Erythropoietic protoporphyria clinical and epidemiological aspects

Sammanfattning: Erythropoietic protoporphyria, EPP, is an inherited disease in which the main clinical manifestations are painful cutaneous sensitivity to intense light and liver disease which in some requires liver transplantation for survival. This thesis originated in questions and perceived limitations in understanding that accompanied the management of the patient in Study I. Study I-II details the successful reversal of liver failure in an EPP patient, compiles treatment modalities in a comprehensive literature review and reports curative hematopoietic stem cell transplantation (HSCT) which had previously never been attempted in this context. HSCT leads to long-standing genotypic correction in the erythroid tissues and that this is enough to prevent the phenotypic manifestations. In Study II, we discuss some differences between EPP mouse models and human EPP and conclude that findings in EPP mice models should be interpreted with caution before they are applied to human EPP. Study III explores the risk for and the protection from phototoxic injuries caused by surgical luminaires. In this study we explored the risk for burn injuries in non-transplant surgery, the characteristics of optimal filters for use during liver transplant surgery, and different models to study light induced phototoxicity in vitro. We concluded that surgical light is harmless for EPP patients that are not in cholestatic liver failure and undergoing liver transplantation, that a yellow filter which blocks wavelengths below 470 nm seems optimal for liver transplantation and that an in vitro erythrocyte assay was a good model for studying phototoxicity. Study IV is a comprehensive review of the Swedish EPP cohort including demographic, clinical, biochemical and genetic features. An extensive questionnaire, genotyping and testing of a large number of biochemical parameters were used to collect data. In 2008 the prevalence in Sweden was 1:180,000. Nine novel ferrochelatase mutations were found. Women had a lower erythrocyte protoporphyrin concentration than men and tended to have a higher vitamin D concentration. Alterations in red blood cell parameters, iron parameters and liver function tests were common and 20% had previously been diagnosed with gall stone disease. Life quality was markedly reduced by the disease and available treatments for phototoxicity had poor efficacy for most. The most common reported age at onset of symptoms was the first year of life, yet the mean age at diagnosis was 22 years. This diagnostic delay had worsened in the 21st century. Study V describes all EPP patients that have been liver transplanted in Europe. We identified 37 transplants in 33 patients and compiled the overall outcome, the frequency of EPP specific complications such as disease recurrence in the graft, phototoxic burn injuries and postoperative neuropathy, any EPP specific treatments that had been used preoperatively and background characteristics including EPP genotype and erythrocyte protoporphyrin concentrations. The overall survival was 80 percent at one year and 66 percent at five and ten years. Recurrent EPPrelated graft disease was common but did not seem to affect long-term survival. None of the patients that had been protected by light filters were burnt, in contrast to 20 % of the unprotected patients. Fifteen percent had prolonged postoperative motor neuropathy. Some of the limitations in knowledge that motivated this thesis have been elucidated but study results also point to several aspects of EPP that deserve further attention.