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Objective: To evaluate current practice and outcomes of pregnancy in women previously diagnosed with Budd–Chiari syndrome and/or portal vein thrombosis, with and without concomitant portal hypertension. Design and setting: Multicentre retrospective cohort study between 2008 and 2021. Population: Women who conceived in the predefined period after the diagnosis of Budd–Chiari syndrome and/or portal vein thrombosis. Methods and main outcome measures: We collected data on diagnosis and clinical features. The primary outcomes were maternal mortality and live birth rate. Secondary outcomes included maternal, neonatal and obstetric complications. Results: Forty‐five women (12 Budd–Chiari syndrome, 33 portal vein thrombosis; 76 pregnancies) were included. Underlying prothrombotic disorders were present in 23 of the 45 women (51%). Thirty‐eight women (84%) received low‐molecular‐weight heparin during pregnancy. Of 45 first pregnancies, 11 (24%) ended in pregnancy loss and 34 (76%) resulted in live birth of which 27 were at term (79% of live births and 60% of pregnancies). No maternal deaths were observed; one woman developed pulmonary embolism during pregnancy and two women (4%) had variceal bleeding requiring intervention. Conclusions: The high number of term live births (79%) and lower than expected risk of pregnancy‐related maternal and neonatal morbidity in our cohort suggest that Budd–Chiari syndrome and/or portal vein thrombosis should not be considered as an absolute contraindication for pregnancy. Individualised, nuanced counselling and a multidisciplinary pregnancy surveillance approach are essential in this patient population. Budd–Chiari syndrome and/or portal vein thrombosis should not be considered as an absolute contraindication for pregnancy. Budd–Chiari syndrome and/or portal vein thrombosis should not be considered as an absolute contraindication for pregnancy. Linked article This article is commented on by YY Chung & MA Heneghan pp. 618 in this issue. To view this minicommentary visit https://doi.org/10.1111/1471-0528.17002. [ABSTRACT FROM AUTHOR]

Background & Aims: Despite several recent international guidelines, no consensus exists on the bleeding risk nor haemostatic parameter thresholds that define the safety of invasive procedures in patients with cirrhosis. The aim of this study was to establish a position paper on the bleeding risk associated with invasive procedures in patients with cirrhosis among the experts involved in various guidelines. Methods: All experts involved in recent guidelines on the management of invasive procedures in patients with cirrhosis were invited to classify 80 procedures as ''high risk'' or ''low risk'' with respect to bleeding. Procedures were considered high risk when the estimated risk of major bleeding was 1.5% or more, or when even minor bleeding might lead to significant morbidity or death. The experts were also asked to choose safety thresholds for laboratory test values at which elective invasive procedures could be safely performed. The predetermined threshold considered as “consensus” was ≥75% agreement. Results: Fifty-two experts participated in the study. Out of 80 procedures, a consensus opinion was reached for 52 procedures (65%): 17 procedures were classified as “high risk”, primarily interventional endoscopic procedures, percutaneous organ biopsies, or procedures involving the central nervous system; and 35 as “low risk”, primarily “diagnostic” procedures. The lowest platelet counts at which performance of a low-risk procedure or a high-risk procedure/surgery were deemed acceptable were 30 × 109/L and 50 × 109/L, respectively. Experts did not believe that international normalised ratio should be considered before performing low-risk procedures; 71% also indicated that it should not be considered before performing high-risk procedures. Conclusions: This experience-based classification may be helpful to refine future study designs and to guide clinical decision making regarding invasive procedures in patients with cirrhosis. Impact and implications: Several risk classifications and management guidelines for invasive procedures in patients with cirrhosis have been proposed, but with conflicting recommendations. By providing a position paper, based on the opinion of a broad panel of experts, on the bleeding risk associated with 52 invasive procedures in patients with cirrhosis, this survey will help to provide a framework for future study design. The consensus on platelet count, international normalised ratio, fibrinogen and activated partial thromboplastin time identified in this survey will inform physicians regarding the laboratory test values considered acceptable by the experts prior to the performance of an elective invasive procedure in patients with cirrhosis.

Background The enhanced liver fibrosis ( ELF) test has been introduced to screen, diagnose and/or monitor liver conditions in large groups of patients with liver diseases. It has not been used in inflammatory skin or joint diseases. Objectives To evaluate the distribution of the ELF test, apply existing cut-offs for hepatic patients and healthy controls, and compare it with the procollagen-3 N-terminal peptide (P3 NP) test in patients with psoriasis ( PSO), psoriatic arthritis (PsA) and rheumatoid arthritis ( RA), and controls. Methods In total, 531 patients were included. Demographic, lifestyle and disease-specific data were collected. ELF and P3 NP tests were performed. Results Prevalence of an increased ELF score (> 11) and P3 NP was highest in patients with RA (7·7% and 6·1%, respectively) followed by patients with PSO (1·7% and 5·2%, respectively) and PsA (0·7% and 1·3%, respectively). Mean ± SD ELF scores for PSO, PsA and RA were, respectively, 9·09 ± 0·86, 8·96 ± 0·76 and 9·55 ± 1·04. All subgroups with moderate-to-severe disease severity had higher (> 9·8) ELF scores ( PSO 27·0% vs. 18·3%; PsA 19·2% vs. 12%; RA 45·8% vs. 30·5%) and P3 NP values. Distribution of the ELF score was smaller than the P3 NP value [mean ± SD: 9·15 ± 0·92 (range 6·53-13·05) vs. 8·37 ± 4·30 (range 0·53-63·88)]. Conclusions ELF score and P3 NP are elevated in PSO, PsA and RA. ELF may be superior to P3 NP alone, but further research should be done to validate the ELF test in determining susceptibility for developing liver fibrosis in PSO, PsA and RA. [ABSTRACT FROM AUTHOR]

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., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background: Small adult patients with end-stage liver disease waitlisted for liver transplantation may face a shortage of size-matched liver grafts. This may result in longer waiting times, increased waitlist removal, and waitlist mortality. This study aims to assess access to transplantation in transplant candidates with below-average bodyweight throughout the Eurotransplant region., Methods: Patients above 16 y of age listed for liver transplantation between 2010 and 2015 within the Eurotransplant region were eligible for inclusion. The effect of bodyweight on chances of receiving a liver graft was studied in a Cox model corrected for lab-Model for End-stage Liver Disease (MELD) score updates fitted as time-dependent variable, blood type, listing for malignant disease, and age. A natural spline with 3 degrees of freedom was used for bodyweight and lab-MELD score to correct for nonlinear effects., Results: At the end of follow-up, the percentage of transplanted, delisted, and deceased waitlisted patients was 49.1%, 17.9%, and 24.3% for patients with a bodyweight <60 kg (n = 1267) versus 60.1%, 15.1%, and 18.6% for patients with a bodyweight ≥60 kg (n = 10 520). To reach comparable chances for transplantation, 60-kg and 50-kg transplant candidates are estimated to need, respectively, up to 2.8 and 4.0 more lab-MELD points than 80-kg transplant candidates., Conclusions: Decreasing bodyweight was significantly associated with decreased chances to receive a liver graft. This resulted in substantially longer waiting times, higher delisting rates, and higher waitlist mortality for patients with a bodyweight <60 kg., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The aim of this open-label, multicenter, randomized controlled study was to investigate whether the life cycle pharma (LCP)-tacrolimus compared with the extended-release (ER)-tacrolimus formulation results in a difference in the prevalence of posttransplant diabetes, hypertension and chronic kidney disease (CKD) at 12 mo after liver transplantation., Methods: Patients were 1:1 randomized to either of the 2 tacrolimus formulations. The primary endpoint was defined as a composite endpoint of any of 3 events: sustained (>3 mo postrandomization) posttransplant diabetes, new-onset hypertension, and/or CKD, defined as estimated glomerular filtration rate <60 mL/min/1.73 m 2 for >3 m during the follow-up., Results: In total, 105 patients were included. In the intention-to-treat analysis, a statistically significant lower proportion of liver transplant recipients in the LCP-tacrolimus group reached the composite primary endpoint at 12 mo compared with the ER-tacrolimus group (50.9% [27/53], 95% confidence interval [CI], 37.9%-63.9% versus 71.2% [37/52], 95% CI, 57.7%-81.7%; risk difference: 0.202; 95% CI, 0.002-0.382; P  = 0.046). No significant difference was found in the per protocol analysis. In the intention-to-treat and per protocol population, fewer liver transplant recipients in the LCP-tacrolimus group developed CKD and new-onset hypertension compared with the ER-tacrolimus group. No differences in rejection rate, graft and patient survival were found., Conclusions: A statistically significant and clinically relevant reduction in the prevalence of the composite primary endpoint was found in the LCP-tacrolimus group compared with the ER-tacrolimus group in the first year after liver transplantation with comparable efficacy., Competing Interests: D.A.H. has received lecture fees and consulting fees from Astellas Pharma, Astra Zeneca, Chiesi Pharma, Medincell, Novartis Pharma, Sangamo Therapeutics, and Vifor Pharma. He has received grant support from Astellas Pharma, Bristol-Myers Squibb, and Chiesi Pharma (paid to his institution). D.A.H. does not have employment or stock ownership at any of these companies, and neither does he have patents or patent applications. H.J.M. has received lecture fees from Astellas Pharma and received grant support from Astellas Pharma, Novartis Pharma, and Chiesi Pharma. C.M.d.H. has received lecture fees and consulting fees from Chiesi Pharma, Takeda, Novartis Pharma, and Abacus medical and travel grants from Orphalan. C.M.d.H. does not have employment or stock ownership at any of these companies, and neither does he have patents or patent applications. The other authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Background and Aims: Since the introduction of SARS-CoV-2 vaccines, several cases of vaccine-induced immune thrombocytopenia and thrombosis (VITT) have been described, especially cerebral vein thrombosis. We aimed to retrospectively collect all new cases of acute onset first or recurrent splanchnic vein thrombosis (SVT) following a recent SARS-CoV-2 vaccination within the Vascular Liver Disease Group network., Approach and Results: New cases of SVT were identified from April 2021 to April 2022; follow-up was completed on December 31, 2022. Criteria to define VITT were derived from previous studies. Data from a pre-COVID cohort of patients with SVT (N=436) were used for comparison of clinical presentation, etiology, and outcome. Twenty-nine patients were identified with SVT occurring with a median of 11 days (range 2-76) after the first (48%), second (41%), or third (10%) vaccination (ChAdOx1 nCov-19 (n=12) or BNT162b2 (n=14), other (n=3) Only 2 patients(7%) fulfilled criteria for definite VITT. Twenty (69%) had SVT at multiple sites, including 4 (14%) with concomitant extra-abdominal thrombosis. Only 28% had an underlying prothrombotic condition, compared to 52% in the pre-COVID SVT cohort ( p =0.01). Five patients (17%) underwent bowel resection for mesenteric ischemia, compared with 3% in pre-COVID SVT ( p <0.001). Two patients died shortly after diagnosis (7%)., Conclusions: Although definite VITT was rare, in 72% of cases, no other cause for SVT could be identified following SARS-CoV-2 vaccination. These cases were different from patients with nonvaccine-related SVT, with lower incidence of prothrombotic conditions, higher rates of bowel ischemia, and poorer outcome. Although SVT after SARS-CoV-2 vaccination is rare in absolute terms, these data remain relevant considering ongoing revaccination programs., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Early detection of liver transplantation (LT) vascular complications enables timely management. Our aim was to assess if routine Doppler ultrasound (rDUS) improves the detection of hepatic artery thrombosis (HAT), portal vein thrombosis (PVT) and hepatic venous outflow obstruction (HVOO). We retrospectively analysed timing and outcomes, number needed to diagnose one complication (NND) and positive predictive value (PPV) of rDUS on post-operative day (POD) 0,1 and 7 in 708 adult patients who underwent primary LT between 2010-2022. We showed that HAT developed in 7.1%, PVT in 8.2% and HVOO in 3.1% of patients. Most early complications were diagnosed on POD 0 (26.9%), 1 (17.3%) and 5 (17.3%). rDUS correctly detected 21 out of 26 vascular events during the protocol days. PPV of rDUS was 53.8%, detection rate 1.1% and NND was 90.5. Median time to diagnosis was 4 days for HAT and 47 days for PVT and 21 days for HVOO. After intervention, liver grafts were preserved in 57.1%. In conclusion, rDUS protocol helps to detect first week's vascular events, but with low PPV and a high number of ultrasounds needed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Minciuna, den Hoed, van der Meer, Sonneveld, Sprengers, de Knegt, de Jonge, Maan, Polak and Darwish Murad.)

Objective: To define benchmark values for liver transplantation (LT) in patients with perihilar cholangiocarcinoma (PHC) enabling unbiased comparisons., Background: Transplantation for PHC is used with reluctance in many centers and even contraindicated in several countries. Although benchmark values for LT are available, there is a lack of specific data on LT performed for PHC., Methods: PHC patients considered for LT after Mayo-like protocol were analyzed in 17 reference centers in 2 continents over the recent 5-year period (2014-2018). The minimum follow-up was 1 year. Benchmark patients were defined as operated at high-volume centers (≥50 overall LT/year) after neoadjuvant chemoradiotherapy, with a tumor diameter <3 cm, negative lymph nodes, and with the absence of relevant comorbidities. Benchmark cutoff values were derived from the 75th to 25th percentiles of the median values of all benchmark centers., Results: One hundred thirty-four consecutive patients underwent LT after completion of the neoadjuvant treatment. Of those, 89.6% qualified as benchmark cases. Benchmark cutoffs were 90-day mortality ≤5.2%; comprehensive complication index at 1 year of ≤33.7; grade ≥3 complication rates ≤66.7%. These values were better than benchmark values for other indications of LT. Five-year disease-free survival was largely superior compared with a matched group of nodal negative patients undergoing curative liver resection (n=106) (62% vs 32%, P <0.001)., Conclusion: This multicenter benchmark study demonstrates that LT offers excellent outcomes with superior oncological results in early stage PHC patients, even in candidates for surgery. This provocative observation should lead to a change in available therapeutic algorithms for PHC., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background & Aims: Liver transplantation (LT) for primary sclerosing cholangitis (PSC) is complicated by recurrence of PSC (rPSC) in up to 25% of recipients. Recurrence has been shown to be detrimental for both graft and patient survival. For both PSC and rPSC, a medical cure is not available. To predict and ideally to prevent rPSC, it is imperative to find risk factors for rPSC that can be potentially modified. Therefore, we aimed to identify such factors for rPSC in a large international multicentre study including 6 centres in PSC-prevalent countries., Methods: In this international multicentre, retrospective cohort study, 531 patients who underwent transplantation for PSC were included. In 25% of cases (n = 131), rPSC was diagnosed after a median follow-up of 6.72 (3.29-10.11) years post-LT., Results: In the multivariable competing risk model with time-dependent covariates, we found that factors representing an increased inflammatory state increase the risk for rPSC. Recurrent cholangitis before LT as indication for LT (hazard ratio [HR] 3.6, 95% CI 2.5-5.2), increased activity of inflammatory bowel disease after LT (HR 1.7, 95% CI 1.08-2.75), and multiple acute cellular rejections (HR: non-linear) were significantly and independently associated with an increased risk of rPSC. In contrast to the findings of previous studies, pretransplant colectomy was not found to be independently protective against the development of rPSC., Conclusions: An increased inflammatory state before and after LT may play a causal and modifiable role in the development of rPSC. Pretransplant colectomy did not reduce the risk of rPSC per se . Recurrent cholangitis as indication for LT was associated with an increased risk of rPSC., Impact and Implications: Recurrence of PSC (rPSC) negatively affects survival after liver transplant (LT). Modifiable risk factors could guide clinical management and prevention of rPSC. We demonstrate that an increased inflammatory state both before and after LT increases the incidence of rPSC. As these are modifiable factors, they could serve as targets for future studies and therapies. We also added further evidence to the ongoing debate regarding preventive colectomy for rPSC by reporting that in our multicenter study, we could not find an independent association between colectomy and risk of rPSC., Competing Interests: The authors who have taken part in this study declared that they do not have any conflict of interest with respect to this manuscript. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Author(s).)

Objective: To evaluate current practice and outcomes of pregnancy in women previously diagnosed with Budd-Chiari syndrome and/or portal vein thrombosis, with and without concomitant portal hypertension., Design and Setting: Multicentre retrospective cohort study between 2008 and 2021., Population: Women who conceived in the predefined period after the diagnosis of Budd-Chiari syndrome and/or portal vein thrombosis., Methods and Main Outcome Measures: We collected data on diagnosis and clinical features. The primary outcomes were maternal mortality and live birth rate. Secondary outcomes included maternal, neonatal and obstetric complications., Results: Forty-five women (12 Budd-Chiari syndrome, 33 portal vein thrombosis; 76 pregnancies) were included. Underlying prothrombotic disorders were present in 23 of the 45 women (51%). Thirty-eight women (84%) received low-molecular-weight heparin during pregnancy. Of 45 first pregnancies, 11 (24%) ended in pregnancy loss and 34 (76%) resulted in live birth of which 27 were at term (79% of live births and 60% of pregnancies). No maternal deaths were observed; one woman developed pulmonary embolism during pregnancy and two women (4%) had variceal bleeding requiring intervention., Conclusions: The high number of term live births (79%) and lower than expected risk of pregnancy-related maternal and neonatal morbidity in our cohort suggest that Budd-Chiari syndrome and/or portal vein thrombosis should not be considered as an absolute contraindication for pregnancy. Individualised, nuanced counselling and a multidisciplinary pregnancy surveillance approach are essential in this patient population., Tweetable Abstract: Budd-Chiari syndrome and/or portal vein thrombosis should not be considered as an absolute contraindication for pregnancy., (© 2021 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Liver transplantation for primary sclerosing cholangitis (PSC) can be complicated by recurrence of PSC (rPSC). This may compromise graft survival but the effect on patient survival is less clear. We investigated the effect of post-transplant rPSC on graft and patient survival in a large European cohort. Registry data from the European Liver Transplant Registry regarding all first transplants for PSC between 1980 and 2015 were supplemented with detailed data on rPSC from 48 out of 138 contributing transplant centres, involving 1,549 patients. Bayesian proportional hazards models were used to investigate the impact of rPSC and other covariates on patient and graft survival. Recurrence of PSC was diagnosed in 259 patients (16.7%) after a median follow-up of 5.0 years (quantile 2.5%-97.5%: 0.4-18.5), with a significant negative impact on both graft (HR 6.7; 95% CI 4.9-9.1) and patient survival (HR 2.3; 95% CI 1.5-3.3). Patients with rPSC underwent significantly more re-transplants than those without rPSC (OR 3.6, 95% CI 2.7-4.8). PSC recurrence has a negative impact on both graft and patient survival, independent of transplant-related covariates. Recurrence of PSC leads to higher number of re-transplantations and a 33% decrease in 10-year graft survival., (© 2021 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.)

Background: Despite immunosuppressive drug regimens, T cell-mediated rejection, antibody-mediated rejection with donor-specific antibodies, and chronic rejection occur after liver transplantation (LTx). Rejection may significantly impact allograft survival and often a standard re-LTx is required. However, in some cases rejection recurs. Little is known on how to approach this and which aspects to consider., Case: Here we describe a case in which two successive liver grafts where lost due to T cell-mediated rejection, possible antibody-mediated rejection with de novo donor-specific antibody formation, and chronic rejection that occurred within a month. In an attempt to avoid recurrence with the third graft, we decided to administer a more rigorous immunosuppressive drug induction regimen with rabbit antithymocyte globulin, while applying HLA matching between recipient and donor. This resulted in rejection free survival for 337 days until a mild T cell-mediated rejection occurred, which could then be easily treated with high dose steroids. Graft survival is now at least 683 days without chronic rejection, antibody-mediated rejection or de novo donor-specific antibody formation., Conclusion: In conclusion, when a liver graft is lost due to multiple forms of rejection short after LTx, the combination applied in this case could be considered as a viable option to improve graft and patient survival instead of a standard re-LTx., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: After liver transplantation (LTx), adherence to immunosuppressive medication and avoidance of contra-indicated drugs is essential for long-term survival. This study aimed to investigate the prevalence, types and severity of medication-related problems (MRPs) and interventions initiated by a clinical pharmacist (CP) in a cohort of LTx recipients in the outpatient setting. Method: This study was a retrospective, observational study in LTx recipients that visited the outpatient clinic for an annual check-up. A 20-minutes consultation with a CP consisted of medication reconciliation and consultation about medication, adherence, and adverse drug reactions (ADRs). Discrepancies between actual and intended drug use, and MRPs were identified and the severity of MRPs was assessed. Potential interventions were discussed with the patient and the treating physician and evaluated after one year. Results: The CP counseled 64 LTx recipients and found 96 discrepancies in 37 patients. Most discrepancies (60.4%, n = 58) concerned missing medications. In total, 98 MRPs were identified in 53 patients (median 2; range 1-5 per patient), with a total of 113 interventions. Most frequent MRPs were: ADRs (22.4%, n = 22), nonadherence (19.3%, n = 19), unnecessary drugs (16.3%, n = 16) and undertreatment (12.2%, n = 12). Interventions most frequently proposed included optimization of dosage regimen (21.2%, n = 24), individualized recommendation regarding compliance (16.8%, n = 19) and drug discontinuation (12.4%, n = 14). After one year, 15 of the 19 patients (79%) experienced no longer compliance issues and 27 of the 29 patients (93%) used no drugs with indication issues anymore. Conclusion: The CP in an outpatient monitoring program for LTx recipients can signal relevant discrepancies and MRPs. This leads to interventions that are accepted by both the patients and the physicians, with a positive effect after one year., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mulder, Borgsteede, Darwish Murad, Landman, Metselaar and Hunfeld.)

Background: Transplantation of livers obtained from donors after circulatory death is associated with an increased risk of nonanastomotic biliary strictures. Hypothermic oxygenated machine perfusion of livers may reduce the incidence of biliary complications, but data from prospective, controlled studies are limited., Methods: In this multicenter, controlled trial, we randomly assigned patients who were undergoing transplantation of a liver obtained from a donor after circulatory death to receive that liver either after hypothermic oxygenated machine perfusion (machine-perfusion group) or after conventional static cold storage alone (control group). The primary end point was the incidence of nonanastomotic biliary strictures within 6 months after transplantation. Secondary end points included other graft-related and general complications., Results: A total of 160 patients were enrolled, of whom 78 received a machine-perfused liver and 78 received a liver after static cold storage only (4 patients did not receive a liver in this trial). Nonanastomotic biliary strictures occurred in 6% of the patients in the machine-perfusion group and in 18% of those in the control group (risk ratio, 0.36; 95% confidence interval [CI], 0.14 to 0.94; P = 0.03). Postreperfusion syndrome occurred in 12% of the recipients of a machine-perfused liver and in 27% of those in the control group (risk ratio, 0.43; 95% CI, 0.20 to 0.91). Early allograft dysfunction occurred in 26% of the machine-perfused livers, as compared with 40% of control livers (risk ratio, 0.61; 95% CI, 0.39 to 0.96). The cumulative number of treatments for nonanastomotic biliary strictures was lower by a factor of almost 4 after machine perfusion, as compared with control. The incidence of adverse events was similar in the two groups., Conclusions: Hypothermic oxygenated machine perfusion led to a lower risk of nonanastomotic biliary strictures following the transplantation of livers obtained from donors after circulatory death than conventional static cold storage. (Funded by Fonds NutsOhra; DHOPE-DCD ClinicalTrials.gov number, NCT02584283.)., (Copyright © 2021 Massachusetts Medical Society.)

Background: Liver transplantation (LT) has been performed in a select group of patients presenting with unresectable or primary sclerosing cholangitis (PSC)-associated perihilar cholangiocarcinoma (pCCA) in the Mayo Clinic with a reported 5-year overall survival (OS) of 53% on intention-to-treat analysis. The objective of this study was to estimate eligibility for LT in a cohort of pCCA patients in two tertiary referral centers., Methods: Patients diagnosed with pCCA between 2002 and 2014 were included from two tertiary referral centers in the Netherlands. The selection criteria used by the Mayo Clinic were retrospectively applied to determine the proportion of patients that would have been eligible for LT., Results: A total of 732 consecutive patients with pCCA were identified, of whom 24 (4%) had PSC-associated pCCA. Overall, 154 patients had resectable disease on imaging and 335 patients were ineligible for LT because of lymph node or distant metastases. An age limit of 70 years led to the exclusion of 50 patients who would otherwise be eligible for LT. After applying the Mayo Clinic criteria, only 34 patients (5%) were potentially eligible for LT. Median survival from diagnosis for these 34 patients was 13 months (95% CI 3-23)., Conclusion: Only 5% of all patients presenting with pCCA were potentially eligible for LT under the Mayo criteria. Without transplantation, a median OS of about 1 year was observed.

Background and Aims: Previous small studies have appraised the gut microbiome (GM) in steatosis, but large-scale studies are lacking. We studied the association of the GM diversity and composition, plasma metabolites, predicted functional metagenomics, and steatosis., Approach and Results: This is a cross-sectional analysis of the prospective population-based Rotterdam Study. We used 16S ribosomal RNA gene sequencing and determined taxonomy using the SILVA reference database. Alpha diversity and beta diversity were calculated using the Shannon diversity index and Bray-Curtis dissimilarities. Differences were tested across steatosis using permutational multivariate analysis of variance. Hepatic steatosis was diagnosed by ultrasonography. We subsequently selected genera using regularized regression. The functional metagenome was predicted based on the GM using Kyoto Encyclopedia of Genes and Genomes pathways. Serum metabolomics were assessed using high-throughput proton nuclear magnetic resonance. All analyses were adjusted for age, sex, body mass index, alcohol, diet, and proton-pump inhibitors. We included 1,355 participants, of whom 472 had steatosis. Alpha diversity was lower in steatosis (P = 1.1∙10 -9 ), and beta diversity varied across steatosis strata (P = 0.001). Lasso selected 37 genera of which three remained significantly associated after adjustment (Coprococcus3: β = -65; Ruminococcus Gauvreauiigroup: β = 62; and Ruminococcus Gnavusgroup: β = 45, Q-value = 0.037). Predicted metagenome analyses revealed that pathways of secondary bile-acid synthesis and biotin metabolism were present, and D-alanine metabolism was absent in steatosis. Metabolic profiles showed positive associations for aromatic and branched chain amino acids and glycoprotein acetyls with steatosis and R. Gnavusgroup, whereas these metabolites were inversely associated with alpha diversity and Coprococcus3., Conclusions: We confirmed, on a large-scale, the lower microbial diversity and association of Coprococcus and Ruminococcus Gnavus with steatosis. We additionally showed that steatosis and alpha diversity share opposite metabolic profiles., (© 2020 by the American Association for the Study of Liver Diseases.)

Background: Fatty liver disease (FLD) is the most common cause of liver dysfunction in developed countries. There is great interest in developing clinically valid and minimally invasive biomarkers to enhance early diagnosis of FLD., Aim: To investigate the potential of circulatory microRNAs (miRNAs) as biomarkers of FLD at the population level., Methods: Plasma levels of 2083 miRNAs were measured by RNA sequencing in 1999 participants from the prospective population-based Rotterdam Study cohort. The Hounsfield Unit (HU) attenuation of liver was measured using non-enhanced computed tomography (CT) scan. Logistic and linear regression models adjusting for potential confounders were used to examine the association of circulatory miRNAs with liver enzymes (n = 1991) and CT-based FLD (n = 954). Moreover, the association of miRNAs with hepatic steatosis and liver fibrosis was assessed longitudinally in individuals who underwent abdominal ultrasound (n = 1211) and transient elastography (n = 777) after a median follow-up of >6 years., Results: Cross-sectional analysis showed 61 miRNAs significantly associated with serum gamma-glutamyl transferase and/or alkaline phosphatase levels (Bonferroni-corrected P < 8.46 × 10 -5 ). Moreover, 17 miRNAs were significantly associated with CT-based FLD (P < 8.46 × 10 -5 ); 14 were among miRNAs associated with liver enzymes. Longitudinal analysis showed that 4 of these 14 miRNAs (miR-193a-5p, miR-122-5p, miR-378d and miR-187-3p) were significantly associated with hepatic steatosis (P < 3.57 × 10 -3 ) and three (miR-193a-5p, miR-122-5p and miR-193b-3p) were nominally associated with liver fibrosis (P < 0.05). Nine of the 14 identified miRNAs were involved in pathways underlying liver diseases., Conclusions: Plasma levels of several miRNAs can be used as biomarkers of FLD, laying the groundwork for future clinical applications., (© 2020 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

With the growing incidence of diabetes mellitus (DM), an increasing number of organ donors with DM can be expected. We sought to investigate the association between donor DM with early post-transplant outcomes. From a national cohort of adult liver transplant recipients (1996-2016), all recipients transplanted with a liver from a DM donor (n = 69) were matched 1:2 with recipients of livers from non-DM donors (n = 138). The primary end-point included early post-transplant outcome, such as the incidence of primary nonfunction (PNF), hepatic artery thrombosis (HAT), and 90-day graft survival. Cox regression analysis was used to analyze the impact of donor DM on graft failure. PNF was observed in 5.8% of grafts from DM donors versus 2.9% of non-DM donor grafts (P = 0.31). Recipients of grafts derived from DM donors had a higher incidence of HAT (8.7% vs. 2.2%, P = 0.03) and decreased 90-day graft survival (88.4% [70.9-91.1] vs. 96.4% [89.6-97.8], P = 0.03) compared to recipients of grafts from non-DM donors. The adjusted hazard ratio for donor DM on graft survival was 2.21 (1.08-4.53, P = 0.03). In conclusion, donor DM is associated with diminished outcome early after liver transplantation. The increased incidence of HAT after transplantation of livers from DM donors requires further research., (© 2020 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.)

Dietary lifestyle intervention is key in treating non-alcoholic fatty liver disease (NAFLD). We aimed to examine the longitudinal relation between well-established dietary patterns as well as population-specific dietary patterns and NAFLD. Participants from two subsequent visits of the Rotterdam Study were included. All underwent serial abdominal ultrasonography (median follow-up: 4.4 years) and filled in a food frequency questionnaire. Secondary causes of steatosis were excluded. Dietary data from 389 items were collapsed into 28 food groups and a posteriori dietary patterns were identified using factor analysis. Additionally, we scored three a priori dietary patterns (Mediterranean Diet Score, Dutch Dietary Guidelines and WHO-score). Logistic mixed regression models were used to examine the relation between dietary patterns and NAFLD. Analyses were adjusted for demographic, lifestyle and metabolic factors. We included 963 participants of whom 343 had NAFLD. Follow-up data was available in 737 participants. Incident NAFLD was 5% and regressed NAFLD was 30%. We identified five a posteriori dietary patterns (cumulative explained variation [R 2 ] = 20%). The patterns were characterised as: vegetable and fish, red meat and alcohol, traditional, salty snacks and sauces, high fat dairy & refined grains pattern. Adherence to the traditional pattern (i.e. high intake of vegetable oils/stanols, margarines/butters, potatoes, whole grains and sweets/desserts) was associated with regression of NAFLD per SD increase in Z-score (0.40, 95% CI 0.15-1.00). Adherence to the three a priori patterns all showed regression of NAFLD, but only the WHO-score showed a distinct association (0.73, 95% CI 0.53-1.00). Hence, in this large elderly population, adherence to a plant-based, high-fibre and low-fat diet was related to regression of NAFLD.

Primary sclerosing cholangitis (PSC) is a common indication for liver transplantation (LT). Up to 25% of patients experience recurrence of PSC (rPSC) after LT, which is associated with significant morbidity and mortality. To date, it is not possible to predict which patients are at risk for rPSC. The aetiology of PSC is complex and is speculated to involve translocation of intestinal bacteria to the liver, because of its frequent co-occurrence with inflammatory bowel diseases (IBD). Here, we investigate whether the mucosal intestinal microbiome of PSC patients (n = 97) at time of first LT can identify those patients who will develop rPSC. 16S gene sequencing of bacterial DNA isolated from formalin-fixed paraffin-embedded biopsies showed that PSC patients with Crohn's disease (n = 15) have a reduced microbial diversity and that inflammation of the mucosa is associated with beta-diversity changes and feature differences. No differences in alpha- or beta diversity were observed between patients with rPSC (n = 14) and without rPSC (n = 83). However, many over-represented bacterial features were detected in patients with rPSC, while surprisingly, those without recurrence of disease were characterized by an increased presence of the Gammaproteobacteria Shigella. This pilot study warrants further investigation into bacterial differences between rPSC and non-rPSC patients., (© 2020 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.)

Introduction  Timely diagnosis and treatment of portal vein thrombosis (PVT) is crucial to prevent morbidity and mortality. However, current imaging tests cannot always accurately differentiate acute from chronic (nonocclusive) PVT. Magnetic resonance noncontrast thrombus imaging (MR-NCTI) has been shown to accurately differentiate acute from chronic venous thrombosis at other locations and may also be of value in the diagnostic management of PVT. This study describes the first phase of the Rhea study (NTR 7061). Our aim was to select and optimize MR-NCTI sequences that would be accurate for differentiation of acute from chronic PVT. Study Design  The literature was searched for different MRI sequences for portal vein and acute thrombosis imaging. The most promising sequences were tested in a healthy volunteer followed by one patient with acute PVT and two patients with chronic PVT, all diagnosed on (repetitive) contrast-enhanced computed tomography (CT) venography to optimize the MR-NCTI sequences. All images were evaluated by an expert panel. Results  Several MR-NCTI sequences were identified and tested. Differentiation of acute from chronic PVT was achieved with 3D T1 TFE (three-dimensional T1 turbo field echo) and 3D T1 Dixon FFE (three-dimensional T1 fast field echo) sequences with best image quality. The expert panel was able to confirm the diagnosis of acute PVT on the combined two MR-NCTI sequences and to exclude acute PVT in the two patients with chronic PVT. Conclusion  Using 3D T1 TFE and 3D T1 Dixon FFE sequences, we were able to distinguish acute from chronic PVT. This clinical relevant finding will be elucidated in clinical studies to establish their test performance., Competing Interests: Conflict of Interest None declared.

Background: Donor hepatectomy time is associated with graft survival after liver transplantation. The aim of this study was to identify the impact of donor hepatectomy time on biliary injury during donation after circulatory death liver transplantation., Methods: First, bile duct biopsies of livers included in (pre)clinical machine perfusion research were analyzed. Secondly, of the same livers, bile samples were collected during normothermic machine perfusion. Lastly, a nationwide retrospective cohort study was performed including 273 adult patients undergoing donation after circulatory death liver transplantation between January 1, 2002 and January 1, 2017. Primary endpoint was development of non-anastomotic biliary strictures within 2 years of donation after circulatory death liver transplantation. Cox proportional-hazards regression analyses were used to assess the influence of hepatectomy time on the development of non-anastomotic biliary strictures., Results: Livers with severe histological bile duct injury had a higher median hepatectomy time (P = .03). During normothermic machine perfusion, livers with a hepatectomy time >50 minutes had lower biliary bicarbonate and bile pH levels. In the nationwide retrospective study, donor hepatectomy time was an independent risk factor for non-anastomotic biliary strictures after donation after circulatory death liver transplantation (Hazard Ratio 1.18 per 10 minutes increase, 95% Confidence Interval 1.06-1.30, P value = .002)., Conclusion: Donor hepatectomy time negatively influences histological bile duct injury before normothermic machine perfusion and bile composition during normothermic machine perfusion. Additionally, hepatectomy time is a significant independent risk factor for the development of non-anastomotic biliary strictures after donation after circulatory death liver transplantation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Due to the growing number of liver transplantations (LTs), there is an increasing number of patients requiring retransplantation (reLT). Data on the use of grafts from extended criteria donors (ECD), especially donation after circulatory death (DCD), for reLT are lacking. We aimed to assess the outcome of patients undergoing reLT using a DCD graft in the Netherlands between 2001 and July 2018. Propensity score matching was used to match each DCD-reLT with three DBD-reLT cases. Primary outcomes were patient and graft survival. Secondary outcome was the incidence of biliary complications, especially nonanastomotic strictures (NAS). 21 DCD-reLT were compared with 63 matched DBD-reLTs. Donors in the DCD-reLT group had a significantly lower BMI (22.4 vs. 24.7 kg/m 2 , P-value = 0.02). Comparison of recipient demographics and ischemia times yielded no significant differences. Patient and graft survival rates were comparable between the two groups. However, the occurrence of nonanastomotic strictures after DCD-reLT was significantly higher (38.1% vs. 12.7%, P-value = 0.02). ReLT with DCD grafts does not result in inferior patient and graft survival compared with DBD grafts in selected patients. Therefore, DCD liver grafts should not routinely be declined for patients awaiting reLT., (© 2020 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.)