Glucose-6-Phosphate Dehydrogenase deficiency is a hereditary, sex-linked enzyme defect that results in the breakdown of red blood cells when the person is exposed to an infection, to certain drugs or to a mechanical stress such as cardiopulmonary bypass.

One of the 23 pairs of human chromosomes is the X and Y- chromosome pair (sex chromosomes) which determine what sex an individual will be, among other characteristics. The X-chromosome carries genes that are critical to human survival. An important gene located on the X-chromosome is the gene for the G6PD enzyme. All X-linked genetic conditions, such as G6PD deficiency, are more likely to affect males than females. G6PD deficiency will only manifest itself in females when there are two defective copies of the gene in the genome [1,2].

Glucose-6-Phosphate Dehydrogenase(G6PD) deficiency in the red cells is the most common human enzyme deficiency. It is estimated that about 400 million people worldwide are affected by this enzymopathy. This deficiency is also sometimes referred to as favism since some G6PD deficient individuals are also allergic to fava beans. Individuals with G6PD deficiency have a curious resistance to infection by malaria. However they are at risk for several pathologic entities, some of which can be potentially lethal if not properly managed.

Caucasian of Mediterranean ancestry, Greeks, Jewish, and Sardinian are prone to present the disease. Most of the affected individuals reside in Africa, the Middle East, and Southeast Asia. Ten percent of African Americans have the deficiency and some isolated tribes in Africa and Southeast Asia exhibit the highest frequency of incidence for any given population; a defective enzyme can be found in as many as one in four people among these populations [1]

PHYSIOLOGY OF G-6-PD

The normal function of the G-6-PD enzyme is critical to human survival. This enzyme catalyzes an oxidation/reduction reaction. Oxidation/reduction reactions function in transferring electrons from one molecule to another; oxidation is the loss of electrons and reduction is the gain of electrons. The G-6-PD catalyzes the oxidation of glucose-6-phosphate to 6-phosphogluconate, while concomitantly reduces nicotinamide adenine dinucleotide phosphate (NADPH). This is the first step of the pentose phosphate pathway. This pathway produces ribose, which is an essential component of both DNA and RNA. There are other metabolic pathways, however, that can produce ribose if there is a deficiency in G6PD [3].

Nicotinamide ademine dinucleotide phosphate is a required cofactor in many biosynthetic reactions. NADPH is also used to keep glutathione, a tri-peptide, in its reduced form. Reduced glutathione acts as a scavenger for dangerous oxidative metabolites in the cell; it converts harmful hydrogen peroxide to water with the help of the enzyme, glutathione peroxidase. There are other metabolic pathways that can generate NADPH in all cells, except in red blood cells where other NADPH-producing enzymes are lacking [1]. This has a profound effect on the stability of red blood cells since they are especially sensitive to oxidative stresses in addition to having only one NADPH-producing enzyme to remove these harmful oxidants. For this reason G-6-PD deficient individuals should not receive oxidative drugs, because the red blood cells in these individuals are not able to handle this stress and as a consequence hemolysis ensues.

CARDIAC SURGERY AND G-6-PD DEFICIENCY

Cardiac surgery and cardiopulmonary bypass involve many processes in which cell damage is likely to occur. Perioperative ischemia and reperfusion, contact of blood and circuit surfaces, hypothermia, and acidosis are common events during cardiac operations. These events lead to an increased production of free radicals, resulting in damage to almost every organ [3]. Lung injury can be worsened as a result of free radicals. It has been postulated that deficiency of G-6-PD potentiates the harmful effect of free radicals in such patients undergoing cardiac surgery [4].

Gerrah et cols [4] compared 42 patients with the Mediterranean variant of G-6-PD deficiency or favism with 42 patients who did not have the enzyme deficiency. All patients underwent cardiac surgery with the support of cardiopulmonary bypass. Patients in the control group were selected on a 1:1 case-control study. One patient (2.4%) on the study group died of multiple organ failure on the ninth postoperative day, and there was no mortality in the control group (not significant). A highly significant difference was found in ventilation time with 13.7±7.6 hours in the G-6-PD deficient group versus 7.7±2.8 hours for the control group (p < 0.0001). The maximal PaO2 value recorded on arrival in the ICU and the minimal value recorded were significantly lower in the study group. Hypoxia was found in 11 patients in the study group, whereas only 1 patient in the control group was hypoxic (p < 0.0001). Hemoglobin values were lower in the study group. Blood transfusions were more commonly administered to the study group (73%) compared with the control group (38%). Postoperative bilirubin was 26±10 µmol/L in the study group versus 17±6.7 µmol/L in the control group (p < 0.0001). Postoperative lactate dehydrogenase levels were 970±496 U/L in the study group versus 505±195 U/L in the control group (p < 0.0001).

Activation of the inflammatory response during CPB with production of oxygen free radicals is one of the many processes of injury resulting from CPB. One of the end results of this process is endothelial injury, which is expressed clinically as capillary leak during the postbypass period. Apparently the lungs are the main organ affected by and sustaining this damage. Hypoxemia after heart surgery may result from imbalance between these injurious stimuli and the compensatory mechanisms. Although the mechanical effect of venting and suction on red blood cell destruction should have been similar for both groups, the significantly increased need for blood among the patients with G-6-PD deficiency and the higher levels of indirect markers of hemolysis in this group are in agreement with the theory that hemolysis is exaggerated when an inborn error such as G-6-PD deficiency exists.

Patients deficient in G-6-PP demonstrated impaired oxygenation, prolonged ventilation, increased hemolysis, and increased need for blood transfusion after cardiac surgery with CPB compared with control patients. On reperfusion after a period of ischemia, the antioxidant system recruits all of its components in an attempt to neutralize the overhelming oxidative stress of free radicals. Every effort should be made to reduce the formation of free radicals and to increase their deactivation in G-6-PD deficient patients.

REFERENCES

1. Scriver, C.R. Glucose-6-Phosphate Dehydrogenase Deficiency. In: The metabolic and molecular bases of inherited disease. 7th ed. n.p.: McGraw- Hill, Inc.:3367-98, 1995.

2. Pai, G.S. Localization of loci for hypoxanthine phophoriboxyltransferase and glucose-6-phosphate dehydrogenase and biochemical evidence of non-random X- chromosome expression from studies of a human X-autosome translocation. Proc. Natl. Acad. Sci. 77:2810, 1980.

3. Boyle EM Jr, Pohlman TH, Johnson MC, Verrier ED. Endothelial cell injury in cardiovascular surgery: the systemic inflammatory response. Ann Thorac Surg 63;277-84, 1997.

4. Gerrah R, Shargal Y, Elami A. Impaired oxygenation and increased hemolysis after cardiopulmonary bypass in patients with glucose-6-phosphate dehydrogenase deficiency. Ann Thorac Surg 76:523-7, 2003.