Phosphate Dehydrogenase Deficiency Disease

Abstract:
Glucose-6-phospate dehydrogenase deficiency (G6PD), an X-linked inherited disease, is due to the lack of glucose-6-phosphate dehydrogenase. This enzyme is present in red blood cells and its deficiency can lead to hemolytic anemia. Red blood cells carry oxygen and G6PD protects these cells from natural oxygen chemicals that may build up when you have a fever or take certain medications. If there are too many of these oxidative chemicals, they can destroy the red blood cells, causing hemolytic anemia. The G6PD enzyme catalyzes the oxidation of glucose-6-phosphate to 6-phosphogluconate while also reducing NADP+ to NADPH, which is a required cofactor in many biosynthetic reactions. NADPH maintains glutathione in its reduced form that serves as a forager for hazardous oxidative metabolites in cells. With the help of the enzyme glutathione peroxidase, reduced glutathione also converts dangerous hydrogen peroxide to H20. Erythrocytes depend on G6PD activity since it is their only source of NADPH. Consequently, people lacking G6PD cannot take oxidative drugs or use certain chemicals because their red blood cells undergo rapid hemolysis under this stress (Carter).

Introduction:
Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme in the pentose phosphate pathway, a metabolic pathway that supplies reducing energy to cells, mainly RBCs. It does this by maintaining the level of the co-enzyme nicotinamide adenine dinucleotide phosphate (NADPH). NADPH in turn maintains the level of glutathione in these cells that helps protect the red blood cells against oxidative damage. Glucose-6-phosphatase dehydrogenase (G-6-PD) deficiency is the most common disease-producing enzymopathy in humans, which affects 400 million people worldwide with more than 300 reported variants (Carter). It also presents with protection against malaria, which most likely accounts for its high gene frequency. Some research has even shown that G6PD seems to decrease the susceptibility to cancer, cardiovascular disease, and stroke. G6PD deficiency is an X-linked recessive inherited disease that predominantly affects men. While it affects all races, there appears to be a higher incidence in people of African, Asian, or Mediterranean inheritance. The high frequency of type 2 diabetes and hypertension in Afro/Caribbeans in the West can also be directly related to a G6PD deficiency (Gaskin). The deficiency is a mutation in the G6PD gene locus at Xq28.

The gene is 18 kilobases long with 13 exons, which makes up an enzyme of 515 amino acids. Most of the mutations are single-base changes that result in an amino acid substitution. Female carriers can have a mild form of G6PD, which is dependent on the degree of inactivation of the unaffected X chromosome. In the rare case of homozygous females, there is co-incidence of a rare immune disorder called chronic granulomatous disease. G6PD deficient RBCs have a rather decreased life span and at risk to lyse when faced with oxidative stress. Patients with G6PD deficiency are at risk of hemolytic anemia in states of oxidative stress.

This can be in severe infection, medication and certain foods. Some drugs that can bring on symptoms include: antimalarial agents, aspirin, nitrofurantoin, quinine, quinidine, sulfonamides, and many others. Broad beans contain high levels of vicine, divicine, convicine and isouramil — all are oxidants. Recent research has also shown chemicals like henna, used in dyes for hair and skin, has also shown to bring on strong reactions. In states of oxidative stress, all remaining glutathione is consumed. Enzymes and other proteins are subsequently damaged by the oxidants, leading to electrolyte imbalance, membrane cross-bonding and phagocytosis and splenic sequestration of red blood cells. The hemoglobin is metabolized to bilirubin, increasing the risk of jaundice, or excreted directly by the kidney, which is known to cause acute renal failure.

Pathway:

Discussion:
Preservation of the integrity of the RBC’s membrane relies mainly on its ability to generate ATP and NADH from glycolysis. NADPH is produced by the pentose phosphate pathway and utilized for the reduction of oxidized glutathione to reduced glutathione. Glutathione is essential for the removal of H2O2 and lipid peroxides generated by reactive oxygen species. In normal red blood cells, the continuous generation of superoxide ion from the nonenzymatic oxidation of hemoglobin provides a source of reactive oxygen species. Under normal circumstances, the RBC removes superoxide with superoxide dismutase, which converts superoxide to hydrogen peroxide. Glutathione peroxidase reduces the hydrogen peroxide to H2O which oxidizes glutathione to the disulfide form.

Glucose-6-phosphate dehydrogenase converts glucose-6-phosphate into 6-phosphoglucono-δ-lactone and is the rate-limiting enzyme of the pentose phosphate pathway. In a person with deficient G6PD, oxidants react with glutathione causing the cellular levels of reduced glutathione to fall to such an extent that critical sulfhydryl groups in some key proteins cannot be maintained in reduced form. In turn, a sufficient amount of NADPH, which is also required for formation of nitric oxide, is not produced. As a result, the pathway promotes Heinz body formation, and hemolysis can occur. Heinz bodies are basically denatured hemoglobin formed by damage to the hemoglobin component molecules and become cross-linked by disulfide bonds. Deficiency of G6PD in the alternative pathway causes the buildup of glucose and thus there is an increase of advanced glycation end products.

In conclusion it is clear to see patients with glucose 6-phosphate dehydrogenase deficiency must be extremely careful in their use of products that could possibly cause oxidative stress. However, it seems that is an extremely hard task since there are so many products on the market and unless more research is done it would be impossible to know what is safe and what is not. Another risk lies not only on the hands of the patients, but also on the physician. Recent research in Iran, where G6PD deficiency is extremely common, was done to test blood bags used for transfusions or exchange. Samples were taken from 261 blood bags and examined by spot fluorescence for G6PD deficiency. In addition, patients receiving blood were examined for hemoglobin, hematocrit, and bilirubin before and after transfusion. They were also examined for hemoglobinuria, factors involved in hemolysis due to G6PD deficiency, and oxidants. The results were astonishing and showed that 37 of the blood bags had the G6PD deficiency and about 81% of the transfusion recipients had at least one risk factor for hemolysis. This just goes to show the seriousness involved in monitoring such a condition.

Works Cited:

Carter SM, Gross SJ. Glucose-6-Phospate Dehydrogenase Deficiency.
http://www.emedicine.com/med/topic900.htm; 29 Aug 2005.
Gaskin RS, Estwick D, Peddi R. G6PD deficiency: its role in the high prevalence of hypertension
and diabetes mellitus. Ethn Dis 2001;11:749-54. PMID 11763298. Nabavizadeh SH, Anushiravani A. The prevalence of G6PD deficiency in blood transfusion
recipients. Hematology 2007 ; Vol. 12 Issue 1, p85-88.