Liver transplantation in the management of porphyria

Abstract

Porphyrias are a group of eight metabolic disorders, each resulting from a mutation that affects an enzyme of the heme biosynthetic pathway. Porphyrias are classified as hepatic or erythropoietic, depending upon the site where the gene defect is predominantly expressed. Clinical phenotypes are classified as follows: (1) acute porphyrias with neurovisceral symptoms: acute intermittent porphyria; delta amino-levulinic acid hydratase deficiency porphyria; hereditary coproporphyria; and variegate porphyria and (2) cutaneous porphyrias with skin blistering and photosensitivity: porphyria cutanea tarda; congenital erythropoietic porphyria; hepatoerythropoietic porphyria and both erythropoietic protoporphyrias: autosomal dominant and X-linked. Liver transplantation (LT) may be needed for recurrent and/or life-threatening acute attack in acute intermittent porphyria or acute liver failure or end-stage chronic liver disease in erythropoietic protoporphyria. LT in acute intermittent porphyria is curative. Erythropoietic protoporphyria patients needing LT should be considered for bone marrow transplantation to achieve cure.

Conclusion: This article provides an overview of porphyria with diagnostic approaches and management strategies for specific porphyrias and recommendations for LT with indications, pretransplant evaluation, and posttransplant management.

Fig. 1

The heme biosynthetic pathway. Reactions shown above the dashed line take place in the mitochondrion, whereas those below this line occur in the cytosol. At every step of the pathway, corresponding porphyria from the respective deficient enzyme is mentioned in italics and in rectangles. ALAS, aminolevulinic acid synthase; EPP, erythropoietic protoporphyria; ALAD, ALA dehydratase; ADP, ALAD-deficient porphyria; PBGD, porphobilinogen deaminase; AIP, acute intermittent porphyria; UROS, uroporphyrinogen III synthase; CEP, congenital erythropoietic porphyria; UROD, uroporphyrinogen III decarboxylase; PCT, porphyria cutanea tarda; CPO, coproporphyrinogen oxidase; HCP, hereditary coproporphyria; PPO, protoporphyrinogen oxidase; VP, variegate porphyria; FECH, ferrochelatase. Hepatoerythropoietic porphyria is the result of autosomal recessive UROD mutation with severe deficiency of UROD in liver and RBCs and causes the same phenotype as PCT with onset of disease in childhood. *ALAS, rate-limiting enzyme in heme biosynthesis has 2 isoforms: ALAS-1 is the general form present in all cells, and ALAS2 is the erythroid-specific variant present only in RBCs. ^†X-linked EPP is caused by a gain-of-function mutation in ALAS2. EPP is also caused by mutations in FECH.

Fig. 2

Liver biopsy in erythropoietic protoporphyria. (A) Early bile duct damage with cholestasis (arrow). (B) Cholestasis with pigment deposits (arrows) within hepatocytes. (C) Red fluorescence in hepatocytes (arrow), as demonstrated by fluorescence microscopy crystals. (D) Birferigence of pigment deposits, as demonstrated by polarization microscopy, showing protoporphyrin crystals (arrows) in a maltese cross shape. (E) Same polarization microscopy but with biferingent crystals in an unstained specimen. (F) Explant from a patient with EPP showing a black liver.

Fig. 3

Suggested approach to management of protoporphyric hepatopathy in a patient with erythropoietic protoporphyria. *Severe disease: liver disease with worsening liver enzymes and/or bilirubin or development of liver failure.