Glucose-6-phosphate dehydrogenase deficiency

Glucose-6-phosphate dehydrogenase deficiency (G6PDD), also known as favism, is the most common enzyme deficiency worldwide.

Affected persons must avoid dietary triggers,[3] notably fava beans.^[7] 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 also 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.^{[citation needed]}

Treatment of acute episodes may include medications for infection, stopping the offending medication, or

Most individuals with G6PD deficiency are asymptomatic.^{[citation needed]}

Most people who develop symptoms are male, due to the

Red blood cell breakdown (also known as hemolysis) in G6PD deficiency can manifest in a number of ways, including the following:^{[citation needed]}

• 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 injury

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 G6PD genetic variant can influence chemical sensitivity.^[8] Other than this, the specifics of the chemical relationship between favism and G6PD are not well understood.^{[citation needed]}

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 reduction in the amount of glucose-6-phosphate dehydrogenase or alteration of structure occurs due to the mutations of G6PD gene, the enzyme loses its protective role and leads to the accumulation of reactive oxygen species and thus damage of red blood cells.^[6]

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 (fava beans is the hallmark trigger for G6PD mutation carriers),
• Certain medicines including aspirin, quinine and other antimalarials derived from quinine.
• Moth balls (naphthalene)^[9]
• Stress from a bacterial or viral infection.^[10]

Drugs

Many substances are potentially harmful to people with G6PD deficiency. Variation in response to these substances makes individual predictions difficult.

Glucose-6-phosphate dehydrogenase (G6PD) is an

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).^{[citation needed]}

Diagnosis

The diagnosis is generally suspected when patients from certain ethnic groups (see epidemiology) develop anemia, jaundice and symptoms of hemolysis after challenges from any of the above causes, especially when there is a positive family history.^[23]

Generally, tests will include:^{[citation needed]}

• blood film
  ;
• Liver enzymes (to exclude other causes of jaundice
  );
• Lactate dehydrogenase (elevated in hemolysis and a marker of hemolytic severity)
• Haptoglobin (decreased in hemolysis);
• A "direct antiglobulin test" (Coombs' test) – this should be negative, as hemolysis in G6PD is not immune-mediated;

When there are sufficient grounds to suspect G6PD, a direct test for G6PD is the "

Testing during and for many weeks after a haemolytic 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 for 3 months after a haemolytic episode before testing for G6PD deficiency. Females should have their G6PD activity measured by quantitative assay to avoid being misclassified by screening tests.[23]

Classification

The World Health Organization classifies G6PD genetic variants into five classes, the first three of which are deficiency states.^[25]

• Class I: Severe deficiency (<10% activity) with chronic (nonspherocytic) hemolytic anemia
• Class II: Severe deficiency (<10% activity), with intermittent hemolysis
• Class III: Moderate deficiency (10–60% activity), hemolysis with stressors only
• Class IV: Non-deficient variant, no clinical sequelae
• Class V: Increased enzyme activity, no clinical sequelae

Differential diagnosis

6-phosphogluconate dehydrogenase (6PGD) deficiency has 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.^{[citation needed]}

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.^[26]

In the acute phase of hemolysis,

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.[28]

Prognosis

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

Epidemiology

G6PD deficiency is the second most common human enzyme defect after ALDH2 deficiency, being present in more than 400 million people worldwide.^[32] G6PD deficiency resulted in 4,100 deaths in 2013 and 3,400 deaths in 1990.^[33] The Mediterranean Basin is where favism is most common, especially among Sardinians, Cypriots, Greeks, Egyptians and some African populations, including those who have these ancestries.^[34][35][36] Favism has also been documented outside of the Mediterranean basin, in other Middle Eastern and East Asian nations like Iran, Kurdistan, Bulgaria and China. Sardinia has the highest reported frequency of favism, with five instances per every 1,000 people.^[34]

A side effect of this disease is that it confers protection against

History

The modern understanding of the condition began with the analysis of patients who exhibited sensitivity to

After studying the mechanism through Cr⁵¹ testing, it was conclusively shown that the hemolytic effect of primaquine was due to an intrinsic defect of erythrocytes.^[41]

Society and culture

In both legend and mythology, favism has been known since antiquity. The priests of various Greco-Roman era cults were forbidden to eat or even mention beans, and Pythagoras had a strict rule that to join the society of the Pythagoreans one had to swear off beans.^[42] 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.^[43]

References