Protoporphyrin accumulation by mitogen stimulated lymphocytes and protoporphyrinogen oxidase activity in patients with porphyria variegata and erythropoietic protoporphyria: evidence for deficiency of protoporphyrinogen oxidase and ferrochelatase in both diseases

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Abstract
In erythropoietic protoporphyria (EPP) and porphyria variegata (PV) excess protoporphyrin is excreted in the stool, suggesting 1 or more enzyme defects in the terminal steps of the heme biosynthetic pathway. Protoporphyrinogen oxidase (PPO), which catalyses the oxidation of protoporphyrinogen to protoporphyrin, in both EPP and PV patients and in the offspring of PV patients. In the same subjects protoporphyrin formation was measured by mitogen stimulated lymphocytes, with delta aminolevulinic acid (ALA) as substrate and with the addition of chelators or Fe, an indirect measure of ferrochelatase activity. PPO activity was reduced by 41% (P < 0.001) in PV patients and in 50% of their offspring, and by 36% (P <0.001) in EPP patients. Protoporphrin accumulation in stimulated lymphocytes was increased by 1.3-fold (P < 0.001) in EPP and 2.5-fold (P < 0.001) in PV patients compared to normal subjects. There was a significant difference in protoporphyrin accumulation between Fe deficient and Fe replete cells from PV patients as compared to normals but not as marked as for EPP cells treated similarly. Stimulated lymphocytes from prepubertal PV offspring with reduced PPO activity accumulated normal amounts of protoporphyrin. PPO is significantly reduced in both diseases. Ferrochelatase becomes defective in PV patients after puberty. This could explain why PV is clinically and biochemically manifest only after puberty. Ferrochelatase apparently is markedly reduced in EPP. Both enzymes apparently are deficient in these 2 porphyrias.