clear-cut than in older individuals but can include: Maternal medications passed through breast milk
Certain topical agents applied to the neonate
Neonatal infections
Hypothermia or acidosis
Oxytetracycline and nitrofurantoin administered to the neonate.
Clinical Features In Newborns:
Jaundice typically appears within the first 24-72 hours of life
The icterus may be severe and progress rapidly
Signs of hemolysis may include pallor, lethargy, and sometimes mild hepatosplenomegaly
Severe hyperbilirubinemia can lead to kernicterus, characterized by lethargy, poor feeding, hypotonia, opisthotonos, seizures, and sensorineural hearing loss.
Triggers Of Hemolysis
Drug Induced Hemolysis:
Certain medications are potent triggers
Common culprits include: Antimalarials: Primaquine, quinine, chloroquine
Sulfonamides: Sulfamethoxazole, sulfasalazine
Analgesics/Antipyretics: Aspirin (high doses), phenacetin
Antibiotics: Dapsone, isoniazid, nitrofurantoin, nalidixic acid
Others: Fava beans (divicine and isouramil), menthol, methylene blue.
Food Induced Hemolysis:
The most notorious food trigger is the fava bean (Vicia faba), leading to the condition known as "favism." Other legumes may also pose a risk for highly sensitive individuals
Consumption of uncooked or partially cooked fava beans is particularly dangerous.
Infection Induced Hemolysis:
Infections, particularly viral hepatitis, infectious mononucleosis, and urinary tract infections, can induce hemolytic crises in G6PD deficient individuals
The oxidative stress generated by the host's immune response to infection can precipitate hemolysis.
Other Triggers:
Other less common triggers include diabetic ketoacidosis, severe burns, and exposure to certain chemicals or dyes
Stressful events and major surgery can also increase oxidative load.
Diagnostic Approach
History Taking:
A detailed history is crucial, focusing on: Onset and progression of jaundice (in neonates)
History of similar episodes in the family
Exposure to potential triggers: medications, fava beans, infections
Ethnic background
Maternal medication history during pregnancy and breastfeeding.
Physical Examination:
In neonates: Assess degree of jaundice (icteric sclera, skin color)
Check for pallor, lethargy, poor feeding
Examine for hepatosplenomegaly
In older children/adults: Look for pallor, jaundice, splenomegaly
Signs of acute hemolysis: dark urine (hemoglobinuria).
Investigations:
Screening: Quantitative G6PD assay (most reliable)
Measure NADPH production by red blood cells
It is important to note that G6PD levels can be falsely normal during an acute hemolytic episode due to the preferential destruction of older red blood cells with lower G6PD activity
therefore, testing should ideally be performed 2-3 months after the crisis
Fluorescent spot test (less sensitive)
Confirm diagnosis by genetic testing if needed
For neonatal jaundice: Total and direct bilirubin levels
Blood group and Coombs test (to rule out other causes of hemolysis)
Complete blood count with reticulocyte count
Peripheral smear for bite cells and blister cells (suggestive of G6PD deficiency)
Liver function tests
Urinary analysis for hemoglobinuria.
Differential Diagnosis:
Neonatal jaundice: Physiologic jaundice, breast milk jaundice, ABO/Rh incompatibility, cephalohematoma, sepsis, hypothyroidism, galactosemia, hereditary spherocytosis, other enzyme deficiencies (e.g., pyruvate kinase deficiency)
Hemolytic anemia in older individuals: Autoimmune hemolytic anemia, hereditary spherocytosis, thalassemia, sickle cell disease, paroxysmal nocturnal hemoglobinuria, drug-induced immune hemolytic anemia.
Management
Neonatal Management:
Immediate discontinuation of any suspected trigger
Phototherapy for mild to moderate hyperbilirubinemia
Exchange transfusion for severe hyperbilirubinemia or signs of kernicterus
Avoidance of triggering medications and agents
Close monitoring of bilirubin levels and signs of hemolysis
Genetic counseling for the family.
Management Of Hemolytic Crisis:
The cornerstone of management is immediate cessation of the offending trigger (drug, food, etc.)
Supportive care includes hydration and monitoring vital signs
Blood transfusions may be required for severe anemia
Folic acid supplementation can be considered to support red blood cell production, though its role in acute crisis is debated.
Prevention Strategies:
Patient and family education regarding triggers is paramount
Provide patients with a list of contraindicated drugs and foods
Advise caution with herbal remedies and over-the-counter medications
Encourage prompt medical attention for any signs of infection
Genetic screening before prescribing certain medications (e.g., primaquine) is recommended in at-risk populations.
Specific Management Considerations:
Avoidance of methylene blue, which is often used to treat methemoglobinemia but is a potent G6PD trigger
Use of alternative therapies for malaria in affected individuals
Careful consideration of drug choices in patients with known G6PD deficiency.
Complications
Early Complications:
Acute hemolytic anemia
Severe hyperbilirubinemia leading to kernicterus in neonates
Acute kidney injury due to hemoglobinuria
Splenic rupture (rarely).
Late Complications:
Chronic hemolytic anemia (mild, in some individuals)
Sensorineural hearing loss (sequela of kernicterus)
Cholelithiasis (gallstones) due to chronic hemolysis
Anemia of chronic disease.
Prevention Strategies:
Primary prevention involves rigorous avoidance of known triggers by affected individuals and their families
Secondary prevention focuses on prompt recognition and management of hemolytic episodes to prevent severe complications like kernicterus and kidney injury
Genetic counseling and carrier screening can help.
Prognosis
Factors Affecting Prognosis:
The severity of the G6PD deficiency genotype
The type and extent of trigger exposure
Promptness of diagnosis and management
Presence of co-existing medical conditions.
Outcomes:
With proper avoidance of triggers, most individuals with G6PD deficiency live normal lives
Neonates with G6PD deficiency, if managed promptly, have a good prognosis
However, delayed diagnosis and treatment of severe hyperbilirubinemia can lead to irreversible neurological damage (kernicterus).
Follow Up:
Regular follow-up is recommended, especially for neonates who experienced severe hyperbilirubinemia, to monitor for developmental milestones and hearing
Patients should be educated to inform all healthcare providers about their condition and to carry an identification card detailing their G6PD deficiency and triggers.
Key Points
Exam Focus:
G6PD deficiency is an X-linked disorder
Triggers include certain drugs (antimalarials, sulfonamides, dapsone), fava beans, and infections
Neonatal jaundice can be severe and lead to kernicterus
G6PD levels can be falsely normal during hemolysis
Avoidance of triggers is key.
Clinical Pearls:
Always consider G6PD deficiency in neonates with unexplained severe hyperbilirubinemia, especially from endemic regions
Educate patients and families thoroughly on trigger avoidance
Remember to test G6PD levels a few months after an acute hemolytic episode for accurate diagnosis.
Common Mistakes:
Prescribing known triggering drugs without checking G6PD status
Misinterpreting normal G6PD levels during an acute hemolytic crisis
Failing to promptly initiate phototherapy or exchange transfusion for severe neonatal jaundice
Inadequate patient education regarding trigger avoidance.