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Background: Early screening may prevent fibrosis progression in metabolic-associated fatty liver disease (MAFLD)., Aims: We developed and validated MAFLD fibrosis score (MFS) for identifying advanced fibrosis (≥F3) among MAFLD patients., Methods: This cross-sectional, multicentre study consecutively recruited MAFLD patients receiving tertiary care (Malaysia as training cohort [n = 276] and Hong Kong and Wenzhou as validation cohort [n = 431]). Patients completed liver biopsy, vibration-controlled transient elastography (VCTE), and clinical and laboratory assessment within 1 week. We used machine learning to select 'highly important' predictors of advanced fibrosis, followed by backward stepwise regression to construct MFS formula., Results: MFS was composed of seven variables: age, body mass index, international normalised ratio, aspartate aminotransferase, gamma-glutamyl transpeptidase, platelet count, and history of type 2 diabetes. MFS demonstrated an area under the receiver-operating characteristic curve of 0.848 [95% CI 0.800-898] and 0.823 [0.760-0.886] in training and validation cohorts, significantly higher than aminotransferase-to-platelet ratio index (0.684 [0.603-0.765], 0.663 [0.588-0.738]), Fibrosis-4 index (0.793 [0.735-0.854], 0.737 [0.660-0.814]), and non-alcoholic fatty liver disease fibrosis score (0.785 [0.731-0.844], 0.750 [0.674-0.827]) (DeLong's test p < 0.05). MFS could include 92.3% of patients using dual cut-offs of 14 and 15, with a correct prediction rate of 90.4%, resulting in a larger number of patients with correct diagnosis compared to other scores. A two-step MFS-VCTE screening algorithm demonstrated positive and negative predictive values and overall diagnostic accuracy of 93.4%, 89.5%, and 93.2%, respectively, with only 4.0% of patients classified into grey zone., Conclusion: MFS outperforms conventional non-invasive scores in predicting advanced fibrosis, contributing to screening in MAFLD patients., (© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: There are limited data on the long-term adverse clinical outcomes of adults with metabolic dysfunction-associated fatty liver disease (MAFLD)., Methods: This is a single-centre prospective study of a well-characterized cohort of MAFLD patients who underwent liver biopsy and followed every 6-12 months for adverse clinical outcomes., Results: The data for 202 patients were analyzed [median age 55.0 (48.0-61.3) years old; male, 47.5%; obese, 88.6%; diabetes mellitus, 71.3%; steatohepatitis, 76.7%; advanced fibrosis, 27.2%]. The median follow-up interval was 7 (4-8) years. The cumulative incidence of liver-related events, cardiovascular events, malignancy and mortality was 0.43, 2.03, 0.60 and 0.60 per 100 person-years of follow-up, respectively. Liver-related events were only seen in patient with advanced fibrosis at 9.1% vs 0% in patient without advanced liver fibrosis (p < 0.001). The cumulative incidence of liver-related events among patients with advanced fibrosis was 1.67 per 100 person-years of follow-up. When further stratified to bridging fibrosis and cirrhosis, the cumulative incidence of liver-related events was 1.47 and 3.85 per 100 person-years of follow-up, respectively. Advanced fibrosis was not significantly associated with cardiovascular events, malignancy or mortality. The cumulative incidence of liver-related events, cardiovascular events, malignancy and mortality were not significantly different between patients with and without steatohepatitis and between obese and non-obese patients. However, liver-related events were only seen among obese patients., Conclusion: Overall, the cumulative incidence of liver-related event is low in patients with MAFLD, but it is much higher among those with advanced fibrosis. However, there is a relatively high cumulative incidence of cardiovascular event among patients with MAFLD., (© 2023. Asian Pacific Association for the Study of the Liver.)

Introduction and Objectives: The Hepamet fibrosis score was introduced for the diagnosis of advanced liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). To date, external validation is limited, and its utility in combination with liver stiffness measurement (LSM) has not been explored., Material and Methods: This is a cross-sectional study on NAFLD patients who had a liver biopsy and LSM on the same day. The diagnostic performance of the Hepamet fibrosis score was evaluated using the area under the receiver operating characteristic curve (AUROC)., Results: The data for 196 patients were analyzed (mean age 50 ± 11 years old, 50% men, 56.6% Malay, 27.6% Chinese, 15.8% Indian, 67.9% NASH, 15.8% advanced liver fibrosis). The AUROC of Hepamet fibrosis score for the diagnosis of advanced liver fibrosis was 0.85 (95% CI, 0.80 - 0.91). Using the <0.12 and ≥0.47 cut-offs from the original study, the sensitivity, specificity, positive predictive value, negative predictive value, the proportion of indeterminate results and misclassification rate were 81.8%, 91.8%, 47.4%, 98.2%, 32.1% and 6.1%, respectively. Using LSM <10 kPa and ≥15 kPa for the diagnosis of absence and presence of advanced liver fibrosis, respectively, in patients with Hepamet fibrosis score ≥0.47 (i.e., the two-step approach) reduced indeterminate results and misclassification to 16.1% and 3.6%, respectively., Conclusions: We found the Hepamet fibrosis score to have good diagnostic accuracy in a population that was largely unrepresented in earlier work and demonstrated its utility in a two-step approach with LSM for the diagnosis of advanced liver fibrosis., (Copyright © 2022 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

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.)

Background: Identifying hepatic fibrosis is crucial for nonalcoholic fatty liver disease (NAFLD) management. The fibrosis-8 (FIB-8) score, recently developed by incorporating four additional variables into the fibrosis-4 (FIB-4) score, showed better performance in predicting significant fibrosis in NAFLD., Aim: To validate the FIB-8 score in a biopsy-proven NAFLD cohort and compare the diagnostic performance of the FIB-8 and FIB-4 scores and NAFLD fibrosis score (NFS) for predicting significant fibrosis., Methods: We collected the data of biopsy-proven NAFLD patients from three Asian centers in three countries. All the patients with available variables for the FIB-4 score (age, platelet count, and aspartate and alanine aminotransferase levels) and FIB-8 score (the FIB-4 variables plus 4 additional parameters: The body mass index (BMI), albumin to globulin ratio, gamma-glutamyl transferase level, and presence of diabetes mellitus) were included. The fibrosis stage was scored using nonalcoholic steatohepatitis CRN criteria, and significant fibrosis was defined as at least fibrosis stage 2., Results: A total of 511 patients with biopsy-proven NAFLD and complete data were included for validation. Of these 511 patients, 271 (53.0%) were female, with a median age of 51 (interquartile range: 41, 58) years. The median BMI was 29 (26.3, 32.6) kg/m 2 , and 268 (52.4%) had diabetes. Among the 511 NAFLD patients, 157 (30.7%) had significant fibrosis (≥ F2). The areas under the receiver operating characteristic curves of the FIB-8 and FIB-4 scores and NFS for predicting significant fibrosis were 0.774, 0.743, and 0.680, respectively. The FIB-8 score demonstrated significantly better performance for predicting significant fibrosis than the NFS ( P = 0.001) and was also clinically superior to FIB-4, although statistical significance was not reached ( P = 0.073). The low cutoff point of the FIB-8 score for predicting significant fibrosis of 0.88 showed 92.36% sensitivity, and the high cutoff point of the FIB-8 score for predicting significant fibrosis of 1.77 showed 67.51% specificity., Conclusion: We demonstrated that the FIB-8 score had significantly better performance for predicting significant fibrosis in NAFLD patients than the NFS, as well as clinically superior performance vs the FIB-4 score in an Asian population. A novel simple fibrosis score comprising commonly accessible basic laboratories may be beneficial to use for an initial assessment in primary care units, excluding patients with significant liver fibrosis and aiding in patient selection for further hepatologist referral., Competing Interests: Conflict-of-interest statement: There are no conflicts of interest to report., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: The effect of modest alcohol intake on prevalence of significant hepatic steatosis and severity of liver disease in patients with type 2 diabetes mellitus (T2DM) is unclear., Methods: This is a cross-sectional study on T2DM patients. Modest alcohol intake was defined as alcohol intake ≤ 21 units/week in men and ≤ 14 units/week in women. Significant hepatic steatosis was diagnosed on the basis of controlled attenuation parameter > 263 dB/m, while advanced fibrosis was diagnosed on the basis of liver stiffness measurement ≥ 9.6 kPa using M probe or ≥ 9.3 kPa using XL probe. Patients with liver stiffness measurement ≥ 8.0 kPa were offered liver biopsy., Results: Five hundred fifty-seven patients underwent transient elastography, and 71 patients underwent liver biopsy. The prevalence of modest drinking was 16.5%. Modest drinking was equally prevalent among ethnic Indians and Chinese at 22.9% and 23.3%, respectively, but uncommon among ethnic Malays at 1.7%. Modest drinkers were more likely to be male, smoked, and had significantly lower glycated hemoglobin, total cholesterol, low-density lipoprotein cholesterol, alkaline phosphatase, and platelet count. There was no significant difference in the prevalence of significant hepatic steatosis or advanced fibrosis based on transient elastography and steatohepatitis or advanced fibrosis between modest drinkers and nondrinkers. The prevalence of significant hepatic steatosis was higher among ethnic Malays and Indians compared with ethnic Chinese, but the Chinese did not have a lower prevalence of more severe liver disease., Conclusion: Modest alcohol intake is not associated with higher prevalence of significant hepatic steatosis or more severe liver disease among patients with T2DM., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Because only a minority of patients with nonalcoholic fatty liver disease (NAFLD) have advanced fibrosis and would eventually develop liver-related complications, current guidelines recommend initial assessment with noninvasive tests of fibrosis. 1-3 Most previous studies focused on overweight and obese patients. Despite a strong association between obesity and NAFLD, 3%-30% of people with relatively normal body mass index (BMI) may still have NAFLD. 4,5 Hence, this study aims to evaluate the performance of the common noninvasive tests in non-obese (BMI <25 kg/m 2 ) and obese (BMI ≥25 kg/m 2 ) NAFLD patients., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aim: Repeating liver stiffness measurement (LSM) was recently reported to improve accuracy to diagnose fibrosis stage in patients with non-alcoholic fatty liver disease (NAFLD). There are to date no other studies confirming this finding. This aims to evaluate the accuracy of repeating LSM for the diagnosis of fibrosis stage in NAFLD patients., Methods: Retrospective analysis of prospectively collected data on adult NAFLD patients who had two FibroScan examination within 6 months prior to liver biopsy. F3-F4 fibrosis was excluded using LSM cut-off of 7.9 kPa., Results: A total of 136 patients were recruited. Eighty-five percent (115/136) of patients had high baseline LSM (≥ 7.9 kPa). Among them, 25% (29/115) had low repeat LSM (< 7.9 kPa), with only two patients having F3 fibrosis. Forty-eight percent (41/86) of patients with high baseline and repeat LSMs had greater than or equal to F3-F4 fibrosis. All 21 patients with low baseline LSM had F0-F2 fibrosis, except one patient with high repeat LSM who had F3 fibrosis. A strategy of repeating LSM, where only patients with high LSM on both baseline and repeat scans are considered for liver biopsy, will be able to reduce the number of patients being considered for liver biopsy from 85% to 63%. The sensitivity, specificity, positive predictive value, and negative predictive value based on only the baseline scan was 98%, 22%, 37%, and 95%, respectively, while based on the strategy of repeating LSM was 93%, 51%, 48%, and 94%, respectively., Conclusion: False positive diagnosis of advanced fibrosis in NAFLD patients can be reduced, and unnecessary liver biopsy can be avoided by repeating LSM., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Objectives: Previous exposure to hepatitis B virus (HBV) may increase the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. We aim to study the impact of previous HBV infection on the severity and outcomes of patients with nonalcoholic fatty liver disease (NAFLD)., Methods: This was a multicenter study of 489 patients with biopsy-proven NAFLD and 69 patients with NAFLD-related or cryptogenic HCC. Antihepatitis B core antibody (anti-HBc) was used to detect the previous HBV infection., Results: In the biopsy cohort, positive anti-HBc was associated with lower steatosis grade but higher fibrosis stage. 18.8% and 7.5% of patients with positive and negative anti-HBc had cirrhosis, respectively (P < 0.001). The association between anti-HBc and cirrhosis remained significant after adjusting for age and metabolic factors (adjusted odds ratio 2.232; 95% confidence interval, 1.202-4.147). At a mean follow-up of 6.2 years, patients with positive anti-HBc had a higher incidence of HCC or cirrhotic complications (6.5% vs 2.2%; P = 0.039). Among patients with NAFLD-related or cryptogenic HCC, 73.9% had positive anti-HBc. None of the patients had positive serum HBV DNA. By contrast, antihepatitis B surface antibody did not correlate with histological severity., Discussion: Positive anti-HBc is associated with cirrhosis and possibly HCC and cirrhotic complications in patients with NAFLD. Because a significant proportion of NAFLD-related HCC may develop in noncirrhotic patients, future studies should define the role of anti-HBc in selecting noncirrhotic patients with NAFLD for HCC surveillance.

Background & Aims: HepaFat-Scan is a magnetic resonance imaging-based method for quantification of hepatic steatosis by volumetric liver fat fraction (VLFF) measurement. We aimed to validate VLFF and to compare it with controlled attenuation parameter (CAP) for determination of hepatic steatosis grade in patients with NAFLD, using histopathology and stereologic analyses of biopsies as the reference standard., Methods: We performed a prospective study of consecutive adults with NAFLD who were scheduled for a liver biopsy at a tertiary hospital in Malaysia. Patients underwent VLFF and CAP measurements on the same day as their liver biopsy. Histopathology analyses of liver biopsy specimens were reported according to the Nonalcoholic Steatohepatitis Clinical Research Network scoring system. Stereologic analysis was performed using grid-point counting method combined with the Delesse principle., Results: We analyzed data from 97 patients (mean age 57.0 ± 10.1 years; 44.33% male; 91.8% obese; 95.9% centrally obese). Based on histopathology analysis, the area under receiver operating characteristic curve (AUROC) for VLFF in detection of steatosis grade ≥S2 was 0.92 and for CAP the AUROC was 0.65 (P < .001). Based on stereological analysis, the AUROC for VLFF for detection of steatosis grade ≥S2 was 0.92 and for CAP the AUROC was 0.63, (P = .002); for identification of steatosis grade S3, the AUROC for VLFF was 0.92 and for CAP the AUROC was 0.68 (P < .001)., Conclusions: In a prospective study of patients with NAFLD undergoing liver biopsy analysis, we found VLFF to more accurately determine grade of hepatic steatosis than CAP., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a novel class of drugs that lower glucose by inducing renal glycosuria. We aimed to explore whether SGLT2 inhibitor added to the usual care for patients with type 2 diabetes mellitus (T2DM) and biopsy-proven nonalcoholic steatohepatitis (NASH) will benefit NASH histology., Methods: In this investigator-initiated, single-arm, open-label, pilot study, nine biopsy-proven NASH patients with T2DM were given empagliflozin 25 mg daily for 24 weeks. Liver biopsy was repeated at the end of treatment. The histological outcomes were compared with the placebo group of a previous 48-week clinical trial., Results: There was a significant reduction in body mass index (median change, Δ = -0.7 kg per m 2 , p = 0.011), waist circumference (Δ = -3 cm, p = 0.033), systolic blood pressure (Δ = -9 mmHg, p = 0.024), diastolic blood pressure (Δ = -6 mmHg, p = 0.033), fasting blood glucose (Δ = -1.7 mmol/L, p = 0.008), total cholesterol (Δ = -0.5 mmol/L, p = 0.011), gamma glutamyl transpeptidase (Δ = -19 U/L, p = 0.013), volumetric liver fat fraction (Δ = -7.8%, p = 0.017), steatosis (Δ = -1, p = 0.014), ballooning (Δ = -1, p = 0.034), and fibrosis (Δ = 0, p = 0.046). All histological components either remained unchanged or improved, except in one patient who had worsening ballooning. Empagliflozin resulted in significantly greater improvements in steatosis (67% vs. 26%, p = 0.025), ballooning (78% vs. 34%, p = 0.024), and fibrosis (44% vs. 6%, p = 0.008) compared with historical placebo., Conclusion: This pilot study provides primary histological evidence that empagliflozin may be useful for the treatment of NASH. This preliminary finding should prompt larger clinical trials to assess the effectiveness of empagliflozin and other SGLT2 inhibitors for the treatment of NASH in T2DM patients. Trial registry number ClincialTrials.gov number, NCT02964715.

Background and Aim: Transient elastography (TE) and point shear wave elastography (pSWE) are noninvasive methods to diagnose fibrosis stage in patients with chronic liver disease. The aim of this study is to compare the accuracy of the two methods to diagnose fibrosis stage in non-alcoholic fatty liver disease (NAFLD) and to study the intra-observer and inter-observer variability when the examinations were performed by healthcare personnel of different backgrounds., Methods: Consecutive NAFLD patients who underwent liver biopsy were enrolled in this study and had two sets each of pSWE and TE examinations by a nurse and a doctor on the same day of liver biopsy procedure. The medians of the four sets of pSWE and TE were used for evaluation of diagnostic accuracy using area under receiver operating characteristic curve (AUROC). Intra-observer and inter-observer variability was analyzed using intraclass correlation coefficients., Results: Data for 100 NAFLD patients (mean age 57.1 ± 10.2 years; male 46.0%) were analyzed. The AUROC of TE for diagnosis of fibrosis stage ≥ F1, ≥ F2, ≥ F3, and F4 was 0.89, 0.83, 0.83, and 0.89, respectively. The corresponding AUROC of pSWE was 0.80, 0.72, 0.69, and 0.79, respectively. TE was significantly better than pSWE for the diagnosis of fibrosis stages ≥ F2 and ≥ F3. The intra-observer and inter-observer variability of TE and pSWE measurements by the nurse and doctor was excellent with intraclass correlation coefficient > 0.96., Conclusion: Transient elastography was significantly better than pSWE for the diagnosis of fibrosis stage ≥ F2 and ≥ F3. Both TE and pSWE had excellent intra-observer and inter-observer variability when performed by healthcare personnel of different backgrounds., (© 2019 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aim: The recommendation in regard to screening for non-alcoholic fatty liver disease (NAFLD) among type 2 diabetes mellitus (T2DM) patients differs in major guidelines. The aim of this paper was to study the prevalence of NALFD and advanced fibrosis among T2DM patients., Methods: This is a cross-sectional study of consecutive adult T2DM patients attending the Diabetes Clinic of a university hospital. Significant hepatic steatosis and advanced fibrosis was diagnosed based on transient elastography if the controlled attenuation parameter was ≥ 263 dB/m, and the liver stiffness measurement was ≥ 9.6 kPa using the M probe or ≥ 9.3 kPa using the XL probe, respectively. Patients with liver stiffness measurement ≥ 8 kPa were referred to the Gastroenterology and Hepatology Clinic for further assessment, including liver biopsy., Results: The data of 557 patients were analyzed (mean age 61.4 ± 10.8 years, male 40.6%). The prevalence of NAFLD and advanced fibrosis based on transient elastography was 72.4% and 21.0%, respectively. On multivariate analysis, independent factors associated with NAFLD were central obesity (OR 4.856, 95% confidence interval [CI] 2.749-8.577, P = 0.006), serum triglyceride (OR 1.585, 95% CI 1.056-2.381, P = 0.026), and alanine aminotransferase levels (OR 1.047, 95% CI 1.025-1.070, P < 0.001) while advanced fibrosis was associated with serum high-density lipoprotein cholesterol (OR 0.355, 95% CI 0.126-0.997, P = 0.049), alanine aminotransferase (OR 1.023, 95% CI 1.009-1.037, P = 0.001), γ-glutamyltransferase (OR 1.005, 95% CI 1.001-1.008, P = 0.017), and platelet levels (OR 0.995, 95% CI 0.992-0.999, P = 0.010). Seventy-one patients underwent liver biopsy. The majority had non-alcoholic steatohepatitis (83.1%) and ≥ F1 fibrosis (87.3%) while advanced fibrosis was seen in 36.6%., Conclusion: The prevalence of NAFLD and advanced fibrosis based on transient elastography is high among T2DM patients., (© 2018 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Introduction: MACK-3 (combination of hoMa, Ast and CK18) was reported to be a good biomarker for the diagnosis of fibrotic non-alcoholic steatohepatitis (NASH). However, there is no external validation to date., Aim: To evaluate the accuracy of MACK-3 for the diagnosis of fibrotic NASH., Methodology: Consecutive adult non-alcoholic fatty liver disease (NAFLD) patients who had liver biopsy in a university hospital were included. MACK-3 was calculated using the online calculator using the following variables: fasting glucose, fasting insulin, aspartate aminotransferase (AST) and cytokeratin 18 (CK18). MACK-3 cut-offs ≤0.134 and ≥0.550 were used to predict absence and presence of fibrotic NASH, respectively. Histopathological examination of liver biopsy specimen was reported according to the NASH Clinical Research Network Scoring System., Results: Data for 196 subjects were analysed. MACK-3 was good for diagnosis of fibrotic NASH (area under receiver-operating characteristics curve [AUROC] 0.80), comparable to the Fibrosis-4 index (FIB4) and the NAFLD fibrosis score (NFS) and superior to the BARD score and CK18. MACK-3 was good for diagnosis of active NASH (AUROC 0.81) and was superior to other blood fibrosis tests. The overall accuracy, percentage of subjects in grey zone, sensitivity, specificity, positive predictive value and negative predictive value of MACK-3 for diagnosis of fibrotic NASH was 79.1%, 46.9%, 100%, 43.8%, 43.1% and 100%, respectively, while for diagnosis of active NASH was 90.0%, 39.3%, 84.2%, 81.4%, 88.9% and 74.5%, respectively., Conclusion: MACK-3 is promising as a non-invasive test for active NASH and fibrotic NASH and may be useful to identify patients who need more aggressive intervention., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Aim: To date, there are limited data on the applicability of cathepsin D for the diagnosis and monitoring of non-alcoholic steatohepatitis (NASH)., Methods: This study included patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD) diagnosed between November 2012 and October 2015. Serum cathepsin D levels were measured using the CatD enzyme-linked immunosorbent assay (USCN Life Science, Wuhan, China) using stored samples collected on the same day of the liver biopsy procedure. The performance of cathepsin D in the diagnosis and monitoring of NASH was evaluated using receiver operating characteristic analysis., Results: Data for 216 liver biopsies and 34 healthy controls were analyzed. The mean cathepsin D level was not significantly different between NAFLD patients and controls; between NASH and non-NASH patients; and across the different steatosis, lobular inflammation, and hepatocyte ballooning grades. The area under receiver operating characteristic curve (AUROC) of cathepsin D for the diagnosis of NAFLD and NASH was 0.62 and 0.52, respectively. The AUROC of cathepsin D for the diagnosis of the different steatosis, lobular inflammation, and hepatocyte ballooning grades ranged from 0.51 to 0.58. Of the 216 liver biopsies, 152 were paired liver biopsies from 76 patients who had a repeat liver biopsy after 48 weeks. There was no significant change in the cathepsin D level at follow-up compared to baseline in patients who had histological improvement or worsening for steatosis, lobular inflammation, and hepatocyte ballooning grades. Cathepsin D was poor for predicting improvement or worsening of steatosis and hepatocyte ballooning, with AUROC ranging from 0.47 to 0.54. It was fair for predicting worsening (AUROC 0.73) but poor for predicting improvement (AUROC 0.54) of lobular inflammation., Conclusion: Cathepsin D was a poor biomarker for the diagnosis and monitoring of NASH in our cohort of Asian patients, somewhat inconsistent with previous observations in Caucasian patients. Further studies in different cohorts are needed to verify our observation., (© 2019 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aim: There are limited studies on controlled attenuation parameter (CAP) using Fibroscan XL probe for the diagnosis of hepatic steatosis grade. The aim of this study was to determine whether previously defined optimal cut-offs for CAP using the M probe could be applied for the XL probe., Methods: Adult patients with chronic liver disease who had a liver biopsy and examination with both the M and XL probes were included. Previously defined optimal cut-offs for CAP using the M probe were used for the diagnosis of steatosis grades ≥S1, ≥S2, and S3 (248, 268, and 280 dB/m, respectively)., Results: Data for 180 patients were analyzed (mean age 53.7 ± 10.8 years; central obesity 84.5%; non-alcoholic fatty liver disease 86.7%). The distribution of steatosis grades was S0, 9.4%; S1, 28.3%; S2, 43.9%, and S3, 18.3%. The sensitivity, specificity, positive predictive value, and negative predictive value of CAP using the M/XL probe for the diagnosis of steatosis grade ≥S1 was 93.9%/93.3%, 58.8%/58.8%, 95.6%/95.6%, and 50.0%/47.6%, respectively. These values were 94.6%/94.6%, 41.2%/44.1%, 72.6%/73.6%, and 82.4%/83.3%, respectively, for ≥S2, and 87.9%/87.9%, 27.2%/27.9%, 21.3%/21.5%, and 90.9%/91.1%, respectively, for S3., Conclusion: The same cut-off values for CAP may be used for the M and XL probes for the diagnosis of hepatic steatosis grade., (© 2018 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Introduction: The value of repeated liver stiffness measurement (LSM) in non-alcoholic fatty liver disease (NAFLD) has not been shown before., Methods: A longitudinal study of biopsy-proven NAFLD patients was conducted at the Asian tertiary hospital from November 2012 to January 2017. Patients with paired liver biopsies and LSM were followed prospectively for liver-related and non-liver related complications, and survival., Results: The data for 113 biopsy-proven NAFLD patients (mean age 51.3 ± 10.6 years, male 50%) were analyzed. At baseline, advanced fibrosis based on histology and LSM was observed in 22 and 46%, respectively. Paired liver biopsy and LSM at 1-year interval was available in 71 and 80% of patients, respectively. High-risk cases (defined as patients with advanced fibrosis at baseline who had no fibrosis improvement, and patients who developed advanced fibrosis on repeat assessment) were seen in 23 and 53% of patients, based on paired liver biopsy and LSM, respectively. Type 2 diabetes mellitus was independently associated with high-risk cases. The median follow-up was 37 months with a total follow-up of 328 person-years. High-risk cases based on paired liver biopsy had significantly higher rates of liver-related complications (p = 0.002) but no difference in other outcomes. High-risk patients based on paired LSM had a significantly higher rate of liver-related complications (p = 0.046), cardiovascular events (p = 0.025) and composite outcomes (p = 0.006)., Conclusion: Repeat LSM can predict liver-related complications, similar to paired liver biopsy, and may be useful in identifying patients who may be at an increased risk of cardiovascular events. Further studies in a larger cohort and with a longer follow-up should be carried out to confirm these observations.

Background & Aims: Silymarin is a complex mixture of 6 major flavonolignans and other minor polyphenolic compounds derived from the milk thistle plant Silybum marianum; it has shown antioxidant, anti-inflammatory and antifibrotic effects, and may be useful in patients with nonalcoholic fatty liver disease (NAFLD). We aimed to study the efficacy of silymarin in patients with nonalcoholic steatohepatitis (NASH)-the more severe form of NAFLD., Methods: We performed a randomized, double-blind, placebo-controlled trial of consecutive adults with biopsy-proven NASH and a NAFLD activity score (NAS) of 4 or more at a tertiary care hospital in Kuala Lumpur, Malaysia, from November 2012 through August 2014. Patients were randomly assigned to groups given silymarin (700 mg; n = 49 patients) or placebo (n = 50 patients) 3 times daily for 48 weeks. After this 48-week period, liver biopsies were repeated. The primary efficacy outcome was a decrease of 30% or more in NAS; findings from 48-week liver biopsies were compared with those from the baseline biopsy. Secondary outcomes included changes in steatosis, lobular inflammation, hepatocyte ballooning, NAS and fibrosis score, and anthropometric measurements, as well as glycemic, lipid, and liver profiles and liver stiffness measurements., Results: The percentage of patients achieving the primary efficacy outcome did not differ significantly between the groups (32.7% in the silymarin group vs 26.0% in the placebo group; P = .467). A significantly higher proportion of patients in the silymarin group had reductions in fibrosis based on histology (reductions of 1 point or more; 22.4%) than did the placebo group (6.0%; P = .023), and based on liver stiffness measurements (decrease of 30% or more; 24.2%) than did the placebo group (2.3%; P = .002). The silymarin group also had significant reductions in mean aspartate aminotransferase to platelet ratio index (reduction of 0.14, P = .011 compared with baseline), fibrosis-4 score (reduction of 0.20, P = .041 compared with baseline), and NAFLD fibrosis score (reduction of 0.30, P < .001 compared with baseline); these changes were not observed in the placebo group (reduction of 0.07, P = .154; increase of 0.18, P = .389; and reduction of 0.05, P = .845, respectively). There was no significant difference between groups in number of adverse events; adverse events that occurred were not attributed to silymarin., Conclusions: In a randomized trial of 99 patients, we found that silymarin (700 mg, given 3 times daily for 48 weeks) did not reduce NAS scores by 30% or more in a significantly larger proportion of patients with NASH than placebo. Silymarin may reduce liver fibrosis but this remains to be confirmed in a larger trial. It appears to be safe and well tolerated. ClinicalTrials.gov: NCT02006498., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+-M2BP) has been suggested to be useful for the assessment of disease severity in non-alcoholic fatty liver disease (NAFLD). Consecutive adult NAFLD patients who had a liver biopsy were included. Serum WFA+-M2BP level was measured using a lectin-antibody sandwich immunoassay using a chemiluminescence enzyme immunoassay machine (HISCL-5000, Sysmex, Kobe, Japan). The measured levels were indexed using the following equation: Cut-off index (COI) = ([WFA+-M2BP]sample-[WFA+-M2BP]NC) / ([WFA+-M2BP]PC-[WFA+-M2BP]NC), where PC = positive control and NC = negative control. Histopathological examination of liver biopsy specimen was reported according to Non-Alcoholic Steatohepatitis (NASH) Clinical Research Network Scoring System. Data for 220 cases were analyzed. The AUROC of the COI for the diagnosis of NASH was 0.65. The AUROC of the COI for the diagnosis of steatosis grade ≥2 and 3 was 0.64 and 0.53, respectively. The AUROC of the COI for the diagnosis of lobular inflammation grade ≥1, ≥2 and 3 was 0.57, 0.68 and 0.59, respectively. The AUROC of the COI for the diagnosis of hepatocyte ballooning grade ≥1 and 2 was 0.64 and 0.65, respectively. The AUROC of the COI for the diagnosis of fibrosis stage ≥1, ≥2, ≥3 and 4 was 0.61, 0.71, 0.74 and 0.84, respectively. Out of the 220 cases, 152 cases were the same 76 patients who had a repeat liver biopsy after 48 weeks of intervention. The AUROC of the change in the COI to detect improvement in steatosis, lobular inflammation, hepatocyte ballooning and fibrosis was 0.57, 0.54, 0.59 and 0.52, respectively. In conclusion, serum WFA+-M2BP was most useful for the diagnosis of significant fibrosis, advanced fibrosis and cirrhosis in NAFLD patients. However, it was less useful for differentiating NASH from non-NASH, and for diagnosis and follow-up of the individual histopathological components of NASH.

Background: The FibroScan® XL probe reduces failure of liver stiffness measurement (LSM) and unreliable results in obese patients., Objective: The objective of this article is to evaluate the accuracy of controlled attenuation parameter (CAP) obtained using the XL probe for the estimation of hepatic steatosis in patients with non-alcoholic fatty liver disease (NAFLD)., Methods: Adult NAFLD patients with a liver biopsy within six months were included and were examined with the FibroScan® M and XL probes. Histopathological findings were reported according to the Non-Alcoholic Steatohepatitis Clinical Research Network Scoring System. Participants who did not have fatty liver on ultrasonography were recruited as controls., Results: A total of 57 NAFLD patients and 22 controls were included. The mean age of the NAFLD patients and controls was 50.1 ± 10.4 years and 20.2 ± 1.3 years, respectively ( p  = 0.000). The mean body mass index was 30.2 ± 5.0 kg per m 2 and 20.5 ± 2.4 kg per m 2 , respectively ( p  = 0.000). The distribution of steatosis grades were: S0, 29%; S1, 17%; S2, 35%; S3, 19%. The AUROC for estimation of steatosis grade ≥ S1, S2 and S3 was 0.94, 0.80 and 0.69, respectively, using the M probe, and 0.97, 0.81 and 0.67, respectively, using the XL probe., Conclusion: CAP obtained using the XL probe had similar accuracy as the M probe for the estimation of hepatic steatosis in NAFLD patients.

Objectives: This is the first study that estimates the incidence and mortality rate for colorectal cancer (CRC) patients in Malaysia by sex and ethnicity., Methods: The 4,501 patients were selected from National Cancer Patient Registry-Colorectal Cancer data. Patient survival status was cross-checked with the National Registration Department. The age-standardised rate (ASR) was calculated as the proportion of CRC cases (incidence) and deaths (mortality) from 2008 to 2013, weighted by the age structure of the population, as determined by the Department of Statistics Malaysia and the World Health Organization world standard population distribution., Results: The overall incidence rate for CRC was 21.32 cases per 100,000. Those of Chinese ethnicity had the highest CRC incidence (27.35), followed by the Malay (18.95), and Indian (17.55) ethnicities. The ASR incidence rate of CRC was 1.33 times higher among males than females (24.16 and 18.14 per 100,000, respectively). The 2011 (44.7%) CRC deaths were recorded. The overall ASR of mortality was 9.79 cases, with 11.85 among the Chinese, followed by 9.56 among the Malays and 7.08 among the Indians. The ASR of mortality was 1.42 times higher among males (11.46) than females (8.05)., Conclusions: CRC incidence and mortality is higher in males than females. Individuals of Chinese ethnicity have the highest incidence of CRC, followed by the Malay and Indian ethnicities. The same trends were observed for the age-standardised mortality rate., Competing Interests: The authors have no conflicts of interest to declare for this study.

Background: A colorectal cancer screening program was piloted in two districts of Kedah in 2013. There is scarcity of information on colorectal cancer screening in Malaysia., Objective: Thus, this research was conducted to evaluate the colorectal cancer screening program in the districts to provide insights intop its efficacy., Materials and Methods: A cross sectional study was conducted using data on the colorectal cancer screening program in 2013 involving Kota Setar and Kuala Muda districts in Malaysia. We determined the response rate of immunochemical fecal occult blood test (iFOBT), colonoscopy compliance, and detection rates of neoplasia and carcinoma. We also compared the response of FOBT by demographic background., Results: The response rate of FOBT for first iFOBT screening was 94.7% while the second iFOBT screening was 90.7%. Participants from Kuala Muda district were 27 times more likely to default while Indians had a 3 times higher risk of default compared to Malays. The colonoscopy compliance was suboptimal among those with positive iFOBT. The most common finding from colonoscopy was hemorrhoids, followed by tubular adenoma. Detection rate of carcinoma and neoplasia for our program was 1.2%., Conclusions: In summary, the response rate of iFOBT was encouraging but the colonoscopy compliance was suboptimal which led to a considerably low detection rate.

Background: The non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS) is indeterminate in a proportion of NAFLD patients. Combining the NFS with liver stiffness measurement (LSM) may improve prediction of advanced fibrosis. We aim to evaluate the NFS and LSM in predicting advanced fibrosis in NAFLD patients., Methods: The NFS was calculated and LSM obtained for consecutive adult NAFLD patients scheduled for liver biopsy. The accuracy of predicting advanced fibrosis using either modality and in combination were assessed. An algorithm combining the NFS and LSM was developed from a training cohort and subsequently tested in a validation cohort., Results: There were 101 and 46 patients in the training and validation cohort, respectively. In the training cohort, the percentages of misclassifications using the NFS alone, LSM alone, LSM alone (with grey zone), both tests for all patients and a 2-step approach using LSM only for patients with indeterminate and high NFS were 5.0, 28.7, 2.0, 2.0 and 4.0 %, respectively. The percentages of patients requiring liver biopsy were 30.7, 0, 36.6, 36.6 and 18.8 %, respectively. In the validation cohort, the percentages of misclassifications were 8.7, 28.3, 2.2, 2.2 and 8.7 %, respectively. The percentages of patients requiring liver biopsy were 28.3, 0, 41.3, 43.5 and 19.6 %, respectively., Conclusions: The novel 2-step approach further reduced the number of patients requiring a liver biopsy whilst maintaining the accuracy to predict advanced fibrosis. The combination of NFS and LSM for all patients provided no apparent advantage over using either of the tests alone.

Background: COX-2 has been shown to play an important role in the development of breast cancer and increased expression has been mooted as a poor prognostic factor. The purpose of this study was to investigate the relationship between COX-2 immunohistochemical expression and known predictive and prognostic factors in breast cancer in a routine diagnostic histopathology setting., Materials and Methods: Formalin-fixed paraffin- embedded tumour tissue of 144 no special type (NST) invasive breast carcinomas histologically diagnosed between January 2009 and December 2012 in Hospital Sultanah Bahiyah, Alor Setar, Kedah were immunostained with COX-2 antibody. COX-2 overexpression was analysed against demographic data, hormone receptor status, HER2- neu overexpression, histological grade, tumour size and lymph node status., Results: COX-2 was overexpressed in 108/144 (75%) tumours and was significantly more prevalent (87%) in hormone receptor-positive tumours. There was no correlation between COX-2 overexpression and HER2/neu status. Triple negative cancers had the lowest prevalence (46%) (p<0.05). A rising trend of COX-2 overexpression with increasing age was observed. There was a significant inverse relationship with tumour grade (p<0.05), prevalences being 94%, 83% and 66% in grades 1, 2 and 3 tumours, respectively. A higher prevalence of COX-2 overexpression in smaller size tumours was observed but this did not reach statistical significance. There was no relationship between COX-2 expression and lymph node status., Conclusions: This study did not support the generally held notion that COX-2 overexpression is linked to poor prognosis, rather supporting a role in tumorigenesis. Larger scale studies with outcome data and basic studies on cancer pathogenetic pathways will be required to cast further light on whether COX-2 inhibitors would have clinical utility in cancer prevention or blockage of cancer progression. In either setting, the pathological assessment for COX-2 overexpression in breast cancers would have an important role in the selection of cancer patients for personalized therapy with COX-2 inhibitors.

Introduction: The utility of Cytokeratin-18 fragment, namely CK18Asp396 (M30), for the diagnosis of non-alcoholic steatohepatitis (NASH) is currently uncertain. We aimed to provide further data in this area among multi-ethnic Asian subjects with NAFLD., Materials and Methods: The accuracy of M30 for detecting NASH was compared with serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyl transpeptidase (GGT) levels in consecutive adult subjects with biopsy-proven non-alcoholic fatty liver disease (NAFLD)., Results: Data for 93 NAFLD subjects (mean age 51.0 ± 11.1 years old and 51.6% males) and 20 healthy controls (mean age 50.2 ± 16.4 years old and 33.3% males) were analyzed. There were 39 NASH subjects (41.9%) and 54 non-NASH subjects (58.1%) among the NAFLD subjects. Plasma M30 (349 U/L vs. 162 U/L), and serum ALT (70 IU/L vs. 26 IU/L), AST (41 IU/L vs. 20 IU/L) and GGT (75 IU/L vs. 33 IU/L) were significantly higher in NAFLD subjects than in healthy controls. Serum ALT (86 IU/L vs. 61 IU/L), AST (58 IU/L vs. 34 IU/L) and GGT (97 IU/L vs. 56 IU/L) were significantly higher in NASH subjects compared to non-NASH subjects, but no significant difference was observed with plasma M30 (435 U/L vs. 331 U/L). The accuracy of plasma M30, and serum ALT, AST and GGT was good for predicting NAFLD (AUROC 0.91, 0.95, 0.87 and 0.85, respectively) but less so for NASH (AUROC 0.59, 0.64, 0.75 and 0.68, respectively). Serum ALT and AST, but not plasma M30 showed a significant trend with increasing grades of ballooning and lobular inflammation., Conclusion: The utility of M30 in the detection of NASH in clinical practice appears limited, in comparison to routine biochemical markers.

Background and Aim: Controlled attenuation parameter (CAP) has been suggested as a noninvasive method for detection and quantification of hepatic steatosis. We aim to study the diagnostic performance of CAP in nonalcoholic fatty liver disease (NAFLD) patients., Methods: Transient elastography was performed in consecutive NAFLD patients undergoing liver biopsy and non-NAFLD controls. The accuracy of CAP for the detection and quantification of hepatic steatosis was assessed based on histological findings according to the Nonalcoholic Steatohepatitis Clinical Research Network Scoring System., Results: Data for 101 NAFLD patients (mean age 50.3 ± 11.3 years old, 51.5% male) and 60 non-NAFLD controls were analyzed. CAP was associated with steatosis grade (odds ratio [OR] = 29.16, P < 0.001), body mass index (BMI; OR = 4.34, P < 0.001) and serum triglyceride (OR = 13.59, P = 0.037) on multivariate analysis. The median CAP for steatosis grades S0, S1, S2, and S3 were 184 dB/m, 305 dB/m, 320 dB/m, and 324 dB/m, respectively. The areas under receiver operating characteristics curves (AUROC) for estimation of steatosis grades ≥ S1, S2, and S3 were 0.97, 0.86, and 0.75, respectively. The optimal CAP cutoffs for estimation of steatosis grades ≥ S1, S2, and S3 were 263 dB/m, 281 dB/m, and 283 dB/m, respectively. Among non-obese patients, the AUROC for estimation of steatosis grades ≥ S1 and S2 were 0.99 and 0.99, respectively. Among obese patients, the AUROC for estimation of steatosis grades ≥ S1, S2, and S3 were 0.92, 0.64, and 0.58, respectively., Conclusions: CAP is excellent for the detection of significant hepatic steatosis. However, its accuracy is impaired by an increased BMI, and it is less accurate to distinguish between the different grades of hepatic steatosis., (© 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Objective: We studied the clinicopathological parameters of adenocarcinoma arising from endocervix (ECA) and from endometrium (EMA) based on the expression of P16ink4a, P21waf1, and p27Kip1 proteins., Study Design: Immunohistochemistry was done on sections of confirmed ECA and EMA from hysterectomy specimens which have had no prior chemotherapy/radiotherapy., Results: There were 40 ECAs and 92 EMAs. The mean age of ECA was 49.82 (SD 10.29); the youngest was 30 years old and the oldest 75 years old. The mean age of EMA was 54.45 (SD 10.92); the youngest was 30 years old and the oldest was 82 years old. For ECA, the size of the tumour is significantly associated with age and with depth of infiltration. FIGO stage is associated with histological grade. p21WAF1 expression is significantly associated with infiltration of the corpus and lymph node metastasis. p27Kip1 expression is significantly associated with lymph node invasion. The presence of lymph node metastasis is strongly associated when p16INK4a and p27Kip1 expressions are analyzed in combination. For EMA, p16INK4a expression is associated with histologic grade., Conclusion: Our study shows that we could use these cell cycle markers as predictors for more aggressive subsets of adenocarcinoma of the cervix and endometrium.