The Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology established the second consensus report to guide therapeutic drug monitoring (TDM) of everolimus (EVR) and its optimal use in clinical practice 7 years after the first version was published in 2016. This version provides information focused on new developments that have arisen in the last 7 years. For the general aspects of the pharmacology and TDM of EVR that have retained their relevance, readers can refer to the 2016 document. This edition includes new evidence from the literature, focusing on the topics updated during the last 7 years, including indirect pharmacological effects of EVR on the mammalian target of rapamycin complex 2 with the major mechanism of direct inhibition of the mammalian target of rapamycin complex 1. In addition, various concepts and technical options to monitor EVR concentrations, improve analytical performance, and increase the number of options available for immunochemical analytical methods have been included. Only limited new pharmacogenetic information regarding EVR has emerged; however, pharmacometrics and model-informed precision dosing have been constructed using physiological parameters as covariates, including pharmacogenetic information. In clinical settings, EVR is combined with a decreased dose of calcineurin inhibitors, such as tacrolimus and cyclosporine, instead of mycophenolic acid. The literature and recommendations for specific organ transplantations, such as that of the kidneys, liver, heart, and lungs, as well as for oncology and pediatrics have been updated. EVR TDM for pancreatic and islet transplantation has been added to this edition. The pharmacodynamic monitoring of EVR in organ transplantation has also been updated. These updates and additions, along with the previous version of this consensus document, will be helpful to clinicians and researchers treating patients receiving EVR.

The rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has led to an increased occurrence of steatotic liver grafts (SLG) in liver transplantation (LT). However, the implications of SLG on post-transplant de novo hepatic steatosis (PTHS) and advanced fibrosis (≥F3) remain uncertain. This study aimed to characterize PTHS and ≥ F3 using magnetic resonance imaging (MRI) in patients who underwent LT for non-MASLD indications and to examine their relationship with SLG.

Post-LT patients with implant biopsy fat content data were recruited for MRI assessments. MRI-proton density fat fraction (MRI-PDFF) and MR elastography (MRE) were performed using a 1.5 Tesla Optima 450 W MR scanner with a 3D volumetric sequence. PTHS and ≥ F3 were defined as MRI-PDFF ≥5% and MRE ≥3.64 kPa, respectively. SLG was defined as implant biopsy fat content ≥5%.

A total of 292 patients (70.5% men, median age at LT: 51.9 years, 22.6% with SLG) were recruited. The majority (73.6%) were transplanted for hepatitis B virus (HBV)-related complications. MRI performed at a median of 12.2 years post-LT identified PTHS in 27.4 and 10.6% of patients. PTHS was independently associated with SLG (OR 2.067, 95% CI 1.082-3.951), central obesity (OR 3.952, 95% CI 1.768-8.832), and hypertension (OR 2.510, 95% CI 1.268-4.966). In contrast, ≥F3 was associated with sex, change in BMI, and abnormal liver biochemistry but not with PTHS or SLG.

MRI identified a high prevalence of PTHS, which was associated with SLG and metabolic risk factors among Chinese patients transplanted for non-MASLD indications. Advanced graft fibrosis was not associated with PTHS or SLG.

Liver transplantation (LT) is an established life-saving procedure. The field of LT has changed in the past 10 years from several perspectives, with the expansion of indications, transplantation of patients with acute-on-chronic liver failure, evolution of transplant oncology, the use of donations after cardiac death, new surgical techniques, and prioritisation of recipients on the waiting list. In addition, the advent of organ perfusion machines, the recognition of new forms of rejection, and the attention paid to the transition from paediatric to adult patients, have all improved the management of LT recipients. The purpose of the EASL guidelines presented here is not to cover all aspects of LT but to focus on developments since the previous EASL guidelines published in 2016.

Orthotopic liver transplantation (OLT) has greatly improved short-term survival for end-stage liver disease. However, cardiovascular events (CVE) still pose a significant threat to long-term post-transplant health. Aim of this study is to assess the occurrence of long-term cardiovascular events and whether it relates to new-onset diabetes after liver transplantation (NODALT).

We conducted a multicentric retrospective analysis of adult OLT recipients with regular follow-up visits spanning from January 1995 to December 2020. Data collection included anamnestic, clinical, anthropometric, and laboratory data from two centers. NODALT was diagnosed following ADA guidelines. The primary outcome was incident CVE (a composite of fatal and non-fatal stroke and myocardial infarction). CVE occurrence was analyzed in relation to NODALT diagnosis, along with clinical characteristics associated with its development.

Ninety-three eligible Caucasian patients, with a median age of 57.0 years (IQR: 49.0-62.0, 69.9% male), were enrolled. Over the median follow-up period of 100.5 months, 29 patients (31.2%) developed NODALT, and 14 patients (15.1%) developed any CVE, with 9 being in the NODALT group. A significant association between NODALT and cardiovascular complications was confirmed by both generalized estimating equation (OR 5.31; 95% CI 1.59-17.72, p = 0.006) and Kaplan-Meier analysis (log-rank = 0.046). Metabolic syndrome and impaired fasting glucose were identified as baseline risk factors for the incident NODALT (OR 5.75; 95% CI 1.44-22.92, p = 0.013 and OR 7.29; 95% CI 1.46-36.41, p = 0.015, respectively).

Post-OLT cardiovascular events are less frequent than previously reported but are notably linked to NODALT, highlighting the interplay between metabolic syndrome and impaired fasting glucose.

Posttransplant diabetes mellitus (PTDM) is associated with significant morbidity and mortality in liver transplant recipients (LTRs). We used the Organ Procurement and Transplantation Network (OPTN) database to compare the incidence of developing PTDM across the United States and develop a risk prediction model for new-onset PTDM using OPTN region as well as donor-related, recipient-related, and transplant-related factors. All US adult, primary, deceased donor, LTRs between January 1, 2007, and December 31, 2016, with no prior history of diabetes noted, were identified. Kaplan-Meier estimators were used to calculate the cumulative incidence of PTDM, stratified by OPTN region. Multivariable Cox proportional hazards models were fitted to estimate hazards of PTDM in each OPTN region and build a risk prediction model, through backward selection. Cumulative incidence of PTDM at 1 year, 3 years, and 5 years after transplant was 12.0%, 16.1%, and 18.9%, respectively. Region 3, followed by regions 8, 2, and 9, had the highest adjusted hazards of developing PTDM. Inclusion of OPTN region in a risk prediction model for PTDM in LTRs (including recipient age, sex, race, education, insurance coverage, body mass index, primary liver disease, cold ischemia time, and donor history of diabetes) modestly improved performance (C-statistic = 0.60). In patients without pre-existing, confirmed diabetes mellitus, the incidence of PTDM in LTRs varied across OPTN regions, with the highest hazards in region 3, followed by regions 8, 2, and 9. The performance of a novel risk prediction model for PTDM in LTRs has improved performance with the inclusion of the OPTN region. Vigilance is recommended to centers in high-risk regions to identify PTDM and mitigate its development.

Calcineurin inhibitors (CNIs) are essential in liver transplantation (LT); however, their long-term use leads to various adverse effects. The anti-intercellular adhesion molecule (ICAM)-1 monoclonal antibody MD3 is a potential alternative to CNI. Despite its promising results with short-term therapy, overcoming the challenge of chronic rejection remains important. Thus, we aimed to investigate the outcomes of long-term MD3 therapy with monthly MD3 monomaintenance in nonhuman primate LT models. Rhesus macaques underwent major histocompatibility complex-mismatched allogeneic LT. The conventional immunosuppression group (Con-IS, n = 4) received steroid, tacrolimus, and sirolimus by 4 months posttransplantation. The induction MD3 group (IN-MD3, n = 5) received short-term MD3 therapy for 3 months with Con-IS. The maintenance MD3 group (MA-MD3, n = 4) received MD3 for 3 months, monthly doses by 2 years, and then quarterly. The MA-MD3 group exhibited stable liver function without overt infection and had significantly better liver allograft survival than the IN-MD3 group. Development of donor-specific antibody and chronic rejection were suppressed in the MA-MD3 group but not in the IN-MD3 group. Donor-specific T cell responses were attenuated in the MA-MD3 group. In conclusion, MD3 monomaintenance therapy without maintenance CNI provides long-term liver allograft survival by suppressing chronic rejection, offering a potential breakthrough for future human trials.

Cardiovascular disease (CVD) is a leading complication after liver transplantation and has a significant impact on patients' outcomes posttransplant. The major risk factors for post-liver transplant CVD are age, preexisting CVD, nonalcoholic fatty liver disease, chronic kidney disease, and metabolic syndrome. This review explores the contemporary strategies and approaches to minimizing cardiometabolic disease burden in liver transplant recipients. We highlight areas for potential intervention to reduce the mortality of patients with metabolic syndrome and CVD after liver transplantation.

Nonalcoholic fatty liver disease (NAFLD), also known as metabolic associated fatty liver disease (MAFLD), is a common liver condition characterized by excessive fat accumulation in the liver which is not caused by alcohol. The main causes of NAFLD are obesity and insulin resistance. Dachaihu decoction (DCHD), a classic formula in traditional Chinese medicine, has been proved to treat NAFLD by targeting different aspects of pathogenesis and is being progressively used in the treatment of NAFLD. DCHD is commonly applied in a modified form to treat the NAFLD. In light of this, it is imperative to conduct a systematic review and meta-analysis to assess the effectiveness and safety of DCHD in the management of NAFLD. There is a need for a systematic review and meta-analysis to assess the effectiveness and safety of modified DCHD in treating NAFLD.

The objective of this meta-analysis was to systematically assess the clinical effectiveness and safety of DCHD in treating NAFLD.

This meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Including seven databases, both Chinese and English databases were searched for relevant studies. The quality of included studies was carefully assessed using the bias risk assessment tool in the Cochrane Handbook. Eligible articles were the source of extracted data which was meta-analyzed by using Review Manager 5.4 and Stata 17.0.

A total of 10 studies containing 825 patients were included. Compared with conventional treatments, combined treatment could clearly improve the liver function of NAFLD patients, which could reduce the levels of ALT (MD = -7.69 U/L, 95% CI: -11.88 to -3.51, p < 0.001), AST (MD = -9.58 U/L, 95% CI: -12.84 to -6.33, p < 0.01), and it also had a certain impact on regulating lipid metabolism, which could reduce the levels of TC (MD = -0.85 mmol/L, 95% CI: -1.22 to 0.48, p < 0.01), TG (MD = -0.45 mmol/L, 95% CI: -0.64 to 0.21, p < 0.01). Adverse event showed that DCHD was relatively safe. Due to the inclusion of less than 10 trials in each group, it was not possible to conduct a thorough analysis of publication bias.

According to the meta-analysis, in the treatment of the NAFLD, it is clear that the combination of DCHD was advantages over conventional treatment alone in improving liver function, regulating lipid metabolism. Additionally, DCHD demonstrates a relatively safe profile. Nevertheless, due to limitations in the quality and quantity of the studies incorporated, the effectiveness and safety of DCHD remain inconclusive. Consequently, further high-quality research is imperative to furnish more substantial evidence supporting the widespread clinical application of DCHD.

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023397353, CRD42023397353.

The development of steatotic liver disease after liver transplant (LT) is widely described, and epidemiological data have revealed an increased incidence in recent times. Its evolution runs from simple steatosis to steatohepatitis and, in a small proportion of patients, to significant fibrosis and cirrhosis. Apparently, post-LT steatotic disease has no impact on the recipient's overall survival; however, a higher cardiovascular and malignancy burden has been reported. Many donors' and recipients' risk factors have been associated with this occurrence, although the recipient-related ones seem of greater impact. Particularly, pre- and post-LT metabolic alterations are strictly associated with steatotic graft disease, sharing common pathophysiologic mechanisms that converge on insulin resistance. Other relevant risk factors include genetic variants, sex, age, baseline liver diseases, and immunosuppressive drugs. Diagnostic evaluation relies on liver biopsy, although non-invasive methods are being increasingly used to detect and monitor both steatosis and fibrosis stages. Management requires a multifaceted approach focusing on lifestyle modifications, the optimization of immunosuppressive therapy, and the management of metabolic complications. This review aims to synthesize the current knowledge of post-LT steatotic liver disease, focusing on the recent definition of metabolic-dysfunction-associated steatotic liver disease (MASLD) and its metabolic and multisystemic concerns.

This review discusses long-term complications from immunosuppressants after liver transplantation and the management of these complications. Common complications of calcineurin inhibitors include nephrotoxicity and metabolic diseases. Nephrotoxicity can be managed by targeting a lower drug level and/or adding an immunosuppressant of a different class. Metabolic disorders can be managed by treating the underlying condition and targeting a lower drug level. Gastrointestinal adverse effects and myelosuppression are common complications of antimetabolites that are initially managed with dose reduction or discontinuation if adverse events persist. Mammalian targets of rapamycin inhibitors are associated with myelosuppression, proteinuria, impaired wound healing, and stomatitis, which may require dose reduction or discontinuation. Induction agents and agents used for steroid-refractory rejection or antibody-mediated rejection are reviewed. Other rare complications of immunosuppressants are discussed as well.

Poor metabolic health and obesity have significant impacts on the outcomes of patients suffering from chronic liver disease, particularly those with metabolic dysfunction-associated steatotic liver disease. Patients with such comorbidities who require liver transplant evaluation for advancing liver disease or liver failure require special consideration due to increased risk of cardiovascular disease, renal dysfunction, sarcopenic obesity, and cancer. Those who have had a history of prior bariatric surgery pose specific anatomical constraints and may also be at increased risk of alcohol use disorder. Pre-operative risk assessment as well as strict control of metabolic risk factors are essential to reduce intra-operative and post-liver transplant complications. As immunosuppressive therapy exacerbates metabolic dysfunction and risk for cancer, post-liver transplant care must focus on balancing the need to prevent rejection and the impact of progressive metabolic dysfunction in this unique, but growing, patient population.

Metabolic complications are a recognized health concern in liver transplant recipients that result in inferior patient-reported outcomes. Patients with MASH are known to be disproportionately affected by metabolic diseases compared to other indications for transplantation.

The aim of this study was to investigate the incidence of metabolic abnormalities in liver recipients with specific focus on differences between patients transplanted for MASH and non-MASH-causes.

An observational, monocentric, and retrospective analysis was performed. Patients who received a cadaveric-donor-liver transplant between 2010 and 2019 were eligible.

282 patients were enrolled with a median age of 52 years (66.7% males). Metabolic dysfunction-associated steatohepatitis (MASH) led to liver transplant in 8.2% of cases. De-novo metabolic syndrome was diagnosed in 36% of the study population. Patients that underwent transplant owing to MASH showed significantly higher incidence of metabolic complications in both pre- and post-transplant period. Considerable differences were noted in the pattern of weight gain between patients transplanted for MASH and non-MASH patients. The MASH etiology (OR: 5.5; 95% CI: 1.624-22.868; P = .010), higher BMI at 1-year post-transplant (OR: 1.321; 95% CI: 1.214-1.449; P = <.001), and older age at transplant (OR: 1.038; 95% CI: 1.006-1.074; P = .022) were independently associated with new-onset metabolic syndrome in liver recipients.

Metabolic complications were prevalent in liver recipients. Liver recipients with underlying MASH significantly surpassed patients transplanted for other indications in terms of metabolic complications incidence and demonstrated an unfavorable trajectory of weight gain post-transplant.

Whether the diagnosis of non-alcoholic fatty liver disease or metabolic dysfunction-associated fatty disease has a different impact on liver transplant recipients with hepatocellular carcinoma is not yet clear.

Data from a two-center retrospective cohort study were collected to compare and investigate the differences between non-alcoholic fatty liver disease and metabolic dysfunction-associated fatty liver disease in clinicopathologic parameters and prognosis among liver transplant recipients with hepatocellular carcinoma.

A total of 268 liver transplant recipients with hepatocellular carcinoma were included. The prevalence among pre- and post-transplant metabolic dysfunction-associated fatty liver disease was 10.82% and 30.22%, while for non-alcoholic fatty liver disease, it was 7.09% and 26.87%, respectively. The clinicopathological parameters were similar between the two pre-transplant groups. In contrast, the post-transplant group with metabolic dysfunction-associated fatty liver disease exhibited a higher prevalence of diabetes mellitus and a greater body mass index. However, the other parameters were similar between the two post-transplant groups (p > 0.05). Factors such as the largest tumor size > 4 cm, microvascular invasion, lack of tumor capsule, post-transplant metabolic dysfunction-associated fatty liver disease, and decreased post-transplant lymphocyte percentage were related to an increased risk of recurrence.

In patients undergone liver transplantation for hepatocellular carcinoma, the diagnosis of metabolic dysfunction-associated fatty disease is more strongly associated with metabolic abnormalities than the diagnosis of non-alcoholic fatty liver disease and is an independent predictor of hepatocellular carcinoma recurrence.

Liver transplantation is a highly complex and challenging field of clinical practice. Although it was originally developed in western countries, it has been further advanced in Asian countries through the use of living donor liver transplantation. This method of transplantation is the only available option in many countries in the Asia-Pacific region due to the lack of deceased organ donation. As a result of this clinical situation, there is a growing need for guidelines that are specific to the Asia-Pacific region. These guidelines provide comprehensive recommendations for evidence-based management throughout the entire process of liver transplantation, covering both deceased and living donor liver transplantation. In addition, the development of these guidelines has been a collaborative effort between medical professionals from various countries in the region. This has allowed for the inclusion of diverse perspectives and experiences, leading to a more comprehensive and effective set of guidelines.

Liver transplantation (LT) offers patients with decompensated cirrhosis the best chance at long-term survival. With the rising prevalence of diabetes, further clarity is needed on the impact of receiving a liver allograft from a donor with diabetes on post-LT outcomes. This study aims to evaluate the impact of donor diabetes on clinical outcomes after LT.

This is a retrospective analysis of the United Network for Organ Sharing registry data of LT recipients from January 1, 2000, to December 31, 2021. Outcomes analysis was performed using Cox proportional model for all-cause mortality and graft failure. Confounding was reduced by coarsened exact matching causal inference analysis.

Of 66 960 donors identified, 7178 (10.7%) had diabetes. Trend analysis revealed a longitudinal increase in the prevalence of donor diabetes ( P  < 0.001). Importantly, donor diabetes was associated with increased all-cause mortality (hazard ratio [HR]: 1.13; 95% confidence interval [CI], 1.07-1.19; P  < 0.001) and graft failure (HR: 1.16; 95% CI, 1.11-1.22; P  < 0.001). Receiving donor organ with diabetes reduced graft survival in patients who received LT for nonalcoholic steatohepatitis cirrhosis (HR: 1.26; 95% CI, 1.13-1.41; P  < 0.001) but not other etiologies of cirrhosis.

Donor diabetes was associated with worse outcomes post-LT, particularly in patients receiving LT for nonalcoholic steatohepatitis cirrhosis. Future studies are needed to better understand the mechanism underlying this association to develop better risk stratification and clinical practice to improve the outcomes of the transplanted patients.

Metabolic dysfunction-associated fatty liver disease was proposed by international consensus to redefine the metabolic abnormal condition. However, its impact on liver transplant recipients with hepatitis B virus-related hepatocellular carcinoma has not been explored.

A two-center retrospective cohort study on liver transplant recipients with hepatitis B virus-related hepatocellular carcinoma was performed to analyze the impact of metabolic dysfunction-associated fatty liver disease on the clinicopathologic parameters and prognosis.

There were 201 liver transplant recipients enrolled from two hospitals in our study. The pre- and post-transplant prevalences of metabolic dysfunction-associated fatty liver disease were 9.95% and 28.86%, respectively. The clinicopathological parameters revealed a similarity between patients with and without pre-transplant metabolic dysfunction-associated fatty liver disease. In contrast, the group with post-transplant metabolic dysfunction-associated fatty liver disease was linked with older age, a higher hepatitis recurrence rate and incidence of cardiovascular disease, usage of calcineurin inhibitors, a greater body mass index and waist circumference, lower albumin and high-density lipoprotein cholesterol levels, and poorer tumor-free survival and overall survival. The multivariate analysis showed the largest tumor size >4 cm (95% confidence intervals: 0.06~0.63, p = 0.006), microvascular invasion (95% confidence intervals: 1.61~14.92, p = 0.005), post-transplant metabolic dysfunction-associated fatty liver disease (95% confidence intervals: 1.40~10.60, p = 0.009), and calcineurin inhibitors-based regimen (95% confidence intervals: 0.33~0.96, p = 0.036) were the independent risk factors for recurrent hepatocellular carcinoma.

Our study suggests that post-transplant metabolic dysfunction-associated fatty liver disease is more closely to metabolic abnormalities and that it can help identify liver transplant recipients at high risk of recurrent hepatocellular carcinoma.

Improvement in immunosuppression has led to a remarkable improvement in short-term and long-term outcomes post-liver transplant (LT). However, with improvements in long-term survival, complications related to immunosuppressive drugs, either directly or indirectly, have also increased. The adverse events could be drug-specific, class-specific, or generic. Calcineurin inhibitors (cyclosporine and tacrolimus) are the backbone of the immunosuppression after LT and the main culprit associated with most of the complications, including renal failure, post-transplant diabetes mellitus (PTDM), and metabolic syndrome. Steroids are also implicated in the development of diabetes, osteoporosis, and metabolic syndrome post-LT. The development of infections and de novo malignancies (DNMs) is a generic effect linked to the overall cumulative immunosuppression. The development of these complications significantly hampers the quality of life and leads to increased morbidity and mortality post-LT. Thus, it is important to minimize the cumulative immunosuppression dose while simultaneously preventing allograft rejection. This review provides up-to-date, comprehensive knowledge of the complications of long-term immunosuppression post-LT along with associated risk factors and strategies to minimize the risk of complications.

Despite advances in posttransplant care, long-term outcomes for liver transplant recipients remain unchanged. Approximately 25% of recipients will advance to graft cirrhosis and require retransplantation. Graft fibrosis progresses in the context of de novo or recurrent disease. Recurrent hepatitis C virus infection was previously the most important cause of graft failure but is now curable in the majority of patients. However, with an increasing prevalence of obesity and diabetes and nonalcoholic fatty liver disease as the most rapidly increasing indication for liver transplantation, metabolic dysfunction-associated liver injury is anticipated to become an important cause of graft fibrosis alongside alloimmune hepatitis and alcoholic liver disease. To better understand the landscape of the graft fibrosis literature, we summarize the associated epidemiology, cause, potential mechanisms, diagnosis, and complications. We additionally highlight the need for better noninvasive methods to ameliorate the management of graft fibrosis. Some examples include leveraging the microbiome, genetic, and machine learning methods to address these limitations. Overall, graft fibrosis is routinely seen by transplant clinicians, but it requires a better understanding of its underlying biology and contributors that can help inform diagnostic and therapeutic practices.

The number of liver transplants (LT) performed worldwide continues to rise, and LT recipients are living longer post-transplant. This has led to an increasing number of LT recipients requiring lifelong care. Optimal care post-LT requires careful attention to both the allograft and systemic issues that are more common after organ transplantation. Common causes of allograft dysfunction include rejection, biliary complications, and primary disease recurrence. While immunosuppression prevents rejection and reduces incidences of some primary disease recurrence, it has detrimental systemic effects. Most commonly, these include increased incidences of metabolic syndrome, various malignancies, and infections. Therefore, it is of utmost importance to optimize immunosuppression regimens to prevent allograft dysfunction while also decreasing the risk of systemic complications. Institutional protocols to screen for systemic disease and heightened clinical suspicion also play an important role in providing optimal long-term post-LT care. In this review, we discuss these common complications of LT as well as unique considerations when caring for LT recipients in the years after transplant.

Liver transplantation (LT) is the treatment of choice for liver failure and selected cases of malignancies. Transplantation activity has increased over the years, and indications for LT have been widened, leading to organ shortage. To face this condition, a high selection of recipients with prioritizing systems and an enlargement of the donor pool were necessary. Several authors published their case series reporting the results obtained with the use of marginal donors, which seem to have progressively improved over the years. The introduction of in situ and ex situ machine perfusion, although still strongly debated, and better knowledge and treatment of the complications may have a role in achieving better results. With longer survival rates, a significant number of patients will suffer from long-term complications. An extensive review of the literature concerning short- and long-term outcomes is reported trying to highlight the most recent findings. The heterogeneity of the behaviors within the different centers is evident, leading to a difficult comparison of the results and making explicit the need to obtain more consent from experts.

Although non-alcoholic fatty liver disease (NAFLD) remains an uncommon indication for liver transplantation (LT) in the Chinese, the prevalence of NAFLD is increasing. We aimed to determine the prevalence of de novo steatosis and metabolic dysfunction-associated fatty liver disease (MAFLD) after LT.

Transient elastography assessment for liver stiffness and controlled attenuation parameter (CAP) were performed after LT in 549 patients at median time of 77 months from LT. CAP was compared with implant liver biopsy, and also validated in 42 patients with post-LT liver biopsy. Longitudinal history including diabetes mellitus (DM), dyslipidemia, hypertension, and immunosuppressive regimen were recorded.

The optimal cut-off level of CAP for diagnosing at least mild (≥ S1) and moderate-to-severe steatosis (≥ S2/3) was 266 and 293 dB/m respectively, with AUROC of 0.740 and 0.954 respectively. Using this newly derived cut-off, 28.9% patients have de novo NAFLD, of which 95.6% fulfilled the criteria for MAFLD. After multivariate analysis, BMI (HR 1.34), DM (HR 2.01), hypertension (HR 2.03), HDL-cholesterol (HR 0.25), LDL-cholesterol (HR 1.5) and cryptogenic cirrhosis (HR 4.85) were associated with the development of S2/3 graft steatosis. de novo NAFLD was associated with higher incidence of new-onset hypertension (p < 0.001), graft dysfunction (defined as ALT > 40 U/L; p = 0.008), but not associated with graft fibrosis (defined as liver stiffness > 12 kPa; p = 0.761).

Although NAFLD remains an uncommon primary liver disease indication for LT in Chinese patients, post-transplant de novo graft steatosis is common and the majority is classified as MAFLD. Development of graft steatosis is not associated with an increase in graft fibrosis but was associated with worse metabolic control and graft dysfunction. Routine CAP measurement to detect de novo graft steatosis should be considered after LT regardless of the primary indication of LT.

Post-transplant metabolic syndrome (PTMS) has been associated with increased cardiovascular risk which significantly impacts the morbidity and mortality rates of liver transplant (LT) recipients. This study sought to conduct a meta-analysis and systematic review on the cumulative incidence, risk factors, and cardiovascular outcomes associated with de novo PTMS.Medline and Embase were searched for articles describing the incidence, risk factors, and cardiovascular outcomes of de novo PTMS. Meta-analysis of proportions was conducted to calculate incidence. Conventional pairwise analysis using random effects model was used to tabulate OR and hazard ratio for risk factors and cardiovascular outcomes, respectively. Fifteen studies involving 2683 LT recipients were included. Overall rate of de novo PTMS was 24.7% (CI: 18.0%-32.9%) over a mean follow-up period of 15.3 months and was highest in patients with NAFLD (60.0%, CI: 52.0%-67.5%) compared with other liver diseases. Older age (OR: 1.05, CI: 1.01-1.09, p = 0.02) and pre-LT type II diabetes mellitus (OR: 5.00, CI: 4.17-5.99, p < 0.01) were predictive factors of de novo PTMS. Patients with de novo PTMS had significantly higher likelihood of cardiovascular disease events compared with those who did not (hazard ratio: 2.42, CI: 1.54-3.81, p < 0.01). De novo PTMS is a common complication and is significantly associated with increased cardiovascular disease morbidity. High-risk patients such as elderly recipients, those with pre-LT type II diabetes mellitus, or NASH-related cirrhosis should undergo routine screening to allow timely intervention.

Tacrolimus (TAC) is an immunosuppressive drug that is widely used for patients who underwent liver transplantation. In addition to inhibiting the action of calcineurin, TAC also exerts its immunosuppressive effects by interfering with mitogen activated protein kinase (MAPK) pathway. In this study, we investigated the impact of both recipient and donor genetic polymorphisms of MAPK kinase kinase (MAP3K) genes on clinical events in Han Chinese liver transplantation recipients taking TAC. Fifty-seven tag SNPs of 11 genes (MEKK1, MEKK2, MEKK4, MLK1, MLK3, ASK1, TAO1, TAO2, Tpl2, TAK1 and ZAK1) in the MAPK pathway were detected by MALDI-TOF MS assay in 175 TAC-treated liver transplant recipients. The associations of SNPs with incidence of acute rejection, TAC-induced acute nephrotoxicity, and post-transplantation liver and kidney function were explored using Kaplan-Meier survival analysis, Cox-proportional hazard model and linear mixed model, respectively. For the sites significantly associated with clinical events, the dual-luciferase reporter gene system was used to perform preliminary function verification. The results showed that (1) Donor-recipient combinational (D-R) MEKK1 rs62355944 and D-R MLK1 rs8006424 genotypes were significant influence factors of post-transplantation γ-glutamyl transpeptidase (GGT) level (P < 0.0001); (2) D-R MLK1 rs8006424 genotypes were found to significantly affect the alkaline phosphatase (ALP) level after transplantation (P < 0.0001). The results of the dual luciferase reporter gene system demonstrated that the luciferase activity of the pGL3-rs8006424A was significantly higher than that of pGL3-rs8006424G (3.47 ± 0.10 vs 2.97 ± 0.08, P = 0.002). Therefore, MEKK1 rs62355944 and MLK1 rs8006424 might serve as biomarkers to predict post-transplant liver function in liver transplant patients.

Nonalcoholic steatohepatitis (NASH) is the leading indication for liver transplant (LT) in women and the elderly. Granular details into factors impacting survival in this population are needed to optimize management and improve outcomes.

Patients receiving LT for NASH cirrhosis from 1997 to 2017 across 7 transplant centers (NailNASH consortium) were analyzed. The primary outcome was all-cause mortality, and causes of death were enumerated. All outcomes were cross referenced with United Network for Organ Sharing and adjudicated at each individual center. Cox regression models were constructed to elucidate clinical factors impacting mortality.

Nine hundred thirty-eight patients with a median follow-up of 3.8 years (interquartile range, 1.60-7.05 years) were included. The 1-, 3-, 5-, 10-, and 15-year survival of the cohort was 93%, 88%, 83%, 69%, and 46%, respectively. Of 195 deaths in the cohort, the most common causes were infection (19%), cardiovascular disease (18%), cancer (17%), and liver-related (11%). Inferior survival was noted in patients >65 years. On multivariable analysis, age >65 (hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.04-2.77; P = .04), end-stage renal disease (HR, 1.55; 95% CI, 1.04-2.31; P = .03), black race (HR, 5.25; 95% CI, 2.12-12.96; P = .0003), and non-calcineurin inhibitors-based regimens (HR, 2.05; 95% CI, 1.19-3.51; P = .009) were associated with increased mortality. Statin use after LT favorably impacted survival (HR, 0.38; 95% CI, 0.19-0.75; P = .005).

Despite excellent long-term survival, patients transplanted for NASH at >65 years or with type 2 diabetes mellitus at transplant had higher mortality. Statin use after transplant attenuated risk and was associated with improved survival across all subgroups, suggesting that careful patient selection and implementation of protocol-based management of metabolic comorbidities may further improve clinical outcomes.

The use of immunosuppressive medications for solid organ transplantation is associated with cardiovascular, metabolic, and oncologic complications. On the other hand, the development of graft rejection is associated with increased mortality and graft dysfunction. Liver transplant recipients can withdraw from immunosuppression without developing graft injury while preserving an adequate antimicrobial response - a characteristic known as immunotolerance. Immunotolerance can be spontaneously or pharmacologically achieved. Contrary to the classic dogma, clinical studies have elucidated low rates of true spontaneous immunotolerance (no serologic or histological markers of immune injury) among liver transplant recipients. However, clinical, serologic, and tissue biomarkers can aid in selecting patients in whom immunosuppression can be safely withdrawn. For those who failed an immunosuppression withdrawal trial or are at high risk of rejection, pharmacological interventions for immunotolerance induction are under development. In this review, we provide an overview of the mechanisms of immunotolerance, the clinical studies investigating predictors and biomarkers of spontaneous immunotolerance, as well as the potential pharmacological interventions for inducing it.

The heterogenous category "specific types of diabetes due to other causes" encompasses disturbances in glucose metabolism due to other endocrine disorders such as acromegaly or hypercortisolism, drug-induced diabetes (e.g. antipsychotic medications, glucocorticoids, immunosuppressive agents, highly active antiretroviral therapy (HAART), checkpoint inhibitors), genetic forms of diabetes (e.g. Maturity Onset Diabetes of the Young (MODY), neonatal diabetes, Down‑, Klinefelter- and Turner Syndrome), pancreatogenic diabetes (e.g. postoperatively, pancreatitis, pancreatic cancer, haemochromatosis, cystic fibrosis), and some rare autoimmune or infectious forms of diabetes. Diagnosis of specific diabetes types might influence therapeutic considerations. Exocrine pancreatic insufficiency is not only found in patients with pancreatogenic diabetes but is also frequently seen in type 1 and long-standing type 2 diabetes.

Transjugular intrahepatic portosystemic shunt (TIPS) relieves hepatic venous obstruction in Budd-Chiari syndrome (BCS), but the effect on liver function is unclear, particularly outside the immediate post-treatment period. This study aims to evaluate the long-term impact of TIPS on liver function and outcomes in BCS patients.

Twenty patients with BCS who underwent TIPS from 1999 to 2018 were included. Demographic data and clinical data at the time of TIPS procedure, 6 months, 12 months, 2 years, 5 years, and 10 years post-TIPS were collected.

There were 13 (13/20, 65%) women and 7 (7/20, 35%) men with a mean age at the time of TIPS of 42.6 ± 12.8 years. The median time from BCS diagnosis to TIPS was 41 (IQR: 4-165) days. The number of patients with severe ascites decreased significantly from 10/17 (58.8%) at the time of TIPS, to 1/16 (7.7%), 1/13 (7.7%), 2/16 (12.5%), 1/14 (7.1%), and 0/8 (0%) at 6 months, 12 months, 2 years, 5 years and 10 years post-TIPS, respectively. 4/20 (20%) patients developed new hepatic encephalopathy post-TIPS procedure. Child-Pugh score significantly decreased from a score of 9.4 ± 1.8 pre-TIPS to 7.6 ± 1.8 at 6 months, 7.4 ± 1.5 at 12 months, 7.3 ± 1.6 at 2 years, 6.8 ± 1.5 at 5 years, and 6.4 ± 0.7 at 10 years post-TIPS. Fifteen (15/20, 75%) patients required TIPS revision including 4 (4/15, 26.7%) within 30 days, 2 (2/15, 13.3% within 1 month to 1 year, and 9 (9/15, 60%) at more than 1 year. Eight (8/20, 40%) patients underwent liver transplantation (LT) at median time of 7.3 (IQR 3.2-12.9) years after TIPS.

TIPS placement for BCS results in sustained resolution of symptoms and improved liver function. Despite the frequent need for revisions, the long-term durability of TIPS can forgo the need for LT in the majority of patients.

The rising tide of non-alcoholic fatty liver disease (NAFLD) associated with the obesity epidemic is a major health concern worldwide. NAFLD - specifically its more advanced form, non-alcoholic steatohepatitis (NASH)-related cirrhosis - is now the fastest growing indication for liver transplantation in the USA and Europe. Although the short-term and mid-term overall survival rates of patients who receive a liver transplant for NASH-related cirrhosis are essentially similar to those of patients who receive a transplant for other liver indications, recipients with NASH-related cirrhosis have an increased risk of waiting-list mortality and of developing recurrent liver disease and cardiometabolic complications in the longer term after liver transplantation. This Review provides a brief overview of the epidemiology of NAFLD and NASH and the occurrence of NAFLD or NASH in patients after liver transplantation for NASH and other liver indications. It also discusses the putative metabolic mechanisms underlying the emergence of NAFLD or NASH after liver transplantation as well as optimal therapeutic approaches for recipients of liver transplants, including the management of cardiometabolic comorbidities, tailored immunosuppression, lifestyle changes and pharmacotherapy for NAFLD.

Liver transplantation (LT) is the definitive treatment for end-stage liver disease. Unfortunately, women are disadvantaged at every stage of the LT process. We conducted a literature review to increase the understanding of this disparity. Hormonal differences, psychological factors, and Model for End-Stage Liver Disease (MELD) score inequalities are some pretransplantation factors that contribute to this disparity. In the posttransplantation setting, women have differing risk than men in most major outcomes (perioperative complications, rejection, long-term renal dysfunction, and malignancy) and assessing the two groups together is disadvantageous. Herein, we propose interventions including standardized criteria for LT referral, using an alternate MELD, education for support of women, and motivating women to seek living donors. Understanding sex-based differences will allow us to improve access, tailor management, and improve overall outcomes for all patients, particularly women.

Post-transplant diabetes mellitus (PTDM) is a significant contributor to morbidity and mortality in liver transplant recipients (LTRs). With concurrent comorbidities and use of various immunosuppression medications, identifying a safe and personalized regimen for management of PTDM is needed. There are many comorbidities associated with the post-transplant course including chronic kidney disease, cardiovascular disease, allograft steatosis, obesity, and de novo malignancy. Emerging data suggest that available diabetes medications may carry beneficial or, in some cases, harmful effects in the setting of these co-existing conditions. Sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide 1 receptor agonists have shown the most promising beneficial results. Although there is a deficiency of LTR-specific data, they appear to be generally safe. Effects of other medications are varied. Metformin may reduce the risk of malignancy. Pioglitazone may be harmful in patients combatting obesity or heart failure. Insulin may exacerbate obesity and increase the risk of developing malignancy. This review thoroughly discusses the roles of these extra-glycemic effects and safety considerations in LTRs. Through weighing the risks and benefits, we conclude that alternatives to insulin should be strongly considered, when feasible, for personalized long-term management based on risk factors and co-morbidities.

Hyperlipidemia is a common complication after liver transplantation (LT) and develops mostly in the early posttransplant period. Recently, some studies have reported a positive correlation between hyperlipidemia and favorable prognosis in patients with hepatocellular carcinoma (HCC) undergoing hepatectomy. This study aimed to evaluate the possibility of predicting prognosis in HCC patients receiving LT by early posttransplant dyslipidemia.

From January 2015 to December 2017, a total of 806 HCC patients from China Liver Transplant Registry database were retrospectively enrolled. The prognostic relevance of early posttransplant hypertriglyceridemia or hypercholesterolemia was examined using survival analysis, and subgroup analysis was implemented based on LT criteria.

Early posttransplant hypercholesterolemia (EPHC) was independently inversely associated with the risk of recurrence [hazard ratio (HR) = 0.630; P = 0.022], but was not significantly correlated with the mortality. However, early posttransplant hypertriglyceridemia was not related to prognosis. Intriguingly, with further classification, we found that borderline EPHC (B-EPHC), instead of significant EPHC, was a predictor of lower risk for both recurrence (HR = 0.504; P = 0.006) and mortality (HR = 0.511; P = 0.023). Compared with non-EPHC patients, B-EPHC patients achieved significantly superior 1-year and 3-year tumor-free survival (89.6% and 83.7% vs. 83.8% and 72.7% respectively; P = 0.023), and 1-year and 3-year overall survival (95.8% and 84.8% vs. 94.6% and 77.6% respectively; P = 0.039). In the subgroup analysis, B-EPHC remained an independent predictor of better prognosis in patients beyond Milan criteria and those within Hangzhou criteria; whereas there was no significant relationship between B-EPHC and prognosis in patients within Milan criteria and those beyond Hangzhou criteria. More interestingly, patients beyond Milan criteria but within Hangzhou criteria were identified as the crucial subpopulation who benefited from B-EPHC (recurrence HR = 0.306, P = 0.011; mortality HR = 0.325, P = 0.031).

B-EPHC could assist transplant teams in dynamically evaluating prognosis after LT for HCC as a postoperative non-oncological biomarker, especially in patients beyond Milan criteria but within Hangzhou criteria.

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.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and has an estimated global prevalence of 25%. NAFLD is found in up to 80% of people with obesity and over 60% of patients with diabetes. Cardiovascular disease is the main cause of mortality, followed by extra-hepatic cancers and then liver-specific complications of cirrhosis and hepatocellular carcinoma. Lifestyle modification remains the primary intervention in NAFLD. Weight loss achieved through dietary modification and exercise can lead to histologic improvement and reversal of metabolic complications. Current drug therapy is limited to pioglitazone and vitamin E; however, several agents are currently under phase III development. This review summarises the current treatment options in NAFLD.

Immunosuppression handling plays a key role in the early and long-term results of transplantation. The development of multiple immunosuppressive drugs led to numerous clincial trials searching to reach the ideal regimen. Due to heterogeneity of the studied patient cohorts and flaws in many, even randomized controlled, study designs, the answer still stands out. Nowadays triple-drug immunosuppression containing a calcineurin inhibitor (preferentially tacrolimus), an antimetabolite (using mycophenolate moffettil or Azathioprine) and short-term steroids with or without induction therapy (using anti-IL2 receptor blocker or anti-lymphocytic serum) is the preferred option in both liver and intestinal transplantation. This chapter aims, based on a critical review of the definitions of rejection, corticoresistant rejection and standard immunosuppression to give some reflections on how to reach an optimal immunosuppressive status and to conduct trials allowing to draw solid conclusions. Endpoints of future trials should not anymore focus on biopsy proven, acute and chronic, rejection but also on graft and patient survival. Correlation between early- and long-term biologic, immunologic and histopathologic findings will be fundamental to reach in much more patients the status of operational tolerance.

Liver transplantation (LT) recipients have experienced a significant improvement in short-term survival during the past 3 decades attributed to advancements in surgical techniques, perioperative management, and effective immunosuppressive regimens. However, long-term survival is affected by a high incidence of metabolic disorders and their consequences, including cardiovascular disease (CVD) and malignancies. Pretransplant metabolic impairments especially in those with nonalcoholic steatohepatitis cirrhosis are aggravated by the addition of posttransplant weight gain, physical inactivity, and reversal from catabolic to anabolic state. Moreover, although immunosuppressants are vital to avoid graft rejection, long-term exposure to these medications is implicated in metabolic impairments after LT. In this review, we summarize the molecular pathogenesis of different metabolic disorders after LT, including diabetes mellitus, dyslipidemia, and nonalcoholic fatty liver disease. Furthermore, CVD, malignancies, and graft rejections were provided as significant complications of post-LT metabolic conditions threatening both the patient and graft survival. Ultimately, emerging preventive and treatment strategies for posttransplant diabetes mellitus are summarized. This review highlights the significant need for more clinical trials of antihyperglycemic agents in LT recipients. Also, translational studies will help us to better understand the molecular and genetic factors underlying these metabolic complications and could lead to more personalized management in this high-risk population.