Formation of methemoglobin and ineffectiveness of MB in individuals with G6PD deficiency

A small amount of methemoglobin forms when oxygen is released from hemoglobin and is converted to reactive oxygen species (ROS). ROS oxidizes ferrous iron (Fe²⁺) to ferric iron (Fe³⁺), creating methemoglobin. ROS can also be generated by certain exogenous substances that cause methemoglobinemia.

• Left side panel - Normally, NADH generated in glycolysis acts as a cofactor for methemoglobin reduction by cytochrome b5 reductase (Cyb5R), keeping methemoglobin levels low.
• Blue-highlighted panel - When Cyb5R activity is low or ROS are high, methemoglobin can accumulate. Therapy with methylene blue (MB) will reduce methemoglobin. First, MB must be reduced to leukomethylene blue by electrons transferred from NADPH. NADPH is produced by the HMP/pentose phosphate shunt in a pathway that requires G6PD.
• Right side panel - In individuals with G6PD deficiency, MB cannot be used because there is not sufficient NADPH to reduce MB to leukomethylene blue. MB will be ineffective, and in its unreduced form, MB can act as an oxidizing agent and precipitate hemolysis in individuals with G6PD deficiency.

Refer to UpToDate for details of management.