Methemoglobinemia

Methemoglobinemia occurs when hemoglobin (Hb) with heme in the ferrous state (Fe²⁺) oxidizes to form heme in the ferric state (Fe³⁺). This MetHb has impaired ability to transport oxygen (O₂), leading to hypoxia. Methemoglobinemia, which can be either congenital or acquired, is one of the causes of cyanosis in infants and children associated with significant morbidity and mortality.

The normal Hb molecule is composed of 4 globular protein subunits, with each subunit tightly associated with heme in the ferrous state. Red blood cells (RBCs) are very susceptible to oxidant stress because they carry O₂ in high concentrations and are, therefore, continuously exposed to free radicals. O₂ free radicals are able to oxidize Hb, resulting in the formation of MetHb. This process involves the removal of an electron from an iron atom of the heme group in the ferrous state, forming heme in the ferric state, which, unlike normal Hb, is unable to bind O₂. In the presence of ferric heme, the heme that remains in the ferrous state develops an increased affinity for O₂, binding it more tightly. These 2 changes lead to a left shift of the oxygen-Hb dissociation curve and decreased delivery of O₂ to the tissues. Under normal conditions, MetHb levels are kept low by the RBC enzyme cytochrome b5 reductase (CYB5R), which reduces Hb from the ferric state to the ferrous state by adding an electron to the iron (Fig 1). An alternative pathway for MetHb reduction involves the enzyme nicotinamide adenine dinucleotide phosphate MetHb reductase, which usually plays a negligible role but can be activated by the therapeutic agent methylene blue (Fig 2). Continuously produced at low levels during normal RBC metabolism, MetHb usually amounts to approximately 1% of the total blood Hb. Methemoglobinemia develops …