Management of the high cardiac risk liver transplant candidate: multidisciplinary best practices and recommendations.

In a setting characterized by a growing prevalence of patients with alcohol- and metabolic dysfunction-associated steatotic liver diseases, coupled with an aging patient demographic, the incidence of cardiac comorbidities in liver transplant candidates is on the rise. These comorbidities not only pose barriers to transplant eligibility but also impact the intraoperative course and affect post-transplant outcomes. As such, there is a significant need to optimize the clinical management of these cardiac comorbidities. However, there is a scarcity of evidence regarding the best practices for managing cardiac comorbidities such as coronary and valvular heart diseases, arrhythmia and cardiomyopathy in this population, both before and during transplant surgery. These conditions necessitate a coordinated and multidisciplinary approach to care. In this manuscript, we conduct a comprehensive review of the most recent evidence pertaining to the pre- and intra-operative management of these cardiac comorbidities in liver transplant candidates. Our aim is to provide recommendations that improve and standardize their clinical care.

The role of HBIG in real life for patients undergoing liver transplantation due to HDV-related cirrhosis.

Recommended post-liver transplant (LT) prophylaxis in patients with hepatitis delta includes a nucleos(t)ide analogue (NA) and anti-hepatitis B immunoglobulin (HBIG) indefinitely. We analysed the use of HBIG in real-life clinical practice and its impact on HBV/HDV recurrence in 174 HDV-related LT patients from 10 Spanish liver transplant centres (1988-2018). Median post-LT follow-up was 7.8 (2.3-15.1) years and patient survival at 5 years was 90%. Most patients (97%) received HBIG in the immediate post-LT, but only 42% were on HBIG at the last control. Among those discontinuing HBIG, the median time on treatment was 18 (7-52) months. Post-LT HBsAg+ was detected in 16 (9%) patients and HBV-DNA in 12 (7%). Despite HBsAg positivity, HDV recurrence was reported only in three patients (1.7%), all of whom were not receiving NA and had discontinued HBIG. Our data suggest that a finite HBIG prophylaxis in HDV-LT is feasible, especially if high-barrier NAs are used.

CACS, CCTA and mCAD-LT score in the pre-transplant assessment of coronary artery disease and the prediction of post-transplant cardiovascular events.

BACKGROUND: The optimal cardiovascular assessment of liver transplant (LT) candidates is unclear. We aimed to evaluate the performance of CT-based coronary tests (coronary artery calcium score [CACS] and coronary CT angiography [CCTA]) and a modification of the CAD-LT score (mCAD-LT, excluding family history of CAD) to diagnose significant coronary artery disease (CAD) before LT and predict the incidence of post-LT cardiovascular events (CVE). METHODS: We retrospectively analysed a single-centre cohort of LT candidates who underwent non-invasive tests; invasive coronary angiography (ICA) was performed depending on the results of non-invasive tests. mCAD-LT was calculated in all patients. RESULTS: Six-hundred-and-thirty-four LT candidates were assessed and 351 of them underwent LT. CACS, CCTA and ICA were performed in 245, 123 and 120 LT candidates, respectively. Significant CAD was found in 30% of patients undergoing ICA. The AUROCs of mCAD-LT (.722) and CCTA (.654) were significantly higher than that of CACS (.502) to predict the presence of significant CAD. Specificity of the tests ranged between 31% for CCTA and 53% for CACS. Among patients who underwent LT, CACS ≥ 400 and mCAD-LT were independently associated with the incidence of CVE; in patients who underwent CCTA before LT, significant CAD at CCTA also predicted post-LT CVE. CONCLUSION: In this cohort, mCAD-LT score and CT-based tests detect the presence of significant CAD in LT candidates, although they tend to overestimate it. Both mCAD-LT score and CT-based tests classify LT recipients according to their risk of post-LT CVE and can be used to improve post-LT risk mitigation.

Evolution of pretransplant cardiac risk factor burden and major adverse cardiovascular events in liver transplant recipients over time.

Major adverse cardiovascular events (MACEs) are the leading cause of early (<1 y) complications after liver transplantation (LT). NASH, the leading indication for waitlisting for LT, is associated with high cardiac risk factor burden. The contemporary prevalence and temporal trends in pretransplant cardiac risk factor burden and post-LT MACE among LT recipients (LTRs) with and without NASH are unknown. The aim of this study was to evaluate (1) the evolution of post-LT cardiac risk factors in LTRs over time and (2) post-LT MACE over time, stratified by NASH status. This is a retrospective cohort of 1775 adult LTRs at a single transplant center (2003-2020). MACE was defined as death or hospitalization from myocardial infarction, revascularization, stroke, heart failure during the first post-LT year. Between 2003 and 2020, there was a significant increase in pre-LT NASH ( ptrend <0.05). There was also a significant increase in pre-LT obesity, atherosclerotic cardiovascular (CV) disease, and older age (≥65 y old) ( ptrend <0.05 for all). There was no significant change in the proportion of LTRs with diabetes, chronic kidney disease, or heart failure. Unexpectedly, there were no changes in the rate of post-LT MACE over the study period (-0.1% per year, ptrend =0.44). The lack of change in MACE despite an increase in CV risk factor prevalence may reflect advancement in the identification and management of CV risk factors in LTRs. With projected continued increase in cardiac risk burden and the proportion of patients transplanted for NASH, it is critical for LT programs to develop and implement quality improvement efforts to optimize CV care in LTRs.

Factors associated with mechanical ventilation longer than 24 h after liver transplantation in patients at risk for bleeding.

BACKGROUND: This risk analysis aimed to explore all modifiable factors associated with prolonged mechanical ventilation (lasting > 24 h) after liver transplantation, based on prospectively collected data from a clinical trial. METHODS: We evaluated 306 candidates. Ninety-three patients were excluded for low risk for transfusion (preoperative haemoglobin > 130 g.l-1), and 31 patients were excluded for anticoagulation therapy, bleeding disorders, familial polyneuropathy, or emergency status. Risk factors were initially identified with a log-binomial regression model. Relative risk was then calculated and adjusted for age, sex, and disease severity (Model for End-Stage Liver Disease [MELD] score). RESULTS: Early tracheal extubation was performed in 149 patients (84.7%), and 27 patients (15.3%) required prolonged mechanical ventilation. Reoperations were required for 6.04% of the early extubated patients and 44% of patients who underwent prolonged ventilation (p = 0.001). A MELD score > 23 was the main risk factor for prolonged ventilation. Once modifiable risk factors were adjusted for MELD score, sex, and age, three factors were significantly associated with prolonged ventilation: tranexamic acid (p = 0.007) and red blood cell (p = 0.001) infusion and the occurrence of postreperfusion syndrome (p = 0.004). The median (IQR) ICU stay was 3 (2-4) days in the early extubation group vs. 5 (3-10) days in the prolonged ventilation group (p = 0.001). The median hospital stay was also significantly shorter after early extubation, at 14 (10-24) days, vs. 25 (14-55) days in the prolonged ventilation group (p = 0.001). Eight patients in the early-extubation group (5.52%) were readmitted to the ICU, nearly all for reoperations, with no between-group differences in ICU readmissions (prolonged ventilation group, 3.7%). CONCLUSION: We conclude that bleeding and postreperfusion syndrome are the main modifiable factors associated with prolonged mechanical ventilation and length of ICU stay, suggesting that trials should explore vasopressor support strategies and other interventions prior to graft reperfusion that might prevent potential fibrinolysis. TRIAL REGISTRATION: European Clinical Trials Database (EudraCT 2018-002510-13,) and on ClinicalTrials.gov (NCT01539057).

Urinary L-FABP is a promising prognostic biomarker of ACLF and mortality in patients with decompensated cirrhosis.

BACKGROUND & AIMS: Decompensated cirrhosis (DC) is associated with high mortality, mainly owing to the development of acute-on-chronic liver failure (ACLF). Identifying the patients with DC who are at high risk of mortality and ACLF development is an unmet clinical need. Liver fatty acid-binding protein (L-FABP) is expressed in several organs and correlates with liver and systemic inflammation. Herein, we aimed to assess the prognostic value of L-FABP in patients with DC. METHODS: A prospective series of 444 patients hospitalized for DC was divided into 2 cohorts: study cohort (305 patients) and validation cohort (139 patients). L-FABP was measured in urine and plasma samples collected at admission. Neutrophil gelatinase-associated lipocalin (NGAL) was also measured in urine samples for comparison. RESULTS: Urine but not plasma L-FABP correlated with 3-month survival on univariate analysis. On multivariate analysis, urine L-FABP and model for end-stage liver disease (MELD)-Na were the only independent predictors of prognosis. Urine L-FABP levels were higher in patients with ACLF than in those without and also predicted the development of ACLF, together with MELD-Na, during follow-up. In patients with ACLF, urine L-FABP correlated with liver, coagulation, and circulatory failure. Urine L-FABP levels were also increased in patients with acute kidney injury, particularly in those with acute tubular necrosis. The ability of urinary L-FABP to predict survival and ACLF development was confirmed in the validation cohort. Urine NGAL predicted outcome on univariate but not multivariate analysis. CONCLUSIONS: Urinary L-FABP levels are independently associated with the 3-month clinical course in patients with DC, in terms of mortality and ACLF development. Urinary L-FABP is a promising prognostic biomarker for patients with DC. LAY SUMMARY: Increased levels of liver fatty acid-binding protein (L-FABP), a protein related to lipid metabolism, have been associated with liver-related diseases. The present study analyzed urinary L-FABP levels in 2 independent groups of patients with decompensated cirrhosis and showed that higher urinary L-FABP levels correlated with increased mortality and risk of acute-on-chronic liver failure development. Therefore, urinary L-FABP levels could be useful as a new tool to predict complications in patients with decompensated cirrhosis.

Non-invasive tests for clinically significant portal hypertension after HCV cure.

BACKGROUND & AIMS: Non-invasive tests (NITs) for clinically significant portal hypertension (CSPH; hepatic venous pressure gradient [HVPG] ≥10 mmHg) have predominantly been studied in patients with active HCV infection. Investigations after HCV cure are limited and have yielded conflicting results. We conducted a pooled analysis to determine the diagnostic/prognostic utility of liver stiffness measurement (LSM)/platelet count (PLT) in this setting. METHODS: A total of 418 patients with pre-treatment HVPG ≥6 mmHg who achieved sustained virological response (SVR) and underwent post-treatment HVPG measurement were assessed, of whom 324 (HVPG/NIT-cohort) also had paired data on pre-/post-treatment LSM/PLT. The derived LSM/PLT criteria were then validated against the direct endpoint decompensation in 755 patients with compensated advanced chronic liver disease (cACLD) with SVR (cACLD-validation-cohort). RESULTS: HVPG/NIT-cohort: Among patients with cACLD, the pre-/post-treatment prevalence of CSPH was 80%/54%. The correlation between LSM/HVPG increased from pre- to post-treatment (r = 0.45 vs. 0.60), while that of PLT/HVPG remained unchanged. For given LSM/PLT values, HVPG tended to be lower post- vs. pre-treatment, indicating the need for dedicated algorithms. Combining post-treatment LSM/PLT yielded a high diagnostic accuracy for post-treatment CSPH in cACLD (AUC 0.884; 95% CI 0.843-0.926). Post-treatment LSM <12 kPa & PLT >150 G/L excluded CSPH (sensitivity: 99.2%), while LSM ≥25 kPa was highly specific for CSPH (93.6%). cACLD-validation-cohort: the 3-year decompensation risk was 0% in the 42.5% of patients who met the LSM <12 kPa & PLT >150 G/L criteria. In patients with post-treatment LSM ≥25 kPa (prevalence: 16.8%), the 3-year decompensation risk was 9.6%, while it was 1.3% in those meeting none of the above criteria (prevalence: 40.7%). CONCLUSIONS: NITs can estimate the probability of CSPH after HCV cure and predict clinical outcomes. Patients with cACLD but LSM <12 kPa & PLT>150 G/L may be discharged from portal hypertension surveillance if no co-factors are present, while patients with LSM ≥25 kPa require surveillance/treatment. LAY SUMMARY: Measurement of liver stiffness by a specific ultrasound device and platelet count (a simple blood test) are broadly used for the non-invasive diagnosis of increased blood pressure in the veins leading to the liver, which drives the development of complications in patients with advanced liver disease. The results of our pooled analysis refute previous concerns that these tests are less accurate after the cure of hepatitis C virus (HCV) infection. We have developed diagnostic criteria that facilitate personalized management after HCV cure and allow for a de-escalation of care in a high proportion of patients, thereby decreasing disease burden.

Results of a multidisciplinary strategy to improve the management of cardiovascular risk factors after liver transplantation.

Although liver transplantation (LT) recipients are at high cardiovascular risk (CVR), the management of CVR factors (CVRF) after LT is far from optimal and needs to be improved. For this reason, we developed a multidisciplinary protocol to standardize the identification, risk stratification, management, and targets of therapy of CVRF during the first post-LT year. The grade of identification and control of CVRF 12 months after LT in the postintervention cohort (LT January 2018-January 2020, n = 150) were compared with a control cohort who underwent LT between July 2015 and December 2016 (n = 100). Before LT, the prevalence of metabolic-associated fatty liver disease as the indication of LT and the presence of obesity were significantly higher in the postintervention cohort, whereas the prevalence of other CVRF and renal dysfunction tended to be higher. Cyclosporine A was used less frequently in the postintervention cohort, whereas everolimus tended to increase. At 12 months after LT, the proportion of patients with measured blood pressure (88% vs. 56%), glycosilated hemoglobin (HbA1c; 96% vs. 72%), and high-density lipoprotein/low-density lipoprotein cholesterol (67% vs. 33%) was higher in the postintervention than in the control cohort (all p < 0.001). Blood pressure (64% vs. 36%, p = 0.02) and HbA1c (85% vs. 70%, p = 0.1) were within target in more individuals with hypertension and diabetes mellitus, respectively, in the postintervention cohort. Median total cholesterol levels were lower in the postintervention (184 mg/dl; interquartile range [IQR], 160-210 mg/dl) than in the control cohort (212 mg/dl; IQR, 186-240 mg/dl; p = 0.02). At 2 years after LT, the incidence of cardiovascular events was 14% in the control cohort and 6% in the postintervention cohort (p = 0.063). In conclusion, a multidisciplinary, multiprofessional strategy can achieve a higher grade of assessment and management of post-LT CVR despite a worsening metabolic profile of LT recipients.

Which preoperative assessment modalities best identify patients who are suitable for enhanced recovery after liver transplantation? A systematic review of the literature and expert panel recommendations.

BACKGROUND: To implement Enhanced Recovery After Surgery (ERAS) protocols for liver transplant (LT) candidates, it is essential to identify tools that can help risk stratify patients by their risk of early adverse post-LT outcomes. OBJECTIVE: We aimed to identify pre-LT tools that assess functional capacity, frailty, and muscle mass that can best risk stratify patients by their risk of adverse post-LT outcomes. METHODS: We first conducted a systematic review following PRISMA guidelines, expert panel review and recommendations using the GRADE approach (PROSPERO ID CRD42021237434). After confirming there are no studies evaluating assessment modalities for ERAS protocols for LT recipients specifically, the approach of the review focused on pre-LT modalities that identify LT recipients at higher risk of worse early post-LT outcomes (≤90 days), considering that this is particularly pertinent when evaluating candidates for ERAS. RESULTS: Twenty-two studies were included in the review, encompassing three different types of pre-LT modalities: evaluation of physical function (including frailty and general physical scores like the Karnofsky Performance Status (KPS), assessment of cardiopulmonary capacity, and estimation of muscle mass and composition. The majority of studies evaluated frailty assessment and muscle mass. Most studies, except for liver frailty index (LFI), were retrospective and single-center. All assessment modalities could identify, in different grade, LT recipients with higher risk of early post-LT mortality, length of stay or postoperative complications. CONCLUSIONS: We identified four pre-LT assessment tools that could be used to identify patients who are suitable for ERAS protocols: (1) KPS (quality of evidence moderate, grade of recommendation strong); (2) LFI (quality of evidence moderate, grade of recommendation strong); (3) abdominal muscle mass by CT (quality of evidence moderate, grade of recommendation strong); and (4) cardiopulmonary exercise testing (CPET) (quality of evidence moderate, grade of recommendation weak). We recommend that selection of the appropriate tool depends on the specific clinical setting and available resources to administer the tool, and that use of a tool be incorporated into the routine preoperative assessment when considering implementation of ERAS protocols for LT.

Effects of everolimus plus minimized tacrolimus on kidney function in liver transplantation: REDUCE, a prospective, randomized controlled study.

BACKGROUND AND AIM: reduction in calcineurin inhibitor levels is considered crucial to decrease the incidence of kidney dysfunction in liver transplant (LT) recipients. The aim of this study was to evaluate the safety and impact of everolimus plus reduced tacrolimus (EVR + rTAC) vs. mycophenolate mofetil plus tacrolimus (MMF + TAC) on kidney function in LT recipients from Spain. METHODS: the REDUCE study was a 52-week, multicenter, randomized, controlled, open-label, phase 3b study in de novo LT recipients. Eligible patients were randomized (1:1) 28 days post-transplantation to receive EVR + rTAC (TAC levels ≤ 5 ng/mL) or to continue with MMF + TAC (TAC levels = 6-10 ng/mL). Mean estimated glomerular filtration rate (eGFR), clinical benefit in renal function, and safety were evaluated. RESULTS: in the EVR + rTAC group (n = 105), eGFR increased from randomization to week 52 (82.2 [28.5] mL/min/1.73 m2 to 86.1 [27.9] mL/min/1.73 m2) whereas it decreased in the MMF + TAC (n = 106) group (88.4 [34.3] mL/min/1.73 m2 to 83.2 [25.2] mL/min/1.73 m2), with significant (p < 0.05) differences in eGFR throughout the study. However, both groups had a similar clinical benefit regarding renal function (improvement in 18.6 % vs. 19.1 %, and stabilization in 81.4 % vs. 80.9 % of patients in the EVR + rTAC vs. MMF + TAC groups, respectively). There were no significant differences in the incidence of acute rejection (5.7 % vs. 3.8 %), deaths (5.7 % vs. 2.8 %), and serious adverse events (51.9 % vs. 44.0 %) between the 2 groups. CONCLUSION: EVR + rTAC allows a safe reduction in tacrolimus exposure in de novo liver transplant recipients, with a significant improvement in eGFR but without significant differences in renal clinical benefit 1 year after liver transplantation.

A notable proportion of liver transplant candidates with alcohol-related cirrhosis can be delisted because of clinical improvement.

BACKGROUND & AIMS: To what extent patients with alcohol-related decompensated cirrhosis can improve until recovery from decompensation remains unclear. We aimed to investigate the probability of recovery and delisting due to improvement in patients with alcohol-related decompensated cirrhosis on the waiting list (WL) for liver transplantation (LT). METHODS: We conducted a registry-based, multicenter, retrospective study including all patients admitted to the LT WL in Catalonia (Spain) with the indication of alcohol-, HCV-, cholestasis- or non-alcoholic steatohepatitis-related decompensated cirrhosis between January 2007 and December 2018. Competing-risk analysis was used to investigate variables associated with delisting due to improvement in patients with alcohol-related decompensated cirrhosis. Criteria for delisting after improvement were not predefined. Outcomes of patients after delisting were also studied. RESULTS: One-thousand and one patients were included, 420 (37%) with alcohol-related decompensated cirrhosis. Thirty-six (8.6%) patients with alcohol-related decompensated cirrhosis were delisted after improvement at a median time of 29 months after WL admission. Lower model for end-stage liver disease (MELD) score, higher platelets and either female sex or lower height were independently associated with delisting due to improvement, while time of abstinence did not reach statistical significance in multivariate analysis (p = 0.055). Five years after delisting, the cumulative probability of remaining free from liver-related death or LT was 76%, similar to patients with HCV-related decompensated cirrhosis delisted after improvement. CONCLUSIONS: A significant proportion of LT candidates with alcohol-related cirrhosis can be delisted due to improvement, which is predicted by low MELD score and higher platelet count at WL admission. Women also have a higher probability of being delisted after improvement, partially due to reduced early access to LT for height discrepancies. Early identification of patients with potential for improvement may avoid unnecessary transplants. LAY SUMMARY: Patients with alcohol-related cirrhosis can improve until being delisted in approximately 9% of cases. Low model for end-stage liver disease score and high platelet levels at admission predict delisting after improvement, and women have higher probabilities of being delisted due to improvement. Long-term outcomes after delisting are generally favorable.

Regorafenib Efficacy After Sorafenib in Patients With Recurrent Hepatocellular Carcinoma After Liver Transplantation: A Retrospective Study.

Safety of regorafenib in hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) has been recently demonstrated. We aimed to assess the survival benefit of regorafenib compared with best supportive care (BSC) in LT patients after sorafenib discontinuation. This observational multicenter retrospective study included LT patients with HCC recurrence who discontinued first-line sorafenib. Group 1 comprised regorafenib-treated patients, whereas the control group was selected among patients treated with BSC due to unavailability of second-line options at the time of sorafenib discontinuation and who were sorafenib-tolerant progressors (group 2). Primary endpoint was overall survival (OS) of group 1 compared with group 2. Secondary endpoints were safety and OS of sequential treatment with sorafenib + regorafenib/BSC. Among 132 LT patients who discontinued sorafenib included in the study, 81 were sorafenib tolerant: 36 received regorafenib (group 1) and 45 (group 2) received BSC. Overall, 24 (67%) patients died in group 1 and 40 (89%) in group 2: the median OS was significantly longer in group 1 than in group 2 (13.1 versus 5.5 months; P < 0.01). Regorafenib treatment was an independent predictor of reduced mortality (hazard ratio, 0.37; 95% confidence interval [CI], 0.16-0.89; P = 0.02). Median treatment duration with regorafenib was 7.0 (95% CI, 5.5-8.5) months; regorafenib dose was reduced in 22 (61%) patients for adverse events and discontinued for tumor progression in 93% (n = 28). The median OS calculated from sorafenib start was 28.8 months (95% CI, 17.6-40.1) in group 1 versus 15.3 months (95% CI, 8.8-21.7) in group 2 (P < 0.01). Regorafenib is an effective second-line treatment after sorafenib in patients with HCC recurrence after LT.

MicroRNAs 155-5p, 122-5p, and 181a-5p Identify Patients With Graft Dysfunction Due to T Cell-Mediated Rejection After Liver Transplantation.

MicroRNAs (miRNAs) are small noncoding RNAs that can be detected in plasma and whose expression is associated with pathological processes. The role of miRNAs in the noninvasive diagnosis of T cell-mediated rejection (TCMR) after liver transplantation (LT) is unclear. Thus, we aimed to assess the effectiveness of a panel of 4 miRNAs (155-5p, 122-5p, 181a-5p, and 148-3p) in diagnosing TCMR in LT recipients with graft dysfunction (GD), and we compared its accuracy with previously published tests for diagnosing TCMR based on routine laboratory parameters. From a prospective cohort of 145 patients followed during the first year after transplant, 49 developed GD and underwent a liver biopsy and plasma collection for miRNA analysis using quantitative real-time polymerase chain reaction. Patients with GD due to TCMR (n = 21) exhibited significantly higher (P < 0.001) expression of miRNA 155-5p (2.05 versus 0.07), 122-5p (19.36 versus 1.66), and 181a-5p (1.33 versus 0.37) compared with those with GD from other causes (n = 28). The area under the receiver operating characteristic curve of miRNAs 155-5p, 122-5p, and 181a-5p for the diagnosis of TCMR was 0.87, 0.91, and 0.89, respectively, significantly higher than those of the other noninvasive tests (P < 0.001). Furthermore, miRNA 155-5p identified all patients who presented TCMR during the first 2 weeks after transplant. miRNA plasmatic expression differentiates TCMR from other causes of GD in patients who have undergone LT and may be a useful tool in clinical practice.

Ductular reaction and hepatocyte ballooning identify patients with fibrosing cholestatic hepatitits after liver transplantation.

INTRODUCTION: Diagnosis of severe hepatitis C recurrence is based on analytical and histological criteria but there is little information about their correlation. AIM: To assess the accuracy of laboratory criteria for the diagnosis of fibrosing cholestatic hepatitis (FCH). PATIENTS AND METHODS: Retrospective analysis of prospectively collected data form HCV positive patients who underwent liver transplantation (LT) between 2000 and 2014 in two European university hospitals. Patients were classified according to laboratory criteria such as FCH, cholestatic hepatitis (CH) and non-cholestatic acute hepatitis (NCAH). Histological characteristics were also evaluated. RESULTS: Seventy patients with acute HCV recurrence within the first year after LT with an available liver biopsy were included in the study. Most patients were male (70%) with a median age of 58 years (50-64) and infected with genotype 1b (71.4%). Median time from LT to diagnosis of recurrence was 2.96 months (2.1-5.3). Thirty-nine patients were classified as FCH, 21 as CH and 10 as NCAH. Marked hepatocyte ballooning and ductular reaction were associated with the presence of FCH with an OR of 4.66 (p=0.047) and 20.58 (p=0.025), respectively. Considering liver biopsy as the gold standard, the sensitivity, specificity, positive and negative predictive values of the analytical criteria were 0.8, 0.5, 0.3 and 0.9, respectively. However, correlation between histological and analytical criteria was poor (k=0.033). DISCUSSION: Analytical criteria may be used to rule out the presence of FCH, but a biopsy is mandatory to confirm the diagnosis. Ductular reaction and hepatocyte ballooning were independent predictors of FCH.

Preliminary experience on safety of regorafenib after sorafenib failure in recurrent hepatocellular carcinoma after liver transplantation.

Regorafenib is one option for second-line treatment of hepatocellular carcinoma (HCC), improving overall survival (OS) of sorafenib-tolerant patients who develop progression. We aim to evaluate the safety and outcomes of regorafenib as second-line treatment for HCC recurrence after liver transplantation (LT). This is a retrospective, multicenter, international study including regorafenib-treated LT patients (2015-2018), with analysis of baseline characteristics and evolutionary events during sorafenib/regorafenib treatment. Twenty-eight LT patients (57 years, 7% cirrhotics, 54% performance status 1) were included. Median time from LT to regorafenib initiation was 3.9 (1.1-18.5) years; median time on sorafenib was 11.3 (0.7-76.4) months and 14 (1-591) days from sorafenib discontinuation to regorafenib. During regorafenib (6.3 months), all patients had at least one adverse event (AE), the most common grade 3/4 AEs were fatigue (n = 7) and dermatological reaction (n = 5). While no liver rejection was observed, plasma levels of immunosuppressive drugs increased in five. Twenty-four patients developed progression (38% extrahepatic growth, 33% new extrahepatic lesions/vascular invasion). Median OS from regorafenib initiation was 12.9 (95% CI, 6.7-19.1) and 38.4 months (95% CI, 18.5-58.4) for the sorafenib initiation. This is the first study showing safety of regorafenib after LT, thus providing the rational of considering regorafenib in the clinical decision-making in sorafenib-tolerant patients with HCC recurrence after LT.

Hepatitis C virus intrinsic molecular determinants may contribute to the development of cholestatic hepatitis after liver transplantation.

Cholestatic hepatitis C (CHC) is a severe form of hepatitis C virus (HCV) infection recurrence that leads to high graft loss rates early after liver transplantation (LT). To investigate the pathogenic mechanisms of CHC, we analysed HCV quasispecies in CHC patients compared to a control group (mild hepatitis C recurrence) by deep pyrosequencing. At the time of LT, NS5B quasispecies complexity was similar between the two groups but, after LT, it decreased more sharply in CHC patients than in the control group. Interestingly, the major variant before LT propagated efficiently and remained as the dominant sequence after LT in 62 % of CHC patients versus 11 % of controls (P=0.031). Sequence analysis of the complete non-structural region in a limited number of patients revealed a potential 12 aa signature specific to the CHC group. These data suggest that intrinsic molecular determinants in the circulating HCV quasispecies may provide a fitness advantage, contributing to the development of CHC.

Prediction of Alcohol Relapse Among Liver Transplant Candidates With Less Than 6 Months of Abstinence Using the High-Risk Alcoholism Relapse Score.

The selection of liver transplantation (LT) candidates with alcohol-use disorder (AUD) is influenced by the risk of alcohol relapse (AR) after LT. We aimed to investigate the risk factors of AR after LT and its impact on graft and recipient outcomes. A retrospective study was conducted that included all consecutive patients with AUD undergoing LT from January 2004 to April 2016 (n = 309), excluding patients with alcoholic hepatitis. Odds ratios (ORs) and 95% confidence intervals (CIs) for AR were analyzed by multinomial logistic regression. Cox regression with time-dependent covariates was used to analyze patient survival and graft cirrhosis. There were 70 (23%) patients who presented AR (median follow-up, 68 months), most of them (n = 44, 63%) presenting heavy AR. The probability of heavy AR was 2.3%, 7.5%, 12%, and 29% at 1, 3, 5, and 10 years after LT, respectively. The independent risk factors for heavy AR included a High-Risk Alcoholism Relapse (HRAR) score ≥3 (OR, 2.39; 95% CI, 1.02-5.56; P = 0.04) and the duration of abstinence (months) before LT (OR, 0.81; 95% CI, 0.66-0.98; P = 0.03). In recipients with <6 months of abstinence before LT, the probability of heavy AR after LT was higher in patients with an HRAR score ≥3 than in those with an HRAR score <3 (20%, 36.7%, and 47% versus 6.8%, 12.4%, and 27% at 1, 3, and 5 years, respectively; log-rank 0.013). The risk of graft cirrhosis was increased in patients with heavy AR (hazard ratio, 3.44; 95% CI, 1.58-7.57; P = 0.002) compared with nonrelapsers, with no differences in patient survival. In conclusion, the HRAR score is helpful in identifying the risk of harmful AR after LT in candidates with <6 months of alcohol abstinence without alcoholic hepatitis. These patients could benefit from a longterm integrative patient-centered approach after LT until lifestyle changes are implemented.

Torque Teno Virus Is Associated With the State of Immune Suppression Early After Liver Transplantation.

The development of noninvasive biomarkers that reflect the state of immunosuppression (IS) remains an unmet need in liver transplantation (LT). Torque Teno virus (TTV) is a highly prevalent, nonpathogenic DNA virus whose plasma levels may be associated with the immune status of the host. The aim of this study was to assess the role of TTV as a biomarker of IS in LT recipients. TTV DNA in plasma was quantified by real-time polymerase chain reaction at different time points during the first year after transplant in a prospectively followed cohort of 63 de novo LT recipients, and any correlation between TTV DNA and biopsy-proven acute cellular rejection (ACR) and opportunistic infections was then evaluated. In addition, TTV DNA was studied in 10 longterm LT recipients in monotherapy with tacrolimus, 10 tolerant recipients, and 10 healthy controls. TTV was detected in the plasma of all patients. Among the 63 LT recipients, 20 episodes of ACR were diagnosed, and there were 28 opportunistic infections, 26 of them being cytomegalovirus (CMV) infections. TTV viremia was significantly lower during ACR (4.41 versus 5.95 log10 copies/mL; P = 0.002) and significantly higher during CMV infections (5.79 versus 6.59 log10 copies/mL; P = 0.009). The area under the receiver operating characteristic curve of TTV viral load for the diagnosis of moderate ACR was 0.869, with a sensitivity and negative predictive value of 100%, respectively, for a cutoff point of 4.75 log10 copies/mL. There were no statistically significant differences in TTV DNA in either longterm or tolerant patients and healthy controls. In conclusion, plasma TTV DNA levels are associated with immune-related events after LT and could constitute a potential biomarker of the state of IS during the first months after transplant.

Portal pressure and liver stiffness measurements in the prediction of fibrosis regression after sustained virological response in recurrent hepatitis C.

Sustained virological response (SVR) improves survival in post-liver transplant (LT) recurrent hepatitis C. However, the impact of SVR on fibrosis regression is not well defined. In addition, the performance of noninvasive methods to evaluate the presence of fibrosis and portal hypertension (PH) post-SVR has been scarcely evaluated. We aimed to investigate the degree of fibrosis regression (decrease ≥1 METAVIR stage) after-SVR and its associated factors in recurrent hepatitis C, as well as the diagnostic capacity of noninvasive methods in the assessment of liver fibrosis and PH after viral clearance. We evaluated 112 hepatitis C virus-infected LT recipients who achieved SVR between 2001 and 2015. A liver biopsy was performed before treatment and 12 months post-SVR. Hepatic venous pressure gradient (HVPG), liver stiffness measurement (LSM), and Enhanced Liver Fibrosis (ELF) score were also determined at the same time points. Sixty-seven percent of the cohort presented fibrosis regression: 43% in recipients with cirrhosis and 72%-85% in the remaining stages (P = 0.002). HVPG, LSM, and ELF significantly decreased post-SVR. Liver function significantly improved, and survival was significantly better in patients achieving fibrosis regression. Baseline HVPG and LSM as well as decompensations before therapy were independent predictors of fibrosis regression. One year post-SVR, LSM had a high diagnostic accuracy to discard the presence of advanced fibrosis (AF) and clinically significant PH (AUROC, 0.902 and 0.888). CONCLUSION: In conclusion, SVR post-LT induces fibrosis regression in most patients, leading to significant clinical benefits. Pretreatment HVPG and LSM are significant determinants of the likelihood of fibrosis regression. Finally, LSM accurately predicts the presence of AF and PH 1 year after SVR and thus can be used to determine monitoring strategies. (Hepatology 2018;67:1683-1694).