Studies of the pathogenesis and treatment of acute intermittent porphyria
The thesis examines the pathogenesis and treatment of acute intermittent porphyria (AIP), an inherited disorder of haem biosynthesis characterised biochemically by overproduction and increased excretion of porphyrin precursors, and clinically by neurovisceral crises which can be life-threatening. Both prevention and treatment of porphyric crises are considered. Acute attacks can be triggered by either endogenous or exogenous precipitants. A trial of hormonal suppression, using the luteinizing hormone releasing hormone analogue buserelin, in 7 patients suffering premenstrual attacks of AIP, suggested a trend towards clinical improvement on buserelin although response to treatment varied widely between patients. The relationship between endogenous steroids and disease activity in AIP was further examined by measuring urinary steroid metabolite excretion in patients with active, latent, and quiescent disease. In patients with active AIP the ratio of 5α to 5β urinary steroid metabolites was reduced, as was total steroid metabolite excretion. The finding of elevated plasma sex hormone-binding globulin concentrations in patients with active AIP is also reported. Drug porphyrinogenicity is discussed with reference to antidepressants and anticonvulsants. Preliminary anecdotal experience of the use of the haem derivative haem arginate in the treatment of 37 acute attacks of porphyria is described, and the first double-blind controlled trial of haem derivative treatment reported. This studied 21 attacks in 12 patients. While haem arginate invariably produced a marked fall in porphyrin precursor excretion, it did not significantly affect clinical outcome, although there was a trend in favour of haem treatment. In 7 attacks of AIP, haem arginate corrected the impaired hepatic mixed function oxygenase activity which is a recognised feature of AIP : antipyrine clearance was increased. The finding of raised blood lactate levels after glucose loading suggested that cytochrome deficiency affecting the terminal respiratory chain also occurs in AIP. It is postulated that the genetic, metabolic, endocrine and hepatic abnormalities of AIP may be inter-related through haem deficiency.