MARKERS FOR VULNERABILITY IN ACUTE PORPHYRIA - A HYPOTHESIS PAPER

Previously symptomatic and permanently asymptomatic carriers of a gene mutation for acute intermittent porphyria as well as matched controls were screened with regard to a series of variables of possible releva nce to the development of porphyric symptoms. The basis for the study was a concept of acute porphyria as a condition of a permanent system overload of oxidative stress, with long term effects on hepatic and re nal tissue, and with instances of periodic overload of free radicals g iving rise to acute neurologic involvement. Leukocyte concentrations o f manganese, calcium, iron and zinc, as well as erythrocyte calcium di ffered between the groups, acute intermittent porphyria gene carriers, irrespective of previous porphyric illness, showing significantly hig her levels than the controls. Manganese was found to be the most discr iminative component of all the 78 variables investigated, accounting f or about 98 per cent of the variance between the groups. An increment, by a factor of four, in cellular manganese is suggestive of an increa se, in acute intermittent porphyria, of a manganese associated enzyme, e.g. glutamine synthetase, pyruvate carboxylase or mitochondrial supe roxide dismutase. The best fit into the model considered is provided b y a theory focused on superoxide dismutase, induced in response to sup eroxide anion radical produced from aminolaevulinic acid. In porphyria gene carriers seemingly resistent to porphyric manifestations, an inc rease in potentially prooxidant cellular iron is matched by a proporti onal increment in manganese, i. e. presumably by a corresponding mitoc hondrial superoxide dismutase induction. This mechanism is not operati ve in porphyric individuals prone to development of neuropsychiatric s ymptoms. In acute intermittent porphyria with a history of porphyric i llness there is a positive correlation between erythrocyte manganese a nd serum folate and a negative correlation between leukocyte ferrochel atase activity and serum cobalamin concentration. This may mirror a ro le of the cobalamin-folate system in the acute porphyric process. In t he acute intermittent porphyria gene carrier state, activities of eryt hrocyte uroporphyrinogen decarboxylase as well as porphobilinogen deam inase are decreased. The decrease is associated with the active state of the disorder. A correlation between the activities of the two eryth rocyte enzymes in non-porphyric individuals is absent in acute intermi ttent porphyria. In acute intermittent porphyria with a history of por phyric illness, red cell porphobilinogen synthase (aminolaevulinate de hydratase) activity is higher than in the permanently asymptomatic cas es and the controls. The increased enzyme activity is connected with r ecent activation of the porphyric condition. Gene carriers of acute in termittent porphyria with a history of porphyric symptoms have a signi ficantly higher intake of sucrose containing foodstuff. In other respe cts the three groups do not differ in food consumption patterns, nor i n smoking or alcohol ingestion.