The porphyrias are a group of disorders caused by defects in haem biosynthesis (fig 11).). Of the seven main types of porphyria recognised, two are characterised by associated liver disease (table 11).). In porphyria cutanea tarda it is the liver disease which leads to the onset of the porphyria, characterised by blistering, hirsutes and skin fragility of sun‐exposed skin. A number of different liver diseases may precipitate porphyria cutanea tarda including haemochromatosis, alcoholic liver disease and hepatitis C. In contrast, in erythropoietic protoporphyria (EPP) it is the porphyria itself which leads to liver disease, due to progressive deposition and accumulation of insoluble protoporphyrin IX in hepatocytes and bile canaliculi.
EPP is an inborn error of haem biosynthesis caused by mutations in the gene encoding the mitochondrial enzyme ferrochelatase (FECH), the final enzyme in the haem biosynthetic pathway (fig 11).1,2,3,4,5 It was first described by Magnus et al in 1962.6 Ferrochelatase catalyses the insertion of ferrous iron into protoporphyrin to form haem, and when defective or deficient, accumulation of protoporphyrin ensues. Ferrochelatase is active in cells that produce haem including erythroid precursors in the bone marrow7 and hepatocytes.8 However, the majority of protoporphyrin (80% or more) originates from bone marrow with most of the remainder generated by the liver (fig 22).7,9
Protoporphyrin accumulates in the maturing red blood cells during haematopoiesis. When red cells enter the circulation, free protoporphyrin diffuses across the red cell membrane and binds to plasma proteins. The liver extracts protoporphyrin from the plasma, most of which is excreted unchanged into the bile, with the remainder metabolised (by liver ferrochelatase) to haem. Some protoporphyrin is subsequently reabsorbed in an enterohepatic circulation.10
Protoporphyrin‐induced hepatotoxicity is a rare complication occurring in 1–5% of patients, for whom liver transplantation is often required. Since the first liver transplant for EPP in 1980,11 more than 40 further liver transplants have been carried out as treatment for advanced liver disease in this condition. However, liver transplantation fails to correct the underlying metabolic deficiency and protoporphyrin damage to the transplanted liver is likely.
EPP is an inherited disorder with both recessive12,13,14,15,16 and dominant patterns of inheritance (fig 3A, BB).). In most patients with EPP, disease‐causing mutations are present on one allele in association with co‐inheritance of a low‐expression allele.17 This has been demonstrated by case‐control association in 39 families with EPP.18 Using haplotype segregation analysis, a polymorphism was identified in intron 3 (IVS3‐48C) that increases the use of an aberrant splice site.19 The aberrantly spliced mRNA has been shown to be subject to more rapid degradation resulting in a decreased steady‐state level of mRNA, leading to a further reduction in FECH enzyme activity and disease expression.19 The low‐expression variant IVS3‐48C has a prevalence in the white population of France of about 10%.18 Co‐inheritance of a FECH mutation and the low‐expression allele accounts for nearly all cases of expressed EPP,20,21,22,23 with estimated true autosomal recessive inheritance accounting for about 3% of cases.23 Very rarely, alternative mechanisms may reduce FECH activity below the critical threshold for symptomatic disease, including deletion of an FECH gene secondary to leukaemia24 or a dominant negative effect from the mutant FECH allele.25
The FECH gene was cloned and sequenced in 199026 and subsequently localised to the long arm of chromosome 18 (18q22.31).27 It spans 45 kb and contains 11 exons which code for an enzyme with 423 amino acid residues.28 The enzyme functions as a dimer, which may have reduced stability and catalytic activity in the presence of a mutated subunit.29 Allelic heterogeneity of the molecular defects in the FECH gene has been demonstrated.30 Analysis of the genetic mutations in EPP reveals three main categories:
- Nucleotide substitutions: missense and nonsense mutations caused by single nucleotide substitutions in the coding region; nonsense mutations are null.
- Splice site mutations: these may produce truncated proteins but this has never been directly shown for EPP. Furthermore, these mutations do not always produce stable mRNA transcripts; they may be null or may preserve some activity.
- Frameshift mutations resulting in premature stop codons are always null, the mechanism being accelerated RNA decay.
Minder et al described a significant genotype‐phenotype correlation between so‐called “null allele” mutations and protoporphyrin‐related liver disease in EPP.31 This supported an earlier report which showed major structural alteration in the FECH protein in all of eight cases undergoing liver transplantation for EPP‐associated liver failure.32,33 However, as more data accumulate, it is increasingly clear that the FECH gene mutations by themselves do not account for the severe liver disease phenotype, as the same mutations have now been reported both in asymptomatic family members and in patients from families in which liver disease had not occurred.33,34 There is currently no way reliably to identify patients at risk, and no intervention that is uniformly effective in restoring normal liver function once hepatic failure ensues.