Low skeletal muscle mass is associated with non-alcoholic fatty liver disease in Korean adults： the Fifth Korea National Health and Nutrition Examination Survey

BACKGROUND： Sarcopenia and non-alcoholic fatty liver dis- ease （NAFLD） share similar pathophysiological mechanisms, and the relationship between sarcopenia and NAFLD has been recently investigated. The study investigated whether low skel- etal muscle mass is differentially associated with NAFLD by gender in Korean adults. METHODS： We conducted a cross-sectional analysis of the data from the Fifth Korea National Health and Nutrition Examination Survey. The skeletal muscle index （SMI） was obtained by the appendicular skeletal muscle mass divided by the weight. NAFLD was defined as a fatty liver index （FLI） 〉60 in the absence of other chronic liver disease. RESULTS： Among the included subjects, 18.3% （SE： 1.4%） in men and 7.0% （SE： 0.7%） in women were classified as having FLI-defined NAFLD. Most of the risk factors for FLI-defined NAFLD showed a significant negative correlation with the SMI in both genders. Multiple logistic regression analysis showed that low SMI was associated with FLI-defined NAFLD, inde- pendent of other metabolic and lifestyle parameters in both genders [males： odds ratio （OR）=1.35; 95% confidence inter- val （CI）： 1.17-1.54; females： OR=1.36; 95% CI： 1.18-1.55]. The magnitude of the association between FLI-defined NAFLD and low SMI was higher in middle aged to elderly males （OR-1.50; 95% CI： 1.22-1.84） than in males less than 45 years of age （OR=1.25; 95% CI： 1.02-1.52） and in premenopausal females （OR=l.50; 95% CI： 1.12-2.03） than in postmenopausal females （OR-1.36; 95% CI： 1.20-1.54）.CONCLUSIONS： Low SMI is associated with the risk of FLI- defined NAFLD independent of other well-known metabolic risk factors in both genders. This association may differ ac- cording to age group or menopausal status. Further studies are warranted to confirm this relationship.

Diagnostic value of AFP-L3 and PIVKA-Ⅱin hepatocellular carcinoma according to total-AFP

AIM:To evaluate diagnostic value ofα-fetoprotein (AFP)-L3 and prothrombin induced by vitamin K absence-Ⅱ(PIVKA-Ⅱ)in hepatocellular carcinoma(HCC). METHODS:One hundred and sixty-eight patients during routine HCC surveillance were included in this study.Of the 168 patients,90(53.6%)had HCC including newly developed HCC(n=82)or recurrent HCC after treatment(n=8).Sera were obtained during their first evaluation for HCC development and at the time of HCC diagnosis before commencing HCC treatment.HCC was diagnosed by histological examination,appropriate imaging characteristics-computed tomography or magnetic resonance imaging.Control sera were collected from 78 patients with benign liver disease(BLD),which were obtained during routine surveillance with a suspicion of HCC.AFP,AFP-L3 and PIVKA-Ⅱwere measured in the same serum by microchip capillary electrophoresis and liquid-phase binding assay on a micro-total analysis system Wako i30 auto analyzer.The performance characteristics of three tests and combined tests for the diagnosis of HCC were obtained using receiver operating characteristic curves in all populations and subgroups with AFP<20 ng/mL. RESULTS:Of 90 HCC patients,38(42.2%)patients had AFP<20 ng/mL,20(22.2%)patients had AFP 20-200 ng/mL and 32(35.6%)patients had AFP>200 ng/mL.Of the 78 BLD patients,74(94.9%)patients had AFP<20 ng/mL.After adjustment for age and HBV infection status,AFP-L3 levels were higher in HCC than in BLD among patients with low AFP levels(<20 ng/mL)(P<0.001).In a total of 168 patients,areas under the curve(AUC)for HCC were 0.879,0.887,0.801 and 0.939 for AFP,AFP-L3,PIVKA-Ⅱand the combined markers,respectively.The combined AUC for three markers showed higher value than the AUCs of individual marker(P<0.05).AFP-L3 had higher AUC value than PIVKA-Ⅱfor HCC detection in entire patients(P =0.043).With combination of AFP-L3(cut-off>5%) and PIVKA-Ⅱ(cut-off>40 AU/L),the sensitivity were 94.4%and specificity were 75.6%in all patients.In 112 patients with low AFP levels(<20 ng/mL),AUCs of AFP-L3,PIVKA-Ⅱand combine AFP-L3 and PIVKA-Ⅱtests were 0.824,0.774 and 0.939,respectively. AFP-L3 with a cut-off value of 5%showed sensitivity of 71.1%and specificity of 83.8%,and PIVKA-Ⅱwith a cut-off value of 40 AU/L had sensitivity of 57.9%and specificity of 95.9%in patients with low AFP levels. The combination of AFP-L3 and PIVKA-Ⅱincreased the sensitivity and specificity up to 92.1%and 79.7%, respectively,in low AFP group.Combined markers detected 81.8%of early stage HCC(Union for Inter-national Cancer Control stageⅠ),86.7%of small sized tumor(<2 cm)and 91.7%of single tumor of HCC in the low AFP group.In multivariate analysis,AFP-L3 was correlated with AFP and tumor size,and PIVKA-Ⅱwas correlated with laboratory tests including serum aspartate aminotransferase,total bilirubin,platelets and albumin levels.PIVKA-Ⅱhad no correlation with AFP,AFP-L3 or tumor characteristics. CONCLUSION:Combined determination of AFP-L3 and PIVKA-Ⅱcould improve the diagnostic value for HCC detection in patients with or without increased AFP levels.

Sarcopenia in the prognosis of cirrhosis: Going beyond the MELD score

Estimating the prognosis of patients with cirrhosis remains challenging, because the natural history of cirrhosis varies according to the cause, presence of portal hypertension, liver synthetic function, and the reversibility of underlying disease. Conventional prognostic scoring systems, including the Child-Turcotte-Pugh score or model for endstage liver diseases are widely used; however, revised models have been introduced to improve prognostic performance. Although sarcopenia is one of the most common complications related to survival of patients with cirrhosis, the newly proposed prognostic models lack a nutritional status evaluation of patients. This is reflected by the lack of an optimal index for sarcopenia in terms of objectivity, reproducibility, practicality, and prognostic performance, and of a consensus definition for sarcopenia in patients with cirrhosis in whom ascites and edema may interfere with body composition analysis. Quantifying skeletal muscle mass using cross-sectional abdominal imaging is a promising tool for assessing sarcopenia. As radiological imaging provides direct visualization of body composition, it is useful to evaluate sarcopenia in patients with cirrhosis whose body mass index, anthropometric measurements, or biochemical markers are inaccurate on a nutritional assessment. Sarcopenia defined by cross-sectional imaging-based muscular assessment is prevalent and predicts mortality in patients with cirrhosis. Sarcopenia alone or in combination with conventional prognostic systems shows promise for a cirrhosis prognosis. Including an objective assessment of sarcopenia with conventional scores to optimize the outcome prediction for patients with cirrhosis needs further research.

Durability of viral response after off-treatment in HBeAg positive chronic hepatitis B

AIM:To evaluate the durability in hepatitis B e antigen (HBeAg) positive chronic hepatitis B patients who discontinued antiviral treatment. METHODS:A total of 48 HBeAg positive chronic hepatitis B patients who were administered nucleoside analogues and maintained virological response for ≥ 6 mo [hepatitis B virus (HBV) DNA < 300 copies/mL and HBeAg seroconversion] before cessation of treatment were enrolled between February 2007 and January 2010. The criteria for the cessation of the antiviral treatment were defined as follows:(1) achievement of virological response; and (2) duration of consolidation therapy (≥ 6 mo). After treatment cessation, the patients were followed up at 3-6 mo intervals. The primary endpoint was serologic and virologic recurrence rates after withdrawal of antiviral treatment. Serologic recurrence was defined as reappearance of HBeAg positivity after HBeAg seroconversion. Virologic recurrence was defined as an increase in HBV-DNA level > 104 copies/mL after HBeAg seroconversion with previously undetectable HBV-DNA level. RESULTS:During the median follow-up period of 18.2 mo (range:5.1-47.5 mo) after cessation of antiviral treatment, the cumulative serological recurrence rate was 15 % at 12 mo. The median duration between the cessation of antiviral treatment and serologic recurrence was 7.2 mo (range:1.2-10.9 mo). Of the 48 patients with HBeAg positive chronic hepatitis, 20 (41.6%) showed virological recurrence. The cumulative virologic recurrence rates at 12 mo after discontinuing the antiviral agent were 41%. The median duration between off-treatment and virologic recurrence was 7.6 mo (range:4.3-27.1 mo). The mean age of the virological recurrence group was older than that of the non-recurrence group (46.7 ± 12.1 years vs 38.8 ± 12.7 years, respectively; P = 0.022). Age (> 40 years) and the duration of consolidation treatment (≥ 15 mo) were significant predictive factors for offtreatment durability in the multivariate analysis [P = 0.049, relative risk (RR) 0.31, 95% CI (0.096-0.998) and P = 0.005, RR 11.29, 95% CI (2.054-65.12), respectively]. Patients with age (≤ 40 years) who received consolidation treatment (≥ 15 mo) significantly showed durability in HBeAg positive chronic hepatitis B patients (P = 0.014). These results suggest that additional treatment for more than 15 mo after HBeAg seroconversion in patients who are ≤ 40 years old may be beneficial in providing a sustained virological response. CONCLUSION:Our data suggest that HBeAg seroconversion is an imperfect end point in antiviral treatment. Long-term consolidation treatment (≥ 15 mo) in younger patients is important for producing better prognosis in HBeAg positive chronic hepatitis B.

Outcome of transarterial chemoembolization-based multi-modal treatment in patients with unresectable hepatocellular carcinoma

AIM:To investigate the efficacy and safety of transarterial chemoembolization(TACE)-based multimodal treatment in patients with large hepatocellular carcinoma(HCC).METHODS:A total of 146 consecutive patients were included in the analysis,and their medical records and radiological data were reviewed retrospectively.RESULTS:In total,119 patients received TACE-based multi-modal treatments,and the remaining 27 received conservative management.Overall survival(P<0.001)and objective tumor response(P=0.003)were significantly better in the treatment group than in the conservative group.After subgroup analysis,survival benefits were observed not only in the multi-modal treatment group compared with the TACE-only group(P=0.002)but also in the surgical treatment group compared with the loco-regional treatment-only group(P<0.001).Multivariate analysis identified tumor stage(P<0.001)and tumor type(P=0.009)as two independent pre-treatment factors for survival.After adjusting for significant pre-treatment prognostic factors,objective response(P<0.001),surgical treatment(P=0.009),and multi-modal treatment(P=0.002)were identified as independent post-treatment prognostic factors.CONCLUSION:TACE-based multi-modal treatments were safe and more beneficial than conservative management.Salvage surgery after successful downstaging resultedin long-term survival in patients with large,unresectable HCC.

Hepatic arterial infusion chemotherapy in hepatocellular carcinoma with portal vein tumor thrombosis

AIM: To evaluate the prognostic factors and efficacy of hepatic arterial infusion chemotherapy in hepatocellular carcinoma with portal vein tumor thrombosis. METHODS: Fifty hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) were treated using hepatic arterial infusion chemotherapy (HAIC) via a subcutaneously implanted port. The epirubicin-cisplatin-5-fluorouracil (ECF) chemotherapeutic regimen consisted of 35 mg/m 2 epirubicin on day 1, 60 mg/m 2 cisplatin for 2 h on day 2, and 500 mg/m 2 5-fluorouracil for 5 h on days 1-3. The treatments were repeated every 3 or 4 wk. RESULTS: Three (6%) of the 50 patients achieved a complete response (CR), 13 (26%) showed partial responses (PR), and 22 (44%) had stable disease (SD).The median survival and time to progression were 7 and 2 mo, respectively. After 2 cycles of HAIC, CR was achieved in 1 patient (2%), PR in 10 patients (20%) and SD in 26 patients (52%). Significant pre-treatment prognostic factors were a tumor volume of < 400 cm 3 (P = 0.01) and normal levels of protein induced by vitamin K absence or antagonist (PIVKA)-Ⅱ (P = 0.022). After 2 cycles of treatment, disease control (CR + PR + SD) (P = 0.001), PVTT response (P = 0.003) and α-fetoprotein reduction of over 50% (P = 0.02) were independent factors for survival. Objective response (CR + PR), disease control, PVTT response, and combination therapy during the HAIC were also significant prognostic factors. Adverse events were tolerable and successfully managed. CONCLUSION: HAIC may be an effective treatment modality for advanced HCC with PVTT in patients with tumors < 400 cm 3 and good prognostic factors.

Assessment of scoring systems for acute-on-chronic liver failure at predicting short-term mortality in patients with alcoholic hepatitis

AIM To assess the performance of proposed scores specific for acute-on-chronic liver failure in predicting shortterm mortality among patients with alcoholic hepatitis.METHODS We retrospectively collected data from 264 patients with clinically diagnosed alcoholic hepatitis from January to December 2013 at 21 academic hospitals in Korea. The performance for predicting short-term mortality was calculated for Chronic Liver FailureSequential Organ Failure Assessment(CLIF-SOFA), CLIF Consortium Organ Failure score(CLIF-C OFs), Maddrey'sdiscriminant function(DF), age, bilirubin, international normalized ratio and creatinine score(ABIC), Glasgow Alcoholic Hepatitis Score(GAHS), model for end-stage liver disease(MELD), and MELD-Na.RESULTS Of 264 patients, 32(12%) patients died within 28 d. The area under receiver operating characteristic curve of CLIF-SOFA, CLIF-C OFs, DF, ABIC, GAHS, MELD, and MELD-Na was 0.86(0.81-0.90), 0.89(0.84-0.92), 0.79(0.74-0.84), 0.78(0.72-0.83), 0.81(0.76-0.86), 0.83(0.78-0.88), and 0.83(0.78-0.88), respectively, for 28-d mortality. The performance of CLIF-SOFA had no statistically significant differences for 28-d mortality. The performance of CLIF-C OFs was superior to that of DF, ABIC, and GAHS, while comparable to that of MELD and MELD-Na in predicting 28-d mortality. A CLIF-SOFA score of 8 had 78.1% sensitivity and 79.7% specificity, and CLIF-C OFs of 10 had 68.8% sensitivity and 91.4% specificity for predicting 28-d mortality.CONCLUSION CLIF-SOFA and CLIF-C OF scores performed well, with comparable predictive ability for short-term mortality compared to the commonly used scoring systems in patients with alcoholic hepatitis.

Risk factors of biliary intervention by imaging after livingdonor liver transplantation

AIM:To determine the risk factors of biliary intervention using magnetic resonance cholangiopancreatography(MRCP) after living donor liver transplantation(LDLT).METHODS: We retrospectively enrolled 196 patients who underwent right lobe LDLT between 2006 and 2010 at a single liver transplantation center. Direct duct-to-duct biliary anastomosis was performed in all 196 patients. MRCP images routinely taken 1 mo after LDLT were analyzed to identify risk factors for biliary intervention during follow-up, such as retrograde cholangiopancreatography or percutaneous transhepatic biliary drainage. Two experienced radiologists evaluated the MRCP findings, including the anastomosis site angle on three-dimensional images, the length of the filling defect on maximum intensity projection, bile duct dilatation, biliary stricture, and leakage.RESULTS: Eighty-nine patients underwent biliary intervention during follow-up. The anastomosis site angle [hazard ratio(HR) = 0.48; 95% confidence interval(CI), 0.30-0.75, P < 0.001], a filling defect in the anastomosis site(HR = 2.18, 95%CI: 1.41-3.38,P = 0.001), and biliary leakage(HR = 2.52, 95%CI: 1.02-6.20, P = 0.048) on MRCP were identified in the multivariate analysis as significant risk factors for biliary intervention during follow-up. Moreover, a narrower anastomosis site angle(i.e., below the median angle of 113.3°) was associated with earlier biliary intervention(38.5 ± 4.2 mo vs 62. 1 ± 4.1 mo, P < 0.001). Kaplan-Meier analysis comparing biliary intervention-free survival according to the anastomosis site angle revealed that lower survival was associated with a narrower anastomosis site angle(36.3% vs 62.0%, P < 0.001).CONCLUSION: The biliary anastomosis site angle in MRCP after LDLT may be associated with the need for biliary intervention.

A Decade-old Change in the Screening Rate for Hepatocellular Carcinoma Among a Hepatitis B Virus-infected Population in Korea

Background： Evaluating a change in the screening rate for hepatocellular carcinoma （HCC） is critical for understanding screening implementation, and whether targeted population groups are receiving proper screening. This study examined recent nationwide changes in HCC screening use among hepatitis B virus （HBV）-infected populations after the introduction of the Korean National Cancer Screening Program and predictors of screening adherence. Methods： We analyzed 165 and 276 participants 〉40 years of age who were hepatitis B surface antigen-positive fiom 2001 （14,936 participants） to 2010-2011 （9159 participants） Korea National Health and Nutrition Examination Surveys, respectively. Demographic data, socioeconomic factors, and HCC screening use were collected by means of self-reported questionnaires. Results： The rate of HCC screening within the previous 2 years increased significantly from 17.5% in 2001 to 40.3% in 2010- 20I 1 （P〈 0.0001 ）. The rate of HCC screening use increased from 2001 to 2010-2011 in all study populations. Subjects who had a higher income staius and were aware of their infection were more likely to have undergone recent HCC screening. Conclusions： This study showed a substantial increase in HCC screening in high-risk HBV-infected subjects from 2001 to 2010-2011. However, the HCC screening participation rate remained suboptimal despite the introduction of the nationwide screening program. Efforts should be made to identiry high-risk individuals and increase attendance at HCC screening events among high-risk groups.

Relative skeletal muscle mass and non-alcoholic fatty liver disease: from association to causation

The prevalence of nonalcoholic fatty liver disease(NAFLD)and its associated metabolic risk factors,including obesityand metabolic syndrome,have increased over the lastdecade in both developed and developing countries(1).NAFLD is considered to be the hepatic manifestation ofmetabolic syndrome and insulin resistance which is oneof multiple hits leading to NAFLD(2).