Glucose 6 Phosphate Dehydrogenase Deficiency

Although most patients remain asymptomatic throughout their life, the clinical manifestations of G6PD deficiency depend on the age of the patient.

• In newborns, G6PD deficiency is recognized as a serious risk factor for the development of neonatal hyperbilirubinemia. Neonates with G6PD deficiency are two times more likely to develop hyperbilirubinemia than the general population, and approximately 20% of kernicterus cases are associated with G6PD deficiency. Symptoms of kernicterus in a newborn include lethargy, extreme sleepiness, and poor muscle tone. Although rare, G6PD deficiency should be considered in neonates, who develop jaundice in the first 24 hours of life, who have a history of a sibling with neonatal jaundice, or have a bilirubin level of greater than the 95th percentile.

• In adults, common symptoms and exam findings of G6PD deficiency include those of hemolytic anemia or possibly red blood cell sequestration by the spleen. Some of these manifestations include pallor, jaundice, fatigue, splenomegaly, and dark urine.

 Neonatal evaluation:

• In newborn infants, assess the presence of jaundice by first examining the skin for a yellow appearance in a room that is well lit. More objective measurements include obtaining total serum bilirubin (TSB) or transcutaneous bilirubin (TcB) in newborns. An hour-specific bilirubin nomogram can be used to risk stratify newborn patients with elevated bilirubin levels to help determine appropriate treatment.

• Although screening tests for G6PD deficiencies are available, they are not routinely performed in the United States; however, screening should be considered in newborns that have severe jaundice resistant to phototherapy or who have a family history or ethnicity suggestive of G6PD deficiency. The most common screening method includes a rapid fluorescent spot test to detect the generation of NADPH from NADP. Screening can also be performed by a quantitative spectrophotometric analysis.

Children and adult evaluation:

• The evaluation of older patients presenting with complications of G6PD deficiency begins with a complete history to include new medications and screening for a family history of similar symptoms. It is also important to evaluate for possible infection, as the stress of an infection may trigger a hemolytic event in patients with G6PD deficiency.

• Laboratory studies include a complete blood count, bilirubin levels, reticulocyte count, serum aminotransferases, and lactate dehydrogenase. A peripheral blood smear may show signs of hemolysis such as schistocytes.

Neonates:[11][12]

• In the neonatal patient, treatment focuses on managing jaundice and preventing kernicterus. This includes phototherapy based on standard published guidelines. In severe cases, an exchange transfusion may be necessary.

Children and adults:[13][14]

• In older patients, management depends primarily on the overall clinical picture. Less severe presentations may be managed with supportive care and discontinuation and avoidance of the offending agents. Treat any infections as indicated by history and exam. More severe cases may require transfusions.

Many disease processes may resemble the pathophysiology of G6PD deficiency. Therefore differential considerations should include:

• Autoimmune hemolytic anemia
• Bilirubin conjugation disorders (e.g., Gilbert syndrome)
• Hemolytic disease of the newborn
• Hereditary spherocytosis
• Sickle cell anemia
• Thalassemia

A special situation exists in the management of G6PD patients with methemoglobinemia. Methemoglobin (MetHg) forms in red blood cells when the iron in the heme group of hemoglobin molecules undergoes oxidation from the normal ferrous (Fe 2+) state to the ferric (Fe3+) state. This ferric state is a poor binder of oxygen. Symptoms of hypoxia begin to develop when the level of methemoglobin reaches 10%, and death can occur when the level reaches greater than 50%.

Methemoglobinemia should be considered in patients presenting with central cyanosis and hypoxia whose symptoms are resistant to supplemental oxygen. A specific antidote for severe acute methemoglobinemia is methylene blue. Intravenously injected methylene blue is reduced to leucomethylene blue through NADPH-dependent mechanisms. Leucomethylene blue is then used as a substrate to reduce methemoglobin back to hemoglobin. However, patients who are deficient in G6PD lack sufficient NADPH to properly reduce methylene blue. Unreduced methylene blue can cause further oxidative damage in the G6PD-deficient patient resulting in hemolysis and even death. Therefore, it is important that patients who are known or suspected to have any degree of G6PD deficiency not receive methylene blue. Alternative therapies for G6PD deficient patients presenting with methemoglobinemia include transfusing packed red blood cells or providing hyperbaric oxygen therapy.

The diagnosis and management of G6PD deficiency is best done with an interprofessional team that includes a geneticist, pediatrician, internist, laboratory professional, pediatric nurses and a hematologist. In newborns, the treatment focuses on managing jaundice and preventing kernicterus. In older patients, management depends primarily on the overall clinical picture. Less severe presentations may be managed with supportive care and discontinuation and avoidance of the offending agents. Treat any infections as indicated by history and exam. More severe cases may require transfusions. 

The primary caregiver, nurse practitioner, and pharmacist must regularly evaluate the patient medications to ensure that none is associated with this disorder.[15]