Longitudinal Outcomes Associated With Metabolic Dysfunction-Associated Steatotic Liver Disease: A Meta-analysis of 129 Studies.

BACKGROUND & AIMS: The progression of metabolic dysfunction-associated steatotic liver disease (MASLD) has been found to manifest in a series of hepatic and extrahepatic complications. A comprehensive meta-analysis of the longitudinal outcomes associated with MASLD has yet to be conducted. METHODS: To investigate the longitudinal outcomes associated with MASLD, Medline and Embase databases were searched to identify original studies that evaluated the longitudinal risks of incident clinical outcomes among MASLD patients compared with non-MASLD individuals. DerSimonian Laird random-effects meta-analysis was performed. Pooled effect estimates were calculated, and heterogeneity among studies was evaluated. RESULTS: One hundred twenty-nine studies were included in the meta-analysis. Meta-analysis revealed a significant increase in the risk of cardiovascular outcomes (hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.27-1.60; P < .01), various metabolic outcomes such as incident hypertension (HR, 1.75; 95% CI, 1.46-2.08; P < .01), diabetes (HR, 2.56; 95% CI, 2.10-3.13; P < .01), pre-diabetes (HR, 1.69; 95% CI, 1.22-2.35; P < .01), metabolic syndrome (HR, 2.57; 95% CI, 1.13-5.85; P = .02), chronic kidney disease (HR, 1.38; 95% CI, 1.27-1.50; P < .01), as well as all cancers (HR, 1.54; 95% CI, 1.35-1.76; P < .01) among MASLD patients compared with non-MASLD individuals. By subgroup analysis, MASLD patients with advanced liver disease (HR, 3.60; 95% CI, 2.10-6.18; P < .01) were also found to be associated with a significantly greater risk (P = .02) of incident diabetes than those with less severe MASLD (HR, 1.63; 95% CI, 1.0-2.45; P = .02) when compared with non-MASLD. CONCLUSIONS: The present study emphasizes the association between MASLD and its clinical outcomes including cardiovascular, metabolic, oncologic, and other outcomes. The multisystemic nature of MASLD found in this analysis requires treatment targets to reduce systemic events and end organ complications.

The incidence of adverse outcome in donors after living donor liver transplantation: A meta-analysis of 60,829 donors.

The scarcity of liver grafts has prompted developments in living donor liver transplantations (LDLT), with previous literature illustrating similar outcomes in recipients compared to deceased donor transplants. However, significant concerns regarding living donor morbidity and mortality have yet to be examined comprehensively. This study aims to provide estimates of the incidence of various outcomes in living liver donors. In this meta-analysis, Medline and Embase were searched from inception to July 2022 for articles assessing the incidence of outcomes in LDLT donors. Complications in the included studies were classified into respective organ systems. Analysis of incidence was conducted using a generalized linear mixed model with Clopper-Pearson intervals. Eighty-seven articles involving 60,829 living liver donors were included. The overall pooled incidence of complications in LDLT donors was 24.7% (CI: 21.6%-28.1%). The incidence of minor complications was 17.3% (CI: 14.7%-20.3%), while the incidence of major complications was lower at 5.5% (CI: 4.5%-6.7%). The overall incidence of donor mortality was 0.06% (CI: 0.0%-0.1%) in 49,027 individuals. Psychological complications (7.6%, CI: 4.9%-11.5%) were the most common among LDLT donors, followed by wound-related (5.2%, CI: 4.4%-6.2%) and respiratory complications (4.9%, CI: 3.8%-6.3%). Conversely, cardiovascular complications had the lowest incidence among the subgroups at 0.8% (CI: 0.4%-1.3%). This study presents the incidence of post-LDLT outcomes in living liver donors, illustrating significant psychological, wound-related, and respiratory complications. While significant advancements in recent decades have contributed towards decreased morbidity in living donors, our findings call for targeted measures and continued efforts to ensure the safety and quality of life of liver donors post-LDLT.

Examining the interim proposal for name change to steatotic liver disease in the US population.

BACKGROUND AND AIMS: Fatty liver is the commonest liver condition globally and traditionally associated with NAFLD. A consensus meeting was held in Chicago to explore various terminologies. Herein, we explore the proposed changes in nomenclature in a population data set from the US. APPROACH AND RESULTS: Statistical analysis was conducted using survey-weighted analysis. Assessment of fatty liver was conducted with vibration-controlled transient elastography. A controlled attenuation parameter of 288 dB/m was used to identify hepatic steatosis. Patients were classified into nonalcoholic steatotic liver disease, alcohol-associated steatotic liver disease, and viral hepatitis steatotic liver disease. Liver stiffness measures at ≥8.8, ≥11.7, and ≥14 kPa were used to identify clinically significant fibrosis, advanced fibrosis, and cirrhosis, respectively. A total of 5102 individuals were included in the analysis. Using a survey-weighted analysis, a total of 25.43%, 6.95%, and 0.73% of the population were classified as nonalcoholic steatotic liver disease, alcohol-associated steatotic liver disease, and viral hepatitis steatotic liver disease, respectively. A sensitivity analysis at controlled attenuation parameter of 248 dB/m and fatty liver index found similar distribution. In a comparison between nonalcoholic steatotic liver disease, alcohol-associated steatotic liver disease, and viral hepatitis steatotic liver disease, there was no significant difference between the odds of advanced fibrosis and cirrhosis between groups. However, viral hepatitis steatotic liver disease individuals were found to have a significantly higher odds of clinically significant fibrosis (OR: 3.76, 95% CI, 1.27-11.14, p =0.02) compared with nonalcoholic steatotic liver disease. CONCLUSIONS: The current analysis assessed the proposed changes based on discussions from the consensus meeting. Although the definitions are an interim analysis of discussions, steatotic liver disease respects the underlying liver etiology and reduces stigma while increasing awareness of FL among viral and alcohol-associated steatosis/steatohepatitis.

Global prevalence of non-alcoholic fatty liver disease in type 2 diabetes mellitus: an updated systematic review and meta-analysis.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, with type 2 diabetes mellitus (T2DM) as a major predictor. Insulin resistance and chronic inflammation are key pathways in the pathogenesis of T2DM leading to NAFLD and vice versa, with the synergistic effect of NAFLD and T2DM increasing morbidity and mortality risks. This meta-analysis aims to quantify the prevalence of NAFLD and the prevalence of clinically significant and advanced fibrosis in people with T2DM. METHODS: MEDLINE and Embase databases were searched from inception until 13 February 2023. The primary outcomes were the prevalence of NAFLD, non-alcoholic steatohepatitis (NASH) and fibrosis in people with T2DM. A generalised linear mixed model with Clopper-Pearson intervals was used for the analysis of proportions with sensitivity analysis conducted to explore heterogeneity between studies. RESULTS: 156 studies met the inclusion criteria, and a pooled analysis of 1 832 125 patients determined that the prevalence rates of NAFLD and NASH in T2DM were 65.04% (95% CI 61.79% to 68.15%, I2=99.90%) and 31.55% (95% CI 17.12% to 50.70%, I2=97.70%), respectively. 35.54% (95% CI 19.56% to 55.56%, I2=100.00%) of individuals with T2DM with NAFLD had clinically significant fibrosis (F2-F4), while 14.95% (95% CI 11.03% to 19.95%, I2=99.00%) had advanced fibrosis (F3-F4). CONCLUSION: This study determined a high prevalence of NAFLD, NASH and fibrosis in people with T2DM. Increased efforts are required to prevent T2DM to combat the rising burden of NAFLD. PROSPERO REGISTRATION NUMBER: CRD42022360251.

Natural history of NASH cirrhosis in liver transplant waitlist registrants.

BACKGROUND AND AIMS: Non-alcoholic steatohepatitis (NASH) cirrhosis is rapidly growing as an indication for liver transplant(ation) (LT). However, the natural history of NASH cirrhosis among LT waitlist registrants has not been established. The present study aimed to define the natural history of NASH cirrhosis using the Scientific Registry of Transplant Recipients database. METHODS: The study cohort comprised patients registered on the LT waitlist between 1/1/2016 to 12/31/2021. The primary outcomes included probability of LT and waitlist mortality, comparing NASH (n = 8,120) vs. non-NASH (n = 21,409) cirrhosis. RESULTS: Patients with NASH cirrhosis were listed with lower model for end-stage liver disease (MELD) scores despite bearing a greater burden of portal hypertension, especially at lower MELD scores. The overall transplant probability in LT waitlist registrants with NASH [vs. non-NASH] cirrhosis was significantly lower at 90 days (HR 0.873, p <0.001) and 1 year (HR 0.867, p <0.001); this was even more pronounced in patients with MELD scores >30 (HR 0.705 at 90 days and HR 0.672 at 1 year, p <0.001 for both). Serum creatinine was the key contributor to MELD score increases leading to LT among LT waitlist registrants with NASH cirrhosis, while bilirubin was in patients with non-NASH cirrhosis. Finally, waitlist mortality at 90 days (HR 1.15, p <0.001) and 1 year (1.25, p <0.001) was significantly higher in patients with NASH cirrhosis compared to those with non-NASH cirrhosis. These differences were more pronounced in patients with lower MELD scores at the time of LT waitlist registration. CONCLUSIONS: LT waitlist registrants with NASH cirrhosis are less likely to receive a transplant compared to patients with non-NASH cirrhosis. Serum creatinine was the major contributor to MELD score increases leading to LT in patients with NASH cirrhosis. IMPACT AND IMPLICATIONS: This study provides important insights into the distinct natural history of non-alcoholic steatohepatitis (NASH) cirrhosis among liver transplant (LT) waitlist registrants, revealing that patients with NASH cirrhosis face lower odds of transplantation and higher waitlist mortality than those with non-NASH cirrhosis. Our study underscores the significance of serum creatinine as a crucial contributor to model for end-stage liver disease (MELD) score in patients with NASH cirrhosis. These findings have substantial implications, emphasizing the need for ongoing evaluation and refinement of the MELD score to more accurately capture mortality risk in patients with NASH cirrhosis on the LT waitlist. Moreover, the study highlights the importance of further research investigating the impact of the implementation of MELD 3.0 across the US on the natural history of NASH cirrhosis.

Outcomes of Nonalcoholic Steatohepatitis After Liver Transplantation: An Updated Meta-Analysis and Systematic Review.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is the fastest growing indication of liver transplantation (LT) and is projected to be the leading cause of LT in the near future. The systemic pathogenesis of NASH increases risks of adverse clinical outcomes in patients with NASH receiving LT. Thus, this study aimed to conduct a time-dependent survival analysis between LT recipients with and without NASH using hazard ratios. METHODS: A search was conducted on Medline and Embase databases for articles relating to LT outcomes for NASH recipients. A survival analysis was conducted of hazard ratios using the DerSimonian and Laird random-effects model with meta-regression. To account for censoring, survival data were reconstructed from published Kaplan-Meier curves and pooled to derive more accurate hazard estimates and all-cause mortality in NASH patients after LT. Pairwise meta-analysis was conducted to analyze secondary outcomes. RESULTS: Fifteen studies involving 119,327 LT recipients were included in our analysis with a prevalence of NASH of 20.2% (95% CI, 12.9-30.2). The pooled 1-year, 5-year, and 10-year all-cause mortality in NASH patients after LT were 12.5%, 24.4%, and 37.9%, respectively. Overall survival was comparable between LT recipients for NASH vs non-NASH (hazard ratio, 0.910; 95% CI, 0.760 to 1.10; P = .34). Meta-regression showed that a higher model for end-stage liver disease score was associated with significantly worse overall survival in NASH compared with non-NASH after LT (95% CI, -0.0856 to -0.0181; P = .0026). CONCLUSIONS: This study shows that patients undergoing LT for NASH cirrhosis have comparable complication rates, overall survival, and graft survival compared with non-NASH patients, although close monitoring may be indicated for those with higher model for end-stage liver disease scores.

UNOS Down-Staging Criteria for Liver Transplantation of Hepatocellular Carcinoma: Systematic Review and Meta-Analysis of 25 Studies.

BACKGROUND & AIMS: Down-staging is commonly used to select patients with hepatocellular carcinoma (HCC) beyond Milan criteria (MC) for liver transplantation (LT), but outcomes are heterogenous. We aimed to estimate pooled down-staging success rates, HCC recurrence, and overall survival (OS), stratified by criteria used for baseline tumor burden. METHODS: We searched Pubmed and EMBASE databases from inception until August 2021 for studies reporting down-staging success (reduction of tumor burden to within MC) and outcomes of adult HCC patients. In addition, we performed a pooled analysis using reconstructed individual participant data to obtain robust estimates for OS. RESULTS: We screened 1059 articles and included 25 articles involving 3997 patients. Overall, 55.16% (45.49%-64.46%) underwent successful down-staging, and 31.52% (24.03%-40.11%) received LT (by intention-to-treat analysis [ITT]). Among patients who received LT, 16.01% (11.80%-21.37%) developed HCC recurrence. Comparing studies that used the United Network for Organ Sharing Down-Staging (UNOS-DS) criteria versus studies beyond UNOS-DS or did not specify criteria, down-staging success (by ITT) was 83.21% versus 45.93%, P < .001; the proportion who received LT (by ITT) was 48.61% vs 28.60%, P = .030; and HCC recurrence (among patients who received LT) occurred in 9.06% versus 20.42%, P < .001. Among studies that used UNOS-DS criteria, ITT 1- and 5-year OS from the initiation of down-staging treatment was 86% and 58%, respectively, whereas 1- and 5-year post-LT OS was 94% and 74%, respectively. CONCLUSIONS: Among studies that adhered to UNOS-DS criteria, down-staging was successful in four-fifths of patients, >50% received LT, and post-LT outcomes were excellent. These data provide clinical validation for the utilization of UNOS-DS criteria.

An Observational Data Meta-analysis on the Differences in Prevalence and Risk Factors Between MAFLD vs NAFLD.

BACKGROUND & AIMS: The shift to redefine nonalcoholic fatty liver disease (NAFLD) as metabolic associated fatty liver disease (MAFLD) can profoundly affect patient care, health care professionals, and progress within the field. To date, there remains no consensus on the characterization of NAFLD vs MAFLD. Thus, this study sought to compare the differences between the natural history of NAFLD and MAFLD. METHODS: Medline and Embase databases were searched to include articles on prevalence, risk factors, or outcomes of patients with MAFLD or NAFLD. Meta-analysis of proportions was conducted using the generalized linear mix model. Risk factors and outcomes were evaluated in conventional pairwise meta-analysis. RESULTS: Twenty-two articles involving 379,801 patients were included. Pooled prevalence of MAFLD was 39.22% (95% confidence interval [CI], 30.96%-48.15%) with the highest prevalence in Europe and Asia, followed by North America. The current MAFLD Definition only accounted for 81.59% (95% CI, 66.51%-90.82%) of NAFLD diagnoses. Patients had increased odds of being diagnosed with MAFLD compared with NAFLD (odds ratio, 1.37; 95% CI, 1.16-1.63; P < .001). Imaging modality resulted in a significantly higher odds of being diagnosed with MAFLD compared with NAFLD, but not biopsy. MAFLD was significantly associated with males, higher body mass index, hypertension, diabetes, lipids, transaminitis, and greater fibrosis scores compared with NAFLD. CONCLUSIONS: There were stark differences in the prevalence and risk factors between MAFLD and NAFLD. However, in the use of the MAFLD Definition, a greater emphasis on the management of concomitant metabolic diseases and a collaborative effort is required to explore the complex pathophysiologic mechanisms underlying the disease.

Hepatocellular Carcinoma Incidence in Alcohol-Associated Cirrhosis: Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Alcohol is one of the leading causes of hepatocellular carcinoma (HCC). However, pooled estimates of HCC incidence in alcohol-associated cirrhosis have not been evaluated systematically. We performed a pooled analysis of time-to-event data to provide robust estimates for the incidence of HCC in alcohol-associated cirrhosis. METHODS: Medline, Embase, Cochrane Central Register, Scopus, and Web of Science were searched from inception to August 2021. Individual patient data were reconstructed from published Kaplan-Meier curves, and a pooled analysis of cumulative HCC incidence was performed using a random-effects model. RESULTS: We screened 5022 articles and included 18 studies (148,333 patients). In the pooled analysis, the cumulative incidence of HCC in alcohol-associated cirrhosis at 1, 5, and 10 years among studies that accounted for the competing risk of death without HCC was 1%, 3%, and 9%, respectively. A secondary analysis by traditional meta-analysis determined that the HCC incidence rate was higher in cohorts enrolled in a HCC surveillance program (18.6 vs 4.8 per 1000 person-years; P = .001) vs those who were not enrolled in a surveillance program. Meta-regression showed that diabetes, smoking, variceal bleeding, and hepatic decompensation were associated with a higher risk of HCC. CONCLUSIONS: Our analysis determined that the 5- and 10- year cumulative risk of HCC in alcohol-associated cirrhosis was 3% and 9%, respectively, with a higher incidence in cohorts that were enrolled in a HCC surveillance program. These data should be validated further in large prospective studies, and may have important implications for HCC screening and surveillance among patients with alcohol-associated cirrhosis.

De novo metabolic syndrome after liver transplantation: a meta-analysis on cumulative incidence, risk factors, and outcomes.

Post-transplant metabolic syndrome (PTMS) has been associated with increased cardiovascular risk which significantly impacts the morbidity and mortality rates of liver transplant (LT) recipients. This study sought to conduct a meta-analysis and systematic review on the cumulative incidence, risk factors, and cardiovascular outcomes associated with de novo PTMS.Medline and Embase were searched for articles describing the incidence, risk factors, and cardiovascular outcomes of de novo PTMS. Meta-analysis of proportions was conducted to calculate incidence. Conventional pairwise analysis using random effects model was used to tabulate OR and hazard ratio for risk factors and cardiovascular outcomes, respectively. Fifteen studies involving 2683 LT recipients were included. Overall rate of de novo PTMS was 24.7% (CI: 18.0%-32.9%) over a mean follow-up period of 15.3 months and was highest in patients with NAFLD (60.0%, CI: 52.0%-67.5%) compared with other liver diseases. Older age (OR: 1.05, CI: 1.01-1.09, p = 0.02) and pre-LT type II diabetes mellitus (OR: 5.00, CI: 4.17-5.99, p < 0.01) were predictive factors of de novo PTMS. Patients with de novo PTMS had significantly higher likelihood of cardiovascular disease events compared with those who did not (hazard ratio: 2.42, CI: 1.54-3.81, p < 0.01). De novo PTMS is a common complication and is significantly associated with increased cardiovascular disease morbidity. High-risk patients such as elderly recipients, those with pre-LT type II diabetes mellitus, or NASH-related cirrhosis should undergo routine screening to allow timely intervention.

Ethnic disparities in waitlist outcomes of patients with nonalcoholic steatohepatitis listed for liver transplantation in the US.

NASH is the fastest-growing cause of liver cirrhosis and is the leading indication for liver transplantation (LT). However, significant racial and ethnic disparities in waitlist outcomes and LT allocation may unfairly disadvantage minorities. Our aim was to characterize racial and ethnic disparities in waitlist mortality and transplantation probability among patients with NASH. This is a retrospective analysis of the United Network for Organ Sharing registry data of LT candidates from January 1, 2000 to December 31, 2021. Outcomes analysis was performed using competing risk analysis with the Fine and Gray model. The multivariable adjustment was conducted, and mixed-effect regression was used to compare the model for end-stage liver disease scores at listing and removal. Of 18,562 patients with NASH cirrhosis, there were 14,834 non-Hispanic Whites, 349 African Americans, 2798 Hispanics, 312 Asians, and 269 of other races/ethnicities; African American (effect size: 2.307, 95% CI: 1.561-3.053, and p < 0.001) and Hispanic (effect size: 0.332, 95% CI: 0.028-0.637, p = 0.032) patients were found to have a significantly higher model for end-stage liver disease scores at the time of listing than non-Hispanic Whites. African Americans had a higher probability of receiving LT relative to non-Hispanic Whites (subdistribution HR: 1.211, 95% CI: 1.051-1.396, and p = 0.008). However, Hispanic race/ethnicity was associated with a lower transplantation probability (subdistribution HR: 0.793, 95% CI: 0.747-0.842, and p < 0.001) and increased waitlist mortality (subdistribution HR: 1.173, CI: 1.052-1.308, and p = 0.004) compared with non-Hispanic Whites. There are significant racial and ethnic disparities in waitlist outcomes of patients with NASH in the US. Hispanic patients are less likely to receive LT and more likely to die while on the waitlist compared with non-Hispanic Whites despite being listed with a lower model for end-stage liver disease scores.

Placebo effect on progression and regression in NASH: Evidence from a meta-analysis.

BACKGROUND AND AIMS: The evaluation of the natural history of NASH has been limited. Currently, liver biopsy remains the gold standard in the assessment of NASH. Placebo-controlled trials represent a controlled environment with paired biopsies for the evaluation of NASH. This meta-analysis thus seeks to quantify the change severity of NASH over time, with patients on placebo arms from randomized controlled trials (RCTs) to examine the natural history of NASH. METHODS: A search was conducted to include NASH RCTs with placebo treatment arms. Primary outcomes were (1) the resolution of NASH without worsening of fibrosis, (2) two-point reduction in NAFLD activity score without worsening of fibrosis, and (3) at least one-point reduction in fibrosis. Generalized linear mix model was used to estimate pooled proportion and mean differences. RESULTS: This meta-analysis of 43 RCTs included 2649 placebo-treated patients. The pooled estimate of NASH resolution and two-point NAFLD activity score reduction without worsening of fibrosis was 11.65% (95% CI: 7.98-16.71) and 21.11% (95% CI: 17.24-25.57). The rate of ≥1 stage reduction and progression of fibrosis was 18.82% (95% CI: 15.65-22.47) and 22.74% (CI: 19.63-26.17), respectively. Older age and African American ethnicity was associated with lower NASH resolution rate in placebo-treated patients. CONCLUSIONS: Despite the absence of any pharmacological interventions, a significant proportion of patients in the placebo arm demonstrated improvements in liver histology, highlighting the possibility that NASH is a disease that can not only progress but regress spontaneously over time. Additionally, histologic response in placebo-treated patients is helpful in future design of phase 2B and phase 3 trials.

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 Meta-analysis on Associated Risk of Mortality in Nonalcoholic Fatty Liver Disease.

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) affects much of the worldwide population and poses a significant burden to the global healthcare. The rising numbers of individuals with NAFLD and instances of mortality point toward the importance of understanding the association causes of mortality in NAFLD. This meta-analysis aimed to seek the associations of NAFLD with all-cause, cardiovascular disease (CVD)-related, liver-related, and cancer-related mortality. METHODS: MEDLINE and Embase were searched for articles relating to causes of mortality between NAFLD and non-NAFLD. The DerSimonian and Laird random-effects model was used to analyze adjusted hazard ratios (HR), and a sensitivity analysis was conducted to reduce heterogeneity through a graphical display of study heterogeneity. RESULTS: Fifteen studies involving 10 286 490 patients were included. Individuals with NAFLD exhibited an increased risk of all-cause mortality (HR, 1.32; 95% CI, 1.09-1.59; P < .01; I2 = 96.00%), CVD-related mortality (HR, 1.22; 95% CI, 1.06-1.41; P < .01; I2 = 81.00%), and cancer-related mortality (HR, 1.67; 95% CI, 1.15-2.41; P < .01; I2 = 95.00%). However, no significant association was found between liver-related mortality and NAFLD (HR, 3.58; 95% CI, 0.69-18.46; P =.13; I2 = 96.00%). The sensitivity analysis conducted with graphic display of heterogeneity and only population-based studies found similar results. CONCLUSION: NAFLD was associated with an increased risk of all-cause, CVD-related, and cancer-related mortality but not liver-related mortality. The finding is likely because of low fibrosis prevalence in the community. However, the significant burden in other causes of mortality beyond the liver points to a need for multidisciplinary efforts to reduce the mortality risks.

Type 2 diabetes mellitus in metabolic-associated fatty liver disease vs. type 2 diabetes mellitus non-alcoholic fatty liver disease: a longitudinal cohort analysis.

INTRODUCTION AND OBJECTIVES: Type 2 Diabetes Mellitus (T2DM) is comorbidity commonly presenting with fatty liver. A recently proposed definition of "metabolic associated fatty liver disease" (MAFLD) is thought to replace non-alcoholic fatty liver disease (NAFLD). Yet, despite the significant prevalence of T2DM among fatty liver, there remains limited evidence on the impact of the change in the definition of T2DM. MATERIALS AND METHODS: The current study uses data from the United States National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. Survival analysis was conducted with a cox regression and sub-distribution hazard ratio for competing risk events. RESULTS: 6727 patients had a diagnosis of T2DM. 4982 individuals with T2DM had MAFLD and 2032 were MAFLD(+)/NAFLD(-), while 2950 patients were MAFLD(+)/NAFLD(+). The new definition increased fatty liver diagnosis by 68.89%. Patients who were classified as MAFLD(+)/NAFLD(-) were at a higher risk of major adverse cardiovascular events, advanced fibrosis, all-cause and cardiovascular-related mortality compared to MAFLD(+)/NAFLD(+). In MAFLD(+)/NAFLD(-), viral hepatitis significantly increases the odds of advanced fibrosis (OR: 6.77, CI: 3.92 to 11.7, p < 0.001) and all-cause mortality (HR: 1.75, CI: 1.29 to 2.40, p < 0.001). CONCLUSIONS: The identification and treatment of NAFLD in patients with T2DM is a major concern and the premature change to MAFLD results in an over-diagnosis of fatty liver, exaggerated mortality, and morbidity in patients with T2DM. The definition of MAFLD causes further heterogeneity in fatty liver disease/NAFLD.

Clinical characteristics, surveillance, treatment allocation, and outcomes of non-alcoholic fatty liver disease-related hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND: The clinical presentation and outcomes of non-alcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma are unclear when compared with hepatocellular carcinoma due to other causes. We aimed to establish the prevalence, clinical features, surveillance rates, treatment allocation, and outcomes of NAFLD-related hepatocellular carcinoma. METHODS: In this systematic review and meta-analysis, we searched MEDLINE and Embase from inception until Jan 17, 2022, for articles in English that compared clinical features, and outcomes of NAFLD-related hepatocellular carcinoma versus hepatocellular carcinoma due to other causes. We included cross-sectional and longitudinal observational studies and excluded paediatric studies. Study-level data were extracted from the published reports. The primary outcomes were (1) the proportion of hepatocellular carcinoma secondary to NAFLD, (2) comparison of patient and tumour characteristics of NAFLD-related hepatocellular carcinoma versus other causes, and (3) comparison of surveillance, treatment allocation, and overall and disease-free survival outcomes of NAFLD-related versus non-NAFLD-related hepatocellular carcinoma. We analysed proportional data using a generalised linear mixed model. Pairwise meta-analysis was done to obtain odds ratio (OR) or mean difference, comparing NAFLD-related with non-NAFLD-related hepatocellular carcinoma. We evaluated survival outcomes using pooled analysis of hazard ratios. FINDINGS: Of 3631 records identified, 61 studies (done between January, 1980, and May, 2021; 94 636 patients) met inclusion criteria. Overall, the proportion of hepatocellular carcinoma cases secondary to NAFLD was 15·1% (95% CI 11·9-18·9). Patients with NAFLD-related hepatocellular carcinoma were older (p<0·0001), had higher BMI (p<0·0001), and were more likely to present with metabolic comorbidities (diabetes [p<0·0001], hypertension [p<0·0001], and hyperlipidaemia [p<0·0001]) or cardiovascular disease at presentation (p=0·0055) than patients with hepatocellular carcinoma due to other causes. They were also more likely to be non-cirrhotic (38·5%, 27·9-50·2 vs 14·6%, 8·7-23·4 for hepatocellular carcinoma due to other causes; p<0·0001). Patients with NAFLD-related hepatocellular carcinoma had larger tumour diameters (p=0·0087), were more likely to have uninodular lesions (p=0·0003), and had similar odds of Barcelona Clinic Liver Cancer stages, TNM stages, alpha fetoprotein concentration, and Eastern Cooperative Oncology Group (ECOG) performance status to patients with non-NAFLD-related hepatocellular carcinoma. A lower proportion of patients with NAFLD-related hepatocellular carcinoma underwent surveillance (32·8%, 12·0-63·7) than did patients with hepatocellular carcinoma due to other causes (55·7%, 24·0-83·3; p<0·0001). There were no significant differences in treatment allocation (curative therapy, palliative therapy, and best supportive care) between patients with NAFLD-related hepatocellular carcinoma and those with hepatocellular carcinoma due to other causes. Overall survival did not differ between the two groups (hazard ratio 1·05, 95% CI 0·92-1·20, p=0·43), but disease-free survival was longer for patients with NAFLD-related hepatocellular carcinoma (0·79, 0·63-0·99; p=0·044). There was substantial heterogeneity in most analyses (I2>75%), and all articles had low-to-moderate risk of bias. INTERPRETATION: NAFLD-related hepatocellular carcinoma is associated with a higher proportion of patients without cirrhosis and lower surveillance rates than hepatocellular carcinoma due to other causes. Surveillance strategies should be developed for patients with NAFLD without cirrhosis who are at high risk of developing hepatocellular carcinoma. FUNDING: None.

A Meta-Analysis on the Global Prevalence, Risk factors and Screening of Coronary Heart Disease in Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: Cardiovascular disease remains the leading cause of death in patients with nonalcoholic fatty liver disease (NAFLD). Studies examining the association of coronary heart disease (CHD) and NAFLD are cofounded by various cardiometabolic factors, particularly diabetes and body mass index. Hence, we seek to explore such association by investigating the global prevalence, independent risk factors, and influence of steatosis grade on manifestation of CHD among patients with NAFLD. METHODS: Two databases, Embase and Medline, were utilized to search for articles relating to NAFLD and CHD. Data including, but not limited to, continent, diagnostic methods, baseline characteristics, prevalence of CHD, CHD severity, NAFLD severity, and risk factors were extracted. RESULTS: Of the 38 articles included, 14 reported prevalence of clinical coronary artery disease (CAD) and 24 subclinical CAD. The pooled prevalence of CHD was 44.6% (95% confidence interval [CI], 36.0%-53.6%) among 67,070 patients with NAFLD with an odds ratio of 1.33 (95% CI, 1.21%-1.45%; P < .0001). The prevalence of CHD was higher in patients with moderate to severe steatosis (37.5%; 95% CI, 15.0%-67.2%) than those with mild steatosis (29.6%; 95% CI, 13.1%-54.0%). The pooled prevalence of subclinical and clinical CAD was 38.7% (95% CI, 29.8%-48.5%) and 55.4% (95% CI, 39.6%-70.1%), respectively. CONCLUSION: Steatosis was found to be related with CHD involvement, with moderate to severe steatosis related to clinical CAD. Early screening and prompt intervention for CHD in NAFLD are warranted for holistic care in NAFLD.

A Meta-Analysis and Systematic Review on the Global Prevalence, Risk Factors, and Outcomes of Coronary Artery Disease in Liver Transplantation Recipients.

The shift in the changing etiology of cirrhosis requiring liver transplantation (LT) has resulted in an increasing prevalence of coronary artery disease (CAD) that can potentially impact post-LT outcomes. This systematic review and meta-analysis evaluates the prevalence of CAD, risk factors, and outcomes of patients diagnosed with CAD before LT. MEDLINE and EMBASE were searched for articles describing CAD in pre-LT patients. Meta-analysis of proportions using the generalized linear mix model was conducted to analyze the pooled prevalence of CAD in pre-LT patients. Associated risk factors for CAD in pre-LT patients and outcomes were evaluated in conventional pairwise meta-analysis. A total of 39 studies were included. The pooled prevalence of patients diagnosed with CAD before LT was 15.9% (95% CI, 9.8%-24.7%). Age, male sex, diabetes mellitus, hypertension, hyperlipidemia, smoking, nonalcoholic steatohepatitis, hepatitis B virus, and hepatocellular carcinoma were significantly associated with CAD. Patients from high-income countries especially North America, Europe, and South America, with the associated risk factors were at increased risk for CAD before LT. CAD before LT was associated with an increased odds of overall mortality (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.4-1.4; P = 0.01) and cardiac-related mortality (OR, 1.2; 95% CI, 1.1-1.3; P = 0.03). A total of 48.7% of included articles considered the presence of cardiovascular risk factors for CAD screening. However, 10.3% of the studies screened for CAD in pre-LT patients via invasive coronary angiography only, without stress testing or risk stratification. This study demonstrates the high prevalence of CAD in pre-LT patients, associated risk factors, and outcomes. There is heterogeneity among guidelines and practice in screening for pre-LT CAD, and more studies are needed to establish consensus.

A Diagnostic Test Meta-Analysis Evaluating Imaging-Based and Blood Biomarker-Based Assessment Tools for Fibrosis After Liver Transplantation.

Early detection of liver graft fibrosis is crucial for risk stratification to identify patients for liver biopsy and timely treatment. However, diagnostic accuracy of noninvasive tests (NITs) remains unclear. Thus, this study sought to evaluate diagnostic accuracy of NITs in assessing liver allograft fibrosis and compare the differences in specificities and sensitivities among NITs. Medline and Embase databases were searched to include articles on diagnostic tests in liver transplantation (LT) patients with fibrosis. A meta-analysis on diagnostic test accuracy was conducted in a random-effects model. Sensitivities and specificities among the diagnostic tests were compared, and threshold values were calculated where applicable. A total of 25 articles were included. Vibration-controlled transient elastography (VCTE) met the minimum diagnostic accuracy requirements, yielding sensitivity, specificity, and diagnostic odds ratios of 0.9 (CI, 0.8-1.0), 0.9 (CI, 0.8-1.0), and 379.6 (CI, 45.8-1728.7), respectively. In the threshold assessment, the optimal cutoff was 9.30 kPa with a sensitivity, specificity, and area under the curve of 0.7 (CI, 0.5-0.9), 0.9 (CI, 0.8-0.9), and 0.9 (CI, 0.8-0.9), respectively. For significant fibrosis, acoustic radiation force impulse (ARFI) was superior to FibroTest (LabCorp [Burlington, NC]) and magnetic resonance elastography (MRE) in sensitivity. VCTE was superior to FibroTest in specificity. For advanced fibrosis, ARFI was superior to the Fibrosis-4 Index (FIB-4) in sensitivity. VCTE was superior to the AST to Platelet Ratio Index (APRI), MRE, and FIB-4 in specificity. In cirrhosis, VCTE was superior to APRI in specificity (P = 0.004) with comparable sensitivity. This study demonstrates the potential of VCTE and ARFI as diagnostic tools for fibrosis in LT recipients compared with blood-based NITs, which were shown to be less optimal.

Bisphosphonate therapy after liver transplant improves bone mineral density and reduces fracture rates: an updated systematic review and meta-analysis.

To investigate the efficacy of bisphosphonates and compare oral and IV formulations on bone mineral density (BMD) and fracture incidence in post-orthotopic liver transplant (OLT) patients. Electronic databases were searched, and six RCTs and three cohort studies were included out of 711 articles. Main outcomes included post-OLT BMD changes, fracture incidence, and treatment adverse reactions. Pairwise meta-analysis was conducted for binary and continuous outcomes, while pooled fracture incidence utilized single-arm meta-analysis. Post-OLT fracture incidence was reported in nine studies (n = 591). Total fracture incidence was 6.6% (CI: 3.4-12.4%) in bisphosphonate group and 19.1% (CI: 14.3-25.1%) in calcium and vitamin D group. Total fractures were significantly lower in patients on bisphosphonate, compared to calcium and vitamin D (n = 591; OR = 0.037; CI: 0.18-0.77; P = 0.008). Overall fractures were significantly lower in the oral group (n = 263; OR = 0.26; CI: 0.08-0.85; P = 0.02) but not in the IV group (n = 328; OR = 0.45; CI: 0.16-1.26; P = 0.129). Both oral and IV bisphosphonates are effective in reducing fracture incidence post-OLT compared to calcium and vitamin D. Oral formulations may also have an advantage over IV in reducing bone loss and fracture incidence post-OLT.