Glucose-6-phosphate Dehydrogenase Deficiency

Synonyms: G-6-PD deficiency, non-spherocytic haemolytic anaemia

The enzyme glucose-6-phosphate dehydrogenase is one of the enzymes of the pentose phosphate pathway. This pathway is involved in keeping an adequate amount of the co-enzyme nicotinamide adenine dinucleotide phosphate (NADPH) in cells.
NADPH in turn maintains the levels of glutathione which protects the red cell from oxidative damage. G-6-PD is the rate-limiting enzyme in the pentose phosphate pathway. Thus deficiency of the G-6-PD enzyme results in reduced glutathione making the red cells vulnerable to oxidative damage and thus liable to haemolysis.

The disease is X-linked with about 300 variants reported. Most of the variants occur sporadically and are single amino acid defects in a protein of 515 amino acids.

Classes of G6PD Enzyme Variants¹

1. Severe (I) - Chronic nonspherocytic hemolytic anemia
2. Severe (II) - Less than 10 percent of normal
3. Moderate (III) - 10 to 60 percent of normal
4. Mild to none (IV) - 60 to 150 percent of normal
5. None (V) - Greater than 150 percent of normal

More detailed information about variants is available under the OMIM listing.²

• It is the commonest disease-producing enzyme deficiency in the world.
• About 400 million people are affected worldwide with gene frequency between 5 and 25% in tropical Africa, the Middle East, tropical and subtropical Asia, some areas of the Mediterranean, and Papua New Guinea.¹
• It affects all races but is commonest in those of African, Asian or Mediterranean descent. It tends to be milder in those of African origin and more severe in the Mediterranean races.
• As the disease makes erythrocytes vulnerable, this is probably the survival advantage in areas of endemic malaria that accounts for its great frequency.
• In an African population possession of the defect in men or the heterozygous gene in women gave protection of between 48 and 56% against severe malaria but it was estimated from a mathematical model that although G6PD deficiency is now regarded as a generally benign disorder, in earlier environmental conditions it could have been significantly disadvantageous and this limited its spread.³
• Being X-linked the disease affects mainly men but in areas of high frequency it is not uncommon to find homozygous women.⁴

• Certain drugs (see below)

  Drugs to watch out for in G6PD-deficient individuals
  Drugs with definite risks	Drugs with possible risk
  Primaquine - although 30 mg weekly for 8 weeks has been found to be without undue harmful effects in African and Asian people Methylene blue (methylthioninium chloride) Nitrofurantoin and quinolones including ciprofloxacin, moxifloxacin, nalidixic acid, norfloxacin, and ofloxacin Sulphonamides including co-trimoxazole although some sulphonamides like sulfadiazine have been tested and found not to be haemolytic in many with G6PD-deficiency Dapsone Sulphonylureas e.g. glibenclamide	Aspirin although a dose up to 1 gram daily is usually harmless Chloroquine, quinidine and quinine but they may be used in acute malaria Vitamin K analogues like menadione and water-soluble derivatives like menadiol sodium phosphate

• Certain foods e.g. broad beans
• Severe infection
• Diabetic ketoacidosis
• Acute renal failure (causes a severe crises)

History

• Depends upon the severity of the enzyme deficiency
• Most are asymptomatic
• May be a history of neonatal jaundice, even requiring exchange transfusion
• History of drug induced haemolysis
• Gall stones are common

Examination

• Most often examination is unremarkable
• Pallor of anaemia
• During a crisis jaundice occurs
• Back or abdominal pain (usually occurs when >50% haemolysis occurs)
• Splenomegaly may occur

• Full blood count - anaemia
• Macrocytosis - due to reduced folic acid which is required for erythropoiesis
• Reticulocyte count - raised; gives indication of the bone marrow activity (bone marrow sampling thus not needed)
• Blood film - acute haemolysis from G-6-PD deficiency can produce Heinz bodies, which are denatured haemoglobin and bite cells (cells with Heinz bodies that pass through the spleen have part of the membrane removed)
• Haemolysis - reduced levels of haptoglobin and elevated levels of bilirubin; haemoglobinuria
• Direct antiglobulin test - to look for other causes of haemolysis; should be negative in G-6-PD deficiency
• Renal function - to ensure no renal failure as a precipitant
• Liver function tests - to exclude other causes of raised bilirubin
• G-6-PD enzyme activity - is definitive test (as opposed to the amount of G-6-PD protein)
• Performing assays for G-6-PD during haemolysis and reticulocytosis may affect levels and not reflect baseline values
• Ultrasound examination of the abdomen may reveal splenomegaly and gallstones

Management of acute haemolysis

• Seek specialist advice
• Blood transfusions may be needed
• Dialysis may be required in acute renal failure
• Infants - more susceptible to neonatal jaundice, especially if premature and exchange transfusion may be required

Management of chronic haemolysis or stable disease

• Splenectomy may help
• Supplementation with folic acid
• Avoidance of precipitating drugs, broad beans (usually favism occurs in the Mediterranean variety of the disease)
• Avoid naphthalene - found in moth balls

Most people with G6PD deficiency have normal lives and life expectancy despite a predisposition to neonatal jaundice and sensitivity to certain drugs. This may be a hidden risk for kernicterus⁵ if the neonatal jaundice is not energetically treated. However, G6PD activity is higher in premature infants born between 29 and 32 weeks gestation than in term neonates.⁶ Even if G6PD deficiency is anticipated, prophylactic oral phenobarbital to the baby after delivery does not decrease the need for phototherapy or exchange transfusions in G6PD-deficient neonates.⁷ Sn-mesoporphyrin (SnMP) is a potent inhibitor of bilirubin production that is effective in moderating neonatal hyperbilirubinaemia caused by ABO incompatibility, immaturity, and unspecified mechanisms. It also helps in G6PD deficiency.⁸ A paper from Sardinia suggested that as G6PD activity was present in the lens of the eye that men with the condition were less susceptible to cataracts⁹ but another paper, also from Sardinia a few years later, did not find this association.¹⁰

Although the disease is thought to be fairly benign, where enzyme levels are severely deficient there can be inadequate leucocyte function also. ¹¹ This results in chronic granulomatous disease. In Saudi Arabia the G-6-PD status of all children aged 1 month to 14 years who were treated for meningitis, septicaemia, osteomyelitis, or typhoid fever during a 9-year period was reviewed. The observed frequency of G6PD deficiency was significantly higher than expected for the entire group, for females with both catalase-positive and catalase-negative infection, and for males with catalase-positive infections.¹²