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Unit II presentation

Glucose -6-phosphate
dehydrogenase deficiency
Introduction
Most common human enzyme defect
Present in more than 400 million people world
wide
Distribution similar to malaria
X linked ,hereditary genetic defect due to
mutations in the G6PD gene
More than 140 mutations of the G6PD gene
have been identified.
G6PD catalyzes the first reaction in the
Pentose phosphate pathway[PPP]
Producing reduced form of nicotinamide
adenine dinucleotide phosphate[NADPH]
NADPH enables cells to counterbalance
oxidative stress and preserve the reduced
form of glutathione
Red blood cells do not contain mitochondria
PPP is only source of NADPH
Defense against oxidative damage is dependant
on G6PD
Function of G6PD
Through action of G6PD and 6
phosphogluconate dehydrogenase the PPP
provides reducing power in form of NADPH
NADPH serves as an electron donor for
enzymatic reactions essential in biosynthetic
pathways
Its production is crucial to protection of cells
from oxidative stress
G6PD is also necessary to regenerate the
reduced form of glutathione
Glutathione is essential for the reduction of
hydrogen peroxide and oxygen radicals
Also for maintenance of Hg and other RBC
proteins in the reduced state.
Genetics
The inheritance is typically X linked
Males are hemizygous for the G6PD gene
Normal gene expression
G6PD deficient
Females ,who have two copies of the G6PD
gene on each X chromosome
Normal gene expression
Heterozygous
Homozygous[in populations with high
frequency of G6PD]
Heterozygous females are genetic mosaics as
a result of X chromosome inactivation.
The abnormal cells of a heterozygous female
can be as deficient as for G6PD as those of a
G6PD deficient male.
On average heterozygous females have less
severe clinical manifestations than G6PD
deficient males
Epidemiology and malaria
selection
Deficient G6PD alleles are world
Its estimated that at least 400 million people
carry a mutation in the G6PD causing deficincy
Highest prevelance is in Africa,southern
europe,middle east,southeast asia and the
central and southern pacific islands
The worldwide distribution of malaria is
remarkably similar to that of mutated G6PD
alleles.
Ruwende and colleagues noted that
G6PD A-allele is associated with a reduction
in the risk of severe P falciparum,for female
heterozygotes and male hemizygotes
[46% and 58% respectively]
Others have shown that parasite growth is
slowest in G6PD deficient cells.
Intracellular schizogenesis,rather than
invasion is affected in G6PD deficient RBC s
Oxidative injury to parasite
Luzzatto and co-workers showed that RBC s
with normal G6PD activity taken from G6PD
A-heterozygous females
Had 2-80 times more parasite growth than
G6PD deficient RBC s
G6PD deficient RBCs infected with parasites
undergo phagocytosis at an earlier stage
Diagnosis of G6PD deficiency
The definitive diagnosis of G6PD deficiency is
based on the estimation of enzyme activity,by
quantitative spectrophotometric analysis of
the rate of NADPH production from NADP
Several screening test are available
False negative may occur when measuring
enzyme activity during an episode of acute
haemolysis or presence of a high reticulocyte
count
Level of activity higher in young erythrocytes
Clinical manifestation
Fortunately,most individuals are
asymptomatic throughout their life
Generally manifests as acute haemolysis after
oxidative stress
Drugs
Infection
Ingestion of fava beans
Also presents as
neonatal jaundice anaemia
Chronic non-spherocytic haemolytic anaemia
The precise mechanism by which increased
sensitivity to oxidative damage leads to
haemolysis is not fully known.
The sequence of events after an exogenous
trigger factor is present is also unknown
Clinically characterised by
Fatigue,back pain ,anaemia jaundice
Increased unconjugated bilirubin
Reticulocytosis,LDH are markers of the
disorder
Drug induced haemolytic anemia
Clinically detectable haemolysis and jaundice
24-72 hrs of drug dosing.
Dark urine due to haemoglobin is
characteristic
Anaemia worsens until days 7-8
After drug cessation ,Hg begin to recover 8-10
days after
Heinz bodies typical
Infection induced haemolytic
anaemia
Infection is a typical cause of haemolysis
Hepatitis viruses A and B, cytomegaloviruses,
pneumonia and typhoid fever are notable
causes
ARF is a potential complication of viral
hepatitis and concomitant G6PD deficiency
Acute tubular necrosis due to renal failure
Tubular obstruction by Hg casts
Favism
Clinical sequelae of fava bean ingestion
Originally more common in the
mediterranean countries
Presents as acute haemolytic anaemia usually
after24 hrs after the beans are ingested.
Haemoglobinuria is more
Anaemia is generally acute and severe leading
to ARF
Neonatal jaundice
Jaundice 1-4 days of age
Similar to physiological jaundice ,comes later
than ABO incompatibility
More typical and severe in premature infants
Mechanism not fully understood
Haemolysis does not contribute as much as
impaired bilirubin conjugation and clearance
by liver
Congenital non-spherocytic
haemolytic anaemia
Variant of G6PD deficiency causing chronic
haemolysis
Class 1 WHO
Patients typically severe neonatal jaundice,
chronic anaemia worsened by oxidative stress
requiring BT
Also reticulocytosis, gallstones,splenomegally.
management
Most effective is to prevent haemolysis by
avoiding oxidative stressors.
Fortunately,Acute haemolysis is usually short
lived and does not require specific tx
Rare cases of acute haemolysis leads to severe
anaemia requiring transfusion
Neonatal jaundice caused by G6PD deficiency
is treated in the same way as other causes of
NNJ.
May require phototherapy or blood
transfusion
Patients with congenital non-spherocytic
anaemia sometimes have a well compensated
anaemia not requiring BT
However any exacerbating event can severely
worsen the degree of anaemia
Rarely it may be BT dependant
Sometimes develop splenomegally but do not
benefit from splenectomy.
end