Glucose-6-phosphate Dehydrogenase Deficiency
Disease Details
Family Health Simplified
- Description
- Glucose-6-phosphate dehydrogenase deficiency is a genetic disorder affecting red blood cells, leading to hemolytic anemia, especially after exposure to certain medications, foods, or infections.
- Type
- Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive disorder.
- Signs And Symptoms
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Most individuals with G6PD deficiency are asymptomatic.Most people who develop symptoms are male, due to the X-linked pattern of inheritance, but female carriers can be affected due to unfavorable lyonization or skewed X-inactivation, where random inactivation of an X-chromosome in certain cells creates a population of G6PD-deficient red blood cells coexisting 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 as hemolysis) in G6PD deficiency can manifest in a number of ways, including the following:
Prolonged neonatal jaundice, possibly leading to kernicterus (arguably the most serious complication of G6PD deficiency)
Hemolytic crises in response to:
Illness (especially infections)
Certain drugs (see below)
Certain foods, most notably broad beans, from which the word favism derives
Certain chemicals
Diabetic ketoacidosis
Hemoglobinuria (red or brown urine)
Very severe crisis can cause acute kidney injuryFavism is 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 G6PD genetic variant can influence chemical sensitivity. Other than this, the specifics of the chemical relationship between favism and G6PD are not well understood. - Prognosis
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G6PD-deficient individuals do not appear to acquire any illnesses more frequently than other people, and may have less risk than other people for acquiring ischemic heart disease and cerebrovascular disease.
However, a recent study revealed that G6PD deficiency increases the cardiovascular risk 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). - Onset
- Glucose-6-phosphate dehydrogenase (G6PD) deficiency often has an onset at birth or during infancy. However, symptoms may not appear until later in life, usually triggered by specific factors such as infections, certain foods, or medications.
- Prevalence
- The prevalence of glucose-6-phosphate dehydrogenase (G6PD) deficiency varies widely across different populations. It is particularly common in regions where malaria is or was endemic, such as parts of Africa, the Mediterranean, the Middle East, and Asia. In these areas, the prevalence can be as high as 5-25% of the population. In some African countries, the prevalence can exceed 20%. Conversely, it is much less common in most European and North American populations, where prevalence rates typically range from 1-2%.
- Epidemiology
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G6PD deficiency is the second most common human enzyme defect after ALDH2 deficiency, being present in more than 400 million people worldwide. G6PD deficiency resulted in 4,100 deaths in 2013 and 3,400 deaths in 1990. The Mediterranean Basin is where favism is most common, especially among Mizrahi Jews, Sardinians, Cypriots, Greeks, Egyptians, and 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. Sardinia has 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 against malaria, in particular the form of malaria caused by Plasmodium falciparum, the most deadly form of malaria. A similar relationship exists between malaria and sickle-cell disease. One theory to explain this is that cells infected with the Plasmodium parasite are cleared more rapidly by the spleen. This phenomenon might give G6PD deficiency carriers an evolutionary advantage by increasing their fitness in malarial endemic environments.
In vitro studies have shown that the Plasmodium falciparum is very sensitive to oxidative damage. This is the basis for another theory, that is that the genetic defect confers resistance due to the fact that the G6PD-deficient host has a higher level of oxidative agents that, while generally tolerable by the host, are deadly to the parasite. - Intractability
- Glucose-6-phosphate dehydrogenase (G6PD) deficiency is not generally considered intractable. In many cases, the condition can be managed effectively by avoiding triggers that can lead to hemolytic episodes, such as certain foods (e.g., fava beans), infections, and particular medications. Lifestyle modifications and preventive measures are key aspects of managing this condition. However, the underlying enzyme deficiency itself cannot be cured as it is a genetic disorder. Careful management usually allows individuals with G6PD deficiency to lead relatively normal lives.
- Disease Severity
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Glucose-6-phosphate dehydrogenase (G6PD) deficiency disease severity can vary widely:
1. **Asymptomatic:** Many individuals remain asymptomatic and never experience any health issues.
2. **Acute Hemolytic Anemia:** Triggered by certain medications, foods (like fava beans), or infections, leading to symptoms like fatigue, jaundice, and dark urine.
3. **Chronic Hemolytic Anemia:** A rare, more severe form causing ongoing red blood cell breakdown and persistent anemia.
4. **Neonatal Jaundice:** In newborns, can lead to severe hyperbilirubinemia and potential kernicterus.
Severity often depends on specific genetic mutations and environmental factors. - Healthcare Professionals
- Disease Ontology ID - DOID:2862
- Pathophysiology
- Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme in the pentose phosphate pathway (see image, also known as the HMP shunt pathway). G6PD converts glucose-6-phosphate into 6-phosphoglucono-δ-lactone and is the rate-limiting enzyme of this metabolic pathway that supplies reducing energy to cells by maintaining the level of the reduced form of the co-enzyme nicotinamide adenine dinucleotide phosphate (NADPH). The NADPH maintains the supply of reduced glutathione in the cells that is used to mop up free radicals that cause oxidative damage. The pathway also stimulates catalase, an antioxidant enzyme.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.People with G6PD deficiency are therefore at risk of hemolytic anemia in states of oxidative stress. Oxidative stress can result from infection and from chemical exposure to medication and certain foods. Broad beans, e.g., fava beans, contain high levels of vicine, divicine, convicine and isouramil, all of which create oxidants.When all remaining reduced glutathione is consumed, enzymes and other proteins (including hemoglobin) are subsequently damaged by the oxidants, leading to 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 kidney injury.Deficiency of G6PD in the alternative pathway causes the buildup of glucose and thus there is an increase of advanced glycation endproducts (AGE). 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.Although female carriers can have a mild form of G6PD deficiency (dependent on the degree of inactivation of the unaffected X chromosome – see Skewed X-inactivation), homozygous females have been described; in these females there is co-incidence of a rare immune disorder termed chronic granulomatous disease (CGD).
- Carrier Status
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Carrier status for glucose-6-phosphate dehydrogenase (G6PD) deficiency depends on the inheritance pattern of the gene. G6PD deficiency is inherited in an X-linked recessive manner.
### Carrier Status:
- **Males**: Since males have only one X chromosome, if they inherit the affected G6PD gene, they will manifest symptoms of the deficiency.
- **Females**: Females have two X chromosomes. If they inherit one affected G6PD gene, they are typically carriers without significant symptoms because the other X chromosome usually has a normal copy of the gene. However, due to X-chromosome inactivation, some female carriers might experience mild symptoms.
### Nan:
The term "nan" appears to be out of context here. If you meant "Not a Number" (commonly abbreviated as NaN in programming), it does not apply to this medical condition. If you intended to ask about something else related to G6PD deficiency, please provide clarification. - Mechanism
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Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a genetic disorder that affects the enzyme G6PD, which plays a critical role in the pentose phosphate pathway—a metabolic pathway that helps protect red blood cells from oxidative damage.
**Mechanism:**
The primary function of G6PD is to catalyze the conversion of glucose-6-phosphate into 6-phosphogluconolactone, which produces NADPH as a byproduct. NADPH is crucial for maintaining the reduced state of glutathione, a key antioxidant in red blood cells. Reduced glutathione protects red blood cells from oxidative stress by neutralizing reactive oxygen species (ROS).
**Molecular Mechanisms:**
1. **Gene Mutation:** G6PD deficiency is caused by mutations in the G6PD gene located on the X chromosome (Xq28). These mutations result in the production of a G6PD enzyme with reduced activity or stability.
2. **Enzyme Activity Reduction:** Mutations lead to structural changes in the G6PD enzyme, impairing its ability to bind substrates or function efficiently. Reduced enzyme activity means lower NADPH production and decreased glutathione regeneration.
3. **Oxidative Stress:** Without sufficient NADPH, red blood cells are more susceptible to oxidative damage. Oxidative stress can cause hemoglobin to denature and form Heinz bodies, which affect red blood cell membrane integrity and function.
4. **Hemolysis:** The oxidative damage leads to premature destruction of red blood cells (hemolysis). This can be exacerbated by infections, certain medications, or foods (e.g., fava beans) that increase oxidative stress.
5. **Clinical Manifestations:** The result of these molecular mechanisms is a range of clinical symptoms, from mild to severe. Common symptoms include episodes of acute hemolytic anemia, jaundice, dark urine, fatigue, and shortness of breath.
Understanding these mechanisms helps in diagnosing and managing G6PD deficiency, enabling patients to avoid triggers and maintain better health. - Treatment
- The most important measure is prevention – avoidance of the drugs and foods that cause hemolysis. Vaccination against some common pathogens (e.g. hepatitis A and hepatitis B) may prevent infection-induced attacks.In the acute phase of hemolysis, blood transfusions might be necessary, or even dialysis in acute 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 as aspirin.Some patients may benefit from removal of the spleen (splenectomy), as this is an important site of red cell destruction. 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.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.
- Compassionate Use Treatment
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Glucose-6-phosphate dehydrogenase (G6PD) deficiency lacks specific treatments approved by regulatory agencies like the FDA or EMA, but several avenues are under investigation or considered for compassionate use or off-label purposes:
1. **Supportive Care**: Management primarily focuses on avoiding triggers known to precipitate hemolysis, such as certain drugs (e.g., sulfa drugs, aspirin), foods (e.g., fava beans), and infections.
2. **Vitamin E and Folic Acid**: Antioxidants like Vitamin E and folic acid have been suggested off-label to help mitigate oxidative stress and support red blood cell production.
3. **Gene Therapy**: Experimental therapies involving gene editing or gene transfer are being studied to correct the underlying genetic defect causing G6PD deficiency.
4. **L-Glutamine**: This amino acid, used in sickle cell disease, has potential off-label use to reduce oxidative stress and support red blood cell functionality.
5. **Antioxidants and Cytoprotective Agents**: Other investigational compounds aiming to enhance cellular defense mechanisms against oxidative damage are being explored.
Continued research and clinical trials are necessary to confirm the efficacy and safety of these potential treatments in G6PD deficiency. - Lifestyle Recommendations
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For individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, lifestyle recommendations focus on avoiding triggers that can lead to hemolytic anemia. Here are key recommendations:
1. **Avoid certain medications:** Some drugs can precipitate hemolytic episodes. These include certain antibiotics (e.g., sulfonamides, nitrofurantoin), antimalarials (e.g., primaquine), and nonsteroidal anti-inflammatory drugs (NSAIDs).
2. **Avoid certain foods:** Fava beans and anything containing fava beans should be avoided as they can trigger hemolysis.
3. **Be cautious with infections:** Infections can also precipitate hemolytic anemia. Managing infections promptly and seeking medical advice when sick is important.
4. **Avoid mothballs:** Exposure to naphthalene, found in some mothballs, should be avoided.
5. **Regular monitoring:** Regular medical check-ups to monitor for signs of hemolytic anemia can be helpful.
These lifestyle modifications are essential in managing G6PD deficiency and preventing complications. - Medication
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People with glucose-6-phosphate dehydrogenase (G6PD) deficiency should avoid certain medications that can trigger hemolysis (destruction of red blood cells). Some of these medications include:
1. Antimalarials (e.g., primaquine)
2. Sulfonamides (e.g., sulfamethoxazole)
3. Nitrofurantoin
4. Dapsone
5. Aspirin (in high doses)
6. Nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen (in high doses)
Always consult with a healthcare provider before starting any new medication. - Repurposable Drugs
- For glucose-6-phosphate dehydrogenase (G6PD) deficiency, treatment primarily involves avoiding known triggers that can cause hemolytic anemia, such as certain foods, infections, and medications. As of now, there are no specifically identified repurposable drugs for the treatment of G6PD deficiency. Managing the condition focuses on prevention and supportive care rather than drug treatment.
- Metabolites
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In glucose-6-phosphate dehydrogenase (G6PD) deficiency, the affected metabolic pathway is the pentose phosphate pathway. Key metabolites include:
- **Glucose-6-phosphate**: Substrate for the G6PD enzyme.
- **6-Phosphoglucono-δ-lactone**: Product of the G6PD-catalyzed reaction.
- **NADPH**: Reduced nicotinamide adenine dinucleotide phosphate, whose synthesis is impaired in G6PD deficiency. NADPH is crucial for protecting cells from oxidative damage.
- **Ribose-5-phosphate**: Downstream product in the pentose phosphate pathway, important for nucleotide synthesis.
- **Glutathione (GSH)**: Reduced glutathione levels are often observed, as NADPH is required to maintain GSH in its reduced form.
Deficiency in G6PD impairs the ability of cells, especially red blood cells, to manage oxidative stress, leading to hemolysis. - Nutraceuticals
- Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a genetic disorder that affects red blood cells, often leading to hemolytic anemia. Nutraceuticals, which are food-derived products with health benefits, should be considered with caution. Certain antioxidants like vitamin E and selenium might offer some protective effects due to their roles in combating oxidative stress. However, individuals with G6PD deficiency must avoid specific foods and substances that can trigger hemolysis, such as fava beans and certain medications. Always consult with healthcare providers before starting any new nutraceuticals.
- Peptides
- Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a genetic disorder that affects red blood cells. It is not directly related to peptides or nanotechnology (nan), which are distinct scientific fields. G6PD deficiency can cause hemolytic anemia, especially after exposure to certain drugs, foods, or infections. This condition is more common in individuals of African, Mediterranean, or Asian descent. Treatment usually involves avoiding known triggers and managing symptoms.