Glucose-6-phosphate dehydrogenase deficiency
Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency is an X-linked
recessive hereditary disease featuring nonimmune hemolytic anemia in
response to a number of causes. Its classic association to consumption
of fava beans has led to the alternative name favism.
There are four forms of G6PD:
- Hereditary nonspherocytic hemolytic anemia
- Severe deficiency
- Mild deficiency
- Non-deficient variant
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Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme in the pentose
phosphate pathway (see image), a metabolic pathway that supplies energy
to a number of cells (most notably erythrocytes), and maintains the
level of the co-enzyme nicotinamide adenine dinucleotide phosphate (NADPH).
The NADPH in turn maintains the level of glutathione in these cells that
helps protect the red blood cells against oxidative damage. G6PD
converts glucose-6-phosphate into 6-phosphoglucono-δ-lactone and is the
rate-limiting enzyme of the pentose phosphate pathway.
Patients with G6PD are at risk of hemolytic anemia in states of
oxidative stress. This can be in severe infection, medication and
certain foods. Fava beans contain high levels of vicine, divicine,
convicine and isouramil ? all are oxidants.
In states of oxidative stress, all remaining glutathione is consumed.
Enzymes and other proteins (including hemoglobin) are subsequently
damaged by the oxidants, leading to electrolyte imbalance, membrane
cross-bonding and phagocytosis and splenic sequestration of red blood
cells. The hemoglobin is metabolised to bilirubin (causing jaundice at
high concentrations) or excreted directly by the kidney (causing acute
renal failure in severe cases).
Molecular structure of Glucose-6-phosphate dehydrogenase
Deficiency of G6PD in the alternative pathway causes the build up of
glucose and thus there is an increase of advanced glucosylating end
products (AGE). The deficiency also causes a reduction of NADPH which is
necessary for the formation of Nitric Oxide (NO). The high prevalence of
diabetes mellitus type 2 and hypertension in Blacks in the West could be
directly related to G6PD deficiency (Gaskin R. et al). Some other
epidemiological reports have pointed out, however, that G6PD seems to
decrease the susceptibility to cancer, cardiovascular disease and
Although female carriers can have a mild form of G6PD (dependent on
the degree of inactivation of the unaffected X chromosome), but
homozygous females have been described ; in these females there is
co-incidence of a rare immune disorder termed chronic granulomatous
G6PD is said to be the most common enzyme deficiency disease in the
world. 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 anemia. An explanation is that
cells infected with the Plasmodium parasite are cleared more rapidly by
the spleen. This phenomenon might have give G6PD carriers an
Signs and symptoms
G6PD manifests itself in a number of ways:
- Prolonged neonatal icterus
- Hemolytic crises in response to:
- Certain drugs (see below)
- Certain foods, most notably fava beans
- Illness (severe infections)
- Very severe crises can cause acute renal failure
- Patients are almost exclusively male, due to the X-linked
pattern of inheritance, but female carriers can have a mild form of
Drugs that have been linked to G6PD:
- Primaquine (an antimalarial)
- Sulphonamide antibiotics
- Sulphones (e.g. dapsone, used against leprosy)
- Other sulphur-containing drugs: glibenclamide (an anti-diabetic
- Nitrofurantoin (an antibiotic often used for urinary tract
- Several others
The diagnosis is generally suspected when patients from certain
ethnic groups (see below) develop anemia, jaundice and symptoms of
hemolysis after challenge to any of the above causes, especially when
there is a positive family history.
Generally, tests will include:
- Full blood count and reticulocyte count; in active G6PD, "Heinz
bodies" (aggregates of protein) can be seen in red blood cells on a
- Liver enzymes (to exclude other causes of jaundice);
- Haptoglobin (decreased in hemolysis);
- A "direct antiglobulin test" (Coombs' test) - this should be
negative, as hemolysis in G6PD is not immune-mediated;
- TSH measurement.
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 does not fluoresce, the test is positive; it can be
false-positive in patients who are actively hemolysing. It can therefore
only be done several weeks after a hemolytic episode.
The most important measure is prevention - avoidance of the drugs and
foods that cause hemolysis. Vaccination against some common pathogens
(e.g. hepatitis A) 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.
Some patients 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.