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Glucose-6-phosphate dehydrogenase deficiency
Glucose-6-phosphate dehydrogenase deficiency is an X-linked recessive hereditary disease characterised by abnormally low levels of the glucose-6-phosphate dehydrogenase enzyme (abbreviated G6PD or G6PDH). It is a metabolic enzyme involved in the pentose phosphate pathway, especially important in red blood cell metabolism. Individuals with the disease may exhibit nonimmune hemolytic anemia in response to a number of causes. It is closely linked to favism, a disorder characterized by a hemolytic reaction to consumption of broad beans, with a name derived from the Italian name of the broad bean (fava). Sometimes the name, favism, is alternatively used to refer to the enzyme deficiency as a whole.
Signs and symptomsMost individuals with G6PD deficiency are asymptomatic. Patients are almost exclusively male, due to the X-linked pattern of inheritance, but female carriers can be clinically affected due to lyonization where random inactivation of an X-chromosome in certain cells creates a population of G6PD deficient red cells coexisting with normal red cells. Red blood cell breakdown or hemolysis in G6PD deficiency can manifest itself in a number of ways:
All individuals with favism show G6PD deficiency. However, not all individuals with G6PD deficiency show favism. For example, in a small study of 757 Saudi men, more than 42% showed G6PD deficiency, but none reported symptoms of favism, despite fava in the diet.[1] Favism is known to be more prevalent in infants and children, and G6PD genetic variant can influence chemical sensitivity. Other than this, the detailed chemical relationship between favism and G6PD is not well known. Potentially harmful substancesThere are many potentially harmful substances which affect G6PD, although many require high doses to produce symptomatic individials. Antimalarials that can exasperate G6PD deficiency include primaquine, pamaquine and chloroquine. There is evidence that other antimalarials may also exasperate G6PD deficiency but at higher doses. Analgesics such as aspirin can increase symptoms in G6PD deficiency. Sulphanilamide, thiazolesulphone, acetanilide, methylene blue and naphthalene also have links with G6PD deficiency.[2] Henna can cause a haemolytic crisis in G6PD deficient infants.[3] MutationsAll mutations that cause G6PD deficiency are found on the long arm of the X chromosome, on band Xq26. The G6PD gene spans some 18.5 kilobases.[2] The following variants and mutations are well-known and described: !colspan="10" align="center" bgcolor="#FACEDA"|Table 1. Descriptive mutations and variants
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!colspan="4" align="center" bgcolor="#FACEDA"| Variants or mutations
!colspan="3" align="center" bgcolor="#FACEDA"| Gene
!colspan="3" align="center" bgcolor="#FACEDA"| Protein
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!Designation
!Short name
!Isoform DiagnosisThe diagnosis is generally suspected when patients from certain ethnic groups (see below) develop anemia, jaundice and symptoms of hemolysis after challenge to any of the above causes, especially when there is a positive family history. Generally, tests will include:
When there are sufficient grounds to suspect G6PD, a direct test for G6PD is the "Beutler fluorescent spot test", which has largely replaced an older test (the Motulsky dye-decolouration test). Other possibilities are direct DNA testing and/or sequencing of the G6PD gene. The Beutler fluorescent spot test is a rapid and inexpensive test that visually identifies NADPH produced by G6PD under ultraviolet light. When the blood spot does not fluoresce, the test is positive; it can be falsely negative in patients who are actively hemolysing. It can therefore only be done 2-3 weeks after a hemolytic episode. When a macrophage in the spleen "sees" an RBC with a Heinz body, it removes the precipitate and a small piece of the membrane, leading to characteristic "bite cells". However, if a large number of Heinz bodies are produced, as in the case of G6PD deficiency, some Heinz bodies will nonetheless be visible when viewing RBCs that have been stained with crystal violet. This easy and inexpensive test can lead to an initial presumption of G6PD deficiency, which can be confirmed with the other tests. ClassificationThere are four forms of G6PD:
Pathophysiology
Mechanism of G6PD 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. Broad beans contain high levels of vicine, divicine, convicine and isouramil — all are oxidants. In states of oxidative stress, all remaining glutathione is consumed. Enzymes and other proteins (including hemoglobin) 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 (causing jaundice at high concentrations) or excreted directly by the kidney (causing acute renal failure in severe cases). Deficiency of G6PD in the alternative pathway causes the build up of glucose and thus there is an increase of advanced glycation endproducts (AGE). The deficiency also causes a reduction of NADPH which is necessary for the formation of Nitric Oxide (NO). The high prevalence of diabetes mellitus type 2 and hypertension in Afro-Caribbeans in the West could be directly related to G6PD deficiency.[4] Although female carriers can have a mild form of G6PD deficiency (dependent on the degree of inactivation of the unaffected X chromosome - see lyonization), homozygous females have been described; in these females there is co-incidence of a rare immune disorder termed chronic granulomatous disease (CGD). EpidemiologyG6PDH is the most common human enzyme defect, being present in more than 400 million people worldwide.[5] African, Middle Eastern and South Asian people are affected the most along with those who are mixed with any of the above.[6] A side effect of this disease is that it confers protection against malaria,[7] 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. An explanation 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. TreatmentThe most important measure is prevention - avoidance of the drugs and foods that cause hemolysis. Vaccination against some common pathogens (e.g. hepatitis A and hepatitis B) may prevent infection-induced attacks.[8] In the acute phase of hemolysis, blood transfusions might be necessary, or even dialysis in acute renal failure. Blood transfusion is an important symptomatic measure, as the transfused red cells are generally not G6PD deficient. Some patients benefit from removal of the spleen (splenectomy),[9] as this is an important site of red cell destruction. Folic acid should be used in any disorder featuring a high red cell turnover. Although vitamin E and selenium have antioxidant properties, their use does not decrease the severity of G6PD. HistoryFavism is a disorder characterized by hemolytic anemia in response to ingestion of fava beans. Favism as a diagnosis has been known since antiquity. One theory for the Pythagoreans' avoidance of beans is avoidance of favism, but more likely, this was a philosophical matter, such as the belief that beans and humans were created from the same material.[10][11] The modern understanding of the condition began with the analysis of patients who exhibited sensitivity to primaquine.[12] The discovery of G6PD deficiency relieved heavily upon the testing of prisoner volunteers at Illinois State Penitentiary, although today such studies cannot be performed. When some prisoners were given the drug primaquine, some developed hemolytic anemia but others did not. After studying the mechanism through Cr51 testing, it was conclusively shown that the hemolytic effect of primaquine was due to an internal defect of erythrocytes.[13] ReferencesExternal links
bn:???????-?-????? ?????????????? ???????? bg:???????-6-???????????????????? ?????????????? de:G6PD-Mangel es:Deficiencia de glucosa-6-fosfato deshidrogenasa fr:Déficit en glucose-6-phosphate déshydrogénase hr:Manjak enzima glukoza-6-fosfat dehidrogenaze it:Favismo he:???? G6PD ja:?????? pl:Niedobór dehydrogenazy glukozo-6-fosforanowej pt:Deficiência em glucose-6-fosfato desidrogenase simple:Favism th:??????????????? G-6-PD zh:????????????? Source: Wikipedia | The above article is available under the GNU FDL. | Edit this article
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