Repression by Hematin of Porphyrin Biosynthesis in Erythrocyte Precursors in Congenital Erythropoietic Porphyria (negative feedback/erythroblast maturation/hepatic porphyria/transfusions)

Hematin administered intravenously in a patient with congenital erythropoietic porphyria evi- dently entered erythrocyte precursors in the bone marrow, producing the well-known negative feedback repression of porphyrin biosynthesis with marked decline of porphyrin concentrations in urine, circulating plasma, and eryth- rocytes. A delay in the major segment of this effect corresponded roughly with the sum of the average transit times through the maturation compartments of the eryth- rocyte precursors. This delay was considerably longer than previously observed in the decline of porphyrin pre- cursors after administration of hematin in patients with hepatic porphyria. The effect of hematin was compared with that of packed erythrocyte transfusions given at regular intervals in the same patient over a period of 2.5 years. In general, administration of hematin results in a reduction of porphyrin formation of the same order of magnitude, but of shorter duration, possibly in relation to deficiency due to reduced synthesis of protoporphyrin 9. With either mechanism, hematin might be expected to repress or inhibit porphyrin biosynthesis. The activity of a-aminolevulinate synthetase in the cir- culating plasma has been noted to increase with increased erythropoiesis, as gauged by the number of circulating nor- moblasts (19). Such increases were not observed in hepatic porphyria. This difference may be related to the short life span of normoblasts, as compared with liver cells (19). The por- phyric normoblasts lose most of their porphyrin with the ex- trusion of their nuclei, as is readily apparent on fluorescence microscopy of stained blood smears (19). It seemed reasonable that if heme were to enter immature erythrocytes of the bone marrow at a sufficiently early stage, it might exert its usual negative feedback effect on the induc- tion of 3-aminolevulinate synthetase, thus repressing the ex- cessive formation of porphyrin in erythropoietic porphyria.