Favism: Clinical Manifestations and Management of Glucose-6-Phosphate Dehydrogenase Deficiency

What is Favism?

Favism is a genetic disorder that causes a severe reaction to consuming fava beans (also known as broad beans) and certain medications. This inherited condition occurs due to a deficiency in an enzyme called glucose-6-phosphate dehydrogenase (G6PD), which leads to the breakdown of red blood cells when exposed to specific triggers.

Understanding favism is crucial for healthcare providers due to its potentially severe clinical manifestations and widespread genetic prevalence. The condition’s variable expressivity and sex-linked inheritance pattern make it a significant consideration in both acute care settings and genetic counseling.

Pathophysiology

The fundamental defect in favism lies in the inability to maintain adequate NADPH levels within erythrocytes, leading to oxidative stress and cellular damage. This biochemical aberration becomes particularly significant when patients are exposed to oxidative stressors, resulting in rapid hemolysis and potential end-organ damage if not promptly recognized and managed.

The G6PD enzyme catalyzes the rate-limiting step in the pentose phosphate pathway, essential for:

• Generation of NADPH, crucial for glutathione reduction
• Protection of erythrocytes against oxidative stress
• Maintenance of red blood cell membrane integrity

The deficiency results in decreased NADPH production, leading to oxidative damage and subsequent hemolysis when exposed to oxidative stressors.

Molecular Genetics and Epidemiology

The genetic basis of favism demonstrates remarkable complexity, with hundreds of known mutations affecting enzyme activity to varying degrees. Understanding the molecular genetics is essential for proper patient classification and risk assessment, particularly in populations where the condition is endemic.

The G6PD gene, located on chromosome Xq28, exhibits significant allelic heterogeneity with over 400 documented variants. Class variants include:

• Class I: Severe deficiency (<10% activity) with chronic hemolysis
• Class II: Severe deficiency (<10% activity) with intermittent hemolysis
• Class III: Moderate deficiency (10-60% activity)
• Class IV: Normal activity (60-150%)
• Class V: Increased activity (>150%)

Global prevalence shows marked geographic variation:

• Mediterranean region: 5-30%
• African populations: 20%
• Southeast Asian populations: 10-20%
• Correlation with historical malaria endemic regions due to selective advantage

Clinical Manifestations

The presentation of favism can range from mild chronic hemolysis to acute, life-threatening crises requiring immediate medical intervention. Recognition of the various clinical patterns is essential for proper triage and management of affected individuals.

Acute Hemolytic Crisis

Primary manifestations include:

• Onset: 24-48 hours post-exposure
• Severe intravascular hemolysis
• Hemoglobinuria
• Marked elevation in unconjugated bilirubin
• Reticulocytosis
• Heinz body formation
• Significant drop in hemoglobin levels (often >2 g/dL)

Laboratory Findings

Characteristic features during acute episodes:

• Decreased haptoglobin
• Elevated LDH
• Increased indirect bilirubin
• Hemoglobinuria
• Presence of bite cells and blister cells on peripheral smear
• Marked reticulocytosis (typically >5%)

Diagnostic Approach

Accurate diagnosis of G6PD deficiency requires a systematic approach combining clinical assessment, laboratory testing, and sometimes molecular analysis. The timing of testing is crucial, as results may be falsely normal during acute hemolysis when older erythrocytes have been destroyed.

Primary Diagnostic Methods

1. Quantitative G6PD Enzyme Activity Assay
   • Spectrophotometric analysis
   • Normal range: 7-10 IU/g Hb
   • Note: False normal results possible during acute hemolysis
2. Molecular Genetic Testing
   • PCR amplification and sequencing
   • Identification of specific variants
   • Important for genetic counseling
3. Flow Cytometry
   • Useful for female heterozygotes
   • Allows determination of X-chromosome inactivation patterns

Clinical Management

The cornerstone of favism management lies in prevention and rapid recognition of acute episodes. When crises occur, prompt intervention with supportive care and careful monitoring of end-organ function is essential for optimal outcomes.

Acute Crisis Management

1. Immediate discontinuation of oxidative stressors
2. Hemodynamic stabilization
3. Transfusion criteria:
   • Hemoglobin < 7 g/dL
   • Signs of end-organ dysfunction
   • Cardiovascular compromise

Monitoring Parameters

• Serial complete blood counts
• Renal function tests
• Liver function tests
• Arterial blood gases in severe cases
• Continuous cardiac monitoring in significant hemolysis

Pharmacological Considerations

Understanding medication interactions in G6PD deficiency is critical for safe prescribing practices. Healthcare providers must maintain a high index of suspicion for potential drug-induced hemolysis and carefully evaluate all prescribed medications.

Contraindicated Medications

1. Oxidative Drugs:
   • Primaquine
   • Dapsone
   • Nitrofurantoin
   • Rasburicase
   • Methylene blue
2. Potential Triggers:
   • Sulfonamides
   • Quinolones
   • NSAIDs in high doses
   • Vitamin K analogues

Prevention Strategies

Effective prevention in G6PD deficiency requires a comprehensive approach combining patient education, genetic counseling, and careful medication management. Regular reinforcement of preventive measures is essential for reducing the risk of acute hemolytic episodes.

Genetic Counseling

• X-linked inheritance pattern discussion
• Reproductive risk assessment
• Family screening recommendations
• Preconception counseling

Patient Education

1. Medical Alert Documentation:
   • Detailed list of contraindicated medications
   • Emergency contact information
   • G6PD deficiency class and baseline enzyme activity
2. Dietary Counseling:
   • Complete avoidance of fava beans
   • Documentation of other identified triggers
   • Proper food labeling awareness

Research Directions

The field of G6PD deficiency research continues to evolve, with promising developments in both diagnostic and therapeutic approaches. Understanding current research trends is essential for healthcare providers to offer optimal patient care and participate in advancing medical knowledge.

Current areas of investigation include:

• Gene therapy approaches
• Novel enzyme replacement strategies
• Development of rapid point-of-care testing
• Population screening protocols
• Pharmacogenomic implications

Clinical Pearls

The successful management of patients with G6PD deficiency requires both clinical expertise and careful attention to preventive measures. Recognition of high-risk scenarios and appropriate prophylactic interventions can significantly reduce morbidity in affected individuals.

1. Consider G6PD deficiency in:
   • Unexplained hemolysis
   • Drug-induced hemolysis
   • Neonatal jaundice in specific ethnic groups
   • Family history of favism or hemolysis
2. Treatment Considerations:
   • Avoid empiric treatment with oxidative drugs
   • Monitor for renal complications
   • Consider prophylactic folic acid supplementation
   • Regular follow-up for chronic cases

References and Further Reading

Evidence-based management of G6PD deficiency continues to evolve, making it essential for healthcare providers to stay current with the latest research and guidelines. Regular review of updated protocols and emerging therapeutic options helps ensure optimal patient outcomes.