The effects of anti-TNF-α biologics on insulin resistance and insulin sensitivity in patients with rheumatoid arthritis: An update systematic review and meta-analysis.

BACKGROUND AND AIM: Increasing evidence demonstrates a link between the chronic inflammatory state in patients with rheumatoid arthritis (RA) and the development of insulin resistance. It is thought that anti-TNF-α biologic therapy may improve insulin sensitivity and ameliorate insulin resistance by the downregulation of inflammatory cytokines, however, pre-clinical and clinical studies have yielded conflicting results. A meta-analysis on this topic is necessary to summarize current evidence and generate hypotheses for future research. METHODS: Literature search was performed in four databases, namely PubMed, EMBASE, Scopus, and The Cochrane Library, from inception till April 9, 2023, querying studies reporting peripheral insulin resistance with and without anti-TNF-α use in patients with RA. Peripheral insulin resistance or sensitivity was quantified by the Homeostasis Model Assessment of Insulin Resistance (HOMA) index or the Quantitative Insulin Sensitivity Check Index (QUICKI) respectively. The difference in insulin resistance or sensitivity between the treatment and control group was calculated using standardized mean difference (SMD) for the purposes of the meta-analysis. RESULTS: Twelve articles were reviewed, with 10 longitudinal studies with a total of 297 patients included in the meta-analysis. The pooled standardized mean difference (SMD) from baseline HOMA was -0.82 (95% CI: -1.38 to -0.25) suggesting significant beneficial effects of anti-TNF-α therapy on insulin resistance. CONCLUSION: Current evidence supports the significant clinical efficacy of anti-TNF-α biologics in alleviating insulin resistance and improving insulin sensitivity in patients with active RA.

Survival Trends in Sorafenib for Advanced Hepatocellular Carcinoma: A Reconstructed Individual Patient Data Meta-Analysis of Randomized Trials.

Background: Emerging data suggest that outcomes for advanced hepatocellular carcinoma (HCC) treated with sorafenib may have improved over time. We aimed to provide robust, time-to-event estimates of survival outcomes for sorafenib in advanced HCC. Summary: In this systematic review and individual patient data meta-analysis of randomized-controlled trials (RCTs), we searched MEDLINE and Embase from inception till September 2022 for RCTs that provided data for overall survival (OS) and progression-free survival (PFS) for sorafenib monotherapy as first-line systemic therapy for advanced HCC. We performed a pooled analysis using reconstructed individual participant data from published Kaplan-Meier curves to obtain robust estimates for OS and PFS. Of 1,599 articles identified, 29 studies (5,525 patients) met the inclusion criteria. Overall, the median OS was 10.4 (95% CI: 9.6-11.4) months. Median OS increased over time, from 9.8 (95% CI: 8.8-10.7) months in studies before 2015 to 13.4 (95% CI: 11.03-15.24) months in studies from 2015 onwards (p < 0.001). OS did not differ by trial phase, geographical region, or study design. The overall median PFS was 4.4 (95% CI: 3.9-4.8) months, but PFS did not improve over time. Sensitivity analysis of studies from 2015 and onwards to account for the introduction of direct-acting antivirals determined that hepatitis C virus was associated with reduced mortality (p < 0.001). There was minimal heterogeneity in the estimates for OS (all I2 ≤ 33). Key Messages: Survival outcomes for sorafenib in advanced HCC have improved over time. These data have important implications for clinical trial design.

Impact of Pretransplant Diabetes on Outcomes After Liver Transplantation: An Updated Meta-analysis With Systematic Review.

BACKGROUND: Preliver transplant diabetes mellitus (pre-LT DM) is a common comorbidity in LT recipients associated with poorer post-transplant survival. However, its relationship with other important outcomes, including cardiovascular and renal outcomes, remains unclear. This meta-analysis aims to provide an updated analysis of the impact of pre-LT DM on key post-LT outcomes. METHODS: A search was conducted in Medline and Embase databases for articles comparing the post-transplant outcomes between patients with and without pre-LT DM. Pairwise analysis using random effects with hazard ratios (HRs) was used to assess the longitudinal post-LT impacts of pre-LT DM. In the absence of HR, pooled odds ratios analysis was conducted for secondary outcomes. RESULTS: Forty-two studies involving 77,615 LT recipients were included in this analysis. The pooled prevalence of pre-LT DM amongst LT recipients was 24.79%. Pre-LT DM was associated with significantly lower overall survival (HR, 0.65; 95% confidence interval, 0.52-0.81; P<0.01) and significantly increased cardiovascular disease-related mortality (HR, 1.78; 95% confidence interval, 1.11-2.85; P=0.03). Meta-regression of other patient characteristics identified Asian ethnicity and hypertension to be significant predictors of worse overall survival, whereas African-American ethnicity was associated with significantly improved overall survival in patients with pre-LT DM. Further analysis of secondary outcomes revealed pre-LT DM to be a significant predictor of post-LT cardiovascular events and end-stage renal disease. CONCLUSIONS: The present study illustrates the impact of pre-LT DM on post-LT survival, and cardiovascular and renal outcomes and provides a sound basis for revision of preoperative management of pre-LT DM.

Clinical Course, Immunogenicity, and Efficacy of BNT162b2 mRNA Vaccination Against SARS-CoV-2 Infection in Liver Transplant Recipients.

Background: Immunocompromised individuals have been excluded from landmark studies of messenger RNA vaccinations for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). In such patients, the response to vaccination may be blunted and may wane more quickly compared with immunocompetent patients. We studied the factors associated with decreased antibody response to SARS-CoV-2 vaccination and risk factors for subsequent breakthrough infections in liver transplant (LT) patients undergoing coronavirus disease 2019 vaccination with at least 2 doses of messenger RNA vaccine from April 28, 2021, to April 28, 2022. Methods: All LT recipients received at least 2 doses of the BNT162b2 (Pfizer BioNTech) vaccine 21 d apart. We measured the antibody response against the SARS-CoV-2 spike protein using the Roche Elecsys immunoassay to the receptor-binding domain of the SARS-CoV-2 spike protein, and the presence of neutralizing antibodies was measured by the surrogate virus neutralization test (cPass) before first and second doses of vaccination and also between 2 and 3 mo after the second dose of vaccination. Results: Ninety-three LT recipients who received 2 doses of BNT162b2 were included in the analysis. The mean time from LT was 110 ± 154 mo. After 2-dose vaccination, 38.7% of LT recipients (36/93) were vaccine nonresponders on the cPass assay compared with 20.4% (19/93) on the Roche S assay. On multivariable analysis, increased age and increased tacrolimus trough were found to be associated with poor neutralizing antibody response (P = 0.038 and 0.022, respectively). The use of antimetabolite therapy in conjunction with tacrolimus approached statistical significance (odds ratio 0.21; 95% confidence interval, 0.180-3.72; P = 0.062). Breakthrough infection occurred in 18 of 88 LT recipients (20.4%). Female gender was independently associated with breakthrough infections (P < 0.001). Conclusions: Among LT recipients, older age and higher tacrolimus trough levels were associated with poorer immune response to 2-dose SARS-CoV-2 vaccination. Further studies are needed to assess variables associated with breakthrough infections and, hence, who should be prioritized for booster vaccination.

Higher risk of adverse cardiovascular outcomes in females with type 2 diabetes Mellitus: an Umbrella review of systematic reviews.

BACKGROUND: Previous studies have shown that females with type 2 diabetes mellitus (T2DM) may have excess mortality risk compared to their male counterparts. An important next step to address the high global burden of T2DM and cardiovascular disease (CVD) is an umbrella review to summarize data on sex differences in cardiovascular outcomes for patients with T2DM and assess the strength of the evidence observed. METHODS AND RESULTS: Medline and Embase were searched from inception till 7 August 2022 for systematic reviews and meta-analyses studying the effects of sex on cardiovascular outcomes in T2DM patients. Results from reviews were synthesized with a narrative synthesis, with a tabular presentation of findings and forest plots for reviews that performed a meta-analysis. 27 review articles evaluating sex differences in cardiovascular outcomes were included. Females with T2DM had a higher risk of developing coronary heart disease (CHD; RRR: 1.52, 95%CI: 1.32-1.76, P < 0.001), acute coronary syndrome (ACS; RRR: 1.38, 95%CI: 1.25-1.52, P < 0.001), heart failure (RRR: 1.09, 95%CI: 1.05-1.13, P < 0.001) than males. Females had a higher risk of all-cause mortality (RRR: 1.13, 95%CI: 1.07-1.19, P < 0.001), cardiac mortality (RRR: 1.49, 95%CI: 1.11-2.00, P = 0.009) and CHD mortality (RRR: 1.44, 95%CI: 1.20-1.73, P < 0.001) as compared to males. CONCLUSIONS: This umbrella review demonstrates that females with T2DM have a higher risk of cardiovascular outcomes than their male counterparts. Future research should address the basis of this heterogeneity and epidemiological factors for better quality of evidence, and identify actionable interventions that will narrow these sex disparities.

This umbrella review highlights the sex differences in adverse cardiovascular events in patients with type 2 diabetes mellitus (T2DM), with females at a higher risk than males. This is contributed by both biological and healthcare disparities and underscores the need for equitable care and personalized medical therapy.Females with T2DM have a higher risk of coronary heart disease, acute coronary syndrome, heart failure, and cardiac mortality compared to males.Clinicians need to be aware of the substantial heterogeneity across the current T2DM studies, and future meta-analysis and large-scale studies examining sex differences in outcomes should attempt to address the heterogeneity and epidemiological factors for a better quality of evidence.

Safety and tolerability of obeticholic acid in chronic liver disease: a pooled analysis of 1878 individuals.

BACKGROUND AND AIMS: Obeticholic acid (OCA) is a farnesoid X receptor agonist used in primary biliary cholangitis (PBC) treatment. Recent studies have expanded OCA use for NASH treatment and results from phase 3 clinical trial have shown beneficial reduction of ≥1 stage of fibrosis with no NASH worsening. However, safety concerns still preside, thus we systematically examine the safety profile of OCA in chronic liver disease. MATERIALS AND METHODS: A search was conducted in Medline and Embase databases for OCA randomized controlled trials in chronic liver disease. Binary events were pooled with Paule-Mandel random effects model and proportional events were examined in a generalized linear mixed model with Clopper-Pearson intervals. RESULTS: A total of 8 studies and 1878 patients were analyzed. There was a 75% [risk ratio (RR): 1.75, 95% CI: 1.43-2.15, p < 0.01] increased pruritis risk. OCA increased constipation incidence (RR: 1.88, 95% CI: 1.45-2.43, p < 0.01), decreased diarrhea (RR: 0.62, 95% CI: 0.50-0.77, p < 0.01), and increased development of hyperlipidemia (RR: 2.69, 95% CI: 1.85-3.92, p < 0.01) relative to placebo. Sensitivity analysis in NASH-only studies found a dose-dependent effect with pruritis which increases to RR: 3.07 (95% CI: 1.74-5.41) at 25 mg. However, up to 9.98% (95% CI: 5.01%-18.89%) of NAFLD patients with placebo similarly experience pruritis events. Overall, 16.55% (95% CI: 6.47%-36.24%) of patients with NAFLD on OCA experienced pruritis. There was no significant increase in cardiovascular events. CONCLUSIONS: OCA may represent the first pharmacological treatment approved for NASH. However, pruritis, constipation, diarrhea, and hyperlipidemia were major events with evident dose-dependent effect that affect tolerability in NASH. Future long-term studies for longitudinal safety events are required.

Global prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in the overweight and obese population: a systematic review and meta-analysis.

BACKGROUND: The global burden of non-alcoholic fatty liver disease (NAFLD) parallels the increase in obesity rates across the world. Although overweight and obesity status are thought to be an effective indicator for NAFLD screening, the exact prevalence of NAFLD in this population remains unknown. We aimed to report the prevalence of NAFLD, non-alcoholic fatty liver (NAFL), and non-alcoholic steatohepatitis (NASH) in the overweight and obese population. METHODS: In this systematic review and meta-analysis, we searched Medline and Embase from database inception until March 6, 2022, using search terms including but not limited to "non-alcoholic fatty liver disease", "overweight", "obesity", and "prevalence". Cross-sectional and longitudinal observational studies published after Jan 1, 2000, written in or translated into English were eligible for inclusion; paediatric studies were excluded. Articles were included if the number of NAFLD, NAFL, or NASH events in an overweight and obese population could be extracted. Summary data were extracted from published reports. The primary outcomes were the prevalence of NAFLD, NAFL, and NASH in an overweight and obese population and the prevalence of fibrosis in individuals who were overweight or obese and who had NAFLD. A meta-analysis of proportions was done with the generalised linear mixed model. This study is registered with PROSPERO (CRD42022344526). FINDINGS: The search identified 7389 articles. 151 studies met the inclusion criteria and were included in the meta-analysis. In the pooled analysis comprising 101 028 individuals, the prevalence of NAFLD in the overweight population was 69·99% (95% CI 65·40-74·21 I2=99·10%), the prevalence of NAFL was 42·49% (32·55-53·08, I2=96·40%), and the prevalence of NASH was 33·50% (28·38-39·04, I2=95·60%). Similar prevalence estimates were reported in the obese population for NAFLD (75·27% [95% CI 70·90-79·18]; I2=98·50%), NAFL (43·05% [32·78-53·97]; I2=96·30%) and NASH (33·67% [28·45-39·31]; I2=95·60%). The prevalence of NAFLD in the overweight population was the highest in the region of the Americas (75·34% [95% CI: 67·31-81·93]; I2=99·00%). Clinically significant fibrosis (stages F2-4) was present in 20·27% (95% CI 11·32-33·62; I2= 93·00%) of overweight individuals with NAFLD and in 21·60% (11·47-36·92; I2=95·00%) of obese patients with NAFLD while 6·65% (4·35-10·01; I2=58·00%) of overweight individuals with NAFLD and 6·85% (3·85-11·90; I2=90·00%) of obese individuals with NAFLD had advanced fibrosis (stages F3-4). INTERPRETATION: This study summarises the estimated global prevalence of NAFLD, NAFL, and NASH in overweight and obese individuals; these findings are important for improving the understanding of the global NAFLD burden and supporting disease management in the at-risk overweight and obese population. FUNDING: None.

Complete alcohol abstinence increases the risk of NAFLD but not severity. A population analysis with transient elastography.

BACKGROUND & AIMS: As the global prevalence of non-alcoholic fatty liver disease (NAFLD) continues to rise, ubiquity of alcohol use has also prompted discussion regarding the potential interactions between the two. This study aims to examine the effects of modest alcohol consumption on the prevalence and complications of NAFLD in a multi-ethnic population. METHODS: This study analyses the 2017-2018 cycles of NHANES that examined liver fibrosis and steatosis with vibration controlled transient elastography. A coarsened exact matching was conducted to reduce confounding. Logistic regression was done with a multivariate model to assess the relationship between alcohol consumption (modest drinkers and non-drinkers) and risk of NAFLD and its complications. RESULTS: 2,067 individuals were found to have NAFLD and 284 NAFLD patients had a total history of alcohol abstinence. After coarsened exact matching, the prevalence of NAFLD was 49% (CI: 0.41 - 0.58) in non-drinkers and 33% (CI: 0.26 - 0.41) in modest drinkers. Non-drinkers had twice the odds of NAFLD compared to modest drinkers (OR: 1.99, CI: 1.22 - 3.22, p<.01) after adjustment for confounders. There were no significant differences in the odds of significant fibrosis, advance fibrosis, cirrhosis, cardiovascular disease and stroke between non-drinkers and modest drinkers. The odds of malignancy in non-drinkers were almost significantly less than modest drinkers (OR: 0.28, CI:0.08 - 1.02, p=.053). CONCLUSION: Interestingly, modest alcohol consumption is associated with decreased odds of NAFLD. Further investigations are required to examine the relationship between alcohol consumption and NAFLD and subsequently the potential impact on NAFLD management.

A Class Effect Network Meta-analysis of Lipid Modulation in Non-alcoholic Steatohepatitis for Dyslipidemia.

Background and Aims: Pharmaceutical therapy for NASH is associated with lipid modulation, but the consensus on drug treatment is limited and lacks comparative analysis of effectiveness. A network meta-analysis was conducted to compare NASH drug classes in lipid modulation. Methods: Online databases were searched for randomized controlled trails (RCTs) evaluating NASH treatments in biopsy-proven NASH patients. Treatments were classified into four groups: (1) inflammation, (2) energy, (3) bile acids, and (4) fibrosis based on the mechanism of action. A Bayesian network analysis was conducted with outcome measured by mean difference (MD) with credible intervals (Crl) and surface under the cumulative ranking curve (SUCRA). Results: Forty-four RCTs were included in the analysis. Bile acid modulating treatments (MD: 0.05, Crl: 0.03-0.07) were the best treatment for improvement in high-density lipid (HDL) cholesterol, followed by treatments modulating energy (MD: 0.03, Crl: 0.02-0.04) and fibrosis (MD: 0.01, Crl: -0.12 to 0.14) compared with placebo. The top three treatments for reduction in triglycerides were treatments modulating energy (MD: -0.46, Crl: -0.49 to -0.43), bile acids (MD: -0.22, Crl: -0.35 to -0.09), and inflammation (MD: -0.08, Crl: -0.13 to -0.03) compared with placebo. SUCRA found treatment modulating fibrosis (MD: -1.27, Crl: -1.76 to -0.79) was the best treatment for reduction in low-density lipid (LDL) cholesterol followed by treatment modulating inflammation (MD: -1.03, Crl: -1.09 to -0.97) and energy (MD: -0.37, Crl: -0.39 to -0.34) compared with placebo, but LDL cholesterol was worsened by treatments modulating bile acids. Conclusions: Network analysis comparing the class effects of dyslipidemia modulation in NASH found that treatment targets can include optimization of atherogenic dyslipidemia. Future studies are required to evaluate the cardiovascular outcomes.

DEXA Scan Body Fat Mass Distribution in Obese and Non-Obese Individuals and Risk of NAFLD-Analysis of 10,865 Individuals.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide yet predicting non-obese NAFLD is challenging. Thus, this study investigates the potential of regional fat percentages obtained by dual-energy X-ray absorptiometry (DXA) in accurately assessing NAFLD risk. Using the United States National Health and Nutrition Examination Survey (NHANES) 2011−2018, multivariate logistic regression and marginal analysis were conducted according to quartiles of regional fat percentages, stratified by gender. A total of 23,752 individuals were analysed. Males generally showed a larger increase in marginal probabilities of NAFLD development than females, except in head fat, which had the highest predictive probabilities of non-obese NAFLD in females (13.81%, 95%CI: 10.82−16.79) but the lowest in males (21.89%, 95%CI: 20.12−23.60). Increased percent of trunk fat was the strongest predictor of both non-obese (OR: 46.61, 95%CI: 33.55−64.76, p < 0.001) and obese NAFLD (OR: 2.93, 95%CI: 2.07−4.15, p < 0.001), whereas raised percent gynoid and leg fat were the weakest predictors. Ectopic fat deposits are increased in patients with non-obese NAFLD, with greater increases in truncal fat over gynoid fat. As increased fat deposits in all body regions can increase odds of NAFLD, therapeutic intervention to decrease ectopic fat, particularly truncal fat, may decrease NAFLD risk.

Depression in non-alcoholic fatty liver disease is associated with an increased risk of complications and mortality.

Background and aims: The global prevalence of non-alcoholic fatty liver disease (NAFLD) is expected to rise continuously. Furthermore, emerging evidence has also shown the potential for concomitant depression in NAFLD. This study aims to examine the prevalence, risk factors, and adverse events of depression in NAFLD and evaluate whether treated depression can reverse the increased risks of adverse outcomes. Materials and methods: This study analyses the 2000-2018 cycles of NHANES that examined liver steatosis with fatty liver index (FLI). The relationship between NAFLD and depression was assessed with a generalized linear mix model and a sensitivity analysis was conducted in the no depression, treated depression, and untreated depression groups. Survival analysis was conducted with cox regression and fine gray sub-distribution model. Results: A total of 21,414 patients were included and 6,726 were diagnosed with NAFLD. The risk of depression in NAFLD was 12% higher compared to non-NAFLD individuals (RR: 1.12, CI: 1.00-1.26, p = 0.04). NAFLD individuals with depression were more likely to be older, females, Hispanics or Caucasians, diabetic, and have higher BMI. Individuals with depression have high risk for cardiovascular diseases (CVD) (RR: 1.40, CI: 1.25-1.58, p < 0.01), stroke (RR: 1.71, CI: 1.27-2.23, p < 0.01), all-cause mortality (HR: 1.50, CI: 1.25-1.81, p < 0.01), and cancer-related mortality (SHR: 1.43, CI: 1.14-1.80, p = 0.002) compared to NAFLD individuals without depression. The risk of CVD, stroke, all-cause mortality, and cancer-related mortality in NAFLD individuals with treated depression and depression with untreated treatment was higher compared to individuals without depression. Conclusion: This study shows that concomitant depression in NAFLD patients can increase the risk of adverse outcomes. Early screening of depression in high-risk individuals should be encouraged to improve the wellbeing of NAFLD patients.

Living in the non-alcoholic fatty liver disease silent epidemic: a qualitative systematic review of patients' perspectives.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) affects one-fourth of the global population. Yet, the care of these patients is limited and awareness of NAFLD remains low in the general public. Investigations into the lives of these patients are often forgotten and traditional quantitative studies only paint part of the picture. AIM: To assess the first-hand accounts of these individuals and their perspective on living with NAFLD. METHODS: A systematic search was conducted on Medline, Embase, CINAHL, PsycINFO and Web of Science database for qualitative literature regarding patients' perspectives on NAFLD. An inductive thematic analysis was conducted to generate themes and supportive subthemes. RESULTS: We incuded eight articles in the review. There were three major themes including the impact on the quality of life, knowledge and information, and attitudes and perceptions on care. The impact of the quality of life details the emotional and physical distress of NAFLD. Knowledge and information include the lack of sufficient communication between healthcare providers and patients with a distinct knowledge gap. Attitudes and perceptions on care extrapolate the current active participation of patients and needs of the patients and the future care that they desire. CONCLUSION: This review synthesises first-hand accounts of individuals with NAFLD. With the growing burden of NAFLD, future public interventions must consider individual views for success to be found. The identified themes serve as a forefront for consideration for public policies. Ultimately, NAFLD is a multisystem disease, which must be managed by a multidisciplinary team.

Risk of Hepatocellular Carcinoma With Tenofovir vs Entecavir Treatment for Chronic Hepatitis B Virus: A Reconstructed Individual Patient Data Meta-analysis.

Importance: Conventional meta-analyses with aggregated study-level data have yielded conflicting results for the comparative effectiveness of tenofovir disoproxil fumarate vs entecavir in reducing hepatocellular carcinoma (HCC) risk among patients with chronic hepatitis B virus. Within-study heterogeneity, between-study heterogeneity, and the inability of conventional meta-analyses to capture time-to-event data were associated with these results. Objective: To perform a reconstructed individual patient data meta-analysis of high-quality propensity score-matched studies to provide robust estimates for comparative HCC risk between groups receiving tenofovir or entecavir. Data Sources: Medline and Embase databases were searched from inception to October 6, 2021. Study Selection: The initial search yielded 3435 articles. Fourteen studies that used propensity score matching to balance baseline characteristics were included in the final analysis. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was followed. Individual patient data were reconstructed from Kaplan-Meier curves. Risk of HCC was evaluated using random-effects hazard ratios (HRs) via a shared-frailty model and a Cox proportional hazards model stratified by study group. Restricted mean survival time (RMST) analysis was conducted to account for varying estimated treatment effect across time. Main Outcomes and Measures: The comparative risk of HCC with tenofovir vs entecavir treatment. Results: From analysis of 14 studes with 24 269 patients (10 534 receiving tenofovir and 13 735 receiving entecavir; mean age, 49.86 [95% CI, 48.35-51.36] years; 65.05% [95% CI, 58.60%-71.00%] men), tenofovir was associated with decreased HCC incidence compared with entecavir (stratified Cox HR, 0.85 [95% CI, 0.76-0.94] at 5 years; P = .002). However, there was no significant difference in subanalysis of clinical cohort studies (stratified Cox HR, 0.92 [95% CI, 0.80-1.06] at 5 years; P = .24). Among administrative database studies, proportionality was violated, and HRs could not be obtained via Cox proporational hazards-based models. The mean time to HCC development in RMST analysis was 2.8 (95% CI, 1.8-3.7) weeks longer (P < .001) for tenofovir vs entecavir at 5 years. The RMST analyses for other subgroups revealed either insignificant or minimal differences (<3 weeks) in the mean time to HCC at 5 years. Conclusions and Relevance: In this meta-analysis, there was no clinically meaningful difference in the risk of HCC between patients who received entecavir and patients who received tenofovir. There was no difference between tenofovir and entecavir among clinical cohort studies, whereas the mean time to HCC development was less than 3 weeks longer for patients who received tenofovir vs those who received entecavir at year 5 among administrative database studies. The choice between tenofovir or entecavir should be decided based on patient convenience and tolerability.

Global Prevalence and Clinical Characteristics of Metabolic-associated Fatty Liver Disease: A Meta-Analysis and Systematic Review of 10 739 607 Individuals.

BACKGROUND AND AIMS: Metabolic-associated fatty liver disease (MAFLD) was proposed as a better definition of nonalcoholic fatty liver disease (NAFLD) to encompass the metabolic dysregulation associated with NAFLD. This redefinition challenges our understanding of the disease. Hence, this study sought to conduct an updated analysis of the prevalence, clinical characteristics, and associated factors of MAFLD, with a further sensitivity analysis done based on lean and nonobese MAFLD individuals. METHODS: Medline and Embase databases were searched to include articles on MAFLD. Meta-analysis of proportions was conducted using the generalized linear mix model. Associating factors were evaluated in conventional pairwise meta-analysis with sensitivity analysis on lean and nonobese MAFLD. RESULTS: From pooled analysis involving 3 320 108 individuals, the overall prevalence of MAFLD was 38.77% (95% CI 32.94% to 44.95%); 5.37% (95% CI 4.36% to 6.59%) and 29.78% (95% CI 26.06% to 33.79%) of lean and nonobese individuals, respectively, had MAFLD. Metabolic complications such as hypertension [odds ratio (OR) 2.63, 95% CI 1.85 to 3.74, P < 0.0001 and OR 2.03; 95% CI 1.74 to 2.38, P < 0.0001, respectively] and diabetes (OR 3.80, 95% CI 2.65 to 5.43, P < 0.0001 and OR 3.46, 95% CI 2.81 to 4.27, P < 0.0001, respectively) were found as significant associating factors associated with lean and nonobese MAFLD. CONCLUSIONS: This meta-analysis supports previous studies in reporting MAFLD to affect more than a third of the global population. While exploration of the pathogenic basis of fatty liver disease without metabolic dysregulation is required, the emphasis on management of concomitant metabolic disease in MAFLD can improve multidisciplinary efforts in managing the complex disease.

Metabolic Associated Fatty Liver Disease Increases the Risk of Systemic Complications and Mortality. A Meta-Analysis and Systematic Review of 12 620 736 Individuals.

OBJECTIVE: The recent introduction of the term metabolic associated fatty liver disease (MAFLD) sought to reclassify nonalcoholic fatty liver disease (NAFLD). MAFLD is thought to improve the encapsulation of metabolic dysregulation. However, recent evidence has found significant differences between MAFLD and NAFLD, and prevailing knowledge has largely arisen from studies on NAFLD. Hence, we conducted a meta-analysis and systematic review of the outcomes associated with MAFLD. METHODS: MEDLINE and Embase databases were searched for articles relating to outcomes in MAFLD. Analysis was conducted in random effects with hazard ratios (HRs) to account for longitudinal risk assessment of mortality and systemic complications. RESULTS: A total of 554 articles were identified, of which 17 articles were included. MAFLD resulted in an increase in the overall mortality (HR, 1.24; confidence interval [CI], 1.13-1.34), cancer-related mortality (HR, 1.27; CI, 1.01-1.54), and cardiovascular disease mortality (HR, 1.28, 1.03-1.53; P = .04) compared with non-MAFLD. MAFLD also increases the risk of cardiovascular events (HR, 1.49; CI, 1.34-1.64; P < .01), stroke (HR, 1.55; CI, 1.37-1.73; P < .01), and chronic kidney disease (HR, 1.53; CI, 1.38-1.68). The presence of MAFLD was also associated with an increased risk of heart failure, obstructive sleep apnea, and malignancy. CONCLUSION: MAFLD can significantly elevate the risk of systemic diseases and mortality. The care of MAFLD thus requires interdisciplinary collaboration, and future clinical trials conducted on MAFLD should aim to reduce the incidence of end-organ damage aside from improving liver histology.

Non-alcoholic fatty liver disease association with structural heart, systolic and diastolic dysfunction: a meta-analysis.

OBJECTIVE: Several studies have documented a relationship between non-alcoholic fatty liver disease (NAFLD) and structural heart disease, particularly diastolic function. This meta-analysis will be the first to examine the echocardiographic-derived cardiac function and structural characteristics in NAFLD patients, and its association with liver disease severity and metabolic profile. METHODS: Medline and Embase were searched and pairwise meta-analysis was conducted in DerSimonian and Laird to obtain the odds ratio (OR) and mean difference (MD) for dichotomous and continuous variables, respectively, to compare the effects of NAFLD on the echocardiography parameters. RESULTS: Forty-one articles involving 33,891 patients underwent echocardiography. NAFLD patients had worse systolic indices with lower ejection fraction (EF, MD: - 0.693; 95% CI: - 1.112 to - 0.274; p = 0.001), and worse diastolic indices with higher E/e' (MD: 1.575; 95% CI: 0.924 to 2.227; p < 0.001) compared to non-NAFLD patients. NAFLD patients displayed increased left ventricular mass (LVM, MD: 34.484; 95% CI: 26.236 to 42.732; p < 0.001) and epicardial adipose thickness (EAT, MD: 0.1343; 95% CI: 0.055 to 0.214; p = 0.001). An increased severity of NAFLD was associated with worse diastolic indices (decreased E/A ratio, p = 0.007), but not with systolic indices. CONCLUSIONS: NAFLD is associated with impaired systolic and diastolic function with changes in cardiac structure. Concomitant metabolic risk factors and liver disease severity are independently associated with worsening systolic and diastolic function.

Non-alcoholic fatty liver disease increases risk of carotid atherosclerosis and ischemic stroke: An updated meta-analysis with 135,602 individuals.

BACKGROUND/AIMS: Non-alcoholic fatty liver disease (NAFLD) is associated with the development of cardiovascular disease. While existing studies have examined cardiac remodeling in NAFLD, there has been less emphasis on the development of carotid atherosclerosis and stroke. We sought to conduct a meta-analysis to quantify the prevalence, risk factors, and degree of risk increment of carotid atherosclerosis and stroke in NAFLD. METHODS: Embase and Medline were searched for articles relating to NAFLD, carotid atherosclerosis, and stroke. Proportional data was analysed using a generalized linear mixed model. Pairwise meta-analysis was conducted to obtain odds ratio or weighted mean difference for comparison between patients with and without NAFLD. RESULTS: From pooled analysis of 30 studies involving 7,951 patients with NAFLD, 35.02% (95% confidence interval [CI], 27.36-43.53%) had carotid atherosclerosis with an odds ratio of 3.20 (95% CI, 2.37-4.32; P<0.0001). Pooled analysis of 25,839 patients with NAFLD found the prevalence of stroke to be 5.04% (95% CI, 2.74-9.09%) with an odds ratio of 1.88 (95% CI, 1.23-2.88; P=0.02) compared to non-NAFLD. The degree of steatosis assessed by ultrasonography in NAFLD was closely associated with risk of carotid atherosclerosis and stroke. Older age significantly increased the risk of developing carotid atherosclerosis, but not stroke in NAFLD. CONCLUSION: This meta-analysis shows that a stepwise increment of steatosis of NAFLD can significantly increase the risk of carotid atherosclerosis and stroke development in NAFLD. Patients more than a third sufferred from carotid atherosclerosis and routine assessment of carotid atherosclerosis is quintessential in NAFLD.

A systematic review and meta-analysis on the impact of pre-existing and new-onset atrial fibrillation on outcomes before and after liver transplantation.

BACKGROUND AND AIMS: Atrial Fibrillation (AF) is the most commonly diagnosed cardiac arrhythmia. It is associated with significant morbidity and mortality, as it is a major risk factor for cerebral vascular accidents (CVA). Our aim was to determine the prevalence of pre-existing and new-onset AF among patients undergoing liver transplantation (LT) and its impact on post-transplant outcomes. METHODS: Medline and Embase were searched. Single-arm analysis was conducted using the generalized linear mixed model to determine the prevalence of pre-existing and new-onset AF. Logistic regression was performed to analyze risk factors. Comparative meta-analysis in odds ratio was conducted for binary outcomes. RESULTS: Twenty articles were included, with 17 studies on pre-existing AF, and 7 including data on new-onset AF post-LT. The prevalence of pre-existing AF was 3.3% (CI 2.3-4.7) (14 studies, 45,070 patients) in pooled analysis. Significantly higher prevalence of pre-existing AF patients from North America was noted when compared to Europe (4.5%, CI 3.4-5.8 vs 1.5%, CI 0.8-2.7; p = 0.001). Body mass index (BMI), history of hypertension, diabetes, coronary artery disease (CAD), and cerebrovascular accidents (CVA) were risk factors for pre-existing AF. Pre-existing AF was significantly associated with major adverse cardiac or cerebrovascular events (MACCE) postoperatively (OR 8.02, 95%CI 5.40-11.90, p < 0.001). New-onset AF post-LT had an incidence of 6.8% (CI 4.9-9.3), and was associated with increased risk of mortality (OR 2.31, 95% CI 1.76-3.02, p < 0.001) and graft failure (OR 2.98, CI 1.99-4.47, p < 0.001). CONCLUSION: AF is relatively more common among patients undergoing LT compared to the general non-transplant population. Additionally, it is associated with adverse outcomes including MACCE, thus warranting clinical attention. Thorough cardiac assessment, and close surveillance of post-operative AF may be clinically prudent.