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Survival of Liver Transplant Recipients With Hemochromatosis in the United States

  • Lei Yu
    Affiliations
    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
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  • George N. Ioannou
    Correspondence
    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. fax: (206) 764-2232.
    Affiliations
    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
    Search for articles by this author
      Background & Aims: Earlier studies have suggested that patients with hemochromatosis have poor post-transplantation survival. We aimed to compare patients with hemochromatosis to those with other causes of liver disease with regard to post-transplantation survival. Methods: We compared the post-transplant survival of patients with and without hemochromatosis 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 survival of patients with hemochromatosis (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%) survival 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 hemochromatosis (n = 217) had excellent 1-year (86.1%), 3-year (80.8%), and 5-year (77.3%) post-transplantation survival, which was not different from the 1-year (88.4%), 3-year (80.3%), and 5-year (74.0%) post-transplantation survival 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 hemochromatosis, those with hemochromatosis were more likely to die of cardiovascular diseases and less likely to die as a result of graft failure. Conclusions: The post-transplantation survival of patients with hemochromatosis, which was previously reported to be poor, has been excellent in the United States during the past 10 years.

      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)
      It has been suggested that patients who undergo liver transplantation for cirrhosis related to hemochromatosis have a higher than average post-transplantation mortality. Kilpe et al
      • Kilpe V.E.
      • Krakauer H.
      • Wren R.E.
      An analysis of liver transplant experience from 37 transplant centers as reported to Medicare.
      reported that 1-year survival after liver transplantation for hemochromatosis between 1982 and 1991 in 37 US centers was 54% (30/56), whereas the 1-year post-transplantation survival of all patients was 80% (4092/5180). Kowdley et al
      • Kowdley K.V.
      • Hassanein T.
      • Kaur S.
      • Farrell F.J.
      • Van Thiel D.H.
      • Keeffe E.B.
      • Sorrell M.F.
      • Bacon B.R.
      • Weber Jr, F.L.
      • Tavill A.S.
      Primary liver cancer and survival in patients undergoing liver transplantation for hemochromatosis.
      reported that among 37 patients with hemochromatosis-related cirrhosis who underwent liver transplantation in 5 US centers between 1988 and 1993, 1-year post-transplantation survival was 58%. More recently, Kowdley et al
      • Kowdley K.V.
      • Brandhagen D.J.
      • Gish R.G.
      • Bass N.M.
      • Weinstein J.
      • Schilsky M.L.
      • Fontana R.J.
      • McCashland T.
      • Cotler S.J.
      • Bacon B.R.
      • Keeffe E.B.
      • Gordon F.
      • Polissar N.
      Survival after liver transplantation in patients with hepatic iron overload: the national hemochromatosis transplant registry.
      reported that the 1-year post-transplantation survival of 25 patients with HFE-related hemochromatosis who underwent liver transplantation at 1 of 12 US centers before 1996 was 64% which was lower than the 1-year post-transplantation survival (84%) of all liver transplant recipients in these 12 centers before 1996.
      Those studies may not accurately reflect the current post-transplantation survival of patients with hemochromatosis for a number of reasons. All those studies analyzed liver transplantations performed before 1996, and survival in patients with hemochromatosis may have improved since then (for instance, as a result of more aggressive iron depletion before and after transplantation or more careful patient selection).
      • Niederau C.
      • Fischer R.
      • Purschel A.
      • Stremmel W.
      • Haussinger D.
      • Strohmeyer G.
      Long-term survival in patients with hereditary hemochromatosis.
      • Niederau C.
      • Fischer R.
      • Sonnenberg A.
      • Stremmel W.
      • Trampisch H.J.
      • Strohmeyer G.
      Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis.
      • Powell L.W.
      Hemochromatosis: the impact of early diagnosis and therapy.
      Those studies included a relatively small number of patients because hemochromatosis is a rare indication for liver transplantation. As a result, none of the previous studies adequately adjusted for other predictors of post-transplantation survival, such as donor age, cold ischemia time, recipient age, and causes of liver disease,
      • Ioannou G.N.
      Development and validation of a model predicting graft survival after liver transplantation.
      or directly compared the post-transplantation survival of patients with hemochromatosis-related cirrhosis with the post-transplantation survival 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 hemochromatosis-related cirrhosis with worse survival than the average post-transplantation survival of all patients with hemochromatosis-related cirrhosis in the United States.
      To resolve these issues, we compared the post-transplantation survival of patients with hemochromatosis to the post-transplantation survival of patients with other causes of liver disease with and without adjusting for predictors of post-transplantation survival using data reported to the United Network for Organ Sharing (UNOS) for all liver transplantations performed in the United States from January 1, 1990, until July18, 2006.

      United Network for Organ Sharing. http://www.unos.org. Accessed February 2, 2007.

      Materials and Methods

       Data Collection

      Transplantation centers and organ procurement organizations in the United States are required to submit to UNOS

      United Network for Organ Sharing. http://www.unos.org. Accessed February 2, 2007.

      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 survival of patients with hemochromatosis in more recent years for which no data are currently available.
      We additionally wanted to explore whether any difference in post-transplantation survival between patients with and without hemochromatosis 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/m2]; 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: hemochromatosis, 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 hemochromatosis 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 hemochromatosis who also had hepatocellular carcinoma.

       Predictors of Post-Transplantation Survival

      We wanted to investigate whether any observed difference in post-transplantation survival between patients with and without hemochromatosis was due to differences in the following donor and recipient characteristics that are predictors of post-transplantation survival: donor age, cold ischemia time, race, and sex; recipient age, race, sex, BMI, serum albumin, bilirubin, and creatinine.
      • Ioannou G.N.
      Development and validation of a model predicting graft survival after liver transplantation.
      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 hemochromatosis causes diabetes; hence, diabetes may be one of the mechanisms by which hemochromatosis could lead to worse post-transplantation survival.

       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 survival at 1, 3, and 5 years after transplantation. Cox proportional-hazards regression was used to compare patients with hemochromatosis to patients with other liver diseases with regard to patient and graft survival after liver transplantation with and without adjusting for the predictors of post-transplantation survival listed earlier.
      • Cox D.R.
      Regression models and life tables.
      For the analysis of post-transplantation survival, 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 hemochromatosis was 1.1% (177/16,286) in 1990–1996 and 0.6% (217/34,020) in 1997–2006. Compared with transplant recipients without hemochromatosis, those with hemochromatosis 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 hemochromatosis. BMI and serum levels of bilirubin, creatinine, and albumin were similar in recipients with and without hemochromatosis. Also, recipients with hemochromatosis were similar to patients without hemochromatosis with respect to donor characteristics in both time periods (Table 1).
      Table 1Donor and Recipient Characteristics of Liver Transplantations for Patients With and Without Hemochromatosis
      1990–19961997–2006
      Patients with hemochromatosis (N = 177)Patients without hemochromatosis (N = 16,109)Patients with hemochromatosis (N = 217)Patients without hemochromatosis (N = 33,803)
      Donor characteristics
       Age (y), mean ± SD35.5 ± 14.833.8 ± 15.641.3 ± 17.540.0± 16.7
       Cold ischemia time (h), mean ± SD9.4 ± 3.410.1 ± 3.78.0 ± 2.97.9 ± 3.0
      Race or ethnicity
       White, %84.180.474.073.7
       Black and African American, %8.510.213.012.8
       Hispanic, %6.87.811.611.0
       Others (mostly Asian), %0.61.61.42.5
       Male, %70.663.359.261.3
      Recipient characteristics
       Body mass index (kg/m2), mean ± SD27.4 ± 5.726.7 ± 5.528.8 ± 5.528.2 ± 5.6
       Age (y), mean ± SD53.5 ± 9.548.6 ± 11.254.7 ± 9.051.2 ± 10.1
       Male, %81.957.486.266.2
      Race or ethnicity
       White, %88.681.290.376.2
       Black and African American, %2.36.10.98.0
       Hispanic, %6.39.25.611.4
       Other (mostly Asian)2.83.53.24.4
       Diabetes, %NANA8.13.7
       Albumin (g/dL), mean ± SD2.8 ± 0.63.0 ± 0.62.8 ± 0.72.9 ± 0.7
      Total bilirubin (mg/dL), mean ± SD7.6 ± 8.26.9 ± 8.86.1 ± 7.26.4 ± 8.4
      Serum creatinine (mg/dL), mean ± SD1.2 ± 0.81.3 ± 1.11.3 ± 0.81.3 ± 1.0
      During 1990–1996, the post-transplantation survival of recipients with hemochromatosis at 1 year (79.1%), 3 years (71.8%), and 5 years (64.6%) was lower than the post-transplantation survival of recipients without hemochromatosis at 1 year (86.4%), 3 years (79.5%), and 5 years (73.8%) (Table 2). Compared with recipients without hemochromatosis, those with hemochromatosis 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 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 hemochromatosis had the worst post-transplantation survival of any other recipient group defined by cause of liver disease other than hepatocellular carcinoma (Table 3;Figure 1A).
      Table 2Comparison 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)Patient-years (n)Patient deaths (n)Mortality per 100 patient-yearsHazard ratio (95% CI) for patient survivalHazard ratio (95% CI) for graft survival1-Year patient survival (%)3-Year patient survival (%)5-Year patient survival (%)
      Time period 1990–1996
       No hemochromatosis16,109108,9286,3175.81186.479.573.8
       Hemochromatosis1771058868.11.38 (1.12–1.71)1.27 (1.04–1.54)79.171.864.6
      Time period 1997–2006
       No hemochromatosis33,80396,42067137.01188.480.374.0
       Hemochromatosis217640396.10.89 (0.65–1.22)0.96 (0.74–1.25)86.180.877.3
      Table 3Patient Survival After Transplantation for Selected Causes of Liver Disease for Periods 1990–1996 and 1997–2006
      1-Year survival3-Year survival5-Year survival
      1990–1996
       Hepatocellular carcinoma73.253.144.1
       Hemochromatosis79.171.864.6
        Cryptogenic-NASH83.376.269.1
        Hepatitis B virus83.073.770.2
        Alcohol86.279.072.4
        Hepatitis C virus87.879.472.6
        Acute hepatic failure80.777.776.0
        Autoimmune hepatitis86.883.178.8
        PSC91.186.782.4
        PBC90.086.282.9
      1997–2006
       Hepatocellular carcinoma86.671.862.2
       Hepatitis C virus88.078.070.4
       Cryptogenic-NASH86.580.273.5
       Alcohol88.780.774.4
       Acute hepatic failure84.079.674.9
       Hemochromatosis86.180.877.3
        Hepatitis B virus90.084.481.3
        Autoimmune hepatitis90.485.980.8
        PBC91.687.483.4
        PSC93.687.683.4
      NOTE. Causes of liver disease are arranged in order of increasing 5-year survival.
      NASH, nonalcoholic steatohepatitis; PSC, primary sclerosing cholangitis; PBC, primary biliary cirrhosis.
      Figure thumbnail gr1
      Figure 1Kaplan–Meier curves of patient survival after liver transplantation for recipients with hemochromatosis and selected causes of liver disease during 1990–1996 (A) and 1997–2006 (B).
      In contrast, during 1997–2006, recipients with hemochromatosis had similar post-transplantation survival at 1 year (86.1%), 3 years (80.8%), and 5 years (77.3%) to recipients without hemochromatosis (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 hemochromatosis did not show any significant difference. During 1997–2006, recipients with hemochromatosis had 5-year post-transplantation survival 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 hepatic failure (Table 3; Figure 1B). Compared with recipients without hemochromatosis, those with hemochromatosis were more likely to die of cardiovascular diseases and less likely to die as a result of graft failure (Table 4).
      Table 4Causes of Post-Transplantation Death Among Recipients With and Without Hemochromatosis During the Periods 1990–1996, 1997–2006, and Combined 1990–-2006
      1990–19961997–20061990–2006
      Cause of deathHemochromatosis, n (%)No hemochromatosis, n (%)Hemochromatosis, n (%)No hemochromatosis, n (%)Hemochromatosis, n (%)No hemochromatosis, n (%)P value
      The P value refers to the comparison of patients with hemochromatosis to patients without hemochromatosis with respect to the proportion with each cause of death for the entire study period (1990–2006).
      Cardiovascular23 (27)922 (15)6 (15)864 (13)29 (23)1786 (14).002
      Graft failure4 (5)843 (13)3 (8)981 (15)7 (6)1824 (14).07
      Infection18 (21)1213 (19)11 (28)1142 (17)29 (23)2355 (18).1
      Malignancy11 (13)886 (14)3 (8)777 (12)14 (11)1663 (13).6
      Multiple organ system failure5 (6)424 (7)2 (5)663 (10)7 (6)1087 (8).3
      Other25 (29)2,023 (32)14 (36)2299 (34)39 (31)4322 (33).6
      Total86 (100)6311 (100)39 (100)6726 (100)125 (100)13,037 (100)
      a The P value refers to the comparison of patients with hemochromatosis to patients without hemochromatosis with respect to the proportion with each cause of death for the entire study period (1990–2006).
      In the period 1990–1996 we could only identify 3 patients (of 177) with hemochromatosis 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 hemochromatosis 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 survival of patients with hemochromatosis 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 survival of patients with hemochromatosis in the United States was excellent. Post-transplantation survival in patients with hemochromatosis during 1997–2006 was almost identical to the average survival of all liver transplant recipients and was better than the survival of recipients with hepatocellular carcinoma, HCV infection, NASH-induced 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 survival in patients with hemochromatosis in the United States was worse than average. In fact, during that time period, patients with hemochromatosis had the worst post-transplantation survival 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 survival “improved” by 13% (from 64.6% to 77.3%) in patients with hemochromatosis, whereas it remained almost unchanged in all other patients without hemochromatosis (73.8% to 74%).
      We can only speculate as to the causes of the difference in post-transplantation survival of patients with hemochromatosis 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 hemochromatosis to have significantly higher proportion of cardiac disease–related mortality than recipients with other liver diseases.
      • Kowdley K.V.
      • Hassanein T.
      • Kaur S.
      • Farrell F.J.
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      • Weber Jr, F.L.
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      Primary liver cancer and survival in patients undergoing liver transplantation for hemochromatosis.
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      • Bacon B.R.
      • Keeffe E.B.
      • Kowdley K.V.
      Long-term follow-up after liver transplantation in patients with hepatic iron overload.
      In more recent years, transplantation centers may have been more rigorous at identifying cardiac disease in patients with hemochromatosis and excluding them from transplantation. This is suggested by our finding that cardiovascular deaths were more common in patients with hemochromatosis 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 survival after transplantation among recipients with hemochromatosis,
      • Kowdley K.V.
      • Hassanein T.
      • Kaur S.
      • Farrell F.J.
      • Van Thiel D.H.
      • Keeffe E.B.
      • Sorrell M.F.
      • Bacon B.R.
      • Weber Jr, F.L.
      • Tavill A.S.
      Primary liver cancer and survival in patients undergoing liver transplantation for hemochromatosis.
      • Tung B.Y.
      • Farrell F.J.
      • McCashland T.M.
      • Gish R.G.
      • Bacon B.R.
      • Keeffe E.B.
      • Kowdley K.V.
      Long-term follow-up after liver transplantation in patients with hepatic iron overload.
      we suspect hepatocellular carcinoma was another important reason for the low post-transplantation survival during 1990–1996, particularly if patients had large tumors such that they would not have received transplants in more recent years.
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      • Elias E.E.
      Patient and graft survival after liver transplantation for hereditary hemochromatosis: implications for pathogenesis.
      For example, in the study by Crawford et al,
      • Crawford D.H.
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      • Kerlin P.
      • Powell L.W.
      • Elias E.E.
      Patient and graft survival after liver transplantation for hereditary hemochromatosis: implications for pathogenesis.
      6 of 22 recipients with hemochromatosis had hepatocellular carcinoma, including 4 patients with tumors 7, 9, 10, and 12 cm in diameter. All 4 patients died of recurrent hepatocellular cancer.
      • Crawford D.H.
      • Fletcher L.M.
      • Hubscher S.G.
      • Stuart K.A.
      • Gane E.
      • Angus P.W.
      • Jeffrey G.P.
      • McCaughan G.W.
      • Kerlin P.
      • Powell L.W.
      • Elias E.E.
      Patient and graft survival after liver transplantation for hereditary hemochromatosis: implications for pathogenesis.
      We cannot tell for sure in our study exactly what proportion of patients with hemochromatosis also had hepatocellular carcinoma. However, since 1997 hepatocellular carcinoma within the Milan criteria
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      Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.
      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 hemochromatosis in the period 1997–2006 would likely be within the Milan criteria, for which post-transplantation survival is generally good. In contrast, it is likely that many of the patients with hemochromatosis 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 survival that we observed in patients with hemochromatosis 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 survival in patients with hemochromatosis. Two small studies reported that a total of 8 patients with hemochromatosis who underwent adequate iron depletion before transplantation had good post-transplantation survival.
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      • Starzl T.E.
      Orthotopic liver transplantation for hemochromatosis.
      • Poulos J.E.
      • Bacon B.R.
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      Whether iron depletion before transplantation really improves post-transplantation survival and whether it has been widely adopted since 1997 is unclear. In addition, previous reports highlighted excess infectious complications in liver transplant recipients with hemochromatosis,
      • Brandhagen D.J.
      • Alvarez W.
      • Therneau T.M.
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      • Ludwig J.
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      Iron overload in cirrhosis-HFE genotypes and outcome after liver transplantation.
      which may have led to greater awareness and early treatment of such infections.
      Our study is limited by the fact that the diagnosis of hemochromatosis was based on the diagnosis reported to UNOS by the transplantation centers. We do not have data on hepatic iron concentration or hemochromatosis-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 hemochromatosis as the cause of liver disease requiring liver transplantation. We doubt that the diagnosis of hemochromatosis made under these circumstances would be wrong in more than an insignificant minority of cases. The proportion of transplant recipients with hemochromatosis 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 hemochromatosis were individually identified and the diagnosis confirmed.
      • Kowdley K.V.
      • Brandhagen D.J.
      • Gish R.G.
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      • Cotler S.J.
      • Bacon B.R.
      • Keeffe E.B.
      • Gordon F.
      • Polissar N.
      Survival after liver transplantation in patients with hepatic iron overload: the national hemochromatosis transplant registry.
      • Crawford D.H.
      • Fletcher L.M.
      • Hubscher S.G.
      • Stuart K.A.
      • Gane E.
      • Angus P.W.
      • Jeffrey G.P.
      • McCaughan G.W.
      • Kerlin P.
      • Powell L.W.
      • Elias E.E.
      Patient and graft survival after liver transplantation for hereditary hemochromatosis: implications for pathogenesis.
      • Brandhagen D.J.
      • Alvarez W.
      • Therneau T.M.
      • Kruckeberg K.E.
      • Thibodeau S.N.
      • Ludwig J.
      • Porayko M.K.
      Iron overload in cirrhosis-HFE genotypes and outcome after liver transplantation.
      Another limitation of our study is that we cannot determine accurately what proportion of patients with hemochromatosis also had hepatocellular carcinoma, which precluded us from analyzing its association with the observed change in post-transplantation survival in hemochromatosis 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 hemochromatosis who also had hepatocellular carcinoma even in the period 1997–2006. However, the post-transplantation survival of patients with hemochromatosis in 1997–2006 was excellent despite the fact that this group included a proportion of recipients with concurrent hepatocellular carcinoma, and the survival 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 hemochromatosis. In 5 previous studies, the cumulative proportion of patients with HFE-hemochromatosis (C282Y homozygotes or C282Y/H63D compound heterozygotes) among patients who underwent liver transplantation for hemochromatosis was 46/84 or 55% (2/4,
      • Fiel M.I.
      • Schiano T.D.
      • Bodenheimer H.C.
      • Thung S.N.
      • King T.W.
      • Varma C.R.
      • Miller C.M.
      • Brunt E.M.
      • Starnes S.
      • Prass C.
      • Wolff R.K.
      • Bacon B.R.
      Hereditary hemochromatosis in liver transplantation.
      4/7,
      • Stuart K.A.
      • Fletcher L.M.
      • Clouston A.D.
      • Lynch S.V.
      • Purdie D.M.
      • Kerlin P.
      • Crawford D.H.
      Increased hepatic iron and cirrhosis: no evidence for an adverse effect on patient outcome following liver transplantation.
      3/5,
      • Brandhagen D.J.
      • Alvarez W.
      • Therneau T.M.
      • Kruckeberg K.E.
      • Thibodeau S.N.
      • Ludwig J.
      • Porayko M.K.
      Iron overload in cirrhosis-HFE genotypes and outcome after liver transplantation.
      17/22,
      • Crawford D.H.
      • Fletcher L.M.
      • Hubscher S.G.
      • Stuart K.A.
      • Gane E.
      • Angus P.W.
      • Jeffrey G.P.
      • McCaughan G.W.
      • Kerlin P.
      • Powell L.W.
      • Elias E.E.
      Patient and graft survival after liver transplantation for hereditary hemochromatosis: implications for pathogenesis.
      and 20/46
      • Kowdley K.V.
      • Brandhagen D.J.
      • Gish R.G.
      • Bass N.M.
      • Weinstein J.
      • Schilsky M.L.
      • Fontana R.J.
      • McCashland T.
      • Cotler S.J.
      • Bacon B.R.
      • Keeffe E.B.
      • Gordon F.
      • Polissar N.
      Survival after liver transplantation in patients with hepatic iron overload: the national hemochromatosis transplant registry.
      ). 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.
      • Crawford D.H.
      • Fletcher L.M.
      • Hubscher S.G.
      • Stuart K.A.
      • Gane E.
      • Angus P.W.
      • Jeffrey G.P.
      • McCaughan G.W.
      • Kerlin P.
      • Powell L.W.
      • Elias E.E.
      Patient and graft survival after liver transplantation for hereditary hemochromatosis: implications for pathogenesis.
      It is possible that among patients with hemochromatosis, those with homozygosity for the C282Y mutation or compound heterozygosity for the C282Y/H63D mutation may have worse post-transplantation survival than patients without these mutations in the HFE gene. This was suggested by a recent study,
      • Kowdley K.V.
      • Brandhagen D.J.
      • Gish R.G.
      • Bass N.M.
      • Weinstein J.
      • Schilsky M.L.
      • Fontana R.J.
      • McCashland T.
      • Cotler S.J.
      • Bacon B.R.
      • Keeffe E.B.
      • Gordon F.
      • Polissar N.
      Survival after liver transplantation in patients with hepatic iron overload: the national hemochromatosis transplant registry.
      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, hemochromatosis 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 survival among patients with hemochromatosis in 1997–2006. It is also possible that since the discovery of the HFE gene in 1996, the proportion of patients with HFE-hemochromatosis among those transplanted for hemochromatosis has increased. However, if this were true and if patients with HFE-hemochromatosis have worse post-transplantation survival than patients with non–HFE-hemochromatosis or iron overload as suggested by Kowdley et al,
      • Kowdley K.V.
      • Brandhagen D.J.
      • Gish R.G.
      • Bass N.M.
      • Weinstein J.
      • Schilsky M.L.
      • Fontana R.J.
      • McCashland T.
      • Cotler S.J.
      • Bacon B.R.
      • Keeffe E.B.
      • Gordon F.
      • Polissar N.
      Survival after liver transplantation in patients with hepatic iron overload: the national hemochromatosis transplant registry.
      then this would have led to a decrease in post-transplantation survival of patients with hemochromatosis 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 hemochromatosis in the United States in 1997–2006 had excellent survival that was comparable to all other transplant recipients. This reflects a significant improvement in post-transplantation survival among recipients with hemochromatosis who before 1997 had one of the worst post-transplantation survivals compared with recipients with other liver disease causes. Our findings are important for patients with hemochromatosis-related cirrhosis who are contemplating liver transplantation and for liver transplantation centers evaluating such patients because they suggest that a diagnosis of hemochromatosis alone does not necessarily predict poor post-transplantation survival. 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 survival, future research should attempt to confirm these hypotheses by analyzing recent cohorts of recipients with hemochromatosis with more complete clinical data before and after transplantation.

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        GastroenterologyVol. 133Issue 3
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          Yu L, Ioannou GN. Survival of liver transplant recipients with hemochromatosis in the United States. Gastroenterology 2007;133;489-495.
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