GLUCOSE -6- PHOSPHATE DEHYDROGENASE DEFICIENCY

MembersLLANES, Theresa Dianne *LOCANDO, Edmarie *LLEMOS, John Zandro *LLANES, Christian DarwinLISING, JeruLIMPALAN, Melanie

GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY

“a hereditary disease characterized by abnormally

low levels of glucose-6-phosphate dehydrogenase

causing hemolytic anemia due to inability to detoxify oxidizing

agents”

WHAT IS GLUCOSE-6-PHOSPHATE DEHYDROGENASE?

• It is an enzyme in the pentose phosphate pathway.

• It converts glucose-6-phosphate into 6-phosphoglucono-δ-lactone

• It is the rate-limiting enzyme of this metabolic pathway.

PENTOSE PHOSPHATE PATHWAY(HMP SHUNT)

• a process that generates NADPH and PENTOSES.

• an alternative to glycolysis • takes place in the cytosol• two distinct PHASES : an oxidative phase, in

which NADPH is generated, and a non-oxidative phase involving synthesis of 5-carbon sugars.

G6PD/NADPH PATHWAY IN RED BLOOD CELLS (ERYTHROCYTES)

• The G6PD/NADPH pathway via HMP shunt is the only source of reduced glutathione in red blood cells.

• HMP shunt supplies reducing energy by maintaining the level of the co-enzyme nicotinamide adenine dinucleotide phosphate(NADPH). NADPH prevents oxidative stress by reducing glutathione via glutathione reductase, which converts reactive H2O2 into H2O by glutathione peroxidase.

• Any defect in the production of NADPH could have profound effects on erythrocyte survival.

FIVE CLASSES OF G6PD

EPIDEMIOLOGY• most common human enzyme

defect, affecting more than 400M people worldwide

• highest prevelance in tropical Africa, Middle East, South Asia and parts of the Mediterranean

CLASSIFICATION• I-Very Severe deficiency (<2% activity) with chronic

(nonspherocytic) hemolytic anemia • II-Severe deficiency (<10% activity), with intermittent

hemolysis • III-Mild deficiency (10-60% activity), hemolysis with

stressors only • IV-Non-deficient variant, no clinical consequence • V-Increased enzyme activity, no clinical consequence

Summary

• located on the long (q) arm of the X chromosome at position 28

• Generally in males• Females can also be affected provided

both X gene is variant

GENETICS• X-linked recessive disorder• due to more than 400 different missense, point

mutations in G6PD gene, present on long arm of X chromosome

EXAMPLES:• G6PD-A(+): Asparagine→Aspartic acid, Class IV• G6PD-A(-): Valine→Methionine,

Asparagine→Aspartic acid, Class III• G6PD-Mediterran: Serine→Phenylalanine, Class II• G6PD-Cosenza: Arginine→Proline, Class II

SIGNS AND SYMPTOMS• nonimmune hemolytic anemia in

response to environmental triggers• Prolonged neonatal jaundice,

possibly leading to kernicterus• In severe cases, acute renal failure

INFECTION:• Inflammatory response to infection results in

generation of free radicals in macrophages, which diffuse into red cells causing oxidative damage.

FAVISM: (Italian: fava=broad beans)• Definition: “haemolytic response to the

consumption of broad beans”. • All individuals with favism show G6PD deficiency.

However, not all individuals with G6PD deficiency show favism.

• Broad beans contain high levels of vicine, divicine, convicine and isouramil, all of which are oxidants.

JAUNDICE: resulting from impaired hepatic catabolism of heme or increased production of bilirubin

ACUTE RENAL FAILURE: • due to red cells disintegration in the

circulation, causing hemoglobin excretion directly by the kidneys.

HEINZ BODIES: • are inclusions within red blood cells

composed of denatured hemoglobin. • Oxidation of reduced sulfhydryl groups of

proteins including hemoglobin in red cells causes their denaturation into insoluble masses attached to red cell membrane.

G6PD DEFICIENCY & MALARIA• A side effect of G6PD deficiency is that it

confers protection against malaria, in particular the form of malaria caused by Plasmodium falciparum, the most deadly form of malaria.

• Basis for this resistance may be a weakening of the red cell membrane (the erythrocyte is the host cell for the parasite) such that it cannot sustain the parasitic life cycle long enough for productive growth.

DIAGNOSIS• Complete blood count and reticulocyte count; Heinz

bodies 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.• Beutler test, also known as the fluorescent spot test,

is a screening test used to identify enzyme defects. It 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 i.e. G6PD deficiency present.

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

• Dialysis in acute renal failure • 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.

4. Explain the role of glutathione in the development of hemolytic anemia in

G6PD deficiency.

5. Enumerate drugs that an precipitate hemolytic anemia among patients with

G6PD deficiency.

Glutathione

helps maintain the reduced states of sulfhydryl groups in proteins, including hemoglobin

removes H2O2 via glutathione peroxidase

Accumulation of H202

Decrease RBC lifespan

hemolysis

Commonly used drugs that produce hemolytic anemia in patients with G6PD deficiency

ENVIRONMENTAL TRIGGERSFactors causing Oxidative Stress precipitate clinical

manifestations of G6PD Deficiency. OXIDANT DRUGS:• Antibiotics: Sulfonamides (such as sulfanilamide,

sulfamethoxazole and mafenide), a few non-sulfa antibiotics (nalidixic acid, nitrofurantoin, isoniazid, furazolidone and chloramphenicol)

• Antimalarials: primaquine, pamaquine and chloroquine• Antipyretics: aspirin, phenazopyridine and acetanilide• Henna has been known to cause haemolytic crisis in

G6PD-deficient infants.

Why is it that G6PD deficiency have lesser tendency to contract malaria?

A reduction in the amount of functional glucose-6-dehydrogenase appears to make it more difficult for this parasite to invade red blood cells.

The P. Falciparum parasite invades the G6PD deficient cell, but intracellular development is impaired.

What complications of G6PD deficiency make DNA analysis best identification of carriers and patient diagnosis?

• G6PD enzyme testing is primarily performed when an individual has signs and symptoms associated with hemolytic anemia and jaundice.