Diagnosis and Management

of G6PD Deficiency
jENNIfEr E. frANk, MAj, MC, USA, Martin Army Community Hospital, Fort Benning, G
eorgia
Glucose-6-phosphate dehydrogenase deficiency, the most common enzyme deficiency
worldwide,
causes a spectrum of disease including neonatal hyperbilirubinemia, acute hemoly
sis,
and chronic hemolysis. Persons with this condition also may be asymptomatic. Thi
s X-linked
inherited disorder most commonly affects persons of African, Asian, Mediterranea
n, or Middle-
Eastern descent. Approximately 400 million people are affected worldwide. Homozy
gotes and
heterozygotes can be symptomatic, although the disease typically is more severe
in persons
who are homozygous for the deficiency. The conversion of nicotinamide adenine di
nucleotide
phosphate to its reduced form in erythrocytes is the basis of diagnostic testing
for the deficiency.
This usually is done by fluorescent spot test. Different gene mutations cause di
fferent levels of
enzyme deficiency, with classes assigned to various degrees of deficiency and di
sease manifestation.
Because acute hemolysis is caused by exposure to an oxidative stressor in the fo
rm of an
infection, oxidative drug, or fava beans, treatment is geared toward avoidance o
f these and other
stressors. Acute hemolysis is self-limited, but in rare instances it can be seve
re enough to warrant
a blood transfusion. Neonatal hyperbilirubinemia may require treatment with phot
otherapy
or exchange transfusion to prevent kernicterus. The variant that causes chronic
hemolysis is
uncommon because it is related to sporadic gene mutation rather than the more co
mmon inherited
gene mutation. (Am Fam Physician 2005;72:1277-82. Copyright © 2005 American Academ
y
of Family Physicians.)
Pathophysiology

G
G
lucose-6-phosphate dehydrogenase
(G6PD) deficiency increases G6PD catalyzes nicotinamide adenine dinuthe
vulnerability of erythrocytes cleotide phosphate (NADP) to its reduced
to oxidative stress. Clinical pre-form, NADPH, in the pentose phosphate
sentations include acute hemolytic anemia, pathway (Figure 14). NADPH protects c
ells
chronic hemolytic anemia, neonatal hyper-from oxidative damage. Because erythroc
ytes
bilirubinemia, and an absence of clinical do not generate NADPH in any other way
,3
symptoms. The disease is rarely fatal. they are more susceptible than other cell
s to
destruction from oxidative stress. The level of
Epidemiology
G6PD activity in affected erythrocytes generG6PD
deficiency occurs with increased fre-ally is lower than in other cells.5 Normal
red
quency throughout Africa, Asia, the Mediter-blood cells that are not under oxida
tive stress
ranean, and the Middle East. In generally exhibit G6PD activity at approxi

the United States, black males mately 2 percent of total capacity.1 Even with
Glucose-6-phosphate
are most commonly affected, enzyme activity that is substantially reduced,
dehydrogenase
deficiency
with a prevalence of approxi-there may be few or no clinical symptoms.
occurs
with
increased
fre-mately 10 percent. Prevalence A total deficiency of G6PD is incompatible
quency
throughout
Africa,
of the deficiency is correlated with life.6 The G6PD-deficient variants are
Asia,
the
Mediterranean,
with the geographic distribu-grouped into different classes corresponding
and
the
Middle
East.
tion of malaria, which has led with disease severity (Table 11,7).
to the theory that carriers of
G6PD deficiency may incur par-Genetics
tial protection against malarial infection.1-3 The gene mutations affecting enco
ding of
Cases of sporadic gene mutation occur in all G6PD are found on the distal long a
rm of the
populations. X chromosome. More than 400 mutations
.
October 1, 2005 Volume 72, Number 7 www.aafp.org/afp American Family Physician 1
277
G6PD
Deficiency

SORT:KEyREcOMMEnDATiOnS fOR PRAcTicE

Evidence
Clinical recommendation rating References
Patients with G6PD deficiency should avoid exposure to oxidative C 3
drugs (Table 3) and ingestion of fava beans.
Neonates should be screened for G6PD deficiency when family history, C 23
ethnic or geographic origin, or the timing of the appearance of
neonatal jaundice suggests the possibility of G6PD deficiency.
G6PD can be diagnosed with a quantitative spectrophotometric C 7
analysis or, more commonly, by a rapid fluorescent spot test.
G6PD = glucose-6-phosphate dehydrogenase.
A = consistent, good-quality patient-oriented evidence; B = inconsistent or limi
ted-quality patient-oriented evidence;
C = consensus, disease-oriented evidence, usual practice, expert opinion, or cas
e series. For information
about the SORT evidence rating system, see page 1154 or http://www.aafp.org/afps
ort.xml.
have been identified, most being missense
mutations.6 Most of the variants occur sporadically,
although the G6PD Mediterranean
and the G6PD A variants occur with
increased frequency in certain populations
(Table 23,6,7).
Diagnosis

The diagnosis of G6PD deficiency is made by

a quantitative spectrophotometric analysis
or, more commonly, by a rapid fluorescent
spot test detecting the generation of NADPH
from NADP.7 The test is positive if the blood
spot fails to fluoresce under ultraviolet light.8
In field research, where quick screening of
a large number of patients is needed, other
Pentose
Phosphate
Pathway

Hexokinase G6PD
Glucose 6

6 phospho-
Glucose
phosphate
gluconate
ATP NADP+
NADPH
Glutathione
reductase
GSSG
ADP

GSH
figure
1.
G6PD catalyzes NADP+ to its reduced form, NADPH, in the
pentose phosphate pathway. (G6PD = glucose-6-phosphate dehydrogenase;
ATP = adenosine triphosphate; ADP = adenosine diphosphate;
NADP+ = nicotinamide adenine dinucleotide phosphate [oxidized
form]; NADPH = reduced NADP; GSSG = oxidized glutathione; GSH =
reduced glutathione.)
Adapted with permission from Glucose 6 phosphate dehydrogenase deficiency. Acces
sed
online July 20, 2005, at: http://www.malariasite.com/malaria/g6pd.htm.
tests have been used; however, they require
definitive testing to confirm an abnormal
result.9,10 Tests based on polymerase chain
reaction detect specific mutations and are
used for population screening, family studies,
or prenatal diagnosis.6
In patients with acute hemolysis, testing
for G6PD deficiency may be falsely negative
because older erythrocytes with a higher
enzyme deficiency have been hemolyzed.
Young erythrocytes and reticulocytes have
normal or near-normal enzyme activity.
female heterozygotes may be hard to diagnose
because of X-chromosome mosaicism
leading to a partial deficiency that will not be
detected reliably with screening tests.7,11,12
G6PD deficiency is one of a group of congenital
hemolytic anemias, and its diagnosis
should be considered in children with a
family history of jaundice, anemia, splenomegaly,
or cholelithiasis, especially in those
of Mediterranean or African ancestry.13
Testing should be considered in children
and adults (especially males of African,
Mediterranean, or Asian descent) with an
acute hemolytic reaction caused by infection,
exposure to a known oxidative drug, or
ingestion of fava beans.
Although rare, G6PD deficiency should
be considered as a cause of any chronic
nonspherocytic hemolytic anemia across all
population groups.
Newborn screening for G6PD deficiency
is not performed routinely in the United
States, although it is done in countries with
high disease prevalence. The World Health
Organization recommends screening all
newborns in populations with a prevalence
of 3 to 5 percent or more in males.3
.
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American Family Physician www.aafp.org/afp Volume 72, Number 7 October 1, 2005
TAble 1
classes
of
G6PD
Enzyme
Variants
G6PD
Deficiency
Class
Level of
deficiency Enzyme activity Prevalence
I
II
III
IV
V
Severe
Severe
Moderate
Mild to none
None
Chronic nonspherocytic hemolytic
anemia in the presence of normal
erythrocyte function
Less than 10 percent of normal
10 to 60 percent of normal
60 to 150 percent of normal
Greater than 150 percent of normal
Uncommon; occurs across
populations
Varies; more common in Asian
and Mediterranean populations
10 percent of black males in the
United States
Rare
Rare
G6PD = glucose-6-phosphate dehydrogenase.
Information from references 1 and 7.
neonatal
Hyperbilirubinemia

The prevalence of neonatal hyperbilirubinemia

is twice that of the general population14
in males who carry the defective gene and
in homozygous females. It rarely occurs in
heterozygous females.15,16
The mechanism by which G6PD deficiency
causes neonatal hyperbilirubinemia is not
completely understood. Although hemolysis
may be observed in neonates who have
G6PD deficiency and are jaundiced,17 other
mechanisms appear to play a more important
role in the development of hyperbilirubinemia.
6,18,19 Hyperbilirubinemia is likely
secondary to impairment of bilirubin conjugation
and clearance by the liver leading to
indirect hyperbilirubinemia.6,20 Infants with
G6PD deficiency and a mutation of uridine
diphosphoglucuronate glucuronosyltransferase-
1 gene promoter (UDPGT-1) are particularly
susceptible to hyperbilirubinemia
secondary to decreased liver clearance of
bilirubin.21 UDPGT-1 is the enzyme affected
in Gilbert disease.
G6PD deficiency should be considered
in neonates who develop hyperbilirubinemia
within the first 24 hours of life, a history
of jaundice in a sibling, bilirubin levels
greater than the 95th percentile, and in Asian
males.22,23
G6PD deficiency can lead to an increased
risk and earlier onset of hyperbilirubinemia,
24,25 which may require phototherapy or
exchange transfusion.6,25 In certain populations,
hyperbilirubinemia secondary to
G6PD deficiency results in an increased
rate of kernicterus and death,26,27 whereas
in other populations this has not been
observed.18 This may reflect genetic mutations
specific to different ethnic groups.18,19
Acute
Hemolysis

Acute hemolysis is caused by infection, ingestion

of fava beans, or exposure to an oxidative
drug.3 Medications that should be avoided in
patients with G6PD deficiency are listed in
Table 3,6 and drugs that can be used safely in
these patients are listed in Table 4.6 Hemolysis
occurs after exposure to the stressor but does
not continue despite continued infection or
ingestion. This is thought to be a result of
older erythrocytes having the greatest enzyme
deficiency and undergoing hemolysis first.
Once the population of deficient erythrocytes
has been hemolyzed, younger erythrocytes
TAble 2
comparison
of
the
Two
Most
common
Variants
of
G6PD
Deficiency
G6PD Mediterranean G6PD A
World Health Class II Class III
Organization class
Populations affected Italian, Grecian, Spanish, Arabic, African
Jewish (Kurdish) descent descent
Neonatal Yes, may be more severe Yes
hyperbilirubinemia
Favism More common Less common
Hemolysis with Yes Yes
oxidative drugs
G6PD = glucose-6-phosphate dehydrogenase.
Information from references 3, 6, and 7.
.
October 1, 2005 Volume 72, Number 7 www.aafp.org/afp American Family Physician 1
279
G6PD
Deficiency

TAble 3
Medications
That
Should
Be
Avoided
By
Persons
with
G6PD
Deficiency*

Drug name Use

Dapsone Antimicrobial for treatment of leprosy
Flutamide (eulexin) Antiandrogen for treatment of prostate cancer
Mafenide cream (Sulfamylon) Topical antimicrobial
Methylene blue (Urolene Blue) Antidote for drug-induced methemoglobinemia
Nalidixic acid (NegGram) Antibiotic used primarily for urinary tract infections
Nitrofurantoin (Macrodantin) Antibiotic used primarily for urinary tract infecti
ons
Phenazopyridine (Pyridium) Analgesic for treatment of dysuria
Primaquine Antimalaria agent
Rasburicase (elitek) Adjunct to antineoplastic agents
Sulfacetamide (Klaron) Antibiotic (ophthalmic and topical preparations)
Sulfamethoxazole (Gantanol) Antibiotic used in combination preparations (i.e., t
rimethoprim

sulfamethoxazole [TMP-SMX; Bactrim, Septra])

Sulfanilamide (AVC) Antifungal agent for treatment of vulvovaginal Candida albic
ans
infection
G6PD = glucose-6-phosphate dehydrogenase.
* Classes I, II, and III.
Information from reference 6.

and reticulocytes that typically have higher

levels of enzyme activity are able to sustain
the oxidative damage without hemolysis.7
Clinically, acute hemolysis can cause back or
abdominal pain and jaundice secondary to
a rise in unconjugated bilirubin (Table 521).
jaundice, in the setting of normal liver function,
typically does not occur until greater
than 50 percent of the erythrocytes have been
hemolyzed.21
Drugs that cause hemolysis in G6PDdeficient
persons inflict oxidative damage
to erythrocytes leading to erythrocyte
destruction. Hemolysis typically occurs
24 to 72 hours after ingestion, with resolution
within four to seven days.21 Oxidative
drugs ingested by a woman who is breast-
feeding may be transmitted in breast milk
and can cause acute hemolysis in a G6PDdeficient
child.16,28
TAble 4
Drugs
That
can
Be
Administered
Safely
in
Therapeutic
Doses
to
Patients
with
G6PD
Deficiency*

The rightsholder did not

grant rights to reproduce
this item in electronic
media. For the missing
item, see the original print
version of this publication.
The
Author

JeNNIFeR e. FRANK, MAJ, MC, USA, is a residency staff member in the

Department of Family Medicine at Martin Army Community Hospital in Fort
Benning, Ga. She received her medical degree from Boston University School of
Medicine and completed a family practice residency at Dewitt Army Community
Hospital in Fort Belvoir, Va.
Address correspondence to Jennifer E. Frank, MAJ, MC, USA, Department of
Family Medicine, Martin Army Community Hospital, 7950 Martin Loop, Fort
Benning, GA 31905 (e-mail: Jennifer.Frank.@se.amedd.army.mil). Reprints are
not available from the author.
.
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American Family Physician www.aafp.org/afp Volume 72, Number 7 October 1, 2005
G6PD
Deficiency

TAble 5
Symptoms
and
Laboratory
Evaluation
in
Patients
with
G6PD
and
Acute
Hemolysis

Findings in patients with G6PD deficiency

Symptoms Laboratory evaluation and associated acute hemolysis
Back pain Complete blood count Mild to severe anemia
Abdominal pain Reticulocyte count Increases four to seven days after hemolysis
Jaundice Peripheral blood smear Heinz bodies
Transient splenomegaly Haptoglobin Decreased
Hemoglobinuria Liver function tests elevated indirect bilirubin
Scleral icterus Coombs test Negative
G6PD = glucose-6-phosphate dehydrogenase.
Information from reference 21.
TAble 6
Synonyms
for
fava
Beans

Bell beans Horse beans

Broad beans Pigeon beans
english dwarf beans Silkworm beans
Fever beans Tick beans
Haba beans
Although persons who experience hemolysis
after the ingestion of fava beans can be
presumed to have G6PD deficiency, not all
of them will exhibit hemolysis.6,7 favism is
most common in persons with G6PD class II
variants, but rarely it can occur in patients
with the G6PD A variant.5 fava beans
(Table 6) are presumed to cause oxidative
damage by an unknown component, possibly
vicine, convicine, or isouramil.6,7
Infection is the most common cause of
acute hemolysis in G6PD-deficient persons,6
although the exact mechanism by which this
occurs is unknown. Leukocytes may release
oxidants during phagocytosis that cause oxidative
stress to the erythrocytes; however,
this explanation alone would not account
for the variety of infections associated with
hemolysis in G6PD-deficient persons. The
most common infectious agents causing
hemolysis include Salmonella, Escherichia
coli, beta-hemolytic streptococci, rickettsial
infections, viral hepatitis, and influenza A.
A peripheral smear taken during an acute
hemolytic reaction in a G6PD-deficient person
may demonstrate Heinz bodies, although
this rarely is seen in clinical practice.7
chronic
Hemolysis

In chronic nonspherocytic hemolytic anemia,

which usually is caused by a sporadic gene
mutation, hemolysis occurs during normal
erythrocyte metabolism.5,6 The severity of the
hemolysis varies, causing mild hemolysis to
transfusion-dependent anemia. Exposure to
oxidative stress can cause acute hemolysis in
these persons.
Other
clinical
considerations

G6PD-deficient persons are predisposed to

the development of sepsis and complications
related to sepsis after a severe injury.29
Although research has failed to consistently
show a clinically significant risk to patients
receiving G6PD-deficient donor blood,
blood banks generally do not accept G6PDdeficient
blood donors.30
Treatment

The main treatment for G6PD deficiency is

avoidance of oxidative stressors. rarely, anemia
may be severe enough to warrant a blood
transfusion. Splenectomy generally is not
recommended. folic acid and iron potentially
are useful in hemolysis, although G6PD
deficiency usually is asymptomatic and the
associated hemolysis usually is short-lived.
Antioxidants such as vitamin E and selenium
have no proven benefit for the treatment of
G6PD deficiency.6,31 research is being done
to identify medications that may inhibit oxidative-
induced hemolysis of G6PD-deficient
red blood cells.32
The author thanks Benjamin S. Frank, M.D., Ph.D., for
reviewing the manuscript.
Author disclosure: Nothing to disclose.

.
October 1, 2005 Volume 72, Number 7 www.aafp.org/afp American Family Physician 1
281
G
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REfEREncES

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