Anthony W.H. Chan

Universals and cultural differences in the judgments of facial expressions of emotion.

We present here new evidence of cross-cultural agreement in the judgement of facial expression. Subjects in 10 cultures performed a more complex judgment task than has been used in previous cross-cultural studies. Instead of limiting the subjects to selecting only one emotion term for each expression, this task allowed them to indicate that multiple emotions were evident and the intensity of each emotion. Agreement was very high across cultures about which emotion was the most intense. The 10 cultures also agreed about the second most intense emotion signaled by an expression and about the relative intensity among expressions of the same emotion. However, cultural differences were found in judgments of the absolute level of emotional intensity.

Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in affluent countries. Accurate noninvasive tests for liver injury are urgently needed. The aim of this study was to evaluate the accuracy of transient elastography for the diagnosis of fibrosis and cirrhosis in patients with NAFLD and to study factors associated with discordance between transient elastography and histology. Two hundred forty‐six consecutive patients from two ethnic groups had successful liver stiffness measurement and satisfactory liver biopsy specimens. The area under the receiver‐operating characteristics curve (AUROC) of transient elastography for F3 or higher and F4 disease was 0.93 and 0.95, respectively, and was significantly higher than that of the aspartate aminotransferase–to–alanine aminotransferase ratio, aspartate aminotransferase–to–platelet ratio index, FIB‐4, BARD, and NAFLD fibrosis scores (AUROC ranged from 0.62 to 0.81, P < 0.05 for all comparisons). At a cutoff value of 7.9 kPa, the sensitivity, specificity, and positive and negative predictive values for F3 or greater disease were 91%, 75%, 52%, and 97%, respectively. Liver stiffness was not affected by hepatic steatosis, necroinflammation, or body mass index. Discordance of at least two stages between transient elastography and histology was observed in 33 (13.4%) patients. By multivariate analysis, liver biopsy length less than 20 mm and F0‐2 disease were associated with discordance. Conclusion: Transient elastography is accurate in most NAFLD patients. Unsatisfactory liver biopsy specimens rather than transient elastography technique account for most cases of discordance. With high negative predictive value and modest positive predictive value, transient elastography is useful as a screening test to exclude advanced fibrosis. Liver biopsy may be considered in NAFLD patients with liver stiffness of at least 7.9 kPa. (HEPATOLOGY 2010;51:454–462.)

Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years

Background Patients with non-alcoholic steatohepatitis (NASH) have increased mortality and liver-related complications. In contrast, simple steatosis is considered benign and non-progressive. Objective To investigate disease progression in patients with different degrees of non-alcoholic fatty liver disease (NAFLD) activity. Design Prospective longitudinal hospital-based cohort study. Patients Fifty-two patients (age 44±9 years) with biopsy-proven NAFLD had liver biopsies repeated at month 36. Results Among 13 patients with simple steatosis at baseline, 2 (15%) had a normal liver at month 36, 3 (23%) continued to have simple steatosis, 5 (39%) developed borderline NASH and 3 (23%) developed NASH. Among 22 patients with borderline NASH at baseline, 4 (18%) had simple steatosis and 13 (59%) had borderline NASH at month 36, while 5 (23%) developed NASH. Among 17 patients with NASH at baseline, 10 (59%) continued to have NASH and 6 (35%) had borderline NASH at month 36. Only 1 (6%) patient regressed to simple steatosis. Overall, 14 (27%) patients had fibrosis progression, 25 (48%) had static disease, and 13 (25%) had fibrosis regression. Reduction in body mass index and waist circumference was independently associated with non-progressive disease activity and fibrosis. The baseline serum levels and month 36 changes in adiponectin, tumour necrosis factor α, interleukin 6 and leptin were not associated with disease progression. Serum cytokeratin-18 fragment level reflected disease activity and its change correlated with the change in NAFLD activity score (R=0.51, p<0.001). Conclusions Patients with simple steatosis may still develop NASH and fibrosis progression. Weight reduction is associated with non-progressive disease. All patients with NAFLD should undergo periodic assessment and lifestyle modification.

Liver stiffness measurement using XL probe in patients with nonalcoholic fatty liver disease.

OBJECTIVES:Liver stiffness measurement (LSM) by transient elastography is a noninvasive test of liver fibrosis, but cannot be performed in a significant proportion of obese patients. The aim of this study was to evaluate the performance of the new XL probe in patients with nonalcoholic fatty liver disease (NAFLD).METHODS:Liver biopsy and paired LSM by both the original M probe and XL probe were performed on 193 consecutive NAFLD patients in France and Hong Kong.RESULTS:Compared with M probe, XL probe was more likely to achieve 10 valid measurements (95% vs. 81%; P<0.001) and a success rate of over 60% (90% vs. 74%; P<0.001). The areas under receiver operating characteristics curves of XL probe for F2, F3, and F4 disease were 0.80, 0.85, and 0.91, respectively. XL probe tended to generate lower LSM than M probe in the same patient. At a cutoff of 7.2 kPa, the sensitivity, specificity, positive, and negative predictive values for F3 or greater disease were 78%, 78%, 60%, and 89%, respectively. Discordance of at least two stages between XL probe and histology was observed in 16 (9%) patients. Body mass index (BMI) over 35 kg/m2 was independently associated with discordance (adjusted odds ratio 9.09; 95% confidence interval 1.10–75.43). Reliable measurements by XL probe were obtained in 75% of the overall population and 65% of patients with BMI over 30 kg/m2.CONCLUSIONS:LSM by XL probe can be performed successfully in most NAFLD patients, but obesity is associated with less accurate and reliable measurements.

Viral-Human Chimeric Transcript Predisposes Risk to Liver Cancer Development and Progression

The mutagenic effect of hepatitis B (HBV) integration in predisposing risk to hepatocellular carcinoma (HCC) remains elusive. In this study, we performed transcriptome sequencing of HBV-positive HCC cell lines and showed transcription of viral-human gene fusions from the site of genome integrations. We discovered tumor-promoting properties of a chimeric HBx-LINE1 that, intriguingly, functions as a hybrid RNA. HBx-LINE1 can be detected in 23.3% of HBV-associated HCC tumors and correlates with poorer patient survival. HBx-LINE1 transgenic mice showed heightened susceptibility to diethylnitrosamine-induced tumor formation. We further show that HBx-LINE1 expression affects β-catenin transactivity, which underlines a role in activating Wnt signaling. Thus, this study identifies a viral-human chimeric fusion transcript that functions like a long noncoding RNA to promote HCC.

Assessment of Fibrosis by Transient Elastography Compared With Liver Biopsy and Morphometry in Chronic Liver Diseases

BACKGROUND & AIMS Liver stiffness measurement (LSM) with transient elastography (Fibroscan) can accurately diagnose advanced liver fibrosis, but its performance in early liver fibrosis is less satisfactory. We aimed to study the diagnostic performance of LSM for histologic bridging fibrosis and cirrhosis in various chronic liver diseases and to investigate the effects of liver fibrosis distribution on LSM. METHODS We prospectively studied consecutive patients with chronic liver diseases undergoing liver biopsy and transient elastography examinations. Morphometric analysis was performed to evaluate the distribution of liver fibrosis. RESULTS One hundred thirty-three patients (50% chronic hepatitis B, 14% chronic hepatitis C, and 24% nonalcoholic fatty liver disease) were studied. Morphometric analysis revealed a higher correlation between LSM and pericellular fibrosis (r = 0.43) than periportal (r = 0.21) or perivenular fibrosis (r = 0.25). Area under receiver operating characteristic curve (ROC) of LSM for bridging fibrosis was 0.87 (95% confidence interval, 0.81-0.93) and for cirrhosis was 0.89 (95% confidence interval, 0.83-0.94). Higher LSM was associated with higher serum ALT level. Patients with the same fibrosis staging but higher ALT levels tend to have higher LSM. The area under ROC curve of LSM for cirrhosis was lower among patients who had ALT above the upper limit of normal (0.86) as compared with that of patients with normal ALT levels (0.93, P = .03). CONCLUSIONS Transient elastography can diagnose severe fibrosis because of its good correlation with pericellular fibrosis. Transient elastography might overestimate liver fibrosis when ALT is elevated.

High prevalence of colorectal neoplasm in patients with non-alcoholic steatohepatitis

Objective Non-alcoholic fatty liver disease (NAFLD) affects 20–40% of the general adult population. Due to shared risk factors, it is postulated that NAFLD patients have an increased risk of colorectal neoplasm and should be a target group for screening. The aim of this study was to examine the prevalence of colorectal neoplasm in NAFLD patients and the risk of colorectal neoplasm in relation to the severity of NAFLD histology. Design Cross-sectional study. Setting University hospital with case recruitment from the community and clinics. Patients Subjects aged 40–70 years were recruited for colonoscopic screening from two study cohorts: (1) community subjects; and (2) consecutive patients with biopsy proven NAFLD. In the community cohort, hepatic fat was measured by proton-magnetic resonance spectroscopy. Main outcome measures Prevalence of colorectal adenomas. Advanced colorectal neoplasm was defined as cancer or adenomas with villous architecture or high grade dysplasia. Results NAFLD patients (N=199) had a higher prevalence of colorectal adenomas (34.7% vs 21.5%; p=0.043) and advanced neoplasms (18.6% vs 5.5%; p=0.002) than healthy controls (N=181). Thirteen of 29 (45%) NAFLD patients with advanced neoplasms had isolated lesions in the right sided colon. Among patients with biopsy proven NAFLD, patients with non-alcoholic steatohepatitis (N=49) had a higher prevalence of adenomas (51.0% vs 25.6%; p=0.005) and advanced neoplasms (34.7% vs 14.0%; p=0.011) than those with simple steatosis (N=86). After adjusting for demographic and metabolic factors, non-alcoholic steatohepatitis remained associated with adenomas (adjusted OR 4.89, 95% CI 2.04 to 11.70) and advanced neoplasms (OR 5.34, 95% CI 1.92 to 14.84). In contrast, the prevalence of adenomas and advanced neoplasms was similar between patients with simple steatosis and control subjects. Conclusions Non-alcoholic steatohepatitis is associated with a high prevalence of colorectal adenomas and advanced neoplasms. The adenomas are found more commonly in the right sided colon. Colorectal cancer screening is strongly indicated in this high risk group.

Quantitative Elastography of Liver Fibrosis and Spleen Stiffness in Chronic Hepatitis B Carriers: Comparison of Shear-Wave Elastography and Transient Elastography with Liver Biopsy Correlation

PURPOSE To document utility of shear-wave (SW) elastography for assessing liver fibrosis in chronic hepatitis B and to compare its performance with that of transient elastography. MATERIALS AND METHODS Ethics committee approved the study, and informed consent was obtained. Patients with liver biopsy correlation (n = 226) and healthy patients (n = 171) were analyzed. Results of SW elastography of liver, SW elastography of spleen, and transient elastography of liver were compared and correlated according to METAVIR scores. Areas under the receiver operating characteristic curve (AUCs), binary logistic regression, and Delong test were used. RESULTS AUC for SW elastography of liver, transient elastography of liver, and SW elastography of spleen was, respectively, 0.86, 0.80, and 0.81 for fibrosis (≥ F1 stage); 0.88, 0.78, and 0.82 for moderate fibrosis (≥ F2 stage); 0.93, 0.83, and 0.83 for severe fibrosis (≥ F3 stage); and 0.98, 0.92, and 0.84 for cirrhosis (F4 stage). SW elastography of liver showed significantly higher accuracy than transient elastography of liver and SW elastography of spleen in all fibrosis stages (P = .01-.04). SW elastography of spleen showed similar accuracy with transient elastography of liver (P = .21-.99). Combination SW elastography of liver and SW elastography of spleen to predict fibrosis staging showed diagnostic accuracy not further improved compared with SW elastography of liver alone (similar AUC; ≥ F1, P = .87; ≥ F2, P = .81; ≥ F3, P = .84; ≥ F4, P = .88). SW elastography of liver had higher successful rate than transient elastography of liver (98.9% vs 89.6%). Prevalence of discordance in at least two stages with liver histologic staging was 10.2% (23 of 226) for SW elastography of liver and 28.2% (58 of 206) for SW elastography of spleen. CONCLUSION SW elastography provides more accurate correlation of liver elasticity with liver fibrosis stage compared with transient elastography, especially in identification of stage F2 or greater.

Non-invasive diagnosis of non-alcoholic steatohepatitis by combined serum biomarkers.

BACKGROUND & AIMS The diagnosis of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is limited by the need for liver biopsy. We aimed at testing the accuracy of cytokeratin-18 fragment (CK-18), adipocyte fatty acid binding protein (AFABP) and fibroblast growth factor 21 (FGF21) for the diagnosis of NAFLD and NASH. METHODS 146 patients with biopsy-proven NAFLD and 74 age- and gender-matched healthy controls were included. Serum CK-18, AFABP and FGF21 levels were determined by enzyme-linked immunosorbent assay. RESULTS Serum CK-18, AFABP, and FGF21 increased in a stepwise fashion in control subjects (median 103 U/L, 15.4 ng/ml, and 104 pg/ml), patients with non-NASH NAFLD (263 U/L, 18.9 ng/ml, and 249 pg/ml) and NASH (418 U/L, 19.4 ng/ml, and 354 pg/ml) (p<0.001, 0.060, and 0.016, respectively). The area under receiver-operating characteristics curve to diagnose NAFLD and NASH was 0.91 and 0.70 for CK-18, 0.66 and 0.59 for AFABP, and 0.84 and 0.62 for FGF21. At cut-offs of 203 and 670 U/L, CK-18 had 71% negative predictive value (NPV) and 77% positive predictive value (PPV) to exclude and diagnose NASH. A 2-step approach measuring CK-18 followed by FGF21 further improved the NPV to 74% and PPV to 82%. In a validation cohort of 51 patients with paired liver biopsies, the NPV and PPV of the 2-step approach were 67% and 78%, respectively. CONCLUSIONS CK-18 is the most accurate biomarker for NAFLD and NASH. A two-step approach using CK-18 and FGF21 further improves the accuracy in diagnosing NASH.

Epigenetic Therapy Using Belinostat for Patients With Unresectable Hepatocellular Carcinoma: A Multicenter Phase I/II Study With Biomarker and Pharmacokinetic Analysis of Tumors From Patients in the Mayo Phase II Consortium and the Cancer Therapeutics Research Group

PURPOSE Epigenetic aberrations have been reported in hepatocellular carcinoma (HCC). In this study of patients with unresectable HCC and chronic liver disease, epigenetic therapy with the histone deacetylase inhibitor belinostat was assessed. The objectives were to determine dose-limiting toxicity and maximum-tolerated dose (MTD), to assess pharmacokinetics in phase I, and to assess activity of and explore potential biomarkers for response in phase II. PATIENTS AND METHODS Major eligibility criteria included histologically confirmed unresectable HCC, European Cooperative Oncology Group performance score ≤ 2, and adequate organ function. Phase I consisted of 18 patients; belinostat was given intravenously once per day on days 1 to 5 every 3 weeks; dose levels were 600 mg/m(2) per day (level 1), 900 mg/m(2) per day (level 2), 1,200 mg/m(2) per day (level 3), and 1,400 mg/m(2) per day (level 4). Phase II consisted of 42 patients. The primary end point was progression-free survival (PFS), and the main secondary end points were response according to Response Evaluation Criteria in Solid Tumors (RECIST) and overall survival (OS). Exploratory analysis was conducted on pretreatment tumor tissues to determine whether HR23B expression is a potential biomarker for response. RESULTS Belinostat pharmacokinetics were linear from 600 to 1,400 mg/m(2) without significant accumulation. The MTD was not reached at the maximum dose administered. Dose level 4 was used in phase II. The median number of cycles was two (range, one to 12). The partial response (PR) and stable disease (SD) rates were 2.4% and 45.2%, respectively. The median PFS and OS were 2.64 and 6.60 months, respectively. Exploratory analysis revealed that disease stabilization rate (complete response plus PR plus SD) in tumors having high and low HR23B histoscores were 58% and 14%, respectively (P = .036). CONCLUSION Epigenetic therapy with belinostat demonstrates tumor stabilization and is generally well-tolerated. HR23B expression was associated with disease stabilization.