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Background and Aim. Endoscopic therapy is the method of choice in the management of biliary strictures after orthotopic liver transplantation (OLT). Even though the mainstay approach for OLT stricture complications is represented by consecutive procedures of multiple plastic stents (MPS) insertion, a valuable alternative is the use of fully covered self-expandable metal stents (FCSEMS). The aim of the study was to compare MPS with FCSEMS used in the management of OLT biliary strictures, in terms of clinical outcomes and complications. Material and Methods. This is a retrospective, single-center study conducted between February 2014 and November 2019 in the Clinical Emergency Hospital of Bucharest, Romania. We enrolled all consecutive patients who developed biliary strictures after OLT and were treated by endoscopic retrograde cholangiopancreatography (ERCP) either with MPS or FCSEMS. Results. Thirty-six patients were included in the study, 27 patients had MPS and nine patients had FCSEMS. 106 ERCP procedures were performed and 159 stents were inserted. The mean number of ERCP procedures required per patient was significantly higher for MPS than for FCSEMS (3.34 ± 1.46 vs. 2.11 ± 0.33, p < 0.001). In the FCSEMS group only one patient had three procedures, due to stent migration. Difficult cannulation was encountered in 22 patients, 18 patients from MPS group and four patients from FCSEMS group. Dilation was performed in 20 (77%) MPS patients and in four FCSEMS patients (44%). Overall, we used 159 stents for stricture resolution, 149 plastic stents and 10 FCSEMS. Mean number of stents inserted was significantly lower in the FCSEMS group compared to MPS group (1.16 ± 0.40 vs. 5.73 ± 2.64, p < 0.001). Conclusions. Stricture resolution using FCSEMS is comparable to MPS and even has some advantages. In line with prior studies, FCSEMS are effective, with fewer complications and similar outcome compared to plastic stents. Other particular aspects should be further assessed, especially long-term follow up of FCSEMS and their cost efficiency. [ABSTRACT FROM AUTHOR]

Purpose To compare the efficacy and safety of two distinct doses of ulinastatin on late-onset acute renal failure (LARF) following orthotopic liver transplantation (OLT). Methods The high-risk recipients that underwent OLT were divided into two groups according to ulinastatin dose: low-dose (LD) ulinastatin group, 0.8 million U/d; high-dose (HD) ulinastatin group, 1.6 million U/d. The primary outcome was the incidence of LARF, which was defined the newly onset acute kidney injury (AKI) stage III (KDIGO, 2012) within 7–28 post-transplant days. The second outcomes were early multiple organ retrieval assessments, length of hospital stay and safety events. Results A total of 174 recipients were included (LD ulinastatin group, n = 55; HD ulinastatin group, n = 119). There was no significant difference in the incidence of LARF between LD (8/55, 14.50%) and HD (9/119, 7.56%) ulinastatin groups (HD vs. LD, HR, 0.49; 95%CI, 0.17–1.37; p = .1295). Multivariate Cox proportion risk regression model revealed HD ulinastatin (HR, 0.57; 95%CI, 0.38–0.98; p = .0464) was an independent protective factor for LARF. Early lactate level, oxygenation, AKI stage, graft function, and sequential organ failure assessment [SOFA] score were significantly improved in HD ulinastatin group versus LD ulinastatin group. No significant adverse events were observed in either group. Conclusions Higher dose of ulinastatin (1.6 million U/d) might be preferable to prevent LARF after OLT, and it may contribute to the enhancement of early multiple organ recovery and thus attenuate the incidence of LARF.

Background and Aim. Endoscopic therapy is the method of choice in the management of biliary strictures after orthotopic liver transplantation (OLT). Even though the mainstay approach for OLT stricture complications is represented by consecutive procedures of multiple plastic stents (MPS) insertion, a valuable alternative is the use of fully covered self-expandable metal stents (FCSEMS). The aim of the study was to compare MPS with FCSEMS used in the management of OLT biliary strictures, in terms of clinical outcomes and complications. Material and Methods. This is a retrospective, single-center study conducted between February 2014 and November 2019 in the Clinical Emergency Hospital of Bucharest, Romania. We enrolled all consecutive patients who developed biliary strictures after OLT and were treated by endoscopic retrograde cholangiopancreatography (ERCP) either with MPS or FCSEMS. Results. Thirty-six patients were included in the study, 27 patients had MPS and nine patients had FCSEMS. 106 ERCP procedures were performed and 159 stents were inserted. The mean number of ERCP procedures required per patient was significantly higher for MPS than for FCSEMS (3.34 ± 1.46 vs. 2.11 ± 0.33, p < 0.001). In the FCSEMS group only one patient had three procedures, due to stent migration. Difficult cannulation was encountered in 22 patients, 18 patients from MPS group and four patients from FCSEMS group. Dilation was performed in 20 (77%) MPS patients and in four FCSEMS patients (44%). Overall, we used 159 stents for stricture resolution, 149 plastic stents and 10 FCSEMS. Mean number of stents inserted was significantly lower in the FCSEMS group compared to MPS group (1.16 ± 0.40 vs. 5.73 ± 2.64, p < 0.001). Conclusions. Stricture resolution using FCSEMS is comparable to MPS and even has some advantages. In line with prior studies, FCSEMS are effective, with fewer complications and similar outcome compared to plastic stents. Other particular aspects should be further assessed, especially long-term follow up of FCSEMS and their cost efficiency.

To compare the efficacy and safety of two distinct doses of ulinastatin on late-onset acute renal failure (LARF) following orthotopic liver transplantation (OLT). The high-risk recipients that underwent OLT were divided into two groups according to ulinastatin dose: low-dose (LD) ulinastatin group, 0.8 million U/d; high-dose (HD) ulinastatin group, 1.6 million U/d. The primary outcome was the incidence of LARF, which was defined the newly onset acute kidney injury (AKI) stage III (KDIGO, 2012) within 7–28 post-transplant days. The second outcomes were early multiple organ retrieval assessments, length of hospital stay and safety events. A total of 174 recipients were included (LD ulinastatin group, n = 55; HD ulinastatin group, n = 119). There was no significant difference in the incidence of LARF between LD (8/55, 14.50%) and HD (9/119, 7.56%) ulinastatin groups (HD vs. LD, HR, 0.49; 95%CI, 0.17–1.37; p =.1295). Multivariate Cox proportion risk regression model revealed HD ulinastatin (HR, 0.57; 95%CI, 0.38–0.98; p =.0464) was an independent protective factor for LARF. Early lactate level, oxygenation, AKI stage, graft function, and sequential organ failure assessment [SOFA] score were significantly improved in HD ulinastatin group versus LD ulinastatin group. No significant adverse events were observed in either group. Higher dose of ulinastatin (1.6 million U/d) might be preferable to prevent LARF after OLT, and it may contribute to the enhancement of early multiple organ recovery and thus attenuate the incidence of LARF. [ABSTRACT FROM AUTHOR]

Background: Platelets (PLT) play an essential functional role in cellular injury and liver regeneration following partial hepatectomy and orthotopic liver transplantation (OLT). Here, we investigated the association of postoperative PLT counts with short- and long-term outcomes in adult OLT recipients.Methods: Three hundred consecutive patients from our prospective OLT database were analyzed retrospectively (May 2010-November 2017). Ninety-day post-OLT complications were graded using the Clavien-Dindo (CD) classification and quantified by the comprehensive complication index (CCI). To determine the prognostic accuracy of PLT counts, the area under the receiver operating characteristic curve (AUROC) was calculated for major complications (CD ≥ 3b). Parametric and non-parametric tests were applied for subgroup analyses. Uni- and multivariable logistic regression analyses were performed to identify risk factors for major complications. Graft and patient survival were analyzed using the Kaplan-Meier method as well as uni- and multivariable Cox regression analyses.Results: Postoperative day 6 PLT counts < 70 × 109/L (POD6-70) were identified as the best cutoff for predicting major complications (AUROC = 0.7; p < 0.001; Youden index 0.317). The stratification of patients into low- (n = 113) and high-PLT (n = 187) groups highlighted significant differences in major complications (CCI 68 ± 29 vs. 43 ± 28, p < 0.001); length of hospital and intensive care unit (ICU) stay (53 ± 43 vs. 31 ± 25, p < 0.001; 21 ± 29 vs. 7 ± 11, p < 0.001, respectively) and estimated procedural costs. POD6-70 was associated with inferior 5-year graft survival. Multivariable logistic regression analysis identified POD6-70 as an independent predictor of major complications (odds ratio 2.298, confidence intervals 1.179-4.478, p = 0.015).Conclusion: In OLT patients, a PLT count on POD6 of less than 70 × 109/L bears a prognostic significance warranting further investigations. [ABSTRACT FROM AUTHOR]

Donor-derived infections with multidrug-resistant gram-negative bacteria are associated with poor outcomes, in part because of limited treatment options. Here, we describe a case of donor-derived, disseminated infection with colistin-resistant, carbapenemase-producing Klebsiella pneumoniae in a liver transplant recipient that was cured with addition of intravenous fosfomycin to a multidrug regimen, in conjunction with aggressive surgical source control. Intravenous fosfomycin represents a promising adjunctive agent for use in treatment of extensively drug-resistant infections in immunocompromised hosts. [ABSTRACT FROM AUTHOR]

Objective: We examined the value of inflammatory and oxidative biomarkers in predicting acute kidney injury (AKI) following orthotopic liver transplantation (OLT). Methods: Urinary excretion of tumour necrosis factor-α (TNF-α), interleukin-8 (IL-8), interleukin-10 (IL-10), superoxide dismutase (SOD), malondialdehyde (MDA), 6-keto prostaglandin F1α (6-keto-PGF1α), hydrogen peroxide (H2O2), and 8-keto prostaglandin F2α (8-iso-PGF2α), serum creatinine (SCr), blood urea nitrogen (BUN), urinary N-acetyl-beta-D-glucosaminidase (NAG), β2-microglobulin (β2-MG) and γ-glutamyl-transferase (γ-GT), were measured before surgery (baseline), at 2 h after graft reperfusion and 24 h after OLT in 28 liver transplantation patients. Results: The levels of TNF-α, IL-8, IL-10, SOD, MDA, 6-keto-PGF1α, H2O2 and 8-iso-PGF2α in urine were all significantly higher in patients who had AKI than in those who did not at 2 h after graft reperfusion and 24 h after OLT ( p < 0.01). [ABSTRACT FROM AUTHOR]

Background & Aims: Serum ferritin is a known marker of hepatic necro-inflammation and has been studied to predict 1year mortality and post-transplant survival in decompensated cirrhotics. However, there are no studies evaluating ferritin as a predictor of early mortality. We investigated whether serum ferritin levels could predict 15day and 30day mortality in patients with decompensated cirrhosis. Methods: 318 patients with decompensated cirrhosis were included. Results: Patients of decompensated cirrhosis [257 males, mean age of 51 [±13]years, were followed for a median of 31days. Serum ferritin levels were significantly different between survivors and non-survivors [p <0.001] and showed significant correlation with MELD score [p <0.001], CTP score [p <0.001], leucocyte counts [TLC] [p <0.001], serum sodium [p <0.001], ACLF grades [p =0.005], spontaneous bacterial peritonitis [SBP] [p =0.02], hepatic encephalopathy [HE] [p <0.001] and hepatorenal syndrome [HRS] [p =0.012]. Serum ferritin, etiology, MELD, HE, CTP score, sodium, TLC, and ACLF grades were significant predictors of mortality on univariate analysis. Ferritin [p =0.04, HR 1.66 95% CI (1.02–2.73)] was a significant predictor of early mortality on multivariate analysis along with HE [p =0.006, HR 3.47 95% CI (2.13–8.41)] (Model 1), TLC [p =0.02, HR 1.81 95% CI (1.06–3.07)] (Model 2), ACLF grades [p =0.018, HR 2.013,95% CI (1.126–3.60)], and CTP score [p <0.0001, HR 1.36 95% CI (1.17–1.59)] (Model 3). Conclusion: Serum ferritin levels correlate with severity of hepatic decompensation and are associated with early liver related death independent of the MELD score in hospitalized patients with decompensated cirrhosis. This could also have a potential therapeutic implication. [Copyright &y& Elsevier]

Abstract: Antithrombin (AT) is a 65kDa glycoprotein belonging to a group of inhibitory factors known as serpins (serine protease inhibitors). It plays a critical role in the inhibition of coagulation and inflammation processes within the environment of the vascular endothelium. Inadequate levels of functional AT in plasma results in an increased risk of thrombotic events, both venous and arterial. AT deficiency can be inherited or acquired. Congenital AT deficiency is the most severe inherited thrombophilic condition with an odds ratio of 20 for the increased risk of venous thrombosis. Acquired AT deficiency occurs in a variety of physiologic and pathologic medical conditions with similar risks of increased thrombosis. In this article, we review clinical settings characterized by an acquired AT deficiency largely or partly subsequent to protein microvascular leakage. Other different mechanisms of AT depletion are implied in some clinical conditions together with endothelial loss, and, therefore, outlined. In addition, we provide a description of the current knowledge on the specific mechanisms underlying endothelial AT leakage and on the consequences of this protein decrease, specifically looking at thrombosis. We identify potential directions of research that might prove useful in patients with acquired AT deficiency. [Copyright &y& Elsevier]

Background & Aims: Augmented susceptibility to infections increases mortality in patients with end-stage liver disease (ESLD). We sought to determine the contribution of selected genetic variants involved in inflammatory signalling downstream of the Toll-like receptor 4 (TLR4) to severe bacterial infections (SBIs) in patients with ESLD. Methods: We retrospectively assessed incidence of SBIs in 336 adult ESLD patients enlisted for orthotopic liver transplantation (OLT) and genotyped them for TLR4 c.+1196C/T, CD14 c.−159C/T, TNFA c.−238G/A, TNFA c.−863C/A, IL1B c.−31C/T and IL1RN variable number of tandem repeats allelic variants. Principal findings were validated in an independent cohort of 332 ESLD patients. Results: Thirty-four percent of patients from the identification cohort and 40% of patients from the validation cohort presented with SBI while enlisted for OLT. The presence of the variant allele TNFA c.−238A (rs361525) was associated with lower serum levels of TNF-α, and with significantly decreased risk of SBI in both cohorts. Multivariate analysis showed that the relative protection from SBI associated with this allele almost completely negated the increased susceptibility to SBI owed to advanced ESLD. Although not predictive of overall mortality, the presence of the TNFA c.−238A allele was associated with a complete prevention of SBI-related pre-transplant deaths. Conclusions: Our results suggest that genetic variability in inflammatory signalling is associated with the development of SBI in patients with ESLD. Specifically, we identified the importance of the TNFA c.−238A allele as a strong predictor of protection from SBI, and as a genetic marker associated with significantly improved pre-transplant survival in patients with SBI. [Copyright &y& Elsevier]

Background: Orthotopic liver transplantation (OLT) is the gold standard treatment for patients with early hepatocellular carcinoma (HCC). There are concerns about the efficacy of OLT for HCC in older patients, who we hypothesized might have poorer outcomes. Therefore, we sought to examine advanced age and its impact on OLT outcomes. Study Design: The United Network for Organ Sharing database was queried for patients who underwent OLT for HCC from 1987 to 2009. Patients were divided into 3 age groups: 35 to 49 years old, 50 to 64 years old, and 65 years or older, and patient characteristics were compared. Univariate and multivariate analyses were performed to assess the impact of age on OLT outcomes. Results: Of 10,238 patients with OLT for HCC, 16.5% (n = 1,688) of patients were 35 to 49 years old, 67.8% (n = 6,937) were 35 to 49 years old, and 15.8% (n = 1,613) were 65 years and older. By Kaplan-Meier method, the 50- to 64-year-old age group had the highest overall survival, despite having one of the highest rates of hepatitis C positivity (70%), but this group also had the lowest rate of diabetes mellitus (8.7%). The lowest overall survival was observed in the 65-year or older age group (p < 0.001). Finally, there was no difference in disease-specific survival among the age groups (p = 0.858), and patients aged 65 years and older had the highest rate of death from nonhepatic causes (17.5%). Conclusions: Although OS was prolonged in younger patients who underwent OLT for HCC, there was no observed difference in disease-specific survival among the age groups. Our results suggest that carefully selected patients 65 years of age and older can derive equal benefit from OLT for HCC when compared with their younger counterparts. [Copyright &y& Elsevier]

Background & Aims: Patients with hepatocellular carcinoma (HCC) receiving living donor liver transplantation appear to possess significantly higher tumor recurrence than the recipients receiving deceased donor liver transplantation. The underlying mechanism for HCC recurrence after transplantation remains unclear. Here, we aim to investigate the impact of small-for-size liver graft injury on HCC recurrence after transplantation. Methods: The correlation between tumor recurrence, liver graft injury, CXCL10 expression and endothelial progenitor cell (EPC) mobilization was studied in 115 liver transplant recipients and rat orthotopic liver transplantation (OLT) models. The direct role of CXCL10/CXCR3 signaling on EPC mobilization was investigated in CXCL10 −/− mice and CXCR3 −/− mice. The role of EPCs on tumor growth and angiogenesis was further investigated in an orthotopic liver tumor model. Results: Clinically, patients with small-for-size liver grafts (<60% of standard liver weight, SLW) had significantly higher HCC recurrence (p =0.04), accompanied by more circulating EPCs and higher early-phase intragraft and plasma CXCL10 levels, than the recipients with large grafts (⩾60% of SLW), which were further validated in rat OLT models. Circulatory EPC mobilization was reduced after liver injury both in CXCL10 −/− mice and CXCR3 −/− mice in comparison to wild-type controls. CXCL10 recruited EPCs in dose-dependent and CXCR3-dependent manners in vitro. Early-phase EPC/CXCL10 injection enhanced orthotopic liver tumor growth, angiogenesis and metastasis in nude mice. Conclusions: Post-transplant enhanced CXCL10/CXCR3 signaling in small-for-size liver grafts directly induced EPC mobilization, differentiation and neovessel formation, which further promotes tumor growth. Targeting CXCL10/CXCR3 signaling may attenuate early-phase liver graft injury and prevent late-phase tumor recurrence/metastasis after transplantation. [Copyright &y& Elsevier]

Background & Aims: The Keap1-Nrf2 signaling pathway regulates host cell defense responses against oxidative stress and maintains the cellular redox balance. Methods: We investigated the function/molecular mechanisms by which Keap1-Nrf2 complex may influence liver ischemia/reperfusion injury (IRI) in a mouse model of hepatic cold storage (20h at 4°C) followed by orthotopic liver transplantation (OLT). Results: The Keap1 hepatocyte-specific knockout (HKO) in the donor liver ameliorated post-transplant IRI, evidenced by improved hepatocellular function and OLT outcomes (Keap1 HKO→Keap1 HKO; 100% survival), as compared with controls (WT→WT; 50% survival; p <0.01). By contrast, donor liver Nrf2 deficiency exacerbated IRI in transplant recipients (Nrf2 KO→Nrf2 KO; 40% survival). Ablation of Keap1 signaling reduced macrophage/neutrophil trafficking, pro-inflammatory cytokine programs, and hepatocellular necrosis/apoptosis, while simultaneously promoting anti-apoptotic functions in OLTs. At the molecular level, Keap1 HKO increased Nrf2 levels, stimulated Akt phosphorylation, and enhanced expression of anti-oxidant Trx1, HIF-1α, and HO-1. Pretreatment of liver donors with PI3K inhibitor (LY294002) disrupted Akt/HIF-1A signaling and recreated hepatocellular damage in otherwise IR-resistant Keap1 HKO transplants. In parallel in vitro studies, hydrogen peroxide-stressed Keap1-deficient hepatocytes were characterized by enhanced expression of Nrf2, Trx1, and Akt phosphorylation, in association with decreased release of lactate dehydrogenase (LDH) in cell culture supernatants. Conclusions: Keap1-Nrf2 complex prevents oxidative injury in IR-stressed OLTs through Keap1 signaling, which negatively regulates Nrf2 pathway. Activation of Nrf2 induces Trx1 and promotes PI3K/Akt, crucial for HIF-1α activity. HIF-1α-mediated overexpression of HO-1/Cyclin D1 facilitates cytoprotection by limiting hepatic inflammatory responses, and hepatocellular necrosis/apoptosis in a PI3K-dependent manner. [Copyright &y& Elsevier]

Abstract: Recent studies strongly suggest an increasing role for immune responses against self-antigens (Ags) which are not encoded by the major histocompatibility complex in the immunopathogenesis of allograft rejection. Although, improved surgical techniques coupled with improved methods to detect and avoid sensitization against donor human leukocyte antigen (HLA) have improved the immediate and short term function of transplanted organs. However, acute and chronic rejection still remains a vexing problem for the long term function of the transplanted organ. Immediately following organ transplantation, several factors both immune and non immune mechanisms lead to the development of local inflammatory milieu which sets the stage for allograft rejection. Traditionally, development of antibodies (Abs) against mismatched donor HLA have been implicated in the development of Ab mediated rejection. However, recent studies from our laboratory and others have demonstrated that development of humoral and cellular immune responses against non-HLA self-Ags may contribute in the pathogenesis of allograft rejection. There are reports demonstrating that immune responses to self-Ags especially Abs to the self-Ags as well as cellular immune responses especially through IL17 has significant pro-fibrotic properties leading to chronic allograft failure. This review summarizes recent studies demonstrating the role for immune responses to self-Ags in allograft immunity leading to rejection as well as present recent evidence suggesting there is interplay between allo- and autoimmunity leading to allograft dysfunction. [Copyright &y& Elsevier]

Abstract: Objective: Acetaminophen intoxication is a leading cause of acute liver failure. Liver transplantation for acute liver failure is limited by the availability of donor organs. In this study, we aimed at identifying if the transplantation of adipose tissue-mesenchymal stem cells (ASCs) may exert therapeutic effects on acetaminophen-induced liver injury. Methods: ASCs were isolated from human subcutaneous tissue and were transfected with a green fluorescent protein (GFP). Sprague–Dawley rats were administrated 300mg/kg of acetaminophen intraperitoneally and were transplanted with ASCs or vehicle. After 24h from acetaminophen administration, rats were sacrificed. Hepatic levels of isoprostanes, 8-hydroxyguanosine (8-OHG), nitrites/nitrates and reduced glutathione (GSH) were determined as markers of oxidative stress; JNK phosphorylation and hepatic levels of inflammatory cytokines and regeneration factors were also assessed. Results: Transplantation of ASCs decreased AST, ALT and prothrombin time to the levels observed in control rats. Transplanted animals had normal plasma ammonia and did not display clinical encephalopathy. Liver sections of intoxicated rats treated with vehicle showed lobular necrosis and diffuse vacuolar degeneration; in rats transplanted with ASCs liver injury was almost absent. Transplantation of ASCs decreased liver isoprostanes, 8-OHG and nitrite–nitrates to the levels of control rats, while preserving GSH. Consistently, hepatic levels of TNF-α, MCP-1, IL-1β, ICAM-1 and phospho-JNK were markedly increased in rats treated with vehicle and were restored to the levels of controls in animals transplanted with ASCs. Furthermore, ASC transplantation increased liver expression of cyclin D1 and PCNA, two established hepatocyte regeneration factors, whereas ASCs were not able to metabolize acetaminophen in vitro. Conclusion: In this study, we demonstrated that ASC transplantation is effective in treating acetaminophen liver injury by enhancing hepatocyte regeneration and inhibiting liver stress and inflammatory signaling. [Copyright &y& Elsevier]

Background & Aims: Occult hepatitis B virus infection (OBI) frequently occurs in patients with hepatitis C virus (HCV) related chronic hepatitis (CHC), but the influence of OBI on the CHC outcome is still uncertain. This observational cohort study evaluated the clinical evolution of CHC patients according to their OBI status. Methods: From 1991 to 2000, 326 hepatitis B surface antigen negative CHC patients were tested for OBI by the analysis of liver biopsy DNA extracts. A total of 128/326 cases (39.2%) tested OBI positive and 198/326 (60.8%) OBI negative. Ninety-four of 326 patients (37 OBI positive, 57 OBI negative) were followed-up for a median time of 11years (range 5–19years). During the follow-up, 79/94 patients underwent anti-HCV treatments and 26 achieved a sustained virological response that occurred independently of their OBI status. Results: Eighteen patients (13/37 OBI positive, 5/57 OBI negative, p <0.01) developed hepatocellular carcinoma (HCC). Among the 76 non-HCC individuals, 15 subjects (8/24 OBI positive, 7/52 OBI negative, p <0.05) developed advanced forms of cirrhosis. Eighteen patients died during follow-up and 2 underwent liver transplantation. OBI positive individuals had a cumulative survival rate significantly shorter than OBI negative individuals (p =0.003). Liver-related deaths were more frequently found in OBI positive than OBI negative patients (12/37 OBI positive vs. 6/57 OBI negative patients respectively, p <0.01). Finally, non-response to anti-HCV therapy was significantly associated with lower survival (p =0.02). Conclusions: Among CHC patients, occult HBV co-infected individuals are a category at high risk of progression toward cirrhosis, HCC development, and lower survival. [Copyright &y& Elsevier]

Abstract: Background: After orthotopic liver transplantation (OLT) in chronic hepatitis B (HBV), adequate prophylaxis for recurrence of HBV in the graft is mandatory. Objectives: Evaluate safety of HBV prophylaxis with tenofovir and emtricitabine (TDF/FTC) after cessation of hepatitis B immunoglobulin (HBIG) after OLT in chronic HBV. Study design: In 17 consecutive patients after OLT in chronic HBV we started TDF/FTC after cessation of HBIG. All had received HBIG >6 months. 15/17 were HBsAg negative and 16/17 had undetectable HBV-DNA. Results: After mean follow-up of 2 years 16/17 patients were alive, one died due to urosepsis. All 16 with undetectable HBV-DNA remained HBV-DNA negative. From 15 HBsAg negative patients at start, in one seroconversion to positive HBsAg occurred, without detectable HBV-DNA. Liver biochemistry remained within the normal ranges. There were no cases of drug discontinuation. No major side effects were reported. TDF/FTC use saves €16,262/year over standard-of-care (HBIG+LAM). This prospective follow-up study shows that in liver transplantation for chronic hepatitis B, after initial treatment including HBIG for at least 6 months combined with or followed by (dual) nucleos(t)ide analog therapy, TDF/FTC provides adequate prophylaxis against recurrent HBV infection without major side effects and leads to substantial cost savings over a regimen with HBIG. Conclusion: Combined prophylaxis with TDF/ETV nucleoside plus nucleotide analogs and cessation of immunoglobulin after liver transplantation in chronic hepatitis B is safe and effective. [Copyright &y& Elsevier]

Background: Split liver transplantation is an excellent option for expansion of the donor organ pool. However, reports of increased morbidity in split liver recipients may limit use of this technique. Study Design: This was a single center retrospective analysis investigating split liver transplantation. Between August 1, 1995 and March 30, 2012, 53 of 1,261 (4.2%) recipients received split liver grafts. Results: The 1-, 5-, and 10-year patient and graft survivals in adult recipients of split grafts were 95.5%, 89.5%, and 89.5%, respectively. Survival was similar to that of whole organ recipients (p = 0.15). Twenty-three adults received split grafts: 18 (78%) were right trisegment grafts, 4 (17.4%) were right lobes, and 1 (4.3%) was a left lobe. The mean cold ischemic time was 5.7 hours (±2.4 hours [SD]) and warm ischemic time was 36 minutes (±5.5 minutes). Four (17%) recipients required hepatic artery reconstruction; 5 (21.7%) required a caval-venous patch, and 5 (21.7%) had Roux-en-Y reconstruction of the bile duct. No venous conduits were required. Thirty children received split grafts (median age 1.2 years, range 0.1 to 16.4 years) and had a median weight of 8.6 kg (range 3.6 to 45 kg). Pediatric split 1-, 5-, and 10-year overall and graft survival rates were 96.7%, 80.0%, 80.0%, and 93.3%, 76.8, and 76.8%, respectively. Complications included retransplantation in 3 (10.0%), bile leak in 5 (16.7%), hepatic arterial thrombosis in 2 (6.7%), bowel perforation in 2 (6.7%), and bleeding in 2 (6.7%). The mean donor age was 22.4 months (±8.9) months and body mass index was 22.8 kg/m2 (±3.3 kg/m2). Conclusions: We demonstrated excellent outcomes in adult and pediatric recipients using carefully selected donors for liver splitting. We recommend escalation of the use of split liver transplants to expand the donor pool for cadaveric liver transplantation. [Copyright &y& Elsevier]

Abstract: Domino liver transplantation is a method used to increase the number of liver grafts available for orthotopic liver transplantation (OLT). Reports indicate that livers from patients with metabolic liver disease can be safely transplanted into select recipients if the donor's defect and the recipient's metabolic needs are carefully considered. The liver of patients with many types of metabolic liver disease is morphologically and biochemically normal, except for the mutation that characterizes that disease. Other biochemical functions normally performed by the liver are present and presumably “normal” in these hepatocytes. Hepatocytes were isolated from the liver of 35 organ donors and 35 liver tissues taken at OLT from patients with liver disease were analyzed for 9 different measures of viability and function. The data indicate that cells isolated from some diseased livers performed as well or better than those isolated from organ donors with respect to viability, cell yield, plating efficiency and in assays of liver function, including drug metabolism, conjugation reactions and ammonia metabolism. Cells from metabolic diseased livers rapidly and efficiently repopulated a mouse liver upon transplantation. Conclusions: As with domino liver transplantation, domino cell transplantation deserves consideration as method to extend the pool of available organs and cells for transplantation. [Copyright &y& Elsevier]

Background & Aims: Extrapyramidal and cerebellar symptoms belong to the most prominent features of episodic hepatic encephalopathy, and usually decrease upon ammonia-lowering therapy. Rapidly progressing parkinsonian symptoms, which are unresponsive to treatment of hepatic encephalopathy, indicate cirrhosis-related Parkinsonism. This study aims at analyzing the prevalence of cirrhosis-related Parkinsonism in patients with liver cirrhosis, and to study the functional status of the striatal dopaminergic system in these patients. Methods: 214 patients with liver cirrhosis who were consecutively seen at the out-patient clinic for liver transplant candidates and/or at the transplantation wards at Hannover Medical School, between August 1, 2008 and March 31, 2011, underwent a standardized neurological examination while on the waiting list or immediately after liver transplantation. Single photon emission computer tomography (SPECT) using 123I-beta-CIT, for the evaluation of the striatal dopamine transporter function, and 123I-IBZM for the evaluation of the striatal dopamine D2 receptor availability, was performed in 6 patients with cirrhosis-related Parkinsonism. Results: Cirrhosis-related Parkinsonism was diagnosed in 9 of 214 patients (4.2%). SPECT revealed significantly decreased dopamine receptor availability in 5 of 6 patients studied, and significantly decreased dopamine transporter availability in 3. Levodopa improved motor dysfunction in two of four patients treated, although only temporarily. Incomplete recovery was observed in two patients after liver transplantation. Conclusions: Cirrhosis-related Parkinsonism is more frequent than presumed. The presented data suggest pre- and postsynaptic alteration of striatal dopaminergic neurotransmission as a possible cause of cirrhosis-related Parkinsonism and reveal the limited effects of dopaminergic therapy. [Copyright &y& Elsevier]

Background: Tc-99m-BrIDA hepatobiliary scans are noninvasive tests for detecting biliary leaks and obstructions. However, there is low sensitivity and specificity in patients with hyperbilirubinemia. Biliary complications (BC) are the Achilles heel of orthotopic liver transplantation (OLT). We questioned whether hyperbilirubinemia in liver transplant recipients rendered HIDA scanning less dependable. Methods: HIDA findings were compared to endoscopic retrograde cholangiopancreatography, laparotomy, and clinical course. Results were categorized as follows: true positive (TP), true negative (TN), false positive (FP), false negative (FN), or nondiagnostic/inconclusive. We searched for variables associated with erroneous or nondiagnostic tests which we defined as all examinations determined to be FP, FN and/or nondiagnostic/inconclusive. Results: Thirty-four patients underwent a HIDA scan. The sensitivity and specificity were 70 and 100%. The sensitivity of HIDA improved to 100% in patients with a total bilirubin (TB) <5 mg/dl. Inconclusive and FN patients had a total bilirubin >5 mg/dl. One FN had a TB <5 mg/dl, but was determined inconclusive due to the roux-en-Y. Conclusion: HIDA scans performed when the total bilirubin was <5 mg/dl had a high sensitivity and specificity for detecting biliary complications after OLT. However, when the total bilirubin exceeded 5 mg/dl, the specificity was still 100% but the numbers of nondiagnostic/inconclusive and FN exams were increased. [ABSTRACT FROM AUTHOR]

Background: Measurement of intracranial pressure (ICP) is recommended in comatose acute liver failure (ALF) patients due to risk of rapid global cerebral edema. External ventricular drains (EVD) can be placed to drain cerebrospinal fluid and monitor ICP simultaneously although this remains controversial in the neurosurgical community given the risk of hemorrhagic complications. We describe a patient with ALF and global cerebral edema whose EVD failed immediately before orthotopic liver transplantation (OLT) in which a lumbar drain (LD) was used temporarily to monitor ICP. Methods: We describe a 36 year old patient with ALF and brain edema from acetaminophen overdose who had an EVD placed for ICP monitoring and management. The EVD failed repeatedly (i.e., lost CSF drainage and ICP waveform) despite several saline irrigations and three doses intraventricular tissue plasminogen activator (1 mg) in the hours that immediately preceded her planned emergency OLT. An LD was placed emergently and controlled cerebrospinal fluid (CSF) drainage and ICP measurement was performed by setting the LD at 20 mmHg and leveling at the ear level (foramen of Monro). The LD was removed once the EVD flow was re-established post-OLT. Results: The EVD and LD ICP measurements were reported to be the same just prior to removing the LD. Conclusions: Controlled CSF drainage using a lumbar drain can be used to monitor ICP when leveled at the foramen of Monro if EVD failure occurs perioperatively. The LD can temporarily guide ICP management until the EVD flow can be re-established after OLT. [ABSTRACT FROM AUTHOR]

Abstract: A condition defined as nonalcoholic fatty liver disease (NAFLD) is frequently found in humans. Deemed as a benign condition until recently, more emphasis is now put on the potential harmful evolution of the inflammatory form, that is, nonalcoholic steatohepatitis (NASH), toward end-stage liver disease. This review highlights the major morphologic and pathophysiological features of NASH. The link between experimental biochemical findings in animal models and clinical and therapeutic approaches in humans is discussed. Once all the other causes of persistent elevation of serum transaminase levels have been excluded, the diagnosis of NASH can be only confirmed by liver histology. Other noninvasive diagnostic tools, however, are being investigated to assess specific subcellular functions and to allow the follow-up of patients at higher risk for major liver dysfunction. A better understanding of various pathogenic aspects of NASH will help in identifying potential therapeutic approaches in these patients. [Copyright &y& Elsevier]

Abstract: Highly active antiretroviral therapy has revolutionised HIV management. However, many of these drugs are potentially hepatotoxic. Here, we report the first adult case of efavirenz induced acute liver failure successfully treated by liver transplantation. Furthermore, genetic analysis revealed our patient to be a slow efavirenz metaboliser, contributing to the severity of clinical presentation. [Copyright &y& Elsevier]

Background: Studies on patients' societal reintegration following orthotopic liver transplantation (OLT) are scarce., Methods: Between September 2006 and January 2008, all adults who were alive after 3 years post OLT were included in this prospective cohort study. Validated questionnaires were administered to all candidates with the primary aim of investigating the rate of their social re-integration following OLT and potential barriers they might have encountered., Results: Among 157 eligible patients 110 (70%) participated. Mean participants' age was 57 years (SD 11.4) and 43% were females. Prior to OLT, 75% of patients were married and 6% were divorced. Following OLT there was no significant difference in marital status. Employment rate fell from 72% to 30% post-OLT. Patients who had been employed in either low-skill or advanced-skill jobs were less likely to return to work. After OLT, personal income fell an average of 4,363 Canadian dollars (CAN$) (SD 20,733) (P=0.03) but the majority of recipients (80%) reported high levels of satisfaction for their role in society., Conclusions: Although patients' satisfaction post-OLT is high, employment status is likely to be negatively affected for individuals who are not self-employed. Strategies to assist recipients in returning to their pre-OLT jobs should be developed to improve patients' economical status and societal ability to recoup resources committed for OLT.

Background & Aims: Hy's Law, which states that hepatocellular drug-induced liver injury (DILI) with jaundice indicates a serious reaction, is used widely to determine risk for acute liver failure (ALF). We aimed to optimize the definition of Hy's Law and to develop a model for predicting ALF in patients with DILI. Methods: We collected data from 771 patients with DILI (805 episodes) from the Spanish DILI registry, from April 1994 through August 2012. We analyzed data collected at DILI recognition and at the time of peak levels of alanine aminotransferase (ALT) and total bilirubin (TBL). Results: Of the 771 patients with DILI, 32 developed ALF. Hepatocellular injury, female sex, high levels of TBL, and a high ratio of aspartate aminotransferase (AST):ALT were independent risk factors for ALF. We compared 3 ways to use Hy's Law to predict which patients would develop ALF; all included TBL greater than 2-fold the upper limit of normal (×ULN) and either ALT level greater than 3 × ULN, a ratio (R) value (ALT × ULN/alkaline phosphatase × ULN) of 5 or greater, or a new ratio (nR) value (ALT or AST, whichever produced the highest ×ULN/ alkaline phosphatase × ULN value) of 5 or greater. At recognition of DILI, the R- and nR-based models identified patients who developed ALF with 67% and 63% specificity, respectively, whereas use of only ALT level identified them with 44% specificity. However, the level of ALT and the nR model each identified patients who developed ALF with 90% sensitivity, whereas the R criteria identified them with 83% sensitivity. An equal number of patients who did and did not develop ALF had alkaline phosphatase levels greater than 2 × ULN. An algorithm based on AST level greater than 17.3 × ULN, TBL greater than 6.6 × ULN, and AST:ALT greater than 1.5 identified patients who developed ALF with 82% specificity and 80% sensitivity. Conclusions: When applied at DILI recognition, the nR criteria for Hy's Law provides the best balance of sensitivity and specificity whereas our new composite algorithm provides additional specificity in predicting the ultimate development of ALF. [Copyright &y& Elsevier]

Abstract: Purpose: To investigate prospectively the safety, tolerability, and efficacy of transarterial chemoembolization using superabsorbent polymer (SAP) microspheres loaded with doxorubicin for the treatment of hepatocellular carcinoma (HCC). Materials and Methods: During the years 2006–2011, 64 patients underwent 144 transarterial chemoembolization with SAP microspheres procedures. Most of the patients were staged as Barcelona Clinic Liver Cancer class B (65%). The most frequent underlying liver diseases were hepatitis C (35%) and alcoholic liver disease (28%) resulting in Child-Pugh A (73.4%) or Child-Pugh B (17%) liver cirrhosis. Tumor response was assessed using modified Response Evaluation Criteria in Solid Tumors with magnetic resonance (MR) imaging performed 4–6 weeks after each procedure. Results: Serious adverse events (n = 9) were ischemic or infectious in nature. Transarterial chemoembolization with SAP microspheres resulted in objective response rates of 67.5%, 44.5%, and 25% after first, second, and third sessions. There were 16 patients (25%) who underwent orthotopic liver transplantation after transarterial chemoembolization with SAP microspheres, of whom 2 experienced recurrent disease. During a median follow-up time of 14 months (range, 2–55 mo), 26 patients (40.5%) died. Median overall and transplant-free survivals were 20.5 months (95% confidence interval, 13.2–27.7) and 18 months (95% confidence interval, 14.2–21.8), respectively. Conclusions: Transarterial chemoembolization with SAP microspheres has an excellent safety profile in cirrhotic patients, even in the presence of advanced liver disease (Child-Pugh B) or advanced stages of HCC. This treatment produced meaningful tumor response rates as assessed by MR imaging. [Copyright &y& Elsevier]

Disseminated intravascular coagulation (DIC) and liver diseases are complex clinical conditions. Both disorders frequently disturb the finely tuned coagulation and fibrinolysis equilibrium. In DIC, a wide range of underlying disorders can induce a systemic activation of the coagulation system with generation of soluble fibrin, possible deposition of platelet-rich fibrin clots in the microvasculature and subsequent micro- or macroembolism, impaired organ perfusion and organ failure. Such coagulation activation depletes platelets, coagulation factors, and inhibitors and clinically can result in severe, sometimes untreatable bleeding, especially when bone marrow or liver function is diminished or invasive procedures are performed. In addition, a secondary counterbalancing activation of the fibrinolytic system to dissolve microcirculatory clots adds to the bleeding tendency. In conjunction with other options based on prompt and rigorous treatment of the underlying cause of DIC, fresh frozen plasma plays an important role in therapeutic management when overt bleeding is present or anticipated in DIC patients with disturbed coagulation or when an invasive procedure is being planned.In liver disease, factor and inhibitor synthesis in both the coagulation and fibrinolytic system is impaired, both quantitatively and qualitatively. This destabilizes the balance between the two systems. In addition, the clearance of activated coagulation factors and fibrin(ogen) degradation products (FDP) from the systemic circulation is impaired. In patients with liver diseases and acute or imminent bleeding, or before invasive procedures, fresh frozen plasma (FFP) offers advantages over clotting factor concentrates. However, hypervolemia following the required doses of FFP might pose a problem in some liver disease patients.The complex pathophysiology both in DIC and in liver disease requires early diagnosis and adequate management including plasma and platelet substitution after treatment of the underlying disease. Due to the heterogeneity of DIC and liver disease, prospective randomized trials are difficult to perform. Therefore, treatment recommendations are mostly empirical and less evidence-based. Therapy must be accompanied by close and repeated clinical and laboratory monitoring. [Copyright &y& Elsevier]

Background: The level of lipopolysaccharides (LPS) and inflammatory factors were higher in end stage liver disease patient than in normal person for the damage of intestinal mucosal barrier function. Hepatopulmonary syndrome (HPS) was a common pulmonary complication in end stage liver disease. But the association of LPS and inflammatory factors such as toll like receptor 2 (TLR2), TNF-α and ET-1 with the development of HPS was undefined., Methods: Thirty-one HPS patients were researched (26 patients were performed liver transplantation, five were not). Ten healthy volunteers were recruited as negative control. Blood was collected from the 26 HPS patients before and 3, 7, 14, 21 and 28 days after orthotopic liver transplantation (OLT), and from five HPS patients without OLT and ten healthy volunteers once to detect TLR2 mRNA and iNOS mRNA in peripheral blood monocytes and plasma LPS, TNF-α and ET-1 level. Their levels before and after OLT were compared., Results: TLR2 mRNA, iNOS mRNA, LPS, TNF-α and ET-1 before OLT in HPS patients were 336,594.1±366,901.1, 63,982.2±74,127.5 copies/ugRNA, 4.3±3.3, 90.1±76.0 and 319.9±124.4 ng/L, respectively. They were 10,338.3±3,814.6, 19,168.5±2,417.4 copies/ugRNA, 0.94±0.69, 2.7±0.1 and 84.2±10.6 ng/L in normal control group. They were significantly higher in HPS patients than those in control group (P<0.05). After OLT, liver function improved to normal. Also TLR2 mRNA, TNF-α and ET-1 decreased in HPS patients after OLT compared with those before OLT. And PaO2 and PaO2/FiO2 improved greatly with intrapulmonary shunt decreased to normal after OLT., Conclusions: Lipopolysaccharides at the end stage of liver disease with the release of series of inflammatory factors may be associated with the development of HPS.