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Older age and liver transplantation: A review
 
 
  Older age and liver transplantation: A review
 
Liver Transplantation
Volume 10, Issue 8, August 2004
 
Rajesh N. Keswani, Aijaz Ahmed, Emmet B. Keeffe *Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
 
ABSTRACT
 
Patients older than 60 are undergoing transplantation with increasing frequency. Reports from several transplant centers document that overall short-term patient survival rates in seniors undergoing liver transplantation are comparable to survival rates of younger adults.
 
However, specific subgroups of older patients may not fare as well. Seniors with far-advanced end-stage liver disease are high-risk for liver transplantation and have poor survival rates. In addition, seniors older than 65 have worse outcomes than those who are 60 to 65, and studies have shown increased mortality with increasing age as a continuous variable.
 
On the other hand, the majority of seniors who survive liver transplantation have full or only minimally limited functional status. Preoperative evaluation of older patients for transplantation requires careful screening to exclude cardiopulmonary disease, malignancy, and other diseases of the aged.
 
Paradoxically, seniors may benefit from a senescent immune system, which results in decreased requirements for immunosuppressive drugs, and possibly a lower rate of acute allograft rejection. Despite good overall short-term survival in the elderly, long-term survival may be worse because of an increased rate of long-term complications, such as malignancy and heart disease.
 
In conclusion, although advanced age is a negative risk factor, advanced age alone should not exclude a patient from liver transplantation; however, it mandates thorough pretransplant evaluation and careful long-term follow-up with attention to usual health maintenance issues in the elderly.
 
BACKGROUND
 
Liver transplantation is standard treatment of end-stage liver disease, and 1-year survival rates of 85 to 90% are typical at most centers. The number of liver transplants performed annually from 1998 to 2002 in the United States increased only slightly from 4,516 to 5,329, in part related to greater application of living donor liver transplantation.[1] However, as of the beginning of 2004, there were more than 17,000 potential liver transplant candidates on the United Network for Organ Sharing (UNOS) waiting list, and thus far fewer patients with chronic liver disease who might benefit from liver transplantation can actually undergo the procedure. The discrepancy between available donor organs and patients awaiting transplantation has led to reevaluation of selection and listing criteria for liver transplantation, including transplantation of patients older than 60, with the goal of maximizing survival outcomes.[2][3] In this review, the outcomes of liver transplantation in patients older than 60, as reported from national databases and individual transplant centers, are analyzed and discussed, along with the pretransplant evaluation and posttransplant management of older patients.
 
Liver Donor and Recipient Populations
 
The supply of donor livers is insufficient to meet the current need for liver transplantation, and organ donation has remained relatively stagnant in recent years in spite of many efforts to increase donation.[4] The growing disparity between the number of liver transplants performed each year and the number of patients on the liver transplant waiting list has reached a critical point in the United States. Although the number of liver transplants increased 3-fold from 1988 to 2002 (1,713 to 5,329 transplants), the number of patients on the UNOS liver waiting list increased 28-fold (616 to more than 17,000 patients listed), and the number of deaths while on the waiting list increased 10-fold (195 to 1,881 deaths) over the same period of time.[1] More recently, however, the number of deaths actually decreased 11% from 2001 to 2002 (2,034 to 1,881 deaths), and interpretation of waiting list deaths is complicated by a number of factors. For example, when the number of deaths is analyzed in comparison to the number of patients listed, which has increased over the years, the death rate per 1,000 patient years can be shown to have declined since 1993, possibly reflecting factors such as improved pretransplant care, better allocation of organs to sicker patients, and/or more patients listed with lower short-term mortality.
 
The current situation is expected to only worsen over the next decade as more patients with chronic hepatitis C and decompensated cirrhosis or hepatocellular carcinoma are listed for liver transplantation. As a result of the growing discrepancy between the need for transplantation and available donors, patients who are listed wait an increasingly long period of time - more than 3 years in some UNOS regions - before transplantation. This increased waiting time has led to the transplantation of patients at progressively more advanced stages of liver disease.[5] Thus, the longer waiting time is a particularly important consideration when listing patients over 60 for liver transplantation because these patients may be 3 or more years older before actually undergoing transplantation.
 
Liver Allocation and Distribution Policies
 
This discrepancy between the number of donated organs and need for liver transplantation has led to frequent revisions of UNOS policies regarding allocation and distribution of livers.[1-3] Distribution determines over which geographical area livers are allocated; allocation determines which patients within a geographical area receive the available livers. The traditional allocation scheme, which continues to be in effect, has dictated that the sickest patients who have waited the longest undergo transplantation first, and patients listed at a transplant center within a local organ procurement organization have the first priority for livers obtained locally.[6] The debate on allocation focuses on the balance of the competing factors of justice (also termed urgency) and medical utility. Utility factors focus on maximizing the overall benefits of transplantation to society, giving priority to the patient who maximizes the chances of a successful outcome by having the least risk of dying after a transplant. Urgency recognizes the needs of the individual transplant patient, giving priority to the sickest patient, who has the greatest risk of dying before a transplant. Neither urgency nor utility ensure that an organ will be transplanted at the most efficient time.[7] Factors related to efficiency dictate that an organ be allocated to a patient at a time that is most beneficial to the individual; they do not address which patients should receive the organ. Finally, as a result of local use of donor livers, waiting times for liver transplantation differ among patients listed in different regions in the United States. It has recently been argued that donor livers are a national resource and waiting times should be equalized across the United States so that all patients, including older transplant candidates, would share equally the burden of an inadequate donor supply.[8][9]
 
Recently, UNOS approved use of the Model for End-Stage Liver Disease (MELD) score as a more accurate and reproducible assessment of disease severity to determine liver transplant priority and identify which patients with chronic liver disease are most at risk for death in the ensuing 3 months.[10-12] The MELD score is calculated from a mathematical model that includes serum total bilirubin, international normalized ratio for prothrombin time, and serum creatinine. The MELD score addresses urgency, but not utility. Physician judgment, which is not standardized and is strongly influenced by urgency, still determines the utility of a transplant for an individual patient. It remains unknown whether introduction of the MELD-based prioritization system will increase or decrease the waiting time for liver transplantation and its impact on the efficiency of transplantation - a key factor to be considered in transplantation in the elderly.
 
The transplant community has become cognizant of cost-outcome analyses and the reality of managed care, which has transferred financial risk from insurers to providers. High-risk patients represent a significant liability in the managed care marketplace. Thus, fair organ distribution and allocation policies, as well as appropriate selection of patients, including those at a reasonable upper age limit, are both important issues that are undergoing continuous scrutiny and revision. Several years ago, uniform minimal listing criteria were developed for patients with miscellaneous chronic liver diseases.[13] These criteria, which were adopted by UNOS, allowed listing of patients only when they had a Child-Turcotte-Pugh score of 7 or greater or the development of variceal bleeding or spontaneous bacterial peritonitis. Listing older patients prior to decompensation of chronic liver disease had been done by some transplant physicians before adoption of the minimal listing criteria to facilitate earlier transplantation, a practice that may have maximized transplant efficiency by improving outcomes in this group of patients; however, this practice is no longer acceptable.
 
Prevalence and Significance of Liver Disease in Elderly Patients
 
Improved medical management of cirrhosis has resulted in an increased number of elderly patients with chronic liver disease. From 1980 to 1989, mortality from chronic liver disease was highest in patients aged 65 to 74.[14] Elderly patients with cirrhosis are at increased risk of having comorbid conditions that complicate management, and cirrhosis in the elderly is a cause of increased mortality from both hepatic and nonhepatic causes.[15]
 
There are relatively few studies addressing the distribution of causes of liver failure in the elderly compared to a younger adult population. In the general adult population, chronic hepatitis C and/or alcoholic liver disease are the most common etiologies of end-stage liver disease leading to transplantation. However, viral hepatitis is generally less common in the elderly than in younger individuals. The prevalence of hepatitis C virus (HCV) infection, based on seroprevalence of anti-HCV, is 0.9% between the ages of 60 and 69, as compared with 3.0% in persons aged 30 to 39.[16] The incidence of HCV infection in the younger population has increased over the past 20 years, and, as this population ages, the prevalence of chronic hepatitis C and its complications will likely increase in the elderly. In addition, age at time of HCV infection is significantly associated with progression of disease.[17][18] The elderly are at a low risk for exposure to hepatitis B virus secondary to lifestyle differences compared with younger persons. Acute hepatitis A is also less common in the elderly, but it is associated with increased mortality.[19]
 
Alcoholic liver disease may be relatively more common in seniors. Alcoholic liver disease often presents initially in the elderly, with one study reporting that 28% of patients first presented after age 60.[20] In this study, the 1-year mortality rate for cirrhotic patients over age 60 was 50% versus 7% for patients under age 60.
 
The peak incidence of primary biliary cirrhosis occurs in the elderly, with the median age of diagnosis just over age 60,[21]; thus, it is likely that patients with this diagnosis are disproportionately represented in older subjects undergoing liver transplantation. Moreover, the mortality rate from liver-related deaths in patients with primary biliary cirrhosis who are diagnosed after age 65 is increased in comparison to that of younger patients.[22] Newton et al.[23] studied 12 elderly patients with autoimmune hepatitis, noting that diagnosis was more difficult and treatment was frequently withheld. Despite this, the prognosis was similar to younger patients with the same diagnosis.
 
Pretransplant Evaluation of Older Transplant Candidates
 
Pretransplant evaluation of the senior transplant candidate differs from that of a younger patient because of the increased prevalence of medical comorbidities. While certain elements of the pretransplant evaluation are routine for all patients, others are determined by comorbid conditions common to the elderly patient. The pretransplant evaluation of a potential liver transplant candidate, especially the elderly patient, is increasingly multidisciplinary in nature, under the direction of a transplant hepatologist and liver transplant surgeon. Issues of particular relevance to the pretransplant evaluation of an elderly candidate are reviewed and summarized in Table 1.
 
Table 1. Preoperative Evaluation of Older Liver Transplant Recipients
 
Coronary artery disease
--Symptoms or history: Cardiac catheterization
--Diabetes mellitus : Cardiac catheterization or noninvasive stress test
--All other patients: Noninvasive stress test
 
Bone disease: Serum vitamin D level; Bone densitometry
 
Malignancy—
--Males and females Screening colonoscopy, if not done within previous 10 years; Complete skin examination
--Males : Digital rectal examination; Prostate specific antigen testing
--Females: Mammogram, if not done within previous year
 
Coronary Artery Disease
 
Advancing age is an independent risk factor for the development of coronary artery disease (CAD),[24] and the prevalence of CAD in patients with end-stage liver disease is similar to and may even exceed that of the general population. Carey et al.[25] demonstrated a 27% prevalence of moderate to severe CAD in patients with liver disease and age greater than 50 (or age greater than 45 in patients with cholestatic liver disease). Moreover, the mortality of patients with CAD who undergo liver transplantation may be as high as 50%.[26]
 
Older liver transplant candidates require careful evaluation for the presence of heart disease. Exercise electrocardiography has variable sensitivity and specificity and is not currently recommended for screening of asymptomatic patients, whose pretest probability for coronary artery disease is low.[27] The utility of routine stress echocardiography and nuclear myocardial perfusion testing has not been well studied in the general population, and its role in pretransplant evaluation has been recently reviewed.[28] Kryzhanovski et al.[29] reported 63 candidates for liver transplantation who underwent nuclear myocardial perfusion studies. Eight patients had abnormal scans, with only 1 patient (with a history of CAD) having a high-risk scan, and 87% of patients had a normal study. One patient with a moderate-risk scan had cardiac catheterization that demonstrated normal coronary arteries, i.e., a false-positive study. There were no perioperative cardiac events in either group. The authors concluded that, using perioperative death and nonfatal myocardial infarction as end points, routine myocardial function testing is not useful for preoperative risk assessment. This study did not assess the long-term morbidity from possible indolent CAD in their patients and thus does not negate the importance of pretransplant stress imaging in elderly patients.
 
Dobutamine stress echocardiography (DSE) has also been studied as a method of screening for coronary artery disease. Donovan et al.[30] studied 165 patients with either a history of CAD or significant risk factors, including age greater than 45 years. Eleven patients had inducible ischemia on DSE. Cardiac catheterization was performed on 9 of these patients, with 3 patients having significant CAD by angiography. Nine patients with a history strongly suggestive of CAD and a negative DSE underwent cardiac catheterization. One of these patients was found to have 3-vessel coronary disease. The remaining 145 patients had a negative DSE and did not receive catheterization. There were no cardiac events in this group. Based on these data, a negative stress echocardiogram is helpful in ruling out perioperative cardiac events in patients without typical anginal symptoms or a history of CAD. A positive stress echocardiogram is suggestive of CAD but, given its poor predictive value, must be confirmed by a cardiac catheterization. This study did not address the ability of a negative stress echocardiogram to predict cardiac events after liver transplantation.
 
In another study evaluating the utility of DSE in patients undergoing liver transplantation, Plotkin et al.[31] studied 80 patients with risk factors for CAD, including age greater than 60 years. Six patients had an abnormal study, with only 2 patients having wall motion abnormalities with stress. All 6 patients underwent cardiac catheterization, and only patients with wall motion abnormalities had significant CAD. Outcome information was available for 40 patients. For the purpose of this study, a patient who had a negative DSE and underwent liver transplantation without cardiac events was assumed to have normal coronary arteries or at least clinically insignificant CAD. With these assumptions, DSE had a 100% positive and negative predictive value for CAD. However, an elderly patient who does not have a perioperative cardiac event may still have CAD that may become clinically significant years after transplantation.
 
Cardiac catheterization remains the gold standard for identifying CAD. Many centers proceed with cardiac catheterization as a first test for patients with a strong clinical history for CAD.[28] A history of CAD or symptoms of exertional angina are clear indications for performing cardiac catheterization prior to transplantation. Diabetes mellitus may be the most important risk factor for the presence of CAD in patients with liver disease.[25] Cardiac catheterization, regardless of stress test results, may be advisable in these patients. A positive cardiac stress test should also lead to cardiac catheterization for confirmation of CAD.
 
Given that older age is a strong risk factor for CAD, all patients over age 60 should be screened for heart disease. If clinical history strongly suggests CAD (previous CAD, diabetes mellitus, exertional angina), the clinician may elect to proceed directly to cardiac catheterization because a negative cardiac stress test is not sufficient to exclude cardiac disease. For all other elderly patients, DSE should be used as an initial evaluation. A negative test confers a low risk of perioperative cardiac events. Whether DSE can identify patients at risk for long-term cardiac morbidity has not yet been studied.
 
Bone Disease
 
Older patients with end-stage liver disease, particularly those with cholestatic liver diseases, are also at risk for osteopenia or osteoporosis. In one study, 36.6% of patients awaiting liver transplantation had osteoporosis, compared to 5% in age-matched normal subjects.[32] Increasing age is noted to be an independent risk factor for osteoporosis and postoperative osteoporotic fractures.[32-34] Postoperative corticosteroid therapy also contributes to bone loss, resulting in compression fractures. Patients awaiting liver transplantation are known to have low serum vitamin D levels, with deficiency reported in 74% of patients in one study.[35] For all elderly patients, determination of vitamin D serum levels and baseline bone densitometry is advisable. One prospective trial demonstrated no improvement with 1 dose of intravenous pamidronate compared with placebo prior to transplantation.[36] This negative result may be secondary to lack of efficacy using a single dose of pamidronate. Despite this study, preoperative calcium supplementation and bisphosphonate therapy for all postmenopausal women awaiting liver transplantation appears to be advisable, and should be considered for men as well.
 
Malignancy
 
Screening for malignancy is a significant component of pretransplant evaluation. Colonoscopy is a recommended method of screening for colorectal cancer in patients over age 50.[37] Selingo et al.[38] reviewed 86 patients who underwent screening colonoscopy prior to liver transplantation. Nineteen percent of patients had polyps, and 1 patient had carcinoma in situ, with 76% of polyps distal to the splenic flexure. Zaman et al.[39] reported a 21% prevalence of adenomatous polyps in liver transplant candidates. The prevalence of polyps did not increase with age in either study. Patients with end-stage liver disease are at greater risk of complications from colonoscopy, including oversedation and postcolonoscopy peritonitis.[38][40] Similar to the general population, elderly patients undergoing evaluation for liver transplantation should undergo colonoscopy to screen for colorectal polyps and cancer.
 
Prostate cancer is the second leading cause of death in males in the United States, increasing in incidence with age. Recommendations regarding prostate cancer screening are variable. Digital rectal examination and prostate specific antigen (PSA) testing both detect cancer at an earlier stage, but data regarding improved mortality is not yet available.[41] Jin et al.[42] demonstrated an inverse correlation between severity of liver disease with both serum level of PSA and prostate volume. However, this finding has not been confirmed in other studies.[43] Liver disease may have a protective effect on the prostate from decreased circulating hormones.[44] A reasonable approach to preoperative prostate cancer screening is the performance of a digital rectal examination and determination of serum PSA.
 
Female patients awaiting transplantation should receive annual mammography to screen for breast malignancy. Data regarding the incidence of breast cancer in patients with chronic liver disease has been studied in greatest detail for patients with primary biliary cirrhosis, with more recent studies failing to demonstrate an increased risk.[45]
 
Outcome of Liver Transplantation in Older Patients
 
An early summary of data from UNOS found a 1-year survival of 60% in older subjects (age greater than 65) compared to 72% in the general population.[46] Thus, in the early years of liver transplantation, many programs set an upper age limit of 50 years for candidates. However, in the late 1980s and early 1990s, continued refinement in the selection criteria for liver transplantation led to increased performance of liver transplantation in patients over age 60 (seniors) with generally good outcomes (Table 2 and Figure 1). In 2002, data from UNOS revealed that 6.8% of all transplants took place in patients over age 65, an increase from 4.9% in 1991.[1] A favorable outcome of liver transplantation in seniors was supported by data from individual transplant centers in the early 1990s, in contrast to the earlier data from UNOS.[1][47-57] In 1991, the University of Pittsburgh reviewed 156 liver transplant patients over age 60.[49] Three-year patient survival in the senior population and younger adults was comparable (65.5% and 71.4%, respectively). In addition, 67% of the seniors who survived liver transplantation were reported to be fully functional, and a further 27% were functional with some limitation, leaving only 6% significantly disabled after transplantation. The authors concluded that advanced age was not a contraindication to liver transplant. Multiple other studies published in the 1990s confirmed these findings.
 
In 1998, a multicenter review of 735 liver transplant recipients analyzed by age revealed a lower patient survival for recipients over age 60 than for younger adults (81% vs. 90%; P = .004), largely secondary to nonhepatic causes (infectious, cardiac, and neurologic diseases).[47] A proportional hazards analysis model revealed recipient age to be significantly associated with mortality. The intensive care unit and hospital stays were longer for the elderly patients. Although elderly patients had significantly fewer retransplantations than their younger counterparts, this factor did not account for the difference in mortality: the excess deaths in the elderly population were secondary to nonhepatic causes within 6 months of transplantation. Preoperative risk factors that were associated with increased mortality were not identified. Quality of life at 1 year was reported to be similar in the older and younger subjects. The authors recommended that age by itself should not be used as a factor to preclude transplantation but that elderly patients should be more aggressively screened for the presence of medical comorbidities.
 
The outcome of liver transplantation in older patients has been reported from several liver transplant centers. Analysis of earlier data from the University of Nebraska revealed a significantly poorer than expected outcome in the older patients identified preoperatively as being high-risk.[50][52] A risk scoring system that takes into account age, serum bilirubin, prothrombin time, encephalopathy, ascites, and nutrition was used to stratify patients into low-, medium-, and high-risk groups.[58] Low-risk senior transplant patients had a 94.5% 1-year survival compared to the previously reported 90.5% expected survival for low-risk adult patients.[54][58] Seniors who were medium-risk had a 60% survival compared to an 85.2% expected survival for medium-risk adults; high-risk seniors had a 28.6% actual survival compared to a 44.5% expected survival in high-risk adults (Table 2). A study from Baylor University Medical Center analyzing 241 patients over age 60 confirmed the University of Nebraska experience.[59] For patients at home, no influence on mortality was noted with increasing age. Elderly patients who were in the hospital (including the intensive care unit) prior to transplant had significantly worse outcomes than hospitalized younger adults. Elevated serum bilirubin, elevated prothrombin time, low serum albumin, and higher Child-Turcotte-Pugh scores all had a significantly negative impact on mortality in patients over age 60, but not for those under age 60. The authors concluded that transplantation should be withheld in seniors who are hospitalized, whose serum albumin is less than 3 g/dL, whose total bilirubin exceeds 10 mg/dL, or whose prothrombin time is greater than 20 seconds. Pretransplant creatinine, known to be an independent risk factor for poor outcomes,[60] was not analyzed in the Baylor study. Garcia et al.[61] noted that when age was assessed as a continuous variable, an adverse effect was seen on outcome as age increased, and that this was more marked in Child's class C patients.
 
The studies reviewed led to the general conclusion that elderly patients should undergo transplantation at an earlier time point in the spectrum of end-stage liver disease. It remains uncertain if this goal can be achieved in the current MELD-based allocation system. Moreover, not all studies have reached the same conclusion. Emre et al.[53] found that more ill elderly patients (UNOS status 3-4 using the former UNOS designation) fared just as well as younger patients. They concluded that properly selected patients could undergo transplantation even at advanced stages of liver disease. This study was limited, however, by a short follow-up period of only 1 year.
 
There are scant data published on the outcome of liver transplantation in the very elderly. In 1999, Rudich et al.[57] published outcomes for 33 patients over age 70 who underwent liver transplantation. Three-year survival for patients over age 70 versus those under age 60 was comparable, though there was a trend for decreased patient survival (58% vs. 70%; P value not significant). When stratified by UNOS status, elderly patients who were UNOS status 3 or 4 (in the former UNOS designation) showed a trend toward worse survival compared to younger cohorts. The authors concluded that there was no justification for withholding liver transplantation from the very elderly. However, long-term data have not been published for this patient population.
 
Many of the studies advocated allocation of liver transplants to low-risk seniors. The data suggest that long-term mortality of low-risk patients would be similar to their younger counterparts. In 2000, however, data published on 91 seniors who underwent transplantation at the University of Wisconsin showed poor long-term patient survival after liver transplantation in the elderly population.[62] Five-year patient survival was 52% for patients over age 60 and 75% for patients under age 60; 10-year patient survival was 35% and 60% in seniors and young adults, respectively. The difference in survival was not attributable to increased severity of liver disease, but rather to an increased incidence of malignancies. Fatal cardiac events were equally distributed between the study groups, with a trend toward a higher rate of fatal strokes in the younger population, likely due to more aggressive pretransplant screening in the older population. The authors noted that the death rate in the senior transplant population exceeded that which would be predicted by the Wisconsin Life Table.
 
Thus, the ability of older patients with far advanced liver disease tolerate liver transplantation and its associated complications appears to be reduced. For low-risk seniors who survive the perioperative period, long-term survival appears to still be worse than for younger transplant patients - in excess of age-expected mortality. Scant data regarding transplantation of the very elderly (age greater than 70) makes transplant decisions in this group of patients more difficult. The limited information on liver transplantation in the elderly suggests that the estimated physiologic age of the patient at the time of transplantation is a better predictor of outcome than the chronological age. These data have led to the recommendation that patients older than 60 undergo transplantation earlier in the spectrum of end-stage liver disease, if referral patterns, listing policies, and donor availability allow this optimal timing. There are no data to support exclusion of patients older than 60 from liver transplantation on the basis of age alone. Increased age at time of transplantation is a poor prognostic indicator, however. A rational approach to the decision of whether to proceed with liver transplantation in the elderly patient should take into account age, severity of illness, and comorbid conditions. For example, a 65-year-old patient being treated at home for end-stage liver disease, without significant medical comorbidities, can be expected to have a reasonable outcome. A 61-year-old patient with diabetes mellitus and who is in the intensive care unit is likely to have a poor outcome, and transplantation may not be justifiable in this patient.
 
There is evidence that the effects of aging on the immune system may be beneficial in seniors undergoing organ transplantation. Advancing age is associated with diminished immune function manifested by a high incidence of neoplasia, decreased response to immunizations, and probable increased susceptibility to infection.[63][64] Alterations in the function of T cells and, to a lesser degree, B cells have been proposed as biomarkers of aging. This seemingly undesirable immunosenescence might paradoxically improve outcome in older transplant recipients by theoretically reducing the incidence and severity of allograft rejection. However, data from UNOS show a 5-year graft survival rate for patients over age 65 of 57.8% versus 65.7% in patients ages 35 to 49[1], although this is influenced by patient mortality from nonhepatic causes. Experience from multiple transplant centers indicate that the number of rejection episodes per patient and the need for rescue therapy were equal in seniors and younger adults.[49][62] However, other centers noted significantly fewer acute rejection episodes in the elderly compared to younger adults, all with immunosuppression regimens containing cyclosporine.[52][53][65] Reduction in drug dosage used after transplantation to reduce side effects (cataracts, diabetes mellitus, infection, and osteopenia) can often be achieved and is particularly beneficial to older patients.
 
A factor that may support favorable outcomes in senior liver transplant recipients is a process of self-selection: individuals who survive to an older age and undergo liver transplantation are less likely to have concurrent or prior serious medical problems. Older patients with major comorbidities are usually not considered for transplantation. On the other hand, younger patients with multiple medical problems that pose a higher risk for liver transplantation are more likely to be accepted for transplantation and may have poorer survival rates based on comorbidities. These selection factors may complicate the comparison of outcomes of liver transplantation between older and younger recipients.
 
Postoperative Care of Older Liver Transplant Recipients
 
Postoperative care of the senior transplant patient differs minimally from the approach to the younger patient. In order to avoid worsening bone disease and the development of steroid-dependent diabetes mellitus and cataracts, it is important to minimize the use of or discontinue corticosteroids.[49] As noted, the immunosenescence of aging probably facilitates this approach by virtue of a lesser requirement for immunosuppressive drugs, particularly prednisone.[63][64]
 
Patients with end-stage liver disease have a high prevalence of CAD, which does not regress after transplantation. In one study, cardiac disease was the third leading cause of death for elderly transplant recipients.[62] Therefore, transplant recipients should be screened for heart disease and associated risk factors, including hyperlipidemia, hypertension, and diabetes mellitus.[66] Guidelines for the management of cardiac disease in liver transplant patients do not exist, so treatment often parallels that of the general population and has been detailed elsewhere.[28]
 
Osteoporotic fractures after liver transplantation may result in significant morbidity. The incidence of bone disease posttransplant is elevated.[66-68] Glucocorticoids directly suppress osteoblast function, inhibit intestinal calcium absorption, stimulate osteocyte apoptosis, and stimulate renal calcium excretion.[69] Studies on the treatment of osteoporosis after liver transplantation have shown inconsistent results.[68][70][71] Cyclosporine-based regimens are associated with an increased risk of osteoporosis, possibly secondary to the greater reliance on corticosteroids in these regimens.[67][72] The incidence of osteoporotic fractures may be decreasing with increased use of tacrolimus-based regimens.[36] Treatment with calcium and vitamin D is standard for patients with osteoporosis. Therapy with intravenous bisphosphonates, even if not started immediately posttransplantation, appears to be effective in decreasing incidence of fractures.[68][71] All elderly patients are at increased risk for bone disease after liver transplantation and should be screened with bone densitometry and offered treatment if appropriate.
 
Postoperative surveillance for malignancy is of even greater importance in the elderly transplant recipient. The incidence of de novo malignancies is increased for all patients after liver transplantation.[66][73][74] Collins et al.[62] found that malignancy in seniors partially contributed to their poorer outcomes. Skin cancer is the most common malignancy in the posttransplant period.[75] In addition, age is a known risk factor for the development of skin cancer in liver transplant recipients, making this cancer of particular concern in the setting of liver transplantation in the elderly.[76] Annual mammography is recommended in all elderly females. A decreased risk of gynecologic malignancies has been demonstrated posttransplantation. However, breast malignancy has been associated with a greater incidence of ovarian cancer.[77] Sheiner et al.[66] found prostate cancer to be the second most common malignancy after transplantation (3 cases out of 121). As discussed, increasing age is a risk factor for development of prostate cancer, and surveillance should be performed annually. Colorectal cancer screening should be performed as standard practice.
 
Conclusions
 
Liver transplantation is standard treatment for end-stage liver disease. Prudent allocation of this precious resource is required because of organ shortage. The prevalence of liver disease in the elderly is higher than often appreciated and is associated with a higher mortality than in younger adults. Preoperative screening in this population should be detailed to exclude CAD, bone disease, and malignancy. Low-risk elderly patients with end-stage liver disease (decreased disease severity with lack of medical comorbidities) have success rates similar to younger populations, but long-term outcomes may be somewhat worse secondary to nonhepatic causes. Thus, elderly patients should undergo transplantation earlier in the spectrum of end-stage liver disease, although it is uncertain if this ideal goal can be achieved in the current MELD-based allocation system. An important question is whether a different allocation scheme, e.g., extra MELD points, should be considered for elderly patients to facilitate this goal. High-risk patients, including patients with significant comorbidities (i.e., CAD, diabetes mellitus) and patients in the intensive care unit with far-advanced liver disease, have poor short-term outcomes and should not undergo transplantation unless there is a compelling reason to do so. Posttransplant care of the elderly patient requires increased vigilance regarding health care maintenance, treatment of bone disease, and management of medical comorbidities.
 
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