Glucose-6-phosphate dehydrogenase deficiency (G6PDD) is an inborn
error of metabolism that predisposes to red blood cell breakdown.
Most of the time, those who are affected have no symptoms.
Following a specific trigger, symptoms such as yellowish skin, dark
urine, shortness of breath, and feeling tired may develop.
Complications can include anemia and newborn jaundice. Some people
never have symptoms.
It is an
X-linked recessive disorder that results in defective
glucose-6-phosphate dehydrogenase enzyme.
Red blood cell
Red blood cell breakdown
may be triggered by infections, certain medication, stress, or foods
such as fava beans. Depending on the specific mutation the
severity of the condition may vary. Diagnosis is based on symptoms
and supported by blood tests and genetic testing.
Avoiding triggers is important. Treatment of acute episodes may
include medications for infection, stopping the offending medication,
or blood transfusions.
Jaundice in newborns may be treated with
special lights. It is recommended that people be tested for G6PDD
before certain medications, such as primaquine, are taken.
About 400 million people have the condition globally. It is
particularly common in certain parts of Africa, Asia, the
Mediterranean, and the Middle East. Males are affected more often
than females. In 2015 it is believed to have resulted in 33,000
deaths. Carriers of the G6PDD allele may be partially protected
1 Signs and symptoms
4.2 Differential diagnosis
9 Society and culture
11 External links
Signs and symptoms
Most individuals with G6PD deficiency are asymptomatic.
Symptomatic patients are almost exclusively male, due to the X-linked
pattern of inheritance, but female carriers can be clinically affected
due to unfavorable lyonization, where random inactivation of an
X-chromosome in certain cells creates a population of G6PD-deficient
red blood cells coexisting with unaffected red blood cells. A female
with one affected
X chromosome will show the deficiency in
approximately half of her red blood cells. However, in rare cases,
including double X-deficiency, the ratio can be much more than half,
making the individual almost as sensitive as males.
Red blood cell
Red blood cell breakdown (also known as hemolysis) in G6PD deficiency
can manifest in a number of ways, including the following:
Prolonged neonatal jaundice, possibly leading to kernicterus (arguably
the most serious complication of G6PD deficiency)
Hemolytic crises in response to:
Illness (especially infections)
Certain drugs (see below)
Certain foods, most notably broad beans from which the word favism
Very severe crises can cause acute kidney failure
Favism may be formally defined as a hemolytic response to the
consumption of fava beans, also known as broad beans. Important to
note is that all individuals with favism show G6PD deficiency, but 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
Carriers of the underlying mutation do not show any symptoms unless
their red blood cells are exposed to certain triggers, which can be of
three main types:
Foods (fava beans is the hallmark trigger for G6PD mutation carriers),
Medicines and other chemicals such as those derived from quinine (see
Stress from a bacterial or viral infection.
In order to avoid the hemolytic anemia, G6PD carriers have to avoid a
large number of drugs and foods. List of such "triggers" can be
obtained from medical providers.
Many substances are potentially harmful to people with G6PD
deficiency. Variation in response to these substances makes individual
predictions difficult. Antimalarial drugs that can cause acute
hemolysis in people with G6PD deficiency include primaquine,
pamaquine, and chloroquine. There is evidence that other antimalarials
may also exacerbate G6PD deficiency, but only at higher doses.
Sulfonamides (such as sulfanilamide, sulfamethoxazole, and mafenide),
thiazolesulfone, methylene blue, and naphthalene should also be
avoided by people with G6PD deficiency as they antagonize folate
synthesis, as should certain analgesics (such as phenazopyridine and
acetanilide) and a few non-sulfa antibiotics (nalidixic acid,
nitrofurantoin, isoniazid, dapsone, and furazolidone). Henna
has been known to cause hemolytic crisis in G6PD-deficient
Rasburicase is also contraindicated in G6PD deficiency.
High dose intravenous vitamin C has also been known to cause
haemolysis in G6PD deficiency carriers, thus G6PD deficiency
testing is routine before infusion of doses of 25g or more.
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 and
Plasmodium vivax malaria. It is
particularly frequent in the Kurdish Jewish population, wherein
approximately 1 in 2 males have the condition and the same rate of
females are carriers. It is also common in African American, Saudi
Arabian, Sardinian males, some African populations, and Asian
All mutations that cause G6PD deficiency are found on the long arm of
the X chromosome, on band Xq28. The G6PD gene spans some 18.5
kilobases. The following variants and mutations are well-known and
Aspartic acid (ASN126ASP)
No enzyme defect (variant)
Aspartic acid (ASN126ASP)
G6PD-activity <10%, thus high portion of patients.
NADP-binding place affected. Higher stability than other variants.
Substitution nucleotide (several)
Aspartic acid (ASN126ASP)
Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme in the pentose
phosphate pathway (see image, also known as the HMP shunt pathway).
G6PD converts glucose-6-phosphate into
is the rate-limiting enzyme of this metabolic pathway that supplies
reducing energy to cells by maintaining the level of the reduced form
of the co-enzyme nicotinamide adenine dinucleotide phosphate (NADPH).
The NADPH in turn maintains the supply of reduced glutathione in the
cells that is used to mop up free radicals that cause oxidative
The G6PD / NADPH pathway is the only source of reduced glutathione in
red blood cells (erythrocytes). The role of red cells as oxygen
carriers puts them at substantial risk of damage from oxidizing free
radicals except for the protective effect of G6PD/NADPH/glutathione.
People with G6PD deficiency are therefore at risk of hemolytic anemia
in states of oxidative stress.
Oxidative stress can result from
infection and from chemical exposure to medication and certain foods.
Broad beans, e.g., fava beans, contain high levels of vicine,
divicine, convicine and isouramil, all of which create oxidants.
When all remaining reduced glutathione is consumed, enzymes and other
proteins (including hemoglobin) are subsequently damaged by the
oxidants, leading to cross-bonding and protein deposition in the red
cell membranes. Damaged red cells are phagocytosed and sequestered
(taken out of circulation) in the spleen. The hemoglobin is
metabolized to bilirubin (causing jaundice at high concentrations).
The red cells rarely disintegrate in the circulation, so hemoglobin is
rarely excreted directly by the kidney, but this can occur in severe
cases, causing acute renal failure.
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), homozygous females have been
described; in these females there is co-incidence of a rare immune
disorder termed chronic granulomatous disease (CGD).
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.
Generally, tests will include:
Complete blood count
Complete blood count and reticulocyte count; in active G6PD
deficiency, Heinz bodies can be seen in red blood cells on a blood
Liver enzymes (to exclude other causes of jaundice);
Lactate dehydrogenase (elevated in hemolysis and a marker of hemolytic
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 "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
Beutler fluorescent spot test is a rapid and inexpensive test that
visually identifies NADPH produced by G6PD under ultraviolet light.
When the blood spot does not fluoresce, the test is positive; it can
be falsely negative in patients who are actively hemolysing. It can
therefore only be done 2–3 weeks after a hemolytic episode.
When a macrophage in the spleen identifies 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.
World Health Organization
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
Class III: Moderate deficiency (10-60% activity), hemolysis with
Class IV: Non-deficient variant, no clinical sequelae
Class V: Increased enzyme activity, no clinical sequelae
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.
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
In the acute phase of hemolysis, blood transfusions might be
necessary, or even dialysis in acute kidney failure. Blood transfusion
is an important symptomatic measure, as the transfused red cells are
generally not G6PD deficient and will live a normal lifespan in the
recipient's circulation. Those affected should avoid drugs such as
Some patients may benefit from removal of the spleen
(splenectomy), as this is an important site of red cell
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-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.
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, 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.
The modern understanding of the condition began with the analysis of
patients who exhibited sensitivity to 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. 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 had a strict rule that to join the
society of the 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.
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V · T · D
Glucose-6-phosphate dehydrogenase deficiency
G6PD Deficiency Association
Family Practice Notebook/G6PD Deficiency (Favism)
Diseases of red blood cells (D50–69,74, 280–287)
Micro-: Iron-deficiency anemia
Macro-: Megaloblastic anemia
membrane: Hereditary spherocytosis
Southeast Asian ovalocytosis
Hemolytic disease of the newborn
Hereditary: Fanconi anemia
Inborn error of carbohydrate metabolism: monosaccharide metabolism
disorders (E73–E74, 271)
Including glycogen storage diseases (GSD)
Inborn errors of renal tubular transport (Renal glycosuria)
Hexose → glucose
Galactose / galactosemia:
GALT deficiency/GALE deficiency
Glucose ⇄ glycogen
GSD type 0 (glycogen synthase deficiency)
GSD type IV (Andersen's disease, branching enzyme deficiency)
Adult polyglucosan body disease (APBD)
GSD type III (Cori's disease, debranching enzyme deficiency)
GSD type VI (Hers' disease, liver glycogen phosphorylase deficiency)
GSD type V (McArdle's disease, myophosphorylase deficiency)
GSD type IX (phosphorylase kinase deficiency)
GSD type II (Pompe's disease, glucosidase deficiency)
Glucose ⇄ CAC
GSD type VII (Tarui's disease, phosphofructokinase deficiency)
Triosephosphate isomerase deficiency
Pyruvate kinase deficiency
Fructose bisphosphatase deficiency
GSD type I (von Gierke's disease, glucose 6-phosphatase deficiency)
Pentose phosphate pathway
Glucose-6-phosphate dehydrogenase deficiency
6-phosphogluconate dehydrogenase deficiency
Aldolase A deficiency
Chronic granulomatous disease
Chronic granulomatous disease (CYBB)
X-linked severe combined immunodeficiency
Hyper-IgM syndrome type 1
X-linked lymphoproliferative disease
X-linked sideroblastic anemia
Androgen insensitivity syndrome/Spinal and bulbar muscular atrophy
KAL1 Kallmann syndrome
X-linked adrenal hypoplasia congenita
Amino acid: Ornithine transcarbamylase deficiency
Glucose-6-phosphate dehydrogenase deficiency
Pyruvate dehydrogenase deficiency
Danon disease/glycogen storage disease Type IIb
Lipid storage disorder: Fabry's disease
Mucopolysaccharidosis: Hunter syndrome
Purine–pyrimidine metabolism: Lesch–Nyhan syndrome
Mineral: Menkes disease/Occipital horn syndrome
X-linked mental retardation: Coffin–Lowry syndrome
Alpha-thalassemia mental retardation syndrome
X-linked mental retardation syndrome
Eye disorders: Color blindness (red and green, but not blue)
Ocular albinism (1)
Charcot–Marie–Tooth disease (CMTX2-3)
Skin and related tissue
Hypohidrotic ectodermal dysplasia
Hypohidrotic ectodermal dysplasia (EDA)
X-linked endothelial corneal dystrophy
Becker's muscular dystrophy/Duchenne
Centronuclear myopathy (MTM1)
Emery–Dreifuss muscular dystrophy
Emery–Dreifuss muscular dystrophy 1
X-linked nephrogenic diabetes insipidus
AMELX Amelogenesis imperfecta
No primary system
Focal dermal hypoplasia
Fragile X syndrome
Orofaciodigital syndrome 1