Acute intermittent porphyria : studies of chronic disease, recombinant enzyme therapy and late complications

This thesis comprise five studies on patients with acute intermittent porphyria (AIP) observed under different clinical conditions associated with the disorder. They have generally been monitored at the porphyria out-patient clinic in Stockholm South Hospital, and were biochemically monitored at Porphyria Centre Sweden. Acute intermittent porphyria is an autosomal dominant metabolic disorder with comparatively high prevalence in Sweden; 1:10 000. The disease is caused by a partial deficiency of porphobilinogen deaminase (PBGD), the third enzyme in heme biosynthesis. The clinical penetrance of the underlying gene mutation is relatively limited and characterized by attacks of painful and potentially life threatening symptoms, mainly from the nervous system, and accompanied by accumulation and excretion of the porphyrin precursors porphobilinogen (PBG) and the possibly neurotoxic 5-aminolevulinic acid (ALA). Estimation of the current extent of porphyrin precursor excretion is presently the only tool for assessment of an acute attack of porphyria in the patient with AIP. In this process, precise knowledge of the physiological and pathophysiological fluctuations of these markers is essential for the accurate evaluation of the clinical situation at hand. Beside the few recently reported liver transplantations, there is presently no available way to bring about permanent cure for the metabolic error in AIP. In wait for gene therapy, the obvious measure would be to compensate for the underlying enzyme deficiency by supplementation via administration of the deficient enzyme. In success, would not only acute attacks be inhibited, the lethal late manifestations from liver and kidneys would also be blocked. Our studies thus approach questions concerning the kinetics of PBG and ALA in AIP monitored also under conditions secondary to renal engagement and hepatic tumour. In order to be able to measure the low plasma concentrations of these metabolites, we developed a novel HPLC-MS procedure. One study defines the ...