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 expressionG6PD deficient

• Females ,who have two copies of the G6PD gene on each X chromosome

Normal gene expressionHeterozygousHomozygous[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

DrugsInfectionIngestion of fava beans

• Also presents asneonatal jaundice anaemiaChronic 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 byFatigue,back pain ,anaemia jaundiceIncreased unconjugated bilirubinReticulocytosis,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 failureTubular 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.

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