MYELOPROLIFERATIVE DISEASE COMPLICATED BY LATE-ONSET ERYTHROPOIETIC PROTOPORPHYRIA AND LIVER DISEASE

Badminton MN1, Whatley SD1, Goodwin RG2, Kell J3, Laidler P4, Long CC2, Burnett AK3, Elder GH1

 

Departments of 1Medical Biochemistry and Immunology, 2Dermatology, 3Haematology, and 4Histopathology University Hospital of Wales, Cardiff, UK.

 

Erythropoietic protoporphyria (EPP) normally presents in childhood with acute photosensitivity. Onset after the age of 40 years is very rare. Most cases have been associated with myelodysplasia and may result from an acquired deletion of the ferrochelatase (FECH) gene at chromosome 18q21.3. Liver failure is a rare complication of the classical form of EPP but no type of liver disease has been reported in association with late-onset disease. We report a 66 year old man with longstanding polycythaemia rubra vera who presented with a short history of jaundice, intense burning and tingling of the hands and feet on exposure to sunlight and a haemorrhagic, blistering eruption on his right foot. Histology of this area was consistent with a severe photo-burn; no changes typical of EPP were seen. However, investigation confirmed that diagnosis; erythrocyte total porphyrin was 112 Âµmol/L (normal < 1.7) with > 95% free protoporphyrin and plasma porphyrin was markedly increased at 1673 nmol/L (normal <11) with a fluorescence emission peak at 635 nm. Serum bilirubin, alkaline phosphatase and aspartate aminotransferase were 188 μmol/L, 433 IU/L and 349 IU/L, respectively. Despite attempts at minimizing enterohepatic recirculation of protoporphyrin with cholestyramine and oral charcoal, his liver disease progressed rapidly. He died with an associated coagulopathy, a bleeding duodenal ulcer and a perforated abdominal viscus.  Liver biopsy showed scattered porphyrin deposits, bile stasis without signs of biliary obstruction, feathery degeneration of hepatocytes and expansion of sinusoids by histiocytes, some containing porphyrin-like pigment. There was no fibrosis, cirrhosis or iron overload. A liver biopsy 2 years previously had shown only extramedullary erythropoiesis. The bone marrow was hypercellular with some erythroid dysplasia. The cytoplasm of erythroid cells showed intense red fluorescence indicating the presence of large amounts of porphyrin. Bone marrow cytogenetic analysis revealed an abnormal karyotype with partial deletion of chromosome 18. Fluorescent in situ hybridization and molecular analysis of the FECH gene in bone marrow DNA was consistent with predominance of a clone of erythroid cells lacking a FECH gene allelic to a low expression ferrochelatase allele. No FECH mutation was detected by sequencing the gene in germ line DNA. Exogenous infusion of protoporphyrin is known to cause acute cholestasis in rats. We believe that this man's cholestatic liver disease was similarly caused by an acute hepatotoxic reaction to protoporphyrin released rapidly from erythroid cells that had developed an acquired ferrochelatase deficiency as his myeloproliferative disease deteriorated. This is the first report of this combination of events.