Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme found in the cytoplasm of all cells in the body. It is a housekeeping enzyme that plays a vital role in the prevention of cellular damage from reactive oxygen species (ROS). It does this by providing substrates to prevent oxidative damage. Erythrocytes are particularly vulnerable to ROS due to their role in oxygen transport and inability to replace cellular proteins as mature cells. Inherited deficiencies of G6PD can result in acute hemolytic anemia during times of increased ROS production. This may be caused by stress or exposure to certain foods that contain high amounts of oxidative substances, for example, fava beans, or certain medications. In particular, anti-malarial agents have a strong association with inducing hemolytic anemia in patients with G6PD deficiency. Below are medications more commonly used in the United States that have been shown to trigger a hemolytic crisis in those with G6PD deficiency; however, a more comprehensive list of medications to be avoided has been published by the Italian G6PD Deficiency Association and can be found at www.g6pd.org.
Common medications to be avoided or used with caution in G6PD-deficient patients include:
The Gd gene codes for the G6PD enzyme. This gene is located on the long arm of the X chromosome and therefore follows X-linked inheritance. Deficiency of G6PD may be due to mutations that change the protein structure and therefore reduce its activity, or the amount of enzyme produced. There are currently 186 known human G6PD mutations, and most are point mutations affecting a single nucleotide. None of the mutation patterns seen in humans cause complete inactivation of G6PD since this would be lethal to a developing embryo.
G6PD is the most common human enzyme defect known, affecting upward of 400 million people worldwide. Men are more commonly affected than women due to X-linked inheritance. It is most prevalent in tropical and subtropical areas. Interestingly, there is evidence to suggest that G6PD deficiency is protective against uncomplicated malaria, but not severe malaria cases. The protective mechanism for G6PD deficiency and malaria is still being investigated. With regards to ethnicity, G6PD deficiency is more common in people of African, Mediterranean, or Asian descent, likely owing to its suggested protective effect from malaria.
G6PD is the catalyst in the rate-limiting first step of the pentose phosphate pathway, which uses glucose-6-phosphate to convert nicotinamide adenine dinucleotide phosphate (NADP) into its reduced form, NADPH. In red blood cells, NADPH is critical in preventing damage to cellular structures caused by oxygen-free radicles. It does this by serving as a substrate to the enzyme glutathione reductase. Reduced glutathione can be used to convert hydrogen peroxide to water and prevent damage to cellular structures, particularly the cell wall of red blood cells (RBCs) since they have limited capacity for repair once mature.
Although most patients remain asymptomatic throughout their life, the clinical manifestations of G6PD deficiency depend on the age of the patient.
Children and adult evaluation:
Many disease processes may resemble the pathophysiology of G6PD deficiency. Therefore differential considerations should include:
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.
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