Transcript Unit II presentation

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 Aheterozygous 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