Relationships between acute hepatic porphyrias due to genetic variability of primary enzyme defects and limiting function of uroporphyrinogen synthase

Abstract

1. 1. Clinical and biochemical analogies and progressions exist among the hereditary acute hepatic porphyrias (AHP), acute intermittent porphyria (AIP). variegate porphyria (PV) and hereditary coproporphyria (HCP). 2. 2. The AHP are essentially regulatory disorders at the molecular level, and have several features in common: drug idiosyncracy, enhanced excretion of porphyrins and their precursors (ALA and PBG) in typical constellations in the urine, elevated porphyrin excretion in the stool (in PV and HCP, and occasionally in AIP). enhanced inducibility of hepatic ALA synthase due to partial enzyme defects in the biosynthetic sequence favorable response to treatment with glucose, propranolol, and hematin, and development in a four-stage progression: phase of the genetic defect→ latency phase (compensated → decompensated) → clinical manifestation. 3. 3. Cutaneous signs can be fully lacking not only in AIP, but also in HCP and PV. 4. 4. The absolute extent of the enzyme defect can vary considerably (overlapping with normal). 5. 5. Gradual transitions between AIP and PV, and probably among AIP, HCP and PV as well. are suggested by several observations: PV can occur without cutaneous signs, thus imitating AIP: in AIP, elevated excretion of porphyrins in the stool is occasionally seen in both the manifest and latent phases, and coproporphyrin can be the dominant urinary porphyrin in AIP: both of these findings can cause confusion of AIP with PV. 6. 6. In HCP fecal excretion of protoporphyrin can reach the same level as that of coproporphyrin. If in AIP patients fecal porphyrin excretion is increased, one obtains the first complete overlapping between AIP and PV. 7. 7. In both AIP and in normals PBG in elevated concentrations can not enzymatically be converted to porphyrinogens in equimolar amounts by liver tissue (“physiologic URO'gen synthase defect”). Thus the step catalysed by URO'gen synthase apparently is the bottleneck or limiting step in porphyrin formation. 8. 8. Similar excretion profiles of porphyrin precursors and porphyrins (COPRO > URO >PENTA or URO >COPRO >PENTA) in AIP indicate limitation of uroporphyrinogen synthesis which due to the kinetics of URO'gen synthase (very low activity in human liver) becomes apparent when there is a massive oversupply of PBG (e.g. oral loading with ALA in normals or induction of ALA synthase in AHP). 9. 9. The increased porphyrin synthesis in AIP can therefore be interpreted as part of a compensatory mechanism or regulatory adaptive process to insure formation of adequate amounts of heme. 10. 10. The elevated substrate supply is due to counterregulation. and compensates the partial defect: elevated excretion of metabolites distal to URO'gen synthase masks the deficiency of this enzyme; elevated porphyrin excretion in a clinical-biochemical sign of compensation in AIP. 11. 11. The enzyme defect in the red cells has no regulatory consequence for hemoglobin synthesis.