Acute intermittent porphyria (AIP) is a hereditary disease characterized biochemically by a defect in the heme pathway enzyme uroporphyrinogen I synthase (UROS) such that its activity is reduced to approximately 50 per cent of normal in all subjects who inherit the disorder. The UROS defect is transmitted in an autosomal dominant fashion, occurs in the liver as well as in other tissues, and appears not to vary with disease activity. There is wide variability in clinical expression of AIP, and the disorder remains latent in most UROS-deficient subjects. The natural history of the disease suggests a significant relationship between endocrine influences and full clinical expression of the disease after puberty. In exploring the interactions of endocrine and genetic factors in this disorder we previously found a substantial deficiency in the hepatic 5α-reductive transformation of steroid hormones in patients with clinically expressed AIP. In the present study utilizing radiolabeled hormone tracers we examined the relationship between this defect in steroid metabolism and clinical expression of the disorder in a large group of subjects including 39 UROS-deficient subjects with either clinically expressed AIP (21 subjects) or clinically latent porphyria (18 UROS-deficient subjects who had never had symptoms of AIP) and 20 normal controls. We found ratios of 5β to 5α metabolites of [4-14C]testosterone to be substantially higher in the group with clinically expressed AIP (3.4 ± 0.5 mean ± standard error [SE], range 1.1 to 9.0) as compared with the group with latent AIP (1.0 ± 0.1, range 0.5 to 2.3) or the normal controls (1.1 ± 0.1, range 0.5 to 2.0), indicating a deficient 5α-reduction of the hormone only in the group with expressed AIP. Similarly the per cent 5α-metabolism of the adrenal hormone [1,2-3H]11-hydroxyandrostenedione was significantly lower in those with expressed AIP (46 ± 3.6 per cent) as compared with those with latent AIP (71 ± 2.4 per cent) or normal subjects (73 ± 2.3 per cent). Erythrocyte UROS activity was not different in those with clinically latent and expressed AIP in keeping with previous findings. Thus, although the groups with expressed and latent AIP were homogeneous with respect to the extent of erythrocyte UROS deficiency, impaired 5α-reduction of steroid hormones was found only in the group with a history of clinical expression of the disorder. The reason for the defect in 5α-reduction of steroid hormones in expressed AIP is not known, but its presence supports the view that in some patients, subtle endocrine abnormalities are involved in clinical expression of the genetic defect in AIP.
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