Stanford Advisors


All Publications


  • MAFLD fibrosis score: Using routine measures to identify advanced fibrosis in metabolic-associated fatty liver disease. Alimentary pharmacology & therapeutics Cheung, J. T., Zhang, X., Wong, G. L., Yip, T. C., Lin, H., Li, G., Leung, H. H., Lai, J. C., Mahadeva, S., Nik Mustapha, N. R., Wang, X., Liu, W., Wong, V. W., Chan, W., Zheng, M. 2023

    Abstract

    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 1week. 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.

    View details for DOI 10.1111/apt.17722

    View details for PubMedID 37724633

  • Clinical care pathway to detect advanced liver disease in patients with type 2 diabetes through automated fibrosis score calculation and electronic reminder messages: a randomised controlled trial GUT Zhang, X., Yip, T., Wong, G., Leow, W., Liang, L., Lim, L., Li, G., Ibrahim, L., Lin, H., Lai, J., Chim, A., Chan, H., Kong, A., Chan, W., Wong, V. 2023

    Abstract

    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.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.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).Automated fibrosis score calculation and electronic reminders can increase referral of patients with type 2 diabetes and abnormal fibrosis scores at non-hepatology settings.NCT04241575.

    View details for DOI 10.1136/gutjnl-2023-330269

    View details for Web of Science ID 001046443700001

    View details for PubMedID 37549979

  • Duration of type 2 diabetes and liver-related events in nonalcoholic fatty liver disease: A landmark analysis HEPATOLOGY Zhang, X., Yip, T., Tse, Y., Hui, V., Li, G., Lin, H., Liang, L., Lai, J., Chan, H., Chan, S., Kong, A., Wong, G., Wong, V. 2023: 1816-1827

    Abstract

    We aimed to determine the impact of the duration of type 2 diabetes (T2D) on the risk of liver-related events and all-cause mortality in patients with NAFLD.We conducted a territory-wide cohort study of adult patients with NAFLD diagnosed between January 1, 2000, and July 31, 2021, in Hong Kong. T2D was defined by the use of any antidiabetic agents, laboratory tests, and/or diagnosis codes. The primary endpoint was liver-related events, defined as a composite endpoint of HCC and cirrhotic complications. To conduct a more granular assessment of the duration of T2D, we employed landmark analysis in four different ages of interest (biological age of 40, 50, 60, and 70 years). By multivariable analysis with adjustment of non-liver-related deaths, compared with patients without diabetes at age 60 (incidence rate of liver-related events: 0.70 per 1,000 person-years), the adjusted subdistribution HR (SHR) of liver-related events was 2.51 (95% CI: 1.32-4.77; incidence rate: 2.26 per 1,000 person-years) in patients with T2D duration < 5 years, 3.16 (95% CI: 1.59-6.31; incidence rate: 2.54 per 1,000 person-years) in those with T2D duration of 6-10 years, and 6.20 (95% CI: 2.62-14.65; incidence rate: 4.17 per 1000 person-years) in those with T2D duration more than 10 years. A similar association between the duration of T2D and all-cause mortality was also observed.Longer duration of T2D is significantly associated with a higher risk of liver-related events and all-cause mortality in patients with NAFLD.

    View details for DOI 10.1097/HEP.0000000000000432

    View details for Web of Science ID 001096737100001

    View details for PubMedID 37119179

  • Editorial: improvement of cardiovascular risk factor control in patients with type 2 diabetes and nonalcoholic fatty liver disease-time for action! Authors' reply. Alimentary pharmacology & therapeutics Zhang, X., Wong, G. L., Wong, V. W., Yip, T. C. 2023; 57 (10): 1172-1173

    View details for DOI 10.1111/apt.17474

    View details for PubMedID 37094323

  • Trends in risk factor control and treatment among patients with non-alcoholic fatty liver disease and type 2 diabetes between 2000 and 2020: A territory-wide study ALIMENTARY PHARMACOLOGY & THERAPEUTICS Zhang, X., Yip, T., Tse, Y., Hui, V., Li, G., Lin, H., Liang, L., Lai, J., Lai, M., Cheung, J. K., Chan, H., Chan, S., Kong, A., Wong, G., Wong, V. 2023; 57 (10): 1103-1116

    Abstract

    We aimed to determine the trends in risk factor control and treatment among patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) in 2000-2020.We conducted a territory-wide cohort study of adult patients with NAFLD and T2D diagnosed between 1 January 2000 and 31 July 2021 in Hong Kong. T2D was defined by use of any anti-diabetic agents, laboratory tests and/or diagnosis codes.This study included 16,084 patients with NAFLD and T2D (mean age, 54.8 ± 12.0 years; 7124 male [44.3%]). The percentage of patients achieving individualised haemoglobin A1c (HbA1c ) targets increased from 44.5% (95% confidence interval [CI], 42.9-46.1) to 64.8% (95% CI, 64.1-65.5), and percentage of patients achieving individualised low-density lipoprotein-cholesterol (LDL-C) targets increased from 23.3% (95% CI, 21.9-24.7) to 54.3% (95% CI, 53.5-55.1) from 2000-2005 to 2016-2020, whereas percentage of patients achieving blood pressure control (<140/90 mm Hg) remained static at 53.1-57.2%. Combination therapy for diabetes increased, especially among those with poor glycaemic control, but there was no increase in combination therapy for hypertension. Fewer cirrhotic patients achieved blood pressure control and individualised LDL-C targets, but they were more likely to achieve individualised HbA1c targets than non-cirrhotics. Metformin and statins were underused in cirrhotic patients. Younger patients (18-44 years) were less likely to achieve individualised HbA1c targets than middle-aged (45-64 years) and older ones (≥65 years).From 2000 to 2020, glycaemic and lipid control improved significantly, whereas blood pressure control remained static among patients with NAFLD and T2D.

    View details for DOI 10.1111/apt.17428

    View details for Web of Science ID 000936426600001

    View details for PubMedID 36815548

  • Risk of liver-related events by age and diabetes duration in patients with diabetes and nonalcoholic fatty liver disease. Hepatology (Baltimore, Md.) Zhang, X., Wong, G. L., Yip, T. C., Cheung, J. T., Tse, Y. K., Hui, V. W., Lin, H., Lai, J. C., Chan, H. L., Kong, A. P., Wong, V. W. 2022; 76 (5): 1409-1422

    Abstract

    Several guidelines recommend screening for NAFLD in patients with type 2 diabetes (T2D). We aimed to determine if there is a threshold of age and duration of T2D for liver-related event development to guide screening strategies.We conducted a territory-wide retrospective cohort study of adult patients with NAFLD and T2D diagnosed between 2000 and 2014 in Hong Kong to allow for at least 5 years of follow-up. The primary endpoint was liver-related events, defined as a composite of HCC and cirrhotic complications. This study included 7028 patients with NAFLD with T2D (mean age, 56.1 ± 13.3 years; 3363 male [47.9%]). During a follow-up of 77,308 person-years, there was a threshold effect with 1.1%, 4.9%, and 94.0% of patients developing liver-related events at the age of <40, 40-50, and ≥50 years, respectively. Similarly, 3.1%, 5.1%, and 91.8% of patients developed cirrhosis at the age of <40, 40-50, and ≥50 years, respectively. In contrast, liver-related events increased linearly with diabetes duration, with no difference in the annual incidence rate between the first 10 years of T2D diagnosis and subsequent years (0.06% vs. 0.10%; p = 0.136). On multivariable analysis, baseline age ≥50 years (adjusted HR [aHR] 2.01) and cirrhosis (aHR 3.12) were the strongest risk factors associated with liver-related events. Substitution of cirrhosis with the aspartate aminotransferase-to-platelet ratio index or the Fibrosis-4 index yielded similar results.Age rather than duration of T2D predicts liver-related events in patients with NAFLD and T2D. It is reasonable to screen patients with NAFLD and T2D for advanced liver disease starting at 50 years of age.

    View details for DOI 10.1002/hep.32476

    View details for PubMedID 35334125

  • Angiotensin-converting enzyme inhibitors prevent liver-related events in nonalcoholic fatty liver disease. Hepatology (Baltimore, Md.) Zhang, X., Wong, G. L., Yip, T. C., Tse, Y. K., Liang, L. Y., Hui, V. W., Lin, H., Li, G. L., Lai, J. C., Chan, H. L., Wong, V. W. 2022; 76 (2): 469-482

    Abstract

    Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) can inhibit liver fibrogenesis in animal models. We aimed to evaluate the impact of ACEI/ARB use on the risk of liver cancer and cirrhosis complications in patients with NAFLD.We conducted a retrospective, territory-wide cohort study of adult patients with NAFLD diagnosed between January 2000 and December 2014 to allow for at least 5 years of follow-up. ACEI or ARB users were defined as patients who had received ACEI or ARB treatment for at least 6 months. The primary endpoint was liver-related events (LREs), defined as a composite endpoint of liver cancer and cirrhosis complications. We analyzed data from 12,327 NAFLD patients (mean age, 54.2 ± 14.7 years; 6163 men [50.0%]); 6805 received ACEIs, and 2877 received ARBs. After propensity score weighting, ACEI treatment was associated with a lower risk of LREs (weighted subdistribution hazard ratio [SHR], 0.48; 95% CI, 0.35-0.66; p < 0.001), liver cancer (weighted SHR, 0.46; 95% CI, 0.28-0.75; p = 0.002), and cirrhosis complications (weighted SHR, 0.42; 95% CI, 0.27-0.66; p < 0.001), but ARB was not. In subgroup analysis, ACEI treatment was associated with greater reduction in LREs in patients with chronic kidney diseases (CKDs) than those without (CKD-weighted SHR, 0.74; 95% CI, 0.52-0.96; p = 0.036; non-CKD-weighted SHR, 0.15; 95% CI, 0.07-0.33; p < 0.001).ACEI, rather than ARB, treatment is associated with a lower risk of LREs in NAFLD patients, especially among those with CKD.

    View details for DOI 10.1002/hep.32294

    View details for PubMedID 34939204

  • Epidemiology and Clinical Outcomes of Metabolic (Dysfunction)-associated Fatty Liver Disease. Journal of clinical and translational hepatology Lin, H., Zhang, X., Li, G., Wong, G. L., Wong, V. W. 2021; 9 (6): 972-982

    Abstract

    Metabolic (dysfunction)-associated fatty liver disease (MAFLD) is currently the most common chronic liver disease and affects at least a quarter of the global adult population. It has rapidly become one of the leading causes of hepatocellular carcinoma and cirrhosis in Western countries. In this review, we discuss the nomenclature and definition of MAFLD as well as its prevalence and incidence in different geographical regions. Although cardiovascular disease remains the leading cause of death in MAFLD patients, the proportion of patients dying from hepatic complications increases sharply as the disease progresses to advanced liver fibrosis and cirrhosis. In addition, patients with MAFLD are at increased risk of various extrahepatic cancers. Although a causal relationship between MAFLD and extrahepatic cancers has not been established, clinicians should recognize the association and consider cancer screening (e.g., for colorectal cancer) as appropriate.

    View details for DOI 10.14218/JCTH.2021.00201

    View details for PubMedID 34966660

    View details for PubMedCentralID PMC8666360

  • Colonoscopy and Risk of Colorectal Cancer in Patients With Nonalcoholic Fatty Liver Disease: A Retrospective Territory-Wide Cohort Study. Hepatology communications Zhang, X., Wong, V. W., Yip, T. C., Tse, Y. K., Liang, L. Y., Hui, V. W., Li, G. L., Chan, H. L., Wong, G. L. 2021; 5 (7): 1212-1223

    Abstract

    The benefit of colonoscopy and/or polypectomy for colorectal cancer (CRC) prevention in patients with nonalcoholic fatty liver disease (NAFLD) remains unclear. We aimed to estimate the incidence rate of CRC in patients with NAFLD who had and had not undergone colonoscopy. We conducted a retrospective territory-wide cohort study for patients aged over 40 years with NAFLD identified with the International Classification of Diseases, Ninth Revision, Clinical Modification codes between January 1, 2000, and December 31, 2014. Patients were followed until CRC diagnosis, death, or December 31, 2017. We estimated CRC incidence and standardized incidence ratio (SIR) using the general population of Hong Kong as reference. We included 8,351 patients with NAFLD in the final analysis (median age, 56.2 years; interquartile ratio [IQR], 49.2-65.3 years; 45.4% male; median follow-up, 7.4 years; IQR, 5.4-9.6 years). Compared with the general population, patients with NAFLD who had not undergone colonoscopy had a higher incidence of CRC (SIR, 2.20; 95% confidence interval [CI], 1.64-2.88; P < 0.001). Patients with NAFLD who had undergone colonoscopy had a lower incidence of CRC (SIR, 0.54; 95% CI, 0.37-0.75; P < 0.001), especially among those aged above 50 years or with diabetes mellitus (DM). Patients with NAFLD with a high fibrosis-4 (FIB-4) score (>2.67) had a significantly higher risk of CRC after adjusting for demographic and metabolic factors. Conclusion: Patients with NAFLD who had undergone colonoscopy had a lower incidence of CRC than the general population, especially among those aged ≥50 years or with DM. A high FIB-4 index was associated with a higher risk of CRC.

    View details for DOI 10.1002/hep4.1705

    View details for PubMedID 34278170

    View details for PubMedCentralID PMC8279466

  • Unhealthy lifestyle habits and physical inactivity among Asian patients with non-alcoholic fatty liver disease. Liver international : official journal of the International Association for the Study of the Liver Zhang, X., Goh, G. B., Chan, W. K., Wong, G. L., Fan, J. G., Seto, W. K., Huang, Y. H., Lin, H. C., Lee, I. C., Lee, H. W., Kim, S. U., Chow, W. C., Wong, V. W. 2020; 40 (11): 2719-2731

    Abstract

    Lifestyle modification is the cornerstone for the management of non-alcoholic fatty liver disease (NAFLD). We aim to understand lifestyle habits of NAFLD patients, compare across Asian regions and identify area of deficiency.In the multi-centre controlled attenuation parameter (CAP)-Asia study, we collected clinical data and lifestyle habit data of NAFLD patients from Singapore, mainland China, Hong Kong, Taiwan and Malaysia. Physical activity was assessed using the International Physical Activity Questionnaire.A total of 555 patients were included in the final analysis (mean age 54.5 ± 11.2 years, 54.1% men and median liver stiffness 6.7 kPa). More patients from mainland China (27.4%) and Taipei (25.0%) were smokers. Modest drinking was more common in Taiwan (25.0%) and Hong Kong (18.2%); only 1.3% had binge drinking. Majority of patients drank coffee (64.0%) and tea (80.2%), with varying amounts and durations in different regions. Soft drinks consumption was most common in Singapore (62.2%) and Malaysia (57.7%). Only 29.7% of patients met the Physical Activity Guidelines Recommendations, with no major differences across regions. Patients with liver stiffness <10 kPa were more likely to report any vigorous activity, and sitting time was an independent factor associated with high CAP. Tea and coffee consumption were independently associated with high CAP and liver stiffness, respectively.Despite some heterogeneity, unhealthy lifestyle and physical inactivity are common across Asian regions. Patients with liver stiffness <10 kPa were more likely to report any vigorous activity. Healthcare providers may use the comparative data to identify areas of deficiency.

    View details for DOI 10.1111/liv.14638

    View details for PubMedID 32799384

  • Application of transient elastography in nonalcoholic fatty liver disease. Clinical and molecular hepatology Zhang, X., Wong, G. L., Wong, V. W. 2020; 26 (2): 128-141

    Abstract

    Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease worldwide. Although it has become one of the leading causes of cirrhosis and hepatocellular carcinoma in the Western world, the proportion of NAFLD patients developing these complications is rather small. Therefore, current guidelines recommend noninvasive tests for the initial assessment of NAFLD. Among the available non-invasive tests, transient elastography by FibroScan® (Echosens, Paris, France) is commonly used by hepatologists in Europe and Asia, and the machine has been introduced to the United States in 2013 with rapid adoption. Transient elastography measures liver stiffness and the controlled attenuation parameter simultaneously and can serve as a one-stop examination for both liver steatosis and fibrosis. Liver stiffness measurement also correlates with clinical outcomes and can be used to select patients for varices screening. Although obesity is a common reason for measurement failures, the development of the XL probe allows successful measurements in the majority of obese patients. This article reviews the performance and limitations of transient elastography in NAFLD and highlights its clinical applications. We also discuss the reliability criteria for transient elastography examination and factors associated with false-positive liver stiffness measurements.

    View details for DOI 10.3350/cmh.2019.0001n

    View details for PubMedID 31696690

    View details for PubMedCentralID PMC7160347

  • A liver stiffness-based etiology-independent machine learning algorithm to predict hepatocellular carcinoma. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association Lin, H., Li, G., Delamarre, A., Ahn, S. H., Zhang, X., Kim, B. K., Liang, L. Y., Lee, H. W., Lai-Hung Wong, G., Yuen, P., Lik-Yuen Chan, H., Chan, S. L., Wai-Sun Wong, V., de Ledinghen, V., Kim, S. U., Cheuk-Fung Yip, T. 2023

    Abstract

    BACKGROUND & AIMS: The existing hepatocellular carcinoma (HCC) risk scores have modest accuracy and most are specific to chronic hepatitis B infection. In this study, we developed and validated a liver stiffness-based machine learning algorithm (ML) for prediction and risk stratification of HCC in various chronic liver diseases (CLDs).METHODS: MLs were trained for prediction of HCC in 5155 adult patients with various CLDs in Korea and further tested in two prospective cohorts from Hong Kong (HK, N=2732) and Europe (N=2384). Model performance was assessed according to Harrell's C-index and time-dependent receiver operating characteristic (ROC) curve.RESULTS: We developed the SMART-HCC score, a liver stiffness-based ML HCC risk score, with liver stiffness measurement ranked as the most important among 9 clinical features. The Harrell's C-index of the SMART-HCC score in HK and Europe validation cohorts were 0.89 (95% confidence interval [CI] 0.85-0.92) and 0.91 (95%CI 0.87-0.95), respectively. The area under ROC curves of the SMART-HCC score for HCC in 5 years were ≥0.89 in both validation cohorts. The performance of SMART-HCC score was significantly better than existing HCC risk scores including aMAP score, Toronto HCC risk index, and seven hepatitis B related risk scores. Using dual cut-offs of 0.043 and 0.080, the annual HCC incidence was 0.09%-0.11% for low-risk group, and 2.54%-4.64% for high-risk group in the HK and Europe validation cohorts.CONCLUSION: The SMART-HCC score is a useful machine learning-based tool for clinicians to stratify HCC risk in patients with CLDs.

    View details for DOI 10.1016/j.cgh.2023.11.005

    View details for PubMedID 37993034

  • COMPARISON OF CHARACTERISTICS AND OUTCOMES IN PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASE WHO DID OR DIDN'T RECEIVE LIVER BIOPSY Zhang, X., Kam, L., Barnett, S. D., Henry, L., Cheung, R., Nguyen, M. H. LIPPINCOTT WILLIAMS & WILKINS. 2023: S931
  • Diagnostic and prognostic performance of the SAFE score in non-alcoholic fatty liver disease. Liver international : official journal of the International Association for the Study of the Liver Li, G., Lin, H., Sripongpun, P., Liang, L. Y., Zhang, X., Wong, V. W., Wong, G. L., Kim, W. R., Yip, T. C. 2023

    Abstract

    The steatosis-associated fibrosis estimator (SAFE) score was developed to detect clinically significant liver fibrosis in patients with NAFLD in the United States. We compare the performance of the SAFE score and other non-invasive tests to diagnose liver fibrosis and to correlate the scores with liver-related outcomes in patients with NAFLD in Hong Kong.This was a retrospective cohort study involving two data sets. The first cohort was a biopsy cohort of NAFLD patients (n = 279), and the second was a territory-wide cohort of NAFLD patients (n = 4603) retrieved from a territory-wide electronic healthcare database in Hong Kong.In detecting significant fibrosis, liver stiffness measured by transient elastography had the highest area under the receiver operating characteristic curve (AUROC) (.844), followed by SAFE score (.773). SAFE score had the highest AUROC among blood-based algorithms (.773 vs. .746 for FIB-4, .697 for APRI). Based on cut-off values of SAFE score (0 and 100 points), 854 (18.6%), 1596 (34.6%) and 2153 (46.8%) were in the low-, intermediate- and high-risk groups, respectively, in the territory-wide cohort. Six (.7%), 15 (.9%) and 59 (2.7%) developed liver-related events in those three groups respectively. Among patients who had liver-related events at 5 years, using the high cut-off, SAFE score could predict 84.9% of patients accurately, compared to 40.9% for FIB-4 and 27.2% for APRI.The SAFE score performed well and better than other blood-based markers in diagnosing significant fibrosis and predicting liver-related events in Asian patients with NAFLD.

    View details for DOI 10.1111/liv.15718

    View details for PubMedID 37650363

  • Dynamic Glucose-Enhanced Imaging of the Liver Using Breath-Hold Black Blood Quantitative T1ρ MRI at 3.0 T. Journal of magnetic resonance imaging : JMRI Qian, Y., Wong, V. W., Wang, Y. X., Hou, J., Jiang, B., Zhang, X., Wong, G. L., Chan, Q., Yu, S. C., Chu, W. C., Chen, W. 2023

    View details for DOI 10.1002/jmri.28829

    View details for PubMedID 37317614

  • Diagnostic and prognostic performance of the SAFE score in nonalcoholic fatty liver disease Li, G., Lin, H., Sripongpun, P., Liang, Y., Zhang, X., Wong, V., Wong, G., Kim, W., Yip, T. ELSEVIER. 2023: S663-S664
  • Age and the relative importance of liver-related deaths in nonalcoholic fatty liver disease HEPATOLOGY Lin, H., Yip, T., Zhang, X., Li, G., Tse, Y., Hui, V., Liang, L., Lai, J., Chan, S., Chan, H., Wong, G., Wong, V. 2023; 77 (2): 573-584

    Abstract

    It is unclear if the leading causes of death in patients with NAFLD differ by age. We aimed to investigate if the relative importance of liver-related deaths is lower and overshadowed by cardiovascular and cancer-related deaths in the elderly population.We conducted a territory-wide retrospective cohort study of adult patients with NAFLD between 2000 and 2021 in Hong Kong. The outcomes of interest were all-cause and cause-specific mortality. Age groups at death were studied at 10-year intervals. During 662,471 person-years of follow-up of 30,943 patients with NAFLD, there were 2097 deaths. The top three causes of death were pneumonia, extrahepatic cancer, and cardiovascular diseases. Liver disease was the sixth leading cause of death in patients aged 70-79 and 80-89 years, accounting for 5.1% and 5.9% of deaths, respectively, but only accounted for 3% or fewer of the deaths in the other age groups. Nonetheless, liver disease was the leading cause of death in patients with NAFLD-related cirrhosis, accounting for 36.8% of all deaths. The incidence of liver-related death was higher in men younger than age 70 but higher in women afterwards. The incidence of liver-related death in women increased from 0.62 to 7.14 per 10,000 person-years from age 60-69 to 70-79 years.The relative importance of liver-related death increases with age in patients with NAFLD, especially among women. In patients with cirrhosis, liver disease is the leading cause of death.

    View details for DOI 10.1002/hep.32633

    View details for Web of Science ID 000927039600035

    View details for PubMedID 35790018

  • Trimethylamine-N-Oxide Aggravates Kidney Injury via Activation of p38/MAPK Signaling and Upregulation of HuR. Kidney & blood pressure research Lai, Y., Tang, H., Zhang, X., Zhou, Z., Zhou, M., Hu, Z., Zhu, F., Zhang, L., Nie, J. 2022; 47 (1): 61-71

    Abstract

    Trimethylamine-N-oxide (TMAO) is an intestinal metabolic toxin, which is produced by gut flora via metabolizing high-choline foods. TMAO is known to increase the risk of atherosclerosis and cardiovascular events in chronic kidney disease (CKD) patients.The objective of this study was to explore the role and mechanism of TMAO aggravating kidney injury.We used the five-sixths nephrectomy (5/6 Nx)-induced CKD rats to investigate whether TMAO could aggravate kidney damage and its possible mechanisms. Six weeks after the operation, the two groups of 5/6 Nx rats were subjected to intraperitoneal injection with 2.5% glucose peritoneal dialysis fluid (2.5% PDF) and 2.5% PDF plus TMAO 20 mg/kg/day.In this study, we provided evidence showing TMAO significantly aggravated renal failure as well as inflammatory cell infiltration and in five-sixths nephrectomy-induced CKD rats. We found that TMAO could upregulate inflammatory factors including MCP-1, TNF-α, IL-6, IL-1β, and IL-18 by activating p38 phosphorylation and upregulation of human antigen R. TMAO could aggravate oxidative stress by upregulating NOX4 and downregulating SOD. The result also confirmed that TMAO promoted NLRP3 inflammasome formation as well as cleaved caspase-1 and IL-1β activation in the kidney tissue.Taken together, the present study validates TMAO as a pro-inflammatory factor that causes renal inflammatory injury and renal function impairment. Inhibition of TMAO synthesis or promoting its clearance may be a potential therapeutic approach of CKD in the future.

    View details for DOI 10.1159/000519603

    View details for PubMedID 34788763

  • Universal HBV vaccination dramatically reduces the prevalence of HBV infection and incidence of hepatocellular carcinoma. Alimentary pharmacology & therapeutics Wong, G. L., Hui, V. W., Yip, T. C., Liang, L. Y., Zhang, X., Tse, Y. K., Lai, J. C., Chan, H. L., Wong, V. W. 2022; 56 (5): 869-877

    Abstract

    Universal vaccination of newborns with hepatitis B virus (HBV) vaccine is the most important strategy to prevent chronic HBV infection and its complications of which hepatocellular carcinoma (HCC) as the deadliest.To evaluate the impact of universal HBV vaccination on the prevalence of chronic HBV infection, and the incidences of HCC and hepatic events in young adults born before and after the introduction of the universal HBV vaccination programme in 1988 in Hong Kong METHODS: This was a territory-wide retrospective observational cohort study of consecutive adult subjects born in 1970-2002 with hepatitis B surface antigen (HBsAg) checked. Subjects born during the vaccination era (1988-2002) were included in the vaccinated cohort; subjects born between 1970 and 1987 were included in the unvaccinated cohort.We included 695,925 subjects for HBV prevalence analysis. Chronic HBV infection dropped from 14.3% in subjects born in 1970, to 6.7% in subjects born in 1988. In total, 53,960 vaccinated and 318,290 unvaccinated subjects who had available clinical data were included for event analysis. HCC and hepatic events occurred in 44 (0.1%) and 75 (0.1%) of the vaccinated subjects and in 1305 (0.4%) and 1806 (0.6%) of the unvaccinated subjects, respectively. All incidence rates remained numerically lower in vaccinated subjects after adjustment for age, gender and antiviral treatment, but failed to reach statistical significance due to very low incidence rates.Universal HBV vaccination markedly reduces the prevalence of chronic HBV infection and may contribute to the decreased incidences of HCC and hepatic events.

    View details for DOI 10.1111/apt.17120

    View details for PubMedID 35864571

  • Reply. Hepatology (Baltimore, Md.) Zhang, X., Wong, G. L., Yip, T. C., Wong, V. W. 2022; 76 (2): E34-E35

    View details for DOI 10.1002/hep.32431

    View details for PubMedID 35220620

  • Gut microbial metabolite TMAO increases peritoneal inflammation and peritonitis risk in peritoneal dialysis patients. Translational research : the journal of laboratory and clinical medicine Zhang, L., Xie, F., Tang, H., Zhang, X., Hu, J., Zhong, X., Gong, N., Lai, Y., Zhou, M., Tian, J., Zhou, Z., Xie, L., Hu, Z., Zhu, F., Jiang, J., Nie, J. 2022; 240: 50-63

    Abstract

    Trimethylamine-N-oxide (TMAO), a gut microbiota-produced metabolite, is accumulated in chronic kidney disease (CKD) patients. It is well known to contribute to CKD-related cardiovascular complications. However, the effect of TMAO on peritoneal dialysis (PD)-related peritonitis remains largely unknown. Here, we demonstrate that serum concentrations of TMAO were positively correlated with C-reactive protein levels, and the appearance rate of dialysate IL-6 and PAI-1, in PD patients. During the follow-up period of 28.3 ± 8.0 months, patients with higher TMAO levels (≥50 μM) had a higher risk of new-onset peritonitis (HR, 3.60; 95%CI, 1.18-10.99; P=0.025) after adjusting for sex, age, diabetes, PD duration, BUN, rGFR, C-reactive protein, BMI and β2-M. In CKD rat models, TMAO significantly promoted peritoneal dialysate-induced inflammatory cell infiltration, inflammatory cytokines production in the peritoneum. In vitro study revealed that TMAO directly induced primary peritoneal mesothelial cell necrosis, together with increased production of pro-inflammatory cytokines including CCL2, TNF-α, IL-6, and IL-1β. In addition, TMAO significantly increased TNF-α-induced P-selectin production in mesothelial cells, as well as high glucose-induced TNF-α and CCL2 expression in endothelial cells. In conclusion, our data demonstrate that higher levels of TMAO exacerbate peritoneal inflammation and might be a risk factor of incidence of peritonitis in PD patients.

    View details for DOI 10.1016/j.trsl.2021.10.001

    View details for PubMedID 34673277

  • U-shaped relationship between urea level and hepatic decompensation in chronic liver diseases. Clinical and molecular hepatology Lin, H., Wong, G. L., Zhang, X., Yip, T. C., Liu, K., Tse, Y. K., Hui, V. W., Lai, J. C., Chan, H. L., Wong, V. W. 2022; 28 (1): 77-90

    Abstract

    We aimed to determine the association between blood urea level and incident cirrhosis, hepatic decompensation, and hepatocellular carcinoma in chronic liver disease (CLD) patients.The association between blood urea level and liver fibrosis/liver-related events were evaluated on continuous scale with restricted cubic spline curves based on generalized additive model or Cox proportional hazards models. Then, the above associations were evaluated by urea level within intervals.Among 4,282 patients who had undergone liver stiffness measurement (LSM) by transient elastography, baseline urea level had a U-shaped association with LSM and hepatic decompensation development after a median follow-up of 5.5 years. Compared to patients with urea of 3.6-9.9 mmol/L, those with urea ≤3.5 mmol/L (adjusted hazard ratio [aHR], 4.15; 95% confidence interval [CI], 1.68-10.24) and ≥10 mmol/L (aHR, 5.22; 95% CI, 1.86-14.67) had higher risk of hepatic decompensation. Patients with urea ≤3.5 mmol/L also had higher risk of incident cirrhosis (aHR, 3.24; 95% CI, 1.50-6.98). The association between low urea level and incident cirrhosis and hepatic decompensation was consistently observed in subgroups by age, gender, albumin level, and comorbidities. The U-shaped relationship between urea level and LSM was validated in another population screening study (n=917). Likewise, urea ≤3.5 mmol/L was associated with a higher risk of incident cirrhosis in a territory-wide cohort of 12,476 patients with nonalcoholic fatty liver disease at a median follow-up of 9.9 years (aHR, 1.27; 95% CI, 1.03-1.57).We identified a U-shaped relationship between the urea level and liver fibrosis/incident cirrhosis/hepatic decompensation in patients with CLD.

    View details for DOI 10.3350/cmh.2021.0188

    View details for PubMedID 34736312

    View details for PubMedCentralID PMC8755470

  • Association of metformin use on metabolic acidosis in diabetic patients with chronic hepatitis B-related cirrhosis and renal impairment. Health science reports Yip, T. C., Chan, R. N., Wong, V. W., Tse, Y. K., Liang, L. Y., Hui, V. W., Zhang, X., Li, G. L., Chan, H. L., Wong, G. L. 2021; 4 (3): e352

    Abstract

    Metformin is an oral anti-hyperglycemic recommended by the American Diabetes Association (ADA) as a preferred initial pharmacologic agent for type 2 diabetes. Metabolic acidosis is a rare yet severe side effect of it. We examined the association of metformin use and dosage on the risk of metabolic acidosis in diabetic patients with different degrees of chronic hepatitis B (CHB)-related cirrhosis and chronic kidney disease (CKD).Metabolic acidosis was defined by blood pH ≤7.35, together with lactate >5 mmol/L or arterial bicarbonate ≤18 mmol/L or venous bicarbonate ≤21 mmol/L, and/or diagnosis codes. Child-Pugh class and CKD stage were included in the model as time-dependent covariates. Age, gender, comorbidities, and use of relevant medications were adjusted as covariates. Maximum daily dose of metformin was classified into ≤1000 mg and >1000 mg.We identified 4431 diabetic patients with CHB-related cirrhosis between 2000 and 2017 from a territory-wide database in Hong Kong. The risk of metabolic acidosis increased with Child-Pugh class B and C cirrhosis regardless of CKD stage (adjusted subdistribution hazard ratio [aSHR] ranged from 3.50 to 86.16). Metformin use was associated with a higher risk in patients with Child-Pugh class B or C cirrhosis and stage 3A CKD or above (aSHR ranged from 1.55 to 2.46). In stage 4/5 CKD, a daily dose of metformin ≤1000 mg was still associated with a higher risk of metabolic acidosis regardless of the severity of cirrhosis (aSHR ranged from 2.45 to 3.92).In conclusion, patients with Child-Pugh class B cirrhosis or above were at a higher risk of metabolic acidosis. Metformin further increased the risk in patients with Child-Pugh class B cirrhosis or above and stage 3A CKD or above. Dose adjustment in stage 4/5 CKD did not reduce the risk of metabolic acidosis.

    View details for DOI 10.1002/hsr2.352

    View details for PubMedID 34401527

    View details for PubMedCentralID PMC8358231

  • Similarly low risk of hepatocellular carcinoma after either spontaneous or nucleos(t)ide analogue-induced hepatitis B surface antigen loss. Alimentary pharmacology & therapeutics Yip, T. C., Wong, V. W., Tse, Y. K., Liang, L. Y., Hui, V. W., Zhang, X., Li, G. L., Lui, G. C., Chan, H. L., Wong, G. L. 2021; 53 (2): 321-331

    Abstract

    It is unknown whether patients with chronic hepatitis B (CHB) who achieved hepatitis B surface antigen (HBsAg) seroclearance spontaneously or following anti-viral therapy have similar clinical outcomes.To compare the risk of hepatocellular carcinoma (HCC) in patients with CHB who either cleared HBsAg spontaneously or following anti-viral therapy METHODS: Adult CHB-monoinfected patients who cleared HBsAg between January 2000 and March 2019 were identified from a territory-wide database in Hong Kong. Patients with liver transplantation and/or HCC before HBsAg loss were excluded. Patients' demographics, comorbidities, anti-viral treatment, laboratory parameters and HCC development were analysed.Of 7,124 identified patients with CHB who cleared HBsAg, mean age was 58.1 ± 13.8 years; 4,340 (60.9%) were male; 451 (6.3%) had cirrhosis; 5,917 (83.1%) and 1,207 (16.9%) had spontaneous and nucleos(t)ide analogue (NA)-induced HBsAg seroclearance, respectively. Most patients had normal liver function at HBsAg loss. Patients with NA-induced HBsAg seroclearance were younger, and more likely to be male and cirrhotic than patients with spontaneous HBsAg loss. At a median (interquartile range) follow-up of 4.3 (2.2-7.6) years, 97 (1.6%) and 16 (1.3%) patients with spontaneous and NA-induced HBsAg loss developed HCC, respectively. Patients who achieved NA-induced HBsAg loss had comparable HCC risk as those with spontaneous HBsAg loss (adjusted subdistribution hazard ratio 0.75, 95% CI 0.43-1.32, P = 0.323). The results remained robust in propensity score weighting and matching analyses.The HCC risk was similarly low after either spontaneous or NA-induced HBsAg seroclearance in a territory-wide cohort of patients with CHB who had cleared HBsAg.

    View details for DOI 10.1111/apt.16174

    View details for PubMedID 33222272