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Postgrad Med J 83:739-748 doi:10.1136/gut.2006.097576
  • RECENT ADVANCES IN CLINICAL PRACTICE
    • Review

Liver disease in erythropoietic protoporphyria: insights and implications for management

  1. A V Anstey1,
  2. R J Hift2
  1. 1
    Royal Gwent Hospital, Newport, Gwent and Department of Dermatology, Cardiff University, Cardiff, UK
  2. 2
    Lennox Eales Porphyria Laboratories, MRC/UCT Liver Research Centre and Department of Medicine, University of Cape Town and Groote Schuur Hospital, South Africa
  1. Dr Alex Anstey, Royal Gwent Hospital, Cardiff Road, Newport, Gwent NP20 2UB, UK; alex.anstey{at}gwent.wales.nhs.uk

    The porphyrias are a group of disorders caused by defects in haem biosynthesis (fig 1). Of the seven main types of porphyria recognised, two are characterised by associated liver disease (table 1). 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.

    Figure 1 The haem biosynthetic pathway showing the enzyme deficiency associated with porphyria cutanea tarda (PCT) and erythropoietic protoporphyria (EPP). The final step in this pathway involves the incorporation of iron into the middle of the ring structure of protoporphyrin IX to form haem.
    View this table:
    Table 1 Liver disease and the porphyrias: names and patterns of inheritance for the seven main clinical variants of porphyria, highlighting those characterised by concomitant liver disease

    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 1).15 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 2).7 9

    Figure 2 The fate of protoporphyrin IX in erythropoietic protoporphyria.

    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 …