Glucose-6-phosphate dehydrogenase deficiency

Glucose-6-phosphate dehydrogenase deficiency(G6PDD), also known asfavism, is the most common enzyme deficiencyanemiaworldwide.It is aninborn error of metabolismthat predisposes tored blood cell breakdown.Most of the time, those who are affected have no symptoms.Following a specific trigger, symptoms such asyellowish skin, dark urine,shortness of breath, and feeling tired may develop.Complications can includeanemiaandnewborn jaundice.Some people never have symptoms.
It is anX-linked recessivedisorder that results in defectiveglucose-6-phosphate dehydrogenaseenzyme.Glucose-6-phosphate dehydrogenase is an enzyme that protectsred blood cells, which carry oxygen from the lungs to tissues throughout the body. A defect of the enzyme results in the premature breakdown of red blood cells. This destruction of red blood cells is calledhemolysis.Red blood cell breakdown may be triggered byinfections, certain medication, stress, or foods such asfava beans.Depending on the specificmutationthe severity of the condition may vary.Diagnosis is based on symptoms and supported by blood tests andgenetic testing.
Affected persons must avoid dietary triggers,notably fava beans.This can be difficult, as fava beans may be called "broad beans" and are used in many foods, whole or as flour.Falafelis probably the best known, but fava beans are often used as filler in meatballs and other foods. Since G6PD deficiency is not an allergy, food regulations in most countries do not require that fava beans be highlighted as an allergen on the label.
Treatment of acute episodes may include medications for infection, stopping the offending medication, orblood transfusions.Jaundice in newborns may be treated withbili lights.It is recommended that people be tested for G6PDD before certain medications, such asprimaquine, are taken.
About 400 million people have the condition globally.It is particularly common in certain parts of Africa, Asia, theMediterranean, and theMiddle East.Males are affected more often than females.In 2015 it is believed to have resulted in 33,000 deaths.
Most individuals with G6PD deficiency areasymptomatic. When it induces hemolysis, the effect is usually short-lived.
Most people who develop symptoms are male, due to theX-linkedpattern of inheritance, but female carriers can be affected due to unfavorablelyonizationorskewed X-inactivation, where random inactivation of an X-chromosome in certain cells creates a population of G6PD-deficientred blood cellscoexisting with unaffected red blood cells. A female with one affected X chromosome will show the deficiency in approximately half of her red blood cells. However, in some cases, including double X-deficiency, the ratio can be much more than half, making the individual almost as sensitive as males.
Red blood cell breakdown (also known ashemolysis) in G6PD deficiency can manifest in a number of ways, including the following:
Favismis a hemolytic response to the consumption of fava beans, also known as broad beans. Though all individuals with favism show G6PD deficiency, not all individuals with G6PD deficiency show favism. The condition is known to be more prevalent in infants and children, and the G6PD genetic variant can influence chemical sensitivity.Other than this, the specifics of the chemical relationship between favism and G6PD are not well understood.
G6PD deficiency results from mutations in the G6PD gene. G6PD gene contributes to the production ofglucose-6-phosphate dehydrogenase. Chemical reactions involving glucose-6-phosphate dehydrogenase produce compounds that preventreactive oxygen speciesfrom building up to toxic levels within red blood cells. If a reduction in the amount of glucose-6-phosphate dehydrogenase or alteration of structure occurs due to the mutations of the G6PD gene, the enzyme loses its protective role and leads to the accumulation of reactive oxygen species and thus damages red blood cells.
Carriers of the underlying mutation do not show any symptoms unless their red blood cells are exposed to certain triggers, which can be of four main types:
Many substances are potentially harmful to people with G6PD deficiency. Variation in response to these substances makes individual predictions difficult.Antimalarial drugsthat can cause acute hemolysis in people with G6PD deficiency includeprimaquine,pamaquine,chloroquine, andhydroxychloroquine.There is evidence that other antimalarials may also exacerbate G6PD deficiency, but only at higher doses.Sulfonamides(such assulfanilamide,sulfamethoxazole, andmafenide), thiazolesulfone,methylene blue, andnaphthaleneshould also be avoided by people with G6PD deficiency as they antagonize folate synthesis, as should certainanalgesics(such asphenazopyridineandacetanilide) and a few non-sulfa antibiotics (nalidixic acid,nitrofurantoin,isoniazid,dapsone, andfurazolidone).Hennahas been known to cause hemolytic crisis in G6PD-deficient infants.Rasburicaseis also contraindicated in G6PD deficiency. High doseintravenousvitamin Chas also been known to cause hemolysis in G6PD deficiency carriers;therefore, G6PD deficiency testing is routine before infusion of doses of 25 g or more.
Two variants (G6PD A− and G6PD Mediterranean) are the most common in human populations. G6PD A− has an occurrence of 10% of Africans and African-Americans while G6PD Mediterranean is prevalent in the Middle East. The known distribution of the mutated allele is largely limited to people of Mediterranean origins (Spaniards, Italians, Greeks, Armenians, Sephardi Jews, and other Semitic peoples).Both variants are believed to stem from a strongly protective effect againstPlasmodium falciparumandPlasmodium vivaxmalaria.It is particularly frequent in theKurdish Jewishpopulation, wherein approximately 1 in 2 males have the condition and the same rate of females are carriers.It is also common inAfrican American,Saudi Arabian,Sardinianmales, some African populations, and Asian groups.
All mutations that cause G6PD deficiency are found on the long arm of theX chromosome, on band Xq28. The G6PD gene spans some 18.5kilobases.The following variants and mutations are well-known and described:
Glucose-6-phosphate dehydrogenase (G6PD) is anenzymein thepentose phosphate pathway(see image, also known as the HMP shunt pathway). G6PD convertsglucose-6-phosphateinto6-phosphoglucono-δ-lactoneand is the rate-limiting enzyme of thismetabolic pathwaythat suppliesreducingenergy to cells by maintaining the level of the reduced form of theco-enzymenicotinamide adenine dinucleotide phosphate(NADPH). The NADPH maintains the supply of reducedglutathionein the cells that are used to mop up free radicals that causeoxidativedamage. The pathway also stimulates catalase, an antioxidant enzyme.
The G6PD / NADPH pathway is theonlysource 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.
People with G6PD deficiency are therefore at risk ofhemolytic anemiain states ofoxidative stress. Oxidative stress can result from infection and from chemical exposure tomedicationand certain foods.Broad beans, e.g., fava beans, contain high levels ofvicine,divicine, convicine andisouramil, all of which createoxidants.
When all remaining reducedglutathioneis consumed, enzymes and other proteins (includinghemoglobin) are subsequently damaged by the oxidants, leading to cross-bonding and protein deposition in the redcell membranes. Damaged red cells arephagocytosedand sequestered (taken out of circulation) in thespleen. The hemoglobin is metabolized tobilirubin(causingjaundiceat high concentrations). The red cells rarely disintegrate in the circulation, so hemoglobin is rarely excreted directly by thekidney, but this can occur in severe cases, causingacute kidney injury.
Deficiency of G6PD in the alternative pathway causes the buildup of glucose and thus there is an increase ofadvanced glycation endproducts(AGE). The deficiency also reduces the amount of NADPH, which is required for the formation of nitric oxide (NO). The high prevalence ofdiabetes mellitus type 2andhypertensionin Afro-Caribbeans in the West could be directly related to the incidence of G6PD deficiency in those populations.
Although female carriers can have a mild form of G6PD deficiency (dependent on the degree of inactivation of the unaffected X chromosome – seeSkewed X-inactivation), homozygous females have been described; in these females, there is co-incidence of arareimmune disordertermedchronic granulomatous disease(CGD).
The diagnosis is generally suspected when patients from certain ethnic groups (see epidemiology) developanemia,jaundice, and symptoms ofhemolysisafter challenges from 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.
TheBeutler fluorescent spot testis a rapid and inexpensive test that visually identifiesNADPHproduced by G6PD underultraviolet 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 identifies 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.
Testing during and for many weeks after a hemolytic episode will lead to false negative results as the G6PD deficient RBC will have been excreted and the young RBC (reticulocytes) will not yet be G6PD deficient. False-negative results will also be likely following any blood transfusions.  For this reason, many hospitals wait three months after a hemolytic episode before testing for G6PD deficiency. Females should have their G6PD activity measured by quantitative assay to avoid being misclassified by screening tests.
TheWorld Health Organizationclassifies G6PD genetic variants into five classes, the first three of which are deficiency states.
6-phosphogluconate dehydrogenase (6PGD) deficiencyhas similar symptoms and is often mistaken for G6PD deficiency, as the affected enzyme is within the same pathway, however, these diseases are not linked and can be found within the same person.
The most important measure is prevention – avoidance of the drugs and foods that cause hemolysis.Vaccinationagainst some common pathogens (e.g.hepatitis Aandhepatitis B) may prevent infection-induced attacks.
In the acute phase of hemolysis,blood transfusionsmight be necessary, or evendialysisinacute kidney failure. Blood transfusion is an important symptomatic measure, as the transfused red cells are generally not G6PD deficient and will live a normal lifespan in the recipient's circulation. Those affected should avoid drugs such asaspirin.
Some patients may benefit from the removal of thespleen(splenectomy),as this is an important site of red cell destruction.Folic acidshould be used in any disorder featuring a high red cell turnover. Althoughvitamin Eandseleniumhave antioxidant properties, their use does not decrease the severity of G6PD deficiency.
AG1, a recently discovered small molecule, has been shown to increase the activity of the G6PD enzyme in the three common variants of the deficiency. Due to the absence of medications to treat G6PD, AG1 is a promising precursor in developing a pharmacological treatment effective for multiple G6PD enzymopathies.
G6PD-deficient individuals do not appear to acquire any illnesses more frequently than other people, and may have less risk than other people for acquiringischemic heart diseaseandcerebrovascular disease.However, a recent study revealed that G6PD deficiency increases cardiovascular risk by up to 70%. The risk conferred by G6PD deficiency is moderate compared with the impact of primary cardiovascular risk factors.Besides, a published review hypothesized that G6PD deficiency could reduce the antiplatelet efficacy of clopidogrel (clopidogrel resistance).
G6PD deficiency is the second most common human enzyme defect afterALDH2deficiency, being present in more than 400 million people worldwide.G6PD deficiency resulted in 4,100 deaths in 2013 and 3,400 deaths in 1990.TheMediterranean Basinis where favism is most common, especially amongKurds,Sardinians,Cypriots,Greeks,Egyptiansand some African populations, including those who have these ancestries.Favism has also been documented outside of the Mediterranean basin, in other Middle Eastern and East Asian nations like Iraq, Iran, Bulgaria and China.Sardiniahas the highest reported frequency of favism, with five instances per every 1,000 people.
A side effect of this disease is that it confers protection againstmalaria,in particular the form of malaria caused byPlasmodium falciparum, the most deadly form of malaria. A similar relationship exists between malaria andsickle-cell disease. One theory to explain this is that cells infected with thePlasmodiumparasite are cleared more rapidly by thespleen. This phenomenon might give G6PD deficiency carriers an evolutionary advantage by increasing their fitness in malarial endemic environments.
In vitro studies have shown thatPlasmodium falciparumis very sensitive to oxidative damage. This is the basis for another theory: the genetic defect confers resistance since the G6PD-deficient host has a higher level of oxidative agents that, while generally tolerable by the host, are deadly to the parasite.
The modern understanding of the condition began with the analysis of patients who exhibited sensitivity toprimaquine.The discovery of G6PD deficiency relied heavily upon the testing of prisoner volunteers atIllinois State Penitentiary, a type of study which today is considered unethical and cannot be performed. When some prisoners were given the drug primaquine, some developedhemolytic anemiabut others did not. Despite these results, the US military administered the drug widely during the Korean War to prevent the relapsing infection caused byPlasmodium vivaxhypnozoites. Numerous cases of hemolytic anemia were observed in US soldiers of North African and Mediterranean descent.
After studying the mechanism throughCrtesting, it was conclusively shown that the hemolytic effect of primaquine was due to an intrinsic defect of erythrocytes.
In both legend and mythology, favism has been known since antiquity. The priests of variousGreco-Roman eracults were forbidden to eat or even mention beans, andPythagorashad a strict rule that to join the society of thePythagoreansone had to swear off beans.This ban was supposedly because beans resembled male genitalia, but it is possible that this was because of a belief that beans and humans were created from the same material.