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Copy of g6pd
Transcript of Copy of g6pd
IT is an X-linked recessive hereditary disease characterized by abnormally low levels of glucose-6-phosphate dehydrogenase.
It is characterized by hemolytic anemia caused by the inability to detoxify oxidizing agents.
It is the rate limiting enzyme of an important pathway called HMP (hexose mono phosphate pathway).
It is the most important in RBCs.
Types and classification
decreased quantity of the enzyme reduces the number of produced NADPH+H)
decreased catalytic activity of the enzyme due to:
Decreased stability of the protein (
ex: in aging RBCs physiological decrease in G6PD activity is accelerated
Severe deficiency with
intermittent acute hemolysis
-associated with infections and drugs (antimalarials, sulfonamides, antibiotics, antibacterials, analgesics)
functions to maintain plentiful supplies of
such as divicine, isouramil, and hydrogen peroxide are normally
and rendered inactive
by exposure to reduced glutathione
to block the destruction of red cell membranes by these oxidants.
1. Drug and Environmental triggers
* Antimalarial drugs
* certain analgesics
* a few non-sulfa antibiotics
G6PD A- and G6PD Mediterranean
a protective effect against Plasmodium falciparum and Plasmodium vivax malaria.
All mutations that cause G6PD deficiency are found on the long arm of the X chromosome, on band Xq28. The G6PD gene spans some 18.5 kilobases. The following variants and mutations are well-known and described
G6PD catalyzes nicotinamide adenine dinucleotide phosphate (NADP) to its reduced form, NADPH, in the pentose phosphate pathway . NADPH protects cells from oxidative damage. Because erythrocytes do not generate NADPH in any other way, they are more susceptible than other cells to destruction from oxidative stress. The level of G6PD activity in affected erythrocytes generally is lower than in other cells. Normal red blood cells that are not under oxidative stress generally exhibit G6PD activity at approximately 2 percent of total capacity
.Even with enzyme activity that is substantially reduced, there may be few or no clinical symptoms. A total deficiency of G6PD is incompatible with life. The G6PD-deficient variants are grouped into different classes corresponding with disease severity
The G6PD / NADPH pathway is the only source of reduced glutathione in red blood cells (erythrocytes). The role of red cells as oxygen carriers puts them at substantial risk of damage from oxidizing free radicals except for the protective effect of G6PD/NADPH/glutathione.
When all remaining reduced glutathione is consumed, enzymes and other proteins (including hemoglobin) are subsequently damaged by the oxidants, leading to electrolyte imbalance, cross-bonding and protein deposition in the red cell membranes. Damaged red cells are phagocytosed and sequestered (taken out of circulation) in the spleen.
The hemoglobin is metabolized to bilirubin (causing jaundice at high concentrations). The red cells rarely disintegrate in the circulation, so hemoglobin is rarely excreted directly by the kidney, but this can occur in severe cases, causing acute renal failure .
The prevalence of neonatal hyperbilirubinemia is twice that of the general population in males who carry the defective gene and in homozygous females. It rarely occurs in heterozygous females.
The mechanism by which G6PD deficiency causes neonatal hyperbilirubinemia is not completely understood. Although hemolysis may be observed in neonates who have G6PD deficiency and are jaundiced, other mechanisms appear to play a more important role in the development of hyperbilirubinemia
In certain populations, hyperbilirubinemia secondary to G6PD deficiency results in an increased rate of kernicterus and death, whereas in other populations this has not been observed. This may reflect genetic mutations specific to different ethnic groups.
Acute hemolysis is caused by infection, ingestion of fava beans, or exposure to an oxidative .
Clinically, acute hemolysis can cause back or abdominal pain and jaundice secondary to a rise in unconjugated bilirubin .
Drugs that cause hemolysis in G6PD-deficient persons inf lict oxidative damage to erythrocytes leading to erythrocyte destruction.
Although persons who experience hemolysis after the ingestion of fava beans can be presumed to have G6PD deficiency, not all of them will exhibit hemolysis.6Favism is most common in persons with G6PD class II variants, but rarely it can occur in patients with the G6PD A–variant.
Fava beans are presumed to cause oxidative damage by an unknown component, possibly vicine, convicine, or isouramil.
Infection is the most common cause of acute hemolysis in G6PD-deficient persons, although the exact mechanism by which this occurs is unknown. Leukocytes may release oxidants during phagocytosis that cause oxidative stress to the erythrocytes; however, this explanation alone would not account for the variety of infections associated with hemolysis in G6PD-deficient persons. The most common infectious agents causing hemolysis include Salmonella,Escherichia coli, beta-hemolytic streptococci, rickettsial infections, viral hepatitis, and influenza A.
Deficiency of G6PD in the alternative pathway causes the build up of glucose and thus there is an increase of advanced glycation endproducts (AGE).
In human nutrition and biology, advanced glycation end products, known as AGEs, are substances that can be a factor in the development or worsening of many degenerative diseases, such as diabetes, atherosclerosis and chronic renal failure.
These harmful compounds can affect nearly every type of cell and molecule in the body and are thought to be one factor in aging and in some age-related chronic diseases. They are also believed to play a causative role in the blood-vessel complications of diabetes mellitus. AGEs are seen as speeding up oxidative damage to cells and in altering their normal behavior.
The deficiency also reduces the amount of NADPH, which is required 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 the incidence of G6PD deficiency in those populations.[10
Some symptoms also seen are:
Appearing very pale
Sudden rise in body temperature
Rapid heart beats
Shortness of breath
Pain in the back or abdomen
Urine appears very dark, red, red-brown, brownish or tea colored
Yellow coloring of the eyes and skin (jaundice)
Spleen may be enlarged
Generally, tests will include:
Complete blood count and reticulocyte count; in active G6PD deficiency, Heinz bodies can be seen in red blood cells on a blood film;
Liver enzymes ? (to exclude other causes of jaundice);
Lactate dehydrogenase (elevated in hemolysis and a marker of hemolytic severity)
Heinz bodies :
A "direct antiglobulin test" (Coombs' test) – this should be negative, as hemolysis in G6PD is not immune-mediated
Beutler fluorescent spot test
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. ?
Female heterozygotes may be hard to diagnose because of X-chromosome mosaicism leading to a partial deficiency that will not be detected reliably with screening tests.
Testing should be considered in children and adults (especially males of African, Mediterranean, or Asian descent) with an acute hemolytic reaction caused by infection, exposure to a known oxidative drug, or ingestion of fava beans.
Limited clinical evidence indicates that G6PD deficiency may be associated with hypertension. However, there are also data to support a protective role of G6PD deficiency in decreasing the risk of heart disease and cardiovascular-associated deaths, perhaps through a decrease in cholesterol synthesis. Studies in G6PD-deficient (G6PDX) mice are mixed and provide evidence for both protective and deleterious effects. G6PD deficiency may provide a protective effect through decreasing cholesterol synthesis, superoxide production, and reductive stress. However, recent studies indicate that G6PDX mice are moderately more susceptible to ventricular dilation in response to myocardial infarction or pressure overload-induced heart failure.
Does G6PD deficiency protect against cancer?
Previous observations on the lower mortality for cancer experienced in populations with a higher frequency of G6PD deficiency support biochemical studies on the role of G6PD during cell proliferation. The general agreement among experimental studies prevented a deeper analysis of the sources of what has been called "epidemiological evidence of the protective role of G6PD deficiency against cancer". This review analyses the methods and findings in those papers, stressing their limitations and emphasising that no final conclusions can be drawn from them. Preliminary results of ongoing epidemiological studies of G6PD deficiency and cancer are presented, although they do not prove or disprove the hypothesis that G6PD deficiency protects against cancer.
Patients of this disease typically have no symptoms and can have a normal live span. Additionally they don’t appear to acquire any illness more frequently than other people.
But if a patient precipitates to either neonatal jaundice or sensitivity to certain drugs or fava beans, patient might suffer from many problems; including:
Sensitivity to certain
drugs or fava beans
non – immune hemolytic
There can be inadequate leukocyte function (no coma) when enzyme levels are severely deficient . (period, not coma) This results in chronic Granulomatous disease (genetically heterogeneous immunodeficiency disorder )
The observed frequency of G6PD deficiency was significantly higher than expected for the entire group, for females with both catalase-positive and catalase-negative infection, and for males with catalase-positive infections.
Even if G6PD deficiency is anticipated, prophylactic oral phenobarbital given to the baby after delivery does not decrease the need for phototherapy or exchange transfusions in G6PD-deficient neonates.
Most individuals with the G6PD defect are asymptomatic and unaware of their status.
About 400 million people are affected worldwide. Gene frequency is between 5% and 25% in tropical Africa, the Middle East, tropical and subtropical Asia, some areas of the Mediterranean, and Papua New Guinea.
This makes it the most common disease-producing enzyme deficiency in the world.
It affects all races but is most common in those of African, Asian or Mediterranean descent. It tends to be milder in those of African origin and more severe in the Mediterranean races.
The epidemiology of G6PD deficiency has been noted to be remarkably similar to that of malaria, adding support to the 'malaria protection hypothesis'. Also, in vitro work has shown that malarial parasites grow slowest in G6PD-deficient cells.
Being X-linked, the disease affects mainly men but in areas of high frequency it is not uncommon to find homozygous women.
Molecular screening for glucose-6-phosphate (G6PD) mutations in two Jordanian populations revealed six different mutations and higher incidences of G6PD deficiency and G6PD A- (376A-->G + 202G-->A) mutation in Jordan Valley than in the Amman area. These observations may be explained by historically higher rates of malaria and African ancestral origins, respectively.
A total of 181 male and female babies born at Princess Basma Teaching Hospital, randomly selected, and cord blood samples were collected, and the erythrocyte G6PD activity was measured, and the hemoglobin electrophoresis for blood lysate was conducted and scanned for HbS scanning.
The frequencies of two major red cell genetic defects, sickle hemoglobin (HbS) and deficiency G6PD was determined, of the studied subjects 10 (11%) females and 11 (12%) males were found to be deficient in the G6PD gene. The frequency of HbS carriers among the females was 4% while it was 6% among males. The coincidence of both G6PD deficiency and sickle cell hemoglobin in the samples was 1%. No coincidence was found between G6PD deficiency and hyperbilirubinemia.
Avoidance of drugs and foods that cause hemolysis.
Vaccination against some common pathogens ex. Hepatitis A and hepatitis B to develop adaptive immunity to a pathogen .
In acute phase of hemolysis , blood transfusion might be necessary or even dialysis in acute renal failure .
removal of the spleen (splenectomy)
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 deficiency.
By : Dina Oweis
By : Nour Aldeen Manassrah
By :Sura Al Hunaifat
Sura Al Hunaifat
Nour Aldeen manassrah
Stem cells are biological cells found in all multicellular organisms that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells .
Mouse embryonic stem (ES) glucose-6-phosphate (G6P) dehydrogenase-deleted cells (G6pdD), obtained by transient Cre recombinase expression in a G6pd-loxed cell line, are unable to produce G6P dehydrogenase (G6PD) protein . These G6pdD cells proliferate in vitro without special requirements but are extremely sensitive to oxidative stress.
Treatment by stem cells
Under normal growth conditions, ES G6pdD cells show a high ratio of NADPH to NADP+ and a normal intracellular level of GSH.In the presence of the thiol scavenger oxidant, azodicarboxylic acid bis[dimethylamide], at concentrations lethal for G6pdD but not for wild-type ES cells, NADPH and GSH in G6pdDcells dramatically shift to their oxidized forms. In contrast, wild-type ES cells are able to increase rapidly and intensely the activity of the pentose-phosphate pathway in response to the oxidant. This process, mediated by the [NADPH]/[NADP+] ratio, does not occur in G6pdD cells. G6PD has been generally considered essential for providing NADPH-reducing power.
We now find that other reactions provide the cell with a large fraction of NADPH under non-stress conditions, whereas G6PD is the only NADPH-producing enzyme activated in response to oxidative stress, which can act as a guardian of the cell redox potential. Moreover, bacterial G6PD can substitute for the human enzyme, strongly suggesting that a relatively simple mechanism of enzyme kinetics underlies this phenomenon.