In this study we report a long-term series of patients undergoing liver transplantation for EPP in the UK, which includes all adult patients transplanted for this indication between 1987 and 2009.
In contrast to acute porphyrias, where the majority of severely affected patients are female, in this study there was no significant gender difference in patients undergoing transplantation for EPP. These findings are consistent with the US series of 20 patients where a 3:2 male:female ratio was observed(McGuire et al. 2005
). It remains possible that this slight male predominance may reflect the increased frequency of XLDPP in males, which may also be more likely to cause hepatopathy, (Elder et al. 2009
) although ferrochetolase gene abnormalities were present in each of the ten patients in this study in whom DNA analysis was performed. (McGuire et al. 2005
Median age at transplant was 40 years which is considerably younger than the traditional elective liver transplant population (van der Meulen et al. 2007
). Three EPP recipients (60%) remain alive at between 55 months and 22.4 years and there were two deaths at 44 and 95 months from causes not directly related to the porphyria. This data is again in keeping with reports of patients transplanted for this indication in the US, where a 69% patient and graft survival was seen (McGuire et al. 2005
). It has been reported that liver disease is more prevalent in patients with autosomal recessive EPP (Elder et al. 2009
;Whatley et al. 2008
) and XLDPP (Whatley et al. 2008
). In this cohort, all patients had an erythrocyte protoporphyrin screen to identify the presence of free and or zinc protoporphyrin, and XLDPP was considered unlikely because of the absence of the typical pattern of increased zinc and free protoporphyrin associated with this disorder. Although the proportion of transplanted patients with XLDPP is not presently known, and this subgroup of patients does warrant more careful monitoring, it is likely that these patients account for a minority of the liver disease burden in EPP.
As EPP patients undergo liver transplantation for end-stage liver disease this is reflected by MELD scores which are comparable to patients transplanted for other diagnoses (Freeman 2008
). Although LT is associated with good survival rates, it does not correct the underlying enzyme defects and excessive protoporphyrin production in the bone marrow continues (Samuel et al. 1988
) leading to almost universal recurrence of liver damage. In our series 80% of patients had histological evidence of recurrent liver damage, of which one case is particularly advanced. Disease recurrence was usually also reflected in a deterioration in liver function tests, with a rise in bilirubin and other markers of cholestasis. This is similar to the US experience where 65% had recurrence and 15% required re-transplantation (McGuire et al. 2005
). Attention should therefore be focussed on strategies to minimise the extent of recurrent liver damage after transplantation.
Biliary complications are very common after liver transplantation for EPP, and were observed in 80% of patients in this cohort. A 45% biliary complication rate was reported in the US series (McGuire et al. 2005
) which, although lower than our experience, remains significantly higher than the reported rate of 15-30% observed in the general liver transplant population.(Welling et al. 2008
) Biliary outflow obstruction, whether from anastomotic strictures or disease-related accumulation of stones/sludge, is particularly detrimental in these patients as impairment of bile flow causes hepatic protoporphyrin accumulation and promotes recurrence of EPP in the graft (McGuire et al. 2005
). The early identification and correction of such complications is therefore essential. One patient transplanted at our centre underwent Roux-en-Y biliary reconstruction several years after transplantation following recurrent biliary obstructive complications. This procedure led to complete histological resolution of biliary features, with no further biliary complications during eight subsequent years of follow-up. Although there is little direct experience in the setting of EPP, in the general liver transplant population Roux-en-Y choledochojejunostomy at the time of transplant has been associated with a significantly lower rate of biliary complications compared with conventional common duct anastomosis.(Leonardi et al. 2005
;Welling et al. 2008
). Thus we would suggest that biliary reconstruction with a Roux loop at the time of liver transplant may further reduce the rate of biliary complications and hence decrease EPP-mediated liver damage in the allograft.
The occurrence of light–induced skin burns in the first patient transplanted for EPP in our centre led to the use of intra-operative light filters during subsequent procedures to prevent light-induced skin and intestinal damage (McGuire et al. 2005
;Seth et al. 2007
), although minor burns may still occur (McGuire et al. 2005
). However this could be reduced by adopting a recently proposed combination of light filters (Wahlin et al. 2008
). In our experience such filters do not cause significant distortion of vision or interference with surgery(Seth et al. 2007
The presence of anaemia, from haemolysis, iron deficiency or chronic disease, drives the haem synthesis pathway, further increasing the production of hepatotoxic protoporphyrins. It is therefore recommended that adequate haemoglobin levels (≥12 g/dl) are maintained to reduce protoporphyrin production. Recurrent red cell transfusion has been demonstrated to reduce erythrocyte and plasma protoporphyrin levels in association with improvements in photosensitivity and hepatic function, although does carry the risk of iron overload (Dobozy et al. 1983
;Spiva and Lewis 1984
;van Wijk et al. 1988
;Wahlin et al. 2007
). Other therapeutic options which may be considered include inhibiting protoporphyrin production with intravenous hemin infusion, (Do et al. 2002
), and removal of protoporphyrin using plasmapheresis (Do et al. 2002
), and/or red cell exchange (Eichbaum et al. 2005
). Both hemin infusion and plasmapheresis have been demonstrated in a small number of patients to improve plasma and erythrocyte protophorphyin levels in addition to liver biochemistry and histology(Dellon et al. 2002
;Do et al. 2002
;Dobozy et al. 1983
;Reichheld et al. 1999
). Similar improvements have been demonstrated with red cell exchange transfusion (Eichbaum et al. 2005
) although such treatment is seldom used and generally reserved for severe or rapidly deteriorating cases (Anstey and Hift 2007
). Whilst red cell exchange has been helpful in one of our cases with severe recurrent EPP-mediated liver damage, plasmapheresis was not found to be of benefit in another of the EPP patients in this cohort.
Bone marrow transplantation (BMT) is at present the only treatment able to correct the underlying bone marrow defect resulting in excessive protoporphyrin production (Fontanellas et al. 2000
;Wahlin et al. 2007
). BMT has been successfully used early post-transplant to stabilise or prevent recurrent EPP liver disease (Rand et al. 2006
) and, although experience is limited, this option may be considered in patients undergoing LT for EPP if a compatible related donor is available. This is reinforced by survival data for BMT for non-malignant disease, which range from a 3-year survival rate of 70-90% in matched sibling donors to 36-65% in unrelated donors (Appelbaum 2003
), underlining the importance of identifying sibling donors. The single BMT undertaken in our cohort was performed one year after liver transplantation due to rapid EPP disease recurrence. Although BMT did cure the EPP, this patient unfortunately died 32 months later, with a fully functioning liver, from cerebral tuberculosis related to complications of immunosuppression. Concurrent liver and bone marrow transplantation has not to our knowledge been attempted.
In conclusion, patients transplanted for EPP have a good long-term survival, although given the high rate of biliary complications and recurrent EPP-mediated liver damage we would suggest consideration of Roux loop formation at the time of transplant. BMT should be considered for patients with sibling donors as this will result in cure of the EPP.