*Review* **New Indications for Liver Transplantation**

**Alberto Zanetto, Sarah Shalaby, Martina Gambato, Giacomo Germani, Marco Senzolo, Debora Bizzaro , Francesco Paolo Russo and Patrizia Burra \***

> Multivisceral Transplant Unit, Department of Surgery Oncology and Gastroenterology, University of Padova, Via Giustiniani 2, 35128 Padova, Italy; alberto.zanetto@yahoo.it (A.Z.); sarahshalaby18@gmail.com (S.S.); martina.gambato@gmail.com (M.G.); germani.giacomo@gmail.com (G.G.); marcosenzolo@hotmail.com (M.S.); debora.bizzaro@gmail.com (D.B.); francescopaolo.russo@unipd.it (F.P.R.)

**\*** Correspondence: burra@unipd.it

**Abstract:** Liver transplantation (LT) is an important therapeutic option for the treatment of several liver diseases. Modern LT is characterized by remarkable improvements in post-transplant patient survival, graft survival, and quality of life. Thanks to these great improvements, indications for LT are expanding. Nowadays, clinical conditions historically considered exclusion criteria for LT, have been considered new indications for LT, showing survival advantages for patients. In this review, we provide an updated overview of the principal newer indications for LT, with particular attention to alcoholic hepatitis, acute-on-chronic liver failure (ACLF), cholangiocarcinoma and colorectal cancer metastases.

**Keywords:** alcoholic hepatitis; acute-on-chronic liver failure; cholangiocarcinoma; colorectal cancer metastases

### **1. Introduction**

Since the first procedure performed in 1963, liver transplantation (LT) has become an important therapeutic option for the treatment of inborn metabolic disorders, acute liver failure, end-stage chronic liver disease, and primary hepatic cancers [1].

Over the past several decades LT has continued to grow and evolve with huge improvements in surgical techniques, organ preservation and procurement, and immunosuppression. Therefore, the modern LT is characterized by remarkable improvements in post-transplant patient survival, graft survival, and quality of life. Thanks to these ever-increasing improvements in overall survival, with one-year graft and patient survival nowadays around 90% [2], indications for LT are expanding, also as a result of a better understanding of liver diseases and innovative therapies.

Nowadays, clinical conditions historically considered exclusion criteria for LT, such as severe alcoholic hepatitis (AH), acute-on-chronic liver failure (ACLF), colorectal cancer metastases and cholangiocarcinoma are now considered new indications for LT, showing survival advantages for patients. In this review, we provide an updated overview of these newer indications for LT (Figure 1).

**Citation:** Zanetto, A.; Shalaby, S.; Gambato, M.; Germani, G.; Senzolo, M.; Bizzaro, D.; Russo, F.P.; Burra, P. New Indications for Liver Transplantation. *J. Clin. Med.* **2021**, *10*, 3867. https://doi.org/10.3390/ jcm10173867

Academic Editors: Pierluigi Toniutto and Hidekazu Suzuki

Received: 30 July 2021 Accepted: 27 August 2021 Published: 28 August 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

**Figure 1.** New indications for liver transplantation. *Controversial* indications include severe alcoholic hepatitis and ACLF grade 3. *Questionable* indications include non-hepatocellular carcinoma liver cancer, and liver metastases from colorectal cancer. CCA: cholangiocarcinoma; ACLF: acute-onchronic liver failure.

#### **2. Alcoholic Hepatitis**

Worldwide, alcohol-related liver disease (ALD) is one of the most prevalent liver diseases and the second most frequent indication for LT [3], representing around 30% of all primary LT procedures in Europe and approximately 25% in the USA [4,5].

The first cornerstone in the treatment of patients with ALD is abstinence from alcohol. An adequate time of abstinence may decrease hepatic fibrosis, reduce the risk of progression to cirrhosis, improve the prognosis of cirrhotic patients and reduce the mortality [6–8]. Abstinence is important, but usually it cannot reverse advanced ALD and in many cases the only definitive treatment for ALD is LT. Despite the fact post-LT outcomes and survival rates are analogous with those of other etiologies [4], ALD is still judged a controversial indication for LT. The discussion is generated mainly by the opinion that ALD is a selfinflicted disease, and by the possible risk of harmful effects to the graft after alcohol relapse [9]. In the majority of transplant programs, a period of 6-month of abstinence ("six-month rule") is a compulsory condition to consider a patient eligible for LT. This rule has a double scope: first, to avoid LT in those patients in whom liver function and general clinical status will improve after alcohol removal, second to identify patients at higher risk of relapse after LT.

Nevertheless, the role of the pre-LT extent of abstinence as a predictor of alcohol relapse post-LT has not been clearly confirmed and the enforceability of this rule is still controversial [10]. Indeed, in a systematic review including 22 studies, in only two of them the six months of alcohol abstinence was predictive of post-LT relapse [11]. Furthermore, the ideal period of abstinence pre-LT is still controversial, although there are data confirming that a shorter prelisting abstinence period is associated with a faster post-LT relapse [12].

In recent years, an alarming increase in incidence of hospitalization for AH and mortality rates has been observed both in the US [13] and in Europe [14]. AH presents with fatigue, anorexia, nausea, jaundice, mild-to-moderate increase of transaminases, hyperbilirubinemia, hypoalbuminemia, elevation of neutrophils and prothrombin time (PT) prolongation [3]. The most used validated prognostic scoring system is the Maddrey Discriminant Function (MDF). Usually AH is defined by a MDF >32 [15]. The role of pharmacological treatments, especially corticosteroids, in patients with AH is still debated, with studies demonstrating efficacy in improving survival [16–18] and others showing a negligible effect on reducing mortality [19,20]. In patients not responding to medical therapy the prognosis is very poor, with a 6-month mortality rate of 75%.

In accordance with the "six-month rule", AH patients are ineligible for LT at most transplant centers. Nonetheless, there is growing evidence that, in selected patients after the first episode of AH not responding to medical therapy, LT represents an effective treatment [21,22]. it was demonstrated that the post-LT outcomes are good, with survival rates significantly higher compared to not transplanted patients with AH not responding to steroid therapy [23–25].

Like with ALD cirrhotic LT recipients some ethical and social concerns remain. These are mostly originated by the public opinion that a graft is afforded to patients who were actively consuming alcohol immediately previous to admission on the waiting list, with higher risk of post-LT alcohol relapse. However, the existing data on LT in these patients demonstrate that relapse rates are analogous to those observed in patients with ALD that respected the "6-month rule", if a rigorous and appropriate selection process is applied [23–25].

Multiple arguments for either "tight" or "loose" selection criteria have been proposed for LT in AH [26]. One major argument for tight selection is that current models for predicting survival without LT are not adequately precise for use in an individual patient, which implies not only that some patients will be subjected to LT unnecessarily, but also that others will be denied a potentially lifesaving LT. Additionally, most criteria for listing rely on clinical judgment, which may vary across different centers, thus leading to inequity of access to LT. On the other hand, real-life patients with AH undergoing LT often present with ACLF and a high risk of short-term mortality, thus making unnecessary LT very rare. Furthermore, a careful selection of patients at the first event of liver decompensation has repeatedly yielded excellent outcomes and low risk of relapse [26].

Like other indications for LT, further refinement of selection criteria is expected to evolve gradually over time. However, without the establishment of national and international agreement on criteria for admitting in waiting list and transplanting patients with AH, a high variability persists in terms of admittance to LT for those patients, with disparities that are manifest also at a national level with a potential inequality among patients with the same clinical conditions [27].

Data reporting good outcomes of early LT in selected patients were published in the last years. In the study by Mathurin et al. [23], 26 patients with AH with no response to corticosteroids were subjected to early LT as rescue therapy, after a strict multidisciplinary selection process. Survival after 6 and 24 months post-LT were significantly higher than in matched not transplanted controls (77% vs. 23%). Alcohol relapse was detected up to three years after LT in about 10% of patients.

A US study, published by Im et al. [28] confirmed the good outcomes of early LT in 94 patients with AH, in whom the 6-month survival rate was higher compared with matched not transplanted patients (89% vs. 11%). Alcohol relapse was diagnosed in only one recipient at 180 days after LT. Similarly, in a retrospective study published by Lee et al. [29], cumulative patient survival percentages after LT for AH were 94% and 84% at 1 year and 3 years, respectively After LT, 72% were abstinent, 18% had occasionally relapses, and 11% had sustained alcohol intake.

In Italy, Germani et al. coordinated the first Italian experience in a pilot study on early LT for AH from four different LT centers. Among those centers, the coordinating center is the Multivisceral Transplant Unit of Padua University Hospital. The inclusion criteria were AH, as a first episode of decompensation in chronic liver disease and no responses to medical therapies, but more importantly, the patient should have been socially integrated and have supportive family members, with psychiatric assessment and addiction profile and no comorbidities [30]. Preliminary data coming from Padua Liver Transplant center demonstrated a significantly higher survival rate amongst patients who underwent early LT compared to non-responding patients who were denied early LT.

The Spanish Society of Liver Transplantation has recently published a consensus statement on the potential expansion of indications for LT including patients with a first episode of severe AH not responding to medical therapy [31], whereas no specific guidelines or position statements have been published with this regards in Germany. In UK a pilot program for LT in patients with severe AH was developed. Over a 3-year period 20 patients aged between 18 and 40 years were evaluated, but none underwent LT, mainly due to the

extremely stringent criteria for listing and the need for unanimity among members of the transplant panel [27].

The most significant concern in patients actively drinking before admission, is the post-LT risk of relapse. In the already mentioned landmark paper [23], about 10% of patients had a relapse up to three years after LT. This could be important not only from the "single-patient" perspective, but also for the possible negative effects on donation rate. Nevertheless, a recent multicenter survey suggests that organ donation was not negatively influenced by the early LT for AH [32]. Given the complexity of the selection and management of patients with AH, a multidisciplinary approach, involving various stakeholders including transplant hepatologists and transplant surgeons, but also psychiatrists, psychologists, and addiction specialists is becoming compulsory to accurately evaluate LT candidates [33,34]. The SALT prognostic score, developed including four objective pre-LT variables, was proposed in order to foresee the risk of sustained alcohol intake after early LT for AH assisting in the selection of patient candidates for early LT or in advising controls post-LT [35].

The psychosocial assessment of LT candidates and the evaluation of social background, including the presence of an active and effective support by the family, are essential parts of the pre-transplant evaluation process. In fact, the transplant outcome is undoubtedly influenced also by psychosocial and behavioral issues along with the usual medical factors [36]. This concept is even more important in the context of early LT where the psychosocial assessment is essential for the establishment of the real probability of long-term abstinence. Indeed, alcohol abuse is frequently associated with depression, personality disorders and other psychiatric disease, that can affect the post-transplant outcome of these patients [37,38].

To ensure to the LT candidates for AH the best long-term outcomes, globally accepted clinical and psychosocial selection criteria should be identified [39]. Very strict criteria should be explored for the early LT in this setting, as indicated in an Italian position statement [34]. Notably, a transparent and direct interaction between clinicians and society, based on the concept of no "a priori" exclusion to the evaluation for LT in the case of AH is essential.
