Long-Term Outcomes of Everolimus Therapy in De Novo Liver Transplantation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

BACKGROUND: Risk of nephrotoxicity in liver transplant patients on calcineurin inhibitors (CnIs) is a concern. Several controlled trials reported benefit of everolimus (EVR) in minimizing this risk when combined with a reduced CnI dose. BACKGROUND: To systematically review the efficacy and safety of EVR, alone or with reduced CnI dose, as compared to CnI alone post-liver transplantation. METHODS: We searched MEDLINE, Scopus, and the Cochrane Library for randomized controlled trials comparing EVR- and CnI-based regimens post-liver transplantation. Assessment of studies and data extraction were undertaken independently. RESULTS: Eight studies were selected, describing 769 patients. Cockcroft-Gault GFR was higher at one (P = .05), 3, and 5 years (P = .030) in patients on EVR compared to those receiving CnI therapy. The composite endpoint of efficacy failure was similar between the 2 arms after 1, 3, and 5 years of study. More patients discontinued EVR due to adverse effects in 1 year; however, no difference was noted after 3 or 5 years. A higher rates of proteinuria, peripheral edema, and incisional hernia occurred in patients on EVR. CONCLUSIONS: The analysis confirms noninferiority of EVR and reduced CnI combination. Combination regimen resulted in better renal function compared to standard CnI therapy

The Association of Toll-Like Receptor 4 Polymorphism with Hepatitis C Virus Infection in Saudi Arabian Patients

Hepatitis C virus (HCV) is a single stranded RNA virus. It affects millions of people worldwide and is considered as a leading cause of liver diseases including cirrhosis and hepatocellular carcinoma. A recent study reported that TLR4 gene polymorphisms are good prognostic predictors and are associated with protection from liver fibrosis among Caucasians. This study aims to investigate the implication of genetic polymorphisms of TLR4 gene on the HCV infection in Saudi Arabian patients. Two SNPs in the TLR4 gene, rs4986790 (A/G) and rs4986791 (C/T), were genotyped in 450 HCV patients and 600 uninfected controls. The association analysis confirmed that both SNPs showed a significant difference in their distribution between HCV-infected patients and uninfected control subjects ( < 0.0001; OR = 0.404, 95% CI = 0.281-0.581) and ( < 0.0001; OR = 0.298, 95% CI = 0.201-0.443), respectively. More importantly, haplotype analysis revealed that four haplotypes, AC, GT, GC, and AT (rs4986790, rs4986791), were significantly associated with HCV infection when compared with control subjects. One haplotype AC was more prominently found when chronic HCV-infected patients were compared with cirrhosis/HCC patients (frequency = 94.7% and = 0.04). Both TLR4 SNPs under investigation were found to be significantly implicated with HCV-infection among Saudi Arabian population

The Correlation Between Hepatitis B Virus Precore/Core Mutations and the Progression of Severe Liver Disease

Viral mutations acquired during the course of chronic hepatitis B virus (HBV) infection are known to be associated with the progression and severity of HBV-related liver disease. This study of HBV-infected Saudi Arabian patients aimed to identify amino acid substitutions within the precore/core (preC/C) region of HBV, and investigate their impact on disease progression toward hepatocellular carcinoma (HCC). Patients were categorized according to the severity of their disease, and were divided into the following groups: inactive HBV carriers, active HBV carriers, liver cirrhosis patients, and HCC patients. Two precore mutations, W28* and G29D, and six core mutations, F24Y, E64D, E77Q, A80I/T/V, L116I, and E180A were significantly associated with the development of cirrhosis and HCC. Six of the seven significant core mutations that were identified in this study were located within immuno-active epitopes; E77Q, A80I/T/V, and L116I were located within B-cell epitopes, and F24Y, E64D, and V91S/T were located within T-cell epitopes. Multivariate risk analysis confirmed that the core mutations A80V and L116I were both independent predictors of HBV-associated liver disease progression. In conclusion, our data show that mutations within the preC/C region, particularly within the immuno-active epitopes, may contribute to the severity of liver disease in patients with chronic hepatitis. Furthermore, we have identified several distinct preC/C mutations within the study population that affect the clinical manifestation and progression of HBV-related disease. The specific identity of HBV mutations that are associated with severe disease varies between different ethnic populations, and so the specific preC/C mutations identified here will be useful for predicting clinical outcomes and identifying the HBV-infected patients within the Saudi population that are at high risk of developing HCC

Acute onset autoimmune hepatitis: Clinical presentation and treatment outcomes

Introduction and aim: Autoimmune hepatitis (AIH) may present acutely, which can rapidly progress to fulminant type. This pattern has been described worldwide but is generally under-reported. We aim to describe the clinical presentation and treatment outcomes of patients with acute onset AIH. Materials and methods: A multicenter retrospective cohort study of patients with acute onset AIH. Clinical, biochemical, and histological data were analyzed and the outcomes were reported. Results: Seventy patients were included. The mean age was 33.8 ± 1.5 years and 58.6% were female. Upon initial presentation, 94% had jaundice, 44% had fatigue, 31% had pruritus, and 29% had abdominal pain. Biochemical analysis revealed elevated alanine transaminase (733 ± 463.6), aspartate transaminase (699 ± 423), and total bilirubin (210 ± 181.8). Antinuclear antibody (ANA) was positive in 61% of patients, anti-smooth muscle antibody (ASMA) in 69%, and both in 31%; immunoglobulin G (IgG) was elevated in 86% of patients. Advanced fibrosis was found in 39%. Complete remission was achieved in 74.3%, two patients required liver transplants and six died. No specific biomarkers were identified as predictive of remission; however, advanced age was associated with poor prognosis. Conclusion: Acute onset AIH is a disease that requires early diagnosis and management. We confirmed that elevated transaminases are the hallmark of biochemical presentation of acute AIH. High IgG, ANA and ASMA are typically present in such patients upon presentation, however, their absence does not totally exclude the diagnosis. Initial response to treatment was excellent; however, the long-term mortality was higher than the general patient population

Efficacy and safety of once daily tacrolimus compared to twice daily tacrolimus after liver transplantation

BACKGROUND Once daily tacrolimus regimen was found to exhibits similar bioavailability, safety and efficacy properties compared to twice-daily tacrolimus in kidney transplantation patients. AIM To compare the efficacy and safety of once-daily prolonged release tacrolimus compared to twice-daily tacrolimus in liver transplantation patients. METHODS MEDLINE, EMBASE, CENTRAL databases were searched for clinical trials until December 2020. Efficacy outcome measured as the rate of treatment failure indicated by biopsy-proven acute rejection, Serum creatinine, graft loss, or death. Two reviewers independently selected studies, collected data and assessed risk of bias. The results are reported as risk ratio with 95% confidence interval (CI) for dichotomous data. RESULTS Seven studies included with 965 patients. All the included studies were of moderate quality according to the risk of bias assessment using Cochrane Risk of Bias tool. Biopsy-proven acute rejection was reported in four studies, and pooled analysis of those studies indicated similar rejections in both twice daily and once daily tacrolimus groups (risk ratio: 1.06, 95%CI: 0.84-1.34, n = 758, I2 = 0%) and also we found no significant difference between both groups for renal outcome (serum creatinine; mean difference, 0.001 mg/dL, 95%CI: -0.042 to 0.043, n = 846, I2 = 18.6%). Similarly, there was similar number of adverse events such as hypertension, headache, back pain, blood related disorders, infections and nausea observed in both groups. CONCLUSION The analysis findings confirm that both once daily and twice daily tacrolimus formulations are comparable in terms of efficacy and safety outcomes

Is it justified to use liver grafts from living donors for retransplant? A single-center experience

Objectives: Liver retransplant is considered the only hope for patients with irreversible graft failure after primary transplant. In most Western centers, retrans-plant is done mainly from deceased donors; so far, only few published studies have reported on outcomes of liver retransplant with living donors. In this study, our aim was to analyze the outcomes of living-donor liver retransplant. Materials and Methods: Patients who underwent liver retransplant between February 2011 and February 2019 were included in the study. Preoperative, operative, and postoperative data were analyzed. Results from 2 patient groups were compared: liver retransplant with living donors and liver retransplant with deceased donors. Results: Thirty-two patients underwent liver retrans-plant (21 adult and 11 pediatric patients). The most common indications for liver retransplant were hepatic artery thrombosis (28.5%) and primary graft nonfunction (23.8%) in adults and hepatic artery thrombosis (45.5%) and chronic rejection (36.4%) in pediatric patients. Seventeen retransplant patients (53.1%) required early retransplant (within 1 mo), mainly due to hepatic artery thrombosis (52.9%) and primary graft nonfunction (35.3%). Late retransplant was mainly due to chronic rejection (40%) and recurrence of primary disease (26.7%). Seventeen patients (53.1%) underwent living-donor retransplant, and 5 donors underwent robotic right hepatectomy. Graft and patient survival rates at 1, 3, and 5 years were 81.3% for living-donor and 51.4% for deceased-donor liver retransplant recipients (P =.08). On multivariate analyses, we observed significant differences between both groups in pretransplant Model for End-Stage Liver Disease and Pediatric End-Stage Liver Disease scores (P =.05), preoperative international normalized ratio (P =.012), and cold ischemia time (P =.046). Conclusions: The use of living donors for liver retransplant, despite its technical demand, was shown to be a safe and feasible option, especially when there is scarcity of deceased donors

Validating controlled attenuation parameter in the assessment of hepatic steatosis in living liver donors

Introduction Hepatic steatosis (HS) negatively impacts transplant outcomes in living liver donors. To date, liver biopsy is preferred for HS evaluation. This study aims to evaluate the measurement of controlled attenuation parameter (CAP) as a diagnostic tool of HS in living liver donors. Methods Candidates recruited to this study, conducted from April 2016 to February 2020, were potential donors who had undergone transient elastography using Fibroscan® and CAP measurements at liver segments VI and VII, followed by liver biopsy. The HS grades from liver biopsy were classified as S0 (66%). For CAP, they were S0 (≤218dB/m), S1 (218-249dB/m)), S2 (250-305dB/m)), and S3 (>305dB/m)). The CAP measurements were compared with the liver biopsy results. Results Of the 150 potential donors [male, 73.3%; mean age, 30.0±7.0 years; body mass index (BMI), 24.7±3.5kg/m2], 92 (61.3%) had no or mild HS, while 58 (38.7%) and 10% had moderate to severe HS based on CAP and liver biopsy, respectively. Subjects with moderate to severe HS per CAP were mostly males (0.014), and had higher BMI (p = .006), alanine aminotransferase (ALT) (.001), gamma-glutamyl transferase (.026), and high-density lipoprotein (.008). On multivariate analysis, high ALT (OR, 1.051; 95% CI, 1.016-1.087; p = .004) was a predictor of significant HS. The sensitivity, specificity, positive and negative predictive values of CAP to detect significant HS were 93.3%, 67.4, 24.1%, and 98.9%, respectively. Conclusion The high sensitivity and negative predictive values of CAP make it a good screening test to exclude significant HS in potential living liver donors which, in turn, can help avoid unnecessary liver biopsies

Conventional Transarterial Chemoembolization Versus Drug-Eluting Beads in Patients with Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

Hepatocellular carcinoma (HCC) occurs in nearly three-quarters of all primary liver cancers, with the majority not amenable to curative therapies. We therefore aimed to re-evaluate the safety, efficacy, and survival benefits of treating patients with drug-eluting beads transcatheter arterial chemoembolization (DEB-TACE) compared to the conventional transcatheter arterial chemoembolization (C-TACE). Several databases were searched with a strict eligibility criterion for studies reporting on adult patients with unresectable or recurrent HCC. The pooled analysis included 34 studies involving 4841 HCC patients with a median follow-up of 1.5 to 18 months. There were no significant differences between DEB-TACE and C-TACE with regard to complete response, partial response and disease stability. However, disease control (OR: 1.42 (95% CI (1.03,1.96) and objective response (OR: 1.33 (95% CI (0.99, 1.79) were significantly more effective for DEB-TACE treatment with fewer severe complications and all-cause mortality. The pooled-analysis did not find superiority of DEB-TACE in complete or partial response, disease stability, controlling disease progression, and 30 day or end-mortality. However, results showed that DEB-TACE is associated with a better objective response, disease control, and lower all-cause mortality with severe complications compared to C-TACE treatment. Given that the safety outcomes are based on limited studies with a potential for bias, there was no clear improvement of DEB-TACE over C-TACE treatment