Inherited metabolic disorders (G6PD deficiency)

Question 1

What is the pathophysiology of G6PD deficiency? How is it acquired?

Answer 1

↓ G6PD → ↓ reduced NADPH → ↓ reduced glutathione → increased red cell susceptibility to oxidative stress

• G6PD is the rate-limiting enzyme in the pentose phosphate pathway
  
  • which converts glucose-6-phosphate→ 6-phosphogluconolactone
  • this reaction also results in nicotinamide adenine dinucleotide phosphate (NADP) → NADPH
  • i.e. glucose-6-phosphate + NADP → 6-phosphogluconolactone + NADPH
  • NADPH is important for converting oxidised glutathione back to its reduced form
• Reduced glutathione is essential for preventing oxidative damage to red cells.
• Red cells lacking G6PD are susceptible to oxidant induced haemolysis (usually caused by certain drugs
• G6PD deficiency is X linked recessive and so predominantly symptomatic in males

Question 2

Which drugs/chemicals can trigger haemolysis in children with G6PD?

Answer 2

Question 3

Can females be affected by G6PD deficiency?

Answer 3

Females who are heterozygotes are usually clinically normal as they have about half the
normal G6PD activity BUT they may be affected if:

1. Homozygous
2. By extreme Lyonisation - more common, when by chance more of the normal than the abnormal X chromosomes have been inactivated (the Lyon hypothesis is that, in every XX cell, one of the X chromosomes is inactivated and that this is random

Question 4

What is the epidemiology of G6PD deficiency?

Answer 4

More common in people from the Mediterranean and Africa

• Mediterranean, Middle Eastern and Oriental population males have very low or absent enzyme activity
• Affected African Americans have 10-15% norrmal enzyme activity

Most common cause of severe neonatal jaundice requiring exchange transfusion worldwide

Question 5

What are the clinical features of G6PD deficiency?

Answer 5

Neonatal jaundice - onset within first 3 days of life

Acute intravascular haemolysis - fever, malaise, abdo pain, dark urine (contains uribilinogen and Hb; precipitated by:

• infection (most common)
• drugs
• fava beans/broad beans
• naphthalene in mothballs

Splenomegaly

Gallstones are common

Question 6

How is G6PD deficiency diagnosed?

Answer 6

G6PD enzyme assay - check 3 months after crisis as retiiculocytes have higher enzyme activity in crises and RBCs with lowest G6PD will have been haemolysed

Other:

• FBC - Normal bloods between episodes but during haemolytic crisis Hb can drop below 50g/L over 24-48hrs.
• Blood film - Heinz bodies on blood films. Bite and blister cells may also be seen.

Question 7

What is the management of G6PD deficiency?

Answer 7

Advice - parents should know signs of acute haemolysis (jaundice, pallor. dark urine). Provide list of drugs, chemicals and food to avoid.

Transfusions are rarely required even for severe episodes.

Question 8

Compare and contrast G6PD with hereditary spherocytosis.

Answer 8

Question 9

Compare and contrast the following between G6PD deficiency and hereditary spherocytosis:

• Gender
• Epidemiology
• Typical history
• Blood film
• Diagnostic test

Answer 9

G6PD deficiency // Hereditary spherocytosis

• Gender: Male (X-linked recessive) // Male + female (autosomal dominant)
• Epidemiology: African + Mediterranean descent // Northern European descent
• Typical history:
  
  • G6PD:
    
    • Neonatal jaundice
    • Infection/drugs precipitate haemolysis
    • Gallstones
  • HS:
    
    • Neonatal jaundice
    • Chronic symptoms although haemolytic crises may be precipitated by infection
    • Gallstones
    • Splenomegaly is common
• Blood film: Heinz bodies // Spherocytes (round, lack of central pallor)
• Diagnostic test: Measure enzyme activity of G6PD // EMA binding