Survival of Liver Transplant Recipients With Hemochromatosis in the United States

GASTROENTEROLOGY 2007;133:489 495 Survival of Liver Transplant Recipients With Hemochromatosis in the United States LEI YU*, and GEORGE N. IOANNOU*, *Division of Gastroenterology, Department of Medicine Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle Washington; Research Enhancement Award Program Veterans Affairs Puget Sound Health Care System Background & Aims: Earlier studies have suggested that patients with have poor posttransplantation. We aimed to compare patients with to those with other causes of liver disease with regard to post-transplantation. Methods: We compared the posttransplant of patients with and without using data provided by the United Network for Organ Sharing on 50,306 adult, cadaveric liver transplantations performed in the United States between January 1, 1990, and July 18, 2006. Results: During 1990 1996, the post-transplantation of patients with (n 177) at 1 year (79.1%), 3 years (71.8%), and 5 years (64.6%) was lower than the average 1-year (86.4%), 3-year (79.5%), and 5-year (73.8%) of all other transplant recipients (hazard ratio for death, 1.38; 95% confidence interval [CI], 1.12 1.71). In contrast, during 1997 2006, patients with (n 217) had excellent 1-year (86.1%), 3-year (80.8%), and 5-year (77.3%) post-transplantation, which was not different from the 1-year (88.4%), 3-year (80.3%), and 5-year (74.0%) post-transplantation of all other transplant recipients (hazard ratio for death, 0.89; 95% CI, 0.65 1.22). Adjustment for donor and recipient characteristics did not substantially change these results. Compared with recipients without, those with were more likely to die of cardiovascular diseases and less likely to die as a result of graft failure. Conclusions: The post-transplantation of patients with, which was previously reported to be poor, has been excellent in the United States during the past 10 years. It has been suggested that patients who undergo liver transplantation for cirrhosis related to have a higher than average post-transplantation mortality. Kilpe et al 1 reported that 1-year after liver transplantation for between 1982 and 1991 in 37 US centers was 54% (30/56), whereas the 1-year post-transplantation of all patients was 80% (4092/5180). Kowdley et al 2 reported that among 37 patients with -related cirrhosis who underwent liver transplantation in 5 US centers between 1988 and 1993, 1-year post-transplantation was 58%. More recently, Kowdley et al 3 reported that the 1-year post-transplantation of 25 patients with HFE-related who underwent liver transplantation at 1 of 12 US centers before 1996 was 64% which was lower than the 1-year post-transplantation (84%) of all liver transplant recipients in these 12 centers before 1996. Those studies may not accurately reflect the current post-transplantation of patients with for a number of reasons. All those studies analyzed liver transplantations performed before 1996, and in patients with may have improved since then (for instance, as a result of more aggressive iron depletion before and after transplantation or more careful patient selection). 4 6 Those studies included a relatively small number of patients because is a rare indication for liver transplantation. As a result, none of the previous studies adequately adjusted for other predictors of post-transplantation, such as donor age, cold ischemia time, recipient age, and causes of liver disease, 7 or directly compared the post-transplantation of patients with -related cirrhosis with the posttransplantation of patients with other causes of cirrhosis such as viral hepatitis, alcoholic liver disease, or primary biliary cirrhosis. Finally, it is possible that those studies included patients with -related cirrhosis with worse than the average post-transplantation of all patients with related cirrhosis in the United States. To resolve these issues, we compared the post-transplantation of patients with to the post-transplantation of patients with other causes of liver disease with and without adjusting for predictors of post-transplantation using data reported to the United Network for Organ Sharing Abbreviations used in this paper: BMI, body mass index; CI, confidence interval; HCV, hepatitis C virus; NASH, nonalcoholic steatohepatitis; UNOS, United Network for Organ Sharing. 2007 by the AGA Institute 0016-5085/07/$32.00 doi:10.1053/j.gastro.2007.05.054

490 YU AND IOANNOU GASTROENTEROLOGY Vol. 133, No. 2 (UNOS) for all liver transplantations performed in the United States from January 1, 1990, until July18, 2006. 8 Materials and Methods Data Collection Transplantation centers and organ procurement organizations in the United States are required to submit to UNOS 8 standardized data collection forms, including the Transplant Candidate Registration Form, which contains patient information at the time of listing for liver transplantation; the Deceased Donor Registration Form, which contains information on all consented recovered and nonrecovered donors; the Transplant Recipient Registration Form, which includes the patient status at discharge, clinical information before and after transplantation, as well as treatment data; and the Transplant Recipient Follow-up Form, which is generated 6 months after transplantation and on each subsequent transplantation anniversary and includes patient status and clinical and treatment information. These forms are currently submitted to UNOS electronically, and the information is entered into a single Standard Transplant Analysis and Research file that includes one record per transplantation event and the most recent follow-up information on patient status as of the date the file was created. The Standard Transplant Analysis and Research file created by UNOS on July 18, 2006, was kindly provided to the authors for this study. Study Population Of 63,679 liver transplantations involving recipients 18 years of age which were performed in the United States between January 1, 1990, and July 18, 2006, we excluded patients who had donors 10 or 75 years of age (n 1472), living donors (n 2040), split-liver donors (n 763), and non heart-beating donors (n 916). We also excluded patients with multiple simultaneous organ transplantations (n 2278) or previous liver transplantation (n 5904), leaving 50,306 participants in univariate analyses. We divided these patients into 2 time periods, 1990 1996 (n 16,286) and 1997 2006 (n 34,020) for more direct comparison with previous studies performed before 1996 and to look for any changes in the post-transplantation of patients with in more recent years for which no data are currently available. We additionally wanted to explore whether any difference in post-transplantation between patients with and without could be explained by differences in donor or recipient characteristics. For these multivariate analyses, we excluded patients with missing information in donor characteristics, including cold ischemia time (n 5206), and race (n 353), and recipient characteristics, including age (n 1), body mass index (BMI; calculated as the weight in kilograms divided by the square of height in meters [kg/m 2 ]; n 1375), race (n 281), serum albumin (n 1509), bilirubin (n 368), and creatinine (n 67). Finally, we excluded 943 patients with very abnormal values of cold ischemia time, BMI, serum bilirubin, creatinine, and albumin, (because they might have been recorded erroneously) and 183 with implausible values for these variables (almost certainly recorded erroneously), leaving 40,020 patients in multivariate analyses, including 13,342 who received transplants in 1990 1996 and 26,678 in 1997 2006. ( Very abnormal values were defined as follows: cold ischemia time, 0.5 to 1 hour or 24 to 48 hours; BMI, 10 15 or 55 65; serum creatinine, 0 to 0.1 or 15 to 20 mg/dl; serum total bilirubin, 0 to 0.1 or 45 100 mg/dl; and serum albumin, 0 to 0.5 or 6 to 10 g/dl. Implausible were values even more extreme than the abnormal values). Definition of Hemochromatosis and Comparable Liver Diseases The recipient s primary diagnosis leading to liver transplantation was identified by using the UNOS variable diag. This variable describes the recipient s primary diagnosis that was derived from information at discharge from the hospital after the transplantation, that is, after the explanted liver was also available for analysis. If the recipient s primary diagnosis at the time of discharge was not recorded, then the diagnosis at transplantation was used, and, if that was not available, the diagnosis at listing. By using this variable, we divided liver transplant recipients into the following categories:, hepatitis C virus (HCV; including HCV and alcoholic liver disease or hepatitis B virus), hepatitis B virus, alcoholic liver disease, primary biliary cirrhosis, primary sclerosing cholangitis, cryptogenic cirrhosis and fatty liver or nonalcoholic steatohepatitis (NASH), hepatocellular carcinoma, acute hepatic necrosis (excluding acute viral hepatitis B and C and acute alcoholic hepatitis), and others. We attempted to identify if any of the patients with a diagnosis of also had a diagnosis of hepatocellular carcinoma by looking at secondary diagnoses, which have been reported to UNOS only since April 1, 1994. In addition, since the introduction of the model for end-stage liver disease allocation system on February 27, 2002, an exception has been recorded for patients with hepatocellular carcinoma who receive a high priority score, and this was also used to identify patients with who also had hepatocellular carcinoma. Predictors of Post-Transplantation Survival We wanted to investigate whether any observed difference in post-transplantation between patients with and without was due to differences in the following donor and recipient characteristics that are predictors of post-transplantation sur-

August 2007 HEMOCHROMATOSIS AND LIVER TRANSPLANTATION 491 vival: donor age, cold ischemia time, race, and sex; recipient age, race, sex, BMI, serum albumin, bilirubin, and creatinine. 7 All variables were modeled as continuous variables except for race and sex. All these characteristics were ascertained at the time of transplantation. We did not consider diabetes as a potential confounder because causes diabetes; hence, diabetes may be one of the mechanisms by which could lead to worse post-transplantation. Causes of Death We categorized causes of recipient death, recorded by UNOS variable cod, into cardiovascular, graft failure, infection, malignancy, multiple organ system failure, and others. Statistical Analysis The Kaplan Meier method was used to calculate patient at 1, 3, and 5 years after transplantation. Cox proportional-hazards regression was used to compare patients with to patients with other liver diseases with regard to patient and graft after liver transplantation with and without adjusting for the predictors of post-transplantation listed earlier. 9 For the analysis of post-transplantation, patients were censored at the time when they were last traced alive. Graft failure was defined as liver failure (with or without retransplantation) or patient death from any cause. Time was measured from the date of liver transplantation to the date of liver failure, death, or last follow-up. Patients who remained alive without liver failure were censored at the time they were last traced alive. Results The proportion of transplant recipients with was 1.1% (177/16,286) in 1990 1996 and 0.6% (217/34,020) in 1997 2006. Compared with transplant recipients without, those with were older and more likely to be male and white in both time periods (Table 1). The presence of diabetes was routinely reported after 1997, and it was more common in recipients with. BMI and serum levels of bilirubin, creatinine, and albumin were similar in recipients with and without. Also, recipients with were similar to patients without with respect to donor characteristics in both time periods (Table 1). During 1990 1996, the post-transplantation of recipients with at 1 year (79.1%), 3 years (71.8%), and 5 years (64.6%) was lower than the post-transplantation of recipients without at 1 year (86.4%), 3 years (79.5%), and 5 years (73.8%) (Table 2). Compared with recipients without, those with were more likely to die (hazard ratio, 1.38; 95% confidence interval [CI], 1.12 1.71) or to develop graft failure (hazard ratio, 1.27; 95% CI, 1.04 1.54). Adjustment for all the Table 1. Donor and Recipient Characteristics of Liver Transplantations for Patients With and Without Hemochromatosis Patients with (N 177) 1990 1996 1997 2006 Patients without (N 16,109) Patients with (N 217) Patients without (N 33,803) Donor characteristics Age (y), mean SD 35.5 14.8 33.8 15.6 41.3 17.5 40.0 16.7 Cold ischemia time (h), mean SD 9.4 3.4 10.1 3.7 8.0 2.9 7.9 3.0 Race or ethnicity White, % 84.1 80.4 74.0 73.7 Black and African American, % 8.5 10.2 13.0 12.8 Hispanic, % 6.8 7.8 11.6 11.0 Others (mostly Asian), % 0.6 1.6 1.4 2.5 Male, % 70.6 63.3 59.2 61.3 Recipient characteristics Body mass index (kg/m 2 ), mean SD 27.4 5.7 26.7 5.5 28.8 5.5 28.2 5.6 Age (y), mean SD 53.5 9.5 48.6 11.2 54.7 9.0 51.2 10.1 Male, % 81.9 57.4 86.2 66.2 Race or ethnicity White, % 88.6 81.2 90.3 76.2 Black and African American, % 2.3 6.1 0.9 8.0 Hispanic, % 6.3 9.2 5.6 11.4 Other (mostly Asian) 2.8 3.5 3.2 4.4 Diabetes, % NA NA 8.1 3.7 Albumin (g/dl), mean SD 2.8 0.6 3.0 0.6 2.8 0.7 2.9 0.7 Total bilirubin (mg/dl), mean SD 7.6 8.2 6.9 8.8 6.1 7.2 6.4 8.4 Serum creatinine (mg/dl), mean SD 1.2 0.8 1.3 1.1 1.3 0.8 1.3 1.0

492 YU AND IOANNOU GASTROENTEROLOGY Vol. 133, No. 2 Table 2. Comparison of Liver Transplant Recipients With and Without Hemochromatosis With Regard to Patient and Graft Survival After Transplantation in the United States for Periods 1990 1996 and 1997 2006 Patients (n) Patientyears (n) Patient deaths (n) Mortality per 100 patientyears Hazard ratio (95% CI) for patient Hazard ratio (95% CI) for graft 1-Year patient (%) 3-Year patient (%) 5-Year patient (%) Time period 1990 1996 No 16,109 108,928 6,317 5.8 1 1 86.4 79.5 73.8 Hemochromatosis 177 1058 86 8.1 1.38 (1.12 1.71) 1.27 (1.04 1.54) 79.1 71.8 64.6 Time period 1997 2006 No 33,803 96,420 6713 7.0 1 1 88.4 80.3 74.0 Hemochromatosis 217 640 39 6.1 0.89 (0.65 1.22) 0.96 (0.74 1.25) 86.1 80.8 77.3 donor and recipient characteristics shown in Table 1 had little effect on these hazard ratios (adjusted hazard ratio for patient death, 1.30; 95% CI, 1.03 1.64; adjusted hazard ratio for graft failure, 1.24; 95% CI, 1.0 1.5). During the period 1990 1996, recipients with had the worst post-transplantation of any other recipient group defined by cause of liver disease other than hepatocellular carcinoma (Table 3; Figure 1A). In contrast, during 1997 2006, recipients with had similar post-transplantation at 1 year (86.1%), 3 years (80.8%), and 5 years (77.3%) to recipients without (88.4%, 80.3%, and 74.0% at 1, 3, and 5 years, respectively). Adjusted (hazard ratio for patient death, 0.78; 95% CI, 0.54 1.13; and for graft failure, 0.88; 95% CI, 0.64 1.20) and unadjusted (Table 2) hazard ratios comparing recipients with and without did not show any significant difference. During 1997 2006, recipients with had 5-year post-transplantation that was superior to not only recipients with hepatocellular carcinoma but also those with HCV infection, NASH-induced or cryptogenic cirrhosis, alcoholic liver disease, or acute Table 3. Patient Survival After Transplantation for Selected Causes of Liver Disease for Periods 1990 1996 and 1997 2006 1-Year 3-Year 5-Year 1990 1996 Hepatocellular carcinoma 73.2 53.1 44.1 Hemochromatosis 79.1 71.8 64.6 Cryptogenic-NASH 83.3 76.2 69.1 Hepatitis B virus 83.0 73.7 70.2 Alcohol 86.2 79.0 72.4 Hepatitis C virus 87.8 79.4 72.6 Acute hepatic failure 80.7 77.7 76.0 Autoimmune hepatitis 86.8 83.1 78.8 PSC 91.1 86.7 82.4 PBC 90.0 86.2 82.9 1997 2006 Hepatocellular carcinoma 86.6 71.8 62.2 Hepatitis C virus 88.0 78.0 70.4 Cryptogenic-NASH 86.5 80.2 73.5 Alcohol 88.7 80.7 74.4 Acute hepatic failure 84.0 79.6 74.9 Hemochromatosis 86.1 80.8 77.3 Hepatitis B virus 90.0 84.4 81.3 Autoimmune hepatitis 90.4 85.9 80.8 PBC 91.6 87.4 83.4 PSC 93.6 87.6 83.4 NOTE. Causes of liver disease are arranged in order of increasing 5-year. NASH, nonalcoholic steatohepatitis; PSC, primary sclerosing cholangitis; PBC, primary biliary cirrhosis. Figure 1. Kaplan Meier curves of patient after liver transplantation for recipients with and selected causes of liver disease during 1990 1996 (A) and 1997 2006 (B).

August 2007 HEMOCHROMATOSIS AND LIVER TRANSPLANTATION 493 Table 4. Causes of Post-Transplantation Death Among Recipients With and Without Hemochromatosis During the Periods 1990 1996, 1997 2006, and Combined 1990-2006 1990 1996 1997 2006 1990 2006 Cause of death Hemochromatosis, No, Hemochromatosis, No, Hemochromatosis, No, P value a Cardiovascular 23 (27) 922 (15) 6 (15) 864 (13) 29 (23) 1786 (14).002 Graft failure 4 (5) 843 (13) 3 (8) 981 (15) 7 (6) 1824 (14).07 Infection 18 (21) 1213 (19) 11 (28) 1142 (17) 29 (23) 2355 (18).1 Malignancy 11 (13) 886 (14) 3 (8) 777 (12) 14 (11) 1663 (13).6 Multiple organ 5 (6) 424 (7) 2 (5) 663 (10) 7 (6) 1087 (8).3 system failure Other 25 (29) 2,023 (32) 14 (36) 2299 (34) 39 (31) 4322 (33).6 Total 86 (100) 6311 (100) 39 (100) 6726 (100) 125 (100) 13,037 (100) a The P value refers to the comparison of patients with to patients without with respect to the proportion with each cause of death for the entire study period (1990 2006). hepatic failure (Table 3; Figure 1B). Compared with recipients without, those with were more likely to die of cardiovascular diseases and less likely to die as a result of graft failure (Table 4). In the period 1990 1996 we could only identify 3 patients (of 177) with who were recorded to have a secondary diagnosis of hepatocellular carcinoma (of which one was identified in the explanted liver after transplantation). In 1997 2006, 30 of 217 patients with were identified as also having hepatocellular carcinoma, of which 25 were listed as exceptions for priority score after February 27, 2002. Removing these 30 patients did not change 1-, 3-, and 5-year of patients with appreciably. Discussion The most important finding of this study is that in recent years (1997 2006) the 1-year (86.1%), 3-year (80.8%), and 5-year (77.3%) post-transplantation of patients with in the United States was excellent. Post-transplantation in patients with during 1997 2006 was almost identical to the average of all liver transplant recipients and was better than the of recipients with hepatocellular carcinoma, HCV infection, NASHinduced or cryptogenic cirrhosis, alcoholic liver disease, or acute hepatic failure. In contrast, during 1990 1996, 1-year (79.3%), 3-year (71.8%), and 5-year (64.6%) post-transplantation in patients with in the United States was worse than average. In fact, during that time period, patients with had the worst post-transplantation of any major group of patients defined by cause of liver disease, with the exception of patients with hepatocellular carcinoma. From 1990 1996 to 1997 2006, 5-year post-transplantation improved by 13% (from 64.6% to 77.3%) in patients with, whereas it remained almost unchanged in all other patients without (73.8% to 74%). We can only speculate as to the causes of the difference in post-transplantation of patients with between periods 1990 1996 and 1997 2006. In theory, this could be due to better patient selection that may have been prompted by previous studies that reported recipients with to have significantly higher proportion of cardiac disease related mortality than recipients with other liver diseases. 2,10,11 In more recent years, transplantation centers may have been more rigorous at identifying cardiac disease in patients with and excluding them from transplantation. This is suggested by our finding that cardiovascular deaths were more common in patients with than other patients in the period 1990 1996 but not in 1997 2006. Second, although prior studies failed to show an association between the presence of hepatocellular carcinoma and poor after transplantation among recipients with, 2,11 we suspect hepatocellular carcinoma was another important reason for the low post-transplantation during 1990 1996, particularly if patients had large tumors such that they would not have received transplants in more recent years. 12 For example, in the study by Crawford et al, 12 6 of 22 recipients with had hepatocellular carcinoma, including 4 patients with tumors 7, 9, 10, and 12 cm in diameter. All 4 patients died of recurrent hepatocellular cancer. 12 We cannot tell for sure in our study exactly what proportion of patients with also had hepatocellular carcinoma. However, since 1997 hepatocellular carcinoma within the Milan criteria 13 has been recognized as an indication for transplantation in the United States, and patients have been listed as status 2B for the period 1997 2002 or with a high priority score under the model for end-stage liver disease allocation period (2002 to now). This suggests that any patients with hepatocellular carcinoma among those with in the period 1997 2006 would likely be within the Milan cri-

494 YU AND IOANNOU GASTROENTEROLOGY Vol. 133, No. 2 teria, for which post-transplantation is generally good. In contrast, it is likely that many of the patients with during the period 1990 1996 had large tumors (as was consistently shown by earlier studies) which are associated with high post-transplantation mortality. Therefore, we speculate that one of the reasons for the improvement in post-transplantation that we observed in patients with may be that patients with concurrent large hepatocellular carcinomas have been excluded from transplantation since 1997. It is also theoretically possible that better care before and after transplantation may have improved post-transplantation in patients with. Two small studies reported that a total of 8 patients with who underwent adequate iron depletion before transplantation had good post-transplantation. 14,15 Whether iron depletion before transplantation really improves post-transplantation and whether it has been widely adopted since 1997 is unclear. In addition, previous reports highlighted excess infectious complications in liver transplant recipients with, 16 which may have led to greater awareness and early treatment of such infections. Our study is limited by the fact that the diagnosis of was based on the diagnosis reported to UNOS by the transplantation centers. We do not have data on hepatic iron concentration or related end-organ damage to confirm the diagnosis. However, these diagnoses were all made by experienced hepatologists at transplantation centers with knowledge of the explant liver pathology who recorded as the cause of liver disease requiring liver transplantation. We doubt that the diagnosis of made under these circumstances would be wrong in more than an insignificant minority of cases. The proportion of transplant recipients with in this study (1.1% for period 1990 1996 and 0.6% for period 1997 2006) is similar to the proportion reported in earlier studies in which patients with were individually identified and the diagnosis confirmed. 3,12,16 Another limitation of our study is that we cannot determine accurately what proportion of patients with also had hepatocellular carcinoma, which precluded us from analyzing its association with the observed change in post-transplantation in recipients. We attempted to determine the presence of hepatocellular carcinoma in patients with a diagnosis of hepatocellular carcinoma by seeing whether it was reported as a secondary diagnosis (reported only after 1994) or as an exception with high priority score for liver transplantation (reported after 2002). These techniques probably did not identify all patients with who also had hepatocellular carcinoma even in the period 1997 2006. However, the post-transplantation of patients with in 1997 2006 was excellent despite the fact that this group included a proportion of recipients with concurrent hepatocellular carcinoma, and the would be expected to be even better among those who did not have hepatocellular carcinoma, if we could accurately identify them. Finally, our study is limited by the lack of information on the HFE genotype of patients with a diagnosis of. In 5 previous studies, the cumulative proportion of patients with HFE- (C282Y homozygotes or C282Y/H63D compound heterozygotes) among patients who underwent liver transplantation for was 46/84 or 55% (2/4, 17 4/7, 18 3/5, 16 17/22, 12 and 20/46 3 ). Four of those studies analyzed patients transplanted before the discovery of the HFE gene in1996, and one study analyzed patients transplanted between 1982 and 2001. 12 It is possible that among patients with, those with homozygosity for the C282Y mutation or compound heterozygosity for the C282Y/H63D mutation may have worse post-transplantation than patients without these mutations in the HFE gene. This was suggested by a recent study, 3 which is not directly analogous to ours because the majority (82%) of patients in that study were included on the basis of having elevated hepatic iron concentration or hepatic iron index in the explanted liver irrespective of any additional liver diseases, such as viral hepatitis, which may have caused or contributed to the cirrhosis (ie, was not the primary cause for liver transplantation). This study analyzed patients transplanted before 1996, and the impact of HFE genotype should probably be reassessed in more recent populations of liver transplant recipients, given our finding of a significant change in post-transplantation among patients with in 1997 2006. It is also possible that since the discovery of the HFE gene in 1996, the proportion of patients with HFE- among those transplanted for has increased. However, if this were true and if patients with HFE- have worse post-transplantation than patients with non HFE- or iron overload as suggested by Kowdley et al, 3 then this would have led to a decrease in post-transplantation of patients with in 1997 2006 compared with 1990 2006 (not an increase, as we report here). In conclusion, our study shows that liver transplant recipients with a diagnosis of in the United States in 1997 2006 had excellent that was comparable to all other transplant recipients. This reflects a significant improvement in post-transplantation among recipients with who before 1997 had one of the worst post-transplantation s compared with recipients with other liver disease causes. Our findings are important for patients

August 2007 HEMOCHROMATOSIS AND LIVER TRANSPLANTATION 495 with -related cirrhosis who are contemplating liver transplantation and for liver transplantation centers evaluating such patients because they suggest that a diagnosis of alone does not necessarily predict poor post-transplantation. Although we speculate that more careful patient selection with regard to cardiac diseases and hepatocellular carcinoma and improved care before and after transplantation are potential reasons for this observed change in, future research should attempt to confirm these hypotheses by analyzing recent cohorts of recipients with with more complete clinical data before and after transplantation. References 1. Kilpe VE, Krakauer H, Wren RE. An analysis of liver transplant experience from 37 transplant centers as reported to Medicare. Transplantation 1993;56:554 561. 2. Kowdley KV, Hassanein T, Kaur S, Farrell FJ, Van Thiel DH, Keeffe EB, Sorrell MF, Bacon BR, Weber FL Jr, Tavill AS. Primary liver cancer and in patients undergoing liver transplantation for. Liver Transpl Surg 1995;1:237 241. 3. Kowdley KV, Brandhagen DJ, Gish RG, Bass NM, Weinstein J, Schilsky ML, Fontana RJ, McCashland T, Cotler SJ, Bacon BR, Keeffe EB, Gordon F, Polissar N. Survival after liver transplantation in patients with hepatic iron overload: the national transplant registry. Gastroenterology 2005;129:494 503. 4. Niederau C, Fischer R, Purschel A, Stremmel W, Haussinger D, Strohmeyer G. Long-term in patients with hereditary. Gastroenterology 1996;110:1107 1119. 5. Niederau C, Fischer R, Sonnenberg A, Stremmel W, Trampisch HJ, Strohmeyer G. Survival and causes of death in cirrhotic and in noncirrhotic patients with primary. N Engl J Med 1985;313:1256 1262. 6. Powell LW. Hemochromatosis: the impact of early diagnosis and therapy. Gastroenterology 1996;110:1304 1307. 7. Ioannou GN. Development and validation of a model predicting graft after liver transplantation. Liver Transpl 2006;12: 1594 1606. 8. United Network for Organ Sharing. http://www.unos.org. Accessed February 2, 2007. 9. Cox DR. Regression models and life tables. J Royal Stat Soc Ser B 1972;34:187 202. 10. Farrell FJ, Nguyen M, Woodley S, Imperial JC, Garcia-Kennedy R, Man K, Esquivel CO, Keeffe EB. Outcome of liver transplantation in patients with. Hepatology 1994;20:404 410. 11. Tung BY, Farrell FJ, McCashland TM, Gish RG, Bacon BR, Keeffe EB, Kowdley KV. Long-term follow-up after liver transplantation in patients with hepatic iron overload. Liver Transpl Surg 1999;5: 369 374. 12. Crawford DH, Fletcher LM, Hubscher SG, Stuart KA, Gane E, Angus PW, Jeffrey GP, McCaughan GW, Kerlin P, Powell LW, Elias EE. Patient and graft after liver transplantation for hereditary : implications for pathogenesis. Hepatology 2004;39:1655 1662. 13. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F, Ammatuna M, Morabito A, Gennari L. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693 699. 14. Pillay P, Tzoracoleftherakis E, Tzakis AG, Kakizoe S, Van Thiel DH, Starzl TE. Orthotopic liver transplantation for. Transplant Proc 1991;23:1888 1889. 15. Poulos JE, Bacon BR. Liver transplantation for hereditary. Dig Dis 1996;14:316 322. 16. Brandhagen DJ, Alvarez W, Therneau TM, Kruckeberg KE, Thibodeau SN, Ludwig J, Porayko MK. Iron overload in cirrhosis-hfe genotypes and outcome after liver transplantation. Hepatology 2000;31:456 460. 17. Fiel MI, Schiano TD, Bodenheimer HC, Thung SN, King TW, Varma CR, Miller CM, Brunt EM, Starnes S, Prass C, Wolff RK, Bacon BR. Hereditary in liver transplantation. Liver Transpl Surg 1999;5:50 56. 18. Stuart KA, Fletcher LM, Clouston AD, Lynch SV, Purdie DM, Kerlin P, Crawford DH. Increased hepatic iron and cirrhosis: no evidence for an adverse effect on patient outcome following liver transplantation. Hepatology 2000;32:1200 1207. Received March 1, 2007. Accepted May 10, 2007. Address requests for reprints to: George Ioannou, MD, MS, Veterans Affairs Puget Sound Health Care System, Gastroenterology, S-111- Gastro, 1660 S. Columbian Way, Seattle, Washington 98108. e-mail: georgei@medicine.washington.edu; fax: (206) 764-2232. Supported by American Liver Foundation and American Association for the Study of Liver Diseases Jan Albrecht Award (to G.N.I.), Research Enhancement Award Program, Veterans Affairs Puget Sound Health Care System (to L.Y.). All authors declare that they have no conflict of interest to disclose.