1. Glucose -6-phosphate dehydrogenase deficiency
Unit II presentation
Glucose -6-phosphate dehydrogenase deficiency

2. 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.

3. 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

4. Red blood cells do not contain mitochondria
PPP is only source of NADPH
Defense against oxidative damage is dependant on G6PD

5. 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

6. 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.

9. Genetics The inheritance is typically X linked
Males are hemizygous for the G6PD gene
Normal gene expression
G6PD deficient

10. 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]

11. 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

12. 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

13. 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]

14. 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

15. 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

16. 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

17. 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

18. Clinical manifestation
Fortunately,most individuals are asymptomatic throughout their life
Generally manifests as acute haemolysis after oxidative stress
Drugs
Infection
Ingestion of fava beans

19. 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

20. Clinically characterised by
Fatigue,back pain ,anaemia jaundice
Increased unconjugated bilirubin
Reticulocytosis,LDH are markers of the disorder

22. Drug induced haemolytic anemia
Clinically detectable haemolysis and jaundice 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

25. 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

26. 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

27. 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

28. 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.

29. 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

30. Neonatal jaundice caused by G6PD deficiency is treated in the same way as other causes of NNJ.
May require phototherapy or blood transfusion

31. 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.

32. end