Glucose-6-phosphate dehydrogenase deficiency (G6PDD), which is the most common enzyme deficiency worldwide, is an
inborn error of metabolism
Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrat ...
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
Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing disc ...
, and feeling tired may develop. Complications can include anemia
Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...
and newborn jaundice
Neonatal jaundice is a yellowish discoloration of the white part of the eyes and skin in a newborn baby due to high bilirubin levels. Other symptoms may include excess sleepiness or poor feeding. Complications may include seizures, cerebral pal ...
.[ Some people never have symptoms.][
It is an ]X-linked recessive
X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be always expressed in males (who are necessarily homozygous for the gene mutation because they have one X and one Y ...
disorder that results in defective glucose-6-phosphate dehydrogenase
Glucose-6-phosphate dehydrogenase (G6PD or G6PDH) () is a cytosolic enzyme that catalyzes the chemical reaction
: D-glucose 6-phosphate + NADP+ + H2O 6-phospho-D-glucono-1,5-lactone + NADPH + H+
This enzyme participates in the pentose phosph ...
enzyme.[ Glucose-6-phosphate dehydrogenase is an enzyme which protects red blood cells, which carry oxygen from the lungs to tissues throughout the body. A defect of the enzyme results in the premature breakdown of red blood cells. This destruction of red blood cells is called ]hemolysis
Hemolysis or haemolysis (), also known by several other names, is the rupturing (lysis) of red blood cells (erythrocytes) and the release of their contents (cytoplasm) into surrounding fluid (e.g. blood plasma). Hemolysis may occur in vivo o ...
. Red blood cell breakdown may be triggered by infection
An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dise ...
s, certain medication, stress, or foods such as fava beans
''Vicia faba'', commonly known as the broad bean, fava bean, or faba bean, is a species of vetch, a flowering plant in the pea and bean family Fabaceae. It is widely cultivated as a crop for human consumption, and also as a cover crop. Varieti ...
. Depending on the specific mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
the severity of the condition may vary.[ Diagnosis is based on symptoms and supported by blood tests and ]genetic testing
Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...
.[
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
Falafel (; ar, فلافل, ) is a deep-fried ball or patty-shaped fritter in Middle Eastern cuisine (especially in Levantine and Egyptian cuisines) made from ground chickpeas, broad beans, or both. Nowadays, falafel is often served in a p ...
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.
Treatment of acute episodes may include medications for infection, stopping the offending medication, or blood transfusions
Blood transfusion is the process of transferring blood products into a person's circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used whole blood, but mod ...
.[ Jaundice in newborns may be treated with ]bili light
A bili light is a light therapy tool to treat newborn jaundice (hyperbilirubinemia). High levels of bilirubin can cause brain damage (kernicterus), leading to cerebral palsy, auditory neuropathy, gaze abnormalities and dental enamel hypoplasia. T ...
s.[ It is recommended that people be tested for G6PDD before certain medications, such as ]primaquine
Primaquine is a medication used to treat and prevent malaria and to treat ''Pneumocystis'' pneumonia. Specifically it is used for malaria due to ''Plasmodium vivax'' and ''Plasmodium ovale'' along with other medications and for prevention if othe ...
, are taken.[
About 400 million people have the condition globally.] It is particularly common in certain parts of Africa, Asia, the Mediterranean
The Mediterranean Sea is a sea connected to the Atlantic Ocean, surrounded by the Mediterranean Basin and almost completely enclosed by land: on the north by Western and Southern Europe and Anatolia, on the south by North Africa, and on the e ...
, and the Middle East
The Middle East ( ar, الشرق الأوسط, ISO 233: ) is a geopolitical region commonly encompassing Arabian Peninsula, Arabia (including the Arabian Peninsula and Bahrain), Anatolia, Asia Minor (Asian part of Turkey except Hatay Pro ...
.[ 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
In medicine, any disease is classified asymptomatic if a patient tests as carrier for a disease or infection but experiences no symptoms. Whenever a medical condition fails to show noticeable symptoms after a diagnosis it might be considered asy ...
.
Most people who develop symptoms are male, due to the X-linked
Sex linked describes the sex-specific patterns of inheritance and presentation when a gene mutation (allele) is present on a sex chromosome (allosome) rather than a non-sex chromosome (autosome). In humans, these are termed X-linked recessive, ...
pattern of inheritance, but female carriers can be affected due to unfavorable lyonization
X-inactivation (also called Lyonization, after English geneticist Mary Lyon) is a process by which one of the copies of the X chromosome is inactivated in therian female mammals. The inactive X chromosome is silenced by being packaged into a ...
or skewed X-inactivation
Skewed X-chromosome inactivation (skewed X-inactivation) occurs when the X-inactivation of one X chromosome is favored over the other, leading to an uneven number of cells with each chromosome inactivated. It is usually defined as one allele being ...
, where random inactivation of an X-chromosome in certain cells creates a population of G6PD-deficient red blood cell
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
s 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
Hemolysis or haemolysis (), also known by several other names, is the rupturing (lysis) of red blood cells (erythrocytes) and the release of their contents (cytoplasm) into surrounding fluid (e.g. blood plasma). Hemolysis may occur in vivo o ...
) in G6PD deficiency can manifest in a number of ways, including the following:
* Prolonged neonatal jaundice
Neonatal jaundice is a yellowish discoloration of the white part of the eyes and skin in a newborn baby due to high bilirubin levels. Other symptoms may include excess sleepiness or poor feeding. Complications may include seizures, cerebral pals ...
, possibly leading to kernicterus
Kernicterus is a bilirubin-induced brain dysfunction. The term was coined in 1904 by Christian Georg Schmorl. Bilirubin is a naturally occurring substance in the body of humans and many other animals, but it is neurotoxic when its concentration ...
(arguably the most serious complication of G6PD deficiency)
* Hemolytic crises in response to:
** Illness (especially infections)
** Certain drugs
A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhalat ...
(see below)
** Certain foods, most notably broad bean
''Vicia faba'', commonly known as the broad bean, fava bean, or faba bean, is a species of vetch, a flowering plant in the pea and bean family Fabaceae. It is widely cultivated as a crop for human consumption, and also as a cover crop. Varieti ...
s, from which the word ''favism'' derives
** Certain chemicals
** Diabetic ketoacidosis
Diabetic ketoacidosis (DKA) is a potentially life-threatening complication of diabetes mellitus. Signs and symptoms may include vomiting, abdominal pain, deep gasping breathing, increased urination, weakness, confusion and occasionally loss of ...
* Hemoglobinuria
Hemoglobinuria is a condition in which the oxygen transport protein hemoglobin is found in abnormally high concentrations in the urine. The condition is caused by excessive intravascular hemolysis, in which large numbers of red blood cells (RBCs) ...
(red or brown urine)
* Very severe crisis can cause acute kidney injury
Acute kidney injury (AKI), previously called acute renal failure (ARF), is a sudden decrease in kidney function that develops within 7 days, as shown by an increase in serum creatinine or a decrease in urine output, or both.
Causes of AKI are cla ...
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. 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
Glucose-6-phosphate dehydrogenase (G6PD or G6PDH) () is a cytosolic enzyme that catalyzes the chemical reaction
: D-glucose 6-phosphate + NADP+ + H2O 6-phospho-D-glucono-1,5-lactone + NADPH + H+
This enzyme participates in the pentose phosph ...
. Chemical reactions involving glucose-6-phosphate dehydrogenase produce compounds that prevent reactive oxygen species
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
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 it protective role and leads to the accumulation of reactive oxygen species and thus damage of 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 (fava beans is the hallmark
A hallmark is an official mark or series of marks struck on items made of metal, mostly to certify the content of noble metals—such as platinum, gold, silver and in some nations, palladium. In a more general sense, the term ''hallmark'' can al ...
trigger for G6PD mutation carriers),
* Certain medicines including aspirin
Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat inc ...
, quinine
Quinine is a medication used to treat malaria and babesiosis. This includes the treatment of malaria due to ''Plasmodium falciparum'' that is resistant to chloroquine when artesunate is not available. While sometimes used for nocturnal leg cr ...
and other antimalarials
Antimalarial medications or simply antimalarials are a type of antiparasitic chemical agent, often naturally derived, that can be used to treat or to prevent malaria, in the latter case, most often aiming at two susceptible target groups, young c ...
derived from quinine.
* Moth balls (naphthalene
Naphthalene is an organic compound with formula . It is the simplest polycyclic aromatic hydrocarbon, and is a white crystalline solid with a characteristic odor that is detectable at concentrations as low as 0.08 ppm by mass. As an aromati ...
)
* Stress from a bacterial
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
or viral infection
A viral disease (or viral infection) occurs when an organism's body is invaded by pathogenic viruses, and infectious virus particles (virions) attach to and enter susceptible cells.
Structural Characteristics
Basic structural characteristics, s ...
.
Drugs
Many substances are potentially harmful to people with G6PD deficiency. Variation in response to these substances makes individual predictions difficult. Antimalarial drug
Antimalarial medications or simply antimalarials are a type of antiparasitic chemical agent, often naturally derived, that can be used to treat or to prevent malaria, in the latter case, most often aiming at two susceptible target groups, young c ...
s that can cause acute hemolysis in people with G6PD deficiency include primaquine
Primaquine is a medication used to treat and prevent malaria and to treat ''Pneumocystis'' pneumonia. Specifically it is used for malaria due to ''Plasmodium vivax'' and ''Plasmodium ovale'' along with other medications and for prevention if othe ...
, pamaquine
Pamaquine is an 8-aminoquinoline drug formerly used for the treatment of malaria. It is closely related to primaquine.
Synonyms
*Plasmochin
*Plasmoquine
*Plasmaquine
Uses
Pamaquine is effective against the hypnozoites of the relapsing malarias ...
, chloroquine
Chloroquine is a medication primarily used to prevent and treat malaria in areas where malaria remains sensitive to its effects. Certain types of malaria, resistant strains, and complicated cases typically require different or additional medi ...
, and hydroxychloroquine
Hydroxychloroquine, sold under the brand name Plaquenil among others, is a medication used to prevent and treat malaria in areas where malaria remains sensitive to chloroquine. Other uses include treatment of rheumatoid arthritis, lupus, an ...
. There is evidence that other antimalarials may also exacerbate G6PD deficiency, but only at higher doses. Sulfonamides
In organic chemistry, the sulfonamide functional group (also spelled sulphonamide) is an organosulfur group with the structure . It consists of a sulfonyl group () connected to an amine group (). Relatively speaking this group is unreactive. ...
(such as sulfanilamide
Sulfanilamide (also spelled sulphanilamide) is a sulfonamide antibacterial drug. Chemically, it is an organic compound consisting of an aniline derivatized with a sulfonamide group. Powdered sulfanilamide was used by the Allies in World War II ...
, sulfamethoxazole
Sulfamethoxazole (SMZ or SMX) is an antibiotic. It is used for bacterial infections such as urinary tract infections, bronchitis, and prostatitis and is effective against both gram negative and positive bacteria such as ''Listeria monocytogenes' ...
, and mafenide
Mafenide (INN; usually as mafenide acetate, trade name Sulfamylon) is a sulfonamide-type medication used as an antibiotic. It was approved by the FDA in 1948.
Uses
Mafenide is used to treat severe burns. It is used topically as an adjunctive t ...
), thiazolesulfone, methylene blue
Methylthioninium chloride, commonly called methylene blue, is a salt used as a dye and as a medication. Methylene blue is a thiazine dye. As a medication, it is mainly used to treat methemoglobinemia by converting the ferric iron in hemoglobin ...
, and naphthalene
Naphthalene is an organic compound with formula . It is the simplest polycyclic aromatic hydrocarbon, and is a white crystalline solid with a characteristic odor that is detectable at concentrations as low as 0.08 ppm by mass. As an aromati ...
should also be avoided by people with G6PD deficiency as they antagonize folate synthesis, as should certain analgesic
An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...
s (such as phenazopyridine
Phenazopyridine is a medication which, when excreted by the kidneys into the urine, has a local analgesic effect on the urinary tract. It is often used to help with the pain, irritation, or urgency caused by urinary tract infections, surgery, or ...
and acetanilide
Acetanilide is an odourless solid chemical of leaf or flake-like appearance. It is also known as ''N''-phenylacetamide, acetanil, or acetanilid, and was formerly known by the trade name Antifebrin.
Preparation and properties
Acetanilide can be ...
) and a few non-sulfa antibiotics (nalidixic acid
Nalidixic acid (tradenames Nevigramon, NegGram, Wintomylon and WIN 18,320) is the first of the synthetic quinolone antibiotics.
In a technical sense, it is a naphthyridone, not a quinolone: its ring structure is a 1,8-naphthyridine nucleus that ...
, nitrofurantoin
Nitrofurantoin is an antibacterial medication used to treat urinary tract infections, but it is not as effective for kidney infections. It is taken by mouth.
Common side effects include nausea, loss of appetite, diarrhea, and headaches. Rarely ...
, isoniazid
Isoniazid, also known as isonicotinic acid hydrazide (INH), is an antibiotic used for the treatment of tuberculosis. For active tuberculosis it is often used together with rifampicin, pyrazinamide, and either streptomycin or ethambutol. For l ...
, dapsone
Dapsone, also known as 4,4'-sulfonyldianiline (SDA) or diaminodiphenyl sulfone (DDS), is an antibiotic commonly used in combination with rifampicin and clofazimine for the treatment of leprosy. It is a second-line medication for the treatment a ...
, and furazolidone
Furazolidone is a nitrofuran antibacterial agent and monoamine oxidase inhibitor (MAOI). It is marketed by Roberts Laboratories under the brand name Furoxone and by GlaxoSmithKline as Dependal-M.
Medical uses
Furazolidone has been used in human ...
). Henna
Henna is a dye prepared from the plant ''Lawsonia inermis'', also known as the henna tree, the mignonette tree, and the Egyptian privet, the sole species of the genus ''Lawsonia''.
''Henna'' can also refer to the temporary body art resulting fr ...
has been known to cause hemolytic crisis in G6PD-deficient infants. Rasburicase
Rasburicase (trade names Elitek in the US and Fasturtec in the EU) is a medication that helps to clear uric acid from the blood. It is a recombinant version of urate oxidase, an enzyme that metabolizes uric acid to allantoin. Urate oxidase is kno ...
is also contraindicated in G6PD deficiency. High dose intravenous
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
vitamin C
Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits and vegetables, also sold as a dietary supplement and as a topical 'serum' ingredient to treat melasma (dark pigment spots) an ...
has also been known to cause haemolysis in G6PD deficiency carriers; therefore, G6PD deficiency testing is routine before infusion of doses of 25 g or more.
Genetics
Two variants (G6PD A− and G6PD Mediterranean) 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 (Spaniards, Italians, Greeks, Armenians, Sephardi Jews and other Semitic peoples). Both variants are believed to stem from a strongly protective effect against ''Plasmodium falciparum
''Plasmodium falciparum'' is a Unicellular organism, unicellular protozoan parasite of humans, and the deadliest species of ''Plasmodium'' that causes malaria in humans. The parasite is transmitted through the bite of a female ''Anopheles'' mosqu ...
'' and ''Plasmodium vivax
''Plasmodium vivax'' is a protozoal parasite and a human pathogen. This parasite is the most frequent and widely distributed cause of recurring malaria. Although it is less virulent than ''Plasmodium falciparum'', the deadliest of the five huma ...
'' 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
African Americans (also referred to as Black Americans and Afro-Americans) are an ethnic group consisting of Americans with partial or total ancestry from sub-Saharan Africa. The term "African American" generally denotes descendants of ens ...
, Saudi Arabian
Saudis ( ar, سعوديون, Suʿūdiyyūn) are people identified with the country of Saudi Arabia. This connection may be residential, legal, historical or cultural. The Saudis are composed mainly of Arabs and primarily speak a regional dialect ...
, Sardinian males, some African populations, and Asian groups.[''Glucose-6-Phosphate Dehydogenase Deficiency (G6PD)'' on The Jewish Genetic Disease Consortium (JGDC) websit]
All mutations that cause G6PD deficiency are found on the long arm of the X chromosome
The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex-d ...
, on band Xq28. The G6PD gene spans some 18.5 kilobase
A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA ...
s. The following variants and mutations are well-known and described:
Pathophysiology
Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
in the pentose phosphate pathway
The pentose phosphate pathway (also called the phosphogluconate pathway and the hexose monophosphate shunt and the HMP Shunt) is a metabolic pathway parallel to glycolysis. It generates NADPH and pentoses (5-carbon sugars) as well as ribose 5-pho ...
(see image, also known as the HMP shunt pathway). G6PD converts glucose-6-phosphate
Glucose 6-phosphate (G6P, sometimes called the Robison ester) is a glucose sugar phosphorylated at the hydroxy group on carbon 6. This dianion is very common in cells as the majority of glucose entering a cell will become phosphorylated in this wa ...
into 6-phosphoglucono-δ-lactone
6-Phosphogluconolactone is an intermediate in the pentose phosphate pathway (PPP).
In the PPP pathway, it is produced from glucose-6-phosphate by glucose-6-phosphate dehydrogenase. It is then converted to 6-Phosphogluconic acid by 6-phosphoglucon ...
and is the rate-limiting enzyme of this metabolic pathway
In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical reac ...
that supplies reducing energy to cells by maintaining the level of the reduced form of the co-enzyme
A cofactor is a non-protein chemical compound or metallic ion that is required for an enzyme's role as a catalyst (a catalyst is a substance that increases the rate of a chemical reaction). Cofactors can be considered "helper molecules" that ass ...
nicotinamide adenine dinucleotide phosphate
Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a Cofactor (biochemistry), cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid synth ...
(NADPH). The NADPH maintains the supply of reduced glutathione
Glutathione (GSH, ) is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, pero ...
in the cells that is used to mop up free radicals that cause oxidative
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...
damage. The pathway also stimulates catalase, an antioxidant enzyme.
The G6PD / NADPH pathway is the ''only'' source of reduced glutathione in red blood cells (erythrocyte
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
s). 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
Hemolytic anemia or haemolytic anaemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular). This most commonly ...
in states of oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
. Oxidative stress can result from infection and from chemical exposure to medication
A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...
and certain foods. Broad bean
''Vicia faba'', commonly known as the broad bean, fava bean, or faba bean, is a species of vetch, a flowering plant in the pea and bean family Fabaceae. It is widely cultivated as a crop for human consumption, and also as a cover crop. Varieti ...
s, e.g., fava beans, contain high levels of vicine
Vicine is an alkaloid glycoside found mainly in fava beans, which are also called broad beans (''Vicia faba)''. Vicine is toxic in individuals who have a hereditary loss of the enzyme glucose-6-phosphate dehydrogenase. It causes haemolytic anaemi ...
, divicine
Divicine (2,6-diamino-4,5-dihydroxypyrimidine) is an oxidant and a base with alkaloidal properties found in fava beans and ''Lathyrus sativus''. It is an aglycone of vicine. A common derivative is the diacetate form (2,6-diamino-1,6-dihydro-4,5-p ...
, convicine and isouramil, all of which create oxidant
An oxidizing agent (also known as an oxidant, oxidizer, electron recipient, or electron acceptor) is a substance in a redox chemical reaction that gains or " accepts"/"receives" an electron from a (called the , , or ). In other words, an oxid ...
s.
When all remaining reduced glutathione
Glutathione (GSH, ) is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, pero ...
is consumed, enzymes and other proteins (including hemoglobin
Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyte ...
) are subsequently damaged by the oxidants, leading to cross-bonding and protein deposition in the red cell membranes
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
. Damaged red cells are phagocytosed
Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is ca ...
and sequestered (taken out of circulation) in the spleen
The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes . . The hemoglobin is metabolized to bilirubin
Bilirubin (BR) (Latin for "red bile") is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the ...
(causing jaundice
Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme meta ...
at high concentrations). The red cells rarely disintegrate in the circulation, so hemoglobin is rarely excreted directly by the kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...
, but this can occur in severe cases, causing acute kidney injury
Acute kidney injury (AKI), previously called acute renal failure (ARF), is a sudden decrease in kidney function that develops within 7 days, as shown by an increase in serum creatinine or a decrease in urine output, or both.
Causes of AKI are cla ...
.
Deficiency of G6PD in the alternative pathway causes the buildup of glucose and thus there is an increase of advanced glycation endproduct
Advanced glycation end products (AGEs) are proteins or lipids that become glycated as a result of exposure to sugars. They are a bio-marker implicated in aging and the development, or worsening, of many degenerative diseases, such as diabetes, at ...
s (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
Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...
and hypertension
Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...
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 ''lyonization
X-inactivation (also called Lyonization, after English geneticist Mary Lyon) is a process by which one of the copies of the X chromosome is inactivated in therian female mammals. The inactive X chromosome is silenced by being packaged into a ...
''), homozygous females have been described; in these females there is co-incidence of a rare immune disorder
An immune disorder is a dysfunction of the immune system. These disorders can be characterized in several different ways:
* By the component(s) of the immune system affected
* By whether the immune system is overactive or underactive
* By whether t ...
termed chronic granulomatous disease
Chronic granulomatous disease (CGD), also known as Bridges–Good syndrome, chronic granulomatous disorder, and Quie syndrome, is a diverse group of hereditary diseases in which certain cells of the immune system have difficulty forming the reacti ...
(CGD).
Diagnosis
The diagnosis is generally suspected when patients from certain ethnic groups (see epidemiology) develop anemia
Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...
, jaundice
Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme meta ...
and symptoms of hemolysis
Hemolysis or haemolysis (), also known by several other names, is the rupturing (lysis) of red blood cells (erythrocytes) and the release of their contents (cytoplasm) into surrounding fluid (e.g. blood plasma). Hemolysis may occur in vivo o ...
after challenges from any of the above causes, especially when there is a positive family history.
Generally, tests will include:
* Complete blood count
A complete blood count (CBC), also known as a full blood count (FBC), is a set of medical laboratory tests that provide cytometry, information about the cells in a person's blood. The CBC indicates the counts of white blood cells, red blood cell ...
and reticulocyte
Reticulocytes are immature red blood cells (RBCs). In the process of erythropoiesis (red blood cell formation), reticulocytes develop and mature in the bone marrow and then circulatory system, circulate for about a day in the blood stream before ...
count; in active G6PD deficiency, Heinz bodies Heinz bodies (also referred to as "Heinz-Ehrlich bodies") are inclusions within red blood cells composed of denatured hemoglobin. They are not visible with routine blood staining techniques, but can be seen with supravital staining. The presence o ...
can be seen in red blood cell
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
s on a blood film
A blood smear, peripheral blood smear or blood film is a thin layer of blood smeared on a glass microscope slide and then stained in such a way as to allow the various blood cells to be examined microscopically. Blood smears are examined in the ...
;
* Liver enzyme
Liver function tests (LFTs or LFs), also referred to as a hepatic panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial thromboplastin ti ...
s (to exclude other causes of jaundice
Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme meta ...
);
* Lactate dehydrogenase
Lactate dehydrogenase (LDH or LD) is an enzyme found in nearly all living cells. LDH catalyzes the conversion of lactate to pyruvate and back, as it converts NAD+ to NADH and back. A dehydrogenase is an enzyme that transfers a hydride from on ...
(elevated in hemolysis and a marker of hemolytic severity)
* Haptoglobin
Haptoglobin (abbreviated as Hp) is the protein that in humans is encoded by the ''HP'' gene. In blood plasma, haptoglobin binds with high affinity to ''free'' hemoglobin released from erythrocytes, and thereby inhibits its deleterious oxidative ...
(decreased in hemolysis);
* A "direct antiglobulin test
A Coombs test, also known as antiglobulin test (AGT), is either of two blood tests used in immunohematology. They are the direct and indirect Coombs tests. The direct Coombs test detects antibodies that are stuck to the surface of the red blood ce ...
" (Coombs' test) – this should be negative, as hemolysis
Hemolysis or haemolysis (), also known by several other names, is the rupturing (lysis) of red blood cells (erythrocytes) and the release of their contents (cytoplasm) into surrounding fluid (e.g. blood plasma). Hemolysis may occur in vivo o ...
in G6PD is not immune-mediated;
When there are sufficient grounds to suspect G6PD, a direct test for G6PD is the "Beutler fluorescent spot test
The Beutler test, also known as the fluorescent spot test, is a screening test used to identify enzyme defects.Beutler E, Mitchell M. New rapid for the estimation of red cell galactose-1-phosphate uridyl transferase activity. J Lab Clin Med 1968;7 ...
", which has largely replaced an older test (the Motulsky dye-decolouration 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
Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require NAD ...
produced by G6PD under ultraviolet light
Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nm (with a corresponding frequency around 30 PHz) to 400 nm (750 THz), shorter than that of visible light, but longer than X-rays. UV radiation i ...
. 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 a RBC with a Heinz body, it removes the precipitate and a small piece of the membrane, leading to characteristic "]bite cells A degmacyte or bite cell is an Poikilocytosis, abnormally shaped mature red blood cell with one or more semicircular portions removed from the cell margin, known as "bites". These "bites" result from the mechanical removal of denatured hemoglobin d ...
". 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 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.
Classification
The World Health Organization
The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...
classifies G6PD genetic variants into five classes, the first three of which are deficiency states.
* 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.
Treatment
The most important measure is prevention – avoidance of the drugs and foods that cause hemolysis. Vaccination
Vaccination is the administration of a vaccine to help the immune system develop immunity from a disease. Vaccines contain a microorganism or virus in a weakened, live or killed state, or proteins or toxins from the organism. In stimulating ...
against some common pathogens (e.g. hepatitis A
Hepatitis A is an infectious disease of the liver caused by ''Hepatovirus A'' (HAV); it is a type of viral hepatitis. Many cases have few or no symptoms, especially in the young. The time between infection and symptoms, in those who develop them ...
and hepatitis B
Hepatitis B is an infectious disease caused by the ''Hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection.
Many people have no symptoms during an initial infection. Fo ...
) may prevent infection-induced attacks.
In the acute phase of hemolysis, blood transfusion
Blood transfusion is the process of transferring blood products into a person's circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used whole blood, but mo ...
s might be necessary, or even dialysis Dialysis may refer to:
*Dialysis (chemistry), a process of separating molecules in solution
**Electrodialysis, used to transport salt ions from one solution to another through an ion-exchange membrane under the influence of an applied electric pote ...
in acute kidney failure
Acute kidney injury (AKI), previously called acute renal failure (ARF), is a sudden decrease in kidney function that develops within 7 days, as shown by an increase in serum creatinine or a decrease in urine output, or both.
Causes of AKI are cla ...
. 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
Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat inc ...
.
Some patients may benefit from removal of the spleen
The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes . (splenectomy
A splenectomy is the surgical procedure that partially or completely removes the spleen. The spleen is an important organ in regard to immunological function due to its ability to efficiently destroy encapsulated bacteria. Therefore, removal of ...
), as this is an important site of red cell destruction. Folic acid
Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and ...
should be used in any disorder featuring a high red cell turnover. Although vitamin E
Vitamin E is a group of eight fat soluble compounds that include four tocopherols and four tocotrienols. Vitamin E deficiency, which is rare and usually due to an underlying problem with digesting dietary fat rather than from a diet low in vitami ...
and selenium
Selenium is a chemical element with the symbol Se and atomic number 34. It is a nonmetal (more rarely considered a metalloid) with properties that are intermediate between the elements above and below in the periodic table, sulfur and tellurium, ...
have antioxidant properties, their use does not decrease the severity of G6PD deficiency.
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 ischemic heart disease
Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pla ...
and cerebrovascular disease
Cerebrovascular disease includes a variety of medical conditions that affect the blood vessels of the brain and the cerebral circulation. Arteries supplying oxygen and nutrients to the brain are often damaged or deformed in these disorders. The ...
.
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).
Epidemiology
G6PD deficiency is the second most common human enzyme defect after ALDH2
Aldehyde dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the ''ALDH2'' gene located on chromosome 12. This protein belongs to the aldehyde dehydrogenase family of enzymes. Aldehyde dehydrogenase is the second enzyme of the ...
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
In biogeography, the Mediterranean Basin (; also known as the Mediterranean Region or sometimes Mediterranea) is the region of lands around the Mediterranean Sea that have mostly a Mediterranean climate, with mild to cool, rainy winters and w ...
is where favism is most common, especially among Mizrahi Jews
Mizrahi Jews ( he, יהודי המִזְרָח), also known as ''Mizrahim'' () or ''Mizrachi'' () and alternatively referred to as Oriental Jews or ''Edot HaMizrach'' (, ), are a grouping of Jewish communities comprising those who remained i ...
, Sardinians
The Sardinians, or Sards ( sc, Sardos or ; Italian and Sassarese: ''Sardi''; Gallurese: ''Saldi''), are a Romance language-speaking ethnic group native to Sardinia, from which the western Mediterranean island and autonomous region of Italy deri ...
, Cypriots, Greeks
The Greeks or Hellenes (; el, Έλληνες, ''Éllines'' ) are an ethnic group and nation indigenous to the Eastern Mediterranean and the Black Sea regions, namely Greece, Cyprus, Albania, Italy, Turkey, Egypt, and, to a lesser extent, oth ...
, Egyptians
Egyptians ( arz, المَصرِيُون, translit=al-Maṣriyyūn, ; arz, المَصرِيِين, translit=al-Maṣriyyīn, ; cop, ⲣⲉⲙⲛ̀ⲭⲏⲙⲓ, remenkhēmi) are an ethnic group native to the Nile, Nile Valley in Egypt. Egyptian ...
, 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
Sardinia ( ; it, Sardegna, label=Italian, Corsican and Tabarchino ; sc, Sardigna , sdc, Sardhigna; french: Sardaigne; sdn, Saldigna; ca, Sardenya, label=Algherese and Catalan) is the second-largest island in the Mediterranean Sea, after ...
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
Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. S ...
, in particular the form of malaria caused by ''Plasmodium falciparum
''Plasmodium falciparum'' is a Unicellular organism, unicellular protozoan parasite of humans, and the deadliest species of ''Plasmodium'' that causes malaria in humans. The parasite is transmitted through the bite of a female ''Anopheles'' mosqu ...
'', the most deadly form of malaria. A similar relationship exists between malaria and sickle-cell disease
Sickle cell disease (SCD) is a group of blood disorders typically inherited from a person's parents. The most common type is known as sickle cell anaemia. It results in an abnormality in the oxygen-carrying protein haemoglobin found in red blo ...
. One theory to explain this is that cells infected with the ''Plasmodium'' parasite are cleared more rapidly by the spleen
The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes . . 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.
History
The modern understanding of the condition began with the analysis of patients who exhibited sensitivity to primaquine
Primaquine is a medication used to treat and prevent malaria and to treat ''Pneumocystis'' pneumonia. Specifically it is used for malaria due to ''Plasmodium vivax'' and ''Plasmodium ovale'' along with other medications and for prevention if othe ...
. The discovery of G6PD deficiency relied heavily upon the testing of prisoner volunteers at Illinois State Penitentiary
Stateville Correctional Center (SCC) is a maximum security state prison for men in Crest Hill, Illinois, United States, near Chicago. It is a part of the Illinois Department of Corrections.
History
Opened in 1925, Stateville was built to ac ...
, a type of study which today is considered unethical and cannot be performed. When some prisoners were given the drug primaquine, some developed hemolytic anemia
Hemolytic anemia or haemolytic anaemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular). This most commonly ...
but others did not. In spite of these results, the US military administered the drug widely during the Korean War to prevent the relapsing infection caused by ''Plasmodium vivax
''Plasmodium vivax'' is a protozoal parasite and a human pathogen. This parasite is the most frequent and widely distributed cause of recurring malaria. Although it is less virulent than ''Plasmodium falciparum'', the deadliest of the five huma ...
'' hypnozoites. Numerous cases of hemolytic anemia were observed in US soldiers of North African and Mediterranean descent.
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.
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
Pythagoras of Samos ( grc, Πυθαγόρας ὁ Σάμιος, Pythagóras ho Sámios, Pythagoras the Samos, Samian, or simply ; in Ionian Greek; ) was an ancient Ionians, Ionian Ancient Greek philosophy, Greek philosopher and the eponymou ...
had a strict rule that to join the society of the Pythagoreans
Pythagoreanism originated in the 6th century BC, based on and around the teachings and beliefs held by Pythagoras and his followers, the Pythagoreans. Pythagoras established the first Pythagorean community in the ancient Greek colony of Kroton, ...
one had to swear off beans. 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.
References
External links
Family Practice Notebook/G6PD Deficiency (Favism)
{{DEFAULTSORT:Glucose-6-Phosphate Dehydrogenase Deficiency
Hereditary hemolytic anemias
Inborn errors of carbohydrate metabolism
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