glucose 6 phosphate dehydrogenase deficiency
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Glucose-6-phosphate dehydrogenase deficiency (G6PDD) 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 (substrate ...
that predisposes to
red blood cell breakdown Hemolysis or haemolysis (), also known by several other names, is the rupturing (lysis Lysis ( ; Greek#REDIRECT Greek Greek may refer to: Greece Anything of, from, or related to Greece Greece ( el, Ελλάδα, , ), officially the ...

red blood cell breakdown
. Most of the time, those who are affected have no symptoms. Following a specific trigger, symptoms such as , dark urine,
shortness of breath Shortness of breath (SOB), also known as dyspnea (BrE British English (BrE) is the standard dialect A standard language (also standard variety, standard dialect, and standard) is a language variety that has undergone substantial codificat ...
, and feeling tired may develop. Complications can include
anemia Anemia (American and British English spelling differences#ae and oe, also spelled anaemia) is a decrease in the total amount of red blood cells (RBCs) or hemoglobin in the blood, or a lowered ability of the blood to carry oxygen. When anemia c ...

anemia
and
newborn jaundice Neonatal jaundice is a jaundice, yellowish discoloration of the sclera, 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 seizure ...
. Some people never have symptoms. It is an
X-linked recessive X-linked recessive inheritance is a mode of inheritance Inheritance is the practice of passing on private property, Title (property), titles, debts, entitlements, Privilege (law), privileges, rights, and Law of obligations, obligations upon th ...

X-linked recessive
disorder that results in defective
glucose-6-phosphate dehydrogenase Glucose-6-phosphate dehydrogenase (G6PD or G6PDH) () is a cytosolic enzyme that catalysis, catalyzes the chemical reaction : Glucose 6-phosphate, D-glucose 6-phosphate + NADP+ + H2O 6-Phosphogluconolactone, 6-phospho-D-glucono-1,5-lactone + NADP ...
enzyme. Red blood cell breakdown may be triggered by
infection An infection is the invasion of an organism's body tissues by disease-causing agents, their multiplication, and the reaction of host A host is a person responsible for guests at an event or for providing hospitality during it. Host may ...

infection
s, certain medication, stress, or foods such as
fava beans ''Vicia faba'', also known in the culinary Culinary arts, in which ''wikt:culinary, culinary'' means "related to cooking", are the cuisine arts of outline of food preparation, food preparation, cooking, and presentation of food, usually in ...
. Depending on the specific
mutation In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechan ...
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 Deoxyribonucleic acid (; DNA) is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist o ...
. 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 frying, deep-fried ball or patty-shaped fritter made from ground chickpeas, Vicia faba, broad beans, or both. Falafel is a traditional Middle Eastern cuisine, Middle Eastern food, commonly served in a ...

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. 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 one's Circulatory system, circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used whole ...
. Jaundice in newborns may be treated with
bili light A bili light is a light therapy Light therapy—or phototherapy, classically referred to as heliotherapy—consists either of exposure to daylight Daylight is the combination of all direct and indirect sunlight Sunlight is a portio ...
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 Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms Signs and symptoms are the observed or detectable signs, and experi ...

primaquine
, 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 Europe, Western and Southern Europe and Anatolia, on the south by North Africa ...

Mediterranean
, and the
Middle East The Middle East ( ar, الشرق الأوسط, ISO 233 The international standard An international standard is a technical standard A technical standard is an established norm (social), norm or requirement for a repeatable technical task whi ...

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 In medicine, any disease A disease is a particular abnormal condition that negatively affects the structure A structure is an arrangement and organization of interrelated elements in a material object or system A system is a grou ...
. Most people who develop symptoms are male, due to the
X-linked Sex linked describes the sex-specific patterns of Heredity, inheritance and Phenotype, 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 ...
pattern of inheritance, but female carriers can be affected due to unfavorable
lyonization X-inactivation (also called Lyonization, after English geneticist Mary Lyon Mary Mason Lyon (; February 28, 1797 – March 5, 1849) was an American pioneer in women's education. She established the Wheaton College (Massachusetts), Wheaton ...
or
skewed X-inactivation Skewed X-chromosome inactivation (skewed X-inactivation) occurs when the X-inactivation and calico cats is a visible manifestation of X-inactivation. The black and orange alleles of a fur coloration gene reside on the X chromosome. For any give ...
, 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 language, Greek ''erythros'' for "red" and ''k ...

red blood cell
s coexisting with unaffected red blood cells. A female with one affected X chromosome will show the deficiency in approximately half of their 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 Lysis ( ; Greek#REDIRECT Greek Greek may refer to: Greece Anything of, from, or related to Greece Greece ( el, Ελλάδα, , ), officially the ...

hemolysis
) 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 Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and se ...

neonatal jaundice
, possibly leading to
kernicterus Kernicterus is a bilirubin Bilirubin (BR) is a yellow compound that occurs in the normal catabolic Catabolism () is the set of metabolic pathways that breaks down molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microsc ...

kernicterus
(arguably the most serious complication of G6PD deficiency) * in response to: ** Illness (especially infections) ** Certain
drugs A drug is any chemical substance A chemical substance is a form of matter In classical physics and general chemistry, matter is any substance that has mass and takes up space by having volume. All everyday objects that can be touched ...

drugs
(see below) ** Certain foods, most notably
broad bean ''Vicia faba'', also known in the culinary sense as the broad bean, fava bean, or faba bean, is a species of flowering plant in the pea and bean family Fabaceae The Fabaceae or Leguminosae,
s, from which the word ''favism'' derives ** Certain chemicals **
Diabetic ketoacidosis Diabetic ketoacidosis (DKA) is a potentially life-threatening complication of diabetes mellitus Diabetes mellitus (DM), commonly known as diabetes, is a group of metabolic disorders characterized by a high blood sugar level over a prolonged p ...
* Hemoglobinuria (red or brown urine) * Very severe crisis can cause
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 Creatinine ( or ; from el, κρέας, kreas, flesh) is a ...
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


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 A metal (from Greek#REDIRECT Greek Greek may refer to: Greece Anything of, from, or related to Greece Greece ( el, Ελλάδα, , ), officially the He ...
trigger for G6PD mutation carriers), * Certain medicines including
aspirin Aspirin, also known as acetylsalicylic acid (ASA), is a medication used to reduce pain, fever, or inflammation. Specific inflammatory conditions which aspirin is used to treat include Kawasaki disease, pericarditis, and rheumatic fever. Aspirin ...

aspirin
,
quinine Quinine is a medication used to treat malaria Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms Signs and symptoms are the observed or detectable signs, and experienced sympt ...

quinine
and other
antimalarials Antimalarial medications or simply antimalarials are a type of antiparasitic chemical agent, often natural product, naturally derived, that can be used to treat or to prevent malaria, in the latter case, most often aiming at two susceptible target ...
derived from quinine. * Moth balls (
naphthalene Naphthalene is an organic compound In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, behavio ...

naphthalene
) * Stress from a
bacterial Bacteria (; common noun bacteria, singular bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell The cell (from Latin ''cella'', meaning "small room") is the basic structural, functional, and ...
or
viral infection A viral disease (or viral infection) occurs when an organism's body is invaded by pathogen In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism that can produc ...
.


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 antiparasiticAntiparasitics are a class of medications which are indicated for the treatment of parasitic diseases, such as those caused by helminths, amoeba, parasitic nutrition#Ectop ...
s that can cause acute hemolysis in people with G6PD deficiency include
primaquine Primaquine is a medication used to treat and prevent malaria Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms Signs and symptoms are the observed or detectable signs, and experi ...

primaquine
,
pamaquine Pamaquine is an 8-aminoquinoline drug formerly used for the treatment of malaria Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms Signs and symptoms are the observed or detectab ...

pamaquine
,
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 ...

chloroquine
, and
hydroxychloroquine Hydroxychloroquine, sold under the brand name Plaquenil among others, is a medication used to prevent and treat malaria Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms S ...

hydroxychloroquine
. There is evidence that other antimalarials may also exacerbate G6PD deficiency, but only at higher doses.
Sulfonamides In chemistry Chemistry is the scientific Science () is a systematic enterprise that builds and organizes knowledge Knowledge is a familiarity or awareness, of someone or something, such as facts A fact is an occurrence in ...
(such as
sulfanilamide Sulfanilamide (also spelled sulphanilamide) is a sulfonamide In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, struc ...

sulfanilamide
,
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'' ...

sulfamethoxazole
, and ), thiazolesulfone,
methylene blue Methylthioninium chloride, commonly called methylene blue, is a salt used as a dye A dye is a color Color (American English) or colour (Commonwealth English) is the visual perception, visual perceptual Physical property, property c ...

methylene blue
, and
naphthalene Naphthalene is an organic compound In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, behavio ...

naphthalene
should also be avoided by people with G6PD deficiency as they antagonize folate synthesis, as should certain
analgesic An analgesic or painkiller is any member of the group of Pharmaceutical drug, drugs used to achieve analgesia, relief from pain. They are distinct from anesthetics, which temporarily affect, and in some instances completely eliminate, sense, sens ...
s (such as
phenazopyridine Phenazopyridine is a medication which, when excreted by the kidneys into the urine Urine is a liquid by-product A by-product or byproduct is a secondary product derived from a production process, process or ; it is not the primary product o ...

phenazopyridine
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 p ...

acetanilide
) 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 antibiotic A quinolone antibiotic is a member of a large group of broad-spectrum bacteriocidal A bactericide or bacteriocide, s ...

nalidixic acid
,
nitrofurantoin Nitrofurantoin is an antibacterial medication used to treat bladder infections, but is not as effective for pyelonephritis, kidney infections. It is taken by mouth. Common side effects include nausea, loss of appetite, diarrhea, and headaches. ...

nitrofurantoin
,
isoniazid Isoniazid, also known as isonicotinic acid hydrazide (INH), is an antibiotic An antibiotic is a type of antimicrobial An antimicrobial is an agent that kills microorganism A microorganism, or microbe,, ''mikros'', "small") and ''org ...

isoniazid
,
dapsone Dapsone, also known as 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 and prevention of pneumocystis pneu ...

dapsone
, and
furazolidone Furazolidone is a nitrofuran Nitrofurans are a class of drugs typically used as antibiotics or antimicrobials. The defining structural component is a furan ring with a nitro group. Members of this class of drugs include: * Antibacterials (antib ...

furazolidone
).
Henna Henna is a dye A dye is a color Color (American English) or colour (Commonwealth English) is the visual perception, visual perceptual Physical property, property corresponding in humans to the categories called ''blue'', ''green'', ...

Henna
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 A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, the ...

Rasburicase
is also contraindicated in G6PD deficiency. High dose
intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that delivers fluids, medications and nutrition directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrition ...
vitamin C Vitamin C (also known as ascorbic acid and ascorbate) is a vitamin A vitamin is an organic molecule , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain ca ...

vitamin C
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 A unicellular organism, also known as a single-celled organism, is an organism In biology, an organism () is any organic, life, living system that functions as an individual entity. All org ...

Plasmodium falciparum
'' and ''
Plasmodium vivax ''Plasmodium vivax'' is a protozoa Protozoa (singular protozoon or protozoan, plural protozoa or protozoans) is an informal term for a group of Unicellular organism, single-celled eukaryotes, either free-living or Parasitism, parasitic, that f ...
'' 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 or Afro-Americans) are an ethnic group An ethnic group or ethnicity is a grouping of people A people is any plurality of person A person (plural people or persons) is a being t ...

African American
,
Saudi Arabian Saudis ( ar, سعوديون, Suʿūdiyyūn) or Saudi Arabians are a nation A nation is a community A community is a social unit (a group of living things) with commonality such as Norm (social), norms, religion, values, Convention (norm), ...
,
SardinianSardinian refers to anything related to the Mediterranean Sea, Mediterranean island of Sardinia. More specifically it can refer to: *Sardinian people *History of Sardinia *Sardinian language *Sardinian literature *Music of Sardinia *Cuisine of Sardin ...
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 chromosome A chromosome is a long DNA molecule with part or all of the genome, genetic material of an organism. Most eukaryotic chromosomes include packaging proteins called histones whic ...

X chromosome
, 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 (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates in ...

enzyme
in the
pentose phosphate pathway In chemistry Chemistry is the scientific Science () is a systematic enterprise that builds and organizes knowledge Knowledge is a familiarity or awareness, of someone or something, such as facts A fact is an occurrence in the ...

pentose phosphate pathway
(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 cell (biology), cells as the majority of glucose entering a cell will become phosphoryl ...
into 6-phosphoglucono-δ-lactone 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 (biology), cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence ...
that supplies energy to cells by maintaining the level of the reduced form of the
co-enzyme A cofactor is a non-protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 195 ...
nicotinamide adenine dinucleotide phosphate (NADPH). The NADPH in turn maintains the supply of reduced glutathione in the cells that is used to mop up free radicals that cause oxidation, oxidative damage. 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 phagocytosis, 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 ''
lyonization X-inactivation (also called Lyonization, after English geneticist Mary Lyon Mary Mason Lyon (; February 28, 1797 – March 5, 1849) was an American pioneer in women's education. She established the Wheaton College (Massachusetts), Wheaton ...
''), homozygous females have been described; in these females there is co-incidence of a rare disease, rare immunology, immune disorder termed chronic granulomatous disease (CGD).


Diagnosis

The diagnosis is generally suspected when patients from certain ethnic groups (see epidemiology) develop
anemia Anemia (American and British English spelling differences#ae and oe, also spelled anaemia) is a decrease in the total amount of red blood cells (RBCs) or hemoglobin in the blood, or a lowered ability of the blood to carry oxygen. When anemia c ...

anemia
, jaundice and symptoms of
hemolysis Hemolysis or haemolysis (), also known by several other names, is the rupturing (lysis Lysis ( ; Greek#REDIRECT Greek Greek may refer to: Greece Anything of, from, or related to Greece Greece ( el, Ελλάδα, , ), officially the ...

hemolysis
after challenges from any of the above causes, especially when there is a positive family history. Generally, tests will include: * Complete blood count and reticulocyte count; in active G6PD deficiency, Heinz body, Heinz bodies 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 language, Greek ''erythros'' for "red" and ''k ...

red blood cell
s on a 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 "Coombs test, direct antiglobulin test" (Coombs' test) – this should be negative, as
hemolysis Hemolysis or haemolysis (), also known by several other names, is the rupturing (lysis Lysis ( ; Greek#REDIRECT Greek Greek may refer to: Greece Anything of, from, or related to Greece Greece ( el, Ελλάδα, , ), officially the ...

hemolysis
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", 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 Nicotinamide adenine dinucleotide phosphate, 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 a 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 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 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 deficiency, 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 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 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 Creatinine ( or ; from el, κρέας, kreas, flesh) is a ...
. 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 medication used to reduce pain, fever, or inflammation. Specific inflammatory conditions which aspirin is used to treat include Kawasaki disease, pericarditis, and rheumatic fever. Aspirin ...

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.


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 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).


Epidemiology

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. African, Middle Eastern and South Asian people are affected the most, including those who have these ancestries. A side effect of this disease is that it confers protection against malaria, in particular the form of malaria caused by ''
Plasmodium falciparum ''Plasmodium falciparum'' is a unicellular A unicellular organism, also known as a single-celled organism, is an organism In biology, an organism () is any organic, life, living system that functions as an individual entity. All org ...

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.


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 Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms Signs and symptoms are the observed or detectable signs, and experi ...

primaquine
. The discovery of G6PD deficiency relied heavily upon the testing of prisoner volunteers at Illinois State Penitentiary, 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 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 protozoa Protozoa (singular protozoon or protozoan, plural protozoa or protozoans) is an informal term for a group of Unicellular organism, single-celled eukaryotes, either free-living or Parasitism, parasitic, that f ...
'' hypnozoites. Numerous cases of hemolytic anemia were observed in US soldiers of North African and Mediterranean descent. After studying the mechanism through Chromium, 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 world, 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 Pythagoreanism, Pythagoreans 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 Wikipedia medicine articles ready to translate