Which types of cells are destroyed as a result of an idiosyncratic reaction in a patient with glucose-6-phosphate dehydrogenase G6PD deficiency with certain medications?

G6PD deficiency is a genetic disorder that most often affects males. It happens when the body doesn't have enough of an called glucose-6-phosphate dehydrogenase (G6PD).

G6PD helps red blood cells work. It also protects them from substances in the blood that could harm them.

In people with G6PD deficiency, either the red blood cells do not make enough G6PD or what they do make doesn't work as it should. Without enough G6PD to protect them, the red blood cells break apart. This is called hemolysis (hih-MOL-ih-sis). When many red blood cells are destroyed, a person can develop hemolytic (hee-meh-LIH-tik) anemia. This can cause tiredness, dizziness, and other symptoms.

Red blood cells that don't have enough G6PD are sensitive to some medicines, foods, and infections. When these things trigger a quick loss of red blood cells over a short time, it's called a hemolytic crisis. In these cases, the symptoms stop when the cause is gone. In rare cases, G6PD deficiency leads to anemia regardless of exposure to triggers.

Triggers of hemolysis in kids with G6PD deficiency include:

• illness, such as bacterial and viral infections
• some painkillers and fever-lowering drugs
• some antibiotics (most often those with "sulf" in their names)
• some antimalarial drugs (most often those with "quine" in their names)
• fava beans (also called broad beans)
• naphthalene (a chemical found in mothballs and moth crystals). Mothballs can be very harmful if a child swallows one.

What Are the Signs & Symptoms of G6PD Deficiency?

Most people with G6PD deficiency don't have any symptoms. Others might have symptoms of hemolytic anemia if many RBCs are destroyed.

These can include:

• paleness (in darker-skinned kids, paleness is sometimes best seen in the mouth, especially on the lips or tongue)
• extreme tiredness or dizziness
• fast heartbeat
• fast breathing or shortness of breath
• jaundice (the skin and eyes look yellow)
• an enlarged
• dark, tea-colored pee

Mild symptoms usually don't need medical treatment. As the body makes new red blood cells, the anemia will improve. If symptoms are more severe, a child may need care in a hospital.

What Causes G6PD Deficiency?

G6PD deficiency is inherited. Children who have it are born with it because it was passed down in genes from one or both of the parents. The gene responsible for this condition is on the X .

Who Gets G6PD Deficiency?

G6PD deficiency is most common in males of African heritage. Many females of African heritage are carriers of G6PD deficiency. This means that they can pass the gene for the deficiency to their children but do not have symptoms.

How Is G6PD Deficiency Diagnosed?

G6PD deficiency often isn't found until a child gets symptoms. If doctors suspect G6PD deficiency, blood tests usually can confirm the diagnosis and rule out other causes of anemia.

If you worry that your child might have G6PD deficiency, talk to your doctor about a screening test to check for it.

How Is G6PD Deficiency Treated?

Treating G6PD deficiency symptoms is usually as simple as removing the trigger. Often, this means treating the infection or stopping the use of a drug. A child with severe anemia may need treatment in the hospital to get oxygen and fluids. Sometimes, a child also needs a transfusion of healthy blood cells.

What Can Parents Do?

The best way to care for a child with G6PD deficiency is to limit exposure to anything that triggers symptoms. Check with your doctor for instructions, and a list of medicines and other things that could be a problem for a child with G6PD deficiency.

With the right care, G6PD deficiency should not keep a child from living a healthy, active life.

G6PD deficiency is a lifelong genetic disorder that causes red blood cells to break down when exposed to certain foods, medicines or chemicals (triggers). People with G6PD deficiency — who are almost always male — are normally healthy but must avoid these triggers.

The breakdown of red blood cells, called 'haemolysis', can lead to anaemia (lack of red blood cells) and jaundice (the yellowing of skin and eyes).

Certain triggers can cause red blood cells to be destroyed faster than they can be replaced. In this case, a person with G6PD deficiency can develop acute haemolytic anaemia (AHA), which can be life-threatening, especially in children.

Triggers can include:

• medicines such as some antibiotics, malaria medications (both for the prevention and treatment of malaria), aspirin, some anti-cancer drugs and large doses of vitamin C
• some chemicals, including mothballs (naphthalene)
• some foods, particularly fava beans (broad beans), tonic water or blueberries
• certain infections

Acute haemolytic anaemia requires medical attention. If you or your child develops jaundice (yellow skin and eyes), dark-coloured urine, pale skin or lethargy, see your doctor as soon as possible.

If you’re not sure what to do, you can call the healthdirect helpline to speak with a registered nurse on 1800 022 222, 24 hours a day.

What are the symptoms of G6PD deficiency?

Most people with G6PD live without symptoms most of the time. But the common signs and symptoms include:

In newborn babies, G6PD deficiency usually presents as jaundice.

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What causes G6PD deficiency?

People with G6PD deficiency do not have enough of an enzyme called glucose-6-phosphate dehydrogenase (G6PD). This enzyme helps protects red blood cells from damage.

G6PD deficiency is a lifelong genetic condition that is normally passed down through the mother. It is more common in males, and people with a Mediterranean, African, Asian, South American or Middle Eastern background.

How is G6PD deficiency diagnosed?

The condition is diagnosed with blood tests, which are also used to rule out other conditions. It is recommended that if one child in the family is diagnosed with G6PD deficiency, other children should be tested.

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How is G6PD deficiency treated?

Most people do not need any treatment — they manage their condition by avoiding the triggers. Your doctor will give you a list of things to avoid and tips to manage the condition.

If you develop anaemia, it will need to be treated, potentially with a blood transfusion. Babies with jaundice are treated by being placed under special lights called 'bili lights'. In the most severe cases, an exchange transfusion may be needed (some of the infant’s blood is removed and replaced with donor blood or plasma).

Always tell your doctor about your condition before taking any medicines, so they do not prescribe something that could trigger the condition. If you buy medicine without a prescription, talk to your pharmacist and read the label carefully. You also need to be careful about using any herbal and alternative medicines.

Having a virus or infection can stress the body and lead to haemolysis in people with G6PD deficiency. See your doctor if you or your child develops an infection.

Complications of G6PD deficiency

If a person with G6PD deficiency eats fava beans, they can develop favism. This is an episode of acute haemolytic anaemia . It can happen rapidly and mostly affects children.

Symptoms of favism in children include a slight temperature and change in behaviour, such as being irritable and naughty, or subdued and quiet. They might develop nausea, diarrhoea or a tummy ache. In 6 to 24 hours, their urine will grow dark and their heart rate may get faster. Finally, the jaundice develops.

People with favism are always G6PD-deficient, but not all people with G6PD deficiency react this strongly to fava beans.

Resources and support

For more information and support, you can contact this organisation:

• Genetic Alliance Australia

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:

http://www.who.int/malaria/mpac/mpac_sep13_erg_g6pd_testing.pdf

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.