Hepatology International

Gross type of hepatocellular carcinoma reflects the tumor hypoxia, fibrosis, and stemness-related marker expression Abstract Background Hepatocellular carcinoma (HCC) is subclassified into five gross types, namely, vaguely nodular (VN), single nodular (SN), single nodular with extranodular growth (SNEG), confluent multinodular (CM), and infiltrative (INF) type. However, the pathological background underlying differences in biological behavior of different gross types of HCC remains unclear. Methods The histopathological features, clinical outcomes of HCC gross types, and their relationships with stemness-related marker status and fibrotic/hypoxic tumor microenvironment (TME) were evaluated in 266 resected HCCs. The stemness-related markers (CD24, CD44, CD133, SALL4, YAP1, K19 and EpCAM), fibrous tumor stroma (αSMA), and hypoxia (CAIX) were evaluated with immunohistochemistry. Results Poorer differentiation, reduced capsule formation, higher microvascular invasion, larger tumor size and larger area of necrosis were observed in order of VN-SN-SNEG-CM-INF type (p = 0.005 for all, linear-by-linear association). The expression of summed stemness-related markers and hypoxic/fibrotic TME showed an increasing trend in order of VN-SN-SNEG-CM-INF type (p < 0.005), and their expression well correlated with each other. INF type was found only in HCCs with hypoxic/fibrotic TME or high expression of stemness-related markers. CAIX expression and tumor necrosis ≥ 30% were independent prognostic markers for disease-specific survival. Early recurrence-free survival showed a significant difference based on gross types, revealing best outcome with VN type and worst outcome with INF type. Conclusion The marker expression of stemness-related and hypoxic/fibrotic TME of HCC showed an increasing trend in order of VN-SN-SNEG-CM-INF gross types, and their cross-talk may be involved in the determination of various gross-morphological features and their distinct biological behavior.

Adverse outcomes of proton pump inhibitors in chronic liver disease: a systematic review and meta-analysis Abstract Background and aim Proton pump inhibitors (PPIs) are among the most commonly prescribed medications in the US, but their safety in cirrhosis has recently been questioned. We performed a meta-analysis of observational studies to evaluate the impact of PPIs on adverse clinical outcomes in the setting of chronic liver disease (CLD). Methods We searched several databases from inception to 26 May 2019 to identify comparative studies evaluating the effect of PPIs in CLD. Outcomes of interest were the associations between PPIs use and the occurrence of hepatic encephalopathy, hepatocellular carcinoma, spontaneous bacterial peritonitis, bacterial infections, and mortality in CLD. We performed a meta-analysis in accordance to the PRISMA guidelines. Results Of 14,662 papers evaluated, 47 studies with 169,806 participants were identified. Of these, 35 were cohort studies and 12 were case–control studies. The pooled odds ratio (OR) for hepatic encephalopathy in individuals with PPI users, compared with those without, was 2.31 (95% CI 1.63–3.28). The pooled OR for spontaneous bacterial peritonitis in individuals with PPI users was significantly higher compared with non-PPI users (OR = 1.72, 95% CI 1.42–2.09). Results were also consistent with a higher risk of the bacterial infections and mortality in PPI users compared with non-PPI users. For hepatocellular carcinoma, the final conclusion cannot be drawn because of the limited number of studies. Conclusions This study identifies a significant relationship between PPIs therapies and several specific adverse clinical outcomes in CLD. However, these results should be carefully considered given the potential selection bias and unmeasured confounding variables in observational studies, it may be reasonable to re-evaluate the need for PPIs in patients with CLD.

Sarcopenia: an emerging risk factor for non-alcoholic fatty liver disease

Change in antibiotic regimen for emerging multidrug resistance in nosocomial ascitic fluid infection Graphic abstract

Improving pathological early diagnosis and differential biomarker value for hepatocellular carcinoma via RNAscope technology Abstract Background The diagnostic and prognostic values of glypican3 (GPC3) and glutamine synthetase (GS) proteins in hepatocellular carcinoma (HCC) have been reported, but their specificity and sensitivity remain low. Here, we applied RNAscope to improve HCC early pathological and differential diagnosis by estimating GPC3 and GS mRNAs. Methods We performed RNAscope and immunohistochemistry (IHC) to detect GPC3 and GS biomarkers on the tissue sections of 194 cases, including high- and low-grade liver dysplastic nodules; highly, moderately, and poorly differentiated HCCs; intrahepatic cholangiocarcinomas (ICCs); metastatic HCC; and carcinomas from other organs. Results The results showed that all the cases that were negative for GPC3 by RNAscope were also negative for this protein by IHC. The use of RNAscope assay improved the GPC3 and GS specificity and sensitivity by 20–30%. Hence, HCC shows early recognition and upgrades the metastatic HCC differentiation by 23% compared with IHC (p = 0.0001, 0.0064). Meanwhile, all liver cirrhosis, cholangiocytes and non-HCC samples were negative for GPC3 and GS except lymphocytes in lymphomas, and 2 (8.3%) out of the 24 ICC samples but not in the cancer cells. Conclusion RNAscope for GPC3 and GS panel was highly specific and sensitive for the pathological identification of dysplastic nodules, early stages of HCCs, and would differentiate them from HCCs and metastatic tumors compared with IHC.

Ascitic fluid infection in children with liver disease: time to change empirical antibiotic policy Abstract Background and aims Recent years have shown a rise in occurrence of multidrug resistant ascitic fluid infection (AFI) including resistant to third generation cephalosporins. Our aim was to find the prevalence, antibiotics resistance and outcome of AFI in children with liver disease. Methods Children (≤ 18 years) with liver disease-related ascites were prospectively enrolled from April 2015 to October 2017. Based on the results of ascitic fluid examination and culture, patients were classified as having AFI [spontaneous bacterial peritonitis (SBP), culture negative neutrocytic ascites (CNNA) and monomicrobial non-neutrocytic bacterascites (MNB)] and no-AFI. AFI diagnosed after 48 h of index hospitalization was considered as nosocomial. Results We enrolled 194 children with a median age of 85 [2–216] months. Chronic liver disease was the commonest etiology (153, 79%). AFI was present in 60 (31%) children [SBP (n = 13), CNNA (n = 39), MNB (n = 8)] of which 53% were nosocomial and resulted in high in-hospital mortality. Gram-negative bacilli dominated the ascitic fluid culture (12/21, 57%) and 10/12 (83%) of them were extended spectrum beta-lactamases (ESBL) producers. Six (60%) ESBL producers were sensitive to cefoperazone–sulbactam and 70% to carbapenems. Child–Pugh-Turcotte (CPT) score of ≥ 11 independently determined in-hospital mortality in children with AFI. Conclusions AFI was found in 31% children with liver disease and almost half of them were nosocomial resulting in high mortality. ESBL producing Gram-negative bacteria were the most frequently isolated organisms. Cefoperazone–sulbactam or carbapenems may be useful empirical antibiotics in nosocomial setting. Children with AFI and CPT score ≥ 11 should be evaluated for liver transplantation.

Antimicrobial resistance in chronic liver disease Abstract High levels of antimicrobial drug resistance deleteriously affecting the outcome of treatment with antibacterial agents are causing increasing concern worldwide. This is particularly worrying in patients with cirrhosis with a depressed immune system and heightened susceptibility to infection. Antibiotics have to be started early before results of microbiological culture are available. Current guidelines for the empirical choice of antibiotics in this situation are not very helpful, and embracing antimicrobial stewardship including rapid de-escalation of therapy are not sufficiently emphasised. Multi-drug resistant organism rates to quinolone drugs of up to 40% are recorded in patients with spontaneous bacterial peritonitis on prophylactic antibiotics, leading to a break-through recurrence of intra-peritoneal infection. Also considered in this review is the value of rifaximin-α, non-selective beta-blockers, and concerns around proton pump inhibitor drug use. Fecal microbial transplantation and other gut-targeting therapies in lessening gut bacterial translocation are a promising approach, and new molecular techniques for determining bacterial sensitivity will allow more specific targeted therapy.

Nucleoside analog monotherapy for prophylaxis in Hepatitis B liver transplant patients is safe and efficacious Abstract Background Combination therapy with HBIG and NAs has reduced HBV recurrence post LT. Despite its efficacy, costs of HBIG remain prohibitive. With high-potency NAs, HBIG’s use has been questioned. We aim to evaluate the efficacy and safety of HBIG-free regimens in patients transplanted for HBV-related liver disease. Methods A review of LT patients at the National University Hospital, Singapore from 2001 to 2015 was performed. Patients transplanted for HBV were divided by antiviral treatment received: high- or low-potency NAs, or a combination of HBIG with high-potency NAs. Post-transplant outcomes were reviewed till data censure. Primary outcome was recurrence of HBV viremia post-transplant, while secondary outcomes were HBsAg sero-clearance, graft survival and mortality. Results Among 58 patients, 51 (88%) had persistent HBV viral suppression. Patients on a high-potency agent had significantly higher viral suppression compared to those on a low-potency agent (97% vs 72%, p = 0.02). This was also seen in patients with VL detectable at transplant (100% vs 50%, p < 0.01). None of the 16 patients with VL detectable at transplant and treated with high-potency agents developed recurrence. 42 patients (72%) achieved persistent HBsAg sero-clearance. Although this was higher in the high-potency NA-only group, it was not statistically significant (p = 0.56). There were no graft failures or mortalities attributed to HBV recurrence. Conclusion With the use of high-potency agents, HBIG may not be necessary in the treatment of patients transplanted for HBV-related liver disease, even in the presence of detectable VL at time of transplant.

Retrospective comparison of EASL 2018 and LI-RADS 2018 for the noninvasive diagnosis of hepatocellular carcinoma using magnetic resonance imaging Abstract Purpose We compared the diagnostic performances of the European Association for the Study of the Liver (EASL) 2018 and Liver Imaging Reporting and Data System (LI-RADS) 2018 criteria on magnetic resonance imaging (MRI) for the noninvasive diagnosis of hepatocellular carcinoma (HCC) in high-risk patients and evaluated the difference in diagnostic value between MRI with extracellular contrast agents (ECA-MRI) and MRI with hepatobiliary agents (HBA-MRI). Methods This study included 382 observations from 298 patients at high risk for HCC who underwent preoperative multiphasic contrast-enhanced MRI between January 2015 and December 2016. Two readers assessed all observations according to the EASL 2018 and LI-RADS 2018 criteria, and the per-observation diagnostic performances were compared. Results On ECA-MRI, the LR-5 category of LI-RADS 2018 showed significantly higher sensitivity (78.9% vs. 71.5%, p = 0.005) and accuracy (81.7% vs. 75.0%, p = 0.003) for the diagnosis of HCC than the EASL 2018. On HBA-MRI, the diagnostic performances of the EASL 2018 and LR-5 of LI-RADS 2018 were not significantly different. When using EASL 2018, no statistically significant differences were observed in the diagnostic performances between ECA-MRI and HBA-MRI; however, when using the LR-5 of LI-RADS 2018, ECA-MRI had a higher sensitivity (78.9% vs. 67.5%, p = 0.029) than HBA-MRI. Conclusions On ECA-MRI, the LR-5 category of LI-RADS 2018 provides better sensitivity and accuracy than the EASL 2018 for diagnosing HCC. EASL 2018 provides comparable diagnostic performances between ECA-MRI and HBA-MRI, but the LR-5 category of LI-RADS 2018 provides better sensitivity on ECA-MRI than on HBA-MRI.

Relationship between relative skeletal muscle mass and nonalcoholic fatty liver disease: a systematic review and meta-analysis Abstract Background and Aim Nonalcoholic fatty liver disease (NAFLD) has gradually become one of the most common chronic liver diseases in the world. More and more evidence shows that low skeletal muscle mass index (SMI) may play a role in the development of NAFLD. Our aim was to quantify the association between SMI, sarcopenia and the presence and severity of NAFLD. Methods We systematically searched English relevant studies from PubMed, Embase, the Web of Science and the Cochrane Library updated to December 20th, 2018. Studies in which SMI was compared between NAFLD cases and controls were included. So were studies concerning the odds ratio (OR) of NAFLD, non-alcoholic steatohepatitis (NASH) and significant fibrosis in sarcopenia patients. Pooled weighted mean differences and ORs were calculated. Results Of the 1331 retrieved studies, 19 articles were included. SMI level in NAFLD patients was 1.77 (95% CI 1.15, 2.39) lower than that in normal controls. We also found a significantly higher occurrence risk of NAFLD (OR = 1.33, 95% CI 1.20 to 1.48), NASH (OR = 2.42, 95% CI 1.27 to 3.57) and NAFLD-related significant fibrosis (OR = 1.56, 95% CI 1.34, 1.78) in sarcopenia subjects. Conclusions SMI level in patients with NAFLD was lower than healthy people, and patients with sarcopenia have higher occurrence risk of NAFLD, as well as its advanced stages including NASH or NAFLD-related significant fibrosis. Further well-designed prospective studies are required to strengthen the arguments.