In erythropoietic protoporphyria (EPP), there is excessive production of protoporphyrin, primarily in the bone marrow, resulting in increased biliary excretion of this heme precursor. Some patients will develop progressive liver disease that may ultimately require liver transplantation. However, excessive production of protoporphyrin by the bone marrow continues after transplantation, which may cause recurrent disease in the allograft. This study was performed to define post-transplant survival, the risk of recurrent disease, and specific management issues in patients transplanted for EPP liver disease. The patients studied consisted of twelve males and eight females, with an average age of 31 (range, 13-56) years at the time of transplantation. The estimated maximum MELD score prior to transplant was 21 (range, 15-29). Unique complications in the perioperative period were light induced tissue damage in four patients and neuropathy in six, requiring prolonged mechanical ventilation in four. Patient and graft survival rates were 85% at 1 year, 69% at 5 years, and 47% at 10 years. Recurrent EPP liver disease occurred in 11 of 17 patients (65%) who survived more than 2 months. Three patients were retransplanted at 1.8, 12.6, and 14.5 years after the initial transplant for recurrent EPP liver disease. In conclusion, the 5-year patient survival rate in patients transplanted for EPP liver disease is good, but the recurrence of EPP liver disease appears to diminish long term graft and patient survival. (Liver Transpl 2005;11:1590–1596.)
Erythropoietic protoporphyria (EPP) is a genetic disorder associated with a deficiency of ferrochelatase activity, which catalyzes the formation of heme from protoporphyrin and iron.1–3 Patients with EPP have excessive production of protoporphyrin, primarily in the bone marrow, resulting in increased biliary excretion of this compound.4
The major clinical manifestation in EPP is photosensitivity, which is caused by the photo-active damage to skin by protoporphyrin.5, 6 Some patients also develop liver disease that is caused by the toxic effect of protoporphyrin on hepatobiliary structure and function.7 Experimental studies have shown that protoporphyrin impairs bile formation and alters activity of hepatic membrane-bound enzymes.8, 9 In addition, studies in a mouse model of EPP indicate that toxic bile may be formed, which damages bile duct epithelium and causes biliary fibrosis.10 Patients with progressive EPP liver disease may experience crises with clinical exacerbation of the disease, characterized by acute worsening of liver function and an increase in the erythrocyte protoporphyrin levels that are often accompanied by severe abdominal and back pain.11 Patients who progress to cirrhosis and develop liver failure have been successfully salvaged with liver transplantation.12–22 However, liver transplantation does not alter the excessive production of protoporphyrin by the bone marrow.23 Thus, recipients are at risk for recurrence of disease in the graft.24–27
Unique treatment options have been needed to manage EPP crises and prevent operative and peri-operative complications that occur in patients who undergo liver transplantation. To prevent intra-operative light-induced tissue damage, filters are placed over the operating room lights to absorb wavelengths that excite protoporphyrin.28 To treat EPP crisis and neuropathy, intravenous hematin therapy with or without plasmapheresis has been used.29–32
The largest previous study, which reported the complications and outcomes of nine patients transplanted for EPP, was published in 1996 and showed that intermediate survival was good.18 The present study includes those nine patients and adds eleven others who have been transplanted in the United States. It defines long-term patient and graft survival rates, recurrence rate of EPP liver disease, and management issues for these patients.
EPP, Erythropoietic protoporphyria; MELD, Model for end-stage liver disease; UNOS, United Network for Organ Sharing; INR, International normalized ratio of prothrombin time.
This is a retrospective study of all known patients in the United States who have been transplanted for EPP liver disease. A review of the United Network for Organ Sharing (UNOS) Database confirmed that no additional patients have been transplanted for EPP liver disease in the United States. No patient was lost to follow-up. The diagnosis of EPP was made on the basis of clinical features, marked elevation in erythrocyte protoporphyrin level, and characteristic histological features in liver biopsy specimens. Data included patient demographics, preoperative laboratory studies, clinical status and management prior to liver transplant, date of transplant and surgical data at the time of transplant, perioperative and long-term complications, immunosuppression, and histologic features in liver biopsy specimens obtained post-transplant.
Diagnosis of recurrent EPP liver disease after liver transplant required liver biopsy that documented the presence of birefringent pigment deposits by polarizing microscopy. Graft survival was calculated from the time of the initial transplant to the time of retransplantation or patient death. Patient survival was defined from the time of the initial transplant until patient death. Graft and patient survival rates were compared to non-EPP recipients in the UNOS database, which includes patients who received a liver transplant between 1988 and 2002. We excluded patients receiving multiple organs or undergoing retransplantation. Kaplan-Meier analysis was used to compute overall graft and patient survival, including 95% confidence intervals. Paired t-tests were used to evaluate the change in total serum bilirubin and erythrocyte protoporphyrin levels before and after hematin therapy with or without plasmapheresis. Data collection was obtained by the hepatologists who participated in their care. The study was approved by the Institutional Review Board of the University of Alabama at Birmingham, where the data were collated and analyzed.
The patient population consisted of twelve males and eight females, with an average age of 31 (range, 13-56) years at the time of transplantation, including six pediatric patients; nineteen were Caucasian and one was African American (Table 1). The patients were transplanted at thirteen different United States transplant centers. The first patient was transplanted in 1979, four in the 1980s, eleven in the 1990s, and four subsequently. All patients had severe photosensitivity prior to liver transplant. Ferrochelatase DNA analysis in ten patients showed that each was heterozygous for a mutation in the ferrochelatase gene that caused splicing abnormality in six, frame shift or nonsense in three, and missense in one; nine patients also had a polymorphism in the other ferrochelatase allele (IVS3-48c) that caused low expression of the gene.1–3
Table 1. Demographics of 20 EPP Patients Prior to Liver Transplantation
Data available in 17 patients.
Abbreviations: EPP, Erythropoietic protoporphyria; INR, International normalized ratio of prothrombin time; MELD, Model for end-stage liver disease.
The diagnosis of EPP liver disease was confirmed by examination of the explants, which were enlarged and black in color, and with most having micronodular cirrhosis (Fig. 1). Histologic features included active hepatocellular necrosis, portal inflammation, cholestasis and extensive deposits of dark brown pigment in hepatocytes, Kupffer cells, and biliary structures. Polarization microscopy revealed birefringence of several pigment deposits. The biliary reconstruction used in nineteen patients was a choledochocholedochostomy, and in one patient was a choledochojejunostomy. The primary maintenance immunosuppression after liver transplant was cyclosporine in eleven patients and tacrolimus in eight patients. One patient was treated without a calcineurin inhibitor.
The laboratory data at the time of transplant included an average total bilirubin of 13.2 mg/dl (range, 4.2-35), creatinine of 0.9 mg/dl (range, 0.5-2.6), and INR (measured or estimated from available prothrombin times) of 1.6 (range, 1.0-2.1).33 The estimated MELD score in the patients prior to transplant was 21 (range, 15-29).
Twelve patients had episodes of EPP crisis prior to liver transplantation. EPP crisis was treated by hematin infusions (3-4 mg/kg intravenously) alone in four and by hematin infusions plus plasmapheresis (1-1.5 plasma volume) in three (Fig. 2). A more detailed account of this therapy in some of the patients has been reported previously.11, 30, 31 The average total serum bilirubin level decreased from 9.5 mg/dl (range, 0.7-31.4) before therapy to 5.9 mg/dl (range, 0.7-18.5) at the end of therapy (P = 0.3). In five patients for whom data was available, the average erythrocyte protoporphyrin level decreased from 6,281 mcg/dl (range, 2,307-12,790) before therapy to 2,301 mcg/dl (range, 1,231-4,670) at the end of therapy (P = 0.058).
Special filters (CLS-200-X; Madico Inc., Woburn, MA) were placed over the operating room lights during the liver transplant in 12 of 20 patients to absorb wavelengths that excite protoporphyrin. Four patients did experience tissue burns during surgery. This was mild in two patients who had the special filters in the operating room during the transplant. One of the two patients who did not have the special filters developed third degree skin burns and multiple small bowel perforations, which resulted in uncontrolled sepsis and death within 2 months after liver transplant. The other patient developed second degree skin burns. All of the skin burns were located adjacent to the surgical incisions.
Another unique complication that occurred in the perioperative period was neuropathy, which caused severe motor weakness in six patients. In two patients, it occurred prior to transplant. Four of the patients required prolonged ventilation (19 to 42 days).
Common complications that occurred in the 20 patients after liver transplantation included at least one episode of acute cellular rejection in ten, cytomegalovirus disease in eight, and biliary tract complications in nine. The biliary complications consisted of anastomotic strictures in five, stones obstructing the biliary system in two, anastomotic biliary leak in one, and displacement of the t-tube in one.
Recurrent EPP liver disease, documented by liver biopsy, occurred in 11 of the 17 patients (65%) who survived more than 2 months after liver transplantation (Fig. 3). Of the remaining six patients without evidence of recurrent EPP, their liver functions have showed no signs of cholestasis. There was no association between recurrent EPP liver disease and the type of immunosuppression used, age of the patient at transplant, development of cytomegalovirus infection, or overall episodes of acute cellular rejection. However, in four patients the diagnosis of recurrent EPP liver disease was made within 2 months before or after the time of biliary tract disease (two anastomotic strictures and two with stone disease and obstruction). The earliest liver biopsy showing recurrent EPP liver disease was obtained 8 months after transplantation.
Three patients were retransplanted at 1.8, 12.6, and 14.5 years for recurrent EPP liver disease. Three additional patients died with recurrent EPP disease between 61 and 73 months after liver transplantation, documented by extensive protoporphyrin deposits and bridging fibrosis or cirrhosis on liver biopsy. Two of the three patients were treated with hematin and plasmapheresis for EPP crisis and the third was treated with hematin to delay the progression of liver disease. In addition, four other patients were treated with hematin with or without plasmapheresis after liver transplant for EPP recurrent liver disease. In the seven patients who were treated with hematin with or without plasmapheresis routine laboratory data was available in six patients and erythrocyte protoporphyrin data was available in three patients. The average total serum bilirubin level decreased from 6.4 mg/dl (range, 1.8-20.7) before therapy to 2.3 mg/dl (range, 1.0-6.6) at the end of therapy (P = 0.063). The average erythrocyte protoporphyrin level decreased from 7,447 mcg/dl (range, 2,576-10,300) before therapy to 2,922 mcg/dl (range, 2,136-3,780) at the end of therapy (P = 0.16).
Overall patient and graft survival rates after liver transplantation for EPP patients were 85% at 1 year, 69% at 5 years, and 47% at 10 years (10 years 95% confidence interval are 93% to 25%) (Fig. 4). Pediatric patient and graft survival rates after LTX were 100% at 1, 75% at 5, and 50% at 10 years. Adult survival rates after LTX were 79% at 1, 67% at 5, and 45% at 10 years. There was no apparent difference noted between the adult patients and pediatric patients although the small number of pediatric patients did not allow valid statistical analysis. By comparison, the 1, 5, and 10 years survival rates from the UNOS database of primary liver transplants is 86%, 74%, and 60.5%, respectively, with 10 year 95% confidence interval of 59.9% to 61.2%. A total of nine deaths have occurred after liver transplantation in the EPP patients. The three deaths that occurred within 2 months after initial liver transplantation were related to sepsis, small bowel perforation, and multi-system organ failure. Another death occurred suddenly 5 years after liver transplant in a patient with recurrent EPP liver disease, but autopsy was not performed. Three deaths occurred in patients who developed severe recurrent EPP disease after liver transplantation but were not retransplanted. One death occurred from sepsis 3 months after bone marrow transplant in a patient who had a second liver transplant three months before the bone marrow transplant. A second death occurred within 1 month after second liver transplant from fungal sepsis. The third patient who received a second liver transplant for recurrent EPP liver disease is alive 23 months after the second transplant without recurrent EPP liver disease.
This report is the largest compilation of patients transplanted for EPP liver disease. It includes all patients transplanted for this condition in the United States between 1979 and 2004. No additional patients were identified by a search of the UNOS database.
The overall patient and graft survival rates after liver transplantation were 85% at 1 year, 69% at 5 years, and 47% at 10 years. The recurrence rate of EPP liver disease was 65% in patients surviving greater than 2 months, which impacted long-term patient and graft survival rates. Six graft losses were caused by recurrent EPP liver disease. One additional patient with recurrent EPP liver disease died of an unknown cause. Comparing EPP patients with patients in the UNOS database of primary liver transplants shows no statistically significant difference in graft and patient survival rates, but this maybe due in part to the small number of EPP patients transplanted to date.
Given the continual production of protoporphyrin by the bone marrow after liver transplantation, prophylactic interventions have been considered in EPP patients to decrease photosensitivity and the risk for recurrent EPP liver disease. Prophylaxis interventions to prevent recurrent EPP include chronic therapy with hematin and plasmapheresis or bone marrow transplantation. Hematin and plasmapheresis require placement of a central catheter access and does not correct the deficiency of ferrochelatase activity in the bone marrow. Bone marrow transplantation has the advantage of correcting the deficiency of ferrochelatase activity in the bone marrow. Experimental studies using bone marrow replacement in a mouse model of EPP,34, 35 as well as studies in a human with the disorder,36 indicate that this will be the case. Patients receiving bone marrow transplantation for nonmalignant diseases generally have a 3-year survival rate of 70-90% if the donor is a matched sibling and 36-65% if the donor is unrelated.37 Thus, to prevent or stabilize recurrent EPP liver disease in a patient who has had a liver transplant, bone marrow transplantation should be considered early after liver transplantation if a matched sibling is available.
Complications after liver transplantation that can initiate or exacerbate EPP liver disease include rejection, cytomegalovirus infection, alcohol use, and certain drug use. Biliary tract complications after transplant in patients with EPP may be particularly detrimental. These complications, which include anastomotic strictures that are common after liver transplantation, can impair bile flow and promote the recurrence of EPP liver disease in the graft. Biliary complications occur in 25-30% of patients transplanted for all types of liver disease.38, 39 In this study, biliary tract complications occurred in 45% of the patients, including four cases that were closely associated with recurrent EPP liver disease. Thus biliary tract complications need to be identified and corrected early before protoporphyrin deposits accumulate and cause damage to the bile ducts and the hepatocytes. In addition, a thorough evaluation of the biliary system is indicated if a patient transplanted for EPP liver disease has abnormal liver function tests and evidence of recurrent disease on liver biopsy.
Seventeen of the 20 patients in this report were transplanted before the MELD system began in February 2002. However, it is anticipated that EPP patients will continue to receive transplants under the current system. The cholestatic nature of EPP, exhibited by the average total bilirubin of 13 mg/dl (range, 4.2 to 35) prior to liver transplantation contributed to an average adult MELD score of 21 points. Seven patients were treated with hematin infusions with or without plasmapheresis therapy prior to transplant, which decreased erythrocyte protoporphyrin and serum bilirubin levels. Since this therapy lowers MELD scores, it may require special exemption when listing patients for liver transplantation in EPP crisis.
One of the unique complications of EPP is the photo-activation of protoporphyrin by the operating room lights during the liver transplant surgery, which causes tissue burns. Thus, for any surgery in subjects with EPP it is prudent to use special filters to cover the operating room lights. Since instituting the use of the special filters, there has been one case of second degree skin burns and one case of mild skin burns around the incision site. The filters cause only a minimal distortion of vision and do not impede the operation.
This study establishes that liver transplantation is a viable treatment for EPP end-stage liver disease. EPP has unique complications and treatment modalities that need to be addressed before, during, and after transplantation. Before surgery, EPP crisis should be managed with hematin and plasmapheresis. However, since this therapy lowers MELD scores, consideration should be given for an exemption when listing these patients for liver transplantation. During the surgery special filters should be placed over all lights in the operating room to minimize tissue burns. Finally after liver transplantation, photosensitivity and EPP recurrent liver disease can be treated with hematin and plasmapheresis with bone marrow transplantation a consideration early after transplantation to prevent or stabilize recurrent EPP liver disease.
This work was supported by research grants from the National Institutes of Health to Joseph R. Bloomer (DK 026466) and Herbert R. Bonkovsky (RO1 DK 038825; MO1 RR 01693; UO1 DK 065193; N01 DK 92326).