Transcript G6PD deficiency

DR. OSAMA SULTAN
15 SEPTEMBER 2014
 Otto Heinrich Warburg
 1883 - 1970
 German biochemists
 Nobel price 1931 for the
discovery of G6PD enzyme.
Ernest Beutler
(1928 – 2008)
Epidemiology
 G6PD deficiency is the most prevalent red cell
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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
 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 G6PDdeficient 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%.
G6PD GENE AND ENZYME
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
 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
 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.
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 !!
 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.
 Dapsone
 Methylene blue
 Toluidine blue
 Phenazopyridine
 Primaaquine
 Rasburicase
 Nitrofurantion
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: ß-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.
 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
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.
 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.
Broad beans
Kidney red
beans
Alfaalfa sprouts
Astragalus
Fenugreek
Carob
(chocolate substitute)
Liquorice
Tamarind
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.
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.
 If not treated, may lead to kernicterus (over
30%)and mental retardation and even death.
Laboratory Manifestations
 Qualitative test
 Fluorescent spot test
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Simple
Inexpensive
NADPH production is detected by virtue of its fluorscent
under ultraviolet light
G6P and NADP+ are added to a hemolysate of the patient’s
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.
 Quantitative spectrophotometric analysis
 Molecular diagnostic testing
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
 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.
THANK YOU ALL