Mar 7, 2019 in Medicine

Introduction

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a disorder that is inherited hemolysis or X-linked confusion of the antioxidant homeostasis, which is caused by mutations in the gene responsible for the disease. On the whole, there are about four hundred million of affected persons, which has led to the diseases being considered as the most common enzymopathy across the world. Prevalence of malaria is common among 5% to 25%, while non-endemic afflicted population with the disease is less than 5%. According to a epidemiology study, both Middle East and Asia have the largest occurrence of the disease with 31% and 62% respectively. North American subgroups include blacks and descendants of immigrants from Southeast Asia, Sephardic Jews, Greece, East Asia, and Italy. The occurrence of the disease is high, which has caused a concern of implementing screening of the newborn for the G6PD deficiency.

 In addition, it has to be incorporated into the screening program in many non-western countries, which include Eastern Europe, Southeast Asia, and Middle East. Based on the analysis of the disease, there is cost-effective screening of entire populations in Canada because for over 50 years there has been a significant risk of population influx or immigrants to Canada. Every year, there has been an average of hundred and fifty thousand of new migrants. They come from different regions of the world to establish themselves in the country. In the past decade, an enormous change in Canadian demographics was not pronounced, which led to a huge number of immigrants of more than two hundred thousand yearly in the country. Above 70% of Canadian inhabitants came from the Middle East, the Pacific, Asia, and Africa.

Etiology

The deficiency is a hereditary circumstance whereby red blood cells crash and this leads to an exposure of the body to some infection due to the use of drugs. It also occurs if an individual is missing or has inadequate enzyme termed as glucose-6-phosphate dehydrogenase that assists red blood cells in working properly. In addition, a small amount of disease in the body causes destruction of red blood cells, which is called hemolysis. 

Active occurrence of hemolysis is termed as the hemolytic episode that occurs because red blood cells are continuously produced by the body with normal activity. Severe stress, certain food, infection, and some drugs trigger destruction of blood cells. These drugs include Aspirin, Quinidine, Sulfa drugs, Anti-malarial drugs, Nitrofurantoin, Nonsteroidal anti-inflammatory drugs (NSAIDs), and Quinine. Again, there are chemicals that can trigger an episode, especially those in mothballs. The condition in the United States is as not common among whites as among blacks and men are more likely to contract this disorder than women. Those people who are likely to contract the disease include male African Americans, men with the Middle Eastern decent, especially the Sephardic Jewish or Kurdish, and those whose family history has the deficiency. The whites who are of Mediterranean descent are also likely to afflict the disorder.

Pathophysiology

The condition consists in an enzyme being in the pathway of the pentose phosphate whereby the 6-phosphoglucono-δ-lactone is made for conversion of glucose-6-phosphate. The rate restricts enzyme in the metabolic system, which supplies energy that has been reduced to cells. This happens through maintaining the form of a reduced level of the co-enzyme nicotinamide adenine dinucleotide phosphate (NADPH). The NADPH maintains delivery of lowered glutathione in cells, which is used to clean free radicals that lead to the oxidative damage. Pathway of the NADPH or G6PD is the only cause that lowers glutathione in erythrocytes or red blood cells. The haemoglobin functions as a carrier of oxygen, which exposes it to danger or harm from oxidizing free radicals excluding defensive cause of glutathione. People suffering from such deficiency are at risk of hemolytic anemia in the oxidative strain. This occurs due to the use of chemicals for medication, in food, and infectious items. 

Pathology

Presence of glutathione and oxidants in the body neutralizes the disorder. In case the oxidant attacks are resistant, the level of glutathione will rely on the G6PD and can be reactivated because the G6PD is scarce. Free radicals can attack sulfhydryl assembly of the globin chain and then form the precipitate called the Heinz body, which is a dark substance within red cells. Oxidants include different beans such as fava beans that have the highest levels of divicine, isouramil, vicine, and convicine. Completion of consumption of lowered glutathione and oxidant damages some proteins and enzymes. It leads to imbalance of electrolyte, disposition of protein in red blood cell covering and cross bonding. The damaged haemoglobin is taken out of the circle and phagocytosed in the spleen, metabolizing haemoglobin to bilirubin. Kidney does not often excrete directly haemoglobin because red blood cells are not frequently disintegrated in the flow though it can happen in severe cases, resulting in acute renal failure. Different passage of deficiency has contributed to the establishment of glucose, therefore increasing superior glycation products (AGE). In addition, it reduces the quantity of the NADPH that is needed to form nitric oxide (NO).

 
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Signs and Symptoms

People suffering from the G6PD deficiency are considered to have some symptoms. On the one hand, most of them are male because of X-linked patterns that have been adopted. On the other hand, females who are carriers are likely to be clinically influenced because of adverse lyonization and random inactivation of X-chromosome. 

Diagnosis

Analysis is normally undertaken if persons are from a particular cultural group and have developed symptoms of hemolysis, jaundice, and anemia. The doctor will examine reticulocytes count and total blood adds up in an active deficiency of G6PD and Heinz bodies. It is possible to observe it in the blood, especially the haemoglobin on a blood film, lactate dehydrogenase, direct antiglobulin, which should be negative like hemolysis and liver enzymes. If there is sufficient evidence to suspect the disease, direct examination should be taken, which is the Beutler fluorescent spot experiment that has replaced most past examinations. In addition, different tests such as sequencing of the G6PD gene or straight DNA examination are taken. The examination is economical and a rapid test will visually identify the NADPH that is created under the ultraviolet light by the G6PD. If there is no fluoresce of blood spot, the examination is helpful and can be falsely negative in actively hemolysis of sick individuals, it can be done within two to three weeks after a hemolytic incident. When the RBC with a Heinz body is identified by macrophage in the spleen, it removes a little portion of the covering and the impulse that leads to bite cells.

Treatment

It is important to prevent the deficiency by avoiding foods and drugs, which cause hemolysis. There are vaccinations against various common pathogens such as hepatitis B and hepatitis A that can prevent infection and induced attacks. Blood transfusions can be dialysis at the acute phase of hemolysis, which is important for an acute renal failure. Transfusion is a significant indicative measure because transfused haemoglobins are normally not G6PD deficient and maintain an ordinary lifespan in the recipient's circulation. Affected people are required to avoid drugs that include aspirin. There are patients who are advantaged by the elimination of spleen because it is a significant site of red cell destruction. The use of folic acid is necessary for any confusion predicting significant changes of red cells though selenium and vitamin E have antioxidant elements that cannot decrease harshness of the G6PD deficiency when used.

Epidemiology

In 2001, there were 4,000 deaths all over the world due to the G6PD deficiency; these happened in South Asia, Africa, and the Middle East, as well as those having these ancestries. Side effects of the disease lead to protection against malaria. This happens mostly in the form of malaria that occurs due to plasmodium falciparum, which is the deadly malaria. There exists  a similar connection among the sickle cell disease and malaria because the spleen clears rapidly those cells, which have been infected with the Plasmodium parasite. Through this phenomenon, the G6PD deficiency carriers can get an evolutionary advantage through improving their health in malarial endemic environments.

Prognosis

Those patients suffering from the G6PD-deficiency do not seem to have contracted any illness frequently as compared to other people and are riskier than those who have acquired the disease. Favism has been recognized from the antiquity, for instance, in the mythology and legends. Priests of different Greek-Roman era cults were denied to mention or eat beans and the Pythagoras had a firm law, which unified their society because they had to swear off beans. The ban was accepted because a bean was similar to the genitalia though it may be a scientific or philosophical matter because of the belief that beans were generated from the same substance. Current consideration of the condition has been achieved through analyzing patients with sympathy to primaquine. It shows that the condition relies mostly on examination of prisoners who volunteered at the Illinois State Penitentiary. This is because some prisoners who were given primaquine developed hemolytic anemia, while others did not. Later, a study was conducted on the mechanism through Cr51 testing, which revealed that the hemolytic effect of primaquine was caused by an intrinsic defect of erythrocytes.

Hemolysis

Destruction of erythrocytes at an early stage is termed as hemolysis and if there is no compensation of erythrocyte loss from the bone marrow activity, it will lead to hemolytic anemia. There is identification of the severity of anemia by the onset of hemolysis, which might be abrupt or gradual, and the degree of erythrocyte destruction varies. Furthermore, the anemia with severe hemolysis can threaten life, whereas mild hemolysis can be asymptomatic, which causes decomposition of cardiopulmonary and angina. There are different causes of hemolytic anemia and this can lead to a difference in clinical presentation based on the aetiology. Laboratory examination arrays are accessible to a particular examination aimed at detecting the hemolysis that can directly identify the cause of hemolysis. Management of hemolysis varies based on the hemolysis type. Some of the signs include paleness, fatigue, and existence of fast heart rate, dark urine, shortness of breath, and jaundice. When an individual has a hemolytic anemia episode, the trigger should be removed and, in some cases, a person may require transfusion of red blood cells.

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G6PD in Red Blood Cell Metabolism

The gene has only one structure for G6PD that is associated with autosomal hexose dehydrogenase. The biochemical evidence indicates that protein of the G6PD in red cells is similar to the one in different somatic cells. This has led to severe deficiency of red cells in the G6PD that is also found to some extent in different somatic cells. The outcome is that most somatic cells are subject to G6PD, while any G6PD molecule that goes through proteolytic or denaturation breakdown is not replaced in red cells. The decay of G6PD occurs in normal red cells with a half-life of 60 days. However, it is claimed that it might be a two-slope curve that has a very fast crash of reticulocytes to erythrocytes and then a slower crash later. The term is based on the red cell G6PD activity that is characteristic in terms of being a marker of red cell age. Reticulocytes in normal blood have almost five times more activity as compared to the oldest red cells.

On the one hand, a female whose one gene for G6PD X chromosomes is abnormal and the other X chromosome contains a normal gene does not have any problem because the other gene can make enough G6PD. On the other hand, a female whose both genes are abnormal will have a deficiency of G6PD. In case of a male, since they have one X chromosome, if it becomes abnormal, they will have the disorder. Thus, the deficiency is more common among males than females. Except for anemia episodes, affected persons are completely healthy because the G6PD deficiency provides some protection against malaria. 

The G6PD genes mutations are situated on the X chromosome that is answerable for causing the disease through changing the structure or lowering the amount of G6PD enzyme in blood. Males have one Y chromosome, which they inherit from their fathers, and one X chromosome from their mothers. Since mutation impacts only the X chromosome, it cripples the sole copy that can produce the G6PD enzyme, leading to severe symptoms. On the contrary, females inherit their two X chromosomes from both parents. In such case, mutation occurs in one copy of the gene that is replaced by the other healthy copy of the gene. The main mechanism of enzyme deficiency is enzyme stability in most mutations. This has made females to be carriers of the disease. Hence, they do not show any clinical symptoms. However, in some instances, a female acquires two defective G6PD genes, whereby the hemolytic anemia becomes as harsh as in the affected male. Those females who are carriers of the disease are less resistant to the disease than those in a normal condition or who are non-carriers of malaria. Therefore, there is a high prevalence of G6PD deficiency in areas that are or were endemic with malaria.

Genealogy

It is believed that a number of deficiencies of red blood cells coexist with usual red cells. A woman whose X-chromosome is influenced shows that about half of her red blood cells has deficiencies. Furthermore, those with double X deficiency increase this ratio, hence becoming more sensitive than men. Favism is the hemolytic response due to consumption of broad beans and persons with this condition show the deficiency though not all people suffering from the disease have favism. It is considered to have more prevalence among kids and infants and there is a difference in variants of the G6PD gene that can affect the sympathy of chemicals, hence implying that there is no specific understanding of chemical associations between the two conditions. Since symptoms of the 6PGD deficiency are similar to those of G6PD, enzyme that is influenced is situated within the same passage. However, there is no link between diseases that can affect identically sick persons. Some substances are likely to affect patients who are suffering from the disease, but there is a difference in responses to such substances, which makes individual predictions difficult. People suffering from the disease can experience acute hemolysis caused by anti-malarial drugs, which include chloroquine, pamaquine, and primaquine. Other anti-malarial drugs can exacerbate the G6PD deficiency only at higher doses. These patients are required not to use sulphonamides, naphthalene, thiazolesulfone, and methylene blue because they antagonize folate synthesis to ascertain a small amount of non-sulfa and analgesics antibiotics.

Genetics of G6PD

G6PD A- and G6PD Mediterranean variants are the commonest in the human population. In the Middle East, there is prevalence of the G6PD Mediterranean variant and African Americans have 10% occurrence of G6PD. In addition, there is limited distribution of the disease among people originating from the Mediterranean area such as Italians, Armenians, Jews, Greeks, and Spaniards. It is believed that the variant stems from a defensive effect against plasmodium vivax and plasmodium falciparum malaria. All mutations, which cause the disease, are established on the long arm of the band Xq28 of X chromosome. The G6PD gene is situated around the region of the telomeric where there is extended support of the X chromosome. Gd is considered as a valuable tool to research X-chromosome’s non-functioning phenomenon, a clonal number of somatic cells, and X-linked genetic marker. Furthermore, Gd is one of the first regions of the human genome that have been fully sequenced. The Gd X-linkage contains three main consequences, which include Gd mutations. This shows a distinctive pattern of inherited Mendelian X-linked, outcome of X-chromosome inactivation, and heterozygous of females with two different Gd alleles. It shows somatic cell mosaicism and severe G6PD deficiency that is more common among males than females. It shows that anyone with alleles contains enzyme deficiency and half the cell can be G6PD (+) while half will be G6PD (-). 

However, variation is significant around that average for different reasons, which does not mean that all possible variants are fully known. Earlier, X-inactivation could be assumed to be taken at random, hence leading to the expectation of the binomial distribution. The distribution width is based on the number of individual embryonic tissue or cells in the embryo at the X-inactivation. For instance, should the number range between 32 and 64, it will mean that a fraction of women of approximately 2% is predicted to be with extreme phenotype. It is less than 5% of one of the two types of cells. It is in agreement with the observation of an unselected sample of Gd+/Gd−heterozygote though other studies recommend a larger proportion. This has led in most cases to unbalanced phenotypes occurring simply by chance based on the laws of statistics. 

Molecular Basis of G6pdd

Genetically, the deficiency of G6PD is identified as of any other protein because of either a change of a qualitative feature such as mutation, which influences the structure of the enzyme, or a change of a quantitative feature. The latter group includes mutation, which influences the amount of the enzyme, but not its structure, thus affecting its catalytic or stability efficiency. This investigation has been carried out prior to learning sequences of G6PD based on G6PD of G6PD-deficient cells. It shows that enzymic properties are not similar to those of the normal enzyme and enzyme activity, even if it is reduced, is not completely absent.

The Biochemical Mechanism of G6PD Deficiency

It is a contingent diseased because normal red cells with G6PD decrease the age of red cells with a half-life of approximately 50 days. G6PD is a protein, which is an oligomeric globular. It is possible that many point mutations generate replacement of person’s amino acids that extend the decreasing G6PD stability. The main mechanism of enzyme deficiency is enzyme stability in most mutations. Instability is severe if the amino acid is included at the interface between the two G6PD subunits. The condition applies to mutations of G6PD, which causes severe clinical phenotypes, while in some cases it alters the catalytic function that can be the major mechanism of the G6PD deficiency. Newborns suffering from the G6PD deficiency are diagnosed based on jaundice arising immediately after their birth. 

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