Liver Transplantation for Alcoholic Liver Disease in the United States: 1988 to 1995 Steven H. Belle, Kimberly C. Beringer, and Katherine M. Detre T he Scientific Liver Transplant Registry (LTR) was established at the University of Pittsburgh Graduate School of Public Health under subcontract to the United Network for Organ Sharing (UNOS) in October 1987. 1 The LTR collects baseline and follow-up information on all liver transplantation recipients in the United States for the purpose of obtaining a national profile of recipients and an assessment of their outcome. This registry documents the growth of liver transplantation, from 1,713 procedures at 58 centers in 1988 to 3,705 procedures at 102 centers in 1995. LTR data have been used to demonstrate changes in recipient characteristics over time and the improvement in outcome after liver transplantation. 2 This report presents information on the growth of alcoholic liver disease (ALD) as a primary liver disease for recipients of liver transplantation, the prevalence of ALD for subgroups of recipients, and outcome after transplantation. Materials and Methods Materials. Since October 1, 1987, the LTR has collected baseline and annual follow-up information on all liver transplantation recipients in the United States. The LTR is coordinated in the Epidemiology Data Center at the University of Pittsburgh s Graduate School of Public Health, where data collection forms are received from liver transplant centers. The forms are entered into a computerized database and verified through double entry. The data are passed through edits to check for inconsistencies, and, with the cooperation of the transplant centers, data are corrected. Beyond measures to ensure that data are within established ranges and are consistent with other data for the same recipient and the same transplantation, there are no further checks of data quality. From the Department of Epidemiology Data Center, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania. Supported by United Network for Organ Sharing, Scientific Registry for Organ Transplantation, Richmond, VA (240-93-0052- S11). The data for this study were acquired through contract with the United Network for Organ Sharing. Address reprint requests to Steven H. Belle, PhD, University of Pittsburgh, 127 Parran Hall, 130 DeSoto St, Pittsburgh, PA 15261-2195. Copyright r 1997 by the American Association for the Study of Liver Diseases 1074-3022/97/0303-0004$3.00/0 Sociodemographic and limited clinical data about the recipient at the time of transplantation are available. The centers indicate the primary liver disease for which the transplantation was performed, although criteria for establishing the diagnosis are not standardized. Because ALD is not an indication for liver transplantation in children, these analyses included only recipients at least 18 years old for whom the primary liver disease was known. Recipients with acute liver failure were also excluded. Furthermore, only data on initial transplantations between 1988 and 1995 were used. Information about donors, available from the UNOS registry in Richmond, Virginia, was combined with recipient data at the LTR for these analyses. Variables representing donor-recipient matches with respect to sex, race, blood type, and cytomegalovirus (CMV) serology were created. Methods. The primary liver disease was categorized based on the information provided by each liver transplant center. A diagnosis of Non A Non B hepatitis was combined with one of hepatitis C because the LTR began before a test for hepatitis C was developed. For computation of prevalence rates, the combined diagnosis of hepatitis C and ALD was categorized as ALD. Both patient survival and retransplantation-free survival were examined. Probabilities of remaining event-free for all recipients and within subgroups were estimated using the product-limit method 3 and compared using a log-rank test. 4 Proportional-hazards models 5 were used to identify recipient and donor factors independently associated with each of the two outcomes. Results of these models are presented as relative risks and associated 95% confidence intervals. When there was no relationship between a factor and outcome, the relative risk for that factor was unity. A relative risk of.1 occurred when there was increased risk of the outcome compared with the reference group, and a relative risk of,1 occurred when risk of the outcome was decreased. Reasons for graft failure and causes of death were completed by personnel at the transplant centers and submitted to the LTR on standardized follow-up forms. Rates of occurrence of each cause of death and each type of graft failure were calculated and presented per 100 person-years (PYR). For these analyses, death of a patient with a functioning graft was not considered to be a graft failure. Results Number of Recipients Between 1988 and 1995, 16,190 adult patients (at least 18 years of age) received initial liver transplants in the United States for nonacute liver disease; 3,785 (23.4%) had ALD (Table 1). Only hepatitis C occurred more often as the primary 212 Liver Transplantation and Surgery, Vol 3, No 3 (May), 1997: pp 212-219
Transplantation for Alcoholic Liver Disease 213 Table 1. Primary Diagnosis Among Adult Recipients of Liver Transplantation in the United States: 1988 to 1995 N % Hepatitis C/Non A Non B* 4,016 24.8 Alcoholic liver disease* 3,785 23.4 Cryptogenic cirrhosis 1,889 11.7 Primary biliary cirrhosis 1,785 11.0 Primary sclerosing cholangitis 1,602 9.9 Hepatitis B 916 5.7 Autoimmune diseases 868 5.4 Malignancies 648 4.0 Metabolic disorders 605 3.7 Other 634 3.9 *Includes 558 recipients with ALD and hepatitis C/Non A Non B hepatitis. liver disease for recipients (n 5 4,016; 24.8%), and there was considerable overlap between the two diagnoses, with 558 recipients having both ALD and hepatitis C. In 1995, 32% of recipients with ALD also had hepatitis C recorded as a primary liver disease. The number of recipients with ALD doubled between 1988 and 1989 and increased every year thereafter. However, because the total number of transplantations also increased (Table 2), the proportion of recipients with ALD was constant between 1990 and 1992, then dropped slightly in 1993. Sociodemographics The mean and median ages for recipients with ALD were similar to those for all recipients. However, the prevalence of ALD varied across age groups, being less among those under 40 or over 60 years of age. Men were nearly three times as likely as women to have ALD (32% v 11%). ALD was most common among white and Hispanic recipients, accounting for nearly one quarter of the transplants in these two groups. At the other extreme, only 1 transplant in 17 among Asians was for ALD. The proportion of recipients with ALD differed according to the geographical region in which the transplant center was located. The largest percentage of recipients with ALD (29.8%) was in the smallest UNOS region (UNOS region 6), and more than 25% of recipients in UNOS regions 2, 9, and 10 had ALD. Regions 3 and 4 were the only regions with fewer than 20% of transplants performed for ALD. Clinical Characteristics ALD was rarest among recipients whose total bilirubin levels were at least 10 mg/dl (Table 3) because of the large number of recipients in that Table 2. Prevalence of ALD Among Adult Recipients of Liver Transplantation in the United States: 1988 to 1995 All Initial Transplants % ALD Year of transplantation 1988-1995 16,190 23.4 1988 1,057 13.2 1989 1,396 20.6 1990 1,769 23.5 1991 2,063 23.2 1992 2,156 23.9 1993 2,477 22.6 1994 2,554 25.8 1995 2,718 26.9 Age (yr),40 3,441 17.1 40-49 5,047 27.9 50-59 4,942 25.6 601 2,760 18.9 Mean 6 SE 48.2 6 0.1 49.0 6 0.1 Median 49 49 Sex Male 9,232 32.4 Female 6,958 11.4 Race White 13,005 24.7 Black 849 17.2 Hispanic 1,318 23.0 Asian 495 5.9 Other 511 17.6 UNOS region (states) 1 (ME, VT, NH, MA, CT, RI) 680 21.6 2 (PA, WV, MD, NJ, DE, DC) 3,105 26.2 3 (AR, LA, MS, AL, GA, FL, PR) 1,179 19.3 4 (OK, TX) 1,383 17.8 5 (HI, CA, NV, UT, AZ, NM) 2,713 23.8 6 (AK, WA, OR, ID, MT) 456 29.8 7 (ND, SD, MN, WI, IL) 1,773 23.1 8 (WY, CO, NE, KS, IA, MO) 1,422 21.7 9 (NY) 931 25.0 10 (MI, IN, OH) 1,402 27.3 11 (KY, TN, VA, NC, SC) 1,146 20.7
214 Belle, Beringer, and Detre Table 3. Clinical Characteristics of Adult Recipients of Liver Transplantation in the United States: 1988 to 1995 All Initial Transplants % ALD Total bilirubin (mg/dl),2 4,619 23.0 2-3.9 4,364 25.3 4-9.9 3,719 24.5 101 3,350 20.2 Mean 6 SE 7.3 6 0.1 6.8 6 0.2 Median 3.3 3.2 Prothrombin time (sec),16 10,752 20.7 161 4,735 29.7 Mean 6 SE 15.6 6 0.04 16.3 6 0.08 Median 14.6 15.1 Albumin (mg/dl) 3.51 3,461 21.6 2.8-3.4 5,930 23.1,2.8 5,697 24.9 Mean 6 SE 3.0 6 0.01 3.0 6 0.01 Median 3.0 2.9 Creatinine (mg/dl),2 14,139 22.5 21 1,937 30.2 Mean 6 SE 1.3 6 0.01 1.5 6 0.0 Median 1.0 1.1 Location awaiting transplantation Home 10,004 21.6 Hospital 3,664 24.4 Intensive care unit 1,314 28.4 Life support 1,200 29.3 CMV Negative 4,508 23.0 Positive 9,202 23.6 Multiorgan transplant Yes 424 19.1 No 15,758 23.5 category who had cholestatic disease. Longer prothrombin times, lower albumin levels, and higher creatinine values were all associated with greater prevalence of ALD. This was reflected by an increased proportion of ALD among recipients awaiting transplantation in the intensive care unit or on life support. There was little difference in the prevalence of ALD for recipients who were positive or negative for CMV. ALD was more common among recipients of liver-only transplantations than among multiorgan recipients. Survival Despite the differences in recipient characteristics, particularly clinical factors, the 3-month patient and graft survival for the two groups of recipients were nearly identical (Fig. 1). For the first 3 years after transplantation, both patient and graft survival among ALD recipients was slightly better than among non-ald recipients. By 7 years after transplantation, non-ald recipients had slightly better patient survival, although graft survival was the same. Within 1 year of transplantation, the presence or absence of hepatitis C as a primary liver disease had essentially no effect on either patient or graft survival among ALD recipients (Fig. 2). However, 3 years after transplantation, survival among ALD recipients with hepatitis C was slightly worse than among those without hepatitis C, and the retransplantation rate was greater, as evidenced by the greater discrepancy in graft survival than in patient survival. Because the combined diagnosis of ALD and hepatitis C was allowed in the UNOS LTR relatively recently, only sufficient follow-up data are available to report 3-year results for this group of recipients. Further examination of non-ald showed that crude survival varied widely by primary liver disease (Table 4). Recipients with a cholestatic liver disease (primary biliary cirrhosis and primary sclerosing cholangitis) and those with an autoimmune disease had the best survival, both short-term and long-term. For these diagnoses, more than 70% of recipients and 60% of grafts survived 7 years after transplantation. Recipients with hepatitis B or malignancy had the worst long-term survival, with fewer than half surviving 7 years. Crude survival among recipients with ALD was similar to those with the other primary liver diseases (metabolic, hepatitis C, cryptogenic cirrhosis, and miscellaneous). Because of potential differences in recipient characteristics that might influence survival, comparisons among groups must account for these discrepancies. Similarly, there may be imbalances among groups with respect to donor characteristics or donor-recipient matching variables that must be considered. Hence, multivariate survival analyses were performed to determine whether recipients with ALD had adjusted survival rates that differed from those of other recipients. Recipients of transplants performed earlier in the history of the LTR had poorer survival than more recent recipients. Other recipient characteristics independently associated with poorer survival (P,.05) were being older, black, or Asian; having higher bilirubin levels, longer prothrombin times,
Transplantation for Alcoholic Liver Disease 215 Figure 1. Survival after liver transplantation among adult recipients in the United States: 1988 to 1995. ALD v no ALD. (A) Patient survival. (B) Graft survival. higher creatinine levels; and awaiting transplantation in the hospital or intensive care unit. Older donors and black donors were also independently (P,.05) associated with poorer survival in recipients; therefore, donor age and race were adjusted for in the final multiple-regression models. Donorrecipient matching variables included in the models were blood type (poorer survival among recipients of livers from donors with another ABO blood type) and sex (male recipients of livers from female donors had the poorest survival). Finally, multiorgan transplantation was associated with poorer patient survival but was not significantly associated with the combined outcome of retransplantation or death. Adjusting for these factors, recipients with malignancy as the primary liver disease had the poorest patient and retransplantation-free survival (Table 5), as reflected by the largest relative (compared with ALD) risk of an adverse event. Recipients with viral hepatitis (either B or C) also had significantly worse prognoses than those with ALD. The best survival was among recipients with primary biliary cirrhosis. Causes of Death All cause and cause-specific mortality rates were similar in ALD and non-ald recipients (Fig. 3). Infections were the most common cause of death in recipients, accounting for approximately one third of deaths in both groups. Graft failure (which could have been caused by primary nonfunction, vascular thrombosis, biliary tract complication, hepatitis or other infection, recurrent disease, rejection, or some other factor) was the second leading cause of death, although the associated mortality rate was less than half that of infections. The mortality rate
216 Belle, Beringer, and Detre attributable to cardiovascular causes was slightly greater among recipients with ALD, and malignancies were a more common cause of death among recipients without ALD. Mortality due to hemorrhages and multiorgan failure had similar rates in the two groups of recipients. Causes of death were similar for ALD and non-ald recipients (Fig. 4). However, there were slight differences in causes of death within a year of transplantation and more than 1 year after transplantation. Although not a leading cause of death more than 1 year after transplantation, hemorrhage was the fourth leading cause of early death (1.9/ 100 PYR). Malignancies, which did not commonly cause death soon after transplantation, were the second leading cause of mortality more than 1 year after transplantation (1.1/100 PYR). Infections, graft failures, and cardiovascular diseases were among the leading causes of both early and late deaths in both groups of recipients. Figure 2. Survival after liver transplantation among adult recipients in the United States: 1988 to 1995. ALD and hepatitis C v ALD alone. (A) Patient survival. (B) Graft survival. Causes of Graft Failure The incidence of graft failure was 11.2 per 100 PYR, and graft failure was more common in the non-ald group (11.4/100 PYR) than in the ALD group (10.5/100 PYR) (Fig. 5). Rejection, the most common cause of graft failure, was slightly less common among ALD recipients (2.5/100 PYR) than among non-ald recipients (2.9/100 PYR). Other major reasons for graft failure were primary nonfunction, infections, and vascular complications. As expected, graft failure occurred most frequently in the first year after transplantation, with Table 4. Crude Survival by Primary Liver Disease Among Adult Recipients of Liver Transplantation in the United States: 1988 to 1995 Cumulative Percentage Surviving Primary Liver 3 Months 1 Year 3 Years 7 Years Disease Patient Graft Patient Graft Patient Graft Patient Graft ALD, No hepatitis C 87.3 83.3 81.6 77.1 73.9 69.2 59.6 55.1 ALD 1 hepatitis C 87.7 84.0 81.7 76.5 72.2 63.2 N/A N/A Hepatitis C, No ALD 88.2 83.0 80.7 74.4 71.7 65.4 57.3 50.3 Hepatitis B 88.2 83.9 74.8 69.2 60.5 54.4 49.3 43.6 Cryptogenic cirrhosis 85.5 80.3 79.0 72.6 72.3 65.8 60.4 52.9 PBC 90.1 84.9 85.7 79.9 81.6 75.8 75.9 69.2 PSC 91.6 85.3 86.3 77.9 79.9 71.5 70.1 61.3 Autoimmune 86.7 82.1 81.8 77.0 77.3 71.3 71.8 65.1 Metabolic 84.3 80.1 77.4 72.8 73.4 67.4 60.3 52.8 Malignancy 85.4 80.9 66.1 61.9 40.0 37.5 26.7 23.9 Miscellaneous 84.8 80.8 78.4 73.6 73.9 67.5 65.5 56.3 Abbreviations: PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis.
Transplantation for Alcoholic Liver Disease 217 Table 5. Adjusted Survival Among Adult Recipients of Liver Transplantation in the United States: 1988 to 1995 Death* Relative Risk 95% CI Retransplantation or Death Relative Risk 95% CI Hepatitis C 1.1 1.0, 1.3 1.2 1.1, 1.3 Hepatitis B 1.4 1.2, 1.6 1.4 1.2, 1.5 Cryptogenic 1.1 1.0, 1.2 1.2 1.1, 1.3 PBC 0.7 0.6, 0.8 0.8 0.7, 0.9 PSC 0.8 0.7, 0.9 1.0 0.9, 1.2 Autoimmune 1.0 0.8, 1.2 1.0 0.8, 1.2 Metabolic 1.1 0.9, 1.3 1.1 1.0, 1.3 Malignancy 2.5 2.2, 2.9 2.2 1.9, 2.5 Miscellaneous 1.1 1.0, 1.4 1.2 1.0, 1.4 Abbreviations: 95% CI, 95% confidence interval; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis. *Adjusting for year of transplantation, recipient age, recipient race, location awaiting transplantation, bilirubin, prothrombin time, creatinine, multiorgan transplantation, donor age, donor race, ABO match, and sex match. Adjusting for year of transplantation, recipient age, recipient race, location awaiting transplantation, bilirubin, prothrombin time, creatinine, donor age, donor race, ABO match, and sex match. Compared with ALD. P,.05. incidence rates of 26.3 per 100 PYR in the non- ALD group and 23.2 per 100 PYR in the ALD group. The most common cause of early graft failure (within a year of transplantation) in both groups of recipients was PNF, with incidence rates of 7.0 per 100 PYR and 6.9 per 100 PYR among those with non-ald and ALD, respectively (Fig. 6). Graft loss due to rejections was more common among non-ald recipients (6.7/100 PYR v 5.3/100 PYR). Rates of graft loss due to infections were the same in the two groups of recipients, whereas vascular thrombosis caused a higher rate of graft loss in non-ald recipients. More than 1 year after transplantation, the incidence rates of graft failure were comparable in the two groups (3.3/100 PYR among non-ald recipients and 3.2/100 PYR among ALD recipients), although the reasons for graft failure differed. Among recipients with ALD, the most common cause was infection (0.9/100 PYR), followed by rejection (0.9/100 PYR). Recurrence was considered a cause of graft failure for only 17 recipients with ALD (0.4/100 PYR). Among recipients without ALD, recurrent disease was the most common reason for graft failure (1.2/100 PYR), followed by rejection (0.8/100 PYR) and infection (0.6/100 PYR). Discussion National figures show that ALD was the second leading disease for which liver transplantation was performed among adults in the United States between 1988 and 1995, trailing only hepatitis C. The prevalence of ALD was greatest among recipients between the ages of 40 and 60 years, men, and whites. ALD was most common among Figure 3. Causes of death among adult recipients in the United States: 1988 to 1995.
218 Belle, Beringer, and Detre Figure 4. Causes of death among adult recipients in the United States: 1988 to 1995, by time after transplantation. (A) Within 1 year of transplantation. (B) At least 1 year after transplantation. recipients with prolonged prothrombin times, low albumin levels, and serum creatinine levels.2 mg/dl. ALD was less common among recipients with high bilirubin levels because of particularly high values among recipients with cholestatic liver disease. Because of generally poorer liver and kidney function, the prevalence of ALD was greatest among recipients awaiting transplantation in the hospital. Although the prevalence of ALD was higher among recipients with worse liver and kidney function, risk factors for poorer prognosis after transplantation, their crude survival, was comparable to that of non-ald recipients. Adjusting for differences in recipient and donor characteristics, patients with cholestatic or autoimmune disease had the best survival, whereas patients with hepatitis B or malignancy had the worst survival. Recipients with ALD had survival comparable to that of recipients with metabolic disease, hepatitis C, or cryptogenic cirrhosis. Long-term follow-up is not yet available for recipients who had hepatitis C in addition to ALD, but the survival in this group 3 years after transplantation decreased more rapidly than for ALD recipients without hepatitis C. Longer follow-up is needed to see if this trend continues or is an aberration caused by small numbers of recipients with sufficient follow-up. Causes of death were similar in the two groups
Transplantation for Alcoholic Liver Disease 219 Figure 5. Causes of graft failure among adult recipients in the United States: 1988 to 1995. of recipients; infections were the leading cause of death in both groups and accounted for approximately one third of deaths overall. Graft failures were less common among recipients with ALD; in particular, graft failures within 1 year of transplantation caused by rejection occurred less often among recipients with ALD, perhaps reflecting diminished immunological function in this group of recipients. Recurrence of disease was rarely considered a reason for graft failure among recipients with ALD. Acknowledgment The authors acknowledge Eartha Norwood for her assistance in preparing the manuscript and Julie Reigel at the Liver Transplant Registry and the coordinators at participating liver transplant centers, without whom this research would not be possible. References Figure 6. Causes of graft failure among adult recipients in the United States: 1988 to 1995, by time after transplantation. (A) Within 1 year of transplantation. (B) At least 1 year after transplantation. 1. Belle SH, Beringer KC, Murphy JB, Detre KM. The Pitt-UNOS Liver Transplant registry. In: Terasaki P, Cecka M (eds). Clinical Transplants, 1992. Los Angeles, CA: UCLA Tissue Typing Laboratory, 1993. 2. Belle SH, Beringer KC, Detre KM. An update on liver transplantation in the United States: Recipient characteristics and outcome. In: Terasaki P, Cecka M (eds). Clinical Transplants, 1995. Los Angeles, CA: UCLA Tissue Typing Laboratory, 1996. 3. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-481. 4. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966;50:163-170. 5. Cox DR. Regression models and life tables. J R Statistical Soc 1972;34:187-220.