Disorders of oxidised haemoglobin.

Methaemoglobinaemia arises from the production of non-functional haemoglobin containing oxidised Fe(3+) which results in reduced oxygen supply to the tissues and manifests as cyanosis in the patient. It can develop by three distinct mechanisms: genetic mutation resulting in the presence of abnormal haemoglobin, a deficiency of methaemoglobin reductase enzyme and toxin-induced oxidation of haemoglobin. The normal haemoglobin fold forms a pocket to bind the haem and stabilise its complex with molecular oxygen, simultaneously preventing spontaneous oxidation of the Fe(2+) ion chelated by the haem pyrroles and the globin histidines. In the abnormal, M forms of haemoglobin (Hb Ms) amino acid substitution in or near the haem pocket creates a propensity to form methaemoglobin instead of oxyhaemoglobin in the presence of molecular oxygen. Normally, haemoglobin continually oxidises but significant accumulation of methaemoglobin is prevented by the action of a group of methaemoglobin reductase enzymes. In the autosomal recessive form of methaemoglobinaemia there is a deficiency of one of these reductase enzymes thereby allowing accumulation of oxidised Fe(3+) in methaemoglobin. Oxidising drugs and other toxic chemicals may greatly enhance the normal spontaneous rate of methaemoglobin production and if levels exceed 70% of total haemoglobin, vascular collapse occurs resulting in coma and death. Under these conditions, if the source of toxicity can be eliminated methaemoglobin levels will return to normal. Disorders of oxidised haemoglobin are relatively easily diagnosed and in most cases, except for the presence of congenitally defective haemoglobin M, can be treated successfully.