Management. (By the World Health Organization according to the magnitude of the enzyme deficiency and the severity of hemolysis)

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1 Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency Management Definition: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an inherited disorder caused by a genetic defect in the red blood cell (RBC) enzyme G6PD, which generates NADPH and protects RBCs from oxidative injury. G6PD deficiency is the most common enzymatic disorder of RBCs. G6PD deficiency is an X-linked disorder. As a result, males who inherit a G6PD mutation are hemizygous for the defect, all of their RBCs are affected. Females who inherit a heterozygous G6PD mutation usually do not have severe hemolytic anemia, since half of their RBCs express the normal G6PD allele and half express the abnormal allele. The majority of females who inherit an abnormality in G6PD are unaffected carriers. However, the cells that express the abnormal allele are as vulnerable to hemolysis as the enzyme-deficient RBCs in males. The presence of anemia will vary depending on the severity of deficiency in the affected cells and whether there is skewed X-inactivation (lyonization) that results in a greater expression from the abnormal allele in a large percentage of RBCs. Classification: (By the World Health Organization according to the magnitude of the enzyme deficiency and the severity of hemolysis) Class I Class I variants have severe enzyme deficiency (<10 percent of normal) associated with chronic hemolytic anemia. Class II Class II variants also have severe enzyme deficiency (<10 percent of normal), but there is usually only intermittent hemolysis, typically on exposure to oxidant stress such as fava bean exposure or ingestion of certain drugs. G6PD Mediterranean is the classic example. Class III Class III variants have moderate enzyme deficiency (10 to 60 percent of normal) with intermittent hemolysis, typically associated with significant oxidant stress. G6PD A - (the most common variant in individuals of African ancestry) is the classic example. Class IV Class IV variants have no enzyme deficiency or hemolysis. The wild-type (normal) enzyme is considered a class IV variant, as are numerous other genetic changes that do not alter levels of the enzyme. These variants are of no clinical significance. Class V Class V variants have increased enzyme activity (more than twice normal). These are typically uncovered during testing for G6PD deficiency. They are of no clinical significance.

2 Clinical manifestations: The severity of disease and the likelihood of developing neonatal jaundice or chronic hemolysis, and the magnitude of hemolysis when hemolytic episodes occur depend on the degree of the enzyme deficiency, which in turn is determined by the characteristics of the G6PD variant. The majority of individuals are asymptomatic and do not have hemolysis in the steady state. They have neither anemia, evidence of increased red blood cell (RBC) destruction, nor alteration in blood morphology, although a modest shortening of RBC survival can be demonstrated by isotopic techniques. This includes almost all individuals with the most prevalent G6PD variants, G6PD A- and G6PD Mediterranean. However, episodes of acute hemolysis with hemolytic anemia may be triggered by medications, certain foods, and acute illnesses, especially infections. The rare individuals with severe disease (class I variants) usually have chronic hemolysis. Signs & symptoms: Jaundice, which is when the skin or the whites of the eyes turn yellow Pale skin, or paleness of the lips, tongue, or inside of the eyelid Dark-colored urine Back or belly pain Tiredness, fatigue, or headache caused by anemia - Peripheral blood smear reveals microspherocytes, eccentrocytes or "bite" cells, and "blister cells" with hemoglobin puddled to one side, special stains can document the production of Heinz bodies, which are collections of denatured globin chains often attached to the RBC membrane. Causes: 1. Medications and chemicals

4 2. Foods: Ingestion of fava beans is the classic example. Acute intravascular hemolysis upon ingestion of fava beans, referred to as favism, occurs most commonly in male children between the ages of one and five years. Symptoms begin within 5 to 24 hours after ingestion and include headache, nausea, back pain, chills, and fever, and are followed by hemoglobinuria and jaundice. The fall in hemoglobin concentration is acute, often severe, and, in the absence of transfusion, can be fatal. Other foods such as bitter melon have also been implicated. 3. Medical illnesses: Infection is likely to be the most common inciting factor for hemolytic anemia once the individual is aware of the diagnosis and avoids oxidant medications. Diabetic ketoacidosis, since both acidosis and hyperglycemia are potential precipitating factors. Acute hemolytic anemia Episodes of acute hemolysis in the setting of oxidant injury from medications, acute illnesses, and certain foods associated with an abrupt fall in the hemoglobin concentration by 3 to 4 g/dl. Hemolysis may be mild and self-limiting in some individuals (ends after about one week even with continued drug ingestion), and severe and life-threatening in others (may continue after the drug is discontinued). Neonatal jaundice: The degree of jaundice is quite variable, in severe cases (Class I variants) where anemia and jaundice are often first noted in the newborn period, there is a risk of bilirubin-induced neurologic dysfunction and kernicterus (permanent neurologic damage) if the patient is not treated aggressively. In neonates with Class II or III G6PD-deficiency, jaundice is rarely present at birth, the peak of onset is two to three days after birth. Jaundice here is more prominent than anemia, which is rarely severe.

5 The cause of neonatal hyperbilirubinemia in G6PD-deficient infants is not clear, although one hypothesis suggests that the combination of increased bilirubin production due to accelerated breakdown of RBCs and the immaturity of the liver is responsible. Congenital nonspherocytic hemolytic anemia and chronic hemolysis: Chronic hemolysis is not characteristic of most individuals with G6PD deficiency, but some with severe deficiency (activity <10 percent at baseline) can have chronic hemolysis with or without chronic anemia. Variants that produce chronic hemolytic anemia are referred to as class I variants. These individuals have such severe G6PD deficiency that they may have hemolysis even in the absence of oxidant injury from medications or illnesses, some drugs with relatively mild oxidant potential that are safe in patients with class II or class III G6PD variants may increase hemolysis in patients with class I variants. Characteristics of individuals with chronic hemolysis: o Mild to moderate anemia (hemoglobin 8 to 10 g/dl) o Reticulocyte count of 10 to 15 percent. o Pallor is uncommon o Scleral icterus is intermittent (yellowing of the whites of the eyes) o Splenomegaly is rare The typically mild degree of anemia reflects the ability of increased erythropoiesis (RBCs production) to compensate for the hemolysis. Thus, as with other chronic hemolytic anemias, the anemia may be worsened by diminished erythropoietic capacity due to infection or to parvovirus-induced aplastic crises. Such a crisis may be the event that first leads to examination of the blood and establishment of diagnosis of G6PD deficiency. Indications for evaluation: Neonatal jaundice or any individual of any age with unexplained, direct antiglobulin (Coombs) test (DAT)- negative hemolytic anemia, especially those from families with a history of inherited anemia and those from populations most likely to be affected (Middle Eastern). Asymptomatic individuals at high risk of G6PD deficiency prior to administration of certain medications. Certain other populations (certain newborn screening settings or asymptomatic family members of affected individuals). Testing for G6PD deficiency for individuals at risk and who require treatment with oxidant drugs including dabrafenib, dapsone, chlorpropamide, glipizide, glyburide, methylene blue, pegloticase, primaquine, quinine, rasburicase, etc.

6 Screening tests for G6PD: Several screening tests are available for G6PD deficiency. These assays all work by assaying the normal function of the enzyme, reduction of NADP to NADPH, which is the initial step in the hexose monophosphate shunt. For the most part these tests are semiquantitative. Thus, if positive they typically should be followed by a quantitative confirmatory test. The quantitative tests are confirmatory tests that are performed for individuals with a positive screening test by adding a measured amount of RBC hemolysate to an assay mixture that contains substrate (glucose-6-phosphate) and a cofactor (NADP), the rate of NADPH generation is measured spectrophotometrically (absorbance at a wavelength of 340 nanometers) Timing of G6PD assay: In the setting of an acute hemolytic episode, the RBCs with the most severely reduced G6PD activity will have hemolyzed, and thus their G6PD activity will not be measured in the assay, and this will produce false-negative results. Thus, if initial testing is negative and a suspicion for G6PD deficiency remains, testing should be repeated approximately three months after the hemolytic episode has resolved (the typical time it takes for a new population of circulating RBCs to be produced). During this three-month period, it would be prudent(wise) to avoid potential sources of oxidant injury. MANAGEMENT: 1. Nonpharmacological treatment: The cornerstone of management of G6PD deficiency is the (unsafe drugs in Table 1). avoidance of oxidative stress to red blood cells (RBCs) There may be certain settings in which it is especially important to give one of these drugs, and this may be possible in individuals with mild hemolysis. Examples: - Primaquine has been given to individuals with the G6PD A- variant if a low dose is used (15 mg/day or 45 mg once or twice weekly) and the complete blood count (CBC) is monitored closely. The mild anemia that may ensue is corrected by the compensatory increase in reticulocyte production and does not recur unless the dose of the drug is escalated. - In other cases, the drug may be life-saving and may need to be administered before the results of G6PD testing are available (administration of rasburicase for tumor lysis syndrome). In these situations, it may be prudent to provide the drug and maintain a high index of suspicion for hemolysis that will facilitate rapid treatment if hemolysis occurs. - In other cases, an alternative drug may be effective. The use of ascorbic acid (vitamin C) rather than methylene blue to treat methemoglobinemia in individuals with G6PD deficiency.

7 Dietary restrictions Affected individuals should avoid ingestion of fava beans, also referred to as "broad beans" which can cause hemolysis in some but not all affected individuals. However, unlike certain medications that induce hemolysis in all individuals with G6PD deficiency, sensitivity to the fava bean is more variable. Also, several other foods such as bitter melon and blueberries are potentially associated with hemolysis, although the direct relationship is not clear. 2. Treatment of neonatal jaundice and chronic hemolysis: The management of neonatal jaundice due to G6PD deficiency does not differ from that recommended for neonatal jaundice arising from other causes. - Mild cases generally do not require treatment - Intermediate cases require phototherapy - Severe cases may require exchange blood transfusion For chronic hemolysis, routine supplementation with folic acid 1mg is reasonable & adequate. 3. Treatment of acute hemolytic episodes: 1. Any inciting agent(s) should be removed as soon as possible. 2. Aggressive hydration for acute intravascular hemolysis. 3. Transfusion for severe anemia. Special considerations: Pregnancy: Pregnant and nursing women who are heterozygous for G6PD deficiency should avoid drugs known to be unsafe because some of these drugs gain access to the fetal circulation and to breast milk. For the drugs that are considered "probably safe," there are no published data to suggest that risk of hemolysis would be increased in a breastfed infant who had G6PD deficiency. Decisions about the use of these drugs will depend on the individual case and the availability of good alternatives, as discussed in topic reviews on specific conditions. Blood donation: Individuals with G6PD deficiency can donate blood if they are otherwise able to donate and do not have anemia. This is because the typical lifespan of transfused G6PD-deficient RBCs is thought to be relatively normal, and it is unlikely for a patient to be transfused with multiple units of G6PD-deficient blood and have clinically significant

8 hemolysis, even in areas of high prevalence. One exception may be blood used for exchange transfusion of newborn infants, which poses a theoretical risk if a large enough volume of G6PD-deficient cells is transfused. References: - Glader,B. (2018). Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency. In J.S. Tirnauer (Ed.), UpToDate. Retrieved December 26, 2018, from Prepared by Pharm D students: Heba Alali, Raghad Al khader Supervised by clinical pharmacist: Eshraq Alabweeny

Glucose-6-Phosphate Dehydrogenase

Glucose-6-Phosphate Dehydrogenase Is the major enzyme in the pentose phosphate pathway (also called the phosphogluconate pathway or the hexose monophosphate shunt) which is a metabolic pathway parallel