The acute hepatic porphyrias

Abstract

Heme and porphyriasPorphyrias are inherited disorders of heme biosynthesis. Heme is an essential molecule that carries out a wide array of functions necessary for aerobic life. It is the prosthetic group for essential molecules including hemoglobin, mitochondrial cytochromes and cytochrome P-450s. Heme is synthesized through eight enzymatic steps, and mutations that lead to defective activity in heme synthesis enzymes result in the eight inherited porphyrias. As a result, there is abnormal accumulation of the intermediates that precede the enzyme deficiency. Symptoms for the porphyrias are due to the specific intermediates that accumulate.The acute hepatic porphyrias, acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP) and 5-aminolevulinic acid dehydratase deficiency porphyria (ALAD) all present with similar episodic acute neurovisceral attacks due to abnormal accumulation of the neurotoxic porphyrin precursors delta-aminolevulinic acid (ALA) and porphobilinogen (PBG).The process of heme synthesis is shown in Figure 1. The conversion of glycine and succinyl coenzyme A to ALA by the mitochondrial enzyme ALA synthase (ALAS) is the first and rate limiting step in heme synthesis. In subsequent reactions, two molecules of ALA combine to form the porphyrin precursor PBG. Four PBGs are linked and cyclized to form the first porphyrin of the pathway, uroporphyrinogen I. Subsequent reactions in the pathway produce porphyrin intermediates of progressively decreasing water solubility until the formation of heme (Figure 1). It's important to note that the first two intermediates, ALA and PBG are porphyrin precursors, not porphyrins. The excretion of the hydrophilic ALA, PBG, and uroporphyrin are entirely in urine, whereas coproporphyrin is in both urine and feces, and protoporphyrin only in feces.Though all cells in the human body synthesize heme, it is predominantly formed by erythroblasts in the bone