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.

Shear wave elastography and shear wave dispersion correlated to biopsy at the scheduled follow-up of pediatric liver grafts.

BACKGROUND: It is unknown how shear wave dispersion (SWD) is displayed in pediatric liver transplant recipients and not fully elucidated how ultrasound shear wave elastography (2D-SWE) display within this cohort, which is important to determine to improve noninvasive surveillance of these patients. The study aimed to compare SWE and SWD values with histopathology in pediatric liver recipients. METHODS: Forty-eight pediatric liver recipients were examined with SWE in conjunction with an elective liver biopsy (clinically without complication). Additionally, SWD values were measured in 21 children. SWE and SWD values were compared to histologically determined fibrosis graded as none-to-mild (F0-1) and moderate-to-severe (F2-4), and inflammation graded as low (grade 0-1) and high (grade 2-4). RESULTS: Two children were excluded due to SWE IQR/median > 30% kPa. The mean age across 46 included patients was 10.9 years (range 1.4-18). The number of patients and median (range) SWE value (kPa) for each stage of fibrosis were: F0-1 [n = 23; 5.8 (3.2-16.1)], F2 [n = 22; 6.0 (4.5-25.9)], F3 [n = 1; 33.3], and F4 [n = 0]. Significantly higher SWE values and greater variability were registered in F2-4 vs. F0-1 (p = .05). Grade of fibrosis correlated weakly to SWE values (r = .3; p = .05), but not to SWD values (r = .2; p = .27). In patients with low-grade inflammation, median SWD was 13.7 m/s KHz (10.7-17.6). Only one patient had high-grade inflammation. CONCLUSIONS: Uncomplicated transplanted liver grafts in a small pediatric cohort revealed slightly increased SWE and SWD values compared to previously reported values in healthy children. This likely reflect both the fibrotic and inflammatory elements in the grafts; however, other confounders impacting the liver's viscoelastic properties are also probable factors.

Primary hyperparathyroidism in pregnancy: experience of a tertiary centre.

BACKGROUND AND PURPOSE: The management of primary hyperparathyroidism (PHPT) during pregnancy is challenging and there is no clear consensus on whether it increases the risk of complications in pregnancy. We conducted this study to review the maternal and fetal outcomes of pregnant women treated for PHPT in a single centre. METHODS: Data on relevant clinical parameters, demographics, management strategies, maternal and fetal outcomes were collected from the medical records of pregnant patients with PHPT diagnosed between 2012 and 2019. RESULTS: Of 15 pregnant women with PHPT, 6 were managed medically and 9 underwent surgery. The median age at their index pregnancy was 28 years [range 19-42]. The median highest adjusted calcium level in the medical group was 2.90 [range 2.61-3.25] mmol/L vs. 3.11 [2.78-4.95] mmol/L in the surgical group. There was one miscarriage and the stillbirth of twins in the medical group, but no such outcomes in the surgical group. The median gestational ages were 39 + 3 weeks [range 24 + 2-41 + 2 weeks] and 39 + 4 weeks [range 37 + 1-39 + 5 weeks] in the medical and surgical groups, respectively. No birth was complicated by neonatal tetany or convulsions. CONCLUSION: More complications developed in the pregnant PHPT patients who were managed medically than in those who underwent surgery. Surgery performed during the second trimester resulted in good outcomes. Multi-centre prospective studies are required to ascertain the risk of various complications in women with PHPT during pregnancy.

Renal function after liver transplantation: Real-world experience with basiliximab induction and delayed reduced-dose tacrolimus.

BACKGROUND: Routine use of delayed reduced-dose calcineurin-inhibitor treatment with induction immunosuppression in liver transplantation to minimize post-operative kidney injury is still scarce. AIM: To evaluate real-world experience of basiliximab induction with delayed reduced-dose tacrolimus. METHODS: In a retrospective cohort study, kidney function was evaluated pre- and postoperatively by measured glomerular filtration rate (mGFR). Adult patients undergoing liver transplantation between 2000 and 2017 were divided into a conventional treatment group (immediate-introduction of tacrolimus, target trough levels 10-15 ng/mL, and corticosteroids, n = 203) and a revised treatment group (basiliximab induction, reduced-dose tacrolimus, target through levels 5-8 ng/mL, delayed until day three, and mycophenolate mofetil 2000 mg/day, n = 343). RESULTS: Mean mGFR was similar between groups at wait-listing (85.3 vs 84.1 ml/min/1.73m², p = 0.60), but higher in the revised treatment group at 3 (56.8 vs 63.4 ml/min/1.73m², p = 0.004) and 12 months post-transplant (60.9 vs 69.7 ml/min/1.73m², p<0.001); this difference remained after correcting for multiple confounders and was independent of pre-transplant mGFR. In the revised treatment group, biopsy proven acute rejection rate was lower (38% vs. 21%, p<0.001), and graft-survival better (p = 0.01). CONCLUSION: Basiliximab induction with delayed reduced-dose tacrolimus is associated with less kidney injury when compared to standard-dose tacrolimus, without increased risk of rejection, graft loss or death.

Impact of muscle mass on survival of patients with hepatocellular carcinoma after liver transplantation beyond the Milan criteria.

BACKGROUND: Access to the liver transplant waitlist for patients with hepatocellular carcinoma (HCC) depends on tumour presentation, biology, and response to treatments. The Milan Criteria (MC) represent the benchmark for expanded criteria that incorporate additional prognostic factors. The purpose of this study was to determine the added value of skeletal muscle index (SMI) in HCC patients beyond the MC. METHOD: Patients with HCC that were transplanted beyond the MC were included in this retrospective multicentre study. SMI was quantified using the Computed Tomography (CT) within 3 months prior to transplantation. Cox regression models were used to identify predictors of overall survival (OS). The discriminative performance of SMI extended Metroticket 2.0 and AFP models was also assessed. RESULTS: Out of 889 patients transplanted outside the MC, 528 had a CT scan within 3 months prior to liver transplantation (LT), of whom 176 (33%) were classified as sarcopenic. The median time between assessment of the SMI and LT was 1.8 months (IQR: 0.77-2.67). The median follow-up period was 5.1 95% CI [4.7-5.5] years, with a total of 177 recorded deaths from any cause. In a linear regression model with SMI as the dependent variable, only male gender (8.55 95% CI [6.51-10.59], P < 0.001) and body mass index (0.74 95% CI [0.59-0.89], P < 0.001) were significant. Univariable survival analysis of patients with sarcopenia versus patients without sarcopenia showed a significant difference in OS (HR 1.44 95% CI [1.07 - 1.94], P = 0.018). Also the SMI was significant (HR 0.98 95% CI [0.96-0.99], P = 0.014). The survival difference between the lowest SMI quartile versus the highest SMI quartile was significant (log-rank: P = 0.005) with 5 year OS of 57% and 71%, respectively. Data from 423 patients, describing 139 deaths, was used for multivariate analysis. Both sarcopenia (HR 1.45 95% CI [1.02 - 2.05], P = 0.036) and SMI were (HR 0.98 95% CI [0.95-0.99], P = 0.035) significant. On the survival scale this translates to a 5 year OS difference of 11% between sarcopenia and no sarcopenia. Whereas for SMI, this translates to a survival difference of 8% between first and third quartiles for both genders. CONCLUSIONS: Overall, we can conclude that higher muscle mass contributes to a better long-term survival. However, for individual patients, low muscle mass should not be considered an absolute contra-indication for LT as its discriminatory performance was limited.

The RETREAT score provides valid predictions regarding hepatocellular carcinoma recurrence after liver transplantation.

Prediction of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) with knowledge of explant data is important for guiding post-LT surveillance and treatment. The RETREAT score was recently introduced for this purpose, but has not been validated outside the USA. In a retrospective single-center study of 169 consecutive patients undergoing LT in Gothenburg, through 2000-2017 (mean age 57 years, 80% men), there were 34 HCC recurrences during a median 4.6-year follow-up. The 5-year cumulative incidence of HCC recurrence was 0% with RETREAT scores of 0-1 (18%), 11-22% with scores of 2-4 (58%), and 65% with scores of 5-8 (24%). The C-statistic, as a measure of discrimination for prediction of HCC recurrence was 0.762, 0.664, 0.616, and 0.717, for the RETREAT score, Milan criteria, UCSF criteria, and post-MORAL criteria. The RETREAT score had no significant impact on patient survival after HCC recurrence (HR 1.00, P = 0.97). In conclusion, the RETREAT score provided valid predictions of post-LT HCC recurrence in a European setting, with the ability to discriminate between high, intermediate, and low risk for HCC recurrence in a clinically important way. Prognosis after recurrence did not differ according to the RETREAT score in our study.

Characteristics, Trends, and Outcomes of Liver Transplantation for Primary Sclerosing Cholangitis in Female Versus Male Patients: An Analysis From the European Liver Transplant Registry.

BACKGROUND: The influence of sex on primary sclerosing cholangitis (PSC), pre- and postliver transplantation (LT) is unclear. Aims are to assess whether there have been changes in incidence, profile, and outcome in LT-PSC patients in Europe with specific emphasis on sex. METHODS: Analysis of the European Liver Transplant Registry database (PSC patients registered before 2018), including baseline demographics, donor, biochemical, and clinical data at LT, immunosuppression, and outcome. RESULTS: European Liver Transplant Registry analysis (n = 6463, 32% female individuals) demonstrated an increasing number by cohort (1980-1989, n = 159; 1990-1999, n = 1282; 2000-2009, n = 2316; 2010-2017, n = 2549) representing on average 4% of all transplant indications. This increase was more pronounced in women (from 1.8% in the first cohort to 4.3% in the last cohort). Graft survival rate at 1, 5, 10, 15, 20, and 30 y was 83.6%, 70.8%, 57.7%, 44.9%, 30.8%, and 11.6%, respectively. Variables independently associated with worse survival were male sex, donor and recipient age, cholangiocarcinoma at LT, nondonation after brain death donor, and reduced size of the graft. These findings were confirmed using a more recent LT population closer to the current standard of care (LT after the y 2000). CONCLUSIONS: An increasing number of PSC patients, particularly women, are being transplanted in European countries with better graft outcomes in female recipients. Other variables impacting outcome include donor and recipient age, cholangiocarcinoma, nondonation after brain death donor, and reduced graft size.

A prospective clinical trial on sorafenib treatment of hepatocellular carcinoma before liver transplantation.

BACKGROUND: Patients with hepatocellular carcinoma waiting for liver transplantation are commonly treated with locoregional treatments, such as TACE and ablation, to prevent tumor progression and dropout and to improve long-term outcome after transplantation. We wanted to prospectively assess feasibility of systemic antitumor treatment with sorafenib as neoadjuvant treatment for hepatocellular carcinoma while waiting for liver transplantation, evaluating tolerability, toxicity and posttransplant morbidity. We also wanted to evaluate perfusion CT parameters to assess tumor properties and response early after start of sorafenib treatment in patients with early hepatocellular carcinoma. METHODS: Twelve patients assigned for liver transplantation due to hepatocellular carcinoma, within the UCSF and who fulfilled other criteria, were included January 2012-August 2014. After baseline evaluation, sorafenib treatment was started. Treatment was evaluated by perfusion CT at 1, 4 and 12 weeks and thereafter every 8 weeks. Toxicity and quality of life was assessed at 1 and 4 weeks and every 4 weeks thereafter during treatment. Treatment was stopped when patients were prioritized on the transplantation waiting list or when intolerable side effects or tumor progress warranted other treatments. Posttransplant morbidity after 90 days was registered according to Clavien-Dindo. RESULTS: Baseline perfusion CT parameters in the tumors predicted the outcome according to RECIST/mRECIST at three months, but no change in CTp parameters was detected as a result of sorafenib. Sorafenib as neoadjuvant treatment was associated with intolerability and dose reductions. Therefore the prerequisites for evaluation of the sorafenib effect on both CT parameters and tumor response were impaired. CONCLUSIONS: This study failed to show changes in CTp parameters during sorafenib treatment. Despite the curative treatment intention, tolerability of neoadjuvant sorafenib treatment before liver transplantation was inadequate in this study. TRIAL REGISTRATION: EudraCT number: 2010-024306-36 (date 2011-04-07).

2018 Annual Report of the European Liver Transplant Registry (ELTR) - 50-year evolution of liver transplantation.

The purpose of this registry study was to provide an overview of trends and results of liver transplantation (LT) in Europe from 1968 to 2016. These data on LT were collected prospectively from 169 centers from 32 countries, in the European Liver Transplant Registry (ELTR) beginning in 1968. This overview provides epidemiological data, as well as information on evolution of techniques, and outcomes in LT in Europe over more than five decades; something that cannot be obtained from only a single center experience.

Cancer After Liver Transplantation in Children and Young Adults: A Population-Based Study From 4 Nordic Countries.

Cancer after liver transplantation (LT) constitutes a threat also for young recipients, but cancer risk factors are usually absent in children and large studies on the cancer risk profile in young LT recipients are scarce. Data of patients younger than 30 years who underwent LT during the period 1982-2013 in the Nordic countries were linked with respective national cancer registries to calculate standardized incidence ratios (SIRs). A total of 37 cancer cases were observed in 923 patients with 7846 person-years of follow-up. The SIR for all cancer types, compared with the matched general population, was 9.8 (12.4 for males and 7.8 for females). Cumulative incidence of cancer adjusted for the competing risk of death was 2% at 10 years, 6% at 20 years, and 22% at 25 years after LT. Non-Hodgkin lymphoma was the most common cancer type (n = 14) followed by colorectal (n = 4) and hepatocellular cancer (n = 4). Age was a significant risk factor for cancer, and the absolute risk of most cancers (except for lymphoma) increased considerably in young adults older than 20 years. The cancer risk pattern is different in pediatric and young LT patients compared with adult recipients. The striking increase in cancer incidence in young adulthood after the second decade of life deserves further consideration in transition programs.

Strict Selection Alone of Patients Undergoing Liver Transplantation for Hilar Cholangiocarcinoma Is Associated with Improved Survival.

Liver transplantation for hilar cholangiocarcinoma (hCCA) has regained attention since the Mayo Clinic reported their favorable results with the use of a neo-adjuvant chemoradiation protocol. However, debate remains whether the success of the protocol should be attributed to the neo-adjuvant therapy or to the strict selection criteria that are being applied. The aim of this study was to investigate the value of patient selection alone on the outcome of liver transplantation for hCCA. In this retrospective study, patients that were transplanted for hCCA between1990 and 2010 in Europe were identified using the European Liver Transplant Registry (ELTR). Twenty-one centers reported 173 patients (69%) of a total of 249 patients in the ELTR. Twenty-six patients were wrongly coded, resulting in a study group of 147 patients. We identified 28 patients (19%) who met the strict selection criteria of the Mayo Clinic protocol, but had not undergone neo-adjuvant chemoradiation therapy. Five-year survival in this subgroup was 59%, which is comparable to patients with pretreatment pathological confirmed hCCA that were transplanted after completion of the chemoradiation protocol at the Mayo Clinic. In conclusion, although the results should be cautiously interpreted, this study suggests that with strict selection alone, improved survival after transplantation can be achieved, approaching the Mayo Clinic experience.

Liver transplantation in the Nordic countries - An intention to treat and post-transplant analysis from The Nordic Liver Transplant Registry 1982-2013.

AIM AND BACKGROUND: The Nordic Liver Transplant Registry (NLTR) accounts for all liver transplants performed in the Nordic countries since the start of the transplant program in 1982. Due to short waiting times, donor liver allocation has been made without considerations of the model of end-stage liver disease (MELD) score. We aimed to summarize key outcome measures and developments for the activity up to December 2013. MATERIALS AND METHODS: The registry is integrated with the operational waiting-list and liver allocation system of Scandiatransplant (www.scandiatransplant.org) and accounted at the end of 2013 for 6019 patients out of whom 5198 were transplanted. Data for recipient and donor characteristics and relevant end-points retransplantation and death are manually curated on an annual basis to allow for statistical analysis and the annual report. RESULTS: Primary sclerosing cholangitis, acute hepatic failure, alcoholic liver disease, primary biliary cirrhosis and hepatocellular carcinoma are the five most frequent diagnoses (accounting for 15.3%, 10.8%, 10.6%, 9.3% and 9.0% of all transplants, respectively). Median waiting time for non-urgent liver transplantation during the last 10-year period was 39 days. Outcome has improved over time, and for patients transplanted during 2004-2013, overall one-, five- and 10-year survival rates were 91%, 80% and 71%, respectively. In an intention-to-treat analysis, corresponding numbers during the same time period were 87%, 75% and 66%, respectively. CONCLUSION: The liver transplant program in the Nordic countries provides comparable outcomes to programs with a MELD-based donor liver allocation system. Unique features comprise the diagnostic spectrum, waiting times and the availability of an integrated waiting list and transplant registry (NLTR).

Liver transplantation with deceased ABO-incompatible donors is life-saving but associated with increased risk of rejection and post-transplant complications.

ABO-incompatible (ABOi) liver transplantation (LT) with deceased donor organs is performed occasionally when no ABO-compatible (ABOc) graft is available. From 1996 to 2011, 61 ABOi LTs were performed in Oslo and Gothenburg. Median patient age was 51 years (range 13-75); 33 patients were transplanted on urgent indications, 13 had malignancy-related indications, and eight received ABOi grafts for urgent retransplantations. Median donor age was 55 years (range 10-86). Forty-four patients received standard triple immunosuppression with steroids, tacrolimus, and mycophenolate mofetil, and forty-four patients received induction with IL-2 antagonist or anti-CD20 antibody. Median follow-up time was 29 months (range 0-200). The 1-, 3-, 5-, and 10-year Kaplan-Meier estimates of patient survival (PS) and graft survival (GS) were 85/71%, 79/57%, 75/55%, and 59/51%, respectively, compared to 90/87%, 84/79%, 79/73%, and 65/60% for all other LT recipients in the same period. The 1-, 3-, 5-, and 10-year GS for A2 grafts were 81%, 67%, 62%, and 57%, respectively. In conclusion, ABOi LT performed with non-A2 grafts is associated with inferior graft survival and increased risk of rejection, vascular and biliary complications. ABOi LT with A2 grafts is associated with acceptable graft survival and can be used safely in urgent cases.

Differences in long-term survival among liver transplant recipients and the general population: a population-based Nordic study.

UNLABELLED: Dramatic improvement in first-year outcomes post-liver transplantation (LT) has shifted attention to long-term survival, where efforts are now needed to achieve improvement. Understanding the causes of premature death is a prerequisite for improving long-term outcome. Overall and cause-specific mortality of 3,299 Nordic LT patients (1985-2009) having survived 1 year post-LT were divided by expected rates in the general population, adjusted for age, sex, calendar date, and country to yield standardized mortality ratios (SMRs). Data came from the Nordic Liver-Transplant Registry and WHO mortality-indicator database. Stagnant patient survival rates >1 year post-LT were 21% lower at 10 years than expected survival for the general population. Overall SMR for death before age 75 (premature mortality) was 5.8 (95% confidence interval [CI] 5.4-6.3), with improvement from 1985-1999 to 2000-2010 in hepatitis C (HCV) (SMR change 23.1-9.2), hepatocellular carcinoma (HCC) (SMR 38.4-18.8), and primary sclerosing cholangitis (SMR 11.0-4.2), and deterioration in alcoholic liver disease (8.3-24.0) and acute liver failure (ALF) (5.9-7.6). SMRs for cancer and liver disease (recurrent or transplant-unrelated disease) were elevated in all indications except primary biliary cirrhosis (PBC). Absolute mortality rates underestimated the elevated premature mortality from infections (SMR 22-693) and kidney disease (SMR 13-45) across all indications, and from suicide in HCV and ALF. SMR for cardiovascular disease was significant only in PBC and alcoholic liver disease, owing to high mortality in the general population. Transplant-specific events caused 16% of deaths. CONCLUSION: standardized premature mortality provided an improved picture of long-term post-LT outcome, showing improvement over time in some indications, not revealed by overall absolute mortality rates. Causes with high premature mortality (infections, cancer, kidney and liver disease, and suicide) merit increased attention in clinical patient follow-up and future research.

Choledochoduodenostomy is a safe alternative to Roux-en-Y choledochojejunostomy for biliary reconstruction in liver transplantation.

INTRODUCTION: Bile duct reconstruction during liver transplantation is usually performed by a duct-to-duct anastomosis or a Roux-en-Y choledochojejunostomy (CDJ). Direct anastomosis of the bile duct to the duodenum (choledochoduodenostomy-CDD) is another option for biliary reconstruction. This technique has been used with good outcome for the treatment of choledochal cysts, ampullary stenosis, and major bile duct injuries; however, there is little published experience with CDD in liver transplantation. We provide preliminary evidence that CDD is a safe technique for biliary anastomosis in liver transplant recipients. METHODS: From September 2000 to August 2007 a total of 619 adult first-time cadaveric or living donor liver transplants were performed at the University of Colorado Health and Science Center. Bile duct repair was performed by direct end-to-end anastomosis in 466 patients and by choledocoenterostomy in the remaining 153 patients, 82 of whom were cadaveric recipients. The cadaveric choledocoenterostomy patients were divided into two groups: CDD in 25 and CDJ in 57 recipients. RESULTS: There were no significant differences in the 1-year patient or graft survival between the cadaveric groups. The 1-year patient survival was 100% in the CDD group and 97.1% in the CDJ group. The CDD group did not experience more surgical complications compared to the CDJ group. CONCLUSIONS: Choledochoduodenostomy is a safe alternative to CDJ biliary anastomosis when a duct-to-duct anastomosis cannot be performed. There is no significant difference in mortality, graft survival, or biliary complications. In addition, CDD offers the advantage of postoperative access to the billiary system by endoscopy and avoids complications associated with the CDJ bowel anastomosis.