Glucose-6-phosphate dehydrogenase

deficiency

Glucose-6-phosphate dehydrogenase deficiencyis an X-linked recessive hereditary disease characterised

by abnormally low levels of glucose-6-phosphate dehydrogenase (abbreviated G6PD orG6PDH), a
metabolic enzyme involved in the pentose phosphate pathway, especially important in red blood
cell metabolism. Individuals with the disease may exhibit non immune hemolytic anemia in response to a
number of causes, most commonly infection or exposure to certain medications or chemicals. G6PD
deficiency is closely linked tofavism, a disorder characterized by a hemolytic reaction to consumption
of broad beans, with a name derived from the Italian name of the broad bean (fava). The name favism is
sometimes used to refer to the enzyme deficiency as a whole, although this is misleading as not all
people with G6PD deficiency will manifest a physically observable reaction to consumption of broad
beans. G6PD deficiency is the most common human enzyme defect.

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 normal
red cells. Abnormal red blood cell breakdown (hemolysis) in G6PD deficiency can manifest in a number of
ways:

 Prolonged neonatal jaundice, possibly leading to kernicterus (arguably the most serious complication
of G6PD deficiency)

 Hemolytic crises in response to:

1. Illness (especially infections)

2. Certain drugs (see below)

3. Certain foods, most notably broad beans

4. Certain chemicals

5. Diabetic ketoacidosis

 Very severe crises can cause acute renal failure

Favism may be formally defined as a haemolytic response to the consumption of broad beans. All
individuals with favism show G6PD deficiency. However, not all individuals 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 displayed symptoms of favism. Favism 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.

Potentially harmful substances

Many substances are potentially harmful to people with G6PD deficiency, variation in response to these
substance makes individual predictions difficult. Anti malarial drugs that can cause acute haemolysis 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 should
certain analgesics (such as aspirin, phenazopyridine and acetanilide) and a few non-sulfa antibiotics
(nalidixic acid, nitrofurantoin, and furazolidone).

Diagnosis
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 and reticulocyte count; in active G6PD, Heinz bodies can be seen inred
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 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 NADPHproduced
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.

Classification
The World Health Organization classifies G6PD genetic variants into five classes, the first three of which
are deficiency states.

1. Severe deficiency (<10% activity) with chronic (nonspherocytic) hemolytic anemia

2. Severe deficiency (<10% activity), with intermittent hemolysis

3. Mild deficiency (10-60% activity), hemolysis with stressors only

4. Non-deficient variant, no clinical sequelae

5. Increased enzyme activity, no clinical sequelae

Pathophysiology
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 6-
phosphoglucono-δ-lactone and is the rate-limiting enzyme of this metabolic pathway that
supplies reducing energy to cells by maintaining the level 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 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 are oxidants.

When all remaining reduced glutathione is consumed, enzymes and other proteins (including
hemoglobin) are subsequently damaged by the oxidants, leading to electrolyte 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
tobilirubin (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 build up of glucose and thus there is an
increase of advanced glycation endproducts (AGE). The deficiency also causes a reduction of
NADPH which is necessary for the formation of Nitric Oxide (NO). The high prevalence ofdiabetes
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).

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
renal 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.

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.