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In Africa, there’s one G6PD Deficient person per four people. In areas in which malaria is endemic, G6PD deficiency has a prevalence of 5% to 25%; in nonendemic areas, it has a prevalence of less than 0.5% . An advantage of this disease is that it confers protection against malaria, in particular the form of malaria caused by Plasmodium falciparum, the most deadly form of malaria. A similar relationship exists between malaria and sickle-cell disease. One theory to explain this, is that cells infected with the Plasmodium parasite are cleared more rapidly by the spleen. This phenomenon might give G6PDH deficiency carriers an evolutionary advantage by increasing their fitness in malarial endemic environments. Slide 3: Percent of people who have G6PD Deficiency Slide 4: G6PD deficiency , a hereditary predisposition to hemolysis, is an X-linked disorder of antioxidant homeostasis that is caused by mutations in the G6PD gene at q28 locus. The q28 locus of the X-chromosome… Slide 6: G6PD is the first enzyme in the hexose monophosphate shunt, a pathway critical for generating nicotinamide adenine dinucleotide phosphate (NADPH). NADPH is required for the regeneration of reduced glutathione. Within erythrocytes, reduced glutathione is used for the detoxification of oxidants produced by the interaction of hemoglobin and oxygen and by exogenous factors such as drugs, infection, and metabolic acidosis. Slide 7: Most G6PD deficiency arises because mutations in the X-linked G6PD gene decrease the catalytic activity or the stability of G6PD, or both. When G6PD activity is sufficiently depleted or deficient, insufficient NADPH is available to regenerate reduced glutathione during times of oxidative stress. This results in the oxidation and aggregation of intracellular proteins (Heinz bodies) and the formation of rigid erythrocytes that readily hemolyze. Slide 8: With the more common G6PD alleles, which cause the protein to be unstable, deficiency of G6PD within erythrocytes worsens as erythrocytes age. Because erythrocytes do not have nuclei, new G6PD mRNA cannot be synthesized; thus, erythrocytes are unable to replace G6PD as it is degraded. During exposure to an oxidative stress episode, therefore, hemolysis begins with the oldest erythrocytes and progressively involves younger erythrocytes, depending on the severity of the oxidative stress. Slide 9: As an X-linked disorder, G6PD deficiency predominantly and most severely affects males. Rare symptomatic females have a skewing of X chromosome inactivation such that the X chromosome carrying the G6PD disease allele is the active X chromosome in erythrocyte precursors. Slide 10: Besides gender, the severity of G6PD deficiency depends on the specific G6PD mutation. In general, the mutation common in the Mediterranean basin (i.e., G6PD B- or Mediterranean) tends to be more severe than those mutations common in Africa (i.e., G6PD A- variants) In erythrocytes of patients with the Mediterranean variant, G6PD activity decreases to insufficient levels 5 to 10 days after erythrocytes appear in the circulation, whereas in the erythrocytes of patients with the G6PD A- variants, G6PD activity decreases to insufficient levels 50 to 60 days after erythrocytes appear in the circulation. Therefore, most erythrocytes are susceptible to hemolysis in patients with severe forms of G6PD deficiency, such as G6PD Mediterranean, but only 20% to 30% are susceptible in patients with G6PD A- variants. Slide 11: G6PD deficiency most commonly manifests as either Neonatal jaundice Acute hemolytic anemia. The peak incidence of neonatal jaundice occurs during days 2 and 3 of life. The severity of the jaundice ranges from subclinical to levels compatible with kernicterus. Episodes of acute hemolytic anemia usually begin within hours of an oxidative stress and end when G6PD-deficient erythrocytes have hemolyzed; therefore, the severity of the anemia associated with these acute hemolytic episodes is proportionate to the deficiency of G6PD and the oxidative stress. Viral and bacterial infections are the most common triggers, but many drugs and toxins can also precipitate hemolysis. The disorder favism results from hemolysis secondary to the ingestion of fava beans by patients with more severe forms of G6PD deficiency, such as G6PD Mediterranean; fava beans contain β-glycosides, naturally occurring oxidants : The disorder favism results from hemolysis secondary to the ingestion of fava beans by patients with more severe forms of G6PD deficiency, such as G6PD Mediterranean; fava beans contain β-glycosides, naturally occurring oxidants Slide 13: In addition to neonatal jaundice and acute hemolytic anemia, G6PD deficiency rarely causes congenital or chronic nonspherocytic hemolytic anemia. Patients with chronic nonspherocytic hemolytic anemia generally have a profound deficiency of G6PD that causes chronic anemia and an increased susceptibility to infection. The susceptibility to infection arises because the NADPH supply within granulocytes is inadequate to sustain the oxidative burst necessary for killing of phagocytosed bacteria. Slide 14: Laboratory diagnosis CBC Urinalysis LDH/haptoglobin fractionated bilirubin blood smear with stains for Heinz bodies G6PD fluorescent spot test. test that visually identifies NADPH produced by G6PD under ultraviolet light. When the blood spot does not fluoresce, the test is positive. G6PD deficiency should be suspected in patients of African, Mediterranean, or Asian ancestry who present with either an acute hemolytic episode or neonatal jaundice. The key to management of G6PD deficiency is prevention of hemolysis by prompt: 1- treatment of infections 2- avoidance of oxidant drugs (e.g., sulfonamides, sulfones, nitrofurans) and toxins (e.g., naphthalene). Although most patients with a hemolytic episode will not require medical intervention, those with severe anemia and hemolysis may require resuscitation and erythrocyte transfusions : G6PD deficiency should be suspected in patients of African, Mediterranean, or Asian ancestry who present with either an acute hemolytic episode or neonatal jaundice. The key to management of G6PD deficiency is prevention of hemolysis by prompt: 1- treatment of infections 2- avoidance of oxidant drugs (e.g., sulfonamides, sulfones, nitrofurans) and toxins (e.g., naphthalene). Although most patients with a hemolytic episode will not require medical intervention, those with severe anemia and hemolysis may require resuscitation and erythrocyte transfusions Slide 16: Each son of a mother carrying a G6PD mutation has a 50% chance of being affected, and each daughter has a 50% chance of being a carrier. Each daughter of an affected father will be a carrier, but each son will be unaffected because an affected father does not contribute an X chromosome to his sons. The risk that carrier daughters will have clinically significant symptoms is low because sufficient skewing of X chromosome inactivation is relatively uncommon. Slide 17: L.M., a previously healthy 5-year-old boy, presented to the emergency department febrile, pale, tachycardic, tachypneic, and minimally responsive. The morning before presentation, he had been in good health, but during the afternoon, he had abdominal pain, headache, and fever; by late evening, he was tachypneic and incoherent. He had not ingested any medications or known toxins, and results of a urine toxicology screen were negative. Results of other laboratory tests showed massive nonimmune intravascular hemolysis and hemoglobinuria. After resuscitation, L.M. was admitted to the hospital; the hemolysis resolved without further intervention. Case Report Slide 18: L.M. was of Greek ethnicity; his parents were unaware of a family history of hemolysis, although his mother had some cousins in Europe with a "blood problem." Further inquiry revealed that the morning before admission, L.M. had been eating fava beans from the garden while his mother was working in the yard. The physician explained to the parents that L.M. probably was deficient for glucose-6-phosphate dehydrogenase (G6PD) and that because of this, he had become ill after eating fava beans. Subsequent measurement of L.M.'s erythrocyte G6PD activity confirmed that he had G6PD deficiency. The parents were counseled concerning L.M.'s risk of acute hemolysis after exposure to certain drugs and toxins and given a list of compounds that L.M. should avoid. The End… : The End… You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.