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  1. Abdulaziz Bardi D, Halabi MF, Hassandarvish P, Rouhollahi E, Paydar M, Moghadamtousi SZ, et al.
    PLoS One, 2014;9(10):e109424.
    PMID: 25280007 DOI: 10.1371/journal.pone.0109424
    This study investigated the hepatoprotective effects of ethanolic Andrographis paniculata leaf extract (ELAP) on thioacetamide-induced hepatotoxicity in rats. An acute toxicity study proved that ELAP is not toxic in rats. To examine the effects of ELAP in vivo, male Sprague Dawley rats were given intraperitoneal injections of vehicle 10% Tween-20, 5 mL/kg (normal control) or 200 mg/kg TAA thioacetamide (to induce liver cirrhosis) three times per week. Three additional groups were treated with thioacetamide plus daily oral silymarin (50 mg/kg) or ELAP (250 or 500 mg/kg). Liver injury was assessed using biochemical tests, macroscopic and microscopic tissue analysis, histopathology, and immunohistochemistry. In addition, HepG2 and WRL-68 cells were treated in vitro with ELAP fractions to test cytotoxicity. Rats treated with ELAP exhibited significantly lower liver/body weight ratios and smoother, more normal liver surfaces compared with the cirrhosis group. Histopathology using Hematoxylin and Eosin along with Masson's Trichrome stain showed minimal disruption of hepatic cellular structure, minor fibrotic septa, a low degree of lymphocyte infiltration, and minimal collagen deposition after ELAP treatment. Immunohistochemistry indicated that ELAP induced down regulation of proliferating cell nuclear antigen. Also, hepatic antioxidant enzymes and oxidative stress parameters in ELAP-treated rats were comparable to silymarin-treated rats. ELAP administration reduced levels of altered serum liver biomarkers. ELAP fractions were non-cytotoxic to WRL-68 cells, but possessed anti-proliferative activity on HepG2 cells, which was confirmed by a significant elevation of lactate dehydrogenase, reactive oxygen species, cell membrane permeability, cytochrome c, and caspase-8,-9, and, -3/7 activity in HepG2 cells. A reduction of mitochondrial membrane potential was also detected in ELAP-treated HepG2 cells. The hepatoprotective effect of 500 mg/kg of ELAP is proposed to result from the reduction of thioacetamide-induced toxicity, normalizing reactive oxygen species levels, inhibiting cellular proliferation, and inducing apoptosis in HepG2 cells.
    Matched MeSH terms: Liver Cirrhosis/pathology
  2. Lim SG, Phyo WW, Shah SR, Win KM, Hamid S, Piratvisuth T, et al.
    J Viral Hepat, 2018 12;25(12):1533-1542.
    PMID: 30141214 DOI: 10.1111/jvh.12989
    There is a paucity of information on chronic hepatitis C (CHC) patients treated with direct antiviral agents (DAAs) in Asia. We invited Asia-Pacific physicians to collate databases of patients enrolled for CHC treatment, recording baseline clinical, virologic and biochemical characteristics, sustained virologic response at week 12 (SVR12) and virologic failure. SVR12 outcome was based on intention to treat (ITT). Multivariate analysis was used to assess independent risk factors for SVR12 using SPSS version 20. A total of 2171 patients from India (n = 977), Myanmar (n = 552), Pakistan (n = 406), Thailand (n = 139), Singapore (n = 72) and Malaysia (n = 25) were collected. At baseline, mean age was 49 years, 50.2% were males, and 41.8% had cirrhosis. Overall, SVR12 was 89.5% and by genotype (GT) based on ITT and treatment completion, respectively, was 91% and 92% for GT1, 100% and 100% for GT2, 91% and 97% for GT3, 64% and 95% for GT4, 87% and 87% for GT6 and 79% and 91% for GT untested. Patients with cirrhosis had SVR12 of 85% vs 93% for noncirrhosis (P < 0.001) (RR 2.1, 95% CI 1.4-3.1, P = 0.0002). Patients with GT1 and GT3 treated with sofosbuvir/ribavirin (SR) had 88% and 89% SVR12, respectively, but those GT6 treated with sofosbuvir/ledipasvir (SL) had only 77.6% SVR12. Multivariate analysis showed absence of cirrhosis was associated with higher SVR12 (OR 2.0, 95% CI 1.3-3.1, P = 0.002). In conclusion, patients with GT1 and GT3 with/without cirrhosis had surprisingly high efficacy using SR, suggesting that Asians may respond better to some DAAs. However, poor GT6 response to SL suggests this regimen is suboptimal for this genotype.
    Matched MeSH terms: Liver Cirrhosis/pathology
  3. Canivet CM, Zheng MH, Qadri S, Vonghia L, Chuah KH, Costentin C, et al.
    Clin Gastroenterol Hepatol, 2023 Nov;21(12):3097-3106.e10.
    PMID: 37031715 DOI: 10.1016/j.cgh.2023.03.032
    BACKGROUND & AIMS: Drug development in nonalcoholic steatohepatitis (NASH) is hampered by a high screening failure rate that reaches 60% to 80% in therapeutic trials, mainly because of the absence of fibrotic NASH on baseline liver histology. MACK-3, a blood test including 3 biomarkers (aspartate aminotransferase, homeostasis model assessment, and cytokeratin 18), recently was developed for the noninvasive diagnosis of fibrotic NASH. We aimed to validate the diagnostic accuracy of this noninvasive test in an international multicenter study.

    METHODS: A total of 1924 patients with biopsy-proven nonalcoholic fatty liver disease from 10 centers in Asia, Australia, and Europe were included. The blood test MACK-3 was calculated for all patients. FibroScan-aspartate aminotransferase score (FAST), an elastography-based test for fibrotic NASH, also was available in a subset of 655 patients. Fibrotic NASH was defined as the presence of NASH on liver biopsy with a Nonalcoholic Fatty Liver Disease Activity Score of 4 or higher and fibrosis stage of F2 or higher according to the NASH Clinical Research Network scoring system.

    RESULTS: The area under the receiver operating characteristic of MACK-3 for fibrotic NASH was 0.791 (95% CI 0.768-0.814). Sensitivity at the previously published MACK-3 threshold of less than 0.135 was 91% and specificity at a greater than 0.549 threshold was 85%. The MACK-3 area under the receiver operating characteristic was not affected by age, sex, diabetes, or body mass index. MACK-3 and FAST results were well correlated (Spearman correlation coefficient, 0.781; P < .001). Except for an 8% higher rate of patients included in the grey zone, MACK-3 provided similar accuracy to that of FAST. Both tests included 27% of patients in their rule-in zone, with 85% specificity and 35% false positives (screen failure rate).

    CONCLUSIONS: The blood test MACK-3 is an accurate tool to improve patient selection in NASH therapeutic trials.

    Matched MeSH terms: Liver Cirrhosis/pathology
  4. Sanyal AJ, Foucquier J, Younossi ZM, Harrison SA, Newsome PN, Chan WK, et al.
    J Hepatol, 2023 Feb;78(2):247-259.
    PMID: 36375686 DOI: 10.1016/j.jhep.2022.10.034
    BACKGROUND & AIMS: Currently available non-invasive tests, including fibrosis-4 index (FIB-4) and liver stiffness measurement (LSM by VCTE), are highly effective at excluding advanced fibrosis (AF) (F ≥3) or cirrhosis in people with non-alcoholic fatty liver disease (NAFLD), but only have moderate ability to rule-in these conditions. Our objective was to develop and validate two new scores (Agile 4 and Agile 3+) to identify cirrhosis or AF, respectively, with optimized positive predictive value and fewer indeterminate results, in individuals with NAFLD attending liver clinics.

    METHODS: This international study included seven adult cohorts with suspected NAFLD who underwent liver biopsy, LSM and blood sampling during routine clinical practice or screening for trials. The population was randomly divided into a training set and an internal validation set, on which the best-fitting logistic regression model was built, and performance and goodness of fit were assessed, respectively. Furthermore, both scores were externally validated on two large cohorts. Cut-offs for high sensitivity and specificity were derived in the training set to rule-out and rule-in cirrhosis or AF and then tested in the validation set and compared to FIB-4 and LSM.

    RESULTS: Each score combined LSM, AST/ALT ratio, platelets, sex and diabetes status, as well as age for Agile 3+. Calibration plots for Agile 4 and Agile 3+ indicated satisfactory to excellent goodness of fit. Agile 4 and Agile 3+ outperformed FIB-4 and LSM in terms of AUROC, percentage of patients with indeterminate results and positive predictive value to rule-in cirrhosis or AF.

    CONCLUSIONS: The two novel non-invasive scores improve identification of cirrhosis or AF among individuals with NAFLD attending liver clinics and reduce the need for liver biopsy in this population.

    IMPACT AND IMPLICATIONS: Non-invasive tests currently used to identify patients with advanced fibrosis or cirrhosis, such as fibrosis-4 index and liver stiffness measurement by vibration-controlled transient elastography, have high negative predictive values but high false positive rates, while results are indeterminate for a large number of cases. This study provides scores that will help the clinician diagnose advanced fibrosis or cirrhosis. These new easy-to-implement scores will help liver specialists to better identify (1) patients who need more intensive follow-up, (2) patients who should be referred for inclusion in therapeutic trials, and (3) which patients should be treated with pharmacological agents when effective therapies are approved.

    Matched MeSH terms: Liver Cirrhosis/pathology
  5. Chuah KH, Wan Yusoff WNI, Sthaneshwar P, Nik Mustapha NR, Mahadeva S, Chan WK
    Liver Int, 2019 07;39(7):1315-1324.
    PMID: 30825254 DOI: 10.1111/liv.14084
    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.

    Matched MeSH terms: Liver Cirrhosis/pathology
  6. Adams LA, Chan WK
    Semin Liver Dis, 2020 11;40(4):331-338.
    PMID: 32526784 DOI: 10.1055/s-0040-1713006
    Noninvasive serum and imaging methods offer accessible, accurate, and safe assessment of fibrosis severity in nonalcoholic fatty liver disease. In contrast, current serum and imaging methods for the prediction of nonalcoholic steatohepatitis are not sufficiently accurate for routine clinical use. Serum fibrosis markers that incorporate direct measures of fibrogenesis (for example, hyaluronic acid) or fibrinolysis are generally more accurate than biomarkers not incorporating direct measures of fibrogenesis. Elastography methods are more accurate than serum markers for fibrosis assessment and particularly for the determination of cirrhosis, but have a significant failure and/or unreliability rate in obese individuals. To overcome this, combining serum and elastography methods in a sequential manner minimizes indeterminate results and maintains accuracy. The accuracy of current noninvasive methods for monitoring fibrosis response to treatment are limited; however, new tools derived from "omic" methodologies offer promise for the future.
    Matched MeSH terms: Liver Cirrhosis/pathology
  7. Chong SE, Chang F, Chuah KH, Sthaneshwar P, Nik Mustapha NR, Mahadeva S, et al.
    Ann Hepatol, 2023;28(2):100888.
    PMID: 36586588 DOI: 10.1016/j.aohep.2022.100888
    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.

    Matched MeSH terms: Liver Cirrhosis/pathology
  8. Mahadeva S, Mahfudz AS, Vijayanathan A, Goh KL, Kulenthran A, Cheah PL
    J Dig Dis, 2013 Nov;14(11):604-10.
    PMID: 23859493 DOI: 10.1111/1751-2980.12088
    To determine the accuracy of transient elastography (TE) and factors associated with discordance between TE and liver histology in patients with non-alcoholic fatty liver disease (NAFLD).
    Matched MeSH terms: Liver Cirrhosis/pathology
  9. Tan EX, Lee JW, Jumat NH, Chan WK, Treeprasertsuk S, Goh GB, et al.
    Metabolism, 2022 01;126:154911.
    PMID: 34648769 DOI: 10.1016/j.metabol.2021.154911
    BACKGROUND: A significant proportion of the non-alcoholic fatty liver disease (NAFLD) population is non-obese. Prior studies reporting the severity of NAFLD amongst non-obese patients were heterogenous. Our study, using data from the largest biopsy-proven NAFLD international registry within Asia, aims to characterize the demographic, metabolic and histological differences between non-obese and obese NAFLD patients.

    METHODS: 1812 biopsy-proven NAFLD patients across nine countries in Asia assessed between 2006 and 2019 were pooled into a curated clinical registry. Demographic, metabolic and histological differences between non-obese and obese NAFLD patients were evaluated. The performance of Fibrosis-4 index for liver fibrosis (FIB-4) and NAFLD fibrosis score (NFS) to identify advanced liver disease across the varying obesity subgroups was compared. A random forest analysis was performed to identify novel predictors of fibrosis and steatohepatitis in non-obese patients.

    FINDINGS: One-fifth (21.6%) of NAFLD patients were non-obese. Non-obese NAFLD patients had lower proportions of NASH (50.5% vs 56.5%, p = 0.033) and advanced fibrosis (14.0% vs 18.7%, p = 0.033). Metabolic syndrome in non-obese individuals was associated with NASH (OR 1.59, 95% CI 1.01-2.54, p = 0.047) and advanced fibrosis (OR 1.88, 95% CI 0.99-3.54, p = 0.051). FIB-4 performed better than the NFS score (AUROC 81.5% vs 73.7%, p liver disease.

    CONCLUSION: A substantial proportion of non-obese NAFLD patients has NASH or advanced fibrosis. FIB-4, compared to NFS better identifies non-obese NAFLD patients with advanced liver disease. Serum GGT, cholesterol, haemoglobin and waist circumference, which are neither components of NFS nor FIB-4, are important biomarkers for advanced liver disease in non-obese patients.

    Matched MeSH terms: Liver Cirrhosis/pathology*
  10. Zhu Y, Tan JK, Wong SK, Goon JA
    Int J Mol Sci, 2023 May 23;24(11).
    PMID: 37298120 DOI: 10.3390/ijms24119168
    Nonalcoholic fatty liver disease (NAFLD) has emerged as a global health problem that affects people even at young ages due to unhealthy lifestyles. Without intervention, NAFLD will develop into nonalcoholic steatohepatitis (NASH) and eventually liver cirrhosis and hepatocellular carcinoma. Although lifestyle interventions are therapeutic, effective implementation remains challenging. In the efforts to establish effective treatment for NAFLD/NASH, microRNA (miRNA)-based therapies began to evolve in the last decade. Therefore, this systematic review aims to summarize current knowledge on the promising miRNA-based approaches in NAFLD/NASH therapies. A current systematic evaluation and a meta-analysis were conducted according to the PRISMA statement. In addition, a comprehensive exploration of PubMed, Cochrane, and Scopus databases was conducted to perform article searches. A total of 56 different miRNAs were reported as potential therapeutic agents in these studies. miRNA-34a antagonist/inhibitor was found to be the most studied variant (n = 7), and it significantly improved the hepatic total cholesterol, total triglyceride, Aspartate Aminotransferase (AST), and Alanine Transaminase (ALT) levels based on a meta-analysis. The biological processes mediated by these miRNAs involved hepatic fat accumulation, inflammation, and fibrosis. miRNAs have shown enormous therapeutic potential in the management of NAFLD/NASH, wherein miRNA-34a antagonist has been found to be an exceptional potential agent for the treatment of NAFLD/NASH.
    Matched MeSH terms: Liver Cirrhosis/pathology
  11. Wu X, Zhang S, Lai J, Lu H, Sun Y, Guan W
    Exp Clin Transplant, 2020 12;18(7):823-831.
    PMID: 33349209 DOI: 10.6002/ect.2020.0108
    OBJECTIVES: Liver fibrosis is inevitable in the healing process of liver injury. Liver fibrosis will develop into liver cirrhosis unless the damaging factors are removed. This study investigated the potential therapy of Bama pig adipose-derived mesenchymal stem cells in a carbon tetrachloride-induced liver fibrosis Institute of Cancer Research strain mice model.

    MATERIALS AND METHODS: Adipose-derived mesenchymal stem cells were injected intravenously into the tails of mice of the Institute of Cancer Research strain that had been treated with carbon tetrachloride for 4 weeks. Survival rate, migration, and proliferation of adipose-derived mesenchymal stem cells in the liver were observed by histochemistry, fluorescent labeling, and serological detection.

    RESULTS: At 1, 2, and 3 weeks after adipose-derived mesenchymal stem cell injection, liver fibrosis was significantly ameliorated. The injected adipose-derived mesenchymal stem cells had hepatic differentiation potential in vivo, and the survival rate of adipose-derived mesenchymal stem cells declined over time.

    CONCLUSIONS: The findings in this study confirmed that adipose-derived mesenchymal stem cells derived from the Bama pig can be used in the treatment of liver fibrosis, and the grafted adipose-derived mesenchy-mal stem cells can migrate, survive, and differentiate into hepatic cells in vivo.

    Matched MeSH terms: Liver Cirrhosis/pathology
  12. Ansari AW, Schmidt RE, Shankar EM, Kamarulzaman A
    J Transl Med, 2014;12:341.
    PMID: 25528160 DOI: 10.1186/s12967-014-0341-8
    Even in the era of successful combination antiretroviral therapy (cART), co-infection of Hepatitis C virus (HCV) remains one of the leading causes of non-AIDS-related mortality and morbidity among HIV-positive individuals as a consequence of accelerated liver fibrosis and end-stage liver disease (ESLD). The perturbed liver microenvironment and induction of host pro-inflammatory mediators in response to HIV and HCV infections, play a pivotal role in orchestrating the disease pathogenesis and clinical outcomes. How these viruses communicate each other via chemokine CCL2 and exploit the liver specific cellular environment to exacerbate liver fibrosis in HIV/HCV co-infection setting is a topic of intense discussion. Herein, we provide recent views and insights on potential mechanisms of CCL2 mediated immuno-pathogenesis, and HIV-HCV cross-talk in driving liver inflammation. We believe CCL2 may potentially serve an attractive target of anti-fibrotic intervention against HIV/HCV co-infection associated co-morbidities.
    Matched MeSH terms: Liver Cirrhosis/pathology
  13. Mun KS, Cheah PL, Baharudin NB, Looi LM
    Malays J Pathol, 2006 Dec;28(2):73-7.
    PMID: 18376794 MyJurnal
    Hepatocellular carcinoma (HCC) is among the ten most common cancers in Malaysian males. As cellular proliferation is an important feature of malignant transformation, we studied the proliferation pattern of normal and benign perineoplastic liver versus hepatocellular carcinoma in an attempt to further understand the tumour transformation process. 39 HCC (21 with accompanying and 18 without cirrhosis) histologically diagnosed at the Department of Pathology, University of Malaya Medical Centre between January 1992 and December 2003 were immunohistochemically studied using a monoclonal antibody to PCNA (Clone PC10: Dako). 20 livers from cases who had succumbed to traumatic injuries served as normal liver controls (NL). PCNA labeling index (PCNA-LI) was determined by counting the number of immunopositive cells in 1000 contiguous HCC, benign cirrhotic perineoplastic liver (BLC), benign perineoplastic non-cirrhotic (BLNC) and NL cells and conversion to a percentage. The PCNA-LI was also expressed as Ojanguren et al's grades. PCNA was expressed in 10% NL, 38.9% BLNC, 76.2% BLC and 71.8% HCC with BLNC, BLC and HCC showing significantly increased (p < 0.05) number of cases which expressed PCNA compared with NL. The number of BLC which expressed PCNA was also significantly increased compared with BLNC. PCNA-LI ranged from 0-2.0% (mean = 0.2%) in NL, 0-2.0% (mean = 0.3%) in BLNC, 0-3.6% (mean = 0.7%) in BLC and 0-53.8% (mean = 7.6%) in HCC with PCNA-LI significantly increased (p < 0.05) only in HCC compared with BLC, BLNC and NL. Accordingly, all NL, BLC and BLNC showed minimal (<5% cells being immunopositive) immunoreactivity on Ojanguren et al's grading system and only HCC demonstrated immunoreactivity which ranged up to grade 3 (75% of cells). From this study, there appears to be a generally increasing trend of proliferative activity from NL to BLNC to BLC and HCC. Nonetheless, BLNC and BLC, like NL, retained low PCNA-LI and only HCC had a significantly increased PCNA-LI compared with the benign categories. This is probably related to the malignant nature of HCC and may reflect the uncontrolled proliferation of the neoplastic hepatocytes.
    Matched MeSH terms: Liver Cirrhosis/pathology
  14. Sumithran E, Looi LM
    Cancer, 1985 Sep 1;56(5):1124-7.
    PMID: 2990666
    In West Malaysia, hepatocellular carcinoma (HCC) is common in the Chinese and in the members of the Senoi aboriginal tribe, two racial groups with diametrically opposite life-styles. Certain fundamental differences exist between the liver tumors in the two races. In the Senoi, the tumor occurs in a younger age group and there is a greater male preponderance than in the Chinese. There is also a very close relationship between hepatitis B virus infection, chronic active hepatitis, cirrhosis, liver cell dysplasia, and HCC in the Senoi and the tumors generally present as multiple nodules studding both lobes of the liver. In the Chinese, although a relationship between hepatitis B virus infection, HCC, and cirrhosis exists, this association is not as strong as in the Senoi and the tumors are generally large and solitary. The data suggest that, although the hepatitis B virus is probably an important oncogenic agent in both racial groups, there may be a difference in the pathogenesis of HCC in the two races.
    Matched MeSH terms: Liver Cirrhosis/pathology
  15. Lai LL, Chan WK, Sthaneshwar P, Nik Mustapha NR, Goh KL, Mahadeva S
    PLoS One, 2017;12(4):e0174982.
    PMID: 28369100 DOI: 10.1371/journal.pone.0174982
    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.
    Matched MeSH terms: Liver Cirrhosis/pathology*
  16. Kamarajah SK, Chan WK, Nik Mustapha NR, Mahadeva S
    Hepatol Int, 2018 Jan;12(1):44-55.
    PMID: 29372507 DOI: 10.1007/s12072-018-9843-4
    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.

    Matched MeSH terms: Liver Cirrhosis/pathology
  17. Shahrani S, Gill SS, Sooi CY, Skantha R, Kumar CVC, Limun MF, et al.
    J Gastroenterol Hepatol, 2023 Oct;38(10):1818-1822.
    PMID: 37587719 DOI: 10.1111/jgh.16313
    BACKGROUND: With changes in the epidemiology and treatment of chronic liver disease (CLD), the impact of various etiologies of liver disease on steatosis and advanced fibrosis are uncertain.

    METHODS: A retrospective study was conducted among liver disease patients of various etiologies undergoing transient elastography (TE) over a 9-year duration.

    RESULTS: Data for 2886 patients were analyzed and had the following demographics: The median age was 60 (IQR: 45-69) years, 51% were males, and ethnicity was predominantly Chinese (52.5%), followed by Malays (34%) and Indians (12.3%). The median CAP score was 272 (IQR: 219-319) dB/m and the median liver stiffness measurement (LSM) score was 6.5 (IQR: 4.9-9.7) kPa. Hepatic steatosis occurred across the spectrum of etiologies of CLD. Among patients with steatosis, the most common etiologies were nonalcoholic fatty liver disease (NAFLD) at 62% and chronic hepatitis B (CHB) at 26.3%. TE findings suggestive of cACLD (10.1-15 kPa) and highly suggestive of cACLD (>15 kPa) were observed in 11.3% and 12.4% of patients, respectively. NAFLD was found to be the most common etiology for cases with suggestive of cACLD (47.2%) and highly suggestive of cACLD (41.5%).

    CONCLUSION: Hepatic steatosis is common in CLD, regardless of etiology. Compared with other etiologies, NAFLD is now the leading cause of cACLD.

    Matched MeSH terms: Liver Cirrhosis/pathology
  18. Rengasamy M, Singh G, Fakharuzi NA, Siddikuzzaman, Balasubramanian S, Swamynathan P, et al.
    Stem Cell Res Ther, 2017 06 13;8(1):143.
    PMID: 28610623 DOI: 10.1186/s13287-017-0595-1
    BACKGROUND: Mesenchymal stromal cells (MSCs) from various tissues have shown moderate therapeutic efficacy in reversing liver fibrosis in preclinical models. Here, we compared the relative therapeutic potential of pooled, adult human bone marrow (BM)- and neonatal Wharton's jelly (WJ)-derived MSCs to treat CCl4-induced liver fibrosis in rats.

    METHODS: Sprague-Dawley rats were injected with CCl4 for 8 weeks to induce irreversible liver fibrosis. Ex-vivo expanded, pooled human MSCs obtained from BM and WJ were intravenously administered into rats with liver fibrosis at a dose of 10 × 106 cells/animal. Sham control and vehicle-treated animals served as negative and disease controls, respectively. The animals were sacrificed at 30 and 70 days after cell transplantation and hepatic-hydroxyproline content, histopathological, and immunohistochemical analyses were performed.

    RESULTS: BM-MSCs treatment showed a marked reduction in liver fibrosis as determined by Masson's trichrome and Sirius red staining as compared to those treated with the vehicle. Furthermore, hepatic-hydroxyproline content and percentage collagen proportionate area were found to be significantly lower in the BM-MSCs-treated group. In contrast, WJ-MSCs treatment showed less reduction of fibrosis at both time points. Immunohistochemical analysis of BM-MSCs-treated liver samples showed a reduction in α-SMA+ myofibroblasts and increased number of EpCAM+ hepatic progenitor cells, along with Ki-67+ and human matrix metalloprotease-1+ (MMP-1+) cells as compared to WJ-MSCs-treated rat livers.

    CONCLUSIONS: Our findings suggest that BM-MSCs are more effective than WJ-MSCs in treating liver fibrosis in a CCl4-induced model in rats. The superior therapeutic activity of BM-MSCs may be attributed to their expression of certain MMPs and angiogenic factors.

    Matched MeSH terms: Liver Cirrhosis/pathology
  19. Durier N, Yunihastuti E, Ruxrungtham K, Kinh NV, Kamarulzaman A, Boettiger D, et al.
    J Viral Hepat, 2017 03;24(3):187-196.
    PMID: 27917597 DOI: 10.1111/jvh.12630
    Data on markers of hepatitis C virus (HCV) disease in HIV-HCV-coinfected patients in resource-limited settings are scarce. We assessed HCV RNA, HCV genotype (GT), IL28B GT and liver fibrosis (FibroScan® ) in 480 HIV-infected patients with positive HCV antibody in four HIV treatment centres in South-East Asia. We enrolled 165 (34.4%) patients in Jakarta, 158 (32.9%) in Bangkok, 110 (22.9%) in Hanoi and 47 (9.8%) in Kuala Lumpur. Overall, 426 (88.8%) were male, the median (IQR) age was 38.1 (34.7-42.5) years, 365 (76.0%) reported HCV exposure through injecting drug use, and 453 (94.4%) were on combination antiretroviral therapy. The median (IQR) CD4 count was 446 (325-614) cells/mm3 and 208 (94.1%) of 221 patients tested had HIV-1 RNA <400 copies/mL. A total of 412 (85.8%) had detectable HCV RNA, at a median (IQR) of 6.2 (5.4-6.6) log10 IU/mL. Among 380 patients with HCV GT, 223 (58.7%) had GT1, 97 (25.5%) had GT3, 43 (11.3%) had GT6, eight (2.1%) had GT4, two (0.5%) had GT2, and seven (1.8%) had indeterminate GT. Of 222 patients with IL28B testing, 189 (85.1%) had rs12979860 CC genotype, and 199 (89.6%) had rs8099917 TT genotype. Of 380 patients with FibroScan® , 143 (37.6%) had no/mild liver fibrosis (F0-F1), 83 (21.8%) had moderate fibrosis (F2), 74 (19.5%) had severe fibrosis (F3), and 79 (20.8%) had cirrhosis (F4). One patient (0.3%) had FibroScan® failure. In conclusion, a high proportion of HIV-HCV-coinfected patients had chronic HCV infection. HCV GT1 was predominant, and 62% of patients had liver disease warranting prompt treatment (≥F2).
    Matched MeSH terms: Liver Cirrhosis/pathology*
  20. Wong SW, Chan WK, Mohamed R
    J Viral Hepat, 2020 12;27(12):1297-1305.
    PMID: 32668489 DOI: 10.1111/jvh.13361
    Hepatic steatosis is increasingly common and has been implicated in progression of liver fibrosis in chronic hepatitis B (CHB) patients. We aimed to investigate the impact of hepatic steatosis on liver fibrosis and clinical outcomes in CHB patients. Consecutive CHB patients who underwent transient elastography between 2013 and 2017 at a tertiary hospital were included in this longitudinal cohort study. Presence of hepatic steatosis was defined as controlled attenuation parameter, CAP ≥ 248 dB/m, while advanced liver fibrosis was defined as liver stiffness measurement, LSM ≥ 9.4 kPa. Cardiovascular events, liver-related complications, malignancy and mortality and a composite of these outcomes were evaluated with Kaplan-Meier analysis and Cox proportional hazards regression. Our study cohort included 614 patients with median follow-up of 45 (32-63) months. Hepatic steatosis was present in 294 patients (47.9%), and advanced liver fibrosis was present in 127 patients (21.0%). Presence of hepatic steatosis (OR: 1.956, 95% CI: 1.250-3.060) and diabetes mellitus (OR: 3.507, 95% CI: 2.069-5.944) was independently associated with advanced fibrosis. Advanced fibrosis was independently associated with composite outcome (HR: 2.496, 95% CI: 1.352-4.606), liver-related complications (HR: 3.765, 95% CI: 1.380-10.271) and mortality (HR: 3.632, 95% CI: 1.342-9.826), but not cardiovascular events and malignancy. Hepatic steatosis was not associated with any adverse outcomes. We conclude that hepatic steatosis is common and associated with advanced fibrosis in CHB patients. Unlike advanced fibrosis, hepatic steatosis does not predict adverse outcomes in CHB patients.
    Matched MeSH terms: Liver Cirrhosis/pathology
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