Evolution of Liver Transplantation Indications: Expanding Horizons.

Liver transplantation (LT) has significantly transformed the prognosis of patients with end-stage liver disease and hepatocellular carcinoma (HCC). The traditional epidemiology of liver diseases has undergone a remarkable shift in indications for LT, marked by a decline in viral hepatitis and an increase in metabolic dysfunction-associated steatotic liver disease (MASLD), along with expanded indications for HCC. Recent advancements in surgical techniques, organ preservation and post-transplant patients' management have opened new possibilities for LT. Conditions that were historically considered absolute contraindications have emerged as potential new indications, demonstrating promising results in terms of patient survival. While these expanding indications provide newfound hope, the ethical dilemma of organ scarcity persists. Addressing this requires careful consideration and international collaboration to ensure equitable access to LT. Multidisciplinary approaches and ongoing research efforts are crucial to navigate the evolving landscape of LT. This review aims to offer a current overview of the primary emerging indications for LT, focusing on acute-on-chronic liver failure (ACLF), acute alcoholic hepatitis (AH), intrahepatic and perihilar cholangiocarcinoma (i- and p-CCA), colorectal liver metastasis (CRLM), and neuroendocrine tumor (NET) liver metastases.

Workup and management of liver transplantation in alcohol-related liver disease.

Alcohol-related liver disease (ALD) represents the most common indication for liver transplantation (LT) worldwide. Outcomes of LT for ALD are comparable with those of LT for other etiologies; however, ALD is still considered a controversial indication for LT, mainly because it is considered a self-inflicted disease with a high risk of return to alcohol use after LT. Pre-LT evaluation criteria have changed over time, with a progressive re-evaluation of the required pre-transplant duration of abstinence. Despite the fact that some transplant programs still require 6 months of abstinence in order to consider a patient suitable for LT, there is increasing evidence that a pre-transplant abstinence period of <6 months can be considered for well-selected patients. Early LT for severe alcohol-related hepatitis that has not responded to medical therapy has been shown to be an effective therapeutic option with high survival benefit when performed within strict and well-recognized criteria. However, high variability in LT access exists for these patients due to the presence of social and medical stigma. A psycho-social assessment, together with an evaluation by an addiction specialist, should be mandatory in patients with ALD who are potential candidates for LT in order to assess the risk of post-transplant return to alcohol use and to ensure good long-term outcomes. Finally, before LT, attention should be paid to the presence of other potential comorbidities (i.e., cardiovascular and neurological diseases), which could represent a potential contraindication to LT. Similarly, after LT, patients should be adequately monitored for the development of cardiovascular events and screened for "de novo" tumors, although standardized protocols for this monitoring do not exist at this time.

Long-Term Impact of Direct-Acting Antivirals on Liver Fibrosis and Survival in HCV-Infected Liver Transplant Recipients.

(1) Background: Little is known about the long-term impact of sustained virological response (SVR) on fibrosis progression and patient survival in liver transplantation (LT) recipients treated with direct-acting antivirals (DAAs). We investigated liver fibrosis evolution and patient survival in hepatitis C virus (HCV)-infected patients receiving DAAs after LT. (2) Methods: All consecutive HCV-infected patients treated with DAAs after LT between May 2014 and January 2019 were considered. The clinical and virological features were registered at the baseline and during the follow-up. The liver fibrosis was assessed by liver biopsy and/or transient elastography (TE) at the baseline and at least 1 year after the end of treatment (EoT). (3) Results: A total of 136 patients were included. The SVR12 was 78% after the first treatment and 96% after retreatment. After the SVR12, biochemical tests improved at the EoT and remained stable throughout the 3-year follow-up. Liver fibrosis improved after the SVR12 (p < 0.001); nearly half of the patients with advanced liver fibrosis experienced an improvement of an F ≤ 2. The factors associated with lower survival in SVR12 patients were the baseline platelet count (p = 0.04) and creatinine level (p = 0.04). (4) Conclusions: The long-term follow-up data demonstrated that SVR12 was associated with an improvement in hepatic function, liver fibrosis, and post-LT survival, regardless of the baseline liver fibrosis. The presence of portal hypertension before the DAAs has an impact on patient survival, even after SVR12.

The Role of Antiviral Prophylaxis in Preventing HBV and HDV Recurrence in the Setting of Liver Transplantation.

Hepatitis B virus (HBV) is a prevalent underlying disease, leading to liver transplantation (LT) for both decompensated cirrhosis and hepatocellular carcinoma (HCC). The hepatitis delta virus (HDV) affects approximately 5-10% of HBsAg carriers, accelerating the progression of liver injury and HCC. The initial introduction of HBV immunoglobulins (HBIG), and then of nucleos(t)ide analogues (NUCs), considerably improved the survival of HBV/HDV patients post-transplantation, as they helped prevent re-infection of the graft and recurrence of liver disease. Combination therapy with HBIG and NUCs is the primary post-transplant prophylaxis strategy in patients transplanted for HBV- and HDV-related liver disease. However, monotherapy with high-barrier NUCs, such as entecavir and tenofovir, is safe and also effective in some individuals who are at low risk of HBV reactivation. To address the problems of organ shortage, last-generation NUCs have facilitated the use of anti-HBc and HBsAg-positive grafts to meet the ever-increasing demand for grafts.

Liver transplantation for non-alcoholic fatty liver disease: indications and post-transplant management.

Non-alcoholic fatty liver disease (NAFLD) is currently the fastest growing indication to liver transplantation (LT) in Western Countries, both for end stage liver disease and hepatocellular carcinoma. NAFLD/non-alcoholic steatohepatitis (NASH) is often expression of a systemic metabolic syndrome; therefore, NAFLD/NASH patients require a multidisciplinary approach for a proper pre-surgical evaluation, which is important to achieve a post-transplant outcome comparable to that of other indications to LT. NAFLD/NASH patients are also at higher risk of post-transplant cardiovascular events, diabetes, dyslipidemia, obesity, renal impairment and recurrent NASH. Lifestyle modifications, included diet and physical activity, are key to improve survival and quality of life after transplantation. A tailored immunosuppressive regimen may be proposed in selected patients. Development of new drugs for the treatment of recurrent NASH is awaited.

Nash Up, Virus Down: How the Waiting List Is Changing for Liver Transplantation: A Single Center Experience from Italy.

Background and Objectives: Non-alcoholic steatohepatitis (NASH) has become the leading indication for liver transplantation in many countries, with a growing rate in the Western world. NASH patients are older and share a higher risk of comorbidities and cancer than patients with viral and/or alcoholic etiologies. The aims of this study were to evaluate waiting list (WL) registration and liver transplantation rates in patients with NASH-related cirrhosis at Padua University Hospital in the last fifteen years (1.2006-6.2020) and to compare clinical characteristics and indications for liver transplantation between patients with and without NASH, as well as the WL survival and post-transplant outcome. Materials and Methods: All adult patients with cirrhosis listed for liver transplantation at Padua University Hospital between 1.2006 and 6.2020 were retrospectively collected using a prospectively updated database; patients with NASH-related cirrhosis were divided by indication for liver transplantation (Dec-NASH vs. hepatocellular carcinoma (HCC)-NASH) and compared with patients with other etiologies of liver disease. The outcomes in terms of waiting list survival and post-transplant outcome were assessed. Results: One thousand four hundred and ninety-one adult cirrhotic patients were waitlisted during the study period. NASH patients accounted for 12% of all WL registrations, showing an increasing trend over time (from 2.5% in 2006 to 23% in 2020). In the last five years, NASH was the third, but most rapidly growing, indication for liver transplantation at our center. This trend was confirmed both for patients with decompensated cirrhosis (from 1.8% to 18%) and HCC as leading indication for transplantation (from 4% to 30%). NASH patients were older than non-NASH ones (mean ± SD age 59 ± 9 vs. 56 ± 9 years; p < 0.01), whereas no difference was found in gender or Child-Pugh of the model for end-stage liver disease score at WL registration. A majority (60.9%) of NASH patients underwent liver transplantation, showing 1-, 5- and 10-y post-transplant survivals of 86%, 73% and 60%, respectively. Conclusion: NASH cirrhosis has become a rapidly growing indication for liver transplantation at our center, both for HCC and decompensated disease, with good post-transplant survival.

An Essential Guide for Managing Post-Liver Transplant Patients: What Primary Care Physicians Should Know.

With long-term survival after liver transplantation becoming the rule, care for medical problems arising over time in liver-transplanted patients gained increasing importance. The most common causes of death occurring more than 1 year after liver transplantation are unrelated to liver diseases and facilitated by immunosuppressive treatments; examples are malignancies, renal failure, and cardiovascular, metabolic, and infectious diseases. Recipients receive life-long follow-up care at transplant centers, however, the increasing number of liver-transplanted patients is saturating the health care supply that transplant centers have to offer. Primary care physicians are increasingly exposed to liver-transplanted patients, even in the early periods after transplant, and an understanding of the most common risks and complications faced by these patients would enhance their care. This article reviews the long-term care of liver transplant recipients, emphasizing the key internal medicine-related issues that should be known by primary care physicians. A specific section is devoted to implementing strategies to involve these physicians in the long-term follow-up of liver-transplanted patients in close collaboration with transplant hepatologists.

New Indications for Liver Transplantation.

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.

Hepatocellular carcinoma and the risk of de novo malignancies after liver transplantation - a multicenter cohort study.

Patients with hepatocellular carcinoma (HCC) are at high risk of second primary malignancies. As HCC has become the leading indication of liver transplant (LT), the aim of this study was to investigate whether the presence of HCC before LT could influence the onset of de novo malignancies (DNM). A cohort study was conducted on 2653 LT recipients. Hazard ratios (HR) of DNM development for patients transplanted for HCC (HCC patients) were compared with those of patients without any previous malignancy (non-HCC patients). All models were adjusted for sex, age, calendar year at transplant, and liver disease etiology. Throughout 17 903 person-years, 6.6% of HCC patients and 7.4% of non-HCC patients developed DNM (202 cases). The median time from LT to first DNM diagnosis was shorter for solid tumors in HCC patients (2.7 vs 4.5 years for HCC and non-HCC patients, respectively, P < 0.01). HCC patients were at a higher risk of bladder cancer and skin melanoma. There were no differences in cumulative DNM-specific mortality by HCC status. This study suggests that primary HCC could be a risk factor for DNM in LT recipients, allowing for risk stratification and screening individualization.

Current and future perspective on targeted agents and immunotherapies in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) represents the sixth most commonly diagnosed cancer and the fourth leading cause of cancer-related death worldwide. HCC occurs predominantly in patients with underlying chronic liver disease and cirrhosis, and it presents a poor prognosis in advanced stage. Since its approval, for the following 10 years, sorafenib remained the only systemic agent with proven clinical efficacy for patients with advanced HCC. Recently, more drugs have been studied and several advances in first­line and second­line treatment options should yield significant improvements in survival. Lenvatinib, another tyrosine­kinase inhibitor, was found to be non-inferior to sorafenib in terms of overall survival (OS), with significantly better progression-free survival and objective response rate (ORR). The tyrosinekinase inhibitors, regorafenib and cabozantinib, were shown to significantly improve survival in the second­line setting after sorafenib failure. Ramucirumab, a VEGF inhibitor, can also improve survival in the second­line setting among patients with AFP≥400 ng/dL. Moreover, good efficacy was seen in phase I/II trials of immune checkpoint inhibitors as monotherapy. Ongoing trials are evaluating combination immune checkpoint inhibitor and tyrosine­kinase inhibitors or VEGF inhibitors for increasing overall survival in this patient population with advanced HCC.

Hepatocellular carcinoma risk in patients with HBV-related liver disease receiving antiviral therapy.

Hepatitis B virus (HBV) is a major health problem worldwide, with approximatively 240 million people living with a chronic HBV infection. HBV chronic infection remains the major cause of hepatocellular carcinoma worldwide, with more than half of HCC patients being chronic HBV carriers, even if underlying mechanisms of tumorigenesis are not totally understood. HBV-related HCC can be prevented by reducing the exposure to HBV by vaccination or by treatment of CHB infection. Current treatment of CHB are Peg-IFN alpha and oral NUCs. Treating HBV infection, either with IFN or NUCs, substantially reduces the risk of HCC development, even if antiviral therapy fails to completely eliminate HCC risk. Among treated patients, cirrhosis, HBeAg negative at baseline and failure to remain in virological remission were associated with an increased risk of HCC. The reduction of the risk of developing HCC during antiviral therapy is largely dependent upon the maintenance of virological remission, since viral load is found to be the most important factor leading to cirrhosis and its complications, including liver cancer development. The question whether Peg-IFN-alpha is superior to NUCs and whether there is a superior agent among NUCs is still controversial. Several studies demonstrated that antiviral therapy with NUCs could reduce the risk of HCC recurrence after curative treatment of HBV-related HCC.

Drug induced liver injury: from pathogenesis to liver transplantation.

Drug induced liver injury (DILI) is a necro-inflammatory liver disease caused by several drugs commonly used in clinical practice, herbs and dietary supplements prescribed for medical purposes. Despite its rarity, it represents the major cause of acute liver failure (ALF) requiring liver transplantation in USA and its frequency is increasing in Europe too. Two types of drug induced liver injury have been recognized: intrinsic and idiosyncratic. Predisposing factors may be classified in environmental, drugs- and individual- related risk factors, with the latter further distinguished in genetics and non-genetics. The liver injury can present with a hepatocellular, cholestatic or mixed pattern of disease. A definitive diagnosis of DILI is, nowadays, one of the main challenging issue in the management of these patients. Diagnosis often is based on suspicion derived from clinical history, biochemical exams and eventually on histological examination from liver biopsy. Score system may be helpful in these setting and new markers are gaining more prominence. Evaluation for liver transplantation is indicated when spontaneous resolution does not occur or in cases of ALF. Overall, the 1-year survival rate following liver transplantation is lower than that seen in patients who have been transplanted for chronic liver failure; however long-term survival is higher compared to other indications.

NAFLD and liver transplantation: Disease burden, current management and future challenges.

Non-alcoholic fatty liver disease (NAFLD), specifically its progressive form non-alcoholic steatohepatitis (NASH), represents the fastest growing indication for liver transplantation in Western countries. Diabetes mellitus, morbid obesity and cardiovascular disease are frequently present in patients with NAFLD who are candidates for liver transplantation. These factors require specific evaluation, including a detailed pre-surgical risk stratification, in order to improve outcomes after liver transplantation. Moreover, in the post-transplantation setting, the incidence of cardiovascular events and metabolic complications can be amplified by immunosuppressive therapy, which is a well-known driver of metabolic alterations. Indeed, patients with NASH are more prone to developing early post-transplant complications and, in the long-term, de novo malignancy and cardiovascular events, corresponding to higher mortality rates. Therefore, a tailored multidisciplinary approach is required for these patients, both before and after liver transplantation. Appropriate candidate selection, lifestyle modifications and specific assessment in the pre-transplant setting, as well as pharmacological strategies, adjustment of immunosuppression and a healthy lifestyle in the post-transplant setting, play a key role in correct management.

Impact of COVID-19 on liver transplantation in Europe: alert from an early survey of European Liver and Intestine Transplantation Association and European Liver Transplant Registry.

There are scarce data on the impact of COVID-19 pandemic on liver transplantation (LT) in Europe. The aim of this study was to obtain a preliminary data on incidence, management, and outcome of COVID-19 in liver transplant recipients and candidates in Europe. An Internet-based survey was sent to the centers affiliated with European Liver Transplant Registry (ELTR). One hundred nine out of 149 (73%) of ELTR centers located in 28 European countries (93%) responded. Ninety-four (86%) of the centers tested all donors, and 75 (69%) centers tested all LT recipients for SARS-CoV-2. Seventy-three (67%) centers selected recipients for LT in the COVID-19 pandemic, whereas 33% did not. Eighty-eight centers reported COVID-19 infection in 57 LT candidates and in 272 LT recipients. Overall crude incidence of COVID-19 among LT candidates and recipients was estimated 1.05% (range 0.5-20%) and 0.34% (range 0.1-4.8%), respectively, and it was significantly higher among candidates (P < 0.001). Crude rate of death was 18% (10/57) among candidates and 15% (36/244) among recipients. This first large-scale European snapshot study clearly shows that both LT candidates and recipients are at a high risk for COVID-19. These results plead for an early and pro-active screening of COVID-19 symptoms in these populations.

Current status of liver transplantation in Europe.

Liver transplantation (LT) in Europe became an established life-saving treatment for patients with end-stage liver disease, hepatocellular carcinoma, and acute liver conditions with life-threatening hepatic dysfunction. Although there are substantial disparities in donation and transplant rates among European countries, LT can be offered to almost every European citizen today. In order to maximize the LT benefit beyond national levels, many countries cooperate within transnational organizations including Eurotransplant, Scandiatransplant, and Southern Alliance for Transplantation. In the majority of European countries, liver allocation is based on the Model for End-Stage Liver Disease (MELD). Similar to North America, the ongoing extinction of hepatitis C and increase of non-alcoholic steatohepatitis are also a hallmark of change in LT indications in Europe. Apart from Turkey, the organ pool for LT in European countries is mainly based on organs from donors after brain death, although some countries retrieve a substantial proportion of organs from donors after circulatory death. According to the 2018 report of the European Liver Transplant Registry, 146,762 LT have been performed in Europe until 2016. In the most recent period, LT in Europe achieved respectable 1- and 5-year overall survival rates of 86% and 74%.

Alcohol associated liver disease 2020: A clinical practice guideline by the Italian Association for the Study of the Liver (AISF).

Alcohol use disorder which includes alcohol abuse and dependence represents one of the leading risk factors for premature mortality in Europe and it is responsible of over 200 conditions, including neuropsychiatric disorders, chronic diseases, cancers and accidents leading to permanent disability. Alcohol use disorder represents the most common cause of liver damage in the Western world, with a wide spectrum of diseases ranging from steatosis, steatohepatitis, fibrosis, cirrhosis and cancer. The present clinical practice guidelines by the Italian Association for the Study of the Liver (AISF) are focused on the current knowledge about epidemiology, pathophysiology, clinical features, diagnosis and treatment of alcohol associated liver disease, aiming to provide practical recommendations on the management of this complex pathological condition.

Invasive fungal infection before and after liver transplantation.

Invasive infections are a major complication before liver transplantation (LT) and in the early phase after surgery. There has been an increasing prevalence of invasive fungal disease (IFD), especially among the sickest patients with decompensated cirrhosis and acute-on-chronic liver failure, who suffer from a profound state of immune dysfunction and receive intensive care management. In such patients, who are listed for LT, development of an IFD often worsens hepatic and extra-hepatic organ dysfunction, requiring a careful evaluation before surgery. In the post-transplant setting, the burden of IFD has been reduced after the clinical advent of antifungal prophylaxis, even if several major issues still remain, such as duration, target population and drug type(s). Nevertheless, the development of IFD in the early phase after surgery significantly impairs graft and patient survival. This review outlines presentation, prophylactic and therapeutic strategies, and outcomes of IFD in LT candidates and recipients, providing specific considerations for clinical practice.

Management of Recurrent and De Novo NAFLD/NASH After Liver Transplantation.

Nonalcoholic steatohepatitis (NASH) is a growing indication for liver transplant whether the primary or secondary cause of liver disease, and it is expected to be the leading indication in the years to come. Nonalcoholic steatohepatitis recurs after transplant but the impact of the recurrence on allograft and patient outcomes is unclear. A group of multidisciplinary transplant practice providers convened at the International Liver Transplantation Society NASH consensus conference with the purpose of determining the current knowledge and future directions for understanding the recurrence rates, risk and management of NASH in the transplant allograft. Specific questions relating to posttransplant NASH were proposed and reviewed in detail with recommendations on future actions to fill the knowledge gaps.

Hepatitis C virus related cirrhosis decreased as indication to liver transplantation since the introduction of direct-acting antivirals: A single-center study.

AIM: To evaluate waiting list (WL) registration and liver transplantation (LT) rates in patients with hepatitis C virus (HCV)-related cirrhosis since the introduction of direct-acting antivirals (DAAs). METHODS: All adult patients with cirrhosis listed for LT at Padua University Hospital between 2006-2017 were retrospectively collected using a prospectively-updated database; patients with HCV-related cirrhosis were divided by indication for LT [dec-HCV vs HCV/ hepatocellular carcinoma (HCC)] and into two interval times (2006-2013 and 2014-2017) according to the introduction of DAAs. For each patient, indications to LT, severity of liver dysfunction and the outcome in the WL were assessed and compared between the two different time periods. For patients receiving DAA-based regimens, the achievement of viral eradication and the outcome were also evaluated. RESULTS: One thousand one hundred and ninty-four [male (M)/female (F): 925/269] patients were included. Considering the whole cohort, HCV-related cirrhosis was the main etiology at the time of WL registration (490/1194 patients, 41%). HCV-related cirrhosis significantly decreased as indication to WL registration after DAA introduction (from 43.3% in 2006-2013 to 37.2% in 2014-2017, P = 0.05), especially amongst dec-HCV (from 24.2% in 2006-2013 to 15.9% in 2014-2017, P = 0.007). Even HCV remained the most common indication to LT over time (289/666, 43.4%), there was a trend towards a decrease after DAAs introduction (from 46.3% in 2006-2013 to 39% in 2014-2017, P = 0.06). HCV patients (M/F: 43/11, mean age: 57.7 ± 8 years) who achieved viral eradication in the WL had better transplant-free survival (log-rank test P = 0.02) and delisting rate (P = 0.002) than untreated HCV patients. CONCLUSION: Introduction of DAAs significantly reduced WL registrations for HCV related cirrhosis, especially in the setting of decompensated cirrhosis.

Liver Transplantation for Alcoholic Liver Disease and Hepatocellular Carcinoma.

Hepatocellular carcinoma is one of the main important causes of cancer-related death and its mortality is increasingly worldwide. In Europe, alcohol abuse accounts for approximately half of all liver cancer cases and it will become the leading cause of hepatocellular carcinoma in the next future with the sharp decline of chronic viral hepatitis. The pathophysiology of alcohol-induced carcinogenesis involves acetaldehyde catabolism, oxidative stress and chronic liver inflammation. Genetic background plays also a significant role and specific patterns of gene mutations in alcohol-related hepatocellular carcinoma have been characterized. Survival is higher in patients who undergo specific surveillance programmes than in patients who do not. However, patients with alcohol cirrhosis present a significantly greater risk of liver decompensation than those with cirrhosis due to other aetiologies. Furthermore, the adherence to screening program can be suboptimal. Liver transplant for patients with Milan-in hepatocellular carcinoma represents the best possible treatment in case of tumour recurrence/progression despite loco-regional or surgical treatments. Long-term result after liver transplantation for alcohol related liver disease is good. However, cardiovascular disease and de novo malignancies can significantly hamper patients' survival and should be carefully considered by transplant team. In this review, we have focused on the evolution of alcohol-related hepatocellular carcinoma epidemiology and risk factors as well as on liver transplantation in alcoholic patients with and without hepatocellular carcinoma.