Authors and Disclosures
Posted: 10/03/2011; American Journal of Transplantation. 2011;11(9):1773–1784 © 2011 Blackwell Publishing
Liver transplantation is the gold standard of care in patients with end-stage liver disease and those with tumors of hepatic origin in the setting of liver dysfunction. From 1988 to 2009, liver transplantation in the United States grew 3.7-fold from 1713 to 6320 transplants annually. The expansion of liver transplantation is chiefly driven by scientific breakthroughs that have extended patient and graft survival well beyond those expected 50 years ago. The success of liver transplantation is now its primary obstacle, as the pool of donor livers fails to keep pace with the growing number of patients added to the national liver transplant waiting list. This review focuses on three major challenges facing liver transplantation in the United States and discusses new areas of investigation that address each issue: (1) the need for an expanded number of useable donor organs, (2) the need for improved therapies to treat recurrent hepatitis C after transplantation and (3) the need for improved detection, risk stratification based upon tumor biology and molecular inhibitors to combat hepatocellular carcinoma.
This review focuses on current clinical and research initiatives aimed at addressing the greatest challenges in liver transplantation today. The annual number of recovered deceased donor livers has decreased nationwide from 7017 in 2006 to 6608 in 2010, according to data collected by the Organ Procurement and Transplantation Network (OPTN).
Part 3 addresses the need for improved molecular analysis of HCC to develop improved risk stratification methods and molecular inhibitors. Proper patient selection is critical to posttransplant survival; however, today selection is based primarily on tumor size and number which does not always accurately predict tumor biology. To that end, we identify the development of new biomarkers as a critical challenge that may one day serve as a personalized molecular signature to more accurately select HCC candidates for liver transplantation and provide an optimal treatment regimen of molecular inhibitors to combat advanced HCC.
One of the greatest hurdles that liver transplantation faces today is the growing discrepancy between the demand for, and availability of, donor livers. Although this gap has been slightly reduced since the introduction of the Model for end-stage liver disease (MELD) allocation system in the United States in 2002, there remains twice as many patients on the waiting list in 2008 (12 230 patients) compared to those who were transplanted that same year (6,319 recipients) (Figure 1).
Gap between supply and demand for useable donor livers. Annual number of listed liver transplant candidates at the end of the year (solid circle) are compared to the total liver transplantations (open triangle) performed in the United States since the introduction of the MELD allocation system. Data were retrieved from the 2009 OPTN/SRTR Annual Report (94).
Different strategies have evolved to expand the donor pool (Table 1).
Use of steatotic donor organs
HCV-positive donor organs for HCV-positive recipients
Use of high-risk CDC donor organs
Donation after cardiac death
Split liver transplantation
Living donor liver transplantation
Domino liver transplantation
Distribution of liver transplantations performed in the United States in 2008 according to type of donor organ. DBD = donation after brain death; DCD = donation after cardiac death; LDLT, living donor liver transplantation. Data were retrieved from the 2009 OPTN/SRTR Annual Report (94).
Distribution of alternative liver grafts (donation after cardiac death, living donor split grafts and split grafts from brain dead donors) between 1999 and 2008. Annual number of liver transplantations performed with partial grafts from living donors (open triangle), split grafts from brain death donors (open circle), and full grafts from donation after cardiac death (solid circle ). The total number of this pool is represented by theopen square. Data were retrieved from the 2009 OPTN/SRTR Annual Report (94).
Challenge of ECD Organs:
Although UNOS has defined the standard for ECD kidneys, a universal definition for livers has not yet been established. However, advanced donor age, steatosis and prolonged hospital stay are the most important criteria defining ECD organs by many centers. Donor age,[3–6] cold ischemia time[3,4] and donor hospital stay are significant donor variables in models predicting outcome after liver transplantation. Although each criterion is not a contraindication for transplantation, the accumulation of several criteria significantly increases the risk for poor outcome after liver transplantation.[3,5] One drawback of the prediction models is that none include parenchyma quality such as steatosis. Steatosis, especially macrosteatosis, is an established risk factor for primary nonfunction and graft dysfunction. Microsteatosis, which often appears as a mixed form with macrosteatosis, has a smaller effect on ischemia-reperfusion injury than macrostatosis. While mild macrosteatosis (less then 30%) is acceptable for use in transplantation if cold ischemia time is short, the allocation of livers with moderate macrosteatosis (30–60%) remains challenging due to the significantly increased risk of primary graft failure.
Challenge of Living Donor Liver Transplantation: Living donor liver transplantation (LDLT) peaked in 2001 in the United States with 524 cases (Figure 3).
Challenge of Split Liver Transplantation:
The introduction of this technique has dramatically decreased the need for living donation at many pediatric transplant centers. Our results with over 250 split liver transplants illustrate that proper donor selection with appropriate parenchymal volume can yield equivalent survival compared to whole organ transplantation. Moreover, biliary and arterial complications are not significantly different in segmental grafts compared to whole organs.[22,23] Despite the shortfall between deceased donor whole organ availability and recipient demand, split liver transplantation remains at only 4% to 5% of all livers used for transplantation (Figure 2 and 3).
Challenge of DCD Organs:
Recent reports from the Cleveland Clinic suggest that the administration of tissue plasminogen activator into the donor hepatic artery before implantation might reduce the rate of ischemic-type biliary strictures. As long as patients are dying on the waiting list, it is hard to ignore that DCD liver transplantation has saved many lives even in light of moderate inferior outcome and slightly higher costs. If the outcome of DCD liver transplantation can be improved to the level of DBD liver transplantation, DCD would probably have the greatest growth potential compared to split liver transplantation and LDLT. Therefore, every effort should be promoted in this field to achieve this life-saving goal.
HCV is the most common indication for liver transplantation in the United States, accounting for approximately 40–45% of all transplants. After liver transplantation, infection of the transplanted liver is universal and recurrent HCV directly impacts patient and graft survival.[31,32] Although short-term survival does not appear to be affected by recurrent infection, differences in survival become significant with long-term follow-up.[32–34]
Pretransplant and posttransplant viral load affects HCV recurrence; viral loads above ~1×106 IU/mL around the time of transplantation are associated with a decreased 5-year survival. Approximately 57% of patients were alive at 5 years in the more then 1×106 IU/mL cohort versus 84% in the less then 1×106 IU/mL group.[37,38] Unfortunately, efforts to decrease viral load have been limited by concerns of precipitating hepatic decompensation.
Factors associated with recurrent hepatitis C disease after liver transplantation.
Challenge of Balancing Graft Rejection and HCV Recurrence:
There is increased understanding of the relationship between HCV infection and the immune system. Emerging evidence suggest that regulatory T cells may play an integral role. There is an enhanced expression of regulatory T cells in nontransplant individuals with HCV.[41–43] Indeed, this association persists after liver transplantation and may be one of the paramount means for rapid disease progression in transplant recipients. Immunosuppressant therapy after transplantation likely leads to increased regulatory T cell expression that can contribute to the severity of recurrent disease. Improved insight in immunosuppressive agents and the interaction between HCV and the immune system is needed to help tailor antiviral therapy and achieve successful treatment while minimizing adverse immunological effects.
Immunosupression is the cornerstone of patient and graft survival in liver transplantation.
Other factors that lead to worse outcomes in patients transplanted for HCV include prolonged cold and warm ischemia time (more then 90 min), recipient age, presence of diabetes, female gender and nonwhite race. Viral coinfection with human immunodeficiency virus has also been associated with more severe HCV recurrence and more rapid progression to cirrhosis.[52,53] HCV appears to be particularly more aggressive in recipients transplanted with higher MELD scores. Emerging data suggest the recipient Interleukin-28b (IL-28b) genotype may also be associated with rapid histological recurrence,[55,56] although the exact mechanism is unclear. Interestingly, the IL-28b genotype does not appear to impact overall or liver-related survival.
Challenge of HCV Therapy and Minimization of Side Effects:
Challenge of Achieving a SVR to Treatment:
The likelihood of achieving a SVR is strongly related to the ability to adhere to recommended doses. In the nontransplant setting, there is a substantial decrease in SVR when patients fall below a certain threshold of doses during treatment with pegylated interferon and ribavirin. Therefore, it is critical that patients and physicians adhere to the antiviral regimen, as long as it is safe to do so. Neutropenia and anemia are major limiting complications in liver transplant recipients. Consequently, only about 30% of treated patients are able to achieve target doses and duration of therapy.
Although HCV is one of the most common indications for liver transplantation, patient survival is among the lowest of all indications for transplantation. The ultimate goal of antiviral therapy in patients with recurrent HCV is to improve survival. Indeed, achieving a SVR can lead to fibrosis regression and improve survival. The regression of fibrosis can continue for several years after achieving a SVR. However, the likelihood of achieving SVR among transplant recipients is between 25% and 45% (36,64–66). A 5-year survival of 92% can be expected among patients who are able to achieve a SVR compared to 66% in treatment nonresponders. Infergen (interferon-alphacon-1) and ribavirin are approved for the treatment of interferon nonresponders in the nontransplant population. There is limited experience using this treatment combination in liver transplant recipients and further clinical studies are needed.
Challenge of Evaluating Protease Inhibitors as New Therapies for Recurrent HCV:
Challenge of Retransplantation:
Challenge of Removing Barriers to Liver Transplantation:
Proper Selection of Transplant Recipients With HCC
HCC is the fifth most common cancer worldwide. It develops in the context of cirrhosis in 80% of patients. Current recommendations are to enroll patients who are at risk for HCC in a surveillance program. Screening tests fall into two categories, serological and radiological. As a screening test, ultrasonography is the most commonly used modality and has been reported to have sensitivity between 65% and 80% and specificity greater than 90%. Alpha-fetoprotein (AFP) is the most studied serological marker for HCC. A serum AFP level of 20 ng/mL provides a sensitivity of 60%, which is suboptimal for general use as a screening test alone. AFP still has a role in the diagnosis of HCC, and one challenge for the future is to discover new biomarkers with appropriate predictive value to better screen for and diagnose HCC.
Challenge of Developing New Biomarkers for HCC:
Challenge of Developing Improved Risk Stratification Models for HCC:
There are several prognostic models for HCC that all rely on a combination of radiographic appearance (number of tumors and size), histological assessment (vascular invasion) and overall liver function. Personalized genomic profiling of liver tumors may provide an individualized molecular signature to guide treatment. Such a molecular pattern would link tumor biology to therapy. Studies looking at selected molecular markers of dysregulated signaling pathways and matching those defects to specific inhibitor therapies are already underway in a limited capacity.
The challenge for liver transplantation in HCC is to define an improved preintervention staging algorithm based upon morphologic and genetic criteria that is linked to a personalized cancer treatment program ranging from surgery to the use of new, systemic molecular inhibitors to fight cancer. A new evaluative criterion would include size and number of lesions in addition to expression or mutation of critical genes leading to increased cell cycle progression and metastatic potential.
Several investigators have used microarray technology to sample HCC tumors, dysplastic tissue, or normal surrounding tissue to understand the genetic variation as cells progress toward carcinoma in the liver. The variability in disease progression among patients with HCC may be due to genetic heterogeneity across the population at large. Genetic expression patterns among individual cancers may be able to reduce this complexity by distinguishing between different subgroups of HCC, allowing tumors to be stratified into low and high aggressive potential that conventional histopathology may be unable to accomplish. One such study by Lee and colleagues analyzed gene expression patterns in HCC from rodents and humans and found that the expression of certain genes in aggressive HCC tumors were shared with fetal hepatoblasts, suggesting that an immature cell of origin may confer poorer prognostic consequences.
Vascular invasion is an unfavorable prognostic factor in HCC.
Biomarkers have yet to be incorporated into a formal risk stratification scoring system. However, Kaseb and colleagues have investigated the use of serum vascular endothelial growth factor (VEGF) and applied it to the Cancer of the Liver Italian Program (CLIP) score. The CLIP staging system is based upon liver function (Child's Score) and tumor characteristics including tumor morphology, extension, AFP level and portal vein thrombosis. Although this study was conducted in patients with mostly advanced, unresectable cancer, the authors demonstrated that higher levels of the VEGF (more then 450 ng/mL) led to poorer survival in each of four CLIP score levels. Differences were significant at advanced levels of disease (score 3–4) but poorer survival trended toward those with elevated VEGF levels throughout. These modified scoring systems, based upon tumor biology, require further validation before they are applied to patients. However, a more immediate effect may be seen in clinical trials where the ability to further distinguish patients and predict prognosis based upon the individual biology of their tumor may demonstrate a subset of patients that benefit from a given therapy.
Challenge of Developing Novel Molecular Inhibitors to Treat HCC:
Given the modest benefit in survival with Sorafenib and the discovery of multiple molecular pathways that give rise to HCC, novel molecular inhibitors are in the drug development pipeline and several clinical trials to evaluate combination therapies are ongoing such as Sorafenib, Gemcitabime (NCT 00844688) and Sorafenib and trans-arterial chemoembolization (NCT 00618384). New potential targets for inhibition include growth factor receptors and signal transduction pathways that govern proliferation, motility and the metastatic potential of tumor cells. Candidate downstream targets include Raf, MEK and extracellular signal-regulated kinase of the Ras pathway, the phosphatidylinositol 3-kinase (PI3K)–AKT–mammalian target of rapamycin (mTOR) pathway and the Janus kinases/Signal transducers and activators of transcription pathway.
A primary consideration for new multikinase inhibitors is to select those with an appropriate balance between anticancer efficacy and side effects that may be related to the broad activity of these agents. Sunitinib is an oral multikinase inhibitor of receptor tyrosine kinases VEGF Receptor 1–3, PDGFR-a, PDGFR-B, FLT-3, c-kit, RET and CSF receptor type 1. Sunitinib suppressed tumor growth of five HCC xenografts and demonstrated a progression-free survival of 3.9 months and an overall survival of 9.8 months in a phase II trial. However, higher doses of Sunitinib have been associated with an increase in hematological complications. A phase III trial to evaluate Sunitinib versus Sorafenib in patients with advanced HCC using a modified Sunitinib dosing regimen was terminated in April 2010 due to an increased incidence of adverse effects with Sunitinib and failure to demonstrate comparable efficacy to Sorafenib (http://www.clinicaltrials.gov, NCT 00699374). The early discontinuation of this trial is certainly a set-back for the introduction of new tyrosine kinase inhibitors for clinical use against HCC.
The PI3K/AKT/mTOR pathway is a major protein cascade involved in immune regulation and carcinogenesis. Activation of this pathway indicates poor prognosis in patients with HCC. Mutations in the catalytic domain of PI3K lead to enhanced AKT expression and activation of mTOR. Rapamycin, an immunosuppressant, inhibits replication of HCC cell lines in vitro and expansion of HCC tumors in animal models. A study analyzing rapamycin in postliver transplant patients transplanted for HCC showed improved survival at 6 years compared to counterparts not receiving this drug, suggesting that rapamycin may have both anti-inflammatory and anti-tumor properties. A new rapamycin analog, Everolimus (RAD001), is an oral medication for anti-HCC therapy and has been used in the posttransplant setting in patients at high risk for HCC recurrence, calcineurin toxicity and refractory rejection. Several clinical trials valuating the efficacy of Everolimus in HCC are ongoing (Table 2).
The deregulated expression of membrane bound proteins in HCC may serve as a ligand for targeted drug therapy. Lee and colleagues at the University of Hong Kong showed that HCC cells with increased expression of the epidermal growth factor receptor can be specifically targeted for gene therapy to replace mutated p53. Other groups have used bionanocapsules consisting of hepatitis B virus surface antigen molecules within a lipid bilayer to specifically deliver DNA to liver tissues. Targeted drug delivery systems are important areas of development that concentrate a therapeutic agent in tumor cells while minimizing exposure to healthy tissues.