Long-Term Survival of Recipients of Liver Grafts From Donors Older Than 80 Years: Is It Achievable? Matteo Cescon, Gian Luca Grazi, Giorgio Ercolani, Bruno Nardo, Matteo Ravaioli, Andrea Gardini, and Antonino Cavallari Isolated cases or small series of orthotopic liver transplantation (OLT) with grafts from donors older than 80 years have been reported, but the long-term outcome of patients receiving livers from extremely old donors is unknown. From 1998 to 2003, we performed 17 OLTs with donors older than 80 years (median, 82 years; range, 80 to 87 years). No deaths occurred in the early postoperative period. We analyzed the outcome in 12 patients with a follow-up longer than 1 year. Hepatic insufficiency was caused by hepatitis C virus (HCV)-related cirrhosis in five cases (42%) and non-HCV–related diseases in seven cases (58%). All donors had normal liver function, hemodynamic stability, and no parenchymal alterations. OLT was uneventful in all cases. Median follow-up was 30.3 months (range, 17 to 42 months). No late vascular complications occurred. One patient (8.3%) died 3 years after OLT for causes unrelated to hepatic dysfunction. Twoand 3-year actuarial survival rates were 100% and 75%, respectively. All HCV-positive (HCVⴙ) patients developed hepatitis recurrence (after 2, 3, 4, 5, and 22 months) requiring antiviral treatment in 3 patients and leading to graft cirrhosis in 1 patient. Non-HCVⴙ patients had wellpreserved liver function throughout the observation period. At the end of follow-up, we observed no clinical hepatic decompensation in the entire group and biochemical signs of recurrent disease in 3 patients. Use of grafts for OLT from donors older than 80 years is safe because of their potentially normal functional recovery. A selection among available organs is mandatory to minimize other risk factors for poor outcome. Long-term patient and graft survival seem to be achievable, but the high rate and rapidity of HCV reinfection remain a major concern for HCVⴙ patients. (Liver Transpl 2003;9:1174-1180.)
T
he persistent shortage of organs has expanded the procedures for overcoming the gap between number of donations and number of patients listed for liver transplantation. The most recent acquisitions include the use of marginal donors, non– heart-
beating donors, split livers, and living donors. Marginal donors represent a possible source of grafts, although the isolated or simultaneous presence of factors that contribute to this definition is linked almost invariably to risk for poor outcome.1-3 In this view, use of elderly donors has been shown to negatively impact on short- and long-term survival after orthotopic liver transplantation (OLT),4-6 with very few exceptions.7,8 The ultimate frontier is the use of extremely old donors. Even if some investigators reported satisfying results in the short term with donors older than 70 years,7-9 use of these grafts remains questionable when considering the longterm perspective. Data for donors older than 80 years are even fewer and limited to the description of early outcome.8-11 We have been using donors older than 80 years with caution since 1998, and we report long-term results obtained to date, with a special focus on the impact of hepatitis C recurrence.
Methods From 1998 to February 2003, a total of 17 OLTs were performed at our institution using livers procured from donors older than 80 years, representing 4% of all procedures performed during the same period. Median donor age in this series was 82 years (range, 80 to 87 years). Five patients have a short follow-up (⬍1 year). One patient received a graft from an 80-year-old donor, required early retransplantation for stenosis of the caval anastomosis on postoperative day 10, and had an uneventful postoperative course thereafter. The remaining four patients currently are alive with normal liver function after 1, 4, 5, and 5 months. Twelve patients, who constitute the population of this study, had a survival longer than 1 year.
Donor Selection From the Department of Surgery and Transplantation, Sant’OrsolaMalpighi Hospital, University of Bologna, Italy. Address reprint requests to Gian Luca Grazi, MD, Department of Surgery and Transplantation, Unita` di Chirurgia, Padiglione 25, Sant’Orsola-Malpighi Hospital, Via Massarenti, 9, 40138 Bologna, Italy. Telephone: ⫹39-051-636-4750; FAX: ⫹39-051-397-661; E-mail:
[email protected] Copyright © 2003 by the American Association for the Study of Liver Diseases 1527-6465/03/0911-0007$30.00/0 doi:10.1053/jlts.2003.50234
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Our policy for acceptance of very old donors has been reported previously9 and includes: (1) normal gross aspect of the organ (soft consistency, no apparent fatty infiltration) and no abnormal morphological characteristics shown by biopsy, when indicated; (2) no alteration in liver function test (LFT) results at the time of procurement; and (3) donor hemodynamic stability with the use of low doses of vasopressors before harvesting. In this regard, the 17 grafts used represent 50% of all organs from donors older than 80 years referred to our center in this period. Reasons for discard-
Liver Transplantation, Vol 9, No 11 (November), 2003: pp 1174-1180
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Liver Transplantation With Donors Older Than 80 Years
Table 1. Recipient and Donor Profiles and Surgical Data Recipient Profile
Donor Profile
Surgical Data
Recipient Age UNOS Donor ICU Dopa SAP AST ALT TBIL GGT PT IT OT PRBC FFP No. Gender (yr) Indication for OLT Status Age (yr) Gender (d) (␥/kg/min) (mm Hg) (U/L) (U/L) (mg/dL) (U/L) (%) (min) (min) (mL) (mL) 1 2 3 4 5 6 7 8 9 10
M M F F F F M M M M
60 60 61 65 48 53 60 55 54 35
11 12
M F
60 62
HCV⫹ ⫹ HCC HCV⫹ ⫹ HCC CC HCV⫹ ALD ⫹ HCC HCV⫹ HBsAg⫹ HBsAg⫹ ⫹ HCC ALD ⫹ HCC Acute Wilson’s disease ALD HCV⫹
Patients with follow-up <1 yr 1† M 50 Amanita phalloydes liver failure 2 M 50 HBsAg⫹ ⫹ HCC 3 F 28 HBsAg⫹ acute liver failure 4 M 49 HCV⫹ 5 F 67 HCV⫹
2* 2* 1* 2* 2* 2* 1* 2* 2A 1
80 81 84 87 80 80 87 86 82 82
M M M F F F F F F M
1 12 1 6 4 2 3 2 0 1
3 2.5 4 3 2 16 6 10 6 5
140 120 90 110 135 100 102 90 140 113
79 38 62 33 63 39 21 23 19 15
11 80 18 22 34 15 13 23 23 12
0.3 0.5 1 0.7 0.8 1 0.8 0.5 0.5 0.3
9 269 13 38 16 14 9 27 NA NA
60 77 85 75 53 93 74 52 96 61
519 524 529 450 622 555 500 375 421 613
475 534 442 535 510 480 570 570 450 480
1,500 900 2,100 4,200 3,600 4,300 1,120 1,500 1,200 2,400
2B 2B
80 85
M M
2 2
7 0
120 131
21 16
18 21
0.6 0.5
36 21
95 79
431 424
270 435
1,500 1,750 1,500 2,300
1
80
M
1
2
120
37
10
0.6
25
75
350
365
2A 1
80 86
F F
0 0
0 0
145 115
19 26
19 12
0.6 0.8
8 NA
82 76
502 300
550 310
9,500 6,000 900 1,500
2A 2B
80 84
F F
0 0
0 0
180 80
12 22
16 15
0.6 0.4
NA 22
88 78
552 175
440 315
2,700 3,700 1,200 2,200
600
1,500 0 1,700 4,700 3,400 1,000 1,100 2,300 1,600 3,350
0
Abbreviations: ICU, intensive care unit stay before graft procurement; Dopa, dopamine infusion rate in donors (micrograms per kilograms per minute); SAP, systolic arterial pressure; AST, aspartate aminotransferase; ALT, alanine aminotransferase; TBIL, total bilirubin; PT, prothrombin time; IT, total ischemia time; OT, operation time; PBRC, intraoperative packed red blood cell transfusions; FFP, intraoperative fresh frozen plasma transfusions; HCV⫹, HCV⫹ cirrhosis; HCC, hepatocellular carcinoma; NA, not assessable; CC, cryptogenetic cirrhosis; ALD, alcoholic cirrhosis; HBsAg⫹, HBsAg⫹ cirrhosis. *Status according to the old UNOS classification. †This patient underwent re-OLT postoperative day 10 for stenosis of the caval anastomosis.
ing organs were the presence of cirrhosis or chronic hepatitis of the graft in four cases, extrahepatic neoplasms of the donor in three cases, macrovesicular steatosis greater than 30% in three cases, graft congestion and hypoperfusion in two cases, prolonged ischemia of grafts already refused by other centers in two cases, extrahepatic cholestasis in one case, and macroscopic appearance only in two cases. Recipient and donor profiles, as well as surgical data (including those for patients with a follow-up ⬍ 1 year), are listed in Table 1.
Donor Characteristics All donors were in stable hemodynamic condition with minimal inotropic support, well-preserved liver function, and normal serum sodium levels. Liver biopsies before harvesting were not considered mandatory unless the gross appearance of the liver was judged not perfectly normal by the surgeon in charge of procurement. Biopsies thus were performed in nine cases (75%), showing mild periportal fibrosis and macrovesicular steatosis less than 30% in all cases. In one case (the only donor with an abnormal ␥-glutamyltransferase [GGT] level), mild ductular hyperplasia caused by extrahepatic cholestasis was seen.
Recipient Characteristics There were seven men and five women with a median age of 60 years (range, 35 to 65 years). Causes of liver failure leading
to OLT were hepatitis C virus (HCV)-related cirrhosis in five patients (42%) and non–HCV-related diseases in seven patients (58%). Hepatocellular carcinoma (HCC) was the main indication for OLT in five patients (42%). Very poor preoperative conditions were present in only two patients (United Network for Organ Sharing [UNOS] status 2A and 1).
Surgical Data University of Wisconsin preservation solution (Viaspan; Dupont Pharma, Dordrecht, The Netherlands) was used in four cases, and Celsior (Imtix; Sangstat, Lyon, France) solution, in eight cases. The piggyback technique was performed in 11 patients, and the conventional technique, in 1 patient. OLT was uneventful in all cases. Median surgical time was 8 hours (range, 4 hours 30 minutes to 9 hours 30 minutes), median total ischemia time was 8 hours 30 minutes (range, 6 hours 15 minutes to 10 hours 22 minutes), and median intraoperative packed red blood cell and plasma requirements were 1,500 mL (range, 900 to 4,300 mL) and 1,725 mL (range, 0 to 4,700 mL), respectively. Immunosuppression was established with cyclosporine in seven patients (58%) and tacrolimus in five patients (42%), both associated with tapering doses of steroids.
Statistical Analysis Results are expressed as median and range. Actuarial survival was estimated using the life-table method. Free-of-event sur-
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Cescon et al
Table 2. Postoperative Course ICU Hospital Patient Stay Stay Survival No. (d) (d) (mo) 1
4
18
42
2 3 4 5 6 7 8 9 10
6 3 5 3 3 5 4 3 6
10 18 24 11 20 15 10 34 14
40 37 36 35 31 29 28 23 23
11 12
6 3
15 21
21 17
Adverse Events HCV recurrence, atrial fibrillation, pneumonia HCV recurrence, cholangitis Autoimmune hepatitis HCV recurrence, PTLD bleeding Breast cancer HCV recurrence — Biliary stricture Speech disorders Acute rejection Cerebral abscess — HCV recurrence
AST ALT TBIL SA Status (U/L) (U/L) (mg/dL) INR (g/dL) Ascites PSE Alive
38
Alive 252 Alive 61 Dead 107† Alive 19 Alive 35 Alive 20 Alive 28 Alive 21 Alive 22 Alive Alive
18 134
26
1.2
2.41*
4.3
No
No
135 43 114† 12 27 33 35 13 29
0.9 1.4 2.6† 0.4 0.8 1.2 0.5 0.8 0.3
1.12 1.20 1.27† 1.24 1.08 1.12 1.02 1.09 1.19
4.1 3.5 2.9† 3.8 3.9 4.0 4.5 4.0 4.3
No No Yes‡ No No No No No No
No No No No No No No No No
13 63
0.4 1.2
1.06 1.22
4.1 3.3
No No
No No
Abbreviations: ICU, intensive care unit; AST, aspartate aminotransferase; ALT, alanine aminotransferase; TBIL, total bilirubin; INR, international normalized ratio; SA, serum albumin; PSE, portosystemic encephalopathy; PTLD, posttransplant lymphoproliferative disorder. *INR value altered because of chronic prophylaxis with warfarin sodium. †Data obtained before splenectomy (see text). ‡Ascites caused by posttransplant lymphoproliferative disorder.
vival, defined as survival free from recurrent hepatitis, acute rejection, graft loss, or death,12 was calculated using the Kaplan-Meier method, and differences between groups were analyzed using log-rank test. Data were processed using SPSS software (SPSS Inc, Chicago, IL).
Results The postoperative course of 12 patients with a follow-up longer than 1 year (median, 30.3 months; range, 17 to 42 months) is listed in Table 2. Eight
patients (66.7%) had a follow-up longer than 2 years. There were no cases of primary nonfunction. Graft function normalized quickly in all except one patient, who received a graft with extrahepatic cholestasis and postoperatively showed cholestasis and cholangitis, which resolved after endoscopic papillosphincterotomy. The postoperative course of the main cholestatic parameters (total bilirubin and GGT levels) is shown in Figures 1 and 2. All postoperative cholangiographic controls were normal except for one patient,
Figure 1. Postoperative course (postoperative days 4 to 20) of total bilirubin levels of the 12 patients included in the study (data presented as median, minimum, and maximum values).
Liver Transplantation With Donors Older Than 80 Years
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Figure 2. Postoperative course (postoperative days 4 to 20) of GGT (gamma-GT) levels of the 12 patients included in the study (data presented as median, minimum, and maximum values).
who showed a biliary stricture requiring hepaticojejunostomy 4 months after OLT. Median intensive care unit and hospital stays were 4 days (range, 3 to 6 days) and 16.5 days (range, 10 to 34 days), respectively. No late vascular complications occurred. Only one patient (8.3%) died of hemorrhagic shock after splenectomy performed 3 years after OLT. No re-OLT was required. Two and 3-year actuarial survival rates were 100% and 75%, respectively. HCV-Positive Patients All five patients with HCV-related cirrhosis developed chronic HCV-related hepatitis soon after OLT (2, 3, 4, 5, and 22 months). Hepatitis recurrence was suspected first from alterations in LFT results, then documented by liver biopsy. Because of the severity of the disease with progression to fibrosis (Knodell13 fibrosis staging score, 3), three of five patients required antiviral therapy. Treatment was undertaken in one patient (with hepatitis diagnosed at 2 months) with interferon alfa-2b (3 million units every other day) alone, subsequently switched to peginterferon alfa-2b (50 g/wk) and ribavirin (200 mg/d). Treatment in another patient (with hepatitis diagnosed at 5 months) was with peginterferon alfa-2b (80 g/wk) and ribavirin (800 mg/d). Treatment in the third patient (with hepatitis diagnosed at 22 months) was with interferon alfa-2b (1.5 million units/d) and ribavirin (600 to 800 mg/d). In the latter patient, hepatitis recurrence could be shown only at this late stage, probably because it was masked previously by early histological features of severe cholestasis and cholangitis. Doses of antiviral drugs were adjusted according to symptoms and adverse events. Two patients had a com-
plete clinical and virological response, but hepatitis relapsed in one of these patients 3 months after interruption of treatment. The patient who developed hepatitis 2 months after OLT had a persistent hypertransaminasemia despite a 1-year antiviral treatment, showing well-compensated liver cirrhosis 17 months after OLT. The remaining two patients developed mild and moderate chronic hepatitis 3 and 4 months after OLT, without fibrosis or clinical decompensation and requiring no specific treatment. In one patient, Epstein-Barr virus–related lymphoproliferative disease originating from the spleen and causing remarkable splenomegaly and ascites was shown 30 months after OLT. Splenectomy was performed at another institution because of the impossibility of completing the gancyclovir and anti-CD20 antibody– based treatment with chemotherapy because of severe pancytopenia. The patient died shortly after splenectomy of intra-abdominal bleeding at month 36 post-OLT. Another patient showed prolonged cholangitis and cholestasis requiring successful endoscopic papillosphincterotomy, as previously reported. A third patient experienced bacterial pneumonia, which was treated effectively with antibiotics, and atrial fibrillation requiring long-term prophylaxis with oral anticoagulants. Non–HCV-Positive Patients Among non–HCV-positive (non-HCVⴙ) patients, one patient with a preoperative diagnosis of cryptogenic cirrhosis showed a transient alteration in LFT results caused by the early occurrence of autoimmune hepati-
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Cescon et al
tis, which remained misdiagnosed for nearly 2 years. After administration of more sustained immunosuppression, a trend to complete normalization of liver function was observed. Another patient who underwent OLT for acute Wilson’s disease experienced an acute rejection episode postoperative week 2, requiring pulse doses of steroids, with subsequent normalization of liver function. None of the remaining patients had significant graft malfunction throughout their follow-up. The two patients undergoing OLT for hepatitis B surface antigen (HBsAg)-positive cirrhosis were prophylactically administered long-term antibody to hepatitis B virus immunoglobulin (5,000 or 3,500 U/mo, depending on antibody to HBsAg titers) and lamivudine (100 mg/d), and they had no signs of hepatitis recurrence. Other complications recorded in this group of patients included: (1) a biliary stricture requiring hepaticojejunostomy postoperative month 4; (2) pontine myelinolysis with speech disorders, which disappeared within a few months after switching from FK506 to oral cyclosporine; and (3) a cerebral abscess, occurring after steroid-based treatment of a rejection episode and eventually cured by several courses of antibiotics. One patient who underwent OLT for HCC on alcoholic cirrhosis developed infiltrating breast cancer 3 years after OLT. The tumor was diagnosed and surgically treated, with an ongoing program of chemotherapy. As listed in Table 2, there was no HCC recurrence in the entire series (all patients underwent OLT while fulfilling the Milan criteria14). Free-of-Event Survival Three HCV⫹ patients had abnormalities of LFT results at the end of follow-up, whereas the remaining nine patients still have normal LFT results. Adverse events defining free-of-event survival occurred in four of five (80%) and five of five (100%) HCV⫹ patients at 6 months and 2 years, respectively; all were HCV reinfections. There was one acute rejection episode (14.3%) and no recurrent disease in HCV-negative (HCV⫺) patients at the same intervals. Accordingly, the 6-month free-of-event survival rate was 20% in the group of HCV⫹ patients and 85.7% in the group of HCV⫺ patients (P ⫽ .06). The same figures at 2 years were 0% and 71.4% in the two groups, respectively (P ⫽ .01; Fig. 3). No patient showed hepatic decompensation at the end of follow-up.
Figure 3. Free-of-event survival (see text) of HCVⴙ and HCVⴚ patients receiving a graft from donors older than 80 years. P ⴝ .06 at 6 months. P ⴝ .01 at 2 years. ⴙ HCV pos-censored.
Discussion We reviewed our experience of OLTs using donors older than 80 years and show not only that early results are similar to those achievable using livers from younger donors, but also that this policy may offer transplant recipients a concrete chance of prolonged survival. Use of elderly donors has become a necessity that every transplant team has to deal with nowadays, as well as the resort to every possible tool to decrease the discrepancy between the number of grafts available and number of patients listed for OLT. However, the most numerous series published to date clearly show that advanced donor age negatively affects short- and long-term outcomes.4,5 One recent report confirmed previous findings that donor age older than 70 years represents the main predictive factor of decreased survival after OLT.6 Nevertheless, when other risk factors (i.e., graft steatosis or prolonged ischemia time) are ruled out, organs from very old donors might be used with good results.7,8,10,11 Successful OLTs have been reported with donors older than 80 years8,10 and even older than 90 years,11 suggesting that the liver is much better preserved than other organs from aging-related damage.15 This is thought to be responsible for early function after implantation similar to that achieved with far younger donors. Conversely, the few reported cases of OLT performed with donors older than 80 years cannot provide definite evidence of their safety, and data on longterm reliability of these grafts are totally lacking.
Liver Transplantation With Donors Older Than 80 Years
We have been using donors older than 80 years since 1998, and results obtained to date are fairly encouraging. This series of OLTs with grafts from octogenarians had no vascular complications, except one case of iatrogenic caval stenosis leading to graft loss. The only patient death was not caused by vascular complications. Moreover, this report provides for the first time evidence that long-term survival can be achieved, especially for non-HCV⫹ patients. This finding obviously must be interpreted with caution because median follow-up was 30 months and only four patients survived more than 3 years. However, the absence of graft dysfunction in all patients at the end of the study period seems promising for an even longer global survival. No comparison can be made with other studies because of the paucity of cases and shortness of follow-up. Some preliminary data were reported very recently by a Spanish experience of more than 300 livers from donors older than 70 years, showing that with a number of recipients of grafts from donors older than 80 years similar to ours, the incidence of primary graft failure was 15.8%, the 1-year graft survival rate was 72%, and the 5-year survival rate was only 51%.16 Some issues need to be (re)addressed by analyzing our results. First, advanced donor age must still be considered a “particular” risk factor.7,8 This explains the 50% graft acceptance among organs offered to our institution in the study period. Normality of liver function, absence of morphological alterations other than those correlated with physiological aging, and optimal hemodynamic state of donors were invariably present in all 12 patients. In particular, our policy is to perform a liver biopsy when grafts appear macroscopically steatotic to discard those with moderate or severe macrovesicular fatty infiltration,9 which becomes an unacceptable risk factor for malfunction if combined with advanced donor age itself. Finally, periods of ischemia did not exceed 11 hours, and OLTs were performed without complications, especially arterial ones. These are the fundamental premises to guarantee early functional recovery, which was obtained in our series even without observing the almost constant cholestatic course that some groups, including ours,9,17 have described as typical of older grafts. With the exception of one patient with prolonged cholangitis and another with an acute rejection episode, the main cholestatic parameters were almost normalized within the first postoperative month. The second consideration is on donor-recipient matching. Our study shows that patients with HCVrelated cirrhosis had 100% HCV reinfection with chronic hepatitis, in most cases within the first postop-
1179
erative months, and in one case leading to graft cirrhosis within 17 months. This determined a remarkable difference in problem-free survival compared with the group of HCV⫺ patients. The correlation between donor age and progression toward liver cirrhosis after OLT recently was noted in a large cohort study.18 This finding seems similar to the increased rate of fibrosis progression observed after acute HCV hepatitis in elderly nontransplantation patients.19 The exact mechanisms that regulate this phenomenon probably are linked to the reduced regenerative capacity associated with cell aging after acute or chronic injury in older subjects,20 but they are still largely unknown. Noticeably, none of our HCV⫹ patients was administered reinforced immunosuppression (i.e., high doses of steroids or OKT3), which is considered one of the most important risk factors for severe HCV recurrence,21 supporting the hypothesis that advanced donor age itself is a strongly contributing factor. Even so, three patients had to be treated with antiviral agents, achieving a complete response in two cases, whereas the other two patients developed less severe hepatitis that did not require specific treatment. No HCV⫹ patients had clinically evident hepatic decompensation at the end of a median follow-up of 3 years, and the only death was unrelated to graft dysfunction. Conversely, patients who underwent OLT for other indications showed well-preserved graft function during the entire study period, with a median follow-up similar to that of HCV⫹ patients. In conclusion, data emerging from our report confirm previous findings in a larger series supporting the safe use of donors older than 80 years for OLT because of the ability of these grafts to achieve normal functional recovery. This policy imposes strict selection among available organs to minimize adjunctive risk factors for poor outcome. The life expectancy of patients receiving such organs has not yet been determined, but long-term patient and graft survival seem to be achievable, especially for non-HCV⫹ subjects. The high rate and rapidity of HCV recurrence is a major concern when considering allocation of grafts from older donors to HCV⫹ patients.
References 1. Ploeg R, D’Alessandro AM, Knechtle SJ, Stegall MD, Pirsch JD, Hoffmann RM, et al. Risk factors for primary dysfunction after liver transplantation: A multivariate analysis. Transplantation 1993;55:807-813. 2. Strasberg SM, Howard TK, Molmenti EP, Hertl M. Selecting the donor liver: Risk factors for poor function after orthotopic liver transplantation. Hepatology 1994;20:829-838.
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3. Briceno J, Marchal T, Padillo J, Solorzano G, Pera C. Influence of marginal donors on liver preservation injury. Transplantation 2002;74:522-526. 4. Marino IR, Doyle HR, Aldrighetti L, Doria C, McMichael J, Gayowsky T, et al. Effect of donor age and sex on the outcome of liver transplantation. Hepatology 1995;22:1754-1762. 5. Hoofnagle JH, Lombardero M, Zetterman RK, Lake J, Porayko M, Everhart J, et al. Donor age and outcome of liver transplantation. Hepatology 1996;24:89-96. 6. Busquets J, Xiol X, Figueras J, Jaurrieta E, Torras J, Ramos E, et al. The impact of donor age on liver transplantation: Influence of donor age on early liver function and on subsequent patient and graft survival. Transplantation 2001;71:1765-1771. 7. Emre S, Schwartz ME, Altaca G, Sethi P, Fiel MI, Guy SR, et al. Safe use of hepatic allografts from donors older than 70 years. Transplantation 1996;62:62-65. 8. Jimenez Romero C, Moreno Gonzalez E, Colina Ruiz F, Palma Carazo F, Loinaz Segurola C, Rodriguez Gonzalez F, et al. Use of octogenarian livers safely expands the donor pool. Transplantation 1999;27:572-575. 9. Grazi GL, Cescon M, Ravaioli M, Ercolani G, Pierangeli F, D’Errico A, et al. A revised consideration on the use of very aged donors for liver transplantation. Am J Transplant 2001;1:61-68. 10. Wall W, Grant D, Roy A, Asfar S, Block M. Elderly liver donor. Lancet 1993;341:121. 11. Filipponi F, Romagnoli J, Urbani L, Catalano G, Costa A, Mosca F. Transplantation of a ninety-three-year-old donor liver. Case report. Hepatogastroenterology 2003;50:510-511. 12. Neuhaus P, Clavien PA, Kittur D, Salizzoni M, Rimola A, Abeywickrama K, et al. Improved treatment response with basiliximab immunoprophylaxis after liver transplantation: Results from a double-blind randomized placebo-controlled trial. Liver Transpl 2002;8:132-142.
13. Knodell RG, Ishak KG, Black WC, Chen TS, Craig R, Kaplowitz N, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981;1:431-435. 14. Mazzaferro V, Reagalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693-699. 15. Popper H: Aging and the liver. Prog Liver Dis 1986;8:659-683. 16. Cuende N, Grande L, Sanjuan F, Cuervas-Mons V. Liver transplant with organs from elderly donors: Spanish experience with more than 300 liver donors over 70 years of age. Transplantation 2002;73:1360. 17. Yersiz H, Shaked A, Olthoff K, Imagawa D, Shackleton C, Martin P, Busuttil RW. Correlation between donor age and the pattern of liver graft recovery after transplantation. Transplantation 1995;60:790-794. 18. Berenguer M, Prieto M, San Juan F, Rayon JM, Martinez F, Carrasco D, et al. Contribution of donor age to the recent decrease in patient survival among HCV-infected liver transplant recipients. Hepatology 2002;36:202-210. 19. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. Lancet 1997; 349:825-832. 20. Sigal SH, Rajvanshi P, Gorla GR, Sokhi RP, Saxena R, Gebhard DR, et al. Partial hepatectomy-induced polyploidy attenuates hepatocyte replication and activates cell aging events. Am J Physiol 1999;276:G1260-G1272. 21. Sheiner PA, Schwartz ME, Mor E, Schluger LK, Theise N, Kishikawa K, et al. Severe or multiple rejection episodes are associated with early recurrence of hepatitis C after orthotopic liver transplantation. Hepatology 1995;21:30-34.