June 29, 2017
Years published: 1990, 1995, 1998, 2002, 2017
NORD gratefully acknowledges Ilan Youngster, MD, MMSc, Pediatric Division, Assaf Harofeh Medical Center, Israel, for assistance in the preparation of this report.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a genetic metabolic abnormality caused by deficiency of the enzyme G6PD. This enzyme is critical for the proper function of red blood cells: when the level of this enzyme is too low, red blood cells can break down prematurely (hemolysis). When the body cannot compensate for accelerated loss, anemia develops. However, deficiency of this enzyme is not sufficient to cause hemolysis on its own; additional factors are required to “trigger” the onset of symptoms. Triggers of hemolysis in G6PD-deficient persons include certain infectious diseases, certain drugs, and eating fava beans: this can cause a potentially serious acute hemolytic anemia known as favism. Symptoms can include fatigue, pale color, jaundice or yellow skin color, shortness of breath, rapid heartbeat, dark urine and enlarged spleen (splenomegaly).
Most important, in the absence of triggering factors, the majority of people with G6PD deficiency are normal, and they sail through life without any knowledge or any noticeable symptoms of the disorder. G6PD deficiency is caused by alterations (mutations) in the G6PD gene, and it maps to the X chromosome.
As many as 400 different genetic variants of G6PD deficiency have been reported, and for 186 the precise mutation is known. The World Health Organization (WHO) has classified variants on the basis of residual enzyme activity and of disease severity. Class I are the most severe variants: those in which there is chronic hemolysis even in the absence of any triggering factor. Class II and III are variants with marked enzyme deficiency but no chronic hemolysis; class IV are variants with normal enzyme activity; class V was designed for variants with increased enzyme activity. Among the variants of which the clinical implications have been best characterized are G6PD Mediterranean, G6PD A- and G6PD Mahidol.
As stated above, most G6PD-deficient persons are asymptomatic most of the time; however, any one of them, when exposed to certain triggering factors, can develop acute hemolytic anemia (AHA), which may be life-threatening especially in children. Triggers for AHA in G6PD deficient persons include: (a) certain drugs (see Causes section), (b) certain infectious diseases, (c) ingestion of fava beans. The onset of symptoms is within 2-3 days after exposure to the trigger (even less with fava beans).
A hemolytic anemia episode may be preceded by behavioral changes such as irritability or lethargy. Most episodes, even severe ones, are usually self-limiting and resolve on their own. The severity of episodes can vary greatly. Symptoms can include fatigue, pale color, shortness of breath, rapid heartbeat, dark urine, a sudden rise in body temperature, lower back pain, and an enlarged spleen (splenomegaly). Yellowing of the eyes, mucous membranes and skin (jaundice) is common. Gastrointestinal symptoms such as diarrhea, nausea or abdominal discomfort or pain may also occur.
G6PD deficiency can cause neonatal jaundice, which is one of the most common conditions requiring medical attention in newborns. Jaundice is caused by excess levels of bilirubin in the blood. Bilirubin is an orange-yellow bile pigment that is a byproduct of the natural breakdown of hemoglobin in red blood cells. In rare cases in certain populations, if untreated, neonatal jaundice can progress to cause neurological issues such as kernicterus, a condition characterized by the accumulation of toxic levels of bilirubin in the brain, which cause lack of energy, poor feeding, fever, and vomiting.
Acute hemolytic anemia from eating fava beans (favism) can be rapid. Favism can occur at any age, but occurs more often and more severely in children. A child may have a slightly elevated temperature within 24-48 hours and can become irritable and unruly, or subdued and lethargic. Nausea, abdominal pain and diarrhea may develop. Vomiting only occurs rarely. Within 6 to 24 hours, urine may become noticeably dark and can appear red, brown or even black. Affected children may become pale and their resting heartrate may be high (tachycardia). Jaundice can also develop and the liver and spleen may become enlarged. In severe cases, evidence may be seen of hypovolemic shock, in which blood and fluid loss is so severe that the heart cannot pump enough blood to the body, or, less likely, heart failure.
In rare cases, certain affected individuals (i.e. those with class I variants) may experience chronic hemolytic anemia that is ongoing and occurs without the need for a triggering factor. These individuals may be referred to as having a type of congenital nonspherocytic hemolytic anemia. Such individuals are almost always male and usually develop neonatal jaundice. Affected children may also have an enlarged spleen. Most have a mild to moderate anemia, but severe, transfusion-dependent anemia can develop. Affected individuals can potentially develop severe complications such as hypovolemic shock. In rare cases, severe acute hemolysis has led to acute kidney failure.
G6PD deficiency is caused by an alteration (mutation) in the G6PD gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. In people with G6PD deficiency, the gene mutation and resultant enzyme deficiency is not sufficient by itself to cause symptoms. The development of symptoms requires the specific interaction of an alteration in the G6PD gene in combination with a specific environmental factor.
The G6PD gene contains instructions for creating (encoding) an enzyme known as glucose-6-phosphate dehydrogenase. As part of a chemical reaction, this enzyme brings about (catalyzes) the coenzyme NADPH, which protects cells from oxidative damage. A mutation in the G6PD gene results in low levels of functional glucose-6-phosphate dehydrogenase, which in turn leads to low levels of NADPH and a depletion of an antioxidant known as glutathione, which is necessary to protect the cell’s hemoglobin and its cell wall (red cell membrane) from highly reactive oxygen radicals (oxidative stress). Normally, the amount of NADPH, although reduced, is adequate for the health of a red blood cell. However, this reduction in NADPH makes red blood cells more susceptible to destruction from oxidative stress than other cells, resulting in their premature break down when in the presence of triggering factors. G6PD is a housecleaning enzyme that is expressed in all cells of the body. However, the body can compensate for the effects of G6PD deficiency in cells other than red blood cells.
More than 400 different mutations have been found in individuals with G6PD deficiency. Mutations, with the exception of the G6PD A mutation, are associated with more or less enzyme deficiency, but never with complete enzyme deficiency, which is not compatible with life. The disorder has been classified into variants based upon the degree of deficiency and associated clinical symptoms.
In many cases, a mutation occurs as a new (sporadic or de novo) mutation, which means that in these cases the gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will have the mutation. In cases with a family history, the G6PD gene mutation is inherited in an X-linked manner.
X-linked disorders are conditions caused by an abnormal gene on the X chromosome. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further subdivided into many bands that are numbered. The G6PD gene is located on the long arm (q) of the X chromosome (Xq28).
X-linked disorders affect males and females differently. A male has one X-chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers if the other X chromosome from their mother is normal. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
Females have two X chromosomes. Whether females with a mutation of G6PD gene develop glucose-6-phosphate deficiency depends on a normal process known as random X-chromosome inactivation. Because females have two X chromosomes, certain disease traits on the X chromosome such as a mutated gene may be “masked” by the normal gene on the other X chromosome. This is known as random X-chromosome inactivation. Basically, in each cell of the body one X chromosome is active and one is turned off or “silenced.” This occurs randomly and generally happens as a 50-50 split. However, in some instances, females may have favorable X-inactivation, in which the affected X chromosome is silenced in most of the cells. In such cases, they may have sufficient G6PD enzyme activity as to avoid developing symptoms even in the presence of triggering factors. In other cases, females may have unfavorable X-inactivation, in which the unaffected X chromosome is silenced in most of the cells. In such cases, affected females are similar to affected males and can develop symptoms (e.g. hemolysis) associated with G6PD deficiency when in the presence of triggering factors.
Daughters of female carriers of an X-linked disorder have a 50% chance be carriers themselves, whereas boys have a 50% chance of being affected.
Some females, known as homozygotes, have a mutation in the G6PD gene on both X chromosomes and can develop symptoms in the presence of triggering factors depending upon the specific mutation present. Homozygous females are extremely rare.
As stated previously, several different environmental factors can trigger an episode of acute hemolytic anemia in individuals who are GP6D-deficient. Such factors include certain drugs, eating fava beans, and certain bacterial and viral infections.
Hemolytic anemia episodes can result from exposure to certain drugs. Among the many that have been cited as causative agents are: acetanilid, cotrimoxazole, dapsone, doxorubicin, furazolidone, methylene blue, moxifloxacin, nalidixic acid, naphthalene, niridazole, nitrofuratoin, norfloxacin, pamaquine, pentaquine, phenazopyridine, phenylhydrazine, primaquine, rasburicase, sulfacetamide, sulfanilamide, sulfapyridine, thiazolesulfone, toluidine blue, and trinitrotoluene. The exact degree of susceptibility to a drug varies from one person to another. Other drugs have been suggested as best avoided by individuals with G6PD deficiency; however, determining which additional drugs convey a specific risk of a hemolytic anemia episode is unclear.
One drug of particular note is primaquine, an antimalarial drug that is the only drug that can eradicate dormant forms (hypnozoites) of the malarial-causing parasite, Plasmodium vivax. This is essential in preventing endogenous (“from within”) recurrence of malaria (as opposed to reinfection from becoming exposed to malaria again). Because of its importance in treating malaria, primaquine is probably the drug that has caused the most cases of acute hemolytic anemia in G6PD-deficient people. The World Health Organization has developed recommendations to prevent relapse of P. vivax. Primaquine is given whenever needed to people who have tested G6PD normal, and not given (or given only under medical/health worker surveillance) to those have tested G6PD-deficient. More information on this is available here:
The geographic distribution of G6PD deficiency correlates strongly with the distribution of malaria. This has led researchers to speculate that the G6PD gene mutation conveys protection from malaria in these regions. Additional evidence exists that seems to confirm this theory and several studies have indicated that G6PD deficiency is malaria protective, especially against severe malaria. The specific manner how G6PD deficiency protects against malaria is not fully understood. It is possible that this protective quality is linked to the inability of malaria to grow efficiently in G6PD-deficient cells.
Acute hemolytic anemia in G6PD-deficient people can develop after eating fava beans. This is known as favism. It was once thought that favism was an allergic reaction and that the condition could occur from inhalation of pollen. However, researchers have identified the chemicals, known as vicine and convicine, found within fava beans that trigger acute hemolytic anemia episodes in G6PD-deficient people. These chemicals occur in high concentrations within fava beans, but do not occur in other types of beans. Most individuals with G6PD deficiency do not develop symptoms after eating fava beans and individuals who do develop symptoms will not always do so. This suggests that additional factors such as mutations in other genes (e.g. modifier genes) may be necessary to develop favism.
Episodes of acute hemolytic anemia may also result in some affected individuals when exposed to infectious diseases. Care must be taken to know what drugs can cause acute hemolytic anemia in G6PD-deficient people before they be given to the patient. However, there is significant confusion in the medical literature in this regard. Some drugs are considered dangerous because they were given to G6PD-deficient individuals whose symptoms were caused by the preexisting infection, yet misattributed to the drug.
As described in the medical literature, some G6PD-deficient individuals are at a higher risk of widespread infection of the blood (sepsis) following severe trauma.
G6PD deficiency is one of the most common forms of enzyme deficiency and is believed to affect more than 400 million people worldwide. Although the prevalence is high, the vast majority of people remain clinically asymptomatic throughout their lives. Many medical sources state that the disorder is more common in males, but this is not accurate.
Females who have an altered G6PD gene on one X chromosome (heterozygous females) are more common than males with an altered G6PD gene. Because of random X-chromosome inactivation (described in the ‘Causes’ section above), it is more likely that males will develop full blown G6PD deficiency than will females, but females can develop a similar disease expression as seen in males. Females with a G6PD mutation on both of their X chromosomes (homozygous females) have been reported in the medical literature, but are very rare.
G6PD deficiency affects individuals of all races and ethnic backgrounds. The highest prevalence rates are found in Africa, the Middle East, certain parts of the Mediterranean, and certain areas in Asia. In these regions, the rate ranges from 5% to 30% of the population. The severity of G6PD deficiency can vary based upon specific racial groups. The severe form of the disorders occurs more often in the Mediterranean population.
In the United States, the incidence is much higher among the African-American population than in other sectors. The frequency of a carrier state in which one partner carries a normal gene and the other carries an abnormal variant is as high as 24%. About 10%-14% of African-American males are affected. For example, two common variants occur in many African-American males. Approximately 20 to 25 percent have the near normal G6PD variant called “A+”, while about 10 to 13 percent have another variant called “A-”.
Another relatively common G6PD variant is found particularly among individuals of Sephardic Jewish or Sardinian descent. In addition, another somewhat common variant is present among some individuals of southern Chinese descent.
A diagnosis is based upon the identification of characteristic physical findings and symptoms, a thorough clinical evaluation, a detailed patient history, and/or specialized tests. If a person experiences symptoms, e.g. blood in the urine, and spontaneously reports eating fava beans and comes from an area or a population where G6PD deficiency is common, suspicion of the disorder should be high.
If doctors suspect a person is G6PD-deficient, they will conduct a variety of blood tests to confirm a diagnosis and rule out other conditions that cause similar conditions. The diagnosis depends upon demonstrating decreased activity of the G6PD enzyme through either a quantitative assay or a screening test such as fluorescent spot test
Molecular genetic testing can detect mutations in the specific gene known to cause G6PD, but is available only as diagnostic service at specialized laboratories.
Most affected individuals do not require treatment. G6PD deficiency is often best managed by preventative measures. Individuals should be screened for the G6PD defect before being treated with certain drugs such as certain antibiotics, antimalarials and other medications known to trigger hemolysis in G6PD-deficient individuals. In individuals who are G6PD-deficient, hemolytic anemia from fava beans or from known drugs should not occur because exposure can be avoided.
If an episode of hemolytic anemia is due to the use of a certain medication, the causative drug should be discontinued under a physician’s supervision. If such an episode is due to an underlying infection, appropriate steps should be taken to treat the infection in question.
Some adults may need short-term treatment with fluids to prevent hemodynamic shock (in which there is inadequate supply of blood to the organs) or, in severe cases where the rate of hemolysis is very rapid, even blood transfusions. Blood transfusions are more likely to be indicated in children than adults, and in children with favism can prove life-saving.
Neonatal jaundice is treated by placing the infant under special lights (bili lights) that alleviate the jaundice. In more severe cases, an exchange transfusion may be necessary. This procedure involves removing an affected infant’s blood and replacing it with fresh donor blood or plasma.
Genetic counseling may be of benefit for patients and their families.
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