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  1. Chan WK, Petta S, Noureddin M, Goh GBB, Wong VW
    Aliment Pharmacol Ther, 2024 Jun;59 Suppl 1:S23-S40.
    PMID: 38813831 DOI: 10.1111/apt.17866
    BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most common chronic liver disease and an important cause of cirrhosis and hepatocellular carcinoma. It is strongly associated with type 2 diabetes and obesity. Because of the huge number of patients at risk of MASLD, it is imperative to use non-invasive tests appropriately.

    AIMS: To provide a narrative review on the performance and limitations of non-invasive tests, with a special emphasis on the impact of diabetes and obesity.

    METHODS: We searched PubMed and Cochrane databases for articles published from 1990 to August 2023.

    RESULTS: Abdominal ultrasonography remains the primary method to diagnose hepatic steatosis, while magnetic resonance imaging proton density fat fraction is currently the gold standard to quantify steatosis. Simple fibrosis scores such as the Fibrosis-4 index are well suited as initial assessment in primary care and non-hepatology settings to rule out advanced fibrosis and future risk of liver-related complications. However, because of its low positive predictive value, an abnormal test should be followed by specific blood (e.g. Enhanced Liver Fibrosis score) or imaging biomarkers (e.g. vibration-controlled transient elastography and magnetic resonance elastography) of fibrosis. Some non-invasive tests of fibrosis appear to be less accurate in patients with diabetes. Obesity also affects the performance of abdominal ultrasonography and transient elastography, whereas magnetic resonance imaging may not be feasible in some patients with severe obesity.

    CONCLUSIONS: This article highlights issues surrounding the clinical application of non-invasive tests for MASLD in patients with type 2 diabetes and obesity.

  2. Danpanichkul P, Ng CH, Tan DJH, Wijarnpreecha K, Huang DQ, Noureddin M, et al.
    Clin Gastroenterol Hepatol, 2024 Sep;22(9):1947-1949.e3.
    PMID: 38428708 DOI: 10.1016/j.cgh.2024.02.011
    Alcohol is a substance that impacts premature mortality and morbidity.1 The liver is invariably subjected to the impact of alcohol, which can result in cirrhosis and cancer. Alcohol also has detrimental effects that extend beyond the liver. While traditionally associated with advanced age, emerging data reported a rising burden of cancers and alcohol-associated liver disease in the young.1-3 Thus, the primary objective was to evaluate the trend of alcohol-associated cirrhosis and cancer in young and middle-aged adults (aged 15-49) utilizing the Global Burden of Disease Study (GBD) 2019.4 We chose the age group less than 50 years old based on the definition of early-onset cancer and the inherent selection of the age group in the GBD database.4-6 The detailed methods are provided in the Supplementary Appendix. Briefly, data were sourced from population-based cancer registries, vital registration systems, or verbal autopsy studies. Verbal autopsy is a well-established approach for monitoring health, providing valuable information on mortality patterns and the reasons behind deaths in areas lacking robust medical death certification processes. The researchers employed the Cause of Death Ensemble model to estimate the burden linked to cancer and cirrhosis associated with alcohol use.
  3. Lim WH, Tay P, Ng CH, Tan DJH, Ong C, Koh JH, et al.
    Aliment Pharmacol Ther, 2024 Mar;59(6):730-741.
    PMID: 38303565 DOI: 10.1111/apt.17888
    BACKGROUND: Although alcohol abstinence may be an effective intervention for alcohol-associated cirrhosis, its association with prognosis has not been systematically assessed or quantified.

    AIMS: To determine the prevalence of alcohol abstinence, factors associated with alcohol abstinence and the impact of abstinence on morbidity and overall survival in people with alcohol-associated cirrhosis.

    METHODS: We searched Medline and Embase from inception to 15 April 2023 for prospective and retrospective cohort studies describing alcohol abstinence in people with known alcohol-associated cirrhosis. Meta-analysis of proportions for pooled estimates was performed. The method of inverse variance, employing a random-effects model, was used to pool the hazard ratio (HR) comparing outcomes of abstinent against non-abstinent individuals with alcohol-associated cirrhosis.

    RESULTS: We included 19 studies involving 18,833 people with alcohol-associated cirrhosis. The prevalence of alcohol abstinence was 53.8% (CI: 44.6%-62.7%). Over a mean follow-up duration of 48.6 months, individuals who continued to consume alcohol had significantly lower overall survival compared to those who were abstinent (HR: 0.611, 95% CI: 0.506-0.738). These findings remained consistent in sensitivity/subgroup analysis for the presence of decompensation, study design and studies that assessed abstinence throughout follow-up. Alcohol abstinence was associated with a significantly lower risk of hepatic decompensation (HR: 0.612, 95% CI: 0.473-0.792).

    CONCLUSIONS: Alcohol abstinence is associated with substantial improvement in overall survival in alcohol-associated cirrhosis. However, only half of the individuals with known alcohol-associated cirrhosis are abstinent.

  4. Xiao J, Ng CH, Chan KE, Fu C, Tay P, Yong JN, et al.
    J Clin Exp Hepatol, 2023;13(4):656-665.
    PMID: 37440949 DOI: 10.1016/j.jceh.2022.11.006
    BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease globally. While the prevalence, impact, and causes of mortality have been described in various meta-analyses, a systematic all-encompassing umbrella review has yet to be conducted to consolidate the evidence on outcomes associated with NAFLD.

    METHODS: Search was conducted on Medline and Embase for meta-analysis investigating associated complications and causes of mortality in NAFLD patients. Summary estimates were presented with original units, sample size, and I2 for heterogeneity. The Assessment of Multiple Systematic Reviews 2 was employed for article selection.

    RESULTS: 25 meta-analyses were included in the present review. NAFLD increased the risks of systemic complications, including cardiovascular diseases, systemic malignancies, diabetes, and chronic kidney disease. Regarding hepatic outcomes, the incidence of hepatocellular carcinoma in NAFLD was 2.39 per 100 person years (CI: 1.40 to 4.08). Individuals with NAFLD were also found to have an increased likelihood of cholangiocarcinoma (OR: 1.88, CI: 1.25 to 2.83) and gallstone disease (OR: 1.55, CI: 1.31 to 1.82) compared to individuals without NAFLD. NAFLD was associated with a higher risk of fatal and non-fatal CVD events (HR: 1.45, CI: 1.31 to 1.61) compared to individuals without NAFLD. Coronary heart disease and subclinical and clinical coronary heart disease were also significantly elevated in NAFLD individuals compared to individuals without NAFLD. Additionally, NAFLD was associated with an increased risk of all-cause mortality (HR: 1.34, CI: 1.17 to 1.54) and cardiovascular (HR: 1.30, CI: 1.08 to 1.56) but not cancer-related mortality.

    CONCLUSION: The study summarizes high-level evidence from published meta-analyses to provide a much-needed update on the outcomes in patients with NAFLD. The significant systemic burden associated with NAFLD and impending fatty liver epidemic requires prompt action from multidisciplinary providers, policy providers, and stakeholders to reduce the burden of NAFLD.

  5. Ng CH, Wong ZY, Chew NWS, Chan KE, Xiao J, Sayed N, et al.
    Front Cardiovasc Med, 2022;9:942753.
    PMID: 36003916 DOI: 10.3389/fcvm.2022.942753
    BACKGROUND AND AIMS: Hypertension (HTN) is a common comorbidity in non-alcoholic fatty liver disease (NAFLD) affecting up to 40% of individuals. However, the impact of HTN and its control on outcomes in NAFLD remains unclear. Therefore, we aimed to examine the impact of HTN on survival outcomes in a longitudinal cohort of NAFLD patients.

    METHODS: The analysis consisted of adults in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018 with data on socio-demographic characteristics and comorbidities. NAFLD was diagnosed with fatty liver index (FLI) and United States-FLI at a cut-off of 60 and 30, respectively in the substantial absence of alcohol use. A multivariate regression analysis was conducted to adjust for confounders.

    RESULTS: A total of 45,302 adults were included, and 27.83% were identified to have NAFLD. Overall, 45.65 and 35.12% of patients with NAFLD had HTN and uncontrolled HTN, respectively. A multivariate analysis with confounders demonstrated that hypertensive NAFLD had a significantly increased risk of all-cause mortality (HR: 1.39, CI: 1.14-1.68, p < 0.01) and cardiovascular disease (CVD) mortality (HR: 1.85, CI: 1.06-3.21, p = 0.03). Untreated HTN remained to have a significantly increased risk in all-cause (HR: 1.59, CI: 1.28-1.96, p < 0.01) and CVD mortality (HR: 2.36, CI: 1.36-4.10, p < 0.01) while treated HTN had a non-significant increased risk of CVD mortality (HR: 1.51, CI: 0.87-2.63, p = 0.14) and a lower magnitude of increase in the risk of all-cause mortality (HR: 1.26, CI: 1.03-1.55, p = 0.03).

    CONCLUSION: Despite the significant burden of HTN in NAFLD, up to a fifth of patients have adequate control, and the lack thereof significantly increases the mortality risk. With the significant association of HTN in NAFLD, patients with NAFLD should be managed with a multidisciplinary team to improve longitudinal outcomes.

  6. Mózes FE, Lee JA, Vali Y, Selvaraj EA, Jayaswal ANA, Boursier J, et al.
    Liver Int, 2024 Aug;44(8):1872-1885.
    PMID: 38573034 DOI: 10.1111/liv.15914
    BACKGROUND & AIMS: There is a need to reduce the screen failure rate (SFR) in metabolic dysfunction-associated steatohepatitis (MASH) clinical trials (MASH+F2-3; MASH+F4) and identify people with high-risk MASH (MASH+F2-4) in clinical practice. We aimed to evaluate non-invasive tests (NITs) screening approaches for these target conditions.

    METHODS: This was an individual participant data meta-analysis for the performance of NITs against liver biopsy for MASH+F2-4, MASH+F2-3 and MASH+F4. Index tests were the FibroScan-AST (FAST) score, liver stiffness measured using vibration-controlled transient elastography (LSM-VCTE), the fibrosis-4 score (FIB-4) and the NAFLD fibrosis score (NFS). Area under the receiver operating characteristics curve (AUROC) and thresholds including those that achieved 34% SFR were reported.

    RESULTS: We included 2281 unique cases. The prevalence of MASH+F2-4, MASH+F2-3 and MASH+F4 was 31%, 24% and 7%, respectively. Area under the receiver operating characteristics curves for MASH+F2-4 were .78, .75, .68 and .57 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F2-3 were .73, .67, .60, .58 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F4 were .79, .84, .81, .76 for FAST, LSM-VCTE, FIB-4 and NFS. The sequential combination of FIB-4 and LSM-VCTE for the detection of MASH+F2-3 with threshold of .7 and 3.48, and 5.9 and 20 kPa achieved SFR of 67% and sensitivity of 60%, detecting 15 true positive cases from a theoretical group of 100 participants at the prevalence of 24%.

    CONCLUSIONS: Sequential combinations of NITs do not compromise diagnostic performance and may reduce resource utilisation through the need of fewer LSM-VCTE examinations.

  7. Mózes FE, Lee JA, Vali Y, Alzoubi O, Staufer K, Trauner M, et al.
    Lancet Gastroenterol Hepatol, 2023 Aug;8(8):704-713.
    PMID: 37290471 DOI: 10.1016/S2468-1253(23)00141-3
    BACKGROUND: Histologically assessed liver fibrosis stage has prognostic significance in patients with non-alcoholic fatty liver disease (NAFLD) and is accepted as a surrogate endpoint in clinical trials for non-cirrhotic NAFLD. Our aim was to compare the prognostic performance of non-invasive tests with liver histology in patients with NAFLD.

    METHODS: This was an individual participant data meta-analysis of the prognostic performance of histologically assessed fibrosis stage (F0-4), liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE), fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS) in patients with NAFLD. The literature was searched for a previously published systematic review on the diagnostic accuracy of imaging and simple non-invasive tests and updated to Jan 12, 2022 for this study. Studies were identified through PubMed/MEDLINE, EMBASE, and CENTRAL, and authors were contacted for individual participant data, including outcome data, with a minimum of 12 months of follow-up. The primary outcome was a composite endpoint of all-cause mortality, hepatocellular carcinoma, liver transplantation, or cirrhosis complications (ie, ascites, variceal bleeding, hepatic encephalopathy, or progression to a MELD score ≥15). We calculated aggregated survival curves for trichotomised groups and compared them using stratified log-rank tests (histology: F0-2 vs F3 vs F4; LSM: <10 vs 10 to <20 vs ≥20 kPa; FIB-4: <1·3 vs 1·3 to ≤2·67 vs >2·67; NFS: 0·676), calculated areas under the time-dependent receiver operating characteristic curves (tAUC), and performed Cox proportional-hazards regression to adjust for confounding. This study was registered with PROSPERO, CRD42022312226.

    FINDINGS: Of 65 eligible studies, we included data on 2518 patients with biopsy-proven NAFLD from 25 studies (1126 [44·7%] were female, median age was 54 years [IQR 44-63), and 1161 [46·1%] had type 2 diabetes). After a median follow-up of 57 months [IQR 33-91], the composite endpoint was observed in 145 (5·8%) patients. Stratified log-rank tests showed significant differences between the trichotomised patient groups (p<0·0001 for all comparisons). The tAUC at 5 years were 0·72 (95% CI 0·62-0·81) for histology, 0·76 (0·70-0·83) for LSM-VCTE, 0·74 (0·64-0·82) for FIB-4, and 0·70 (0·63-0·80) for NFS. All index tests were significant predictors of the primary outcome after adjustment for confounders in the Cox regression.

    INTERPRETATION: Simple non-invasive tests performed as well as histologically assessed fibrosis in predicting clinical outcomes in patients with NAFLD and could be considered as alternatives to liver biopsy in some cases.

    FUNDING: Innovative Medicines Initiative 2.

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