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Glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency) also known as fav

ism (after the fava bean) is an X-linked recessive genetic condition that predis
poses to hemolysis (spontaneous destruction of red blood cells) and resultant ja
undice in response to a number of triggers, such as certain foods, illness, or m
edication. It is particularly common in people of Mediterranean and African orig
in. The condition is characterized by abnormally low levels of glucose-6-phospha
te dehydrogenase, an enzyme involved in the pentose phosphate pathway that is es
pecially important in the red blood cell. G6PD deficiency is the most common hum
an enzyme defect.[1] There is no specific treatment, other than avoiding known t
Carriers of the G6PD allele appear to be protected to some extent against malari
a, and in some cases dominant males have shown complete immunity to the disease.
This accounts for the persistence of the allele in certain populations in that
it confers a selective advantage.[2]
1 Classification
2 Signs and symptoms
3 Cause
3.1 Drug and Environmental triggers
3.2 Genetics
4 Pathophysiology
5 Diagnosis
6 Treatment
7 Epidemiology
8 Prognosis
9 History
10 References
11 External links
The World Health Organization classifies G6PD genetic variants into five classes
, the first three of which are deficiency states.[3]
Class I: Severe deficiency (<10% activity) with chronic (nonspherocytic) hemolyt
ic anemia
Class II: Severe deficiency (<10% activity), with intermittent hemolysis
Class III: Mild deficiency (10-60% activity), hemolysis with stressors only
Class IV: Non-deficient variant, no clinical sequelae
Class V: Increased enzyme activity, no clinical sequelae
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 creat
es a population of G6PD-deficient red blood cells coexisting with normal red cel
ls. A typical female with one affected X chromosome will show the deficiency in
approximately half of her red blood cells. However, in rare cases, including dou
ble X deficiency, the ratio can be much more than half, making the individual al
most as sensitive as a male.
Abnormal red blood cell breakdown (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
Certain chemicals
Diabetic ketoacidosis
Very severe crises can cause acute renal failure
Favism may be formally defined as a haemolytic response to the consumption of br
oad beans. All individuals with favism show G6PD deficiency. However, not all in

dividuals with G6PD deficiency show favism. For example, in a small study of 757
Saudi men, more than 42% showed a variant of G6PD deficiency, but none displaye
d symptoms of favism.[4] Favism is known to be more prevalent in infants and chi
ldren, and G6PD genetic variant can influence chemical sensitivity.[5] Other tha
n this, the specifics of the chemical relationship between favism and G6PD are n
ot well understood.
6-phosphogluconate dehydrogenase (6PGD) deficiency has similar symptoms and is o
ften mistaken for G6PD deficiency, as the affected enzyme is within the same pat
hway, however these diseases are not linked and can be found within the same pat
Drug and Environmental triggers
Many substances are potentially harmful to people with G6PD deficiency. Variatio
n in response to these substances makes individual predictions difficult. Antima
larial drugs that can cause acute hemolysis in people with G6PD deficiency inclu
de primaquine, pamaquine, and chloroquine. There is evidence that other antimala
rials may also exacerbate G6PD deficiency, but only at higher doses. Sulfonamide
s (such as sulfanilamide, sulfamethoxazole, and mafenide), thiazolesulfone, meth
ylene blue, and naphthalene should also be avoided by people with G6PD deficienc
y as they antagonize folate synthesis, as should certain analgesics (such as asp
irin, phenazopyridine, and acetanilide) and a few non-sulfa antibiotics (nalidix
ic acid, nitrofurantoin, isoniazid, dapsone, and furazolidone).[1][6][7] Henna h
as been known to cause haemolytic crisis in G6PD-deficient infants.[8]
Two variants (G6PD A- and G6PD Mediterranean) are the most common in human popul
ations. G6PD A- has an occurrence of 10% of American blacks while G6PD Mediterra
nean is prevalent in the Middle East. The known distribution of the disease is l
argely limited to people of Mediterranean origins (Spaniards, Italians, Greeks,
Armenians, and Jews).[9] These variants are believed to stem from a protective e
ffect against Plasmodium falciparum and Plasmodium vivax malaria.[10]
All mutations that cause G6PD deficiency are found on the long arm of the X chro
mosome, on band Xq28. The G6PD gene spans some 18.5 kilobases.[6] The following
variants and mutations are well-known and described:
Table 1. Descriptive mutations and variants
Variants or mutations Gene
Short name
Subtype Position
Structure change
Function change
Gd-A(+) G6PD A +305900.0001
Polymorphism nucleotide A?G
(Exon 5)
Asparagine?Aspartic acid (ASN126ASP)
No enzyme defect (variant)
Gd-A(-) G6PD A +305900.0002
Substitution nucleotide G?A
(Exon 5)
Valine?Methionine (VAL68MET)
Asparagine?Aspartic acid (ASN126ASP)
(Exon 6)

Gd-Med G6PD B +305900.0006

Substitution nucleotide C?T

Serine?Phenylalanine (SER188PHE)
Class II
G6PD B +305900.0021
Substitution nucleotide
Arginine?Leucine (ARG459LEU)
Class II
Substitution nucleotide
Alanine?Threonine (ALA335THR)

Class II

G6PD B +305900.0059
Substitution nucleotide
Arginine?Proline (ARG459PRO)
G6PD-activity <10%, thus high po
rtion of patients.
Substitution nucleotide
(Exon 6)
Glycine?Serine (GLY163SER)
Class III
Substitution nucleotide
Alanine?Glycine (ALA44GLY)
NADP-binding place affected. Higher stab
ility than other variants.
G6PD A- +305900.0054
Substitution nucleotide

(Exon 5)
Asparagine?Aspartic acid (ASN126ASP)
Valine?Methionine (VAL68MET)
Class III.
Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme in the pentose phosphate p
athway (see image, also known as the HMP shunt pathway). G6PD converts glucose-6
-phosphate into 6-phosphoglucono-d-lactone and is the rate-limiting enzyme of th
is metabolic pathway that supplies reducing energy to cells by maintaining the l
evel of the reduced form of the co-enzyme nicotinamide adenine dinucleotide phos
phate (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 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 subs
tantial risk of damage from oxidizing free radicals except for the protective ef
fect 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 chemica
l exposure to medication and certain foods. Broad beans, e.g., fava beans, conta
in high levels of vicine, divicine, convicine and isouramil, all of which are ox
When all remaining reduced glutathione is consumed, enzymes and other proteins (
including hemoglobin) are subsequently damaged by the oxidants, leading to elect
rolyte imbalance, 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 h
igh concentrations). The red cells rarely disintegrate in the circulation, so he
moglobin 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 deficienc
y also reduces the amount of NADPH, which is required for the formation of nitri
c oxide (NO). The high prevalence of diabetes mellitus type 2 and hypertension i
n Afro-Caribbeans in the West could be directly related to the incidence of G6PD
deficiency in those populations.[11]
Although female carriers can have a mild form of G6PD deficiency (dependent on t
see lyonization), homoz
he degree of inactivation of the unaffected X chromosome
ygous females have been described; in these females there is co-incidence of a r
are immune disorder termed chronic granulomatous disease (CGD).
The diagnosis is generally suspected when patients from certain ethnic groups (s
ee epidemiology) develop anemia, jaundice and symptoms of hemolysis after challe
nges from any of the above causes, especially when there is a positive family hi

Generally, tests will include:
Complete blood count and reticulocyte count; in active G6PD deficiency, Heinz bo
dies can be seen in red blood cells 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 "direct antiglobulin test" (Coombs' test)
this should be negative, as hemolysi
s 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 NADPH produced by G6PD under ultraviolet light. When the blood spot d
oes 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 hemol
ytic episode.
When a macrophage in the spleen identifies a RBC with a Heinz body, it removes t
he precipitate and a small piece of the membrane, leading to characteristic "bit
e cells". However, if a large number of Heinz bodies are produced, as in the cas
e 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 w
ith the other tests.
The most important measure is prevention avoidance of the drugs and foods that c
ause hemolysis. Vaccination against some common pathogens (e.g. hepatitis A and
hepatitis B) may prevent infection-induced attacks.[12]
In the acute phase of hemolysis, blood transfusions might be necessary, or even
dialysis in acute renal failure. Blood transfusion is an important symptomatic m
easure, as the transfused red cells are generally not G6PD deficient and will li
ve a normal lifespan in the recipient's circulation. Those affected should avoid
drugs such as aspirin.
Some patients may benefit from removal of the spleen (splenectomy),[13] as this
is an important site of red cell destruction. Folic acid should be used in any d
isorder featuring a high red cell turnover. Although vitamin E and selenium have
antioxidant properties, their use does not decrease the severity of G6PD defici
G6PD deficiency is the most common human enzyme defect, being present in more th
an 400 million people worldwide.[14] In 2010, it resulted in about 4,000 deaths
globally.[15] African, Middle Eastern and South Asian people are affected the mo
st, including those who have these ancestries.[16] A side effect of this disease
is that it confers protection against malaria,[17] in particular the form of ma
laria caused by Plasmodium falciparum, the most deadly form of malaria. A simila
r relationship exists between malaria and sickle-cell disease. One theory to exp
lain this is that cells infected with the Plasmodium parasite are cleared more r
apidly by the spleen. This phenomenon might give G6PD deficiency carriers an evo
lutionary advantage by increasing their fitness in malarial endemic environments
G6PD-deficient individuals do not appear to acquire any illnesses more frequentl
y than other people, and may have less risk than other people for acquiring isch
emic heart disease and cerebrovascular disease.[18]
In both legend and mythology, Favism has been known since antiquity. The priests
of various Greek-Roman era cults were forbade to eat or even mention beans, and
Pythagoras had a strict rule that to join the society of the Pythagoreans' they
must swear off beans.[19] This ban was supposedly because beans somehow resembl

ed the genitalia, but it is possible that this was a philosophical or scientific

matter, being that the belief was that beans and humans were created from the s
ame material.[20]
The modern understanding of the condition began with the analysis of patients wh
o exhibited sensitivity to primaquine.[21] The discovery of G6PD deficiency reli
ed heavily upon the testing of prisoner volunteers at Illinois State Penitentiar
y, although today such studies cannot be performed. When some prisoners were giv
en the drug primaquine, some developed hemolytic anemia but others did not. Afte
r studying the mechanism through Cr51 testing, it was conclusively shown that th
e hemolytic effect of primaquine was due to an intrinsic defect of erythrocytes.