Gadoxetic acid, a hepatocyte-specific magnetic resonance imaging (MRI) contrast agent, has emerged as an important tool for hepatocellular carcinoma (HCC) diagnosis. Gadoxetic acid-enhanced MRI is useful for the evaluation of earlystage HCC, diagnosis of HCC precursor lesions, and highly sensitive diagnosis of HCC. Furthermore, functional information provided by gadoxetic acid-enhanced MRI can aid in the characterization of focal liver lesions. For example, whereas lesions lack functioning hepatocytes appear hypointense in the hepatobiliary phase, preserved or enhanced expression of organic anion transporting polypeptides in some HCCs as well as focal nodular hyperplasia lead to hyperintensity in the hepatobiliary phase; and a targetoid appearance on transitional phase or hepatobiliary phase imaging can be helpful for identifying the histopathological composition of tumors. While gadoxetic acid-enhanced MRI may improve the sensitivity of HCC diagnosis and provide new insights into the characterization of focal liver lesions, there are many challenges associated with its use. This article reviews the pros and cons of HCC diagnosis with gadoxetic acidenhanced MRI and discuss some clues in the radiological differentiation of HCC from HCC mimickers. (Clin Mol Hepatol 2019;25:223-233)

Hepatitis C virus (HCV) infection is a major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC), and is a leading cause of liver-related deaths worldwide. Recently available direct-acting antiviral agent is very safe and highly effective (>95% sustained virologic response, SVR) against all genotypes of HCV. Achievement of SVR has been associated with a significant reduction of hepatic decompensation, development of HCC, and liver-related mortality. However, HCC risk is not eliminated even after SVR. The annual incidences of HCC in advanced fibrosis or cirrhosis have been estimated to be up to 2.5-4.5% even in patients with SVR. Therefore, surveillance for HCC is recommended in this high-risk patients. In this review, we will describe the clinical outcomes and the risk of HCC in patients with SVR and suggest who should receive surveillance for HCC. (Clin Mol Hepatol 2019;25:234-244)

The goal of this review is to present the similarities and differences among the latest guidelines for noninvasive diagnosis of hepatocellular carcinoma (HCC) of American Association for the Study of Liver Disease (AASLD), European Association for the Study of the Liver (EASL), Liver Imaging Reporting and Data System (LI-RADS), Asian Pacific Association for the Study of the Liver (APASL), and Korean Liver Cancer Association-National Cancer Center (KLCA-NCC) of Korea. In 2018, major guideline updates have been proposed by the AASLD, EASL and KLCA-NCC; AASLD newly incorporated LI-RADS into their HCC diagnostic algorithm. The AASLD and EASL guidelines now include magnetic resonance imaging (MRI) using hepatobiliary contrast media as a first-line diagnostic test in addition to dynamic computed tomography and MRI using extracellular contrast media and the KLCA-NCC and EASL guidelines also include contrast-enhanced ultrasound as a second-line diagnostic test. We will comprehensively review the HCC surveillance and diagnostic algorithms and compare and highlight key features for each guideline. We also address limitations of current systems for the noninvasive diagnosis of HCC. (Clin Mol Hepatol 2019;25:245-263)

Hepatocellular carcinoma (HCC) is the third most common cause of cancer related death worldwide. Prognosis and treatment options largely depend on tumor stage at diagnosis, with curative treatments only available if detected at an early stage. However, two thirds of patients with HCC are diagnosed at a late stage and not eligible for cure. Therefore several liver professional societies recommend HCC surveillance using abdominal ultrasound with or without alpha fetoprotein in at-risk populations, including patients with cirrhosis and subsets of those with chronic hepatitis B. Available data suggest HCC surveillance can significantly improve early tumor detection, curative treatment eligibility, and overall survival. However, the potential benefits of HCC surveillance must be considered in light a shifting HCC demographic from a viral-mediated cancer to an increasing proportion of patients having non-alcoholic steatohepatitis, which has been shown to limit ultrasound sensitivity and may mitigate observed benefits. Further, benefits of HCC surveillance must be weighed against potential physical, financial and psychological harms. Continued data for both benefits and harms of HCC surveillance in contemporary populations are necessary. In the interim, providers should continue to strive for high quality HCC surveillance in at-risk patients. (Clin Mol Hepatol 2019;25:264-269)

Sarcopenia (loss of muscle mass and/or strength) frequently complicates liver cirrhosis and adversely affects the quality of life; cirrhosis related liver decompensation and significantly decreases wait-list and post-liver transplantation survival. The main therapeutic strategies to improve or reverse sarcopenia include dietary interventions (supplemental calorie and protein intake), increased physical activity (supervised resistance and endurance exercises), hormonal therapy (testosterone), and ammonia lowering agents (L-ornithine L-aspartate, branch chain amino acids) as well as mechanistic approaches that target underlying molecular and metabolic abnormalities. Besides other factors, hyperammonemia has recently gained attention and increase sarcopenia by various mechanisms including increased expression of myostatin, increased phosphorylation of eukaryotic initiation factor 2a, cataplerosis of α ketoglutarate, mitochondrial dysfunction, increased reactive oxygen species that decrease protein synthesis and increased autophagy-mediated proteolysis. Sarcopenia contributes to frailty and increases the risk of minimal and overt hepatic encephalopathy. (Clin Mol Hepatol 2019;25:270-279)

Background/Aims: The influence of hepatic steatosis (HS) on chronic hepatitis B (CHB) is unclear. We evaluated the influence of the degree of HS, assessed using the controlled attenuation parameter (CAP) of transient elastography (TE), on treatment outcomes in CHB patients initiated on antiviral therapy.
Methods: A total of 334 patients who were initiated on entecavir or tenofovir between 2007 and 2016 with available TE results were recruited.
Results: Of the total study population, 146 (43.7%) patients had HS (CAP >238 dB/m). Three-hundred-three patients (90.7%) achieved complete virological response (CVR) (hepatitis B virus DNA <12 IU/L), and 25 patients (7.5%) developed hepatocellular carcinoma (HCC). Among hepatitis B e antigen (HBeAg)-positive patients (n=172, 51.5%), 37 (21.5%) experienced HBeAg loss. On univariate analysis, CAP value was not associated with the probability of HCC development (P =0.380). However, lower CAP value was independently associated with higher probability of HBeAg loss among HBeAg-positive patients (hazard ratio [HR]=0.991, P =0.026) and with CVR achievement in the entire study population (HR=0.996, P=0.004). The cumulative incidence of HBeAg loss among HBeAg-positive patients was significantly higher in patients without HS than in those with HS (log-rank, P =0.022).
Conclusions: CAP values were not correlated with HCC development in patients initiated on entecavir and tenofovir. However, CAP values were negatively correlated with the probability of HBeAg loss among HBeAg-positive patients and with CVR achievement. (Clin Mol Hepatol 2019;25:283-293)

Background/Aims: Fatty liver is a clinical and pathologic condition in individuals with type 2 diabetes (T2D). The purpose of this study is to examine the effects of different exercise modalities on non-alcoholic fatty liver indices (fatty liver index [FLI], lipid accumulation product [LAP], hepatic steatosis index [HSI], and Framingham Steatosis Index [FSI]) in women with T2D.
Methods: Fifty-two women with T2D and a mean age of 55.07±5.92 yrs, body mass index (BMI) 28.94±4.09 kg/m2, and hemoglobin A1c (HbA1c) 9.41±0.82% were randomized to a sprint interval training (SIT) (n=17), combined aerobic and resistance (A+R) training (n=17), or control group (n=18) for 10 weeks. Two-way repeated analysis of variance (ANOVA) was used to find differences between groups and the effects of time and Time×Group interactions after 10 weeks on non-alcoholic fatty liver indices. After this, ANOVA models were constructed to determine the effects of group allocation and change in non-alcoholic fatty liver indices.
Results: There were significant time interactions for FLI (P<0.001), HSI (P<0.001), and LAP (P<0.001). Also, there were significant Time×Group interactions for fasting blood glucose (P=0.034), and HbA1c (P=0.006).
Conclusions: Results highlight that exercise training, independent of mode of training, is an effective strategy to improve some indices related to hepatic steatosis and blood glucose profiles in women with T2D. (Clin Mol Hepatol 2019;25:294-304)

Background/Aims: Inflammation-based scores, such as the neutrophil-to-lymphocyte ratio (NLR), have been associated with prognosis in hepatocellular carcinoma (HCC); but variable cut-off values and potential lack of specificity have limited the utility of NLR. This study evaluates NLR in a large cohort of HCC patients.
Methods: We retrospectively reviewed 789 HCC cases (1993-2017) for demographics, tumor characteristics, treatment, and survival. NLR was stratified into NLR ≥1.5 and NLR ≥3 and analyzed for correlation with American Joint Committee on Cancer (AJCC) and Barcelona Clinic Liver Cancer (BCLC) stages. In 235 patients who underwent liver resection, survival and recurrence were evaluated by NLR.
Results: In 789 HCC cases, mean NLR was increased with advanced AJCC and BCLC stages. Hepatitis C patients were less likely to have NLR ≥1.5 and ≥3. Non-alcoholic steatohepatitis patients were more likely to have NLR ≥3. Patients with tumor size >5 cm, rupture, or macrovascular invasion were more likely to have NLR ≥3. In patients treated with resection, NLR ≥3 predicted early recurrence (odds ratio [OR] 4.14, P<0.01) and overall recurrence (OR 4.05, P<0.01). Mean NLR was 4.30 in those with recurrence and 2.75 in those without recurrence. Patients with NLR ≥3 showed significantly worse survival compared to those with NLR <3 (P<0.01 by log-rank test).
Conclusions: Elevated NLR is associated with advanced cancer stage and aggressive tumor characteristics, such as large size, rupture, and invasion. NLR ≥3 was associated with early and overall recurrence after resection but varied with etiology. NLR may be a useful biomarker in predicting recurrence for HCC patients undergoing curative resection, but further studies are required to elucidate the effect of disease etiology. (Clin Mol Hepatol 2019;25:305-316)

Background/Aims: Cellulitis is a common infection in patients with liver cirrhosis. We aimed to compare risk factors, microbial aspects, and outcomes of cellulitis in compensated and decompensated hepatitis C virus (HCV)-related cirrhosis.
Methods: Six hundred twenty consecutive HCV-related cirrhotic patients were evaluated for cellulitis. Demographic and clinical data were evaluated, along with blood and skin cultures. Severity of cirrhosis was assessed using Child-Pugh score. In-hospital mortality was assessed.
Results: Seventy-seven (12.4%) cirrhotic patients had cellulitis (25 with compensated and 52 with decompensated disease). Smoking and venous insufficiency were risk factors of cellulitis in compensated cirrhosis. Leg edema, ascites, hyperbilrubinemia and hypoalbuminemia were risk factors in decompensated cirrhosis. Gram-positive bacteria (Staphylococcus spp. and Streptococcus pyogenes) were the infective organisms in compensated patients, while gram negative bacteria (Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa) were the predominant organisms in decompensated cirrhosis. Fungi (Candida albicans and Aspergillus niger) were detected in 3 decompensated cases. In-hospital mortality in patients with cellulitis was 27.3%, approaching 100% in decompensated patients with gram-negative cellulitis. Prolonged hospitalization, higher model for end-stage liver disease (MELD)-Na score, septic shock, local complication, and recurrent cellulitis were predictors of mortality.
Conclusions: Cellulitis in compensated cirrhosis is different from that of decompensated patients regarding microorganisms, pathogenesis, and prognosis. Cellulitis has a poor prognosis, with mortality rates approaching 100% in decompensated patients with gram-negative cellulitis. Stratifying patients according to severity of cirrhosis is important to identify the proper empirical antibiotic and to decide the proper means of care. (Clin Mol Hepatol 2019;25:317-325)