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  1. Yip TC, Lee HW, Chan WK, Wong GL, Wong VW
    J Hepatol, 2022 Mar;76(3):726-734.
    PMID: 34619251 DOI: 10.1016/j.jhep.2021.09.024
    Recent data suggest that non-alcoholic fatty liver disease (NAFLD) has become a major public health problem in Asia, with an updated population prevalence of 34%. In parallel, NAFLD-associated hepatocellular carcinoma (HCC) is also on the rise. In this review, we describe the changing epidemiology of HCC in Asia over the past 30 years. While traditional risk factors for HCC (older age, male sex and metabolic factors) are also important in Asia, the PNPLA3 gene polymorphism is particularly prevalent in East Asia and may increase the risk of HCC. NAFLD among non-obese individuals is also commonly described in Asia. Because NAFLD is often undiagnosed, few patients receive HCC surveillance, and the target surveillance population beyond patients with cirrhosis remains poorly defined. As a result, NAFLD-associated HCC is often diagnosed at an advanced stage, rendering curative treatment impossible. Finally, despite around 20-30 years of universal vaccination, chronic HBV infection remains prevalent in Asia, and emerging evidence highlights the importance of metabolic factors and concomitant hepatic steatosis on HCC development in infected patients. Future studies should explore the role of metabolic treatments in HCC prevention among patients with hepatic steatosis and concomitant liver diseases.
  2. Yip TC, Wong GL, Wong VW, Goh GB, Chan WK
    Med Clin North Am, 2023 May;107(3):449-463.
    PMID: 37001947 DOI: 10.1016/j.mcna.2022.12.003
    Nonalcoholic fatty liver disease (NAFLD) is a global public health problem. NAFLD is bidirectionally correlated with metabolic syndrome, which includes obesity, type 2 diabetes, hypertension, and dyslipidemia as major components. The presence of metabolic syndrome is associated with a higher prevalence of NAFLD, and vice versa. Also, the presence of metabolic syndrome in patients with NAFLD has been linked to a higher risk of cardiovascular diseases, liver-related complications, extrahepatic malignancies, and mortality, and possibly vice versa. Multidisciplinary care pathways including lifestyle modifications, control of metabolic risk, and potentially beneficial treatments are important to improve the clinical outcomes of patients with NAFLD.
  3. Zhang X, Yip TC, Wong GL, Leow WX, Liang LY, Lim LL, et al.
    Gut, 2023 Nov 24;72(12):2364-2371.
    PMID: 37549979 DOI: 10.1136/gutjnl-2023-330269
    OBJECTIVE: We aimed to test the hypothesis that automated fibrosis score calculation and electronic reminder messages could increase the detection of advanced liver disease in patients with type 2 diabetes.

    DESIGN: In this pragmatic randomised controlled trial at five general medical or diabetes clinics in Hong Kong and Malaysia, we randomly assigned patients in a 1:1 ratio to the intervention group with Fibrosis-4 index and aspartate aminotransferase-to-platelet ratio index automatically calculated based on routine blood tests, followed by electronic reminder messages to alert clinicians of abnormal results, or the control group with usual care. The primary outcome was the proportion of patients with increased fibrosis scores who received appropriate care (referred for hepatology care or specific fibrosis assessment) within 1 year.

    RESULTS: Between May 2020 and Oct 2021, 1379 patients were screened, of whom 533 and 528 were assigned to the intervention and control groups, respectively. A total of 55 out of 165 (33.3%) patients with increased fibrosis scores in the intervention group received appropriate care, compared with 4 of 131 (3.1%) patients in the control group (difference 30.2% (95% CI 22.4% to 38%); p<0.001). Overall, 11 out of 533 (2.1%) patients in the intervention group and 1 out of 528 (0.2%) patients in the control group were confirmed to have advanced liver disease (difference 1.9% (95% CI 0.61% to 3.5%); p=0.006).

    CONCLUSION: Automated fibrosis score calculation and electronic reminders can increase referral of patients with type 2 diabetes and abnormal fibrosis scores at non-hepatology settings.

    TRIAL REGISTRATION NUMBER: NCT04241575.

  4. Cheung JTK, Zhang X, Wong GL, Yip TC, Lin H, Li G, et al.
    Aliment Pharmacol Ther, 2023 Dec;58(11-12):1194-1204.
    PMID: 37724633 DOI: 10.1111/apt.17722
    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 

  5. Lin H, Lee HW, Yip TC, Tsochatzis E, Petta S, Bugianesi E, et al.
    JAMA, 2024 Apr 16;331(15):1287-1297.
    PMID: 38512249 DOI: 10.1001/jama.2024.1447
    IMPORTANCE: Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most common chronic liver disease worldwide. It is important to develop noninvasive tests to assess the disease severity and prognosis.

    OBJECTIVE: To study the prognostic implications of baseline levels and dynamic changes of the vibration-controlled transient elastography (VCTE)-based scores developed for the diagnosis of advanced fibrosis (Agile 3+) and cirrhosis (Agile 4) in patients with MASLD.

    DESIGN, SETTING, AND PARTICIPANTS: This cohort study included data from a natural history cohort of patients with MASLD who underwent VCTE examination at 16 tertiary referral centers in the US, Europe, and Asia from February 2004 to January 2023, of which the data were collected prospectively at 14 centers. Eligible patients were adults aged at least 18 years with hepatic steatosis diagnosed by histologic methods (steatosis in ≥5% of hepatocytes) or imaging studies (ultrasonography, computed tomography or magnetic resonance imaging, or controlled attenuation parameter ≥248 dB/m by VCTE).

    MAIN OUTCOMES AND MEASURES: The primary outcome was liver-related events (LREs), defined as hepatocellular carcinoma or hepatic decompensation (ascites, variceal hemorrhage, hepatic encephalopathy, or hepatorenal syndrome), liver transplant, and liver-related deaths. The Agile scores were compared with histologic and 8 other noninvasive tests.

    RESULTS: A total of 16 603 patients underwent VCTE examination at baseline (mean [SD] age, 52.5 [13.7] years; 9600 [57.8%] were male). At a median follow-up of 51.7 (IQR, 25.2-85.2) months, 316 patients (1.9%) developed LREs. Both Agile 3+ and Agile 4 scores classified fewer patients between the low and high cutoffs than most fibrosis scores and achieved the highest discriminatory power in predicting LREs (integrated area under the time-dependent receiver-operating characteristic curve, 0.89). A total of 10 920 patients (65.8%) had repeated VCTE examination at a median interval of 15 (IQR, 11.3-27.7) months and were included in the serial analysis. A total of 81.9% of patients (7208 of 8810) had stable Agile 3+ scores and 92.6% of patients (8163 of 8810) had stable Agile 4 scores (same risk categories at both assessments). The incidence of LREs was 0.6 per 1000 person-years in patients with persistently low Agile 3+ scores and 30.1 per 1000 person-years in patients with persistently high Agile 3+ scores. In patients with high Agile 3+ score at baseline, a decrease in the score by more than 20% was associated with substantial reduction in the risk of LREs. A similar trend was observed for the Agile 4 score, although it missed more LREs in the low-risk group.

    CONCLUSIONS AND RELEVANCE: Findings of this study suggest that single or serial Agile scores are highly accurate in predicting LREs in patients with MASLD, making them suitable alternatives to liver biopsy in routine clinical practice and in phase 2b and 3 clinical trials for steatohepatitis.

  6. Feng G, Mózes FE, Ji D, Treeprasertsuk S, Okanoue T, Shima T, et al.
    PMID: 39362618 DOI: 10.1016/j.cgh.2024.07.045
    BACKGROUND & AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) and fibrotic MASH are significant health challenges. This multi-national study aimed to validate the acMASH index (including serum creatinine and aspartate aminotransferase concentrations) for MASH diagnosis and develop a new index (acFibroMASH) for non-invasively identifying fibrotic MASH and exploring its predictive value for liver-related events (LREs).

    METHODS: We analyzed data from 3004 individuals with biopsy-proven metabolic dysfunction-associated steatotic liver disease (MASLD) across 29 Chinese and 9 international cohorts to validate the acMASH index and develop the acFibroMASH index. Additionally, we utilized the independent external data from a multi-national cohort of 9034 patients with MASLD to examine associations between the acFibroMASH index and the risk of LREs.

    RESULTS: In the pooled global cohort, the acMASH index identified MASH with an area under the receiver operating characteristic curve (AUROC) of 0.802 (95% confidence interval [CI], 0.786-0.818). The acFibroMASH index (including the acMASH index plus liver stiffness measurement) accurately identified fibrotic MASH with an AUROC of 0.808 in the derivation cohort and 0.800 in the validation cohort. Notably, the AUROC for the acFibroMASH index was 0.835 (95% CI, 0.786-0.882), superior to that of the FAST score at 0.750 (95% CI, 0.693-0.800; P < .01) in predicting the 5-year risk of LREs. Patients with acFibroMASH >0.39 had a higher risk of LREs than those with acFibroMASH <0.15 (adjusted hazard ratio, 11.23; 95% CI, 3.98-31.66).

    CONCLUSIONS: This multi-ethnic study validates the acMASH index as a reliable, noninvasive test for identifying MASH. The newly proposed acFibroMASH index is a reliable test for identifying fibrotic MASH and predicting the risk of LREs.

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