Red cell enzymopathies Red cell enzymopathies
Glucose-6-phosphate deficiency
§ G6PD is involved in the pentose phosphate shunt § Failure to generate adequate NADPH, results in insufficient glutathione § Renders red cells susceptible to oxidation § Denatured Hb forms heinz bodies and gets taken out by spleen § XLR § Affects males mainly § Female carriers have 50% normal G6PD activity (phenotype depends on degree of lyonisation) § West Africa, Southern Europe, Middle East, South East Asia
Pathophysiology § Wild type G6PD B § 4 classes of severity depending on the level of enzyme activity relative to G6PD B § At least 127 different variants § The 3 most common variants are § G6PD-A(-) is common in Africa – class III 10- 60% of normal activity § Mediterranean variant – class II <10% activity § Canton variant – class II § Decreased enzyme activity in aged cells § Survival advantage with P falciparum
Classification
Clinical features 1. Neonatal Jaundice § Class I, II and III variants § Potential kernicterus § Starts in utero but becomes clinically apparent on day 2 or 3 § Anaemia is not a feature § Manifestation of liver enzyme deficiency and underdevelopment of neonatal liver function § Phototherapy or exchange transfusion
2. Chronic non spherocytic haemolytic anaemia § Tends to occur in more severely affected (class I) § Extravascular haemolysis
3. Acute episodes of intravascular due to: § Infection § Drugs (dose related) § Antimalarials (Primaquine, ? chloroquine) § Aspirin (<1g/day normally ok) § Antibiotics (Quinolones, nitrofurantoin, sulphonamides eg septrin) § Dapsone § Fava beans § Haemolysis increases 1-3 days after infection/ ingestion of the drug and peaks at 7-10 days § Associated with back and abdominal pain § Urine becomes dark § Haemolysis is typically self limiting (severity related to dose of drug ingested but large amount of heterogeneity) § Favism more rapid onset (hours) and can be much more severe, with shock and can be fatal. Due to divicine which is not present in peas and other beans.
§ May present as neonatal jaundice with kernicterus (largely only in Mediterranean children)
Investigations § Heinz bodies in red cells (methyl violet stain) § Ghost cells § Spherocytes and fragments in film if severe haemolysis § Reticulocytosis / reduced haptoglobins / raised LDH / unconjugated bilirubin / DAT –ve § Assay for G6PD (NB can be difficult in acute haemolysis since reticulocytes have increased levels of the enzyme) § Screening tests eg methaemoglobin reduction test – detect levels below 30% § Enzyme quantifictation – spectrophotometry § Demostration of G6PD deficient cells with staining (normal = all cells stained)
Management § Avoid triggers § Transfusion if severe haemolysis § IV fluids to reduce renal failure in severe haemolysis § Folic acid § Splenectomy may be helpful in recurrent haemolysis
Pyruvate kinase deficiency § Autosomal recessive § Pyruvate kinase is an enzyme in the glycolytic pathway § Glycolytic pathway generates ATP for the erythrocyte § Maintains membrane integrity, ferrous Hb and oxygen affinity § Reduced ATP, 2,3 DPG accumalation leading to right shift of the Hb dissociation curve § 2,3-Diphosphoglycerate
Clinical features § Variable chronic haemolysis § May be apparent in the neonate if severe but often presents in later life § Prone to aplastic crises due to parvovirus B19
Diagnosis § Reticulocytosis / raised LDH / reduced haptoglobins / variable anaemia / acanthocytes § PK assay
Treatment § Folic acid § Transfusion during severe crises § Splenectomy if high transfusion requirements
substrate_____other enzymes (left)______→ 2,3-DPG _____pyruvate kinase (right)_____→ ATP
Other red cell enzymopathies – glycolytic pathway 1. Hexokinase deficiency 2. Glucose phosphate isomerase deficiency 3. Phosphofructokinase deficiency 4. Aldolase deficiency 5. Triosephosphate isomerase deficiency (TPI) 6. Phosphoglycerate kinase deficiency (X-linked)
§ All Autosomal recessive § Prevalence < 1 / million
Clinical features § Similar to PK deficiency although most are more severely affected for the degree of anaemia (glycolytic block results in reduced 2,3 DPG and left shift of the Hb dissociation curve)
§ TPI also causes progressive paraparesis with most dying due to cardiac arrhythmias age <5 § PFK deficiency is associated with myopathy and exertional rhabdomyolysis which may result in renal failure
Diagnosis § Morphology non specific (anisocytosis, macrocytosis and polychromasia) § Assay of enzyme at reference lab
Treatment § Folic acid § Transfusion as necessary (beware of iron overload) § Splenectomy controversial
Nucleotide metabolism – pyramidine 5 nucleotidase deficiency § Autosomal recessive § Lead poisoning causes acquired deficiency
Clinical features § Moderate anaemia (Hb 10) § Reticulocytosis etc § Splenomegaly
§ Prominent basophilc stippling § Diagnosed with pyrimidine 5 nucleotidase assay § Treatment - symptomatic |
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