Red cell enzymopathies

 Red cell enzymopathies:

The mature red cell must produce energy via ATP to maintain a normal internal environment and cell volume while protecting itself from the oxidative stress presented by oxygen carriage. ATP is generated by glycolysis, while the hexose monophosphate shunt produces nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione to protect against oxidative stress. The impact of functional or quantitative defects in the enzymes in these pathways depends on the importance of the steps affected and the presence of alternative pathways. In general, defects in the hexose monophosphate shunt pathway result in periodic haemolysis precipitated by episodic oxidative stress, while those in the glycolysis pathway result in shortened red cell survival and chronic haemolysis.

Glucose-6-phosphate dehydrogenase (G6PD) is pivotal in the hexose monophosphate shunt pathway. Deficiencies result in the most common human enzymopathy, affecting 10% of the world's population, with a geographical distribution that parallels the malaria belt because heterozygotes are protected from malarial parasitisation. The enzyme is a heteromeric structure made of catalytic subunits that are encoded by a gene on the X chromosome. The deficiency therefore affects males and rare homozygous females but it is carried by females. Carrier heterozygous females are usually only affected in the neonatal period or in the presence of skewed X-inactivation. Over 400 subtypes of G6PD are described. The most common types associated with normal activity are the B+ enzyme present in most Caucasians and 70% of Afro-Caribbeans, and the A+ variant present in 20% of Afro-Caribbeans. The two common variants associated with reduced activity are the A- variety in approximately 10% of Afro-Caribbeans, and the Mediterranean or B- variety in Caucasians. In East and West Africa, up to 20% of males and 4% of females (homozygotes) are affected and have enzyme levels of about 15% of normal. The deficiency in Caucasian and East Asian populations is more severe, with enzyme levels as low as 1%.

    Clinical features and investigation findings are shown in the figure.

Figure: Glucose-6-phosphate dehydrogenase deficiency

 

  

 

Management aims to stop the intake of any precipitant drugs or foods and treat any underlying infection. Favism due to the consumption of fava beans is the classically described precipitant of haemolysis in patients with G6PD deficiency. Acute transfusion support may be life-saving.

Pyruvate kinase deficiency:

This is the second most common red cell enzyme defect. It results in deficiency of ATP production and a chronic haemolytic anaemia. It is inherited as an autosomal recessive trait. The extent of anaemia is variable; the blood film shows characteristic 'prickle cells' that resemble holly leaves. Enzyme activity is only 5-20% of normal. Transfusion support may be necessary during periods of haemolysis.

Pyrimidine 5' nucleotidase deficiency:

The pyrimidine 5' nucleotidase enzyme catalyses the dephosphorylation of nucleoside monophosphates and is important during the degradation of RNA in reticulocytes. It is inherited as an autosomal recessive trait and is as common as pyruvate kinase deficiency in Mediterranean, African and Jewish populations. The accumulation of excess ribonucleoprotein results in coarse basophilic stippling, associated with a chronic haemolytic state. The enzyme is very sensitive to inhibition by lead and this is the reason why basophilic stippling is a feature of lead poisoning.