Makindo Medical Notes

Related Subjects: |Iron deficiency Anaemia |Haemolytic anaemia |Macrocytic anaemia |Megaloblastic anaemia |Microcytic anaemia |Myelodysplasia |Myelofibrosis

Carriers of a G6PD mutation may be partially protected against malaria.

About

• Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency is a condition in which the enzyme G6PD is deficient, rendering red blood cells vulnerable to oxidative damage.
• Heterozygous females may exhibit partial protection against falciparum malaria.
• It is inherited as an X-linked recessive disorder.

Epidemiology

• Commonly found in populations in Africa, the Mediterranean region, and the Middle and Far East.
• Approximately 400 million people worldwide are affected.

Aetiology

• A defect in the hexose monophosphate (HMP) shunt reduces the production of NADPH.
• Reduced NADPH levels lead to a deficiency in reduced glutathione, which is crucial for protecting red blood cells from oxidative stress.
• NADPH is necessary to maintain the iron in hemoglobin in its ferrous (Fe²⁺) state and to prevent membrane lipid peroxidation.

Genetics

• Mutations occur in the G6PD gene, with over 400 identified subtypes; some populations have up to 10% mutation prevalence.
• The gene is located on the X chromosome; therefore, all hemizygous males with the mutation are affected.
• Females are typically carriers and may only be affected if homozygous or in cases of extreme lyonisation (skewed X-chromosome inactivation).

Atomic-Level Mechanism: How NADPH Protects Against Oxidative Stress

At the atomic level, NADPH serves as a vital electron donor in redox reactions that protect cells from oxidative damage. Its protective role is best illustrated in the regeneration of reduced glutathione (GSH), a major cellular antioxidant.

• Electron Donation via Hydride Transfer: NADPH contains a nicotinamide ring that holds an extra hydride ion (a hydrogen atom with two electrons). When NADPH interacts with enzymes such as glutathione reductase, it donates this hydride ion to oxidized glutathione (GSSG). This transfer of two electrons (in the form of a hydride, H⁻) converts NADPH into its oxidized form, NADP⁺.
• Reduction of Disulfide Bonds: Oxidized glutathione (GSSG) contains a disulfide bond (–S–S–) linking two glutathione molecules. The donated hydride ion from NADPH breaks this disulfide bond by reducing each sulfur atom, thereby restoring two molecules of reduced glutathione (GSH). In chemical terms, the disulfide bond is cleaved as each sulfur atom gains an electron and a proton, forming thiol (–SH) groups.
• Maintenance of Redox Homeostasis: The regenerated GSH then acts to neutralize reactive oxygen species (ROS) such as hydrogen peroxide. GSH donates an electron to ROS, converting harmful oxidants into less reactive molecules (e.g., water), while itself becoming oxidized back to GSSG. NADPH is continuously required to reduce GSSG back to GSH, thereby sustaining the cell's antioxidant capacity.

Precipitants of Hemolysis

• Oxidative stress triggers hemolysis in G6PD-deficient individuals.
• Drugs: Examples include primaquine, sulfonamides, ciprofloxacin, quinidine, and probenecid.
• Foods: Fava bean ingestion (favism) can provoke hemolysis.
• Other stressors: Diabetic ketoacidosis may also precipitate hemolysis.

Complications

• Severe enzyme deficiency can lead to profound hemolysis, resulting in hemoglobinuria and potential acute kidney injury (AKI).

Clinical Features

• Acute Haemolysis:
  • Favism; neonatal jaundice; symptoms include pallor, jaundice, dark urine, fatigue, shortness of breath, and tachycardia.
  • Onset is usually 2–4 days after exposure to the precipitant (drug or fava beans).
• Drug-Induced Hemolysis: Can occur due to infections or exposure to antimalarials (e.g., quinine) and sulfonamides.
• Chronic hemolysis may also be observed in some cases.

Investigations

• Full Blood Count (FBC): Reveals anemia and increased reticulocyte count.
• Urine Analysis: The hyperbilirubinemia in hemolysis is pre-hepatic (unconjugated) and typically does not cause bilirubinuria; dark urine is usually due to hemoglobinuria and increased urobilinogen.
• Blood Film: May show polychromasia, irregularly contracted red cells, and "bitten-out" cells.
• Biochemical Markers: Elevated serum bilirubin and lactate dehydrogenase (LDH), and low haptoglobin levels.
• Schumm's Test: Positive due to the presence of methemalbumin.
• G6PD Assay: Low enzyme levels confirm G6PD deficiency (note: levels may be normal during an acute hemolytic episode; repeat testing may be required).
• Direct Antiglobulin (DAT) Test: Negative, helping to exclude immune-mediated hemolysis.
• Peripheral Blood Smear: May reveal bite cells, blister cells, reticulocytosis, and Heinz bodies.

Differential Diagnosis

• Exclude malaria and sickle cell disease in the appropriate clinical context.

Management

• Avoid Triggers: Immediate cessation of any causative drugs and avoidance of fava beans.
• Infection Management: Prompt identification and treatment of any infections.
• Monitoring: Monitor hemoglobin levels at least twice daily; transfuse blood products if necessary.
• Renal Protection: Closely monitor urine output, blood urea, and creatinine levels to prevent acute kidney injury.
• Supportive Care: Supportive measures are the mainstay of treatment; transfusions are rarely required unless severe anemia is present.