The short-term and long-term survival after liver transplantation (LT) improved significantly after the introduction of calcineurin inhibitors for immunosuppression. This improvement in outcomes and a better awareness resulted in an increasing demand for liver transplantation around the world. Transplant physicians have responded to this increased demand by developing several strategies including the use of older donors, grafts from hepatitis C virus (HCV)- positive donors or those with previous hepatitis B infection, graft from non-heart beating donors, domino transplantation, split-liver grafts, and live donor liver transplant (LDLT). Although there has been promising research in the fields of xenotransplantation , artificial liver support systems, hepatocyte transplantation and stem cell research, progress in these fields has been very slow. Currently, the only treatment that prolongs survival in those with end-stage acute or chronic liver failure is transplantation of either partial or full liver donor graft . Liver transplantation is also the treatment of choice for those with hepatocellular cancer (HCC) and cirrhosis . Because of the enormous disparity in supply and demand for donor organs, costs, and potential morbidity and mortality of live donors in LDLT, it has become incumbent on the transplant community to ration the available organs in a way that provides the best outcomes and in the process, serves the best interest of the population as a whole. When evaluating a potential candidate for LT, it is imperative to determine whether the recipient is going to benefit from the procedure immediately and in the long term.

The outcome of LT is dependent on many factors including graft quality, surgical techniques, postoperative care, immunosuppressive regimens and most importantly, careful pre-transplant recipient evaluation and selection. Currently, the expected 1-year and 5-year survival rates after LT are 85–95 % and 75–85 %, respectively [1]. The most common causes of mortality after LT are infections, recurrence of primary liver disease or cancer for which LT was performed, cardiovascular events, de novo malignancy, and renal failure [2–6].

The immediate and late outcome of LT is dependent on many recipient factors including age, race, body mass index (BMI), presence of diabetes or coronary artery disease, pre-transplant serum creatinine, etiology, and severity (MELD score, ICU status, or on ventilation) of liver disease at the time of transplantation [7–13]. Cold ischemia time, ABO mismatch, donor age, graft quality, gender, and race are other predictive variables that are known only at the time of transplantation in deceased donor LT [14]. In addition, surgical expertise, ICU care, and immunosuppression regimen may also play a role in the outcome. There have been many attempts to develop models to predict survival, but those models lacked sufficient discriminating power needed for routine clinical care. Artificial neural network has been suggested as a possible alternative to traditional multivariate models, but to date, despite showing some promises, these models have not been used to reliably predict outcome after LT. As discussed earlier, one of the most common causes of mortality is recurrence of primary liver disease or cancer for which LT was initially performed. In this book, well-known authorities in LT review and critically analyze our current knowledge of the incidence and diagnosis of disease recurrence, natural history, and treatment options.

LT for hepatitis B virus (HBV)-related chronic liver failure is becoming less common in Western countries, and when done, it is mostly for HCC or fulminant liver failure [15]. In Chap. 2, Didier Samuel and colleagues review the progress that we have made in the past two decades in the management of transplant recipients with HBV infection. With a combination of pre-LT antiviral therapy and post-LT prophylaxis regimen containing hepatitis B immune globulin (HBIG) and nucleos(t)ide analogues, reinfection rates have come down from 80 % to less than 10 %. Moreover, these regimens have improved 5-year survival rates to over 80 % [16–20]. The authors make evidence-based recommendations on post-LT management of HBV in this section.

HCV-related liver disease and HCC remain the most common indication for LT in most countries [1]. Until recently, HCV reinfection was the Achilles heel of LT. The 5-year survival rate after LT for HCV-related liver disease is 61–75 %, compared with 76–85 % for other causes of liver diseases, including HBV infection [21, 22]. The predominant reason for the lower survival rate after LT in recipients with HCV infection is disease recurrence leading to cirrhosis and liver failure [21–27]. In LT recipients, fibrosis progresses at an accelerated rate, resulting in cirrhosis in 30 % of LT recipients within 5 years after transplantation. In less than 1 % of people with HCV infection, fibrosing cholestatic hepatitis may lead to rapid liver failure and graft loss [27, 28]. In Chap. 3, Marina Berenguer and colleagues discuss risk factors for progressive HCV disease after LT, and in Chap. 4, my colleague and I review the previous, current and future treatment options for HCV reinfection. Until recently, treatment of recurrent HCV was with interferon-based regimens, and these regimens were poorly tolerated and were associated with serious adverse events leading to very high drug discontinuation rates and lower cure rates. The recent approval of effective interferon-free regimens is likely to change the natural history of recurrent hepatitis. Preliminary studies indicate that approximately 90 % of people with recurrent HCV could be cured with a combination of direct acting antiviral drugs with minimal side effects [29–32]. As with LT recipients with HBV infection, we are going to witness a remarkable improvement in the quality of life and long-term survival of HCV-positive LT recipients .

In Chap. 5, Russell Wiesner suggests that 10–40 % of patients develop clinical, biochemical, and histological changes consistent with recurrent primary biliary cirrhosis (PBC) , but recurrence of PBC does not have an impact on 5-year graft and patient survival (~80 %) [33–38]. Diagnosis of recurrent PBC is a major challenge in LT recipients [39–42]. This review indicates that one potential risk factor for recurrence is the type of immunosuppression, with cyclosporine-based regimens, as compared to tacrolimus-based regimens, having a reduced incidence and prolonged time to recurrence [43–46]. The treatment with ursodeoxycholic acid does not appear to delay histological progression [47].

Similar to PBC, recurrent autoimmune hepatitis (AIH ) may recur in a third of LT recipients after a median of 2–4 years post-LT [48–52]. James Neuberger (Chap. 6) eloquently discusses the challenges of making a diagnosis of recurrent AIH, and suggests that de novo AIH in LT recipients may indeed be a type of allograft rejection and better termed plasma cell hepatitis [53–55]. Many studies suggest that long-term use of steroids may reduce the risk of recurrent AIH. While most cases of recurrent AIH respond to increased immunosuppression and increased dose or introduction of corticosteroids , some may progress to graft cirrhosis and failure. Plasma cell hepatitis is also treated with increased immunosuppression [56].

A significant proportion of LT recipients have a history of obvious or occult alcohol or drug use . These recipients are at significant risk of resuming this behavior if it is not appropriately addressed prior to LT. Alcoholic liver disease is the second leading indication for liver transplantation in North American and Europe, and recidivism has been reported in a third of these patients [57]. Rolf Barth and colleagues (Chap. 7) discuss the complexity and controversies in this field including the defined periods of pre-transplant sobriety and appropriateness of LT in those who present with alcoholic hepatitis [58–61]. Although recidivism is common, recurrent alcoholic liver disease (8–19 %) leading to graft failure is less common [62]. The authors point out that alcoholic liver transplant recipients are at greater risk for mortality from cardiovascular disease and aero digestive malignancy, associated with alcohol and tobacco, and reinforce the importance of screening for malignancy and treatment of cardiac disease in these subjects [63–67].

Keith Lindor and colleague discuss the recurrence rates in primary sclerosing cholangitis (PSC), difficulty in distinguishing recurrence from ischemic strictures or chronic rejection, potential risk factors for recurrence and prognosis in a scholarly manner in Chap. 8. It appears that PSC recurs in about ~20 % of patients, and has a negative effect on long-term graft survival and patient survival [68–73]. However, 5-year survival is still around 80 %, but compared to PBC , retransplantation rates are higher (12.4 % vs. 8.5 %) in PSC [73].

In Chaps. 9 and 10, Drs. Bijan Eghtesad, Charles Miller and colleagues discuss the long-term outcomes of patients transplanted for metabolic disorders such as familial amyloidal polyneuropathy (FAP), hemochromatosis, Wilson’s disease, homozygous familial hypercholesterolemia, primary hyperoxaluria type 1 and non-alcoholic fatty liver disease (NAFLD). For metabolic disorders, except NAFLD, the metabolic defect is cured by LT, but the outcomes of end organ damage are unpredictable. FAP is a metabolic disorder for which LT is performed mostly to prevent neurological complications of FAP. According to the FAP registry, to date, over 2060 patients with FAP have been transplanted [74–80]. The estimated 10-year survival probability after LT for common variant amyloid is above 90 % compared to 56 % for non-transplant patients [74]. The result of 5-year survival for LT in non-V30M patients is far inferior (59 %) [75]. The outcomes of neurological and cardiovascular complications following LT for FAP is variable, and in some recipients, it may continue to progress. Similarly, cardiovascular complication is a common cause for mortality after LT for hemochromatosis [81]. NAFLD has become a common indication for LT, but the metabolic derangements that led to NAFLD persist or even get worse after LT resulting in significant cardiovascular morbidity and mortality [82–84]. Moreover, NAFLD recur in majority of patients, as reported in studies where protocol biopsies are performed, and in some it may progress to cirrhosis.

About 20 % of LT is performed for hepatocellular carcinoma (HCC), and the recurrence rates of HCC depend on patient selection [85–90]. Prior to the introduction of Milan criteria , the long-term results of liver transplantation in patients with HCC have been variable and disappointing, with an overall 5-year survival rate ranging from 30 to 40 %. Application of Milan criteria has reduced tumor recurrence rates to ~10 % and has improved 5-year tumor-free survival (~70 %). The UNOS data also suggest that the survival rates have improved after the publication of Milan criteria in the United States. In Chap. 11, my colleagues and I review the Milan criteria, recurrence rates when transplanted within Milan criteria and long-term recurrence-free survival rates. One of the major criticisms of Milan criteria is that it is based on pre-LT imaging findings, and only 70 % of explant pathology findings correlate with imaging. Moreover, imaging techniques, protocols, and interpretations of images are not uniform, and additionally, Milan criteria do not take into consideration the variability of tumor biology. There is an ongoing debate whether Milan criteria could be expanded without having an adverse effect on tumor-free survival. In Chap. 12, Thomas Schiano and colleague examine the expanded criteria by various authors, recurrence rates, predictors of recurrence, the role of down-staging, and the role of expanded criteria in living donor LT in a critical manner. The authors suggest that there will be an increasing demand for LT in those with HCC, and conclude that ongoing evaluation of the different pre-LT staging systems is necessary along with refinement of prognostic tools based on clinical parameters, treatment response, and molecular biologic/genetic markers in order to meet this anticipated transplant need. In Chap. 13, Richard Kim and colleagues examine the role of adjuvant and neoadjuvant treatment in HCC recurrence, and its role in down-staging liver tumors that are outside Milan criteria. Published studies suggest that HCC patients transplanted outside the Milan criteria have 5-year survival rates between 46 and 60 %. Use of multimodality approach, taking advantage of the benefits of different loco-regional therapy for HCC has been adopted as down-staging and bridging therapies for LT. However, the value of adjuvant therapy using systemic cytotoxic chemotherapy after LT has been disappointing, and similarly, the role of sorafenib in this situation has not been well defined; these issues are discussed in detail in Chap. 13.

LT for cholangiocarcinoma has been a controversial area because of high recurrence rates and early experience showed that 1-year survival was as low as 36 %, and the 5-year survival varying between 5 and 38 % [91–94]. Recent data, however, suggest that multimodal therapies, with neoadjuvant chemotherapy and/or radiation, and surgical exploration followed by LT may offer patients acceptable long-term tumor-free survival rates [95–98]. In Chap. 14, Groan Klintmalm and colleague review the literature and suggest that LT for cholangiocarcinoma should be performed using strict multimodal protocols in order to ensure good outcomes.

As discussed earlier, malignancy is a common cause of long-term mortality after LT. Ashokkumar Jain and colleagues discuss the common recurrent non-hepatic and de novo malignancy rates in LT recipients in Chap. 15 [99–107]. Rates of de novo malignancy increase in proportion to age at transplant and length of follow-up with skin cancer being the most common malignancy. The risk factors for other de novo cancers include history of alcoholic cirrhosis, smoking, Barrett’s esophagus, and PSC with inflammatory bowel disease. Authors point out that the rates of gynecological and breast cancers are lower than general population in most studies, and there may be geographical differences in de novo cancer rates after LT. In those with pre-LT non-hepatic malignancies, recurrence of neuroendocrine tumors and skin cancers are high. In this section, authors remind us of the importance of surveillance of LT recipients for recurrence as well as de novo malignancies.

The indications for LT in children are different from adult, and as per UNOS registry, the common indications are biliary atresia (47 %) followed by metabolic disorders (14 %), primary liver malignancy (13 %), and acute liver failure (11 %). In Chap. 16, Ronald Busuttil and colleagues review disease recurrence patterns in children transplanted for primary liver malignancy and metabolic disorders [108–111]. The authors show that disease recurrence is uncommon in children, and the spectrum of recurrent conditions is different from adults. Even in the presence of locally advanced hepatoblastoma , recurrence rates are low when children are transplanted after neoadjuvant chemotherapy followed by liver transplantation. In this chapter, authors discuss recurrence rates of other conditions including AIH, GCH-AIHA, and PSC. Another interesting observation is the recurrence of bile salt export pump deficiency in children [112].

In Chap. 17, Sammy Saab and colleague analyze the literature on quality of life in liver transplant recipients, and discuss potential reasons for poor quality of life and estimate the costs and outcomes associated with retransplantation. Most studies have shown that health-related quality of life improves significantly after LT, and this improvement is sustained for the first decade after LT when compared to the same patients in the pre-transplant period or an equivalent waiting list group of patients with chronic liver disease. Most studies, however, have shown that LT recipients have poorer performance in physical function when compared to the general population. Additionally, the quality of life measurements are poorer in those (transplanted for alcoholic cirrhosis) who resume drinking and in those with recurrent HCV [113]. The difficulty in assessing the quality of life in LT recipients in the absence of a validated, disease-specific measurements tool, and the complexity of patients with confounding variables are well described in this section.

In summary, in this book, eminent authors have described and analyzed all aspects of disease recurrence in great detail based on evidence. I sincerely hope that liver transplant community involved with patients care will find it a useful reference book.