glucose-6-phosphate dehydrogenase deficiency

glucose-6-phosphate dehydrogenase deficiency
Name	Glucose-6-phosphate dehydrogenase deficiency
Synonyms	G6PD deficiency, Favism
Field	Hematology, Medical genetics
Symptoms	Hemolytic anemia, Jaundice, dark urine
Complications	Acute kidney injury, Kernicterus
Onset	Often triggered by infection or certain substances
Duration	Acute episodes are self-limiting
Types	Over 400 variants; classes I-V
Causes	Mutations in the G6PD gene
Risks	Male sex, ancestry from malaria-endemic regions
Diagnosis	Blood tests, Fluorescent spot test
Differential	Pyruvate kinase deficiency, Hereditary spherocytosis
Prevention	Avoiding triggers like fava beans, certain drugs
Treatment	Supportive care, blood transfusion in severe cases
Medication	Avoid Primaquine, Dapsone, sulfonamides
Prognosis	Generally good with trigger avoidance
Frequency	Affects ~400 million people worldwide

glucose-6-phosphate dehydrogenase deficiency. It is an X-linked recessive genetic disorder affecting the Pentose phosphate pathway, leading to impaired production of NADPH and increased susceptibility of red blood cells to Oxidative stress. The condition is most prevalent in populations historically exposed to malarial parasites, such as those from Africa, the Mediterranean Basin, Middle East, and Southeast Asia. Clinical manifestations are typically triggered by specific agents, including certain antimalarial drugs, sulfonamide antibiotics, infections, or ingestion of fava beans, leading to episodes of acute Hemolytic anemia.

Signs and symptoms

Many individuals with the condition are asymptomatic until exposed to a triggering agent. The hallmark acute symptom is a rapid onset of Hemolytic anemia, characterized by fatigue, Pallor, Tachycardia, and Shortness of breath. Significant Hemolysis leads to Jaundice due to elevated Bilirubin and the passage of dark urine from Hemoglobinuria. In severe cases, particularly in newborns, extremely high bilirubin can cause Kernicterus, a form of Brain damage. Chronic, non-spherocytic hemolytic anemia is a rare presentation associated with the most severe genetic variants. Exposure to specific triggers like Primaquine, Dapsone, or Naphthalene (found in mothballs) is a common precipitant.

Genetics

The disorder is caused by mutations in the G6PD gene located on the X chromosome, explaining its X-linked recessive inheritance pattern. Males, having only one X chromosome, are predominantly and more severely affected, while females, with two X chromosomes, can be heterozygous carriers or manifest the condition due to X-inactivation skewing. Over 400 biochemical variants have been identified, classified by the World Health Organization into five classes based on residual enzyme activity and clinical severity, ranging from severe deficiency (Class I) to increased enzyme activity (Class V). The high frequency of mutant alleles in certain populations is attributed to Heterozygote advantage against severe Plasmodium falciparum malaria.

Pathophysiology

The G6PD enzyme catalyzes the first step in the Pentose phosphate pathway, which is the primary source of NADPH in red blood cells. NADPH is essential for maintaining cellular levels of reduced Glutathione, a critical antioxidant that protects against Oxidative stress. Deficient enzyme activity impairs this protective pathway, leaving Hemoglobin and the red cell membrane vulnerable to oxidative damage from triggers like certain drugs or infections. This damage leads to Hemoglobin denaturation, forming Heinz bodies, and ultimately causes premature destruction of red blood cells in the Spleen and Liver (Extravascular hemolysis), manifesting as acute hemolytic anemia.

Diagnosis

Diagnosis is typically confirmed by direct measurement of G6PD enzyme activity in red blood cells, often using the Fluorescent spot test, which is a simple, rapid screening method. More quantitative assays can be performed, and Genetic testing can identify specific mutations, which is particularly useful for family studies and prenatal diagnosis. It is crucial to avoid testing during an acute hemolytic episode, as reticulocytes and young red cells have higher enzyme activity, potentially yielding a false-normal result. The differential diagnosis includes other causes of hemolytic anemia such as Pyruvate kinase deficiency, Hereditary spherocytosis, and Autoimmune hemolytic anemia.

Management

The cornerstone of management is the prevention of hemolytic crises through patient education and avoidance of known triggers. This includes a comprehensive list of oxidative drugs to avoid, such as Primaquine, Dapsone, Sulfamethoxazole, and certain Nitrofurantoin formulations, as well as dietary avoidance of fava beans (favism). Treatment of acute hemolysis is primarily supportive, involving hydration, monitoring for Acute kidney injury, and, in severe cases, Blood transfusion. In neonates with severe Hyperbilirubinemia, treatment with Phototherapy or Exchange transfusion may be necessary to prevent Kernicterus. Vaccination against common infections and prompt treatment of illnesses are also important preventive measures.

Epidemiology

It is the most common human Enzyme deficiency, affecting an estimated 400 million people worldwide. The highest prevalence rates coincide geographically with historical or current malaria endemicity, supporting the theory of selective advantage. Notable high-frequency populations include individuals of ancestry from Sub-Saharan Africa (with variants like G6PD A-), the Mediterranean Basin (G6PD Mediterranean), the Middle East, and Southeast Asia. In the United States, the condition is most commonly identified among individuals with ancestry from these regions. The World Health Organization recognizes it as a significant public health concern in malaria-endemic countries where the use of certain antimalarials like primaquine is complicated by this deficiency.

Category:Hematology Category:Genetic disorders Category:Inborn errors of metabolism