G6PD Enzyme Deficiency

Overview

G6PD enzyme deficiency is an inherited metabolic disorder that affects the glucose-6-phosphate dehydrogenase enzyme, which plays a crucial role in protecting red blood cells from oxidative damage. This enzyme is essential for the pentose phosphate pathway, which generates NADPH, a molecule that helps maintain the integrity of red blood cells by neutralizing harmful reactive oxygen species.

The condition follows an X-linked inheritance pattern, meaning the gene responsible is located on the X chromosome. This inheritance pattern explains why males are more frequently and severely affected than females. Males have only one X chromosome, so a single defective copy of the G6PD gene results in the condition. Females have two X chromosomes, so they typically need defective copies on both chromosomes to be severely affected, though they can be carriers with varying degrees of enzyme activity.

G6PD deficiency has a remarkable geographic distribution that closely follows areas where malaria is or was endemic. This is because having G6PD deficiency provides some protection against malaria, particularly the severe forms caused by Plasmodium falciparum. This selective advantage has led to high frequencies of the condition in populations from Africa, the Mediterranean, the Middle East, and parts of Asia. The World Health Organization estimates that 8% of the world's population carries a variant of the G6PD gene, making it one of the most common genetic polymorphisms in humans.

Most individuals with G6PD deficiency remain asymptomatic throughout their lives unless exposed to specific triggers. However, when exposed to oxidative stress from certain medications, foods, infections, or other triggers, they can develop acute hemolytic anemia, a potentially life-threatening condition where red blood cells are rapidly destroyed faster than they can be replaced.

Symptoms

G6PD deficiency symptoms typically occur only during hemolytic episodes triggered by oxidative stress. Many individuals with the condition remain completely asymptomatic between episodes, while others may experience chronic mild anemia with occasional acute exacerbations.

Acute Hemolytic Episode Symptoms

• Rapid onset fatigue and weakness
• Pale skin and mucous membranes
• Jaundice (yellowing of skin and eyes)
• Dark or tea-colored urine (hemoglobinuria)
• Abdominal pain, particularly in the upper abdomen
• Back pain from rapid red blood cell destruction
• Rapid or irregular heartbeat (tachycardia)
• Shortness of breath during physical activity

Respiratory Symptoms

• Cough - may develop due to compensatory mechanisms
• Shortness of breath on exertion
• Decreased exercise tolerance
• Rapid breathing (tachypnea) to compensate for anemia

Psychological and Emotional Symptoms

• Emotional symptoms - including anxiety and irritability
• Difficulty concentrating
• Memory problems during acute episodes
• Mood changes related to chronic anemia
• Depression in cases of frequent episodes

Chronic Mild Symptoms (in some variants)

• Persistent mild fatigue
• Reduced stamina and endurance
• Increased susceptibility to infections
• Delayed wound healing
• Cold intolerance

Severe Complications Symptoms

• Severe headache
• Confusion or altered mental state
• Chest pain
• Severe shortness of breath
• Fainting or near-fainting episodes
• Heart palpitations
• Signs of kidney dysfunction (decreased urination, swelling)

Neonatal Symptoms

In newborns with G6PD deficiency:

• Severe neonatal jaundice
• Prolonged jaundice beyond normal duration
• Feeding difficulties
• Lethargy and poor activity
• Risk of kernicterus if untreated

Trigger-Specific Symptoms

• Symptoms appearing 1-3 days after exposure to triggers
• Rapid progression from feeling well to severely ill
• Symptoms proportional to the degree of exposure
• Recovery typically occurring 1-2 weeks after trigger removal

Causes

G6PD deficiency is caused by mutations in the G6PD gene located on the X chromosome. Over 400 different variants of this gene have been identified, with varying degrees of enzyme deficiency and clinical significance.

Genetic Basis

The underlying cause is genetic mutations affecting the G6PD enzyme:

• Gene location: X chromosome at position Xq28
• Inheritance pattern: X-linked recessive
• Mutation types: Point mutations, deletions, insertions
• Functional impact: Reduced enzyme stability, activity, or production

Common G6PD Variants

Class I Variants (Severe)

• G6PD Mediterranean: Common in Southern Europe and Middle East
• G6PD Chatham: Associated with chronic hemolytic anemia
• Enzyme activity <10% of normal
• Often associated with chronic symptoms

Class II Variants (Severe)

• Enzyme activity <10% of normal
• Intermittent hemolysis triggered by stress
• No chronic hemolytic anemia between episodes

Class III Variants (Moderate)

• G6PD A-: Most common in African populations
• Enzyme activity 10-60% of normal
• Generally milder clinical course
• Less frequent hemolytic episodes

Evolutionary Background

• Malaria protection: G6PD deficiency provides selective advantage against malaria
• Geographic correlation: High prevalence in malaria-endemic regions
• Balanced polymorphism: Maintained in populations due to heterozygote advantage
• Population genetics: Different variants evolved independently in different populations

Molecular Mechanisms

• Enzyme instability: Mutant enzymes often less stable than normal
• Reduced catalytic activity: Decreased ability to generate NADPH
• Altered protein structure: Changes in enzyme conformation
• Expression defects: Reduced enzyme production in some variants

Environmental Factors

While G6PD deficiency is genetic, environmental factors determine when symptoms occur:

• Oxidative stress triggers: Medications, foods, infections
• Infectious diseases: Viral and bacterial infections
• Chemical exposure: Industrial chemicals, mothballs
• Metabolic stress: Diabetic ketoacidosis, severe illness

Risk Factors

Several factors influence the risk of having G6PD deficiency and experiencing hemolytic episodes. Understanding these risk factors is crucial for prevention and early recognition.

Genetic Risk Factors

• Male gender: Higher risk due to X-linked inheritance
  • Males need only one defective copy to be affected
  • Cannot be carriers - either affected or unaffected
  • All daughters of affected males will be carriers
• Family history: Having affected relatives increases risk
• Maternal carrier status: 50% chance of inheritance from carrier mothers

Ethnic and Geographic Risk Factors

• Mediterranean ancestry: Greeks, Italians, Turkish, Lebanese
  • Prevalence up to 30% in some populations
  • Often more severe variants
• African ancestry: Sub-Saharan African descent
  • Affects 10-15% of African American males
  • Generally milder variants (G6PD A-)
• Middle Eastern ancestry: Arab, Persian, Kurdish populations
• South Asian ancestry: Indian subcontinent populations
• Southeast Asian ancestry: Particularly Chinese and Southeast Asian populations

Trigger Exposure Risk Factors

Medication Triggers

• Antimalarial drugs: Primaquine, chloroquine, quinine
• Antibiotics: Sulfonamides, nitrofurantoin, quinolones
• Analgesics: High-dose aspirin, phenazopyridine
• Other medications: Dapsone, methylene blue, rasburicase

Dietary Triggers

• Fava beans: Fresh, dried, or processed forms
• Legumes: Other beans and lentils (less common)
• Food additives: Certain preservatives and colorings

Infection Risk

• Viral infections: Hepatitis, influenza, COVID-19
• Bacterial infections: Pneumonia, urinary tract infections
• Severe systemic infections: Sepsis, meningitis

Environmental Risk Factors

• Chemical exposure: Mothballs (naphthalene), certain industrial chemicals
• Extreme physical stress: Surgery, severe burns, trauma
• Metabolic stress: Diabetic ketoacidosis, severe dehydration
• Occupational exposure: Chemical industry workers, healthcare workers

Age-Related Risk Factors

• Neonatal period: Increased risk of severe jaundice
• Infancy: Higher susceptibility to infection-triggered episodes
• Elderly: Increased risk due to comorbidities and polypharmacy
• Pregnancy: Physiological stress may trigger episodes in affected females

Protective Factors

• Trigger awareness and avoidance: Significantly reduces episode risk
• Female gender: Generally milder course due to X-inactivation
• Modern medical care: Better infection prevention and treatment
• Genetic counseling: Family planning and risk assessment

Diagnosis

Diagnosis of G6PD deficiency involves a combination of clinical suspicion, laboratory testing, and genetic analysis. Early and accurate diagnosis is crucial for preventing life-threatening hemolytic episodes through appropriate trigger avoidance.

Clinical Assessment

Medical History

• Family history: X-linked inheritance pattern assessment
• Ethnic background: High-risk populations identification
• Previous episodes: History of unexplained anemia or jaundice
• Trigger exposure: Recent medications, foods, or infections
• Neonatal history: Severe or prolonged jaundice

Physical Examination

• Pallor assessment: Skin, conjunctiva, and mucous membranes
• Jaundice evaluation: Scleral icterus, skin yellowing
• Splenomegaly: Enlarged spleen from chronic hemolysis
• Cardiac evaluation: Signs of high-output heart failure
• Respiratory assessment: Compensatory tachypnea

Laboratory Testing

Complete Blood Count (CBC)

• Hemoglobin levels: Assess degree of anemia
• Reticulocyte count: Elevated indicating increased RBC production
• Mean corpuscular hemoglobin concentration: May be elevated
• White blood cell count: May be elevated during acute episodes

Hemolysis Markers

• Lactate dehydrogenase (LDH): Elevated with hemolysis
• Haptoglobin: Decreased or absent during acute episodes
• Indirect bilirubin: Elevated from increased RBC breakdown
• Free hemoglobin: Present in plasma during acute hemolysis

Peripheral Blood Smear

• Heinz bodies: Precipitated hemoglobin visible with special stains
• Bite cells: RBCs with membrane removed by spleen
• Spherocytes: Spherical RBCs from membrane loss
• Polychromasia: Young RBCs indicating increased production

Specific G6PD Testing

Quantitative G6PD Assay

• Gold standard test: Measures enzyme activity in red blood cells
• Normal values: 12-18 U/g hemoglobin at 37°C
• Deficiency levels: <10% (severe), 10-60% (moderate)
• Timing considerations: May be falsely normal during acute hemolysis

Qualitative Screening Tests

• Fluorescent spot test: Rapid screening method
• Methemoglobin reduction test: Historical screening method
• Point-of-care tests: Available for rapid screening
• Limitations: May miss mild deficiency variants

Genetic Testing

DNA Analysis

• Mutation identification: Specific variant determination
• Family screening: Carrier status determination
• Prenatal testing: Available for high-risk pregnancies
• Pharmacogenomics: Personalized medicine applications

Specialized Testing

Flow Cytometry

• Analysis of G6PD activity in different cell populations
• Useful for detecting female heterozygotes
• Research and specialized diagnostic applications

Neonatal Screening

• Universal screening: Recommended in high-prevalence areas
• Cord blood testing: Immediate availability
• Follow-up testing: Confirmation of positive screens
• Family counseling: Genetic counseling for positive cases

Differential Diagnosis

• Other hemolytic anemias: Hereditary spherocytosis, autoimmune hemolysis
• Enzyme deficiencies: Pyruvate kinase deficiency
• Hemoglobinopathies: Sickle cell disease, thalassemia
• Drug-induced hemolysis: Non-G6PD related medication effects

Treatment Options

Treatment of G6PD deficiency focuses primarily on prevention through trigger avoidance and supportive care during acute hemolytic episodes. There is no cure for the genetic deficiency, but with proper management, most individuals can live normal, healthy lives.

Primary Prevention

Trigger Avoidance

The most important aspect of management is avoiding known triggers:

• Medication avoidance:
  • Maintain updated list of contraindicated drugs
  • Inform all healthcare providers about G6PD status
  • Wear medical alert identification
  • Check all medications before taking
• Dietary restrictions:
  • Avoid fava beans in all forms
  • Be cautious with other legumes
  • Read food labels carefully
  • Avoid traditional medicines containing triggers

Infection Prevention

• Vaccination: Stay current with recommended immunizations
• Hygiene practices: Good hand hygiene and wound care
• Prompt treatment: Early treatment of infections to reduce severity
• Avoid sick contacts: When possible during illness seasons

Acute Episode Management

Immediate Care

• Trigger removal: Immediately discontinue causative agent
• Hospital admission: For severe hemolysis or complications
• Close monitoring: Vital signs, urine output, mental status
• Laboratory surveillance: CBC, chemistry panel, hemolysis markers

Supportive Care

• Hydration:
  • Adequate fluid intake to prevent acute kidney injury
  • IV fluids if oral intake inadequate
  • Monitor urine output and kidney function
• Rest and activity modification:
  • Bed rest during acute severe episodes
  • Gradual return to normal activity
  • Avoid strenuous exercise until recovery

Blood Transfusion

Indications

• Severe anemia: Hemoglobin <7 g/dL or symptomatic anemia
• Cardiovascular compromise: Signs of heart failure or ischemia
• Ongoing severe hemolysis: Persistent rapid RBC destruction
• Pregnancy: Severe anemia threatening maternal or fetal health

Transfusion Considerations

• Packed red blood cells: Preferred over whole blood
• Leukocyte-reduced: To minimize transfusion reactions
• Cross-matching: Careful blood typing and compatibility
• Monitoring: Watch for transfusion reactions and iron overload

Pharmacological Treatment

Folic Acid Supplementation

• Indication: Chronic hemolysis or frequent episodes
• Dosage: 5mg daily for adults, weight-based for children
• Rationale: Support increased RBC production
• Duration: During periods of increased hemolysis

Iron Supplements

• Assessment first: Check iron status before supplementing
• Indication: Concurrent iron deficiency anemia
• Caution: Avoid routine iron supplementation without deficiency
• Monitoring: Regular iron studies during treatment

Complications Management

Acute Kidney Injury

• Prevention: Adequate hydration and urine alkalinization
• Monitoring: Serum creatinine, BUN, urine output
• Treatment: Nephrology consultation for severe cases
• Dialysis: Reserved for severe acute kidney injury

Gallstones

• Prevention: Minimize chronic hemolysis
• Screening: Periodic ultrasound for chronic cases
• Treatment: Standard management for symptomatic stones

Special Situations

Neonatal Management

• Phototherapy: For severe neonatal jaundice
• Exchange transfusion: For severe hyperbilirubinemia
• Monitoring: Frequent bilirubin levels
• Feeding: Avoid fava bean exposure through breast milk

Pregnancy Management

• Preconception counseling: Genetic counseling and planning
• Monitoring: Regular CBC and hemolysis markers
• Medication review: Ensure all medications are safe
• Delivery planning: Prepare for potential complications

Emerging Therapies

• Gene therapy: Experimental approaches in development
• Antioxidant therapy: Research into protective agents
• Enzyme replacement: Theoretical future possibility
• Pharmacological chaperones: Molecules to stabilize mutant enzymes

Prevention

Since G6PD deficiency is a genetic condition, primary prevention focuses on genetic counseling and family planning. Secondary prevention involves avoiding triggers and managing the condition to prevent acute hemolytic episodes and complications.

Genetic Counseling and Family Planning

• Preconception counseling:
  • Assess family history and inheritance patterns
  • Discuss risks and implications for offspring
  • Review reproductive options and prenatal testing
  • Provide genetic testing for at-risk individuals
• Prenatal screening:
  • Available for high-risk pregnancies
  • Chorionic villus sampling or amniocentesis
  • Family history-based risk assessment
  • Counseling about results and options

Newborn Screening and Early Detection

• Universal screening programs:
  • Implemented in high-prevalence regions
  • Early identification prevents complications
  • Cost-effective in appropriate populations
  • Enables early family education
• Family screening:
  • Test siblings of affected individuals
  • Maternal testing when infant is affected
  • Extended family testing in some cases

Education and Awareness

• Patient education:
  • Comprehensive list of medications to avoid
  • Dietary restrictions and safe alternatives
  • Recognition of early warning signs
  • When to seek medical attention
• Healthcare provider education:
  • Recognition of G6PD deficiency
  • Appropriate prescribing practices
  • Emergency management protocols
  • Screening recommendations

Environmental Prevention

• Chemical avoidance:
  • Mothballs and naphthalene-containing products
  • Industrial chemicals and solvents
  • Certain household cleaning products
  • Traditional remedies with unknown ingredients
• Occupational safety:
  • Career counseling for high-risk occupations
  • Workplace accommodations when needed
  • Personal protective equipment use

Medical Prevention

• Medical alert systems:
  • Medical alert bracelets or necklaces
  • Emergency medical information cards
  • Electronic health record alerts
  • Smartphone medical alert apps
• Medication management:
  • Pharmacy alerts and counseling
  • Regular medication reviews
  • Alternative medication identification
  • Emergency medication protocols

Community Prevention

• Public health measures:
  • Community education programs
  • Healthcare provider training
  • School and workplace awareness
  • Cultural competency in affected communities
• Support groups:
  • Patient and family support networks
  • Online resources and communities
  • Educational workshops and seminars
  • Advocacy for improved care and research

When to See a Doctor

Seek immediate emergency care (call 911) for:

• Severe shortness of breath or difficulty breathing
• Chest pain or signs of heart problems
• Severe weakness or fainting
• Confusion or altered mental state
• Very dark or black urine
• Signs of severe dehydration
• High fever with severe fatigue

Contact your doctor urgently (within hours) for:

• Rapid onset of fatigue after trigger exposure
• Yellowing of skin or eyes (jaundice)
• Dark tea-colored urine
• Persistent cough with fatigue
• Rapid heartbeat with weakness
• Abdominal pain with nausea
• Emotional symptoms with physical illness

Schedule an appointment within days for:

• Known exposure to triggering medications or foods
• Gradually increasing fatigue over several days
• Recurring episodes of unexplained weakness
• Need for medication that may trigger hemolysis
• Planning surgery or medical procedures
• Pregnancy planning or management

Routine medical care needed for:

• Annual check-ups with G6PD deficiency monitoring
• Medication reviews and updates
• Family screening and genetic counseling
• Preventive care and vaccinations
• Management of other health conditions
• Travel medicine consultations

Related Conditions

• Hemolytic Anemia
• Pyruvate Kinase Deficiency
• Hereditary Spherocytosis
• Sickle Cell Disease
• Thalassemia
• Autoimmune Hemolytic Anemia
• Neonatal Jaundice
• Malaria

References

1. Luzzatto L, Nannelli C, Notaro R. Glucose-6-Phosphate Dehydrogenase Deficiency. Hematol Oncol Clin North Am. 2016;30(2):373-393.
2. Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet. 2008;371(9606):64-74.
3. Frank JE. Diagnosis and management of G6PD deficiency. Am Fam Physician. 2005;72(7):1277-1282.
4. Beutler E. Glucose-6-phosphate dehydrogenase deficiency: a historical perspective. Blood. 2008;111(1):16-24.
5. WHO Working Group. Glucose-6-phosphate dehydrogenase deficiency. Bull World Health Organ. 1989;67(6):601-611.