Glucose-6-phosphate dehydrogenase deficiency


Glucose-6-phosphate dehydrogenase deficiency, also known as favism, is the most common enzyme deficiency anemia worldwide. It is an inborn error of metabolism that predisposes to red blood cell breakdown. Most of the time, those who are affected have no symptoms. Following a specific trigger, symptoms such as yellowish skin, dark urine, shortness of breath, and feeling tired may develop. Complications can include anemia and newborn jaundice. Some people never have symptoms.
It is an X-linked recessive disorder that results in defective glucose-6-phosphate dehydrogenase enzyme. Glucose-6-phosphate dehydrogenase is an enzyme that protects red blood cells, which carry oxygen from the lungs to tissues throughout the body, from reactive oxygen species. A defect of the enzyme results in the premature breakdown of red blood cells. This destruction of red blood cells is called hemolysis. Red blood cell breakdown may be triggered by infections, certain medication, stress, or foods such as fava beans. Depending on the specific mutation the severity of the condition may vary. Diagnosis is based on symptoms and supported by blood tests and genetic 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. Falafel is 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, or blood transfusions. Jaundice in newborns may be treated with bili lights. It is recommended that people be tested for G6PDD before certain medications, such as primaquine, are taken.
About 400 million people have the condition globally. It is particularly common in certain parts of Africa, Asia, the Mediterranean, and the Middle East. Males are affected more often than females. In 2015 it is believed to have resulted in 33,000 deaths.

Signs and symptoms

Most individuals with G6PD deficiency are asymptomatic. When it induces hemolysis, the effect is usually short-lived.
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 in G6PD deficiency can manifest in a number of ways, including the following:
Favism 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 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.

Cause

G6PD deficiency results from mutations in the G6PD gene. G6PD gene contributes to the production of glucose-6-phosphate dehydrogenase. Chemical reactions involving glucose-6-phosphate dehydrogenase produce compounds that prevent reactive oxygen species from 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.

Triggers

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:
  • Foods
  • Certain medicines including rasburicase, primaquine and other antimalarials//www.ncbi.nlm.nih.gov/pubmed/36049896?dopt=Abstract PMID 36049896
  • Moth balls
  • Stress from a bacterial or viral infection

    Drugs

Many substances are potentially harmful to people with G6PD deficiency. Variation in response to these substances makes individual predictions difficult. Antimalarial drugs that can cause acute hemolysis in people with G6PD deficiency include primaquine and tafenoquine. Dapsone, methylene blue, pegloticase, rasburicase and toluidine should also be avoided by people with G6PD deficiency. Henna has been linked to hemolytic crisis in G6PD-deficient infants. Rasburicase is contraindicated in G6PD deficiency. Over 40 medications, including ascorbic acid at high doses and sulfonamides, have been hypothesized to be linked to hemolysis in G6PD deficient individuals, but the evidence supporting most of these medications is lacking.Clinical Pharmacogenetics Implementation Consortium;

Genetics

Two variants 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. Both variants are believed to stem from a strongly protective effect against Plasmodium falciparum and Plasmodium vivax malaria. It is particularly frequent in the Kurdish Jewish population, wherein approximately 1 in 2 males have the condition and the same rate of females are carriers. It is also common in African American, Saudi Arabian, Sardinian males, some African populations, and Asian groups.
All mutations that cause G6PD deficiency are found on the long arm of the X chromosome, on band Xq28. The G6PD gene spans some 18.5 kilobases. The following variants and mutations are well-known and described:

Pathophysiology

Glucose-6-phosphate dehydrogenase is an enzyme in the pentose phosphate 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. The NADPH maintains the supply of reduced glutathione in the cells that are 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. 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 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 in the spleen. The hemoglobin is metabolized to bilirubin. 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. The deficiency also reduces the amount of NADPH, which is required for the formation of nitric oxide. 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, homozygous females have been described; in these females, there is co-incidence of a rare immune disorder termed chronic granulomatous disease.

Diagnosis

The diagnosis is generally suspected when patients from certain ethnic groups develop anemia, jaundice, and symptoms of hemolysis after 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. Other possibilities are direct DNA testing and/or sequencing of the G6PD gene.
The Beutler fluorescent spot test is a rapid and inexpensive test that visually identifies NADPH produced by G6PD under ultraviolet 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 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.