G6PD Deficiency Clinical Presentation
- Author: Lawrence C Wolfe, MD; Chief Editor: George T Griffing, MD more...
The majority of people with G6PD deficiency may remain clinically asymptomatic. However, they can present with exacerbated neonatal jaundice or with episodes of acute hemolytic anemia following exposure to an oxidative agent or with chronic non-spherocytic hemolytic anemia.[3, 15, 6, 7, 8, 9, 10]
G6PD deficiency is one of the major risk factors for severe neonatal jaundice. Jaundice usually appears within first 24 hours of life, usually earlier than physiologic jaundice but later compared to jaundice seen in blood group alloimmunization.
Jaundice can be very severe in some G6PD-deficient babies, especially in association with prematurity, infection, and/or environmental factors (such as naphthalene-camphor balls used in babies' bedding and clothing). Coexistence of a mutation in the uridyl transferase gene (UGT1A1; the same mutations are associated with the Gilbert syndrome) can also exacerbate neonatal jaundice.
Hazardous hyperbilirubinemia defined as a total serum bilirubin greater than 30 mg/dL is a rare event, occurring in 5 per 100 000 live births after universal bilirubin screening. G6PD deficiency is the leading cause of hazardous hyperbilirubinemia when an etiology is identified.
Some G6PD-deficient neonates, if undiagnosed soon after birth, could present later in the first week of life with generalized jaundice, poor feeding, lethargy, breathing difficulty, or seizures. If inadequately managed, neonatal jaundice associated with G6PD deficiency can produce kernicterus or bilirubin encephalopathy and permanent neurologic damage.[6, 7, 8, 9, 10, 16]
Acute hemolytic anemia
Acute episodic hemolytic anemia occurs on exposure to oxidant stress like certain medications, chemicals, infections, ketoacidosis, or after ingestion of fava beans. Hemolysis usually begins 24-72 hours after exposure to oxidant stress and in cases of severe hemolysis, patients present with malaise, irritability, weakness, jaundice, tachycardia due to moderate to severe anemia, and often dark urine (cola- or tea-colored) due to hemoglobinuria usually within 6-24 hours. The onset can be extremely abrupt, especially with favism in children.
Acute hemolysis is usually self-limited and resolves within 8-14 days due to the compensatory production of young red blood cells, which have high levels of G6PD enzyme. Young red blood cells are not vulnerable to oxidative damage and, hence, limit the duration of hemolysis. Acute renal failure is a rare complication of acute hemolytic anemia in adults.[3, 16]
Chronic nonspherocytic hemolytic anemia (CNSHA)
A small percentage of G6PD-deficient patients have chronic nonspherocytic hemolytic anemia (CNSHA) of variable severity. G6PD Brighton, G6PD Harilaou, and G6PD Serres are included in this category.[1, 16, 18]
The patient is usually a male with a history of neonatal jaundice who may present with anemia, unexplained jaundice, or gallstones later in life. Although they have chronic hemolysis, they are also vulnerable to acute oxidative damage on exposure to an oxidative agent.
Jaundice, pallor, and splenomegaly may be present in patients with severe hemolysis. Patients may have right upper quadrant tenderness due to hyperbilirubinemia and cholelithiasis.
G6PD deficiency is an X-linked recessive enzymopathy caused by a missense mutation in the housekeeping G6PD gene. The pattern of inheritance is similar to that of hemophilia and color blindness: males usually manifest the abnormality and females are carriers. Females can be symptomatic if they are homozygous or if their normal X chromosome is inactivated.
The G6PD gene is located in the distal long arm of the X chromosome at the Xq28 locus. More than 160 mutations in the G6PD gene (OMIM #305900) have been reported. Most are single-base changes that result in an amino acid substitution. These substitutions affect enzyme activity by decreasing intracellular stability of the protein or by affecting their catalytic activity.[14, 20, 15]
A large deletion in the G6PD gene is incompatible with life. Although small deletion mutation is rare, it has been reported and presents with severe G6PD deficiency.
Specific G6PD alleles are associated with G6PD variants with different enzyme levels and, thus, different degrees of clinical disease severity. The variation in G6PD levels accounts for differences in sensitivity to oxidants.
The most common G6PD variants includes G6PD A-, G6PD Mediterranean, G6PD Canton, and G6PD Union.
G6PD A- occurs in high frequency in Africa, Southern Europe, and North and South America. It is associated with lower enzyme levels and acute intermittent hemolysis.[3, 15, 21, 16]
G6PD Mediterranean is seen mainly in the Middle East, including Israel, and it accounts for almost all G6PD deficiency in Kurdish Jews, India, and Indonesia.[3, 15, 22, 23, 24, 25, 26, 27, 28, 21, 16] It is characterized by enzyme deficiency that is more severe than G6PD A- alleles. Hemolysis after ingestion of fava beans (Favism) is most frequently associated with the Mediterranean variant of G6PD deficiency.
G6PD Canton is seen mainly in China and G6PD Union is seen worldwide.
G6PD B is the wild type of allele (normal variant). The G6PD A+ variant is associated with high enzyme levels and, hence, no hemolysis.
In addition, severe forms of G6PD deficiency are associated with chronic nonspherocytic hemolytic anemia. Mutations causing severe chronic non-spherocytic hemolytic anemia commonly cluster in Exon 10, a region important for protein dimerization.[15, 9]
The World Health Organization has classified the different G6PD variants according to the degree of enzyme deficiency and severity of hemolysis, into classes I-V:
Class I - Severe enzyme deficiency, chronic nonspherocytic hemolysis
Class II - Severe enzyme deficiency (1-10% residual activity), intermittent acute hemolysis
Class III - Moderate enzyme deficiency (10-60% residual activity), intermittent acute hemolysis
Class IV - No enzyme deficiency 60-150% activity
Class V - Increased enzyme activity (>150%)
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