Essential updates 2018/2019: Liver transplantation

Abstract Among the recent topics in the field of liver transplantation (LT), one of the significant therapeutic breakthroughs is the introduction of direct‐acting antiviral agents (DAAs) against hepatitis C virus (HCV) infection. With cure rates close to 100%, a better proportion of LT candidates and recipients can be cured of HCV infection by DAA therapies that are simple and well‐tolerated. Other critical topics include the issue of indication of LT for patients with hepatocellular carcinoma, which has been continuously studied. Several expanded criteria beyond the Milan criteria with acceptable results have been recently reported. The role of donor‐specific antibodies (DSAs) in intractable rejection is also an important matter that has been studied. Although long recognized as an important factor in antibody‐mediated rejection and even graft survival in renal transplantation, the impact of DSAs on graft and patient survival in LT remains to be elucidated. Including the issues described above, this article focuses on recent advances in LT, management to avoid recurrence of primary diseases, optimization of immunosuppressive treatment, and extended donor criteria.


| INTRODUC TI ON
Liver transplantation (LT) is a prevalent treatment option for end-stage liver disease and acute liver failure, although many characteristic issues remain to be solved. Favorable outcomes require careful screening for eligible recipients, proper selection of well-matched live or cadaveric donors at the appropriate time, optimization of immunosuppressive treatment, and preemptive and/or therapeutic treatment to avoid rejection and recurrence of primary diseases including hepatocellular carcinoma (HCC).
Focusing on those issues, this article summarizes the recent advances in LT.

| Predictors and criteria
Since the Milan criteria was created for the eligibility of LT in patients with HCC, 1 many studies were published aiming to expand the Milan criteria without impairing patient survival or recurrence-free survival. [2][3][4][5] The most important articles aiming at defining predictors or criteria for LT patients with HCC published in the last 2 years between 2018 and 2019 are summarized in Table 1. [6][7][8][9][10][11][12][13][14] In Japan, Shimamura et al 6  LT HCC recurrence probability at 3 years was 1.6% of patients with a RETREAT score of 0, 8.4% with a score of 3, and 29.0% for a score of 5 or higher (P < .001). 9 RETREAT score should be used for standardizing post-LT HCC surveillance strategies.
Small-for-size grafts defined as GRWR <0.8% showed poor oncologic outcomes, including recurrence-free survival and overall survival, among the patients with HCC, beyond the Milan criteria. 10 It has been speculated that one of the possible mechanisms can be that high portal pressure and liver congestion affects inflammation of endothelial cells and tumor immunity in the liver. Another interesting finding would be that a history of prior upper abdominal surgery decreased graft survival and overall survival after LT for HCC, although no convincing mechanism has been elucidated. 14 Besides, TA B L E 1 Prediction of HCC recurrence after liver transplantation published in the 2-y period between 2018 and 2019

| Downstaging
Downstaging would be a potential option for patients with advanced HCC to undergo LT as a curative treatment. The American Association for the Study of Liver Disease (AASLD) guidelines recommended that patients beyond the Milan criteria (T3) should be considered for LT after successful downstaging into the Milan criteria. 16 The problem is that the inclusion criteria and downstaging protocols are not systematically fixed. 17 Essential and the last 2-year updates of downstaging HCC before LT are summarized in significantly correlated with posttransplant mortality or HCC recurrence rates after LT. 20 The same group clarified the efficacy of USCF downstaging criteria compared with patients who had an initial tumor burden exceeding USCF criteria. 21

| Post LT management: immunosuppression and adjuvant therapy
There is no standard management including immunosuppression and adjuvant therapy for LT with HCC after LT. Mechanistic targets of rapamycin (mTOR) inhibitors have antiangiogenic and antiproliferative effects in several experimental models. 24,25 A recent randomized trial could not provide evidence for the preventive effect of mTOR inhibitors on preventing HCC recurrence after LT. 26 On the other hand, the recent meta-analysis of 23 studies including 17 observational and six randomized trials demonstrated that recurrencefree survival and recurrence rate in the mTOR inhibitor group were improved compared with CNI control groups. 27   HCV co-infection within the early phase (4-8 weeks) of DAA treatment. 46 However, Vionnet et al 47  The debate about the optimal timing for treating HCV patients in LT waiting list is ongoing, and this issue very much depends on the medical environment, such as whether a patient can receive organ donation.
Along with the development of antiviral therapy, including HBV and HCV, the idea of transplanting an organ from viral positive donors to negative recipients is spreading to overcome organ shortage. The topic of viral exposed organs will discuss in following donor section. which focus more on liver function than EASL (Table 4). Mahmud et al showed the discordance of ACLF between APASL and EASL, and ACLF that met both definitions had poor survival compared to those with APASL or EASL ACLF alone. 51,52 These data should be considered as an account of the liver allocation system with local organ supply.

| Non-alcoholic steatohepatitis (NASH)
Owing to the improvement of HCV management, non-alcoholic fatty liver (NAFLD)/non-alcoholic steatohepatitis (NASH) became a leading indication of LT in the United States and European countries. 53

| Alcoholic
Alcohol-related liver disease (ALD) is also becoming a leading indication for LT in Western countries. Most organ allocation policies set

TA B L E 4 Definition of acute-on-chronic liver failure
European Association for the Study of the Liver (EASL)

Asia-Pacific Association for the Study of the Liver (APASL)
Acute deterioration of preexisting, chronic liver disease, usually related to a precipitating event and associated with increased mortality at 3 mo due to multisystem organ failure (following definitions).

| Primary biliary cholangitis (PBC)
The proportion of PBC decreased from 20% of LT in 1986 to 4% in 2015, as per the European Liver Transplantation Registry. 65 However, LT remains the only radical treatment for PBC. Although the prognosis of PBC after LT is relatively good, the recurrence rates of PBC were in a range from 9% to 35% after LT. 66 Risk factors for recurrent PBC were reported as recipient/donor age, recipient/donor gender, recipient HLA status, ischemic time, and immunosuppression. 66 Recent multicenter study (785 patients with PBC who underwent LT) from North America and Europe reported that younger age, use of tacrolimus, and liver dysfunction early after LT were associated with an increased risk of PBC recurrence. 67 The authors advocated that cyclosporine might have a protective effect on the recurrence of PBC; however, the opposite result was that cyclosporine was a risk factor of PBC recurrence in a Japanese multicenter study. 68 Early use of UDCA after LT was associated with reduced risk of recurrence of PBC. 69 Some clinical trials for PBC treatments including obeticholic acid 70 or bezafibrate 71,72 need to be investigated in LT patients whether to decrease the risk of recurrent PBC after LT.

| Primary sclerosing cholangitis (PSC)
A Japanese multicenter study of LDLT for primary sclerosing cholangitis (PSC) revealed that MELD score, first-degree relative donors, CMV infection, and early biliary anastomotic complications were risk factors for recurrence of PSC after LT. 73 A recent systematic review including 2159 patients who underwent LT for PSC revealed that cholangiocarcinoma before LT, inflammatory bowel disease, older donor age, higher MELD score, and acute cellular rejection increased the risk of recurrent PSC. It was also showed that colectomy before LT reduced the risk of recurrent PSC. 74 Another systematic review concluded that the data favored a protective role of colectomy in recurrent PSC but the current evidence was not strong enough to recommend routine colectomy for recurrent PSC prevention. 75

| Impact of anti-human leukocyte antigen donorspecific alloantibodies (DSAs) developing after liver transplantation
The Immunogenic HLA regions, known as epitopes, are composed of polymorphic sequences of amino acid residues termed eplets. There is a tendency to suggest that epitope matching is likely to be superior to broad antigen HLA matching such that the allocation of donor organs to patients with a more favorable epitope compatibility profile may lead to better allograft outcomes. Indiana University group demonstrated that donor-recipient HLA epitope mismatch was significantly associated with a risk of de novo DSA formation and rejection after LT. 83

| LIVER TR AN S PL ANTATI ON AND IMMUNE TOLER AN CE
The liver exhibits intrinsic immune tolerogenic properties that con- vitro. 93,94 In contrast, CNIs block T cell receptor signal transduction and IL-2 transcription, both inhibiting Treg generation. [95][96][97] It has been previously demonstrated that CNI to SRL conversion increases systemic Tregs, regulatory DCs, and immunoregulatory proteogenomic signatures in liver transplant recipients, suggesting that it may facilitate immunosuppression minimization or withdrawal. 98 Recently, a prospective trial of SRL monotherapy withdrawal was performed in non-immune, non-viremic LT recipients >3 years post-LT. 99 This study is the first to evaluate immunosuppression withdrawal directly from mTOR-I therapy in LT recipients and achieved >50% operational tolerance. It would be expected that pre-weaning blood/graft gene expression and PBMC profiling will be investigated as useful predictors of successful mTOR-I therapy withdrawal. status was not associated with liver discard but was associated with worse LT graft survival compared to heparin-treated livers in US registry data including 5495 DCD organ recoveries. In addition, the study, which used data from the UK Transplant Registry, suggested a negative impact of prolonged hepatectomy time (HT), which means the time from aortic perfusion to end of hepatectomy, on outcomes on DCD LT. 103 To be more specific, HT longer than 60 minutes was pointed out as an important factor for graft survival together with donor age of older than 45 years, CIT longer than 8 hours, and a recipient's previous abdominal surgery.

| Viral exposed organ
The

| Living donor
Smaller surgical incisions have recently been innovated in living donor liver procurement. The Japanese nationwide survey reported that there were no significant differences in major complications between the standard incision and smaller incision, including laparoscopic approach. 122 Park et al 123 reported the outcome of the initial 91 cases in pure-laparoscopic living-donor right hepatectomy (LLDRH) procedure for LDLT. The incidence of major complication tends to be higher in the LLDRH group than the open laparotomy group but was not statistically significant in the propensity-matched analysis. Further studies and technical improvement are needed to standardize the pure laparoscopic procedures, but smaller incision seems to have been adapted more frequently and be feasible in high-volume centers. As another interesting topic, remote ischemic preconditioning (RIPC), which develops resistance for liver ischemia in living donors by transient ischemia and reperfusion of the arm, has attracted attention to avoid the harmful effects of ischemic reperfusion injury that is asso-