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Orthotopic liver transplantation (OLT) with donation after circulatory death (DCD) often leads to a higher first week peak alanine aminotransferase (ALT) and a higher rate of biliary nonanastomotic strictures (NAS) as compared to donation after brain death (DBD). This retrospective study was to evaluate whether an association exists between peak ALT and the development of NAS in OLT with livers from DBD (n = 399) or DCD (n = 97) from two transplantation centers. Optimal cutoff value of peak ALT for risk of development of NAS post-DCD-OLT was 1300 IU/l. The 4-year cumulative incidence of NAS after DCD-OLT was 49.5% in patients with a high ALT peak post-OLT, compared with 11.3% in patients with a low ALT peak. (P < 0.001). No relation between peak ALT and NAS was observed after DBD-OLT. Multivariate analysis revealed peak ALT ≥1300 IU/l [adjusted hazard ratio (aHR) = 3.71, confidence interval (CI) (1.26-10.91)] and donor age [aHR = 1.04, CI 1.00-1.07] to be independently associated with development of NAS post-DCD-OLT. A peak ALT of <1300 IU/l carries a risk for NAS similar to DBD-OLT. Thus, in DCD-OLT, but not in DBD-OLT, peak ALT discriminates patients at high or low risk for NAS., (© 2015 Steunstichting ESOT.)

Background: Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the bile ducts, frequently necessitating orthotopic liver transplantation (OLT), often accompanied by inflammatory bowel disease (IBD). Matrix metalloproteinases (MMPs) are associated with fibrotic diseases caused by the involvement in tissue remodelling., Aim: To evaluate the contribution of MMP-2 and -9 promoter polymorphisms to disease severity in PSC, as assessed by death or need for OLT., Methods: Matrix metalloproteinase-2 (-1306 C/T) and -9 (-1562 C/T) gene promoter polymorphisms were analyzed in 132 PSC patients. Follow-up was from onset PSC until death, OLT or end of follow-up., Results: Twenty-year cumulative incidence (CI) of death or OLT for PSC patients with MMP-2 CT genotype was 86.5% compared to 52.8% for CC genotype (P = 0.030) and reached 100% at 11.3 years for TT genotype. In patients with IBD, CIs were similar: 20-years CI of death or OLT for MMP-2 CT genotype was 86.0% compared to 49.0% for CC genotype and 100% at 11.3 years for TT genotype. Patients without IBD showed a similar trend in 20 years CI for MMP-2 CT (77.8%) compared to CC (57.8%) and CI for TT genotype reached 100% at 9.3 years. Multivariate analysis showed, along with age at diagnosis, a stepwise increase in hazard ratio for MMP-2 T-allele polymorphism for death or OLT. MMP-9 genotype was not associated with disease severity in PSC., Conclusion: Matrix metalloproteinase-2 C to T-1306 gene promoter polymorphism in PSC is an independent risk factor for disease severity as reflected by the need for OLT or disease progression leading to mortality., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Orthotopic liver transplantation (OLT) is accompanied by a significant postoperative infection risk. Immunosuppression to prevent rejection increases the susceptibility to infections, mainly by impairing the adaptive immune system. Genetic polymorphisms in the lectin complement pathway of the donor have recently been identified as important risk determinants of clinically significant bacterial infection (CSI) after OLT. Another genetic factor involved in innate immunity is NOD2, which was reported to be associated with increased risk of spontaneous bacterial peritonitis in cirrhotic patients., Methods: We assessed association of three genetic NOD2 variants (R702W, G908R and 3020insC) with increased risk of CSI after OLT. 288 OLT recipient-donor pairs from two tertiary referral centers were genotyped for the three NOD2 variants. The probability of CSI in relation to NOD2 gene variants was determined with cumulative incidence curves and log-rank analysis., Results: The R702W NOD2 variant in the recipient was associated with CSI after OLT. Eight out of 15 (53.3%) individuals with a mutated genotype compared to 80/273 (29.3%) with wild type genotype developed CSI (p=0.027, univariate cox regression), illustrated by a higher frequency of CSI after OLT over time (p=0.0003, log rank analysis). Multivariate analysis (including the donor lectin complement pathway profile) showed independence of this R702W NOD2 association from other risk factors (HR 2.0; p=0.04). The other NOD2 variants, G908R and 3020insC, in the recipient were not associated with CSI. There was no association with CSI after OLT for any of the NOD2 variants in the donor., Conclusion: The mutated NOD2 R702W genotype in the recipient is independently associated with an increased risk of bacterial infections after liver transplantation, indicating a predisposing role for this genetic factor impairing the recipient's innate immune system.

Purpose: Chimerism in transplantation medicine refers to the coexistence of cells of donor and recipient origin. Their existence in relation to possible pathological mechanisms remains largely unknown. We used donor-recipient mismatches for matrix metalloproteinases (MMP) gene polymorphisms in liver biopsies and in blood as a marker for chimerism after orthotopic liver transplantation (OLT). The second aim of this study was to evaluate these polymorphisms in relation to clinical outcome such as ischemia-reperfusion injury (IRI) and acute cellular rejection (ACR)., Methods: MMP-2 and MMP-9 promoter polymorphism donor-recipient mismatches were determined in 147 OLT patients. The relationship between these MMP polymorphism mismatches in donor and recipient DNA with the development of IRI and ACR after OLT was evaluated. Liver biopsy specimens and peripheral blood samples were subsequently evaluated for the presence of chimerism, also in relation to these complications., Results: MMP polymorphism donor-recipient mismatches were found in 53.7% (MMP-2) and 35.5% (MMP-9) of the OLT patients but no relation was observed with IRI or ACR. Chimerism in liver biopsy specimens was found to be present in 28.8% (MMP-2) and 16.2% (MMP-9) of the cases. Liver chimerism in MMP-2 was found to be significantly associated with ACR after OLT (χ(2) 6.4, P = .01). Multivariate analysis revealed MMP-2 chimerism to be an independent risk factor for ACR after OLT even adjusted for Model for End-stage Liver Disease score (hazard ratio = 3.83, P = .03). In addition, evidence of donor chimerism was found in peripheral blood samples of the recipients in some cases., Conclusion: Chimerism after OLT can be found in liver biopsy specimens and in peripheral blood. MMP donor-recipient polymorphism mismatches are good markers for assessing chimerism after OLT. In the multivariate analysis, liver chimerism in MMP-2 was found to be significantly associated with the development of ACR after OLT., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Infection is a common cause of morbidity and mortality after liver transplantation. Risk factors relate to transplantation factors, donor and recipient factors. Transplant factors include ischaemia-reperfusion damage, amount of intra-operative blood transfusion, level and type of immunosuppression, rejection, and complications, prolonged intensive care stay with dialysis or ventilation, type of biliary drainage, repeat operations, re-transplantation, antibiotics, antiviral regimen, and environment. Donor risk factors include infection, prolonged intensive care stay, quality of the donor liver (e.g. steatosis), and viral status. For the recipient the most important are MELD score >30, malnutrition, renal failure, acute liver failure, presence of infection or colonisation, and immune status for viruses like cytomegalovirus. In recent years it has become clear that genetic polymorphisms in innate immunity, especially the lectin pathway of complement activation and in Toll-like receptors importantly contribute to the infection risk after liver transplantation. Therefore, the risk for infections after liver transplantation is a multifactorial problem and all factors need attention to reduce this risk., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background & Aims: The lectin pathway of complement activation is a crucial effector cascade of the innate immune response to pathogens. Cytomegalovirus (CMV) infection occurs frequently in immunocompromised patients after orthotopic liver transplantation (OLT). Single-nucleotide polymorphisms (SNPs) in the lectin pathway genes determine their liver-derived protein level and functional activity. We examined the association between these SNPs and the risk for CMV infection in OLT., Methods: OLT patients (n = 295) were genotyped for recipient and donor SNPs in mannose-binding lectin (MBL2), Ficolin-2 (FCN2) and MBL-associated serine protease (MASP2) genes., Results: Combined analysis of independently associated variant MBL2 [HR 1.65, p<0.02] and wild-type FCN2 [1.85; p<0.02] SNPs in the donor liver showed an increased risk of CMV infection for either and both risk genotypes [HR 2.02 and HR 3.26, respectively, p = 0.004], especially in CMV Donor-/Recipient+ (D-/R+) patients [HR 4.7 and HR 10.0, respectively, p = 0.01]. A genetic donor-recipient mismatch for MBL2 and FCN2 increased the CMV risk independently, also combined [HR 5.35; p<0.001], particularly in CMV D-/R+ patients [HR 16.6; p = 0.009]. Multivariate Cox analysis showed a consistent stepwise increase in CMV infection risk with the gene profile of the donor [up to HR 2.77; p<0.005] and the combined MBL2 and FCN2 donor-recipient mismatch profile [up to HR 4.57; p<0.001], independent from donor-recipient CMV serostatus, also at higher CMV (re)infection cut-off values., Conclusions: MBL2 and FCN2 risk alleles of donor liver and recipient constitute independent risk factors for CMV infection after OLT. Patients with these risk genes probably need intensified CMV monitoring and anti-viral therapy., (Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Nonanastomotic biliary strictures (NAS) are a serious complication after orthotopic liver transplantation (OLT). Matrix metalloproteinases (MMPs) are involved in connective tissue remodelling in chronic liver disease and complications after OLT., Aim: To evaluate the relationship between MMP-2 and MMP-9 gene polymorphisms and NAS., Methods: MMP-2 (-1306 C/T) and MMP-9 (-1562 C/T) gene promoter polymorphisms were analysed in 314 recipient-donor combinations. Serum levels of these MMPs were determined in subgroups of patients as well. NAS were identified with various radiological imaging studies performed within 4 years after OLT and defined as any stricture, dilation or irregularity of the intra- or extrahepatic bile ducts of the liver graft followed by an intervention, after exclusion of hepatic artery thrombosis and anastomotic strictures., Results: The average incidence of NAS was 15%. The major clinical risk factor for the development of NAS was PSC in the recipient. The presence of the MMP-2 CT genotype in donor and/or recipient was associated with a significantly higher incidence of NAS, up to 29% when both donor and recipient had the MMP-2 CT genotype (P=0.003). In the multivariate analyses, pre-OLT PSC (hazard ratio 2.1, P=0.02) and MMP-2 CT genotype (hazard ratio 3.5, P=0.003) were found to be independent risk factors for the development of NAS after OLT. No obvious association was found between NAS and the MMP-9 genotype and serum levels of the MMPs., Conclusion: MMP-2 CT genotype of donor and recipient is an independent risk factor, in addition to PSC, for the development of NAS after OLT., (© 2011 John Wiley & Sons A/S.)

Unlabelled: Infectious complications after orthotopic liver transplantation (OLT) are a major clinical problem. The lectin pathway of complement activation is liver-derived and a crucial effector of the innate immune defense against pathogens. Polymorphisms in lectin pathway genes determine their functional activity. We assessed the relationship between these polymorphic genes and clinically significant bacterial infections, i.e., sepsis, pneumonia, and intra-abdominal infection, and mortality within the first year after OLT, in relation to major risk factors in two cohorts from different transplant centers. Single-nucleotide polymorphisms in the mannose-binding lectin gene (MBL2), the ficolin-2 gene (FCN2), and the MBL-associated serine protease gene (MASP2) of recipients and donors were determined. Recipients receiving a donor liver in the principal cohort with polymorphisms in all three components i.e., MBL2 (XA/O; O/O), FCN2+6359T, and MASP2+371A, had a cumulative risk of an infection of 75% as compared to 18% with wild-type donor livers (P = 0.002), an observation confirmed in the second cohort (P = 0.04). In addition, a genetic (mis)match between donor and recipient conferred a two-fold higher infection risk for each separate gene. Multivariate Cox analysis revealed a stepwise increase in infection risk with the lectin pathway gene profile of the donor (hazard ratio = 4.52; P = 8.1 x 10(-6)) and the donor-recipient (mis)match genotype (hazard ratio = 6.41; P = 1.9 x 10(-7)), independent from the other risk factors sex and antibiotic prophylaxis (hazard ratio > 1.7 and P < 0.02). Moreover, patients with a lectin pathway gene polymorphism and infection had a six-fold higher mortality (P = 0.9 x 10(-8)), of which 80% was infection-related., Conclusion: Donor and recipient gene polymorphisms in the lectin complement pathway are major determinants of the risk of clinically significant bacterial infection and mortality after OLT.

Inflammatory processes, aside from cholesterol, play a central role in atherogenesis. Human C-reactive protein (huCRP) signals systemic inflammation and independently predicts future cardiovascular risk. Cholesterol-lowering statins reduce atherosclerosis and plasma huCRP levels. Evidence is sought for a direct anti-inflammatory statin effect in vivo, independent of effects on plasma cholesterol and atherogenesis. The effect of atorvastatin and simvastatin on huCRP expression was studied in nonatherosclerotic huCRP transgenic mice and compared with another class of hypolipidemic drugs, peroxisome proliferator-activated receptor-alpha (PPARalpha) activators, notably fenofibrate and Wy14643. Like statins, PPARalpha activators combine antiatherosclerotic properties with huCRP-lowering effects. Dietary treatment with statins or PPARalpha activators decreased basal and interleukin-1beta (IL-1beta)-induced plasma huCRP levels independently of cholesterol lowering. These direct anti-inflammatory in vivo effects occurred at the transcriptional level and could be confirmed in cultured human liver slices and in human hepatoma cells transiently transfected with a huCRP promoter-driven luciferase reporter. A molecular rationale for the suppression of IL-1-induced huCRP transcription is provided by showing that statins and PPARalpha activators up-regulate IkappaBalpha protein expression. This results in a reduced nuclear translocation of p50-nuclear factor kappa B (NFkappaB) and thereby decreased amounts of nuclear p50-NFkappaB approximately CCAAT/enhancer binding protein beta (C/EBPbeta) complexes, which determine the huCRP transcription rate. Our results provide conclusive evidence for a direct suppressive effect of statins and PPARalpha activators on huCRP expression independent of cholesterol lowering and atherogenesis.