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Background & Aims: Recurrent primary biliary cholangitis (rPBC) develops in approximately 30% of patients and negatively impacts graft and overall patient survival after liver transplantation (LT). There is a lack of data regarding the response rate to ursodeoxycholic acid (UDCA) in rPBC. We evaluated a large, international, multi-center cohort to assess the performance of PBC scores in predicting the risk of graft and overall survival after LT in patients with rPBC., Methods: A total of 332 patients with rPBC after LT were evaluated from 28 centers across Europe, North and South America. The median age at the time of rPBC was 58.0 years [IQR 53.2-62.6], and 298 patients (90%) were female. The biochemical response was measured with serum levels of alkaline phosphatase (ALP) and bilirubin, and Paris-2, GLOBE and UK-PBC scores at 1 year after UDCA initiation., Results: During a median follow-up of 8.7 years [IQR 4.3-12.9] after rPBC diagnosis, 52 patients (16%) had graft loss and 103 (31%) died. After 1 year of UDCA initiation the histological stage at rPBC (hazard ratio [HR] 3.97, 95% CI 1.36-11.55, p = 0.01), use of prednisone (HR 3.18, 95% CI 1.04-9.73, p = 0.04), ALP xULN (HR 1.59, 95% CI 1.26-2.01, p <0.001), Paris-2 criteria (HR 4.14, 95% CI 1.57-10.92, p = 0.004), GLOBE score (HR 2.82, 95% CI 1.71-4.66, p <0.001), and the UK-PBC score (HR 1.06, 95% CI 1.03-1.09, p <0.001) were associated with graft survival in the multivariate analysis. Similar results were observed for overall survival., Conclusion: Patients with rPBC and disease activity, as indicated by standard PBC risk scores, have impaired outcomes, supporting efforts to treat recurrent disease in similar ways to pre-transplant PBC., Impact and Implications: One in three people who undergo liver transplantation for primary biliary cholangitis develop recurrent disease in their new liver. Patients with recurrent primary biliary cholangitis and incomplete response to ursodeoxycholic acid, according to conventional prognostic scores, have worse clinical outcomes, with higher risk of graft loss and mortality in similar ways to the disease before liver transplantation. Our results supportsupport efforts to treat recurrent disease in similar ways to pre-transplant primary biliary cholangitis., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Autoimmune hepatitis can recur after liver transplantation (LT), though the impact of recurrence on patient and graft survival has not been well characterized. We evaluated a large, international, multicenter cohort to identify the probability and risk factors associated with recurrent AIH and the association between recurrent disease and patient and graft survival., Methods: We included 736 patients (77% female, mean age 42±1 years) with AIH who underwent LT from January 1987 through June 2020, among 33 centers in North America, South America, Europe and Asia. Clinical data before and after LT, biochemical data within the first 12 months after LT, and immunosuppression after LT were analyzed to identify patients at higher risk of AIH recurrence based on histological diagnosis., Results: AIH recurred in 20% of patients after 5 years and 31% after 10 years. Age at LT ≤42 years (hazard ratio [HR] 3.15; 95% CI 1.22-8.16; p = 0.02), use of mycophenolate mofetil post-LT (HR 3.06; 95% CI 1.39-6.73; p = 0.005), donor and recipient sex mismatch (HR 2.57; 95% CI 1.39-4.76; p = 0.003) and high IgG pre-LT (HR 1.04; 95% CI 1.01-1.06; p = 0.004) were associated with higher risk of AIH recurrence after adjusting for other confounders. In multivariate Cox regression, recurrent AIH (as a time-dependent covariate) was significantly associated with graft loss (HR 10.79, 95% CI 5.37-21.66, p <0.001) and death (HR 2.53, 95% CI 1.48-4.33, p = 0.001)., Conclusion: Recurrence of AIH following transplant is frequent and is associated with younger age at LT, use of mycophenolate mofetil post-LT, sex mismatch and high IgG pre-LT. We demonstrate an association between disease recurrence and impaired graft and overall survival in patients with AIH, highlighting the importance of ongoing efforts to better characterize, prevent and treat recurrent AIH., Lay Summary: Recurrent autoimmune hepatitis following liver transplant is frequent and is associated with some recipient features and the type of immunosuppressive medications use. Recurrent autoimmune hepatitis negatively affects outcomes after liver transplantation. Thus, improved measures are required to prevent and treat this condition., Competing Interests: Conflicts of interest These authors disclose the following: A.J. Montano-Loza has served on advisory boards for Intercept Pharmaceuticals. B.E. Hansen reports grants from Intercept Pharmaceuticals and Zambon Nederland B.V. and consulting work for Intercept Pharmaceuticals and Novartis. A.E. Kremer reports consulting work for CymaBay, GSK, Intercept Pharmaceuticals, and Mirum and grants from Intercept Pharmaceuticals. A. Parés consults for Intercept and Novartis. A. Floreani reports consulting activities for Intercept Pharmaceuticals. A. Mason consults for, is on the speakers' bureau of, and received grants from Intercept. He received grants from Merk. The remaining authors disclose no conflicts. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Primary sclerosing cholangitis (PSC) is associated with a broad phenotypic spectrum in different populations from diverse ethnic and racial backgrounds. This study aimed to describe the clinical characteristics and outcomes of PSC in a multicenter cohort of patients from Brazil., Methods: Data from the Brazilian Cholestasis Study Group were retrospectively reviewed to assess demographic information and clinical characteristics of PSC, as well as the outcomes, such as transplantation-free survival., Results: This cohort included 210 patients. After excluding 33 (15.7%) patients with PSC and overlap syndrome of autoimmune hepatitis, 177 (97 males, median age 33 (21-42) years) with clear-cut PSC were eligible for this study. Most of the patients ( n  = 139, 78.5%) were symptomatic, and 104 (58.7%) had advanced PSC at the time of diagnosis. Concurrent inflammatory bowel disease was observed in 78 (58.6%) of the investigated patients ( n  = 133), and most of them had ulcerative colitis ( n  = 61, 78.2%). The 1- and 5-year survival free of liver transplantation or death were 92.3 ± 2.1% and 66.9 ± 4.2%, respectively, and baseline advanced PSC, pruritus, and elevated bilirubin levels were independent risk factors for the composite adverse outcome. Females were significantly older and had lower bilirubin levels than males at baseline, but survival was not associated with sex. Approximately 12.4% ( n  = 22) of patients with PSC died, and 32.8% ( n  = 58) underwent liver transplantation at a median follow-up time of 5.3 and 3.2 years., Conclusion: Multiethnic Brazilian PSC patients exhibited a less pronounced male predominance and a lower frequency of inflammatory bowel disease than Caucasians. Adverse outcomes were more frequent, probably due to advanced disease at baseline., Competing Interests: The authors declare that they no conflicts of interest., (Copyright © 2021 Mateus Jorge Nardelli et al.)

Hepatitis E Virus (HEV) is an infection known worldwide for its asymptomatic and self-limited course in most cases. Some cases progressing to chronicity have been described in immunosuppressed patients, especially in recipients of solid organ transplants. We evaluated laboratory parameters of HEV infection (HEV RNA, anti-HEV IgM and anti-HEV IgG) through enzyme-linked immunosorbent assay (Elisa), confirmed by immunoblotting, in a cohort of 294 patients who received liver transplants at the HCFMUSP (Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo). Laboratory and demographic data were collected from the entirety of the transplanted population. Hepatic biopsies of 122 patients transplanted due liver failure secondary to hepatitis C (HCV), with or without serological or molecular markers of HEV, were analyzed according to METAVIR score. Out of 24 (8.2%) patients tested positive for anti-HEV IgG, six (2%) were positive for anti-HEV IgM and 17 (5.8%) for HEV RNA. Of the patients transplanted because of HCV infection, 95 (77.8%) had received treatment including ribavirin for at least six months before blood sample collection. Among patients transplanted due to HCV cirrhosis who tested positive for anti-HEV IgG, only three (37.5%) showed fibrosis beyond stage 2, while five (41.7%) of the HEV RNA-positive patients had liver fibrosis beyond stage 2. Overall, the prevalence of HEV in the post-hepatic transplant scenario appears to be low, and, at least histologically, seemingly not harmful. We conclude that, although some studies reported a risk of HEV chronification, patients who had their livers transplanted due to HCV and showed serological or molecular markers of HEV did not have higher levels of fibrosis compared to patients who showed no indications of HEV infection at the time of the analysis., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2021 Sociedade Brasileira de Infectologia. Published by Elsevier España, S.L.U. All rights reserved.)

Watch a video presentation of this article., (© 2020 by the American Association for the Study of Liver Diseases.)

Background: Cardiovascular disease is a major contributing factor to long-term mortality after liver transplantation (LT)., Methods: This study evaluated the evolution of atherogenic risk in liver transplant recipients (LTRs). Thirty-six subjects were prospectively enrolled at 12 months and followed for 48 months after liver transplantation. Serum biomarkers of endothelial dysfunction (sICAM-1 and sVCAM-1), chronic inflammation (serum amyloid A), and oxidative stress (myeloperoxidase) were measured at 12 and 48 months after LT. Additionally, at 12 months all patients underwent a cardiac computed tomography (CT) scan and a coronary artery calcium score (CACS)., Results: The prevalence of risk factors of metabolic syndrome (MS) increased over the course of the study. The patients' sVCAM-1 and sICAM-1 increased from 1.82 ± 0.44 ng/mL to 9.10 ± 5.82 ng/mL (P < .001) and 0.23 ± 0.09 ng/mL to 2.7 ± 3.3 ng/mL, respectively from month 12 to 48. Serum myeloperoxidase increased from 0.09 ± 0.07 ng/mL to 3.46 ± 3.92 ng/mL (P < .001) over the course of the study. Serum amyloid A also increased from 21.4 ± 40.7 ng/mL at entry to 91.5 ± 143.6 ng/mL at end of study (P < .001)., Conclusion: No association between these biomarkers and MS was noted. The cardiac CT revealed mild and moderate disease in 19% and 25% of the cohort, respectively. No association between serum biomarkers and CACS was noted. Serum biomarkers of atherogenic risk increase rapidly in LTRs and precede coronary plaques., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Between 50% and 86% of patients with autoimmune hepatitis (AIH) relapse after immunosuppression withdrawal; long-term immunosuppression is associated with increased risk of neoplasias and infections. Chloroquine diphosphate (CQ) is an immunomodulatory drug that reduces the risk of flares in rheumatologic diseases. Our aims were to investigate the efficacy and safety of CQ for maintenance of biochemical remission of AIH in a double-blind randomized trial and to define a subgroup that obtained a greater benefit from its use. A total of 61 patients with AIH in histologic remission (90.1% AIH type 1 [AIH-1]) were randomized to receive CQ 250 mg/day or placebo for 36 months. Of the 61 patients, 31 received CQ and 30 placebo. At baseline, clinical, laboratory, histologic findings, and human leukocyte antigen (HLA) profile were similar between the two groups. Relapse-free survival was significantly higher in the CQ group compared to the placebo group (59.3% and 19.9%, respectively P = 0.039). For those patients completing 3-year treatment, relapse rates were 41.6% and 0% after CQ and placebo withdrawal, respectively. Factors associated with a higher risk of relapse in multiple Cox regression were placebo use (hazard ratio, 2.4; 95% confidence interval [CI], 1.055.5; P = 0.039) and anti-soluble liver antigen/liver-pancreas (anti-SLA/LP) seropositivity (hazard ratio, 5.4; 95% CI, 1.91-15.3; P = 0.002). Although it was not possible to define a subgroup that obtained a greater benefit from CQ according to anti-SLA/LP reactivity or HLA profile, 100% of patients who were anti-SLA/LP-positive (+) relapsed with placebo compared to 50% with CQ ( P = 0.055). In the CQ group, 54.8% had side effects and 19.3% interrupted the drug regimen. Conclusion: CQ safely reduced the risk of relapse of AIH, but it was not possible to define a subgroup that obtained a greater benefit with CQ use, probably because of sample size.

Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world in terms of incidence, accounting for approximately 630 thousand new cases per year; in addition, HCC is the third most common cause of cancer death. Worldwide, the greatest risk factors for HCC are the infections caused by hepatitis B and C viruses, which increase the risk of developing the disease by about 20 times. The standard treatment in the early stages of the disease, such as surgical resection, local ablation and liver transplantation, are able to cure a proportion of patients, but most cases of HCC present in advanced stages, precluding the use of such treatments with curative intent. In these advanced stages, systemic treatments are commonly used. Unfortunately, chemotherapy with conventional cytotoxic agents is ineffective and does not seem to modify the natural history of disease. Treatment options for patients with advanced HCC are extremely limited, but the identification of signaling pathways, and the recognition of the role of these pathways in the pathogenesis of the disease resulted in the development of drugs directed at specific therapeutic targets. One such drug is Sorafenib, a kinase inhibitor with antiangiogenic and antiproliferative properties. In conclusion, Sorafenib has demonstrated survival benefits in patients with advanced HCC, thus representing a new standard reference for systemic treatment in these cases.