Malignant hyperthermia (MH): porcine erythrocyte damage from oxidation and glutathione peroxidase deficiency.

Malignant hyperthermia (MH) is a severe familial disease in both the pig and the human, with 70% fatality when fully expressed in humans. MH produces rapid elevation of temperature in response to stresses, of which there are two general kinds: Societal or emotional stress, and chemical stressors. The most commonly encountered stressor is halothane, a general anesthetic in wide use. Besides large temperature increases, there occur some twenty symptoms. Much work in other laboratories has been concentrated on elevated CPK i the plasma. However, all the symptoms are consistent with a single disorder, namely oxidative damage, especially in membranes. A deficiency in the glutathione peroxidase (GPX) system is a prime factor, likely the molecular basis allowing abnormal oxidative damage in the MH pig. Catalase activities are normal in MH pigs, but they have only 20-50% normal GPX activities. The deficiency does not cause oxidative damage. It allows failure or protective mechanisms against it. The nonstressed MH animal exhibits less acute symptoms, e.g. enhanced red cell Heinz bodies, but such animals generally mature. Under stress, their inadequate protective mechanisms dependent on GPX are overwhelmed, resulting in gross symptoms and crisis. It is important to concentrate on the GPX system(s) and their adjacent pentose shunt metabolism. We propose that a deficiency in any of these two systems is the molecular basis of the disease. Many tissues are involve in MH, but the red cell obviously provides a convenient means for assay and for screening. This paper mainly pertains to porcine MH. However, preliminary work with humans indicates that human MH has a similar molecular basis.