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An increasing number of patients are undergoing liver transplantation (LT) assessment for decompensated end stage liver disease. This situation has led to a reevaluation of selection criteria for LT, so that both survival outcomes and organ allocation is optimized.1, 2 Patient cohorts that could therefore potentially be excluded from the evaluation process include those older than 60 and 65 yr of age. Yet, it is also apparent that the age groups from 65 to 74 yr of age represented the patient cohort at greatest risk of death from end-stage liver disease in the United States.3
In many centers, older patients are frequently seen as higher risk recipients, because of comorbidities and an increased mortality related to both hepatic and nonhepatic causes.4 The etiology of cirrhosis differs between different age groups, with the median age for diagnosis of primary biliary cirrhosis in previous studies being 60 yr.5, 6 Alcohol-related liver-disease is more prevalent in older patients, with as many as 28% of first presentations of alcohol-related liver-disease occurring in patients aged over 60 yr,7 while age is increasingly recognized as an important variable in hepatocellular carcinoma.8
Despite many apparent disadvantages of old age vis-a-vis transplantation,9, 10 a potential advantage may be that of immune senescence. This is characterized by a diminished responsiveness of the immune system, and it has been postulated that this declining immune responsiveness may be associated with reduced episodes and severity of graft rejection, as many centers have reported less episodes of acute cellular rejection (ACR) in older patients.11, 12 A potential disadvantage of immune senescence is an increased incidence of infection, decreased responsiveness to immunizations, and an increased risk of neoplasia.13, 14
For these reasons, we were keen to examine the effects of LT in older patients. In this study, we report our experience with patients aged over 60 and 65 yr who underwent LT at King's College Hospital, London, between 1988 and 2003. Our goals were to evaluate patient and graft survival among recipients greater than 65 yr of age at the time of LT and compare them with recipients aged 18-59 yr and aged 60-64 yr. We also evaluated ACR and cellular rejection rates according to age and sought to examine the clinical characteristics of these groups.
LT, liver transplantation; ACR, acute cellular rejection; MELD, Model for End-Stage Liver Disease; TAC, tacrolimus.
PATIENTS AND METHODS
The Liver Transplant service at Kings College Hospital, London, maintains a regularly updated database of 1,814 LT operations in 1,657 adult recipients performed between January 1988 and October 2003. The groups for study were allocated according to age. Three separate age groups were investigated: group 1, patients aged > 65 yr (n = 77); group 2, patients aged between 60-64 yr (n = 137); and group 3, patients aged between 18-59 yr (n = 202). There was no arbitrary cap on age if the patient was fit enough for surgery. All patients aged over 60 yr who underwent LT were included in the study (n = 214). Group 3 patients, aged between 18 and 59 yr were time-matched to form an equivalently-sized comparison group based on immunosuppressant regimens and other characteristics. The histological records on all patients were examined to evaluate the presence of ACR or chronic rejection on liver biopsy. Patients were excluded who were transplanted for acute liver failure since no patient over 65 yr was transplanted for this indication. Neither did we study the role of retransplantation. No patient over 65 yr received more than 1 liver graft, but protocol did not exclude them from retransplantation.
The cardiovascular workup for patients aged over 60 and 65 yr included a routine history and physical examination, EKG and 2-dimensional echocardiography, and coronary arteriography. Echocardiography and coronary arteriography were only performed in patients <60 yr if there were abnormalities on EKG, or a history suggestive of an increased risk of cardiac disease, e.g., previous ischemic heart disease or diabetes mellitus. No patients were delisted because of a need for cardiac revascularization, and no combined LT with coronary artery bypass grafts were performed for any patient over 65 yr. Doppler studies of the carotid, vertebral, and peripheral limb arteries were undertaken for the majority of older recipients. If extensive coronary heart disease was observed, a revascularization strategy was applied prior to listing for LT. Routine cancer screening among potential graft recipients involved measurement of tumor markers, colonoscopy for patients over 50 yr, and cervical and breast cancer screening.
Following LT, patients were commenced on similar immunosuppressive regimens. Patients were followed up in clinic on a weekly basis for the first month, and then monthly thereafter for the first 6 months. Patients were subsequently seen on a 3-month schedule for the first 2 yr posttransplantation and a 6-month schedule thereafter. Investigation into graft dysfunction was initiated when there was an increase of aspartate aminotransferase to levels greater than twice the upper limit of normal or in the presence of unexplained elevation of serum bilirubin or alkaline phosphatase activity. Under those circumstances, liver biopsy was performed following ultrasound evaluation of the hepatic vasculature and biliary tree. In addition, serum was tested for autoantibodies and viral markers if indicated. Liver biopsy specimens were examined in a nonblinded fashion for the presence of ACR, chronic rejection, presence of steatosis, steatohepatitis, features of viral infection, and for evidence of original disease. All episodes of ACR and chronic rejection were documented histologically.
For quantitative data, analysis was performed using the Mann-Whitney and Kruskal Wallis analysis of variance tests for comparison of 2 and more than 2 independent groups, respectively. Differences in proportions were examined using the chi-squared test for 2 × 2 tables when the number of subjects in all cells was >5. The r × c chi-squared test was used to investigate independent categories forming r rows and c columns where appropriate. Survival rates after LT were calculated according to the Kaplan-Meier method and compared using the log-rank test. Data are expressed as means ± standard deviations, or as medians with interquartile ranges where indicated. All analysis was performed using Stats Direct statistical software (Stats Direct Ltd., Cheshire, England).
Between January 1988 and October 2003, LT was performed 1,814 times in 1,657 adult recipients. The baseline recipient and donor characteristics are summarized in Table 1, and the indications for transplantation in the 3 study groups are outlined in Table 2.
Table 1. Baseline Recipient and Donor Characteristics in 416 Patients Undergoing LT, Subdivided by Age of Recipient: Group 1 = Age >65 yr, Group 2 = Age 60-64 yr, Group 3 = 18-59 yr
Group 1 (n = 77)
Group 2 (n = 137)
Group 3 (n = 202)
Abbreviations: MELD, Model for End Stage Liver Disease.
Male gender, n (%)
8.6 (± 2.24)
9.2 (± 2.19)
12.2 (± 5.12)
15.79 (± 7.42)
16.49 (± 7.68)
45 (± 15.38)
44 (± 14.20)
43 (± 15.10)
Male gender, n (%)
Whole graft, n (%)
Cold ischemic time (hr)
10.9 (± 3.33)
11.3 (± 3.23)
11.5 (± 2.90)
Table 2. Indications for Transplantation in 416 Operative Procedures, Subdivided According to Age; Group 1 = Age >65 yr, Group 2 = Age 60-64 yr, Group 3 = 18-59 yr
The mean age at transplantation was 67 yr ± 1.9 for group 1; 62 yr ± 1.4 for group 2, and 42 yr ± 13.0 for group 3. The mean unmodified Model for End-Stage Liver Disease (MELD) scores were as follows: group 1, 12 ± 5.16; group 2, 16 ± 7.42; and group 3, 16 ± 7.68. There were no statistical differences in the MELD scores between group 2 and group 3 (P = 0.583), but there was a significant difference when comparing group 1 to group 3 (P < 0.0001), and between group 1 and group 2 (P < 0.001). The mean Child-Turcotte-Pugh scores were as follows: group 1, 8.64 ± 2.24; group 2, 9.17 ± 2.19; and group 3, 9.26 ± 2.37. There was no statistical significance between group 1 and group 2 (P = 0.137), but statistical significance was approached between group 1 and group 3 (P = 0.06). All patients received cadaveric grafts. LT recipients received immunosuppression according to the protocols of the time; with earlier transplant recipients receiving cyclosporin-based triple therapy. Later recipients received tacrolimus (TAC)-based dual therapy. Cyclosporin was administered to maintain trough level concentrations of 150-250 μg/L in the first 6 months and 100 μg/L thereafter. Azathioprine was given at a dose of 1 mg/kg/day and, from the mid-1990s, prednisolone was given at a dose of 20 mg/day for the first 2 weeks posttransplantation, although prior to this time the dose used was higher. This dose was reduced to a maintenance dose of 5 mg/day over 3 months and withdrawn where possible. For patients on TAC and prednisolone immunosuppression, trough concentrations of 6-10 μg/L were maintained in the first 6 months and a level of 4-8 ng/L was maintained subsequently. Immunosuppressive regimens are summarized in Table 3.
Table 3. Immunosuppression Regimens Used in Patients Who Underwent Transplantation, Subdivided According to Age; Group 1 = Age >65 yr; Group 2 = 60-64 yr; and Group 3 = 18-59 yr
An attempt at corticosteroid withdrawal was made in all patients in the first year posttransplantation other than for those patients transplanted for autoimmune etiologies (autoimmune hepatitis, primary sclerosing cholangitis, or primary biliary cirrhosis). Episodes of rejection were treated with pulsed doses of intravenous methylprednisolone at a dose of 1 gm daily for 3 days. Patients experiencing steroid-resistant rejection on cyclosporin-based triple therapy were converted to TAC and prednisolone 20 mg/day and had steroid withdrawal attempted, if appropriate, once more over a 3-6 month period. Patients on TAC-based immunosuppression who experienced steroid-resistant rejection received higher doses of TAC to achieve trough concentrations of 10-12 ng/L.
To assess the proportions of LT performed according to age group and time within the study, we divided the study into three eras of LT: era 1, 1988-1994; era 2, 1995-1999; and era 3, 2000-2003. The overall percentage of transplants performed for patients >65 yr of age was 1%, 5%, and 8%. The results are summarized in Table 4.
Table 4. Proportions of Liver Transplants Performed (n = 1657), According to Age Group, and Era of Study, 1988-1994, 1995-1999, and 2000-2003
1988-1994 n = 547 (%)
1995-1999 n = 600 (%)
2000-2003 n = 510 (%)
Rates of ACR and Chronic Rejection
Histologic analysis was performed as described previously. A significant difference was noted in the number of episodes of ACR between the 3 groups. A total of 218 episodes of ACR were recorded in the 3 groups (group 1 = 33/77 (43%), group 2 = 62/137 (45%), group 3 = 123/202 (61%), χ2 = 9.93, P = 0.0016). However, there was no significant difference in the number of patients who had ACR between the 3 groups (31/77 (40%) vs. 58/137 (42%) vs. 98/202 (49%), χ2 = 1.95, P = 0.16). There was a nonsignificant trend to lower rates of chronic rejection among patients >65 yr (4/77 (5%) vs. 10/137 (7%) vs. 22/202 (11%), χ2 = 2.69, P = 0.1). There was no difference in the number of episodes of ACR observed according to gender.
The groups were then compared to assess the rates of ACR according to the immunosuppression used. The proportions of ACR according to TAC and cyclosporin were (36% vs. 54%, P = 0.13) for patients over 65 yr, (34% vs. 48%, P = 0.099) for patients aged 60-64 yr, and (43% vs. 43%, P = 0.984) for patients aged 18-59 yr.
The 30-day survival, 1-yr, and 5-yr survival rates are summarized in Table 5. Overall patient survival at 30-days was 99% for patients aged >65 yr, 94% for patients aged 60-64 yr, and 94% for patients aged <60 yr (P = not significant [NS]). The 1-yr survival for these groups was 82%, 86%, and 83%, respectively (P = NS), whereas 5-yr survival was 73%, 80%, and 78%, respectively (P = NS). Over the entire study period, age alone was not associated with decreased survival after LT (P = 0.31), although after 5-yr of follow-up, an apparent dropoff in survival is evident in the patient cohort aged >65 yr, but this did not reach statistical significance. A receiver operating characteristic curve comparing overall deaths among patients and patient age gave an area under the curve of 0.53. Graft survival is summarized in Table 3. Survival curves are illustrated in Figure 1. To further assess survival and to determine whether or not bias could have occurred while choosing the cohort of patients aged 18-60 yr we compared the survival of patients aged >65, 60-64 yr, and all patients receiving transplants at King's College Hospital during the study period (Fig. 2) and no difference in survival was discernable between groups.
Table 5. Thirty-day, 1-yr, and 5-yr Patient and Graft Survival in Patients Who Underwent Transplantation, Subdivided According to Age Group 1 = >65 yr; Group 2 = 60-64 yr; and Group 3 18-59 yr
n = 77 (%)
n = 137 (%)
n = 202 (%)
Causes of Death
Cause of death in the different groups is summarized in Table 6. In patients aged less than 65 yr the commonest causes of death were related to cardiovascular deaths (myocardial infarction, congestive heart failure, cerebrovascular accident, intracranial hemorrhage) and sepsis. In the patients aged greater than 65 yr, the most prevalent cause of death was malignancy (both recurrent and de novo) and sepsis, the latter of which accounted for 35% of deaths. Among patients aged 18-59 yr and 60-64 yr, cardiovascular causes accounted for 30% and 23% of deaths, respectively, and sepsis was responsible for 23% of deaths in both groups. A Cox regression analysis was performed to assess the influence of donor and recipient factors. None of the factors studied, including recipient age, donor age, the presence of malignancy, or sepsis, had an impact on survival at yr 5 after LT. The results of this analysis are summarized in Table 7.
Table 6. Causes of Death in Liver Transplant Recipients Who Received Organs Subdivided According to Age; Group 1 = >65 yr; Group 2 = 60-64 yr; and Group 3 = 18-59 yr
Cause of death
Group 1 (n = 23/77) (%)
Group 2 (n = 31/137) (%)
Group 3 (n = 47/202) (%)
De novo malignancy
Primary graft nonfunction
Acute cellular rejection
Table 7. Cox Regression Analysis Studying the Impact of Recipient and Donor Factors on Survival at Year 5
In transplant centers a potential bias can exist regarding transplantation of older patients. In this study, we have identified that well-selected patients over the age of 65 yr have a comparable survival posttransplantation to younger recipients at 5 yr, and in that regard are acceptable transplant candidates. In addition, we have also identified that patients over the age of 65 yr at the time of transplant are less likely to experience episodes of ACR.
With ever-growing patient numbers on transplant waiting lists, the principles of organ allocation are being critically evaluated. Regarding outcome of older LT recipients, a multicenter review of 735 adult recipients of LT for end-stage liver disease showed a highly significant lower 1-yr survival for patients older than 60 yr at LT compared with those less than 60 yr (81% vs. 90% at 1 yr).15 The excess of deaths was due to nonhepatic causes in the first 6 months posttransplantation. Other groups have also reported worse outcomes in older populations.16, 17 In this series, we demonstrated no significant difference in survival between groups within the first 5 yr after LT, suggesting that age in isolation should not be a contraindication to transplantation, a finding consistent with data from other groups.18–22 However, it is evident that after 5 yr, survival of patients aged 65 yr and older begins to diminish. Data from the European Liver Transplant Registry, reviewed 10-yr post-LT survival in patients 15-45 yr, 45-60 yr, and >60 yr from January 1988 to June 2004. The 5-yr survival rates were similar at 72%, 68%, and 63%, respectively; however, the 10-yr survival of 64%, 58%, and 48%, respectively, demonstrated that survival in patients greater than 60 yr was significantly worse (P log rank = 0.0001).23
In patients over 65 yr, the most common combined causes of death were malignancy and sepsis, reflecting the possible interaction of age-related immune senescence and immunosuppression. In contrast, for patients aged less than 65 yr at the time of LT, cardiovascular causes accounted for the majority of deaths, with sepsis being the next most common cause. This may suggest that the cardiovascular workup for patients <65 yr is less robust at our institution, than for older recipients.
In this analysis, the group with the best survival were those patients receiving transplants between the ages of 60 and 64 yr, although this failed to reach significance. One explanation for this may be that the older recipients are more rigorously assessed for comorbidities that could be detrimental to outcome. Additionally, the better survival observed in the 60-64 yr old and over 65 yr old cohorts may also reflect the greater proportion of patients who received transplants for primary biliary cirrhosis as their primary indication. It is well recognized that patients with primary biliary cirrhosis represent a successful cohort to transplant.24, 25 Interestingly, in the cohort aged over 65 yr, hepatocellular carcinoma was the second most common indication for LT. Although hepatocellular carcinoma recurrence was observed in 5 of 20 patients transplanted for this indication, this did not alter the overall survival, when compared to the other groups. Thus, the older patient cohorts may reflect a selection bias of patients who are deemed likely to have a good outcome from LT despite their age.
A further explanation for the good outcome observed in the >65 yr group is the fact that their mean MELD score was lower than the other 2 groups. Pretransplantation MELD has recently been viewed at as a predictor of posttransplantation survival.26 In a study of 1,472 patients receiving transplants during 1991-2002, a multivariable analysis demonstrated that patient age >65 yr, donor age >50 yr, male gender, retransplantation, and pretransplant MELD scores >25 were associated with poor patient and graft survival. Interestingly, all our patients would have been considered low-risk using the MELD risk scoring stratification (i.e., MELD ≤ 15). In contrast, there may also exist a bias to transplant more marginal younger recipients, given the natural emotive tendency among transplant professionals to offer LT to younger patients, even in the face of potentially less favorable survival outcomes. A recent study that assessed the survival benefit of LT demonstrated that for recipients with lower MELD scores, mortality was higher among LT recipients than for candidates on the waiting list.27 However, patients with hepatocellular carcinoma were excluded from this analysis. Currently, MELD is not used as a criteria for organ acceptance in the UK, and the Child-Turcotte-Pugh scores between the groups were not statistically different. In our patient cohort, hepatocellular carcinoma accounted for 26%, 11%, and 7% of transplants performed in the >65, 60-64, and 18-59 age groups, respectively. Thus, LT was performed with the goal of offering the best chance of cure, irrespective of MELD score.
A further interesting observation from this study relates to the finding of reduced rates of ACR among recipients aged 65 yr and over. A consequence of aging is a reduction in the immune response, including a reduction of both T-cell and B-cell function.13 Manifestations of a blunted immune response may include increased incidence of malignancy and infection.14 Therefore, in the context of transplantation, although immunosenescence may be beneficial in reducing the number of episodes of ACR and enhancing graft survival, this may be at the cost of increased risk of cancer and sepsis. Some centers have reported no difference in episodes of ACR per patient and the need for rescue immunosuppressive therapy among older or younger recipients,16, 18 whereas other reports have noted a reduction in ACR in older patients on cyclosporin-based immunosuppression.16, 17 Taken together, these data support the concept of a more tailored immunosuppressive approach to patients aged over 65 yr.
The main limitation of this study was the absence of serial or protocol liver biopsies, since liver biopsies were mainly performed in the presence of biochemical abnormalities. Therefore, the prevalence of mild cellular rejection may have been underestimated. In addition, it has not been possible to accurately determine the prevalence of disease recurrence in this cohort, nor can comparisons between different immunosuppressive regimens be drawn, as the study was not designed to assess this.
An additional weakness is the long time period during which patients were selected. The improvements in outcomes observed between our study and earlier studies15–17 may be due to several reasons, including advances in surgical technique, improved intensive care, and standardized immunosuppressive therapy. Indeed, the majority of transplants (71/77, 93%) in patients aged >65 yr were performed after 1994, in contrast to the other studies. Moreover, in this series, the proportion of older recipients receiving transplants for primary biliary cirrhosis was high, and the cardiovascular workup for all patients >60 yr was robust. Additionally, the lower MELD scores at transplant in the >65 yr cohort may also be significant, while patients >60 yr were more likely to be delisted for transplant if their clinical condition deteriorated. The study would have been stronger had the groups been etiology-matched, but increasing age is associated with a different spectrum of diseases, and therefore this was not possible. Another potential area of criticism is the use of a single-center study. We would contest that this allows patient groups to be studied in more depth, and gives a consistency to patient management that multicenter studies may fail to do.
In conclusion, this study demonstrates that the 5-yr survival of patients over 60 and 65 yr undergoing LT is comparable to the outcomes demonstrated in those less than 60 yr. Therefore, LT should not be denied to older recipients on the basis of age alone, once a comprehensive screen for comorbidity has been undertaken. In addition, patients over 65 yr have lower rejection rates, and excellent graft survival. It is logical, therefore, based on these findings, that older recipients might benefit from strategies geared toward immunosuppression withdrawal and tolerance induction. However, long-term follow-up of these patients is warranted.