Recent outcomes of liver transplantation for Budd-Chiari syndrome: A study of the European Liver Transplant Registry (ELTR) and affiliated centers.

BACKGROUND AND AIMS: Management of Budd-Chiari syndrome (BCS) has improved over the last decades. The main aim was to evaluate the contemporary post-liver transplant (post-LT) outcomes in Europe. APPROACH AND RESULTS: Data from all patients who underwent transplantation from 1976 to 2020 was obtained from the European Liver Transplant Registry (ELTR). Patients < 16 years, with secondary BCS or HCC were excluded. Patient survival (PS) and graft survival (GS) before and after 2000 were compared. Multivariate Cox regression analysis identified predictors of PS and GS after 2000. Supplemental data was requested from all ELTR-affiliated centers and received from 44. In all, 808 patients underwent transplantation between 2000 and 2020. One-, 5- and 10-year PS was 84%, 77%, and 68%, and GS was 79%, 70%, and 62%, respectively. Both significantly improved compared to outcomes before 2000 ( p < 0.001). Median follow-up was 50 months and retransplantation rate was 12%. Recipient age (aHR:1.04,95%CI:1.02-1.06) and MELD score (aHR:1.04,95%CI:1.01-1.06), especially above 30, were associated with worse PS, while male sex had better outcomes (aHR:0.63,95%CI:0.41-0.96). Donor age was associated with worse PS (aHR:1.01,95%CI:1.00-1.03) and GS (aHR:1.02,95%CI:1.01-1.03). In 353 patients (44%) with supplemental data, 33% had myeloproliferative neoplasm, 20% underwent TIPS pre-LT, and 85% used anticoagulation post-LT. Post-LT anticoagulation was associated with improved PS (aHR:0.29,95%CI:0.16-0.54) and GS (aHR:0.48,95%CI:0.29-0.81). Hepatic artery thrombosis and portal vein thrombosis (PVT) occurred in 9% and 7%, while recurrent BCS was rare (3%). CONCLUSIONS: LT for BCS results in excellent patient- and graft-survival. Older recipient or donor age and higher MELD are associated with poorer outcomes, while long-term anticoagulation improves both patient and graft outcomes.

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.

Women Are Also Disadvantaged in Accessing Transplant Outside the United States: Analysis of the Spanish Liver Transplantation Registry.

Sex inequities in liver transplantation (LT) have been documented in several, mostly US-based, studies. Our aim was to describe sex-related differences in access to LT in a system with short waiting times. All adult patients registered in the RETH-Spanish Liver Transplant Registry (2000-2022) for LT were included. Baseline demographics, presence of hepatocellular carcinoma, cause and severity of liver disease, time on the waiting list (WL), access to transplantation, and reasons for removal from the WL were assessed. 14,385 patients were analysed (77% men, 56.2 ± 8.7 years). Model for end-stage liver disease (MELD) score was reported for 5,475 patients (mean value: 16.6 ± 5.7). Women were less likely to receive a transplant than men (OR 0.78, 95% CI 0.63, 0.97) with a trend to a higher risk of exclusion for deterioration (HR 1.17, 95% CI 0.99, 1.38), despite similar disease severity. Women waited longer on the WL (198.6 ± 338.9 vs. 173.3 ± 285.5 days, p < 0.001). Recently, women's risk of dropout has reduced, concomitantly with shorter WL times. Even in countries with short waiting times, women are disadvantaged in LT. Policies directed at optimizing the whole LT network should be encouraged to guarantee a fair and equal access of all patients to this life saving resource.

Alternative forms of portal vein revascularization in liver transplant recipients with complex portal vein thrombosis.

BACKGROUND & AIMS: Complex portal vein thrombosis (PVT) is a challenge in liver transplantation (LT). Extra-anatomical approaches to portal revascularization, including renoportal (RPA), left gastric vein (LGA), pericholedochal vein (PCA), and cavoportal (CPA) anastomoses, have been described in case reports and series. The RP4LT Collaborative was created to record cases of alternative portal revascularization performed for complex PVT. METHODS: An international, observational web registry was launched in 2020. Cases of complex PVT undergoing first LT performed with RPA, LGA, PCA, or CPA were recorded and updated through 12/2021. RESULTS: A total of 140 cases were available for analysis: 74 RPA, 18 LGA, 20 PCA, and 28 CPA. Transplants were primarily performed with whole livers (98%) in recipients with median (IQR) age 58 (49-63) years, model for end-stage liver disease score 17 (14-24), and cold ischemia 431 (360-505) minutes. Post-operatively, 49% of recipients developed acute kidney injury, 16% diuretic-responsive ascites, 9% refractory ascites (29% with CPA, p <0.001), and 10% variceal hemorrhage (25% with CPA, p = 0.002). After a median follow-up of 22 (4-67) months, patient and graft 1-/3-/5-year survival rates were 71/67/61% and 69/63/57%, respectively. On multivariate Cox proportional hazards analysis, the only factor significantly and independently associated with all-cause graft loss was non-physiological portal vein reconstruction in which all graft portal inflow arose from recipient systemic circulation (hazard ratio 6.639, 95% CI 2.159-20.422, p = 0.001). CONCLUSIONS: Alternative forms of portal vein anastomosis achieving physiological portal inflow (i.e., at least some recipient splanchnic blood flow reaching transplant graft) offer acceptable post-transplant results in LT candidates with complex PVT. On the contrary, non-physiological portal vein anastomoses fail to resolve portal hypertension and should not be performed. IMPACT AND IMPLICATIONS: Complex portal vein thrombosis (PVT) is a challenge in liver transplantation. Results of this international, multicenter analysis may be used to guide clinical decisions in transplant candidates with complex PVT. Extra-anatomical portal vein anastomoses that allow for at least some recipient splanchnic blood flow to the transplant allograft offer acceptable results. On the other hand, anastomoses that deliver only systemic blood flow to the allograft fail to resolve portal hypertension and should not be performed.

Effectiveness and safety of once-daily tacrolimus formulations in de novo liver transplant recipients: The PRETHI study.

Data comparing long-term effectiveness and safety of once-daily tacrolimus formulations in de novo liver transplantation are scarce. We compared the effectiveness, pharmacokinetic profile, and safety of LCPT (Envarsus) and PR-Tac (Advagraf) for up to 12 months post-transplant. Adult de novo liver transplant recipients who started IR-Tac (Prograf) and were converted to LCPT or PR-Tac 3-5 days post-transplant were included. Data from 163 patients were analyzed, 87 treated with LCPT and 76 with PR-Tac. The incidence of treatment failure was 30.5% in the LCPT group versus 23.0% in the PR-Tac group (p = .291). Biopsy-proven acute rejection (BPAR) was reported in 26.8% of patients in the LCPT group and 17.6% in the PR-Tac group (p = .166). Graft loss was experienced in one patient (1.2%) in the LCPT group and three patients (4.1%) in the PR-Tac group (p = .346). Death was registered in three patients (3.7%) in the LCPT group and three patients (4.1%) in the PR-Tac group (p > .999). Patients in the LCPT group showed 45.7% higher relative bioavailability (Cmin /total daily dose [TDD]; p < .01) with similar Cmin and 33.3% lower TDD versus PR-Tac (p < .01). The evolution of renal function, safety profile, and the incidence of post-transplant renal failure, dyslipidemia, obesity, hypertension, and diabetes mellitus were similar in patients treated with LCPT and PR-Tac. In de novo liver transplant patients, LCPT and PR-Tac showed comparable effectiveness with higher relative bioavailability, similar Cmin and lower TDD in the LCPT group. Renal function, safety, and post-transplant complications were comparable in LCPT and PR-Tac groups.

Abdominal normothermic regional perfusion in controlled donation after circulatory determination of death liver transplantation: Outcomes and risk factors for graft loss.

Postmortem normothermic regional perfusion (NRP) is a rising preservation strategy in controlled donation after circulatory determination of death (cDCD). Herein, we present results for cDCD liver transplants performed in Spain 2012-2019, with outcomes evaluated through December 31, 2020. Results were analyzed retrospectively and according to recovery technique (abdominal NRP [A-NRP] or standard rapid recovery [SRR]). During the study period, 545 cDCD liver transplants were performed with A-NRP and 258 with SRR. Median donor age was 59 years (interquartile range 49-67 years). Adjusted risk estimates were improved with A-NRP for overall biliary complications (OR 0.300, 95% CI 0.197-0.459, p < .001), ischemic type biliary lesions (OR 0.112, 95% CI 0.042-0.299, p < .001), graft loss (HR 0.371, 95% CI 0.267-0.516, p < .001), and patient death (HR 0.540, 95% CI 0.373-0.781, p = .001). Cold ischemia time (HR 1.004, 95% CI 1.001-1.007, p = .021) and re-transplantation indication (HR 9.552, 95% CI 3.519-25.930, p < .001) were significant independent predictors for graft loss among cDCD livers with A-NRP. While use of A-NRP helps overcome traditional limitations in cDCD liver transplantation, opportunity for improvement remains for cases with prolonged cold ischemia and/or technically complex recipients, indicating a potential role for complimentary ex situ perfusion preservation techniques.

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.

Transthyretin amyloidosis with cardiomyopathy after domino liver transplantation: Results of a cross-sectional study.

Domino liver transplantation (DLT) has been used widely in patients with hereditary amyloid transthyretin (ATTR) amyloidosis. New-onset polyneuropathy in recipients of DLT has been reported, but there are few cases of cardiac involvement reported. We aimed to perform a cross-sectional study for ATTR amyloidosis with cardiomyopathy (ATTR-CM) in DLT recipients. We evaluated 23 living DLT recipients a median of 9 years since DLT at 2 referral centers with a systematic cardiac evaluation, including bone scintigraphy. Median age was 72 years, 91% had hypertension, 35% had diabetes mellitus, 67% had chronic renal failure, and 8 patients (35%) developed new-onset polyneuropathy. Only 13% had a normal electrocardiogram and a normal echocardiography, and most of them showed some conduction disturbance or increase in left ventricular wall thickness, but only 1 patient with a Glu89Lys mutation developed ATTR-CM diagnosed by bone scintigraphy and endomyocardial biopsy. None of the recipients of a DLT with Val30Met mutation showed cardiac involvement by bone scintigraphy. In conclusion, DLT from Val30Met donors seems to be safe regarding the development of ATTR-CM. Evaluation of cardiomyopathy in DLT recipients is challenging due to concomitant comorbidities and in this context, bone scintigraphy can be helpful to evaluate ATTR-CM.

[National survey on the treatment of cholelitiasis in Spain during the initial period of the COVID-19 pandemic]. / Encuesta nacional sobre el tratamiento de la colelitiasis en España durante la fase inicial de la pandemia por COVID-19.

Introduction: The extraordinary impact of COVID-19 pandemic on Spanish hospitals has led to a redistribution of resources for the treatment of these patients, with a decreased capacity of care for other common diseases. The aim of the present study is to analyse how this situation has affected the treatment of cholecystitis and cholelythiasis. Methods: It is a descriptive national study after online voluntary distribution of a specific questionnaire with Google Drive™ to members of the Spanish Association of Surgeons (AEC). Results: We received 153 answers (one per hospital). Elective cholecystectomies have been cancelled in 96.7% of centres. Conservative treatment for acute cholecystitis has been selected in 90% (previously 18%), and if operated, 95% have been performed laparoscopically. Globally, only 49% perform preoperative diagnostic tests for SARS-CoV-2, and 58.5% recognize there have been cases confirmed postoperatively after other surgeries, with worse surgical outcomes in 54%. Conclusions: This survey shows that most of the Spanish centers are following the surgical societies suggestions during the pandemic. However, some data requires to be taken into account for the next phase of the pandemic.

Molecular Pathways Leading to Induction of Cell Death and Anti-Proliferative Properties by Tacrolimus and mTOR Inhibitors in Liver Cancer Cells.

BACKGROUND/AIMS: Orthotopic liver transplantation (OLT) is the recommended treatment for patients at early stages of hepatocarcinoma (HCC) with portal hypertension and/or increased bilirubinemia, but without vascular-associated diseases. Tumor recurrence, which is the main drawback for the survival of patients submitted to OLT for HCC, has been related to tumor-related variables and the immunosuppressive therapies. We have previously shown that Tacrolimus (FK506) exerts a more potent pro-apoptotic and anti-proliferative effects than the mammalian target of rapamycin (mTOR) inhibitors (Sirolimus and Everolimus) in liver cancer cells. This study identified the role of the immunosuppressant partners such as FK506-binding proteins (FKBPs) in the induction of cell death and arrest of cell proliferation by immunosuppressants in two representative liver cancer cells. METHODS: The regulation of endoplasmic reticulum (ER) stress, apoptosis/autophagy, cell proliferation, and FKBPs expression was determined in Tacrolimus-, Sirolimus- and Everolimus-treated primary human hepatocytes, and hepatoma HepG2 and Huh7 cell lines. The functional repercussion of FKBPs on cell death and proliferation was also addressed using the siRNA technology. The assessed antitumoral properties of the immunosuppressants were associated to microRNAs (miRNAs) pattern. RESULTS: The enhanced pro-apoptotic and anti-proliferative properties of Tacrolimus versus mTOR inhibitors were associated with increased protein kinase RNA-like endoplasmic reticulum kinase (PERK)-related ER stress, Ser15P-p53/p53 ratio and p21 protein expression that may counterbalance the risk of proliferative upregulation caused by enhanced Thr172P-Cdk4/Cdk4 activation in liver cancer cells. The inhibition of the mTOR pathway by Sirolimus and Everolimus was related to an induction of autophagy; and at a high dose, these drugs impaired translation likely at a very early step of the elongation phase. Tacrolimus and mTOR inhibitors increased the protein expression of FKBP12 and FKBP51 that appeared to play pro-survival role. Interestingly, the administration of immunosuppressants yields a specific pattern of miRNAs. Tacrolimus and mTOR inhibitors decreased miR-92a-1-5p, miR-197-3p, miR-483-3p and miR-720, and increased miR-22-3p, miR-376a-3p, miR-663b, miR-886-5p, miR-1300 and miR-1303 expressions in HepG2 cells. CONCLUSION: The more potent pro-apoptotic and anti-proliferative properties of Tacrolimus versus mTOR inhibitors were associated with an increased activation of PERK and p53 signaling, and p21 protein expression. FKBP12 and FKBP51 appeared to be the most relevant partners of Tacrolimus and mTOR inhibitors exerting a pro-survival effect in HepG2 cells. The observed effects of immunosuppressants were related to a specific miRNA signature in liver cancer cells.

Glutathione S-Transferase T1 Mismatch Is a Risk Factor for Chronic Ductopenic Rejection of Liver Allografts.

The underlying causes of chronic rejection (CR) after liver transplantation (LT) are not completely known. The main aim of this study was to explore the involvement of the minor histocompatibility antigen glutathione S-transferase T1 (GSTT1) in CR. We retrospectively studied 611 patients who underwent LTs at University Hospital Virgen del Rocío between 2003 and 2016 with a median follow-up of 7.4 ± 4.2 years. The GSTT1 genotype was determined by polymerase chain reaction. We defined GSTT1 mismatch as a specific donor/recipient combination in which a recipient who was homozygous for the deletion allele received a transplant from a positive donor. The prevalence of CR in our whole cohort was 11.6% (71/611), and the prevalence in the GSTT1-mismatched group was 18.8% (16/85) versus 10.5% (55/526) in the GSTT1-matched group. In the cyclosporine A (CsA) group, the prevalence was 26.3% (26/99), much higher than the 8.8% (45/512) observed in the tacrolimus (Tac) group. For statistical analysis, the patients were distributed into 2 groups: group 1, regarded as GSTT1 mismatched, which included the donor (D)+/recipient (R)- allelic combination; and group 2, regarded as GSTT1 matched, which included the other allelic combinations of D+/R+, D-/R-, and D-/R+. All relevant clinical information was collected, and a diagnosis of CR was always confirmed by liver biopsy. GSTT1 mismatch (hazard ratio [HR], 1.99; 95% confidence interval [CI], 1.08-3.66; P = 0.03) and use of CsA/Tac (P < 0.001) were independent risk factors for CR. CR increased the risk of mortality (HR, 2; 95% CI, 1.2-3.6; P = 0.01). Out of the 71 CR patients, 12 (16.9%) needed retransplantation. In conclusion, the GSTT1 D+/R- allelic mismatch is an independent risk factor for CR. A long follow-up of LT patients is recommended because the incidence of CR in adults seems to be underestimated.

Normothermic regional perfusion vs. super-rapid recovery in controlled donation after circulatory death liver transplantation.

BACKGROUND & AIMS: Although there is increasing interest in its use, definitive evidence demonstrating a benefit for postmortem normothermic regional perfusion (NRP) in controlled donation after circulatory death (cDCD) liver transplantation is lacking. The aim of this study was to compare results of cDCD liver transplants performed with postmortem NRP vs. super-rapid recovery (SRR), the current standard for cDCD. METHODS: This was an observational cohort study including all cDCD liver transplants performed in Spain between June 2012 and December 2016, with follow-up ending in December 2017. Each donor hospital determined whether organ recovery was performed using NRP or SRR. The propensity scores technique based on the inverse probability of treatment weighting (IPTW) was used to balance covariates across study groups; logistic and Cox regression models were used for binary and time-to-event outcomes. RESULTS: During the study period, there were 95 cDCD liver transplants performed with postmortem NRP and 117 with SRR. The median donor age was 56 years (interquartile range 45-65 years). After IPTW analysis, baseline covariates were balanced, with all absolute standardised differences <0.15. IPTW-adjusted risks were significantly improved among NRP livers for overall biliary complications (odds ratio 0.14; 95% CI 0.06-0.35, p <0.001), ischaemic type biliary lesions (odds ratio 0.11; 95% CI 0.02-0.57; p = 0.008), and graft loss (hazard ratio 0.39; 95% CI 0.20-0.78; p = 0.008). CONCLUSIONS: The use of postmortem NRP in cDCD liver transplantation appears to reduce postoperative biliary complications, ischaemic type biliary lesions and graft loss, and allows for the transplantation of livers even from cDCD donors of advanced age. LAY SUMMARY: This is a propensity-matched nationwide observational cohort study performed using livers recovered from donors undergoing cardiac arrest provoked by the intentional withdrawal of life support (controlled donation after circulatory death, cDCD). Approximately half of the livers were recovered after a period of postmortem in situ normothermic regional perfusion, which restored warm oxygenated blood to the abdominal organs, whereas the remainder were recovered after rapid preservation with a cold solution. The study results suggest that the use of postmortem normothermic regional perfusion helps reduce rates of post-transplant biliary complications and graft loss and allows for the successful transplantation of livers from older cDCD donors.

Point-of-care haemostasis monitoring during liver transplantation is cost effective.

Background Optimal haemostasis management in orthotropic liver transplant (OLT) could reduce blood loss and transfusion volume, improve patient outcomes and reduce cost. Methods We performed a study including 336 OLTs to evaluate the clinical and cost effectiveness of a new point-of-care (POC)-based haemostatic management approach in OLT patients. Results In terms of health benefit we found that the new approach showed a significant reduction in transfusion requirements (red blood cell transfusion units were reduced from 5.3±4.6 to 2.8±2.9 [p<0.001], free frozen plasma from 3.1±3.3 to 0.4±1.0 [p<0.001] and platelets from 2.9±3.9 to 0.4±0.9 [p<0.001], transfusion avoidance, 9.7% vs. 29.1% [p<0.001] and massive transfusion, 14.5% vs. 3.8% [p=0.001]); we also found a significant improvement in patient outcomes, such, reoperation for bleeding or acute-kidney-failure (8.3% vs. 2.4%, p=0.015; 33.6% vs. 5.4%, p<0.001), with a significant reduction in the length of the hospital total stay (40.6±13.8 days vs. 38.2±14.4 days, p=0.001). The lowest cost incurred was observed with the new approach (€73,038.80 vs. €158,912.90) with significant patient saving associated to transfusion avoidance (€1278.36), ICU-stay (€3037.26), total-stay (€3800.76) and reoperation for bleeding (€80,899.64). Conclusions POC haemostatic monitoring during OLT is cost effective.

Influence of donor liver CYP3A4*20 loss-of-function genotype on tacrolimus pharmacokinetics in transplanted patients.

OBJECTIVE: Cytochrome P450 3A4 (CYP3A4) metabolizes about half of all drugs on the market; however, the impact of CYP3A4 loss-of-function variants on drug exposures remains poorly characterized. Here, we report the effect of the CYP3A4*20 frameshift allele in two Spanish liver transplant patients treated with tacrolimus. PATIENTS AND METHODS: A series of 90 transplanted patients (with DNA available for 89 of the recipients and 76 of the liver donors) treated with tacrolimus were included in the study. The genotypes of liver donors and of the recipients for CYP3A4*20 (rs67666821), CYP3A4*22 (rs35599367) and CYP3A5*3 (rs776746) were compared with weight-adjusted tacrolimus dose (D), tacrolimus trough concentration (C0), and dose-adjusted tacrolimus trough concentrations (C0/D) using the Mann-Whitney U-nonparametric test. RESULTS: The CYP3A4*20 allele was detected in two of the liver donors. This genotype yielded at all times higher C0/D (2.6-fold, average) than intermediate CYP3A metabolizers (CYP3A4*1/*1 and CYP3A5*3/*3) (P=0.045, 90 days after transplantation). CYP3A4*22 carriers showed a 1.9-fold average increase in C0/D (P=0.047, 0.025, and 0.053; at days 7, 14, and 30 after transplantation, respectively) compared with intermediate metabolizers. In terms of recipients' genotype, CYP3A5*1 had reduced (P=0.025) and CYP3A4*22 increased C0/D (P=0.056) 7 days after transplantation. The incidence of biopsy-proven acute rejection was 0, 12, and 20% for livers with poor, intermediate, and extensive CYP3A-metabolizing capacity, respectively (P=0.0995). CONCLUSION: This first description of CYP3A4*20 null genotype in liver-transplanted patients, supports the relevance of CYP3A genotyping in tacrolimus therapy.

Identification of the cellular components involved in de novo immune hepatitis: a quantitative immunohistochemical analysis.

BACKGROUND: Diagnosis of de novo immune hepatitis (dnIH) after liver transplantation relies on biopsy findings, with an abundance of plasma cells (PCs) in the inflammatory infiltrates a hallmark of the disease. Very little is known about what other types of immune cells exist in the infiltrates mainly located in the portal areas of the liver tissue. METHODS: We analyzed the composition of T cells, B cells, PCs, and macrophages in the liver biopsies of 12 patients with dnIH, 9 of them obtained at the time of diagnosis. For comparison, biopsies from 9 patients with chronic rejection (CR) were included in the study. The results were analyzed by a computer-assisted stereology quantification method. RESULTS: The major components of the infiltrates in the portal areas were CD3+ T lymphocytes in both groups, with 36.6% in the dnIH group versus 49.4% in the CR group. CD20+ B lymphocytes represented 14.9% in the dnIH group and 29.1% in the CR group. Macrophage levels were very similar in the dnIH and CR group (19.7% versus 16.8%, respectively). PCs were much less represented in CR biopsies than those from the dnIH group (mean value of 4.7% versus 28.8%). CONCLUSION: In conclusion, the determination of a characteristic cellular profile could be an important tool for a more reliable diagnosis of dnIH, in support of the histological evaluation made by the pathologist, which in most cases is challenging. Recognition of this condition is crucial because it leads to graft failure if left untreated.

Locoregional treatments before liver transplantation for hepatocellular carcinoma: a study from the European Liver Transplant Registry.

Locoregional treatment while on the waiting list for liver transplantation (Ltx) for hepatocellular carcinoma (HCC) has been shown to improve survival. However, the effect of treatment type has not been investigated. We investigate the effect of locoregional treatment type on survival after Ltx for HCC. We investigated patients registered in the European Liver Transplant Registry database using multivariate Cox regression survival analysis. Information on locoregional therapy was registered for 4978 of 23 124 patients and was associated with improved overall survival [hazard ratio (HR) 0.84 (0.73-0.96)] and HCC-specific survival [HR 0.76 (0.59-0.98)]. Radiofrequency ablation (RFA) was the one monotherapy associated with improved overall survival [HR 0.51 (0.40-0.65)]. In addition, the combination of RFA and transarterial chemoembolization also improved survival [HR 0.74 (0.55-0.99)]. Adjusting for factors related to prognosis, disease severity, and tumor aggressiveness, RFA was highly beneficial for overall and HCC-specific survival. The effect may represent a selection of patients with favorable tumor biology; however, the treatment may be effective per se by halting tumor progression. Clinicaltrials.gov number: NCT02995096.

Prevalence and progression of chronic kidney disease after liver transplant: a prospective, real-life, observational, two-year multicenter study.

INTRODUCTION: chronic kidney disease is a frequent complication after liver transplantation. The use of calcineurin inhibitors is one of the causes of this complication. Current immunsuppression regimens that reduce the use of calcineurin inhibitors may be associated with an improved preservation of renal function. OBJECTIVE: the study aimed to assess the evolution of renal function after liver transplantation in the current routine clinical practice. METHODS: an observational, prospective, multicenter study in adult liver transplant recipients was performed. Two hundred and thirty patients with a good renal function before transplantation were assessed six months post-transplantation (baseline) and every six months until month 30. RESULTS: at baseline, 32% of the patients had a reduction in the glomerular filtration rate below < 60 ml/min/1.73 m2. The mean glomerular filtration rate increased from 72.3 to 75.6 ml/min/1.73 m2 at baseline and month 30 respectively (p < 0.01). The mean serum creatinine levels (mg/dl) decreased from 1.13 to 1.09 (p < 0.01). The percentage of patients with stage 3 chronic kidney disease decreased from 31.7% to 26.4%, whereas the percentage of patients with stage 4 remained unchanged (0.4% at baseline and 0.5% at month 30). No patients progressed to end-stage kidney disease that required dialysis or renal transplantation. CONCLUSION: in the routine clinical practice, a moderate deterioration of renal function is frequent after liver transplantation. However, advanced chronic kidney disease is infrequent in patients with a good pre-transplant renal function.

Vascular invasion and survival after liver transplantation for hepatocellular carcinoma: a study from the European Liver Transplant Registry.

BACKGROUND: Studies suggest that vascular invasion may be a superior prognostic marker compared with traditional selection criteria, e.g. Milan criteria. This study aimed to investigate the prognostic value of micro and macrovascular invasion in a large database material. METHODS: Patients liver transplanted for HCC and cirrhosis registered in the European Liver Transplant Registry (ELTR) database were included. The association between the Milan criteria, Up-to-seven criteria and vascular invasion with overall survival and HCC specific survival was investigated with univariate and multivariate Cox regression analyses. RESULTS: Of 23,124 patients transplanted for HCC, 9324 had cirrhosis and data on explant pathology. Patients without microvascular invasion, regardless of number and size of HCC nodules, had a five-year overall survival of 73.2%, which was comparable with patients inside both Milan and Up-to-seven criteria. Patients without macrovascular invasion had an only marginally reduced survival of 70.7% after five years. Patients outside both Milan and Up-to-seven criteria without micro or macrovascular invasion still had a five-year overall survival of 65.8%. CONCLUSION: Vascular invasion as a prognostic indicator remains superior to criteria based on size and number of nodules. With continuously improving imaging studies, microvascular invasion may be used for selecting patients for transplantation in the future.

Hepatopulmonary syndrome: which blood gas analysis criteria and position should we use for diagnosis?

INTRODUCTION: Different blood gas criteria have been used in the diagnosis of hepatopulmonary syndrome (HPS). PATIENTS AND METHODS: Arterial blood gases were prospectively evaluated in 194 cirrhotic candidates for liver transplantation (LT) in the supine and seated position. Three blood gas criteria were analyzed: classic (partial pressure of oxygen [PaO2] < 70 mmHg and/or alveolar-arterial gradient of oxygen [A-a PO2] ≥ 20 mmHg), modern (A-a PO2 ≥ 15 mmHg or ≥ 20 mmHg in patients over 64) and the A-a PO2 ≥ threshold value adjusted for age. RESULTS: The prevalence of HPS in the supine and seated position was 27.8% and 23.2% (classic), 34% and 25.3% (modern) and 22.2% and 19% (adjusted for age), respectively. The proportion of severe and very severe cases increased in a seated position (11/49 [22.4%] vs 5/66 [7.6%], p = 0.02). No difference was observed in the pre-LT, post-LT and overall mortality in patients with HPS, regardless of the criteria used. CONCLUSION: Obtaining blood gas measurements in the supine position and the use of modern criteria are more sensitive for the diagnosis of HPS. Blood gas analysis with the patient seated detects a greater number of severe and very severe cases. The presence of HPS was not associated with an increase in mortality regardless of blood gas criterion used.