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Background and Aim: We aimed to determine whether lobular inflammation and ballooning grades in the Non-alcoholic Steatohepatitis Clinical Research Network (NASH CRN) scoring system can be directly translated into the same for the Steatosis Activity Fibrosis scoring system (SAF) and to look at intra-observer and inter-observer agreement for each individual histological component and for diagnosis of non-alcoholic steatohepatitis (NASH) using the two scoring systems., Methods: Four pathologists from two Asian centers scored 20 digitalized slides, twice using the NASH CRN, twice using the SAF. Intra-observer and inter-observer agreement was analyzed using Fleiss' kappa, weighted kappa, or Cohen kappa, where appropriate., Results: The intra-observer discrepancy rate when using the NASH CRN compared with the SAF was higher than when using the individual scoring system for lobular inflammation (15% comparing both scoring systems vs 10% and 1.8% for the NASH CRN and the SAF, respectively) and hepatocyte ballooning (33.8% vs 12.5% and 5%, respectively), but not for diagnosis of NASH (6.3% vs 6.3% and 0%, respectively). Intra-observer and inter-observer agreement was substantial to almost perfect, except for inter-observer agreement for lobular inflammation and diagnosis of NASH, which was only fair to moderate in most instances., Conclusion: These findings do not support the direct inter-translation between the NASH CRN and the SAF. However, the diagnosis of NASH during examinations using the NASH CRN may be comparable with diagnosis of NASH using the SAF, vice versa. The inter-observer agreement for lobular inflammation and NASH diagnosis needs to be improved., (© 2022 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Artificial intelligence (AI) has become increasingly widespread in our daily lives, including healthcare applications. AI has brought many new insights into better ways we care for our patients with chronic liver disease, including non-alcoholic fatty liver disease and liver fibrosis. There are multiple ways to apply the AI technology on top of the conventional invasive (liver biopsy) and noninvasive (transient elastography, serum biomarkers, or clinical prediction models) approaches. In this review article, we discuss the principles of applying AI on electronic health records, liver biopsy, and liver images. A few common AI approaches include logistic regression, decision tree, random forest, and XGBoost for data at a single time stamp, recurrent neural networks for sequential data, and deep neural networks for histology and images., (© 2021 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aim: The Baveno VI Consensus recommends repeating examination in patients with high liver stiffness measurement (LSM) by transient elastography to reduce false-positive diagnosis of advanced liver disease. We tested whether repeating transient elastography can increase the overall diagnostic accuracy., Methods: Ninety-seven patients with non-alcoholic fatty liver disease who underwent two FibroScan examinations within 6 months prior to liver biopsy were evaluated. An LSM cut-off of 7.9 kPa was used to exclude F3-4 fibrosis., Results: Seventy-eight patients had high LSM at baseline, among whom 27 had low LSM on repeated testing; only four had F3 and none had cirrhosis. In contrast, 31 of 51 patients with high LSM at both examinations had F3-4. Nineteen patients had low LSM at baseline; none of them had F3-4 regardless of the second LSM results. If we took LSM <7.9 kPa at either examination as sufficient to exclude F3-4, the negative predictive value remained high at 91%. The positive predictive value for F3-4 increased from 45% in patients with high LSM at baseline to 61% in those with high LSM at both examinations. Sensitivity analysis using different cut-offs yielded similar results, with 76% of patients with LSM >12 kPa at both examinations having F3-4., Conclusions: Transient elastography is a highly sensitive screening test to exclude F3-4 fibrosis in non-alcoholic fatty liver disease patients. One-third of patients with high LSM may have normal results on repeated examination. By repeating examination in cases with high LSM, one may spare patients from unnecessary liver biopsy., (© 2018 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aim: The FibroMeter vibration-controlled transient elastography (FM VCTE) is a new formula combining the serum test FM and liver stiffness measurement (LSM) by VCTE. We tested the accuracy and utility of FM VCTE for fibrosis staging in patients with non-alcoholic fatty liver disease (NAFLD)., Methods: Two hundred fifteen NAFLD patients with LSM, FM NAFLD, FM VCTE, and other serum tests (aspartate aminotransferase-to-platelet ratio index, fibrosis-4 index, BARD score, NAFLD fibrosis score, and aspartate aminotransferase-to-alanine aminotransferase ratio) performed 1 day before liver biopsy were evaluated., Results: Sixty-nine (32.1%) and 43 (20.0%) patients had F2-4 and F3-4, respectively. LSM had higher diagnostic accuracy (area under receiver-operating characteristics curves [AUROC] 0.851 for F2-4, 0.940 for F3-4; Obuchowski index 0.937 ± 0.007) than all evaluated serum tests, while FM NAFLD was the most accurate serum test (AUROC 0.775 and 0.774; Obuchowski index 0.891 ± 0.013). FM VCTE had similar accuracy to LSM (AUROC 0.855 and 0.901; Obuchowski index 0.927 ± 0.009). LSM had excellent negative predictive values of 92.4% and 99.2% to exclude F2-4 and F3-4, but the positive predictive values (PPV) were only 71.4% and 61.0%, respectively. In patients with high LSM, the use of FM VCTE improved the PPV from 71.4% to 84.4% for F2-4 and from 61.0% to 88.9% for F3-4. Liver biopsy could be spared in around 50-65% of patients., Conclusions: Liver stiffness measurement alone can confidently exclude significant and advanced fibrosis in NAFLD patients. Using FM VCTE in patients with high liver stiffness can increase the positive predictive value to rule in F2-4 and F3-4., (© 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aims: Concurrent fatty liver in hepatitis B virus (HBV)-infected patients without significant alcohol intake is a frequent and increasingly alarming problem because of the non-alcoholic fatty liver disease pandemic. The risk of HBV-related hepatocellular carcinoma (HCC) development was increased by concomitant obesity and diabetes. Direct evidence of the hepatocarcinogenic effect of fatty liver in chronic HBV remains elusive. We aimed to evaluate the risk of concurrent histologically proven fatty liver in HBV hepatocarcinogenesis., Methods: We conducted a retrospective cohort study on a liver biopsy cohort of HBV-infected patients without significant alcohol intake to evaluate the prevalence of concurrent histologically proven fatty liver and its association with subsequent HCC development. We also examined nine polymorphisms on six non-alcoholic fatty liver disease-related candidate genes (ADIPOQ, APOC3, GCKR, LEPR, PNPLA3, and PPARG)., Results: Among 270 HBV-infected patients, concurrent fatty liver was found in 107 patients (39.6%) and was associated with metabolic risks, cirrhosis (P = 0.016) and PNPLA3 rs738409 CG/GG genotype (P = 0.002). At a median follow-up of 79.9 months, 11 patients (4.1%) developed HCC, and nine of them had concurrent fatty liver. By multivariable Cox analysis, concurrent fatty liver (HR 7.27, 95% confidence interval: 1.52-34.76; P = 0.013), age, cirrhosis, and APOC3 rs2854116 TC/CC genotype (HR 3.93, 95% confidence interval: 1.30-11.84; P = 0.013) were independent factors predicting HCC development., Conclusions: Concurrent fatty liver is common in HBV-infected patients and an independent risk factor potentiating HBV-associated HCC development by 7.3-fold. The risk of HBV-related HCC is increased by APOC3 gene polymorphism, and further characterization is required by its role., (© 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aim: Liver stiffness measurement using transient elastography appears to be an excellent tool for detection of liver fibrosis and cirrhosis with high accuracy. The aim of this study is to evaluate the efficacy of preoperative liver stiffness measurement in predicting post-hepatectomy liver failure., Methods: A prospective cohort study of all consecutive patients undergoing hepatectomy for hepatocellular carcinoma from February 2010 to August 2014 was studied. All patients received detailed preoperative assessments including liver stiffness measurement. The primary outcome was post-hepatectomy liver failure according to the International Study Group of Liver Surgery definition., Results: A total of 255 patients were included. Liver stiffness measurement showed significant correlation with grade B or C post-hepatectomy liver failure. (P = 0.003) Using the cutoff at 12 kPa, liver stiffness measurement had a sensitivity of 52.4% and specificity of 73.3% in predication of high-grade (grade B or C) post-hepatectomy liver failure. Liver stiffness measurement > 12 kPa was also an independent prognostic factor for both high-grade post-hepatectomy liver failure and major postoperative complications by multivariate analysis. The diagnostic accuracy was better in patients without right lobe tumor with an area under the receiver operating characteristic of 0.83 compared with an area under the receiver operating characteristic of only 0.62 in patients with right lobe tumor., Conclusions: Liver stiffness measurement using Fibroscan is good to predict high-grade post-hepatectomy liver failure especially in patients without right lobe tumor., (© 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aims: The albumin-bilirubin (ALBI) grade is a recently emerging alternative of the Child-Pugh (CP) grade. The Cancer of the Liver Italian Program (CLIP) was demonstrated to be a useful prognostic model for hepatocellular carcinoma (HCC) in large prospective cohorts. We aimed to investigate the feasibility of substituting the CP grade by the ALBI grade in the CLIP system and compare the prognostic performance with other existing staging systems., Methods: A large cohort of 1973 Chinese patients with HCC was recruited to evaluate the prognostic performance of CP-based CLIP (CP-CLIP) and ALBI-based CLIP (ALBI-CLIP) systems and nine other staging systems by homogeneity likelihood chi-square, c-index, and corrected Akaike information criterion., Results: The ALBI-CLIP system provided comparable prognostic performance than the CP-CLIP system, which was indicated by homogeneity likelihood chi-squares (ALBI-CLIP 1186.35 vs CP-CLIP 1145.54), c-indices (ALBI-CLIP 0.789 vs CP-CLIP 0.785) and AICs (ALBI-CLIP 15 493.47 vs CP-CLIP 15 534.28). Among 11 staging systems, ALBI-CLIP and CP-CLIP systems were associated with the highest homogeneity chi-squares and c-indices, and the lowest corrected Akaike information criterion. Patients in ALBI-CLIP score 0-4 had better median survival than those in corresponding CP-CLIP score., Conclusions: The ALBI grade performs as well as the CP grade when integrating into the CLIP system. ALBI-CLIP and CP-CLIP systems are the most accurate prognostic models among 11 existing staging systems., (© 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Aims: Steatosis in hepatocellular carcinoma (HCC) has been recognized for decades and found most commonly in small, well-differentiated HCC. However, the clinicopathological features and pathogenesis of HCC with steatosis is not well characterized. There are few data concerning whether HCC with steatosis should be regarded a distinct histological variant, steatotic HCC., Methods and Results: A retrospective cohort of 516 patients undergoing curative surgery for primary HCC was recruited. The median follow-up was 45.5 (range: 0.2-166.0) months. Steatotic HCC was defined as HCC with significant steatosis (≥5% of tumour cells). Associations with immunohistochemical expression of fatty acid binding protein-1 (FABP1), sonic hedgehog (SHH) and gene polymorphism of patatin-like phospholipase 3 (PNPLA3) were analysed. Steatotic HCC was found in 21.1% of patients and was associated with higher metabolic risks [diabetes mellitus (36.7% versus 18.2%) and hypertension (44.0% versus 28.7%)], underlying fatty liver (60.6% versus 37.8%), steatohepatitis (30.3% versus 13.0%), smaller tumour size, lower frequency of major vessel (1.8% versus 11.3%) and microvascular invasion (20.2% versus 32.4%), earlier tumour stages and lower serum alpha-fetoprotein. It was associated with developing late tumour relapse (hazard ratio 2.15, P = 0.002) independently of underlying cirrhosis and non-anatomical excision. Steatotic HCC did not differ from HCC without significant steatosis in immunohistochemical expression of FABP1 and SHH and PNPLA3 gene polymorphism., Conclusion: Steatotic HCC is a common histological variant of HCC with distinct association with underlying fatty liver, steatohepatitis and metabolic risks. Despite more favourable baseline tumour features, it was associated with late tumour relapse., (© 2016 John Wiley & Sons Ltd.)

Background and Aim: The Japan Integrated Staging (JIS) for hepatocellular carcinoma (HCC) has been extensively studied in hepatitis virus C-endemic Japanese population but seldom evaluated outside Japan, while albumin-bilirubin (ALBI)-based JIS (ALBI-T) has never been externally validated. We evaluate the prognostic significance of the ALBI-T score among Chinese patients with hepatitis virus B (HBV)-related HCC, and to explore its potential therapeutic application in selecting patients for appropriate treatments in addition to the Barcelona Clinic Liver Cancer (BCLC) recommendation., Methods: A cohort of 1222 HBV-associated HCC patients was evaluated to compare the prognostic performance of JIS and ALBI-T scores by homogeneity likelihood chi-square and corrected Akaike information criterion. In the subgroup analysis of each BCLC stage, Kaplan-Meier method and log-rank statistics were used to compare overall survival of patients undergoing different treatment options., Results: The ALBI-T score showed better prognostic performance than the JIS score, which were indicated by homogeneity likelihood chi-squares (ALBI-T 580.12 vs JIS 536.35) and Akaike information criteria (ALBI-T 9836.57 vs JIS 9880.23). Treatment options significantly influenced prognosis among patients of the same BCLC stage. With the use of ALBI-T score 4 as the cutoff, the current study identified that a portion of patients (14.7%, 25.2% and 28.6% of BCLC stage B, C and D, respectively) undergoing unnecessary therapy without survival advantage., Conclusions: The ALBI-T score is applicable to Chinese patients with HBV-related HCC to provide reasonable prognostic information as well as potentially helping clinicians to avoid offering non-beneficial aggressive treatments., (© 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aims: The albumin-bilirubin (ALBI) grade is a recently reported, simpler, more objective, and evidence-based alternative to the Child-Pugh (CP) score for hepatocellular carcinoma (HCC). We aimed to study whether ALBI grade could substitute for CP score in Barcelona Clinic Liver Cancer (BCLC) for HCC., Methods: An international multicentre cohort (n = 3696) was accrued to compare the prognostic performance of the CP-based and ALBI-based BCLC system, in terms of homogeneity, discriminatory ability, and monotonicity of gradients that were numerically reflected by homogeneity likelihood, linear trend chi-squares, and c-indices, respectively., Results: The ALBI grade performed as well as CP score when integrated into the BCLC staging system in terms of predicting clinical outcome of HCC regardless of regions, etiology, and treatment options. CP-based and ALBI-based BCLC systems were highly concordant with weighted kappa value of 0.917. All restaged patients showed significantly different clinical outcomes compared with their original stage classification. In particular, ALBI-based BCLC upstaged 83 (2.2%) patients from lower CP-based BC LC stages to ALBI-based BCLC stage D, whose median overall survival was only 3 months., Conclusions: The overall prognostic performance of ALBI-based and CP-based BCLC systems was similar. It also potentially allows more precise patient selection for clinical trials on systemic agents., (© 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aim: Controlled attenuation parameter (CAP) evaluated with transient elastography (FibroScan) is a recent method for non-invasive assessment of steatosis. Its usefulness in non-alcoholic fatty liver disease (NAFLD) is unknown. We prospectively investigated the performance of CAP for the diagnosis of steatosis in NAFLD, factors associated with discordances between CAP and steatosis grades, and relationships between CAP and clinical or biological parameters., Methods: All CAP examinations performed in NAFLD patients with a liver biopsy performed within 1 week of CAP measurement were included. Liver biopsies were assessed for activity and fibrosis stage, NAFLD activity score, and steatosis graded as follows: S0, steatosis < 5%; S1, 5-33%; S2, 34-66%; S3, >66%., Results: Two hundred sixty-one patients (59% male, age 56 years) from two ethnic groups were included. No patient had steatosis < 5%. The area under the receiver-operating characteristics curve of CAP for steatosis ≥S2 and S3 was 0.80 and 0.66, respectively. At a cut-off value of 310 dB/m, the sensitivity, specificity, and positive and negative predictive values for ≥S2 steatosis were 79%, 71%, 86%, and 71%, respectively. Discordance of at least one grade between CAP and steatosis was observed in 81 patients. By multivariate analysis, only steatosis S2S3 was associated with no discordance. By multivariate analysis, only BMI ≥ 30 kg/m(2) was significantly associated with CAP > 310 dB/m., Conclusion: The association of CAP with steatosis, especially in patients with non-alcoholic steatohepatitis, and with elevated BMI could be useful for the diagnosis and follow-up of NAFLD patients., (© 2015 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aims: The BALAD score is developed to provide an objective determination of prognosis for hepatocellular carcinoma (HCC) by incorporating five serum markers, namely albumin, bilirubin, alpha-fetoprotein (AFP), agglutinin-reactive alpha-fetoprotein (AFP-L3), and des-γ-carboxy prothrombin. We aim to study the applicability of BALAD score and prognostication of the three tumor markers in hepatitis B virus-related HCC., Methods: Patients with newly diagnosed HCC were prospectively enrolled. All of the baseline characteristics and serum albumin and bilirubin level were documented at baseline. The levels of the three tumor markers (AFP, AFP-L3, and des-γ-carboxy prothrombin) were determined in archival serum samples. Patients were followed up for survivals according to local practice. The prognostic performances of the three markers and BALAD score were studied in association with overall survival (OS)., Results: A total of 198 patients with hepatitis B-related HCC were recruited. AFP and AFP-L3 levels were independent prognostic factors. The number of elevated tumor markers was also predictive of worse OS. BALAD score could stratify the cohort into different patient groups with distinct median OS. The median OS of BALAD score of 0, 1, 2, 3, and 4 was not reached, 26.6, 8.3, 2.6, and 1.9 months, respectively (P < 0.0001). BALAD score could further stratify outcomes in each Barcelona Clinic Liver Cancer (BCLC) subgroup. In particular, BALAD score of 3-4 had median OS of 2.6 months only in BCLC stage C patients., Conclusion: BALAD score is applicable in the population of hepatitis B virus-related HCC. The combined use of BALAD score and BCLC staging system could help identify more suitable candidates for clinical trial., (© 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Background and Aim: Serum albumin and bilirubin are the most significant independent prognostic factors to predict hepatic events in patients with primary biliary cirrhosis (PBC). We aimed to investigate the prognostic significance of a new prognostic score, the albumin-bilirubin (ALBI) score, among PBC patients., Methods: In a retrospective longitudinal cohort of 61 Chinese PBC patients with follow-up period up to 18.3 years, the prognostic performance of the ALBI in prediction of hepatic events was compared with other well-established prognostic scores: Child-Pugh score, model of end-stage liver disease, Mayo risk score, Yale, European, and Newcastle models., Results: Fifteen patients (24.6%) developed hepatic events during follow-up. The c-index (0.894) and χ(2) by likelihood ratio test (36.34) of the ALBI score were highest in comparison to other models. The ALBI score was the only independent prognostic factor by multivariate analysis and its adjusted hazard ratio of developing hepatic event was 27.8 (P < 0.001). There were three prognostically different groups stratified by the ALBI score: ALBI grade 1 (≤ -2.60), grade 2 (> -2.60 to -1.39), and grade 3 (> -1.39) groups. The 2-, 5-, and 10-year event-free survivals for grade 1, grade 2, and grade 3 groups were 100.0% versus 100.0% versus 57.1%, 100.0% versus 88.5% versus 14.3%, and 100.0% versus 81.7% versus 0.0%, respectively (P < 0.001)., Conclusion: The ALBI score is readily derived from a blood test without using those factors evaluated subjectively or obtained by invasive procedures. It is an independent prognostic factor for PBC patients and provides better/similar prognostic performance compared with other prognostic scores., (© 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Background/aims: Interleukin-28B (IL28B) and patatin-like phospholipase domain containing 3 (PNPLA3) gene polymorphisms are associated with hepatitis C virus (HCV) clearance and fatty liver, respectively. We aimed to test if their polymorphisms are associated with virologic responses in Chinese chronic hepatitis C (CHC) patients., Methods: This was a retrospective-prospective cohort study. Consecutive patients infected by genotype 1 and 6 HCV received antiviral therapy were included. Host IL-28B rs12979860/rs8099917 and PNPLA3 rs738409 genotype were tested. The primary outcome was sustained virologic response (sustained virologic response [SVR]: undetectable HCV RNA 24 weeks post-treatment)., Results: From 305 patients had positive antibody to HCV, 52 and 31 patients infected by genotype 1 and 6 HCV, respectively were recruited. Mean age was 58 ± 11 years; 70% were male. Mean baseline HCV RNA was 6.8 ± 2.7 log IU/ml. The SVR for patients infected by genotype 1 and 6 HCV was 67.3% and 90.3%, respectively. The proportions of IL28B genotypes were 78%, 21%, and 1% for TT/TG/GG at rs8099917, and 81%, 18%, and 1% for CC/TC/TT at rs12979860, respectively. The proportions of PNPLA3 rs738409 genotypes were 16%, 36%, and 48% for GG/GC/CC. IL28B genotype was significantly associated with SVR in patients infected by genotype 1 but not genotype 6 HCV, with 80% versus 38% of patients infected by genotype 1 achieved SVR carried TT versus TG/GG at rs8099917, respectively (P=0.003). PNPLA3 genotype was not associated with SVR., Conclusions: IL28B gene with rs8099917 T allele as an independent predictor of SVR in Chinese CHC patients infected by genotype 1 but not genotype 6 HCV., (© 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Aims: Lymphoepithelioma-like cholangiocarcinoma (LELCC) is a rare variant of intrahepatic cholangiocarcinoma (IHCC). Only 16 cases have reported previously in the literature, and about 62.5% of these cases were associated with Epstein-Barr virus (EBV)., Methods and Results: We present the largest series (seven cases) of LELCC with descriptions of clinical and pathological characteristics, investigations of aberrant DNA methylation and mutation analyses of EGFR and KRAS. The evaluation also included 11 cases of stage-matched conventional IHCC for comparison., Results: All seven patients of LELCC were female and had stage I disease. LELCC had significantly better 2- and 5-year overall survival than IHCC (100% versus 52.8%, and 100% versus 13.2%, respectively, P = 0.003). All seven LELCCs were EBV-associated and composed exclusively of adenocarcinoma with varied glandular differentiation, dense lymphoplasmacytic infiltrate, and variable expression of biliary-type cytokeratins (CK7 and CK19) and stemness markers (CD133 and EpCAM). Gene hypermethylation was more frequent in LELCC than IHCC. CRBPI (85.7% versus 9.1%, P < 0.003) and CRBPIV (85.7% versus 0%, P < 0.001) showed statistically higher methylation frequencies in LELCC than IHCC. No LELCC harboured any EGFR or KRAS mutation., Conclusion: Epstein-Barr virus-associated LELCC is a variant of IHCC, characterized by marked female predominance, favourable overall survival and distinctively frequent DNA hypermethylation., (© 2014 John Wiley & Sons Ltd.)

Aims: A new Japanese histological staging system for primary biliary cirrhosis (PBC) has been proposed. We aimed to evaluate the efficacies of the Scheuer, Ludwig and Japanese staging systems, with emphasis on their clinical and biochemical correlations and prognostic significances., Methods and Results: We conducted a retrospective review of a cohort of 58 Chinese PBC patients, with follow-up of up to 16.9 years. All three systems correlated well with prognostically significant parameters, namely serum bilirubin, Mayo scores and model for end-stage liver disease (MELD) score. Only the Japanese staging system was associated with Child-Pugh score, which was the single independent prognostic factor for liver-related events (log-rank P < 0.001; Cox proportional hazard ratio (HR) 6.723, P < 0.001). The Japanese system (log-rank P = 0.007; Cox proportional HR 10.400, P = 0.025) predicted liver-related events, while Scheuer (log-rank P = 0.112) and Ludwig (log-rank P = 0.147) systems did not. The copper-associated protein (CAP) deposition score, a component of the Japanese system, was the most powerful histological prognostic parameter (log-rank P < 0.001; Cox proportional HR 99.534, P = 0.049) and provided extra prognostic values in additional to serum albumin, serum bilirubin, Child-Pugh score, Mayo scores and MELD score., Conclusion: The Japanese staging system is more effective than classical systems. The degree of CAP deposition is an essential prognostic histological parameter., (© 2014 John Wiley & Sons Ltd.)

Aims: The expression of stemness markers in hepatocellular carcinoma (HCC) is suggested to be associated with poor clinical outcome after surgical resection. There are few data on their independent prognostic role in addition to the existing AJCC TNM staging system., Methods and Results: The immunohistochemical expression of CD133, EpCAM, CK19 and CD56 was studied in a cohort of 282 surgical specimens collected from patients undergoing resection of primary HCC. CD133-positive HCCs were usually smaller in size (P = 0.002) and arose more frequently in cirrhotic liver (P = 0.002). CD133 expression was an independent prognostic factor for overall survival (hazard ratio 2.30, P < 0.001), and a highly potent prognostic factor in patients with stage I disease (hazard ratio 3.91, P = 0.001). EpCAM expression was associated with younger age (P < 0.001), smaller tumour size (P = 0.018) and poorer histological differentiation (P = 0.042). EpCAM immunoreactivity was an independent factor for disease-free survival in HCCs at all stages (hazard ratio 2.05, P = 0.001), stage II (hazard ratio 3.66, P = 0.010) and stages III/IV (hazard ratio 3.22, P = 0.001). Neither CK19 nor CD56 offered any independent prognostic value., Conclusion: The prognostic role of CD133 was most significant in TNM stage I disease, while the prognostic role of EpCAM was more apparent in more advanced TNM stages., (© 2013 John Wiley & Sons Ltd.)

Background and Aims: Non-alcoholic steatohepatitis (NASH) is a common liver disease that may progress to cirrhosis and hepatocellular carcinoma. There is currently no approved pharmacological treatment for NASH. Phyllanthus urinaria is a commonly used hepatoprotective herb that ameliorates NASH in animal studies. We aimed to test the hypothesis that Phyllanthus was superior to placebo in improving histological non-alcoholic fatty liver disease (NAFLD) activity score., Methods: This was a placebo-controlled parallel-group double-blind randomized controlled trial. Patients with histology-proven NASH were randomized to receive Phyllanthus or placebo for 24 weeks. The primary endpoint was change in NAFLD activity score from baseline to week 24. Secondary endpoints included changes in individual histological parameters, liver biochemistry and metabolic profile., Results: We enrolled 60 patients (40 received Phyllanthus and 20 received placebo). The change in NAFLD activity score was -0.8 ± 1.4 in the Phyllanthus group and -0.3 ± 1.3 in the placebo group (P = 0.24). The change in steatosis, lobular inflammation, ballooning and fibrosis was also similar between the two groups. Within the Phyllanthus group, although there was reduction in hepatic steatosis (-0.2 ± 0.7; P = 0.039) and ballooning grades (-0.4 ± 0.5; P < 0.001), the change was small and of limited clinical significance. Furthermore, there was no significant difference in the changes in alanine aminotransferase, aspartate aminotransferase, fasting glucose and lipid profile between the two groups., Conclusions: Phyllanthus is not superior to placebo in improving NAFLD activity score in NASH patients., (© 2012 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Background and Aims: The proposed cut-off values for the degree of fibrosis as assessed by liver stiffness measurement (LSM) might not be applicable in severe acute exacerbation of chronic hepatitis B (CHB). We aimed to assess the effect of necroinflammatory activity on LSM in this condition., Methods: We prospectively recruited consecutive patients with severe acute exacerbation of CHB (alanine aminotransferase or ALT > 10x upper limit of normal). The relationship of ALT levels and LSM were serially assessed and liver biopsy was carried out after ALT normalization., Results: Eleven patients (10 male, median age 43 years) were followed up for 25 weeks; nine patients received antiviral therapy. Overall, LSM was positively correlated with ALT levels (r = 0.67, P < 0.001). At initial presentation, the median serum ALT and LSM was 1136 (581-2210) IU/L and 26.3 (11.1-33.3) kPa. A progressive reduction in LSM was observed during subsequent visits in parallel with the reduction of ALT levels. At the last visit, the median ALT was 27 (11-52) IU/L and LSM was 7.7 (4.7-10.8) kPa. Among the five patients who had liver biopsy carried out at week 25, four patients had F2 fibrosis (LSM 5.7-8.1 kPa) and one patient had F3 fibrosis (LSM 8.6 kPa)., Conclusions: LSM using transient elastography with the current proposed cut-off values might misdiagnose liver cirrhosis in patients suffering from severe acute exacerbation of CHB. LSM should be assessed after normalization of ALT levels in order to accurately assess the degree of fibrosis.

The aim of this study is to know the liver stiffness measurement (LSM) cutoffs for different stages of liver fibrosis in chronic hepatitis B (CHB) and to investigate the effect of alanine aminotransferase (ALT) on LSM. We prospectively studied consecutive CHB patients undergoing liver biopsy and transient elastography examinations. Diagnostic performance of LSM for different degrees of liver fibrosis was evaluated. One hundred and sixty-one CHB patients with adequate liver biopsy sample size were studied. Area under receiver operating characteristics curves of LSM for no fibrosis (F0 vs F1-4), bridging fibrosis (F0-2 vs F3-4) and liver cirrhosis (F0-3 vs F4) was 0.80 (95% CI: 0.68-0.92), 0.87 (95% CI: 0.82-0.93) and 0.93 (95% CI: 0.89-0.97) respectively. For liver cirrhosis, these optimal cutoff values were 8.4 kPa (98% sensitivity), 9.0 kPa (maximum sum of sensitivity and specificity), 13.4 kPa (94% specificity) and 13.4 kPa (maximum diagnostic accuracy, 85%) respectively. Patients with the same fibrosis staging but higher ALT levels tend to have higher LSM, and the diagnostic performance for low stage fibrosis was most seriously affected when ALT was elevated. Different LSM cutoff values and algorithms were derived for normal and elevated ALT levels. Based on these algorithms, liver biopsy can be avoided in 62% and 58% of patients with normal and elevated ALT respectively. In conclusion, transient elastography is a reasonable noninvasive tool to substitute liver biopsy among the lowest and highest risk patients for the assessment of liver fibrosis.

Background and Aim: Hypoadiponectinemia and high tumor necrosis factor-alpha (TNF-alpha) levels are associated with the development of nonalcoholic fatty liver disease (NAFLD). This study aimed to investigate the genetic polymorphisms of adiponectin and TNF-alpha in Chinese NAFLD patients and their association with disease severity., Methods: Seventy-nine patients with histology-proven NAFLD (61 with simple steatosis and 18 with stage 2-4 fibrosis) and 40 controls were tested for the nucleotide polymorphisms at adiponectin -11 391, -11 377, +45, and +276 and TNF-alpha promoters -863, -308, and -238., Results: There was no significant deviation in the adiponectin and TNF-alpha gene polymorphisms between NAFLD patients and controls, or between patients with simple steatosis and those with stage 2-4 fibrosis. NAFLD patients with -11377G and +45G at the adiponectin gene were more likely to have hypertriglyceridemia. On multivariate analysis, older age, higher body mass index, and higher fasting glucose were independent factors associated with stage 2-4 fibrosis in NAFLD patients., Conclusions: Adiponectin and TNF-alpha gene polymorphisms were not shown to be associated with NAFLD or significant fibrosis in Chinese people. The adiponectin -11377G and +45G alleles were associated with hypertriglyceridemia in NAFLD patients. Since the current study is not adequately powered to detect smaller differences in allele frequencies, larger-sized studies in different ethnic groups are required.

Aim: This paper reports a study to examine Chinese older people's perceptions of privacy in residential care homes., Background: With increasing numbers of older people moving into residential care homes in Hong Kong, the emphasis on providing high quality of care is paramount. Yet, studies have identified the poor quality of psychosocial care provided in these homes, particularly the lack of attention given to promoting a sense of privacy. While privacy is a fundamental principle of gerontological care, little is known older people's perceptions of privacy in residential care practices. This lack of understanding makes it difficult to know how to provide appropriate care to this population., Method: A descriptive qualitative study was conducted in 2005 with a purposive sample of 20 informants from four residential care homes in Hong Kong. In-depth interviews were used to collect the data, which were analysed using content analysis., Results: Most informants perceived that privacy was unnecessary and not a pre-requisite in residential living. They had seemingly accepted the expectations of home life, with its emphasis on unity, harmony and meeting the collective needs of the majority rather than focusing on their individual needs. Informants also described the enjoyment of communal living and 'living together'. While at first privacy was perceived as not necessary, further prompting identified that informants used own efforts to support their privacy. There were also day-to-day circumstances/activities in homes where privacy was violated., Conclusion: The emphasis in Chinese culture on the importance of maintaining balance and harmony inevitably shaped participants' perceptions of what privacy meant to them. The findings will inform the development of culturally-sensitive care practices to support Chinese older people's privacy in residential care settings.

Background: Asthmatic inflammation is mediated by a network of cytokines, chemokines and adhesion molecules. Corticosteroids are the only effective agents available to control asthmatic inflammation. We investigated the effect of high-dose montelukast (MK), a selective cysteinyl leukotriene receptor 1 antagonist, on mediators of airway inflammation., Objective: The aim of this study was to determine the effect of a 3-day course of high-dose MK on mediators of airway inflammation induced by a single allergen challenge in sensitized mice., Methods: Ovalbumin (OVA)-sensitized BALB/c mice were treated with 25 mg/kg of MK or saline intravenously for 3 days. On the third day, a single inhalation challenge with OVA was given. Cellular infiltration was assessed in the bronchoalveolar lavage (BAL) and in the lung. Expression of IL-4, IL-5, IL-13 and eotaxin in the BAL, and the lung was determined. Serum IL-5 and total IgE was measured. IL-5 and eotaxin mRNA expression in the lung was determined. Finally, eotaxin and VACM-1 expression in the lung was assessed by immunohistochemistry., Results: MK reduced the number of eosinophils in the BAL by > 90%. There was also significant reduction in IL-5 in the BAL, lung and the serum, and IL-5 mRNA expression in the lung. IL-4 level in the lung and BAL, and IL-13 level in the lung also significantly decreased. Serum IgE level and lung VCAM-1 expression was also significantly lower in treated animals, but eotaxin protein and mRNA expression in the lung remained unchanged., Conclusion: MK exerts its anti-inflammatory effect through the suppression of T helper type-2 (Th2) cytokines. The use of high-dose MK as an anti-inflammatory agent in acute asthma should be further explored.

The purpose of this study was to determine the effects of hand instrumentation using traditional stainless steel K-files and nickel-titanium K-files on the final shape of curved root canals. A total of 24 moderately curved canals in the mesial roots in extracted human mandibular first molars were randomly divided into two groups. These were instrumented manually using either stainless steel or nickel-titanium, K-files with the stepdown technique. The cross-sectional shape of each canal at three different horizontal levels were captured, before and after instrumentation, into a computer for comparison using image analyser software. Three parameters at each level were evaluated: (i) amount of dentine removed; (ii) least remaining dentine thicknesses on mesial and furcal aspects; and (iii) the amount and direction of canal transportation. The results showed that the two file types removed similar amounts of dentine at all three levels examined. The nickel-titanium files left a thicker layer of dentine on both the mesial and furcal aspects than stainless steel files. However, the difference was not significant (pooled T-test, P > 0.05). Both types of files transported the centre of the canals but the nickel-titanium instrument seemed to be safer because of the reduced amount of transportation towards the danger areas.