INTRODUCTION:
Glucose-6-phosphate
dehydrogenase deficiency (G6PD)
is an enzyme which
is essential for
the pentose phosphate pathway
in glucose metabolism it's deficiency (G6PD deficiency) is
also known as favism
after the fava bean (4,14).
Deficiency of gene
which codes for
enzyme is the primary
cause for this condition.
The deficiency is inherited in X-linked recessive manner. Insufficiency
of this enzyme predisposes to hemolysis (spontaneous destruction of red blood
cells)and may result in
jaundice, Hemolyticcrises are
known to occur
in response to illness (especially
infections) (1,15). Certain drugs, certain foods, most notably
favabeans, certain chemicals and
diabetic keto
acidosis, very severe crises can cause acute renal failure(2). Deficiency of glucose-6-phosphate
dehydrogenase (G6PD) is the most common known enzymopathy, and it is estimated
to affect 400 million people worldwide, mainly in tropical regions (11).
HISTORY:
G6PD was
first identified in 1956 by Carson et
al (6). G6PD deficiency was discovered in patients with hemolytic anaemia
who has been treated for malaria with 6-methoxy-8-aminoquinoline drugs(1).The
highest prevalence rates occur
in areas where
malaria is common like tropical Africa
(20% of the
population are affected), the Mediterranean
(4-30% are affected),
tropical and subtropical Asia and
Papua New Guinea.
However, the severity
of the disease
varies among populations with
the milder form
being common in Africans,
while the most
severe form is
found in Mediterranean and
South East Asians(10).
Structure
of G6PD:
The
enzymatically active form
of G6PD is either
a dimer or a
tetramer of a
single protein subunit
of 515 amino
acids with a
molecular mass of 59.26
KDa and contains
tightly bound NADP+.
G6PD is coded by a
gene located on
the long arm
of the human
X-chromosome in the
band Xq28, which is
one of the
best mapped in
the human genome.
NADP appears to
be bound to
the enzyme both as
a structural component
and as one
of the substrates
of the reaction.
Role of G6PD in Pentose Phosphate Pathway:
Glucose-6-phosphatedehydrogenase,
is an enzyme involved
in the pentose phosphate pathway that is especially important in the red blood
cell. 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(3). G6PD
deficiency is the
most common human
enzyme defect. Antimalarial drugs that
can cause acute hemolysis
in people with
G6PD deficiency include
primaquine, pamaquine, chloroquine (4).
Causes:
G6PD
deficiency is an inherited disorder. The gene for it is on the X chromosome.
Females have two X chromosomes. If a
female has the abnormal gene for G6PD on one of her X chromosomes, the other
X chromosome with the normal gene can
make enough G6PD, and she will not have the problem. If the female has two
abnormal genes, she will have a G6PD deficiency. Males have only one X
chromosome, so if they have the abnormal gene, they will have the disorder.
Therefore G6PD deficiency is much more common in males than females. The abnormal gene is most
common in people from Africa, Mediterranean region, and South-East Asia (1,2,6,7).
G6PD Deficiency and Drugs:
When all
remaining reduced glutathione is consumed, enzymes and other proteins
(including hemoglobin) are subsequently damaged by oxidants, leading to
electrolyte imbalance, cross-bonding and protein deposition in the red cell membrane
(12). 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(3). Sulphonamides
(such as sulphanilamide, sulfamethoxazole, and mafenide), thiazolesulfone,
methylene blue, and naphthalene should also be avoided by people with G6PD
deficiency as they antagonise folate synthesis, as do certain analgesics (such as aspirin,
phenazopyridine, and acetanilide) and a few non-sulfa antibiotics (nalidixic
acid, nitrofurantoin, isoniazid, dapsone, and furazolidone).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 are oxidants(4).
Environmental Factors:
Hemolytic anemia
associated with G6PD deficiency
is usually triggered
by bacterial or viral
infections as well
as by certain
drugs. Also, eating fava beans
or inhaling pollen
from fava plants increase
the breakdown of
RBCs in susceptible individuals, thus, leading to
a condition known as
Favism(1,6).
Disorders
Associated with G6PD Deficiency:
Hereditary non Spherocytic Hemolytic
Anaemia:
This
syndrome, first delineated by William Crosby in 1950. It was somewhat of a surprise then, when
Newton and Bass discovered that a
4-year-old Italian boy with this syndrome was G6PD deficient (1). This is observed in people with
chronichemolytic anaemia and oxidative stress, even if unstable conditions
occur as a result of insufficient enzyme activity in erythrocytes. Granulocyte
dysfunction is seen in some cases. In such cases, more severe hemolysis is due
to increased susceptibility to infection (6).
Malaria:
There is a strong relationship between malaria and G6PD deficiency
diseases. Two important facts that lies between glucose-6-phosphate
dehydrogenase deficiency and malaria is that antimalarial drugs can cause life
threatening hemolytic anemia in patients with G6PD deficiency and malaria
patients should be screened for their tendency to G6PD deficiency before their
treatment with antimalarial drugs(6,13). Erythrocyte lysis occurs during the Plasmodium life cycle
to enable the release of daughter merozoites. Acute hemolysis can occur in P. falciparum malaria independent of
drug therapy, and appears to be related linearly to the level of parasitemia.
It is unknown if there is an interaction between disease-related and G6PD
deficiency related hemolysis (4).
Jaundice:
Severe jaundice leading to kernicterus or death in the newborn is
the most devastating consequence of glucose-6-phosphate dehydrogenase
deficiency. Although the bilirubin load in G6PD deficient neonates is
increased, hyperbilirubinemia develops in only a fraction, and the presence or
absence of jaundice is not related to the severity of hemolysis (8). Jaundice
in infants with G6PD enzyme deficiency could be mild or severe to cause kernicterus, a spastic
type of cerebral palsy, and may even
cause death. In addition, infants with
G6PD deficiency, hyperbilirubinemia is more
remarkable than anemia. It facilitates this because of the inadequate physiological conjugation in liver
in the neonatal period. G6PD mediterrian, G6PD Canton variants are known as
types that cause kernicterus and hyperbilirubinemia (6).
Henna:
Henna is
an annual flowering plant belonging to the species Lawsonia inermis used in dying hair and remedy (Ali and Qaiser,
2001). It was also reported to cause severe anemia in G6PD deficient infants by
penetrating their thin, fragile skin of infants and causing oxidative hemolysis
of their red blood cells. In populations that have G6PD deficient individuals,
males will be affected by henna twice more as compared to females. The
populations that have this trait are mostly in the Middle East and North
Africa. This may be why men rarely have henna, or have hennain small
applications, while women have extensive and frequent henna in those regional
traditions (Zinkham WH and Oski FA, 1996) (15).
Medications that
Should be Avoided
by Persons with G6PD
Deficiency:
Dapsone
Flutamide (eulexin), Mafenide
cream (Sulfamylon), Methylene blue (Urolene
Blue), Nalidixic acid
(NegGram), Nitrofurantoin (Macrodantin), Phenazopyridine (Pyridium),
Primaquine Rasburicase Sulfacetamide
(Klaron), Sulfamethoxazole (Gantanol),
Sulfanilamide (AVC) (14).
Diagnosis:
The disease
is diagnosed clinically
by hematological tests
as well as estimation
of the enzyme
activity by biochemical
method, with the techniques of DNA analysis
it is now
emerging that several
variants once considered unique
are instead the
phenotypical expression of
the same mutated gene
and that new
mutations produce indistinguishable mutant enzymes (15).
Management:
Some,
but not
all, newborns with G6PD
deficiency are recognized because
of jaundice occurring soon after
birth. Among many affected
males, the condition remains asymptomatic
and the signs
and symptoms of the disease may
appear at any
age only after the
intake of fava
beans or certain
drugs. Hemolysis due to
G6PD deficiency is
bestprevented by excluding
fava beans from
the diet as well
as avoiding certain
antibiotics (e.g., Sulfonamides, Nitrofurantoin, Dapsone),
antimalarial drugs (e.g.,
Quinine, Chloroquine), anticancer
drugsand other drugs
such as Aspirin
and Hydrazine. In severe hemolysis, blood transfusion may be
required (1).
There are
two major differences between jaundice due to G6PD deficiency and jaundice due
to incompatibility of blood groups. First, the presence of jaundice in G6PD
deficiency is very rare immediately after childbirth and usually it begins on the
second or third day. Second, jaundiceand anaemia are more pronounced in blood group
incompatibility. Severe anaemia is very rare in the
absence of the enzyme (1,2,3,6).
G6PD deficiency is
one of a
group of congenital
hemolytic anaemias, and its
diagnosis should be
considered in children
with a family history of jaundice, anaemia,
paleness, splenomegaly, or
cholelithiasis, especially
in those of
Mediterranean or African
ancestry (15).
The main
treatment for G6PD deficiency is avoidance of oxidative stressors. Rarely,
anemia may be severe enough to warrant a blood transfusion. Splenectomy generallyis not recommended.
Folic acidand ironpotentiallyare useful in hemolysis, although G6PD deficiency
usually is asymptomatic and the associatedhemolysis usually is short-lived.
Antioxidants such as vitamin E and selenium have no proven benefit for the
treatment of G6PD deficiency. Research is being done to identify medications
that may inhibit oxidative-induced hemolysis of G6PD-deficient red blood cells
(14).
CONCLUSION:
Hereditary deficiencies in G6PD are widely thought to pertain only
to red blood cell hemolysis, with the most severe outcome being neonatal
kernicterus(3). G6PD deficiency is
the most common enzymopathologic
disorder in humans and it affects 400
million people worldwide. Inpatients with
G6PD deficiency, oxidative
stress cannot be prevented since G6PD enzyme is the
initial catalyst of the pentose phosphate pathway in erythrocytes
that reduces the peroxides to H2O (6). This review has aimed to increase the
awareness of potential risks and prevention among patients.
REFERENCES:
1.
Glucose-6-phosphate
dehydrogenase deficiency: A historical perspective Ernest Beutler. Blood. 1
January 2008 Volume111, Number 1.
2.
The Hemolytic Effect
of primaquine and related compounds: a review, Ernest Beutler, Journal of Haematology,
Blood, February1959 Volume XIV,Number2.
3.
An
embryoprotective role for glucose-6-phosphate dehydrogenase in developmental
oxidative stress and chemical teratogenesis Christopher J. Nicol, Julian
Zielenski, Lap-chee tsui, and Peter G.
4.
Glucose-6-Phosphate
Dehydrogenase Deficiency and Antimalarial Drug Development Ernest Beutler,
Stephan Duparc, Am. J. Trop. Med. Hyg., 77(4), 2007, pp. 779–789
5.
Glucose-6-phosphate
dehydrogenase deficiency promotes endothelial oxidant stress and decreases
endothelial nitric oxide bioavailability Jane A. Leopold, Andre Cap, Anne W. Scribner,
Robert C. Stanton, and Joseph Loscalzo.
6.
Glucose-6-Phosphate
Dehydrogenase Deficiency and Malaria: A
Method to Detect Primaquine-Induced Hemolysis
in vitro Adil M. Allahverdiyev, Malahat Bagirova, Serhat Elcicek, Rabia Cakir Koc, Sezen Canim Ates, Sera Yesilkir Baydar,
Serkan Yaman, Emrah Sefik Abamor and Olga Nehir Oztel
7.
Molecular
Homogeneity of G6PD Deficiency
Nabeel Al Momen,
Sheikha S Al Arrayed, Ahmed Al Alawi A, Bahrain Medical Bulletin,
Vol. 26, No. 4, December 200.
8.
Gilbert syndrome
and glucose-6-phosphate dehydrogenase deficiency: A dose-dependent genetic
interaction crucial to neonatal hyperbilirubinemia (neonatal jaundice hemolysis
bilirubin conjugation UDP-glucuronosyl transferase 1gene interaction) Michael
Kaplan, Paul Renbaum, Ephrat Levy-lahad, Cathy Hammerman, Amnon Lahad, and Ernest
Beutler.
9.
Diabetes causes
inhibition of glucose-6-phosphate dehydrogenase via activation of PKA, which
contributes to oxidative stress in rat kidney cortex Yizhen Xu, Brent W.
Osborne, and Robert C. Stanton. Am J Physiol Renal Physiol 289
10. Glucose-6-phosphate dehydrogenase deficiency among
children attending the Emergency Paediatric Unit of Usmanu Danfodiyo University
Teaching Hospital, Sokoto, Nigeria, International Journal of General
Medicine 2013:6 557–562
11. An improved, simple screening method for detection of
glucose-6-phosphate dehydrogenase deficiency Indah S. Tantular and Fumihiko. Tropical
Medicine and International Health volume 8 no 6 pp 569–574 June 2003,
12. Red cells from glutathione peroxidase-1 defcient mice
have nearly normal defences against exogenous peroxides Robert M. Johnson,
Gerard Goyette Jr, Yaddanapudi
Ravindranath, and Ye-Shih Ho.
13. Methemoglobinemia and Adverse Events in Plasmodium
vivax Malaria Patients Associated
with High Doses of Primaquine Treatment J Aime
Carmona-Fonseca , Gonzalo
Álvarez , and Amanda
Maestre. Grupo Salud Y., Am. J.
Trop. Med. Hyg., 80(2),
2009, pp. 188–193
14. Diagnosis
and Management of
G6PD Deficiency Jennifer E. Frank,
Maj, MC,
USA, Martin Army
Community Hospital, Fort
Benning, Georgia, October 1,
2005, Volume 72, Number
7.
15. Molecular Identification of the Most Prevalent Mutations
in G6PD Genes of Deficient Patients in Sulaimani City, By Nawzad O. Ahmad B.Sc.
in Biology 2004
