EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Although advanced age is no longer considered an absolute contraindication for liver transplant, transplant in elderly patients with comorbid diseases remains debatable because of high risks with surgery. Here, we report patient outcomes in this population.
Materials and Methods: We retrospectively reviewed medical records of 276 liver transplant recipients, grouped by age. Group 1 (≤59 years old) consisted of 247 recipients, and group 2 (≥60 years old) consisted of 29 recipients. Reviewed data included age, sex, cause of liver disease, presence of hepatocellular carcinoma, Child-Pugh and Model for End-Stage Liver Disease scores, survival, and posttransplant complications.
Results: In both groups, most patients (n = 108) required liver transplant for hepatitis B virus. Mean age was 40 ± 12.3 and 63 ± 2.3 years in groups 1 and 2, respectively, with more men than women in both group 1 (71.7% vs 28.3%) and group 2 (75.9% vs 24.1%). No significant differences were shown between groups for patient characteristics, except group 1 had significantly higher Model for End-Stage Liver Disease score. Group 1 mean survival time was 10.2 ± 0.6 years, with patient survival rates at 1, 5, 10, and 15 years of 65.5%, 53%, 46.3%, and 40%, respectively. In group 2, respective results were 10.6 ± 1.3 years and 75.9%, 68.6%, 61%, and 48.8% (no significant difference vs group 1).
Conclusions: Liver transplant recipients >60 years of age had survival rates, acute rejection rates, and complications similar to younger recipients. Liver transplant should not be withheld from older recipients on the basis of age alone. However, comprehensive screening for comorbidities should be performed.

Key words : Deceased donor, Life expectancy, Living donor

Because of advances in medicine, people’s life expectancy has increased worldwide. According to World Health Organization data, the number of people over the age of 60 years was 900 million in 2015, and this number is expected to reach 2 billion in 2050.¹ Similarly, the life expectancy of patients with end-stage liver disease has increased.^2,3 Definitive treatment of end-stage and acute liver failure is liver transplant (LT). From the start, 55 years of age was considered the upper limit for LT transplant candidates.^4,5 Today, advanced age is not considered an absolute contraindication for LT, but the option of organ transplant for elderly patients with comorbid diseases remains a subject of debate because of the high risk of surgery.⁵ Despite the controversy, transplant surgeons are performing organ transplants for an increasing number of elderly patients.^6,7 The aim of this study was to describe our experience in the recipient evaluation process, as well as the outcomes of elderly patients after LT.

Materials and Methods

Since 1988, we have performed 659 LTs (449 living donors and 210 deceased donors) at our 3 transplant centers (Ankara, Adana, and Istanbul); 357 (54.1%) of the recipients were adults (≥18 years old) and 302 (45.9%) were children (≤17 years old). Patient data were reviewed retrospectively. Data for 276 adults were included in the study, divided into 2 groups according to age (group 1 was ≤59 years old; group 2 was ≥60 years old). There were 247 recipients in group 1 and 29 recipients in group 2.

The following data were included in this study: age, sex, cause of liver disease, presence or absence of hepatocellular carcinoma (HCC), Child-Pugh score, Model for End-stage Liver Disease (MELD) score, patient survival, and incidence of the main posttransplant complications (acute rejection, hepatic artery thrombosis, hepatic artery stenosis, hepatic vein thrombosis, hepatic vein stenosis, portal vein thrombosis, portal vein stenosis, biliary leakage, and bile duct strictures).

Patient evaluation
According to our criteria, the general medical condition of a potential LT recipient is a more important factor than age. At the Baskent University Division of Transplantation, patient selection criteria for LT are as follows. First, LT should be the only treatment option to save the patient’s life. Second, the patient’s vital organs should show well-preserved function. Third, the patient should not have cancer, except intrahepatic HCC is not exclusionary. Fourth, there should be no active infection. Fifth, the patient and the supportive family members should be prepared and able to adapt to the medical treatment after LT. Sixth, for alcohol-related liver failure, patients should stop using alcohol for at least 6 months. Seventh, the Child-Pugh score should be B or C, and the MELD score should be ≥14; however, scores are not examined in patients with HCC. Finally, patients with HCC are eligible for LT only if the tumor is unresectable because of its location or concomitant liver disease. According to Baskent University criteria,⁸ independent of tumor size and number of nodules, eligibility for LT is upheld if all of the following conditions are observed: there is no extrahepatic metastasis, no major vascular invasion, ascites are free of tumor cells, and histopathological results (during laparotomy, if suspicious intra-abdominal lymphoid nodules are found) are negative.

According to these criteria, we evaluated clinical, laboratory, and radiological results for all candidate recipients before surgery. Before LT, all patients are informed about the evaluation process, the details of the surgery, the postoperative care, complications, and the outcomes.

Our surgical evaluation includes thoracic and abdominal computed tomography scans. We also evaluate lung status, vascular anatomy, the presence of vascular thrombosis (hepatic artery, portal vein, hepatic vein, and vena cava), malignancy and metastasis, and ascites and pleural effusion in tomography.

All patients are examined routinely by qualified staff from the departments of gastroenterology, cardiology, chest disease, psychiatry, and infectious diseases; if necessary, other department consultations are available upon request.

Living donor evaluation
All donors were >18 years old. All living donors were relatives of the recipients (child, n = 50; sibling, n = 42; spouse, n = 24; mother, n = 13; uncle, n = 10; father, n = 8; cousin, n = 8; nephew, n = 8; aunt, n = 6). Within our criteria, according to abdominal computed tomographic measurements, if the potential donor’s graft-to-recipient weight ratio is >1 and the residual liver volume is ≥40% of the total liver volume, then a volunteer is accepted as a liver donor. Staff from the departments of cardiology, pulmonology, hepatology, and psychiatry routinely evaluated the patient; if necessary, other department consultations are requested. We perform liver biopsies for all living donors. After histopathological examination, if we confirm chronic hepatitis, cirrhosis, severe hepatocellular injury, moderate diffuse hepatocellular ballooning, or severe macrovesicular fatty changes >20%, then the candidate is rejected.

Deceased donor evaluation
For all deceased donors, biochemical evaluations should be normal, and there should be no known liver diseases and no acute active infections. During procurement, we perform liver biopsy and frozen-section examinations for all deceased donors. After histopathological examination, if we confirm chronic hepatitis, cirrhosis, severe hepato-cellular injury, moderate diffuse hepatocellular ballooning, and severe macrovesicular fatty changes >20%, then the candidate is rejected.

Recipient surgical procedures
At our institution, LTs are performed according to techniques that have been described previously.^9,10 The partial liver graft is perfused with University of Wisconsin solution through the portal vein, the hepatic artery, and the hepatic duct. In the recipient, the diseased liver is removed, leaving the inferior vena cava intact with the right hepatic vein and the trunk of the middle hepatic vein and left hepatic vein clamped separately. For living donor LT (LDLT) procedures, we perform hepatic vein anastomoses, depending on the graft’s vein side. When the right liver lobe is transplanted, we perform hepatic anastomoses to the recipient’s right hepatic vein conduit. When the graft is either a left lobe or a left lateral lobe, we close the right hepatic vein conduit and perform the anastomosis after a venoplasty of the middle-left vein conduit of the recipient. Thus, in some cases, especially in deceased donor transplants, we close both sides of the vena cava conduit of the graft. We then perform a side-to-side vena cava anastomosis. Reconstruction of the portal vein is performed using an end-to-end venovenous anastomosis. The graft’s hepatic artery is anastomosed to the hepatic artery of the recipient. Our first choice for biliary reconstruction is duct-to-duct anastomosis. If the recipient’s biliary tract is thin or if the LT is affecting the biliary tract, such as sclerosing cholangitis or cholangiocellular carcinoma, then we prefer Roux-en-Y hepaticojejunostomy.

Immunosuppression
After transplant, all recipients are treated with the same immunosuppressive protocol. According to our protocol, LT recipients receive triple immunosuppression in the first year (tacrolimus/cyclosporine/mechanistic target of rapamycin [mTOR] inhibitor + mycophenolate mofetil, prednisolone), dual immunosuppression in the second year (tacrolimus/cyclosporine/mTOR inhibitor + mycophenolate mofetil), and single immunosuppression in the third year (tacrolimus/cyclosporine/mTOR inhibitor). The doses of these agents are adjusted according to the whole blood concentration. For patients in our retrospective study, target whole blood levels of tacrolimus varied from 8 to 12 ng/mL during the first 3 months and that of cyclosporine varied from 150 to 200 ng/mL during the same period. The doses were also adjusted according to the results of renal function tests and other side effects of the agents. The initial dose of steroids was reduced rapidly and stopped at 1 year after transplant.

Postoperative follow-up
For early-stage follow-up in all patients, blood tests and Doppler ultrasonography were performed twice a day for the first 7 days after surgery.

Long-term follow-up
At the Division of Transplantation outpatient clinic at our institution, periodic check-ups of the patients are carried out once per month in the first year, every 3 months in the second year, and every 6 months after the second year. Per standard clinic procedures, blood tests of all patients who are seen at the clinic are examined, and liver Doppler ultrasonography is performed. In patients with HCC, thoracic and abdominal computed tomography is performed every 3 months for tumor screening. During the follow-up period, no protocol liver biopsy specimens are obtained, and biopsies are performed only for investigations of biochemical abnormalities or radiological abnormalities.

Statistical analyses
Statistical analyses were performed using SPSS (version 23; IBM). Data are shown as means and standard deviations or medians and ranges. Overall survival was defined as time from transplant until the patient’s death. We used Kaplan-Meier curves to analyze overall patient survival and log-rank tests to compare overall survival in different groups. Means in different groups were compared with the t test in case of normal distribution and with the Mann-Whitney U test in case of nonnormal distributed variables. To compare quantitative values, we used the chi-square test. All tests were 2-sided, and P < .05 was considered statistically significant.

We performed 659 LTs between December 8, 1988, and May 1, 2020. Of these, 449 were LDLTs, and 210 were deceased donor LTs; 357 (54.1%) of the recipients were adults (≥18 years old), and 302 (45.9%) were children (≤17 years old). Data from 276 adult patients were included in the study.

In group 1 (≤59 years old), the most common indication for LT was hepatitis B (n = 108). The other indications for LT were cryptogenic cirrhosis (n = 35), hepatitis C (n = 31), primary sclerosing cholangitis (n = 17), autoimmune hepatitis (n = 16), alcoholic cirrhosis (n = 12), Wilson disease (n = 11), Budd-Chiari syndrome (n = 6), pure HCC (n = 4), cystic hydatid disease (n = 3), hepatitis A (n = 2), familial hypercholesterolemia type 2 (n = 1), and oxalosis (n = 1). Of these 243 patients, 49 also had HCC. In group 2 (≥60 years old), the most common indication for LT was hepatitis B (n = 17). The other indications for LT were hepatitis C (n = 6), alcoholic cirrhosis (n = 3), and cryptogenic cirrhosis (n = 3); 12 of these 29 patients also had HCC.

The mean age of the patients was 40 ± 12.3 years (range, 18-59 years) in group 1 and 63 ± 2.3 years (range, 60-68 years) in group 2. In group 1, there were 177 men (71.7%) and 70 women (28.3%). In group 2, there were 22 men (75.9%) and 7 women (24.1%). There was no statistically significant difference between the 2 groups according to male versus female distributions (P > 0.05). In group 1, 97 recipients had deceased donors (39.3%) and 150 recipients had living donors (60.7%). In group 2, similar to group 1, most of the transplants were LDLTs (10 deceased donor LTs [34.5%]; 19 LDLTs [65.5%]), and there was no statistically significant difference between the 2 groups in terms of donor type (P > .05). The MELD score was significantly higher in group 1 (P < .001). There was no statistically significant difference between the 2 groups according to Child-Pugh scores (Table 1).

The following surgical complications were shown in our study patients: hepatic artery thrombosis in 18 patients (6.5%), hepatic artery stenosis in 11 patients (3.9%), hepatic vein stenosis in 6 patients (2.1%), portal vein thrombosis in 8 patients (2.8%), portal vein stenosis in 11 patients (3.9%), biliary leakage in 45 patients (16.3%), and bile duct strictures in 40 patients (14.4%). We did not observe hepatic vein thrombosis in our patients. When surgical complications were evaluated, there was no statistically significant difference between the 2 groups (Table 2).

Acute rejection rate was 18.8% (n = 52) in all patients, with 44 patients (17.8%) in group 1 and 8 patients (27.6%) in group 2. The difference between the 2 groups was not statistically significant (chi-square value = 0.212; P > .05).

During the follow-up periods, 143 patients (51.8%) died: 132 (53.4%) from group 1 and 11 (37.9%) from group 2. There was no statistically significant difference between the 2 groups in terms of mortality rates (Fisher exact chi-square value = 0.121; P > .05) (Table 3). Overall mean survival time was 10.4 ± 0.6 years (95% CI, 9.2-12.6), and patient survival rates were 67% at 1 year, 54% at 5 years, 48.4% at 10 years, and 40.4% at 15 years (Figure 1). In group 1, mean survival time was 10.2 ± 0.6 years (95% CI, 8.9-11.4), and patient survival rates were 65.5% at 1 year, 53% at 5 years, 46.3% at 10 years, and 40% at 15 years (Figure 2). In group 2, mean survival time was 10.6 ± 1.3 years (95% CI, 8.1-13.2), and patient survival rates were 75.9% at 1 year, 68.6% at 5 years, 61% at 10 years, and 48.8% at 15 years (Figure 2). There was no statistically significant difference in survival rates between the 2 groups (log-rank test, P = .155).

Today, the only treatment method for acute fulminant and chronic liver failure is LT. Because of advances in surgical techniques, postoperative patient care, and developments of immunosuppressive agents, patient and graft survival times have gradually increased.^11,12

From the first successful LT¹³ until the late 1980s, LT was contraindicated in patients over 50 years of age.¹⁴ A prolonged life expectancy has led to an increase in the average age of patients waiting for LT.^2,3,15 After the initiation of LDLT programs in 1990,^16,17 the donor pool has expanded, and successful transplants are being performed in all age groups. Studies have confirmed that transplant surgery can be performed safely in patients older than 60 years.^14,18,19

Recent studies have reported no differences in perioperative events, length of hospitalization, postoperative complications, incidence of rejection, and short-term survival in recipients aged >60 years compared with cohorts of younger adults.^19-22

There are many factors that cause liver failure in adults. According to data from the United States, the most common cause of liver failure is hepatitis C virus infection.^23,24 Because these patients reach advanced ages, hepatitis C virus is also the most common indication for transplant in patients over 60 years of age.²² In a meta-analysis, Gómez Gavara and colleagues²⁵ found that the most common indication for performing transplants for elderly patients was HCC. According to the same meta-analysis, the other indications (such as viral hepatitis and alcoholic liver failure) were significantly more frequent in young patients.²⁵ In Turkey, the most common indication for LT is hepatitis B.²⁶ In our series, hepatitis B was the most common indication for LT in both groups (108 patients in group 1 [43.7%] and 17 patients in group 2 [58.6%]). In group 1, there were 4 patients with pure HCC and 49 patients with HCC concomitant with chronic hepatitis. In group 2, there were 12 patients with HCC concomitant with chronic hepatitis.

There are risks of complications with vascular anastomoses after LT. These complications can occur in the form of thrombosis or stenosis.²⁷ Vascular complications are the most important factors that adversely affect graft survival and thus patient survival. Vascular complications may occur as a result of operative technique, vascular clamp injury, allograft rejection, preservation injury, anastomosis of the small arteries, or procoagulant disorders.^10,28 Arterial complications are more common than venous complications.²⁷ In the literature, hepatic artery thrombosis has been reported to occur in 2.6% to 20% of adult LT recipients.^27-30 Current studies showed that portal vein complications were detected less than arterial complications, with incidence of portal vein complications ranging from 1% to 3%.^10,31 Hepatic vein complications are seen in 2% to 11% of transplant patients, which may lead to venous outflow problems and may result in graft loss due to liver congestion.^10,27 Gómez Gavara and colleagues²⁵ emphasized in their meta-analysis that there was no statistically significant difference in patients ≥60 years old versus younger patients in terms of vascular complications. In this study, our data for vascular complications were similar to the data reported in other articles in the literature. According to our data, hepatic vein thrombosis was seen in 18 patients (6.5%). Hepatic vein thrombosis incidence was 6.5% (n = 16) in group 1 and 6.9% in group 2. The difference between the groups was not statistically significant. Overall incidence of hepatic artery stenosis was 3.9%. The incidence of hepatic artery stenosis was 4% in group 1 and 3.4% in group 2, with no significant difference between the 2 groups. As stated in the literature^10,27,31 and shown in our series, there were less venous complications than arterial complications. In this study, we found portal vein thrombosis in 8 patients (3.2%), portal vein stenosis in 11 patients (3.9%), and hepatic vein stenosis in 6 patients (2.1%). We did not see hepatic vein thrombosis in either group. There was no statistically significant difference between the 2 groups in terms of portal vein complications and hepatic vein complications.

Biliary complications are the most common surgical complication after LT, with a reported incidence of 25% to 50%^32,33; this can lead to early and late graft loss after surgery and even patient mortality.³⁴ The etiologies of biliary complications are multifactorial. These factors can depend on recipient or donor characteristics such as advanced age of donor, marginal graft, prolonged ischemia time, LDLT, partial LT, donation after cardiac death, hepatic arterial thrombosis, organ preservation, and chronic rejection.^33,35,36 Many studies have shown that there is no statistically significant difference between biliary tract complications and advanced age.^3,37-39 In our patients, there were 42 (17%) with biliary leakage in group 1 and 3 (10.3%) with biliary leakage in group 2; there was no statistically significant difference between the 2 groups. Similar to other reports in the literature, there was no statistically significant difference between the 2 groups in terms of bile duct strictures.

Many centers have reported fewer episodes of acute cellular rejection in older patients.^3,19,40 Defects in both cell-mediated and humoral immune systems of elderly patients have been reported.⁴¹ The humoral defect is thought to be the result of an exaggerated anti-idiotypic antibody response to antigens that downregulates the antibody response to those antigens, thus inhibiting the humoral response.^42,43 Depending on this defective immunity, a lower incidence of acute rejection may be expected to occur in elderly LT patients. On the other hand, some studies assert that the development of acute rejection is not related to age and that young patients and advanced age patients have the same acute rejection rates.^19,21,44 In our patients, there was no statistically significant difference in terms of acute rejection between the groups.

There are different comments in the literature about survival after transplant. Some studies have reported that posttransplant survival is lower in advanced age patients, whereas others have reported no statistically significant difference versus younger patients. According to the results of a single-center study conducted by Levy and colleagues,⁴⁵ the survival time in patients over 60 years of age was lower than in younger patients. However, in the results of the study, Levy and colleagues stated that low survival is not only age-dependent but also associated with higher bilirubin levels, higher prothrombin times, lower albumin levels, and poor nutritional status. Specifically, they reported that, in hospitalized patients over 60 years of age, if serum albumin level was less than 3 g/dL, total bilirubin level was more than 10 mg/dL, and prothrombin time was greater than 20 seconds, then mortality risk increases, and therefore LT should be questioned in elderly patients in areas where deceased donor organ procurement is limited.⁴⁵ Similarly, Herrero and colleagues5 also showed that patients ≥ 60 years old had low survival rates. According to that study, survival rates for patients <60 years old were 94% at 1 year, 94% at 2 years, and 92% at 3 years; for patients ≥60 years old, survival rates were 89% at 1 year, 82% at 2 years, and 78% at 3 years.⁵ They concluded that survival was significantly higher in patients <60 years old.⁵ However, other publications have suggested that patients ≥60 years old have rates of posttransplant survival similar to those of younger patients.^21,43,46-48 Some studies have stated that there was no difference in survival between young and advanced age patients; this was attributed to the low MELD score in elderly patients.^2,7 This situation is the result of the application of different criteria in the selection of elderly patients.² In our study, we observed that MELD score was significantly higher in group 1, and there was no statistically significant difference in survival rates between the 2 groups.

In this study, LT recipients older than 60 years had survival rates, acute rejection rates, and complications equivalent to those of younger recipients. Liver transplant should not be withheld from older recipients on the basis of age alone. However, comprehensive screening for comorbidities should be performed.

Volume: 20 Issue: 3 March 2022 - Supplement - 1

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