The Italian data on SARS-CoV-2 infection in transplanted patients support an organ specific immune response in liver recipients.

Introduction: The study of immune response to SARSCoV-2 infection in different solid organ transplant settings represents an opportunity for clarifying the interplay between SARS-CoV-2 and the immune system. In our nationwide registry study from Italy, we specifically evaluated, during the first wave pandemic, i.e., in non-vaccinated patients, COVID-19 prevalence of infection, mortality, and lethality in liver transplant recipients (LTRs), using non-liver solid transplant recipients (NL-SOTRs) and the Italian general population (GP) as comparators. Methods: Case collection started from February 21 to June 22, 2020, using the data from the National Institute of Health and National Transplant Center, whereas the data analysis was performed on September 30, 2020.To compare the sex- and age-adjusted distribution of infection, mortality, and lethality in LTRs, NL-SOTRs, and Italian GP we applied an indirect standardization method to determine the standardized rate. Results: Among the 43,983 Italian SOTRs with a functioning graft, LTRs accounted for 14,168 patients, of whom 89 were SARS-CoV-2 infected. In the 29,815 NL-SOTRs, 361 cases of SARS-CoV-2 infection were observed. The geographical distribution of the disease was highly variable across the different Italian regions. The standardized rate of infection, mortality, and lethality rates in LTRs resulted lower compared to NL-SOTRs [1.02 (95%CI 0.81-1.23) vs. 2.01 (95%CI 1.8-2.2); 1.0 (95%CI 0.5-1.5) vs. 4.5 (95%CI 3.6-5.3); 1.6 (95%CI 0.7-2.4) vs. 2.8 (95%CI 2.2-3.3), respectively] and comparable to the Italian GP. Discussion: According to the most recent studies on SOTRs and SARS-CoV-2 infection, our data strongly suggest that, in contrast to what was observed in NL-SOTRs receiving a similar immunosuppressive therapy, LTRs have the same risk of SARS-CoV-2 infection, mortality, and lethality observed in the general population. These results suggest an immune response to SARS-CoV-2 infection in LTRS that is different from NL-SOTRs, probably related to the ability of the grafted liver to induce immunotolerance.

Economic Impact of European Liver and Intestine Transplantation Association (ELITA) Recommendations for Hepatitis B Prophylaxis After Liver Transplantation.

The European Liver and Intestine Transplant Association, ELITA, promoted a Consensus Conference involving 20 experts across the world which generated updated guidelines on HBV prophylaxis in liver transplant candidates and recipients. This study explores the economic impact associated with the implementation of the new ELITA guidelines. To this aim, a condition-specific cohort simulation model has been developed to compare new and historical prophylaxis, including only pharmaceutical cost and using the European perspective. The target population simulated in the model included both prevalent and incident cases, and consisted of 6,133 patients after the first year, that increased to 7,442 and 8,743 patents after 5 and 10 years from its implementation. The ELITA protocols allowed a cost saving of around € 235.65 million after 5 years and € 540.73 million after 10 years; which was mainly due to early HIBG withdrawal either after the first 4 weeks or after the first year post Liver Transplantation (LT) depending on the virological risk at transplantation. Results were confirmed by sensitivity analyses. The money saved by the implementation of the ELITA guidelines would allow healthcare decision makers and budget holders to understand where costs could be reduced and resources re-allocated to different needs.

Continuous Renal Replacement Therapy after Liver Transplantation: Peri-Operative Associated Factors and Impact on Survival.

Continuous renal replacement therapy (CRRT) following orthotopic liver transplantation (OLT) is usually started for multifactorial reasons, with variable incidence among series. This paper presents a single-center retrospective observational study on the early use (within one week) of CRRT after consecutive cadaveric OLT from January 2008 to December 2016. Preoperative patient characteristics and intraoperative data were collected, and patients were divided into two groups (CRRT and no CRRT) to explore the factors associated with the use of CRRT. Repeated measurements of postoperative creatinine were analyzed with generalized estimating equation (GEE) models. Among 528 OLT patients, 75 (14.2%) were treated with CRRT at least once in the first week. Patients treated with CRRT showed lower survival in a Kaplan−Meier curve (log-rank p value < 0.01). Patients treated with CRRT had a more severe preoperative profile, with a significantly higher age, MELD, BUN, creatinine, and total bilirubin, as well as a longer surgery time and a higher number of transfusions of red blood cells, plasma, and platelets (all p values < 0.05). In a stepwise multiple analysis, the following characteristics remained independently associated with the use of CRRT: the MELD score OR 1.12 (95% CL: 1.07−1.16), p value < 0.001, and the preoperative value for blood urea nitrogen OR 1.016 (95% CL: 1.010−1.023), p value < 0.001. The early use of CRRT after OLT occurred at a low rate in this large cohort; however, it was associated with worse outcomes. Apart from the preoperative severity, repeated intraoperative hypotension episodes, which were likely modifiable or preventable, were associated with the increased use of CRRT and higher postoperative creatinine.

Location and allocation: Inequity of access to liver transplantation for patients with severe acute-on-chronic liver failure in Europe.

There is growing evidence that liver transplantation (LT) is the most effective treatment for acute-on-chronic liver failure grade-3 (ACLF-3). This study examines whether and how this evidence translates into practice by analyzing the variability in intensive care unit (ICU) admissions, listing strategies, and LT activity for patients with ACLF-3 across transplantation centers in Europe. Consecutive patients who were admitted to the ICU with ACLF-3, whether or not they were listed and/or transplanted with ACLF-3, between 2018 and 2019 were included across 20 transplantation centers. A total of 351 patients with ACLF-3 were included: 33 had been listed prior to developing ACLF-3 and 318 had not been listed at the time of admission to the ICU. There was no correlation between the number of unlisted patients with ACLF-3 admitted to the ICU and the number listed or transplanted while in ACLF-3 across centers. By contrast, there was a correlation between the number of patients listed and the number transplanted while in ACLF-3. About 21% of patients who were listed while in ACLF-3 died on the waiting list or were delisted. The percentage of LT for patients with ACLF-3 varied from 0% to 29% for those transplanted with decompensated cirrhosis across centers (average = 8%), with an I2 index of 68% (95% confidence interval, 49%-80%), showing substantial heterogeneity among centers. The 1-year survival for all patients with ACLF-3 was significantly higher in centers that listed and transplanted more patients with ACLF-3 (>10 patients) than in centers that listed and transplanted fewer: 36% versus 20%, respectively (p = 0.012). Patients with ACLF-3 face inequity of access to LT across Europe. Waitlisting strategies for patients with ACLF-3 influence their access to LT and, ultimately, their survival.

Performance of the model for end-stage liver disease score for mortality prediction and the potential role of etiology.

BACKGROUND & AIMS: Although the discriminative ability of the model for end-stage liver disease (MELD) score is generally considered acceptable, its calibration is still unclear. In a validation study, we assessed the discriminative performance and calibration of 3 versions of the model: original MELD-TIPS, used to predict survival after transjugular intrahepatic portosystemic shunt (TIPS); classic MELD-Mayo; and MELD-UNOS, used by the United Network for Organ Sharing (UNOS). We also explored recalibrating and updating the model. METHODS: In total, 776 patients who underwent elective TIPS (TIPS cohort) and 445 unselected patients (non-TIPS cohort) were included. Three, 6 and 12-month mortality predictions were calculated by the 3 MELD versions: discrimination was assessed by c-statistics and calibration by comparing deciles of predicted and observed risks. Cox and Fine and Grey models were used for recalibration and prognostic analyses. RESULTS: In the TIPS/non-TIPS cohorts, the etiology of liver disease was viral in 402/188, alcoholic in 185/130, and non-alcoholic steatohepatitis in 65/33; mean follow-up±SD was 25±9/19±21 months; and the number of deaths at 3-6-12 months was 57-102-142/31-47-99, respectively. C-statistics ranged from 0.66 to 0.72 in TIPS and 0.66 to 0.76 in non-TIPS cohorts across prediction times and scores. A post hoc analysis revealed worse c-statistics in non-viral cirrhosis with more pronounced and significant worsening in the non-TIPS cohort. Calibration was acceptable with MELD-TIPS but largely unsatisfactory with MELD-Mayo and -UNOS whose performance improved much after recalibration. A prognostic analysis showed that age, albumin, and TIPS indication might be used to update the MELD. CONCLUSIONS: In this validation study, the performance of the MELD score was largely unsatisfactory, particularly in non-viral cirrhosis. MELD recalibration and candidate variables for an update to the MELD score are proposed. LAY SUMMARY: While the discriminative performance of the model for end-stage liver disease (MELD) score is credited to be fair to good, its calibration, the correspondence of observed to predicted mortality, is still unsettled. We found that application of 3 different versions of the MELD in 2 independent cirrhosis cohorts yielded largely imprecise mortality predictions particularly in non-viral cirrhosis. Thus, we propose a recalibration and suggest candidate variables for an update to the model.

2020 position statement and recommendations of the European Liver and Intestine Transplantation Association (ELITA): management of hepatitis B virus-related infection before and after liver transplantation.

BACKGROUND: Prophylaxis of HBV recurrence is critical after liver transplantation in HBV patients. Despite new prophylactic schemes, most European LT centres persist on a conservative approach combining hepatitis B immunoglobulin (HBIG) and nucleos(t)ides analogues (NA). AIM: This setting prompted the European Liver Intestine Transplantation Association (ELITA) to look for a consensus on the prevention of HBV recurrence. METHODS: Based on a 4-round Delphi process, ELITA investigated 16 research questions and established 50 recommendations. RESULTS: Prophylaxis should be driven according to 3 simplified risk groups: Low and high virological risk patients, with undetectable and detectable HBV DNA pre-LT, respectively, and special populations (HDV, HCC, poorly adherent patients). In low-risk patients, short-term (4 weeks) combination of third-generation NA+ HBIG, or third generation NA monotherapy can be considered as prophylactic options. In high-risk patients, HBIG can be discontinued once HBV DNA undetectable. Combined therapy for 1 year is advised. HBV-HCC patients should be treated according to their virological risk. In HDV/HBV patients, indefinite dual prophylaxis remains the gold standard. Full withdrawal of HBV prophylaxis following or not HBV vaccination should only be attempted in the setting of clinical trials. Organs from HBsAg+ve donors may be considered after assessment of risks, benefits, and patient consent. They should not be used if HDV is present. In poorly adherent patients, dual long-term prophylaxis is recommended. Budget impact analysis should be taken into account to drive prophylactic regimen. CONCLUSIONS: These ELITA recommendations should stimulate a more rational and homogeneous approach to HBV prophylaxis across LT programs.

Liver transplantation for patients with acute-on-chronic liver failure (ACLF) in Europe: Results of the ELITA/EF-CLIF collaborative study (ECLIS).

BACKGROUND & AIMS: Liver transplantation (LT) has been proposed as an effective salvage therapy even for the sickest patients with acute-on-chronic liver failure (ACLF). This large collaborative study was designed to assess the current clinical practice and outcomes of patients with ACLF who are wait-listed for LT in Europe. METHODS: This was a retrospective study including 308 consecutive patients with ACLF, listed in 20 centres across 8 European countries, from January 2018 to June 2019. RESULTS: A total of 2,677 patients received a LT: 1,216 (45.4%) for decompensated cirrhosis. Of these, 234 (19.2%) had ACLF at LT: 58 (4.8%) had ACLF-1, 78 (6.4%) had ACLF-2, and 98 (8.1%) had ACLF-3. Wide variations were observed amongst countries: France and Germany had high rates of ACLF-2/3 (27-41%); Italy, Switzerland, Poland and the Netherlands had medium rates (9-15%); and the United Kingdom and Spain had low rates (3-5%) (p <0.0001). The 1-year probability of survival after LT for patients with ACLF was 81% (95% CI 74-87). Pre-LT arterial lactate levels >4 mmol/L (hazard ratio [HR] 3.14; 95% CI 1.37-7.19), recent infection from multidrug resistant organisms (HR 3.67; 95% CI 1.63-8.28), and renal replacement therapy (HR 2.74; 95% CI 1.37-5.51) were independent predictors of post-LT mortality. During the same period, 74 patients with ACLF died on the waiting list. In an intention-to-treat analysis, 1-year survival of patients with ACLF on the LT waiting list was 73% for ACLF-1 or -2 and 50% for ACLF-3. CONCLUSION: The results reveal wide variations in the listing of patients with ACLF in Europe despite favourable post-LT survival. Risk factors for mortality were identified, enabling a more precise prognostic assessment of patients with ACLF. LAY SUMMARY: Acute-on-chronic liver failure (ACLF) is a severe clinical condition for which liver transplantation is an effective therapeutic option. This study has demonstrated that in Europe, referral and access to liver transplantation (LT) for patients with ACLF needs to be harmonised to avoid inequities. Post-LT survival for patients with ACLF was >80% after 1 year and some factors have been identified to help select patients with favourable outcomes.

Vitamin D levels in liver transplantation recipients and early postoperative outcomes: Prospective observational DLiverX study.

BACKGROUND & AIMS: In critically ill patients with liver disease, vitamin D deficiency is associated with higher disease severity, increased frequency of infections, and worse outcomes. This study sought to describe the trend of vitamin D in orthotopic liver transplantation (OLT) recipients and its association with outcomes. METHODS: Prospective observational study of 67 consecutive OLT recipients enrolled between September, 2016 and August, 2017 at IRCCS-ISMETT, Palermo (Italy). Trend of vitamin D levels and potential factors influencing it levels were evaluated through a generalized linear mixed regression model. RESULTS: Sixty-four (95.5%) recipients were vitamin D deficient (<20 ng/ml), with a median value of 8.8 ng/ml [6.2-12.9], and forty-seven of these (70.1%) showed severe deficiency (<12 ng/ml) at baseline, 7.9 ng/ml [5.4-8.9]. The baseline vitamin D showed an inverse correlation with liver disease severity: Child-Pugh, MELD score, bilirubin, INR, and organ failure (p < 0.01) at baseline. Vitamin D increased on postoperative day (POD) 28 compared with POD1: +4.5 ng/ml, C.I. 95% 3.6-5.3 ng/ml, p < 0.01. Lower baseline vitamin D, donor age, transfusion of fresh frozen plasma (negative impact, all p < 0.05), and intra-operative bypass (positive impact at POD 28, p < 0.01) were associated with variation of vitamin D levels after transplantation. Incomplete graft recovery was associated with lower vitamin D on POD28: 8.2 ± 4.4 versus 13.8 ± 9.4 ng/ml, p < 0.01; the odds ratio (OR) was 0.84; CI 95% 0.73-0.97, p = 0.014. The OR for infections within POD 28 was inversely associated with baseline vitamin D: 0.87; CI 95% 0.79-0.98, p = 0.02, and with vitamin D level at baseline <12 ng/ml: OR 6.44; CI 95% 1.66-24.94; p < 0.01. CONCLUSIONS: Preoperative Vitamin D is correlated with disease severity, and was highly associated with invasive infection in the first 28 PODs. After OLT, the value on POD 28 had a strong association with graft function.

Immunosuppressive regimens for adult liver transplant recipients in real-life practice: consensus recommendations from an Italian Working Group.

It is a well-recognized fact that implementing new guidelines in clinical practice may be difficult; therefore the Italian Society for Organ and Tissue Transplantation (SITO) set out to define practical immunosuppression tools for the management of liver transplantation patients. In 2017, an Italian Working Group of liver transplant experts and hepatologists issued a set of consensus statements along with evidence-based recommendations on the use of everolimus after liver transplantation. This article presents the evidence- and consensus-based algorithms developed within the Italian Working Group, which are aimed towards guiding clinicians in the selection of immunosuppressive regimens for the management of adult liver transplant recipients in real-life practice. The liver transplant recipient population, typically managed in clinical practice, was divided into the following categories: (1) standard patients; (2) critically ill patients; (3) patients with a specific etiology; (4) patients with hepatocellular carcinoma; (5) and patients with de novo malignancies. The algorithms are divided into two parts, according to the time from transplantation (0-3 months and > 3 months) and are discussed here along with relevant supporting literature, when available. Ultimately, it is hoped that the evidence- and consensus-based algorithms developed within the Italian Working Group, and presented here, contribute to simplify, personalize, and optimize immunosuppression of liver transplantation recipients in clinical practice.

Liver transplantation in hepatocellular carcinoma after tumour downstaging (XXL): a randomised, controlled, phase 2b/3 trial.

BACKGROUND: Indications for liver transplantation for hepatocellular carcinoma are evolving and so-called expanded criteria remain debated. Locoregional therapies are able to downstage hepatocellular carcinoma from beyond to within the Milan criteria. We aimed to investigate the efficacy of liver transplantation after successful hepatocellular carcinoma downstaging. METHODS: We did an open-label, multicentre, randomised, controlled trial designed in two phases, 2b and 3, at nine Italian tertiary care and transplantation centres. Patients aged 18-65 years with hepatocellular carcinoma beyond the Milan criteria, absence of macrovascular invasion or extrahepatic spread, 5-year estimated post-transplantation survival of at least 50%, and good liver function (Child-Pugh A-B7) were recruited and underwent tumour downstaging with locoregional, surgical, or systemic therapies according to multidisciplinary decision. After an observation period of 3 months, during which sorafenib was allowed, patients with partial or complete responses according to modified Response Evaluation Criteria in Solid Tumors were randomly assigned (1:1) by an interactive web-response system to liver transplantation or non-transplantation therapies (control group). A block randomisation (block size of 2), stratified by centre and compliance to sorafenib treatment, was applied. Liver transplantation was done with whole or split organs procured from brain-dead donors. The control group received sequences of locoregional and systemic treatment at the time of demonstrated tumour progression. The primary outcomes were 5-year tumour event-free survival for phase 2b and overall survival for phase 3. Analyses were by intention to treat. Organ allocation policy changed during the course of the study and restricted patient accrual to 4 years. This trial is registered with ClinicalTrials.gov, NCT01387503. FINDINGS: Between March 1, 2011, and March 31, 2015, 74 patients were enrolled. Median duration of downstaging was 6 months (IQR 4-11). 29 patients dropped out before randomisation and 45 were randomly assigned: 23 to the transplantation group versus 22 to the control group. At data cutoff on July 31, 2019, median follow-up was 71 months (IQR 60-85). 5-year tumour event-free survival was 76·8% (95% CI 60·8-96·9) in the transplantation group versus 18·3% (7·1-47·0) in the control group (hazard ratio [HR] 0·20, 95% CI 0·07-0·57; p=0·003). 5-year overall survival was 77·5% (95% CI 61·9-97·1) in the transplantation group versus 31·2% (16·6-58·5) in the control group (HR 0·32, 95% CI 0·11-0·92; p=0·035). The most common registered grade 3-4 serious adverse events were hepatitis C virus recurrence (three [13%] of 23 patients) and acute transplant rejection (two [9%]) in the transplantation group, and post-embolisation syndrome (two [9%] of 22 patients) in the control group. Treatment-related deaths occurred in four patients: two (8%) of 23 patients in the transplantation group (myocardial infarction and multi-organ failure) versus two (9%) of 22 patients in the control group (liver decompensation). INTERPRETATION: Although results must be interpreted with caution owing to the early closing of the trial, after effective and sustained downstaging of eligible hepatocellular carcinomas beyond the Milan criteria, liver transplantation improved tumour event-free survival and overall survival compared with non-transplantation therapies Post-downstaging tumour response could contribute to the expansion of hepatocellular carcinoma transplantation criteria. FUNDING: Italian Ministry of Health.

Direct-acting antivirals ability to clear intestinal HCV-RNA in liver transplant patients.

The hepatitis C virus mainly infects the liver but is also able to infect and replicate in other body compartments by creating an extra-hepatic reservoir that may influence the persistence of the infection after transplantation. It is unknown whether antiviral drugs affect the viral extra-hepatic sites. We evaluated the ability of pegylated/interferon + ribavirin and sofosbuvir + ribavirin to clear the virus from the gastrointestinal mucosa of liver-transplanted patients with HCV recurrence after transplantation. A total of 51 liver-transplanted patients, 30 treated with pegylated/interferon + ribavirin (ERA1) and 21 treated with sofosbuvir + ribavirin (ERA2), were enrolled, and blood serum and gastrointestinal tissues analyzed for the presence of HCV-RNA. In the ERA1 group, the 46.6% of patients had a sustained viral response to antiviral treatment, and gastrointestinal biopsies were positive for HCV in 73.3% of cases, 54.5% of responders, and 45.5% of non-responders. In the ERA2 group, the 66.6% had a sustained viral response, and gastrointestinal HCV-RNA was present in the 14.3% of patients, all relapsers. Sofosbuvir + ribavirin cleared the intestinal HCV in 85.7% of patients with recurrent HCV infection, while pegylated/interferon + ribavirin cleared it in 26.6% of treated patients, demonstrating the better effectiveness of new direct antiviral agents in clearing HCV intestinal reservoir.

Switch from intravenous or intramuscular to subcutaneous hepatitis B immunoglobulin: effect on quality of life after liver transplantation.

BACKGROUND: Hepatitis B immunoglobulin (HBIG) therapy is available in intravenous (IV) or intra-muscular (IM) formulations. Recently, a subcutaneous (SC) formulation was introduced. This study evaluated changes in quality of life when liver transplant (LT) recipients were switched from IV or IM HBIG to the SC formulation. METHODS: This multicentre, observational study involved adults who had undergone LT at least 1 year prior to study entry. Quality of life was evaluated using the ITaLi-Q questionnaire, assessing the impact of HBIG therapy on daily activities and patient satisfaction, and the SF-36 Health Survey. Patients completed the questionnaires prior to switching from IV or IM HBIG to SC HBIG and 6 months later. RESULTS: Eighty-six patients were enrolled; before the switch, 68.6% were receiving IM HBIG and 31.4% IV HBIG. After 6 months, significant improvements in 7 of the 8 ITaLi-Q domains were found, particularly side effects, need for support to adhere to the therapy and satisfaction with the HBIG therapy. Significant improvements in several SF-36 domains were documented, including physical functioning, physical and emotional role limitations, pain, social functioning, physical and mental summary scores. CONCLUSIONS: The SC route of administration reduces side effects and their interference with daily life, ameliorates negative feelings, and increases patient autonomy.

Radiation exposure during transjugular intrahepatic portosystemic shunt creation in patients with complete portal vein thrombosis or portal cavernoma.

BACKGROUND: This study aims to evaluate radiation exposure in patients with complete portal vein thrombosis (CPVT) or portal cavernoma (PC) undergoing transjugular intrahepatic portosystemic shunt (TIPS) creation using real-time ultrasound guidance for portal vein targeting. MATERIALS AND METHODS: This is a single institution retrospective analysis. Between August 2009 and September 2018, TIPS was attempted in 49 patients with CPVT or PC. Radiation exposure (dose area product [DAP], air KERMA (AK) and fluoroscopy time [FT]), technical success, clinical success, complications and survival were analyzed. RESULTS: In total, 29 patients had CPVT and 20 patients had PC. 41/49 patients had cirrhosis. TIPS indications were refractory ascites (n = 25), variceal bleeding (n = 16) and other (n = 8). TIPS was successfully placed in 94% (46/49) of patients via a transjugular approach alone (n = 40), a transjugular/transhepatic approach (n = 5) and a transjugular/transsplenic approach (n = 1). Median DAP was 261 Gy * cm2 (range 29-950), median AK was 0.2 Gy (range 0.05-0.5), and median FT was 28.2 min (range 7.7-93.7). Mean portosystemic pressure gradient decreased from 16.8  ±  5.1 mmHg to 7.5  ±  3.3 mmHg (P <  0.01). There were no major procedural complications. Overall clinical success was achieved in 77% of patients (mean follow-up of 21.1 months). Encephalopathy was observed in 16 patients (34%), grade II-III encephalopathy in 7 patients (15%). TIPS revision was performed in 15 patients (32%). Overall survival rate was 75%. CONCLUSION: In our experience, the use of real-time ultrasound guidance allowed the majority of the TIPS to be performed via a transjugular approach alone with a reasonably low radiation exposure considering the high technical difficulties of the selected cohort of patients with CVPT or PC.

Transjugular Intrahepatic Portosystemic Shunt Using the New Gore Viatorr Controlled Expansion Endoprosthesis: Prospective, Single-Center, Preliminary Experience.

OBJECTIVES: To evaluate short-term clinical efficacy, complications and possible passive stent expansion of transjugular intrahepatic portosystemic shunt (TIPS) creation using the new controlled expansion ePTFE covered stent (VCX), for portal hypertension complications. METHODS: Between 7/2016 and 3/2018, 75 patients received TIPS using VCX. Thirty-nine patients with VCX dilated with an 8-mm angioplasty balloon underwent computed tomography (CT) study during follow-up and CT data were used to measure stent diameter. The CT measurement technique was validated by ex vivo experiment. RESULTS: TIPS indications were: refractory ascites (n = 45), variceal bleeding (n = 22), other (n = 8). Mean follow-up was 5.8 months (± 4.5, range 1-20). In 69 patients, TIPS was dilated to 8 mm of diameter reaching the hemodynamic target of a portosystemic pressure gradient (PSG) < 12 mmHg. In six patients, not reaching the hemodynamic target the stent was dilated to 10 mm of diameter during the same session with a final PSG < 12 mmHg. Overall clinical success was achieved in 66/75 (88%) patients (80% in refractory ascites, 95% variceal bleeding, 100% other). Grade II-III encephalopathy was observed in five patients (6%). TIPS revision with stent dilatation to 10 mm was performed in seven patients: in three patients with ascites persistence, without evidence of stent dysfunction and in four patients for stent stenosis. One patient underwent stent reduction. Fourteen patients (18%) died during follow-up of causes not related to TIPS. Five patients (6%) underwent liver transplant. No passive stent expansion was detected by CT measurements. CONCLUSION: VCX for TIPS creation retains its diameter over a short-term period and is associated with a good clinical outcome with a reasonably low complication rate.

Recurrence of Hepatitis B Infection in Liver Transplant Patients Receiving Long-Term Hepatitis B Immunoglobulin Prophylaxis.

BACKGROUND Long-term real-world data are relatively sparse regarding recurrence of chronic hepatitis B virus (HBV) infection after liver transplantation using hepatitis B immunoglobulin (HBIg) and nucleos(t)ide analogue (NUC) prophylaxis. MATERIAL AND METHODS Data from 371 adults transplanted for HBV-related disease at 20 European centers and given HBIg for ³12 months ± NUC therapy were analyzed retrospectively. RESULTS HBIg comprised Hepatect® (iv HBIgB; n=299), subcutaneous Zutectra® (sc HBIg, n=236), and other HBIg preparations (n=130); 93.5% received NUC therapy. Mean follow-up was 6.8±3.5 years. The primary efficacy variable, freedom from HBV recurrence, occurred in 95.7% of patients (95% CI [93.1%, 97.5%]). The observed incidence of recurrence was 16/371 (4.3%) (annual rate 0.65%); 5/16 patients with recurrence had discontinued HBIg and 7/16 had anti-HBs <100 IU/l. Excluding these 7 patients, the HBV recurrence rate was 2.4%. The recurrence rate while on HBIg therapy was 1 per 2069 months. In patients who discontinued HBIg, risk of HBV recurrence versus sc HBIg users was increased by 5.2-fold (1 per 1 603 versus 1 per 8379 treatment months). The annual rate of HBV-related hepatocellular carcinoma (HCC) recurrence was 1.7%. CONCLUSIONS These results support the long-term use of HBIg with NUC therapy as an effective management strategy to minimize risk of HBV recurrence and virus-related complications after liver transplantation.

Guillain-Barré syndrome after orthotopic liver transplantation: A clinical manifestation of immune reconstitution inflammatory syndrome?

Guillain-Barrè Syndrome, as part of the spectrum of dysimmune neuropathies, is unexpected to occur in immunocompromised hosts. We describe a clinical case of Guillain-Barrè syndrome, occurred a few weeks after a liver transplant, and we postulate that our case would satisfy all requirements to explain this peripheral nervous system complication as a clinical manifestation of an Immune reconstitution inflammatory syndrome. In this setting of liver transplantation, complicated by potentially multiple infective triggers, reduction of immunosuppression and reversal of pathogen-induced immunosuppression, through antimicrobial therapy, may have led to pro-inflammatory response. The pro-inflammatory pattern would have sustained the pathophysiologic mechanism of this immune neuropathy.

Delisting HCV-infected liver transplant candidates who improved after viral eradication: Outcome 2 years after delisting.

BACKGROUNDS & AIMS: Treating patients with decompensated cirrhosis with direct-acting antiviral (DAA) therapy while on the waiting list for liver transplantation results in substantial improvement of liver function allowing 1 in 4 patients to be removed from the waiting list or delisted, as reported in a previous study promoted by the European Liver and Intestine Transplant Association (ELITA). The aim of this study was to report on clinical outcomes of delisted patients, including mortality risk, hepatocellular carcinoma development and clinical decompensation requiring relisting. METHODS: One hundred and forty-two HCV-positive patients on the liver transplant waiting list for decompensated cirrhosis, negative for hepatocellular carcinoma, between February 2014 and June 2015 were treated with DAA therapy and were prospectively followed up. RESULTS: Forty-four patients (30.9%) were delisted following clinical improvement. This percentage was higher than in the original study because of a number of patients being delisted long after starting DAAs. The median Child-Pugh and MELD score of delisted patients was 5.5 and 9 respectively. Four patients were relisted, because of HCC diagnosis in 1 case and 3 patients developed ascites. One further patient died (2.4%) because of rapidly progressing hepatocellular carcinoma twenty-two months after delisting. Of the 70 patients who received a liver graft, 9 died (13%). CONCLUSIONS: Antiviral therapy allows for a long-term improvement of liver function and the delisting of one-third of treated patients with risk of liver-related complications after delisting being very low.

Specific issues concerning the management of patients on the waiting list and after liver transplantation.

The present document is a second contribution collecting the recommendations of an expert panel of transplant hepatologists appointed by the Italian Association for the Study of the Liver (AISF) concerning the management of certain aspects of liver transplantation, including: the issue of prompt referral; the management of difficult candidates; malnutrition; living related liver transplants; hepatocellular carcinoma; and the role of direct acting antiviral agents before and after transplantation. The statements on each topic were approved by participants at the AISF Transplant Hepatology Expert Meeting organized by the Permanent Liver Transplant Commission in Mondello on 12-13 May 2017. They are graded according to the GRADE grading system.