Otto Heinrich Warburg 1883 - 1970 German biochemists Nobel
price 1931 for the discovery of G6PD enzyme.
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Ernest Beutler (1928 2008)
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Epidemiology G6PD deficiency is the most prevalent red cell
enzymes deficiency in the world. 350 400 Million people are
affected worldwide ( prevalence about 5 10%) Coincides with the
geographic distribution of endemic malaria. The highest prevalence
is in Sub-Saharan Africa, followed by middle East, Mediterranean
Europe, and Southeast Asia X-linked recessive inheritance
pattern
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Polymorphic variants od G6PD confer a survival benefit in
malaria-endemic region. Mild G6PD variant have protection against
severe Plasmodium falciparum malaria ( 58% risk reduction in male
hemizygotes, and 46% reduction in female heterozygotes).
Explanation :?? Increased phagocytosis of G6PD-deficient
erythrocytes containing the early ring-stage parasites. the level
of reduced glutathione was lower in the G6PD- deficient cells
compared with normal red cells, leading to membrane damage of
deficient cells containing parasites that may be preferentially
targeted for destruction. G6PD deficiency prevalence among HIV
patients about 6.8%.
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G6PD GENE AND ENZYME
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G6PD variants genotypes/Isoenzymes G6PD B+ : wild type, whites
> blacks G6PD A+ : blacks > whites G6PD A- : blacks with mild
deficiency G6PD Med : whites Mediterranean, Kurdish, severe def.
G6PD Canton : Thailand, Vietnam, Taiwan WHO variants
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Most people with G6PD deficiency have no symptoms and are not
anemic. In fact, the majority of affected individuals live out
their lives unaware of their status. The disease is generally
manifest when the red cells undergoes oxidative stress triggered
by: Certain drugs Infections Ingestion of fava beans Medical
conditions such as DKA, liver disease, renal disease
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G6PD deficiency usually presents as: drug-induced acute
hemolytic episode Infection-induced acute hemolytic episode Favism
Neonatal jaundice Congenital non-spherocytic hemolytic anemia
(CNSHA) G6PD deficiency does not seem to affect life expectancy,
quality of life, or the activity of affected individuals.
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Drug-induced Acute hemolytic episode Primaquine was the first
drug encountered in causing acute hemolysis. It is difficult to
establish that drugs is directly related to triggering this type of
hemolytic episode because: Some drugs are safe for individuals but
not for all Coexistence of another trigger e.g. infection,
diabetes, hemoglobinopathies, etc. Some patients take more than one
drugs Self-limiting process so it may pass unnoticed !!
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The symptoms start after ingesting the offending drug by 2 to 4
days. Fatigue, jaundice, pallor, abdominal or back pain, and dark
urine. Self-limiting, but may be prolonged in severe variants, with
an average of 7 1o days after onset of hemolysis. There are 7 known
drugs that cause such hemolysis according to EBM, but the list is
evolving.
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Dapsone Methylene blue Toluidine blue Phenazopyridine
Primaaquine Rasburicase Nitrofurantion
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Infection-induced Acute Hemolytic Episode The most common
trigger of hemolysis Occurs after 1-2 days from onset of febrile
illness. commonly associated with pneumonia or typhoid fever.
Organisms can be: Bacterial: -hemolytic sterptococci, E.coli,
Salmonella Richettial infections Viral: hepatitis A,B; CMV, EBV,
influenza A The severity of haemolysis can be aff ected by many
factors, including concomitant drug administration, liver function,
and age.
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Acute renal failure may be a serious complication after viral
infection in adult secondary to Acute tubular necrosis due to renal
ischemia Tubular obstruction by hemoglobin casts
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Favism Second most common trigger of hemolysis 5 - 25% in
patients Seen in severe G6PD variants Within 5 - 48 hrs from eating
or inhaling fava beans More in children and breast-fed babies More
with fresh fava beans; but dried and freezed ones can do. Also
peanuts can trigger favism !! Depends on amount, type, mode of
cooking.
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Divicine, isouramil, and convicine, which are thought to be the
toxic constituents ( about 2% of total weight ) of fava beans,
increase the activity of the hexose monophosphate shunt, promoting
hemolysis in G6PD-deficient patients.
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Broad beans Kidney red beans
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Alfaalfa sprouts Astragalus Fenugreek
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Carob (chocolate substitute) Liquorice Tamarind
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Congenital Non-spherocytis Hemolytic Anemia(CNSHA) Seen in
class I G6PD variant Very rare, sporadic Chronic hemolysis
Independent mutations clustering in exons 10 and 11. Infants
present with severe neonatal jaundice, or discovered later when
present with mild anemia that that exacerbated by oxidant
stress.
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Neonatal Jaundice Seen in neonate with severe G6PD variants
Hyperbilirubinemia is likely secondary to impairment of bilirubin
conjugation and clearance by the liver leading to indirect
hyperbilirubinemia. 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. UDPGT-1 is the enzyme affected in Gilbert disease.
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If not treated, may lead to kernicterus (over 30%)and mental
retardation and even death.
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Laboratory Manifestations Qualitative test Fluorescent spot
test Simple Inexpensive NADPH production is detected by virtue of
its fluorscent under ultraviolet light G6P and NADP+ are added to a
hemolysate of the patients red cells Fluorescence under ultraviolet
light indicates enzyme activity, whereas absence of fluorescence
indicates enzyme deficiency False negative results during acute
hemolytic episode, repeat the test after 4 6 weeks.
Management Straightfarward Stop the offending drug Avoid fava
beans, or any other oxidant stersses Adequate intake of fluids
Treat infection with appropriate antibiotic Blood transfusion if
severe anemia Phototherapy and exchange transfusion for neonatal
jaundice Folic acid supplementation
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G6PD deficiency is the most common red cell enzymopathies world
wide. There are different variants and mutations that determine the
severity of the disease which get periodically updated. Hemolysis
is usually triggered by certain drugs and infections in addition to
some medical conditions and fava bean ingestion. Chinese herbs can
trigger hemolysis in some patients.
