G6PD DEFICIENCY ANEMIA

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the commonest RBC enzymopathy, usually presenting as severe hemolysis after exposure to oxidizing drugs or substances (Table 19.10).

Etiopathogenesis: Since RBCs do not contain mito­chondria, glucose is largely metabolized in them by two anaerobic pathways - 90% by Embden-Meyerhof pump (EMP) and 10% by hexose monophosphate shunt (HMS).

G6PD is the most important enzyme of HMS pathway that has an important function to maintain glutathione- an antioxidant intracellular enzyme, in its reduced state

TABLE 19.10: Precipitating oxidants in G6PD deficiency

• Drugs:

- Antimalarials: Primaquine, quinine

- Antibacterials: Sulfonamides, nalidixic acid

- Others: Vitamin K analogs, aspirin, methylene blue

• Chemicals: Naphthalene balls, benzene

• Illness: Viral fevers, hepatitis, diabetic ketoacidosis

• Others: Fava beans (a Mediterranean dietary staple) (GSH). In G6PD deficiency, reduced GSH activity with accumulation of intracellular oxidants leads to increased RBC membrane permeability and denaturation of hemoglobin to form intracellular Heinz bodies.

These abnormal RBCs are then trapped and destroyed in the spleen, producing hemolysis. Over 100 isoenzymes of G6PD with variable activity have been identified, commonest being G6PD B⁺ or A⁺ in normal population and G6PD A^- or B^- mutant enzymes with reduced activity in affected population.

G6PD deficiency is an X-linked recessive disorder with incomplete dominant expression. Affected cases, instead of having normal isoenzyme variants, possess mutant variants with lower activity, i.e. G6PD B^- or G6PD A^-.

Epidemiology: G6PD B^- variant is the commonest cause of G6PD deficiency in Indian population, being more prevalent in jews and in north-west region.

Clinically, G6PD deficiency may present in three distinct forms, depending on the type of enzyme variant, severity of deficiency and the nature/ amount of oxidant exposure.

• Mildest form presents with transient hemolysis only after exposure to strong oxidants, e.g. primaquine. Hemolysis abates after some time even if the offending drug is continued and neonatal hyperbilirubinemia is not seen.

• Commonest form in Indian children with G6PD B variant presents with moderate to severe hemolytic episodes after exposure to oxidant substances. Hemolysis continues till the drug is stopped. These episodes present with sudden hemoglobinuria (red-colored urine), rapidly progressive pallor and hemodynamic collapse. Some cases may present with neonatal hyperbilirubinemia.

• Severe cases present with chronic non-spherocytic hemolytic anemia and splenomegaly due to persistent hemolysis even without oxidant exposure. Neonatal hyperbilirubinemia is common.

Diagnosis depends on:

• Classic clinical presentation with acute hemolytic episodes after exposure to an oxidant drug.

• Presence of intracellular Heinz bodies on supravital staining of RBCs. Heinz bodies are not visible after

3- 4 days of hemolysis, as cells containing these bodies are rapidly cleared by spleen.

• Quantitative G6PD activity estimation should be deferred for at least 3 weeks of hemolytic episode, as immediate results may be misleading due to

preponderance of reticulocytes and younger RBCs in circulation after severe hemolysis, which have significantly higher G6PD activity.

Management is only supportive and includes:

• Immediate stoppage of offending drug.

• Alkalization of urine with IV / PO NaHCO₃ to prevent precipitation of acid hematin in renal tubules and consequent renal failure.

• Correction of fluid and electrolyte imbalance

• Blood transfusion in severe cases.

Prevention of further episodes in known G6PD deficient children is vital. Their case-papers should prominently mention the diagnosis to avoid future exposure with oxidant drugs. In high-risk communities, it is advisable to test G6PD activity before administering oxidant drugs, e.g. primaquine or sulfonamides.

Other uncommon enzyme defects include:

Pyruvate kinase deficiency is an autosomal recessive disorder of EMP pathway — main energy pathway in RBCs. Low ATP production in these cases adversely affects cellular functions and pliability, decreasing their life-span. Heterozygous children have moderate reduction in pyruvate kinase activity.

Clinical presentation varies from severe neonatal hyperbilirubinemia to mild/moderate persistent hemolysis in later life with variably severe anemia, persistent jaundice and splenomegaly.

Diagnosis rests on low pyruvate kinase levels in RBCs with normal osmotic fragility (d/d hereditary spherocytosis).

Management includes folic acid supplements and splenectomy in severe cases. Transfusion is rarely needed.

Methemoglobinemia: Methemoglobin is characterized by presence of heme iron in ferric (F⁺⁺⁺⁾ form, instead of ferrous (Fe⁺⁺) form in hemoglobin, which renders it non-functional and imparts a brown color to the blood.

In normal individuals, methemoglobin contributes lt;2% of total Hb. Methemoglobinemia represents an imbalance in normal process of oxidation and reduction of heme iron, leading to increased methemoglobin concentration.

Etiologically, methemoglobinemia is either an autosomal dominant hemoglobin disorder (Hb-M disease) or an autosomal recessive enzymopathy (cytochrome B-5 reductase deficiency).

Clinically HbM disease presents with persistent central cyanosis due to abnormal color of methemoglobin since birth, without respiratory distress. However, children with enzymopathy are apparently normal till exposed to strong oxidants (Table 19.10), when they present with sudden appearance of cyanosis and mild respiratory distress. Cyanosis appears only when methemoglobin levels exceed 15%.

Diagnosis must be suspected in deeply cyanosed cases with minimal respiratory distress and chocolate-brown color of blood sample, confirmed on Hb electrophoresis. Management of these cases includes:

• IVMethylene blue (1-2 mg/kg) to eliminate acute cya­nosis in enzymopathy, followed by oral maintenance therapy (3-5 mg/kg/day).

• Vitamin C supplements (PO 200-500 mg/d q8-12hr) to reduce methemoglobin concentration lt;10% (and cyanosis), till therapy is continued.

Prevention of attacks involve avoidance of exposure to oxidant drugs/chemicals including naphthalene balls, nitrobenzene products like shoe-polish, perfumes, etc.

19.5.3