Acute Hepatic Porphyria

Abstract

The porphyrias comprise a set of diseases, each representing an individual defect in one of the eight enzymes mediating the pathway of heme synthesis. The diseases are genetically distinct but have in common the overproduction of heme precursors. In the case of the acute (neurologic) porphyrias, the cause of symptoms appears to be overproduction of a neurotoxic precursor. For the cutaneous porphyrias, it is photosensitizing porphyrins. Some types have both acute and cutaneous manifestations. The clinical presentation of acute porphyria consists of abdominal pain, nausea, and occasionally seizures. Only a small minority of those who carry a mutation for acute porphyria have pain attacks. The triggers for an acute attack encompass certain medications and severely decreased caloric intake. The propensity of females to acute attacks has been linked to internal changes in ovarian physiology. Symptoms are accompanied by large increases in delta-aminolevulinic acid and porphobilinogen in plasma and urine. Treatment of an acute attack centers initially on pain relief and elimination of inducing factors such as medications; glucose is administered to reverse the fasting state. The only specific treatment is administration of intravenous hemin. An important goal of treatment is preventing progression of the symptoms to a neurological crisis. Patients who progress despite hemin administration have undergone liver transplantation with complete resolution of symptoms. A current issue is the unavailability of a rapid test for urine porphobilinogen in the urgent-care setting.

Keywords: Delta-aminolevulinic acid; Porphobilinogen; Porphyria.

Fig. 1. The pathway of heme synthesis and the enzymes mediating specific steps.

The building blocks of heme are succinyl CoA and glycine, which combine to form delta-aminolevulinic acid (ALA), the first committed intermediate of the pathway. ALA synthase is encoded by two distinct genes: ALAS2 in the bone marrow and ALAS1 elsewhere, including the liver (see text). The second step involves condensation of two molecules of ALA to form porphobilinogen (PBG), the pyrrole subunit of the heme ring. Four PBGs are linked initially in a linear tetrapyrrole, hydroxymethylbilane, which cyclizes to form the initial porphyrin of the pathway, uroporphyrinogen (UROgen). The sequential conversion of UROgen to coproporphyrinogen (COPROgen) and finally to protoporphyrinogen (PROTOgen) involves successive removal of peripheral carboxyl groups. The dashed arrow indicates that the end-product, heme, exerts feedback regulation on the formation of ALA, the initial committed intermediate. The gene symbols for the pathway enzymes are noted in Table 1. ALA, delta-aminolevulinic acid; PBG, porphobilinogen; URO, uroporphyrin; COPRO, coproporphyrin; PROTO, protoporphyrin.

Fig. 2. The profile of heme precursors in excreta for each of the hepatic porphyrias.

The dashed vertical lines indicate the point at which an inherited enzyme deficiency compromises the flow of precursors. For the specific enzymes affected and key to abbreviations, see Fig. 1. [Not shown: The respective patterns for ALAD (very rare, homozygous recessive acute porphyria), congenital erythropoietic porphyria (rare recessive cutaneous porphyria), and protoporphyria (recessive cutaneous porphyria, in which ~5% of cases have liver disease from protoporphyrin deposition.]