Publications by authors named "Frederik Nevens"

286 Publications

Hepatitis C reinfection in former and active injecting drug users in Belgium.

Harm Reduct J 2021 Oct 12;18(1):102. Epub 2021 Oct 12.

Faculty of Medicine and Life Sciences, Hasselt University, Martelarenlaan 42, Diepenbeek, 3500, Hasselt, Belgium.

Background: There is currently no systematic screening for hepatitis C (HCV) reinfection in people who inject drugs (PWID) after treatment in Belgium. However, in a recent meta-analysis, the overall HCV reinfection rate was 5.9/100 person-years (PY) among PWID. Accordingly, this study was undertaken to investigate the reinfection rate in former and active PWID who achieved the end of treatment response after direct-acting antiviral (DAA) treatment in Belgium.

Methods: This observational cross-sectional study recruited individuals with a history of injecting drug use who had achieved the end of treatment response to any DAA treatment between 2015 and 2020. Participants were offered a post-treatment HCV RNA test.

Results: Eighty-five potential participants were eligible to participate and contacted, of whom 60 participants were enrolled in the study with a median age of 51.0 (IQR 44.3-56.0) years; it was reported that 23.3% continued to inject drugs intravenously after DAA treatment. Liver cirrhosis was present in 12.9%. The majority had genotype 1a (51.7%) or genotype 3 (15.0%) infection. We detected no reinfections in this study population. The total time patients were followed up for reinfection in the study was 78.5 PY (median 1.0 years IQR 0.4-2.0).

Conclusion: Reinfection after successful treatment with DAA initially appears to be very low in Belgian PWID. Therefore, efforts should be made to screen individuals with persistent risk behaviors for reinfection systematically. In addition, a national HCV registry should be established to accurately define the burden of HCV infection and reinfection in Belgium and support the elimination of viral hepatitis C in Europe. Trial registration clinicaltrials.gov NCT04251572, Registered 5 Feb 2020-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04251572 .
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http://dx.doi.org/10.1186/s12954-021-00552-xDOI Listing
October 2021

Telemedicine based remote monitoring after liver transplantation: Feasible in a select group and a more stringent control of immunosuppression.

Clin Transplant 2021 Oct 1:e14494. Epub 2021 Oct 1.

Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium.

Telemedicine gained interest in liver transplant patients but focused until now on the early post-operative period. This prospective cohort study assessed feasibility, safety, and clinical beneficial effects of a telemedicine based remote monitoring program (TRMP) for the chronic follow-up of adult liver transplant recipients. Between November 2017 and August 2019, a total of 87 of the 115 selected patients (76%) started the TRMP. Over the 2 years study period, none of the patients switched to standard follow-up: 39/87 (45%) continued to do this autonomously and 48/87 (55%) stopped to report their data personally but communicated their lab values to the nurse. The other 28/115 (11%) patients who did not accept the TRMP continued the standard follow-up. There was no difference in educational level between the three groups. Remote monitoring did not result in an increase in liver graft rejection and need of hospitalization. TRMP was associated with a higher number of tacrolimus level determinations and tacrolimus blood level concentrations could be kept lower. In conclusion, our results show that in patients with a stable clinical condition there is a high willingness to participate in TRMP and that this approach is safe. Remote monitoring allowed a stringent follow-up of tacrolimus levels.
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http://dx.doi.org/10.1111/ctr.14494DOI Listing
October 2021

Liver and/or Kidney Transplantation After SARS-CoV-2 Infection: Prevalence, Short-Term Outcome and Kinetics of Serum IgG Antibodies.

Transplantation 2021 Sep 16. Epub 2021 Sep 16.

Department of Gastroenterology & Hepatology, University Hospitals Leuven; Laboratory of Hepatology, Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium Clinical Department of Laboratory Medicine and National Reference Center for Respiratory Pathogens, University Hospitals Leuven; Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium Department of Abdominal Transplant Surgery, University Hospitals Leuven; Transplantation Research Group, Lab of Abdominal Transplantation, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium Department of Respiratory Diseases, University Hospitals Leuven; Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium. Department of Cardiology, University Hospitals Leuven; Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium Department of Nephrology & Renal Transplantation, University Hospitals Leuven; Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.

Background: There is paucity of data on the prevalence, adequate timing and outcome of solid organ transplantation after SARS-CoV-2 infection and the kinetics of IgG antibodies in these patients.

Methods: SARS-CoV-2 anti-nucleocapsid (N) IgG and PCR via nasopharyngeal swab were analyzed in all patients within 24h before liver and/or kidney transplantation. Kinetics of IgG antibodies were analysed and compared with an immune-competent cohort.

Results: Between May 1st 2020 and March 18th 2021, 168 patients underwent liver and/or kidney transplantation in our centre, of which 11 (6.54%) patients with previous SARS-CoV-2 infection were identified. Median interval between SARS-CoV-2 infection and transplantation was 4.5 months (range 0.9-11). After a median post-transplant follow-up of 4.9 months, 10 out of 11 patients were alive without clinical signs of viral shedding or recurrent or active infection. One patient without symptom resolution at time of transplantation died after combined liver-kidney transplantation. In 9 out of 11 patients with previously PCR confirmed infection, SARS-CoV-2 anti-N and anti-spike (S) IgG were detectable at day of transplantation. Absolute levels of anti-N and anti-S IgG were positively correlated, declined over time in all patients and were significantly lower compared with immune-competent individuals. All patients remained anti-S IgG positive until last post-transplant follow-up, while three patients became anti-N negative.

Conclusions: We observed an uncomplicated course of liver and/or kidney transplantation after SARS-CoV-2 infection in selected patients. Although having lower absolute IgG antibody levels than immune-competent individuals, all seroconverted patients remained anti-S IgG positive. These encouraging data need validation in larger studies.
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http://dx.doi.org/10.1097/TP.0000000000003955DOI Listing
September 2021

Non-invasive alloimmune risk stratification of long-term liver transplant recipients.

J Hepatol 2021 Aug 23. Epub 2021 Aug 23.

Institute of Liver Studies, King's College London University and King's College Hospital, London, United Kingdom. Electronic address:

Background And Aims: Management of long-term immunosuppression following liver transplantation (LT) remains empirical. Surveillance liver biopsies in combination with transcriptional profiling could overcome this challenge by identifying recipients with active alloimmune-mediated liver damage despite normal liver tests, but has low applicability. Our aim was to investigate the utility of non-invasive tools in stratifying stable long-term LT recipients according to their immunological risk and need for immunosuppression.

Methods: We conducted a cross-sectional multicentre study of 190 adult liver recipients assessed to determine their eligibility to participate in an immunosuppression withdrawal trial. Patients had stable liver allograft function and had been transplanted for non-autoimmune non-replicative viral liver disease >3 years before inclusion. We performed histological, immunogenetic and serological studies and measured the intrahepatic transcript levels of an 11-gene classifier highly specific for T cell-mediated rejection (TCMR).

Results: 36% patients harboured clinically-silent fibro-inflammatory liver lesions, which were scored as moderate-to-severe in 22%. The severity of liver allograft damage was positively associated with TCMR-related transcripts, class II donor-specific antibodies (DSA), ALT/AST and liver stiffness measurements (LSM), and negatively correlated with serum creatinine and tacrolimus trough levels. Liver biopsies were stratified according to their TCMR transcript levels using a cut-off derived from biopsies with clinically-significant TCMR. Two multivariable prediction models, integrating ALT/LSM or ALT/class II DSA, respectively, had a high discriminative capacity in classifying patients with or without alloimmune damage. The latter model had a good performance in an independent cohort of 156 liver biopsies obtained from paediatric liver recipients with similar inclusion/exclusion criteria.

Conclusion: ALT, class II DSA and LSM are valuable tools to non-invasively identify stable LT recipients without significant underlying alloimmunity, who could benefit from immunosuppression minimisation.

Lay Summary: A large proportion of liver transplant patients with normal liver tests have liver inflammatory lesions, which in 17% of cases are molecularly indistinguishable from those seen at the time of rejection. ALT, class II donor-specific antibodies and liver stiffness are useful in identifying patients with this form of subclinical rejection. We propose these markers as a useful tool to help clinicians determine if the immunosuppression administered is adequate.
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http://dx.doi.org/10.1016/j.jhep.2021.08.007DOI Listing
August 2021

On-site testing and case management to improve hepatitis C care in drug users: a prospective, longitudinal, multicenter study in the DAA era.

BMC Public Health 2021 08 20;21(1):1574. Epub 2021 Aug 20.

Faculty of Medicine and Life Sciences, Hasselt University, Martelarenlaan 42, 3500, Hasselt, Diepenbeek, Belgium.

Background: Screening and treatment of hepatitis C virus (HCV) infection in people who use drugs (PWUD) remains insufficient. Reducing the burden of HCV infection in PWUD requires interventions focusing on the different steps of the HCV care cascade.

Methods: We performed a prospective, multicenter study, evaluating the impact of an HCV care model on the HCV care cascade among PWUD attending an addiction care center in Belgium between 2015 and 2018. Interventions within the care model consisted of pre-test counseling, on-site HCV screening and case management services. A multiple logistic regression model was performed to identify the independent factors influencing the outcomes.

Results: During the study period, 441 PWUD were registered at the addiction care center, 90% (395/441) were contacted, 88% (349/395) were screened for HCV infection. PWUD were more likely to be screened if they had ever injected drugs (p < .001; AOR 6.411 95% CI 3.464-11.864). In 45% (157/349), the HCV antibody (Ab) test was positive, and in 27% (94/349) HCV RNA was positive. Within the Belgian reimbursement criteria (fibrosis stage ≥ F2), 44% (41/94) were treated. Specialist evaluation at the hospital was lower for PWUD receiving decentralized opioid agonist therapy (p = .005; AOR 0.430 95% CI 0.005-0.380), PWUD with unstable housing in the past 6 months before inclusion (p = .015; AOR 0.035 95% CI 0.002-0.517) or if they were recently incarcerated (p = .001; AOR 0.010 95% CI 0.001-0.164).

Conclusions: This HCV care model demonstrated high screening, linkage to care, and treatment initiation among PWUD in Belgium. Using the cascade of care to guide interventions is easy and necessary to monitor results. This population needs guidance, not only for screening and treatment initiation but also for the long-term follow-up since one in six had cirrhosis and could develop hepatocellular carcinoma. Further interventions are necessary to increase linkage to care and treatment initiation. Universal access to direct-acting antiviral therapy from 2019 will contribute to achieving HCV elimination in the PWUD population.

Trial Registration: Clinical trial registration details: www.clinicaltrials.gov ( NCT03106194 ).
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http://dx.doi.org/10.1186/s12889-021-11608-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379886PMC
August 2021

Treatment of severe alcoholic hepatitis: A systematic review.

Curr Opin Pharmacol 2021 Oct 5;60:91-101. Epub 2021 Aug 5.

Laboratory of Hepatology, Department of Chronic Diseases and Metabolism, Catholic University of Leuven, Belgium; Department of Gastroenterology & Hepatology, University Hospitals Leuven, Leuven, Belgium. Electronic address:

Severe alcoholic hepatitis is the most severe form of alcohol-related liver disease. Corticosteroids remain the first choice of treatment. However, they are only effective in a subset of patients and are associated with an increased infection risk. Furthermore, nonresponders to corticosteroids have a poor prognosis with a mortality of 70% over 6 months. As such, there is a high need for a more personalized use of corticosteroids and the development and identification of alternative therapeutic strategies. In this review, we summarize the recent and ongoing randomized controlled trials concerning the treatment of severe alcoholic hepatitis.
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http://dx.doi.org/10.1016/j.coph.2021.06.011DOI Listing
October 2021

Recanalization of portal axis after cavoportal hemitransposition in a liver transplant recipient with complete splanchnic thrombosis.

Pediatr Transplant 2021 Jul 21:e14097. Epub 2021 Jul 21.

Department of Abdominal Transplant Surgery and Transplant Coordination, University Hospitals Leuven, Leuven, Belgium.

Background: Diffuse splanchnic thrombosis may render standard LTx difficult or even technically impossible. A 19-year-old woman with acute-on-chronic Budd-Chiari syndrome and complete splanchnic thrombosis underwent conventional LTx. Only limited anatomical portal inflow could be restored, and urgent re-transplantation for recurrent splanchnic vein thrombosis became necessary.

Methods: At re-transplant, and in addition to the reestablishment of some portal inflow through the preserved original porto (native)-portal (graft) connection, a cavoportal shunt was created (first partial via 30% tapering of the vena cava, but eventually complete by total occlusion of the vena cava).

Results: The postoperative course was then uneventful, and interestingly, the native portomesenteric axis gradually reopened. Two years post-transplant, the liver graft is perfused via both physiological and non-physiological sources. Liver function is normal. There is no IVC syndrome and no residual PHT. She is leading a normal life.

Conclusion: Creation of CPHT, in addition to the preservation of portal inflow from the native splanchnic system, should be considered in patients with diffuse splanchnic thrombosis, when sufficient physiological portal inflow cannot be restored at the time of LTx, but in whom the splanchnic circulation may reopen up later.
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http://dx.doi.org/10.1111/petr.14097DOI Listing
July 2021

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.

Aliment Pharmacol Ther 2021 09 19;54(5):583-605. Epub 2021 Jul 19.

Valencia, Spain.

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.
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http://dx.doi.org/10.1111/apt.16374DOI Listing
September 2021

Long-term, Prolonged-release Tacrolimus-based Immunosuppression in De Novo Liver Transplant Recipients: 5-year Prospective Follow-up of Patients in the DIAMOND Study.

Transplant Direct 2021 Aug 9;7(8):e722. Epub 2021 Jul 9.

Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.

Background: Immunosuppression with calcineurin inhibitors (CNIs) is reportedly associated with risk of renal impairment in liver transplant recipients. It is believed that this can be mitigated by decreasing initial exposure to CNIs or delaying CNI introduction until 3-4 d posttransplantation. The ADVAGRAF studied in combination with mycophenolate mofetil and basiliximab in liver transplantation (DIAMOND) trial evaluated different administration strategies for prolonged-release tacrolimus (PR-T).

Methods: DIAMOND was a 24-wk, open-label, phase 3b trial in de novo liver transplant recipients randomized to: PR-T 0.2 mg/kg/d (Arm 1); PR-T 0.15-0.175 mg/kg/d plus basiliximab (Arm 2); or PR-T 0.2 mg/kg/d delayed until day 5 posttransplant plus basiliximab (Arm 3). In a 5-y follow-up, patients were maintained on an immunosuppressive regimen according to standard clinical practice (NCT02057484). Primary endpoint: graft survival (Kaplan-Meier analysis).

Results: Follow-up study included 856 patients. Overall graft survival was 84.6% and 73.5% at 1 and 5 y post transplant, respectively. Five-year rates for Arms 1, 2, and 3 were 74.7%, 71.5%, and 74.5%, respectively. At 5 y, death-censored graft survival in the entire cohort was 74.7%. Overall graft survival in patients remaining on PR-T for ≥30 d was 79.1%. Graft survival in patients who remained on PR-T at 5 y was 87.3%. Patient survival was 86.6% at 1 y and 76.3% at 5 y, with survival rates similar in the 3 treatment arms at 5 y. Estimated glomerular filtration rate at the end of the 24-wk initial study and 5 y posttransplant was 62.1 and 61.5 mL/min/1.73 m, respectively, and was similar between the 3 treatment arms at 5 y. Overall, 18 (2.9%) patients had ≥1 adverse drug reaction, considered possibly related to PR-T in 6 patients.

Conclusions: In the DIAMOND study patient cohort, renal function, graft survival, and patient survival were similar between treatment arms at 5 y posttransplant.
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http://dx.doi.org/10.1097/TXD.0000000000001166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274734PMC
August 2021

A phase II study of human allogeneic liver-derived progenitor cell therapy for acute-on-chronic liver failure and acute decompensation.

JHEP Rep 2021 Aug 18;3(4):100291. Epub 2021 Apr 18.

UCLouvain, Institute of Experimental and Clinical Research (IREC), Laboratory of Pediatric Hepatology and Cell Therapy (PEDI), Brussels, Belgium.

Background & Aims: Human allogeneic liver-derived progenitor cells (HALPC, HepaStem®; Promethera Biosciences, Mont-Saint-Guibert, Belgium) are an advanced therapy medicinal product that could potentially alleviate systemic inflammation and ameliorate liver function in patients with acute-on-chronic liver failure (ACLF) or acute decompensation of cirrhosis (AD).

Methods: This open-label phase II study was conducted in 9 centres in Belgium, Spain, and Bulgaria between 2016 and 2019. The primary objective was to assess the safety of HALPC therapy up to Day 28 and the secondary objectives were to assess its safety and preliminary efficacy up to Month 3.

Results: The 24 treated patients (mean age: 51 years) were mostly male with an alcoholic cirrhosis. On pre-infusion Day 1, 15 patients had ACLF and 9 patients had AD. Two of the 3 initial patients treated with high HALPC doses (∼5×10 cells/kg body weight [BW]) had severe adverse bleeding events attributed to treatment. In 21 patients subsequently treated with lower HALPC doses (0.6 or 1.2×10 cells/kg BW, 1 or 2 times 7 days apart), no serious adverse events were related to treatment, and the other adverse events were in line with those expected in patients with ACLF and AD. Overall, markers of systemic inflammation and altered liver function decreased gradually for the surviving patients. The Day-28 and Month-3 survival rates were 83% (20/24) and 71% (17/24), and at Month 3, no patient had ACLF.

Conclusions: The treatment of patients with ACLF or AD with up to 2 doses of 1.2×10 HALPC/kg BW appeared safe. The results of this study support the initiation of a proof-of-concept study in a larger cohort of patients with ACLF to further confirm the safety and evaluate the efficacy of HALPC therapy.

Clinical Trials Registration: EudraCT 2016-001177-32.

Lay Summary: Patients with liver cirrhosis may suffer from the rapid onset of organ failure or multiple organ failure associated with a high risk of death in the short term. This clinical study of 24 patients suggests that an advanced therapy based on the intravenous infusion of low doses of human allogeneic liver-derived progenitor cells is safe and supports the next phase of clinical development of this type of therapy.
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http://dx.doi.org/10.1016/j.jhepr.2021.100291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207211PMC
August 2021

Development and validation of a prognostic score for long-term transplant-free survival in autoimmune hepatitis type 1.

United European Gastroenterol J 2021 Jul 24;9(6):662-671. Epub 2021 Jun 24.

Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands.

Background: No prognostic score is currently available for long-term survival in autoimmune hepatitis (AIH) patients.

Objective: The aim of this study was to develop and validate such a prognostic score for AIH patients at diagnosis.

Methods: The prognostic score was developed using uni- & multivariate Cox regression in a 4-center Dutch cohort and validated in an independent 6-center Belgian cohort.

Results: In the derivation cohort of 396 patients 19 liver transplantations (LTs) and 51 deaths occurred (median follow-up 118 months; interquartile range 60-202 months). In multivariate analysis age (hazard ratio [HR] 1.045; p < 0.001), non-caucasian ethnicity (HR 1.897; p = 0.045), cirrhosis (HR 3.266; p < 0.001) and alanine aminotransferase level (HR 0.725; p = 0.003) were significant independent predictors for mortality or LT (C-statistic 0.827; 95% CI 0.790-0.864). In the validation cohort of 408 patients death or LT occurred in 78 patients during a median follow-up of 74 months (interquartile range: 25-142 months). Predicted 5-year event rate did not differ from observed event rate (high risk group 21.5% vs. 15.7% (95% CI: 6.3%-24.2%); moderate risk group 5.8% versus 4.3% (95% CI: 0.0%-9.1%); low risk group 1.9% versus 5.4% (95% CI: 0.0%-11.4%); C-statistic 0.744 [95% CI 0.644-0.844]).

Conclusions: A Dutch-Belgian prognostic score for long-term transplant-free survival in AIH patients at diagnosis was developed and validated.
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http://dx.doi.org/10.1002/ueg2.12112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281048PMC
July 2021

Liver-Related and Cardiovascular Outcome of Patients Transplanted for Nonalcoholic Fatty Liver Disease: A European Single-Center Study.

Transplant Proc 2021 Jun 18;53(5):1674-1681. Epub 2021 May 18.

Department of Gastroenterology and Hepatology, University Hospital KU Leuven, Leuven, Belgium. Electronic address:

Background: The increasing rate of liver transplantation (LT) for nonalcoholic fatty liver disease (NAFLD) raises concerns on cardiovascular morbidity and mortality after LT in these patients.

Methods: We collected variables regarding the presence of metabolic risk factors, NAFLD recurrence, cardiovascular morbidity, and overall survival at time of listing and after LT of 112 patients with NAFLD and a control group of 120 patients with hepatitis C (HCV).

Results: Metabolic syndrome and cardiovascular morbidity component rates (24.1% vs 12.5%) at the time of LT listing were higher in patients with NAFLD compared with patients with HCV (for all, P < .0390). Median follow-up after LT was 5.6 years in patients with NAFLD vs 13.5 years in patients with HCV (P = .0009). There was no difference in 6-weeks postoperative mortality (1.7% vs 2.5%) (P =1.0000). Metabolic syndrome components after LT were more frequent in patients with NAFLD than in patients with HCV (for all, P < .0008). The incidence of NAFLD 5 years after LT was higher in patients transplanted for NAFLD compared with HCV (43.5% vs 4.2%) (P < .0001). Patients with recurrent NAFLD more often had myocardial infarction compared with those without recurrence (8.3% vs 0%) (P = .0313). Five years after LT, cardiovascular morbidity was more frequent in the NAFLD group than in the HCV group (12.8% vs 9.3%) (P = .0256), whereas no difference in overall survival was observed.

Conclusion: LT for NAFLD is associated with satisfactory 5-year outcomes; however, our data underscore the need for close monitoring and aggressive management of cardiovascular risk factors in these patients.
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http://dx.doi.org/10.1016/j.transproceed.2021.02.025DOI Listing
June 2021

Is there a role for neuregulin 4 in human nonalcoholic fatty liver disease?

PLoS One 2021 14;16(5):e0251822. Epub 2021 May 14.

Laboratory of Hepatology, Department Chronic Diseases, Metabolism & Ageing (CHROMETA), KU Leuven, Leuven, Belgium.

Background: Neuregulin 4 (Nrg4), a novel adipokine enriched in brown adipose tissue has been observed to negatively regulate de novo hepatic lipogenesis and limit nonalcoholic fatty liver disease (NAFLD) progression to nonalcoholic steatohepatitis (NASH) in rodents. However, the role of Nrg4 in human NAFLD remains unclear to date. We analysed Nrg4 plasma levels and its association with liver disease severity together with the transcriptional profile of the Nrg4 pathway in liver and visceral adipose tissue (VAT) of NAFLD patients.

Methods: Plasma Nrg4 levels were measured in 65 NAFLD patients and 43 healthy controls (HC). Hepatic steatosis and fibrosis were diagnosed and quantified with chemical shift MRI and transient elastography respectively. Furthermore, blood lipid levels, HOMA-IR and systemic pro-inflammatory cytokines (TNF-α, IL-6 and IFN-γ) were analysed. Microarray analyses to assess differences in the Nrg4 and its receptor family ErbB pathway in liver and VAT from an independent patient group with biopsy proven NAFL (simple steatosis) (n = 4), NASH (n = 5) and normal liver (n = 6) were performed.

Results: Plasma Nrg4 levels were not significantly different between NAFLD patients and HC (p = 0.622). Furthermore, plasma Nrg4 levels did not correlate with the hepatic fat fraction (r = -0.028, p = 0.829) and were not significantly different between NAFLD patients with or without hepatic fibrosis (p = 0.087). Finally, the expression profile of 82 genes related to the Nrg4-ErbB pathway in liver and VAT was not significantly different between NAFL, NASH or obese controls.

Conclusion: Our study does not support a role for Nrg4 in the pathophysiology of human NAFLD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251822PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121306PMC
May 2021

Hepatitis B virus prevalence in first-time blood donors in Flanders, Belgium: Impact of universal vaccination and migration.

Transfusion 2021 07 6;61(7):2125-2136. Epub 2021 May 6.

Blood Service, Belgian Red Cross, Mechelen, Belgium.

Background: Transfusion-transmissible infections such as hepatitis B virus (HBV) remain a major concern for the safety of blood transfusion. This cross-sectional study aimed to assess the trend of HBV prevalence and associated risk factors among a first-time donor population in a low endemic country.

Study Design And Methods: Between 2010 and 2018, blood samples were collected from first-time donors presented at donor collection sites of Belgian Red Cross-Flanders. They were tested for hepatitis B surface antigen (HBsAg), hepatitis B core antibodies (anti-HBc), and HBV DNA, HIV and hepatitis virus C (HCV) antibodies and RNA, and syphilis antibodies.

Results: A total of 211,331 first-time blood donors (43.7% males, median age 25 years) were analyzed. HBsAg prevalence decreased from 0.06% in 2010 to 0.05% in 2018 (p = .004) and this declining trend was accompanied by an increased number of donors in the HBV vaccinated birth cohort (p < .001). HBsAg prevalence was 0.33% in foreign-born donors and 0.02% in Belgian natives (p < .001). Multivariate risk profiling showed that anti-HBc positivity was significantly associated with mainly foreign-born donors (odds ratio [OR] = 9.24) but also with older age (OR = 1.06), male gender (OR = 1.32), year of blood donation (OR = 0.94), and co-infections with HCV (OR = 4.31) or syphilis (OR = 4.91).

Discussion: The decreasing trend in HBV prevalence could mainly be explained by the introduction of the universal HBV vaccination. Being born in endemic areas was the most important predictor for HBV infection while the co-infections with syphilis suggest unreported sexual risk contacts.
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http://dx.doi.org/10.1111/trf.16431DOI Listing
July 2021

A Comparison of Prognostic Scores (Mayo, UK-PBC, and GLOBE) in Primary Biliary Cholangitis.

Am J Gastroenterol 2021 07;116(7):1514-1522

Liver Unit, Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain.

Introduction: Comparative data on scores that predict outcome in primary biliary cholangitis (PBC) are scarce. We aimed to assess and compare the prognostic value of the Mayo Risk Score (MRS, 1989 and 1994), UK-PBC score, and GLOBE score in a large international cohort of patients with PBC.

Methods: Ursodeoxycholic acid-treated patients from 7 centers participating in the GLOBAL PBC Study Group were included. The discriminatory performance of the scores was assessed with concordance statistics at yearly intervals up to 5 years. Model for End-stage Liver Disease was included for comparison. Prediction accuracy was assessed by comparing predicted survival and actual survival in Kaplan-Meier analyses.

Results: A total of 1,100 ursodeoxycholic acid-treated patients with PBC were included, with a mean (SD) age of 53.6 (12.0) years, of whom 1,003 (91%) were female. During a median follow-up of 7.6 (interquartile range 4.1-11.7) years, 42 patients underwent liver transplantation, and 127 patients died. At 1 year, the concordance statistic for Model for End-stage Liver Disease was 0.68 (95% confidence interval [CI] 0.64-0.72), 0.74 (95% CI 0.67-0.80) for the UK-PBC score, 0.76 (95% CI 0.72-0.81) for the MRS (1989 and 1994), and 0.80 (95% CI 0.76-0.84) for the GLOBE score. The GLOBE score showed superior discriminatory performance, but differences were not statistically different. For all scores, discriminatory performance increased in those with bilirubin >0.6 × ULN and advanced fibrosis estimated with Fibrosis-4. The predicted (median) minus observed 5-year transplant-free survival was +0.4% and +2.5% for the MRS (1989) and GLOBE score, respectively.

Discussion: All prognostic scores developed for PBC (GLOBE, UK-PBC, and MRS) demonstrated comparable discriminating performance for liver transplantation or death as well as good prediction accuracy.
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http://dx.doi.org/10.14309/ajg.0000000000001285DOI Listing
July 2021

Bacterial infections in patients with acute variceal bleeding in the era of antibiotic prophylaxis.

J Hepatol 2021 08 12;75(2):342-350. Epub 2021 Jun 12.

Gastroenterology Department, University Hospital of the Canary Islands, La Laguna, Tenerife, Spain.

Background & Aims: Antibiotic prophylaxis reduces the risk of infection and mortality in patients with cirrhosis and acute variceal bleeding (AVB). This study examines the incidence of, and risk factors for, bacterial infections during hospitalization in patients with AVB on antibiotic prophylaxis.

Methods: A post hoc analysis was performed using the database of an international, multicenter, observational study designed to examine the role of pre-emptive transjugular intrahepatic portosystemic shunts in patients with cirrhosis and AVB. Data were collected on patients with cirrhosis hospitalized for AVB (n = 2,138) from a prospective cohort (October 2013-May 2015) at 34 referral centers, and a retrospective cohort (October 2011-September 2013) at 19 of these centers. The primary outcome was incidence of bacterial infection during hospitalization.

Results: A total of 1,656 patients out of 1,770 (93.6%) received antibiotic prophylaxis; third-generation cephalosporins (76.2%) and quinolones (19.0%) were used most frequently. Of the patients on antibiotic prophylaxis, 320 patients developed bacterial infection during hospitalization. Respiratory infection accounted for 43.6% of infections and for 49.7% of infected patients, and occurred early after admission (median 3 days, IQR 1-6). On multivariate analysis, respiratory infection was independently associated with Child-Pugh C (odds ratio [OR] 3.1; 95% CI 1.4-6.7), grade III-IV encephalopathy (OR 2.8; 95% CI 1.8-4.4), orotracheal intubation for endoscopy (OR 2.6; 95% CI 1.8-3.8), nasogastric tube placement (OR 1.7; 95% CI 1.2-2.4) or esophageal balloon tamponade (OR 2.4; 95% CI 1.2-4.9).

Conclusion: Bacterial infections develop in almost one-fifth of patients with AVB despite antibiotic prophylaxis. Respiratory infection is the most frequent, is an early event after admission, and is associated with advanced liver failure, severe hepatic encephalopathy and use of nasogastric tube, orotracheal intubation for endoscopy or esophageal balloon tamponade.

Lay Summary: Bacterial infections develop during hospitalization in close to 20% of patients with acute variceal bleeding despite antibiotic prophylaxis. Respiratory bacterial infections are the most frequent and occur early after admission. Respiratory infection is associated with advanced liver disease, severe hepatic encephalopathy and a need for a nasogastric tube, orotracheal intubation for endoscopy or esophageal balloon tamponade.
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http://dx.doi.org/10.1016/j.jhep.2021.03.026DOI Listing
August 2021

Combination of fibrates with obeticholic acid is able to normalise biochemical liver tests in patients with difficult-to-treat primary biliary cholangitis.

Aliment Pharmacol Ther 2021 05 25;53(10):1138-1146. Epub 2021 Mar 25.

Paris, France.

Background: Obeticholic acid (OCA) and fibrates are second-line therapies for patients with primary biliary cholangitis (PBC) with an inadequate response to ursodeoxycholic acid (UDCA).

Aim: To know whether OCA and fibrates, administered together in combination with UDCA, have additive beneficial effects in patients with difficult-to-treat PBC.

Methods: PBC patients treated for ≥3 months with UDCA, OCA and fibrates (bezafibrate or fenofibrate) due to failure of either second-line therapy were included in a multicentre, uncontrolled retrospective cohort study. Changes in biochemical liver tests and pruritus were analysed using a generalised linear mixed-effect model.

Results: Among 58 patients included, half received OCA as second-line and fibrates as third-line therapy (Group OCA-Fibrate), while the other half had the inverse therapeutic sequence (Group Fibrate-OCA). The mean duration of triple therapy was 11 months (range 3-26). Compared to dual therapy, triple therapy was associated with a significant gain in alkaline phosphatase (ALP) reduction: 22% per first year (95% CI 12%-31%), an effect that was stronger in OCA-Fibrate than in Fibrate-OCA group. Triple therapy was associated with a 3.4 (95% CI 1.4-8.2) odds ratio (OR) of reaching normal ALP and with a significant decrease in gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin. The ORs of achieving the Paris-2 and Toronto criteria of adequate biochemical response were 6.8 (95% CI 2.8-16.7) and 9.2 (95% CI 3.4-25.1) respectively. Finally, triple therapy significantly improved pruritus in OCA-Fibrate but not in Fibrate-OCA group.

Conclusions: Triple therapy with UDCA, OCA and fibrates is able to normalise biochemical liver tests and improve pruritus in patients with difficult-to-treat PBC.
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http://dx.doi.org/10.1111/apt.16336DOI Listing
May 2021

Efficacy and Safety of Everolimus With Reduced Tacrolimus in Liver Transplant Recipients: 24-month Results From the Pooled Analysis of 2 Randomized Controlled Trials.

Transplantation 2021 07;105(7):1564-1575

University of Toronto, Toronto, Canada.

Background And Methods: Data from 2 randomized liver transplant trials (N = 772; H2304 [deceased donor, n = 488], H2307 [living donor, n = 284]) were pooled to further evaluate the efficacy and safety of everolimus with reduced tacrolimus (EVR + rTAC) versus standard tacrolimus (sTAC) regimen at month 24.

Results: EVR + rTAC was comparable to sTAC for composite efficacy failure of treated biopsy-proven acute rejection, graft loss, or death (9.8% versus 10.8%; difference, -1.0%; 95% confidence interval, -5.4 to 3.4; P = 0.641) at month 24. EVR + rTAC was superior to sTAC for the mean change in estimated glomerular filtration rate (eGFR) from randomization to month 24 (-8.37 versus -13.40 mL/min/1.73 m2; P = 0.001). A subanalysis of renal function by chronic kidney disease (CKD) stage at randomization showed significantly lower decline in eGFR from randomization to month 24 for patients with CKD stage 1/2 (eGFR ≥ 60 mL/min/1.73 m2) in EVR + rTAC group versus sTAC (-12.82 versus -17.67 mL/min/1.73 m2, P = 0.009). In patients transplanted for hepatocellular carcinoma (HCC) beyond Milan criteria, HCC recurrence was numerically lower although not statistically significant with EVR + rTAC versus sTAC group (5.9% [1 of 17] versus 23.1% [6 of 26], P = 0.215), while comparable in patients within Milan criteria (2.9% [3 of 102] versus 2.1% [2 of 96], P = 1.000), irrespective of pretransplant alpha-fetoprotein levels.

Conclusions: EVR + rTAC versus sTAC showed comparable efficacy and safety with significantly better renal function, particularly in patients with normal/mildly decreased renal function (CKD stage 1/2) at randomization and a trend toward lower HCC recurrence in patients transplanted with HCC beyond Milan at month 24. Further long-term data would be required to confirm these results.
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http://dx.doi.org/10.1097/TP.0000000000003394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221719PMC
July 2021

Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency.

Gut 2021 Feb 25. Epub 2021 Feb 25.

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Vienna, Austria.

Objective: Alpha-1 antitrypsin deficiency (AATD) is a common, potentially lethal inborn disorder caused by mutations in alpha-1 antitrypsin (AAT). Homozygosity for the 'Pi*Z' variant of AAT (Pi*ZZ genotype) causes lung and liver disease, whereas heterozygous 'Pi*Z' carriage (Pi*MZ genotype) predisposes to gallstones and liver fibrosis. The clinical significance of the more common 'Pi*S' variant remains largely undefined and no robust data exist on the prevalence of liver tumours in AATD.

Design: Baseline phenotypes of AATD individuals and non-carriers were analysed in 482 380 participants in the UK Biobank. 1104 participants of a multinational cohort (586 Pi*ZZ, 239 Pi*SZ, 279 non-carriers) underwent a comprehensive clinical assessment. Associations were adjusted for age, sex, body mass index, diabetes and alcohol consumption.

Results: Among UK Biobank participants, Pi*ZZ individuals displayed the highest liver enzyme values, the highest occurrence of liver fibrosis/cirrhosis (adjusted OR (aOR)=21.7 (8.8-53.7)) and primary liver cancer (aOR=44.5 (10.8-183.6)). Subjects with Pi*MZ genotype had slightly elevated liver enzymes and moderately increased odds for liver fibrosis/cirrhosis (aOR=1.7 (1.2-2.2)) and cholelithiasis (aOR=1.3 (1.2-1.4)). Individuals with homozygous Pi*S mutation (Pi*SS genotype) harboured minimally elevated alanine aminotransferase values, but no other hepatobiliary abnormalities. Pi*SZ participants displayed higher liver enzymes, more frequent liver fibrosis/cirrhosis (aOR=3.1 (1.1-8.2)) and primary liver cancer (aOR=6.6 (1.6-26.9)). The higher fibrosis burden was confirmed in a multinational cohort. Male sex, age ≥50 years, obesity and the presence of diabetes were associated with significant liver fibrosis.

Conclusion: Our study defines the hepatobiliary phenotype of individuals with the most relevant AATD genotypes including their predisposition to liver tumours, thereby allowing evidence-based advice and individualised hepatological surveillance.
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http://dx.doi.org/10.1136/gutjnl-2020-323729DOI Listing
February 2021

The hepatitis C cascade of care in the Belgian HIV population: One step closer to elimination.

Int J Infect Dis 2021 Apr 18;105:217-223. Epub 2021 Feb 18.

Faculty of Health and Life Sciences, Hasselt University, Diepenbeek, Belgium; Department of Gastroenterology and Hepatology, Ziekenhuis Oost-Limburg, Genk, Belgium; Department of Gastroenterology and Hepatology, University Hospitals KU Leuven, Leuven, Belgium.

Objectives: The Belgian population of people living with HIV (PLHIV) has unrestricted access to direct-acting antiviral (DAA) treatment for hepatitis C virus (HCV) infection, since 2017. International literature claims that half of the patients remain untreated in high-income countries with unrestricted access to DAA. This study was initiated to provide an overview of the present situation in Belgium and recommendations for HCV care in PLHIV in other regions.

Methods: This was a retrospective, multicenter study of PLHIV in Belgium, from January 1, 2007 to December 31, 2018. The HCV cascade of care was examined.

Results: Out of 4607 unique PLHIV, 322 (7.0%) tested positive for HCV antibody and HCV RNA positivity was seen in 289 (6.3%). Of those with a proven HCV infection, 207/289 (71.6%) initiated treatment. Of the 171 (82.6%) persons with a sustained virologic response (SVR), 16 (9.4%) subjects were reinfected.

Conclusions: We present a care cascade of 4607 PLHIV in Belgium. Treatment initiation and SVR rates were high compared to other regions. Implementation of a national HCV register to track progress and yearly screening, especially in PLHIV with high-risk behavior, remains crucial. Identifying reasons for not initiating treatment is necessary to achieve elimination of HCV in PLHIV by 2030.
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http://dx.doi.org/10.1016/j.ijid.2021.02.068DOI Listing
April 2021

Polycystic liver disease genes: Practical considerations for genetic testing.

Eur J Med Genet 2021 Mar 6;64(3):104160. Epub 2021 Feb 6.

Department of Gastroenterology and Hepatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands. Electronic address:

The development of a polycystic liver is a characteristic of the monogenic disorders: autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), and autosomal dominant polycystic liver disease (ADPLD). Respectively two and one genes mainly cause ADPKD and ARPKD. In contrast, ADPLD is caused by at least six different genes which combined do not even explain the disease development in over half of the ADPLD population. Genetic testing is mainly performed to confirm the likelihood of developing PKD and if renal therapy is essential. However, pure ADPLD patients are frequently not genetically screened as knowledge about the genotype-phenotype correlation is currently limited. This paper will clarify the essence of genetic testing in ADPLD patients.
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http://dx.doi.org/10.1016/j.ejmg.2021.104160DOI Listing
March 2021

Simplified care-pathway selection for nonspecialist practice: the GLOBAL Primary Biliary Cholangitis Study Group Age, Bilirubin, Alkaline phosphatase risk assessment tool.

Eur J Gastroenterol Hepatol 2020 Dec 14. Epub 2020 Dec 14.

Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.

Background: Opportunity to redefine the care journeys for those living with primary biliary cholangitis (PBC) includes facilitating access to enhanced (PBC-dedicated) programmes by nonspecialist risk 'flagging' of patients.

Objective: To develop a nonexpert PBC stratification tool to help care pathway choices (standard vs. enhanced) choices in PBC.

Methods: We included ursodeoxycholic acid-treated patients with PBC from the Global PBC Study Group. The performance of baseline and 1-year clinical markers with transplant-free survival was assessed to develop the 'ABA' tool using Age (A), Bilirubin (B), and Alkaline phosphatase (A). Added value of fibrosis estimation was assessed.

Results: 'ABA' classification mapped three risk groups (n = 2226): low [Age > 50 years, bilirubin ≤ 1 × ULN, alkaline phosphatase (ALP) ≤ 3 × ULN], high (Age ≤ 50 years, bilirubin > 1 × ULN, ALP > 3 × ULN), and intermediate (other). Transplant-free survival at 10 years in the low-, intermediate-, and high-risk groups were 89, 77, and 59% at baseline and 86, 76, and 40% at 1 year, respectively. We propose that high-risk patients at baseline be directly triaged to enhanced (PBC-dedicated) care and the remaining be reassessed at 1 year. Modelling showed after 1 year 46% patients were proposed to enhanced care and 54% to standard care. The 'ABA' mapped pathways facilitated identification of patients at risk based on a young age, as compared to traditional liver biochemical stratification. In patients proposed to standard care, estimated fibrosis stage had ongoing prognostic value.

Conclusion: Nonspecialist use of the 'ABA' risk tool could prioritize care journey choices for patients with PBC.
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http://dx.doi.org/10.1097/MEG.0000000000002029DOI Listing
December 2020

The Role of Brown Adipose Tissue in the Development and Treatment of Nonalcoholic Steatohepatitis: An Exploratory Gene Expression Study in Mice.

Horm Metab Res 2020 Dec 1;52(12):869-876. Epub 2020 Dec 1.

Department of Gastroenterology and Hepatology, University Hospitals KU Leuven, Leuven, Belgium.

Brown adipose tissue (BAT) might be a beneficial mediator in the development and treatment of nonalcoholic steatohepatitis (NASH). We aim to evaluate the gene expression of BAT activity-related genes during the development and the dietary and surgical treatment of NASH. BAT was collected from male mice that received a high fat-high sucrose diet (HF-HSD) or a normal chow diet (NCD) for 4 and 20 weeks (n=8-9 per dietary group and timepoint) and from mice that underwent dietary intervention (return to NCD) (n=8), roux-en-y gastric bypass (RYGB) (n=6), or sham procedure (n=6) after 12 weeks HF-HSD. Expression of BAT genes involved in lipid metabolism (Cd36 and Cpt1b; p<0.05) and energy expenditure (Ucp1 and Ucp3; p<0.05) were significantly increased after 4 weeks HF-HSD compared with NCD, whereas in the occurrence of NASH after 20 weeks HF-HSD no difference was observed. We observed no differences in gene expression regarding lipid metabolism or energy expenditure at 8 weeks after dietary intervention (no NASH) compared with HF-HSD mice (NASH), nor in mice that underwent RYGB compared with SHAM. However, dietary intervention and RYGB both decreased the BAT gene expression of inflammatory cytokines (Il1b, Tnf-α and MCP-1; p<0.05). Gene expression of the neuregulin 4 was significantly decreased after 20 weeks HF-HSD (p<0.05) compared with NCD, but was restored by dietary intervention and RYGB (p<0.05). In conclusion, BAT is hallmarked by dynamic alterations in the gene expression profile during the development of NASH and can be modulated by dietary intervention and bariatric surgery.
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http://dx.doi.org/10.1055/a-1301-2378DOI Listing
December 2020

Diagnostic Accuracy of Biomarkers of Alcohol Use in Patients With Liver Disease: A Systematic Review.

Alcohol Clin Exp Res 2021 01 25;45(1):25-37. Epub 2020 Dec 25.

Department of Gastroenterology and Hepatology, (FN, JV), University Hospitals KU Leuven, Leuven, Belgium.

Background And Aims: Alcohol-related liver disease is the most frequent cause of cirrhosis and a major indication for liver transplantation. Several alcohol use biomarkers have been developed in recent years and are already in use in several centers. However, in patients with liver disease their diagnostic performance might be influenced by altered biomarker formation by hepatic damage, altered excretion by kidney dysfunction and diuretics use, and altered deposition in hair and nails. We systematically reviewed studies on the diagnostic accuracy of biomarkers of alcohol use in patients with liver disease and performed a detailed study quality assessment.

Methods: A structured search in PubMed/Medline/Embase databases was performed for relevant studies, published until April 28, 2019. The risk of bias and applicability concerns was assessed according to the adapted quality assessment of diagnostic accuracy studies-2 (QUADAS-2) checklist.

Results: Twelve out of 6,449 studies met inclusion criteria. Urinary ethyl glucuronide and urinary ethyl sulfate showed high sensitivity (70 to 89 and 73 to 82%, respectively) and specificity (93 to 99 and 86 to 89%, respectively) for assessing any amount of alcohol use in the past days. Serum carbohydrate-deficient transferrin showed low sensitivity but higher specificity (40 to 79 and 57 to 99%, respectively) to detect excessive alcohol use in the past weeks. Whole blood phosphatidylethanol showed high sensitivity and specificity (73 to 100 and 90 to 96%, respectively) to detect any amount of alcohol use in the previous weeks. Scalp hair ethyl glucuronide showed high sensitivity (85 to 100%) and specificity (97 to 100%) for detecting chronic excessive alcohol use in the past 3 to 6 months. Main limitations of the current evidence are the lack of an absolute gold standard to assess alcohol use, heterogeneous study populations, and the paucity of studies.

Conclusions: Urinary and scalp hair ethyl glucuronide are currently the most validated alcohol use biomarkers in patients with liver disease with good diagnostic accuracies. Phosphatidylethanol is a highly promising alcohol use biomarker, but so far less validated in liver patients. Alcohol use biomarkers can complement each other regarding diagnostic time window. More validation studies on alcohol use biomarkers in patients with liver disease are needed.
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http://dx.doi.org/10.1111/acer.14512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898850PMC
January 2021

Renal disease in the allograft recipient.

Best Pract Res Clin Gastroenterol 2020 Jun - Aug;46-47:101690. Epub 2020 Sep 25.

Department of Gastroenterology and Hepatology, Department of Abdominal Transplant Surgery and Coordination, University Hospitals KU Leuven, Herestraat 49, 3000, Leuven, Belgium. Electronic address:

Chronic renal failure after liver transplantation (LT) is significantly more frequent than after lung or heart transplantation and it results in an increased short and long-term mortality. Renal impairment may occur before LT (functional or due to preexisting parenchymal kidney disease), in the peri-operative period or later after LT. The number of patients with renal failure after LT has increased due to the liver allocation based on MELD and to the more liberal use of higher risk grafts. Calcineurin inhibitor (CNI) nephrotoxicity is the most important cause of renal dysfunction but is a modifiable factor. Strategy to prevent CNI-associated nephrotoxicity is post-op CNI minimization by induction therapy and reduced dose and/or delayed introduction of CNI in combination with mycophenolate mofetil (MMF) or everolimus with no penalty in term of rejection. With everolimus, usually started one month after LT, a drastic minimization of CNI is possible and this results in superior kidney function until at least 3 years follow up. At the moment of renal impairment a drastic reduction of CNI dose together with the introduction of MMF results in an improvement in GFR at 6 to 2 years with a low rate of acute rejection. However, secondary prevention fails to normalize renal function in most of the patients once e GFR <60 ml/min/1.73mml.
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http://dx.doi.org/10.1016/j.bpg.2020.101690DOI Listing
December 2020

Improved Markers of Cholestatic Liver Injury in Patients With Primary Biliary Cholangitis Treated With Obeticholic Acid and Bezafibrate.

Hepatology 2021 Jun 25;73(6):2598-2600. Epub 2021 May 25.

Laboratory of Hepatology, CHROMETA Department, KU Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1002/hep.31613DOI Listing
June 2021

Donor Hepatectomy and Implantation Time Are Associated With Early Complications After Liver Transplantation: A Single-center Retrospective Study.

Transplantation 2021 05;105(5):1030-1038

Lab of Abdominal Transplantation, Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.

Background: Donor hepatectomy and liver implantation time reduce long-term graft and patient survival after liver transplantation. It is not known whether these surgical times influence early outcomes after liver transplantation.

Methods: This single-center study evaluated the effect of donor hepatectomy and implantation time on the risk of nonanastomotic biliary strictures (NAS) occurring within 1 year and of early allograft dysfunction (EAD) after deceased-donor solitary liver transplantation, adjusting for other donors, recipient, and surgical factors.

Results: Of 917 transplants performed between January 2000 and December 2016, 106 (11.56%) developed NAS and 247 (27%) developed EAD. Donor hepatectomy time (median 35 min, IQR: 26-46) was an independent risk factor of NAS [adjusted hazard ratio, 1.19; 95% CI, 1.04-1.35; P = 0.01]. Implantation time (median 80 min, IQR: 69-95) was independently associated with EAD [adjusted odds ratio (OR), 1.15; 95% CI,1.07-1.23; P < 0.0001). The risk of EAD was increased by anastomosis time of both portal vein (adjusted OR, 1.26; 95% CI, 1.12-14.42; P = 0.0001) and hepatic artery (adjusted OR, 1.13; 95% CI, 1.04-1.22; P = 0.005). The magnitude of these effects was similar in donation after circulatory death liver grafts.

Conclusions: Donor hepatectomy and implantation time negatively affect short-term outcomes.
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http://dx.doi.org/10.1097/TP.0000000000003335DOI Listing
May 2021

The effect of universal infant vaccination on the prevalence of hepatitis B immunity in adult solid organ transplant candidates.

J Viral Hepat 2021 01 14;28(1):105-111. Epub 2020 Oct 14.

Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium.

Background: Hepatitis B virus (HBV) immunity is recommended to optimize outcomes after solid organ transplantation (SOT). This study assessed the prevalence and predictors of HBV immunity at the time patients were placed on transplant waiting list over a period from 1997 to 2019 in a low HBV endemic region.

Methods: Data were obtained from the University Hospitals Leuven transplant database. Minors and patients with past/current HBV infection were excluded. From 1986, Belgian patients are covered by the universal infant vaccination; therefore, birth cohort was stratified in those born ≥1986 vs <1986.

Results: The study population consisted of 3297 SOT candidates. HBV immunity rate was superior in renal transplant candidates (55.3%), and this number was 21.5%, 15.4% and 16.8% for liver, cardiac and pulmonary transplant candidates, respectively, P < .001. Among liver transplant candidates, HBV immunity rate was 14.8% in decompensated cirrhotic patients and 27.9% in those without advanced cirrhosis (P < .001). The overall immunity rate increased from 19.3% in period 1997-2008 to 32.8% in 2009-2019, P < .001. In multivariable analyses, younger age (odds ratio (OR) 95% confidence interval (CI): 0.97-0.98, P < .001) and birth cohort ≥ 1986 (OR 95% CI: 1.18-2.66, P = .006) were associated with increased HBV immunity.

Conclusion: An increase in HBV immunity was observed over a 20-year period related to the introduction of universal infant HBV vaccination. Nevertheless, this study highlights the low overall HBV immunity at the time of listing for organ transplantation and points out the need of an increased awareness and vaccination strategy at an early disease stage.
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http://dx.doi.org/10.1111/jvh.13414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756211PMC
January 2021

Clinical relevance of plasma virome dynamics in liver transplant recipients.

EBioMedicine 2020 Oct 24;60:103009. Epub 2020 Sep 24.

KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory for Clinical and Epidemiological Virology, Herestraat 49, Post box 1040, BE-3000 Leuven, Belgium; Health Policy Research Centre, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran; Blood Transfusion Research Centre, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran. Electronic address:

Background: The role of the microbiome in liver transplantation (LT) outcome has received a growing interest in the past decades. In contrast to bacteria, the role of endogenous viral communities, known as the virome, is poorly described. Here, we applied a viral metagenomic approach to study the dynamic evolution of circulating viruses in the plasma of LT recipients and its effect on the clinical course of patients.

Methods: Patients chronically infected with hepatitis B virus (HBV) that received a LT due to endstage liver disease were included in this study. Longitudinal plasma samples were collected pre- and post-LT. Intact viral particles were isolated and sequenced on an Illumina HiSeq 2500 platform. Short read libraries were analysed with an in-house bioinformatics pipeline. Key endpoints were the dynamics of viral families and post-LT complications.

Findings: The initiation of immunosuppression induced a bloom of the Anelloviridae that dominated the post-LT plasma virome. A variety of post-LT complication were observed. Nephrotoxicity was reported in 38% of the patients and was associated with a high abundance of anelloviruses. Besides nephrotoxicity, 16 (67%) patients experienced flares of viral or bacterial infections in post-transplant follow-up. These flares were recognized by an increased burden of anelloviruses (p < 0.05). Interestingly, no mortality was observed in patients infected with human pegivirus.

Interpretation: These findings suggest a diagnostic potential for the Anelloviridae family in post-LT complications. Furthermore, the impact of human pegivirus infection on post-transplant survival should be further investigated.

Funding: This trial was supported by Gilead Sciences grant number BE-2017-000133.
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http://dx.doi.org/10.1016/j.ebiom.2020.103009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519289PMC
October 2020

Measurement of Gamma Glutamyl Transferase to Determine Risk of Liver Transplantation or Death in Patients With Primary Biliary Cholangitis.

Clin Gastroenterol Hepatol 2021 08 7;19(8):1688-1697.e14. Epub 2020 Aug 7.

Bicocca Bioinformatics Biostatistics and Bioimaging Centre - B4, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.

Background & Aims: Gamma-glutamyltransferase (GGT) is a serum marker of cholestasis. We investigated whether serum level of GGT is a prognostic marker for patients with primary biliary cholangitis (PBC).

Methods: We analyzed data from patients with PBC from the Global PBC Study Group, comprising 14 centers in Europe and North America. We obtained measurements of serum GGT at baseline and time points after treatment. We used Cox model hazard ratios to evaluate the association between GGT and clinical outcomes, including liver transplantation and liver-related death.

Results: Of the 2129 patients included in our analysis, 281 (13%) had a liver-related clinical endpoint. Mean age at diagnosis was 53 years and 91% of patients were female patients. We found a correlation between serum levels of GGT and alkaline phosphatase (ALP) (r = 0.71). Based on data collected at baseline and yearly for up to 5 years, higher serum levels of GGT were associated with lower hazard for transplant-free survival. Serum level of GGT at 12 months after treatment higher than 3.2-fold the upper limit of normal (ULN) identified patients who required liver transplantation or with liver-related death at 10 years with an area under the receiver operating characteristic curve of 0.70. The risk of liver transplantation or liver-related death in patients with serum level of GGT above 3.2-fold the ULN, despite level of ALP lower than 1.5-fold the ULN, was higher compared to patients with level of GGT lower than 3.2-fold the ULN and level of ALP lower than 1.5-fold the ULN (P < .05). Including information on level of GGT increased the prognostic value of the Globe score.

Conclusions: Serum level of GGT can be used to identify patients with PBC at risk for liver transplantation or death, and increase the prognostic value of ALP measurement. Our findings support the use of GGT as primary clinical endpoint in clinical trials. In patients with low serum level of ALP, a high level of GGT identifies those who might require treatment of metabolic disorders or PBC treatment escalation.
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http://dx.doi.org/10.1016/j.cgh.2020.08.006DOI Listing
August 2021
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